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Articles by Jack T.C. Davis in JoVE

 JoVE Applied Physics

Bringing the Visible Universe into Focus with Robo-AO

1Caltech Optical Observatories, California Institute of Technology, 2Department of Astronomy, California Institute of Technology, 3Dunlap Institute for Astronomy and Astrophysics, University of Toronto, 4Inter-University Centre for Astronomy & Astrophysics, 5Observatories of the Carnegie Institution for Science, 6Benoziyo Center for Astrophysics, Weizmann Institute of Science


JoVE 50021

Light from astronomical objects must travel through the earth's turbulent atmosphere before it can be imaged by ground-based telescopes. To enable direct imaging at maximum theoretical angular resolution, advanced techniques such as those employed by the Robo-AO adaptive-optics system must be used.

Other articles by Jack T.C. Davis on PubMed

Alterations to Functional Analysis Methodology to Clarify the Functions of Low Rate, High Intensity Problem Behavior

Current research provides few suggestions for modifications to functional analysis procedures to accommodate low rate, high intensity problem behavior. This study examined the results of the extended duration functional analysis procedures of Kahng, Abt, and Schonbachler (2001) with six children admitted to an inpatient hospital for the treatment of severe problem behavior. Results of initial functional analyses (Iwata, Dorsey, Slifer, Bauman, & Richman, 1982/1994) were inconclusive for all children because of low levels of responding. The altered functional analyses, which changed multiple variables including the duration of the functional analysis (i.e., 6 or 7 hrs), yielded clear behavioral functions for all six participants. These results add additional support for the utility of an altered analysis of low rate, high intensity problem behavior when standard functional analyses do not yield differentiated results.

Priapism in Teenage Boys Following Depot Testosterone

Abstract Priapism is rare in children and may result in erectile dysfunction and sexual aversion behaviours. Testosterone therapy is commonly regarded as safe in children and is widely used in constitutional delay of growth and puberty, hypogonadism, hypospadias and micropenis. We report two cases of priapism in teenage boys with constitutional delay of growth and puberty after a change in the formulation of depot testosterone. One case required surgical intervention and the other was preceded by stuttering priapism. These cases illustrate the importance of patient and/or parent counselling before testosterone administration and consideration of lower doses in at-risk patients.

Design and Synthesis of D(1) Agonist/D(2) Antagonist for Treatment of Schizophrenia

A series of tetrahydroisoquinolines were designed, synthesized and evaluated as the first non-natural product type of compounds with dual D(1) receptor (D(1)R) agonism and D(2) receptor (D(2)R) antagonism properties for treatment of schizophrenia. The initial SAR of the series was explored. The lead in the series, 3g, exhibited high affinity and good potency. Compound 3g displayed 95% of D(1)R occupancy (10mg/kg, sc) and 75% of D(2)R occupancy (10mg/kg, sc) in the striatum of male CD-1 mice. The series exhibited unique pharmacology and merit as tool compounds for target validation and future optimizations.

Alcohol and Scuba Diving

Stereotactic Body Radiation Therapy in the Treatment of Oligometastatic Prostate Cancer

Purpose/objective(s): To report outcomes and toxicity for patients with oligometastatic (≤5 lesions) prostate cancer (PCa) treated with stereotactic body radiation therapy (SBRT). Materials/methods: Seventeen men with 21 PCa lesions were treated with SBRT between February 2009 and November 2011. All patients had a detectable prostate-specific antigen (PSA) at the time of SBRT, and 11 patients (65%) had hormone-refractory (HR) disease. Treatment sites included bone (n = 19), lymph nodes (n = 1), and liver (n = 1). For patients with bone lesions, the median dose was 20 Gy (range, 8-24 Gy) in a single fraction (range, 1-3). All but two patients received some form of anti-androgen therapy after completing SBRT. Results: Local control (LC) was 100%, and the PSA nadir was undetectable in nine patients (53%). The first post-SBRT PSA was lower than pre-treatment levels in 15 patients (88%), and continued to decline or remain undetectable in 12 patients (71%) at a median follow-up of 6 months (range, 2-24 months). Median PSA measurements before SBRT and at last follow-up were 2.1 ng/dl (range, 0.13-36.4) and 0.17 ng/dl (range, <0.1-140), respectively. Six (55%) of the 11 patients with HR PCa achieved either undetectable or declining PSA at a median follow-up of 4.8 months (range, 2.2-6.0 months). Reported toxicities included one case each of grade 2 dyspnea and back pain, there were no cases of grade ≥3 toxicity following treatment. Conclusion: We report excellent LC with SBRT in oligometastatic PCa. More importantly, over half the patients achieved an undetectable PSA after SBRT. Further follow-up is necessary to assess the long-term impact of SBRT on LC, toxicity, PSA response, and clinical outcomes.

What is Social About Social Perception Research?

A growing consensus in social cognitive neuroscience holds that large portions of the primate visual brain are dedicated to the processing of social information, i.e., to those aspects of stimuli that are usually encountered in social interactions such as others' facial expressions, actions, and symbols. Yet, studies of social perception have mostly employed simple pictorial representations of conspecifics. These stimuli are social only in the restricted sense that they physically resemble objects with which the observer would typically interact. In an equally important sense, however, these stimuli might be regarded as "non-social": the observer knows that they are viewing pictures and might therefore not attribute current mental states to the stimuli or might do so in a qualitatively different way than in a real social interaction. Recent studies have demonstrated the importance of such higher-order conceptualization of the stimulus for social perceptual processing. Here, we assess the similarity between the various types of stimuli used in the laboratory and object classes encountered in real social interactions. We distinguish two different levels at which experimental stimuli can match social stimuli as encountered in everyday social settings: (1) the extent to which a stimulus' physical properties resemble those typically encountered in social interactions and (2) the higher-level conceptualization of the stimulus as indicating another person's mental states. We illustrate the significance of this distinction for social perception research and report new empirical evidence further highlighting the importance of mental state attribution for perceptual processing. Finally, we discuss the potential of this approach to inform studies of clinical conditions such as autism.

Multiple Categories of Resistance to Wheat Curl Mite (Acari: Eriophyidae) Expressed in Accessions of Aegilops Tauschii

The wheat curl mite, Aceria tosichella Keifer, is an important pest in the western plains of the United States as well as in most major wheat-growing regions of the world. This mite is a vector of the economically important diseases wheat streak mosaic virus (WSMV), Triticum mosaic virus (TriMV), and High Plains virus (HPV). This study looked at seven accessions of Aegilops tauschii (Coss) Schmal to determine if they exhibit antibiosis, tolerance, and/or antixenosis to the wheat curl mite using 'Jagger', a known wheat curl mite-susceptible variety, and OK05312, a known wheat curl mite-resistant variety, as controls. Four of the seven tested accessions showed antibiotic effects on the population growth of wheat curl mite, as demonstrated by low number of wheat curl mite adults and nymphs at the end of the experiment. Three accessions and the commercial wheat variety Jagger showed some level of tolerance to wheat curl mite infestations, as demonstrated by a significantly reduced percentage proportional tissue dry weight and by tolerance index values. Four accessions demonstrated a strong antixenotic effect on the wheat curl mite, as demonstrated by significantly reduced numbers of mite adults at the end of the experiment. This study also established an effective method for determining antixenosis to the wheat curl mite in wheat that can be used for future experiments. All accessions demonstrated at least one type of plant resistance that could provide a genetic source for control of the wheat curl mite that may have the potential to be transferred into commercial wheat varieties.

Behaving Badly or Goodly: Is It Because I Feel Guilty, Shameful, or Sympathetic? Or is It a Matter of What I Think?

The article provides a brief review of theory and research on the roles of guilt, shame, and sympathy in predicting moral behaviors. Two models are presented and contrasted. The guilt-based model proposes that guilt and shame jointly predict prosocial and aggressive behaviors. In contrast, the sympathy-based model suggests that perspective taking and sympathy are linked to such behaviors. In both models, prosocial moral reasoning is proposed as a possible mediator in these relations. Results from a study of college students suggest support for both models. Moreover, there is evidence that prosocial moral reasoning mediates the relations between these moral emotions and moral behaviors. The implications for the need to incorporate moral emotions and cognitions into existing models of morality are discussed and emphasized.

Unusual Presentation of Toxoplasma Gondii Encephalitis

We report a case of altered mental status secondary to acute Toxoplasma Gondii encephalitis. The patient had no medical or surgical history and presented with acute onset of lethargy with no clear precipitant. A physical exam revealed no focal neurological deficits and a subsequent medical workup revealed multiple intracranial lesions with a biopsy confirming the diagnosis of Toxoplasma Gondii encephalitis in the setting of newly diagnosed human immunodeficiency virus (HIV). A literature review revealed that this is a unique case of toxoplasmic encephalopathy in the United States in a previously undiagnosed HIV positive patient presenting to an emergency department.

What is Life Worth? A Rough Guide to Valuation

In this speculative article, the aim is to elaborate a definition of life that is not biological, and a valuation of it that is not commodified. This is undertaken by the development of an understanding of death as a process which is embedded in the life of a community. The idea is that we can best understand what life is worth by first understanding what death means.

The Use of a Novel Carbon Nanotube Coated Microelectrode Array for Chronic Intracortical Recording and Microstimulation

Micro-electrode arrays (MEAs) have been used in a variety of intracortical neural prostheses. While intracortical MEAs have demonstrated their utility in neural prostheses, in many cases MEA performance declines after several months to years of in vivo implantation. The application of carbon nanotubes (CNTs) may increase the functional longevity of intracortical MEAs through enhanced biocompatibility and charge injection properties. An MEA metalized with platinum (Pt) on all electrodes had a CNT coating applied to the electrodes on half of the array. This Pt/Pt-CNT MEA was implanted into feline motor cortex for >1 year. Recordings of action potentials and 1 kHz impedance measurements were made on all electrodes to evaluate device functionality. Additionally, electromyogram (EMG) responses were evoked using micro-stimulation via the MEA to measure device performance. These metrics were compared between Pt and Pt-CNT electrodes. There was no significant difference in the data acquisition or micro-stimulation performance of Pt and the Pt-CNT electrodes. However, impedances were lower on the Pt-CNT electrodes. These results demonstrate the functionality of CNT coatings during chronic in vivo implantation. The lower impedances suggest that for microstimulation applications CNT coatings may impart enhanced interface properties.

Detecting Distance Between Injected Microspheres and Target Tumor Via 3D Reconstruction of Tissue Sections

One treatment increasing in use for solid tumors in the liver is radioembolization via the delivery of (90)Y microspheres to the vascular bed within or near the location of the tumor. It is desirable as part of the treatment for the microspheres to embed preferentially in or near the tumor. This work details an approach for analyzing the deposition of microspheres with respect to the location of the tumor. The approach used is based upon thin-slice serial sectioning of the tissue sample, followed by high resolution imaging, microsphere detection, and 3-D reconstruction of the tumor surface. Distance from the microspheres to the tumor was calculated using a fast deterministic point inclusion method.

Decoding Hand Trajectories from Micro-electrocorticography in Human Patients

A Kalman filter was used to decode hand trajectories from micro-electrocorticography recorded over motor cortex in human patients. In two cases, signals were recorded during stereotyped tasks, and the trajectories were decoded offline, with maximum correlation coefficients between actual and predicted trajectories of 0.51 (x-direction position) and 0.54 (y-direction position). In a third setting, a human patient with full neural control of a computer cursor acquired onscreen targets within 6.24 sec on average, with no algorithmic constraints on the output trajectory. These practical results illustrate the potential utility of signals recorded at the cortical surface with high spatial resolution, demonstrating that surface potentials contain relevant and sufficient information to drive sophisticated brain-computer interface systems.

Baseband Signal Transmission Experiment for Intra-brain Communication with Implantable Image Sensor

We demonstrate image signal transmission for wireless intra-brain communication. As a preliminary experiment, transmission characteristics of the brain phantom were measured. The baseband output signal from an implantable complementary metal-oxide-semiconductor (CMOS) image sensor is transmitted through the phantom. The image was successfully reproduced from the received signal.

Translational Health Research: Perspectives from Health Education Specialists

ABSTRACT: The phrase "from bench to bedside to curbside" is a common definition of translational research among health disparities researchers. Health Education Specialists can make important contributions to the field of clinical translational medicine, particularly in light of U.S. health care reform and a renewed emphasis on medical home or health care home models.Health Education Specialists have the training and experience to engage in and facilitate translational research, as well as the opportunity to learn from the translational efforts of other professions and enhance our research, practice, and community partnerships through translational efforts. In this paper, a Translational Health Education Research framework for health education researchers is suggested to foster increased translational efforts within our profession as well as to promote interdisciplinary collaborations to translate a variety of health-related research. A conceptual framework adapted from translational health disparities research that highlights the level and scope of translational research necessary for changes in practice and policy is also provided.

Simulation Based Design and Evaluation of a Transcatheter Mitral Heart Valve Frame

In certain populations, open heart surgery to replace a diseased mitral valve is not an option, leaving percutaneous delivery a viable alternative. However, a surgical transcatheter based delivery of a metallic support frame incorporating a tissue derived valve puts considerable constraints on device specifications. Expansion to a large diameter from the catheter diameter without mechanical fracture involves advanced device design and appropriate material processing and selection. In this study, a new frame concept is presented with a desirable feature that incorporates wings that protrude during expansion to establish adequate fixation. Expansion characteristics of the design in relation to annulus fixation were quantified through finite element analysis predictions of the frame wing span and angles. Computational modeling and simulation was used to identify many favorable design features for the transcatheter mitral valve frame and obtain desired expansion diameters (35-45mm), acceptable radial stiffness (2.7N/mm), and ensure limited risk of failure based on predicted plastic deformations.

Finger Agnosia and Cognitive Deficits in Patients with Alzheimer's Disease

The purpose of this study was to examine the presence of finger agnosia in patients with Alzheimer's disease (AD) and to determine if level of finger agnosia was related to cognitive impairment. Finger agnosia is a sensitive measure of cerebral impairment and is associated with neurofunctional areas implicated in AD. Using a standardized and norm-referenced approach, results indicated that patients with AD evidenced significantly decreased performance on tests of bilateral finger agnosia compared with healthy age-matched controls. Finger agnosia was predictive of cognitive dysfunction on four of seven domains, including: Crystallized Language, Fluid Processing, Associative Learning, and Processing Speed. Results suggest that measures of finger agnosia, a short and simple test, may be useful in the early detection of AD.

The Relationship Between the WAIS-III Digit Symbol Coding and Executive Functioning

The current study examined the performance of college students (N = 63) on the Coding subtest of the Wechsler Adult Intelligence Scale-Third Edition and examined whether differences in performance could in part be explained by performance on the Delis-Kaplan Executive Functions System Trail-Making Test. The results of a multiple regression analysis indicated that performance on Coding was correlated most with Letter-Number Sequencing and to a lesser extent with Visual Scanning and with Number Sequencing approaching significance. There was no significant relationship with Letter Sequencing or Motor Speed. The three significant predictor variables were then entered into a stepwise hierarchical regression analysis. Subsequent models using Visual Scanning and Number Sequencing did not improve the predictive value of the model. These results are consistent with other recent reports suggesting that performance on Coding taps cognitive skills and abilities beyond that of simple motor speed or paired-associative learning. The findings also suggest a limited improvement in understanding test performance using a process analysis approach.

Posterior Cortical Atrophy: A Case Study of Benson's Syndrome That Initially Presented As Anxiety Disorder

The postmortem pathology of posterior cortical atrophy (PCA) and Alzheimer's disease (AD) are often identical. In contrast to AD, PCA is clinically different in that visuoperceptual skills are severely impaired, yet memory is relatively intact. In addition, patients with PCA often report depression with preserved insight. The present case study is a 56-year-old female who initially presented with anxiety and panic-like symptoms. The neuropsychological evaluation and imaging studies were consistent with PCA. This case study is relatively unique in that symptom onset presented as an anxiety disorder, yet formal evaluation revealed severe visuospatial impairment with minimal insight into the severity of cognitive impairment. Anxiety was alleviated following cessation of employment. This case highlights the importance of differential diagnostic consideration of affective and mood disorders and early forms of dementia.

Subjective Organization, Verbal Learning, and Forgetting Across the Life Span: from 5 to 89

Background/Study Context: Previous tests of the relationship between subjective organization during encoding, aging, and recall have produced inconsistent findings. The present study investigates subjective organization and the acquisition and recall of verbal material across the life span (from 5 to 89 years of age) using two measures, the intertrial repetition paired frequency (PF) measure and the unidirectional subjective organization (SO) measure. Methods: Participants (N = 2656) were administered a version of the Rey Auditory Verbal Learning Test, including a delayed recall trial. Analyses of variance (ANOVAs) were performed to examine the relationship between age and subjective organization and between age and recall. Mediation and growth curve analyses were performed to further examine the relationship between age, verbal acquisition, and subjective organization. Results: Subjective organization was not predictive of verbal forgetting. Deficits in verbal acquisition and subjective organization were detected among children and elderly adults. Mediational analyses showed that age affected the number of words recalled as well as subjective organization, and that subjective organization affected the number of words recalled in children, young adults and elderly. Latent growth curve modeling suggests that increases in subjective organization over time are related to increases in recall over time for each age group. Conclusion: Subjective organization is predictive of recall, and both subjective organization and recall are lowest among children and elderly individuals. Age has direct effects on recall but this effect is partially mediated by subjective organization. Brain imaging studies showing increased prefrontal cortex activation during encoding of remembered words bolster our findings that age affects the relationship between verbal learning and organization of material during encoding.

Quantitative Structure-Activity Relationship Models That Stand the Test of Time

The pharmaceutical industry is in a period of intense change. While this has many drivers, attrition though the development process continues to be an important pressure. The emerging definitions of "compound quality" that are based on retrospective analyses of developmental attrition have highlighted a new direction for medicinal chemistry and the paradigm of "quality at the point of design". The time has come for retrospective analyses to catalyze prospective action. Quality at the point of design places pressure on the quality of our predictive models. Empirical QSAR models when built with care provide true predictive control, but their accuracy and precision can be improved. Here we describe AstraZeneca's experience of automation in QSAR model building and validation, and how an informatics system can provide a step-change in predictive power to project design teams, if they choose to use it.

Audiometry Screening and Interpretation

The prevalence of hearing loss varies with age, affecting at least 25 percent of patients older than 50 years and more than 50 percent of those older than 80 years. Adolescents and young adults represent groups in which the prevalence of hearing loss is increasing and may therefore benefit from screening. If offered, screening can be performed periodically by asking the patient or family if there are perceived hearing problems, or by using clinical office tests such as whispered voice, finger rub, or audiometry. Audiometry in the family medicine clinic setting is a relatively simple procedure that can be interpreted by a trained health care professional. Pure-tone testing presents tones across the speech spectrum (500 to 4,000 Hz) to determine if the patient's hearing levels fall within normal limits. A quiet testing environment, calibrated audiometric equipment, and appropriately trained personnel are required for in-office testing. Pure-tone audiometry may help physicians appropriately refer patients to an audiologist or otolaryngologist. Unilateral or asymmetrical hearing loss can be symptomatic of a central nervous system lesion and requires additional evaluation.

Cecal Diverticulitis After Laparoscopic Resection of Appendiceal Diverticulitis with Perforation

Ulcerative Lesions in an Advanced AIDS Patient

Urinary Incontinence in Young Nulligravid Women

Projection Imaging of Photon Beams Using ÄŒerenkov-excited Fluorescence

Full 3D beam profiling and quality assurance (QA) of therapeutic megavoltage linear accelerator (LINAC) x-ray photon beams is not routinely performed due to the slow point-by-point measurement nature of conventional scanning ionization chamber systems. In this study we explore a novel optical-based dose imaging approach using a standard commercial camera, water tank, and fluorescent dye, which when excited by the Čerenkov emission induced by the radiation beam, allows 2D projection imaging in a fast timeframe, potentially leading toward 3D tomographic beam profiling. Detailed analysis was carried out to optimize the imaging parameters in the experimental setup. The results demonstrate that the captured images are linear with delivered dose, independent of dose rate, and comparison of experimentally captured images to a reference dose distribution for a 4 × 4 cm(2) 6 MV x-ray photon beam yielded results with improved accuracy over a previous study which used direct imaging and Monte Carlo calibration of the Čerenkov emission itself. The agreement with the reference dose distribution was within 1-2% in the lateral direction, and ±3% in the depth direction. The study was restricted to single 2D image projection, with the eventual goal of creating full 3D profiles after tomographic reconstruction from multiple projections. Given the increasingly complex advances in radiation therapy, and the increased emphasis on patient-specific treatment plans, further refinement of the technique could prove to be an important tool for fast and robust QA of x-ray photon LINAC beams.

Reformulating the Federal Match As a Key to the Sustainability of Medicaid

Dietary Fat Increases Quercetin Bioavailability in Overweight Adults

SCOPE: Epidemiologic evidence supports that dietary quercetin reduces cardiovascular disease (CVD) risk, but its oral bioavailability is paradoxically low. The aim of this study was to determine whether dietary fat would improve quercetin bioavailability in adults at high risk for CVD and to assess lipid-mediated micellarization of quercetin in vitro. METHODS AND RESULTS: In a randomized, cross-over study, overweight/obese men and postmenopausal women (n = 4 M/5 F; 55.9 ± 2.1 years; 30.8 ± 1.4 kg/m(2) ) ingested 1095 mg of quercetin aglycone with a standardized breakfast that was fat-free (<0.5 g), low-fat (4.0 g), or high-fat (15.4 g). Plasma was obtained at timed intervals for 24 h to measure quercetin and its methylated metabolites isorhamnetin and tamarixetin. Compared to the fat-free trial, plasma quercetin maximum concentration (C(max) ), and area under curve (AUC(0-24 h) ) increased (p < 0.05) by 45 and 32%, respectively, during the high-fat trial. During the high-fat trial, isorhamnetin C(max) and AUC(0-24 h) also increased by 40 and 19%, respectively, whereas C(max) and AUC(0-24 h) of tamarixetin increased by 46 and 43%, respectively. Dietary fat dose-dependently increased micellarization efficiency of quercetin aglycone in vitro. CONCLUSION: Dietary fat improves quercetin bioavailability by increasing its absorption, likely by enhancing its micellarization at the small intestine.

Associations of Objectively Measured Physical Activity with Lower Limb Function in Older Men and Women: Findings from the Older People and Active Living (OPAL) Study

Associations of objectively measured physical activity (PA) with objectively measured lower limb function in adults aged 70 and older were studied. Lower limb function was assessed using the Short Physical Performance Battery (SPPB) and PA by an accelerometer providing mean daily counts per minute (CPM), mean daily steps and minutes of moderate or vigorous PA (MVPA) per day. A minority (32 (13%)) scored low (≤6 out of a maximum of 12) on the SPPB, but only 3 (1%) achieved recommended PA levels. Adjusting for confounders, the odds ratio of low SPPB (≤6) comparing those in the lowest one-third to highest two-thirds of mean CPM was 55 (95%CI: 6, 520); for mean steps per day it was 23 (95%CI: 4, 137) and for minutes of MVPA per day 56 (95%CI: 6, 530). Low levels of PA are common and are associated with poor levels of lower limb function in older adults.

ADFM'S 3-Year Strategic Plan 2012-2015: Helping Departments of Family Medicine Lead During Transformative Times

Reversible Recruitment and Emission of DO3A-Derived Lanthanide Complexes at Ligating Molecular Films on Gold

The recruitment of DO3A-derived lanthanide complexes by ligation to isophthalic acid and catechol-modified gold surfaces, and their resulting sensitization, is reported herein. Predictably pH-dependent surface recruitment is associated with the expected fingerprint europium and terbium emission characteristics. The intensity of the lanthanide luminescence scales exponentially with spacer length, indicating a strong quenching interaction between the lanthanide and the gold surface. The switchable catechol oxidation state provides a means of electrochemically triggering the release of prior ligated complexes.

A Randomised, Double-blind Phase III Study of Pazopanib in Patients with Advanced And/or Metastatic Renal Cell Carcinoma: Final Overall Survival Results and Safety Update

BACKGROUND: In this randomised phase III study (VEG105192; NCT00334282), pazopanib previously demonstrated statistically and clinically meaningful improvement of progression-free survival versus placebo in patients with advanced/metastatic renal cell carcinoma (mRCC). Final overall survival (OS) and updated safety results are now reported. METHODS: Treatment-naive or cytokine-pretreated mRCC patients (n=435) stratified and randomised (2:1) to pazopanib 800mg daily or placebo, were treated until disease progression, death or unacceptable toxicity. Upon progression, placebo patients could receive pazopanib through an open-label study. Final OS in the intent-to-treat population was analysed using a stratified log-rank test. Rank-preserving structural failure time (RPSFT) and inverse probability of censoring weighted (IPCW) analyses were performed post-hoc to adjust for crossover. FINDINGS: The difference in final OS between pazopanib- and placebo-treated patients was not statistically significant (22.9 versus 20.5months, respectively; hazard ratio [HR]=0.91; 95% confidence interval [CI], 0.71-1.16; one-sided P=.224). Early and frequent crossover from placebo to pazopanib and prolonged duration of crossover treatment confounded the OS analysis. In IPCW analyses, pazopanib decreased mortality (HR=0.504; 95% CI, 0.315-0.762; two-sided P=.002). Similar, albeit non-significant, results were obtained in RPSFT analyses (HR=0.43; 95% CI, 0.215-1.388; two-sided P=.172). Since the last cutoff, cumulative exposure to pazopanib increased by 30%. The pazopanib safety profile showed no new safety signals or changes in the type, frequency and severity of adverse events. INTERPRETATION: Although no significant difference in OS was observed in this study, extensive crossover from placebo to pazopanib confounded final OS analysis. Post-hoc analyses adjusting for crossover suggest OS benefit with pazopanib treatment for mRCC patients.

A Subtypes Based Analysis of Urological Chronic Pelvic Pain Syndrome in Men

PURPOSE: The current conceptualization of Urological Chronic Pelvic Pain Syndrome (UCPPS) in men recognizes a wide variety of pain, psychosocial, sexual, and urological symptoms and markers that may contribute to lowered quality of life. Unfortunately, this syndrome is difficult to clearly define and treat due to heterogeneous symptom profiles. The present study systematically described these heterogeneous symptoms and investigated whether these symptoms can be subtypes into distinct syndromes. MATERIALS AND METHODS: 171 men diagnosed with UCPPS filled out validated questionnaires, a structured genital pain interview, digital pain threshold testing, and urological assessment. The results of the pain interview are systematically presented as descriptive information. In addition, k-means cluster analysis was employed to define subtypes. RESULTS: Seven homogenous and distinct clusters were defined, each with remarkably different symptom presentation. These clusters were then described and related to previous hypotheses of UCPPS etiology. CONCLUSIONS: These clusters may represent distinct subtypes of UCPPS, and can then be used to guide treatments more effectively. Definition of subtypes may also improve understanding of the underlying mechanisms in UCPPS.

Constitutive Cdk2 Activity Promotes Aneuploidy While Altering the Spindle Assembly and Tetraploidy Checkpoints

The cell contains many mechanisms for protecting the integrity of its genome. These mechanisms are often weakened or absent in many cancers, leading to high rates of chromosomal instability in tumors. Control of the cell cycle is crucial for the function of these checkpoints, and is frequently lost in cancers as well. Overexpression of Cyclin D1 in a large number of breast cancers causes overactivation of the Cyclin Dependent Kinases, including Cdk2. Constitutive Cdk2 activation through Cyclin D1 generates tumors in mice that are aneuploid and contain many characteristics indicative of chromosomal instability. Expression of these complexes in the MCF10A cell line leads to Rb hyperphosphorylation, a subsequent increase in proliferation rate, and increased expression of the spindle assembly checkpoint protein Mad2. This leads to a strengthening of the spindle assembly checkpoint and renders cells more sensitive to the spindle poison paclitaxel. Constitutive Rb phosphorylation also causes a weakening of the p53-dependent tetraploidy checkpoint. Cells with overactive Cdk2 fail to arrest after mitotic slippage in the presence of paclitaxel or cytokinesis failure during treatment with cytochalasin-B, generating 8N populations. This additional increase in DNA content appears to further intensify the tetraploidy checkpoint in a step-wise manner. These polyploid cells are not viable long-term, either failing to undergo division or creating daughter cells that are unable to undergo subsequent division. This study raises intriguing questions about the treatment of tumors with overactive Cdk2.

Employer-incurred Health Care Costs and Productivity Losses Associated with Influenza

The primary objective of this study was to assess trends in employer expenditures for both direct medical costs and indirect productivity losses associated with influenza. A retrospective analysis was performed using two of the MarketScan family of databases for 2005-2009. Patients with at least one diagnosis claim for influenza during an influenza season were selected. We estimated seasonal incidence of influenza in the employed population from the MarketScan Commercial Claims and Encounters database. Health care utilization and costs and productivity losses were assessed during the 21-d period following the influenza diagnosis date. Compared with the 2005-2006 season (493 per 100,000 plan members), influenza incidence increased during the 2006-2007 (598 per 100,000 plan members) and 2007-2008 (1,142 per 100,000 plan members) seasons and had a dramatic increase during the pandemic season of 2008-2009 (1,715 per 100,000 plan members) . The total influenza-related employer spending per 100,000 plan members also increased by over 400% during the 2008-2009 influenza season [$623,248; confidence interval (CI]):$601,518-$644,991], compared with 2005-2006 ($145,834; 95% CI: $135,067-$156,603). The primary drivers of the increased costs were emergency room, outpatient and inpatient visits. Total costs associated with influenza-related missed work time per 100,000 plan members increased over 4-fold from $26,479 in the 2005-2006 influenza season to $122,811 in 2008-2009. Overall, as expected, considerably higher direct and indirect costs were observed during the 2008-2009 influenza pandemic season than during other influenza seasons. In recent years, the influenza-related employer burden has increased considerably. In future, employers may need efficient resource allocation in order to address the productivity losses and increasing direct medical costs associated with increased influenza incidence. One of the strategies that employers may consider is increasing influenza vaccination rates among employees, which likely will help lower the influenza incidence and the associated downstream direct and indirect costs.

Ripples in the Pond - Using a Systems Approach to Decipher the Cellular Functions of Membrane Microdomains

Membrane microdomains such as lipid rafts and caveolae regulate a myriad of cellular functions including cell signalling, protein trafficking, cell viability, and cell movement. They have been implicated in diseases such as cancer, diabetes and Alzheimer's disease, highlighting the essential role they play in cell processes. Despite much research and debate on the size, composition and dynamics of membrane microdomains, the molecular mechanism(s) of their action remain poorly understood. Most studies have dealt solely with the content and properties of the membrane microdomain as an entity in itself. However, recent work shows that membrane microdomain disruption has wide ranging effects on other subcellular compartments, and the cell as a whole. Hence we propose that a systems approach incorporating many cellular attributes such as subcellular localisation is required in order to understand the global impact of microdomains on cell function. Although analysis of sub-proteome changes already provides additional insight, we further propose biological network analysis of functional proteomics data to capture effects at the systems level. In this review, we highlight the use of protein-protein interactions networks and mixed networks to portray and visualize the relationships between proteins within and between subcellular fractions. Such a systems analysis will be required to improve our understanding of the full cellular function of membrane microdomains.

The SCF-Fbw7 Ubiquitin Ligase Degrades MED13 and MED13L and Regulates CDK8 Module Association with Mediator

The Mediator complex is an essential transcription regulator that bridges transcription factors with RNA polymerase II. This interaction is controlled by dynamic interactions between Mediator and the CDK8 module, but the mechanisms governing CDK8 module-Mediator association remain poorly understood. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association. Our work reveals a novel mechanism regulating CDK8 module-Mediator association and suggests an expanded role for Fbw7 in transcriptional control and an unanticipated relationship with the CDK8 oncogene.

The Amino-terminal Region of the DNA-dependent Protein Kinase Catalytic Subunit (DNA-PKcs) is Required for Its DNA Double-strand Break-mediated Activation

DNA-dependent protein kinase (DNA-PK) plays an essential role in the repair of DNA double-strand breaks (DSBs) mediated by the non-homologous end-joining pathway. DNA-PK is a holoenzyme consisting of a DNA binding (Ku70/Ku80) and catalytic (DNA-PKcs) subunit. DNA-PKcs is a serine/threonine protein kinase which is recruited to DSBs via Ku70/80 and is activated once the kinase is bound to the DSB ends. In this study, two large, distinct fragments of DNA-PKcs, consisting of the N-terminus (amino acids 1-2713) termed N-PKcs and C-terminus (amino acids 2714-4128) termed C-PKcs were produced to determine the role of each terminal region in regulating the activity of DNA-PKcs. N-PKcs but not C-PKcs interacts with the Ku-DNA complex and is required for the ability of DNA-PKcs to localize to DSBs. C-PKcs has increased basal kinase activity compared to DNA-PKcs suggesting the N-terminal region of DNA-PKcs keeps basal activity low. The kinase activity of C-PKcs is not stimulated by Ku70/80 and DNA, further supporting that the N-terminal region of is required for binding to the Ku-DNA complex and full activation of kinase activity. Collectively, the results show the N-terminal region mediates the interaction between DNA-PKcs and the Ku-DNA complex and is required for its DSB-induced enzymatic activity.

SRAdb: Query and Use Public Next-generation Sequencing Data from Within R

ABSTRACT:

Managing Information and Knowledge Within Maternity Services: Privacy and Consent Issues

Objective Electronic Patient Records have improved vastly the quality and efficiency of care delivered. However, the formation of single demographic database and the ease of electronic information sharing give rise to many concerns including issues of consent, by whom and how data are accessed and used. This paper examines the organizational and socio-technical issues related to privacy, confidentiality and security when employing electronic records within a maternity service hospital in England. Methods A preliminary questionnaire was administered (n  =  52), in total, 24 responses were received. Sixteen responses were from personnel in the information technology department, 5 from health information department and 3 from midwifery managers. This was followed by a semi-structured interview with representatives from the clinical and technological side. Results A number of issues related to information governance (IG) have been identified, especially breaches on sharing personal information without consent from the patients have been identified as one immediate challenge that needs to be fixed. Conclusion There is an immediate need for more robust, realistic, built-in accountability both locally and nationally on data sharing. A culture of ownership and strict adherence to IG principles is paramount. Focused training in the area of data, information and knowledge sharing will bring in a balance of legitimate usage against the individual's rights to confidentiality and privacy.

What Have We Learned from the Partin Table Update?

A Mononuclear Non-Heme Manganese(IV)-Oxo Complex Binding Redox-Inactive Metal Ions

Redox-inactive metal ions play pivotal roles in regulating the reactivities of high-valent metal-oxo species in a variety of enzymatic and chemical reactions. A mononuclear non-heme Mn(IV)-oxo complex bearing a pentadentate N(5) ligand has been synthesized and used in the synthesis of a Mn(IV)-oxo complex binding scandium ions. The Mn(IV)-oxo complexes were characterized with various spectroscopic methods. The reactivities of the Mn(IV)-oxo complex are markedly influenced by binding of Sc(3+) ions in oxidation reactions, such as a ∼2200-fold increase in the rate of oxidation of thioanisole (i.e., oxygen atom transfer) but a ∼180-fold decrease in the rate of C-H bond activation of 1,4-cyclohexadiene (i.e., hydrogen atom transfer). The present results provide the first example of a non-heme Mn(IV)-oxo complex binding redox-inactive metal ions that shows a contrasting effect of the redox-inactive metal ions on the reactivities of metal-oxo species in the oxygen atom transfer and hydrogen atom transfer reactions.

Retrospective Analysis of Tissue Plasminogen Activator As an Adjuvant Treatment for Calciphylaxis

OBJECTIVE To report our experience with low-dose tissue plasminogen activator in the treatment of calciphylaxis, a rare, usually fatal thrombotic condition that results in ischemia, necrosis, and infarction of adipose and cutaneous tissue. DESIGN Retrospective chart review. SETTING Tertiary care academic medical center. PATIENTS Fifteen patients (4 men and 11 women) with calciphylaxis, treated from January 1, 2002, through December 31, 2010. INTERVENTION Treatment with tissue plasminogen activator, concomitant wound care, and management of calcium-phosphate status. MAIN OUTCOME MEASURES Short-term ulcer healing, long-term survival. RESULTS Patients received daily low-dose infusions of tissue plasminogen activator (mean treatment duration, 11 days). Six patients had no adverse reactions, 3 had minor bleeding, 6 required blood transfusions, and 3 had life-threatening bleeding. No patients died of treatment-related complications. Ten patients died (median time to death, 3.6 months; range, 23 days to 4.2 years). Of the remaining 5 patients, the median duration of follow-up was 36.8 months (range, 70 days to 4.3 years). Patients treated with tissue plasminogen activator had approximately 30% greater survival than controls, but the difference was not significant (P = .14). Our results were limited by the use of concomitant therapies, referral bias for advanced disease, and retrospective case-series design. CONCLUSIONS Thrombolytic tissue plasminogen activator may be a useful adjunctive treatment in the management of patients with calciphylaxis. However, a multidisciplinary approach that includes aggressive wound care, débridement, thrombolytic therapy, restoration of tissue oxygenation, avoidance of infection, and control of calcium-phosphate homeostasis also is essential.

Preoperative Malalignment Increases Risk of Failure After Total Knee Arthroplasty

Implant survival after total knee arthroplasty has historically been dependent on postoperative knee alignment, although failure may occur when alignment is correct. Preoperative knee alignment has not been thoroughly evaluated as a possible risk factor for implant failure after arthroplasty. The purpose of this study was to analyze the effect of preoperative knee alignment on implant survival after total knee arthroplasty.

Dynamic Upper Airway Obstruction Secondary to Severe Feline Asthma

A 2 yr old castrated male cat presented to an emergency referral facility for several episodes of gagging, nonproductive coughing, and increased respiratory effort. He was diagnosed with inspiratory stridor and referred to another emergency referral practice for further diagnostics. Three separate, sedated oral examinations, nasal computed tomography (CT), rhinoscopic biopsies, and tracheoscopy showed no structural causes for the cat's stridor. An endotracheal wash was consistent with feline asthma. Blood work showed a peripheral eosinophilia and exposure to Dirofilaria immitis (D. immitis). The feline asthma was treated with albuterol, fluticasone, dexamethasone sodium phosphate, and terbutaline. Despite aggressive therapy for feline asthma, the cat had several episodes of severe inspiratory respiratory distress and stridor secondary to an upper airway obstruction. After 3 days of hospitalization, a temporary tracheostomy was performed and no further episodes of respiratory distress were noted. The tracheostomy tube was removed 3 days later, and the cat was discharged on the fourth day. At a 14 mo follow-up examination, the client reported no further episodes of respiratory distress, coughing, or gagging. To the authors' knowledge, this is the first report of dynamic upper airway obstruction secondary to feline asthma.

Validation of a Free Phenytoin Assay on Cobas C501 Analyzer Using Calibrators From Cobas Integra Free Phenytoin Assay by Comparing Its Performance With Fluorescence Polarization Immunoassay for Free Phenytoin on the TDx Analyzer

For many years, fluorescence polarization immunoassay (FPIA) on the TDx analyzer has been used for determination of free phenytoin concentration. Recently Abbott Laboratories decided to discontinue the TDx analyzer and related assays on this analyzer. Free phenytoin assay is also available from Roche Diagnostics for application on the Cobas Integra analyzer (fluorescence polarization assay) but not on Cobas c510 analyzer. Free phenytoin calibrators from the Cobas Integra free phenytoin assay and the reagents from the KIMSphenytoin assay were used for the determination of free phenytoin on the Cobas c501 analyzer. The intra-run and inter-run precisions were both <7.2%. The assay was linear from 0.2 to 4 μg/ml. The free phenytoin assay on the Cobas c501 was compared with the FPIAassay on the TDx analyzer using sera from 25 patients receiving phenytoin (phenytoin concentration between 0.3 and 3.7 μg/ml). The following regression equation was observed: y = 0.9899 x + 0.0408 (r = 0.98, n = 25). In conclusion, the free phenytoin assay on the Cobas c501 analyzer is a valid alternative to free phenytoin assay on the TDx analyzer. J. Clin. Lab. Anal. 27:1-4, 2013. © 2012 Wiley Periodicals, Inc.

Something Darwin Didn't Know About Barnacles: Spermcast Mating in a Common Stalked Species

Most free-living barnacles are hermaphroditic, and eggs are presumed to be fertilized either by pseudo-copulation or self-fertilization. Although the common northeast Pacific intertidal gooseneck barnacle, Pollicipes polymerus, is believed only to cross-fertilize, some isolated individuals well outside penis range nonetheless bear fertilized eggs. They must therefore either self-fertilize or-contrary to all prior expectations about barnacle mating-obtain sperm from the water. To test these alternative hypotheses, we collected isolated individuals bearing egg masses, as well as isolated pairs where at least one parent carried egg masses. Using 16 single nucleotide polymorphism markers, we confirmed that a high percentage of eggs were fertilized with sperm captured from the water. Sperm capture occurred in 100 per cent of isolated individuals and, remarkably, even in 24 per cent of individuals that had an adjacent partner. Replicate subsamples of individual egg masses confirmed that eggs fertilized by captured sperm occurred throughout the egg mass. Sperm capture may therefore be a common supplement to pseudo-copulation in this species. These observations (i) overturn over a century of beliefs about what barnacles can (or cannot) do in terms of sperm transfer, (ii) raise doubts about prior claims of self-fertilization in barnacles, (iii) raise interesting questions about the capacity for sperm capture in other species (particularly those with short penises), and (iv) show, we believe for the first time, that spermcast mating can occur in an aquatic arthropod.

A Homogeneous, High-throughput Assay for Phosphatidylinositol 5-phosphate 4-kinase with a Novel, Rapid Substrate Preparation

Phosphoinositide kinases regulate diverse cellular functions and are important targets for therapeutic development for diseases, such as diabetes and cancer. Preparation of the lipid substrate is crucial for the development of a robust and miniaturizable lipid kinase assay. Enzymatic assays for phosphoinositide kinases often use lipid substrates prepared from lyophilized lipid preparations by sonication, which result in variability in the liposome size from preparation to preparation. Herein, we report a homogeneous 1536-well luciferase-coupled bioluminescence assay for PI5P4Kα. The substrate preparation is novel and allows the rapid production of a DMSO-containing substrate solution without the need for lengthy liposome preparation protocols, thus enabling the scale-up of this traditionally difficult type of assay. The Z'-factor value was greater than 0.7 for the PI5P4Kα assay, indicating its suitability for high-throughput screening applications. Tyrphostin AG-82 had been identified as an inhibitor of PI5P4Kα by assessing the degree of phospho transfer of γ-(32)P-ATP to PI5P; its inhibitory activity against PI5P4Kα was confirmed in the present miniaturized assay. From a pilot screen of a library of bioactive compounds, another tyrphostin, I-OMe tyrphostin AG-538 (I-OMe-AG-538), was identified as an ATP-competitive inhibitor of PI5P4Kα with an IC(50) of 1 µM, affirming the suitability of the assay for inhibitor discovery campaigns. This homogeneous assay may apply to other lipid kinases and should help in the identification of leads for this class of enzymes by enabling high-throughput screening efforts.

Urine IL-18, NGAL, IL-8 and Serum IL-8 Are Biomarkers of Acute Kidney Injury Following Liver Transplantation

ABSTRACT:

Valproic Acid Reduces the Tolerability of Temsirolimus in Children and Adolescents with Solid Tumors

A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mg/m intravenously/week. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response. Patients were treated with VPA (5 mg/kg orally three times daily) with a target serum level of 75-100 mcg/ml. Tem was started at an initial dose of 60 mg/m/week. Pharmacokinetics and HA measurements were performed during weeks 1 and 5. Two of the first three patients experienced dose-limiting toxicity (grade 3 mucositis). Tem at 35 mg/m/week was found to be tolerable. Peak Tem concentrations were higher in all patients compared with those in previously published reports of single agent Tem. Increases in HA are correlated with VPA levels. All tumor samples expressed mTORC1 and mTORC2. An objective response was observed in one patient (melanoma), whereas transient stable disease was observed in four other patients (spinal cord ependymoma, alveolar soft part sarcoma, medullary thyroid carcinoma, and hepatocellular carcinoma). The MTD of Tem when administered with VPA is considerably lower than when used as a single agent, with mucositis the major dose-limiting toxicity. The combination merits further study and may have activity in melanoma. Attention to drug-drug interactions will be important in future multiagent trials including Tem.

Quantitative Magneto-Mechanical Detection and Control of the Barkhausen Effect

Quantitative characterization of intrinsic and artificial defects in ferromagnetic structures is critical to future magnetic storage based on vortices or domain walls moving through nanostructured devices. Using torsional magnetometry, we observe finite size modifications to the Barkhausen effect in the limiting case of a single vortex core interacting with individual point-like pinning sites in a magnetic thin film. The Barkhausen effect in this limit becomes a quantitative two-dimensional nanoscale probe of local energetics in the film. Tailoring the pinning potential using single-point focused ion beam implantation demonstrates control of the effect and points the way to integrated magneto-mechanical devices incorporating quantum pinning effects.

Enhanced Hematopoietic Protection from Radiation by the Combination of Genistein and Captopril

The hematopoietic system is sensitive to radiation injury, and mortality can occur due to blood cell deficiency and stem cell loss. Genistein and the angiotensin converting enzyme (ACE) inhibitor captopril are two agents shown to protect the hematopoietic system from radiation injury. In this study we examined the combination of genistein with captopril for reduction of radiation-induced mortality from hematopoietic damage and the mechanisms of radiation protection. C57BL/6J mice were exposed to 8.25Gy (60)Co total body irradiation (TBI) to evaluate the effects of genistein and captopril alone and in combination on survival, blood cell recovery, hematopoietic progenitor cell recovery, DNA damage, and erythropoietin production. 8.25Gy TBI resulted in 0% survival after 30days in untreated mice. A single subcutaneous injection of genistein administered 24h before TBI resulted in 72% survival. Administration of captopril in the drinking water, from 1h through 30days postirradiation, increased survival to 55%. Genistein plus captopril increased survival to 95%. Enhanced survival was reflected in a reduction of radiation-induced anemia, improved recovery of nucleated bone marrow cells, splenocytes and circulating red blood cells. The drug combination enhanced early recovery of marrow progenitors: erythroid (CFU-E and BFU-E), and myeloid (CFU-GEMM, CFU-GM and CFU-M). Genistein alone and genistein plus captopril protected hematopoietic progenitor cells from radiation-induced micronuclei, while captopril had no effect. Captopril alone and genistein plus captopril, but not genistein alone, suppressed radiation-induced erythropoietin production. These data suggest that genistein and captopril protect the hematopoietic system from radiation injury via independent mechanisms.

Implications for Human Leukocyte Antigen Antibodies After Lung Transplantation: A 10 Year Experience in 441 Patients

ABSTRACT BACKGROUND: Long-term survival after lung transplant is limited by the development of chronic and progressive airflow obstruction, a condition known as bronchiolitis obliterans syndrome (BOS). While prior studies strongly implicate cellular rejection as a strong risk factor for BOS, less is known about the clinical significance of human leukocyte antigen (HLA) antibodies and donor HLA specific antibodies (DSA) in long term outcomes. METHODS: A single center cohort of 441 lung transplant recipients spanning a 10 year period was prospectively screened for HLA antibodies after transplant using flow cytometry based methods. The prevalence of and predictors for HLA antibodies were determined. The impact of HLA antibodies on survival after transplant and the development of BOS were determined using Cox models. RESULTS: Of the 441 recipients, 139 (32%) had detectable antibodies to HLA. Of these 139 recipients, 54 (39%) developed antibodies specific to donor HLA. The detection of posttransplant HLA antibodies was associated with BOS (HR 1.54, p=0.04) and death (HR 1.53, p=0.02) in multivariable models. The detection of donor specific HLA antibodies was associated with death (HR 2.42, p<0.0001). The detection of posttransplant HLA antibodies was associated with pretransplant HLA antibody detection, platelet transfusions, the development of BOS and CMV pneumonitis. CONCLUSIONS: Approximately one-third of lung transplant recipients have detectable HLA antibodies which is associated with a worse prognosis with regards to graft function and patient survival.

Risk of Cardiovascular Disorders in Psoriasis Patients : Current and Future

Psoriasis is an inflammatory autoimmune disease that affects the skin. Recently, psoriasis and its consequential lifestyle and dietary habits have been associated with increased risks for cardiovascular diseases. This article discusses the connection between cardiovascular disorders and psoriasis and the effects of available treatment options on cardiovascular risk. A PubMed search revealed 11 articles that were analyzed for information regarding this association, its effects, and potential courses of treatment. Both the presence and severity of psoriasis increases the risk for cardiovascular disorders and co-morbidities. Forty percent of psoriasis patients met metabolic syndrome criteria as compared with 23 % of non-psoriasis control subjects. Rate ratios for atrial fibrillation are correlated with the severity of psoriasis; patients with severe and mild psoriasis produced rate ratios of 1.63 and 1.31, respectively. Studies also show an increase in the risks for myocardial infarction, atherosclerosis, ischemic stroke, and other cardiovascular disorders. The exact mechanisms behind this affiliation are still uncertain; however, the psychological and physiological effects of psoriasis and the overlapping pathogenesis behind atherosclerosis and psoriasis may play a role. Since the risk for cardiovascular disorders increases with the presence and severity of psoriasis, psoriasis treatment should not only address the disease and its symptoms, but also its co-morbidities. Recent National Psoriasis Foundation (NPF) guidelines have provided recommendations for psoriasis patient care. Histories of co-morbidities, screenings for potential diseases, increased exercise, decreased alcohol consumption, and smoking cessation should be implemented. Unfortunately, while there are data for the increased risk for cardiovascular diseases within psoriasis patients, there are presently no data stating that increasing cardiovascular screening rates in patients produces a significant difference.

The Effects of Intensive Care Unit Staffing on Patient Outcomes Following Microvascular Free Flap Reconstruction of the Head and Neck: a Pilot Study

OBJECTIVE To determine if the implementation of the closed intensive care unit (ICU) at our institution altered clinical outcomes in patients who had undergone microvascular free flap reconstruction of the head and neck by the Otolaryngology-Head and Neck Surgery Service. DESIGN Retrospective medical chart review. SETTING A single tertiary medical center. PATIENTS The open ICU cohort had 52 flaps performed on 50 patients, and the closed ICU cohort had 52 flaps performed on 52 patients. MAIN OUTCOME MEASURES Fifty-two free flap reconstructions of head and neck defects were performed on 50 patients who were admitted to an open ICU. The length of stay (LOS) in the ICU and hospital and incidence of complications were compared with those of 52 patients who underwent 52 free flap reconstructions and were admitted to a closed ICU over a separate period. RESULTS The mean length of stay in the ICU was 44 and 45 hours in the open and closed ICU cohorts, respectively (P = .90). The incidence of surgical and medical complications was similar in the open and closed ICU cohorts (P > .05). CONCLUSIONS There does not appear to be a significant difference in patient outcome between open and closed ICU care in our study.

Expression of the Calpain System is Associated with Poor Clinical Outcome in Gastro-oesophageal Adenocarcinomas

BACKGROUND: Surgery is critical in the management of gastro-oesophageal cancer, and the addition of neo-adjuvant chemotherapy has proved to be of benefit. The calpain system has been implicated in tumour progression and response to various anti-cancer therapies, and therefore expression of the system was determined in this tumour type. METHODS: Two cohorts of gastro-oesophageal adenocarcinomas were investigated for calpain-1, calpain-2, calpain-9 and calpastatin expression using conventional immunohistochemistry. 88 patients who received neo-adjuvant chemotherapy and 140 patients who received surgery alone were investigated using a tissue microarray approach. RESULTS: Calpain-1, calpain-2 and calpastatin expression was associated with adverse cancer-specific survival in the neo-adjuvant cohort (P = 0.004, P = 0.001 and P = 0.012 respectively); which remained significant in multivariate analysis (Hazard ratio (HR) = 0.337; 95 % confidence interval (CI) = 0.140-0.81; P = 0.015, HR = 0.375; 95 % CI = 0.165-0.858; P = 0.020 and HR = 0.481; 95 % CI = 0.257-0.900; P = 0.022 respectively). Calpain-1 and calpastatin expression was also associated with adverse cancer specific survival in the primary surgery cohort (P = 0.001 and P = 0.013 respectively); which remained significant in multivariate analysis (HR = 0.309; 95 % CI = 0.159-0.601; P = 0.001 and HR = 0.418; 95 % CI = 0.205-0.850; P = 0.016 respectively). Calpain-9 expression was not associated with cancer-specific survival in the neo-adjuvant and primary surgery cohorts. CONCLUSION: Determining the expression levels of calpain-1, calpain-2 and calpastatin may provide clinically relevant prognostic information for gastro-oesophageal adenocarcinomas; these findings warrant further studies in larger cohorts of patients.

Functional and Developmental Significance of Amplitude Variance Asymmetry in the BOLD Resting-State Signal

It is known that the brain's resting-state activity (RSA) is organized in low frequency oscillations that drive network connectivity. Recent research has also shown that elements of RSA described by high-frequency and nonoscillatory properties are non-random and functionally relevant. Motivated by this research, we investigated nonoscillatory aspects of the blood-oxygen-level-dependent (BOLD) RSA using a novel method for characterizing subtle fluctuation dynamics. The metric that we develop quantifies the relative variance of the amplitude of local-maxima and local-minima in a BOLD time course (amplitude variance asymmetry; AVA). This metric reveals new properties of RSA activity, without relying on connectivity as a descriptive tool. We applied the AVA analysis to data from 3 different participant groups (2 adults, 1 child) collected from 3 different centers. The analyses show that AVA patterns a) identify 3 types of RSA profiles in adults' sensory systems b) differ in topology and pattern of dynamics in adults and children, and c) are stable across magnetic resonance scanners. Furthermore, children with higher IQ demonstrated more adult-like AVA patterns. These findings indicate that AVA reflects important and novel dimensions of brain development and RSA.

Internet Connectivity Among Rural Alabama Veterans: Baseline Findings from the Alabama Veterans Rural Health Initiative Project

The purpose of this secondary data analysis was to characterize the Internet usage of rural veterans (n=201) who had either never enrolled, or had previously enrolled but not accessed, Veterans Affairs (VA) health services in at least 2 years. The VA Office of Rural Health (ORH)(ie part of the United States Government Department of Veterans Affairs) is a government agency with the mission to improve access and quality of care for enrolled rural and highly rural US veterans. The ORH seeks to use evidence-based policies and innovative practices to support the unique needs of enrolled veterans residing in geographically remote areas. These individuals represent a population considered to experience health disparities secondary to reduced health care access.

All Monofilament Knots Assume Sliding Conformation In Vivo

BACKGROUND: Surgeons are not always cognizant of the knots they tie. It has been thought that suture material does not determine what types of knots are tied. DESIGN: Experienced surgeons were asked to tie square monofilament knots that were salvaged and microscopically evaluated. RESULTS: Tightly cinched monofilament knots assume sliding conformation in vivo regardless of configuration, instrumentation, suture polymer, or surgeon. CONCLUSIONS: When monofilament suture is securely cinched in vivo, kinetic energy forces even a flat throw into sliding conformation. A well-crafted, intentionally sliding square knot appears compacter than any other monofilament knot.

Decreased Injecting is Associated with Increased Alcohol Consumption Among Injecting Drug Users in Northern Vietnam

BACKGROUND: Reducing injecting frequency may reduce the risk of HIV infection and improve health outcomes among injection drug users (IDUs). However, the reduction of one risk behavior may be associated with an increase in other risk behaviors, including the use of other risk-associated substances. Our objective was to determine if an association exists between a reduction in injecting and level of alcohol use among IDU. METHODS: We conducted a longitudinal analysis of data collected for a randomized controlled trial examining the efficacy of a peer education intervention in reducing HIV risk among IDU and their network members in Thai Nguyen, Vietnam. Our analysis included active male injectors (n=629) who were study participants and attended both baseline and 3-month visits. Frequency of alcohol consumption was assessed as the number of alcoholic drinks in the past 30days. Change in risk and outcome behaviors was calculated as the difference in frequencies of behaviors between baseline and 3-month follow-up visits. The outcome of interest was concurrent decreased drug injection and increased alcohol consumption. RESULTS: The mean difference between baseline and 3-month follow-up of alcohol consumption and injection frequency in the past 30days was 19.03 drinks (93.68 SD) and 20.22 injections (35.66 SD), respectively. Participants who reported reduced injection frequency were almost three times as likely to report increased alcohol consumption (OR 2.8; 95% CI, 2.0, 4.0). The proportion that both decreased injecting and increased alcohol by any amount in the past 30days was 35.6%. In multivariate analysis higher education was significantly associated with an increase in alcohol and decrease in injecting of any amount. CONCLUSION: Male IDU may be at risk for increasing alcohol consumption when they reduce injection frequency. Interventions with male IDU that encourage reduction of injection may need to review specific strategies to limit alcohol consumption.

Operative Challenges in Management of Concurrent Interrupted Aortic Arch and Descending Thoracic Aortic Aneurysm

Interrupted aortic arch is a rare finding in the adult patient. This condition in combination with a descending thoracic aortic aneurysm is an even more exceptional occurrence. Surgical management includes open, endovascular, and hybrid options. We present the case of a 57-year-old man with interrupted aortic arch and concomitant descending thoracic aortic aneurysm, review characterization of this entity, and discuss management options with consideration to associated risks.

Marked Selective Impairment in Autism on an Index of Magnocellular Function

Atypical high-level vision in autism is sometimes attributed to a core deficit in the function of lateral geniculate nucleus magnocells or their retinal drives. While some physiological measures provide indirect, suggestive evidence for such a deficit, support from behavioural measures is lacking and contradictory. We assessed luminance contrast increment thresholds on pulsed- and steady- pedestals in 17 children with autism spectrum conditions (ASC) compared to 17 typically developing children; these two conditions correspond to widely-used indices of magnocellular and parvocellular function. As a group, children with ASC had strikingly elevated thresholds on the steady pedestal-paradigm, yet performed similarly to controls on the pulsed pedestal paradigm, a finding that would typically be interpreted to reflect impaired magnocellular function. The effect size of the impairment was large and a substantial minority (41.2%) of the ASC group showed significantly impaired performance on an individual basis. This finding is consistent with a selective magnocellular deficit. It directly contradicts previous claims that such deficits are confined to 'complex' visual stimuli and likely does not reflect atypical attention, adaptation or high-level vision. The pattern of results is not clearly predicted by notions of imbalance of excitation versus inhibition, atypical lateral connectivity or enhanced perceptual function that account for a range of other findings associated with perception in autism. It may be amenable to explanation in terms of decreased endogenous neural noise, a novel alternative we outline here.

Vitamin D Intake Is Inadequate in Spinal Muscular Atrophy Type I Cohort: Correlations With Bone Health

Children with type I spinal muscular atrophy commonly demonstrate reduced bone mineral density. Our objectives were to evaluate and assess adequacy of vitamin D intake, serum levels, and association with bone mineral density. Assessments were completed using 3-day food records and dual energy x-ray absorptiometry scans. The spinal muscular atrophy type I cohort included 22 males and 18 females (N = 40), with a mean age of 18.6 months. Data collection occurred from 2001 to 2011. Seventy-five percent of patients had inadequate intake of vitamin D at the initial visit. Using mixed-effects analyses, vitamin D and calcium intakes correlated positively with bone mineral density (r = 0.31 and r = 0.53, respectively). Increased vitamin D and calcium consumption were associated with an increase in bone mineral density (P = .04 and P = .01, respectively). Vitamin D intake correlated positively with serum levels (r = 0.65). Further study is needed to determine optimal intakes of vitamin D and calcium in the spinal muscular atrophy type I population.

Vascular Endothelial Growth Factor C is Increased in Endometrium and Promotes Endothelial Functions, Vascular Permeability and Angiogenesis and Growth of Endometriosis

Endometriosis is an angiogenesis-dependent disease. Many studies demonstrated inhibition of angiogenesis leads to inhibition of endometriotic growth, however underlying mechanism is still not fully understood. Our previous study suggested vascular endothelial growth factor C (VEGF-C) as a target of anti-angiogenesis therapy for endometriosis. In this study, VEGF-C in endometrium and its role in angiogenesis of endometriosis were studied. Human endometrium were obtained from women with and without endometriosis for molecular studies. VEGF-A, VEGF-B, VEGF-C and VEGF-D mRNA and proteins in eutopic and ectopic endometrium were measured. Human endothelial cells were transfected with VEGF-C siRNA in vitro, effects of VEGF-C on endothelial cell migration, invasion and tube formation were investigated in vitro. Angiogenesis was inhibited in wild type mice, vascular permeability in dermal skin was determined in vivo. Transplanted endometrium were inhibited by VEGF-C siRNA in immunocompromised mice, development, growth and angiogenesis of the experimental endometriosis were compared in vivo. The results showed that VEGF-C mRNA and protein were increased in eutopic and ectopic endometrium of endometriosis patients. VEGF-C siRNA significantly inhibited endothelial cell migration and tube formation. VEGF-C siRNA significantly inhibited development and angiogenesis of the experimental endometriotic lesions in mice. Supplementation and over-expression of VEGF-C significantly reversed the inhibitory effects on the endothelial functions, vascular permeability and endometriotic growth. In conclusion, VEGF-C is increased in endometrium and it promotes endothelial functions, vascular permeability and development of experimental endometriosis. VEGF-C is important for angiogenesis in endometriosis.

Molecular Composition and Extinction Coefficient of Native Botulinum Neurotoxin Complex Produced by Clostridium Botulinum Hall A Strain

Seven distinct strains of Clostridium botulinum (type A to G) each produce a stable complex of botulinum neurotoxin (BoNT) along with neurotoxin-associated proteins (NAPs). Type A botulinum neurotoxin (BoNT/A) is produced with a group of NAPs and is commercially available for the treatment of numerous neuromuscular disorders and cosmetic purposes. Previous studies have indicated that BoNT/A complex composition is specific to the strain, the method of growth and the method of purification; consequently, any variation in composition of NAPs could have significant implications to the effectiveness of BoNT based therapeutics. In this study, a standard analytical technique using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and densitometry analysis was developed to accurately analyze BoNT/A complex from C. botulinum type A Hall strain. Using 3 batches of BoNT/A complex the molar ratio was determined as neurotoxin binding protein (NBP, 124 kDa), heavy chain (HC, 90 kDa), light chain (LC, 53 kDa), NAP-53 (50 kDa), NAP-33 (36 kDa), NAP-22 (24 kDa), NAP-17 (17 kDa) 1:1:1:2:3:2:2. With Bradford, Lowry, bicinchoninic acid (BCA) and spectroscopic protein estimation methods, the extinction coefficient of BoNT/A complex was determined as 1.54 ± 0.26 (mg/mL)(-1)cm(-1). These findings of a reproducible BoNT/A complex composition will aid in understanding the molecular structure and function of BoNT/A and NAPs.

'Candidatus Phytoplasma Solani', a Novel Taxon Associated with Stolbur and Bois Noir Related Diseases of Plants

Phytoplasmas classified in group 16SrXII infect a wide range of plants and are transmitted by polyphagous planthoppers of the family Cixiidae. Based on 16S rRNA gene sequence identity and biological properties, group 16SrXII encompasses several species, including 'Candidatus Phytoplasma australiense', 'Ca. Phytoplasma japonicum', and 'Ca. Phytoplasma fragariae'. Other group 16SrXII phytoplasma strains are associated with stolbur disease in wild and cultivated herbaceous and woody plants and with bois noir disease in grapevines (Vitis vinifera L.). Such latter strains have been informally proposed to represent a separate species, 'Candidatus Phytoplasma solani', but a formal description of this taxon has not previously been published. In the present work, stolbur disease strain STOL11 was distinguished from reference strains of previously described 'Ca. Phytoplasma' species based on 16S rRNA gene sequence (16S rDNA) similarity and a unique signature sequence in 16S rDNA. Other stolbur and bois noir associated ('Ca. Phytoplasma solani') strains shared >99% 16S rDNA sequence similarity with strain STOL11 and contained the signature sequence. 'Ca. Phytoplasma solani' is the only phytoplasma known to be transmitted by Hyalesthes obsoletus. Insect vectorship and molecular characteristics are consistent with the concept that diverse 'Ca. Phytoplasma solani' strains share common properties and represent an ecologically distinct gene pool. Phylogenetic analyses of 16S rRNA, tuf, secY, and rplV-rpsC gene sequences supported this view and yielded congruent trees on which 'Ca. Phytoplasma solani' strains formed, within the group 16SrXII clade, a monophyletic subclade that was most closely related to, but distinct from, that of 'Ca. Phytoplasma australiense'-related strains. Based on distinct molecular and biological properties, stolbur and bois noir associated strains are proposed to represent a novel species level taxon, 'Ca. Phytoplasma solani'; STOL11 is designated the reference strain.

Validation of an Algorithm to Estimate Gestational Age in Electronic Health Plan Databases

PURPOSE: To validate an algorithm that uses delivery date and diagnosis codes to define gestational age at birth in electronic health plan databases. METHODS: Using data from 225 384 live born deliveries to women aged 15-45 years in 2001-2007 within eight of the 11 health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program, we compared (1) the algorithm-derived gestational age versus the "gold-standard" gestational age obtained from the infant birth certificate file and (2) the prenatal exposure status of two antidepressants (fluoxetine and sertraline) and two antibiotics (amoxicillin and azithromycin) as determined by the algorithm-derived versus the gold-standard gestational age. RESULTS: The mean algorithm-derived gestational age at birth was lower than the mean obtained from the birth certificate file among singleton deliveries (267.9 vs 273.5 days) but not among multiple-gestation deliveries (253.9 vs 252.6 days). The algorithm-derived prenatal exposure to the antidepressants had a sensitivity and a positive predictive value of ≥95%, and a specificity and a negative predictive value of almost 100%. Sensitivity and positive predictive value were both ≥90%, and specificity and negative predictive value were both >99% for the antibiotics. CONCLUSIONS: A gestational age algorithm based upon electronic health plan data correctly classified medication exposure status in most live born deliveries, but trimester-specific misclassification may be higher for drugs typically used for short durations. Copyright © 2013 John Wiley & Sons, Ltd.

One-Month Serotonin Infusion Results in a Prolonged Fall in Blood Pressure in the Deoxycorticosterone Acetate (DOCA) Salt Hypertensive Rat

A 7-day infusion of serotonin (5-hydroxytryptamine, 5-HT) causes a sustained fall in elevated blood pressure in the male deoxycorticosterone acetate (DOCA)-salt rat. As hypertension is a long-term disease, we presently test the hypothesis that a longer (30 day) 5-HT infusion could cause a sustained fall in blood pressure in the established hypertensive DOCA-salt rat. This time period (∼4 weeks) was also sufficient to test whether 5-HT could attenuate the development of DOCA-salt hypertension. 5-HT (25 μg/kg/min; sc) or vehicle (Veh) was delivered via osmotic pump to (1) established DOCA-salt rats for one month, (2) Sprague-Dawley rats prior to DOCA-salt administration for one month, and blood pressure and heart rate measured telemetrically. On the final day of 5-HT infusion, free platelet poor plasma 5-HT concentrations were significantly higher in 5-HT versus Veh-infused rats, and mean arterial pressure was significantly lower in 5-HT-infused (135 ± 4 mmHg vs Veh-infused 151 ± 7 mmHg) established DOCA-salt rats. By contrast, 5-HT-infusion did not prevent the development of DOCA-salt hypertension (144 ± 7 mmHg vs Veh = 156 ± 6 mmHg). Isometric contraction of aortic strips was measured, and neither the potency nor maximum contraction to the alpha adrenergic receptor agonist phenylephrine (PE) or 5-HT were modified by infusion of 5-HT (established or preventative infusion), and maximum aortic relaxation to acetylcholine (ACh) was modestly but not significantly enhanced (∼15% improvement). This study demonstrates 5-HT is capable of lowering blood pressure in established DOCA-salt hypertensive rats over the course of one month in a mechanism that does not significantly modify or is dependent on modified vascular responsiveness. This finding opens the possibility that elevation of 5-HT levels could be useful in the treatment of hypertension.

Thrombolysis in the Developing World: is There a Role for Streptokinase?

Intravenous thrombolysis with tissue plasminogen activator is the only proven acute therapy for ischemic stroke. This therapy has not been translated into clinical practice in the developing world primarily due to economic constraints. Streptokinase, a lower cost alternative thrombolytic agent, is widely available in developing countries where it is utilized to treat patients with acute coronary syndromes. Although this drug has previously been found to be ineffective in ischemic stroke, the lack of benefit may have been related to a number of factors related to trial design rather than the drug itself. Specific features of prior trial designs that may have adversely affected outcomes include a prolonged treatment window, inclusion of patients with established infarction on computed tomography scan, failure to treat excessive arterial pressures, a fixed dose of streptokinase, and concomitant use of antithrombotic medications. Given the lack of therapeutic alternatives in developing countries, a new trial of streptokinase in acute stroke, utilizing stricter inclusion criteria similar to those in more recent thrombolytic studies, appears warranted.

Rewriting the Bacterial Glycocalyx Via Suzuki-Miyaura Cross-coupling

Suzuki-Miyaura cross-coupling has been used to couple novel carbohydrate-based boronic acids, site-selectively, to the surface of E. coli at an unnatural amino acid. In this way, benign metal-catalyzed cellular switching allowed modulation of interactions with biomolecular partners via prokaryotic O-glycosylation mimics.

Integrating Spatial and Temporal Oxygen Data to Improve the Quantification of in Situ Petroleum Biodegradation Rates

Accurate estimation of biodegradation rates during remediation of petroleum impacted soil and groundwater is critical to avoid excessive costs and to ensure remedial effectiveness. Oxygen depth profiles or oxygen consumption over time are often used separately to estimate the magnitude and timeframe for biodegradation of petroleum hydrocarbons in soil and subsurface environments. Each method has limitations. Here we integrate spatial and temporal oxygen concentration data from a field experiment to develop better estimates and more reliably quantify biodegradation rates. During a nine-month bioremediation trial, 84 sets of respiration rate data (where aeration was halted and oxygen consumption was measured over time) were collected from in situ oxygen sensors at multiple locations and depths across a diesel non-aqueous phase liquid (NAPL) contaminated subsurface. Additionally, detailed vertical soil moisture (air-filled porosity) and NAPL content profiles were determined. The spatial and temporal oxygen concentration (respiration) data were modeled assuming one-dimensional diffusion of oxygen through the soil profile which was open to the atmosphere. Point and vertically averaged biodegradation rates were determined, and compared to modeled data from a previous field trial. Point estimates of biodegradation rates assuming no diffusion ranged up to 58 mg kg(-1) day(-1) while rates accounting for diffusion ranged up to 87 mg kg(-1) day(-1). Typically, accounting for diffusion increased point biodegradation rate estimates by 15-75% and vertically averaged rates by 60-80% depending on the averaging method adopted. Importantly, ignoring diffusion led to overestimation of biodegradation rates where the location of measurement was outside the zone of NAPL contamination. Over or underestimation of biodegradation rate estimates leads to cost implications for successful remediation of petroleum impacted sites.

Patterns of Use of Oral Adjuvant Endocrine Therapy in Australian Breast Cancer Survivors 5 Years from Diagnosis

OBJECTIVE: Oral adjuvant endocrine therapy (OAET) substantially improves the survival of women with hormone receptor-positive (HR) breast cancer. However, we reported previously that at 3 to 4 years after diagnosis, 18% of affected women are not using OAET primarily because of estrogen deficiency symptoms. The aim of this study was to determine the use of OAET in women with HR breast cancer 5 to 6 years from diagnosis. METHODS: Analysis was carried out using data from the Bupa Health Foundation's Health and Wellbeing After Breast Cancer Study, a cohort study of 1,683 women with breast cancer who were recruited in Victoria, Australia between 2004 and 2006. All women completed an enrollment questionnaire within 12 months of diagnosis and an annual follow-up questionnaire (FQ) for 5 years. The fifth FQ was completed 5.7 years from the time of diagnosis. Use of OAET was self-reported in response to a series of questions. RESULTS: A minimal exposure to OAET of at least 5 years (OAET in all six FQs) was reported by 19.7% of the women (n = 212), and another 46.7% (n = 503) received a minimal exposure of at least 4 years (OAET in five questionnaires). In total, 82.1% (n = 883) of the women would have received at least 3 years of treatment (OAET in at least four questionnaires). Only 7.8% (n = 84) reported never using OAET. CONCLUSIONS: Most women with HR breast cancer who survive at least 5 years have persisted with OAET despite the adverse effects of estrogen depletion.

Vaccination for the Prevention and Treatment of Breast Cancer with Special Focus on Her-2/neu Peptide Vaccines

Immunologic interventions in a subset of breast cancer patients represent a well-established therapeutic approach reflecting individualized treatment modalities. Thus, the therapeutic administration of monoclonal antibodies targeting tumor-associated antigens (TAA), such as Her-2/neu, represents a milestone in cancer treatment. However, passive antibody administration suffers from several drawbacks, including frequency and long duration of treatment. These undesirables may be avoidable in an approach based on generating active immune responses against these same targets. Only recently has the significance of tumors in relation to their microenvironments been understood as essential for creating an effective cancer vaccine. In particular, the immune system plays an important role in suppressing or promoting tumor formation and growth. Therefore, activation of appropriate triggers (such as induction of Th1 cells, CD8+ T cells, and suppression of regulatory cells in combination with generation of antibodies with anti-tumor activity) is a desirable goal. Current vaccination approaches have concentrated on therapeutic vaccines using certain TAA. Many cancer antigens, including breast cancer antigens, have been described and also given priority ranking for use as vaccine antigens by the US National Cancer Institute. One of the TAA antigens which has been thoroughly examined in numerous trials is Her-2/neu. This review will discuss delivery systems for this antigen with special focus on T and B cell peptide vaccines. Attention will be given to their advantages and limitations, as well as the use of certain adjuvants to improve anti-cancer responses.

Identification and Characterization of Proteins Involved in Nuclear Organization Using Drosophila GFP Protein Trap Lines

Strains from a collection of Drosophila GFP protein trap lines express GFP in the normal tissues where the endogenous protein is present. This collection can be used to screen for proteins distributed in the nucleus in a non-uniform pattern.

Record-breaking Early Flowering in the Eastern United States

Flowering times are well-documented indicators of the ecological effects of climate change and are linked to numerous ecosystem processes and trophic interactions. Dozens of studies have shown that flowering times for many spring-flowering plants have become earlier as a result of recent climate change, but it is uncertain if flowering times will continue to advance as temperatures rise. Here, we used long-term flowering records initiated by Henry David Thoreau in 1852 and Aldo Leopold in 1935 to investigate this question. Our analyses demonstrate that record-breaking spring temperatures in 2010 and 2012 in Massachusetts, USA, and 2012 in Wisconsin, USA, resulted in the earliest flowering times in recorded history for dozens of spring-flowering plants of the eastern United States. These dramatic advances in spring flowering were successfully predicted by historical relationships between flowering and spring temperature spanning up to 161 years of ecological change. These results demonstrate that numerous temperate plant species have yet to show obvious signs of physiological constraints on phenological advancement in the face of climate change.

Dual Patterning of a Polyacrylic Acid Layer by Electron Beam and Block Copolymer Lithographies

We show controllable patterning of palladium nanoparticles in both one and two dimensions using electron beam lithography and reactive ion etching of a thin film of polyacrylic acid (PAA). After initial patterning of the PAA, a monolayer of polystyrene-b-poly-2-vinylpyridine micelles is spun cast onto the surface. A short reactive ion etch is then used to transfer the micelle pattern into the patterned polyacrylic acid. Finally, PdCl2 is loaded from solution into the patterned polyacrylic acid features, and a reactive-ion etch process is used to remove the remaining polymer and form Pd nanoparticles. This method yields location-controlled patches of nanoparticles, including single and double file lines, and nanoparticle pairs. Locational accuracy of 9 nm or less in one direction was achieved by optimizing the size of the PAA features.

VERBâ„¢ Summer Scorecard: Increasing Tween Girls' Vigorous Physical Activity

We assessed changes in the frequency of self-reported physical activity (PA) among tween girls exposed and not exposed to the VERBâ„¢ Summer Scorecard (VSS) intervention in Lexington, Kentucky, during 2004, 2006, and 2007.

CHILE: An Evidence-Based Preschool Intervention for Obesity Prevention in Head Start

Obesity is a major concern among American Indians and Hispanics. The Child Health Initiative for Lifelong Eating and Exercise (CHILE) is an evidence-based intervention to prevent obesity in children enrolled in 16 Head Start (HS) Centers in rural communities. The design and implementation of CHILE are described.

Targeted Drug Delivery to Treat Pain and Cerebral Hypoxia

Limited drug penetration is an obstacle that is often encountered in treatment of central nervous system (CNS) diseases including pain and cerebral hypoxia. Over the past several years, biochemical characteristics of the brain (i.e., tight junction protein complexes at brain barrier sites, expression of influx and efflux transporters) have been shown to be directly involved in determining CNS permeation of therapeutic agents; however, the vast majority of these studies have focused on understanding those mechanisms that prevent drugs from entering the CNS. Recently, this paradigm has shifted toward identifying and characterizing brain targets that facilitate CNS drug delivery. Such targets include the organic anion-transporting polypeptides (OATPs in humans; Oatps in rodents), a family of sodium-independent transporters that are endogenously expressed in the brain and are involved in drug uptake. OATP/Oatp substrates include drugs that are efficacious in treatment of pain and/or cerebral hypoxia (i.e., opioid analgesic peptides, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors). This clearly suggests that OATP/Oatp isoforms are viable transporter targets that can be exploited for optimization of drug delivery to the brain and, therefore, improved treatment of CNS diseases. This review summarizes recent knowledge in this area and emphasizes the potential that therapeutic targeting of OATP/Oatp isoforms may have in facilitating CNS drug delivery and distribution. Additionally, information presented in this review will point to novel strategies that can be used for treatment of pain and cerebral hypoxia.

Metabolic Acclimation to Excess Light Intensity in Chlamydomonas Reinhardtii

There are several well-described acclimation responses to excess light in green algae but the effect on metabolism has not been thoroughly investigated. This study examines the metabolic changes during photoacclimation to high-light (HL) stress in Chlamydomonas reinhardtii using nuclear magnetic resonance and mass spectrometry. Using principal component analysis, a clear metabolic response to HL intensity was observed on global metabolite pools, with major changes in the levels of amino acids and related nitrogen metabolites. Amino acid pools increased during short-term photoacclimation, but were especially prominent in HL-acclimated cultures. Unexpectedly, we observed an increase in mitochondrial metabolism through downstream photorespiratory pathways. The expression of two genes encoding key enzymes in the photorespiratory pathway, glycolate dehydrogenase and malate synthase, were highly responsive to the HL-stress. We propose that this pathway contributes to metabolite pools involved in nitrogen assimilation and may play a direct role in photoacclimation. Our results suggest that primary and secondary metabolism is highly pliable and plays a critical role in coping with the energetic imbalance during HL exposure and a necessary adjustment to support an increased growth rate that is an effective energy sink for the excess reducing power generated during HL stress.

Free Fructose Is Conformationally Locked

Fructose has been examined under isolation conditions using a combination of UV ultrafast laser vaporization and Fourier-transform microwave (FT-MW) spectroscopy. The rotational spectra for the parent, all (six) monosubstituted (13)C species, and two single D species reveal unambiguously that the free hexoketose is conformationally locked in a single dominant β-pyranose structure. This six-membered-chair skeleton adopts a (2)C(5) configuration (equivalent to (1)C(4) in aldoses). The free-molecule structure sharply contrasts with the furanose form observed in biochemically relevant polysaccharides, like sucrose. The structure of free fructose has been determined experimentally using substitution and effective structures. The enhanced stability of the observed conformation is primarily attributed to a cooperative network of five intramolecular O-H···O hydrogen bonds and stabilization of both endo and exo anomeric effects. Breaking a single intramolecular hydrogen bond destabilizes the free molecule by more than 10 kJ mol(-1). The structural results are compared to ribose, recently examined with rotational resolution, where six different conformations coexist with similar conformational energies. In addition, several DFT and ab initio methods and basis sets are benchmarked with the experimental data.

Ovarian Cellular Fibroma Harbouring an Isocitrate Dehydrogenase 1 (1DH1) Mutation in a Patient with Ollier Disease: Evidence for a Causal Relationship

Emergency Ultrasound in the Diagnosis of Traumatic Extrathoracic Lung Herniation

Hippocampal Gα(q/11) but Not Gα(o)-coupled Receptors Are Altered in Aging

Normal aging may limit the signaling efficacy of certain GPCRs by disturbing the function of specific Gα-subunits and leading to deficient modulation of intracellular functions that subserve synaptic plasticity, learning and memory. Evidence suggests that Gα(q/11) is more sensitive to the effects of aging relative to other Gα-subunits, including Gα(o). To test this hypothesis, the functionality of Gα(q/11) and Gα(o) were compared in the hippocampus of young (6 months) and aged (24 months) F344 × BNF(1) hybrid rats assessed for spatial learning ability. Basal GTPγS-binding to Gα(q/11) was significantly elevated in aged rats relative to young and but not reliably associated with spatial learning. mAChR stimulation of Gα(q/11) with oxotremorine-M produced equivocal GTPγS-binding between age groups although values tended to be lower in the aged hippocampus and were inversely related to basal activity. Downstream Gα(q/11) function was measured in hippocampal subregion CA1 by determining changes in [Ca(2+)](i) after mAChR and mGluR (DHPG) stimulation. mAChR-stimulated peak change in [Ca(2+)](i) was lower in aged CA1 relative to young while mGluR-mediated integrated [Ca(2+)](i) responses tended to be larger in aged. GPCR modulation of [Ca(2+)](i) was observed to depend on intracellular stores to a greater degree in aged than young. In contrast, measures of Gα(o)-mediated GTPγS-binding were stable across age, including basal, mAChR-, GABA(B)R (baclofen)-stimulated levels. Overall, the data indicate that aging selectively modulates the activity of Gα(q/11) within the hippocampus leading to deficient modulation of [Ca(2+)](i) following stimulation of mAChRs but these changes are not related to spatial learning.

Long-term Response in High-grade Optic Glioma Treated with Medically Induced Hypothyroidism and Carboplatin: a Case Report and Review of the Literature

Glioblastoma multiforme (GBM) is the most malignant and frequent brain tumor, with an aggressive growth pattern and poor prognosis despite best treatment modalities. Long-term survival of patients with GBM is rare. Optic glioma represents 0.6-1.2% of all brain tumors. Unlike low-grade optic gliomas in children, optic gliomas in adults are highly aggressive and death usually occurs in less than a year. Prolonged progression-free survival and survival rates have been reported in association with induced hypothyroidism in two clinical trials for recurrent GBM. We present the clinical, radiological, and pathological findings in a patient with inoperable GBM of the optic chiasm. Following failure of initial, standard radiation and temozolomide therapy, chemical hypothyroidism was induced using the antithyroid thioamide, propylthiouracil, followed by carboplatin chemotherapy. Initial thyroid stimulating hormone, free T4, and free T3 analysis was carried out and then monthly. This patient responded rapidly to treatment (clinically and with tumor regression within 4 weeks) on two separate occasions with an extended remission period (2.5 years) and prolonged overall survival (4.5 years). We report the successful long-term tumor response to medically induced chemical hypothyroidism in conjunction with carboplatinum chemotherapy of an adult patient with grade IV GBM of the optic chiasm. These clinical observations find mechanistic support from the recent identification of potent mitogenic actions of the thyroid hormone, L-thyroxine, in malignant glioma through binding to a cognate thyroid hormone receptor on the αvβ3 integrin. Approaches to block its activity are now explored in preclinical studies.

Differential Effects of Aging and Exercise on Intra-abdominal Adipose Arteriolar Function and Blood Flow Regulation

During exercise, an old age-associated inability to increase vascular resistance within the intra-abdominal adipose tissue (AT) may compromise the ability to redistribute blood flow. We tested the hypotheses that 1) there would be an elevated perfusion of AT during exercise with old age that was associated with diminished vasoconstrictor responses of adipose resistance arteries, and 2) chronic exercise training would mitigate age-associated alterations in AT blood flow and vascular function. Young (6 mo; n=40) and old (24 mo; n=28) male Fischer 344 rats were divided into young sedentary (YSed), old sedentary (OSed), young exercise-trained (YET) or old exercise-trained (OET) groups, where training consisted of 10-12 weeks of treadmill exercise. In vivo blood flow at rest and during exercise and in vitro α-adrenergic and myogenic vasoconstrictor responses in resistance arteries from AT were measured in all groups. In response to exercise there was a directionally opposite change in AT blood flow in OSed group (~150% increase) and YSed (~ 55% decrease) versus resting values. Both α-adrenergic and myogenic vasoconstriction were diminished in OSed versus YSed AT resistance arteries. Exercise training resulted in a similar AT hyperemic response between age groups during exercise (YET, 9.9 ± 0.5; OET, 8.1 ± 0.9 ml/min/100 g) and was associated with enhanced myogenic and α-adrenergic vasoconstriction of AT resistance arteries from the OET group relative to OSed. These results indicate that there is an inability to increase vascular resistance in AT during exercise with old age due, in part, to a diminished vasoconstriction of AT arteries.

Mechanisms of Neuroprotection by Hemopexin: Modeling the Control of Heme and Iron Homeostasis in Brain Neurons in Inflammatory States

Hemopexin provides neuroprotection in mouse models of stroke and intracerebral hemorrhage and protects neurons in vitro against heme or reactive oxygen species (ROS) toxicity via heme oxygenase-1 (HO1) activity. To model human brain neurons experiencing hemorrhages and inflammation, we used human neuroblastoma cells, heme-hemopexin complexes and physiologically-relevant ROS, e.g. H(2) O(2) and HOCl, to provide novel insights into the underlying mechanism whereby hemopexin safely maintains heme and iron homeostasis. Human amyloid precursor protein (hAPP), needed for iron export from neurons, is induced ~2-fold after heme-hemopexin endocytosis by iron from heme catabolism via the iron regulatory element of hAPP mRNA. Heme-hemopexin is relatively resistant to damage by ROS and retains its ability to induce the cytoprotective HO1 after exposure to tert-butylhydroperoxide, although induction is impaired, but not eliminated, by exposure to high concentrations of H(2) O(2) in vitro. Apo-hemopexin, which predominates in non-hemolytic states, resists damage by H(2) O(2) and HOCl except for the highest concentrations likely in vivo. Heme-albumin and albumin are preferential targets for ROS; thus, albumin protects hemopexin in biological fluids like CSF and plasma where it is abundant. These observations provide strong evidence that hemopexin will be neuroprotective after traumatic brain injury, with heme release in the CNS, and during the ensuing inflammation. Hemopexin sequesters heme thus preventing unregulated heme uptake that leads to toxicity; it safely delivers heme to neuronal cells; and it activates the induction of proteins including HO1 and hAPP that keep heme and iron at safe levels in neurons. © 2013 International Society for Neurochemistry, J. Neurochem. (2013) 10.1111/jnc.12165.

Many Young Men with Prostate-specific Antigen (PSA) Screen-detected Prostate Cancers May Be Candidates for Active Surveillance

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Little is known as to the potential for over-treatment of young men diagnosed with prostate cancer. We show that for men aged ≤55 years with PSA screen-detected disease, 45% of the tumours are classified as very low risk and 85% of these have favourable pathology, yet most are actively treated. These findings raise the spectre of over-treatment for a group of men likely to be affected by treatment side-effects. OBJECTIVE: To identify a population of young men (aged <55 years at diagnosis) with very-low-risk prostate cancer (stage cT1c, with prostate-specific antigen [PSA] density of <0.15 ng/mL/g, Gleason score ≤6, and ≤2 positive biopsy cores with <50% tumour involvement) that may be candidates for active surveillance (AS). PATIENTS AND METHODS: We queried a Department of Defense tumour registry and hard-copy records for servicemen diagnosed with prostate cancer from 1987 to 2010. Statistical analyses were undertaken using Fisher's exact and chi-square testing. RESULTS: From 1987-1991 and 2007-2010, PSA screen-detected tumours diagnosed in men aged ≤55 years rose >30-fold. Data for a subset of men (174) with PSA screen-detected cancer were evaluable for disease risk assessment. Of the 174 men with screen-detected disease, 81 (47%) had very-low-risk disease. Of that group, 96% (78/81) selected treatment and, of 57 men undergoing radical prostatectomy (RP), the tumours of 49 (86%) carried favourable pathology (organ confined, <10% gland involvement, Gleason ≤6). CONCLUSIONS: Nearly half of young men with PSA screen-detected prostate cancer are AS candidates but the overwhelming majority seek treatment. Considering that many tumours show favourable pathology at RP, there is a possibility that these patients may benefit from AS management.

Tumor Biology and Pre-transplant Locoregional Treatments Determine Outcomes in Patients with T3 Hepatocellular Carcinoma Undergoing Liver Transplantation

Liver transplantation is the optimal treatment for patients with hepatocellular carcinoma (HCC) and cirrhosis. This study was conducted to determine the impact of pre-transplant locoregional therapy (LRT) on HCC and our institution's experience with expansion to United Network of Organ Sharing Region 4 T3 (R4T3) criteria. Two hundred and twenty-five patients with HCC (176 meeting Milan and 49 meeting R4T3 criteria) underwent liver transplantation from 2002 to 2008. Compared with the Milan criteria, HCCs in R4T3 criteria displayed less favorable biological features such as higher median alpha-fetoprotein level (21.9 vs. 8.5 ng/mL, p = 0.01), larger tumor size, larger tumor number, and higher incidence of microvascular invasion (22% vs. 5%, p = 0.002). As a result, patients meeting Milan criteria had better five-yr survival (79% vs. 69%, p = 0.03) and a trend toward lower HCC recurrence rates (5% vs. 13%, p = 0.05). Pre-transplant LRT did not affect post-transplant outcomes in patients meeting Milan criteria but did result in lower three-yr HCC recurrence (7% vs. 75%, p < 0.001) and better three-yr survival (p = 0.02) in patients meeting R4T3 criteria. Tumor biology and pre-transplant LRT are important factors that determine the post-transplant outcomes in patients with HCC who meet R4T3 criteria.

A Comprehensive Investigation of Variants in Genes Encoding Adiponectin (ADIPOQ) and Its Receptors (ADIPOR1/R2), and Their Association with Serum Adiponectin, Type 2 Diabetes, Insulin Resistance and the Metabolic Syndrome

ABSTRACT: BACKGROUND: Low levels of serum adiponectin have been linked to central obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. Variants in ADIPOQ, the gene encoding adiponectin, have been shown to influence serum adiponectin concentration, and along with variants in the adiponectin receptors (ADIPOR1 and ADIPOR2) have been implicated in metabolic syndrome and type 2 diabetes. This study aimed to comprehensively investigate the association of common variants in ADIPOQ, ADIPOR1 and ADIPOR2 with serum adiponectin and insulin resistance syndromes in a large cohort of European-Australian individuals. METHODS: Sixty-four tagging single nucleotide polymorphisms in ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in two general population cohorts consisting of 2,355 subjects, and one cohort of 967 subjects with type 2 diabetes. The association of tagSNPs with outcomes were evaluated using linear or logistic modelling. Meta-analysis of the three cohorts was performed by random-effects modelling. RESULTS: Meta-analysis revealed nine genotyped tagSNPs in ADIPOQ significantly associated with serum adiponectin across all cohorts after adjustment for age, gender and BMI, including rs10937273, rs12637534, rs1648707, rs16861209, rs822395, rs17366568, rs3774261, rs6444175 and rs17373414. The results of haplotype-based analyses were also consistent. Overall, the variants in the ADIPOQ gene explained <5% of the variance in serum adiponectin concentration. None of the ADIPOR1/R2 tagSNPs were associated with serum adiponectin. There was no association between any of the genetic variants and insulin resistance or metabolic syndrome. A multi-SNP genotypic risk score for ADIPOQ alleles revealed an association with 3 independent SNPs, rs12637534, rs16861209, rs17366568 and type 2 diabetes after adjusting for adiponectin levels (OR=0.86, 95%CI=(0.75, 0.99), P=0.0134). CONCLUSIONS: Genetic variation in ADIPOQ, but not its receptors, was associated with altered serum adiponectin. However, genetic variation in ADIPOQ and its receptors does not appear to contribute to the risk of insulin resistance or metabolic syndrome but did for type 2 diabetes in a European-Australian population.

Characterizing Biobank Organizations in the U.S.: Results from a National Survey

ABSTRACT: BACKGROUND: Effective translational biomedical research hinges on the operation of "biobanks," repositories which assemble, store, and manage collections of human specimens and related data. Some are established intentionally to address particular research needs; many, however, have arisen opportunistically, in a variety of settings and with a variety of expectations regarding their functions and longevity. Despite their rising prominence, little is known about how biobanks are organized and function beyond simple classification systems ("government, academia, industry"). Methods: In 2012, we conducted the first national survey of biobanks in the U.S., collecting information on their origins, specimen collections, organizational structures, and market contexts and sustainability. From a list of 636 biobanks assembled through a multi-faceted search strategy, representatives from 456 U.S. biobanks were successfully recruited for a 30 minute online survey (72% response rate). Both closed and open-ended responses were analyzed using descriptive statistics. Results: While nearly two-thirds of biobanks were established within the last decade, 17% have been in existence for over 20 years. Fifty-three percent listed research on a particular disease as the most important reason for establishment; 29% listed research generally. Other reasons included response to a grant or gift, and intent to centralize, integrate, or harmonize existing research structures. Biobank collections are extraordinarily diverse in number and types of specimens and in sources (often multiple) from which they are obtained, including from individuals, clinics/hospitals, public health programs, and research studies. Forty-four percent of biobanks store pediatric specimens, and 36% include post-mortem specimens. Most biobanks are affiliated in one or multiple ways with other entities: 88% are part of at least one or more larger organizations (67% of these are academic, 23% hospitals, 13% research institutes). The majority of biobanks seem to fill a particular "niche" within a larger organization or research area; a minority are concerned about competition for services, although many are worried about underutilization of specimens and long term funding. Conclusions: Effective utilization of biobank collections and effective policies to govern their use will require understanding the immense diversity found in organizational features, including the very different history and primary goals that many biobanks have.

A Flea and Tick Collar Containing 10% Imidacloprid and 4.5% Flumethrin Prevents Flea Transmission of Bartonella Henselae in Cats

ABSTRACT: BACKGROUND: Bartonella henselae is transmitted amongst cats by Ctenocephalides felis and is associated with multiple clinical syndromes in cats and people. In a previous study, monthly spot-on administration of 10% imidacloprid/1% moxidectin was shown to block transmission of B. henselae amongst cats experimentally exposed to infected C. felis. The purpose of this study was to determine whether application of a flea and tick collar containing 10% imidacloprid and 4.5% flumethrin would lessen C. felis transmission of B. henselae amongst cats for 8 months. METHODS: Specific pathogen free cats (n = 19) were housed in three adjoining enclosures that were separated by mesh to allow C. felis to pass among groups but prevent cats in different enclosures from contacting one another. One group of 4 cats was inoculated intravenously with B. henselae and after infection was confirmed in all cats based on positive PCR assay results, the cats were housed in the middle enclosure. The B. henselae infected cat group was flanked by a group of 8 cats that had the collar placed and maintained for the duration of the study and a group of 7 cats that were not treated. Ctenocephalides felis (50 males and 50 females) raised in an insectary were placed on each of the 4 cats in the B. henselae infected group monthly for 7 applications and then every 2 weeks for 4 applications starting the day the collar was applied. Blood was collected from all cats weekly for Bartonella spp. PCR, serology and culture. RESULTS: While side-effects associated with the collars were not noted, persistent fever necessitating enrofloxacin therapy occurred in two of the untreated cats. While B. henselae infection was ultimately confirmed in 4 of 7 of the untreated cats, none of the cats with collars became infected (P = 0.026). CONCLUSIONS: In this study design, use of a collar containing 10% imidacloprid and 4.5% flumethrin was well tolerated and prevented C. felis transmission of B. henselae amongst cats for 8 months.

Association of Out-of-hospital Advanced Airway Management with Outcomes After Traumatic Brain Injury and Hemorrhagic Shock in the ROC Hypertonic Saline Trial

OBJECTIVE: Prior studies suggest adverse associations between out-of-hospital advanced airway management (AAM) and patient outcomes after major trauma. This secondary analysis of data from the Resuscitation Outcomes Consortium Hypertonic Saline Trial evaluated associations between out-of-hospital AAM and outcomes in patients suffering isolated severe traumatic brain injury (TBI) or haemorrhagic shock. METHODS: This multicentre study included adults with severe TBI (GCS ≤8) or haemorrhagic shock (SBP ≤70 mm Hg, or (SBP 71-90 mm Hg and heart rate ≥108 bpm)). We compared patients receiving out-of-hospital AAM with those receiving emergency department AAM. We evaluated the associations between airway strategy and patient outcomes (28-day mortality, and 6-month poor neurologic or functional outcome) and airway strategy, adjusting for confounders. Analysis was stratified by (1) patients with isolated severe TBI and (2) patients with haemorrhagic shock with or without severe TBI. RESULTS: Of 2135 patients, we studied 1116 TBI and 528 shock; excluding 491 who died in the field, did not receive AAM or had missing data. In the shock cohort, out-of-hospital AAM was associated with increased 28-day mortality (adjusted OR 5.14; 95% CI 2.42 to 10.90). In TBI, out-of-hospital AAM showed a tendency towards increased 28-day mortality (adjusted OR 1.57; 95% CI 0.93 to 2.64) and 6-month poor functional outcome (1.63; 1.00 to 2.68), but these differences were not statistically significant. Out-of-hospital AAM was associated with poorer 6-month TBI neurologic outcome (1.80; 1.09 to 2.96). CONCLUSIONS: Out-of-hospital AAM was associated with increased mortality after haemorrhagic shock. The adverse association between out-of-hospital AAM and injury outcome is most pronounced in patients with haemorrhagic shock.

CYP3A5 Gene Variation Influences Cyclosporine A Metabolite Formation and Renal Cyclosporine Disposition

BACKGROUND: Higher concentrations of AM19 and AM1c9, secondary metabolites of cyclosporine A (CsA), have been associated with nephrotoxicity in organ transplant patients. The risk of renal toxicity may depend on the accumulation of CsA and its metabolites in the renal tissue. We evaluated the hypothesis that CYP3A5 genotype, and inferred enzyme expression, affects systemic CsA metabolite exposure and intrarenal CsA accumulation. METHODS: An oral dose of CsA was administered to 24 healthy volunteers who were selected based on their CYP3A5 genotype. CsA and its six main metabolites in whole blood and urine were measured by liquid chromatography-mass spectometry. In vitro incubations of CsA, AM1, AM9, and AM1c with recombinant CYP3A4 and CYP3A5 were performed to evaluate the formation pathways of AM19 and AM1c9. RESULTS: The mean CsA oral clearance was similar between CYP3A5 expressors and nonexpressors. However, compared with CYP3A5 nonexpressors, the average blood area under the concentration-time curve (AUC) for AM19 and AM1c9 was 47.4% and 51.3% higher in CYP3A5 expressors (P=0.040 and 0.011, respectively), corresponding to 30% higher AUCmetabolite/AUCCsA ratios for AM19 and AM1c9 in CYP3A5 expressors. The mean apparent urinary CsA clearance based on a 48-hr collection was 20.4% lower in CYP3A5 expressors compared with CYP3A5 nonexpressors (4.2±1.0 and 5.3±1.3 mL/min, respectively; P=0.037), which is suggestive of CYP3A5-dependent intrarenal CsA metabolism. CONCLUSIONS: At steady state, intrarenal accumulation of CsA and its secondary metabolites should depend on the CYP3A5 genotype of the liver and kidneys. This may contribute to interpatient variability in the risk of CsA-induced nephrotoxicity.

FKBP10/FKBP65 Expression in High-grade Ovarian Serous Carcinoma and Its Association with Patient Outcome

The frequent loss of chromosome 17 in epithelial ovarian carcinomas (EOC), particularly high-grade serous carcinomas (HGSC), has been attributed to the disruption of TP53 (at 17p13.1) and other chromosome 17 genes suspected to play a role in tumour suppressor pathways. In a transcriptome analysis of HGSC, we showed underexpression of a number of chromosome 17 genes, which included FKBP10 (at 17q21.1) and collagen I α 1 (COL1A1; at 17q21.33). FKBP10 codes for the immunophilin FKBP65 and is suspected to act as a chaperone for COL1A1. We have investigated FKBP10 (gene) and FKBP65 (protein) expression in HGSC samples and EOC cell lines that differ in their tumourigenic potential. COL1A1 expression was also investigated given the purported function of FKBP65. RT-PCR analysis verified underexpression of FKBP10 and COL1A1 in HGSCs (n=14) and six tumourigenic EOC cell lines, relative to normal ovarian surface epithelial cells and a non‑tumourigenic EOC cell line. Immunohistochemistry analyses of 196 HGSC samples using tissue microarrays revealed variable staining intensities in the epithelial tumour component where only 7.8% and 1.0% of samples stained intensely for FKBP65 and COL1A1, respectively. Variable staining intensities were also observed for the stromal component where 23.6% and 24.1% stained intensely for FKBP65 and COL1A1, respectively. There was no significant correlation of staining intensity of either protein with disease stage. Staining of FKBP65 was clearly visible in normal epithelial cells of the ovarian surface and fallopian tube. There was a significant correlation between absence of FKBP65 staining in the epithelial cell component of the tumour and prolonged overall survival (p<0.001). Our results suggest that underexpression of FKBP65 protein is characteristic of HGSCs and that this expression profile may be linked to molecular pathways associated with an unfavourable outcome in cancer patients.

Identification of the Mutation Responsible for the Temperature-Sensitive Lipopolysaccharide O-Antigen Defect in the Pseudomonas Aeruginosa Cystic Fibrosis Isolate 2192

Pseudomonas aeruginosa in the lungs of cystic fibrosis patients is characterized by a series of genotypic and phenotypic changes that reflect the transition from acute to chronic infection. These include the overproduction of the exopolysaccharide alginate and the loss of complete lipopolysaccharide (LPS). LPS is a major component of the Gram-negative outer-membrane and is composed of lipid A, core oligosaccharide, and O-antigen. In this report, we show that the LPS-defect of the P. aeruginosa chronic infection isolate strain 2192 is temperature sensitive. When grown at 25°C, 2192 expresses serotype O1 LPS of moderate chain length and reduced amount when compared to a wild-type serotype O1 laboratory strain (stO1). In contrast, 2192 does not express any LPS O antigen when grown at 37°C. This is the first time that a temperature-sensitive defect in O antigen production has been reported. Using complementation analyses with a constructed wbpM deletion mutant of stO1, we demonstrate that the temperature-sensitive O antigen production defect in 2192 is due to a mutation in wbpM, which encodes a UDP-4,6-GlcNAc dehydratase involved in O-antigen synthesis. The mutation, a deletion of a single amino acid (V636) from the extreme C-terminus of WbpM, renders the protein less stable than its wild-type counterpart. This residue of WbpM, which is critical for stability and function, is located outside of the recognized domains of the protein and may provide more insight into the structure-function relationship of this enzyme, which is found in all 20 serotypes of P. aeruginosa. We also identify a promoter of wbpM and map a transcriptional start site of wbpM and show that mucoidy plays a role in the loss of expression of high molecular weight LPS in this CF isolate.

No REST for Fibroids

Microneedle Biosensor: A Method for Direct Label-free Real Time Protein Detection

Here we present the development of an array of electrical micro-biosensors in a microfluidic channel, called microneedle biosensors. A microneedle biosensor is a real-time, label-free, direct electrical detection platform, which is capable of high sensitivity detection, measuring the change in ionic current and impedance modulation, due to the presence or reaction of biomolecules such as proteins and nucleic acids. In this study, we successfully fabricated and electrically characterized the sensors and demonstrated successful detection of target protein. In this study, we used biotinylated bovine serum albumin as the receptor and streptavidin as the target analyte.

CT Perfusion Improves Diagnostic Accuracy and Confidence in Acute Ischaemic Stroke

BACKGROUND AND OBJECTIVE: CT perfusion (CTP) is rapid and accessible for emergency ischaemic stroke diagnosis. The feasibility of introducing CTP and diagnostic accuracy versus non-contrast CT (NCCT) in a tertiary hospital were assessed. METHODS: All patients presenting <9 h from stroke onset or with wake-up stroke were eligible for CTP (Siemens 16-slice scanner, 2×24 mm slabs) unless they had estimated glomerular filtration rate (eGFR)<50 ml/min or diabetes with unknown eGFR. NCCT was assessed by a radiologist and stroke neurologist for early ischaemic change and hyperdense arteries. CTP was assessed for prolonged time to peak and reduced cerebral blood flow. Technical adequacy was defined as 2 CTP slabs of sufficient quality to diagnose stroke. RESULTS: Between January 2009 and September 2011, 1152 ischaemic stroke patients were admitted, 475 (41%) were <9 h/wake-up onset. Of these, 276 (58%) had CTP. Reasons for not performing CTP were diabetes with unknown eGFR (48 (10%)), known kidney disease (36 (8%)), established infarct on NCCT (27 (6%)), posterior circulation syndrome (25 (5%)) and patient motion/instability (16 (3%)). Clinician discretion excluded a further 47 (10%). CTP was more frequently diagnostic than NCCT (80% vs 50%, p<0.001). Non-diagnostic CTP was due to lacunar infarction (28 (10%)), infarct outside slab coverage (21 (8%)), technical failure (4 (1%)) and reperfusion (2 (0.7%)). Normal CTP in 86/87 patients with stroke mimics supported withholding tissue plasminogen activator. CTP technical adequacy improved from 56% to 86% (p<0.001) after the first 6 months. Median time for NCCT/CTP/arch-vertex CT angiogram (including processing and interpretation) was 12 min. No clinically significant contrast nephropathy occurred. CONCLUSIONS: CTP in suspected stroke is widely applicable, rapid and increases diagnostic confidence.

Preparing Synthetic Biology for the World

Synthetic Biology promises low-cost, exponentially scalable products and global health solutions in the form of self-replicating organisms, or "living devices." As these promises are realized, proof-of-concept systems will gradually migrate from tightly regulated laboratory or industrial environments into private spaces as, for instance, probiotic health products, food, and even do-it-yourself bioengineered systems. What additional steps, if any, should be taken before releasing engineered self-replicating organisms into a broader user space? In this review, we explain how studies of genetically modified organisms lay groundwork for the future landscape of biosafety. Early in the design process, biological engineers are anticipating potential hazards and developing innovative tools to mitigate risk. Here, we survey lessons learned, ongoing efforts to engineer intrinsic biocontainment, and how different stakeholders in synthetic biology can act to accomplish best practices for biosafety.

Mathematical Modeling of an Oscillating Gene Circuit to Unravel the Circadian Clock Network of Arabidopsis Thaliana

The Arabidopsis thaliana circadian clock is an interconnected network highly tractable to systems approaches. Most elements in the transcriptional-translational oscillator were identified by genetic means and the expression of clock genes in various mutants led to the founding hypothesis of a positive-negative feedback loop being the core clock. The identification of additional clock genes beyond those defined in the core led to the use of systems approaches to decipher this angiosperm oscillator circuit. Kinetic modeling was first used to explain periodicity effects of various circadian mutants. This conformed in a flexible way to experimental details. Such observations allowed a recursive use of hypothesis generating from modeling, followed by experimental corroboration. More recently, the biochemical finding of new description of a DNA-binding activity for one class of clock components directed improvements in feature generation, one of which revealed that the core of the oscillator is a negative-negative feedback loop. The recursive use of modeling and experimental validation has thus revealed many essential transcriptional components that drive negative arms in the circadian oscillator. What awaits is to more fully describe the positive arms and an understanding of how additional pathways converge on the clock.

Persistent Ovarian Masses and Pregnancy Outcomes

Abstract Objective: To determine if persistent ovarian masses in pregnancy are associated with increased adverse outcomes. Methods: This is a retrospective cohort of 126 pregnant women with a persistent ovarian mass measuring 5cm or greater who delivered at two university hospitals between 2001 and 2009. Maternal outcomes included gestational age at diagnosis, delivery and surgery as well as miscarriage, preterm birth (PTB), ovarian torsion and hospital admission for pain. Neonatal outcomes included birth weight, RDS, IVH, death and sepsis. Results: 1225 ovarian masses were identified (4.9%) in 24,868 patients. A persistent ovarian mass was found in 0.7%. Average gestational age at diagnosis was 17.8 weeks. Miscarriage rate was 3.3%. Average gestational age at delivery was 37.9weeks. 8.5% had ovarian torsion, 10.3% had admission for pain, and 9.3% had preterm births. The mean Cesarean delivery rate was 46.3%. The average neonatal weight was 3,273 grams. There was 1 neonatal death in this cohort. The rate of RDS was 2.8%, IVH 0.9%, and Neonatal sepsis 1.9%. The most common surgical pathologic diagnosis was dermoids (37.6%). No overt malignancies were seen. Conclusion: A persistent ovarian mass in pregnancy does not confer an increased risk of adverse pregnancy outcomes.

Degree of Specialization is Related to Body Size in Herbivorous Insects: a Phylogenetic Confirmation

Numerous studies have suggested a general relationship between the degree of host specialization and body size in herbivorous animals. In insects, smaller species are usually shown to be more specialized than larger-bodied ones. Various hypotheses have attempted to explain this pattern but rigorous proof of the body size-diet breadth relationship has been lacking, primarily because the scarceness of reliable phylogenetic information has precluded formal comparative analyses. Explicitly using phylogenetic information for a group of herbivores (geometrid moths) and their host plant range, we perform a comparative analysis to study the body size-diet breadth relationship. Considering several alternative measures of body size and diet breadth, our results convincingly demonstrate without previous methodological issues-a first for any taxon-a positive association between these traits, which has implications for evaluating various central aspects of the evolutionary ecology of herbivorous insects. We additionally demonstrate how the methods used in this study can be applied in assessing hypotheses to explain the body size-diet breadth relationship. By analyzing the relationship in tree-feeders alone and finding that the positive relationship remains, the result suggests that the body size-diet breadth relationship is not solely driven by the type of host plant that species feed on.

A Case-mix-adjusted Comparison of Early Oncological Outcomes of Open and Robotic Prostatectomy Performed by Experienced High Volume Surgeons

Quantitative Profiling of PrP(Sc) Peptides by HPLC-MS to Investigate the Diversity of Prions

Prions are proteins that can exist in two (or more) folding states - a normal or cellular form and a (series of) infectious or prion forms, which are prone to aggregate. The prion form can induce conversion of the cellular form and so transmit phenotypic effects of this structural re-arrangement within and between cells and organisms. The conversion of PrP(C), the mammalian prion glycoprotein, to its prion form, PrP(Sc), in the brain is a precursor to progressive, neurological degeneration and the various folded forms of PrP(Sc) (defined by the size and glycosylation of protease-resistant core peptides of the PrP aggregates, PrP(res)) are characteristic for a particular neurodegenerative phenotype or prion disease. Here, quantitative multiplex mass spectrometry is used for N-terminal amino acid profiling (N-TAAP) of PrP(res) from sheep affected by scrapie, the prion disease of small ruminants, to rapidly assess the diversity of prions within particular flocks. In 29 cases, PrP(res) concentrations varied from below the limit of detection (350 fmol/g) to 15 pmol/g wet brain. While most had a single N-TAAP profile, two novel variants were identified: one common to the ARH/ARQ animals in this study, and one in an animal of the wild-type sheep PrP genotype (ARQ/ARQ).

Twenty Years of Pediatric Gunshot Wounds: an Urban Trauma Center's Experience

BACKGROUND: Pediatric gunshot wounds remain an important cause of morbidity and mortality in the United States. Recent experience in the urban pediatric population has not been extensively documented. METHODS: A retrospective review of the trauma registry identified all pediatric (age 0-16 y) gunshot wound injuries between October 1991 and August 2011. We evaluated demographic, injury location, disposition, and outcome data. We applied descriptive statistics and χ(2) with significance level set to P ≤ 0.05. RESULTS: We treated 740 patients at our trauma center. Patients tended to be male (82%) and African American (72%), and most frequently were shot in the abdomen, back, or pelvic regions (26%). Patients with head or neck injuries experienced the highest mortality rate (35%), whereas the mortality rate overall was 12.7%. A total of 23% of patients were discharged directly, but 32% required an operation. We grouped data into five equal time periods, demonstrating that after decreasing through the 1990s, pediatric gunshot wounds presenting to our hospital are steadily increasing. CONCLUSIONS: We identified certain demographic and temporal trends regarding pediatric gunshot wounds, and the overall number of injuries appears to be increasing.

Mechanisms of Chronic Pain from Whiplash Injury

This article is to provide insights into the mechanisms underlying chronic pain from whiplash injury. Studies show that injury produces plasticity changes of different neuronal structures that are responsible for amplification of nociception and exaggerated pain responses. There is consistent evidence for hypersensitivity of the central nervous system to sensory stimulation in chronic pain after whiplash injury. Tissue damage, detected or not by the available diagnostic methods, is probably the main determinant of central hypersensitivity. Different mechanisms underlie and co-exist in the chronic whiplash condition. Spinal cord hyperexcitability in patients with chronic pain after whiplash injury can cause exaggerated pain following low intensity nociceptive or innocuous peripheral stimulation. Spinal hypersensitivity may explain pain in the absence of detectable tissue damage. Whiplash is a heterogeneous condition with some individuals showing features suggestive of neuropathic pain. A predominantly neuropathic pain component is related to a higher pain/disability level.

Fostering Informed Decisions: A Randomized Controlled Trial Assessing the Impact of a Decision Aid Among Men Registered to Undergo Mass Screening for Prostate Cancer

OBJECTIVE: Screening asymptomatic men for prostate cancer is controversial and informed decision making is recommended. Within two prostate cancer screening programs, we evaluated the impact of a print-based decision aid (DA) on decision-making outcomes. METHODS: Men (N=543) were 54.9 (SD=8.1) years old and 61% were African-American. The 2(booklet type: DA vs. usual care (UC))×2(delivery mode: Home vs. Clinic) randomized controlled trial assessed decisional and screening outcomes at baseline, 2-months, and 13-months. RESULTS: Intention-to-treat linear regression analyses using generalized estimating equations revealed that DA participants reported improved knowledge relative to UC (B=.41, p<.05). For decisional conflict, per-protocol analyses revealed a group by time interaction (B=-.69, p<.05), indicating that DA participants were less likely to report decisional conflict at 2-months compared to UC participants (OR=.49, 95% CI: .26-.91, p<.05). CONCLUSION: This is the first randomized trial to evaluate a DA in the context of free mass screening, a challenging setting in which to make an informed decision. The DA was highly utilized by participants, improved knowledge and reduced decisional conflict. PRACTICE IMPLICATIONS: These results are valuable in understanding ways to improve the decisions of men who seek screening and can be easily implemented within many settings.

Estimated Contribution of Hemoglobin and Myoglobin to Near Infrared Spectroscopy

We calculated the light absorbing potential (LAP) of hemoglobin (Hb) and myoglobin (Mb) in mammalian skeletal muscle at rest based on analysis of published chemical and morphometric data (Part 1), interpreted changes in total[Hb+Mb] from NIRS during exercise (Part 2), and estimated the potential contribution of Hb and Mb to changes in NIRS from rest to exercise (Part 3). Part 1: [Hb] in skeletal muscle was estimated from microvascular volume, systemic blood [Hb], and microvascular hematocrit and saturation at rest and during exercise. Part 2: Changes in total[Hb+Mb] (as t[Hb+Mb]) during cycling or knee extension exercise were interpreted using the results of Part 1. Part 3: Using estimates of mean microvascular PO(2), Hb and Mb contribution at peak exercise was estimated. Across several species, [Mb] contributed ∼50-70% of the total LAP to NIRS at rest in skeletal muscle. With exercise, increases in t[Hb+Mb] of up to 30% could be entirely explained by the predicted increase in microvascular hematocrit with exercise. Finally, Mb was estimated to contribute ∼70% of the changes in NIRS from rest to peak exercise.

Pharmacokinetics and Safety of Sirukumab Following a Single Subcutaneous Administration to Healthy Japanese and Caucasian Subjects

Objective: Sirukumab (CNTO 136) is a human mAb with high affinity and specificity for binding to interleukin-6. This Phase 1 study evaluated the pharmacokinetics, immunogenicity, safety, and tolerability of sirukumab following a single subcutaneous (s.c.) administration in healthy male Japanese and Caucasian subjects. Methods: Japanese and Caucasian subjects were randomized to placebo or 25, 50, or 100 mg sirukumab. Blood samples were collected to measure serum sirukumab concentration and antibodies to sirukumab. Noncompartmental analysis and population pharmacokinetic modeling were conducted to characterize sirukumab pharmacokinetics. Adverse events were monitored at each visit. Results: 25 Japanese and 24 Caucasian subjects received sirukumab and were included in the pharmacokinetic evaluation. Mean Cmax and AUC0-∞of sirukumab increased in an approximately dose-proportional manner in both Japanese and Caucasian subjects. Median tmax was 3 -5 days after s.c. administration of sirukumab. Mean t1/2 was 15 -16 days in Japanese and 15 -18 days in Caucasian subjects. A one-compartment population pharmacokinetic model adequately described sirukumab pharmacokinetics following s.c. administration. The estimated population means for CL/F, V/F, and Ka were 0.54 ±0.03 l/day, 12.2 ±0.55 l, and 0.77 ±0.07 day-, respectively. Race was not a significant covariate on CL/F or V/F. No subject was positive for antibodies to sirukumab. Adverse events were generally mild and did not appear to be dose-related or lead to study discontinuation. Conclusions: Sirukumab pharmacokinetics following subcutaneous administration was linear at doses ranging 25 -100 mg and was comparable between Japanese and Caucasian subjects. A single subcutaneous administration of 25, 50, or 100 mg sirukumab appeared to be well tolerated by both Japanese and Caucasian healthy male subjects.

Childhood Intelligence is Heritable, Highly Polygenic and Associated with FNBP1L

Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17 989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.Molecular Psychiatry advance online publication, 29 January 2013; doi:10.1038/mp.2012.184.

Safety and Feasibility of Targeted Agent Combinations in Solid Tumours

The plethora of novel molecular-targeted agents (MTAs) has provided an opportunity to selectively target pathways involved in carcinogenesis and tumour progression. Combination strategies of MTAs are being used to inhibit multiple aberrant pathways in the hope of optimizing antitumour efficacy and to prevent development of resistance. While the selection of specific agents in a given combination has been based on biological considerations (including the role of the putative targets in cancer) and the interactions of the agents used in combination, there has been little exploration of the possible enhanced toxicity of combinations resulting from alterations in multiple signalling pathways in normal cell biology. Owing to the complex networks and crosstalk that govern normal and tumour cell proliferation, inhibiting multiple pathways with MTA combinations can result in unpredictable disturbances in normal physiology. This Review focuses on the main toxicities and the lack of tolerability of some common MTA combinations, particularly where evidence of enhanced toxicity compared to either agent alone is documented or there is development of unexpected toxicity. Toxicities caused by MTA combinations highlight the need to introduce new preclinical testing paradigms early in the drug development process for the assessment of chronic toxicities resulting from such combinations.

Fidelity of Administrative Data When Researching Down Syndrome

OBJECTIVE:: To compare the fidelity of administrative data with clinical data when researching Down syndrome (DS). METHODS:: From outpatient, inpatient, and emergency department administrative claims within our institution, we identified 252 patients aged 18-45 years with encounters coded for DS by the ICD9=758.0 from 2000 to 2008. We evaluated these cases for false-positive errors-cases in which DS was not actually present in clinical descriptions. Subsequently, we identified false-negative errors (cases in which DS was present without encounters coded as such) by examination of the medical records for all patients within our study frame who had one of several common DS comorbidities, including congenital heart disease, hypothyroidism, and atlantoaxial instability. RESULTS:: Among the 252 people with an administrative code for DS, 53 (21%) did not have DS documented in their medical record (false-positive error). While searching for false-negative errors, 29 additional patients were discovered with DS documented in the medical record who had not been previously identified. This led to a final cohort of 228 patients with DS. The presence of a billing code for DS had moderate sensitivity (87%) and positive predictive value (79%), but high specificity (99.9%). DISCUSSION:: Administrative claims misclassify a sizeable proportion of patients with DS. Judgments about quality of care on the basis of samples identified using administrative claims may not accurately reflect the experience of patients with the conditions in question. When using administrative databases to study the quality of care for patients with DS, diagnostic verification within the clinical record is advisable whenever possible.

A Pediatric Case of Severe Pandysautonomia Responsive to Plasmapheresis

We describe a 13-year-old female with abrupt onset urinary retention progressing rapidly to pandysautonomia with symptoms of postural orthostatic tachycardia syndrome, gastroparesis, anhidrosis, pupillary dysfunction, and abdominal pain. Pandysautonomia has been reported frequently in adults, but is less commonly described in children. Autonomic nervous system dysfunction usually has a self-limiting course with gradual near-complete or complete recovery. Most patients with pure pandysautonomia produce an antibody targeted against the ganglionic nicotinic acetylcholine receptor and titers have been shown to correlate with symptom severity. The clinical presentation described in this report is consistent with a progressive form of acute autoimmune autonomic neuropathy, but she was initially seronegative for known autoantibodies. She responded promptly to plasmapheresis. This case report emphasizes the importance of recognizing features of autonomic nervous system dysfunction and discusses the medical evaluation and treatment options for pediatric patients based on symptom severity.

Primary Pediatric Cardiac Malignancies: the SEER Experience

PURPOSE: Pediatric cardiac malignancies are exceedingly rare. We sought to examine demographics, presentation, and outcomes for this pathology. METHODS: The SEER registry from 1973 to 2008 was queried for all patients <20 years of age with cardiac malignancies. RESULTS: A total of 25 pediatric patients were identified with primary cardiac malignancies, with age-adjusted incidence of 0.00686 per 100,000 United States population. Median age at diagnosis was 10 years. The majority of patients were adolescent (n = 13, 52 %), Caucasian (n = 17, 68 %) and males (n = 14, 56 %). The most common histology was soft tissue sarcoma (n = 10, 40%), followed by non-Hodgkin lymphoma and teratoma (both n = 3, 12 %). Six patients presented with distant disease. More than half of patients (n = 16, 64 %) underwent surgical resection, while four patients (16 %) underwent radiation. The mean survival time for the cohort was 47 ± 67 months, with 14 (56 %) patients dying over the study period. Lymphomas had significantly longer survival than other malignancies (108 ± 66 vs. 36 ± 66, p = 0.03), while lack of surgical treatment was associated with worse survival (p = 0.016). CONCLUSIONS: Primary malignant cardiac tumors are exceedingly rare in pediatric patients. They are most commonly soft tissue sarcomas and lymphomas demonstrated longer survival.

β1 Integrins Mediate Resistance to Ionizing Radiation in Vivo by Inhibiting C-Jun Amino Terminal Kinase1

This study was carried out to dissect the mechanism by which β1 integrins promote resistance to radiation. For this purpose, we conditionally ablated β1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of β1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to β1, AIIB2, in a xenograft model. The role of β1 integrins and of a β1 downstream target, c-Jun amino-terminal kinase 1 (JNK1), in regulating radiation-induced apoptosis in vivo and in vitro was studied. We show that β1 integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, β1 integrins are shown here to suppress activation of JNK1 and, consequently apoptosis, in response to irradiation. Downregulation of JNK1 is necessary to preserve the effect of β1 on resistance to radiation in vitro and in vivo. Finally, given the established cross-talk between β1 integrins and type1 insulin-like growth factor receptor (IGF-IR), we analyzed the ability of IGF-IR to modulate β1 integrin levels. We report that IGF-IR regulates the expression of β1 integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that β1 integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.

Household Risk Factors for Colonization with Multidrug-Resistant Staphylococcus Aureus Isolates

Antimicrobial resistance, particularly in pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), limits treatment options and increases healthcare costs. To understand patient risk factors, including household and animal contact, potentially associated with colonization with multidrug-resistant MRSA isolates, we performed a prospective study of case patients colonized with MRSA on admission to a rural tertiary care hospital. Patients were interviewed and antimicrobial resistance patterns were tested among isolates from admitted patients colonized with MRSA in 2009-10. Prevalence of resistance was compared by case-patient risk factors and length-of-stay outcome among 88 MRSA case patients. Results were compared to NHANES 2003-04. Overall prevalence of multidrug resistance (non-susceptibility to ≥four antimicrobial classes) in MRSA nasal isolates was high (73%) and was associated with a 1.5-day increase in subsequent length of stay (p = 0.008). History of hospitalization within the past six months, but not antimicrobial use in the same time period, was associated with resistance patterns. Within a subset of working-age case patients without recent history of hospitalization, animal contact was potentially associated with multidrug resistance. History of hospitalization, older age, and small household size were associated with multidrug resistance in NHANES data. In conclusion, recent hospitalization of case patients was predictive of antimicrobial resistance in MRSA isolates, but novel risk factors associated with the household may be emerging in CA-MRSA case patients. Understanding drivers of antimicrobial resistance in MRSA isolates is important to hospital infection control efforts, relevant to patient outcomes and to indicators of the economic burden of antimicrobial resistance.

The Effect of Small-molecule Inhibition of MAPKAPK2 on Cell Ageing Phenotypes of Fibroblasts from Human Werner Syndrome

ABSTRACT: Fibroblasts derived from the progeroid Werner syndrome (WS) show reduced replicative lifespan and a "stressed" morphology, both phenotypes being alleviated by using the p38 MAP kinase inhibitor SB203580. Because p38 is a major hub for the control of stress-signalling pathways we were interested in examining the possible role for downstream kinases in order to refine our understanding of the role of p38 signalling in regulation of WS cell growth. To this end we treated WS and normal fibroblasts with MK2 inhibitors to determine whether MK2 inhibition would affect either the growth or morphology of WS cells. The first inhibitor, 7,8-dihydroxy-2,4-diamino-3-cyanobenzopyranopyridine (inhibitor 2), resulted in inhibition of WS cell growth and had no effect on morphology, effects that occurred below the level needed to inhibit MK2 and thus suggestive of inhibitor toxicity. The second inhibitor, 2-(2-quinolin-3-ylpyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo-[3,2-c]pyridin-4-one (CMPD16), resulted in a significant extension of WS fibroblast replicative capacity compared to normal cells. In addition, CMPD16 reverted the WS cellular morphology to that seen in normal dermal fibroblasts. These data suggest that MK2 activity plays a substantial role in proliferation control in WS cells. CMPD16 was not as effective in cellular lifespan extension as SB203580, however, suggesting that, although MK2 is a downstream kinase involved in cell cycle arrest, other p38 targets may play a role. Alternatively, as CMPD16 is toxic to cell growth at levels just above those that extend lifespan, it is possible that the therapeutic window is too small. However, as CMPD16 does show significant effects in WS fibroblasts, this acts as proof-of-principle for the efforts to design and synthesise improved MK2 inhibitors. As MK2 is involved in inflammatory processes and inflammation plays a major role in WS phenotypes, these data suggest MK2 as a potential therapeutic target for the treatment of Werner syndrome.

An Evaluation of Community Assessment for Public Health Emergency Response (CASPER) in North Carolina, 2003-2010

Introduction Community Assessment for Public Health Emergency Response (CASPER) is a group of tools and methods designed by the US Centers for Disease Control and Prevention (CDC) to provide rapid, reliable, and accurate population-based public health information. Since 2003, North Carolina public health professionals have used CASPERs to facilitate public health emergency responses and gather information on other topics including routine community health assessments. Problem To date, there has been no evaluation of CASPER use by public health agencies at the state or local level in the US. METHODS: Local health departments of North Carolina reported when and how CASPERs were used during the period 2003 to 2010 via an online survey. Data on barriers and future plans for using CASPERs also were collected. RESULTS: Fifty-two of North Carolina's 85 local health departments (61%) completed the survey. Twenty-eight departments reported 46 instances of CASPER use during 2003 to 2010. The majority of CASPERs were performed for community health assessments (n = 20, 43%) or exercises (n = 11, 24%). Fifty-six percent of respondents indicated they were "likely" or "very likely" to use CASPERs in the future; those who had prior experience with CASPERs were significantly more likely (P = .02) to report planned future use of CASPERs compared to those without prior experience with the tool. Lack of training, equipment, and time were the most frequently reported barriers to using CASPERs. CONCLUSIONS: Local public health agencies with clear objectives and goals can effectively use CASPERs in both routine public health practice and disaster settings. Horney J , Davis MK , Davis SEH , Fleischauer A . An evaluation of Community Assessment for Public Health Emergency Response (CASPER) in North Carolina, 2003-2010. Prehosp Disaster Med. 2013;28(2):1-5 .

Characterization of Polymeric Microcapsules Containing a Low Molecular Weight Peptide for Controlled Release

A need exists to prolong the release of rapidly metabolized peptides of a low molecular weight, while delivering this peptide without environmental interference. Previous studies have used bovine serum albumin (BSA) as a model peptide to study release characteristics from alginate microcapsules. BSA is 66 kDa in size, while the peptide of interest here, connexin-43 carboxyl-terminus mimetic peptide (αCT1), is only 3.4 kDa. Such a change in size results in a much different set of release parameters. Our overall goal is a sustained release over a 24+ h period. Prolonged application of the peptide to a wound site to investigate therapeutic effects is ideal. As a result, a diffusion method using alginate microcapsules, along with the addition of poly-l-lysine and poly-l-ornithine, has been explored. We first aimed to establish and characterize our parameters through a set of parametric tests. Variations in polymer coating, change in pH, and changes in loading ratio have previously been shown to effect release using model compounds. Here we test specific changes in these parameters to show effects on the release of αCT1. Additionally, the microcapsules were attached to several biomaterials and surgical implants by ultraviolet cross-linking to study the effectiveness of attachment and delivery. Analysis and measurements using phase contrast microscopy, scanning electron microscopy, and atomic force microscopy were used to characterize changes in microcapsule morphology.

Retroperitoneal Metastatic Germ Cell Tumor Presenting As a Psoas Abscess: A Diagnostic Pitfall

ABSTRACT:: Most testicular neoplasms are germ cell tumors, the vast majority of which represent seminomas. Most seminomas present localized to the testis, whereas nonseminomatous germ cell tumors more often present with lymph node metastases. Psoas abscesses generally arise from a contiguous intra-abdominal or pelvic infectious process, an adjacent focus of osteomyelitis or septic emboli from distant infectious foci. In this study, the case of a 24-year-old man who presented with a right psoas mass presumptively diagnosed as an abscess secondary to fever and leukocytosis is presented. The patient had a history of right testicular seminoma, and normal serum levels of alpha-fetoprotein and human chorionic gonadotropin. Surgical exploration and biopsy demonstrated seminoma metastasis. This case represents an extremely unusual clinical presentation of metastatic germ cell tumor presenting as a psoas abscess. This unique case represents an unusual presentation of a recurrent germ cell tumor mimicking a psoas abscess. Awareness of possible metastatic testicular germ cell neoplasm as a psoas abscess could prevent diagnosis delay before retroperitoneal tumor debulking.

Homicide by Poisoning

ABSTRACT: By studying the number and method of homicidal poisoning in Miami-Dade County, Florida; New York City, NY; Oakland County, Michigan; and Sweden, we have confirmed that this is an infrequently established crime.Several difficulties come with the detection of homicidal poisonings. Presenting symptoms and signs are often misdiagnosed as natural disease, especially if the crime is committed in a hospital environment, suggesting that an unknown number of homicides go undetected.In the reported cases analyzed, the lethal agent of choice has changed over the years. In earlier years, traditional poisons such as arsenic, cyanide, and parathion were frequently used. Such poisonings are nowadays rare, and instead, narcotics are more commonly detected in victims of this crime.

Prognostic Significance of Silent Myocardial Infarction in Newly-Diagnosed Type 2 Diabetes: UKPDS 79

BACKGROUND: We aimed to determine the prevalence of silent myocardial infarction (SMI) in people with newly-diagnosed type 2 diabetes (T2D), and its relationship to future myocardial infarction (MI) and all-cause mortality. METHODS AND RESULTS: We examined data from the 5,102 patients in the 30-year UK Prospective Diabetes Study (UKPDS) and used Cox proportional hazards regression to examine outcomes by SMI status. Of 1,967 patients with complete baseline data, 326 (16.6%) had ECG evidence of SMI (Minnesota codes 1.1 or 1.2) at enrolment. Those with SMI were more likely to be older, female, sedentary and non-smokers compared with those without SMI. Their mean blood pressure was greater despite more intensive antihypertensive treatment, they were more likely to be taking aspirin and lipid-lowering therapy, and they had a greater prevalence of microangiopathy. Fully-adjusted hazard ratios (95% CI) for those with, vs. those without, SMI in multivariate models that included UKPDS Risk Engine variables were 1.58 (1.22-2.05) for first fatal MI, and 1.31 (1.10-1.56) for all-cause mortality. Hazard ratios for first fatal or non-fatal MI, and for first non-fatal MI, were non-significant. The Net Reclassification Index showed no improvement when SMI was added to these models and the Integrated Discrimination Index showed that SMI marginally improved prediction of fatal MI and all-cause mortality. CONCLUSIONS: Around one in six UKPDS patients with newly-diagnosed T2D had evidence of SMI, which was independently associated with an increased risk of fatal MI and all-cause mortality. However, identification of SMI does not add substantively to current UKPDS Risk Engine predictive variables. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.controlled-trials.com. Identifier: ISRCTN number: 75451837.

Functional Analysis of Genes in Regions Commonly Amplified in High-grade Serous and Endometrioid Ovarian Cancer

PURPOSE: Ovarian cancer has the highest mortality rate of all the gynecologic malignancies and is responsible for ~140,000 deaths annually worldwide. Copy number amplification is frequently associated with activation of oncogenic drivers in this tumor type, but their cytogenetic complexity and heterogeneity has made it difficult to determine which gene(s) within an amplicon represent the genuine oncogenic driver. We sought to identify amplicon targets by conducting a comprehensive functional analysis of genes located in regions of amplification in high-grade serous and endometrioid ovarian tumors. EXPERIMENTAL DESIGN: High-throughput siRNA screening was used to systematically assess all genes within regions commonly amplified in high grade serous and endometrioid cancer. We describe the results from a boutique siRNA screen of 272 genes in a panel of 18 ovarian cell lines. Hits identified by the functional viability screen were further interrogated in primary tumor cohorts to determine the clinical outcomes associated with amplification and gene over expression. RESULTS: We identified a number of genes as critical for cellular viability when amplified, including URI1, PAK4, GAB2 and DYRK1B. Integration of primary tumor gene expression and outcome data provided further evidence for the therapeutic utility of such genes, particularly URI1 and GAB2, which were significantly associated with survival in two independent tumor cohorts. CONCLUSIONS: By taking this integrative approach to target discovery we have streamlined the translation of high-resolution genomic data into pre-clinical in vitro studies, resulting in the identification of a number of genes that may be specifically targeted for the treatment of ovarian tumors.

Are There Cognitive and Neurobehavioural Correlates of Hormonal Neuroprotection for Women After TBI?

This study examined possible cognitive correlates of hormonal neuroprotection following traumatic brain injury (TBI) using archival neuropsychological findings for 1563 individuals undergoing acute TBI rehabilitation between 1989 and 2002. Presumed age of menopause was based on the STRAW (Stages of Reproductive Aging) staging system (Soules, 2005; Soules et al., 2001) and general linear model (GLM) analysis of performance on neuropsychological testing by participants across gender and age groups (25-34, 35-44, 45-54, and 55-64) was performed. Hypotheses were (1) women with TBI in the oldest age group would have lower scores on neuropsychological tests and functional outcome measures than women in the younger groups, and (2) men in the oldest age group would have higher scores than women of the same age group. Analyses revealed that oldest females had significantly worse Trails B and SDMT written and oral scores than the youngest females. In addition, oldest females had significantly better Trails B, Rey AVLT and SDMT written scores than the oldest males. Possible cohort exposure to hormone replacement therapy, unknown hormonal status at time of testing, and sample-specific injury characteristics may have contributed to these findings.

Transfusion-transmitted Human T-lymphotropic Virus Type I Infection in a United States Military Emergency Whole Blood Transfusion Recipient in Afghanistan, 2010

BACKGROUND: The United States introduced human T-lymphotropic virus Type I (HTLV-I) screening of blood donors in 1988. The US military uses freshly collected blood products for life-threatening injuries when available stored blood components in theater have been exhausted or when these components are unsuccessful for resuscitation. These donors are screened after donation by the Department of Defense (DoD) retrospective testing program. All recipients of blood collected in combat are tested according to policy soon after and at 3, 6, and 12 months after transfusion. CASE REPORT: A 31-year-old US Army soldier tested positive for HTLV-I 44 days after receipt of emergency blood transfusions for severe improvised explosive device blast injuries. One donor's unit tested HTLV-I positive on the DoD-mandated retrospective testing. Both the donor and the recipient tested reactive with enzyme immunoassay and supplemental confirmation by HTLV-I Western blot. The donor and recipient reported no major risk factors for HTLV-I. Phylogenetic analysis of HTLV-I sequences indicated Cosmopolitan subtype, Subgroup B infections. Comparison of long terminal repeat and env sequences revealed molecular genetic linkage of the viruses from the donor and recipient. CONCLUSION: This case is the first report of transfusion transmission of HTLV-I in the US military during combat operations. The emergency fresh whole blood policy enabled both the donor and the recipient to be notified of their HTLV-I infection. While difficult in combat, predonation screening of potential emergency blood donors with Food and Drug Administration-mandated infectious disease testing as stated by the DoD Health Affairs policy should be the goal of every facility engaged with emergency blood collection in theater.

Sexual Concurrency Among Young African American Women

Young African-American women are disproportionately affected by human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) sexually transmitted infections (STI), and engage in greater sexual concurrency than other race/ethnicities. It is important to evaluate behaviors and characteristics associated with the risk of sexual concurrency, so that interventions can target factors most likely to affect positive change. An emphasis on correlates of concurrency beyond individual-level factors has been suggested. The purpose of this study, therefore, was to identify individual- and partner-level characteristics associated with sexual concurrency among high-risk, young African-American women. Data were collected from 570 African-American adolescent women (aged 15-21) recruited from a STI clinic, a family planning clinic, and a teen clinic located in Atlanta, GA from March 2002 through August 2004. Logistic regression analysis was conducted in 2012 to evaluate correlates of sexual concurrency. Results show that almost one-quarter of participants reported sexually concurrent partnerships and 28.4% suspected male partner concurrency. Logistic regression results indicated the number of lifetime sexual partners and relationship factors were the primary contributors to engaging in concurrency in this sample. These findings suggest relationship factors may be important contributors to the prevalence of sexual concurrency among young African-American women. Interventions targeted toward sexual health among young African-American women may need to specifically address partner/relationship factors. Through these findings, we hope to better understand sexual risk taking and develop strategies that would overcome barriers to existing interventions aimed at improving the sexual health outcomes of young African-American women.

Evaluating Ion Exchange Resin Efficiency and Oxidative Capacity for the Separation of Uranium(IV) and Uranium(VI)

ABSTRACT:

Prevalence and Characterization of Methicillin-resistant Staphylococcus Aureus Isolated from Retail Meat and Humans in Georgia

There is increasing interest in the presence of Staphylococcus aureus, specifically methicillin-resistant S. aureus (MRSA), on retail meat products. In this study, staphylococci were isolated from retail pork and retail beef in Georgia and MRSA from the products were compared to human MRSA from the same geographic area using broth microdilution antimicrobial susceptibility testing, Multilocus sequence typing (MLST), spa typing, SCCmec typing, and Pulsed-Field Gel Electrophoresis (PFGE). S. aureus was isolated from 45% (45/100) of pork products and 63% (63/100) of beef products; mecA was detected in S. aureus from both pork (3/100; 3%) and beef (4/100; 4%). Fifty percent (50/100) of human S. aureus also contained mecA. Multidrug resistance was detected among MRSA from all sources. All MRSA (n=57) were SCCmec type IV and nine different spa types were present among the isolates (t002, t008, t012, t024, t179, t337, t548, t681, and t1062). Four sequence types (ST5, ST8, ST9, and ST30) were detected using MLST; the majority of MRSA were ST8 followed by ST5. One retail beef MRSA was ST8, while the remaining three were ST5. In retail pork MRSA, ST5, ST9, and ST30 were observed. The majority of human MRSA were ST8. Thirty-seven MRSA isolates were pvl+, one of which was a retail beef MRSA. Using PFGE, MLST, and spa typing, three retail beef MRSA were identical in PFGE pattern, ST, and spa type to two human clonal MRSA (USA100 and USA300). One additional retail beef MRSA had a similar PFGE pattern to a human MRSA isolate, whereas none of the retail pork MRSA had similar PFGE patterns to human MRSA. This data suggests that the retail beef samples were contaminated from a human source possibly during processing of the meat and may present a source of MRSA to consumers and others who handle raw meat.

Investigating Urinary Tract Infections in Children

Preexisting Mental Illness and Risk for Developing a New Disorder After Hurricane Katrina

ABSTRACT: To investigate predisaster mental illness as a risk factor of poor postdisaster mental health outcomes, veterans with (n = 249) and without (n = 250) preexisting mental illness residing in the Gulf Coast during Hurricane Katrina were surveyed after Katrina and screened for posttraumatic stress disorder (PTSD), depression, generalized anxiety disorder, and panic. Logistic regression examined the association between preexisting mental disorders and positive screens after the hurricane, adjusting for demographics and exposure to hurricane-related stressors. The odds of screening positive for any new mental disorder were 6.8 times greater for those with preexisting mental illness compared with those without preexisting mental illness. Among those with preexisting PTSD, the odds of screening positive for any new mental illness were 11.9 times greater; among those with schizophrenia, 9.1 times greater; and among those with affective disorders, 4.4 times greater. Persons with preexisting mental illnesses, particularly PTSD, should be considered a high-risk group for poor outcomes after a disaster.

Disruption of the Putative Vascular Leak Peptide Sequence in the Stabilized Ricin Vaccine Candidate RTA1-33/44-198

Vitetta and colleagues identified and characterized a putative vascular leak peptide (VLP) consensus sequence in recombinant ricin toxin A-chain (RTA) that contributed to dose-limiting human toxicity when RTA was administered intravenously in large quantities during chemotherapy. We disrupted this potentially toxic site within the more stable RTA1-33/44-198 vaccine immunogen and determined the impact of these mutations on protein stability, structure and protective immunogenicity using an experimental intranasal ricin challenge model in BALB/c mice to determine if the mutations were compatible. Single amino acid substitutions at the positions corresponding with RTA D75 (to A, or N) and V76 (to I, or M) had minor effects on the apparent protein melting temperature of RTA1-33/44-198 but all four variants retained greater apparent stability than the parent RTA. Moreover, each VLP(-) variant tested provided protection comparable with that of RTA1-33/44-198 against supralethal intranasal ricin challenge as judged by animal survival and several biomarkers. To understand better how VLP substitutions and mutations near the VLP site impact epitope structure, we introduced a previously described thermal stabilizing disulfide bond (R48C/T77C) along with the D75N or V76I substitutions in RTA1-33/44-198. The D75N mutation was compatible with the adjacent stabilizing R48C/T77C disulfide bond and the T(m) was unaffected, whereas the V76I mutation was less compatible with the adjacent disulfide bond involving C77. A crystal structure of the RTA1-33/44-198 R48C/T77C/D75N variant showed that the structural integrity of the immunogen was largely conserved and that a stable immunogen could be produced from E. coli. We conclude that it is feasible to disrupt the VLP site in RTA1-33/44-198 with little or no impact on apparent protein stability or protective efficacy in mice and such variants can be stabilized further by introduction of a disulfide bond.

Effective Contractile Effect of Voltage-gated Na+ Channels Revealed by a Channel Activator

This study investigated the molecular identity and impact of enhancing voltage-gated sodium channels (Na(V)) in the control of vascular tone. In rat isolated mesenteric and femoral arteries mounted for isometric tension recording, the vascular actions of the Na(V) activator veratridine were examined. Na(V) expression was probed by molecular techniques and immunocytochemistry. In mesenteric arteries, veratridine induced potent contractions (pEC50 = 5.19 ± 0.20, Emax = 12.0 ± 2.7 mN), which were inhibited by 1 µM tetrodotoxin (blocker of all Na(V) isoforms except NaV1.5, Na(V)1.8-1.9) but not by selective blockers of NaV1.7 (ProTx-II; 10 nM) or NaV1.8 (A-80347; 1 µM). The responses were insensitive to endothelial removal but were partly (~60%) reduced by chemical destruction of sympathetic nerves (6-hydroxydopamine; 2 mM) or antagonism at α1-adrenoceptor (prazosin; 1 µM). KB-R7943, a blocker of the reverse mode of Na(+)/Ca(2+) exchanger (3 µM), inhibited veratridine contractions in the absence or presence of prazosin. T16Ainh-A01, a Ca(2+)-activated Cl(-) channel blocker (10 µM), also inhibited the prazosin-resistant contraction to veratridine. NaV immunoreactivity was detected in freshly isolated mesenteric myocytes with apparent co-localisation with the Na(+)/Ca(2+) exchanger. Veratridine induced similar contractile effects in the femoral artery and mRNA transcripts for Na(V)1.2 and Na(V)1.3 were evident in both vessel types. We conclude that, in addition to sympathetic nerves, Na(V) are expressed in vascular myoctyes where they are functionally coupled to the reverse mode of Na(+)/Ca(2+) exchanger and subsequent activation of Ca(2+)-activated Cl(-) channels causing contraction. The TTX-sensitive isoforms, Na(V)1.2 and Na(V)1.3 are likely involved in vascular control.

In a Niche of Time: Do Specialty Hospitals Outperform General Services Hospitals?

Niche hospitals represent a growing segment in the health care industry. Niche facilities are primarily engaged in the treatment of cardiac or orthopedic conditions. The effectiveness of this strategy is of interest because niche hospitals focus on only the most profitable services. The purpose of this research was to assess the financial effectiveness of the niche strategy. We theorize that firm and market-level factors concomitantly with the strategy of the hospital-niche versus traditional-are associated with financial performance. This research used 2 data sources, the 2003 Medicare Cost Report and the 2003 Area Resource File. The sample was limited to only for-profit, urban, nongovernmental hospitals (n = 995). The data were analyzed using hierarchical least squares regression. Financial performance was operationalized using the hospital's return on assets. The principal finding of this project is that niche hospitals had significantly higher performance than traditional facilities. From the organizational perspective, the niche strategy leads to better financial performance. From a societal perspective, the niche strategy provides increased focus and efficiencies through repetition. Despite the limited focus of this strategy, patients who can access these providers may experience better outcomes than patients in more traditional hospitals.

A Black-hole Mass Measurement from Molecular Gas Kinematics in NGC4526

The masses of the supermassive black holes found in galaxy bulges are correlated with a multitude of galaxy properties, leading to suggestions that galaxies and black holes may evolve together. The number of reliably measured black-hole masses is small, and the number of methods for measuring them is limited, holding back attempts to understand this co-evolution. Directly measuring black-hole masses is currently possible with stellar kinematics (in early-type galaxies), ionized-gas kinematics (in some spiral and early-type galaxies) and in rare objects that have central maser emission. Here we report that by modelling the effect of a black hole on the kinematics of molecular gas it is possible to fit interferometric observations of CO emission and thereby accurately estimate black-hole masses. We study the dynamics of the gas in the early-type galaxy NGC 4526, and obtain a best fit that requires the presence of a central dark object of  × 10(8) solar masses (3σ confidence limit). With the next-generation millimetre-wavelength interferometers these observations could be reproduced in galaxies out to 75 megaparsecs in less than 5 hours of observing time. The use of molecular gas as a kinematic tracer should thus allow one to estimate black-hole masses in hundreds of galaxies in the local Universe, many more than are accessible with current techniques.

Neurturin Overexpression in Skin Enhances Expression of TRPM8 in Cutaneous Sensory Neurons and Leads to Behavioral Sensitivity to Cool and Menthol

Neurturin (NRTN) is a member of the glial cell line-derived neurotrophic factor family of ligands that exerts its actions via Ret tyrosine kinase and GFRα2. Expression of the Ret-GFRα2 coreceptor complex is primarily restricted to the peripheral nervous system and is selectively expressed by sensory neurons that bind the isolectin B(4) (IB(4)). To determine how target-derived NRTN affects sensory neuron properties, transgenic mice that overexpress NRTN in keratinocytes (NRTN-OE mice) were analyzed. Overexpression of NRTN increased the density of PGP9.5-positive, but not calcitonin gene-related peptide-positive, free nerve endings in footpad epidermis. GFRα2-immunopositive somata were hypertrophied in NRTN-OE mice. Electron microscopic analysis further revealed hypertrophy of unmyelinated sensory axons and a subset of myelinated axons. Overexpression of NRTN increased the relative level of mRNAs encoding GFRα2 and Ret, the ATP receptor P2X(3) (found in IB(4)-positive, GFRα2-expressing sensory neurons), the acid-sensing ion channel 2a, and transient receptor potential cation channel subfamily member M8 (TRPM8) in sensory ganglia. Behavioral testing of NRTN-OE mice revealed an increased sensitivity to mechanical stimuli in glabrous skin of the hindpaw. NRTN-OE mice also displayed increased behavioral sensitivity to cool temperature (17°C-20°C) and oral sensitivity to menthol. The increase in cool and menthol sensitivity correlated with a significant increase in TRPM8 expression and the percentage of menthol-responsive cutaneous sensory neurons. These data indicate that the expression level of NRTN in the skin modulates gene expression in cutaneous sensory afferents and behavioral sensitivity to thermal, chemical, and mechanical stimuli.

High-Throughput Directed Self-Assembly of Core-Shell Ferrimagnetic Nanoparticle Arrays

Magnetic nanoparticles (MNPs) provide a set of building blocks for constructing stimuli-responsive nanoscale materials with properties that are unique to this scale. The size and the composition of MNPs are tunable to meet the requirements for a range of applications including biosensors and data storage. Although many of these technologies would significantly benefit from the organization of nanoparticles into higher-order architectures, the precise placement and arrangement of nanoparticles over large areas of a surface remain a challenge. Herein, we demonstrate the viability of magnetic nanoparticles for patterned recording media utilizing a template-directed self-assembly process to afford well-defined nanostructures of magnetic nanoparticles and access these assemblies using magnetic force microscopy and a magnetic recording head. Photolithographically defined holes were utilized as templates to form assemblies of ferrimagnetic nanoparticle rings or pillars selectively over a large area (>1 cm(2)) in just 30 s. This approach is applicable to other nanoparticle systems as well and enables their high-throughput self-assembly for future advanced device fabrication.

Massage Therapy for Patients with Metastatic Cancer: A Pilot Randomized Controlled Trial

Abstract Objectives: The study objectives were to determine the feasibility and effects of providing therapeutic massage at home for patients with metastatic cancer. Design: This was a randomized controlled trial. Settings/location: Patients were enrolled at Oncology Clinics at a large urban academic medical center; massage therapy was provided in patients' homes. Subjects: Subjects were patients with metastatic cancer. Interventions: There were three interventions: massage therapy, no-touch intervention, and usual care. Outcome measures: Primary outcomes were pain, anxiety, and alertness; secondary outcomes were quality of life and sleep. Results: In this study, it was possible to provide interventions for all patients at home by professional massage therapists. The mean number of massage therapy sessions per patient was 2.8. A significant improvement was found in the quality of life of the patients who received massage therapy after 1-week follow-up, which was not observed in either the No Touch control or the Usual Care control groups, but the difference was not sustained at 1 month. There were trends toward improvement in pain and sleep of the patients after therapeutic massage but not in patients in the control groups. There were no serious adverse events related to the interventions. Conclusions: The study results showed that it is feasible to provide therapeutic massage at home for patients with advanced cancer, and to randomize patients to a no-touch intervention. Providing therapeutic massage improves the quality of life at the end of life for patients and may be associated with further beneficial effects, such as improvement in pain and sleep quality. Larger randomized controlled trials are needed to substantiate these findings.

Report of the Third Havemeyer Workshop on Infection Control in Equine Populations

Predictors of Job Satisfaction Among Peer Providers on Professional Treatment Teams in Community-based Agencies

OBJECTIVE The purpose of this study was to examine factors that predict job satisfaction among peer providers employed on professional treatment teams in community-based behavioral health agencies. METHODS Surveys via Internet and postal mail gathered data from 100 members of the National Association of Peer Specialists who met study criteria. A multiple regression analysis was conducted to evaluate role clarity, psychological empowerment, supervisory alliance, coworker support, and inclusion and exclusion in organizational processes as predictors of job satisfaction. RESULTS The regression analysis revealed that of the five predictors, role clarity and psychological empowerment were significant predictors of job satisfaction when analyses controlled for age, level of education, and tenure. CONCLUSIONS The results of this study reveal that peer providers found satisfaction in an integrated work environment that included clearly defined roles, independent functioning, and respect for the expertise that peer providers possess.

Breaking Symmetry with Symmetry: Bifacial Selectivity in the Asymmetric Cycloaddition of Anthracene Derivatives

Push to activate: A new catalytic strategy for the activation of anthracene derivatives has been developed. From symmetrical starting materials, enantioselective cycloaddition reactions can be achieved by employing a C(2) -symmetric aminocatalyst. This selectivity is due to the gain or loss of conjugation between the enamine and the anthracene in the two transition-state structures. This methodology is demonstrated in 14 examples with 70-96 % yield and 76-95 % ee.

The Effects of Initial Testing on False Recall and False Recognition in the Social Contagion of Memory Paradigm

In three experiments, participants studied photographs of common household scenes. Following study, participants completed a category-cued recall test without feedback (Exps. 1 and 3), a category-cued recall test with feedback (Exp. 2), or a filler task (no-test condition). Participants then viewed recall tests from fictitious previous participants that contained erroneous items presented either one or four times, and then completed final recall and source recognition tests. The participants in all conditions reported incorrect items during final testing (a social contagion effect), and across experiments, initial testing had no impact on false recall of erroneous items. However, on the final source-monitoring recognition test, initial testing had a protective effect against false source recognition: Participants who were initially tested with and without feedback on category-cued initial tests attributed fewer incorrect items to the original event on the final source-monitoring recognition test than did participants who were not initially tested. These data demonstrate that initial testing may protect individuals' memories from erroneous suggestions.

Documentation and Management of CKD in Rural Primary Care

BACKGROUND AND OBJECTIVES: Recognition of CKD by primary care practitioners is essential in rural communities where nephrology access is limited. This study determined the prevalence of undocumented CKD in patients cared for in rural primary care practices and evaluated characteristics associated with undocumented CKD as well as CKD management. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A retrospective cohort study, conducted within the Oregon Rural Practice Based Research Network, consisted of 865 CKD patients with serum creatinine≥1.5 mg/dl in males and ≥1.3 mg/dl in females and an estimated GFR<60 ml/min per 1.73 m(2). Documentation of a CKD diagnosis and laboratory values were abstracted by chart review. RESULTS: Of CKD patients, 51.9% had no documentation of CKD. Undocumented CKD occurred more frequently in female patients (adjusted odds ratio=2.93, 95% confidence interval=2.04, 4.21). The association of serum creatinine reporting versus automating reporting of estimated GFR on CKD documentation was dependent on patient sex, years of practitioner experience, and practitioner clinical training. Hypertensive patients with documented CKD were more likely to have a BP medication change than patients with undocumented CKD (odds ratio=2.07, 95% confidence interval=1.15, 3.73). Only 2 of 449 patients with undocumented CKD were comanaged with a nephrologist compared with 20% of patients with documented CKD (odds ratio=53.20, 95% confidence interval=14.90, 189.90). CONCLUSIONS: Undocumented CKD in a rural primary care setting is frequent, particularly in female patients. Depending on practitioner characteristics, automatic reporting of estimated GFR might improve documentation of CKD in this population.

Attribution of Intentional Causation Influences the Perception of Observed Movements: Behavioral Evidence and Neural Correlates

Recent research on human agency suggests that intentional causation is associated with a subjective compression in the temporal interval between actions and their effects. That is, intentional movements and their causal effects are perceived as closer together in time than equivalent unintentional movements and their causal effects. This so-called intentional binding effect is consistently found for one's own self-generated actions. It has also been suggested that intentional binding occurs when observing intentional movements of others. However, this evidence is undermined by limitations of the paradigm used. In the current study we aimed to overcome these limitations using a more rigorous design in combination with functional Magnetic Resonance Imaging (fMRI) to explore the neural underpinnings of intentional binding of observed movements. In particular, we aimed to identify brain areas sensitive to the interaction between intentionality and causality attributed to the observed action. Our behavioral results confirmed the occurrence of intentional binding for observed movements using this more rigorous paradigm. Our fMRI results highlighted a collection of brain regions whose activity was sensitive to the interaction between intentionality and causation. Intriguingly, these brain regions have previously been implicated in the sense of agency over one's own movements. We discuss the implications of these results for intentional binding specifically, and the sense of agency more generally.

Multi-Centre Observational Study of Transplacental Transmission of Influenza Antibodies Following Vaccination with AS03(A)-Adjuvanted H1N1 2009 Vaccine

Illness and death from influenza increase during pregnancy. In the United Kingdom pregnant women were targeted in a national programme for vaccination during the H1N1 2009-10 pandemic.

Global Spatio-temporal Patterns in Human Migration: a Complex Network Perspective

Migration is a powerful adaptive strategy for humans to navigate hardship and pursue a better quality of life. As a universal vehicle facilitating exchanges of ideas, culture, money and goods, international migration is a major contributor to globalization. Consisting of countries linked by multiple connections of human movements, global migration constitutes a network. Despite the important role of human migration in connecting various communities in different parts of the world, the topology and behavior of the international migration network and its changes through time remain poorly understood. Here we show that the global human migration network became more interconnected during the latter half of the twentieth century and that migrant destination choice partly reflects colonial and postcolonial histories, language, religion, and distances. From 1960 to 2000 we found a steady increase in network transitivity (i.e. connectivity between nodes connected to the same node), a decrease in average path length and an upward shift in degree distribution, all of which strengthened the 'small-world' behavior of the migration network. Furthermore, we found that distinct groups of countries preferentially interact to form migration communities based largely on historical, cultural and economic factors.

Access to Musculoskeletal Specialists and Resources in Free and Charitable Clinics: A Survey of Clinic Directors

OBJECTIVE: To evaluate the capabilities and resources of free and charitable clinics in the United States to deliver musculoskeletal care to an indigent population. DESIGN: A voluntary, anonymous, cross-sectional survey. SETTING: Electronic mailing list for the National Association of Free and Charitable Clinics in September 2011, and in person at the Annual Summit for the National Association of Free and Charitable Clinics in October 2011. At the time of survey, 427 member-clinics were eligible for participation. PARTICIPANTS: One hundred forty-five (34%) respondents were included in data analysis. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Answers to a questionnaire. RESULTS: The average annual clinic volume was 5690 patient visits. Low back pain was the most common orthopedic complaint. Access to musculoskeletal specialty consultants was rated as poor or worse in 83% of clinics surveyed. The majority of respondents (63%) believed that their staff was able to treat only half or fewer of the patients who presented with musculoskeletal complaints in their clinic. The resource most needed to treat these conditions was musculoskeletal physician consultants. CONCLUSIONS: Indigent populations have a strong need for musculoskeletal care, but affordable access to physiatrists and other musculoskeletal specialists is extremely limited. Personnel at surveyed clinics believed that the greatest need to improve care is better access to these specialty physicians.

Spatio-temporal Expression Patterns of Anterior Hox Genes During Nile Tilapia (Oreochromis Niloticus) Embryonic Development

Hox genes encode transcription factors that function to pattern regional tissue identities along the anterior-posterior axis during animal embryonic development. Divergent nested Hox gene expression patterns within the posterior pharyngeal arches may play an important role in patterning morphological variation in the pharyngeal jaw apparatus (PJA) between evolutionarily divergent teleost fishes. Recent gene expression studies have shown the expression patterns from all Hox paralog group (PG) 2-6 genes in the posterior pharyngeal arches (PAs) for the Japanese medaka (Oryzias latipes) and from most genes of these PGs for the Nile tilapia (Oreochromis niloticus). While several orthologous Hox genes exhibit divergent spatial and temporal expression patterns between these two teleost species in the posterior PAs, several tilapia Hox gene expression patterns from PG3-6 must be documented for a full comparative study. Here we present the spatio-temporal expression patterns of hoxb3b, c3a, b4a, a5a, b5a, b5b, b6a and b6b in the neural tube and posterior PAs of the Nile tilapia. We show that several of these tilapia Hox genes exhibit divergent expression patterns in the posterior PAs from their medaka orthologs. We also compare these gene expression patterns to orthologs in other gnathostome vertebrates, including the dogfish shark.

β-Funaltrexamine Inhibits Chemokine (CXCL10) Expression in Normal Human Astrocytes

Neuroinflammation is an integral component of neurodegenerative disorders, CNS infection and trauma. Astroglial chemokines, such as CXCL10, are instrumental in neuroinflammatory signaling as well as neurotoxicity. We have utilized proinflammatory-induced CXCL10 expression in normal human astrocytes (NHA) as a model in which to assess the anti-inflammatory actions of the selective, mu-opioid receptor (MOR) antagonist, β-funaltrexamine (β-FNA). Interferon (IFN)γ+HIV-1 Tat-induced CXCL10 expression (secreted protein and mRNA) was inhibited by co-treatment with β-FNA. Neither the MOR-selective antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Pen-Thr-NH(2) (CTAP) nor the nonselective opioid receptor antagonist, naltrexone inhibited IFNγ+HIV-1 Tat-induced CXCL10 expression. Furthermore, co-treatment with excess CTAP or naltrexone did not prevent β-FNA mediated inhibition of IFNγ+HIV-1 Tat-induced CXCL10 expression. Additionally, we utilized an inhibitor of NF-κB activation (SN50) to demonstrate that IFNγ+HIV-1 Tat-induced CXCL10 expression is NF-κB-dependent in NHA. Subsequent experiments revealed that β-FNA did not significantly affect NF-κB activation. Interestingly, we discovered that β-FNA inhibited p38 activation as indicated by decreased expression of phospho-p38. Together, these findings suggest that the inhibitory actions of β-FNA are MOR-independent and mediated, in part, via a transcriptional mechanism. These findings add to our understanding of the mechanism by which chemokine expression is inhibited by β-FNA. In conjunction with future investigations, these novel findings are expected to provide insights into the development of safe and effective treatments for neuroinflammation.

Cytotoxic Sesquiterpene Lactones from the Leaves of Vernonia Guineensis Benth. (Asteraceae)

ETHNOPHARMACOLOGICAL RELEVANCE: Vernonia guineensisBenth. (Asteraceae) preparations are used in folk medicine in Cameroon to treat a number of ailments including prostate cancer, malaria, and is used as anthelmintic, adaptogen and antidote. The aim of this study was to continue the validation of the activity of Vernonia guineensisBenth. extracts and isolated molecules against cancer cell lines following the previous isolation of an anti-prostate cancer sugar ester from the root extract. MATERIALS AND METHODS: Acetone extracts of Vernonia guineensisBenth. leaves were tested for activity against 10 cancer cell lines (Breast -MDA-MB-231, Breast-MCF-7, Colon-HCT-116, Leukaemia-HL-60, Lung-A549, Melanoma-A375, Ovarian-OVCAR3, Pancreas-Mia-paca, Prostate-PC-3 and Prostate- DU-145). The acetone extract was subjected to bioactivity guided fractionation. Anti-proliferation and clonogenic activity of the isolated compounds were tested. The WST-1 assay was used for the anti-proliferation activity meanwhile the standard clonogenic test was used to determine the clonogenic activity. RESULTS: The acetone extract of Vernonia guineensisBenth. demonstrated in vitro activity ranging from IC(50) 4µg/mL - 26µg/mL against the ten cell lines. Activity guided fractionation of this extract yielded two sesquiterpene lactones, isolated for the first time from the genus Vernonia. The compounds were characterized using spectroscopic experiments including a combination of 1D and 2D NMR data. Vernopicrin (1) and Vernomelitensin (2) demonstrated in-vitro activity against the human cancer cell lines with IC(50) ranging from 0.35µM-2.04µM (P<0.05) and 0.13µM-1.5µM (P<0.05), respectively between the most and least sensitive cell lines for each compound. Vernopicrin was most active against the human melanoma (A375) cell line and least active against the lung cancer (A549) cell line while vernomelitensin was also most active against the human melanoma (A375) cell line and least active against the breast cancer (MCF-7) cell line. Both compounds also demonstrated anticlonogenic activity. CONCLUSION: The cytotoxicity demonstrated by the crude extract and isolated sesquiterpenes against cancer cell lines highlights the medicinal potential of V. guineensis. The selective anti-proliferation and dose dependent anticlonogenic activities suggest that the identified sesquiterpenes could be potential antitumor agents.

A Novel AX+/BX- Paradigm to Assess Fear Learning and Safety-signal Processing with Repeated-measure Designs

One of the core symptoms of anxiety disorders, such as post-traumatic stress disorder is the failure to overcome feelings of danger despite being in a safe environment. This inability likely stems from an inability to fully process safety signals, which are cues in the environment, that enable healthy individuals to over-ride fear in aversive situations. Studies examining safety signal learning in rodents, humans, and non-human primates currently rely on between-groups designs. Because repeated-measure designs reduce the number of subjects required, and facilitate a broader range of safety signal studies, the current project sought to develop a repeated-measures safety-signal learning paradigm in non-human primates. Twelve healthy rhesus macaques of both sexes received three rounds of auditory fear-potentiated startle training and testing using an AX+/BX- design with all visual cues. Cue AX was paired with an aversive blast of air, whereas the same X cue in compound with another B cue (BX) signaled the absence of an air blast. Hence, cue B served as a safety signal. Once animals consistently discriminated between the aversive (AX+) and safe (BX-) cues, measured by greater startle amplitude in the presence of AX vs. BX, they were tested for conditioned inhibition by eliciting startle in the presence of a novel ambiguous combined cue (AB). Similar to previous AX+/BX- studies, healthy animals rapidly learned to discriminate between the AX+ and BX- cues as well as demonstrate conditioned inhibition in the presence of the combined AB cue (i.e. lower startle amplitude in the presence of AB vs. AX). Additionally, animals performed consistently across three rounds of testing using three new cues each time. The results validate this novel method that will serve as a useful tool for better understanding the mechanisms for the regulation of fear and anxiety.

Anxiogenic Effects of CGRP Within the BNST May Be Mediated by CRF Acting at BNST CRFR1 Receptors

Calcitonin gene-related peptide (CGRP) acting within the bed nucleus of the stria terminalis (BNST) increases anxiety as well as neural activation in anxiety-related structures, and mediates behavioral stress responses. Similar effects have been described following intra-ventricular as well as intra-BNST infusions of the stress-responsive neuropeptide, corticotropin releasing factor (CRF). Interestingly, CGRP-positive terminals within the lateral division of the BNST form perisomatic baskets around neurons that express CRF, suggesting that BNST CGRP could exert its anxiogenic effects by increasing release of CRF from these neurons. With this in mind, the present set of experiments was designed to examine the role of CRFR1 signaling in the anxiogenic effects of CGRP within the BNST and to determine whether CRF from BNST neurons contributes to these effects. Consistent with previous studies, we found that 400ng CGRP infused bilaterally into the BNST increased the acoustic startle response and induced anxiety-like behavior in the elevated plus maze compared to vehicle. Both of these effects were attenuated by 10mg/kg PO of the CRFR1 antagonist, GSK876008. GSK876008 alone did not affect startle. An intra-BNST infusion of the CRFR1 antagonist CP376395 (2μg) also blocked increases in acoustic startle induced by intra-BNST infusion of CGRP, as did virally-mediated siRNA knockdown of CRF expression locally within the BNST. Together, these results suggest that the anxiogenic effects of intra-BNST CGRP may be mediated by CRF from BNST neurons acting at local CRFR1 receptors.

Distinct TCR Signaling Pathways Drive Proliferation and Cytokine Production in T Cells

The physiological basis and mechanistic requirements for a large number of functional immunoreceptor tyrosine-based activation motifs (ITAMs; high ITAM multiplicity) in the complex of the T cell antigen receptor (TCR) and the invariant signaling protein CD3 remain obscure. Here we found that whereas a low multiplicity of TCR-CD3 ITAMs was sufficient to engage canonical TCR-induced signaling events that led to cytokine secretion, a high multiplicity of TCR-CD3 ITAMs was required for TCR-driven proliferation. This was dependent on the formation of compact immunological synapses, interaction of the adaptor Vav1 with phosphorylated CD3 ITAMs to mediate the recruitment and activation of the oncogenic transcription factor Notch1 and, ultimately, proliferation induced by the cell-cycle regulator c-Myc. Analogous mechanistic events were also needed to drive proliferation in response to weak peptide agonists. Thus, the TCR-driven pathways that initiate cytokine secretion and proliferation are separable and are coordinated by the multiplicity of phosphorylated ITAMs in TCR-CD3.

Psoriasis and Cardiovascular Screening Rates in the United States

Background: Guidelines to screen for cardiovascular (CV) risk factors in psoriasis patients have been established. However, the frequency with which dermatologists and nondermatologists screen psoriasis patients for CV risk factors is not well characterized. Purpose: To determine how frequently psoriasis patients are screened for CV risk factors in the ambulatory care setting and to identify factors affecting screening rates. Methods: Data from the 2005 to 2009 National Ambulatory Medical Care Survey (NAMCS) were analyzed to determine screening rates for blood pressure, glucose, cholesterol, and body mass index (BMI). The probability of a patient having at least 1 of the 4 risk factors screened was determined and was termed the "composite" score. Screening rates were assessed by physician specialty, patient demographics, and clinical practice characteristics. Results: There were an estimated 11.4 million psoriasis patient visits from 2005 to 2009. Blood pressure, glucose, cholesterol, and BMI were evaluated at 32.2%, 5.9%, 9%, and 26% of psoriasis visits, respectively, with a composite score of 41.2%. Patients without psoriasis were screened for these CV risk factors at 59.0%, 6%, 8%, and 38.1% of outpatient visits, respectively, with a composite score of 66.3%. The results of a multivariate analysis accounting for patient age differences indicated psoriasis had a statistically significant effect on rates of blood pressure and BMI screening. In general, screening rates were higher if the patient was male, African American, or non-Hispanic, and screening rates were relatively equal across age groups. Higher screening rates were also associated with primary care specialties, faculty practice or community health clinics with contracted physicians, clinics that utilized electronic medical records, practices with a higher percentage of revenue from a Medicare/Medicaid payer, or offices with discounted fees and capitation payment structures. Limitations: Data from NAMCS are cross-sectional, permitting assessment of screening rates based on visits but not on patients. Conclusions: Screening for high blood pressure, diabetes, hypercholesterolemia, and obesity are not performed at most outpatient visits for psoriasis. Care should be taken to ensure that patients do receive appropriate screening for the comorbidities associated with psoriasis. J Drugs Dermatol. 2013;12(1):e14-e19.

Mathematical Models of Memory CD8(+) T-Cell Repertoire Dynamics in Response to Viral Infections

Immunity to diseases is conferred by pathogen-specific memory cells that prevent disease reoccurrences. A broad repertoire of memory T-cells must be developed and maintained to effectively protect against viral invasions; yet, the total number of memory T-cells is constrained between infections. Thus, creating memory to new infections can require attrition of some existing memory cells. Furthermore, some viruses induce memory T-cell death early in an infection, after which surviving cells proliferate to refill the memory compartment.We develop mathematical models of cellular attrition and proliferation in order to examine how new viral infections impact existing immunity. With these probabilistic models, we qualitatively and quantitatively predict how the composition and diversity of the memory repertoire changes as a result of viral infections. In addition, we calculate how often immunity to prior diseases is lost due to new infections. Comparing our results across multiple general infection types allows us to draw conclusions about, which types of viral effects most drastically alter existing immunity. We find that early memory attrition does not permanently alter the repertoire composition, while infections that spark substantial new memory generation drastically shift the repertoire and hasten the decline of existing immunity.

A Tailored Prostate Cancer Education Intervention for Low-income African Americans: Impact on Knowledge and Screening

Abstract:African American men bear disproportionate burden of prostate cancer (PCa) that can be reduced by early detection. A 15-minute culturally appropriate PCa education intervention developed to communicate effective, relevant, and balanced PCa screening information to low-income African American men was evaluated in men 42 years and older who had not been screened in one year. Of 539 men enrolled, 392 (72.7%) completed the six-month follow-up. Mean age was 54.4±8.9, 34.7% had no high school diploma, and 65.3% earned less than $25,000 annually. Barriers to screening included health insurance (41.4%), discomfort of digital rectal exam (32.1%), and fear of cancer diagnosis (29.9%). Mean knowledge score of 21 points increased from 13.27±3.51 to 14.95±4.14 (p<.001), and prostate-specific antigen screening from 22.1% to 62.8%. Men without high school diploma recorded the lowest post-intervention PCa knowledge and screening rate (47.7%), suggestive of the need for more than a single education session. Annual physicals with free prostate examination can maintain the positive trend observed.

The Development of a Validated Checklist for Nasogastric Tube Insertion: Preliminary Results

Nasogastric (NG) tube insertion is known to result in complications. Validated checklists are central to teaching and assessing procedural skills and may result in improved health care quality. The results of the first step of the validation of an NG tube insertion checklist are described. A comprehensive literature review of articles published on NG tube insertion did not yield a checklist validated by the Delphi method. A modified Delphi technique, involving a panel of 9 interdisciplinary, interinstitutional experts, was used to develop an NG tube insertion checklist. The internal consistency coefficient using Cronbach's α was .80. Developing a 19-item checklist for teaching and assessing NG tube insertion is the first step in the validation process. For this checklist to become further validated, it should be implemented and studied in the simulation and clinical environments.

Neonatal Outcomes After Antenatal Influenza Immunization During the 2009 H1N1 Influenza Pandemic: Impact on Preterm Birth, Birth Weight, and Small for Gestational Age Birth

Background. Influenza infection during pregnancy is associated with adverse fetal outcomes such as preterm birth and small for gestational age (SGA). Maternal influenza immunization may prevent these adverse infant outcomes during periods of influenza circulation.Methods. We conducted a retrospective cohort study of live births within Kaiser Permanente (KP) Georgia and Mid-Atlantic States (n=3,327) during the period of 2009 influenza A (H1N1) virus circulation. Primary outcomes were third trimester preterm birth (27-36 weeks), birth weight, low birth weight (LBW, <2500 grams), and SGA.Results. There were 327 (9.8%) preterm, 236 (7.4%) LBW, and 267 (8.4%) SGA births. Among H1N1-vaccinated mothers (n=1125), there were 86 (7.6%) preterm, 68 (6.4%) LBW, and 99 (9.3%) SGA births, and the mean birth weight was 3308.5 grams (95% CI: 3276.6-3340.4). Among unvaccinated mothers (n=1581), there were 191 (12.1%) preterm, 132 (8.8%) LBW, and 123 (8.2%) SGA births, and the mean birth weight was 3245.3 grams (95% CI: 3216.5-3274.2). Infants of H1N1-vaccinated mothers had 37% lower odds of being born preterm than infants of unvaccinated mothers (aOR: 0.63, 95% CI: 0.47-0.84). The mean birth weight difference between infants of H1N1-vaccinated mothers and infants of unvaccinated mothers was 45.1 grams (95% CI: 1.8-88.3). There was no significant association between maternal H1N1 influenza immunization and LBW or SGA.Conclusions. Pregnant women who received H1N1 influenza vaccine were less likely to give birth preterm, and gave birth to heavier infants. The findings validate U.S. vaccine policy choices to prioritize pregnant women during the 2009 influenza A (H1N1) pandemic.

An Outbreak of Foodborne Illness Among Attendees of a Wedding Reception in Wisconsin Likely Caused by Arcobacter Butzleri

Abstract Background: Arcobacter species, primarily Arcobacter butzleri, are widely distributed among animals, infrequently isolated from humans, and previously not associated with outbreaks of foodborne illness. We report results of an investigation of a foodborne outbreak that occurred among attendees of a wedding reception in Wisconsin, United States, and was likely caused by A. butzleri. Methods: We conducted a case-control study among reception attendees and a laboratory investigation to determine the extent, source, and cause of the outbreak. A clinical case was defined as diarrhea in an attendee with illness onset ≤7 days following the wedding reception. Results: The case-control study included 47 of 51 case patients and 43 non-ill attendees. Results demonstrated that consuming broasted chicken was the only factor significantly associated with illness (odds ratio 10.51; 95% confidence interval 1.28, 476.4). Five patients provided stool specimens. Comprehensive culture and polymerase chain reaction (PCR) testing did not detect common bacterial or viral pathogens. Subsequent testing with PCRs targeting 16S/23S rDNA of the three most clinically relevant Arcobacter spp. and the rpoB/C gene of A. butzleri provided products confirmed as A. butzleri (four patients) and A. cryaerophilus (one patient) by sequence analysis. Conclusions: The results of this investigation suggest that A. butzleri should be considered an agent that can cause outbreaks of foodborne illness. Rigorous investigation of outbreaks of undetermined etiology is valuable for incrementally increasing our understanding of emerging agents causing foodborne illnesses.

Oil, Fatty Acid, Flavonoid, and Resveratrol Content Variability and FAD2A Functional SNP Genotypes in the U.S. Peanut Mini-Core Collection

Peanut seeds contain high amounts of oil and protein as well as some useful bioactive phytochemicals which can contribute to human health. The U.S. peanut mini-core collection is an important genetic resource for improving seed quality and developing new cultivars. Variability of seed chemical composition within the mini-core was evaluated from freshly harvested seeds for two years. Oil, fatty acid composition, and flavonoid/ resveratrol content were quantified by NMR, GC, and HPLC, respectively. Significant variability was detected in seed chemical composition among accessions and botanical varieties. Accessions were further genotyped with a functional SNP marker from the FAD2A gene using real-time PCR and classified into three genotypes with significantly different O/L ratios: wild type (G/G with a low O/L ratio <1.7), heterozygote (G/A with O/L ratio >1.4 but <1.7), and mutant (A/A with a high O/L ratio >1.7). The results from real-time PCR genotyping and GC fatty acid analysis were consistent. Accessions with high amounts of oil, quercetin, high seed weight, and O/L ratio were identified. The results from this study may be useful not only for peanut breeders, food processors, and product consumers to select suitable accessions or cultivars, but also for curators to potentially expand the mini-core collection.

The SF-36v2 and SF-12v2 Health Surveys in New Zealand: Norms, Scoring Coefficients and Cross-country Comparisons

Objective : To provide New Zealand population norms for version 2 of the SF-36 and SF-12 health surveys and report scoring coefficients that enable the construction of Physical and Mental Component Summary scores from New Zealand SF-36v2 and SF-12v2 data. Approach : Norms for the SF-36v2 and scoring coefficients for the Physical and Mental Component Summary scores are estimated using 2006/07 New Zealand Health Survey data, which included 12,488 adults (aged 15 years and over). Norms for the SF-12v2 are derived from 2008 New Zealand General Social Survey data, including 8,721 adults. Comparisons are made between New Zealand norms for versions 1 and 2 of the SF-36 instrument. In addition, New Zealand SF-36v2 and SF-12v2 norms and the scoring coefficients are compared with those for the United States and South Australia. Conclusion : Differences between: 1) New Zealand population norms for the SF-36 versions 1 and 2; and 2) SF-36v2 and SF-12v2 population norms for New Zealand and those for the United States and South Australia highlight the importance of using version-specific and country-specific population norms. Implications: The analysis reported here allows for the appropriate use of the SF-36v2 and SF-12v2 instruments in New Zealand.

[In Process Citation]

Racial Differences in the Association Between Night Shift Work and Melatonin Levels Among Women

Reduced suppression of melatonin in response to working the night shift among people of Asian ancestry has been suggested as a possible explanation for the null results observed in a recent analysis of shift work and breast cancer risk in a Chinese cohort. The authors analyzed the impact of Asian versus white race on previously reported differences in urinary 6-sulfatoxymelatonin levels in a 2003-2008 study in Seattle, Washington, of female health-care workers that exclusively worked night or day shifts. A total of 225 white and 51 Asian participants were included in the analysis. Although 6-sulfatoxymelatonin levels were affected by night shift work in both racial groups, Asian night shift workers consistently showed 6-sulfatoxymelatonin levels that were closer to levels in day shift workers than did white night shift workers. Furthermore, differences in 6-sulfatoxymelatonin levels between white and Asian night shift workers relative to day shift workers were statistically significant in every instance (P < 0.05). These results suggest that Asians may be better able to maintain a "normal" circadian pattern of melatonin production compared with whites and suggest a biological mechanism by which Asian night shift workers may be at a reduced risk of cancer.

Aging Baby Boomers and the Rising Cost of Chronic Back Pain: Secular Trend Analysis of Longitudinal Medical Expenditures Panel Survey Data for Years 2000 to 2007

The purposes of this study were to analyze data from the longitudinal Medical Expenditures Panel Survey (MEPS) to evaluate the impact of an aging population on secular trends in back pain and chronicity and to provide estimates of treatment costs for patients who used only ambulatory services.

Quantitative High Contrast X-ray Microtomography for Dental Research

OBJECTIVES: X-ray microtomography (XMT or micro-CT) is a miniaturized version of medical CT and has been used extensively for in vitro dental research. The technique allows three dimensional analyses of both structure and density (or concentration); the latter requiring some a priori knowledge of composition. Commercial XMT systems tend to be optimized for high throughput imaging with less emphasis on accuracy and contrast sensitivity required for mapping mineral concentration in teeth. The aim here is to demonstrate the capabilities of an XMT scanner specifically designed for dental research, especially for studies requiring high contrast resolution or accurate mineral concentration quantification. METHODS: The MuCAT scanners use high dynamic range CCD cameras with time-delay integration readout to provide high quality tomographic images, albeit at the cost of long data acquisition times. Accuracy in mineral concentration quantification is achieved using a modeling approach to beam hardening correction, a problem encountered in all XMT systems using conventional X-ray sources. RESULTS: A provisional result shows that the accuracy for quantification of hydroxyapatite concentration of better than 1%. CONCLUSION: In dentistry, the improved accuracy and contrast sensitivity, together with the non-destructive nature of XMT in general, facilitates studies of de- and re-mineralization and other dynamic processes in teeth. The ability to differentiate subtle differences in mineral concentration allows dead tracts to be traced in three dimensions, linking external pathology in teeth to reactive processes in the pulp. Three examples are presented which demonstrate the utilization of the MuCAT scanners in current dental research. CLINICAL SIGNIFICANCE: The MuCAT X-ray microtomography scanners at Queen Mary, University of London have been optimized for quantification of mineral concentration and are particularly useful for in vitro studies of de- and re-mineralization, excavation and other treatment methodologies as well as gaining further insight into tooth morphology and pathology. Results from such studies will inform development of clinical treatment and management.

Evaluation of the Criterion and Predictive Validity of the Alcohol Reduction Strategies-Current Confidence (ARS-CC) in a Natural Drinking Environment

To evaluate several psychometric properties of a questionnaire designed to assess young people's self-efficacy to employ 31 alcohol reduction strategies, we assessed breath alcohol concentration, self-reported drinking, current strategy self-efficacy, and recent past use of these strategies in 100 young adults as they walked to and from the local bar district of a Midwestern college town. In support of criterion and predictive validity of the questionnaire, we found that lower self-efficacy at the initial assessment was significantly correlated with higher scores on a screening measure of consumption, with having engaged in more heavy drinking episodes in the past 30days, and with higher levels of intoxication and use of fewer reduction strategies later that evening. Frequency counts indicate that 10 of the alcohol reduction strategies had been used by at least half of the sample to reduce their drinking earlier that evening.

The Affordable Care Act's Plan For Consumer Assistance With Insurance Moves States Forward But Remains A Work In Progress

The Affordable Care Act provides support for state-run consumer assistance programs to help privately insured consumers who experience problems with their coverage. Its provisions signify the first national commitment to such assistance and to using cases aggregated by these state programs to inform policy. We interviewed state-level administrators and analyzed program documents to assess whether federal support for state-run consumer assistance programs achieved certain goals. We found that some federally supported programs made substantial progress in supporting and empowering patients by reorienting state agencies to become active advocates for their citizens. Yet progress across the country was inconsistent, and there was little evidence that programs addressed systemic problems experienced by consumers. On balance, the consumer assistance provisions of health care reform do not yet ensure protection for all privately insured Americans because of uneven implementation-a problem likely to be of further concern as coverage is expanded and health insurance exchanges come on line in 2014. At the same time, the demonstrated impact of consumer assistance programs in the most innovative states is arguably a useful "proof of concept" for this young federal program.

A Peptide Antagonist Disrupts NK Cell Inhibitory Synapse Formation

Productive engagement of MHC class I by inhibitory NK cell receptors depends on the peptide bound by the MHC class I molecule. Peptide:MHC complexes that bind weakly to killer cell Ig-like receptors (KIRs) can antagonize the inhibition mediated by high-affinity peptide:MHC complexes and cause NK cell activation. We show that low-affinity peptide:MHC complexes stall inhibitory signaling at the step of Src homology protein tyrosine phosphatase 1 recruitment and do not go on to form the KIR microclusters induced by high-affinity peptide:MHC, which are associated with Vav dephosphorylation and downstream signaling. Furthermore, the low-affinity peptide:MHC complexes prevented the formation of KIR microclusters by high-affinity peptide:MHC. Thus, peptide antagonism of NK cells is an active phenomenon of inhibitory synapse disruption.

Lessons Learned from Study of Depression in Cardiovascular Patients in an Acute-care Heart and Vascular Hospital

Depression is highly prevalent in patients with cardiovascular disease, but questions about the effectiveness of screening and intervention remain unanswered. To evaluate the effects of proactive intervention at an acute-care heart and vascular hospital, patients who reported depressive symptoms on admission were randomized to an active, counseling-based depression intervention plus standard care (referral to a primary or psychiatric care physician) or to standard care alone. Despite early termination of patient enrollment because of lower-than-expected recruitment rates, the project had a positive impact. By involving and educating staff, the investigators raised awareness and improved the process of identifying and helping depressed patients. The lessons in study design and execution gained from this experience will help ensure success in future studies of this condition.

A Molecular Phylogeny for Yponomeutoidea (insecta, Lepidoptera, Ditrysia) and Its Implications for Classification, Biogeography and the Evolution of Host Plant Use

Yponomeutoidea, one of the early-diverging lineages of ditrysian Lepidoptera, comprise about 1,800 species worldwide, including notable pests and insect-plant interaction models. Yponomeutoids were one of the earliest lepidopteran clades to evolve external feeding and to extensively colonize herbaceous angiosperms. Despite the group's economic importance, and its value for tracing early lepidopteran evolution, the biodiversity and phylogeny of Yponomeutoidea have been relatively little studied.

Patterns of Alcohol Use and Expectancies Predict Sexual Risk Taking Among Non-problem Drinking Women

ABSTRACT. Objective: Although alcohol consumption and sexual risk taking are associated, not everyone who drinks alcohol engages in risky sexual behavior. The purposes of the present study were to identify patterns of alcohol use behaviors and alcohol expectancies among women who are non-problem drinkers and to examine how these patterns are associated with indices of sexual risk. Method: Data from 758 non-problem drinking women who have sex with men and were not in committed relationships were analyzed using latent profile analysis to determine patterns of alcohol use and alcohol-related expectancies. Results: Of the four patterns observed, three classes had similar alcohol-related expectancies but differed with respect to drinking behavior (moderate drinking, regular heavy episodes, and frequent heavy episodes), and the fourth class consisted of moderate drinkers with low expectancies (low expectancies). Results revealed that those in the frequent heavy episodes class had the greatest number of sexual partners in the past year and drank the most alcohol before having sex compared with the other women. Both the regular and frequent heavy episodes classes reported greater likelihood of having unprotected sex in the future, more positive beliefs about casual sex, and greater subjective intoxication before having sex than women in the moderate drinking or low expectancies classes. Women in the low expectancies class reported less positive beliefs about condoms than those in the moderate drinking and regular heavy episodes classes. Conclusions: Results suggest that different patterns of expectancies and drinking behaviors are associated with different indices of sexual risk taking and highlight the importance of individually tailored programs for prevention of sexually transmitted infections. (J. Stud. Alcohol Drugs, 74, 223-232, 2013).

Survival of Endometrial Cancer Patients with Lymphatic Invasion and Deficient Mismatch Repair Expression

OBJECTIVE: This study examines patients under the age of 70 with endometrial cancer and lymphatic invasion or lymph node metastases. Survival of patients with loss of tumor mismatch repair expression is compared to survival of patients with normal mismatch repair expression. METHODS: This is a retrospective review of patients treated from 1998-2009 for carcinoma of the endometrium. All patients with lymphatic invasion, including lymph node metastases, had immunohistochemical staining of the primary tumor for loss of expression of the mismatch repair genes MLH1, PMS2, MSH6, and MSH2. Overall survival and disease specific survival were compared using Kaplan-Meier plots. RESULTS: Sixty-six patients were identified for inclusion; 26 demonstrated loss of mismatch repair expression and 40 demonstrated normal mismatch repair expression. Overall survival and disease specific survival were significantly better in the group with defective mismatch repair expression. Subgroup analysis of FIGO stage 3C patients also showed significantly better survival in patients with deficient mismatch repair expression. CONCLUSION: For patients with endometrial cancer and lymphatic invasion, patients demonstrating loss of mismatch repair expression in the primary tumor appear to have a significantly better survival than patients with normal mismatch repair expression. Further investigation appears warranted to examine a possible role of mismatch repair expression as a prognostic marker for high risk patients with endometrial cancer.

Effect of Cognitive Status on Self-Regulatory Driving Behavior in Older Adults: An Assessment of Naturalistic Driving Using In-Car Video Recordings

Previous findings that older drivers engage in strategic self-regulatory behaviors to minimize perceived safety risks are primarily based on survey reports rather than actual behavior. This study analyzed in-car video recording of naturalistic driving of 18 patients with Alzheimer disease (AD) and 20 age-matched controls in order to (1) characterize self-regulatory behaviors engaged by older drivers and (2) assess how behaviors change with cognitive impairment. Only participants who were rated "safe" on a prior standardized road test were selected for this study. Both groups drove primarily in environments that minimized the demands on driving skill and that incurred the least risk for involvement in major crashes. Patients with AD displayed further restrictions of driving behavior beyond those of healthy elderly individuals, suggesting additional regulation on the basis of cognitive status. These data provide critical empirical support for findings from previous survey studies indicating an overall reduction in driving mobility among older drivers with cognitive impairment.

Erratum: Virus-like Glycodendrinanoparticles Displaying Quasi-equivalent Nested Polyvalency Upon Glycoprotein Platforms Potently Block Viral Infection

Use of Dietary Linoleic Acid for Secondary Prevention of Coronary Heart Disease and Death: Evaluation of Recovered Data from the Sydney Diet Heart Study and Updated Meta-analysis

To evaluate the effectiveness of replacing dietary saturated fat with omega 6 linoleic acid, for the secondary prevention of coronary heart disease and death.

Expanding the Reach of Antimicrobial Stewardship

Patient-reported Outcome Measures in Nonmelanoma Skin Cancer of the Face: a Systematic Review

Nonmelanoma skin cancer (NMSC) is the most common malignancy in the western world, with an incidence of 98 000 in the U.K. Since 2009 the Department of Health (DoH) has collected patient-reported outcome measure (PROM) data following four common surgical procedures. However, a DoH PROM for NMSC does not exist. A systematic review of questionnaires published on patient concerns due to NMSC of the face was conducted. Keywords relevant to PROMs, NMSC and the facial region were comprehensively searched in medical databases. Inclusion criteria stipulated questionnaires from relevant papers that recruited patients with NMSC for both the item formulation and subsequent validation.

Application of Vibro-acoustography in Prostate Tissue Imaging

Purpose: To evaluate the potential of the imaging modality vibro-acoustography (VA) for imaging of the prostate.Methods: Excised cadaver prostate specimens were embedded in tissue mimicking gel to simulate the properties of surrounding soft tissues. The samples were imaged at various depths using a laboratory prototyped VA imaging system. The recorded signals were used for offline processing and image reconstruction. In a selected subgroup of tissue samples, conventional ultrasound (B-mode) and x-ray imaging were performed for further analysis, evaluation, and validation of the VA images.Results: The imaging results of prostate tissue samples indicate the capability of VA imaging to detect prostatic nodules and lesions. In the prostate sample with an adenocarcinoma, the lesion appears with a clear contrast with respect to its surrounding tissue. The VA images could also identify the presence of calcifications deep inside the prostate tissue. Further, quantifications of the imaging results demonstrate that VA imaging has higher sensitivity to detect the calcifications compared to conventional ultrasound imaging. VA is also capable of visualizing prostatic tissue structures and in some cases can identify the anatomical zones. More specifically, the observed higher texture level in peripheral zones demonstrates the ability of VA to differentiate between prostatic anatomical zones.Conclusions: Imaging results of ex vivo prostate tissues, reveals the potency of VA as a promising tool to detect abnormalities, delineate tissue structures and anatomical zones, and locate calcifications. The results of this pilot study suggest that in vivo VA imaging of the prostate may be of clinical utility.

A Randomized Controlled Effectiveness Trial of Reciprocal Peer Support in Heart Failure

BACKGROUND: -Disease management programs for patients hospitalized with heart failure (HF) although effective, are often resource intensive, limiting their uptake. Peer support programs have led to improved outcomes among patients with other chronic conditions and may result in similar improvements for HF patients. METHODS AND RESULTS: -In this randomized controlled trial, Reciprocal Peer Support (RSP) arm patients participated in a HF nurse practitioner (NP)-led goal setting group session, received brief training in peer communication skills, and were paired with another participant in their cohort with whom they were encouraged to talk weekly using a telephone platform. Participants were also encouraged to attend three NP-facilitated peer support group sessions. Patients in the Nurse Care Management (NCM) arm attended a NP-led session to address their HF care questions and receive HF educational materials and information on how to access care management services. The median age of the patients was 69 years, 51% were female, and 26% were racial/ethnic minorities. Only 55% of RPS patients participated in peer calls or group sessions. In intention-to-treat analyses, the RPS and NCM groups did not differ in time to first all-cause rehospitalization or death or in mean numbers of rehospitalizations or deaths. There were no differences in improvements in 6-month measures of HF-specific quality of life or social support. CONCLUSIONS: -Among patients recently hospitalized for HF, over half of RPS participants had no or minimal engagement with the reciprocal peer support program, and the program did not improve outcomes compared to usual HF-nurse care management. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00508508.

Barriers and Facilitators of Consumer Use of Nutrition Labels at Sit-down Restaurant Chains

OBJECTIVE: Numerous localities have mandated that chain restaurants post nutrition information at the point of purchase. However, some studies suggest that consumers are not highly responsive to menu labelling. The present qualitative study explored influences on full-service restaurant customers' noticing and using menu labelling. DESIGN: Five focus groups were conducted with thirty-six consumers. A semi-structured script elicited barriers and facilitators to using nutrition information by showing excerpts of real menus from full-service chain restaurants. SETTING: Participants were recruited from a full-service restaurant chain in Philadelphia, Pennsylvania, USA, in September 2011. SUBJECTS: Focus group participants were mostly female, African American, with incomes <$US 60 000, mean age 36 years and education 14·5 years. At recruitment, 33 % (n 12) reported changing their order after seeing nutrition information on the menu. RESULTS: Three themes characterized influences on label use in restaurants: nutrition knowledge, menu design and display, and normative attitudes and behaviours. Barriers to using labels were low prior knowledge of nutrition; displaying nutrition information using codes; low expectations of the nutritional quality of restaurant food; and restaurant discounts, promotions and social influences that overwhelmed interest in nutrition and reinforced disinterest in nutrition. Facilitators were higher prior knowledge of recommended daily intake; spending time reading the menu; having strong prior interest in nutrition/healthy eating; and being with people who reinforced dietary priorities. CONCLUSIONS: Menu labelling use may increase if consumers learn a few key recommended dietary reference values, understand basic energy intake/expenditure scenarios and if chain restaurants present nutrition information in a user-friendly way and promote healthier items.

Knowledge and Usability of a Trauma Training System For general Surgery Residents

BACKGROUND: Resident work-hour restrictions challenge educators to supplement residents' surgical education. We evaluated a computer-based trauma surgery system's ability to increase residents' surgical knowledge. METHODS: Modules on thoracic and abdominal surgical approaches were evaluated. Surgical residents with 1 or more years of experience completed the pretest, an interactive module, the post-test, and a usability survey. RESULTS: Fifteen participants completed both modules. Thoracic module pretest and post-test scores were 56 ± 11 (mean ± standard deviation) and 90 ± 10, respectively (P < .0001). Mean abdominal module scores were 48 ± 20 and 85 ± 14, respectively (P < .0001). The usability survey showed that 87% of participants would use these modules to supplement their trauma training, 93% could easily distinguish anatomic detail, and 100% thought that procedures were shown clearly. CONCLUSIONS: This novel computer-based trauma education training system improved residents' knowledge of anatomy, surgical incisions, exposures, and technique. As innovative didactic tools arise in postgraduate medical education, it is crucial to document their effects on educational processes, learning satisfaction, and knowledge outcomes.

Living-Donor Follow-up Attitudes and Practices in U.S. Kidney and Liver Donor Programs

BACKGROUND: Although U.S. transplantation programs must submit living-donor follow-up data through 2 years after donation, the submissions have high rates of incomplete or missing data. It is important to understand barriers programs face in collecting follow-up information. METHODS: Two hundred thirty-one programs performing living kidney donor (LKD) and/or living liver donor (LLD) transplantation were contacted to complete a survey about program attitudes concerning donor follow-up, follow-up practices, and barriers to success. RESULTS: Respondents representing 147 programs (111 with only LKD and 36 with both LKD and LLD) participated. Sixty-eight percent of LKD and 83% of LLD respondents said that achieving follow-up was a high priority. The majority agreed that donors should be followed at least 2 years (61% LKD programs and 73% LLD programs), and sizeable percentages (31% LKD and 37% LLD) endorsed 5 years of follow-up. However, approximately 40% of programs lost contact with more than 75% of their donors by 2 years after donation. Follow-up barriers included donors not wanting to return to the program (87%), out-of-date contact information (73%), and lack of program (54%) or donor (49%) reimbursement for follow-up costs. Whereas 92% of LKD and 96% of LLD programs inform potential donors about follow-up requirements, fewer (67% LKD and 78% LLD) develop plans with donors to achieve follow-up. CONCLUSIONS: Most respondents agree that donor follow-up is important, but they report difficulty achieving it. Improvements may occur if programs work with donors to develop plans to achieve follow-up, programmatic standards are set for completeness in follow-up data reporting, and sufficient staff resources are available to ensure ongoing postdonation contact.

Prevalence and Trends in the Use of Antipsychotic Medications During Pregnancy in the U.S., 2001-2007: a Population-based Study of 585,615 Deliveries

This study aims to estimate the prevalence of and temporal trends in prenatal antipsychotic medication use within a cohort of pregnant women in the U.S. We identified live born deliveries to women aged 15-45 years in 2001-2007 from 11 U.S. health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program. We ascertained prenatal exposure to antipsychotics from health plan pharmacy dispensing files, gestational age from linked infant birth certificate files, and ICD-9-CM diagnosis codes from health plan claims files. We calculated the prevalence of prenatal use of atypical and typical antipsychotics according to year of delivery, trimester of pregnancy, and mental health diagnosis. Among 585,615 qualifying deliveries, 4,223 (0.72 %) were to women who received an atypical antipsychotic and 548 (0.09 %) were to women receiving a typical antipsychotic any time from 60 days before pregnancy through delivery. There was a 2.5-fold increase in atypical antipsychotic use during the study period, from 0.33 % (95 % confidence interval: 0.29 %, 0.37 %) in 2001 to 0.82 % (0.76 %, 0.88 %) in 2007, while the use of typical antipsychotics remained stable. Depression was the most common mental health diagnosis among deliveries to women with atypical antipsychotic use (63 %), followed by bipolar disorder (43 %) and schizophrenia (13 %). The number and proportion of pregnancies exposed to atypical antipsychotics has increased dramatically in recent years. Studies are needed to examine the comparative safety and effectiveness of these medications relative to other therapeutic options in pregnancy.

Is There a Cure for Corporate Crime in the Drug Industry?

Lineage Structure of the Human Antibody Repertoire in Response to Influenza Vaccination

The human antibody repertoire is one of the most important defenses against infectious disease, and the development of vaccines has enabled the conferral of targeted protection to specific pathogens. However, there are many challenges to measuring and analyzing the immunoglobulin sequence repertoire, including that each B cell's genome encodes a distinct antibody sequence, that the antibody repertoire changes over time, and the high similarity between antibody sequences. We have addressed these challenges by using high-throughput long read sequencing to perform immunogenomic characterization of expressed human antibody repertoires in the context of influenza vaccination. Informatic analysis of 5 million antibody heavy chain sequences from healthy individuals allowed us to perform global characterizations of isotype distributions, determine the lineage structure of the repertoire, and measure age- and antigen-related mutational activity. Our analysis of the clonal structure and mutational distribution of individuals' repertoires shows that elderly subjects have a decreased number of lineages but an increased prevaccination mutation load in their repertoire and that some of these subjects have an oligoclonal character to their repertoire in which the diversity of the lineages is greatly reduced relative to younger subjects. We have thus shown that global analysis of the immune system's clonal structure provides direct insight into the effects of vaccination and provides a detailed molecular portrait of age-related effects.

Outbreak of Shiga Toxin-Producing Escherichia Coli (STEC) O157:H7 Associated with Romaine Lettuce Consumption, 2011

Shiga toxin-producing Escherichia coli (STEC) O157:H7 is the causal agent for more than 96,000 cases of diarrheal illness and 3,200 infection-attributable hospitalizations annually in the United States.

Emergency Contraception: No. 280 (replaces No. 131, August 2003)

To review current knowledge about emergency contraception (EC), including available options, their modes of action, efficacy, safety, and the effective provision of EC within a practice setting.

Serotonin Syndrome Manifesting As Patient Movement During Total Intravenous Anesthesia with Propofol and Remifentanil

A patient who manifested signs of serotonin syndrome during an intravenous anesthetic with remifentanil and propofol is presented. The patient displayed lower extremity clonus, nystagmus, and diaphoresis. At the time of surgery, the patient was being treated with fluoxetine (a selective serotonin reuptake inhibitor). A presumptive diagnosis of serotonin syndrome was made intraoperatively and all opioids were discontinued. His symptoms resolved in the Postanesthesia Care Unit without incident.

Horizontal Gene Transfer: Linking Sex and Cell Fate

Integrative conjugative elements (ICEs) enable horizontal gene transfer among bacteria. In Pseudomonas, only a phenotypically distinct subpopulation of ICE-bearing cells can mobilize ICE DNA to new hosts. Transfer competence is a terminal state; division is limited, and many cells lyse.

A Review of Antithrombotic Therapy for Transcatheter Aortic Valve Replacement

Aortic stenosis (AS) is a common valvular pathological finding in older adults. A latent period followed by rapid progression after the onset of symptoms can result in a high rate of death if left untreated. Aortic valve replacement (AVR) remains the standard of care for patients with severe symptomatic AS; however, due to comorbidities and age, patients may be ineligible for surgical AVR. Transcatheter AVR (TAVR) is an alternative treatment for patients with severe symptomatic AS for whom surgery is not an option. The most recent guidelines and consensus statement discussing TAVR support the use of antithrombotic therapy during and after TAVR procedures to prevent thrombotic complications. Intravenous unfractionated heparin titrated to target activated clotting times during the procedure and dual antiplatelet therapy before and after TAVR with aspirin and clopidogrel may be used. However, it is unclear which antithrombotic regimen may provide optimal protection for early and late thrombotic events in patients who undergo TAVR. This review evaluates the current guidelines, trials, and registry data discussing antithrombotic regimens for TAVR.

Childhood Obesity and Asthma Control in a Diverse Sample: Examining Age and Racial/Ethnic Differences

RATIONALE: Obesity is associated with increased asthma morbidity, lower drug responsiveness to inhaled corticosteroids, and worse asthma control. However, most prior investigations on obesity and asthma control have not focused on pediatric populations, considered environmental exposures, or included minority children. OBJECTIVE: To examine the association between body mass index (BMI) categories and asthma control among boys and girls; and whether these associations are modified by age and race/ethnicity. METHODS: Children and adolescents ages 8 to 19 years (n=2,174) with asthma were recruited from the Genes-environments & Admixture in Latino Asthmatics (GALA II) Study and the Study of African Americans, Asthma, Genes, & Environments (SAGE II). Ordinal logistic regression was used to estimate odds ratios (OR) and their confidence intervals (95% CI) for worse asthma control. MEASUREMENTS AND MAIN RESULTS: In adjusted analyses, boys who were obese had a 33% greater chance of having worse asthma control than their normal weight counterparts (OR: 1.33; 1.04-1.71). However, for girls, this association varied with race/ethnicity (p-interaction=0.008). When compared to their normal weight counterparts, obese African American girls (OR:0.65; 95%CI:0.41-1.05) were more likely to have better controlled asthma while Mexican American girls had a 1.91 (95%CI:1.12-3.28) greater odds of worse asthma control. CONCLUSIONS: Worse asthma control is uniformly associated with increased BMI in boys. Among girls, the direction of this association varied with race/ethnicity.

Long-Term Inhibition of Xanthine Oxidase by Febuxostat Does Not Decrease Blood Pressure in Deoxycorticosterone Acetate (DOCA)-Salt Hypertensive Rats

Xanthine oxidase and its products, uric acid and ROS, have been implicated in the pathogenesis of cardiovascular disease, such as hypertension. We have previously reported that allopurinol inhibition of XO does not alter the progression of deoxycorticosterone acetate (DOCA)-salt hypertension in rats. However other researchers have observed a reduction in blood pressure after allopurinol treatment in the same model. To resolve this controversy, in this study we used the newer and more effective XO inhibitor febuxostat, and hypothesized that a more complete XO blockade might impair hypertension development and its end-organ consequences. We used DOCA-salt hypertensive rats and administered vehicle (salt water) or febuxostat (orally, 5 mg/kg/day in salt water) in a short-term "reversal" experiment (2 weeks of treatment 3 weeks after DOCA-salt beginning) and a long-term "prevention" experiment (treatment throughout 4 weeks of DOCA-salt). We confirmed XO inhibition by febuxostat by measuring circulating and tissue levels of XO metabolites. We found an overall increase in hypoxanthine (XO substrate) and decrease in uric acid (XO product) levels following febuxostat treatment. However, despite a trend for reduced blood pressure in the last week of long-term febuxostat treatment, no statistically significant difference in hemodynamic parameters was observed in either study. Additionally, no change was observed in relative heart and kidney weight. Aortic media/lumen ratio was minimally improved by long-term febuxostat treatment. Additionally, febuxostat incubation in vitro did not modify contraction of aorta or vena cava to norepinephrine, angiotensin II or endothelin-1. We conclude that XO inhibition is insufficient to attenuate hypertension in the rat DOCA-salt model, although beneficial vascular effects are possible.

Looking at the Label and Beyond: the Effects of Calorie Labels, Health Consciousness, and Demographics on Caloric Intake in Restaurants

ABSTRACT: BACKGROUND: Recent legislation has required calorie labels on restaurant menus as a means of improving Americans' health. Despite the growing research in this area, no consensus has been reached on the effectiveness of menu labels. This suggests the possibility of heterogeneity in responses to caloric labels across people with different attitudes and demographics. The purpose of this study was to explore the potential relationships between caloric intake and diners' socio-economic characteristics and attitudes in a restaurant field experiment that systematically varied the caloric information printed on the menus. METHODS: We conducted a field experiment in a full service restaurant where patrons were randomly assigned to one of three menu treatments which varied the amount of caloric information printed on the menus (none, numeric, or symbolic calorie label). At the conclusion of their meals, diners were asked to complete a brief survey regarding their socio-economic characteristics, attitudes, and meal selections. Using regression analysis, we estimated the number of entree and extra calories ordered by diners as a function of demographic and attitudinal variables. Additionally, irrespective of the menu treatment to which a subject was assigned, our study identified which types of people are likely to be low-, medium-, and high-calorie diners. RESULTS: Results showed that calorie labels have the greatest impact on those who are least health conscious. Additionally, using a symbolic calorie label can further reduce the caloric intake of even the most health conscious patrons. Finally, calorie labels were more likely to influence the selection of the main entree as opposed to supplemental items such as drinks and desserts. CONCLUSIONS: If numeric calorie labels are implemented (as currently proposed), they are most likely to influence consumers who are less health conscious -- probably one of the key targets of this legislation. Unfortunately, numeric labels did little for those consumers who were already more knowledgeable about health and nutrition. To reach a broader group of diners, a symbolic calorie label may be preferred as it reduced caloric intake across all levels of health consciousness.

An Examination of Successful Aging Among Southern Black and White Older Adults

Research on successful aging in minority older adults and those from certain regions of the United States, such as the South, is lacking. It is important to learn whether disparities exist in Southern Black older adults' perceptions of successful aging compared to those of majority older adults. Thus, this study examined successful aging using focus groups to obtain a regionally and racially sensitive understanding of the phenomenon. Focus group sessions were facilitated with Southern Black and White older adults with questions on successful aging, using content analysis to interpret the findings. Four central themes were found: Connecting and Relating; Temporality; Perception and Interpretation; and Activity. Beliefs and decisions about managing oneself through life events, including health problems and disability, may have a major influence on the trajectory of progressive, chronic illness, and consequently, successful aging.

Virus-Specific CD4(+) Memory-Phenotype T Cells Are Abundant in Unexposed Adults

Although T cell memory is generally thought to require direct antigen exposure, we found an abundance of memory-phenotype cells (20%-90%, averaging over 50%) of CD4(+) T cells specific to viral antigens in adults who had never been infected. These cells express the appropriate memory markers and genes, rapidly produce cytokines, and have clonally expanded. In contrast, the same T cell receptor (TCR) specificities in newborns are almost entirely naïve, which might explain the vulnerability of young children to infections. One mechanism for this phenomenon is TCR cross-reactivity to environmental antigens, and in support of this, we found extensive cross-recognition by HIV-1 and influenza-reactive T lymphocytes to other microbial peptides and expansion of one of these after influenza vaccination. Thus, the presence of these memory-phenotype T cells has significant implications for immunity to novel pathogens, child and adult health, and the influence of pathogen-rich versus hygienic environments.

Transcriptional Insights into the CD8(+) T Cell Response to Infection and Memory T Cell Formation

After infection, many factors coordinate the population expansion and differentiation of CD8(+) effector and memory T cells. Using data of unparalleled breadth from the Immunological Genome Project, we analyzed the CD8(+) T cell transcriptome throughout infection to establish gene-expression signatures and identify putative transcriptional regulators. Notably, we found that the expression of key gene signatures can be used to predict the memory-precursor potential of CD8(+) effector cells. Long-lived memory CD8(+) cells ultimately expressed a small subset of genes shared by natural killer T and γδ T cells. Although distinct inflammatory milieu and T cell precursor frequencies influenced the differentiation of CD8(+) effector and memory populations, core transcriptional signatures were regulated similarly, whether polyclonal or transgenic, and whether responding to bacterial or viral model pathogens. Our results provide insights into the transcriptional regulation that influence memory formation and CD8(+) T cell immunity.

Noncanonical EF-hand Motif Strategically Delays Ca(2+) Buffering to Enhance Cardiac Performance

EF-hand proteins are ubiquitous in cell signaling. Parvalbumin (Parv), the archetypal EF-hand protein, is a high-affinity Ca(2+) buffer in many biological systems. Given the centrality of Ca(2+) signaling in health and disease, EF-hand motifs designed to have new biological activities may have widespread utility. Here, an EF-hand motif substitution that had been presumed to destroy EF-hand function, that of glutamine for glutamate at position 12 of the second cation binding loop domain of Parv (ParvE101Q), markedly inverted relative cation affinities: Mg(2+) affinity increased, whereas Ca(2+) affinity decreased, forming a new ultra-delayed Ca(2+) buffer with favorable properties for promoting cardiac relaxation. In therapeutic testing, expression of ParvE101Q fully reversed the severe myocyte intrinsic contractile defect inherent to expression of native Parv and corrected abnormal myocardial relaxation in diastolic dysfunction disease models in vitro and in vivo. Strategic design of new EF-hand motif domains to modulate intracellular Ca(2+) signaling could benefit many biological systems with abnormal Ca(2+) handling, including the diseased heart.

Study of PcaV from Streptomyces Coelicolor Yields New Insights into Ligand-responsive MarR Family Transcription Factors

MarR family proteins constitute a group of >12 000 transcriptional regulators encoded in bacterial and archaeal genomes that control gene expression in metabolism, stress responses, virulence and multi-drug resistance. There is much interest in defining the molecular mechanism by which ligand binding attenuates the DNA-binding activities of these proteins. Here, we describe how PcaV, a MarR family regulator in Streptomyces coelicolor, controls transcription of genes encoding β-ketoadipate pathway enzymes through its interaction with the pathway substrate, protocatechuate. This transcriptional repressor is the only MarR protein known to regulate this essential pathway for aromatic catabolism. In in vitro assays, protocatechuate and other phenolic compounds disrupt the PcaV-DNA complex. We show that PcaV binds protocatechuate in a 1:1 stoichiometry with the highest affinity of any MarR family member. Moreover, we report structures of PcaV in its apo form and in complex with protocatechuate. We identify an arginine residue that is critical for ligand coordination and demonstrate that it is also required for binding DNA. We propose that interaction of ligand with this arginine residue dictates conformational changes that modulate DNA binding. Our results provide new insights into the molecular mechanism by which ligands attenuate DNA binding in this large family of transcription factors.

Both Young and Older Adults Discount Suggestions from Older Adults on a Social Memory Test

In the present study, we examined the impacts of participant age and confederate age on social memory processes. During a collaborative recall phase, young and older adult participants were exposed to the erroneous memory reports of a young or an older adult confederate. On a subsequent individual recall test, young and older adult participants were equally likely to incorporate the confederates' erroneous suggestions into their memory reports, suggesting that participant age had a minimal effect on social memory processes. However, confederate age did have a marked effect: Young adult participants were less likely to incorporate misleading suggestions from older adult confederates and less likely to report "remembering" items suggested by older adult confederates. Critically, older adult participants were also less likely to incorporate misleading information from fellow older adult confederates. Both young and older adult participants discounted older adult confederates' contributions to a memory test.

First-in-human Phase 1/2a Trial of CRLX101, a Cyclodextrin-containing Polymer-camptothecin Nanopharmaceutical in Patients with Advanced Solid Tumor Malignancies

Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m(2) and later bi-weekly at 12, 15, and 18 mg/m(2). The maximum tolerated dose (MTD) was determined at 15 mg/m(2) bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n = 44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT T(max) values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.

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