A Health Promotion Curriculum for Adolescent Young Citizens: Deliberation and Public Action for HIV/AIDS-competent Communities

The American Journal of Orthopsychiatry. Oct, 2011  |  Pubmed ID: 21977929

Characterization of the Cellular and Antitumor Effects of MPI-0479605, a Small-molecule Inhibitor of the Mitotic Kinase Mps1

Molecular Cancer Therapeutics. Dec, 2011  |  Pubmed ID: 21980130

Mps1 is a dual specificity protein kinase that is essential for the bipolar attachment of chromosomes to the mitotic spindle and for maintaining the spindle assembly checkpoint until all chromosomes are properly attached. Mps1 is expressed at high levels during mitosis and is abundantly expressed in cancer cells. Disruption of Mps1 function induces aneuploidy and cell death. We report the identification of MPI-0479605, a potent and selective ATP competitive inhibitor of Mps1. Cells treated with MPI-0479605 undergo aberrant mitosis, resulting in aneuploidy and formation of micronuclei. In cells with wild-type p53, this promotes the induction of a postmitotic checkpoint characterized by the ATM- and RAD3-related-dependent activation of the p53-p21 pathway. In both wild-type and p53 mutant cells lines, there is a growth arrest and inhibition of DNA synthesis. Subsequently, cells undergo mitotic catastrophe and/or an apoptotic response. In xenograft models, MPI-0479605 inhibits tumor growth, suggesting that drugs targeting Mps1 may have utility as novel cancer therapeutics.

MiMIC: a Highly Versatile Transposon Insertion Resource for Engineering Drosophila Melanogaster Genes

Nature Methods. Sep, 2011  |  Pubmed ID: 21985007

We demonstrate the versatility of a collection of insertions of the transposon Minos-mediated integration cassette (MiMIC), in Drosophila melanogaster. MiMIC contains a gene-trap cassette and the yellow+ marker flanked by two inverted bacteriophage ΦC31 integrase attP sites. MiMIC integrates almost at random in the genome to create sites for DNAmanipulation. The attP sites allow the replacement of the intervening sequence of the transposon with any other sequence through recombinase-mediated cassette exchange (RMCE). We can revert insertions that function as gene traps and cause mutant phenotypes to revert to wild type by RMCE and modify insertions to control GAL4 or QF overexpression systems or perform lineage analysis using the Flp recombinase system. Insertions in coding introns can be exchanged with protein-tag cassettes to create fusion proteins to follow protein expression and perform biochemical experiments. The applications of MiMIC vastly extend the D. melanogaster toolkit.

Heterobilharzia Americana Infection As a Cause of Hepatic Parasitic Granulomas in a Horse

Journal of the American Veterinary Medical Association. Oct, 2011  |  Pubmed ID: 21985355

CASE DESCRIPTION-A 22-year-old American Paint Horse gelding from the Gulf Coast region of Texas was evaluated for regrowth of a perirectal squamous cell carcinoma that had been surgically removed 11 months previously. CLINICAL FINDINGS-A necrotic and ulcerated mass was present below the anus. The horse had paraphimosis and was having difficulty with urination. Histologic examination of the mass revealed that it was squamous cell carcinoma, and the horse was euthanized because of the unlikelihood that the mass could be adequately resected and its close proximity to the urethra. OUTCOME-At necropsy, in addition to the squamous cell carcinoma, hundreds of round, white to pale yellow nodules were disseminated throughout the liver, resulting in a so-called starry-sky appearance. Similar granulomas were seen in the right caudal lung lobe and small intestinal serosa. A single granuloma in the liver, which differed from the others by its larger size, contained a pair of adult schistosomes. Several hepatic granuloma specimens were used for PCR amplification and sequencing. Use of primers specific for a portion of the Heterobilharzia americana small subunit rRNA gene resulted in amplification of a 487-base pair product that had 100% sequence identity with H americana. CLINICAL RELEVANCE-Severe cases of disseminated granulomas in the liver of horses may result in a liver with a grossly abnormal starry-sky pattern. To our knowledge, this is the first report documenting the association of granulomas with H americana infection along with adult schistosomes in the liver of a horse.

A Live-attenuated Chlamydial Vaccine Protects Against Trachoma in Nonhuman Primates

The Journal of Experimental Medicine. Oct, 2011  |  Pubmed ID: 21987657

Blinding trachoma is an ancient neglected tropical disease caused by Chlamydia trachomatis for which a vaccine is needed. We describe a live-attenuated vaccine that is safe and efficacious in preventing trachoma in nonhuman primates, a model with excellent predictive value for humans. Cynomolgus macaques infected ocularly with a trachoma strain deficient for the 7.5-kb conserved plasmid presented with short-lived infections that resolved spontaneously without ocular pathology. Multiple infections with the attenuated plasmid-deficient strain produced no inflammatory ocular pathology but induced an anti-chlamydial immune response. Macaques vaccinated with the attenuated strain were either solidly or partially protected after challenge with virulent plasmid-bearing organisms. Partially protected macaques shed markedly less infectious organisms than controls. Immune correlates of protective immunity were not identified, but we did detect a correlation between MHC class II alleles and solid versus partial protection. Epidemiological models of trachoma control indicate that a vaccine with this degree of efficacy would significantly reduce the prevalence of infection and rates of reinfection, known risk factors which drive blinding disease.

Oral Maxillary Squamous Carcinoma: an Indication for Neck Dissection in the Clinically Negative Neck

Head & Neck. Nov, 2011  |  Pubmed ID: 21990223

This multicenter study was undertaken to characterize the metastatic behavior of oral maxillary squamous carcinoma and to determine the role of selective neck dissection.

Broadening Bipolar Disorder ˆ� by Design or by Accident?

World Psychiatry : Official Journal of the World Psychiatric Association (WPA). Oct, 2011  |  Pubmed ID: 21991275

Pediatric Hospital Medicine: A Strategic Planning Roundtable to Chart the Future

Journal of Hospital Medicine : an Official Publication of the Society of Hospital Medicine. Oct, 2011  |  Pubmed ID: 21994159

Given the growing field of Pediatric Hospital Medicine (PHM) and the need to define strategic direction, the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association sponsored a roundtable to discuss the future of the field. Twenty-one leaders were invited plus a facilitator utilizing established health care strategic planning methods. A "vision statement" was developed. Specific initiatives in 4 domains (clinical practice, quality of care, research, and workforce) were identified that would advance PHM with a plan to complete each initiative. Review of the current issues demonstrated gaps between the current state of affairs and the full vision of the potential impact of PHM. Clinical initiatives were to develop an educational plan supporting the PHM Core Competencies and a clinical practice monitoring dashboard template. Quality initiatives included an environmental assessment of PHM participation on key committees, societies, and agencies to ensure appropriate PHM representation. Three QI collaboratives are underway. A Research Leadership Task Force was created and the Pediatric Research in Inpatient Settings (PRIS) network was refocused, defining a strategic framework for PRIS, and developing a funding strategy. Workforce initiatives were to develop a descriptive statement that can be used by any PHM physician, a communications tool describing "value added" of PHM; and a tool to assess career satisfaction among PHM physicians. We believe the Roundtable was successful in describing the current state of PHM and laying a course for the near future. Journal of Hospital Medicine 2011. © 2011 Society of Hospital Medicine.

A Diversity of Synaptic Filters Are Created by Temporal Summation of Excitation and Inhibition

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Oct, 2011  |  Pubmed ID: 21994388

Temporal filtering is a fundamental operation of nervous systems. In peripheral sensory systems, the temporal pattern of spiking activity can encode various stimulus qualities, and temporal filtering allows postsynaptic neurons to detect behaviorally relevant stimulus features from these spike trains. Intrinsic excitability, short-term synaptic plasticity, and voltage-dependent dendritic conductances have all been identified as mechanisms that can establish temporal filtering behavior in single neurons. Here we show that synaptic integration of temporally summating excitation and inhibition can establish diverse temporal filters of presynaptic input. Mormyrid electric fish communicate by varying the intervals between electric organ discharges. The timing of each discharge is coded by peripheral receptors into precisely timed spikes. Within the midbrain posterior exterolateral nucleus, temporal filtering by individual neurons results in selective responses to a particular range of presynaptic interspike intervals. These neurons are diverse in their temporal filtering properties, reflecting the wide range of intervals that must be detected during natural communication behavior. By manipulating presynaptic spike timing with high temporal resolution, we demonstrate that tuning to behaviorally relevant patterns of presynaptic input is similar in vivo and in vitro. We reveal that GABAergic inhibition plays a critical role in establishing different temporal filtering properties. Further, our results demonstrate that temporal summation of excitation and inhibition establishes selective responses to high and low rates of synaptic input, respectively. Simple models of synaptic integration reveal that variation in these two competing influences provides a basic mechanism for generating diverse temporal filters of synaptic input.

Paying for Best Practices. Program Links Providers, Mayo Clinic Resources

Modern Healthcare. Sep, 2011  |  Pubmed ID: 21995136

Bumpy Road for Equal Visitation. HIPAA, State Rules May Be Problem for Gay Couples

Modern Healthcare. Sep, 2011  |  Pubmed ID: 21995202

CSPG4, a Potential Therapeutic Target, Facilitates Malignant Progression of Melanoma

Pigment Cell & Melanoma Research. Dec, 2011  |  Pubmed ID: 22004131

Chondroitin sulfate proteoglycan 4 (CSPG4), a transmembrane proteoglycan originally identified as a highly immunogenic tumor antigen on the surface of melanoma cells, is associated with melanoma tumor formation and poor prognosis in certain melanomas and several other tumor types. The complex mechanisms by which CSPG4 affects melanoma progression have started to be defined, in particular the association with other cell surface proteins and receptor tyrosine kinases (RTKs) and its central role in modulating the function of these proteins. CSPG4 is essential to the growth of melanoma tumors through its modulation of integrin function and enhanced growth factor receptor-regulated pathways including sustained activation of ERK 1,2. This activation of integrin, RTK, and ERK1,2 function by CSPG4 modulates numerous aspects of tumor progression. CSPG4 expression has further been correlated to resistance of melanoma to conventional chemotherapeutics. This review outlines recent advances in our understanding of CSPG4-associated cell signaling, describing the central role it plays in melanoma tumor cell growth, motility, and survival, and explores how modifying CSPG4 function and protein-protein interactions may provide us with novel combinatorial therapies for the treatment of advanced melanoma.

Defining the Genetic Architecture Underlying Female- and Male-mediated Nonrandom Mating and Seed Yield Traits in Arabidopsis

Plant Physiology. Dec, 2011  |  Pubmed ID: 22007025

Postpollination nonrandom mating among compatible mates is a widespread phenomenon in plants and is genetically undefined. In this study, we used the recombinant inbred line (RIL) population between Landsberg erecta and Columbia (Col) accessions of Arabidopsis (Arabidopsis thaliana) to define the genetic architecture underlying both female- and male-mediated nonrandom mating traits. To map the genetic loci responsible for male-mediated nonrandom mating, we performed mixed pollinations with Col and RIL pollen on Col pistils. To map the genetic loci responsible for female-mediated nonrandom mating, we performed mixed pollinations with Col and Landsberg erecta pollen on RIL pistils. With these data, we performed composite interval mapping to identify two quantitative trait loci (QTLs) that control male-mediated nonrandom mating. We detected epistatic interactions between these two loci. We also explored female- and male-mediated traits involved in seed yield in mixed pollinations. We detected three female QTLs and one male QTL involved in directing seed number per fruit. To our knowledge, the results of these experiments represent the first time the female and male components of seed yield and nonrandom mating have been separately mapped.

Cell-free Protein Synthesis: Applications Come of Age

Biotechnology Advances. Oct, 2011  |  Pubmed ID: 22008973

Cell-free protein synthesis has emerged as a powerful technology platform to help satisfy the growing demand for simple and efficient protein production. While used for decades as a foundational research tool for understanding transcription and translation, recent advances have made possible cost-effective microscale to manufacturing scale synthesis of complex proteins. Protein yields exceed grams protein produced per liter reaction volume, batch reactions last for multiple hours, costs have been reduced orders of magnitude, and reaction scale has reached the 100-liter milestone. These advances have inspired new applications in the synthesis of protein libraries for functional genomics and structural biology, the production of personalized medicines, and the expression of virus-like particles, among others. In the coming years, cell-free protein synthesis promises new industrial processes where short protein production timelines are crucial as well as innovative approaches to a wide range of applications.

A Fast Slam Approach to Freehand 3-d Ultrasound Reconstruction for Catheter Ablation Guidance in the Left Atrium

Ultrasound in Medicine & Biology. Dec, 2011  |  Pubmed ID: 22014856

We present a method for real-time, freehand 3D ultrasound (3D-US) reconstruction of moving anatomy, with specific application towards guiding the catheter ablation procedure in the left atrium. Using an intracardiac echo (ICE) catheter with a pose (position/orientation) sensor mounted to its tip, we continually mosaic 2D-ICE images of a left atrium phantom model to form a 3D-US volume. Our mosaicing strategy employs a probabilistic framework based on simultaneous localization and mapping (SLAM), a technique commonly used in mobile robotics for creating maps of unexplored environments. The measured ICE catheter tip pose provides an initial estimate for compounding 2D-ICE image data into the 3D-US volume. However, we simultaneously consider the overlap-consistency shared between 2D-ICE images and the 3D-US volume, computing a "corrected" tip pose if need be to ensure spatially-consistent reconstruction. This allows us to compensate for anatomic movement and sensor drift that would otherwise cause motion artifacts in the 3D-US volume. Our approach incorporates 2D-ICE data immediately after acquisition, allowing us to continuously update the registration parameters linking sensor coordinates to 3D-US coordinates. This, in turn, enables real-time localization and display of sensorized therapeutic catheters within the 3D-US volume for facilitating procedural guidance.

Resolution of Untoward Nonauditory Stimulation and Cochlear Implant Performance Gain After Extraction of a Stainless Steel Dental Crown in a Patient with Cochlear Otosclerosis

Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. Dec, 2011  |  Pubmed ID: 22015943

To report a unique case of untoward nonauditory stimulation and cochlear implant performance deterioration after the placement of a stainless steel dental crown.

Large-scale Discovery of ERK2 Substrates Identifies ERK-mediated Transcriptional Regulation by ETV3

Science Signaling. 2011  |  Pubmed ID: 22028470

The mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 2 (ERK2) is ubiquitously expressed in mammalian tissues and is involved in a wide range of biological processes. Although MAPKs have been intensely studied, identification of their substrates remains challenging. We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. The 80 substrates are associated with diverse cellular processes, including regulation of transcription and translation, mRNA processing, and regulation of the activity of the Rho family guanosine triphosphatases. We found that one of the newly identified substrates, ETV3 (a member of the E twenty-six family of transcriptional regulators), was extensively phosphorylated on sites within canonical and noncanonical ERK motifs. Phosphorylation of ETV3 regulated transcription by preventing its binding to DNA at promoters for several thousand genes, including some involved in negative feedback regulation of itself and of upstream signals.

Individual Differences in Verbal Abilities Associated with Regional Blurring of the Left Gray and White Matter Boundary

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Oct, 2011  |  Pubmed ID: 22031871

Blurring of the cortical gray and white matter border on MRI is associated with normal aging, pathological aging, and the presence of focal cortical dysplasia. However, it remains unclear whether normal variations in signal intensity contrast at the gray and white matter junction reflect the functional integrity of subjacent tissue. This study explores the relationship between verbal abilities and gray and white matter contrast (GWC) in healthy human adults. Participants were scanned at 3 T MRI and administered standardized measures of verbal expression and verbal working memory. GWC was estimated by calculating the non-normalized T1 image intensity contrast above and below the cortical gray/white matter interface. Spherical averaging and whole-brain correlational analyses were performed. Sulcal regions exhibited higher contrast compared to gyral regions. We found a strongly lateralized and regionally specific profile with reduced verbal expression abilities associated with blurring in left hemisphere inferior frontal cortex and temporal pole. Reduced verbal working memory was associated with blurring in widespread left frontal and temporal cortices. Such lateralized and focal results provide support for GWC as a measure of regional functional integrity and highlight its potential role in probing the neuroanatomical substrates of cognition in healthy and diseased populations.

Molecular and Cellular Organization of the Taste System in the Drosophila Larva

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Oct, 2011  |  Pubmed ID: 22031876

We examine the molecular and cellular basis of taste perception in the Drosophila larva through a comprehensive analysis of the expression patterns of all 68 Gustatory receptors (Grs). Gr-GAL4 lines representing each Gr are examined, and 39 show expression in taste organs of the larval head, including the terminal organ (TO), the dorsal organ (DO), and the pharyngeal organs. A receptor-to-neuron map is constructed. The map defines 10 neurons of the TO and DO, and it identifies 28 receptors that map to them. Each of these neurons expresses a unique subset of Gr-GAL4 drivers, except for two neurons that express the same complement. All of these neurons express at least two drivers, and one neuron expresses 17. Many of the receptors map to only one of these cells, but some map to as many as six. Conspicuously absent from the roster of Gr-GAL4 drivers expressed in larvae are those of the sugar receptor subfamily. Coexpression analysis suggests that most larval Grs act in bitter response and that there are distinct bitter-sensing neurons. A comprehensive analysis of central projections confirms that sensory information collected from different regions (e.g., the tip of the head vs the pharynx) is processed in different regions of the suboesophageal ganglion, the primary taste center of the CNS. Together, the results provide an extensive view of the molecular and cellular organization of the larval taste system.

The Surface Composition and Temperature of Asteroid 21 Lutetia As Observed by Rosetta/VIRTIS

Science (New York, N.Y.). Oct, 2011  |  Pubmed ID: 22034430

The Visible, InfraRed, and Thermal Imaging Spectrometer (VIRTIS) on Rosetta obtained hyperspectral images, spectral reflectance maps, and temperature maps of the asteroid 21 Lutetia. No absorption features, of either silicates or hydrated minerals, have been detected across the observed area in the spectral range from 0.4 to 3.5 micrometers. The surface temperature reaches a maximum value of 245 kelvin and correlates well with topographic features. The thermal inertia is in the range from 20 to 30 joules meter(-2) kelvin(-1) second(-0.5), comparable to a lunarlike powdery regolith. Spectral signatures of surface alteration, resulting from space weathering, seem to be missing. Lutetia is likely a remnant of the primordial planetesimal population, unaltered by differentiation processes and composed of chondritic materials of enstatitic or carbonaceous origin, dominated by iron-poor minerals that have not suffered aqueous alteration.

Searching for the Sequential Line-up Advantage: a Distinctiveness Explanation

Memory (Hove, England). Nov, 2011  |  Pubmed ID: 22035407

Gronlund ( 2005 ) proposed that one factor leading to a sequential line-up advantage could be the greater likelihood of recollecting distinctive information about a perpetrator when using a sequential line-up. Since then questions have been raised about the robustness of the sequential advantage and the possible moderating role of line-up fairness and suspect position. We manipulated these factors as well as suspect/target distinctiveness in two experiments. A sequential advantage occurred only after encoding a distinctive target, both for biased line-ups (Experiment 1) and fair line-ups (Experiment 2). Remember-Know results were consistent with the greater use of a recall-to-reject strategy in target-absent sequential line-ups. This provided support for the first process-based explanation of the sequential line-up advantage. No consistent position effects were found, but this might be due to the line-up recognition paradigm used, in which each participant viewed a line-up for each of several targets. Theory-based explorations of eyewitness identification are necessary to continue to delineate the underpinnings of the sequential line-up advantage.

Illicit Use of Buprenorphine in a Community Sample of Young Adult Non-medical Users of Pharmaceutical Opioids

Drug and Alcohol Dependence. Oct, 2011  |  Pubmed ID: 22036303

BACKGROUND: There is growing evidence about illicit use of buprenorphine in the U.S. The study aims to: (1) identify prevalence and predictors of illicit buprenorphine use in a community sample of 396 young adult (18-23 years old) non-medical users of pharmaceutical opioids and (2) describe knowledge, attitudes and behaviors linked to illicit buprenorphine use as reported by a qualitative sub-sample (n=51). METHODS: Participants were recruited using respondent-driven sampling. Qualitative interview participants were selected from the larger sample. The sample (n=396) was 54% male and 50% white; 7.8% reported lifetime illicit use of buprenorphine. RESULTS: Logistic regression analysis results indicate that white ethnicity, intranasal inhalation of pharmaceutical opioids, symptoms of opioid dependence, and a greater number of pharmaceutical opioids used in lifetime were statistically significant predictors of illicit buprenorphine use. Qualitative interviews revealed that buprenorphine was more commonly used by more experienced users who were introduced to it by their "junkie friends." Those who used buprenorphine to self-medicate withdrawal referred to it as a "miracle pill." When used to get high, reported experiences ranged from "the best high ever" to "puking for days." Participants reported using buprenorphine/naloxone orally or by intranasal inhalation. Injection of buprenorphine without naloxone was also reported. CONCLUSION: Our findings suggest that illicit buprenorphine use is gaining ground primarily among whites and those who are more advanced in their drug use careers. Continued monitoring is needed to better understand evolving patterns and trends of illicit buprenorphine use.

A Protein Complex Network of Drosophila Melanogaster

Cell. Oct, 2011  |  Pubmed ID: 22036573

Determining the composition of protein complexes is an essential step toward understanding the cell as an integrated system. Using coaffinity purification coupled to mass spectrometry analysis, we examined protein associations involving nearly 5,000 individual, FLAG-HA epitope-tagged Drosophila proteins. Stringent analysis of these data, based on a statistical framework designed to define individual protein-protein interactions, led to the generation of a Drosophila protein interaction map (DPiM) encompassing 556 protein complexes. The high quality of the DPiM and its usefulness as a paradigm for metazoan proteomes are apparent from the recovery of many known complexes, significant enrichment for shared functional attributes, and validation in human cells. The DPiM defines potential novel members for several important protein complexes and assigns functional links to 586 protein-coding genes lacking previous experimental annotation. The DPiM represents, to our knowledge, the largest metazoan protein complex map and provides a valuable resource for analysis of protein complex evolution.

Genetic Variants Associated with the White Blood Cell Count in 13,923 Subjects in the EMERGE Network

Human Genetics. Oct, 2011  |  Pubmed ID: 22037903

White blood cell count (WBC) is unique among identified inflammatory predictors of chronic disease in that it is routinely measured in asymptomatic patients in the course of routine patient care. We led a genome-wide association analysis to identify variants associated with WBC levels in 13,923 subjects in the electronic Medical Records and Genomics (eMERGE) Network. We identified two regions of interest that were each unique to subjects of genetically determined ancestry to the African continent (AA) or to the European continent (EA). WBC varies among different ancestry groups. Despite being ancestry specific, these regions were identifiable in the combined analysis. In AA subjects, the region surrounding the Duffy antigen/chemokine receptor gene (DARC) on 1q21 exhibited significant association (p value = 6.71e-55). These results validate the previously reported association between WBC and of the regulatory variant rs2814778 in the promoter region, which causes the Duffy negative phenotype (Fy-/-). A second missense variant (rs12075) is responsible for the two principal antigens, Fya and Fyb of the Duffy blood group system. The two variants, consisting of four alleles, act in concert to produce five antigens and subsequent phenotypes. We were able to identify the marginal and novel interaction effects of these two variants on WBC. In the EA subjects, we identified significantly associated SNPs tagging three separate genes in the 17q21 region: (1) GSDMA, (2) MED24, and (3) PSMD3. Variants in this region have been reported to be associated with WBC, neutrophil count, and inflammatory diseases including asthma and Crohn's disease.

Two Opinions About One Child--what's the Clinician to Do?

Journal of Child and Adolescent Psychopharmacology. Oct, 2011  |  Pubmed ID: 22040183

Diagnostic Implications of Informant Disagreement for Manic Symptoms

Journal of Child and Adolescent Psychopharmacology. Oct, 2011  |  Pubmed ID: 22040185

This study examines diagnoses that occur in an outpatient sample when both parent and teacher endorse significant manic symptoms and when only a parent observes them. We hypothesized that the diagnosis of mania/bipolar (BP) disorder would occur when there is parent/teacher concordance on high mania symptom scores.

Post-traumatic Stress Disorder and Health Risk Behaviors Among Afghanistan and Iraq War Veterans Attending College

American Journal of Health Behavior. Jul, 2011  |  Pubmed ID: 22040585

To determine if post-traumatic stress disorder (PTSD) is associated with health risk behaviors among Operations Enduring and Iraqi Freedom (OEF/OIF) veterans attending college.

Introduction: a Life Course Perspective on Activity and Neurocognitive Health

Journal of the International Neuropsychological Society : JINS. Nov, 2011  |  Pubmed ID: 22040895

Development of a Pediatric Hospitalist Sedation Service: Training and Implementation

Journal of Hospital Medicine : an Official Publication of the Society of Hospital Medicine. Oct, 2011  |  Pubmed ID: 22042550

OBJECTIVE: There is growing demand for safe and effective procedural sedation in pediatric facilities nationally. Currently, these needs are being met by a variety of providers and sedation techniques, including anesthesiologists, pediatric intensivists, emergency medicine physicians, and pediatric hospitalists. There is currently no consensus regarding the training required by non-anesthesiologists to provide safe sedation. We will outline the training method developed at St. Louis Children's Hospital. METHODS: In 2003, the Division of Pediatric Anesthesia at St. Louis Children's Hospital approached the Division of Pediatric Hospitalist Medicine as a resource to provide pediatric sedation outside of the operating room. Over the last seven years, Pediatric Hospitalist Sedation services have evolved into a three-tiered system of sedation providers. The first tier provides sedation services in the emergency unit (EU) and the Center for After Hours Referral for Emergency Services (CARES). The second tier provides sedation throughout the hospital including the EU, CARES, inpatient units, Ambulatory Procedure Center (APC), and Pediatric Acute Wound Service (PAWS); it also provides night/weekend sedation call for urgent needs. The third tier provides sedation in all of the second-tier locations, as well as utilizing propofol in the APC. RESULTS: This training program has resulted in a successful pediatric hospitalist sedation service. Based on fiscal year 2009 billing data, the division performed 2,471 sedations. We currently have 43 hospitalists providing Tier-One sedation, 18 Tier-Two providers, and six Tier-Three providers. CONCLUSIONS: A pediatric hospitalist sedation service with proper training and oversight can successfully augment sedation provided by anesthesiologists. Journal of Hospital Medicine 2011;. © 2011 Society of Hospital Medicine.

Use of Amino-terminal Pro-B-type Natriuretic Peptide to Guide Outpatient Therapy of Patients with Chronic Left Ventricular Systolic Dysfunction

Journal of the American College of Cardiology. Oct, 2011  |  Pubmed ID: 22018299

The aim of this study was to evaluate whether chronic heart failure (HF) therapy guided by concentrations of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is superior to standard of care (SOC) management.

The Clinical Diagnostic Accuracy of Rapid Detection of Healthcare-associated Bloodstream Infection in Intensive Care Using Multipathogen Real-time PCR Technology

BMJ Open. Jan, 2011  |  Pubmed ID: 22021785

Background There is growing interest in the potential utility of real-time PCR in diagnosing bloodstream infection by detecting pathogen DNA in blood samples within a few hours. SeptiFast is a multipathogen probe-based real-time PCR system targeting ribosomal DNA sequences of bacteria and fungi. It detects and identifies the commonest pathogens causing bloodstream infection and has European regulatory approval. The SeptiFast pathogen panel is suited to identifying healthcare-associated bloodstream infection acquired during complex healthcare, and the authors report here the protocol for the first detailed health-technology assessment of multiplex real-time PCR in this setting. Methods/design A Phase III multicentre double-blinded diagnostic study will determine the clinical validity of SeptiFast for the rapid detection of healthcare-associated bloodstream infection, against the current service standard of microbiological culture, in an adequately sized population of critically ill adult patients. Results from SeptiFast and standard microbiological culture procedures in each patient will be compared at study conclusion and the metrics of clinical diagnostic accuracy of SeptiFast determined in this population setting. In addition, this study aims to assess further the preliminary evidence that the detection of pathogen DNA in the bloodstream using SeptiFast may have value in identifying the presence of infection elsewhere in the body. Furthermore, differences in circulating immune-inflammatory markers in patient groups differentiated by the presence/absence of culturable pathogens and pathogen DNA will help elucidate further the patho-physiology of infection developing in the critically ill. Ethics and dissemination Ethical approval has been granted by the North West 6 Research Ethics Committee (09/H1003/109). Based on the results of this first non-commercial study, independent recommendations will be made to The Department of Health (open-access health technology assessment report) as to whether SeptiFast has sufficient clinical diagnostic accuracy to move forward to efficacy testing during the provision of routine clinical care.

Investigation of the Metabolism of Rufinamide and Its Interaction With Valproate

Drug Metabolism Letters. Oct, 2011  |  Pubmed ID: 22022867

Rufinamide was evaluated in vitro to determine which enzyme(s) are responsible for rufinamide hydrolysis and whether valproate, one of its metabolites (valproyl-CoA), and/or the rufinamide hydrolysis product (CGP 47292) could inhibit hydrolysis. Rufinamide hydrolysis was mediated primarily by human carboxylesterase (hCE) 1 and was non-saturable up to 500 µM. Two-thirds of rufinamide hydrolysis was estimated to occur in human microsomes and one-third in cytosol. Valproate was a selective inhibitor for hCE1 compared to hCE2 and inhibition had a greater impact on rufinamide hydrolysis in microsomes than in cytosol. Valproyl-CoA caused similar inhibition of rufinamide hydrolysis in both microsomes and cytosol. Carboxylesterases were not significantly inhibited by CGP 47292. Inhibition of in vitro rufinamide hydrolysis by valproate could offer an explanation for the observed in vivo drug-drug interaction between the two antiepileptic drugs.

Elevated Infant Mortality Rates Among Oral Cleft and Isolated Oral Cleft Cases: A Meta-analysis of Studies from 1943-2010

The Cleft Palate-craniofacial Journal : Official Publication of the American Cleft Palate-Craniofacial Association. Oct, 2011  |  Pubmed ID: 22023166

Abstract Objective: To review available published literature in order to obtain a more comprehensive assessment of the association between infant mortality and oral clefts, overall and isolated. Design: A wide-ranging search of published studies relating infant mortality rates to oral clefts and congenital malformations was conducted yielding applicable data sets. Settings of the included studies varied to a limited extent, although all were conducted within high income countries with superior health indicators. These results were tabulated and meta-analyzed. Random effects odds ratios comparing each data set to their respective population have been utilized to account for differing settings and specific infant mortality rates. Results: Nine articles with relatable data were included in these meta-analyses. The calculated odds ratio of infant mortality associated with oral cleft cases, including those with associated malformations, was substantial, 9.466 [95% confidence interval 6.153 - 14.560]. Excluding oral cleft cases with associated malformations, the odds ratio, although lower, was still significant, 2.073 [1.390 - 3.092]. Conclusions: Compared with the overall population, infants with oral clefts have nine times the odds of dying within the first year of life. Furthermore, even without additional malformations, infants with oral clefts are still twice as likely to die before one year of age. Current research points to a substantially higher relative risk of infant mortality among oral cleft cases in developing countries. Additional research is essential to determine the sources of these raised infant mortality rates and possible interventions to decrease them. Key words: oral cleft, infant mortality, cleft lip, malformation.

Dietary Fiber and Nutrient Density Are Inversely Associated with the Metabolic Syndrome in US Adolescents

Journal of the American Dietetic Association. Nov, 2011  |  Pubmed ID: 22027051

There is no consensus as to whether low dietary intakes of saturated fat or cholesterol, or high intakes of dietary fiber are related to a lower prevalence of metabolic syndrome (MetS) in adolescent children.

Predictors of Computer Use in Community-dwelling, Ethnically Diverse Older Adults

Human Factors. Oct, 2011  |  Pubmed ID: 22046718

In this study, we analyzed self-reported computer use, demographic variables, psychosocial variables, and health and well-being variables collected from 460 ethnically diverse, community-dwelling elders to investigate the relationship computer use has with demographics, well-being, and other key psychosocial variables in older adults.

Security Lapses. Critics Urge Execs to Take Safety Issues More Seriously

Modern Healthcare. Oct, 2011  |  Pubmed ID: 22049777

Violence in hospitals remains high a year after the Joint Commission's Sentinel Event Alert for it, but experts say CEOs can reduce violence by encouraging staff to report incidents and planning for when the unthinkable strikes. "I think we'd all be better served to give a little more forethought to what you would do if that kind of event takes place," says David Banks, left, of Forida Hospital.

Veiled Disclosures. Providers Eager to Know Extent of CMS' Leniency for Stark Law Violators

Modern Healthcare. Sep, 2011  |  Pubmed ID: 22049842

Path Set for ACA? Proponents, Foes of Law Appeal to Supreme Court

Modern Healthcare. Oct, 2011  |  Pubmed ID: 22049853

Accuracy of Blood Pressure Measurements Reported in an Electronic Medical Record During Routine Primary Care Visits

Journal of Clinical Hypertension (Greenwich, Conn.). Nov, 2011  |  Pubmed ID: 22051427

Electronic medical records (EMRs) allow for real-time access to blood pressure (BP) information on a population basis and improve identification and treatment of individuals with hypertension. Despite the potential uses of the data available from EMRs, relatively little research has examined the reliability of this data. To address this gap, the authors examined the reliability of BP taken at primary care visits and recorded in an EMR with those taken at a research study visit at which standard protocols were used to measure BP among all adults as well as by sex and age. Systolic BP (SBP) averaged 3.7 (17.3) points and diastolic BP (DBP) was 2.8 (10.6) points lower in the EMR than in the study visit across age and sex groups, with all differences statistically significant. For this cohort of patients with a diagnosis of hypertension, there was moderate correlation between BP measurements taken in clinic and at research. However, BP control for individuals, as defined by an SBP <140 mm Hg and DBP 90 mm Hg, differed by almost 25%. Known variability of BP and clinic procedures for measuring and recording BP may account for these differences.

Mapping the Route to Visual Awareness

Journal of Vision. 2011  |  Pubmed ID: 22052219

The "neural correlate" of perceptual awareness is much sought-after. Here, we present an novel approach to the identification of possible neural correlates, in which we exploit the temporal connection that inevitably links the selection process that determines what we become aware of, and the development of awareness itself. Because the speed of selection determines when downstream processes can first become involved in generating awareness, the latency of neural processes provides a way to isolate the neural correlates of awareness. We recorded event-related potentials (ERPs) while observers carried out a visual behavioral task designed to estimate attentional selection latency. We show that within-task trial-by-trial behavioral variability in attentional selection latency correlates to trial-by-trial variability in ERP latency. This was true in a posterior contralateral region, and in central and frontal areas, thereby implicating these as waypoints along which visual information flows on the way to visual awareness.

Diversification of CYCLOIDEA-like Genes in Dipsacaceae (Dipsacales): Implications for the Evolution of Capitulum Inflorescences

BMC Evolutionary Biology. 2011  |  Pubmed ID: 22054400

CYCLOIDEA (CYC)-like genes have been implicated in the development of capitulum inflorescences (i.e. flowering heads) in Asteraceae, where many small flowers (florets) are packed tightly into an inflorescence that resembles a single flower. Several rounds of duplication of CYC-like genes have occurred in Asteraceae, and this is hypothesized to be correlated with the evolution of the capitulum, which in turn has been implicated in the evolutionary success of the group. We investigated the evolution of CYC-like genes in Dipsacaceae (Dipsacales), a plant clade in which capitulum inflorescences originated independently of Asteraceae. Two main inflorescence types are present in Dipsacaceae: (1) radiate species contain two kinds of floret within the flowering head (disk and ray), and (2) discoid species contain only disk florets. To test whether a dynamic pattern of gene duplication, similar to that documented in Asteraceae, is present in Dipsacaceae, and whether these patterns are correlated with different inflorescence types, we inferred a CYC-like gene phylogeny for Dipsacaceae based on representative species from the major lineages.

Radiation Therapy in the Management of Unilesional Primary Cutaneous T-cell Lymphomas

The British Journal of Dermatology. Nov, 2011  |  Pubmed ID: 22059744

Background:  Unilesional presentations of mycosis fungoides (MF)-type cutaneous T-cell lymphoma (CTCL) may offer opportunities for definitive treatment with intent to cure, as opposed to more advanced disease involving multiple body areas, where remissions are not expected to be long term. Objective:  To determine the disease-free survival for patients with unilesional or clustered oligolesional cutaneous T-cell lymphoma treated with radiation therapy. Methods:  We reviewed the records of all patients brought before the Multidisciplinary Cutaneous Oncology Tumor Board at University Hospitals Case Medical Center from 1997 to 2010. A total of 10 patients diagnosed with unilesional or oligolesional cutaneous T-cell lymphoma were treated with radiation therapy. Results:  100% of patients treated with radiation therapy achieved a complete response verified by clinical examination within 2 months after radiation therapy. Following radiation therapy, 30% of patients reported a relapse, of which two-thirds occurred within the previously irradiated area. Among patients who relapsed, the mean time to relapse was 42.3 months. We conducted a pooled data analysis which showed that the 1 and 5 year disease-free survivals after radiation therapy were 92.7% and 83.4% respectively. Conclusion:  Local radiation therapy appears to be an effective treatment for patients presenting with unilesional or localized cutaneous T-cell lymphoma.

A Randomized Controlled Trial of Subantimicrobial-dose Doxycycline to Prevent Unscheduled Bleeding with Continuous Oral Contraceptive Pill Use

Contraception. Sep, 2011  |  Pubmed ID: 22067758

BACKGROUND: Unscheduled bleeding is the main side effect of continuous oral contraceptive pills (OCPs) and has been correlated with the up-regulation of matrix metalloprotineases (MMPs). The study objective was to determine if prophylactic administration of doxycycline (an MMP inhibitor at low subantimicrobial doses) would prevent unscheduled bleeding during the initiation of a continuous OCP. STUDY DESIGN: Subjects using cyclic hormonal contraceptives (combined OCPs, patch or ring) without unscheduled bleeding were switched to continuous OCPs (20 mcg ethinyl estradiol/100 mcg levonorgestrel). They were randomized to receive daily doxycycline [sustained-release subantimicrobial dose (40 mg daily)] or placebo for the first 84 days and then observed for an additional 28 days on the continuous OCP alone. The number of bleeding/spotting days and the time in days it took to achieve amenorrhea were compared using a t test. RESULTS: Sixty-five subjects were randomized. Although the use of doxycycline did not significantly decrease the number of mean bleeding/spotting days in the first 84 days of the study [doxycycline 14.75 (SE 2.30), placebo 17.78 (2.31), p=.36], women who received doxycycline had a significantly earlier onset of amenorrhea [mean last day of bleeding/spotting doxycycline 61.7 (7.7), placebo 85.2 (6.7), p=.03]. CONCLUSION: The coadministration of subantimicrobial-dose doxycycline during initiation of continuous OCPs results in a significant reduction in the length of time needed to achieve amenorrhea.

Increased Frequency of Complement C4B Deficiency in Rheumatoid Arthritis

Arthritis and Rheumatism. Nov, 2011  |  Pubmed ID: 22076784

OBJECTIVE: To assess the Copy Number Variation (CNV) of complement C4A and C4B genes in patients with Rheumatoid Arthritis. METHODS: DNA from 299 patients and volunteers were obtained and analyzed for CNV of total complement C4, C4A, and C4B genes. These results were analyzed by chi-square analysis and odds ratios calculated. RESULTS: Chi-square analysis revealed similar distribution patterns of total C4 alleles in RA (n=160), non-RA (n=88) rheumatology patients and normal volunteers (n=51). There was no trend to C4A deficiency as in lupus. Significant differences in C4B distribution were observed in RA patients, where a ∼ two-fold increase in the frequency (40%) of homozygous and/or heterozygous C4B deficiency (0 or 1 allele) was present relative to non-RA patients (21%) or healthy controls (22%). The C4B deficiency concentrated in the seropositive relative to seronegative RA patients (44% vs 31%). The odds of C4B deficiency were 2.99 (1.58-5.65, p=0.0006) in seropositive RA patients relative to non-RA controls. These findings were confirmed in a larger healthy control cohort yielding an odds ratio of 1.83 (1.21-2.76, p=0.0056). The association of SE with C4B deficiency was significantly greater in the seropositive RA patient population relative to non-seropositive RA controls (96% vs 54.5%, p<0.0001), suggesting that C4B deficiency interacts with the SE in the development of seropositive RA. CONCLUSIONS: C4B CNV exhibits a relationship with RA that approximates that seen with C4A CNV and SLE. The concurrence of C4B deficiency and SE in seropositive RA can have broad implications for our understanding of RA pathogenesis. © 2011 American College of Rheumatology.

Who Attends Antenatal Care and Expanded Programme on Immunization Services in Chad, Mali and Niger? The Implications for Insecticide-treated Net Delivery

Malaria Journal. 2011  |  Pubmed ID: 22078175

Malaria remains one of the largest public health problems facing the developing world. Insecticide-treated nets (ITNs) are an effective intervention against malaria. ITN delivery through routine health services, such as antenatal care (ANC) and childhood vaccination (EPI), is a promising channel of delivery to reach individuals with the highest risk (pregnant women and children under five years old). Decisions on whether to deliver ITNs through both channels depends upon the reach of each of these systems, whether these are independent and the effectiveness and cost effectiveness of each. Predictors of women attending ANC and EPI separately have been studied, but the predictors of those who attend neither service have not been identified.

Phase 2 Trial of Linifanib (ABT-869) in Patients with Advanced Renal Cell Cancer After Sunitinib Failure

European Journal of Cancer (Oxford, England : 1990). Dec, 2011  |  Pubmed ID: 22078932

This study assessed the efficacy and safety of linifanib in patients with advanced renal cell carcinoma (RCC) who were previously treated with sunitinib.

Parent and Child Usual Source of Care and Children's Receipt of Health Care Services

Annals of Family Medicine. Nov-Dec, 2011  |  Pubmed ID: 22084261

PURPOSE In the United States, children who have a usual source of care (USC) have better access to health care than those who do not, but little is known about how parental USC affects children's access. We examined the association between child and parent USC patterns and children's access to health care services. METHODS We undertook a secondary analysis of nationally representative, cross-sectional data from children participating in the 2002-2007 Medical Expenditure Panel Survey (n = 56,302). We assessed 10 outcome measures: insurance coverage gaps, no doctor visits in the past year, less than yearly dental visits, unmet medical and prescription needs, delayed care, problems getting care, and unmet preventive counseling needs regarding healthy eating, regular exercise, car safety devices, and bicycle helmets. RESULTS Among children, 78.6% had a USC and at least 1 parent with a USC, whereas 12.4% had a USC but no parent USC. Children with a USC but no parent USC had a higher likelihood of several unmet needs, including an insurance coverage gap (adjusted risk ratio [aRR] 1.33; 95% confidence interval [CI], 1.21-1.47), an unmet medical or prescription need (aRR 1.70; 95% CI 1.09-2.65), and no yearly dental visits (aRR 1.12; 95% CI 1.06-1.18), compared with children with a USC whose parent(s) had a USC. CONCLUSIONS Among children with a USC, having no parent USC was associated with a higher likelihood of reporting unmet needs when compared with children whose parent(s) had a USC. Policy reforms should ensure access to a USC for all family members.

Addressing Health Care Disparities Using Public Reporting

American Journal of Medical Quality : the Official Journal of the American College of Medical Quality. Nov, 2011  |  Pubmed ID: 22102162

The literature highlights that disparities in health care performance exist. Publicly reporting data about disparities at an actionable level is needed. The Minnesota Health Care Disparities Report is designed to publicly report medical group health care performance rates for patients enrolled in state/federally funded programs. In addition, differences between patients enrolled in state-funded public programs and those in private or Medicare programs at statewide and medical group levels are presented. The endeavor is a cooperative one between Minnesota Community Measurement, an independent nonprofit community organization, and the Minnesota Department of Human Services, the state Medicaid agency. Public reporting makes transparent the gaps in the delivery of health care between patients enrolled in these programs at a medical group level and can facilitate quality improvement locally, where accountability lies and actions to address disparities can occur.

Dislocation of the Donor Graft to the Posterior Segment in Descemet Stripping Automated Endothelial Keratoplasty

American Journal of Ophthalmology. Nov, 2011  |  Pubmed ID: 22105800

PURPOSE: To report a series of dislocations of the donor graft into the posterior segment associated with Descemet stripping endothelial keratoplasty (DSAEK) and to identify possible risk factors for dislocation and clinical outcomes. DESIGN: Retrospective case series. METHODS: Cases of donor graft dislocation into the posterior segment associated with endothelial keratoplasty were identified from the clinical experience of 7 surgeons. Observations included the preoperative surgical history of each eye, preoperative and postoperative visual acuity, management of the complication, and the postoperative clinical course. No identified cases were excluded from this series. RESULTS: Eight posterior graft dislocations were associated with DSAEK surgery. Each eye had a history of vitrectomy. Five eyes had sutured posterior chamber intraocular lenses, 1 eye had a sulcus intraocular lens, and 2 eyes were aphakic. Each eye required repeat grafting, and in 6 of 8 eyes, pars plana vitrectomy was used to remove the dislocated graft. Final visual acuities ranged from 20/30 to no light perception. CONCLUSIONS: Graft dislocation into the posterior segment is a rare complication of DSAEK surgery that can lead to permanent vision loss. It has occurred in eyes that have undergone previous vitrectomy and complicated intraocular lens placement or were aphakic. As is the case with a dropped lens nucleus during cataract extraction, visual acuities after a dropped DSAEK graft range from very good to no light perception. Better postoperative results seem to be associated with prompt removal of the posteriorly dislocated graft.

Maurice J. Jurkiewicz: "I Am a Teacher"

Annals of Plastic Surgery. Nov, 2011  |  Pubmed ID: 22106452

Dodging an ACO Chilling Effect. Regulators Ease Up on Provider Collusion Warnings

Modern Healthcare. Oct, 2011  |  Pubmed ID: 22106523

Recipe for Success. Panelists See 'advocacy' Representation, Grooming Leaders As Building Blocks

Modern Healthcare. Oct, 2011  |  Pubmed ID: 22106529

Inspecting the Inspectors. Investigators Should Examine Quality: HHS Report

Modern Healthcare. Nov, 2011  |  Pubmed ID: 22106774

Optimizing Intracavity High Harmonic Generation for XUV Fs Frequency Combs

Optics Express. Nov, 2011  |  Pubmed ID: 22109209

Previous work has shown that use of a passive enhancement cavity designed for ultrashort pulses can enable the up-conversion of the fs frequency comb into the extreme ultraviolet (XUV) spectral region utilizing the highly nonlinear process of high harmonic generation. This promising approach for an efficient source of highly coherent light in this difficult to reach spectral region promises to be a unique tool for precision spectroscopy and temporally resolved measurements. Yet to date, this approach has not been extensively utilized due in part to the low powers so far achieved and in part due to the challenges in directly probing electronic transitions with the frequency comb itself. We report on a dramatically improved XUV frequency comb producing record power levels to date in the 50-150 nm spectral region based on intracavity high harmonic generation. We measure up to 77 μW at the 11th harmonic of the fundamental (72 nm) with μW levels down to the 15th harmonic (53nm). Phase-matching and related design considerations unique to intracavity high harmonic generation are discussed, guided by numerical simulations which provide insight into the role played by intracavity ionization dynamics. We further propose and analyze dual-comb spectroscopy in the XUV and show that the power levels reported here permit this approach for the first time. Dual-comb spectroscopy in this physically rich spectral region promises to enable the study of a significantly broader range of atomic and molecular spectra with unprecedented precision and accuracy.

The Effect of Disease Activity on Body Composition and Resting Energy Expenditure in Patients with Rheumatoid Arthritis

Journal of Inflammation Research. 2011  |  Pubmed ID: 22096370

Cachexia is associated with rheumatoid arthritis (RA), but whether it is attributable primarily to reduced dietary intake or increased metabolism is unclear, as is the association with inflammation. To examine whether rheumatoid cachexia is related to increased energy expenditure, reduced food intake, or an inflammatory cytokine response we undertook a prospective, longitudinal study of patients with RA, during periods of relative relapse and remission of inflammation.

A Mechanism-Based Approach to Predict the Relative Biological Effectiveness of Protons and Carbon Ions in Radiation Therapy

International Journal of Radiation Oncology, Biology, Physics. Nov, 2011  |  Pubmed ID: 22099045

PURPOSE: The physical and potential biological advantages of proton and carbon ions have not been fully exploited in radiation therapy for the treatment of cancer. In this work, an approach to predict proton and carbon ion relative biological effectiveness (RBE) in a representative spread-out Bragg peak (SOBP) is derived using the repair-misrepair-fixation (RMF) model. METHODS AND MATERIALS: Formulas linking dose-averaged linear-quadratic parameters to DSB induction and processing are derived from the RMF model. The Monte Carlo Damage Simulation (MCDS) software is used to quantify the effects of radiation quality on the induction of DNA double-strand breaks (DSB). Trends in parameters α and β for clinically relevant proton and carbon ion kinetic energies are determined. RESULTS: Proton and carbon ion RBE are shown to increase as particle energy, dose, and tissue α/β ratios decrease. Entrance RBE is ∼1.0 and ∼1.3 for protons and carbon ions, respectively. For doses in the range of 0.5 to 10 Gy, proton RBE ranges from 1.02 (proximal edge) to 1.4 (distal edge). Over the same dose range, the RBE for carbon ions ranges from 1.5 on the proximal edge to 6.7 on the distal edge. CONCLUSIONS: The proposed approach is advantageous because the RBE for clinically relevant particle distributions is guided by well-established physical and biological (track structure) considerations. The use of an independently tested Monte Carlo model to predict the effects of radiation quality on DSB induction also minimizes the number of ad hoc biological parameters that must be determined to predict RBE. Large variations in predicted RBE across an SOBP may produce undesirable biological hot and cold spots. These results highlight the potential for the optimization of physical dose for a uniform biological effect.

Putting on the Brakes. FTC Takes Aim at Hospital Deals in Ohio, Georgia

Modern Healthcare. Oct, 2011  |  Pubmed ID: 22111497

Fueling Productivity. Sorting out the Metrics and Efficiencies of a Complex Healthcare System

Modern Healthcare. Oct, 2011  |  Pubmed ID: 22111499

Down-regulation of Shadoo in Prion Infections Traces a Pre-clinical Event Inversely Related to PrP(Sc) Accumulation

PLoS Pathogens. Nov, 2011  |  Pubmed ID: 22114562

During prion infections of the central nervous system (CNS) the cellular prion protein, PrP(C), is templated to a conformationally distinct form, PrP(Sc). Recent studies have demonstrated that the Sprn gene encodes a GPI-linked glycoprotein Shadoo (Sho), which localizes to a similar membrane environment as PrP(C) and is reduced in the brains of rodents with terminal prion disease. Here, analyses of prion-infected mice revealed that down-regulation of Sho protein was not related to Sprn mRNA abundance at any stage in prion infection. Down-regulation was robust upon propagation of a variety of prion strains in Prnp(a) and Prnp(b) mice, with the exception of the mouse-adapted BSE strain 301 V. In addition, Sho encoded by a TgSprn transgene was down-regulated to the same extent as endogenous Sho. Reduced Sho levels were not seen in a tauopathy, in chemically induced spongiform degeneration or in transgenic mice expressing the extracellular ADan amyloid peptide of familial Danish dementia. Insofar as prion-infected Prnp hemizygous mice exhibited accumulation of PrP(Sc) and down-regulation of Sho hundreds of days prior to onset of neurologic symptoms, Sho depletion can be excluded as an important trigger for clinical disease or as a simple consequence of neuronal damage. These studies instead define a disease-specific effect, and we hypothesize that membrane-associated Sho comprises a bystander substrate for processes degrading PrP(Sc). Thus, while protease-resistant PrP detected by in vitro digestion allows post mortem diagnosis, decreased levels of endogenous Sho may trace an early response to PrP(Sc) accumulation that operates in the CNS in vivo. This cellular response may offer new insights into the homeostatic mechanisms involved in detection and clearance of the misfolded proteins that drive prion disease pathogenesis.

Boron Stress Activates the General Amino Acid Control Mechanism and Inhibits Protein Synthesis

PloS One. 2011  |  Pubmed ID: 22114689

Boron is an essential micronutrient for plants, and it is beneficial for animals. However, at high concentrations boron is toxic to cells although the mechanism of this toxicity is not known. Atr1 has recently been identified as a boron efflux pump whose expression is upregulated in response to boron treatment. Here, we found that the expression of ATR1 is associated with expression of genes involved in amino acid biosynthesis. These mechanisms are strictly controlled by the transcription factor Gcn4 in response to boron treatment. Further analyses have shown that boron impaired protein synthesis by promoting phosphorylation of eIF2α in a Gcn2 kinase dependent manner. The uncharged tRNA binding domain (HisRS) of Gcn2 is necessary for the phosphorylation of eIF2α in the presence of boron. We postulate that boron exerts its toxic effect through activation of the general amino acid control system and inhibition of protein synthesis. Since the general amino acid control pathway is conserved among eukaryotes, this mechanism of boron toxicity may be of general importance.

Diagnostic Stability and Bipolar Disorder in Youth

Journal of the American Academy of Child and Adolescent Psychiatry. Dec, 2011  |  Pubmed ID: 22115139

Modern Cataract Surgery: Unfinished Business and Unanswered Questions. Foreword

Survey of Ophthalmology. Nov-Dec, 2011  |  Pubmed ID: 22117903

Rett Syndrome Mutation MeCP2 T158A Disrupts DNA Binding, Protein Stability and ERP Responses

Nature Neuroscience. 2011  |  Pubmed ID: 22119903

Mutations in the MECP2 gene cause the autism spectrum disorder Rett syndrome (RTT). One of the most common MeCP2 mutations associated with RTT occurs at threonine 158, converting it to methionine (T158M) or alanine (T158A). To understand the role of T158 mutations in the pathogenesis of RTT, we generated knockin mice that recapitulate the MeCP2 T158A mutation. We found a causal role for T158A mutation in the development of RTT-like phenotypes, including developmental regression, motor dysfunction, and learning and memory deficits. These phenotypes resemble those present in Mecp2 null mice and manifest through a reduction in MeCP2 binding to methylated DNA and a decrease in MeCP2 protein stability. The age-dependent development of event-related neuronal responses was disrupted by MeCP2 mutation, suggesting that impaired neuronal circuitry underlies the pathogenesis of RTT and that assessment of event-related potentials (ERPs) may serve as a biomarker for RTT and treatment evaluation.

Treated Whipple Disease With Erythema Nodosum Leprosum-Like Lesions: Cutaneous PAS-Positive Macrophages Slowly Decrease With Time and Are Associated With Lymphangiectases: A Case Report

The American Journal of Dermatopathology. Nov, 2011  |  Pubmed ID: 22123268

Pathologically, Whipple disease (WD) is characterized by the accumulation of myriad macrophages parasitized by Tropheryma whipplei (TW) bacilli denoted by periodic acid-Schiff (PAS) positivity. These PAS+ macrophages are typically found in the duodenum associated with lymphangiectasia. Recently, we reported the presence of PAS+ macrophages and free TW in erythema nodosum leprosum (ENL)-like lesions and normal skin in a patient with WD who suffered from the immune reconstitution inflammatory syndrome (IRIS). We extend that report by describing the clinical and pathologic findings over 5 years of follow-up. First, the IRIS gradually diminished and abated over 18-month time. Second, at no point did WD recur, and all duodenal and skin biopsies tested by polymerase chain reaction were negative for TW DNA. Third, PAS+ macrophages were identified in 26 of 27 skin biopsies (96%) and decreased along with free TW over time. Fourth, ENL-like lesions had significantly greater numbers of PAS+ macrophages than normal skin. Moreover, normal abdominal skin (region of ENL-like lesions) had greater PAS+ counts than arm skin (not a site of IRIS). Last, lymphangiectases, a histologic sign of lymphostasis, was found in all skin biopsies. Overall, these findings implicate bacillary burden as a factor in the immune tolerance to live TW in active WD and the initiation of ENL-like nodules against dead/nonreplicative TW in treated WD. In addition, poor lymphatic drainage is likely responsible for the gradual clearance of TW from the skin and the impaired delayed-type hypersensitivity reaction (absence of activated macrophages) against TW found in WD, presumptively due to reduced/absent immune cell trafficking necessary for lymphocyte-macrophage interactions and induction of adaptive immunity.

Volunteering, Mentoring, and Relational Aggression: All in the Same Profession?

Orthopaedic Nursing / National Association of Orthopaedic Nurses. Nov-Dec, 2011  |  Pubmed ID: 22124194

Pitfalls of Merging GWAS Data: Lessons Learned in the EMERGE Network and Quality Control Procedures to Maintain High Data Quality

Genetic Epidemiology. Dec, 2011  |  Pubmed ID: 22125226

Genome-wide association studies (GWAS) are a useful approach in the study of the genetic components of complex phenotypes. Aside from large cohorts, GWAS have generally been limited to the study of one or a few diseases or traits. The emergence of biobanks linked to electronic medical records (EMRs) allows the efficient reuse of genetic data to yield meaningful genotype-phenotype associations for multiple phenotypes or traits. Phase I of the electronic MEdical Records and GEnomics (eMERGE-I) Network is a National Human Genome Research Institute-supported consortium composed of five sites to perform various genetic association studies using DNA repositories and EMR systems. Each eMERGE site has developed EMR-based algorithms to comprise a core set of 14 phenotypes for extraction of study samples from each site's DNA repository. Each eMERGE site selected samples for a specific phenotype, and these samples were genotyped at either the Broad Institute or at the Center for Inherited Disease Research using the Illumina Infinium BeadChip technology. In all, approximately 17,000 samples from across the five sites were genotyped. A unified quality control (QC) pipeline was developed by the eMERGE Genomics Working Group and used to ensure thorough cleaning of the data. This process includes examination of sample and marker quality and various batch effects. Upon completion of the genotyping and QC analyses for each site's primary study, eMERGE Coordinating Center merged the datasets from all five sites. This larger merged dataset reentered the established eMERGE QC pipeline. Based on lessons learned during the process, additional analyses and QC checkpoints were added to the pipeline to ensure proper merging. Here, we explore the challenges associated with combining datasets from different genotyping centers and describe the expansion to eMERGE QC pipeline for merged datasets. These additional steps will be useful as the eMERGE project expands to include additional sites in eMERGE-II, and also serve as a starting point for investigators merging multiple genotype datasets accessible through the National Center for Biotechnology Information in the database of Genotypes and Phenotypes. Our experience demonstrates that merging multiple datasets after additional QC can be an efficient use of genotype data despite new challenges that appear in the process.

Effects of Coral Reef Benthic Primary Producers on Dissolved Organic Carbon and Microbial Activity

PloS One. 2011  |  Pubmed ID: 22125645

Benthic primary producers in marine ecosystems may significantly alter biogeochemical cycling and microbial processes in their surrounding environment. To examine these interactions, we studied dissolved organic matter release by dominant benthic taxa and subsequent microbial remineralization in the lagoonal reefs of Moorea, French Polynesia. Rates of photosynthesis, respiration, and dissolved organic carbon (DOC) release were assessed for several common benthic reef organisms from the backreef habitat. We assessed microbial community response to dissolved exudates of each benthic producer by measuring bacterioplankton growth, respiration, and DOC drawdown in two-day dark dilution culture incubations. Experiments were conducted for six benthic producers: three species of macroalgae (each representing a different algal phylum: Turbinaria ornata--Ochrophyta; Amansia rhodantha--Rhodophyta; Halimeda opuntia--Chlorophyta), a mixed assemblage of turf algae, a species of crustose coralline algae (Hydrolithon reinboldii) and a dominant hermatypic coral (Porites lobata). Our results show that all five types of algae, but not the coral, exuded significant amounts of labile DOC into their surrounding environment. In general, primary producers with the highest rates of photosynthesis released the most DOC and yielded the greatest bacterioplankton growth; turf algae produced nearly twice as much DOC per unit surface area than the other benthic producers (14.0±2.8 µmol h⁻¹ dm⁻²), stimulating rapid bacterioplankton growth (0.044±0.002 log10 cells h⁻¹) and concomitant oxygen drawdown (0.16±0.05 µmol L⁻¹ h⁻¹ dm⁻²). Our results demonstrate that benthic reef algae can release a significant fraction of their photosynthetically-fixed carbon as DOC, these release rates vary by species, and this DOC is available to and consumed by reef associated microbes. These data provide compelling evidence that benthic primary producers differentially influence reef microbial dynamics and biogeochemical parameters (i.e., DOC and oxygen availability, bacterial abundance and metabolism) in coral reef communities.

Renal Colic

Nursing. Dec, 2011  |  Pubmed ID: 22089915

Evaluation of the Effect of Dapagliflozin on Cardiac Repolarization: a Thorough QT/QTc Study

Diabetes Therapy : Research, Treatment and Education of Diabetes and Related Disorders. Sep, 2011  |  Pubmed ID: 22127822

Dapagliflozin is a first-in-class sodium-glucose transporter 2 (SGLT2) inhibitor under investigation for the treatment of type 2 diabetes mellitus. A thorough QTc study was conducted, according to International Conference on Harmonization E14 guidelines, to characterize the effect of dapagliflozin on cardiac repolarization.

Replication of Loci Influencing Ages at Menarche and Menopause in Hispanic Women: the Women's Health Initiative SHARe Study

Human Molecular Genetics. Dec, 2011  |  Pubmed ID: 22131368

Several genome-wide studies have identified loci associated with reproductive traits, such as ages of menarche and menopause, in women of European ancestry. In this study, we investigated the relevance of these loci in minority US Hispanic women. We utilized data from 3468 women who were genotyped as a part of the Women's Health Initiative SNP Health Association Resource. We replicated associations of eight loci (LRP18, LIN28B, CENPW, INHBA, TMEM38B, ZNF483, NFAT5 and OLFM2) with age at menarche, and of two loci (MCM8 and BRSK1/TMEM150B) with age at menopause. The MCM8 locus was also associated with early menopause risk. Three loci (CENPW, MCM8 and BRSK1/TMEM150B) were associated with the length of reproductive lifespan. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in minority US Hispanic women.

Screening for Distress, the Sixth Vital Sign: Examining Self-referral in People with Cancer over a One-year Period

Psycho-oncology. Dec, 2011  |  Pubmed ID: 22135205

PURPOSE: Although research has indicated a diagnosis of cancer is most often distressing for patients and their families, few studies have examined which patients access resources to manage distress or how distress levels affect resource utilization. This study explored psychosocial and supportive care resource utilization in a large cancer population at a Canadian tertiary cancer centre over a 12-month period in a usual care setting. METHODS: Patients who were new to the Tom Baker Cancer Centre completed the Distress Thermometer, the Pain and Fatigue Thermometers, the Psychological Screen for Cancer (Part C) that measures anxiety and depression, self-report questions on resources accessed and a demographic form at baseline, 3, 6 and 12 months. No feedback or specific triage to services was provided in order to observe usual care practices. RESULTS: A total of 714 patients provided baseline data with 505 retained at 12 months. Twenty-four percent indicated they accessed at least one service (e.g. individual counselling, nutritionist or resource social worker) over the 12 months. Patients who were older, less educated and with lower income were less likely to access services. People who reported higher symptom burden were more likely to access services at each time point. CONCLUSIONS: Overall levels of access of psychosocial services were relatively low in this population and varied by socio-demographic variables and symptom burden. Routine monitoring of psychosocial, practical and physical concerns is a potential strategy for targeting individuals who may require additional information or support in accessing available services to manage their concerns. Copyright © 2011 John Wiley & Sons, Ltd.

Developing Mechanistic Insights into Cardiovascular Cell Therapy: Cardiovascular Cell Therapy Research Network Biorepository Core Laboratory Rationale

American Heart Journal. Dec, 2011  |  Pubmed ID: 22137069

Moderate improvements in cardiac performance have been reported in some clinical settings after delivery of bone marrow mononuclear cells to patients with cardiovascular disease. However, mechanistic insights into how these cells impact outcomes are lacking. To address this, the National Heart, Lung and Blood Institute (NHLBI) Cardiovascular Cell Therapy Research Network (CCTRN) established a Biorepository Core for extensive phenotyping and cell function studies and storing bone marrow and peripheral blood for 10 years. Analyzing cell populations and cell function in the context of clinical parameters and clinical outcomes after cell or placebo treatment empower the development of novel diagnostic and prognostics. Developing such biomarkers that define the safety and efficacy of cell therapy is a major Biorepository aim.

The Repertoire of G Protein-coupled Receptors in the Human Parasite Schistosoma Mansoni and the Model Organism Schmidtea Mediterranea

BMC Genomics. 2011  |  Pubmed ID: 22145649

ABSTRACT:

Congenital Absence of Gluteal Muscles, Optic Nerve Hypoplasia, and Central Nervous System Hamartomas

Clinical Dysmorphology. Nov, 2011  |  Pubmed ID: 22146147

Tumor Hypoxia is an Important Mechanism of Radioresistance in Hypofractionated Radiotherapy and Must Be Considered in the Treatment Planning Process

Medical Physics. Dec, 2011  |  Pubmed ID: 22149817

Driving Themselves to Drink: Qualitative Perspectives from "hardcore" DUI Repeat Offenders in Ohio

Journal of Ethnicity in Substance Abuse. Oct, 2011  |  Pubmed ID: 22150132

Despite the continuing problem of repeat drunk driving (DUI) offenders, little is known of the characteristics of this population. This article reports findings from qualitative interviews with 12 incarcerated men who had been convicted for 5 or more DUIs. Participants' sociodemographic characteristics, patterns of substance abuse, treatment history, attitudes toward positive behavioral change, and recommendations for improving treatment are described. Three groups were identified in regard to the degree of recognition of substance abuse and level of motivation to engage in treatment and post-release rehabilitation. Participants also offered suggestions to improve treatment strategies for repeat DUI offenders by tailoring diverse educational and counseling programs that target the differing types of DUI recidivists. The findings provide preliminary qualitative insight into a unique population that may be used to inform future studies.

Military to Civilian Questionnaire: a Measure of Postdeployment Community Reintegration Difficulty Among Veterans Using Department of Veterans Affairs Medical Care

Journal of Traumatic Stress. Dec, 2011  |  Pubmed ID: 22162082

The primary objective of this study was to describe the development, reliability, and construct validity of scores on the Military to Civilian Questionnaire (M2C-Q), a 16-item self-report measure of postdeployment community reintegration difficulty. We surveyed a national, stratified sample of 1,226 Iraq and Afghanistan veterans who used U.S. Department of Veterans Affairs (VA) medical care; 745 completed the M2C-Q and validated mental health screening measures. All analyses were based on weighted estimates. The internal consistency of the M2C-Q was .95 in this sample. Factor analyses indicated a single total score was the best-fitting model. Total scores were associated with measures theoretically related to reintegration difficulties including perception of overall difficulty readjusting back into civilian life (R(2) = .49), probable PTSD (d = 1.07), probable problem drug or alcohol use (d = 0.34), and overall mental health (r = -.83). Subgroup analyses revealed a similar pattern of findings in those who screened negative for PTSD. Nonwhite and unemployed veterans reported greater community reintegration difficulty (d = 0.20 and 0.45, respectively). Findings offer preliminary support for the reliability and construct validity of M2C-Q scores.

A Cabled Acoustic Telemetry System for Detecting and Tracking Juvenile Salmon: Part 1. Engineering Design and Instrumentation

Sensors (Basel, Switzerland). 2011  |  Pubmed ID: 22163918

In 2001 the U.S. Army Corps of Engineers, Portland District (OR, USA), started developing the Juvenile Salmon Acoustic Telemetry System, a nonproprietary sensing technology, to meet the needs for monitoring the survival of juvenile salmonids through eight large hydroelectric facilities within the Federal Columbia River Power System (FCRPS). Initial development focused on coded acoustic microtransmitters and autonomous receivers that could be deployed in open reaches of the river for detection of the juvenile salmonids implanted with microtransmitters as they passed the autonomous receiver arrays. In 2006, the Pacific Northwest National Laboratory began the development of an acoustic receiver system for deployment at hydropower facilities (cabled receiver) for detecting fish tagged with microtransmitters as well as tracking them in two or three dimensions for determining route of passage and behavior as the fish passed at the facility. The additional information on route of passage, combined with survival estimates, is used by the dam operators and managers to make structural and operational changes at the hydropower facilities to improve survival of fish as they pass the facilities through the FCRPS.

A Cabled Acoustic Telemetry System for Detecting and Tracking Juvenile Salmon: Part 2. Three-dimensional Tracking and Passage Outcomes

Sensors (Basel, Switzerland). 2011  |  Pubmed ID: 22163919

In Part 1 of this paper, we presented the engineering design and instrumentation of the Juvenile Salmon Acoustic Telemetry System (JSATS) cabled system, a nonproprietary sensing technology developed by the U.S. Army Corps of Engineers, Portland District (Oregon, USA) to meet the needs for monitoring the survival of juvenile salmonids through the hydroelectric facilities within the Federal Columbia River Power System. Here in Part 2, we describe how the JSATS cabled system was employed as a reference sensor network for detecting and tracking juvenile salmon. Time-of-arrival data for valid detections on four hydrophones were used to solve for the three-dimensional (3D) position of fish surgically implanted with JSATS acoustic transmitters. Validation tests demonstrated high accuracy of 3D tracking up to 100 m upstream from the John Day Dam spillway. The along-dam component, used for assigning the route of fish passage, had the highest accuracy; the median errors ranged from 0.02 to 0.22 m, and root mean square errors ranged from 0.07 to 0.56 m at distances up to 100 m. For the 2008 case study at John Day Dam, the range for 3D tracking was more than 100 m upstream of the dam face where hydrophones were deployed, and detection and tracking probabilities of fish tagged with JSATS acoustic transmitters were higher than 98%. JSATS cabled systems have been successfully deployed on several major dams to acquire information for salmon protection and for development of more "fish-friendly" hydroelectric facilities.

Design and Implementation of an Underwater Sound Recording Device

Sensors (Basel, Switzerland). 2011  |  Pubmed ID: 22164089

To monitor the underwater sound and pressure waves generated by anthropogenic activities such as underwater blasting and pile driving, an autonomous system was designed to record underwater acoustic signals. The underwater sound recording device (USR) allows for connections of two hydrophones or other dynamic pressure sensors, filters high frequency noise out of the collected signals, has a gain that can be independently set for each sensor, and allows for 2 h of data collection. Two versions of the USR were created: a submersible model deployable to a maximum depth of 300 m, and a watertight but not fully submersible model. Tests were performed on the USR in the laboratory using a data acquisition system to send single-frequency sinusoidal voltages directly to each component. These tests verified that the device operates as designed and performs as well as larger commercially available data acquisition systems, which are not suited for field use. On average, the designed gain values differed from the actual measured gain values by about 0.35 dB. A prototype of the device was used in a case study to measure blast pressures while investigating the effect of underwater rock blasting on juvenile Chinook salmon and rainbow trout. In the case study, maximum positive pressure from the blast was found to be significantly correlated with frequency of injury for individual fish. The case study also demonstrated that the device withstood operation in harsh environments, making it a valuable tool for collecting field measurements.

Syndecan-4 is Essential for Development of Concentric Myocardial Hypertrophy Via Stretch-induced Activation of the Calcineurin-NFAT Pathway

PloS One. 2011  |  Pubmed ID: 22164265

Sustained pressure overload leads to compensatory myocardial hypertrophy and subsequent heart failure, a leading cause of morbidity and mortality. Further unraveling of the cellular processes involved is essential for development of new treatment strategies. We have investigated the hypothesis that the transmembrane Z-disc proteoglycan syndecan-4, a co-receptor for integrins, connecting extracellular matrix proteins to the cytoskeleton, is an important signal transducer in cardiomyocytes during development of concentric myocardial hypertrophy following pressure overload. Echocardiographic, histochemical and cardiomyocyte size measurements showed that syndecan-4(-/-) mice did not develop concentric myocardial hypertrophy as found in wild-type mice, but rather left ventricular dilatation and dysfunction following pressure overload. Protein and gene expression analyses revealed diminished activation of the central, pro-hypertrophic calcineurin-nuclear factor of activated T-cell (NFAT) signaling pathway. Cardiomyocytes from syndecan-4(-/-)-NFAT-luciferase reporter mice subjected to cyclic mechanical stretch, a hypertrophic stimulus, showed minimal activation of NFAT (1.6-fold) compared to 5.8-fold increase in NFAT-luciferase control cardiomyocytes. Accordingly, overexpression of syndecan-4 or introducing a cell-permeable membrane-targeted syndecan-4 polypeptide (gain of function) activated NFATc4 in vitro. Pull-down experiments demonstrated a direct intracellular syndecan-4-calcineurin interaction. This interaction and activation of NFAT were increased by dephosphorylation of serine 179 (pS179) in syndecan-4. During pressure overload, phosphorylation of syndecan-4 was decreased, and association between syndecan-4, calcineurin and its co-activator calmodulin increased. Moreover, calcineurin dephosphorylated pS179, indicating that calcineurin regulates its own binding and activation. Finally, patients with hypertrophic myocardium due to aortic stenosis had increased syndecan-4 levels with decreased pS179 which was associated with increased NFAT activation. In conclusion, our data show that syndecan-4 is essential for compensatory hypertrophy in the pressure overloaded heart. Specifically, syndecan-4 regulates stretch-induced activation of the calcineurin-NFAT pathway in cardiomyocytes. Thus, our data suggest that manipulation of syndecan-4 may provide an option for therapeutic modulation of calcineurin-NFAT signaling.

Lifestyle Activities and Memory: Variety May Be the Spice of Life. The Women's Health and Aging Study II

Journal of the International Neuropsychological Society : JINS. Dec, 2011  |  Pubmed ID: 22172155

This study examined whether participation in a variety of lifestyle activities was comparable to frequent participation in cognitively challenging activities in mitigating impairments in cognitive abilities susceptible to aging in healthy, community-dwelling older women. Frequencies of participation in various lifestyle activities on the Lifestyle Activities Questionnaire (LAQ) were divided according to high (e.g., reading), moderate (e.g., discussing politics), and low (e.g., watching television) cognitive demand. We also considered the utility of participation in a variety of lifestyle activities regardless of cognitive challenge. Immediate and delayed verbal recall, psychomotor speed, and executive function were each measured at baseline and at five successive exams, spanning a 9.5-year interval. Greater variety of participation in activities, regardless of cognitive challenge, was associated with an 8 to 11% reduction in the risk of impairment in verbal memory and global cognitive outcomes. Participation in a variety of lifestyle activities was more predictive than frequency or level of cognitive challenge for significant reductions in risk of incident impairment on measures sensitive to cognitive aging and risk for dementia. Our findings offer new perspectives in promoting a diverse repertoire of activities to mitigate age-related cognitive declines. (JINS, 2011, 18, 1-9).

Evaluation of the Effect of Systolic Blood Pressure and Pulse Pressure on Cognitive Function: the Women's Health and Aging Study II

PloS One. 2011  |  Pubmed ID: 22174760

Evidence suggests that elevated systolic blood pressure (SBP) and pulse pressure (PP) in midlife is associated with increased risk for cognitive impairment later in life. There is mixed evidence regarding the effects of late life elevated SBP or PP on cognitive function, and limited information on the role of female gender.

A Swing and a Miss: Judge's Ruling Draws Reaction from Both Sides

Modern Healthcare. Nov, 2011  |  Pubmed ID: 22175188

Somebody's Watching: Technology Helping Hospitals Stay Safe and Secure

Modern Healthcare. Nov, 2011  |  Pubmed ID: 22175197

FTC Challenges Illinois Hospital Deal Merger Raises Antitrust Concerns for Combined System, Commission Says

Modern Healthcare. Nov, 2011  |  Pubmed ID: 22175205

Final Judgment: High Court to Focus on Four Questions in ACA Case

Modern Healthcare. Nov, 2011  |  Pubmed ID: 22175209

Unscheduled Bleeding with Continuous Oral Contraceptive Pills: a Comparison of Progestin Dose

Contraception. Dec, 2011  |  Pubmed ID: 22176792

BACKGROUND: Although the use of continuous oral contraceptive pills (OCPs) eliminates scheduled uterine bleeding, unscheduled bleeding is common. The objective of this study was to determine whether progestin dose influences bleeding with use of continuous OCPs. STUDY DESIGN: This was a secondary data analysis of two other studies of continuous OCPs. Women were eligible if they were switching from a cyclic hormonal contraceptive to a continuous OCP. Women took a 20-mcg ethinyl estradiol (EE)/100-mcg levonorgestrel (LNG) pill or a 20-mcg EE/90-mcg LNG pill for 112 days. The number of bleeding/spotting days was compared between groups using a t test. Sample size was adequate to detect a difference of 8 days of bleeding/spotting over the 112 day study period (β=0.80, α=0.05). RESULTS: Sixty-six subjects were enrolled, 33 in each group. There were no differences in baseline characteristic, missed OCPs or side effects. There were no differences in the mean number of bleeding/spotting days in the first 84 days of the study (90 mcg LNG mean 20.8 (SE 3.6) days versus 100 mcg LNG 17.8 (SE 2.3) days, p=.48), nor was there a difference in the time to amenorrhea (p=.35). CONCLUSION: Our results do not support the use of one LNG dose over another to decrease the amount of unscheduled bleeding women experience when initiating a continuous OCP.

Hemispheric Asymmetries of Cortical Volume in the Human Brain

Cortex; a Journal Devoted to the Study of the Nervous System and Behavior. Nov, 2011  |  Pubmed ID: 22176871

Hemispheric asymmetry represents a cardinal feature of cerebral organization, but the nature of structural and functional differences between the hemispheres is far from fully understood. Using Magnetic Resonance Imaging morphometry, we identified several volumetric differences between the two hemispheres of the human brain. Heteromodal inferoparietal and lateral prefrontal cortices are more extensive in the right than left hemisphere, as is visual cortex. Heteromodal mesial and orbital prefrontal and cingulate cortices are more extensive in the left than right hemisphere, as are somatosensory, parts of motor, and auditory cortices. Thus, heteromodal association cortices are more extensively represented on the lateral aspect of the right than in the left hemisphere, and modality-specific cortices are more extensively represented on the lateral aspect of the left than in the right hemisphere. On the mesial aspect heteromodal association cortices are more extensively represented in the left than right hemisphere.

GEP Constitutes a Negative Feedback Loop with MyoD and Acts As a Novel Mediator in Controlling Skeletal Muscle Differentiation

Cellular and Molecular Life Sciences : CMLS. Dec, 2011  |  Pubmed ID: 22179841

Granulin-epithelin precursor (GEP) is an autocrine growth factor that has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation. Here we report that GEP was expressed in skeletal muscle tissue and its level was differentially altered in the course of C2C12 myoblast fusion. The GEP expression during myoblast fusion was a consequence of MyoD transcription factor binding to several E-box (CANNTG) sequences in the 5'-flanking regulatory region of GEP gene, followed by transcription. Recombinant GEP potently inhibited myotube formation from C2C12 myoblasts whereas the knockdown of endogenous of GEP via a siRNA approach accelerated the fusion of myoblasts to myotubes. Interestingly, the muscle fibers of GEP knockdown mice were larger in number but noticeably smaller in size when compared to the wild-type. Mechanistic studies revealed that during myoblast fusion, the addition of GEP led to remarkable reductions in the expressions of muscle-specific transcription factors, including MyoD. In addition, the regulation of myotube formation by GEP is mediated by the anti-myogenic factor JunB, which is upregulated following GEP stimulation. Thus, GEP growth factor, JunB, and MyoD transcription factor form a regulatory loop and act in concert in the course of myogenesis.

The Intraparotid Facial Nerve Schwannoma: a Diagnostic and Management Conundrum

American Journal of Otolaryngology. Dec, 2011  |  Pubmed ID: 22185683

OBJECTIVES: The aims of the study were (1) to review the management strategy and clinical outcomes of all intraparotid facial nerve (FN) schwannomas (PFNSs) treated at a single tertiary academic center from 1975 to 2010 and (2) to summarize all previously reported cases of PFNS in the international literature. STUDY DESIGN: A retrospective cohort study and literature review. METHODS: Fifteen patients were diagnosed and treated at the authors' institution from 1975 to 2010. In addition, 124 published cases were systematically reviewed. RESULTS: The most common presentation of PFNS was a painless parotid mass with normal FN function. Eccentric, loosely attached intraparotid tumors underwent gross total resection with nerve preservation granting satisfactory postoperative FN function, whereas "inseparable" intraparotid tumors were observed in 8 cases with stable long-term size. Lesions that extended into the fallopian canal underwent complete resection with FN sacrifice and nerve grafting in 10 cases, whereas 1 patient received subtotal resection of the intraparotid portion with stereotactic radiotherapy targeting the intratemporal component. CONCLUSIONS: Intraparotid FN schwannomas present similar to other primary salivary gland neoplasms, making an early diagnosis challenging. Intraoperative recognition of gross tumor characteristics and early histologic diagnosis with strategic biopsy are critical. Information including tumor location and extent, preoperative FN function, and the gross relationship between the tumor and the FN may guide the surgeon toward an optimal treatment plan emphasizing long-term neurologic preservation.

High-throughput Small Molecule Screening Reveals Structurally Diverse Compounds That Inhibit the Growth of Escherichia Coli O157:H7 in Vitro

Journal of Food Protection. Dec, 2011  |  Pubmed ID: 22186057

Escherichia coli O157:H7 colonizes the gastrointestinal tract of ruminants asymptomatically and may enter the human food supply through fecal contamination. A fraction of individuals infected by E. coli O157:H7 develop hemolytic uremic syndrome, a life-threatening condition. When individuals infected by E. coli O157:H7 are treated with certain antibiotics, an increased incidence of hemolytic uremic syndrome may result. This finding supports the need to identify novel compounds that can either reduce the load of E. coli O157:H7 entering the human food supply or serve as alternative therapeutic treatments for infected individuals. We developed a high-throughput turbidometric assay to identify novel compounds that inhibit E. coli O157:H7 growth. Pin transfers were performed to introduce small molecule libraries into 384-well plates, where each well contained approximately 5.0 log CFU of E. coli O157:H7. Plates were incubated at 37°C for 18 h, and the optical density was measured to determine the effect of each small molecule. A total of 64,562 compounds were screened in duplicate, and 43 unique compounds inhibited E. coli O157:H7 growth. Thirty-eight of the 43 inhibitory compounds belonged to known bioactive libraries, and the other 5 compounds were from commercial libraries derived from splitting and pooling. Inhibitory compounds from known bioactive libraries were most frequently therapeutic antibiotics (n = 34) but also included an antiviral compound, a compound that disrupts the citric acid cycle, and two biguanide compounds, which have been used for various nonclinical applications. We identified two novel compounds (i.e., biguanides) that should be studied further for their ability to reduce pathogen populations in foods.

Variables Associated with Successful Intubation Attempts Using Video Laryngoscopy: A Preliminary Report in a Helicopter Emergency Medical Service

Prehospital Emergency Care : Official Journal of the National Association of EMS Physicians and the National Association of State EMS Directors. Dec, 2011  |  Pubmed ID: 22191806

Abstract Background. Multiple studies have demonstrated varying rates of successful endotracheal intubation (ETI). Until the application of video laryngoscopy, little information regarding prehospital intubation could be analyzed objectively by individuals other than the provider performing the ETI. Objective. To evaluate the association of variables recorded during video laryngoscopy and successful ETI attempts, defined as placing the endotracheal tube in the trachea. Methods. We retrospectively reviewed intubations performed by a single helicopter emergency medical service (HEMS) using a video larygoscope from March 1, 2010, to October 1, 2010. All videos were de-identified and analyzed by a single researcher. Time intervals (e.g., attempt time) and intubation process variables (e.g., Cormack-Lehane [C-L] view) were abstracted from all videos. Time intervals were begun when the laryngoscope blade passed the lips and entered the oral cavity (entry). We describe variables using means and standard deviations (continuous), medians with interquartile ranges (ordinal), and percentages with 95% confidence intervals (categorical). We then looked at univariate associations between these variables and ETI success using logistic regression. Results. We recorded 116 intubations during the study period. Twenty-nine recordings were either incomplete (n = 26) or of insufficient quality for analysis (n = 3). The remaining 87 videos represented 87 different patients with a total of 102 attempts at laryngoscopy. Thirty-six providers performed 64 cases, with the majority of providers (n = 21) performing only one intubation. The first-pass success rate in this series was 76% (n = 66), with 98% success within three attempts. Successful ETI attempts had lower entry-to-percentage of glottic opening (POGO) times (16.6 sec vs. 32.1 sec, p = 0.013), entry-to-first view of the endotracheal tube or entry-to-tube times (17.6 sec vs. 27.4 sec, p = 0.04), higher POGO scores (76 vs. 39, p < 0.001), and lower number of C-L view (one vs. three, p < 0.001). Recognized esophageal intubation was more likely to occur during unsuccessful ETI attempts (43% vs. 8%, p < 0.001). Conclusion. Video laryngoscopy can measure multiple components of ETI performance. Successful ETI attempts have significantly shorter entry-to-POGO times and entry-to-tube times, obtain better views of the glottic opening (POGO and C-L view), and have a lower incidence of recognized esophageal intubation.

Chemoreception: Identifying Friends and Foes

Current Biology : CB. Dec, 2011  |  Pubmed ID: 22192835

The vomeronasal organ detects chemical cues that trigger sexual, aggressive and defensive behaviors. An in situ hybridization analysis has identified the specificities of nearly a hundred VNO receptors and elucidated the logic by which they encode these cues.

Usability Evaluation of a Personal Health Record

AMIA ... Annual Symposium Proceedings / AMIA Symposium. AMIA Symposium. 2011  |  Pubmed ID: 22195184

The electronic personal health record (PHR) has been championed as a mediator of patient-centered care, yet its usability and utility to patients, key predictors of success, have received little attention. Human-centered design (HCD) offers validated methods for studying systems effects on users and their cognitive tasks. In HCD, user-centered activities allow potential users to shape the design of the end product and enhance its usability. We sought to evaluate the usability and functionality of HealthView, the PHR of the Duke University Health System, using HCD methods. Study participants were asked to think aloud as they carried out tasks in HealthView. They then completed surveys and interviews eliciting their reactions to the web portal. Findings were analyzed to generate redesign recommendations, which will be incorporated in a future release of HealthView.

Diagnostic Error: the Hidden Epidemic

Physician Executive. Nov-Dec, 2011  |  Pubmed ID: 22195411

The Impact of Skin-Sparing Mastectomy with Immediate Reconstruction in Patients with Stage III Breast Cancer Treated with Neoadjuvant Chemotherapy and Postmastectomy Radiation

International Journal of Radiation Oncology, Biology, Physics. Dec, 2011  |  Pubmed ID: 22197232

PURPOSE: The safety and efficacy of skin-sparing mastectomy (SSM) with immediate reconstruction (IR) in patients with locally advanced breast cancer are unclear. The purpose of this study is to compare the outcomes of women with noninflammatory Stage III SSM with IR vs. non-SSM-treated women who underwent neoadjuvant chemotherapy and adjuvant radiation therapy (XRT). METHODS AND MATERIALS: Between October 1997 and March 2010, 100 consecutive patients (40 SSM with IR vs. 60 non-SSM) with Stage III breast cancer received anthracycline- and/or taxane-based neoadjuvant chemotherapy, mastectomy, and adjuvant XRT. Clinical stage (SSM with IR vs. for non-SSM) was IIIA (75% vs. 67%), IIIB (8% vs. 18%), and IIIC (8% vs. 8%). Tumors greater than 5 cm were found in 74% vs. 69%; 97% of patients in both groups were clinically node positive; and 8% vs. 18% had T4b disease. RESULTS: The time from initial biopsy to XRT was prolonged for SSM-IR patients (274 vs. 254 days, p = 0.04), and there was a trend toward XRT delay of more than 8 weeks (52% vs. 31%, p = 0.07) after surgery. The rate of complications requiring surgical intervention was higher in the SSM-IR group (37.5% vs. 5%, p < 0.001). The 2-year actuarial locoregional control, breast cancer-specific survival, and overall survival rates for SSM with IR vs. non-SSM were 94.7% vs. 97.4%, 91.5% vs. 86.3%, and 87.4% vs. 84.8%, respectively (p = not significant). CONCLUSIONS: In our small study with limited follow-up, SSM with IR prolonged overall cancer treatment time and trended toward delaying XRT but did not impair oncologic outcomes. Complication rates were significantly higher in this group. Longer follow-up is needed.

Cefoperazone-treated Mice As an Experimental Platform to Assess Differential Virulence of Clostridium Difficile Strains

Gut Microbes. Nov, 2011  |  Pubmed ID: 22198617

The toxin-producing bacterium C. difficile is the leading cause of antibiotic-associated colitis, with an estimated 500,000 cases C. difficile infection (CDI) each year in the U.S with a cost approaching 3 billion dollars. Despite the significance of CDI, the pathogenesis of this infection is still being defined. The recent development of tractable murine models of CDI will help define the determinants of C. difficile pathogenesis in vivo. To determine if cefoperazone-treated mice could be utilized to reveal differential pathogenicity of C. difficile strains, 5-8 week old C57BL/6 mice were pretreated with a 10 d course of cefoperazone administered in the drinking water. Following a 2-d recovery period without antibiotics, the animals were orally challenged with C. difficile strains chosen to represent the potential range of virulence of this organism from rapidly fatal to nonpathogenic. Animals were monitored for loss of weight and clinical signs of colitis. At the time of harvest, C. difficile strains were isolated from cecal contents and the severity of colitis was determined by histopathologic examination of the cecum and colon. Cefoperazone treated mice challenged with C. difficile strains VPI 10463 and BI1, exhibited signs of severe colitis while infection with 630 and F200 was subclinical. This increased clinical severity was correlated with more severe histopathology with significantly more edema, inflammation and epithelial damage encountered in the colons of animals infected with VPI 10463 and BI1. Disease severity also correlated with levels of C. difficile cytotoxic activity in intestinal tissues and elevated blood neutrophil counts. Cefoperazone treated mice represent a useful model of C. difficile infection that will help us better understand the pathogenesis and virulence of this re-emerging pathogen.

Genetic Variability in EGFR, Src and HER2 and Risk of Colorectal Adenoma and Cancer

International Journal of Molecular Epidemiology and Genetics. 2011  |  Pubmed ID: 22199994

The EGFR signaling pathway is involved in carcinogenesis at multiple sites, particularly colorectal cancer, and is a target of colorectal cancer chemotherapy. EGFR signaling is linked to pro-carcinogenic mechanisms, including cell proliferation, survival, angiogenesis, and more recently prostaglandin synthesis. Genetic variability in this pathway has not yet been studied in relation to colorectal carcinogenesis. In three case-control studies of colorectal adenoma (n=485 cases/578 controls), colon cancer (n=1424 cases/1780 controls) and rectal cancer (n=583 cases/775 controls), we investigated associations between candidate SNPs, tagSNPs and haplotypes in EGFR signaling (EGFR, Src, and HER2) and risk. We also examined associations with tumor subtypes: TP53 and KRAS2 mutations, CpG island methylator phenotype, and microsatellite instability. All three studies were genotyped using an identical Illumina GoldenGate assay, allowing thorough investigation of genetic variability across stages and locations of colorectal neoplasia. The EGFR tagSNP 142572T>C (rs3752651) CC genotype was associated with a suggested increased risk for both colon (OR: 1.40; 95% CI: 1.00-1.96; p-trend=0.04) and rectal cancer (OR: 1.39; 95% CI: 0.81-2.41; p-trend=0.65). In tumor subtype analyses, the association was limited to TP53-mutated colon tumors. Using the Chatterjee 1 df Tukey test to assess gene-gene interactions, we observed a statistically significant (p<0.01) interaction between SNPs in EGFR and Src for colorectal adenoma risk. The association with EGFR 142572 should be investigated in additional studies and the significant gene-gene interaction between EGFR and Src in relation to adenoma risk suggests that these two genes are jointly affecting early stages in colorectal carcinogenesis and requires further follow-up.

Neural Reactivity Tracks Fear Generalization Gradients

Biological Psychology. Dec, 2011  |  Pubmed ID: 22200657

Recent studies on fear generalization have demonstrated that fear-potentiated startle and skin conductance responses to a conditioned stimulus (CS) generalize to similar stimuli, with the strength of the fear response linked to perceptual similarity to the CS. The aim of the present study was to extend this work by examining neural correlates of fear generalization. An initial experiment (N=8) revealed that insula reactivity tracks the conditioned fear gradient. We then replicated this effect in a larger independent sample (N=25). Activation in the insula, anterior cingulate, right supplementary motor cortex and caudate increased reactivity as generalization stimuli (GS) were more similar to the CS, consistent with participants' overall ratings of perceived shock likelihood and pupillary response to each stimulus.

Physical and Mental Impact of Psoriasis Severity As Measured by the Compact Short Form-12 Health Survey (SF-12) Quality of Life Tool

The Journal of Investigative Dermatology. Dec, 2011  |  Pubmed ID: 22205305

The Short Form-12 Health Survey (SF-12) is used to assess the patient's quality of life (QoL) using the physical component score (PCS) and the mental component score (MCS). The purpose of this study was to determine whether the SF-12 PCS and MCS are associated with psoriasis severity and to compare QoL between Murdough Family Center for Psoriasis (MFCP) patients and patients with other major chronic diseases included in the National Survey of Functional Health Status data. We used data from 429 adult patients enrolled in MFCP. Psoriasis Area Severity Index (PASI) was used to assess psoriasis severity at the time of completion of the SF-12 questionnaire. Other variables included age, sex, body mass index, psoriatic arthritis, psychiatric disorders, and comorbidities. Linear regression models were used to estimate effect sizes ±95% confidence intervals. For every 10-point increase in PASI, there was a 1.1±1.3 unit decrease in MCS (P=0.100) and a 2.4±1.3 unit decrease in PCS (P<0.001). Psoriasis severity was associated with PCS and MCS after adjusting for variables, although the strength of the relationship was attenuated in some models. Psoriasis severity is associated with decreased QoL. SF-12 may be a useful tool for assessing QoL among psoriasis patients.Journal of Investigative Dermatology advance online publication, 29 December 2011; doi:10.1038/jid.2011.427.

Brief Physical Activity-Related Psychosocial Measures: Reliability and Construct Validity

Journal of Physical Activity & Health. Dec, 2011  |  Pubmed ID: 22207589

BACKGROUND: Psychosocial factors have been related to physical activity (PA) and are used to evaluate mediation in PA interventions. METHODS: Brief theory-based psychosocial scales were compiled from existing measures and evaluated. Study 1 assessed factor structure and construct validity with self-reported PA and accelerometry in overweight/obese men (N = 441) and women (N = 401). Study 2 assessed two-week reliability and internal consistency in 49 college students. RESULTS: Confirmatory factor analysis indicated good fit in men and women (CFI = .90; RMSEA = .05). Construct validity was supported for change strategies (r's = .29 to .46), self-efficacy (r's = .19 to .22) and enjoyment (r's = .21 to .33) in men and women, and for cons in women (r's = -.19 to -.20). PA pros (r's = -.02 to .11) and social support (r's = -.01 to .12) were not supported for construct validity. Test-retest reliability ICCs ranged from .49 to .81. Internal consistency alphas ranged from .55 to .90. Reliability was supported for most scales with further testing needed for cons (alphas = .55 to .63) and enjoyment (ICC = .49). CONCLUSIONS: Many of the brief scales demonstrated adequate reliability and validity, while some need further development. The use of these scales could advance research and practice in the promotion of PA.

Implementing Interpersonal and Social Rhythm Therapy for Mood Disorders Across a Continuum of Care

Psychiatric Services (Washington, D.C.). Nov, 2011  |  Pubmed ID: 22211221

Interpersonal and social rhythm therapy (IPSRT) is an evidence-based psychotherapy for mood disorders. The goal of this quality improvement initiative was to demonstrate feasibility of implementing IPSRT across the continuum of outpatient and inpatient care within an academic medical center.

Manualization of Occupational Therapy Interventions: Illustrations from the Pressure Ulcer Prevention Research Program

The American Journal of Occupational Therapy. : Official Publication of the American Occupational Therapy Association. Nov-Dec, 2011  |  Pubmed ID: 22214116

The manualization of a complex occupational therapy intervention is a crucial step in ensuring treatment fidelity for both clinical application and research purposes. Toward the latter end, intervention manuals are essential for ensuring trustworthiness and replicability of randomized controlled trials that aim to provide evidence of the effectiveness of occupational therapy. In this article, we review the literature on the process of intervention manualization. We then illustrate the prescribed steps through our experience in implementing the University of Southern California/Rancho Los Amigos National Rehabilitation Center's collaborative Pressure Ulcer Prevention Project. In this research program, qualitative research provided the initial foundation for manualization of a multifaceted occupational therapy intervention designed to reduce the incidence of medically serious pressure ulcers in adults with spinal cord injury.

Parenthood, Life Course Expectations, and Mental Health

Society and Mental Health. Mar, 2011  |  Pubmed ID: 22229115

Although past research indicates that early and premarital childbearing negatively affect mental health, little is known about the role of individual expectations in shaping these associations. Using data from the National Longitudinal Survey of Youth 1979, we consider how individual expectations, measured prior to the entry into parenthood, shape mental health outcomes associated with premarital childbearing and birth timing, and consider gender and race/ethnic variations. Results indicate that expecting children before marriage ameliorates the negative mental health consequences of premarital first births and that subsequently deviating from expected birth timing, either early or late, results in increased distress at all birth ages. In both cases, however, the degree and manner in which expectations matter differ by gender and race/ethnicity. Results indicate that expectations for premarital childbearing matter only for African-Americans' mental health and although later than expected births are associated with decreased mental health for all groups, earlier than expected births are only associated with decreased mental health for women, Hispanics, and non-Hispanic whites.

Arcuate, Red Plaques with Pustules on the Trunk

American Family Physician. Dec, 2011  |  Pubmed ID: 22230276

Deficiency in the 15 KDa Selenoprotein Inhibits Human Colon Cancer Cell Growth

Nutrients. Sep, 2011  |  Pubmed ID: 22254125

Selenium is an essential micronutrient for humans and animals, and is thought to provide protection against some forms of cancer. These protective effects appear to be mediated, at least in part, through selenium-containing proteins (selenoproteins). Recent studies in a mouse colon cancer cell line have shown that the 15 kDa selenoprotein (Sep15) may also play a role in promoting colon cancer. The current study investigated whether the effects of reversing the cancer phenotype observed when Sep15 was removed in mouse colon cancer cells, were recapitulated in HCT116 and HT29 human colorectal carcinoma cells. Targeted down-regulation of Sep15 using RNAi technology in these human colon cancer cell lines resulted in similarly decreased growth under anchorage-dependent and anchorage-independent conditions. However, the magnitude of reduction in cell growth was much less than in the mouse colon cancer cell line investigated previously. Furthermore, changes in cell cycle distribution were observed, indicating a delayed release of Sep15 deficient cells from the G(0)/G(1) phase after synchronization. The potential mechanism by which human colon cancer cells lacking Sep15 revert their cancer phenotype will need to be explored further.

Emerging Technology for Advancing the Treatment of Epilepsy Using a Dynamic Control Framework

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. Aug, 2011  |  Pubmed ID: 22254420

We briefly describe a dynamic control system framework for neuromodulation for epilepsy, with an emphasis on its practical challenges and the preliminary validation of key prototype technologies in a chronic animal model. The current state of neuromodulation can be viewed as a classical dynamic control framework such that the nervous system is the classical "plant", the neural stimulator is the controller/actuator, clinical observation, patient diaries and/or measured bio-markers are the sensor, and clinical judgment applied to these sensor inputs forms the state estimator. Technology can potentially address two main factors contributing to the performance limitations of existing systems: "observability," the ability to observe the state of the system from output measurements, and "controllability," the ability to drive the system to a desired state. In addition to improving sensors and actuator performance, methods and tools to better understand disease state dynamics and state estimation are also critical for improving therapy outcomes. We describe our preliminary validation of key "observability" and "controllability" technology blocks using an implanted research tool in an epilepsy disease model. This model allows for testing the key emerging technologies in a representative neural network of therapeutic importance. In the future, we believe these technologies might enable both first principles understanding of neural network behavior for optimizing therapy design, and provide a practical pathway towards clinical translation.

Brain-controlled Telepresence Robot by Motor-disabled People

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. Aug, 2011  |  Pubmed ID: 22255272

In this paper we present the first results of users with disabilities in mentally controlling a telepresence robot, a rather complex task as the robot is continuously moving and the user must control it for a long period of time (over 6 minutes) to go along the whole path. These two users drove the telepresence robot from their clinic more than 100 km away. Remarkably, although the patients had never visited the location where the telepresence robot was operating, they achieve similar performances to a group of four healthy users who were familiar with the environment. In particular, the experimental results reported in this paper demonstrate the benefits of shared control for brain-controlled telepresence robots. It allows all subjects (including novel BMI subjects as our users with disabilities) to complete a complex task in similar time and with similar number of commands to those required by manual control.

Genetic Variability in IL23R and Risk of Colorectal Adenoma and Colorectal Cancer

Cancer Epidemiology. Dec, 2011  |  Pubmed ID: 22154103

Inflammatory processes, including, specifically, the inflammatory conditions Crohn's disease (CD) and ulcerative colitis (UC) predispose to colorectal cancer. Interleukin-23 is involved in pro-inflammatory signaling; genetic variation in the interleukin-23 receptor (IL23R) has been consistently associated with CD and UC risk. In three case-control studies of colorectal adenoma (n=485 cases/578 controls), colon cancer (n=1424 cases/1780 controls) and rectal cancer (n=583 cases/775 controls), we investigated associations with 18 candidate and tagSNPs in IL23R. The three studies used an identical Illumina GoldenGate assay, allowing thorough investigation across stages and locations of colorectal neoplasia. We further explored associations with molecular cancer subtypes (MSI+, CIMP+, KRAS2mut, TP53mut). In this comprehensive study of genetic variability in IL23R across the spectrum of colorectal carcinogenesis, as well as within colon and rectal tumor molecular subtypes, we observed associations between SNPs in IL23R and risk of rectal cancer: the 88413 C>A (rs10889675) and 69450 C>A (rs7542081) polymorphisms were associated with decreased rectal cancer risk overall (p-trend=0.04 and 0.05 respectively), and specifically with rectal tumors bearing a TP53 mutation (88413 CA/AA vs. CC OR: 0.66; 95% CI: 0.46-94; 69450 CA/AA vs. CC OR: 0.60; 95% CI: 0.37-0.98). However, none of associations remained statistically significant after correction for multiple testing. These data provide some evidence that genetic variability in IL23R may contribute to rectal cancer risk and should be evaluated in additional studies.

Procedural Sedation for Diagnostic Imaging in Children by Pediatric Hospitalists Using Propofol: Analysis of the Nature, Frequency, and Predictors of Adverse Events and Interventions

The Journal of Pediatrics. Dec, 2011  |  Pubmed ID: 22177990

OBJECTIVE: To evaluate the nature, frequency, and predictors of adverse events during the use of propofol by pediatric hospitalists. STUDY DESIGN: We reviewed 1649 charts of patients sedated with propofol by pediatric hospitalists at St Louis Children's Hospital between January 2005 and September 2009. RESULTS: Hospitalists were able to complete 1633 of the 1649 sedations reviewed (99%). Major complications included 2 patients with aspiration and 1 patient intubated to complete the study. We observed a 74% reduction in the number of patients with respiratory events and airway interventions from 2005 to 2009. Predictors of respiratory events were history of snoring (OR, 2.40; 95% CI, 1.52-3.80), American Society of Anesthesiologists (ASA) physical status classification of ASA 3 (OR, 2.30; 95% CI, 1.22-4.33), age >12 years (OR, 4.01; 95% CI, 2.02-7.98), premedication with midazolam (OR, 1.85; 95% CI, 1.15-2.98), and use of adjuvant glycopyrrolate (OR, 4.70; 95% CI, 2.35-9.40). All except ASA 3 status were also predictors for airway intervention. There was a decline in the prevalence of all of these predictors over the study years (P < .05) except for use of glycopyrrolate. CONCLUSION: Our pediatric hospitalists implemented a successful propofol sedation program that realized a 74% reduction in respiratory events and airway interventions between 2005 and 2009. Decreased prevalence of the predictors of adverse events that we identified likely contributed to this reduction.

Membrane Topology of the Bacillus Anthracis GerH Germinant Receptor Proteins

Journal of Bacteriology. Dec, 2011  |  Pubmed ID: 22178966

Bacillus anthracis spores are the etiologic agent of anthrax. Nutrient germinant receptors (nGRs) packaged within the inner membrane of the spore sense the presence of specific stimuli in the environment and trigger the process of germination, quickly returning the bacterium to the metabolically active, vegetative bacillus. This ability to sense the host environment and initiate germination is a required step in the infectious cycle. The nGRs are comprised of three subunits: the A-, B-, and C-type proteins. To date there is limited structural data for the A- and B-type nGR subunits. Here the transmembrane topologies of the B. anthracis GerH(A), GerH(B) and GerH(C) proteins are presented. C-terminal GFP fusions to varying lengths of the GerH proteins were overexpressed in vegetative bacteria and the subcellular locations of these GFP fusion sites were analyzed by flow cytometry and protease sensitivity. GFP fusion to full length GerH(C) confirmed that the C-terminus of this protein is extracellular as predicted. GerH(A) and GerH(B) were both predicted to be integral membrane proteins by topology modeling. Analysis of C-terminal GFP fusions to full length GerH(B) and nine truncated GerH(B) proteins support either an eight or ten transmembrane domain topology. For GerH(A), C-terminal GFP fusions to full length GerH(A) and six truncated GerH(A) proteins were consistent with a four transmembrane domain topology. Understanding the membrane topology of these proteins is an important step in determining potential ligand binding and protein-protein interaction domains, as well as providing new information for interpreting previous genetic work.

Hospital Merger Challenged. FTC Keeps Up Interest in Healthcare Deals

Modern Healthcare. Nov, 2011  |  Pubmed ID: 22250359

Pressure Point. Downsized NLRB Rules Don't Appease Critics

Modern Healthcare. Dec, 2011  |  Pubmed ID: 22250492

Technical Advances in Skin Sparing Mastectomy

International Journal of Surgical Oncology. 2011  |  Pubmed ID: 22312504

Skin sparing mastectomy has resulted in marked improvement in the aesthetic results of immediate breast reconstruction. Mature data has confirmed its oncological safety in the treatment of breast cancer. The procedure has gained wide acceptance and has undergone numerous technical advances since its introduction over twenty years ago. Careful patient selection and choice of skin incisions are necessary to avoid complications.

Assertive or Antiquated: ProMedica Vows to Appeal Loss Against FTC As Questions Loom over Whether Mergers Lead to Efficiencies or Clout

Modern Healthcare. Dec, 2011  |  Pubmed ID: 22299225

ProMedica vows to fight the feds over the acquisition of St. Luke's Hospital. Here is what they have to say. "The cost of healthcare is a real problem for all Americans, and the commission seeks to address this national problem by using all the tools Congress gave to us, and by devoting significant resources so that competition will enable market participants to deliver on the promises of cost-containment and continued excellence and innovation," says the FTC's Jon Leibowitz.

Impulsivity is Not Always Associated with Student Drinking: A Moderation Study of Impulsivity and Drinking by Positive Alcohol Expectancies

Addictive Behaviors. Dec, 2011  |  Pubmed ID: 22226477

Student drinking is a major problem on North American campuses and impulsivity is a significant risk factor for heavy drinking. The present study investigates the moderation of the impulsivity-drinking relationship by the expectation that having a drink will lead to positive experiences. Undergraduate drinkers (n=292) completed measures of impulsivity (Barratt Impulsiveness Scale 11; BIS-11), positive drinking expectancies, and alcohol use. Expectancies moderated the relationship between BIS-11 scores and alcohol use. BIS-11 scores were significantly related to typical alcohol quantity, frequency, quantity X frequency, and binge drinking frequency for individuals with average and high levels of positive expectancies, but not for those with few positive expectancies. Implications for interventions targeted at highly impulsive students, using expectancy modification are discussed.

The Role of Iron in Learning and Memory

Advances in Nutrition (Bethesda, Md.). Mar, 2011  |  Pubmed ID: 22332040

Iron deficiency (ID) is the most common nutrient deficiency, affecting 2 billion people and 30% of pregnant women and their offspring. Early life ID affects at least 3 major neurobehavioral domains, including speed of processing, affect, and learning and memory, the latter being particularly prominent. The learning and memory deficits occur while the infants are iron deficient and persist despite iron repletion. The neural mechanisms underlying the short- and long-term deficits are being elucidated. Early ID alters the transcriptome, metabolome, structure, intracellular signaling pathways, and electrophysiology of the developing hippocampus, the brain region responsible for recognition learning and memory. Until recently, it was unclear whether these effects are directly due to a lack of iron interacting with important transcriptional, translational, or post-translational processes or to indirect effects such as hypoxia due to anemia or stress. Nonanemic genetic mouse models generated by conditionally altering expression of iron transport proteins specifically in hippocampal neurons in late gestation have led to a greater understanding of iron's role in learning and memory. The learning deficits in adulthood likely result from interactions between direct and indirect effects that contribute to abnormal hippocampal structure and plasticity.

Biosynthesis of Selenocysteine, the 21st Amino Acid in the Genetic Code, and a Novel Pathway for Cysteine Biosynthesis

Advances in Nutrition (Bethesda, Md.). Mar, 2011  |  Pubmed ID: 22332041

The biosynthetic pathway for selenocysteine (Sec), the 21st amino acid in the genetic code whose codeword is UGA, was recently determined in eukaryotes and archaea. Sec tRNA, designated tRNA([Ser]Sec), is initially aminoacylated with serine by seryl-tRNA synthetase and the resulting seryl moiety is converted to phosphoserine by O-phosphoseryl-tRNA kinase to form O-phosphoseryl-tRNA([Ser]Sec). Sec synthase (SecS) then uses O-phosphoseryl-tRNA([Ser]Sec) and the active donor of selenium, selenophosphate, to form Sec-tRNA([Ser]Sec). Selenophosphate is synthesized from selenide and ATP by selenophosphate synthetase 2 (SPS2). Sec was the last protein amino acid in eukaryotes whose biosynthesis had not been established and the only known amino acid in eukaryotes whose biosynthesis occurs on its tRNA. Interestingly, sulfide can replace selenide to form thiophosphate in the SPS2-catalyzed reaction that can then react with O-phosphoseryl-tRNA([Ser]Sec) in the presence of SecS to form cysteine-(Cys-)tRNA([Ser]Sec). This novel pathway of Cys biosynthesis results in Cys being decoded by UGA and replacing Sec in normally selenium-containing proteins (selenoproteins). The selenoprotein, thioredoxin reductase 1 (TR1), was isolated from cells in culture and from mouse liver for analysis of Cys/Sec replacement by MS. The level of Cys/Sec replacement in TR1 was proportional to the level of selenium in the diet of the mice. Elucidation of the biosynthesis of Sec and Sec/Cys replacement provides novel ways of regulating selenoprotein functions and ultimately better understanding of the biological roles of dietary selenium.

Prevalence of Sleep Apnea in Patients With Keratoconus

Cornea. Feb, 2012  |  Pubmed ID: 22333661

PURPOSE: To determine the prevalence of obstructive sleep apnea (OSA) in patients with keratoconus and evaluate the risk of developing OSA in this patient population. METHODS: Three hundred sixty-two patients diagnosed with keratoconus by a single physician at the Duke Eye Center over a 14-year period were identified. A power calculation was done a priori, and based on this, the first 101 patients were enrolled. All patients were administered a standardized questionnaire regarding medical and ocular health. Those without the history of OSA were administered the Berlin questionnaire to determine their risk for developing OSA. Statistical analysis was performed to determine the prevalence of OSA and to compare it with previously reported prevalence data in the general population. RESULTS: The prevalence of previously diagnosed OSA was 18% (18 of 101); all reported having a formal sleep study in the past. Of the remaining patients (n = 83), 47% (39 of 83) were determined to be at high risk for the development of OSA determined by the Berlin questionnaire score. Comorbid health conditions included hypertension (37%), acid reflux (30%), diabetes mellitus (20%), and seasonal allergies (66%). A history of penetrating keratoplasty was found in 48%. The average body mass index of the study population was 31.2 (median, 28.4). CONCLUSIONS: Keratoconus patients have a higher prevalence of OSA compared with that accepted for the general population. A striking number of our patients without previous diagnosis of OSA seem to be at high risk for developing OSA, supporting our recommendation for a greater awareness among clinicians who might otherwise overlook this systemic condition and its consequences.

Prevalence and Costs of Co-occurring Traumatic Brain Injury With and Without Psychiatric Disturbance and Pain Among Afghanistan and Iraq War Veteran VA Users

Medical Care. Jan, 2012  |  Pubmed ID: 22228249

BACKGROUND:: Traumatic brain injury (TBI) is the "signature injury" in the Afghanistan and Iraq wars [Operation Enduring Freedom in Afghanistan (OEF)/Operation Iraqi Freedom (OIF)]. Patients with combat-related TBI also have high rates of psychiatric disturbances and pain. OBJECTIVES:: To determine the prevalence of TBI alone and TBI with other conditions and the average cost of medical care for veterans with these diagnoses. METHODS:: Observational study using national inpatient, outpatient, and pharmacy data from Veterans Health Administration (VHA) datasets. Costs are estimated from utilization related to care within the VHA system. Participants were all OEF/OIF VHA users in 2009. RESULTS:: Among 327,388 OEF/OIF veterans using VHA services in 2009, 6.7% were diagnosed with TBI. Among those with TBI diagnoses, 89% were diagnosed with a psychiatric diagnosis [the most frequent being posttraumatic stress disorder (PTSD) at 73%], and 70% had a diagnosis of head, back, or neck pain. The rate of comorbid PTSD and pain among those with and without TBI was 54% and 11%, respectively. The median annual cost per patient was nearly 4-times higher for TBI-diagnosed veterans as compared with those without TBI ($5831 vs. $1547). Within the TBI group, cost increased as diagnostic complexity increased, such that those with TBI, pain, and PTSD demonstrated the highest median cost per patient ($7974). CONCLUSIONS:: The vast majority of VHA patients diagnosed with TBI also have a diagnosed mental disorder and more than half have both PTSD and pain. Patients with these comorbidities incur substantial medical costs and represent a target population for future research aimed at improving health care efficiency.

Autophagy Plays an Essential Role in the Clearance of Pseudomonas Aeruginosa by Alveolar Macrophages

Journal of Cell Science. Feb, 2012  |  Pubmed ID: 22302984

Intracellular bacteria have been shown to cause autophagy, which impacts infectious outcomes, whereas extracellular bacteria have not been reported to activate autophagy. Here, we demonstrate that Pseudomonas aeruginosa, a Gram-negative extracellular bacterium, activates autophagy with considerably increased LC3 punctation in both an alveolar macrophage cell line (MH-S) and primary alveolar macrophages. Using the LC3 Gly120 mutant, we successfully demonstrated a hallmark of autophagy, conjugation of LC3 to phosphatidylethanolamine (PE). The accumulation of typical autophagosomes with double membranes was identified morphologically by transmission electron microscopy (TEM). Furthermore, the increase of PE-conjugated LC3 was indeed induced by infection rather than inhibition of lysosome degradation. P. aeruginosa induced autophagy through the classical beclin-1-Atg7-Atg5 pathway as determined by specific siRNA analysis. Rapamycin and IFN-γ (autophagy inducers) augmented bacterial clearance, whereas beclin-1 and Atg5 knockdown reduced intracellular bacteria. Thus, P. aeruginosa-induced autophagy represents a host protective mechanism, providing new insight into the pathogenesis of this infection.

Activin-like Kinase 3 is Important for Kidney Regeneration and Reversal of Fibrosis

Nature Medicine. Feb, 2012  |  Pubmed ID: 22306733

Molecules associated with the transforming growth factor β (TGF-β) superfamily, such as bone morphogenic proteins (BMPs) and TGF-β, are key regulators of inflammation, apoptosis and cellular transitions. Here we show that the BMP receptor activin-like kinase 3 (Alk3) is elevated early in diseased kidneys after injury. We also found that its deletion in the tubular epithelium leads to enhanced TGF-β1-Smad family member 3 (Smad3) signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3-mediated signaling in the kidney. A structure-function analysis of the BMP-Alk3-BMP receptor, type 2 (BMPR2) ligand-receptor complex, along with synthetic organic chemistry, led us to construct a library of small peptide agonists of BMP signaling that function through the Alk3 receptor. One such peptide agonist, THR-123, suppressed inflammation, apoptosis and the epithelial-to-mesenchymal transition program and reversed established fibrosis in five mouse models of acute and chronic renal injury. THR-123 acts specifically through Alk3 signaling, as mice with a targeted deletion for Alk3 in their tubular epithelium did not respond to therapy with THR-123. Combining THR-123 and the angiotensin-converting enzyme inhibitor captopril had an additive therapeutic benefit in controlling renal fibrosis. Our studies show that BMP signaling agonists constitute a new line of therapeutic agents with potential utility in the clinic to induce regeneration, repair and reverse established fibrosis.

Surface Multiheme C-type Cytochromes from Thermincola Potens and Implications for Respiratory Metal Reduction by Gram-positive Bacteria

Proceedings of the National Academy of Sciences of the United States of America. Jan, 2012  |  Pubmed ID: 22307634

Almost nothing is known about the mechanisms of dissimilatory metal reduction by Gram-positive bacteria, although they may be the dominant species in some environments. Thermincola potens strain JR was isolated from the anode of a microbial fuel cell inoculated with anaerobic digester sludge and operated at 55 °C. Preliminary characterization revealed that T. potens coupled acetate oxidation to the reduction of hydrous ferric oxides (HFO) or anthraquinone-2,6-disulfonate (AQDS), an analog of the redox active components of humic substances. The genome of T. potens was recently sequenced, and the abundance of multiheme c-type cytochromes (MHCs) is unusual for a Gram-positive bacterium. We present evidence from trypsin-shaving LC-MS/MS experiments and surface-enhanced Raman spectroscopy (SERS) that indicates the expression of a number of MHCs during T. potens growth on either HFO or AQDS, and that several MHCs are localized to the cell wall or cell surface. Furthermore, one of the MHCs can be extracted from cells with low pH or denaturants, suggesting a loose association with the cell wall or cell surface. Electron microscopy does not reveal an S-layer, and the precipitation of silver metal on the cell surface is inhibited by cyanide, supporting the involvement of surface-localized redox-active heme proteins in dissimilatory metal reduction. These results provide unique direct evidence for cell wall-associated cytochromes and support MHC involvement in conducting electrons across the cell envelope of a Gram-positive bacterium.

Utility of Routine Follow-up Head CT Scanning After Mild Traumatic Brain Injury: a Systematic Review of the Literature

Emergency Medicine Journal : EMJ. Feb, 2012  |  Pubmed ID: 22307924

ObjectiveTo evaluate the efficacy of routine follow-up CT scans of the head after complicated mild traumatic brain injury (TBI).Methods74 English language studies published from 1999 to February 2011 were reviewed. The papers were found by searching the PubMed database using a combination of keywords according to Cochrane guidelines. Excluding studies with missing or inappropriate data, 1630 patients in 19 studies met the inclusion criteria: complicated mild TBI, defined as a GCS score 13-15 with abnormal initial CT findings and the presence of follow-up CT scans. For these studies, the progression and type of intracranial haemorrhage, time from trauma to first scan, time between first and second scans, whether second scans were obtained routinely or for neurological decline and the number of patients who had a neurosurgical intervention were recorded.ResultsRoutine follow-up CT scans showed hemorrhagic progression in 324 patients (19.9%). Routine follow-up head CT scans did not predict the need for neurosurgical intervention (p=0.10) but a CT scan of the head performed for decline in status did (p=0.00046). For the 56 patients (3.4%) who declined neurologically, findings on the second CT scan were worse in 38 subjects (67%) and unchanged in the rest. Overall, 39 patients (2.4%) underwent neurosurgical intervention.ConclusionRoutine follow-up CT scans rarely alter treatment for patients with complicated mild TBI. Follow-up CT scans based on neurological decline alter treatment five times more often than routine follow-up CT scans.

The Intracarotid Amobarbital Procedure: When is It Worth Repeating?

Epilepsia. Feb, 2012  |  Pubmed ID: 22309160

Purpose:  Despite the reported diagnostic value of the intracarotid amobarbital procedure (IAP) or "Wada test" for determining hemispheric lateralization and memory functioning, it has never undergone formal reliability testing because a prospective test-retest study design is neither feasible nor ethical. However, some patients require repeat testing for clinical purposes, a circumstance that allows for exploration of issues related to reliability. The current investigation sought to: (1) evaluate the frequency of and reasons for repeated IAPs and (2) describe the test-retest reliability of repeated IAPs in a large tertiary epilepsy center. Methods:  A 10-year review (2001-2011) of the New York University Langone Medical Center Comprehensive Epilepsy Center patient registry revealed 630 IAPs. Review of medical records identified 20 individuals who underwent two or more IAPs on separate days. Because IAPs repeated due to technical problems should be considered separate from IAPs repeated for other reasons because these IAPs likely included a change in the procedure (e.g., lower medication dose) in an attempt to ameliorate the complication, patients were grouped accordingly. Six patients underwent repeated IAPs due to technical complication and 14 patients underwent a repeated IAP due to other reasons (e.g., unexpected memory outcome, reconsideration of surgery years after a previous surgical work-up in which no surgery was performed, and/or consideration of a second surgery). Given that data obtained from injections ipsilateral to a seizure focus are sometimes considered in a manner clinically different from data obtained from injections contralateral to the seizure focus, memory outcome was classified relative to the side of identified seizure focus. The degree to which language and memory data were consistent across repeated IAPs was examined. Key Findings:  Language functioning was consistently lateralized across IAPs in all but one case. Among the six patients who experienced technical problems in the first IAP, three were fully participatory in the second procedure such that valid data were obtained. For the other three, the technical problem recurred with no change in outcome across procedures. Among the 14 patients with repeated IAPs due to other reasons, 79% of the available ipsilateral and 73% of the contralateral pass/fail outcomes were consistent across procedures. No difference between ipsilateral or contralateral injections was observed for the likelihood of a change in results (p = 0.57). Significance:  Our data identified overall high reliability for both the ipsilateral and contralateral sides with repeated IAP testing. Results indicated that although patients for whom a correctable technical problem was identified during the IAP may benefit from a repeat study, there is little benefit to repeating the IAP in patients with discordant or unexpected results (i.e., results are not likely to change). These data support the overall reliability of both the language and memory data obtained from the IAP.

Caring for Grieving Family Members: Results From a National Hospice Survey

Medical Care. Feb, 2012  |  Pubmed ID: 22310561

BACKGROUND:: A founding principle of hospice is that the patient and family is the unit of care; however, we lack national information on services to family members. Although Medicare certification requires bereavement services be provided, reimbursement rates are not tied to the level or quality of care; therefore, limited financial incentives exist for hospice to provide more than a minimal benefit. OBJECTIVES:: To assess the scope and intensity of services provided to family members by hospice. RESEARCH DESIGN:: We fielded a national survey of hospices between September 2008 and November 2009. PARTICIPANTS:: A national sample of US hospices with an 84% response rate (N=591). MEASURES:: Bereavement services to the family, bereavement services to the community, labor-intensive family services, and comprehensive family services. RESULTS:: Most hospices provided bereavement services to the family (78%) and to the community (76%), but only a minority of hospices provided labor-intensive (23%) or comprehensive (27%) services to grieving family members. Larger hospice size was positively and significantly associated with each of the 4 measures of family services. We found no significant difference in provision of bereavement services to the family, labor-intensive services, or comprehensive services by ownership type; however, nonprofit hospices were more likely than for-profit hospices to provide bereavement services to the community. CONCLUSIONS:: Our results show substantial diversity in the scope and intensity of services provided to families of patients with terminal illnesses, suggesting a need for clearer guidance on what hospices should provide to exemplify best practices. Consensus within the field on more precise guidelines in this area is essential.

Correlating Novice Nurses' Perceptions of Nursing Orientation and First-year Support with Direct Preceptor Interventions

Journal of Continuing Education in Nursing. Feb, 2012  |  Pubmed ID: 22313130

Can preceptors correlate novices' experiences of the transition into nursing with interventions for support? A medical specialty preceptor committee representing more than 300 nurses at a large academic medical center conducted educational sessions for 46 inpatient nurses who had successfully completed orientation, but were still in the first year of practice. The novice forum used literature themes to guide exploration of the novices' perceptions. In the two novice forum sessions, the new nurses were invited to reflect on their experiences using a Turning Point Query(©). The questions posed addressed the themes in the literature concerning the transition into professional practice. After noting and discussing the group responses, each preceptor committee representative held a discussion with two novices about their struggles and successes. The preceptors, after learning about novices' needs in this way, planned and directed forums for preceptor development of their peers. Concepts and teaching activities addressed the novices' identified concerns, which targeted greater need for feedback, affirmation, and debriefing, as well as reflective discussions on practice. This group thus correlated novices' perceptions with preceptor development activities.

Correlating Novice Nurses' Perceptions of Nursing Orientation and First-year Support with Direct Preceptor Interventions

Journal of Continuing Education in Nursing. Feb, 2012  |  Pubmed ID: 22313131

Can preceptors correlate novices' experiences of the transition into nursing with interventions for support? A medical specialty preceptor committee representing more than 300 nurses at a large academic medical center conducted educational sessions for 46 inpatient nurses who had successfully completed orientation, but were still in the first year of practice. The novice forum used literature themes to guide exploration of the novices' perceptions. In the two novice forum sessions, the new nurses were invited to reflect on their experiences using a Turning Point Query(©). The questions posed addressed the themes in the literature concerning the transition into professional practice. After noting and discussing the group responses, each preceptor committee representative held a discussion with two novices about their struggles and successes. The preceptors, after learning about novices' needs in this way, planned and directed forums for preceptor development of their peers. Concepts and teaching activities addressed the novices' identified concerns, which targeted greater need for feedback, affirmation, and debriefing, as well as reflective discussions on practice. This group thus correlated novices' perceptions with preceptor development activities.

Superheating Water by CW Excitation of Gold Nanodots

Nano Letters. Feb, 2012  |  Pubmed ID: 22313363

A temperature-dependent photoluminescent thin film of Al(0.94)Ga(0.06)N doped with Er(3+) is used to measure the temperature of lithographically prepared gold nanodots. The gold nanodots and thin film are excited simultaneously with a continuous wave (CW) Nd:YAG 532 nm laser. The gold nanodot is submersed under water, and the dot is subsequently heated. The water immediately surrounding the nanodot is superheated beyond the boiling point up to the spinodal decomposition temperature at 594 ± 17 K. The spinodal decomposition has been confirmed with the observation of critical opalescence. We characterize the laser scattering that occurs in unison with spinodal decomposition due to an increased coherence length associated with the liquid-liquid transition.

Exploring Salivary Proteomes in Edentulous Patients with Type 2 Diabetes

Molecular BioSystems. Feb, 2012  |  Pubmed ID: 22314925

Type 2 diabetes and tooth loss are linked both epidemiologically and pathophysiologically. We applied label-free differential protein expression analysis using multidimensional liquid chromatography/tandem mass spectrometry (2D-LC-MS/MS) to explore the proteomic profile of saliva samples collected from selected type 2 diabetic edentulous patients and non-diabetic controls. Ninety-six peptides corresponding to 52 proteins were differentially expressed between the diabetic edentulous patients and controls (p < 0.05). Some diabetes-related inflammatory biomarkers including glyceraldehyde-3-phosphate dehydrogenase and serum amyloid A were detected with levels increased in diabetic samples. Other biomarkers including amylase, palate, lung and nasal epithelium associated protein (PLUNC), and serotransferrin levels were decreased in diabetic samples. In contrast with previous findings, salivary carbonic anhydrase 6 and alpha-2 macroglobulin levels, however, were decreased in this diabetic patient population. Cluster analysis and principle component analysis demonstrated a differential pattern of protein biomarker expression between diabetic and control subjects. Western blot analysis was completed to confirm the relatively lower expression level of two biomarkers, including PLUNC and amylase in the diabetic group compared to control subjects. The presence of salivary biomarkers specific for diabetes in edentulous subjects mimics those in serum, especially those related to inflammatory/lipid metabolism. While this exploratory study requires further validation with a larger population, it provides proof-of-principle for salivary proteomics for edentulous subjects with diabetes.

Stimulation of Natural Killer Cells with a CD137-specific Antibody Enhances Trastuzumab Efficacy in Xenotransplant Models of Breast Cancer

The Journal of Clinical Investigation. Feb, 2012  |  Pubmed ID: 22326955

Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2; also known as HER-2/neu), is indicated for the treatment of women with either early stage or metastatic HER2+ breast cancer. It kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. Here, we have shown that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells become activated and express the costimulatory receptor CD137. CD137 activation, which was dependent on NK cell expression of the FcγRIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. Stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently both in vitro and in vivo in xenotransplant models of human breast cancer, including one using a human primary breast tumor. The enhanced cytotoxicity was restricted to antibody-coated tumor cells. This sequential antibody strategy, combining a tumor-targeting antibody with a second antibody that activates the host innate immune system, may improve the therapeutic effects of antibodies against breast cancer and other HER2-expressing tumors.

Outcomes of Liver Transplantation in HCV-HIV Coinfected Recipients

Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Feb, 2012  |  Pubmed ID: 22328294

BACKGROUND: Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in HIV-infected patients due to reportedly poor outcomes. METHODS: This prospective U.S. multicenter cohort study compared patient and graft survival in 89 HCV-HIV coinfected versus 2 different controls groups: 235 HCV monoinfected LT controls and all U.S. transplant recipients ≥65 years. RESULTS: The 3-year patient and graft survival rates (95% CI) were 60% (47-71%) and 53% (40-64%) in HCV-HIV versus 79% (72-84%) and 74% (66-79%) in HCV recipients (both p<0.001) and HIV infection was the only factor significantly associated with reduced patient and graft survival. Among HCV-HIV patients, older donor age (HR=1.3 per decade), combined kidney-LT (HR=3.8), HCV-positive donor (HR=2.5), and body mass index (BMI) less than 21 kg/m(2) (HR=3.2) were independent predictors of graft loss. In patients without these latter 3 factors, patient and graft survival were similar to those in U.S. LT recipients. The 3-year incidence of treated acute rejection was 1.6-fold higher in HCV-HIV versus HCV (log rank p=0.02) but cumulative incidence of severe HCV disease (29% versus 23% at 3 years, respectively) were not significantly different (p=0.21). CONCLUSIONS: Patient and graft survival are lower in HCV-HIV compared to HCV alone LT patients. Importantly, rates of treated acute rejection but not HCV disease severity are significantly higher in HCV-HIV compared to HCV recipients. Our results indicate that HCV per se is not a contraindication to LT in HIV patients but recipient and donor selection as well as management of acute rejection strongly influence outcomes. © 2012 American Association for the Study of Liver Diseases.

Early Determinants of Four-year Clinical Outcomes in Bipolar Disorder with Psychosis

Bipolar Disorders. Feb, 2012  |  Pubmed ID: 22329469

Carlson GA, Kotov R, Chang S-W, Ruggero C, Bromet EJ. Early determinants of four-year clinical outcomes in bipolar disorder with psychosis. Bipolar Disord 2012: 14: 19-30. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective:  Bipolar disorder with psychosis is common in inpatient settings and is associated with diverse outcomes after hospital discharge, which can range from a return to premorbid functioning with no recurrence, to a chronic or recurring illness. Less is known, however, about factors that can predict a better or worse clinical outcome. The present study sought to assess four-year clinical outcomes and their predictors in patients hospitalized for bipolar I disorder with psychosis. Methods:  Participants from the Suffolk County Mental Health Project (SCMHP) with a baseline diagnosis of bipolar I disorder with psychotic features (N = 126) were reassessed using face-to-face interviews at six months, two years, and four years following their first hospitalization. At each time point, clinical status, role functioning, and treatment were assessed by highly trained interviewers using standardized instruments. Results:  The majority of participants (73.2%) returned to their premorbid level of role functioning by the four-year follow-up and the median percentage of time ill during the interval was less than 20%. Nevertheless, almost half of the sample (46.9%) was rehospitalized at least once. Psychotic symptoms at baseline (particularly Schneiderian symptoms), depressive phenomenology, childhood psychopathology, and younger age at first hospitalization predicted worse outcome, whereas mood-incongruent psychotic features and age of mood disorder onset did not. Conclusions:  The four-year outcomes of a first-admission cohort with bipolar I disorder with psychosis were generally favorable. Poorer premorbid functioning, Schneiderian delusions, greater depressive symptoms, and a younger age of first hospitalization portend a worse course.

Aripiprazole in Combination with Lamotrigine for the Long-term Treatment of Patients with Bipolar I Disorder (manic or Mixed): a Randomized, Multicenter, Double-blind Study (CN138-392)

Bipolar Disorders. Feb, 2012  |  Pubmed ID: 22329471

Carlson BX, Ketter TA, Sun W, Timko K, McQuade RD, Sanchez R, Vester-Blokland E, Marcus R. Aripiprazole in combination with lamotrigine for the long-term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double-blind study (CN138-392). Bipolar Disord 2012: 14: 41-53. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives:  To evaluate the efficacy and safety of aripiprazole (ARI) plus lamotrigine (LTG) compared with placebo (PBO) plus LTG, for long-term treatment in bipolar I disorder patients with a recent manic/mixed episode. Methods:  After a 9-24 week stabilization phase receiving single-blind ARI (10-30 mg/day) plus open-label LTG (100 or 200 mg/day), patients maintaining stability (Young Mania Rating Scale/Montgomery-Åsberg Depression Rating Scale total scores ≤ 12) with ARI + LTG for eight consecutive weeks were randomized to continue on double-blind ARI + LTG or to receive PBO + LTG, after removing ARI from ARI + LTG treatment, and followed up for 52 weeks. The primary outcome measure was time from randomization to relapse into a manic/mixed episode. Results:  A total of 787 patients entered the stabilization phase, and 351 were randomized to ARI + LTG (n = 178) or PBO + LTG (n = 173). ARI + LTG yielded a numerically longer time to manic/mixed relapse than PBO + LTG, but it was not statistically significant [hazard ratio (HR) = 0.55; 95% confidence interval (CI): 0.30-1.03; p = 0.058]. The estimated relapse rates at Week 52 were 11% for ARI + LTG and 23% for PBO + LTG, yielding a number needed-to-treat of nine (95% CI: 5-121). The three most common adverse events were akathisia [10.8%, 6.1% for ARI + LTG and PBO + LTG, respectively; number needed-to-harm (NNH) = 22], insomnia (7.4%, 11.5%), and anxiety (7.4%, 3.6%). Mean weight change was 0.43 kg and -1.81 kg, respectively (last observation carried forward, p = 0.001). Rates of ≥ 7% weight gain with ARI + LTG and PBO + LTG were 11.9% and 3.5%, respectively (NNH = 12). Conclusions:  ARI + LTG delayed the time to manic/mixed relapse but did not reach statistical significance. Safety and tolerability results revealed no unexpected adverse events for ARI combination with LTG.

Perinephric Extramedullary Haematopoiesis in Primary Myelofibrosis

British Journal of Haematology. Feb, 2012  |  Pubmed ID: 22329535

Global Climate Evolution During the Last Deglaciation

Proceedings of the National Academy of Sciences of the United States of America. Feb, 2012  |  Pubmed ID: 22331892

Deciphering the evolution of global climate from the end of the Last Glacial Maximum approximately 19 ka to the early Holocene 11 ka presents an outstanding opportunity for understanding the transient response of Earth's climate system to external and internal forcings. During this interval of global warming, the decay of ice sheets caused global mean sea level to rise by approximately 80 m; terrestrial and marine ecosystems experienced large disturbances and range shifts; perturbations to the carbon cycle resulted in a net release of the greenhouse gases CO(2) and CH(4) to the atmosphere; and changes in atmosphere and ocean circulation affected the global distribution and fluxes of water and heat. Here we summarize a major effort by the paleoclimate research community to characterize these changes through the development of well-dated, high-resolution records of the deep and intermediate ocean as well as surface climate. Our synthesis indicates that the superposition of two modes explains much of the variability in regional and global climate during the last deglaciation, with a strong association between the first mode and variations in greenhouse gases, and between the second mode and variations in the Atlantic meridional overturning circulation.

Treatment of Youth Depression in Primary Care Under Usual Practice Conditions: Observational Findings from Youth Partners in Care

Journal of Child and Adolescent Psychopharmacology. Jan, 2012  |  Pubmed ID: 22251025

Abstract Objectives: The effectiveness of treatments for youth depression in primary care, under usual practice conditions, is largely unstudied. This study aims at estimating the effect of "appropriate treatment," defined as treatment that approximates guideline standards, on clinical outcomes for depressed primary care youth patients by using observational analyses from a randomized trial. Methods: Participants were 344 youths aged 13-21 enrolled in the Youth Partners in Care trial. Youths screening positive for depression from six primary care practices in five different health care organizations were randomly assigned to either (1) usual care enhanced by provider education on depression evaluation and management, or (2) a quality improvement (QI) intervention designed to improve access to antidepressant medications and/or cognitive behavior therapy for depression; usual practice conditions otherwise applied. Observational analysis was conducted on the effects of appropriate treatment (antidepressant medication use by algorithms or 6 or more psychotherapy visits) on severe depression (Center for Epidemiologic Studies-Depression score ≥24) at 6 months. Selection into treatment is accounted for by using instrumental variables analysis, with randomized QI intervention status as the instrument. Results: At 6 months, youths receiving "appropriate treatment," compared with others, were significantly less likely to have severe depression (10.9% vs. 45.2%, p<0.0001). Similar findings were observed among youths with depressive disorders and sub-syndromal depressive symptoms, and among Latino and other youths. Conclusions: Among depressed primary care youths, care that approximates guideline standards but retains leniency substantially reduces the likelihood of severe depression at 6 months. Such findings apply to youths with or without depressive disorder, and among Latino youth.

Social Factors in the Development of Early Executive Functioning: a Closer Look at the Caregiving Environment

Developmental Science. Jan, 2012  |  Pubmed ID: 22251288

This study investigated prospective links between quality of the early caregiving environment and children's subsequent executive functioning (EF). Sixty-two families were met on five occasions, allowing for assessment of maternal interactive behavior, paternal interactive behavior, and child attachment security between 1 and 2 years of age, and child EF at 2 and 3 years. The results suggested that composite scores of parental behavior and child attachment were related to child performance on EF tasks entailing strong working memory and cognitive flexibility components (conflict-EF). In particular, child attachment security was related to conflict-EF performance at 3 years above and beyond what was explained by a combination of all other social antecedents of child EF identified thus far: child verbal ability and prior EF, family SES, and parenting behavior. Attachment security may thus play a meaningful role in young children's development of executive control.

Magnetic Resonance Imaging Surveillance Following Vestibular Schwannoma Resection

The Laryngoscope. Feb, 2012  |  Pubmed ID: 22252688

To describe the incidence, pattern, and course of postoperative enhancement within the operative bed using serial gadolinium-enhanced magnetic resonance imaging (MRI) following vestibular schwannoma (VS) resection and to identify clinical and radiologic variables associated with recurrence.

Are You Having a Good Day: a Passing Nicety or a Fundamental Question in the Intensive Care Unit?

Critical Care Medicine. Jan, 2012  |  Pubmed ID: 22179375

Alkylpurine-DNA-N-glycosylase Confers Resistance to Temozolomide in Xenograft Models of Glioblastoma Multiforme and is Associated with Poor Survival in Patients

The Journal of Clinical Investigation. Jan, 2012  |  Pubmed ID: 22156195

Glioblastoma multiforme (GBM) is the most common and lethal of all gliomas. The current standard of care includes surgery followed by concomitant radiation and chemotherapy with the DNA alkylating agent temozolomide (TMZ). O⁶-methylguanine-DNA methyltransferase (MGMT) repairs the most cytotoxic of lesions generated by TMZ, O⁶-methylguanine. Methylation of the MGMT promoter in GBM correlates with increased therapeutic sensitivity to alkylating agent therapy. However, several aspects of TMZ sensitivity are not explained by MGMT promoter methylation. Here, we investigated our hypothesis that the base excision repair enzyme alkylpurine-DNA-N-glycosylase (APNG), which repairs the cytotoxic lesions N³-methyladenine and N⁷-methylguanine, may contribute to TMZ resistance. Silencing of APNG in established and primary TMZ-resistant GBM cell lines endogenously expressing MGMT and APNG attenuated repair of TMZ-induced DNA damage and enhanced apoptosis. Reintroducing expression of APNG in TMZ-sensitive GBM lines conferred resistance to TMZ in vitro and in orthotopic xenograft mouse models. In addition, resistance was enhanced with coexpression of MGMT. Evaluation of APNG protein levels in several clinical datasets demonstrated that in patients, high nuclear APNG expression correlated with poorer overall survival compared with patients lacking APNG expression. Loss of APNG expression in a subset of patients was also associated with increased APNG promoter methylation. Collectively, our data demonstrate that APNG contributes to TMZ resistance in GBM and may be useful in the diagnosis and treatment of the disease.

Sourcebook on Violence Against Women, Edited by Claire M. Renzetti, Jeffrey L. Edleson, and Raquel K. Bergen (2011). Second Edition. Los Angeles, CA: Sage, 407 Pages

Journal of Women & Aging. Jan, 2012  |  Pubmed ID: 22256880

Correlation of HLA-A02* Genotype and HLA Class I Antigen Down-regulation with the Prognosis of Epithelial Ovarian Cancer

Cancer Immunology, Immunotherapy : CII. Jan, 2012  |  Pubmed ID: 22258792

BACKGROUND: In recent years, evidence is accumulating that cancer cells develop strategies to escape immune recognition. HLA class I HC down-regulation is one of the most investigated. In addition, different HLA haplotypes are known to correlate to both risk of acquiring diseases and also prognosis in survival of disease or cancer. We have previously shown that patients with serous adenocarcinoma of the ovary in advanced surgical stage disease have a particularly poor prognosis if they carry the HLA-A02* genotype. We aimed to study the relationship between HLA-A02* genotype in these patients and the subsequent HLA class I HC protein product defects in the tumour tissue. MATERIALS AND METHODS: One hundred and sixty-two paraffin-embedded tumour lesions obtained from Swedish women with epithelial ovarian cancer were stained with HLA class I heavy chain (HC) and β(2)-microglobulin (β(2)-m)-specific monoclonal antibodies (mAb). Healthy ovary and tonsil tissue served as a control. The HLA genotype of these patients was determined by PCR/sequence-specific primer method. The probability of survival was calculated using the Kaplan-Meier method, and the hazard ratio (HR) was estimated using proportional hazard regression. RESULTS: Immunohistochemical staining of ovarian cancer lesions with mAb showed a significantly higher frequency of HLA class I HC and β(2)-m down-regulation in patients with worse prognosis (WP) than in those with better prognosis. In univariate analysis, both HLA class I HC down-regulation in ovarian cancer lesions and WP were associated with poor survival. In multivariate Cox-analysis, the WP group (all with an HLA-A02* genotype) had a significant higher HR to HLA class I HC down-regulation. CONCLUSIONS: HLA-A02* is a valuable prognostic biomarker in epithelial ovarian cancer. HLA class I HC loss and/or down-regulation was significantly more frequent in tumour tissues from HLA-A02* positive patients with serous adenocarcinoma surgical stage III-IV. In multivariate analysis, we show that the prognostic impact is reasonably correlated to the HLA genetic rather than to the expression of its protein products.

Osteoma Cutis (nevus of Nanta) of the Eyebrow

Ophthalmic Plastic and Reconstructive Surgery. Jan, 2012  |  Pubmed ID: 22262294

Reply Re: "Trichoblastic Fibroma of the Eyelid"

Ophthalmic Plastic and Reconstructive Surgery. Jan, 2012  |  Pubmed ID: 22262300

The Sodium Iodide Symporter (NIS) As an Imaging Reporter for Gene, Viral, and Cell-based Therapies

Current Gene Therapy. Jan, 2012  |  Pubmed ID: 22263922

Preclinical and clinical tomographic imaging systems increasingly are being utilized for non-invasive imaging of reporter gene products to reveal the distribution of molecular therapeutics within living subjects. Reporter gene and probe combinations can be employed to monitor vectors for gene, viral, and cell-based therapies. There are several reporter systems available; however, those employing radionuclides for positron emission tomography (PET) or single-photon emission computed tomography (SPECT) offer the highest sensitivity and the greatest promise for deep tissue imaging in humans. Within the category of radionuclide reporters, the thyroidal sodium iodide symporter (NIS) has emerged as one of the most promising for preclinical and translational research. NIS has been incorporated into a remarkable variety of viral and non-viral vectors in which its functionality is conveniently determined by in vitro iodide uptake assays prior to live animal imaging. This review on the NIS reporter will focus on 1) differences between endogenous NIS and heterologously-expressed NIS, 2) qualitative or comparative use of NIS as an imaging reporter in preclinical and translational gene therapy, oncolytic viral therapy, and cell trafficking research, and 3) use of NIS as an absolute quantitative reporter.

Combined SPECT and Multidetector CT for Prostate Cancer Evaluations

American Journal of Nuclear Medicine and Molecular Imaging. 2012  |  Pubmed ID: 22267999

(111)In-capromab pendetide is an imaging probe for noninvasive detection of prostate cancer dissemination, and can be difficult to interpret because of low photon statistics resulting in noisy images with limited anatomical precision. We examined if a 16-slice multidetector computed tomography (MDCT) combined with single photon emission computed tomography (SPECT) could increase the impact on the clinical management and improve confidence in SPECT image interpretations in comparison to a relatively low-mA (limited resolution) CT. 17 scans were reviewed from a SPECT combined with low-mA CT scanner; 21 scans were reviewed from a SPECT combined with 16-slice MDCT scanner. Reports of the clinical interpretations from the imaging studies, additional examinations performed by referring physicians as a follow-up to the imaging results, and long-term clinical and laboratory follow-ups were used to define confidence of the SPECT/CT readings and impact of the readings on the patient management. The impact was defined as: the occurrence of the (111)In-capromab pendetide interpretation resulted in additional imaging studies or biopsies. MDCT improved the quality and confidence in the characterization of small lymph nodes with or without uptake of (111)In-capromab pendetide. The increased confidence with MDCT in SPECT/CT readings was evident in all cases reviewed in this study, and the impact on the clinical management was higher (8 out of 21) using SPECT/MDCT than the impact using SPECT combined with low-mA CT (2 out of 17). The dual-modality SPECT/CT provides a quantifiable benefit when MDCT is used instead of low-mA CT, particularly for prostate cancer evaluations using (111)In-capromab pendetide.

Who Benefits from Psychosocial Interventions in Oncology? A Systematic Review of Psychological Moderators of Treatment Outcome

Journal of Behavioral Medicine. Jan, 2012  |  Pubmed ID: 22271329

Medical and demographic characteristics and psychological morbidity of individuals with cancer prior to a psychosocial intervention can influence the efficacy of interventions. However, little is known about the moderating role of patients' psychosocial characteristics on intervention effects. This review sought to identify and synthesize the impacts of psychosocial moderators of the effect of psychosocial interventions on the psychological well-being of cancer patients. A systematic review of the published literature was conducted. Databases searched included PsycINFO, PubMed, MEDLINE, Scopus, CINAHL, Web of Science, and Psychology and Behavioural Sciences Collection. Randomized controlled studies examining a moderator effect of patients' psychosocial characteristics other than baseline depression and anxiety levels were included. Of 199 potential papers, a total of 20 studies, involving 3,340 heterogeneous cancer patients are included. Of the 17 potential psychosocial moderators examined in this review, 14 significantly moderated the effects of interventions. Moderators were categorized into personality traits, mental and physical quality of life, social environment, and self-efficacy. Patients with poorer quality of life, interpersonal relationships and sense of control benefitted more from interventions than those who already had adequate resources. Patients with low levels of optimism and neuroticism, high levels of emotional expressiveness, interpersonal sensitivity, and dispositional hypnotizability also showed greater benefits from various interventions. This review adds to the growing literature aimed at personalizing psychosocial cancer treatment by identifying who benefits from which psychosocial interventions.

Pharmacogenetics of the Effects of Colesevelam on Colonic Transit in Irritable Bowel Syndrome with Diarrhea

Digestive Diseases and Sciences. Jan, 2012  |  Pubmed ID: 22271411

BACKGROUND: Protein products of klothoβ (KLB) and fibroblast growth factor receptor 4 (FGFR4) impact fibroblast growth factor 19-mediated feedback inhibition of hepatic bile acid (BA) synthesis. Variants of KLB and FGFR4 influence colonic transit (CT) in diarrhea-predominant irritable bowel syndrome (IBS-D). AIM: The purpose of this study was to test the hypothesis that colesevelam's slowing effects on CT in IBS-D patients is influenced by genetic variants in KLB and FGFR4. METHODS: We examined pharmacogenetic effects of KLB and FGFR4 coding variants (SNPs) on scintigraphic CT response to the BA sequestrant, colesevelam 1.875 g b.i.d. versus placebo (PLA) for 14 days in 24 female IBS-D patients. RESULTS: FGFR4 rs351855 and KLB rs497501 were associated with differential colesevelam effects on ascending colon (AC) half-emptying time (t (1/2), P = 0.046 and P = 0.085 respectively) and on overall CT at 24 h (geometric center, GC24: P = 0.073 and P = 0.042, respectively), with slower transit for rs351855 GA/AA (but not for GG) and rs497501 CA/AA (but not CC) genotypes. CONCLUSION: FGFR4 rs351855 and KLB rs4975017 SNPs may identify a subset of IBS-D patients with beneficial response to colesevelam.

Prioritization in Comparative Effectiveness Research: The CANCERGEN Experience

Medical Care. Jan, 2012  |  Pubmed ID: 22274803

BACKGROUND:: Systematic approaches to stakeholder-informed research prioritization are a central focus of comparative effectiveness research. Genomic testing in cancer is an ideal area to refine such approaches given rapid innovation and potentially significant impacts on patient outcomes. OBJECTIVE:: To develop and pilot test a stakeholder-informed approach to prioritizing genomic tests for future study in collaboration with the cancer clinical trials consortium SWOG. METHODS:: We conducted a landscape analysis to identify genomic tests in oncology using a systematic search of published and unpublished studies, and expert consultation. Clinically valid tests suitable for evaluation in a comparative study were presented to an external stakeholder group. Domains to guide the prioritization process were identified with stakeholder input, and stakeholders ranked tests using multiple voting rounds. RESULTS:: A stakeholder group was created including representatives from patient-advocacy groups, payers, test developers, regulators, policy makers, and community-based oncologists. We identified 9 domains for research prioritization with stakeholder feedback: population impact; current standard of care, strength of association; potential clinical benefits, potential clinical harms, economic impacts, evidence of need, trial feasibility, and market factors. The landscape analysis identified 635 studies; of 9 tests deemed to have sufficient clinical validity, 6 were presented to stakeholders. Two tests in lung cancer (ERCC1 and EGFR) and 1 test in breast cancer (CEA/CA15-3/CA27.29) were identified as top research priorities. CONCLUSIONS:: Use of a diverse stakeholder group to inform research prioritization is feasible in a pragmatic and timely manner. Additional research is needed to optimize search strategies, stakeholder group composition, and integration with existing prioritization mechanisms.

Collaborative Control for a Robotic Wheelchair: Evaluation of Performance, Attention, and Workload

IEEE Transactions on Systems, Man, and Cybernetics. Part B, Cybernetics : a Publication of the IEEE Systems, Man, and Cybernetics Society. Jan, 2012  |  Pubmed ID: 22275718

Powered wheelchair users often struggle to drive safely and effectively and, in more critical cases, can only get around when accompanied by an assistant. To address these issues, we propose a collaborative control mechanism that assists users as and when they require help. The system uses a multiple-hypothesis method to predict the driver's intentions and, if necessary, adjusts the control signals to achieve the desired goal safely. The main emphasis of this paper is on a comprehensive evaluation, where we not only look at the system performance but also, perhaps more importantly, characterize the user performance in an experiment that combines eye tracking with a secondary task. Without assistance, participants experienced multiple collisions while driving around the predefined route. Conversely, when they were assisted by the collaborative controller, not only did they drive more safely but also they were able to pay less attention to their driving, resulting in a reduced cognitive workload. We discuss the importance of these results and their implications for other applications of shared control, such as brain-machine interfaces, where it could be used to compensate for both the low frequency and the low resolution of the user input.

Design and Validation of a Fully Implantable, Chronic, Closed-Loop Neuromodulation Device With Concurrent Sensing and Stimulation

IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society. Jan, 2012  |  Pubmed ID: 22275720

Chronically implantable, closed-loop neuromodulation devices with concurrent sensing and stimulation hold promise for better understanding the nervous system and improving therapies for neurological disease. Concurrent sensing and stimulation are needed to maximize usable neural data, minimize time delays for closed-loop actuation, and investigate the instantaneous response to stimulation. Current systems lack concurrent sensing and stimulation primarily because of stimulation interference to neural signals of interest. While careful design of high performance amplifiers has proved useful to reduce disturbances in the system, stimulation continues to contaminate neural sensing due to biological effects like tissue-electrode impedance mismatch and constraints on stimulation parameters needed to deliver therapy. In this work we describe systematic methods to mitigate the effect of stimulation through a combination of sensing hardware, stimulation parameter selection, and classification algorithms that counter residual stimulation disturbances. To validate these methods we implemented and tested a completely implantable system for over one year in a large animal model of epilepsy. The system proved capable of measuring and detecting seizure activity in the hippocampus both during and after stimulation. Furthermore, we demonstrate an embedded algorithm that actuates neural modulation in response to seizure detection during stimulation, validating the capability to detect bioelectrical markers in the presence of therapy and titrate it appropriately. The capability to detect neural states in the presence of stimulation and optimally titrate therapy is a key innovation required for generalizing closed-loop neural systems for multiple disease states.

Barotrauma in Fish and Barotrauma Metrics

Advances in Experimental Medicine and Biology. 2012  |  Pubmed ID: 22278488

Assessment of Barotrauma Injury and Cumulative Sound Exposure Level in Salmon After Exposure to Impulsive Sound

Advances in Experimental Medicine and Biology. 2012  |  Pubmed ID: 22278489

Workshop One: Risk Analysis

Advances in Experimental Medicine and Biology. 2012  |  Pubmed ID: 22278586

Phase 1 Trial of Linifanib (ABT-869) in Patients with Refractory or Relapsed Acute Myeloid Leukemia

Leukemia & Lymphoma. Jan, 2012  |  Pubmed ID: 22280537

Abstract Linifanib, a potent oral inhibitor of fms-like tyrosine kinase 3 (FLT3) and vascular endothelial growth factor receptor tyrosine kinases, has demonstrated promising preclinical single-agent and synergistic anti-leukemic activity in combination with cytarabine. In this phase-1, multi-center, open-label, dose-escalation study, 45 adults with relapsed/refractory acute myeloid leukemia (AML) received linifanib alone in Arm A (n=29) and linifanib plus intermediate-dose cytarabine in Arm B (n=16). Median treatment duration was 21 days (range 5-110). Linifanib was well tolerated overall. The most common Grade 3/4 events were fatigue (Arm A) and febrile neutropenia (Arm B). The recommended phase-2 dose was 15 mg (alone), and 10 mg (with cytarabine). Evidence of on-target kinase inhibition in FLT3-mutant and wild-type AML patients was seen. Decreased phosphorylated FLT3 was seen in 3/3 FLT3-ITD patients with peripheral blast reductions and in 8/24 (33%) patients with wild-type, D835, or unknown FLT3 mutation. Eight/29 (28%) patients had decreased phosphorylated ERK.

Identification and Structure-Activity Relationships of a Novel Series of Estrogen Receptor Ligands Based on 7-Thiabicyclo[2.2.1]hept-2-ene-7-oxide

Journal of Medicinal Chemistry. Jan, 2012  |  Pubmed ID: 22283328

To develop ligands for the estrogen receptor (ER) that have novel structures and activities, we have explored compounds in which the central hydrophobic core has, overall, a more three-dimensional topology than is typically found in both steroidal and non-steroidal estrogen ligands. Extension to the third dimension is designed to exploit the unfilled space above and below the ligand in the ER ligand-binding pocket and thereby enhance receptor binding or subtype selectivity. In this study, we build upon our previous investigations on the three-dimensional core structure ligand, 7-oxabicyclo[2.2.1]heptene or heptadiene, by replacing the oxygen bridge with a sulfoxide. These new 7-thiabicyclo[2.2.1]hept-2-ene-7-oxide compounds were conveniently prepared by a Diels-Alder reaction of various 3,4-diarylthiophenes with a variety of dienophiles in the presence of an oxidant. Structure-activity relationships (SARs) for these derivatives were then investigated. Several of these new compounds demonstrated high binding affinities with excellent selectivity for the ERα subtype. Unlike oxabicyclic compounds, which showed little ER agonist activity, many thiabicyclic compounds demonstrated potent, ERα-selective agonist activity in transcriptional assays. Molecular models suggest that the observed gain in activity is due to key differences in stereoselectivity that enable the thiabicyclic compounds to stabilize the active conformation of ERα. Further, our data suggests that the disposition of methyl groups in the appended phenyl substituents in the C-5 and C-6 positions of the bicyclic core unit contribute to the binding affinity and subtype selectivity exhibited by these novel ER ligands.

Superior Methadone Treatment Outcome in Hmong Compared with Non-Hmong Patients

Journal of Substance Abuse Treatment. Jan, 2012  |  Pubmed ID: 22285835

The Hmong are a distinct ethnic group from Laos. Little is known about how opiate-addicted Hmong respond to methadone maintenance treatment. Therefore, opium-addicted Hmong (exclusive route of administration: smoking) attending an urban methadone maintenance program in Minneapolis, MN, were matched by gender and date of admission with predominately heroin-addicted non-Hmong (predominant route of administration: injection) attending the same program, and both groups were evaluated for 1-year treatment retention, stabilization dose of methadone, and urine drug screen results. Hmong had greater 1-year treatment retention (79.8%) than non-Hmong (63.5%; p < .01). In both groups, methadone dose was significantly associated with retention (p = .005). However, Hmong required lower doses of methadone for stabilization (M = 49.0 vs. 77.1 mg; p < .0001). For both groups, positive urine drug screens were associated with stopping treatment. Further research to determine levels of tolerance and psychosocial and pharmacogenetic factors contributing to differences in methadone treatment outcome and dosing in Hmong may provide further insight into opiate addiction and its treatment.

Translating Standards into Practice: Experience and Lessons Learned at the Department of Veterans Affairs

Journal of Biomedical Informatics. Jan, 2012  |  Pubmed ID: 22285982

The increased need for interoperable electronic health records in health care organizations underscores the importance of standards. The US Department of Veterans Affairs (VA) has a long history of developing and adopting various types of health care data standards. The authors present in detail their experience in this domain. A formal organization within VA is responsible for helping to develop and implement standards. This group has produced a Standards Life Cycle (SLC) process endorsed by VA key business and information technology (IT) stakeholders. It coordinates the identification, description, and implementation of standards aligned with VA business requirements. In this paper, we review the adoption of four standards in the categories of security and privacy, terminology, health information exchange, and modeling tools; emphasizing the implementation approach used in each. In our experience, adoption is facilitated by internal staff with expertise in standards development and adoption. Use of processes such as an SLC and tools such as an enterprise requirement repository help formally track and ensure that IT development and acquisition incorporate these standards. An organization should adopt standards that are aligned with its business priorities and favor those that are more readily implementable. To assist with this final point, we offer a standard "Likelihood of Adoption Scale," which changes as standards specifications evolve from PDF documents only, to PDF documents with construction and testing tools, to fully functional reference implementations.

Randomized Pharmacodynamic and Pharmacogenetic Trial of Dronabinol Effects on Colon Transit in Irritable Bowel Syndrome-diarrhea

Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society. Jan, 2012  |  Pubmed ID: 22288893

Background  Genetic variation in endocannabinoid metabolism is associated with colonic transit in irritable bowel syndrome (IBS) with diarrhea (IBS-D). The nonselective cannabinoid (CB) receptor agonist, dronabinol (DRO), reduced fasting colonic motility in nonconstipated IBS. FAAH and CNR1 variants influenced DRO's effects on colonic motility. Our aims were: (i) to compare dose-related effects of DRO to placebo (PLA) on gut transit in IBS-D, and (ii) to examine influence of genetic variations in CB mechanisms on DRO's transit effects. Methods  Thirty-six IBS-D volunteers were randomized (double-blind, concealed allocation) to twice per day PLA (n = 13), DRO 2.5 mg (n = 10), or DRO 5 mg (n = 13) for 2 days. We assessed gastric, small bowel, and colonic transit by validated radioscintigraphy and genotyped the single nucleotide polymorphisms CNR1 rs806378 and FAAH rs324420. Data analysis utilized a dominant genetic model. Key Results  Overall treatment effects of DRO on gastric, small bowel, or colonic transit were not detected. CNR1 rs806378 CT/TT was associated with a modest delay in colonic transit at 24 h compared with CC (P = 0.13 for differential treatment effects on postminus pretreatment changes in colonic transit by genotype). No significant interaction of treatment with FAAH rs324420 was detected. Conclusions & Inferences  Overall, DRO 2.5 or 5 mg twice per day for 2 days had no effect on gut transit in IBS-D. There appears to be a treatment-by-genotype effect, whereby DRO preferentially delays colonic transit in those with the CNR1 rs806378 CT/TT genotypes. Further study of CB pharmacogenetics may help identify a subset of IBS-D patients most likely to benefit from CB agonist therapy.

Aripiprazole in Bipolar Depression: a Pooled, Post-hoc Analysis by Severity of Core Depressive Symptoms

International Journal of Psychiatry in Clinical Practice. Feb, 2012  |  Pubmed ID: 22296512

Objective. This post-hoc analysis of pooled data from two similarly designed trials assessed the impact of aripiprazole monotherapy vs. placebo on treatment outcomes based on baseline severity of core depressive symptoms in patients with bipolar I disorder. Methods. Patients were classified as severely depressed (Bech-6 Total score > 15) or less severely depressed (Bech-6 Total score < 15). Efficacy was assessed by mean changes in Montgomery-Åsberg Depression Rating Scale (MADRS) Total and MADRS-6 subscale scores from baseline to endpoint using a mixed model repeated measures analysis. Results. A total of 133 patients (n = 62 on active aripiprazole) were classified as severely depressed and 612 patients (n = 309 aripiprazole) as less severely depressed. At endpoint, the mean MADRS Total score reduction for severely depressed patients receiving aripiprazole compared with placebo was -19.4 vs. -15.4 (P = 0.14), whereas MADRS-6 subscale score reduction for patients receiving aripiprazole compared with placebo was -13.8 vs. -10.3 (P = 0.07). Adverse event profiles were similar between the two severity groups. Conclusions. Symptomatic improvements assessed here suggest that aripiprazole monotherapy at the doses studied may provide some improvements in core symptoms of depression in patients with bipolar I disorder who were more severely depressed.

Fraud Prosecutions Up 69%: Shift in Investigators' Tactics, Evolution in Technology Seen As Reasons

Modern Healthcare. Jan, 2012  |  Pubmed ID: 22299221

Structure of the Carboxy-terminal Region of a KCNH Channel

Nature. Jan, 2012  |  Pubmed ID: 22230959

The KCNH family of ion channels, comprising ether-à-go-go (EAG), EAG-related gene (ERG), and EAG-like (ELK) K(+)-channel subfamilies, is crucial for repolarization of the cardiac action potential, regulation of neuronal excitability and proliferation of tumour cells. The carboxy-terminal region of KCNH channels contains a cyclic-nucleotide-binding homology domain (CNBHD) and C-linker that couples the CNBHD to the pore. The C-linker/CNBHD is essential for proper function and trafficking of ion channels in the KCNH family. However, despite the importance of the C-linker/CNBHD for the function of KCNH channels, the structural basis of ion-channel regulation by the C-linker/CNBHD is unknown. Here we report the crystal structure of the C-linker/CNBHD of zebrafish ELK channels at 2.2-Å resolution. Although the overall structure of the C-linker/CNBHD of ELK channels is similar to the cyclic-nucleotide-binding domain (CNBD) structure of the related hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channels, there are marked differences. Unlike the CNBD of HCN, the CNBHD of ELK displays a negatively charged electrostatic profile that explains the lack of binding and regulation of KCNH channels by cyclic nucleotides. Instead of cyclic nucleotide, the binding pocket is occupied by a short β-strand. Mutations of the β-strand shift the voltage dependence of activation to more depolarized voltages, implicating the β-strand as an intrinsic ligand for the CNBHD of ELK channels. In both ELK and HCN channels the C-linker is the site of virtually all of the intersubunit interactions in the C-terminal region. However, in the zebrafish ELK structure there is a reorientation in the C-linker so that the subunits form dimers instead of tetramers, as observed in HCN channels. These results provide a structural framework for understanding the regulation of ion channels in the KCNH family by the C-linker/CNBHD and may guide the design of specific drugs.

Dislocation of the Fifth Metatarsal Base Following Partial Fourth and Fifth Ray Amputation: a Case Report

Journal of the American Podiatric Medical Association. Jan-Feb, 2012  |  Pubmed ID: 22232325

This case report presents a rare postoperative dislocation of the fifth metatarsal base following a healed open partial fourth and fifth ray amputation of a 62-year-old male veteran with poorly controlled diabetes mellitus. The dislocated fifth metatarsal base subsequently created a chronic ulceration and an inhibition of normal gait. The patient was taken to the operating room where the fifth metatarsal base was resected with transfer of the peroneus brevis tendon to the cuboid to maintain biomechanical stability.

Subclinical Atrial Fibrillation and the Risk of Stroke

The New England Journal of Medicine. Jan, 2012  |  Pubmed ID: 22236222

One quarter of strokes are of unknown cause, and subclinical atrial fibrillation may be a common etiologic factor. Pacemakers can detect subclinical episodes of rapid atrial rate, which correlate with electrocardiographically documented atrial fibrillation. We evaluated whether subclinical episodes of rapid atrial rate detected by implanted devices were associated with an increased risk of ischemic stroke in patients who did not have other evidence of atrial fibrillation.

Enhancing Attachment Organization Among Maltreated Children: Results of a Randomized Clinical Trial

Child Development. Jan, 2012  |  Pubmed ID: 22239483

Young children who have experienced early adversity are at risk for developing disorganized attachments. The efficacy of Attachment and Biobehavioral Catch-up (ABC), an intervention targeting nurturing care among parents identified as being at risk for neglecting their young children, was evaluated through a randomized clinical trial. Attachment quality was assessed in the Strange Situation for 120 children between 11.7 and 31.9 months of age (M = 19.1, SD = 5.5). Children in the ABC intervention showed significantly lower rates of disorganized attachment (32%) and higher rates of secure attachment (52%) relative to the control intervention (57% and 33%, respectively). These results support the efficacy of the ABC intervention in enhancing attachment quality among parents at high risk for maltreatment.

Microenvironmental Regulation by Fibrillin-1

PLoS Genetics. Jan, 2012  |  Pubmed ID: 22242013

Fibrillin-1 is a ubiquitous extracellular matrix molecule that sequesters latent growth factor complexes. A role for fibrillin-1 in specifying tissue microenvironments has not been elucidated, even though the concept that fibrillin-1 provides extracellular control of growth factor signaling is currently appreciated. Mutations in FBN1 are mainly responsible for the Marfan syndrome (MFS), recognized by its pleiotropic clinical features including tall stature and arachnodactyly, aortic dilatation and dissection, and ectopia lentis. Each of the many different mutations in FBN1 known to cause MFS must lead to similar clinical features through common mechanisms, proceeding principally through the activation of TGFβ signaling. Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice. WMS mice confirm that this mutation does not cause MFS. The mutation deletes three domains in fibrillin-1, abolishing a binding site utilized by ADAMTSLIKE-2, -3, -6, and papilin. Our results place these ADAMTSLIKE proteins in a molecular pathway involving fibrillin-1 and ADAMTS-10. Investigations of microfibril ultrastructure in WMS humans and mice demonstrate that modulation of the fibrillin microfibril scaffold can influence local tissue microenvironments and link fibrillin-1 function to skin homeostasis and the regulation of dermal collagen production. Hence, pathogenetic mechanisms caused by dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of TGFβ signaling in multiple tissues. We conclude that local tissue-specific microenvironments, affected in WMS, are maintained by a fibrillin-1 microfibril scaffold, modulated by ADAMTSLIKE proteins in concert with ADAMTS enzymes.

Epilepsy Control Following Intracranial Monitoring Without Resection in Young Children

Epilepsia. Feb, 2012  |  Pubmed ID: 22242686

Purpose:  Intracranial monitoring (IM) is a key diagnostic procedure for select patients with treatment-resistant epilepsy (TRE). Seizure focus resection may improve seizure control in both lesional and nonlesional TRE. IM itself is not considered to have therapeutic potential. We describe a cohort of patients with improved seizure control following IM without resective surgery. Methods:  Over 12.5 years, 161 children underwent 496 surgeries including intracranial monitoring. We retrospectively reviewed the patients' charts, operative reports, and radiologic scans, under an institutional review board-approved protocol. Key Findings:  Seventeen patients underwent only IM, without additional resective surgery, and seven had a dramatic improvement in their epilepsy; six of the seven patients are seizure-free (Engel class I), and one rarely has seizures (Engel class II). All seven patients had frequent seizures that led to IM: either daily (five patients) or 1-2 per week (two patients). The mean age (± standard deviation, SD) at seizure onset was 1.6 ± 1.3 years (range 0.5-4 years). Etiologies were tuberous sclerosis (3 patients), trauma (1 patient), and unknown (3 patients). Mean age at surgery (± SD) was 4.1 ± 2 years (range 1-7 years), and duration of epilepsy 2.5 ± 1.1 years (range 0.5-4 years). Duration of IM was 11.7 ± 5.6 days (5-19 days). Six patients had bilateral and one unilateral invasive electrodes. At last follow-up, four patients required fewer antiepileptic drugs (AEDs), one had the same medication but a higher dose, and two patients were taking additional AEDs. Follow-up was 30.6 ± 9.5 months (range 19-41 months). Significance:  Although uncommon, patients with TRE may improve after IM alone. The explanation for this observation remains unclear; however, perioperative medications including steroids, direct cortical manipulation, or other factors may influence the epileptogenic network.

Controlling Airborne Cues to Study Small Animal Navigation

Nature Methods. Jan, 2012  |  Pubmed ID: 22245808

Small animals such as nematodes and insects analyze airborne chemical cues to infer the direction of favorable and noxious locations. In these animals, the study of navigational behavior evoked by airborne cues has been limited by the difficulty of precisely controlling stimuli. We present a system that can be used to deliver gaseous stimuli in defined spatial and temporal patterns to freely moving small animals. We used this apparatus, in combination with machine-vision algorithms, to assess and quantify navigational decision making of Drosophila melanogaster larvae in response to ethyl acetate (a volatile attractant) and carbon dioxide (a gaseous repellant).

Tumor Progression-related Transmembrane Protein Aspartate-β-hydroxylase is a Target for Immunotherapy of Hepatocellular Carcinoma

Journal of Hepatology. Jan, 2012  |  Pubmed ID: 22245894

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has a poor survival rate due to recurrent intrahepatic metastases and lack of effective adjuvant therapy. Aspartate-β-hydroxylase (ASPH) is an attractive cellular target since it is a highly conserved transmembrane protein overexpressed in both murine and human HCC tumors, and promotes a malignant phenotype as characterized by enhanced tumor cell migration and invasion. METHODS: Dendritic cells (DCs), expanded and isolated from the spleen, were incubated with a cytokine cocktail to optimize IL-12 secretion and co-stimulatory molecule expression, then subsequently loaded with ASPH protein for immunization. Mice were injected with syngeneic BNL HCC tumor cells followed by subcutaneous inoculation with 5-10×10(5) ASPH loaded DCs using a prophylactic and therapeutic experimental approach. Tumor infiltrating lymphocytes (TILs) were characterized, and their role in producing anti-tumor effects determined. The immunogenicity of ASPH protein with respect to activating antigen specific CD4+ T cells derived from human peripheral blood mononuclear cells (PBMCs) was also explored. RESULTS: We found that immunotherapy with ASPH-loaded DCs suppressed and delayed established HCC and tumor growth when administered prophylactically. Ex-vivo re-stimulation experiments and in vivo depletion studies demonstrated that both CD4+ and CD8+ cells contributed to anti-tumor effects. Using PBMCs derived from healthy volunteers and HCC patients, we showed that ASPH stimulation led to significant development of antigen-specific CD4+ T-cells. CONCLUSIONS: Immunization with ASPH-loaded DCs has substantial anti-tumor effects which could reduce the risk of HCC recurrence.

MeCP2+/- Mouse Model of RTT Reproduces Auditory Phenotypes Associated with Rett Syndrome and Replicate Select EEG Endophenotypes of Autism Spectrum Disorder

Neurobiology of Disease. Jan, 2012  |  Pubmed ID: 22249109

Impairments in cortical sensory processing have been demonstrated in Rett syndrome (RTT) and Autism Spectrum Disorders (ASD) and are thought to contribute to high-order phenotypic deficits. However, underlying pathophysiological mechanisms for these abnormalities are unknown. This study investigated auditory sensory processing in a mouse model of RTT with a heterozygous loss of MeCP2 function. Cortical abnormalities in a number of neuropsychiatric disorders, including ASD are reflected in auditory evoked potentials and fields measured by EEG and MEG. One of these abnormalities, increased latency of cortically sourced components, is associated with language and developmental delay in autism. Additionally, gamma-band abnormalities have recently been identified as an endophenotype of idiopathic autism. Both of these cortical abnormalities are potential clinical endpoints for assessing treatment. While ascribing similar mechanisms of idiopathic ASD to Rett syndrome (RTT) has been controversial, we sought to determine if mouse models of RTT replicate these intermediate phenotypes. Mice heterozygous for the null mutations of the gene MeCP2, were implanted for EEG. In response to auditory stimulation, these mice recapitulated specific latency differences as well as select gamma and beta band abnormalities associated with ASD. MeCP2 disruption is the predominant cause of RTT, and reductions in MeCP2 expression predominate in ASD. This work further suggests a common cortical pathophysiology for RTT and ASD, and indicates that the MeCP2+/- model may be useful for preclinical development targeting specific cortical processing abnormalities in RTT with potential relevance to ASD.

Phase I Clinical Trial of O6-Benzylguanine and Topical Carmustine in the Treatment of Cutaneous T-Cell Lymphoma, Mycosis Fungoides Type

Archives of Dermatology. Jan, 2012  |  Pubmed ID: 22250189

Objectives  To evaluate the toxic effects and maximum tolerated dose of topical carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea] following intravenous O6-benzylguanine in the treatment of cutaneous T-cell lymphoma (CTCL), and to determine pharmacodynamics of O6-alkylguanine DNA alkyltransferase activity in treated CTCL lesions. DESIGN: Open-label, dose-escalation, phase I trial. SETTING: Dermatology outpatient clinic and clinical research unit at a university teaching hospital. Patients  A total of 21 adult patients (11 male, 10 female) with early-stage (IA-IIA) refractory CTCL, mycosis fungoides type, treated with topical carmustine following intravenous O6-benzylguanine. Intervention  Treatment once every 2 weeks with 120 mg/m(2) intravenous O6-benzylguanine followed 1 hour later by whole-body, low-dose topical carmustine starting at 10 mg, with 10-mg incremental dose-escalation in 3 patient cohorts. Cutaneous T-cell lymphoma lesional skin biopsy specimens were taken at baseline and 6 hours, 24 hours, and 1 week after the first O6-benzylguanine infusion for analysis of O6-alkylguanine-DNA alkyltransferase activity. MAIN OUTCOME MEASURES: Clinical response measured by physical examination and severity-weighted assessment tool measurements, safety data acquired by review of adverse events at study visits, and O6-alkylguanine-DNA alkyltransferase activity in treated lesion skin biopsy specimens. RESULTS: A minimal toxic effect was observed through the 40-mg carmustine dose level with 76% of adverse events being grade 1 based on the National Cancer Institute Common Terminology Criteria for Adverse Events. Mean baseline O6-alkylguanine-DNA alkyltransferase activity in CTCL lesions was 3 times greater than in normal controls and was diminished by a median of 100% at 6 and 24 hours following O6-benzylguanine with recovery at 1 week. Clinical disease reduction correlated positively with O6-alkylguanine-DNA alkyltransferase activity at 168 hours (P = .02) and inversely with area under the curve of O6-alkylguanine-DNA alkyltransferase over 1 week (P = .01). Twelve partial responses and 4 complete responses were observed (overall response, 76% [95% CI, 0.55-0.89]). Five patients discontinued therapy owing to adverse events with a possible, probable, or definite relationship to the study drug. Conclusion  O6-benzylguanine significantly depletes O6-alkylguanine-DNA alkyltransferase in CTCL lesions and in combination with topical carmustine is well tolerated and shows meaningful clinical responses in CTCL at markedly reduced total carmustine treatment doses. Trial Registration  clinicaltrials.gov Identifier: NCT00003613.

Caregiver Reports of Subsequent Injuries Among Veterans with Traumatic Brain Injury After Discharge from Inpatient Polytrauma Rehabilitation Programs

The Journal of Head Trauma Rehabilitation. Jan-Feb, 2012  |  Pubmed ID: 22218200

: We examined prevalence of, and potential risk factors for, nonfatal injuries among Veterans with traumatic brain injury (TBI) postdischarge from Veterans Affairs inpatient polytrauma rehabilitation programs.

A Phase II Study to Evaluate the Efficacy and Toxicity of Oxaliplatin in Combination with Gemcitabine in Carcinoma of Unknown Primary

International Journal of Clinical Oncology / Japan Society of Clinical Oncology. Jan, 2012  |  Pubmed ID: 22218909

BACKGROUND: Preclinical and clinical data suggest synergy for gemcitabine and oxaliplatin. These agents were tested in several known cancers that also comprise the common carcinoma of unknown primary (CUP) subtypes; namely, lung and pancreaticobiliary profiles. METHODS: The study enrolled 29 patients of whom 28 patients were eligible for treatment. Gemcitabine was given at 1,000 mg/m(2) as a fixed dose rate infusion and oxaliplatin was infused at 100 mg/m(2) every 2 weeks with restaging performed after 3 cycles at 6 weeks. RESULTS: The study reported one complete response (CR) (4%), 6 patients with a partial response (PR) (25%), and 13 with stable disease (SD) (54%); and 4 patients had progressive disease (PD) (17%) on restaging. Median overall survival (OS) and progression-free survival were 12.8 months (95% confidence interval [CI] 8.5-18.5) and 3.1 months (95% CI 1.7-6), respectively. The 1-year OS was 54%. The most common grade 3 toxicities were nausea (22%), vomiting (15%), and fatigue (11%). There were no grade 4 toxicities. This study was closed early as we moved from an empiric therapy platform to a more individualized approach. CONCLUSIONS: Gemcitabine and oxaliplatin is a well-tolerated regimen in CUP with similar outcomes to previously documented CUP studies. In selected good performance status patients this combination may serve as a first-line doublet chemotherapy option for CUP patients (clinicaltrials.gov ID:NCT00353145).

Basin-scale Patterns in the Abundance of SAR11 Subclades, Marine Actinobacteria (OM1), Members of the Roseobacter Clade and OCS116 in the South Atlantic

Environmental Microbiology. Jan, 2012  |  Pubmed ID: 22225975

Bacterioplankton are major biogeochemical agents responsible for mediating the flux of dissolved organic matter (DOM) and subsequent cycling of nutrients in the oceans. Most information about the composition of bacterioplankton communities has come from studies along well-defined biogeochemical gradients in the northern hemisphere. This study extends observations of spatial and temporal dynamics for SAR11, Actinobacteria and OCS116 in the North Atlantic by demonstrating distinct spatial variability in the abundance and distribution of these and other lineages across the South Atlantic gyre and in the Benguela upwelling system. We identified shifts in SAR11, Actinobacteria, OCS116, SAR86, SAR116 and members of the Roseobacter clade along basin-scale gradients in nutrients, chlorophyll and dissolved organic carbon (DOC). Distinct SAR11 subclades dominated the western and eastern regions of the gyre, and Actinobacteria, OCS116 and members of the Roseobacter lineages were most abundant at the deep chlorophyll maxima. SAR86 and SAR116 accounted for a significant fraction of coastal and open ocean communities, respectively, and members of the gamma sulfur oxidizer (GSO) clade persisted in the Benguela upwelling system. These data suggest that distinct communities are partitioned along basin-scale biogeochemical gradients, that SAR11 community structure varies across the gyre and that Actinobacteria, OCS116, and members of the Roseobacter clade are closely associated with phytoplankton in the gyre.

Skilled Nursing Facility Referral and Hospital Readmission Rates After Heart Failure or Myocardial Infarction

The American Journal of Medicine. Jan, 2012  |  Pubmed ID: 22195535

Substantial hospital-level variation in the risk of readmission after hospitalization for heart failure (HF) or acute myocardial infarction (AMI) has been reported. Prior studies have documented considerable state-level variation in rates of discharge to skilled nursing facilities (SNFs), but evaluation of hospital-level variation in SNF rates and its relationship to hospital-level readmission rates is limited.

Sun-protection Behaviors of Melanoma Survivors

Journal of the American Academy of Dermatology. Jan, 2012  |  Pubmed ID: 22177654

The Mismatch Negativity (MMN) - A Unique Window to Disturbed Central Auditory Processing in Ageing and Different Clinical Conditions

Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology. Mar, 2012  |  Pubmed ID: 22169062

In this article, we review clinical research using the mismatch negativity (MMN), a change-detection response of the brain elicited even in the absence of attention or behavioural task. In these studies, the MMN was usually elicited by employing occasional frequency, duration or speech-sound changes in repetitive background stimulation while the patient was reading or watching videos. It was found that in a large number of different neuropsychiatric, neurological and neurodevelopmental disorders, as well as in normal ageing, the MMN amplitude was attenuated and peak latency prolonged. Besides indexing decreased discrimination accuracy, these effects may also reflect, depending on the specific stimulus paradigm used, decreased sensory-memory duration, abnormal perception or attention control or, most importantly, cognitive decline. In fact, MMN deficiency appears to index cognitive decline irrespective of the specific symptomatologies and aetiologies of the different disorders involved.

Volume of the Human Septal Forebrain Region is a Predictor of Source Memory Accuracy

Journal of the International Neuropsychological Society : JINS. Jan, 2012  |  Pubmed ID: 22152217

Septal nuclei, components of basal forebrain, are strongly and reciprocally connected with hippocampus, and have been shown in animals to play a critical role in memory. In humans, the septal forebrain has received little attention. To examine the role of human septal forebrain in memory, we acquired high-resolution magnetic resonance imaging scans from 25 healthy subjects and calculated septal forebrain volume using recently developed probabilistic cytoarchitectonic maps. We indexed memory with the California Verbal Learning Test-II. Linear regression showed that bilateral septal forebrain volume was a significant positive predictor of recognition memory accuracy. More specifically, larger septal forebrain volume was associated with the ability to recall item source/context accuracy. Results indicate specific involvement of septal forebrain in human source memory, and recall the need for additional research into the role of septal nuclei in memory and other impairments associated with human diseases.

Impact of Cancer Therapies on Ovarian Reserve

Fertility and Sterility. Jan, 2012  |  Pubmed ID: 22137491

To determine whether measures of ovarian reserve differ between females exposed to cancer therapies in a dose-dependent manner as compared with healthy controls of similar age and late reproductive age.

Synaptic Release and Extracellular Actions of Zn2+ Limit Propagation of Spreading Depression and Related Events in Vitro and in Vivo

Journal of Neurophysiology. Feb, 2012  |  Pubmed ID: 22131381

Cortical spreading depression (CSD) is a consequence of a slowly propagating wave of neuronal and glial depolarization (spreading depolarization; SD). Massive release of glutamate contributes to SD propagation, and it was recently shown that Zn(2+) is also released from synaptic vesicles during SD. The present study examined consequences of extracellular Zn(2+) accumulation on the propagation of SD. SD mechanisms were studied first in murine brain slices, using focal KCl applications as stimuli and making electrical and optical recordings in hippocampal area CA1. Elevating extracellular Zn(2+) concentrations with exogenous ZnCl(2) reduced SD propagation rates. Selective chelation of endogenous Zn(2+) (using TPEN or CaEDTA) increased SD propagation rates, and these effects appeared due to chelation of Zn(2+) derived from synaptic vesicles. Thus, in tissues where synaptic Zn(2+) release was absent [knockout (KO) of vesicular Zn(2+) transporter ZnT-3], SD propagation rates were increased, and no additional increase was observed following chelation of endogenous Zn(2+) in these tissues. The role of synaptic Zn(2+) was then examined on CSD in vivo. ZnT-3 KO animals had higher susceptibility to CSD than wild-type controls as evidenced by significantly higher propagation rates and frequencies. Studies of candidate mechanisms excluded changes in neuronal excitability, presynaptic release, and GABA receptors but left open a possible contribution of N-methyl-d-aspartate (NMDA) receptor inhibition. These results suggest the extracellular accumulation of synaptically released Zn(2+) can serve as an intrinsic inhibitor to limit SD events. The inhibitory action of extracellular Zn(2+) on SD may counteract to some extent the neurotoxic effects of intracellular Zn(2+) accumulation in acute brain injury models.

Cardiac O-GlcNAc Signaling is Increased in Hypertrophy and Heart Failure

Physiological Genomics. Feb, 2012  |  Pubmed ID: 22128088

Reversible protein O-GlcNAc modification has emerged as an essential intracellular signaling system in several tissues, including cardiovascular pathophysiology related to diabetes and acute ischemic stress. We tested the hypothesis that cardiac O-GlcNAc signaling is altered in chronic cardiac hypertrophy and failure of different etiologies. Global protein O-GlcNAcylation and the main enzymes regulating O-GlcNAc, O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), and glutamine-fructose-6-phosphate amidotransferase (GFAT) were measured by immunoblot and/or real-time RT-PCR analyses of left ventricular tissue from aortic stenosis (AS) patients and rat models of hypertension, myocardial infarction (MI), and aortic banding (AB), with and without failure. We show here that global O-GlcNAcylation was increased by 65% in AS patients, by 47% in hypertensive rats, by 81 and 58% post-AB, and 37 and 60% post-MI in hypertrophic and failing hearts, respectively (P < 0.05). Noticeably, protein O-GlcNAcylation patterns varied in hypertrophic vs. failing hearts, and the most extensive O-GlcNAcylation was observed on proteins of 20-100 kDa in size. OGT, OGA, and GFAT2 protein and/or mRNA levels were increased by pressure overload, while neither was regulated by myocardial infarction. Pharmacological inhibition of OGA decreased cardiac contractility in post-MI failing hearts, demonstrating a possible role of O-GlcNAcylation in development of chronic cardiac dysfunction. Our data support the novel concept that O-GlcNAc signaling is altered in various etiologies of cardiac hypertrophy and failure, including human aortic stenosis. This not only provides an exciting basis for discovery of new mechanisms underlying pathological cardiac remodeling but also implies protein O-GlcNAcylation as a possible new therapeutic target in heart failure.

Lack of Association Between HLA Class II Alleles and in Vitro Replication Capacities of Recombinant Viruses Encoding HIV-1 Subtype C Gag-protease from Chronically Infected Individuals

Journal of Virology. Jan, 2012  |  Pubmed ID: 22090116

It is unknown whether favorable HLA class II alleles may attenuate HIV-1 through selection pressure in a manner similar to that of protective HLA class I alleles. We investigated the relationship between HLA class II alleles and in vitro replication capacities of recombinant viruses encoding HIV-1 subtype C Gag-protease from chronically infected individuals. No associations were found between individual alleles and lower replication capacity, suggesting no significant HIV-1 attenuation by HLA class II-restricted Gag-specific CD4(+) T cell immune pressure.

Structure and Dynamics of the 1-hydroxyethyl-4-amino-1,2,4-triazolium Nitrate High-energy Ionic Liquid System

The Journal of Physical Chemistry. B. Jan, 2012  |  Pubmed ID: 22126259

An investigation of the structure and dynamics of the high-energy ionic liquid, 1-hydroxyethyl-4-amino-1,2,4-triazolium nitrate (HEATN), was undertaken. Both experimental and computational methods were employed to understand the fundamental properties, characteristics, and behavior of HEATN. The charge separation, according to the electrostatic potential derived charges, was assessed. The MP2 (second-order perturbation theory) geometry optimizations find six dimer and five tetramer structures and allow one to see the significant highly hydrogen bonded network predicted within the HEATN system. Due to the prohibitive scaling of ab initio methods, the fragment molecular orbital (FMO) method was employed and assessed for feasibility with highly energetic ionic liquids using HEATN as a model system. The FMO method was found to adequately treat the HEATN ionic liquid system as evidenced by the small relative error obtained. The experimental studies involved the investigation of the solvation dynamics of the HEATN system via the coumarin 153 (C153) probe at five different temperatures. The rotational dynamics through the HEATN liquid were also measured using C153. Comparisons with previously studied imidazolium and phosphonium ionic liquids show surprising similarity. To the authors' knowledge, this is the first experimental study of solvation dynamics in a triazolium-based ionic liquid.

Targeted Overexpression of an Activated N-ras Gene Results in B-cell and Plasma Cell Lymphoproliferation and Cooperates with C-myc to Induce Fatal B-cell Neoplasia

Experimental Hematology. Mar, 2012  |  Pubmed ID: 22120021

Multiple myeloma is an incurable malignant expansion of plasma cells in the bone marrow. Although there is no pathognomonic genetic lesion among multiple myeloma patients, activation of the ras gene has been identified as a common mutation. We have previously described the use of the 3' κ immunoglobulin light chain enhancer (3'KE) to target transgenic expression in murine B and plasma cells, resulting in bcl-X(L) and c-myc-driven murine models of multiple myeloma. In this report, we characterize the role of activated mutant N-ras in B and plasma cells in transgenic mice. We constructed transgenic mice that use 3'KE to direct expression of a mutant activated N-ras. We also crossed the N-ras mice with mice bearing a c-myc transgene to study the cooperative effects of the transgenic constructs. Mice were sacrificed when moribund or at specific time intervals and characterized by serology, light microscopy, and flow cytometry. The transgenic N-ras animals develop B- and plasma cell lymphoproliferation, and aged mice develop immunoglobulinemia, renal hyaline tubular casts, and microscopic foci of abnormal plasma cells in extramedullary sites, including the liver and kidney. Bitransgenic 3'KE/N-Ras V12 × Eμ-c-Myc mice develop fatal B-cell neoplasia, with a median survival of 10 weeks. These data indicate that activated N-ras can play a role in B- and plasma cell homeostasis and that activated N-Ras and c-Myc can cooperate to induce B-cell neoplasia.

Decoding Cell Lineage from Acquired Mutations Using Arbitrary Deep Sequencing

Nature Methods. Jan, 2012  |  Pubmed ID: 22120468

Because mutations are inevitable, the genome of each cell in a multicellular organism becomes unique and therefore encodes a record of its ancestry. Here we coupled arbitrary single primer PCR with next-generation DNA sequencing to catalog mutations and deconvolve the phylogeny of cultured mouse cells. This study helps pave the way toward construction of retrospective cell-fate maps based on mutations accumulating in genomes of somatic cells.

Diarylpropionitrile (DPN) Enantiomers: Synthesis and Evaluation of Estrogen Receptor β-selective Ligands

Journal of Medicinal Chemistry. Jan, 2012  |  Pubmed ID: 22122563

Two estrogen receptor (ER) subtypes, ERα and ERβ, mediate the actions of estrogens in diverse reproductive and nonreproductive target tissues. ER subtype-selective ligands, which bind to and activate these subtypes differentially, have proved to be useful in elucidating which actions of estrogens proceed through ERα vs ERβ. Some of these ligands show potential as novel therapeutic agents. Diarylpropionitrile (DPN), an ERβ selective ligand that we developed, is a chiral molecule, but it has been studied almost exclusively as the racemic mixture (rac-DPN, 1). Herein we report the development of an efficient enantioselective synthesis of the two isomers, R-DPN (3) and S-DPN (2), and we have compared the in vitro ligand binding affinities, coactivator binding affinities, recruitment potencies, and cellular transcriptional potencies of these isomers. Both enantiomers show a very high affinity and potency preference for ERβ over ERα, typically in the range of 80-300-fold. Although the enantioselectivity is only modest (3-4-fold), the R-enantiomer is the higher affinity and more potent isomer. While ERβ can be effectively and selectively stimulated by rac-DPN or by either R-DPN or S-DPN, R-DPN might be the preferred member of this isomeric series for biological studies of ERβ function.

Cochlear Implantation: Current and Future Device Options

Otolaryngologic Clinics of North America. Feb, 2012  |  Pubmed ID: 22115692

Today most cochlear implant users achieve above 80% on standard speech recognition in quiet testing, and enjoy excellent device reliability. Despite such success, conventional designs often fail to provide the frequency resolution required for complex listening tasks. Furthermore, performance variability remains a vexing problem, with a select group of patients performing poorly despite using the most recent technologies and processing strategies. This article provides a brief history of the development of cochlear implant technologies, reviews current implant systems from all 3 major manufacturers, examines recently devised strategies aimed at improving device performance, and discusses potential future developments.

Cortical Thickness Abnormalities Associated with Depressive Symptoms in Temporal Lobe Epilepsy

Epilepsy & Behavior : E&B. Jan, 2012  |  Pubmed ID: 22099527

Depression in patients with temporal lobe epilepsy (TLE) is highly prevalent and carries significant morbidity and mortality. Its neural basis is poorly understood. We used quantitative, surface-based MRI analysis to correlate brain morphometry with severity of depressive symptoms in 38 patients with TLE and 45 controls. Increasing severity of depressive symptoms was associated with orbitofrontal cortex (OFC) thinning in controls, but with OFC thickening in TLE patients. These results demonstrate distinct neuroanatomical substrates for depression with and without TLE, and suggest a unique role for OFC, a limbic region for emotional processing strongly interconnected with medial temporal structures, in TLE-related depressive symptoms.

Use of Diverse Electronic Medical Record Systems to Identify Genetic Risk for Type 2 Diabetes Within a Genome-wide Association Study

Journal of the American Medical Informatics Association : JAMIA. Mar, 2012  |  Pubmed ID: 22101970

Objective Genome-wide association studies (GWAS) require high specificity and large numbers of subjects to identify genotype-phenotype correlations accurately. The aim of this study was to identify type 2 diabetes (T2D) cases and controls for a GWAS, using data captured through routine clinical care across five institutions using different electronic medical record (EMR) systems. Materials and Methods An algorithm was developed to identify T2D cases and controls based on a combination of diagnoses, medications, and laboratory results. The performance of the algorithm was validated at three of the five participating institutions compared against clinician review. A GWAS was subsequently performed using cases and controls identified by the algorithm, with samples pooled across all five institutions. Results The algorithm achieved 98% and 100% positive predictive values for the identification of diabetic cases and controls, respectively, as compared against clinician review. By standardizing and applying the algorithm across institutions, 3353 cases and 3352 controls were identified. Subsequent GWAS using data from five institutions replicated the TCF7L2 gene variant (rs7903146) previously associated with T2D. Discussion By applying stringent criteria to EMR data collected through routine clinical care, cases and controls for a GWAS were identified that subsequently replicated a known genetic variant. The use of standard terminologies to define data elements enabled pooling of subjects and data across five different institutions to achieve the robust numbers required for GWAS. Conclusions An algorithm using commonly available data from five different EMR can accurately identify T2D cases and controls for genetic study across multiple institutions.

Jarid2 (Jumonji, AT Rich Interactive Domain 2) Regulates NOTCH1 Expression Via Histone Modification in the Developing Heart

The Journal of Biological Chemistry. Jan, 2012  |  Pubmed ID: 22110129

Jarid2/Jumonji, the founding member of the Jmj factor family, critically regulates various developmental processes, including cardiovascular development. The Jmj family was identified as histone demethylases, indicating epigenetic regulation by Jmj proteins. Deletion of Jarid2 in mice resulted in cardiac malformation and increased endocardial Notch1 expression during development. Although Jarid2 has been shown to occupy the Notch1 locus in the developing heart, the precise molecular role of Jarid2 remains unknown. Here we show that deletion of Jarid2 results in reduced methylation of lysine 9 on histone H3 (H3K9) at the Notch1 genomic locus in embryonic hearts. Interestingly, SETDB1, a histone H3K9 methyltransferase, was identified as a putative cofactor of Jarid2 by yeast two-hybrid screening, and the physical interaction between Jarid2 and SETDB1 was confirmed by coimmunoprecipitation experiments. Concurrently, accumulation of SETDB1 at the site of Jarid2 occupancy was significantly reduced in Jarid2 knock out (KO) hearts. Employing genome-wide approaches, putative Jarid2 target genes regulated by SETDB1 via H3K9 methylation were identified in the developing heart by ChIP-chip. These targets are involved in biological processes that, when dysregulated, could manifest in the phenotypic defects observed in Jarid2 KO mice. Our data demonstrate that Jarid2 functions as a transcriptional repressor of target genes, including Notch1, through a novel process involving the modification of H3K9 methylation via specific interaction with SETDB1 during heart development. Therefore, our study provides new mechanistic insights into epigenetic regulation by Jarid2, which will enhance our understanding of the molecular basis of other organ development and biological processes.

Characterization of Galacturonosyl Transferase Genes RgtA, RgtB, RgtC, RgtD, and RgtE Responsible for Lipopolysaccharide Synthesis in Nitrogen-fixing Endosymbiont Rhizobium Leguminosarum: Lipopolysaccharide Core and Lipid Galacturonosyl Residues Confer Membrane Stability

The Journal of Biological Chemistry. Jan, 2012  |  Pubmed ID: 22110131

Rhizobium lipopolysaccharide (LPS) contains four terminally linked galacturonic acid (GalA) residues; one attached to the lipid A and three attached to the core oligosaccharide moiety. Attachment of the GalA residues requires the lipid donor dodecaprenyl-phosphate GalA (Dod-P-GalA), which is synthesized by the GalA transferase RgtE reported here. The galacturonosyl transferases RgtA, -B, and -C utilize Dod-P-GalA to attach GalAs on the LPS core region, and RgtD attaches GalA to the lipid A 4' position. As reported here, the functions of the rgtD and rgtE genes were determined via insertion mutagenesis and structural characterization of the mutant lipid A. The rgtE(-) mutant lacked Dod-P-GalA as determined by mass spectrometry of total lipid extracts and the inability of rgtE(-) mutant membranes to provide the substrate for heterologously expressed RgtA activity. In addition, we created single mutations in each of the rgtA, -B, -C, -D, and -E genes to study the biological function of the GalA residues. The structures of the core oligosaccharide region from each of the rgt mutants were elucidated by glycosyl linkage analysis. Each mutant was assayed for its sensitivity to sodium deoxycholate and to the antimicrobial cationic peptide, polymyxin B (PmxB). The rgt mutants were more sensitive than the parent strain to deoxycholate by varying degrees. However, the rgtA, -B, and -C mutants were more resistant to PmxB, whereas the rgtD and E mutants were less resistant in comparison to the parent strain.

Physical Activity and Dietary Behavior Change in Internet-based Weight Loss Interventions: Comparing Two Multiple-behavior Change Indices

Preventive Medicine. Jan, 2012  |  Pubmed ID: 22085706

To investigate the effects of two Internet-based weight loss interventions on physical activity (PA) and dietary behaviors using two approaches for computing combined behavior change.

A Review of Methods Used for Identifying Structural Changes in a Large Protein Complex

Methods in Molecular Biology (Clifton, N.J.). 2012  |  Pubmed ID: 22052488

This chapter explores the structural responses of a massive, hetero-oligomeric protein complex to a single allosteric activator as probed by a wide range of chemical, biochemical, and biophysical approaches. Some of the approaches used are amenable only to large protein targets, whereas others push the limits of their utility. Some of the techniques focus on individual subunits, or portions thereof, while others examine the complex as a whole. Despite the absence of crystallographic data for the complex, the diverse techniques identify and implicate a small region of its catalytic subunit as the master allosteric activation switch for the entire complex.

Interactions Between Psychosocial and Built Environment Factors in Explaining Older Adults' Physical Activity

Preventive Medicine. Jan, 2012  |  Pubmed ID: 22027402

To evaluate ecological model predictions of cross-level interactions among psychosocial and environmental correlates of physical activity in 719 community-dwelling older adults in the Baltimore, Maryland and Seattle, Washington areas during 2005-2008.

An Implantable Triple-function Device for Local Drug Delivery, Cerebrospinal Fluid Removal and EEG Recording in the Cranial Subdural/subarachnoid Space of Primates

Journal of Neuroscience Methods. Jan, 2012  |  Pubmed ID: 22027491

Transmeningeal pharmacotherapy for cerebral cortical disorders requires drug delivery through the subdural/subarachnoid space, ideally with a feedback controlled mechanism. We have developed a device suitable for this function. The first novel component of the apparatus is a silicone rubber strip equipped with (a) fluid-exchange ports for both drug delivery and local cerebrospinal fluid (CSF) removal, and (b) EEG recording electrode contacts. This strip can be positioned between the dura and pia maters. The second novel component is an implantable dual minipump that directs fluid movement to and from the silicone strip and is accessible for refilling and emptying the drug and CSF reservoirs, respectively. This minipump is regulated by a battery-powered microcontroller integrating a bi-directional radiofrequency (RF) communication module. The entire apparatus was implanted in 5 macaque monkeys, with the subdural strip positioned over the frontal cortex and the minipump assembly secured to the cranium under a protective cap. The system was successfully tested for up to 8 months for (1) transmeningeal drug delivery using acetylcholine (ACh) and muscimol as test compounds, (2) RF-transmission of neocortical EEG data to assess the efficacy of drug delivery, and (3) local CSF removal for subsequent diagnostic analyses. The device can be used for (a) monitoring neocortical electrophysiology and neurochemistry in freely behaving nonhuman primates for more than 6 months, (b) determining the neurobiological impact of subdural/subarachnoid drug delivery interfaces, (c) obtaining novel neuropharmacological data on the effects of central nervous system (CNS) drugs, and (d) performing translational studies to develop subdural pharmacotherapy devices.

Combined Effect of Low-penetrant SNPs on Breast Cancer Risk

British Journal of Cancer. Jan, 2012  |  Pubmed ID: 22045194

Background:Although many low-penetrant genetic risk factors for breast cancer have been discovered, knowledge about the effect of multiple risk alleles is limited, especially in women <50 years. We therefore investigated the association between multiple risk alleles and breast cancer risk as well as individual effects according to age-approximated pre- and post-menopausal status.Methods:Ten previously described breast cancer-associated single-nucleotide polymorphisms (SNPs) were analysed in a joint European biobank-based study comprising 3584 breast cancer cases and 5063 cancer-free controls. Genotyping was performed using MALDI-TOF mass spectrometry, and odds ratios were estimated using logistic regression.Results:Significant associations with breast cancer were confirmed for 7 of the 10 SNPs. Analysis of the joint effect of the original 10 as well as the statistically significant 7 SNPs (rs2981582, rs3803662, rs889312, rs13387042, rs13281615, rs3817198 and rs981782) found a highly significant trend for increasing breast cancer risk with increasing number of risk alleles (P-trend 5.6 × 10(-20) and 1.5 × 10(-25), respectively). Odds ratio for breast cancer of 1.84 (95% confidence interval (CI): 1.59-2.14; 10 SNPs) and 2.12 (95% CI: 1.80-2.50; 7 SNPs) was seen for the maximum vs the minimum number of risk alleles. Additionally, one of the examined SNPs (rs981782 in HCN1) had a protective effect that was significantly stronger in premenopausal women (P-value: 7.9 × 10(-4)).Conclusion:The strongly increasing risk seen when combining many low-penetrant risk alleles supports the polygenic inheritance model of breast cancer.

Synthetic Escherichia Coli Consortia Engineered for Syntrophy Demonstrate Enhanced Biomass Productivity

Journal of Biotechnology. Jan, 2012  |  Pubmed ID: 22015987

Synthetic Escherichia coli consortia engineered for syntrophy demonstrated enhanced biomass productivity relative to monocultures. Binary consortia were designed to mimic a ubiquitous, naturally occurring ecological template of primary productivity supported by secondary consumption. The synthetic consortia replicated this evolution-proven strategy by combining a glucose positive E. coli strain, which served as the system's primary producer, with a glucose negative E. coli strain which consumed metabolic byproducts from the primary producer. The engineered consortia utilized strategic division of labor to simultaneously optimize multiple tasks enhancing overall culture performance. Consortial interactions resulted in the emergent property of enhanced system biomass productivity which was demonstrated with three distinct culturing systems: batch, chemostat and biofilm growth. Glucose-based biomass productivity increased by ∼15, 20 and 50% compared to appropriate monoculture controls for these three culturing systems, respectively. Interestingly, the consortial interactions also produced biofilms with predictable, self-assembling, laminated microstructures. This study establishes a metabolic engineering paradigm which can be easily adapted to existing E. coli based bioprocesses to improve productivity based on a robust ecological theme.

Synchronous Head and Neck Tumors After Low-dose Radiation to the Temporal Bone

Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. Jan, 2012  |  Pubmed ID: 21993220