Seroepidemiology of Respiratory (group 2) Canine Coronavirus, Canine Parainfluenza Virus, and Bordetella Bronchiseptica Infections in Urban Dogs in a Humane Shelter and in Rural Dogs in Small Communities

The Canadian Veterinary Journal. La Revue Vétérinaire Canadienne. Aug, 2011  |  Pubmed ID: 22294792

This prospective study evaluated seroepidemiologic features of canine respiratory coronavirus (CRCoV), canine parainfluenza virus (CPIV), and Bordetella bronchiseptica infections in dogs in an urban humane shelter and in rural/small community dog populations in western Canada. Seroprevalence of CRCoV and CPIV was low compared with other countries; seroprevalence of B. bronchiseptica was moderate to high in most populations examined. Rural dogs were 0.421 times (P ≤ 0.0001) less likely to be positive for CRCoV than dogs admitted to the shelter. There were no statistical differences in prevalence of antibodies to B. bronchiseptica and CPIV between urban and rural populations. Dogs from Fort Resolution, NWT were significantly (P < 0.05) less likely to have moderate or high antibody titers to the 3 agents than dogs in the shelter. Seroconversion to CRCoV was common in dogs in the shelter, but was not associated (P = 0.18) with respiratory disease. Antibodies to CRCoV, CPIV, or B. bronchiseptica on arrival were not significantly (P > 0.05) associated with disease-sparing after entry into the shelter.

The Accuracy of an Automasking Algorithm in Plantar Pressure Measurements

HSS Journal : the Musculoskeletal Journal of Hospital for Special Surgery. Feb, 2011  |  Pubmed ID: 22294959

Masking algorithms provide a way to analyze plantar pressure parameters based on distinct anatomical regions of the foot. No study has addressed their accuracy. The purpose of this study was to determine the accuracy of the Novel® ten-region standard masking algorithm in both dynamic and static measurements in normal feet. Static and dynamic plantar pressure measurements were collected from ten normal subjects (20 ft) with and without 10-mm radiopaque markers placed under the first through fifth metatarsal heads, fifth metatarsal base, and first proximal phalanx. The automask was then applied to subdivide the foot into distinct anatomical areas. Weight-bearing AP radiographs were obtained with and without markers. Plantar pressures and radiographs were overlaid. The percent accuracy of each marker within its appropriate mask region was calculated. The average accuracies of the automasking algorithm regions for dynamic and static measurements, respectively, were 98.8% and 90.4% (1MH), 89.9% and 80.6% (2MH), 98.6% and 81.4% (3MH), 96.8% and 82.3% (4MH), 93.1% and 80.8% (5MH), 97.3% and 92.5% (5MB), and 91.2% and 64.2% (1PPH). Marker presence did not alter foot structure or function as determined by intermetatarsal angles (range, p = 0.361 to p = 0.649) and the center of pressure excursion index (p = 0.727), respectively. The automasking algorithm accurately identifies most foot regions in normal feet, particularly in gait. Such accuracy may be reduced in the setting of foot deformity. Understanding the accuracy of masking algorithms may help guide the interpretation of plantar pressure measurements and ultimately both conservative and operative treatment decisions.

Quantifying Loss of Independent Joint Control in Acute Stroke with a Robotic Evaluation of Reaching Workspace

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2011  |  Pubmed ID: 22256253

Early recovery after stroke is significant for slow emergence of volitional movement. Initial movements are constrained by stereotypical co-activation of muscle groups such as shoulder abductors and distal limb flexors resulting in the loss of independent joint control. The objective of this study was to utilize new quantitative methods to evaluate the emergence and progression of the loss of independent joint control in the acute phase of recovery from stroke. Fifteen participants have been followed a maximum range of 2 to 32 weeks post-stroke. Participants underwent weekly and monthly robotic evaluations of horizontal plane reaching workspace as a function of abduction loading (0%-200% of limb weight). The magnitude of loss of independent joint control, indicated by the rate of work area reduction as a function of abduction loading, was evident even as early as 2 weeks post-stroke. Group analysis indicated that individuals with mild stroke show immediate presence of the impairment with an exponential rate of recovery over time while individuals with severe stroke show persistent impairment. Early detection and quantification of reaching impairments, such as the loss of independent joint control, will allow clinicians to more efficiently identify patients who would benefit from impairment-based targeted interventions. For example, patients with severe loss of independent joint control will likely benefit from early administration of an intervention attempting to reduce abnormal shoulder abductor/distal limb flexor co-activations during reaching. The field of rehabilitation robotics has demonstrated such interventions to be promising in the chronic severe stroke population.

Delays in the Diagnosis of Lung Cancer

Journal of Thoracic Disease. Sep, 2011  |  Pubmed ID: 22263086

Many patients with lung cancer report delays in diagnosing their disease. This may contribute to advanced stage at diagnosis and poor long term survival. This study explores the delays experienced by patients referred to a regional cancer centre with lung cancer.

The Early Days of Spinal Tumour Surgery

Journal of Perioperative Practice. Dec, 2011  |  Pubmed ID: 22263323

In numerous examples in this series of essays on 'The Early Days of ...' there is argument and debate about who should be given the credit for introducing a particular major advance in treatment. However, in the story of the management of tumours involving the spinal cord, there is no doubt at all about priority; the surgeon was Victor Horsley and the date was June 1887! The patient was a Captain Gilbey, a business man and a retired Army officer. In 1884, shortly after his wife's death following a road traffic accident, he developed severe upper thoracic back pain. He was seen over succeeding months and years by numbers of specialists, whose diagnoses ranged from an aneurysm to neurasthenia, and whose treatments included advice to take a long sea voyage, to have Turkish baths and to take the cure at the medicinal baths at Aix-la-Chapelle. His various medical advisors thought his condition to be functional, even though he was gradually losing sensation and movement in his legs and trunk, was having considerable difficulty in passing his urine and was now requiring morphia for the pain.

A Sensory Garden

South African Medical Journal = Suid-Afrikaanse Tydskrif Vir Geneeskunde. Oct, 2011  |  Pubmed ID: 22272845

Impact of Longitudinal Power Budget in Coherent Transmission Systems Employing Digital Back-propagation

Optics Express. Dec, 2011  |  Pubmed ID: 22274049

We report the impact of longitudinal signal power profile on the transmission performance of coherently-detected 112 Gb/s m-ary polarization multiplexed quadrature amplitude modulation system after compensation of deterministic nonlinear fibre impairments. Performance improvements up to 0.6 dB (Q(eff)) are reported for a non-uniform transmission link power profile. Further investigation reveals that the evolution of the transmission performance with power profile management is fully consistent with the parametric amplification of the amplified spontaneous emission by the signal through four-wave mixing. In particular, for a non-dispersion managed system, a single-step increment of 4 dB in the amplifier gain, with respect to a uniform gain profile, at ~2/3(rd) of the total reach considerably improves the transmission performance for all the formats studied. In contrary a negative-step profile, emulating a failure (gain decrease or loss increase), significantly degrades the bit-error rate.

Polarization Multiplexed 16QAM Transmission Employing Modified Digital Back-propagation

Optics Express. Dec, 2011  |  Pubmed ID: 22274106

We experimentally demonstrate performance enhancements enabled by weighted digital back propagation method for 28 Gbaud PM-16QAM transmission systems, over a 250 km ultra-large area fibre, using only one back-propagation step for the entire link, enabling up to 3 dB improvement in power tolerance with respect to linear compensation only. We observe that this is roughly the same improvement that can be obtained with the conventional, computationally heavy, non-weighted digital back propagation compensation with one step per span. As a further benchmark, we analyze performance improvement as a function of number of steps, and show that the performance improvement saturates at approximately 20 steps per span, at which a 5 dB improvement in power tolerance is obtained with respect to linear compensation only. Furthermore, we show that coarse-step self-phase modulation compensation is inefficient in wavelength division multiplexed transmission.

A Practical Phase Sensitive Amplification Scheme for Two Channel Phase Regeneration

Optics Express. Dec, 2011  |  Pubmed ID: 22274122

A "black-box" phase sensitive amplifier is presented achieving simultaneous suppression of deterministic phase distortion on two independent 42.66 Gbit/s DPSK modulated signal wavelengths.

Air Embolism After Percutaneous Transhepatic Biliary Drainage and Subsequent Endoscopic Retrograde Cholangiopancreatography (ERCP)

Endoscopy. Dec, 2011  |  Pubmed ID: 22275020

Tips and Tricks in Triple-negative Breast Cancer: How to Manage Patients in Real-life Practice?

Ecancermedicalscience. 2011  |  Pubmed ID: 22276059

Evaluating Distinctive Features for Early Diagnosis of Primary Sclerosing Cholangitis Overlap Syndrome in Adults with Autoimmune Hepatitis

The Ulster Medical Journal. Jan, 2011  |  Pubmed ID: 22347734

Overlap syndromes constitute a significant proportion of autoimmune liver disease. Our aim was to describe our cohort and evaluate practical methods of correctly diagnosing autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome as early as possible clinically.

Functional Metagenomics Reveals Previously Unrecognized Diversity of Antibiotic Resistance Genes in Gulls

Frontiers in Microbiology. 2011  |  Pubmed ID: 22347872

Wildlife may facilitate the spread of antibiotic resistance (AR) between human-dominated habitats and the surrounding environment. Here, we use functional metagenomics to survey the diversity and genomic context of AR genes in gulls. Using this approach, we found a variety of AR genes not previously detected in gulls and wildlife, including class A and C β-lactamases as well as six tetracycline resistance gene types. An analysis of the flanking sequences indicates that most of these genes are present in Enterobacteriaceae and various Gram-positive bacteria. In addition to finding known gene types, we detected 31 previously undescribed AR genes. These undescribed genes include one most similar to an uncharacterized gene in Verrucomicrobium and another to a putative DNA repair protein in Lactobacillus. Overall, the study more than doubled the number of clinically relevant AR gene types known to be carried by gulls or by wildlife in general. Together with the propensity of gulls to visit human-dominated habitats, this high diversity of AR gene types suggests that gulls could facilitate the spread of AR.

Shear Bond Strengths of a Selenium Containing and a Conventional Light Cured Adhesive for Orthodontic Bonding

Texas Dental Journal. Dec, 2011  |  Pubmed ID: 22375444

The objectives of this study were to evaluate the debonding strength and mode of failure of a selenium containing adhesive compared to an established orthodontic adhesive.

SRT1720 Improves Survival and Healthspan of Obese Mice

Scientific Reports. 2011  |  Pubmed ID: 22355589

Sirt1 is an NAD(+)-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity. Using a conditional SIRT1 knockout mouse and specific gene knockdowns we show SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1α-dependent manner. These findings indicate that SRT1720 has long-term benefits and demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals.

Jizz and the Joy of Pattern Recognition: Virtuosity Discipline and the Agency of Insight in UK Naturalists' Arts of Seeing

Social Studies of Science. Dec, 2011  |  Pubmed ID: 22400419

Approaches to visual skilling from anthropology and STS have tended to highlight the forces of discipline and control in understanding how shared visual accounts of the world are created in the face of potential differences brought about by multi-sensorial perception. Drawing upon a range of observational and interview material from an immersion in naturalist training and biological recording activities between 2003 and 2009, I focus upon jizz, a distinct form of gestalt perception much coveted by naturalist communities in the UK. Jizz is described as a tacit and embodied way of seeing that instantaneously reveals the identity of a species, relying upon but simultaneously suspending the arduous and meticulous study of an organism's diagnostic characteristics. I explore the potential and limitations of jizz to allow for both visual precision and an enchanted and varied form of encounter with nature. In so doing, I explore how the specific characteristics of wild, intangible and irreverent virtuoso performance work closely together with disciplining taxonomic standards. As such, discipline and irreverence work together, are mutually enabling, and allow for an accommodation rather than a segregation of potential difference brought about by perceptual variety.

Effects of Health Disparities on Survival After Neonatal Heart Surgery: Why Should Racial, Ethnic, Gender, and Socioeconomic Status Be Included in the Risk Analysis?

The Journal of Extra-corporeal Technology. Dec, 2011  |  Pubmed ID: 22416603

Health disparities are "differences in the quality of health and health care across different populations." Potential disparities associated with race, ethnicity, gender, and socioeconomic status should be considered when attempting to develop models for survival and neurodevelopmental outcomes in neonates undergoing congenital heart surgery. Each of the aforementioned sociodemographic factors is related to postsurgical mortality because they are frequently linked to measures of access to care in addition to location of care (geographically) and the type of institution (teaching vs. nonteaching) where patients receive care. Traditionally these factors have not been considered in models of surgical treatment outcomes in conditions such as hypoplastic left heart syndrome. However, we believe these factors should at least be included in risk analysis models to help explain their impact on outcomes and in predicting outcomes. Therefore, the purpose of this article is to highlight some of the nonsurgical influences that affect survival after neonatal heart surgery such as race, ethnicity, gender, and socioeconomic status.

Neonatal Extracorporeal Membrane Oxygenation Devices, Techniques and Team Roles: 2011 Survey Results of the United States' Extracorporeal Life Support Organization Centers

The Journal of Extra-corporeal Technology. Dec, 2011  |  Pubmed ID: 22416604

In early 2011, surveys of active Extracorporeal Life Support Organization (ELSO) centers within the United States were conducted by electronic mail regarding neonatal Extracorporeal Membrane Oxygenation (ECMO) equipment and professional staff. Seventy-four of 111 (67%) U.S. centers listed in the ELSO directory as neonatal centers responded to the survey. Of the responding centers, 53% routinely used roller pumps for neonatal ECMO, 15% reported using centrifugal pumps and 32% reported using a combination of both. Of the centers using centrifugal pumps, 51% reported that they do not use a compliance bladder in the circuit. The majority (95%) of roller pump users reported using a compliance bladder and 97% reported using Tygon" S-97-E tubing in the raceway of their ECMO circuits. Silicone membrane oxygenators were reportedly used by 25% of the respondents, 5% reported using micro-porous hollow fiber oxygenators (MPHF), 70% reported using polymethylpentene (PMP) hollow fiber oxygenators and 5% reported using a combination of the different types. Some form of in-line blood monitoring was used by 88% of the responding centers and 63% of responding centers reported using a circuit surface coating. Anticoagulation monitoring via the activated clotting time (ACT) was reported by 100% of the reporting centers. The use of extracorporeal cardiopulmonary resuscitation (ECPR) was reported by 53% of the responding centers with 82% of those centers using a crystalloid primed circuit to initiate ECPR. A cooling protocol was used by 77% of the centers which have an ECPR program. When these data are compared with surveys from 2002 and 2008 it shows that the use of silicone membrane oxygenators continues to decline, the use of centrifugal pumps continues to increase and ECMO personnel continues to be comprised of multidisciplinary groups of dedicated allied health care professionals.

Quality Assessment of Filtered Smoked Yellowfin Tuna (Thunnus Albacares) Steaks

Journal of Food Science. Aug, 2011  |  Pubmed ID: 22417519

  Filtered smoke (FS) has been used to preserve taste, texture, and/or color in tuna and other fish species. This treatment is particularly important in color preservation during frozen storage. The objective of this study was to compare changes in the quality profiles of FS-treated and untreated (UT) yellowfin tuna (Thunnus albacares) steaks stored in 3 ways: room temperature (21 to 22 °C), refrigerated (4 to 5 °C), and iced (0 °C). FS and UT steaks were processed from the same lot of fish and analyzed for chemical, microbiological, lipid oxidation, color, and sensory profiles. Similar trends were seen for microbial proliferation and accumulation of apparent ammonia and total volatile base nitrogen (TVB-N) during the storage temperatures evaluated. Notable exception in quality profile was found in lipid oxidation which was, as expected, lower for treated samples at all storage temperatures for TBARS (P < 0.05) and lower or significantly (P < 0.05) lower for POV values. FS increased the initial redness value significantly (P < 0.05). Unlike UT product, there was no loss of color value concomitant with quality changes for FS-treated tuna for all storage temperatures evaluated. Practical Application:  The overall goal of this project was to evaluate filtered smoked tuna steaks as to the impact on the overall quality profile. As a color-stabilizing technology, it could mask deteriorating quality.

Offering HIV Testing in an Acute Medical Admissions Unit in Newcastle Upon Tyne

Clinical Medicine (London, England). Dec, 2011  |  Pubmed ID: 22268305

The objective of this study was to offer HIV testing to all patients attending the acute medical admissions unit (AMU) in Newcastle upon Tyne to assess feasibility, acceptability and point prevalence in accordance with the 2008 UK National HIV testing guidelines. A prospective audit was performed offering HIV testing to all patients with the capacity to give verbal consent who attended the AMU. In total, 3,753 eligible patients were admitted during the audit period and 586 (15.6%) were considered for testing. Of those approached, 108 (18.4%) were clinically ineligible to test and 478 were offered a test. In the 396 patients who consented (82.8%), there were two new HIV diagnoses (point prevalence 0.5%). Offering HIV testing in an AMU setting is feasible and acceptable to patients. The high uptake rate but low proportion of admissions tested suggests a lack of confidence of medical staff in offering a test. Misconceptions regarding HIV testing remain and greater education is required for healthcare workers.

Multiple Determinants of Specific Modes of Prescription Opioid Diversion

Journal of Drug Issues. 2011  |  Pubmed ID: 22287798

Numerous national surveys and surveillance programs have shown a substantial rise in the abuse of prescription opioids over the past 15 years. Accessibility of these drugs to non-patients is the result of their unlawful channeling from legal sources to the illicit marketplace (diversion). Empirical data on diversion remain absent from the literature. This paper examines abusers' sources of diverted drugs from two large studies: 1) a national sample of opioid treatment clients (N=1983), and 2) a South Florida study targeting diverse populations of opioid abusers (N=782). The most common sources of diverted medications were dealers, sharing/trading, legitimate medical practice (e.g., unknowing medical providers), illegitimate medical practice (e.g., pill mills), and theft, in that order. Sources varied by users' age, gender, ethnicity, risk-aversiveness, primary opioid of abuse, injection drug use, physical health, drug dependence, and either access to health insurance or relative financial wealth. Implications for prescription drug control policy are discussed.

Update on the Prevalence of Allergic Sensitization to Russian Thistle in South-eastern Ontario: Retrospective Chart Review

Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology. Nov, 2011  |  Pubmed ID: 22373058

Mcl-1 and Bcl-xL Co-ordinately Regulate Megakaryocyte Survival

Blood. Feb, 2012  |  Pubmed ID: 22374700

Mature megakaryocytes depend on the function of Bcl-x(L), a member of the Bcl-2 family of pro-survival proteins, to proceed safely through the process of platelet shedding. Despite this, loss of Bcl-x(L) does not prevent the growth and maturation of megakaryocytes, suggesting redundancy with other pro-survival proteins. We therefore generated mice with a megakaryocyte-specific deletion of Mcl-1, which is known to be expressed in megakaryocytes. Megakaryopoiesis, platelet production and platelet life span were unperturbed in Mcl-1(Pf4Δ/Pf4Δ) animals. However, treatment with ABT-737, a BH3 mimetic compound that inhibits the pro-survival proteins Bcl-2, Bcl-xL and Bcl-w, resulted in the complete ablation of megakaryocytes and platelets. Genetic deletion of both Mcl-1 and Bcl-x(L) in megakaryocytes resulted in pre-weaning lethality. Megakaryopoiesis in Bcl-x(Pf4Δ/Pf4Δ) Mcl-1(Pf4Δ/Pf4Δ) embryos was severely compromised, and these animals exhibited ectopic bleeding. Our studies indicate that the combination of Bcl-x(L) and Mcl-1 is essential for the viability of the megakaryocyte lineage.

Therapeutic Amprenavir Concentrations in Cerebrospinal Fluid

Antimicrobial Agents and Chemotherapy. Jan, 2012  |  Pubmed ID: 22290964

Antiretrovirals that reach higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV in CSF and possibly better neurocognitive performance. The objective of this study was to determine whether amprenavir (APV) concentrations in CSF are in the therapeutic range. Individuals were selected based on the use of regimens that included fosamprenavir (FPV), a prodrug of APV, and the availability of stored CSF and matched plasma. Total APV was measured in 119 matched CSF-plasma pairs from 75 subjects by high-performance liquid chromatography (HPLC) (plasma) or liquid chromatography tandem mass spectrometry (LC/MS/MS) (CSF). Concentrations were compared to the 50% inhibitory concentration (IC(50)) for wild-type HIV (5.6 ng/ml). Subjects were predominantly middle-aged (median 44 years) white (57%) men (78%) with AIDS (77%). APV was detected in all but 4 CSF specimens, with a median concentration of 24.8 ng/ml (interquartile range [IQR], 16.2 to 44.0). The median CSF-to-plasma ratio was 0.012 (IQR, 0.008 to 0.018). CSF concentrations correlated with plasma concentrations (rho = 0.61; P < 0.0001) and with postdose sampling interval (rho = -0.29; P = 0.0019). APV concentrations in CSF exceeded the median IC(50) for wild-type HIV in more than 97% of CSF specimens with detectable APV by a median of 4.4-fold (IQR, 2.9 to 7.9). We conclude that administration of fosamprenavir should contribute to control of HIV replication in the central nervous system (CNS) as a component of effective antiretroviral regimens.

Impact of Fathers on Risky Sexual Behavior in Daughters: a Genetically and Environmentally Controlled Sibling Study

Development and Psychopathology. Feb, 2012  |  Pubmed ID: 22293012

Girls receiving lower quality paternal investment tend to engage in more risky sexual behavior (RSB) than peers. Whereas paternal investment theory posits that this effect is causal, it could arise from environmental or genetic confounds. To distinguish between these competing explanations, the current authors employed a genetically and environmentally controlled sibling design (N = 101 sister pairs; ages 18-36), which retrospectively examined the effects of differential sibling exposure to family disruption/father absence and quality of fathering. Consistent with a causal explanation, differences between older and younger sisters in the effects of quality of fathering on RSB were greatest in biologically disrupted families when there was a large age gap between the sisters (thus maximizing differential exposure to fathers), with greater exposure within families to higher quality fathering serving as a protective factor against RSB. Further, variation around the lower end of fathering quality appeared to have the most influence on RSB. In contrast, differential sibling exposure to family disruption/father absence (irrespective of quality of fathering) was not associated with RSB. The differential sibling-exposure design affords a new quasi-experimental method for evaluating the causal effects of fathers within families.

Sex-specific Pathways to Early Puberty, Sexual Debut, and Sexual Risk Taking: Tests of an Integrated Evolutionary-developmental Model

Developmental Psychology. Jan, 2012  |  Pubmed ID: 22268605

The current study tested sex-specific pathways to early puberty, sexual debut, and sexual risk taking, as specified by an integrated evolutionary-developmental model of adolescent sexual development and behavior. In a prospective study of 238 adolescents (n = 129 girls and n = 109 boys) followed from approximately 12-18 years of age, we tested for longitudinal relations between ecological stressors, family relationships, pubertal maturation, self-perceived mate value, and sexual risk taking in both boys and girls. Consistent with the theory, (a) higher levels of familial and ecological stress predicted earlier sexual debut and greater sexual risk taking; (b) pubertal maturation partially mediated these relations among girls but not among boys; (c) father absence had unique effects on female sexual outcomes but not on male sexual outcomes; (d) higher self-perceived mate value directly predicted earlier sexual debut and, through it, greater sexual risk taking; and (e) relations between pubertal maturation and early sexual debut were partially mediated by higher self-perceived mate value in boys but not in girls. Discussion focuses on the contribution of an integrated evolutionary-developmental theory to the adolescent sexual health literature. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

MacA is a Second Cytochrome C Peroxidase of Geobacter Sulfurreducens

Biochemistry. Apr, 2012  |  Pubmed ID: 22417533

The metal-reducing δ-proteobacterium Geobacter sulfurreducens produces a large number of c-type cytochromes, many of which have been implicated in the transfer of electrons to insoluble metal oxides. Among these, the dihemic MacA was assigned a central role. Here we have produced G. sulfurreducens MacA by recombinant expression in Escherichia coli and have solved its three-dimensional structure in three different oxidation states. Sequence comparisons group MacA into the family of diheme cytochrome c peroxidases, and the protein indeed showed hydrogen peroxide reductase activity with ABTS(-2) as an electron donor. The observed K(M) was 38.5 ± 3.7 μM H(2)O(2) and v(max) was 0.78 ± 0.03 μmol of H(2)O(2)·min(-1)·mg(-1), resulting in a turnover number k(cat) = 0.46 · s(-1). In contrast, no Fe(III) reductase activity was observed. MacA was found to display electrochemical properties similar to other bacterial diheme peroxidases, in addition to the ability to electrochemically mediate electron transfer to the soluble cytochrome PpcA. Differences in activity between CcpA and MacA can be rationalized with structural variations in one of the three loop regions, loop 2, that undergoes conformational changes during reductive activation of the enzyme. This loop is adjacent to the active site heme and forms an open loop structure rather than a more rigid helix as in CcpA. For the activation of the protein, the loop has to displace the distal ligand to the active site heme, H93, in loop 1. A H93G variant showed an unexpected formation of a helix in loop 2 and disorder in loop 1, while a M297H variant that altered the properties of the electron transfer heme abolished reductive activation.

Letter from the Editor

Human Vaccines & Immunotherapeutics. Mar, 2012  |  Pubmed ID: 22418878

Cattle MHC Nomenclature: is It Possible to Assign Sequences to Discrete Class I Genes?

Immunogenetics. Mar, 2012  |  Pubmed ID: 22419150

The cattle major histocompatibility complex (MHC) region contains a variable number of classical class I genes encoding polymorphic molecules involved in antigen presentation. Six classical class I genes have been described, but assigning sequences to these genes has proved problematic. We propose a refinement of the existing nomenclature, which currently names the 97 known classical class I sequences in a single series. Phylogenetic analysis of the 3' portion of the coding region allows segregation of these into six groups; thus, we have prefixed existing names with the appropriate number. Although it is clear that some of these groups correspond to discrete genes, it is currently not possible to state definitively that all do. However, the main groupings are consistent, and in conjunction with other evidence, we feel it is now appropriate to rename the sequences accordingly. Segregation of sequences into groups in this way will facilitate ongoing research and future use of the cattle MHC section of the Immuno Polymorphism Database.

Coordination Structures and Supramolecular Architectures in a Cerium(III)-Malonamide Solvent Extraction System

Langmuir : the ACS Journal of Surfaces and Colloids. Apr, 2012  |  Pubmed ID: 22420768

The process chemistry and solution structures investigated in the title system bridge the three ostensibly disparate fields of separation sciences, soft matter research, and coordination chemistry. We have explored this subject with synchrotron radiation research and advanced analyses leading to original insights into aggregation phenomena in solvent extraction. Herein we present findings showing the coagulation of reverse micelles into wormlike aggregates in organic phases (N,N'-dimethyl-N,N'-dibutyltetradecylmalonamide-abbreviated as DMDBTDMA-in n-dodecane) obtained by liquid-liquid extraction following contact with acidic and neutral aqueous media containing trivalent cerium. The growth of solute architectures was shown to prelude phase transition (i.e., the formation of a "third phase"). The presence of acid was shown to promote the growth of these micellar chains and, therefore, promoted third-phase formation. Acid was also shown to hydrate and swell the reverse micelle units, preorganizing them to allow for incorporation of cerium, leading to different coordination structures and enhanced metal extraction. The approach of linking both the coordination environment and supramolecular structures to the process properties of a solvent extraction system in a single study provides perspectives that are not available from independent, uncorrelated experimentation. Moreover, the analysis of small-angle X-ray scattering data from a solvent extraction system using the generalized indirect Fourier transform method to gain real-space information led to insights not otherwise available, showing that micellar assemblies are larger and more ordered than previously thought. This multipronged and multidisciplinary investigation opens new avenues in the evolving understanding of solute architectures in organic phases of practical relevance to solvent extraction and, simultaneously, of fundamental relevance to structured fluids and, in particular, phase transition phenomena.

Role of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in Patients with Chronic Sinopulmonary Disease

Chest. Mar, 2012  |  Pubmed ID: 22423042

ABSTRACT INTRODUCTION:Previous studies report a high frequency of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in patients with idiopathic bronchiectasis. However, most studies have based their findings on pre-selected patient groups or have performed limited testing for CFTR dysfunction. The objective of our study was to evaluate the prevalence of CFTR gene mutations and/or CFTR-related ion channel abnormalities among subjects with idiopathic chronic sinopulmonary disease and the prevalence of CF or a CFTR-related disorder in this population. METHODS:We evaluated 72 prospectively enrolled patients from 1995-2005 at the Hospital for Sick Children and St. Michael's Hospital with idiopathic chronic sinopulmonary disease for evidence of CFTR-mediated abnormalities. We performed CFTR genotyping and assessed CFTR function using sweat testing and nasal potential difference testing. The results were compared with data from healthy controls, CF heterozygotes and CF patients. RESULTS:The CFTR functional tests in idiopathic sinopulmonary patients showed a continuous spectrum, ranging from normal to values typically seen in individuals with CF. Forty eight patients (66%) demonstrated CFTR mutations and/or abnormalities of CFTR function. Twenty two (31%) fulfilled criteria for a CF diagnosis and 26 (36%) for a CFTR-related disorder with a strong female preponderance. Functional tests, more than genotyping, were instrumental in establishing a CF diagnosis. Clinical features failed to distinguish CF subjects from those with CFTR-related or idiopathic disease. CONCLUSION:The high prevalence of CF and CFTR dysfunction among patients with idiopathic chronic sinopulmonary disease underscores the need for extensive diagnostic evaluation for CF.

KRAS Mutation Spectrum Notably Diverges Between Non-small Cell Lung and Colorectal Carcinomas

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer. Apr, 2012  |  Pubmed ID: 22425935

Letter from the Editor

Human Vaccines & Immunotherapeutics. Feb, 2012  |  Pubmed ID: 22426365

Development of a Self-Assessed Consumer Recovery Outcome Measure: My Voice, My Life

Administration and Policy in Mental Health. Mar, 2012  |  Pubmed ID: 22426650

We report the development of a self-assessed consumer recovery outcome measure by way of a consumer led and focused iterative process, informed by exploratory and confirmatory factor analysis. The process began with a deliberately over-inclusive preliminary measure of 127 items, based on 12 presumptive domains derived from the recovery literature and consumer consultation, being piloted with over 500 mental health consumers. The full 504 participant data set was randomly split into two discrete sets of 300 and 204 to provide one for the initial exploratory factor analysis and another (of independence) for the subsequent confirmatory factor analysis and reliability estimation. Analyses identified and confirmed (using the separate data sets) a robust factor structure, with 11 distinct and relatively independent factors (relationships; day-to-day life; culture; physical health; quality of life; mental health; recovery; hope and empowerment; spirituality; resources; and satisfaction with services) underlying one substantial principal construct (that we refer to as consumer recovery). The measure was refined to 65 items, between three and ten items for each of the 11 domains, the reliabilities for which are uniformly high.

Microvascular Flow Modeling Using In Vivo Hemodynamic Measurements in Reconstructed 3D Capillary Networks

Microcirculation (New York, N.Y. : 1994). Mar, 2012  |  Pubmed ID: 22429386

We describe a systematic approach to modeling blood flow using reconstructed capillary networks and in vivo hemodynamic measurements. Our objective was to produce flow solutions that represent convective O(2) delivery in vivo. Two capillary networks, I & II, (84x168x342 & 70x157x268 μm(3) ) were mapped using custom software. Total network red blood cell supply rate (SR) was calculated from in vivo data and used as a target metric for the flow model. To obtain inlet hematocrits, mass balances were applied recursively from downstream vessels. Pressure differences across the networks were adjusted to achieve target SR. Baseline flow solutions were used as inputs to existing O(2) transport models. To test the impact of flow redistribution, asymmetric flow solutions (Asym) were generated by applying a ±20% pressure change to network outlets. Asym solutions produced a mean absolute difference in SR per capillary of 27.6 ± 33.3% in network I & 33.2 ± 40.1% in network II vs. baseline. The O(2) transport model calculated mean tissue PO(2) of 28.2 ± 4.8 & 28.1 ± 3.5 mmHg for baseline and 27.6 ± 5.2 & 27.7 ± 3.7 mmHg for Asym. This illustrates that moderate changes in flow distribution within a capillary network have little impact on tissue PO(2) provided that total SR remains unchanged. © 2012 John Wiley & Sons Ltd.

Characterization of the Colorectal Cancer-associated Enhancer MYC-335 at 8q24: the Role of Rs67491583

Cancer Genetics. Jan, 2012  |  Pubmed ID: 22429595

Recent genome-wide association studies have identified multiple regions at 8q24 that confer susceptibility to many cancers. In our previous work, we showed that the colorectal cancer (CRC) risk variant rs6983267 at 8q24 resides within a TCF4 binding site at the MYC-335 enhancer, with the risk allele G having a stronger binding capacity and Wnt responsiveness. Here, we searched for other potential functional variants within MYC-335. Genetic variation within MYC-335 was determined in samples from individuals of European, African, and Asian descent, with emphasis on variants in putative transcription factor binding sites. A 2-bp GA deletion rs67491583 was found to affect a growth factor independent (GFI) binding site and was present only in individuals with African ancestry. Chromatin immunoprecipitation performed in heterozygous cells showed that the GA deletion had an ability to reduce binding of the transcriptional repressors GFI1 and GFI1b. Screening of 1,027 African American colorectal cancer cases and 1,773 healthy controls did not reveal evidence for association (odds ratio: 1.17, 95% confidence interval: 0.97-1.41, P = 0.095). In this study, rs67491583 was identified as another functional variant in the CRC-associated enhancer MYC-335, but further studies are needed to establish the role of rs67491583 in the colorectal cancer predisposition of African Americans.

The Organization of the Gymnotiform Fish Pallium in Relation to Learning and Memory: IV. Expression of Conserved Transcription Factors and Implications for the Evolution of Dorsal Telencephalon

The Journal of Comparative Neurology. Mar, 2012  |  Pubmed ID: 22430363

We have cloned the apteronotid homologs of FoxP2, Otx1 and FoxO3. There was, in the case of all three genes, good similarity between the apteronotid and human amino acid sequences: FoxP2 - 78%, Otx1 - 54%, FoxO3 - 71%. The functional domains of these genes were conserved to a far greater extent - on average: FoxP2 - 89%, Otx1 - 76%, FoxO3 - 82%. This led us to hypothesize that the cellular functions of these genes may also be conserved. We then used in situ hybridization to examine the distribution of the mRNA transcripts of these genes in the apteronotid telencephalon. We confined our analysis to the pallial regions previously associated with learning about social signals, and whose circuitry has been closely examined in the other papers of this series. We found that AptFoxP2 and AptOtx1 transcripts were expressed predominantly in the dorsocentral division of the pallium (DC); the dorsolateral division of the pallium (DL) contained only weakly labeled neurons. In both cases, the distribution of labeled neurons was very heterogeneous and unlabeled neurons could be found adjacent to strongly labeled ones. In contrast, we found that most neurons in DL strongly expressed AptFoxO3 mRNA, while there was only weak expression in a small number of cells within DC. We briefly discuss the relevance of our results regarding the functional roles of AptFoxP2/AptOtx1-expressing neurons in DC for communication versus foraging behavior. We extensively discuss the implications of our results on possible homologies between DL and DC and medial and dorsal pallium of tetrapods, respectively. J. Comp. Neurol., 2012. © 2012 Wiley Periodicals, Inc.

The Organization of the Gymnotiform Fish Pallium in Relation to Learning and Memory: II. Extrinsic Connections

The Journal of Comparative Neurology. Mar, 2012  |  Pubmed ID: 22430442

This study describes the extrinsic connections of the dorsal telencephalon (pallium) of gymnotiform fish. We show that the afferents to the dorsolateral and dorsomedial pallial subdivisions of gymnotiform fish arise from the preglomerular complex. The preglomerular complex receives input from four clearly distinct regions: (a) descending input from pallium itself: dorsomedial and dorsocentral subdivisions and nucleus taenia; (b) other diencephalic nuclei- centroposterior, glomerular and anterior tuberal nuclei and nucleus of the posterior tuberculum; (c) mesencephalic sensory structures (optic tectum, dorsal and ventral torus semicircularis); and (d) basal forebrain, preoptic area and hypothalamic nuclei. Previous studies have implicated the majority of the diencephalic and mesencephalic nuclei in electrosensory, visual and acousticolateral functions. Herein we discuss the implications of preglomerular/pallial electrosensory-associated afferents with respect to a major functional dichotomy of the electric sense. The results allow us to hypothesize that a functional distinction between electrocommunication versus electrolocation is maintained within the input and output pathways of the gymnotiform pallium. Electrocommunication information is conveyed to the pallium through complex indirect pathways that originate in the nucleus electrosensorius, while electrolocation processing follows a conservative pathway inherent to all vertebrates, through the optic tectum. We hypothesize that cells responsive to communication signals do not converge onto the same targets in the preglomerular complex as cells responsive to moving objects. We also hypothesize that efferents from the dorsocentral (DC) telencephalon project to the dorsal torus semicircularis to regulate processing of electrocommunication signals, while DC efferents to the tectum modulate sensory control of movement. J. Comp. Neurol., 2012. © 2012 Wiley Periodicals, Inc.

Letter About Invisalign Practices--important!

Journal - Oklahoma Dental Association. Jan, 2012  |  Pubmed ID: 22432353

Addition of an External Electron Donor to in Vitro Assays of Cysteine Dioxygenase Precludes the Need for Exogenous Iron

Archives of Biochemistry and Biophysics. Mar, 2012  |  Pubmed ID: 22433531

Cysteine dioxygenase (CDO) utilizes a 3-His facial triad for coordination of its metal center. Recombinant CDO present in cellular lysate exists primarily in the ferrous form and exhibits significant catalytic activity. Removal of CDO from the reducing cellular environment during purification results in the loss of bound iron and oxidation of greater than 99% of the remaining metal centers. The as-isolated recombinant enzyme has comparable activity as the background level of l-cysteine oxidation confirming that CDO is inactive under the aerobic conditions required for catalysis. Including exogenous ferrous iron in assays resulted in non-enzymatic product formation; however, addition of an external reductant in assays of the purified protein resulted in the recovery of CDO activity. EPR spectroscopy of CDO in the presence of a reductant confirms that the recovered activity is consistent with reduction of iron to the ferrous form. The as-isolated enzyme in the presence of l-cysteine was nearly unreactive with the dioxygen analog, but had increased affinity when pre-incubated with an external reductant. These studies shed light on the discrepancies among reported kinetic parameters for CDO and also juxtapose the stability of the 3-His and 2-His/1-carboxylate ferrous enzymes in the presence of dioxygen.

The Organization of the Gymnotiform Fish Pallium in Relation to Learning and Memory: III. Intrinsic Connections

The Journal of Comparative Neurology. Mar, 2012  |  Pubmed ID: 22434647

The present study reports on the telencephalic connections of regions of the dorsal telencephalon of the weakly electric fish, Apteronotus leptorhynchus and Gymnotus sp, implicated in learning and memory - the lateral (DL), central (DC), dorsal (DD) regions of the pallium and the intermediate region between DL and DC (Dx). We find that the main route of transmission consists of diencephalic (preglomerular complex; PG) glutamatergic input to DL, glutamatergic projections from DL to DC and Dx, and glutamatergic output from DC/Dx to di-, mes- and rhombencephalic nuclei. While PG efferents to DL are spatially organized, the projection from DL to DC appears to be diffuse. The connections of DD are entirely intrinsic to the pallium: DL projects to DD (glutamatergic) and DD feeds back to DL (glutamatergic); DD also projects to DC and has strong contralateral connections. In addition, DL and DD receive input from subpallial regions; we suggest that these are associated with the previously identified GABAergic, dopaminergic and somatostatin positive input to these regions. The DL/DD connections are very complex since DL projects to and receives input from different subdivisions of DD. These subdivsions are linked by circuitry intrinsic to DD itself. DL and DD both contain recurrent putatively excitatory (glutamatergic) connections, as well as local putatively inhibitory (GABAergic) interneurons. In contrast, recurrent excitatory connections appears to be absent in DC, and local inhibition is also hardly present. Finally, we speculate on the implications of this pattern of connectivity for theories of short-term memory and long-term associative memory. J. Comp. Neurol., 2012. © 2012 Wiley Periodicals, Inc.

Full Dates (day, Month, Year) Should Be Used in Population-based Cancer Survival Studies

International Journal of Cancer. Journal International Du Cancer. Mar, 2012  |  Pubmed ID: 22438030

Accurate survival estimates are essential for monitoring cancer survival trends, for health care planning and for resource allocation. In order to obtain precise estimates of survival, full dates (day, month and year) rather than partial dates (month and year) are required. In some jurisdictions, however, cancer registries are constrained from providing full dates on the grounds of confidentiality. The bias resulting from the use of partial dates in the estimation and comparison of survival makes it impossible to determine precisely the differences in the risk of death from cancer between population groups or in successive calendar periods. Important operational arguments also exist against the use of incomplete dates for survival analysis, including increased workload for cancer registry staff and the introduction of avoidable complexity for quality control of survival data. Cancer survival is one of the most widely known outputs produced by population-based cancer registries, and it is a crucial metric for the comparative effectiveness of health services. The bodies that set data access guidelines must take a more balanced view of the risks and benefits of using full dates for the estimation of cancer survival. © 2012 Wiley-Liss, Inc.

Rational Diversification of a Promoter Providing Fine-tuned Expression and Orthogonal Regulation for Synthetic Biology

PloS One. 2012  |  Pubmed ID: 22442681

Yeast is an ideal organism for the development and application of synthetic biology, yet there remain relatively few well-characterised biological parts suitable for precise engineering of this chassis. In order to address this current need, we present here a strategy that takes a single biological part, a promoter, and re-engineers it to produce a fine-graded output range promoter library and new regulated promoters desirable for orthogonal synthetic biology applications. A highly constitutive Saccharomyces cerevisiae promoter, PFY1p, was identified by bioinformatic approaches, characterised in vivo and diversified at its core sequence to create a 36-member promoter library. TetR regulation was introduced into PFY1p to create a synthetic inducible promoter (iPFY1p) that functions in an inverter device. Orthogonal and scalable regulation of synthetic promoters was then demonstrated for the first time using customisable Transcription Activator-Like Effectors (TALEs) modified and designed to act as orthogonal repressors for specific PFY1-based promoters. The ability to diversify a promoter at its core sequences and then independently target Transcription Activator-Like Orthogonal Repressors (TALORs) to virtually any of these sequences shows great promise toward the design and construction of future synthetic gene networks that encode complex "multi-wire" logic functions.

Teaching Management of Contrast Reactions: Does It Work and How Often Do We Need to Refresh?

Academic Radiology. Apr, 2012  |  Pubmed ID: 22444675

Knowledge of the management of acute contrast reactions is lacking among radiologists. Training in the management of acute contrast reactions occurs at the investigators' institution and others, but the durability of that training and the need for refresher training have not been assessed.

Impact of American College of Surgeons Oncology Group Z0011 and National Surgical Adjuvant Breast and Bowel Project B-32 Trial Results on Surgeon Practice in the Pacific Northwest

American Journal of Surgery. Mar, 2012  |  Pubmed ID: 22445745

BACKGROUND: Recent clinical trials have suggested no survival benefit for completion axillary node dissection (CALND) after sentinel lymph node biopsy (American College of Surgeons Oncology Group Z0011) and no clinically meaningful benefit for the routine use of immunohistochemistry (National Surgical Adjuvant Breast and Bowel Project B-32) in clinically node-negative breast cancer. METHODS: A 12-question electronic survey was distributed to members of 3 Pacific Northwest surgical societies. Surgeons were queried regarding the impact of the trial results on their surgical management of breast cancer. RESULTS: The 181 respondents reported performing fewer CALNDs (63%), fewer intraoperative frozen sections (21%), and no immunohistochemistry (12%) because of trial data. However, 28% of surgeons continued to perform CALND in patients with 1 to 2 positive sentinel lymph nodes undergoing lumpectomy and postoperative radiation. CONCLUSIONS: Recent trial data have impacted the performance of CALNDs and the pathological evaluation of sentinel lymph nodes among Pacific Northwest surgeons. Our results suggest a need for regional surgical societies to disseminate practice-changing trial data to members.

Targeting Chk1 in P53-deficient Triple-negative Breast Cancer is Therapeutically Beneficial in Human-in-mouse Tumor Models

The Journal of Clinical Investigation. Apr, 2012  |  Pubmed ID: 22446188

Patients with triple-negative breast cancer (TNBC) - defined by lack of estrogen receptor and progesterone receptor expression as well as lack of human epidermal growth factor receptor 2 (HER2) amplification - have a poor prognosis. There is a need for targeted therapies to treat this condition. TNBCs frequently harbor mutations in TP53, resulting in loss of the G1 checkpoint and reliance on checkpoint kinase 1 (Chk1) to arrest cells in response to DNA damage. Previous studies have shown that inhibition of Chk1 in a p53-deficient background in response to DNA damage. We therefore tested whether inhibition of Chk1 could potentiate the cytotoxicity of the DNA damaging agent irinotecan in TNBC using xenotransplant tumor models. Tumor specimens from patients with TNBC were engrafted into humanized mammary fat pads of immunodeficient mice to create 3 independent human-in-mouse TNBC lines: 1 WT (WU-BC3) and 2 mutant for TP53 (WU-BC4 and WU-BC5). These lines were tested for their response to irinotecan and a Chk1 inhibitor (either UCN-01 or AZD7762), either as single agents or in combination. The combination therapy induced checkpoint bypass and apoptosis in WU-BC4 and WU-BC5, but not WU-BC3, tumors. Moreover, combination therapy inhibited tumor growth and prolonged survival of mice bearing the WU-BC4 line, but not the WU-BC3 line. In addition, knockdown of p53 sensitized WU-BC3 tumors to the combination therapy. These results demonstrate that p53 is a major determinant of how TNBCs respond to therapies that combine DNA damage with Chk1 inhibition.

Genetics of Gene Expression in Primary Immune Cells Identifies Cell Type-specific Master Regulators and Roles of HLA Alleles

Nature Genetics. Mar, 2012  |  Pubmed ID: 22446964

Trans-acting genetic variants have a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B cells, we identify new predominantly cell type-specific cis and trans expression quantitative trait loci (eQTLs), including multi-locus trans associations to LYZ and KLF4 in monocytes and B cells, respectively. Additionally, we observe a B cell-specific trans association of rs11171739 at 12q13.2, a known autoimmune disease locus, with IP6K2 (P = 5.8 × 10(-15)), PRIC285 (P = 3.0 × 10(-10)) and an upstream region of CDKN1A (P = 2 × 10(-52)), suggesting roles for cell cycle regulation and peroxisome proliferator-activated receptor γ (PPARγ) signaling in autoimmune pathogenesis. We also find that specific human leukocyte antigen (HLA) alleles form trans associations with the expression of AOAH and ARHGAP24 in monocytes but not in B cells. In summary, we show that mapping gene expression in defined primary cell populations identifies new cell type-specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility.

Effect of Transendocardial Delivery of Autologous Bone Marrow Mononuclear Cells on Functional Capacity, Left Ventricular Function, and Perfusion in Chronic Heart Failure: The FOCUS-CCTRN Trial

JAMA : the Journal of the American Medical Association. Mar, 2012  |  Pubmed ID: 22447880

Context Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy.Objective To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina.Design, Setting, and Patients A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011.Intervention Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group).Main Outcome Measures Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory.Results Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement.Conclusion Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT.Trial Registration clinicaltrials.gov Identifier: NCT00824005.

Observer Agreement Comparing the Use of Virtual Slides with Glass Slides in the Pathology Review Component of the POSH Breast Cancer Cohort Study

Journal of Clinical Pathology. Mar, 2012  |  Pubmed ID: 22447915

Aims(1) To compare the use of scanned virtual slide images (virtual microscopy) with glass slides (conventional microscopy) in the assessment of morphological characteristics of breast cancers within the setting of the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH), involving a cohort of women under 40 years of age, presenting with breast cancer. (2) To assess the acceptability to histopathologists of the use of virtual slide images.Methods13 histopathologists from the UK and Australia participated in the POSH pathology review. The observers were asked to assess multiple morphological features such as tumour grade and type. Comparisons were made for a single observer using both virtual images and glass slides. Intra- and inter-observer variability was calculated using the κ statistic and a comparison was made between the use of each image modality.ResultsDiagnostic performance with virtual slides was comparable to conventional microscopic assessment, with the measurement of agreement best for vascular invasion, necrosis and the presence of a central scar (κ=0.37-0.78), and poor for more subjective parameters such as pleomorphism, stroma, the nature of the tumour border and the degree of lymphocytic infiltrate (κ=0.1).ConclusionVirtual slides represent an acceptable methodology for central review of breast cancer histopathology and can circumvent the need for either travel to view material, or the potential problems of sending it by post.

Serum Protein Electrophoresis Values for Free-ranging and Zoo-based Koalas (Phascolarctos Cinereus)

Journal of Zoo and Wildlife Medicine : Official Publication of the American Association of Zoo Veterinarians. Mar, 2012  |  Pubmed ID: 22448529

In a clinical setting, especially with species of special interest, it is important to use all clinical pathology testing options for general health monitoring and diagnosis. Protein electrophoresis (EPH) has previously been shown to be an important adjunct tool in veterinary medicine. Serum samples from 18 free-ranging and 12 zoo-based koalas (Phascolarctos cinereus) were subject to EPH analysis. Significant differences were found between the two groups for the following values: total protein, albumin, beta globulins, and albumin-globulin ratio (P < 0.05). By using the combined data, the minimum-maximum values for the EPH fractions were as follows: total protein 5.0-7.8 g/dl, albumin 2.8-4.7 g/dl, alpha-1 globulins 0.5-1.1 g/dl, alpha-2 globulins 0.3-0.7 g/dl, beta globulins 0.4-1.0 g/dl, gamma globulins 0.2-1.0 g/dl, and albumin-globulin ratio 1.0-2.1.

High Prevalence of Insulation Failure with Externalized Cables in St. Jude Medical Riata Family ICD Leads; Fluoroscopic Grading Scale and Correlation to Extracted Leads

Heart Rhythm : the Official Journal of the Heart Rhythm Society. Mar, 2012  |  Pubmed ID: 22449742

BACKGROUND: Inside-out abrasion with externalization of sensing ring or high voltage cables in St. Jude Medical Riata ICD leads has been reported. The prevalence of extruded cables, rate of electrical abnormalities, and predictors of failure in Riata leads are unknown. OBJECTIVE: Estimate the incidence of lead failure in the St. Jude Medical Riata ICD leads, and to propose a standard for fluoroscopic assessment of insulation breakdown. METHODS: Patients undergoing cine-fluoroscopy on Riata ICD leads, at our institution, before January 25, 2012 were included (n=87). Leads were graded as Type 0-3 (0= normal, 1= abnormal conductor spacing, 2= < 1 cm cable extrusion, 3 = > 1 cm length extrusion). Comparison to extracted leads (n=15) was documented. Device interrogation data were used for electrical analysis. RESULTS: Mean time from implant was 5.9 ± 3.45 years. Structural lead failure with externalized cables was seen in 33.3% (29/87) of patients. 31% (9/29) of leads with exposed cables showed electrical failure, and 29.7% (19/64) of leads with normal electrical data contained externalized cables. Time from implant ≥ 5 years predicted structural lead failure, p=0.04. X-Ray grade compared to extracted leads demonstrated a sensitivity and specificity of 86% and 100%. CONCLUSIONS: Cine-fluoroscopy using a simple scale correlated with structural integrity of extracted Riata leads. A high percentage of leads with extrusion showed electrical failure. Leads ≥ 5 years from implant showed a high rate of externalized cables. A large independent multi-center study to determine the prevalence and clinical sequelae of Riata lead failures is warranted.

Mental Health Difficulties in Children with Developmental Coordination Disorder

Pediatrics. Apr, 2012  |  Pubmed ID: 22451706

To explore the associations between probable developmental coordination disorder (DCD) defined at age 7 years and mental health difficulties at age 9 to 10 years.

Constraints on Haplotype Structure and Variable Gene Frequencies Suggest a Functional Hierarchy Within Cattle MHC Class I

Immunogenetics. Mar, 2012  |  Pubmed ID: 22454046

Six major histocompatibility complex (MHC) classical class I genes have been identified in cattle, and up to three of these are expressed in variable combinations on different haplotypes. The origin and functional significance of this genetic complexity is unknown. However, an improved assembly of the cattle genome, an expanded database of full-length cDNA sequences and high-resolution frequency data concerning expressed class I genes in an economically important cattle breed combine to provide a new opportunity to study the significance of cattle MHC class I diversity. Analysis of these new data supports assignment of alleles to six discrete genes and further shows that all these classical genes share a common ancestor with a single non-classical gene, NC1. While haplotype structure is variable, with thirteen gene configurations identified, there are nevertheless clear constraints relating to both the number and combination of genes. Haplotypes expressing two classical genes are most frequently observed, and the classical class I gene 2 is almost invariably present. The frequency data support the dominance of gene 2, showing that close to 100 % of individuals carry at least one copy. This indicates a hierarchy in the functional importance of particular genes and haplotype structures. Haplotype frequency in cattle populations is therefore likely to impact on differential disease susceptibilities. This knowledge will be important for development of informed breeding strategies aimed at increasing the ability of cattle to survive in the face of future unpredictable pathogen exposure.

Dissecting the Heterogeneity of Triple-Negative Breast Cancer

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Mar, 2012  |  Pubmed ID: 22454417

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chemotherapy lack durability. Early-stage clinical studies suggested impressive potential when a poly (ADP-ribose) polymerase (PARP) inhibitor is given for the treatment of advanced TNBC with BRCA gene dysfunction. The molecular complexity of TNBC has led to proposed subclassifications, which will be of great value for the development of targeted therapies. In this review, we discuss the biology of TNBC at the pathologic and the molecular levels. We also elaborate on the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib, a novel investigational anticancer agent that does not possess characteristics typical of the PARP inhibitor class, in combination with chemotherapy in advanced TNBC.

Acceptability of Providing Self-taken Vaginal Samples and Allowing Access to NHS Numbers and Medical Records: Feasibility Study in Young Female Genitourinary Medicine Clinic Attenders

Sexually Transmitted Infections. Mar, 2012  |  Pubmed ID: 22457315

Drug Development: Raise Standards for Preclinical Cancer Research

Nature. Mar, 2012  |  Pubmed ID: 22460880

Infiltrative Epitheliosis of the Breast

Journal of Clinical Pathology. Mar, 2012  |  Pubmed ID: 22461653

Accuracy of Perception of Ovulation Day in Women Trying to Conceive

Current Medical Research and Opinion. Apr, 2012  |  Pubmed ID: 22462529

Abstract Background: The likelihood of conception is increased if intercourse is timed to coincide with the fertile period (5 days prior to ovulation). However, to be effective, this requires good awareness of the day of ovulation. The aim of this study was to examine the accuracy of women's perceived ovulation day, compared with actual fertile days, in a cohort of women trying to conceive. Main outcome measures: Comparison of women's estimated day of ovulation with their actual ovulation day (determined by detecting luteinising hormone). Methods: This was a sample collection study and volunteer women were recruited via online advertising. At recruitment volunteers reported the cycle day they believed they ovulated. They then used a home urine fertility monitor to test their daily fertility status to time intercourse to try and achieve conception, in addition to collecting early morning urine samples for laboratory analysis. The main outcome measure was a comparison of women's estimated day of ovulation with their actual ovulation day, as determined by urine detection of luteinising hormone. Results: Three hundred and thirty women were recruited onto the study and data was available for 102 volunteers who became pregnant. Thirteen women (12.7%) correctly estimated their ovulation day; median difference +2 days, range -10 to +27 days. The most common days for estimation of ovulation were day 14 (35.5%) and day 15 (15.7%). Only 55% of estimated ovulation days fell within the volunteers' fertile window; only 27% on days of peak fertility. Conclusions: Women trying to conceive may benefit from using a prospective method to identify their fertile phase, as a significant proportion could be incorrectly estimating their fertile days. These observations were made on women who were actively looking for knowledge on fertility and considered only cycles where conception occurred, inaccuracy could be greater if a broader population is considered.

An Exo-β-(1→3)-d-galactanase from Streptomyces Sp. Provides Insights into Type II Arabinogalactan Structure

Carbohydrate Research. May, 2012  |  Pubmed ID: 22464224

An exo-β-(1→3)-d-galactanase (SGalase1) that specifically cleaves the β-(1→3)-d-galactan backbone of arabinogalactan-proteins (AGPs) was isolated from culture filtrates of a soil Streptomyces sp. Internal peptide sequence information was used to clone and recombinantly express the gene in E. coli. The molecular mass of the isolated enzyme was ∼45kDa, similar to the 48.2kDa mass predicted from the amino acid sequence. The pI, pH and temperature optima for the enzyme were ∼7.45, 3.8 and 48°C, respectively. The native and recombinant enzymes specifically hydrolysed β-(1→3)-d-galacto-oligo- or poly-saccharides from the upstream (non-reducing) end, typical of an exo-acting enzyme. A second homologous Streptomyces gene (SGalase2) was also cloned and expressed. SGalase2 was similar in size (47.9kDa) and enzyme activity to SGalase1 but differed in its pH optimum (pH 5). Both SGalase1 and SGalase2 are predicted to belong to the CAZy glycosyl hydrolase family GH 43 based on activity, sequence homology and phylogenetic analysis. The K(m) and V(max) of the native exo-β-(1→3)-d-galactanase for de-arabinosylated gum arabic (dGA) were 19mg/ml and 9.7μmol d-Gal/min/mg protein, respectively. The activity of these enzymes is well suited for the study of type II galactan structures and provides an important tool for the investigation of the biological role of AGPs in plants. De-arabinosylated gum arabic (dGA) was used as a model to investigate the use of these enzymes in defining type II galactan structure. Exhaustive hydrolysis of dGA resulted in a limited number of oligosaccharide products with a trisaccharide of Gal(2)GlcA(1) predominating.

Genetic Diversity in European Pisum Germplasm Collections

TAG. Theoretical and Applied Genetics. Theoretische Und Angewandte Genetik. Apr, 2012  |  Pubmed ID: 22466957

The distinctness of, and overlap between, pea genotypes held in several Pisum germplasm collections has been used to determine their relatedness and to test previous ideas about the genetic diversity of Pisum. Our characterisation of genetic diversity among 4,538 Pisum accessions held in 7 European Genebanks has identified sources of novel genetic variation, and both reinforces and refines previous interpretations of the overall structure of genetic diversity in Pisum. Molecular marker analysis was based upon the presence/absence of polymorphism of retrotransposon insertions scored by a high-throughput microarray and SSAP approaches. We conclude that the diversity of Pisum constitutes a broad continuum, with graded differentiation into sub-populations which display various degrees of distinctness. The most distinct genetic groups correspond to the named taxa while the cultivars and landraces of Pisum sativum can be divided into two broad types, one of which is strongly enriched for modern cultivars. The addition of germplasm sets from six European Genebanks, chosen to represent high diversity, to a single collection previously studied with these markers resulted in modest additions to the overall diversity observed, suggesting that the great majority of the total genetic diversity collected for the Pisum genus has now been described. Two interesting sources of novel genetic variation have been identified. Finally, we have proposed reference sets of core accessions with a range of sample sizes to represent Pisum diversity for the future study and exploitation by researchers and breeders.

Antischistosomal Activities of Mefloquine Related Aminoalcohols

Antimicrobial Agents and Chemotherapy. Apr, 2012  |  Pubmed ID: 22470113

Interesting antischistosomal properties have been documented for the antimalarial mefloquine, a 4-quinolinemethanol. We evaluated the antischistosomal activities of nine mefloquine related compounds, belonging to the 4-pyridinemethanols, 4-phenanthrenmethanols and related 4-quinolinemethanols. Eight compounds revealed high activities against Schistosoma mansoni in vitro, with two drugs (4-quinolinemethanols WR7573 and WR7930) characterized by significantly lower IC(50)s (2.7 and 3.5 μM, respectively) when compared to mefloquine (11.4 μM). Mefloquine and WR7930 showed significantly decreased IC(50) values when incubated in the presence of hemoglobin. High worm burden reductions (WBR) were obtained with enpiroline (WBR: 82.7%, dosage 200 mg/kg), its threo-isomers ((+)-threo WBR: 100%, (-)-threo WBR: 89%) and WR7930 (WBR: 87%, dosage 100 mg/kg) against adult S. mansoni in mice. Furthermore excellent in vitro and in vivo antischistosomal activity was observed for two WR7930 related structures (WR29252, WR7524). In addition, mefloquine (WBR: 81 %), enpiroline (WBR: 77 %) and WR7930 (WBR: 100 %) showed high activities on S. haematobium harbored in mice following single oral doses of 200 mg/kg. These results provide a deeper insight into the structural features of the aminoalcohols that rule antischistosomal activity. Further studies should be launched with enpiroline and WR7930.

X-chromosome Inactivation in Rett Syndrome Human Induced Pluripotent Stem Cells

Frontiers in Psychiatry / Frontiers Research Foundation. 2012  |  Pubmed ID: 22470355

Rett syndrome (RTT) is a neurodevelopmental disorder that affects girls due primarily to heterozygous mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MECP2). Random X-chromosome inactivation (XCI) results in cellular mosaicism in which some cells express wild-type (WT) MECP2 while other cells express mutant MECP2. The generation of patient-specific human induced pluripotent stem cells (hiPSCs) facilitates the production of RTT-hiPSC-derived neurons in vitro to investigate disease mechanisms and identify novel drug treatments. The generation of RTT-hiPSCs has been reported by many laboratories, however, the XCI status of RTT-hiPSCs has been inconsistent. Some report RTT-hiPSCs retain the inactive X-chromosome (post-XCI) of the founder somatic cell allowing isogenic RTT-hiPSCs that express only the WT or mutant MECP2 allele to be isolated from the same patient. Post-XCI RTT-hiPSCs-derived neurons retain this allele-specific expression pattern of WT or mutant MECP2. Conversely, others report RTT-hiPSCs in which the inactive X-chromosome of the founder somatic cell reactivates (pre-XCI) upon reprogramming into RTT-hiPSCs. Pre-XCI RTT-hiPSC-derived neurons exhibit random XCI resulting in cellular mosaicism with respect to WT and mutant MECP2 expression. Here we review and attempt to interpret the inconsistencies in XCI status of RTT-hiPSCs generated to date by comparison to other pluripotent systems in vitro and in vivo and the methods used to analyze XCI. Finally, we discuss the relative strengths and weaknesses of post- and pre-XCI hiPSCs in the context of RTT, and other X-linked and autosomal disorders for translational medicine.

An Overview of Drug Development for Metastatic Breast Cancer

British Journal of Nursing (Mark Allen Publishing). Feb 23-Mar 7, 2012  |  Pubmed ID: 22470903

The prevalence of breast cancer is increasing as more women are living with the disease. Outcomes have improved as a result of progress in all major aspects of multidisciplinary care. These include surgery, radiotherapy, hormonal therapy, chemotherapy and newer targeted drugs. Two aspects merit particular attention here. First, there is an understanding now that cancer is a heterogenous disease and a 'one-size-fits-all' approach is becoming redundant, albeit slowly. Second, basic science and an appreciation of cellular molecular targets in those different types of breast cancer is being translated into the clinic and has led to the development of exciting new drugs for both triple negative and HER2-positive relapsed disease. An improved understanding of endocrine resistance remains an unmet need in drug development and here, it appears worthwhile to adopt less conventional approaches. Better trial design with a focus on biomarkers should lower barriers to regulatory approval as well as increase cost effectiveness.

The Top 10 Fungal Pathogens in Molecular Plant Pathology

Molecular Plant Pathology. May, 2012  |  Pubmed ID: 22471698

The aim of this review was to survey all fungal pathologists with an association with the journal Molecular Plant Pathology and ask them to nominate which fungal pathogens they would place in a 'Top 10' based on scientific/economic importance. The survey generated 495 votes from the international community, and resulted in the generation of a Top 10 fungal plant pathogen list for Molecular Plant Pathology. The Top 10 list includes, in rank order, (1) Magnaporthe oryzae; (2) Botrytis cinerea; (3) Puccinia spp.; (4) Fusarium graminearum; (5) Fusarium oxysporum; (6) Blumeria graminis; (7) Mycosphaerella graminicola; (8) Colletotrichum spp.; (9) Ustilago maydis; (10) Melampsora lini, with honourable mentions for fungi just missing out on the Top 10, including Phakopsora pachyrhizi and Rhizoctonia solani. This article presents a short resumé of each fungus in the Top 10 list and its importance, with the intent of initiating discussion and debate amongst the plant mycology community, as well as laying down a bench-mark. It will be interesting to see in future years how perceptions change and what fungi will comprise any future Top 10.

The Prognostic and Predictive Power of Redox Protein Expression for Anthracycline-based Chemotherapy Response in Locally Advanced Breast Cancer

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc. Apr, 2012  |  Pubmed ID: 22481283

Neoadjuvant chemotherapy has become the standard of care for locally advanced primary breast cancer. Anthracycline-based regimens have proven to be one of the most effective treatments in this setting. As certain cytotoxic antineoplastic agents, such as anthracyclines, generate reactive oxygen species as a by-product of their mechanism of action, we examined whether redox protein expression was involved in the response to anthracycline-based chemotherapy and with clinical outcome. Pre-treatment needle core biopsy and post-anthracycline treatment tumour sections were analysed from 98 cases. In all, 32 individuals had a complete clinical response and 17 had a complete pathological response. Immunohistochemical staining was performed for eight redox proteins: thioredoxin, thioredoxin reductase, thioredoxin interacting protein (TxNIP), glutathione S-transferase (GST) π, θ and α, catalase and manganese superoxide dismutase. GST π (P=0.05) and catalase (P=0.045) were associated with pathological complete response in pre-chemotherapy samples. TxNIP (P=0.017) and thioredoxin reductase (P=0.022) were independent prognostic factors for distant metastasis-free survival and TxNIP for overall survival (P=0.014). In oestrogen receptor negative patients that are known to have a poor overall survival, a considerably worse prognosis was seen in cases that exhibited low expression of TxNIP (P=0.000003), stratifying patients into more defined groups. This study indicates the importance of redox regulation in determining breast cancer response to anthracycline-based chemotherapy and provides ways of further stratifying pre-chemotherapy patients to potentially allow more tailored treatments.Modern Pathology advance online publication, 6 April 2012; doi:10.1038/modpathol.2012.60.

Effects of Habitual Diet on Ethnic Differences in Serum Total Ghrelin

Endocrine. Apr, 2012  |  Pubmed ID: 22481313

Ghrelin, an orexigenic hormone, may be involved in the etiology of obesity. African Americans (AA) experience higher obesity rates than European Americans (EA), but it is unclear whether ghrelin differs with ethnicity. This study was designed to compare ghrelin concentrations between overweight AA and EA adults in a post absorptive state, in response to a standard meal, and after 8-week habituation to diets of differing macronutrient profiles. Sixty-one overweight men and women (31 EA and 30 AA) were assigned to either a higher-carbohydrate/lower-fat diet (55 % CHO, 18 % PRO, 27 % FAT) or a lower-carbohydrate/higher-fat diet (43 % CHO, 18 % PRO, 39 % FAT) for 8 weeks. At baseline and week 8, participants ingested a standard liquid mixed meal. Blood was sampled before the meal and serially after ingestion to measure total ghrelin and insulin. Hunger was assessed with a visual analog scale. Composite scores for ghrelin, insulin, and hunger were calculated as area under the curve (AUC), and ghrelin suppression was calculated as the change from fasting concentration. Fasting ghrelin and ghrelin AUC were higher among EA at baseline and week 8 (p < 0.001), and these differences were not affected by diet habituation. Despite greater postprandial ghrelin suppression, EA displayed greater hunger immediately following the test meal (p < 0.05). Overweight EA displayed higher circulating ghrelin and greater ghrelin suppression compared to AA. Further study is warranted to explore the physiological basis for these ethnic differences and to determine whether they may relate to higher obesity rates among AA.

FEBio: Finite Elements for Biomechanics

Journal of Biomechanical Engineering. Jan, 2012  |  Pubmed ID: 22482660

In the field of computational biomechanics, investigators have primarily used commercial software that is neither geared toward biological applications nor sufficiently flexible to follow the latest developments in the field. This lack of a tailored software environment has hampered research progress, as well as dissemination of models and results. To address these issues, we developed the FEBio software suite (http://mrl.sci.utah.edu/software/febio), a nonlinear implicit finite element (FE) framework, designed specifically for analysis in computational solid biomechanics. This paper provides an overview of the theoretical basis of FEBio and its main features. FEBio offers modeling scenarios, constitutive models, and boundary conditions, which are relevant to numerous applications in biomechanics. The open-source FEBio software is written in C++, with particular attention to scalar and parallel performance on modern computer architectures. Software verification is a large part of the development and maintenance of FEBio, and to demonstrate the general approach, the description and results of several problems from the FEBio Verification Suite are presented and compared to analytical solutions or results from other established and verified FE codes. An additional simulation is described that illustrates the application of FEBio to a research problem in biomechanics. Together with the pre- and postprocessing software PREVIEW and POSTVIEW, FEBio provides a tailored solution for research and development in computational biomechanics.

Pilot Candidate Gene Analysis of Patients ‰�60 Years Old With Aortic Stenosis Involving a Tricuspid Aortic Valve

The American Journal of Cardiology. Apr, 2012  |  Pubmed ID: 22483387

The potential genetic basis of aortic stenosis in older people is poorly understood. A total of 265 patients with aortic stenosis involving tricuspid aortic valves and 961 controls were genotyped for ≤660 candidate single nucleotide polymorphisms (SNPs). After dividing the patients and controls into training and validation sets, we tested the correlation of the SNPs with the age-adjusted aortic valve area, determined by echocardiography or cardiac catheterization. A bootstrapped global p value of ≤0.005 was considered evidence of a possible significant correlation. The cases were aged 73 ± 7 years, and 72.7% were men. The median aortic valve area was 1.0 cm(2) (interquartile range 0.7 to 1.5). The controls were aged 69 ± 6 years, and 69.8% were men. The minor allele frequency was 21% ± 15% (37% <0.20). Three SNPs met the criteria for significant correlation (rs2276288 [MYO7A], p = 0.001; rs5194 [AGTR1], p = 0.004; rs207 307 [ELN], p = 0.005). Another 2 SNPs reached borderline significance (p ≤0.008). In conclusion, we report 3 SNPs to be associated with aortic stenosis involving tricuspid aortic valves in older subjects. Given the concerns regarding the problem of multiple statistical testing, validation studies are required to further assess these correlations.

Gradient Forests: Calculating Importance Gradients on Physical Predictors

Ecology. Jan, 2012  |  Pubmed ID: 22486096

In ecological analyses of species and community distributions there is interest in the nature of their responses to environmental gradients and in identifying the most important environmental variables, which may be used for predicting patterns of biodiversity. Methods such as random forests already exist to assess predictor importance for individual species and to indicate where along gradients abundance changes. However, there is a need to extend these methods to whole assemblages, to establish where along the range of these gradients the important compositional changes occur, and to identify any important thresholds or change points. We develop such a method, called "gradient forest," which is an extension of the random forest approach. By synthesizing the cross-validated R2 and accuracy importance measures from univariate random forest analyses across multiple species, sampling devices, and surveys, gradient forest obtains a monotonic function of each predictor that represents the compositional turnover along the gradient of the predictor. When applied to a synthetic data set, the method correctly identified the important predictors and delineated where the compositional change points occurred along these gradients. Application of gradient forest to a real data set from part of the Great Barrier Reef identified mud fraction of the sediment as the most important predictor, with highest compositional turnover occurring at mud fraction values around 25%, and provided similar information for other predictors. Such refined information allows for more accurate capturing of biodiversity patterns for the purposes of bioregionalization, delineation of protected areas, or designing of biodiversity surveys.

Selective Forces Shaping Diversity in the Class I Region of the Major Histocompatibility Complex in Dairy Cattle

Animal Genetics. Jun, 2012  |  Pubmed ID: 22486494

The major histocompatibility complex (MHC) is one of the most diverse regions of the mammalian genome. Diversity in MHC genes is integral to their function in the immune system, and while pathogens play a key role in shaping this diversity, the contribution of other selective forces remains unclear. The controlled breeding of cattle offers an excellent model for the identification and exploration of these forces. We characterized the MHC class I genes present in a sample of Canadian Holstein A.I. bulls and compared the results with those obtained in an earlier study. No evidence for a reduction in MHC diversity over 20 years was observed, but the relative frequency of some haplotypes had changed: the formerly rare A12 (w12B) haplotype had become the most common, together with A15, while A19, which dominated the earlier sample, had significantly reduced in frequency. Only 7% of bulls in the current study were MHC homozygous compared with the 14% expected under Hardy-Weinberg. To identify the selective forces at work, a gene substitution model was used to calculate the effects of MHC on selection traits using estimated breeding values for each bull. Significant associations between MHC and production, disease and fertility traits were identified, suggesting that MHC diversity is not merely shaped by disease in this controlled breeding system. The decrease in a common haplotype, the reduced number of homozygous bulls and the associations with disease and production traits together indicate that MHC diversity in dairy cattle is maintained by heterozygote advantage.

Using Video-tracking to Assess Sublethal Effects of Pesticides on Honey Bees (Apis Mellifera L.)

Environmental Toxicology and Chemistry / SETAC. Apr, 2012  |  Pubmed ID: 22488825

Concern about the role of pesticides in honey bee decline has highlighted the need to examine the effects of sublethal exposure on bee behaviors. The video-tracking system EthoVisionXT (Noldus Information Technologies) was used to measure the effects of sublethal exposure to tau-fluvalinate and imidacloprid on honey bee locomotion, interactions, and time spent near a food source over a 24-h observation period. Bees were either treated topically with 3 × 10(-4) , 1.5 × 10(-3) , and 3 × 10(-3)  µg tau-fluvalinate or exposed to 0.05, 0.5, 5.0, 50, and 500 ppb imidacloprid in a sugar agar cube. Tau-fluvalinate caused a significant reduction in distance moved at all dose levels (p < 0.05), as did 50 and 500 ppb imidacloprid (p < 0.001). A stimulatory effect was detected in bees exposed to 0.05 and 0.5 ppb imidacloprid, whereas groups exposed to 50 and 500 ppb spent significantly more time near the food source than control bees (p < 0.05). Interaction time decreased as time in the food zone increased for both chemicals. This study documents that video-tracking of bee behavior can enhance current protocols for measuring the effects of pesticides on honey bees at sublethal levels. It may provide a means of identifying problematic compounds for further testing. Environ. Toxicol. Chem. © 2012 SETAC.

Promoting Good Clinical Laboratory Practices and Laboratory Accreditation to Support Clinical Trials in Sub-Saharan Africa

The American Journal of Tropical Medicine and Hygiene. Apr, 2012  |  Pubmed ID: 22492138

Abstract. Laboratory capacity in the developing world frequently lacks quality management systems (QMS) such as good clinical laboratory practices, proper safety precautions, and adequate facilities; impacting the ability to conduct biomedical research where it is needed most. As the regulatory climate changes globally, higher quality laboratory support is needed to protect study volunteers and to accurately assess biological parameters. The University of Bamako and its partners have undertaken a comprehensive QMS plan to improve quality and productivity using the Clinical and Laboratory Standards Institute standards and guidelines. The clinical laboratory passed the College of American Pathologists inspection in April 2010, and received full accreditation in June 2010. Our efforts to implement high-quality standards have been valuable for evaluating safety and immunogenicity of malaria vaccine candidates in Mali. Other disease-specific research groups in resource-limited settings may benefit by incorporating similar training initiatives, QMS methods, and continual improvement practices to ensure best practices.

The B Gene of Pea (Pisum Sativum L.) Encodes a Defective Flavonoid 3' 5' Hydroxylase and Confers Pink Flower Colour

Plant Physiology. Apr, 2012  |  Pubmed ID: 22492867

The inheritance of flower colour in pea (Pisum sativum L.) has been studied for more than a century, but many of the genes corresponding to these classical loci remain unidentified. Anthocyanins are the main flower pigments in pea. These are generated via the flavonoid biosynthetic pathway, which has been studied in detail and is well conserved among higher plants. A previous proposal that the B gene of pea controls hydroxylation at the 5' position of the B ring of flavonoid precursors of the anthocyanins, suggested to us that the gene encoding flavonoid 3' 5' hydroxylase (F3'5'H), the enzyme which hydroxylates the 5' position of the B ring, was a good candidate for B. In order to test this hypothesis, we examined mutants generated by fast neutron bombardment. We found allelic pink flowered b mutant lines that carried a variety of lesions in an F3'5'H gene, including complete gene deletions. The b mutants lacked glycosylated delphinidin and petunidin, the major pigments present in the progenitor purple flowered wild type pea. These results, combined with the finding that the F3'5'H gene cosegregates with b in a genetic mapping population, strongly support our hypothesis that the B gene of pea corresponds to a F3'5'H. The molecular characterisation of genes involved in pigmentation in pea provides valuable anchor markers for comparative legume genomics and will help to identify differences in anthocyanin biosynthesis that lead to variation in pigmentation among legume species.

Validated SNPs for EGFR and Their Associations with Albuminuria

Human Molecular Genetics. Apr, 2012  |  Pubmed ID: 22492995

BackgroundAlbuminuria and reduced glomerular filtration rate are manifestations of chronic kidney disease (CKD) that predict end-stage renal disease, acute kidney injury, cardiovascular disease, and death. We hypothesized that SNPs identified in association with estimated GFR (eGFR) would also be associated with albuminuria.MethodsWithin the CKDGen consortium cohort (n=31,580, European ancestry), we tested 16 eGFR-associated SNPs for association with urinary albumin-to-creatinine ratio (UACR) and albuminuria (UACR>25mg/g [women]; 17mg/g [men]). In parallel, within the CARe Renal Consortium (n=5,569, African ancestry), we tested 7 eGFR-associated SNPs for association with UACR. We used a Bonferroni-corrected p-value of 0.003 (0.05/16) in CKDGen and 0.007 (0.05/7) in CARe. We also assessed whether the 16 eGFR SNPs were associated with UACR in aggregate using a beta-weighted genotype score.ResultsIn CKDGen, the minor A allele of rs17319721 in the SHROOM3 gene, known to be associated with lower eGFR, was associated with lower ln(UACR) levels (beta=-0.034, p-value=0.0002). No additional eGFR-associated SNPs met the Bonferroni-corrected p-value threshold of 0.003 for either UACR or albuminuria. In the CARe Renal consortium, there were no associations between SNPs and UACR with a p<0.007. Although we found that the genotype score to be associated with albuminuria (p=0.0006), this result was driven almost entirely by the known SHROOM3 variant, rs17319721. Removal of rs17319721 resulted in a p value 0.03, indicating a weak residual aggregate signal.ConclusionsNo alleles, previously demonstrated to be associated with lower eGFR, were associated with UACR or albuminuria, suggesting there may be distinct genetic components for these traits.

Ecology and Geography of Human Monkeypox Case Occurrences Across Africa

Journal of Wildlife Diseases. Apr, 2012  |  Pubmed ID: 22493109

As ecologic niche modeling (ENM) evolves as a tool in spatial epidemiology and public health, selection of the most appropriate and informative environmental data sets becomes increasingly important. Here, we build on a previous ENM analysis of the potential distribution of human monkeypox in Africa by refining georeferencing criteria and using more-diverse environmental data to identify environmental parameters contributing to monkeypox distributional ecology. Significant environmental variables include annual precipitation, several temperature-related variables, primary productivity, evapotranspiration, soil moisture, and pH. The potential distribution identified with this set of variables was broader than that identified in previous analyses but does not include areas recently found to hold monkeypox in southern Sudan. Our results emphasize the importance of selecting the most appropriate and informative environmental data sets for ENM analyses in pathogen transmission mapping.

Celiac Disease: Management of Persistent Symptoms in Patients on a Gluten-free Diet

World Journal of Gastroenterology : WJG. Mar, 2012  |  Pubmed ID: 22493548

To investigate all patients referred to our center with non-responsive celiac disease (NRCD), to establish a cause for their continued symptoms.

The Early Days of Surgery for Cancer of the Rectum

Journal of Perioperative Practice. Mar, 2012  |  Pubmed ID: 22493878

Long before being aware of tumours elsewhere along the alimentary canal, surgeons from the earliest days of the profession were all too familiar with cancer of the rectum. The vivid local symptoms of rectal bleeding and mucous discharge, bowel disturbance and then intractable local pain, and the ready detection of the growth by a finger inserted into the fundament made diagnosis all too easy and with it, of course, a hopeless outlook for the poor sufferer. Until quite recent times, treatment was entirely palliative, with the use of hot baths, emollient enemas and dilatations of the constricting growth with bougies. Opium and laudanum, (opium dissolved in alcohol), would be prescribed in advanced cases. Some bold surgeons would use the cautery--an iron heated to red heat--to burn down a fungating growth presenting at the anal margin.

Cam Morphology in the Human Hip

Orthopedics. Apr, 2012  |  Pubmed ID: 22495842

A growing interest exists in the diagnosis and treatment of femoroacetabular impingement. Although cam morphology of the proximal femur may conceptually appear to be a relatively simple topographical aberrancy, it is actually positioned amid a complex developmental, kinematic, and biomechanical region of the human body. The authors introduce a new classification scheme and review the historical and anthropological considerations, biomechanics, and genetic factors involved in cam morphology.

Impact of Drug-Eluting Stents on Distal Vessels

Circulation. Cardiovascular Interventions. Apr, 2012  |  Pubmed ID: 22496083

BACKGROUND: PREVIOUS STUDIES HAVE NOT ADDRESSED VESSEL RESPONSE 5 MM DISTAL TO THE STENT EDGE. THEREFORE, WE INVESTIGATED THE IMPACT OF PACLITAXEL-ELUTING STENTS (PES) VERSUS BARE METAL STENTS (BMS) ON DISTAL VESSELS IN THE SERIAL INTRAVASCULAR ULTRASOUND SUBSTUDIES OF TAXUS IV, V, AND VI. METHODS AND RESULTS: TAXUS IV, V, AND VI WERE DOUBLE-BLIND, RANDOMIZED, MULTICENTER, CONTROLLED TRIALS COMPARING PES WITH BMS. IN THEIR INTRAVASCULAR ULTRASOUND SUBSTUDIES, 103 PATIENTS (54 BMS, 49 PES) HAD INTRAVASCULAR ULTRASOUND DATA 10 MM DISTAL TO THE STENT BOTH POSTPROCEDURE AND AT 9 MONTHS FOLLOW-UP. BASELINE CHARACTERISTICS WERE SIMILAR BETWEEN THE 2 GROUPS. MULTILEVEL MODELING WAS USED TO ACCOUNT FOR THE VARIATION BETWEEN PATIENTS AND WITHIN PATIENTS AMONG DISTAL SEGMENTS. EFFECT OF STENT TYPE, TIME, AND THEIR INTERACTION WAS TESTED USING A MIXED EFFECT MODEL CONTROLLING FOR DISTAL SEGMENTS. POSTPROCEDURE LUMEN AND VESSEL WERE NOT SIGNIFICANTLY DIFFERENT BETWEEN PES VERSUS BMS; HOWEVER, LUMEN (P=0.006) AND VESSEL (P=0.0001) WERE SIGNIFICANTLY REDUCED FOR BMS AT 9-MONTH FOLLOW-UP BUT NOT FOR PES. CONVERSELY, THERE WAS A SIGNIFICANT PLAQUE INCREASE FROM POSTPROCEDURE TO 9-MONTH FOLLOW-UP FOR PES (P=0.0008) BUT NOT FOR BMS. THESE VESSEL RESPONSES WERE STATISTICALLY CONSISTENT AMONG 0- TO 5-MM VERSUS 5- TO 10-MM VERSUS 10- TO 15-MM SEGMENTS DISTAL TO THE STENT IN BOTH GROUPS. CONCLUSIONS: PES USE WAS ASSOCIATED WITH PLAQUE INCREASE FROM BASELINE TO 9-MONTH FOLLOW-UP 5 MM DISTAL TO THE STENT ALONG WITH POSITIVE REMODELING, WHEREAS BMS USE WAS ASSOCIATED WITH NEGATIVE REMODELING AND NO PLAQUE INCREASE. THESE VESSEL RESPONSES WERE CONSISTENT IN 5-MM LONG SUBSEGMENTS: 0 TO 5 MM VERSUS 5 TO 10 MM VERSUS 10 TO 15 MM DISTAL TO THE STENT. CLINICAL TRIAL REGISTRATION: URL: HTTP://WWW.CLINICALTRIAL.GOV. UNIQUE IDENTIFIERS: TAXUS IV: NCT00292474; TAXUS V: NCT00301522; TAXUS VI: NCT00297804.

An Overview of the Biology and Status of Undulate Ray Raja Undulata in the North-east Atlantic Ocean

Journal of Fish Biology. Apr, 2012  |  Pubmed ID: 22497373

The undulate ray Raja undulata is one of the lesser-known skates occurring on the continental shelf of the north-east Atlantic Ocean. It is patchily distributed throughout its range, with sites of local abundance in the central English Channel and off the coasts of Ireland, France, Spain and Portugal. Raja undulata is most abundant in coastal waters (<50 m deep) and is often found in proximity to large estuaries, rias and bays. It is a relatively large-bodied species, attaining a maximum total length (L(T) ) of at least 114 cm, with females maturing at an L(T) of c. 84 cm in Portuguese waters. Although infrequently taken in existing trawl surveys, it can be locally abundant in certain areas, where it can be the dominant skate species. Given its large size, patchy distribution and concern over the possibilities of localized depletions, the IUCN listed R. undulata as an endangered species and, since 2009, the European Union has established regulations to prohibit commercial fisheries landing the species. Given the increased interest in the species, a synopsis of current knowledge is provided, and available data from internationally co-ordinated trawl surveys presented.

Species Composition of Skates (Rajidae) in Commercial Fisheries Around the British Isles and Their Discarding Patterns

Journal of Fish Biology. Apr, 2012  |  Pubmed ID: 22497403

Recent regulations have required European nations to report commercial landings of Rajidae (skates) to species level since 2008. Morphological similarities between some species, variability in colouration and regional differences in common names may compromise the accuracy of some of these data. An increased proportion of rajid landings reported by the U.K. (England, Wales and Northern Ireland) are now reported to species level (42% in 2008, rising to 92% in 2010). Recent landings (2007-2010) of Rajidae by the U.K. indicated that the majority of reported landings were made by otter trawl (55·9%), tangle and gillnet (18·7%) and beam trawl (15·5%). Approximately 70% of recent landings originated from four ICES Divisions: the Irish Sea (VIIa), western English Channel (VIIe), Bristol Channel (VIIf) and southern North Sea (IVc). Recent species-specific landings of Rajidae are appraised in terms of the species reported and the overall composition, and potential problems identified. Data from observer trips have been used to estimate the species composition of Rajidae taken in some of the main commercial fisheries operating around the British Isles, and these data are compared to landings. Although there was typically broad agreement between these data sets in terms of the main species landed, misidentification issues were apparent and Rajidae with highly patchy distributions may be under-represented in observer data. Data from observer trips were also used to examine the discard and retention pattern. Most rajid species were first retained from total lengths, L(T) , of 27-34 cm, with 50% retention occurring at between 49 and 51 cm and near-full retention at L(T) of 60-67 cm. Beam trawls captured a higher proportion of smaller individuals, whilst gillnets (>150 mm mesh size) caught proportionally more larger rajids.

Angiographic Lesion Severity and Subsequent Myocardial Infarction

The American Journal of Cardiology. Apr, 2012  |  Pubmed ID: 22497675

We sought to determine the angiographic severity of coronary lesions leading to ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) with a focus on determining the impact of interval from initial angiogram to subsequent clinical event. In the late 1980s angiographic data on lesion characteristics that culminated in STEMI and NSTEMI were obtained from angiograms obtained several months before MI. It is not clear whether the conclusions on lesion severity would be different if elapsed interval from baseline angiogram to clinical event was factored in the analysis. From 2003 through 2010, we identified 84 patients with NSTEMI and 41 patients with STEMI in vessels without previous intervention. These patients had ≥1 previous angiographic study at our center. Angiograms were reanalyzed with quantitative coronary angiography, and relevant clinical data were obtained from medical records. Similar to previous studies, 71% of patients with STEMI and 63% of patients with NSTEMI had <50% baseline stenosis at the culprit site when the interval from initial angiogram to MI was >3 months. Interestingly, lesions that led to STEMI ≤3 months after evaluation were more severe than those leading to STEMI in >3 months (59 ± 31% vs 36 ± 21%, p = 0.02) with 57% of lesions having >50% stenosis. Although most MIs occurred at sites that did not have significant obstruction when examined >3 months before MI, most baseline lesions showed significant luminal narrowing when examined ≤3 months before STEMI. In conclusion, high-grade coronary stenosis may be an important predictor of STEMI in subsequent months.

Gene Expression in Honey Bee (Apis Mellifera) Larvae Exposed to Pesticides and Varroa Mites (Varroa Destructor)

Journal of Insect Physiology. Apr, 2012  |  Pubmed ID: 22497859

Honey bee (Apis mellifera) larvae reared in vitro were exposed to one of nine pesticides and/or were challenged with the parasitic mite, Varroa destructor. Total RNA was extracted from individual larvae and first strand cDNAs were generated. Gene-expression changes in larvae were measured using quantitative PCR (qPCR) targeting transcripts for pathogens and genes involved in physiological processes, bee health, immunity, and/or xenobiotic detoxification. Transcript levels for Peptidoglycan Recognition Protein (PGRPSC), a pathogen recognition gene, increased in larvae exposed to Varroa mites (P<0.001) and were not changed in pesticide treated larvae. As expected, Varroa-parasitized brood had higher transcripts of Deformed Wing Virus than did control larvae (P<0.001). Varroa parasitism, arguably coupled with virus infection, resulted in significantly higher transcript abundances for the antimicrobial peptides abaecin, hymenoptaecin, and defensin1. Transcript levels for Prophenoloxidase-activating enzyme (PPOact), an immune end product, were elevated in larvae treated with myclobutanil and chlorothalonil (both are fungicides)(P<0.001). Transcript levels for Hexameric storage protein (Hsp70) were significantly upregulated in imidacloprid, fluvalinate, coumaphos, myclobutanil, and amitraz treated larvae. Definitive impacts of pesticides and Varroa parasitism on honey bee larval gene expression were demonstrated. Interactions between larval treatments and gene expression for the targeted genes are discussed.

An Evaluation of the Multiple Mini-interview As a Selection Tool for Dental Students

British Dental Journal. 2012  |  Pubmed ID: 22498535

Objective This research evaluated the mutliple mini-interview (MMI) process as part of the admissions procedure for a dental school.Design The thematic analysis of a paper-based questionnaire.Materials and methods Following screening an MMI was arranged for 190 candidates applying to study dentistry with written feedback obtained from candidates and interviewers.Results A 100% response rate to the paper-based questionnaire was achieved for candidates and a 90% response rate was obtained from interviewers. With specific reference to how candidates perceived their performance, 127 (67.9%) felt they had performed well with 24 (19.3%) unsure and 36 (12.8%) saying their performance was not ideal. Candidates generally thought that they had prepared as well as they could have done for the MMIs and 146 (77.2%) thought that they had done enough at interview to merit being offered a place to study dentistry. The MMI experience was considered favourable and from 137 written comments received by candidates 39 were most positive with reference to the MMIs. A thematic analysis of the comments identified a number of emergent themes including lack of control, anxiety and nervousness, preparedness and comparisons with conventional interviews.Conclusion The MMI appears to be useful in the selection of dental students.

A Calorie is Not Necessarily a Calorie: Technical Choice, Nutrient Bioaccessibility, and Interspecies Differences of Edible Plants

Proceedings of the National Academy of Sciences of the United States of America. Apr, 2012  |  Pubmed ID: 22499793

Measurement of the ZZ Production Cross Section and Limits on Anomalous Neutral Triple Gauge Couplings in Proton-proton Collisions at Sqrt[s] = 7 TeV with the ATLAS Detector

Physical Review Letters. Jan, 2012  |  Pubmed ID: 22400826

A measurement of the ZZ production cross section in proton-proton collisions at sqrt[s] = 7 TeV using data corresponding to an integrated luminosity of 1.02 fb(-1) recorded by the ATLAS experiment at the LHC is presented. Twelve events containing two Z boson candidates decaying to electrons and/or muons are observed, with an expected background of 0.3 ± 0.3(stat)(-0.3)(+0.4)(syst) events. The cross section measured in a phase-space region with good detector acceptance and for dilepton masses within the range 66 to 116 GeV is σ(ZZ → ℓ+ ℓ- ℓ+ ℓ-)(fid) = 19.4(-5.2)(+6.3)(stat)(-0.7)(+0.9)(syst) ± 0.7(lumi) fb. The resulting total cross section for on-shell ZZ production, σ(ZZ)(tot) = 8.5(-2.3)(+2.7)(stat)(-0.3)(+0.4)(syst) ± 0.3(lumi) pb, is consistent with the standard model expectation of 6.5(-0.2)(+0.3) pb calculated at the next-to-leading order in QCD. Limits on anomalous neutral triple gauge boson couplings are derived.

Search for New Phenomena in Tt Events with Large Missing Transverse Momentum in Proton-proton Collisions at Sqrt[s] = 7 TeV with the ATLAS Detector

Physical Review Letters. Jan, 2012  |  Pubmed ID: 22400827

A search for new phenomena in tt events with large missing transverse momentum in proton-proton collisions at a center-of-mass energy of 7 TeV is presented. The measurement is based on 1.04 fb(-1) of data collected with the ATLAS detector at the LHC. Contributions to this final state may arise from a number of standard model extensions. The results are interpreted in terms of a model where new top-quark partners are pair produced and each decay to an on-shell top (or antitop) quark and a long-lived undetected neutral particle. The data are found to be consistent with standard model expectations. A limit at 95% confidence level is set excluding a cross section times branching ratio of 1.1 pb for a top-partner mass of 420 GeV and a neutral particle mass less than 10 GeV. In a model of exotic fourth generation quarks, top-partner masses are excluded up to 420 GeV and neutral particle masses up to 140 GeV.

Multitargeted Anti-angiogenic Agents and NSCLC: Clinical Update and Future Directions

Critical Reviews in Oncology/hematology. Mar, 2012  |  Pubmed ID: 22405734

Increasing understanding of the molecular abnormalities driving cell growth and proliferation has resulted in extensive research into molecularly targeted therapies. Angiogenesis is an appealing target for the treatment of non small cell lung cancer (NSCLC). Bevacizumab, a monoclonal antibody against circulating vascular endothelial growth factor (VEGF), is already approved for the treatment of NSCLC. Many other anti-angiogenic agents under development form the focus of this review. A variety of agents, including sorafenib, sunitinib, cediranib, axitinib, motesanib, linifinib and brivanib inhibit VEGF in addition to either platelet derived growth factor (PDGF), or fibroblast derived growth factor (FGF). To date, none of these agents in combination with chemotherapy have resulted in improvements in overall survival for patients with advanced NSCLC. Triple angiokinase inhibitors, which inhibit VEGF, PDGF and FGF, have potential to improve the therapeutic outcomes for patients with NSCLC. However, there is a need for identification of appropriate biomarkers to improve patient selection and identify those patients benefiting from anti-angiogenesis therapy.

Influence of Seasonality on the Genetic Diversity of Vibrio Parahaemolyticus in New Hampshire Shellfish Waters As Determined by Multi-locus Sequence Analysis

Applied and Environmental Microbiology. Mar, 2012  |  Pubmed ID: 22407686

Gastric infection risk by Vibrio parahaemolyticus increases with favorable environmental conditions and population shifts that increase prevalence of infective strains. Genetic analysis of New Hampshire strains revealed a unique population with some isolates similar to outbreak-causing strains and high diversity that increased as waters warmed.

Graphene Functionalisation with a Conjugated Poly(fluorene) by Click Coupling: Striking Electronic Properties in Solution

Chemistry (Weinheim an Der Bergstrasse, Germany). Apr, 2012  |  Pubmed ID: 22407731

Graphene flakes covalently modified with a conjugated polymer, poly[(9,9-dihexylfluorene)-co-alt-(9,9-bis-(6-azidohexyl)fluorene)] (PFA), were efficiently synthesised by a Cu-catalysed Huisgen 1,3-dipolar cycloaddition between alkyne-modified graphene and an azide-functionalised polymer. Two approaches for the modification of graphene with alkyne groups were investigated (coupling with a diazonium salt generated in situ or an amidation reaction) and the optimum conditions determined. The success of the click-coupling approach was confirmed by FTIR, (1) H NMR, Raman, and X-ray photoelectron spectroscopy (XPS). The absorption and emission spectra of the click product show a strong solvent dependency.

Genome Sequence of Mycoplasma Hyorhinis Strain GDL-1

Journal of Bacteriology. Apr, 2012  |  Pubmed ID: 22408248

Mycoplasma hyorhinis impacts swine health and production in many countries, either as a primary pathogen or as a component of a polymicrobial infection. Isolates of this species are also common contaminants of tissue culture lines. The genome sequence of the cell culture isolate M. hyorhinis GDL-1 is presented herein.

Acute Appendicitis

British Journal of Hospital Medicine (London, England : 2005). Mar, 2012  |  Pubmed ID: 22411604

Dextrocardia may be associated with transposition of all the viscera, with the caecum and appendix being situated on the left side of the abdomen. Most experienced surgeons (including the author) will have dealt with a true left-sided appendicitis in such circumstances.

Sophia Jex-Blake: the First Woman Medical Graduate to Practise in the UK

British Journal of Hospital Medicine (London, England : 2005). Mar, 2012  |  Pubmed ID: 22411648

This year marks the centenary of the death of Dr Sophia Jex-Blake, one of the handful of women who, in the face of enormous professional opposition and of legal difficulties, established the right of women both to train in and to practise medicine in this country.

Association of Patient-Centered Outcomes With Patient-Reported and ICD-9-Based Morbidity Measures

Annals of Family Medicine. Mar, 2012  |  Pubmed ID: 22412004

PURPOSE Evaluating patient-centered care for complex patients requires morbidity measurement appropriate for use with a variety of clinical outcomes. We compared the contributions of self-reported morbidity and morbidity measured using administrative diagnosis data for both patient-reported outcomes and utilization outcomes. METHODS Using a cohort of 961 persons aged 65 years or older with 3 or more medical conditions, we explored 9 health outcomes as a function of 4 independent variables representing different types of morbidity measures: International Classification of Diseases, Ninth Revision (ICD-9), a self-reported weighted count of conditions, and self-reported symptoms of depression and of anxiety. Outcomes varied from self-reported health status to utilization. Depending on the outcome measure, we used multivariate linear, negative binomial, or logistic regression, adjusting for demographic characteristics and length of enrollment to assess associations between dependent and all 4 independent variables. RESULTS Higher morbidity measured by ICD-9 diagnoses was independently associated with less favorable levels of 7 of the 9 clinical outcomes. Higher self-reported disease burden was significantly associated with less favorable levels of 8 of the outcomes, controlling for the 3 other morbidity measures. Morbidity measured by diagnosis code was more strongly associated with higher utilization, whereas self-reported disease burden and emotional symptoms were more strongly associated with patient-reported outcomes. CONCLUSIONS A comprehensive assessment of morbidity requires both subjective and objective measurement of disease burden as well as an assessment of emotional symptoms. Such multidimensional morbidity measurement is particularly relevant for research or quality assessments involving the delivery of patient-centered care to complex patient populations.

Fatal Cases of Influenza A(H3N2) in Children: Insights from Whole Genome Sequence Analysis

PloS One. 2012  |  Pubmed ID: 22412998

During the Northern Hemisphere winter of 2003-2004 the emergence of a novel influenza antigenic variant, A/Fujian/411/2002-like(H3N2), was associated with an unusually high number of fatalities in children. Seventeen fatal cases in the UK were laboratory confirmed for Fujian/411-like viruses. To look for phylogenetic patterns and genetic markers that might be associated with increased virulence, sequencing and phylogenetic analysis of the whole genomes of 63 viruses isolated from fatal cases and non fatal "control" cases was undertaken. The analysis revealed the circulation of two main genetic groups, I and II, both of which contained viruses from fatal cases. No associated amino acid substitutions could be linked with an exclusive or higher occurrence in fatal cases. The Fujian/411-like viruses in genetic groups I and II completely displaced other A(H3N2) viruses, but they disappeared after 2004. This study shows that two A(H3N2) virus genotypes circulated exclusively during the winter of 2003-2004 in the UK and caused an unusually high number of deaths in children. Host factors related to immune state and differences in genetic background between patients may also play important roles in determining the outcome of an influenza infection.

Personalized Medicine in the Genomics Era: Highlights from an International Symposium on Childhood Heart Disease

Future Cardiology. Mar, 2012  |  Pubmed ID: 22413975

As the population of childhood heart disease survivors grows, a better understanding of the genetic underpinnings of heart disease is needed to improve diagnostics, therapeutics and outcomes. The Trans-Atlantic Research Network, GenomeHeart and The SickKids Heart Centre Biobank hosted an international symposium on childhood heart disease titled 'Personalized Medicine in the Genomics Era'. Experts in cardiology, developmental biology, genomics, pharmacology, bioinformatics, stem cell biology, ethics and biobanking shared their knowledge and expertise. The 2-day symposium hosted participants from North America, Europe and Asia including scientists, physicians, nurses, trainees and representatives from industry partners, federal and provincial funding agencies, and patient and community groups. The symposium focused on international research partnerships and application of current state-of-the-art in genomics and stem cell medicine towards personalized healthcare for childhood onset heart disease.

HLA DR15 Antigen Status Does Not Impact Graft-versus-Host Disease or Survival in HLA-Matched Sibling Transplantation for Hematologic Malignancies

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Mar, 2012  |  Pubmed ID: 22414493

The HLA class II DRB1 antigen DR15 is an important prognostic marker in immune mediated marrow failure states. DR15 has also been associated with favorable outcomes (reduced acute graft-versus-host disease [aGVHD] and relapse) after allogeneic hematopoietic cell transplant. To elucidate the impact of DR15 on transplantation outcomes, we conducted a retrospective study of 2891 recipients of first allogeneic stem cell transplant from HLA-matched sibling donors for the treatment of acute leukemia, chronic myeloid leukemia, or myelodysplastic syndrome between 1990 and 2007. All patients received conventional myeloablative conditioning, T-replete grafts, and cyclosporine plus methotrexate-based GVHD prophylaxis. DNA-based HLA typing allowed categorization of 732 patients (25.3%) as positive and 2159 patients (74.7%) as negative for DRB1*15:01 or *15:02 (DR15). There were no significant differences in baseline characteristics between the HLA DR15-positive and negative groups. In univariate analysis, HLA-DR15 status had no impact on neutrophil engraftment, aGVHD, chronic GVHD (cGVHD), treatment-related mortality, relapse, disease-free survival (DFS), or overall survival (OS). In multivariate analysis, DR15 status showed no significant difference in aGVHD, cGVHD, OS, or relapse. In conclusion, DR15 status had no impact on major HLA-matched sibling donor hematopoietic cell transplant outcomes in this large and homogenous cohort of patients with leukemia and myelodysplastic syndrome (MDS).

Angioarchitectural Features Associated with Hemorrhagic Presentation in Pediatric Cerebral Arteriovenous Malformations

Journal of Neurointerventional Surgery. Mar, 2012  |  Pubmed ID: 22416111

Background and objectiveTo date, there have been few published studies examining the relationship between arteriovenous malformation (AVM) angioarchitecture and hemorrhagic presentation among children with cerebral AVMs. This study examines this relationship in this unique population, in whom symptomatic presentation of cerebral AVM is the norm rather than the exception.MethodsA cohort of children with AVMs from 2000 to 2011 were included. Predictors studied included patient age, gender and angioarchitectural features, including AVM location, nidus size and morphology, venous drainage, presence of venous outflow lesions and associated aneurysms. Predictors of hemorrhagic presentation were assessed using multivariate logistic regression.Results135 children (70 males, mean age 10.1 years) were included. 86/135 (63.7%) children presented with hemorrhage, 18 (13.3%) with seizures, 17 (12.6%) with headaches or neurological deficits and 14 (10.4%) were asymptomatic. AVM location, morphology and the presence of associated aneurysm, venous ectasia, draining vein stenosis and single draining vein were not significantly associated factors. After multivariate analysis, AVM size (OR 0.57, 95% CI 0.43 to 0.77; p<0.01), exclusive deep venous drainage (OR 4.94, 95% CI 1.30 to 18.8; p=0.02) and infratentorial location (OR 9.94, 95% CI 1.71 to 51.76; p=0.01) were independently associated with hemorrhagic presentation.ConclusionSmaller AVM size, exclusive deep venous drainage and infratentorial location are specific angioarchitectural factors independently associated with initial hemorrhagic presentation in children with AVMs.

A Randomised Trial of Primary Tamoxifen Versus Mastectomy Plus Adjuvant Tamoxifen in Fit Elderly Women with Invasive Breast Carcinoma of High Oestrogen Receptor Content: Long-term Results at 20 Years of Follow-up

Annals of Oncology : Official Journal of the European Society for Medical Oncology / ESMO. Feb, 2012  |  Pubmed ID: 22357257

BACKGROUND: Long-term analysis of a randomised trial in Nottingham comparing tamoxifen versus surgery as initial treatment demonstrated that in oestrogen receptor (ER)-unselected cases, surgery achieved better local control, with no difference in overall survival. It was suggested that for patients with ER-rich tumours, local control and survival may be comparable. We now present long-term follow-up of a randomised trial designed to address this clinical scenario. PATIENTS AND METHODS: One hundred and fifty three fit elderly (≥70 years) women with clinically node-negative primary invasive breast carcinoma <5 cm of high ER content [histochemical (H) score ≥ 100] were randomised 2:1 to primary tamoxifen (Tam) (N = 100) or mastectomy with adjuvant tamoxifen (Mx + Tam) (N = 53). RESULTS: With median follow-up of 78 months, there was no statistically significant difference in 10-year rates of regional recurrence (9.0% versus 7.5%), metastasis (8.0% versus 13.2%), breast cancer-specific survival (89.0% versus 86.8%) or overall survival (64.0% versus 66.0%) between Tam and Mx + Tam; however, local control was inferior with Tam (local failure rates 43.0% versus 1.9%; P < 0.001). CONCLUSION: Irrespective of the degree of ER positivity, surgery achieved better local control. However, there was excellent and similar survival in both groups. Tam could be considered in those who are 'frail', refuse or prefer not to initially undergo surgery.

Patterns of Failure After Treatment of Atypical Meningioma with Gamma Knife Radiosurgery

Journal of Neuro-oncology. Feb, 2012  |  Pubmed ID: 22359231

Atypical meningiomas have poor local control with emerging literature indicating the use of radiosurgery in treatment. The purpose of this study was to evaluate clinical outcomes including local control and failure pattern after Gamma Knife radiosurgery (GKRS) and factors that may affect these outcomes. Between 1999 and 2008, 24 patients were treated with GKRS as either primary or salvage treatment for pathologically proven atypical meningiomas. Treatment failures were determined by serial magnetic resonance imaging. A median marginal dose of 14 Gy was used (range 10.5-18 Gy). Overall local control rates at 1, 2, and 5 years were 75, 51, and 44%, respectively. With median follow-up time of 42.5 months, 14 of 24 patients experienced a treatment failure at time of last follow-up. Eight recurrences were in-field, four were marginal failures, and two were distant failures. Wilcoxon analysis revealed that the conformality index (CI) was a significant predictor of local recurrence (P = 0.04). CI did not predict for distant recurrences (P = 0.16). On multivariate analysis evaluating factors predicting progression free survival, dose >14 Gy was found to be statistically significant (P = 0.01). There appears to be a dose response using GKRS beyond 14 Gy but given the suboptimal local control rates in this study, higher doses may still be needed to obtain better local control.

Plasma Proteomic Profiling in HIV-1 Infected Methamphetamine Abusers

PloS One. 2012  |  Pubmed ID: 22359561

We wanted to determine whether methamphetamine use affects a subset of plasma proteins in HIV-infected persons. Plasma samples from two visits were identified for subjects from four groups: HIV+, ongoing, persistent METH use; HIV+, short-term METH abstinent; HIV+, long term METH abstinence; HIV negative, no history of METH use. Among 390 proteins identified, 28 showed significant changes in expression in the HIV+/persistent METH+ group over the two visits, which were not attributable to HIV itself. These proteins were involved in complement, coagulation pathways and oxidative stress. Continuous METH use is an unstable condition, altering levels of a number of plasma proteins.

Electronic Spectroscopy of Jet-cooled YbNH3

The Journal of Chemical Physics. Feb, 2012  |  Pubmed ID: 22360185

We report the first spectroscopic study of a complex consisting of a rare earth atom in combination with ammonia. Using two-color resonance-enhanced multiphoton ionization (REMPI) spectroscopy, the lowest energy electronic transition of YbNH(3) has been found in the near-infrared. The spectrum arises from a spin-forbidden transition between the (1)A(1) ground electronic state and the lowest (3)E excited electronic state. The transition is metal centered and approximately correlates with the Yb 6s6p (3)P ← 6s(2) (1)S transition. The observation of clear spin-orbit structure in the spectrum confirms the C(3v) symmetry of YbNH(3). Vibrational structure is also observed in the REMPI spectrum, which is dominated by excitation of the Yb-N stretching vibration.

Effect of Prostaglandin Duration on Outcomes in Transposition of the Great Arteries with Intact Ventricular Septum

Congenital Heart Disease. Feb, 2012  |  Pubmed ID: 22360739

Objective.  To study the effects of duration of preoperative prostaglandin E1 (PGE) exposure on perioperative outcomes of the arterial switch operation in patients with transposition of the great arteries with an intact ventricular septum. Design.  Retrospective chart review. Setting.  Pediatric cardiac intensive care unit in a tertiary care children's hospital. Patients.  All patients with transposition of the great arteries with an intact ventricular septum from 1995 to 2008. Outcome Measures.  Inotropic score was calculated for all patients in the first 5 postoperative days and maximum inotropic score was recorded. Length of postoperative mechanical ventilation, fluid balance, mechanical ventilation time, as well as intensive care unit and hospital stay were recorded for all patients. Results.  Study population included 59 patients, 41 (69%) underwent balloon atrial septostomy. PGE was used in 52 patients, median exposure of 59 hours, range 0 to 272 hours. Longer preoperative PGE exposure was associated with longer preoperative mechanical ventilation (P < .001). There was no association between preoperative PGE duration and cardiopulmonary bypass time, cross-clamp time, or total hospital stay. Patients with longer preoperative PGE exposure had a lower postoperative inotrope score (10 vs. 15 P = .02). Conclusion.  Greater preoperative PGE exposure was associated with prolonged preoperative mechanical ventilation. Longer PGE exposure was associated with lower postoperative inotrope requirements. Aggressive efforts to avoid or shorten PGE infusion duration may not be warranted in this population.

A Whole-genome Massively Parallel Sequencing Analysis of BRCA1 Mutant Oestrogen Receptor-negative and -positive Breast Cancers

The Journal of Pathology. May, 2012  |  Pubmed ID: 22362584

BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In more than 80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative; however, up to 15% are ER-positive. It has been suggested that BRCA1 ER-positive breast cancers constitute sporadic cancers arising in the context of a BRCA1 germline mutation rather than being causally related to BRCA1 loss-of-function. Whole-genome massively parallel sequencing of ER-positive and ER-negative BRCA1 breast cancers, and their respective germline DNAs, was used to characterize the genetic landscape of BRCA1 cancers at base-pair resolution. Only BRCA1 germline mutations, somatic loss of the wild-type allele, and TP53 somatic mutations were recurrently found in the index cases. BRCA1 breast cancers displayed a mutational signature consistent with that caused by lack of HR DNA repair in both ER-positive and ER-negative cases. Sequencing analysis of independent cohorts of hereditary BRCA1 and sporadic non-BRCA1 breast cancers for the presence of recurrent pathogenic mutations and/or homozygous deletions found in the index cases revealed that DAPK3, TMEM135, KIAA1797, PDE4D, and GATA4 are potential additional drivers of breast cancers. This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild-type allele are not sufficient for hereditary breast cancers to display an ER-negative phenotype, and has led to the identification of three potential novel breast cancer genes (ie DAPK3, TMEM135, and GATA4). Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mouse Betaine-homocysteine S-Methyltransferase Deficiency Reduces Body Fat Via Increasing Energy Expenditure and Impairing Lipid Synthesis and Enhancing Glucose Oxidation in White Adipose Tissue

The Journal of Biological Chemistry. Feb, 2012  |  Pubmed ID: 22362777

Betaine-homocysteine S-methyltransferase (BHMT) catalyzes the synthesis of methionine from homocysteine. In our initial report, we observed a reduced body weight in Bhmt(-/-) mice. We initiated this study to investigate the potential role of BHMT in energy metabolism. Compared to the controls (Bhmt(+/+)), Bhmt(-/-) mice had less fat mass, smaller adipocytes, and better glucose and insulin sensitivities. Compared to the controls, Bhmt(-/-), mice had increased energy expenditure, with no changes in food intake, fat uptake or absorption, or in locomotor activity. The reduced adiposity in Bhmt(-/-) mice was not due to hyperthermogenesis. Bhmt(-/-) mice failed to maintain a normal body temperature upon cold exposure due to limited fuel supplies. In vivo and ex vivo tests showed that Bhmt(-/-) mice had normal lipolytic function. The rate of [(14)C] fatty acid incorporated into [(14)C] triacylglycerol was the same in Bhmt(+/+) and Bhmt(-/-) gonadal fat depots (GWAT), but was 62% lower in Bhmt(-/-) inguinal fat depots (IWAT) compared to that of Bhmt(+/+)mice. The rate of [(14)C] fatty acid oxidation was the same in both GWAT and IWAT from Bhm(+/+) and Bhmt(-/-) mice. At basal level, Bhmt(-/-) GWAT had the same [(14)C] glucose oxidation as did the controls. When stimulated with insulin, Bhmt(-/-) GWAT oxidized 2.4-fold more glucose than did the controls. Compared to the controls, the rate of [(14)C] glucose oxidation was 2.4 and 1.8 fold higher respectively in Bhmt(-/-) IWAT without or with insulin stimulus. Our results show for the first time a role for BHMT in energy homeostasis.

Bringing Trees into the Fuel Line

The New Phytologist. Apr, 2012  |  Pubmed ID: 22364116

Outcomes Using a Bioprosthetic Mesh at the Time of Permanent Stoma Creation in Preventing a Parastomal Hernia: a Value Analysis

American Journal of Surgery. Mar, 2012  |  Pubmed ID: 22364901

A retrospective review of the medical records of all patients who had a prosthetic placed at the time of stoma creation for the prevention of a parastomal hernia was performed. The purpose of this study was to evaluate the safety, efficacy, and cost-effectiveness of bioprosthetics.

Peroxisomal Acyl-CoA Synthetases

Biochimica Et Biophysica Acta. Feb, 2012  |  Pubmed ID: 22366061

Peroxisomes carry out many essential lipid metabolic functions. Nearly all of these functions require that an acyl group-either a fatty acid or the acyl side chain of a steroid derivative-be thioesterified to coenzyme A (CoA) for subsequent reactions to proceed. This thioesterification, or "activation", reaction, catalyzed by enzymes belonging to the acyl-CoA synthetase family, is thus central to cellular lipid metabolism. However, despite our rather thorough understanding of peroxisomal metabolic pathways, surprisingly little is known about the specific peroxisomal acyl-CoA synthetases that participate in these pathways. Of the 26 acyl-CoA synthetases encoded by the human and mouse genomes, only a few have been reported to be peroxisomal, including ACSL4, SLC27A2, and SLC27A4. In this review, we briefly describe the primary peroxisomal lipid metabolic pathways in which fatty acyl-CoAs participate. Then, we examine the evidence for presence and functions of acyl-CoA synthetases in peroxisomes, much of which was obtained before the existence of multiple acyl-CoA synthetase isoenzymes was known. Finally, we discuss the role(s) of peroxisome-specific acyl-CoA synthetase isoforms in lipid metabolism. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of Peroxisomes in Health and Disease.

Acetone, Butanol, and Ethanol Production from Wastewater Algae

Bioresource Technology. May, 2012  |  Pubmed ID: 22366611

Acetone, butanol, and ethanol (ABE) fermentation by Clostridium saccharoperbutylacetonicum N1-4 using wastewater algae biomass as a carbon source was demonstrated. Algae from the Logan City Wastewater Lagoon system grow naturally at high rates providing an abundant source of renewable algal biomass. Batch fermentations were performed with 10% algae as feedstock. Fermentation of acid/base pretreated algae produced 2.74g/L of total ABE, as compared with 7.27g/L from pretreated algae supplemented with 1% glucose. Additionally, 9.74g/L of total ABE was produced when xylanase and cellulase enzymes were supplemented to the pretreated algae media. The 1% glucose supplement increased total ABE production approximately 160%, while supplementing with enzymes resulted in a 250% increase in total ABE production when compared to production from pretreated algae with no supplementation of extraneous sugar and enzymes. Additionally, supplementation of enzymes produced the highest total ABE production yield of 0.311g/g and volumetric productivity of 0.102g/Lh. The use of non-pretreated algae produced 0.73g/L of total ABE. The ability to engineer novel methods to produce these high value products from an abundant and renewable feedstock such as algae could have significant implications in stimulating domestic energy economies.

The Application of LTR Retrotransposons As Molecular Markers in Plants

Methods in Molecular Biology (Clifton, N.J.). 2012  |  Pubmed ID: 22367869

Retrotransposons are a major agent of genome evolution. Various molecular marker systems have been developed that exploit the ubiquitous nature of these genetic elements and their property of stable integration into dispersed chromosomal loci that are polymorphic within species. The key methods, SSAP, IRAP, REMAP, RBIP, and ISBP, all detect the sites at which the retrotransposon DNA, which is conserved between families of elements, is integrated into the genome. Marker systems exploiting these methods can be easily developed and inexpensively deployed in the absence of extensive genome sequence data. They offer access to the dynamic and polymorphic, nongenic portion of the genome and thereby complement methods, such as gene-derived SNPs, that target primarily the genic fraction.

Collaborative Assessment and Management of Suicidality in an Inpatient Setting: Results of a Pilot Study

Psychotherapy (Chicago, Ill.). Mar, 2012  |  Pubmed ID: 22369081

Patients hospitalized for psychiatric reasons exhibit significantly elevated risk of suicide, yet the research literature contains very few outcome studies of interventions designed for suicidal inpatients. This pilot study examined the inpatient feasibility and effectiveness of The Collaborative Assessment and Management of Suicidality (CAMS), a structured evidence-based method for risk assessment and treatment planning (Jobes, 2006). The study used an open-trial, case-focused design to assess an inpatient adaptation of CAMS, spread over a period averaging 51 days. The intervention was provided via individual therapy to a convenience sample of 20 patients (16 females and four males, average age 36.9) who were hospitalized with recent histories of suicidal ideation and behavior. Results showed statistically and clinically significant reductions in depression, hopelessness, suicide cognitions, and suicidal ideation, as well as improvement on factors considered "drivers" of suicidality. Treatment effect sizes were in the large range (Cohen's d > .80) across several outcome measures, including suicidal ideation. Although these findings must be considered preliminary due to the lack of a randomized control group, they merit attention from clinicians working with patients at risk for suicide. This study also supports the feasibility of implementing a structured, suicide-specific intervention for at-risk patients in inpatient settings.

Use of Neoadjuvant Data to Design Adjuvant Endocrine Therapy Trials for Breast Cancer

Nature Reviews. Clinical Oncology. 2012  |  Pubmed ID: 22371132

Mature outcomes from adjuvant endocrine therapy trials in estrogen receptor-positive breast cancer have enabled comparisons with neoadjuvant clinical trials that have parallel randomizations of treatment in terms of the response of disseminated disease versus the local response within the breast. Imprecise end points, such as 'clinical response', have produced inconsistent results regarding the relationship between neoadjuvant and adjuvant endocrine therapy outcomes. However, the proliferation marker Ki-67, measured during neoadjuvant treatment, has predicted accurately and consistently the results of much larger studies in the adjuvant setting. In this Review, we summarize these trials and discuss the implications for the design of future adjuvant endocrine therapy trials. We conclude that there is sufficient evidence supporting the view that the degree of Ki-67 suppression is a reliable short-term surrogate for the adjuvant potential of endocrine drugs, at least in postmenopausal women. We propose that adjuvant endocrine therapy trials should only be conducted once adequately-powered neoadjuvant studies have indicated superior Ki-67 suppression in patients receiving experimental endocrine treatment versus the standard treatment.

The Arabidopsis SYN3 Cohesin Protein is Important for Early Meiotic Events

The Plant Journal : for Cell and Molecular Biology. Mar, 2012  |  Pubmed ID: 22381039

α-kleisins are core components of meiotic and mitotic cohesin complexes. Arabidopsis contains four genes that encode α-kleisin proteins: SYN1-4. SYN1, a REC8 ortholog, is essential for meiosis, while SYN2 and SYN4 appear to be SCC1 orthologs and function in mitosis. SYN3 is essential for megagametogenesis and is enriched in the nucleolus of meiotic and mitotic cells. In this study the role of SYN3 during meiosis was investigated by characterizing plants that express SYN3 RNAi constructs from either the meiotic DMC1, native SYN3, or inducible PX7 promoters. Reduction of SYN3 caused defects in homologous chromosome synapsis and synaptonemal complex (SC) formation during male and female meiosis. Consistent with this observation relatively little signal for the SC component ZYP1 was detected on the chromosomes of SYN3-RNAi plants. While ZYP1 transcript levels were relatively normal, several transcripts for genes that encode proteins involved in meiotic recombination were altered, suggesting that a reduction in SYN3 may inhibit meiotic progression by altering meiotic gene expression. © 2012 The Authors. The Plant Journal © 2012 Blackwell Publishing Ltd.

Alteration of Lipids and the Transcription of Lipid-related Genes in Myelodysplastic Syndromes Via a TP53-related Pathway

Experimental Hematology. Feb, 2012  |  Pubmed ID: 22381680

Myelodysplastic syndromes (MDS) are clonal stem cell diseases of the bone marrow characterized by abnormalities in maturation of hematopoietic cells of all lineages. MDS patients frequently have lower lipids and high rates of apoptosis and p53 (TP53) expression. An association between the reduced lipids in MDS and the expression of lipid-related genes was sought. We further evaluated whether 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGcoAR) and low-density lipoprotein receptor (LDL-R) are regulated by TP53 in vivo and in vitro. Gene expression was measured using real-time reverse transcription polymerase chain reaction on RNA extracted from bone marrow and peripheral blood from eight newly diagnosed MDS patients and eight controls and from mice livers. Serum lipid profile was measured using colorimetric enzymatic procedures. Total- and LDL cholesterol were lower in MDS patients in comparison to controls (p = 0.04 and p = 0.01, respectively). HMGcoAR messenger RNA increased in peripheral blood and bone marrow of MDS patients compared to controls (p = 0.04 and p = 0.01, respectively). LDL-R messenger RNA was higher only in the peripheral blood of MDS patients (p = 0.05). Comparable results were obtained in vivo. The transcription of these genes correlates with TP53 activation as documented by p21 messenger RNA elevation, a surrogate for TP53 activation and by using TP53 temperature-sensitive cells treated with adriamycin. To conclude, an association between reduced lipids in MDS and expression of HMGcoAR and LDL-R genes was documented. The transcription of these genes can be regulated by TP53.

Stress Fractures About the Tibia, Foot, and Ankle

The Journal of the American Academy of Orthopaedic Surgeons. Mar, 2012  |  Pubmed ID: 22382289

In competitive athletes, stress fractures of the tibia, foot, and ankle are common and lead to considerable delay in return to play. Factors such as bone vascularity, training regimen, and equipment can increase the risk of stress fracture. Management is based on the fracture site. In some athletes, metabolic workup and medication are warranted. High-risk fractures, including those of the anterior tibial diaphysis, navicular, proximal fifth metatarsal, and medial malleolus, present management challenges and may require surgery, especially in high-level athletes who need to return to play quickly. Noninvasive treatment modalities such as pulsed ultrasound and extracorporeal shock wave therapy may have some benefit but require additional research.

The Effect of Targeted Agents on Outcomes in Patients with Brain Metastases from Renal Cell Carcinoma Treated with Gamma Knife Surgery

Journal of Neurosurgery. Mar, 2012  |  Pubmed ID: 22385005

Object Gamma Knife surgery (GKS) has been reported as an effective modality for treating brain metastases from renal cell carcinoma (RCC). The authors aimed to determine if targeted agents such as tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and bevacizumab affect the patterns of failure of RCC after GKS. Methods Between 1999 and 2010, 61 patients with brain metastases from RCC were treated with GKS. A median dose of 20 Gy (range 13-24 Gy) was prescribed to the margin of each metastasis. Kaplan-Meier analysis was used to determine local control, distant failure, and overall survival rates. Cox proportional hazard regression was performed to determine the association between disease-related factors and survival. Results Overall survival at 1, 2, and 3 years was 38%, 17%, and 9%, respectively. Freedom from local failure at 1, 2, and 3 years was 74%, 61%, and 40%, respectively. The distant failure rate at 1, 2, and 3 years was 51%, 79%, and 89%, respectively. Twenty-seven percent of patients died of neurological disease. The median survival for patients receiving targeted agents (n = 24) was 16.6 months compared with 7.2 months (n = 37) for those not receiving targeted therapy (p = 0.04). Freedom from local failure at 1 year was 93% versus 60% for patients receiving and those not receiving targeted agents, respectively (p = 0.01). Multivariate analysis showed that the use of targeted agents (hazard ratio 3.02, p = 0.003) was the only factor that predicted for improved survival. Two patients experienced post-GKS hemorrhage within the treated volume. Conclusions Targeted agents appear to improve local control and overall survival in patients treated with GKS for metastastic RCC.

Re-audit of Revised Method for Assessing the Mitotic Component of Histological Grade in Needle Core Biopsies of Invasive Carcinoma of the Breast

Histopathology. Mar, 2012  |  Pubmed ID: 22385388

Applying Best-Worst Scaling Methodology to Establish Delivery Preferences of a Symptom Supportive Care Intervention in Patients with Lung Cancer

Lung Cancer (Amsterdam, Netherlands). Feb, 2012  |  Pubmed ID: 22385926

BACKGROUND: Delivering a non-pharmacological symptom management intervention in patients with lung cancer is often challenging due to difficulties with recruitment, high attrition rates, high symptom burden, and other methodological problems. The aim of the present study was to elicit quantitative estimates of utility (benefit) associated with different attribute levels (delivery options) of a symptom management intervention in lung cancer patients. METHODS: An application of Best-Worst scaling methodology was used. Effects (attributes) tested included the location of the intervention (home or hospital), type of trainer (health professional or trained volunteer), caregiver involvement or not, and intervention delivered individually or in groups of patients. Participants were asked to evaluate and compare their preferences (utilities) towards the different attribute levels within scenarios and select the pair of attribute levels that they consider to be furthest apart. RESULTS: Eighty-seven patients with lung cancer participated. The most important preferences for an intervention included the location (being delivered at home) and delivered by a health care professional. The least important preference was the involvement of a caregiver. Gender had an effect on preferences, with females being less inclined than men to prefer to receive an intervention in the home than the hospital and less inclined than men to have no other patients present. Furthermore, older participants and those in advanced stages of their disease were less inclined to have no other patients present compared to younger participants and those with earlier stages of disease, respectively. CONCLUSION: Considering patient preferences is an important step in developing feasible, patient-centred, appropriate and methodologically rigorous interventions and this study provided indications of such patient preferences.

Distinct Models of Induced Hyperactivity in Zebrafish Larvae

Brain Research. Apr, 2012  |  Pubmed ID: 22386495

The analysis of behavioural hyperactivity can provide insights into how perturbations in normal activity may be linked to the altered function of the nervous system and possibly the symptoms of disease. As a small vertebrate zebrafish have numerous experimental advantages that are making them a powerful model for these types of studies. While the majority of behavioural studies have focused on adult zebrafish, it has become apparent that larvae can also display complex stereotypical patterns of behaviour. Here we have used three compounds (pentylenetetrazole (PTZ), aconitine and 4-aminopyridine) that have different neuronal targets (GABA, sodium and potassium channels), to induce distinct patterns of hyperactivity in larvae. Our studies have revealed that each compound produces a number of distinct concentration-dependent activity patterns. This work has shown for the first time that at sub-convulsive concentrations, PTZ can reverse the normal behavioural response to alternating periods of light and dark in zebrafish larvae. It also appears that both PTZ and 4-aminopyridine produce distinct changes in the normal startle response patterns immediately following light/dark transitions that may be the result of an elevation in stress/anxiety. Aconitine produces a general elevation in activity that eliminates the normal response to light and dark. In addition to differences in the patterns of behaviour each compound also produces a unique pattern of c-fos (an immediate early gene) expression in the brain. While more work is required to make direct links between region specific neuronal activity and individual behaviours, these models provide a framework with which to study and compare mechanistically different types of inducible behaviours.

Circulating Ghrelin and GLP-1 Are Not Affected by Habitual Diet

Regulatory Peptides. Feb, 2012  |  Pubmed ID: 22387702

BACKGROUND: Ghrelin and glucagon-like peptide-1 (GLP-1) are gut hormones known to induce hunger and satiety, respectively. Current knowledge about the effects of different macronutrients on circulating ghrelin and GLP-1 comes mainly from acute test meals, whereas little is known about the effects of chronic dietary intake on gut hormone secretion. This study was designed to examine whether 8-week habituation to diets with different percentages of carbohydrate and fat would affect serum ghrelin, GLP-1, and subjective hunger in a postabsorptive state and in response to a standard liquid mixed meal. METHODS: Sixty-one overweight men and women were provided all food for 8weeks of either a higher-carbohydrate/lower-fat diet (High-CHO/Low-FAT; 55% CHO, 18% PRO, 27% FAT) or a lower-carbohydrate/higher-fat diet (Low-CHO/High-FAT; 43% CHO, 18% PRO, 39% FAT). After overnight fasts at baseline and week 8, participants consumed a standard liquid meal (7kcals/kg, 58.6% CHO, 17.4% PRO, 24% FAT). Blood was sampled before the meal and at 15, 60, 90, 120, 180, and 240min to determine total serum ghrelin and active GLP-1. Hunger was assessed by a visual analog scale. Mixed models were used to evaluate whether the temporal patterns of total serum ghrelin and active GLP-1 differed with diet. RESULTS: Although both diet groups reported greater hunger after 8weeks (p=0.03), circulating ghrelin and GLP-1 were not affected by acclimation to different macronutrients. CONCLUSION: Habituation to different diets does not appear to influence fasting ghrelin, fasting GLP-1, or responses of these gut hormones to a standard meal.

Is Reporting Race and Ethnicity Essential to Occupational Therapy Evidence?

The American Journal of Occupational Therapy. : Official Publication of the American Occupational Therapy Association. Jan-Feb, 2012  |  Pubmed ID: 22389947

Cognitive and Functional Status After Vein of Galen Aneurysmal Malformation Endovascular Occlusion

World Journal of Radiology. Mar, 2012  |  Pubmed ID: 22468188

To study the clinical outcomes of treating vein of Galen aneurysmal malformations (VGAM), we assessed our patient cohort using standardized cognitive and functional measures.

Author Reply to "last-observation-carried-forward Threatens the Validity of Intention-to-treat Analysis in Fibromyalgia Trials"

Arthritis and Rheumatism. Apr, 2012  |  Pubmed ID: 22488609

Antiemesis

Journal of the National Comprehensive Cancer Network : JNCCN. Apr, 2012  |  Pubmed ID: 22491046

The Top 10 Fungal Pathogens in Molecular Plant Pathology

Molecular Plant Pathology. Mar, 2012  |  Pubmed ID: 22390547

The aim of this review was to survey all fungal pathologists with an association with the journal Molecular Plant Pathology and ask them to nominate which fungal pathogens they would place in a 'Top 10' based on scientific/economic importance. The survey generated 495 votes from the international community, and resulted in the generation of a Top 10 fungal plant pathogen list for Molecular Plant Pathology. The Top 10 list includes, in rank order, (1) Magnaporthe oryzae; (2) Botrytis cinerea; (3) Puccinia spp.; (4) Fusarium graminearum; (5) Fusarium oxysporum; (6) Blumeria graminis; (7) Mycosphaerella graminicola; (8) Colletotrichum spp.; (9) Ustilago maydis; (10) Melampsora lini, with honourable mentions for fungi just missing out on the Top 10, including Phakopsora pachyrhizi and Rhizoctonia solani. This article presents a short resumé of each fungus in the Top 10 list and its importance, with the intent of initiating discussion and debate amongst the plant mycology community, as well as laying down a bench-mark. It will be interesting to see in future years how perceptions change and what fungi will comprise any future Top 10.

Total Preservation of Patency and Valve Function After Percutaneous Pharmacomechanical Thrombolysis Using the Trellis®-8 System for an Acute, Extensive Deep Venous Thrombosis

Annals of the Royal College of Surgeons of England. Mar, 2012  |  Pubmed ID: 22391378

Pharmacomechanical thrombolysis is being used increasingly for the treatment of deep vein thrombosis (DVT) and aims to reduce the severity of post-thrombotic syndrome. We report the case of a 60-year-old woman with extensive lower limb DVT that was treated using pharmacomechanical thrombolysis leading to complete recovery of her deep venous system. The prompt use of pharmacomechanical thrombolysis for the acute management of extensive DVT should be considered when treating patients with extensive DVT in order to facilitate return of normal function.

Distressing Adverse Events After Antidepressant Switch in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial: Influence of Adverse Events During Initial Treatment with Citalopram on Development of Subsequent Adverse Events with an Alternative Antidepressant

Pharmacotherapy. Mar, 2012  |  Pubmed ID: 22392456

To determine whether distressing adverse events (DAEs) experienced during initial antidepressant treatment are associated with subsequent DAEs after switching to a second antidepressant.

Distressing Adverse Events After Antidepressant Switch in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial: Influence of Adverse Events During Initial Treatment with Citalopram on Development of Subsequent Adverse Events with an Alternative Antidepressant

Pharmacotherapy. Jan, 2012  |  Pubmed ID: 22392571

STUDY OBJECTIVE: To determine whether distressing adverse events (DAEs) experienced during initial antidepressant treatment are associated with subsequent DAEs after switching to a second antidepressant. DESIGN: Secondary analysis of data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. SETTING: Primary care and psychiatric care facilities. PATIENTS: A total of 727 outpatients aged 18-75 years with nonpsychotic major depressive disorder who failed first-step therapy with citalopram and were switched to second-step monotherapy with an alternative antidepressant. MEASUREMENTS AND MAIN RESULTS: In the STAR*D trial, patient-reported DAEs were entered into the Patient-Rated Inventory of Side Effects (PRISE). In this secondary analysis, data from PRISE were used to determine the incidence of DAEs during first-step treatment with citalopram and second-step treatment with sustained-release bupropion, sertraline, or extended-release venlafaxine. Regression models were used to compare the risk of adverse events during second-step treatment between those who reported similar adverse events during first-step treatment and those who did not, while controlling for potential confounders. Of the 727 patients analyzed, DAEs were reported by 514 patients (70.7%) during first-step treatment and 626 (86.1%) during second-step treatment; no significant differences were observed among the three second-step treatment groups. Overall, patients reporting DAEs during first-step treatment were more likely to report DAEs during second-step treatment (risk ratio [RR] 1.11, 95% confidence interval [CI] 1.03-1.20). After controlling for confounders, patients were significantly more likely to report DAEs specific to a body function or organ system, such as those involving the genitourinary system (RR 3.39, 95% CI 2.41-4.78) or sexual functioning (RR 2.75, 95% CI 2.29-3.29), if the patients had reported similar events during initial treatment. CONCLUSION: Patients who experienced DAEs with initial antidepressant treatment were likely to report similar adverse events after switching to an alternative antidepressant, even when subsequent treatment is from a different class of antidepressants.

Preservation of Neurons of the Nucleus Basalis in Subcortical Ischemic Vascular Disease

Archives of Neurology. Mar, 2012  |  Pubmed ID: 22393167

OBJECTIVE: To investigate loss of neurons in the nucleus basalis (NB) of Meynert in patients with subcortical ischemic vascular disease (SIVD) compared with healthy controls, patients with Alzheimer disease (AD), and patients with mixed AD and SIVD. DESIGN: Autopsied cases drawn from a longitudinal observational study of patients with SIVD, patients with AD, and healthy controls. SETTING: Multi center, university-affiliated, program project neuropathology core. Patients  Patients with pathologically defined SIVD (n = 16), AD (n = 20), and mixed AD and SIVD (n = 10) and healthy controls matched by age and educational level (n = 17) were studied. MAIN OUTCOME MEASURES: The NB neuronal cell counts in each group and their correlation with the extent of magnetic resonance imaging white matter lesions and Clinical Dementia Rating (CDR) scores closest to death. RESULTS: No significant loss of neurons was found in SIVD patients compared with age-matched controls in contrast to the AD and mixed groups, who had significant neuronal loss. A significant inverse correlation between NB neurons and CDR scores was found in the AD group but not in the SIVD and mixed groups. The NB cell counts were not correlated with either the extent of white matter lesions or cortical gray matter volume in the SIVD or AD groups. CONCLUSIONS: These findings inveigh against primary loss of cholinergic neurons in SIVD patients but do not rule out the possibility of secondary cholinergic deficits due to disruptions of cholinergic projections to cerebral cortex.

Whole Blood Gene Expression Testing for Coronary Artery Disease in Nondiabetic Patients: Major Adverse Cardiovascular Events and Interventions in the PREDICT Trial

Journal of Cardiovascular Translational Research. Mar, 2012  |  Pubmed ID: 22396313

The majority of first-time angiography patients are without obstructive coronary artery disease (CAD). A blood gene expression score (GES) for obstructive CAD likelihood was validated in the PREDICT study, but its relation to major adverse cardiovascular events (MACE) and revascularization was not assessed. Patients (N = 1,160) were followed up for MACE and revascularization 1 year post-index angiography and GES, with 1,116 completing follow-up. The 30-day event rate was 23% and a further 2.2% at 12 months. The GES was associated with MACE/revascularizations (p < 0.001) and added to clinical risk scores. Patients with GES >15 trended towards increased >30 days MACE/revascularization likelihood (odds ratio = 2.59, 95% confidence interval = 0.89-9.14, p = 0.082). MACE incidence overall was 1.5% (17 of 1,116) and 3 of 17 patients had GES ≤15. For the total low GES group (N = 396), negative predictive value was 90% for MACE/revascularization and >99% for MACE alone, identifying a group of patients without obstructive CAD and highly unlikely to suffer MACE within 12 months.

Common Variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 Are Associated with Breast Cancer Risk for BRCA1 And/or BRCA2 Mutation Carriers

Breast Cancer Research : BCR. Feb, 2012  |  Pubmed ID: 22348646

ABSTRACT: INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). CONCLUSIONS: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

One-Year Clinical Outcomes After Sirolimus-Eluting Coronary Stent Implantation for Acute Myocardial Infarction in the Worldwide E-SELECT Registry

Journal of Interventional Cardiology. Feb, 2012  |  Pubmed ID: 22348733

Background: The aim was to ascertain the 1-year clinical outcomes of 1,234 patients who underwent implantations of sirolimus-eluting stents (SES) for acute myocardial infarction (MI) in the multinational e-SELECT registry. Methods: Fifteen thousand and one hundred and forty-seven patients treated with SES were entered in the e-SELECT registry, of whom 1,234 presented within <24 hours of onset of acute MI. Results: At 1 year, the rates of major adverse cardiac events (MACE) (5.5% vs. 4.8%; P = 0.28) were similarly low in the acute and no acute MI groups. The rates of definite/probable stent thrombosis (ST) were higher in the acute MI group (2.1%vs; 0.88%, P < 0.001). ST was a strong independent predictor of death at 1 year (HR 13.4; 95% CI 5.0, 36.0; P < 0.001) and MI (HR 58.9; 95% CI 26.9, 129.1; P < 0.001). Dual antiplatelet therapy (DAPT) compliance at 6 months was 96.0% in the acute MI versus 94.5% in the no acute MI group (P = 0.03). Conclusion: In selected patients presenting within <24 hours of acute MI onset and highly compliant with DAPT, SES implantation was associated with similar rates of MACE, though higher rates of ST, as compared to no acute MI patients. Condensed abstract  In the e-SELECT registry which included 15,147 patients treated with sirolimus-eluting stent (SES), we ascertained the 1-year clinical outcomes of 1,234 patients who presented within <24 hours of acute MI onset. In acute MI patients SES implantation was associated with similar rates of MACE, though higher rates of ST, as compared to no acute MI patients (MACE: 5.5% vs. 4.8%; P = 0.28; ST: 2.1 vs. 0.88%, P < 0.001). (J Interven Cardiol 2012;**:1-9).

Differentiating Maturational and Training Influences on FMRI Activation During Music Processing

NeuroImage. Apr, 2012  |  Pubmed ID: 22348885

Two major influences on how the brain processes music are maturational development and active musical training. Previous functional neuroimaging studies investigating music processing have typically focused on either categorical differences between "musicians versus nonmusicians" or "children versus adults." In the present study, we explored a cross-sectional data set (n=84) using multiple linear regression to isolate the performance-independent effects of age (5 to 33years) and cumulative duration of musical training (0 to 21,000 practice hours) on fMRI activation similarities and differences between melodic discrimination (MD) and rhythmic discrimination (RD). Age-related effects common to MD and RD were present in three left hemisphere regions: temporofrontal junction, ventral premotor cortex, and the inferior part of the intraparietal sulcus, regions involved in active attending to auditory rhythms, sensorimotor integration, and working memory transformations of pitch and rhythmic patterns. By contrast, training-related effects common to MD and RD were localized to the posterior portion of the left superior temporal gyrus/planum temporale, an area implicated in spectrotemporal pattern matching and auditory-motor coordinate transformations. A single cluster in right superior temporal gyrus showed significantly greater activation during MD than RD. This is the first fMRI which has distinguished maturational from training effects during music processing.

Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. Apr, 2012  |  Pubmed ID: 22351618

BACKGROUND: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). METHODS: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. RESULTS: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)). CONCLUSIONS: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645-57. ©2012 AACR.

Responsiveness of Intrinsic Subtypes to Adjuvant Anthracycline Substitution in the NCIC.CTG MA.5 Randomized Trial

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Feb, 2012  |  Pubmed ID: 22351696

PURPOSE: Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens. We examined this hypothesis on NCIC.CTG MA.5, a clinical trial randomizing pre-menopausal women with node positive breast cancer to adjuvant CMF (cyclophosphamide-methotrexate-fluorouracil) vs. CEF (cyclophosphamide-epirubicin-fluorouracil) chemotherapy.EXPERIMENTAL DESIGN: Intrinsic subtype was determined for 476 tumors using the RT-qPCR PAM50 gene expression test. Luminal A, Luminal B, HER2-Enriched (HER2-E), and Basal-like subtypes were correlated with relapse-free (RFS) and overall survival (OS), estimated using Kaplan-Meier plots and log-rank testing. Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes.RESULTS: Intrinsic subtypes were associated with RFS (p=0.0005) and OS (p less than 0.0001) on the combined cohort. The HER2-E demonstrated the greatest benefit from CEF vs. CMF, with absolute 5-yr RFS and OS differences exceeding 20%, whereas there was a less than 2% difference for non-HER2-E tumors (interaction test p=0.03 for RFS and 0.03 for OS). Within clinically defined Her2+ tumors, 79% (72/91) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF vs. CMF (62% vs. 22%, p = 0.0006). There was no significant difference in benefit between CEF and CMF in Basal-like tumors (n = 94, HR 1.1 [95% CI 0.6-2.1] for RFS and 1.3 [95% CI 0.7-2.5] for OS).CONCLUSIONS: HER2-E strongly predicted anthracycline-sensitivity. The chemotherapy-sensitive Basal-like tumors showed no added benefit for CEF over CMF, suggesting that non-anthracycline regimens may be adequate in this subtype although further investigation is required.

Probing the Non-pairwise Interactions Between CO Molecules Moving on a Cu(111) Surface

Journal of Physics. Condensed Matter : an Institute of Physics Journal. Mar, 2012  |  Pubmed ID: 22353494

The coverage dependent dynamics of CO on a Cu(111) surface are studied on an atomic scale using helium spin-echo spectroscopy. CO molecules occupy top sites preferentially, but also visit intermediate bridge sites in their motion along the reaction coordinate. We observe an increase in hopping rate as the CO coverage grows; however, the motion remains uncorrelated up to at least 0.10 monolayers (ML). From the temperature dependence of the diffusion rate, we find an effective barrier of 98 ± 5 meV for diffusion. Thermal motion is modelled with Langevin molecular dynamics, using a potential energy surface having adsorption sites at top and bridge positions and the experimental data are well represented by an adiabatic barrier for hopping of 123 meV. The sites are not degenerate and the rate changes observed with coverage are modelled successfully by changing the shape of the adiabatic potential energy surface in the region of the transition state without modifying the energy barrier. The results demonstrate that sufficient detail exists in the experimental data to provide information on the principal adsorption sites as well as the energy landscape in the region of the transition state.

High-performance Vision Training Improves Batting Statistics for University of Cincinnati Baseball Players

PloS One. 2012  |  Pubmed ID: 22276103

Baseball requires an incredible amount of visual acuity and eye-hand coordination, especially for the batters. The learning objective of this work is to observe that traditional vision training as part of injury prevention or conditioning can be added to a team's training schedule to improve some performance parameters such as batting and hitting.

Mechanisms of the Proteinuria Induced by Rho GTPases

Kidney International. Jan, 2012  |  Pubmed ID: 22278020

Podocytes are highly differentiated cells that play an important role in maintaining glomerular filtration barrier integrity; a function regulated by small GTPase proteins of the Rho family. To investigate the role of Rho A in podocyte biology, we created transgenic mice expressing doxycycline-inducible constitutively active (V14 Rho) or dominant-negative Rho A (N19 Rho) in podocytes. Specific induction of either Rho A construct in podocytes caused albuminuria and foot process effacement along with disruption of the actin cytoskeleton as evidenced by decreased expression of the actin-associated protein synaptopodin. The mechanisms of these adverse effects, however, appeared to be different. Active V14 Rho enhanced actin polymerization, caused a reduction in nephrin mRNA and protein levels, promoted podocyte apoptosis, and decreased endogenous Rho A levels. In contrast, the dominant-negative N19 Rho caused a loss of podocyte stress fibers, did not alter the expression of either nephrin or Rho A, and did not cause podocyte apoptosis. Thus, our findings suggest that Rho A plays an important role in maintaining the integrity of the glomerular filtration barrier under basal conditions, but enhancement of Rho A activity above basal levels promotes podocyte injury.Kidney International advance online publication, 25 January 2012; doi:10.1038/ki.2011.472.

Percutaneous Coronary Intervention in Patients with Severe Aortic Stenosis: Implications for Transcatheter Aortic Valve Replacement

Circulation. Feb, 2012  |  Pubmed ID: 22282327

With the availability of transcatheter aortic valve replacement, management of coronary artery disease in patients with severe aortic stenosis (AS) is posing challenges. Outcomes of percutaneous coronary intervention (PCI) in patients with severe AS and coronary artery disease remain unknown. We sought to compare the short-term outcomes of PCI in patients with and without AS.

A Fresh Look at the Predictors of Naming Accuracy and Errors in Alzheimer's Disease

Journal of Neuropsychology. Jan, 2012  |  Pubmed ID: 22284909

In recent years, a considerable number of studies have tried to establish which characteristics of objects and their names predict the responses of patients with Alzheimer's disease (AD) in the picture-naming task. The frequency of use of words and their age of acquisition (AoA) have been implicated as two of the most influential variables, with naming being best preserved for objects with high-frequency, early-acquired names. The present study takes a fresh look at the predictors of naming success in Spanish and English AD patients using a range of measures of word frequency and AoA along with visual complexity, imageability, and word length as predictors. Analyses using generalized linear mixed modelling found that naming accuracy was better predicted by AoA ratings taken from older adults than conventional ratings from young adults. Older frequency measures based on written language samples predicted accuracy better than more modern measures based on the frequencies of words in film subtitles. Replacing adult frequency with an estimate of cumulative (lifespan) frequency did not reduce the impact of AoA. Semantic error rates were predicted by both written word frequency and senior AoA while null response errors were only predicted by frequency. Visual complexity, imageability, and word length did not predict naming accuracy or errors.

Safety and Efficacy of Esreboxetine in Patients with Fibromyalgia: A 14-week, Randomized, Double-blind, Placebo-controlled, Multicenter Clinical Trial

Arthritis and Rheumatism. Jan, 2012  |  Pubmed ID: 22275142

OBJECTIVE.: To evaluate the efficacy, tolerability, and safety of multiple fixed doses of esreboxetine for the treatment of fibromyalgia. METHODS.: Patients meeting American College of Rheumatology criteria for fibromyalgia were randomized to receive 4- (n = 277), 8- (n = 284), or 10-mg/d (n = 283) esreboxetine, or matching placebo (n = 278), for 14 weeks. Primary efficacy outcomes were weekly mean pain score and Fibromyalgia Impact Questionnaire (FIQ) total score at week 14. Secondary efficacy measures included Patient Global Impression of Change (PGIC), Global Fatigue Index (GFI), and 36-item Short-Form Health Survey (SF-36; Physical Functioning scale only) scores at week 14. Esreboxetine's safety profile was evaluated based on adverse events and other safety measures. RESULTS.: All doses of esreboxetine demonstrated statistically significant improvements over placebo on pain (P ≤ 0.025), FIQ (P ≤ 0.023), and PGIC (P ≤ 0.007). Additionally, the 4- and 8-mg/d esreboxetine demonstrated statistically significant improvements over placebo on the GFI (P = 0.001). No significant improvements over placebo were evident for any dose of esreboxetine on the SF-36 Physical Functioning scale. Adverse events were mostly mild to moderate in severity; insomnia, constipation, dry mouth, nausea, dizziness, hot flush, headache, hyperhidrosis, and palpitations were reported most frequently. CONCLUSION.: Esreboxetine was generally well tolerated and associated with significant improvements in pain, FIQ, PGIC, and fatigue scores compared with placebo. The lack of a dose-response relationship in both the efficacy and safety analyses suggests that 4-mg/d esreboxetine would offer clinical benefit with the least risk of drug exposure.

Considerations in Developing and Delivering a Non-pharmacological Intervention for Symptom Management in Lung Cancer: the Views of Health Care Professionals

Supportive Care in Cancer : Official Journal of the Multinational Association of Supportive Care in Cancer. Jan, 2012  |  Pubmed ID: 22270088

BACKGROUND: A respiratory distress symptom cluster has recently been identified in lung cancer associated with breathlessness, cough and fatigue, and the study reported here is part of a wider body of work being undertaken to develop a novel non-pharmacological intervention (NPI) for the management of this symptom cluster. The current paper reports the views of health care professionals (HCPs) involved with cancer care regarding the most appropriate ways of developing and delivering such a novel intervention. METHODS: Five focus groups, supplemented with additional telephone interviews, were conducted with a range of both community- and acute-based HCPs involved in symptom management for lung cancer patients. Participants included oncologists, palliative care consultants, specialist nurses, occupational therapists and physiotherapists. The focus groups were transcribed verbatim and analysed using NVIVO to support a framework analysis approach. RESULTS: The current delivery of NPIs was found to be ad hoc and varied between sites both in terms of what was delivered and by which health care professionals. The provision of NPIs within acute medical settings faced common problems concerning staffing time and space, and there was a recognition that the preference of most patients to make as few hospital visits as possible also complicated NPI teaching. Moreover, there may only be a small window of opportunity in which to effectively teach lung cancer patients a novel NPI as the period between diagnosis and the onset of severe symptoms is often short. DISCUSSION: The participants agreed that the novel symptom management NPI should be individually personalised to the needs of each patient and be available for patients when they become receptive to it. Moreover, they agreed that the intervention would be most effective if delivered to patients individually rather than in groups, outside acute medical settings where possible and closer to patient's homes, should be delivered by an HCP rather than a trained volunteer or lay person and should involve informal carers wherever practicable.

Docetaxel-containing Adjuvant Chemotherapy in Patients with Early Stage Breast Cancer. Consistency of Effect Independent of Nodal and Biomarker Status: a Meta-analysis of 14 Randomized Clinical Trials

Breast Cancer Research and Treatment. Jan, 2012  |  Pubmed ID: 22270929

The benefit of taxanes in the adjuvant setting for node-negative (N0) early breast cancer (EBC) has not yet been established. We conducted a meta-analysis of randomized adjuvant trials comparing docetaxel-containing versus non-taxane-containing regimens. The purpose of this study was to determine whether the incorporation of docetaxel improves disease-free survival (DFS) and overall survival (OS) in early stage breast cancer. Studies were retrieved by searching major databases and the proceedings of leading breast cancer conferences. We extracted hazard ratios (HRs) and 95% confidence intervals (CIs) for DFS and OS and obtained pooled estimates using an inverse-variance model. Fourteen randomized phase III studies were included (25,067 patients). The pooled HR estimate was 0.84 (95% CI 0.78-0.89; P < 0.001) favoring docetaxel for DFS and 0.86 (0.78-0.94; P < 0.001) for OS. In N0 patients (4,274 patients), the pooled HR estimate for DFS was 0.86 (0.73-1.00; P = 0.05). The HR for OS was equal to 1 (0.75-1.34). The improvement in DFS with docetaxel-containing regimens was observed across all subgroups (age, under or over 50; number of involved nodes; hormone receptor or HER2 status (including triple negative status), or administration schedule (sequential or concomitant). The addition of docetaxel to a non-taxane-containing regimen improves DFS and OS in high risk EBC patients. The benefit in DFS was seen across all subgroups regardless of nodal status, age, hormone receptor or HER2 status (including triple negative status), or administration schedule.

Overexpression of a Novel Cell Cycle Regulator Ecdysoneless in Breast Cancer: a Marker of Poor Prognosis in HER2/neu-overexpressing Breast Cancer Patients

Breast Cancer Research and Treatment. Jan, 2012  |  Pubmed ID: 22270930

Uncontrolled proliferation is one of the hallmarks of breast cancer. We have previously identified the human Ecd protein (human ortholog of Drosophila Ecdysoneless, hereafter called Ecd) as a novel promoter of mammalian cell cycle progression, a function related to its ability to remove the repressive effects of Rb-family tumor suppressors on E2F transcription factors. Given the frequent dysregulation of cell cycle regulatory components in human cancer, we used immunohistochemistry of paraffin-embedded tissues to examine Ecd expression in normal breast tissue versus tissues representing increasing breast cancer progression. Initial studies of a smaller cohort without outcomes information showed that Ecd expression was barely detectable in normal breast tissue and in hyperplasia of breast, but high levels of Ecd were detected in benign breast hyperplasia, ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDCs) of the breast. In this cohort of 104 IDC patients, Ecd expression levels showed a positive correlation with higher grade (P = 0.04). Further analyses of Ecd expression using a larger, independent cohort (954) confirmed these results, with a strong positive correlation of elevated Ecd expression with higher histological grade (P = 0.013), mitotic index (P = 0.032), and Nottingham Prognostic Index score (P = 0.014). Ecd expression was positively associated with HER2/neu (P = 0.002) overexpression, a known marker of poor prognosis in breast cancer. Significantly, increased Ecd expression showed a strong positive association with shorter breast cancer specific survival (BCSS) (P = 0.008) and disease-free survival (DFS) (P = 0.003) in HER2/neu overexpressing patients. Taken together, our results reveal Ecd as a novel marker for breast cancer progression and show that levels of Ecd expression predict poorer survival in Her2/neu overexpressing breast cancer patients.

A Proposed Staging System for Amyotrophic Lateral Sclerosis

Brain : a Journal of Neurology. Mar, 2012  |  Pubmed ID: 22271664

Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons, with a median survival of 2-3 years. Although various phenotypic and research diagnostic classification systems exist and several prognostic models have been generated, there is no staging system. Staging criteria for amyotrophic lateral sclerosis would help to provide a universal and objective measure of disease progression with benefits for patient care, resource allocation, research classifications and clinical trial design. We therefore sought to define easily identified clinical milestones that could be shown to occur at specific points in the disease course, reflect disease progression and impact prognosis and treatment. A tertiary referral centre clinical database was analysed, consisting of 1471 patients with amyotrophic lateral sclerosis seen between 1993 and 2007. Milestones were defined as symptom onset (functional involvement by weakness, wasting, spasticity, dysarthria or dysphagia of one central nervous system region defined as bulbar, upper limb, lower limb or diaphragmatic), diagnosis, functional involvement of a second region, functional involvement of a third region, needing gastrostomy and non-invasive ventilation. Milestone timings were standardized as proportions of time elapsed through the disease course using information from patients who had died by dividing time to a milestone by disease duration. Milestones occurred at predictable proportions of the disease course. Diagnosis occurred at 35% through the disease course, involvement of a second region at 38%, a third region at 61%, need for gastrostomy at 77% and need for non-invasive ventilation at 80%. We therefore propose a simple staging system for amyotrophic lateral sclerosis. Stage 1: symptom onset (involvement of first region); Stage 2A: diagnosis; Stage 2B: involvement of second region; Stage 3: involvement of third region; Stage 4A: need for gastrostomy; and Stage 4B: need for non-invasive ventilation. Validation of this staging system will require further studies in other populations, in population registers and in other clinic databases. The standardized times to milestones may well vary between different studies and populations, although the stages themselves and their meanings are likely to remain unchanged.

All is Not Loss: Plant Biodiversity in the Anthropocene

PloS One. 2012  |  Pubmed ID: 22272360

Anthropogenic global changes in biodiversity are generally portrayed in terms of massive native species losses or invasions caused by recent human disturbance. Yet these biodiversity changes and others caused directly by human populations and their use of land tend to co-occur as long-term biodiversity change processes in the Anthropocene. Here we explore contemporary anthropogenic global patterns in vascular plant species richness at regional landscape scales by combining spatially explicit models and estimates for native species loss together with gains in exotics caused by species invasions and the introduction of agricultural domesticates and ornamental exotic plants. The patterns thus derived confirm that while native losses are likely significant across at least half of Earth's ice-free land, model predictions indicate that plant species richness has increased overall in most regional landscapes, mostly because species invasions tend to exceed native losses. While global observing systems and models that integrate anthropogenic species loss, introduction and invasion at regional landscape scales remain at an early stage of development, integrating predictions from existing models within a single assessment confirms their vast global extent and significance while revealing novel patterns and their potential drivers. Effective global stewardship of plant biodiversity in the Anthropocene will require integrated frameworks for observing, modeling and forecasting the different forms of anthropogenic biodiversity change processes at regional landscape scales, towards conserving biodiversity within the novel plant communities created and sustained by human systems.

Incorporation of Expert Variability into Breast Cancer Treatment Recommendation in Designing Clinical Protocol Guided Fuzzy Rule System Models

Journal of Biomedical Informatics. Jan, 2012  |  Pubmed ID: 22265814

It has been often demonstrated that clinicians exhibit both inter-expert and intra-expert variability when making difficult decisions. In contrast, the vast majority of computerized models that aim to provide automated support for such decisions do not explicitly recognize or replicate this variability. Furthermore, the perfect consistency of computerized models is often presented as a de facto benefit. In this paper, we describe a novel approach to incorporate variability within a fuzzy inference system using non-stationary fuzzy sets in order to replicate human variability. We apply our approach to a decision problem concerning the recommendation of post-operative breast cancer treatment; specifically, whether or not to administer chemotherapy based on assessment of five clinical variables: NPI (the Nottingham Prognostic Index), estrogen receptor status, vascular invasion, age and lymph node status. In doing so, we explore whether such explicit modeling of variability provides any performance advantage over a more conventional fuzzy approach, when tested on a set of 1310 unselected cases collected over a fourteen year period at the Nottingham University Hospitals NHS Trust, UK. The experimental results show that the standard fuzzy inference system (that does not model variability) achieves overall agreement to clinical practice around 84.6% (95% CI: 84.1-84.9%), while the non-stationary fuzzy model can significantly increase performance to around 88.1% (95% CI: 88.0-88.2%), p<0.001. We conclude that non-stationary fuzzy models provide a valuable new approach that may be applied to clinical decision support systems in any application domain.

Sustained Ocular Delivery of Ciprofloxacin Using Nanospheres and Conventional Contact Lens Materials

Investigative Ophthalmology & Visual Science. 2012  |  Pubmed ID: 22266514

Purpose. To formulate conventional contact lenses that incorporate nanosphere-encapsulated antibiotic and demonstrate that the lenses provide for sustained antibacterial activity. Methods. A copolymer composed of pullulan and polycaprolactone (PCL) was used to synthesize core-shell nanospheres that encapsulated ciprofloxacin. Bactericidal activity of the nanosphere-encapsulated ciprofloxacin (nanosphere/cipro) was tested by using liquid cultures of either Staphylococcus aureus or Pseudomonas aeruginosa. Nanosphere/cipro was then incorporated into HEMA-based contact lenses that were tested for growth inhibition of S. aureus or P. aeruginosa in liquid cultures inoculated daily with fresh bacteria. Lens designs included thin or thick lenses incorporating nanosphere/cipro and ciprofloxacin-HCl-soaked Acuvue lenses (Acuvue; Johnson & Johnson Vision Care, Inc., Jacksonville, FL). Results. Less than 2 μg/mL of nanosphere/cipro effectively inhibited the proliferation of cultures inoculated with 10(7) or 10(8) bacteria/mL of S. aureus and P. aeruginosa, respectively. HEMA-based contact lenses polymerized with nanosphere/cipro were transparent, effectively inhibited the proliferation of greater than 10(7)/mL of bacteria added daily over 3 days of culture, and killed up to 5 × 10(9) total microbes in a single inoculation. A thicker lens design provided additional inhibition of bacterial growth for up to 96 hours. Conclusions. Core-shell nanospheres loaded with an antibiotic can be incorporated into a conventional, transparent contact lens and provide for sustained and effective bactericidal activity and thereby provide a new drug delivery platform for widespread use in treating ocular disorders.

Comparative Investigation of I.v. Iohexol and Iopamidol: Effect on Renal Function in Low-risk Outpatients Undergoing CT

AJR. American Journal of Roentgenology. Feb, 2012  |  Pubmed ID: 22268183

The purpose of our study was to compare the effects of i.v. iohexol and iopamidol on renal function in outpatients undergoing CT.

A Review of Canine Parainfluenza Virus Infection in Dogs

Journal of the American Veterinary Medical Association. Feb, 2012  |  Pubmed ID: 22256842

Novel Polypropylene/inorganic Fullerene-like WS2 Nanocomposites Containing a β-nucleating Agent: Isothermal Crystallization and Melting Behavior

The Journal of Physical Chemistry. B. Feb, 2012  |  Pubmed ID: 22257171

The isothermal crystallization and subsequent melting behavior of isotactic polypropylene (iPP) nucleated with different nucleating agents (NAs) are investigated. Tungsten disulfide (IF-WS(2)) and N,N'-dicyclohexyl-2,6-naphthalene (NJ) and dual-additive mixtures are introduced into an iPP matrix to generate new materials that exhibit variable α- and β-polymorphism. As shown in previous work, small amounts of IF-WS(2) or NJ have a nucleating effect during the crystallization of iPP. However, the isothermal crystallization and melting behavior of iPP nucleated by dual α(IF-WS(2))/β(NJ) additive systems are dependent on both the NA composition balance and the crystallization temperature. In particular, our results demonstrate that it is possible to obtain any α-phase to β-phase content ratio by controlling the composition of NAs under appropriate isothermal crystallization conditions. The nucleating behavior of the additives can be illustrated by competitive nucleation, and the correlation between crystallization and melting temperatures and relative α- and β-crystals content in iPP in the nanocomposites is discussed.

Impairment in Material-specific Long-term Memory Following Unilateral Mediodorsal Thalamic Damage and Presumed Partial Disconnection of the Mammillo-thalamic Tract

Journal of Neuropsychology. Mar, 2012  |  Pubmed ID: 22257705

Neuropsychological findings suggest material-specific lateralization of the medial temporal lobe's role in long-term memory, with greater left-sided involvement in verbal memory, and greater right-sided involvement in visual memory. Whether material-specific lateralization of long-term memory also extends to the anteromedial thalamus remains uncertain. We report two patients with unilateral right (OG) and left (SM) mediodorsal thalamic pathology plus probable correspondingly lateralized damage of the mammillo-thalamic tract. The lesions were mapped using high-resolution structural magnetic resonance imaging and schematically reconstructed. Mean absolute volume estimates for the mammillary bodies, hippocampus, perirhinal cortex, and ventricles are also presented. Estimates of visual and verbal recall and item recognition memory were obtained using the Doors and People, the Rey Complex Figure Test, and the Logical Memory subtests of the Wechsler Memory Scales. Each patient's performance was compared to a group of healthy volunteers matched for demographic characteristics, premorbid IQ, and current levels of functioning. A striking double dissociation was evident in material-specific long-term memory, with OG showing significant impairments in visual memory but not verbal memory, and SM showing the opposite profile of preserved visual memory and significantly impaired verbal memory. These impairments affected both recall and item recognition. The reported double dissociation provides the strongest evidence yet that material-specific lateralization of long-term memory also extends to the anteromedial thalamus. The findings are also discussed in relation to proposals that distinct anatomical regions within the medial temporal lobe, anteromedial thalamus, and associated tracts make qualitatively different contributions to recall and item recognition.

Zinc-finger Nuclease-mediated Gene Correction Using Single AAV Vector Transduction and Enhancement by Food and Drug Administration-approved Drugs

Gene Therapy. Jan, 2012  |  Pubmed ID: 22257934

An emerging strategy for the treatment of monogenic diseases uses genetic engineering to precisely correct the mutation(s) at the genome level. Recent advancements in this technology have demonstrated therapeutic levels of gene correction using a zinc-finger nuclease (ZFN)-induced DNA double-strand break in conjunction with an exogenous DNA donor substrate. This strategy requires efficient nucleic acid delivery and among viral vectors, recombinant adeno-associated virus (rAAV) has demonstrated clinical success without pathology. However, a major limitation of rAAV is the small DNA packaging capacity and to date, the use of rAAV for ZFN gene delivery has yet to be reported. Theoretically, an ideal situation is to deliver both ZFNs and the repair substrate in a single vector to avoid inefficient gene targeting and unwanted mutagenesis, both complications of a rAAV co-transduction strategy. Therefore, a rAAV format was generated in which a single polypeptide encodes the ZFN monomers connected by a ribosome skipping 2A peptide and furin cleavage sequence. On the basis of this arrangement, a DNA repair substrate of 750 nucleotides was also included in this vector. Efficient polypeptide processing to discrete ZFNs is demonstrated, as well as the ability of this single vector format to stimulate efficient gene targeting in a human cell line and mouse model derived fibroblasts. Additionally, we increased rAAV-mediated gene correction up to sixfold using a combination of Food and Drug Administration-approved drugs, which act at the level of AAV vector transduction. Collectively, these experiments demonstrate the ability to deliver ZFNs and a repair substrate by a single AAV vector and offer insights for the optimization of rAAV-mediated gene correction using drug therapy.Gene Therapy advance online publication, 19 January 2012; doi:10.1038/gt.2011.211.

Which Anticholinergic Drug for Overactive Bladder Symptoms in Adults

Cochrane Database of Systematic Reviews (Online). 2012  |  Pubmed ID: 22258963

Around 16% to 45% of adults have overactive bladder symptoms (urgency with frequency and/or urge incontinence - 'overactive bladder syndrome'). Anticholinergic drugs are common treatments.

RHBDF2 Mutations Are Associated with Tylosis, a Familial Esophageal Cancer Syndrome

American Journal of Human Genetics. Feb, 2012  |  Pubmed ID: 22265016

Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.

A Pilot Study of Motivational Interviewing Targeting Weight-related Behaviors in Overweight or Obese African American Adolescents

The Journal of Adolescent Health : Official Publication of the Society for Adolescent Medicine. Feb, 2012  |  Pubmed ID: 22265118

To pilot motivational interviewing (MI) targeting weight-related behaviors in African American adolescents with body mass index ≥85th percentile.

Identity Development As a Buffer of Adolescent Risk Behaviors in the Context of Peer Group Pressure and Control

Journal of Adolescence. Jan, 2012  |  Pubmed ID: 22265669

We examined identity development as a moderator of the relation between peer group pressure and control and adolescents' engagement in risk behaviors. Participants (n=1070; M(age)=15.45 years) completed a self-report measure of identity exploration, the degree to which they have explored a variety of self-relevant values, beliefs and goals, and identity commitment, the degree to which they have secured a personal identity. Participants further reported on their frequency of risk behaviors (substance use and general deviancy) and experienced peer group pressure and control. Results confirmed that identity commitment was a buffer of substance use and identity exploration was a buffer of general deviancy in more pressuring peer groups. In more controlling peer groups, teens with greater identity commitment engaged in less risk behavior than teens with low-identity commitment. Thus, identity development may be a suitable target to deter negative effects of peer pressure in high-risk adolescents.

Understanding the Commission on Collegiate Nursing Education Accreditation Process and the Role of the Continuous Improvement Progress Report

Journal of Professional Nursing : Official Journal of the American Association of Colleges of Nursing. Jan-Feb, 2012  |  Pubmed ID: 22261601

Continuous quality improvement is an essential element of the accreditation process. This article describes the content and process for writing the Continuous Improvement Progress Report (CIPR) required by the Commission on Collegiate Nursing Education (CCNE) at the midpoint of the accreditation cycle. The rationale for writing the report and the purpose for the contents of the report are reviewed. The content of the CIPR addresses all standards and key elements of the CCNE Standards for Accreditation of Baccalaureate and Graduate Degree Nursing Programs, amended April 2009. Many program administrators and faculty lack an understanding of the significance of the report, how to write the report, or what should be included. This article is designed to help guide the writers of the report through the process.

Skull Fracture Secondary to Application of a Mayfield Skull Clamp in an Adult Patient: Case Report and Review of the Literature

Clinical Neurology and Neurosurgery. Jan, 2012  |  Pubmed ID: 22261664

Molecular Basis of Triple Negative Breast Cancer and Implications for Therapy

International Journal of Breast Cancer. 2012  |  Pubmed ID: 22295242

Triple negative breast cancer is an aggressive form of breast cancer with limited treatment options and is without proven targeted therapy. Understanding the molecular basis of triple negative breast cancer is crucial for effective new drug development. Recent genomewide gene expression and DNA sequencing studies indicate that this cancer type is composed of a molecularly heterogeneous group of diseases that carry multiple somatic mutations and genomic structural changes. These findings have implications for therapeutic target identification and the design of future clinical trials for this aggressive group of breast cancer.

Transient Depletion of B Cells in Young Mice Results in Activation of Regulatory T Cells That Inhibit Development of Autoimmune Disease in Adults

International Immunology. Apr, 2012  |  Pubmed ID: 22298883

B-cell depletion therapy can be effective for treating B-cell lymphomas as well as many human and murine autoimmune diseases. B-cell-deficient mice are normally resistant to spontaneous autoimmune thyroiditis (SAT), but they develop SAT if regulatory T cells are transiently depleted during the first 3-6 weeks after birth. This was also a critical time when B-cell depletion effectively inhibited development of SAT in adult mice. The current study was undertaken to test the hypothesis that transient depletion of B cells using anti-CD20 would be sufficient to suppress SAT if B cells were depleted early in life and that inhibition of SAT would be due to the activity of Treg that functioned most effectively when B cells were absent or low. The results presented here support this hypothesis and indicate that development of autoimmune disease in adults is effectively inhibited when anti-CD20 is administered 1-3 weeks after birth. After 3 weeks, transient B-cell depletion is no longer effective, and B-cell depletion must be maintained to effectively suppress autoimmune disease. B-cell depletion in 1- to 3-week-old mice depletes all B-cell subsets, whereas B-cell depletion initiated in adults spares many marginal zone B cells. Following early B-cell depletion, splenic Treg increase in number, and depletion of Treg reverses the inhibitory effect of anti-CD20 on disease development. Early transient depletion of B cells could be useful for preventing autoimmune disease in individuals at high risk for developing autoimmune diseases as adults.

Thoracic Ultrasound Demonstrates Variable Location of the Intercostal Artery

Respiration; International Review of Thoracic Diseases. 2012  |  Pubmed ID: 22301442

Background: Ultrasound (US) guidance is advocated to reduce complications from thoracocentesis or intercostal catheter (ICC) insertion. Although imaging of the intercostal artery (ICA) with Doppler US has been reported, current thoracic guidelines do not advocate this, and bleeding from a lacerated ICA continues to be a rare but serious complication of thoracocentesis or ICC insertion. Objectives: It was the aim of this study to describe a method to visualise the ICA at routine US-guided thoracocentesis and map its course across the posterior chest wall. Method: The ICA was imaged in 22 patients undergoing US-guided thoracocentesis, at 4 positions across the back to the axilla. Its location, relative to the overlying rib, was calculated as the fraction of the intercostal space (ICS) below the inferior border of that rib. Results: An ICA was identified in 74 of 88 positions examined. The ICA migrated from a central 'vulnerable' location within the ICS near the spine (0.28, range 0.21-0.38; p < 0.001) towards the overlying rib (0.08, range 0.05-0.11; p < 0.001) in the axilla. Conclusions: The ICA can be visualised with US and is more exposed centrally within the ICS in more posterior positions; however, there is a marked variation between individuals, such that the ICA may lie exposed in the ICS even as far lateral as the axilla. Future studies need to identify which patients are at risk for a 'low-lying' ICA to further define the role of US imaging of the ICA during thoracocentesis or ICC insertion.

Relationship Between Memory Performance and β-Amyloid Deposition at Different Stages of Alzheimer's Disease

Neuro-degenerative Diseases. Feb, 2012  |  Pubmed ID: 22301812

Background: Postmortem studies have suggested that β-amyloid (Aβ) deposition was only weakly related to the degree of cognitive impairment in Alzheimer's disease (AD). The development of Aβ ligands for in vivo PET imaging has greatly facilitated the assessment of this question. Objective: The objective of the present study was to provide an overview of our current knowledge regarding the relationship between Aβ deposition and episodic memory deficits in nondemented elderly and in patients with mild cognitive impairment or AD. Methods: Information was obtained both from studies comparing memory performance in individuals with high Pittsburgh compound B (PiB) and those with low PiB and from studies performing correlation analyses between memory performance and PiB retention considered as a continuous variable. Results: Previous studies assessing the relationship between memory and global neocortical PiB reported conflicting findings, and overall suggest that this link is weak, probably indirect, and detectable only in early stages. Assessing the relationship with regional instead of global neocortical PiB, we found a specific relationship between episodic memory deficits and neocortical temporal PiB, independent from hippocampal atrophy, in the predementia stage of the disease. Conclusion: There is a relationship between regional Aβ deposition and episodic memory deficits in the presymptomatic stage of AD.

Accelerated Cortical Atrophy in Cognitively Normal Elderly with High β-amyloid Deposition

Neurology. Feb, 2012  |  Pubmed ID: 22302548

Given the recent and growing interest in the concepts of prodromal and presymptomatic Alzheimer disease, it is crucial to determine whether the presence of β-amyloid (Aβ) in the brain of asymptomatic elderly individuals is a pathologic condition associated with accelerated neuronal and synaptic loss. The aim of the present study was to assess whether Aβ influences the rate of atrophy in cognitively normal elderly individuals.

Detection and Transmission of Dientamoeba Fragilis from Environmental and Household Samples

The American Journal of Tropical Medicine and Hygiene. Feb, 2012  |  Pubmed ID: 22302854

Dientamoeba fragilis is a commonly occurring pathogenic protozoan often detected at higher rates in stool samples than Giardia intestinalis. However, little is known about its life cycle and mode of transmission. A total of 210 environmental and household samples were examined for the presence of D. fragilis by culture and polymerase chain reaction. Of 100 environmental samples, D. fragilis was detected only in untreated sewage. In the household samples D. fragilis was detected in 30% of household contacts tested and was not detected in any domestic pets. This study provides evidence that environmental transmission of D. fragilis is unlikely and that pets played no role in transmission of the disease in this study. Direct transmission from infected persons is the most likely mode of transmission for D. fragilis. The study also highlights the need for household contacts to be screened, given the propensity of close contacts to become infected with the organism.

Class I Histone Deacetylase Inhibitor Entinostat Suppresses Regulatory T Cells and Enhances Immunotherapies in Renal and Prostate Cancer Models

PloS One. 2012  |  Pubmed ID: 22303460

Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been reported to have antitumor activity in different malignancies and immunomodulatory effects. Herein, we report the Tregs-targeting and immune-promoting effect of a class I specific HDAC inhibitor, entinostat, in combination with either IL-2 in a murine renal cell carcinoma (RENCA) model or a survivin-based vaccine therapy (SurVaxM) in a castration resistant prostate cancer (CR Myc-CaP) model.

Boronate-mediated Biologic Delivery

Journal of the American Chemical Society. Feb, 2012  |  Pubmed ID: 22303837

Inefficient cellular delivery limits the landscape of macromolecular drugs. Boronic acids readily form boronate esters with the 1,2- and 1,3-diols of saccharides, such as those that coat the surface of mammalian cells. Here pendant boronic acids are shown to enhance the cytosolic delivery of a protein toxin. Thus, boronates are a noncationic carrier that can deliver a polar macromolecule into mammalian cells.

Novel Systemic Drugs Under Investigation for the Treatment of Psoriasis

Journal of the American Academy of Dermatology. Feb, 2012  |  Pubmed ID: 22305044

In the last few years, there has been progress in identifying some of the risk genes for psoriasis. This has resulted in a major impetus toward drug development as many of the same pathways and processes identified in psoriasis have been shown to have major roles in other chronic inflammatory diseases, suggesting that psoriasis can be used as a treatment model for many other diseases. This has resulted in a shift in research toward a select number of biological processes and has been accompanied by a surge in drug development with over 20 systemic agents currently in clinical testing for psoriasis, many of which target the pathways identified through genetic and basic research. Although it is too early to tell for many of these agents how effective and safe they will be, and where they will fit into treatment algorithms, it is evident that our range of options in treating this often perplexing disease will greatly increase in the future.

The Impact of Lung Cancer on Patients and Carers

Chronic Respiratory Disease. Feb, 2012  |  Pubmed ID: 22308553

This article aims to provide a brief review of the literature with regard to the impact of lung cancer on patients and their informal carers. Compared to other types of cancer, the distress associated with lung cancer has been found to be the most intense. Rather than focusing on symptoms in isolation recent emphasis regarding the symptom experience has been on symptoms clusters, as understanding these clusters may improve the management of ongoing and unrelieved symptoms. However, the disparities in methodology are significant barriers to producing comparable results, although recent efforts have been made to address these. Whilst research into symptoms has enormous potential for the management of symptom clusters, it needs to move away from the essentially reductionist stance which currently dominates and broaden its scope to one that acknowledges the complexity of the experience of symptom clusters from the perspective of the patient and their informal carer. Poor management of symptoms complicates patient care and potentially contributes to the heavy burden which often falls on family caregivers, especially as the disease progresses. The majority of studies focus on the experiences of primary care providers, most often the partner/spouse. Such studies have shown that spouses of patients with lung cancer exhibit significant distress and lower levels of quality of life than the general population. Research also indicates that significant others go through a transition process due to changes brought about by the diagnosis of lung cancer and struggle to endure and overcome difficulties and distress. Significant others were seen to suffer during this process of transition and experienced altered relationships. Clinicians working with patients suffering from lung cancer and their carers should intervene to enhance their quality of life from diagnosis, during the disease trajectory and during bereavement. Interventions need to be developed to support both patients and carers.

Construction of Synthetic Regulatory Networks in Yeast

FEBS Letters. Feb, 2012  |  Pubmed ID: 22309848

Yeast species such as Saccharomyces cerevisiae have been exploited by humans for millennia and so it is therefore unsurprising that they are attractive cells to re-engineer for industrial use. Despite many beneficial traits yeast has for synthetic biology, it currently lags behind Escherichia coli in the number of synthetic networks that have been described. While the eukaryotic nature of yeast means that its regulation is not as simple to predict as it is for E. coli, once initial considerations have been made yeast is pleasingly tractable. In this review we provide a loose guide for constructing and implementing synthetic regulatory networks in S. cerevisiae using examples from previous research to highlight available resources, specific considerations and potential future advances.

The Spiritual Needs and Resources of Hospitalized Primary Care Patients

Journal of Religion and Health. Feb, 2012  |  Pubmed ID: 22311475

Previous studies have recognized the importance of hospitalized primary care patients' spiritual issues and needs. The sources patients consult to address these spiritual issues, including the role of their attending physician, have been largely unstudied. We sought to study patients' internal and external resources for addressing spiritual questions, while also exploring the physician's role in providing spiritual care. Our multicenter observational study evaluated 326 inpatients admitted to primary care physicians in four midwestern hospitals. We assessed how frequently these patients identified spiritual concerns during their hospitalization, the manner in which spiritual questions were addressed, patients' desires for spiritual interaction, and patient outcome measures associated with spiritual care. Nearly 30% of respondents (referred to as "R/S respondents") reported religious struggle or spiritual issues associated specifically with their hospitalization. Eight-three percent utilized internal religious coping for dealing with spiritual issues. Chaplains, clergy, or church members visited 54% of R/S respondents; 94% found those visits helpful. Family provided spiritual support to 45% of R/S respondents. Eight percent of R/S respondents desired, but only one patient actually received, spiritual interaction with their physician, even though 64% of these patients' physicians agreed that doctors should address spiritual issues with their patients. We conclude that inpatients quite commonly utilize internal resources and quite rarely utilize physicians for addressing their spiritual issues. Spiritual caregiving is well received and is primarily accomplished by professionals, dedicated laypersons, or family members. A significantly higher percentage of R/S patients desire spiritual interaction with their physician than those who actually receive it.

The Role of Surgery, Radiosurgery and Whole Brain Radiation Therapy in the Management of Patients with Metastatic Brain Tumors

International Journal of Surgical Oncology. 2012  |  Pubmed ID: 22312545

Brain tumors constitute the most common intracranial tumor. Management of brain metastases has become increasingly complex as patients with brain metastases are living longer and more treatment options develop. The goal of this paper is to review the role of stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), and surgery, in isolation and in combination, in the contemporary treatment of brain metastases. Surgery and SRS both offer management options that may help to optimize therapy in selected patients. WBRT is another option but can lead to late toxicity and suboptimal local control in longer term survivors. Improved prognostic indices will be critical for selecting the best therapies. Further prospective trials are necessary to continue to elucidate factors that will help triage patients to the proper brain-directed therapy for their cancer.

Developmentally Equivalent Tissue Sampling Based on Growth Kinematic Profiling of Arabidopsis Inflorescence Stems

The New Phytologist. Apr, 2012  |  Pubmed ID: 22313381

• Directional growth in Arabidopsis thaliana during bolting of the inflorescence stem makes this an attractive system for study of the underlying processes of tissue elongation and cell wall extension. Analysis of local molecular events accompanying Arabidopsis inflorescence stem elongation is hampered by difficulties in isolating developmentally matched tissue samples from different plants. • Here, we present a novel sampling approach in which specific developmental stages along the developing stem are defined nonintrusively in terms of their relative elemental growth rate by use of time-lapse imagery and subsequent derivation of growth kinematic profiles for individual plants. • Growth kinematic profiling reveals that key developmental transitions such as the point of maximum elongation rate and the point of cessation of elongation occur over broad and overlapping ranges across individuals within a population of the Columbia (Col-0) ecotype. The position of these transitions is only weakly correlated with overall plant height, which undermines the common assumption that physically similar plants have closely matched growth profiles. • This kinematic profiling approach provides high-resolution growth phenotyping of the developing stem and thereby enables the harvest, pooling and analysis of developmentally matched tissue samples from multiple Arabidopsis plants.

Lifestyle and Late Life Cognitive Health: Sufficient Evidence to Act Now?

International Psychogeriatrics / IPA. May, 2012  |  Pubmed ID: 22313892

Lower Than Expected Maraviroc Concentrations in Cerebrospinal Fluid Exceed the Wild-type CC Chemokine Receptor 5-tropic HIV-1 50% Inhibitory Concentration

AIDS (London, England). Feb, 2012  |  Pubmed ID: 22313954

To measure maraviroc total cerebrospinal fluid (CSF) concentrations and compare them with total and unbound plasma concentrations. Total maraviroc was measured by reverse-phase high-performance liquid chromatography with tandem mass spectrometry, whereas ultrafiltration was used for unbound maraviroc. Maraviroc was detected in all nine CSF/plasma pairs with a median CSF total concentration of 2.4 ng/ml. CSF concentrations exceeded the 50% inhibitory concentration of wild-type CC chemokine receptor 5-tropic HIV-1 in all specimens. CSF concentrations are lower than expected based on plasma concentrations and physicochemical characteristics. Unbound maraviroc plasma concentrations may be informative in estimating concentrations in CSF.

Genetic Variants Within Ultraconserved Elements and Susceptibility to Right- and Left-sided Colorectal Adenocarcinoma

Carcinogenesis. Apr, 2012  |  Pubmed ID: 22318908

We investigated whether single nucleotide polymorphisms within ultraconserved elements (UCEs) are associated with susceptibility to overall colorectal cancer (CRC) and susceptibility to tumor site-specific CRC. The study included 787 CRC patients and 551 healthy controls. The study comprised of a training set (520 cases and 341 controls) and a replication set (267 cases and 210 controls). We observed associations in rs7849 and rs1399685 with CRC risk. For example, a dose-dependent trend (per-allele odds ratio (OR), 0.78; 95% confidence interval (CI), 0.63-1.00; P for trend = 0.05) associated with the variant allele of rs7849 in the training set. The significant trend toward a decrease in CRC risk was confirmed in the replication set (per-allele OR, 0.72; 95% CI, 0.52-0.99; P for trend = 0.044). When stratified by tumor location, for left-sided CRC (LCRC) risk, significant association was observed for the variant-containing genotypes of rs1399685 (OR, 1.77; 95% CI, 1.02-3.06) and the risk was replicated in the replication population (OR, 2.04; 95% CI, 1.02-4.07). The variant genotypes of rs9784100 and rs7849 conferred decreased risk but the associations were not replicated. Three right-sided CRC (RCRC) susceptibility loci were identified in rs6124509, rs4243289 and rs12218935 but none of the loci was replicated. Joint effects and potential higher order gene-gene interactions among significant variants further categorized patients into different risk groups. Our results strongly suggest that several genetic variants in the UCEs may contribute to CRC susceptibility, individually and jointly, and that different genetic etiology may be involved in RCRC and LCRC.

A Genome Wide Association Study for Coronary Artery Disease Identifies a Novel Susceptibility Locus in the Major Histocompatibility Complex

Circulation. Cardiovascular Genetics. Feb, 2012  |  Pubmed ID: 22319020

BACKGROUND: -Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with CAD and/or MI risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered. METHODS AND RESULTS: -We performed a discovery meta-analysis of 5 GWASs involving 13,949 subjects (7123 cases, 6826 controls) imputed at approximately 5 million SNPs using pilot 1000 Genomes based haplotypes. Promising loci were followed up in an additional 5 studies with 11,032 subjects (5211 cases, 5821 controls). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome wide significance in the combined analysis (rs3869109; p(discovery)=3.3x10(-7), p(replication)=5.3x10(-4) p(combined)=1.12x10(-9)). A sub-analysis combining discovery GWASs showed an attenuation of significance when stringent corrections for European population structure were employed (p=4.1x10(-10) versus 3.2x10(-7)) suggesting the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity and self cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association. CONCLUSIONS: -We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).

Concordance of HER2 Status Assessed on Needle Core Biopsy and Surgical Specimens of Invasive Carcinoma of the Breast

Histopathology. Feb, 2012  |  Pubmed ID: 22320892

Lee A H S, Key H P, Bell J A, Hodi Z & Ellis I O (2012) Histopathology Concordance of HER2 status assessed on needle core biopsy and surgical specimens of invasive carcinoma of the breast Aims:  Human epidermal growth factor receptor 2 (HER2) status of invasive breast cancers is vital for selection of patients for trastuzumab treatment. This study aimed to assess the level of agreement of HER2 status in core biopsy and excision specimens using immunohistochemistry, with in-situ hybridisation for equivocal cases. Methods and results:  300 consecutive invasive carcinomas with core biopsy and surgical specimens had HER2 assessed on both specimens. Immunohistochemistry was performed first. Fluorescence in-situ hybridization (FISH) was automatically performed if the immunohistochemistry was scored as equivocal (2+). There was agreement between the HER2 status of the two specimens in 294 tumours (98%). In two carcinomas the core was negative and the excision specimen showed focal strong staining with amplification. In four carcinomas the core biopsy was negative and the excision showed 2+ staining with amplification in at least one block (although in three there was no amplification in a second block). Conclusion:  There is excellent agreement between HER2 assessed in core biopsy and surgical specimens. Discrepancies arise most frequently due to focal amplification or levels of gene amplification around the cut-off for defining positivity.

Age-of-acquisition Affects Word Naming in Italian Only when Stress is Irregular

Acta Psychologica. Mar, 2012  |  Pubmed ID: 22321454

In Italian, effects of age of acquisition (AoA) have been found in object naming, semantic categorization of words and lexical decision, but not in word naming (reading aloud). The lack of an AoA effect in Italian word naming is replicated in Experiment 1 which involved reading aloud two-syllable words which all have regular spelling-sound correspondences and regular stress patterns. Studies of English word naming have reported stronger effects of AoA for irregular or exception words than for words with regular, consistent spelling-sound correspondences. There are no grapheme-phoneme irregularities in Italian, but words containing three or more syllables can carry either regular stress on the penultimate syllable or irregular stress on the antepenultimate syllable. Experiment 2 found effects of AoA on reading three-syllable words for words with irregular stress. The results are interpreted in terms of the 'mapping hypothesis' of AoA, with effects arising as a result of a difficulty to generalize earlier-acquired patterns to irregular late-acquired words.

The Early Days of Diverticula of the Colon

Journal of Perioperative Practice. Jan, 2012  |  Pubmed ID: 22324120

As a 17 year old first-year medical student at Oxford University in 1943, busily dissecting a cadaver in the Anatomy Department, I could not help noticing a series of peculiar pea-sized swellings along the course of the sigmoid colon. I showed these to our Professor of Anatomy, the much respected Sir Wilfred Le Gros Clarke FRS, who said 'Those are diverticula, my boy. As an Oxford student you should know, (which, in fact, I did not!), that the word 'diverticulum' is Latin for a 'wayside house of ill fame or ill repute', and well do they deserve that descriptive term'. I carefully excised the affected piece of colon, put it in a bottle of formalin and, at the end of term, put it onto the mantelpiece of my bedroom at home. A few years later, my mother, in a clearing-up mode, threw the dusty bottle away. What a pity that I am unable to produce a photograph of my specimen to illustrate this article!

Psychometric Properties of the Revised Parental Monitoring of Diabetes Care Questionnaire in Adolescents with Type 1 Diabetes

The Journal of Adolescent Health : Official Publication of the Society for Adolescent Medicine. Mar, 2012  |  Pubmed ID: 22325135

We evaluated the psychometric properties of a revised version of the Parental Monitoring of Diabetes Care questionnaire (PMDC-R) designed to evaluate parental supervision and monitoring of adolescent diabetes care behaviors. The revised measure was intended to capture a broad range of ways used by parents to gather information about youth adherence to diabetes care.

How Affordances Associated with a Distractor Object Affect Compatibility Effects: A Study with the Computational Model TRoPICALS

Psychological Research. Feb, 2012  |  Pubmed ID: 22327121

Seeing an object activates both visual and action codes in the brain. Crucial evidence supporting this view is the observation of object to response compatibility effects: perception of an object can facilitate or interfere with the execution of an action (e.g., grasping) even when the viewer has no intention of interacting with the object. TRoPICALS is a computational model that proposes some general principles about the brain mechanisms underlying compatibility effects, in particular the idea that top-down bias from prefrontal cortex, and whether it conflicts or not with the actions afforded by an object, plays a key role in such phenomena. Experiments on compatibility effects using a target and a distractor object show the usual positive compatibility effect of the target, but also an interesting negative compatibility effect of the distractor: responding with a grip compatible with the distractor size produces slower reaction times than the incompatible case. Here, we present an enhanced version of TRoPICALS that reproduces and explains these new results. This explanation is based on the idea that the prefrontal cortex plays a double role in its top-down guidance of action selection producing: (a) a positive bias in favour of the action requested by the experimental task; (b) a negative bias directed to inhibiting the action evoked by the distractor. The model also provides testable predictions on the possible consequences of damage to volitional circuits such as in Parkinsonian patients.

Indwelling Supradural Catheters for Induction of Facial Allodynia: Surgical Procedures, Application of Inflammatory Stimuli, and Behavioral Testing

Methods in Molecular Biology (Clifton, N.J.). 2012  |  Pubmed ID: 22351084

Migraine headaches are debilitatingly painful and poorly managed. Facial allodynia is often associated with migraine, and clinical evidence indicates that it is a critical point in migraine progression. That is, if the migraine can be treated prior to the onset of facial allodynia, the migraine can be halted using triptans, whereas if treatment is administered after facial allodynia has begun, the treatment is ineffective. The meninges and the immune cells therein have been implicated in migraine facial pain. Indeed, application of inflammatory mediators over the meninges has been used to study changes in pain responsive neurons in trigeminal complex, and changes in their receptive fields. Much of this research has been carried out in anesthetized rats, which limits the clinical application. Our indwelling supradural catheter model, in which inflammatory mediators can be administered to the meninges in awake and freely moving rats, allows for the assessment of behavioral changes shortly after injection. Following administration of inflammatory soup (histamine, serotonin, bradykinin, and prostaglandin E2) or the immunogenic HIV-1 coat protein gp120 results in reliable periorbital mechanical allodynia. This model provides an additional means to study the neurocircuitry and neuropharmacology of facial allodynia. Here, we describe detailed methods for the placement of the catheter, injection procedures, and assessment of facial allodynia.

Unilateral T13 and L1 Dorsal Root Avulsion: Methods for a Novel Model of Central Neuropathic Pain

Methods in Molecular Biology (Clifton, N.J.). 2012  |  Pubmed ID: 22351090

Central neuropathic pain is associated with many disease states including multiple sclerosis, stroke, and spinal cord injury, and is poorly managed. One type of central neuropathic pain that is particularly debilitating and challenging to treat is pain that occurs below the level of injury (below-level pain). The study of central neuropathic pain is commonly performed using animal models of stroke and spinal cord injury. Most of the spinal cord injury models currently being used were originally developed to model the gross physiological impact of clinical spinal cord injury. In contrast, the T13/L1 dorsal root avulsion model of spinal cord injury described here was developed specifically for the study of central pain, and as such, was developed to minimize confounding complications, such as paralysis, urinary tract infections, and autotomy. As such, this model induces robust and reliable hindpaw mechanical allodynia. Two versions of the model are described. The first is optimal for testing systemically administered pharmacological manipulations. The second was developed to accommodate intrathecal application of pharmacological manipulations. This model provides an additional means by which to investigate central pain states associated with spinal cord injury, including below-level pain. Finally, a brief discussion of at-level pain measurement is described as it has been suggested in the literature that the mechanisms underlying below- and at-level pain are different.

Bell Palsy Following a Minor Dermatologic Procedure

Archives of Dermatology. Feb, 2012  |  Pubmed ID: 22351840

2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: Executive Summary: a Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions

Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. Feb, 2012  |  Pubmed ID: 22328235

Role of Pemetrexed in Advanced Non-small-cell Lung Cancer: Meta-analysis of Randomized Controlled Trials, with Histology Subgroup Analysis

Current Oncology (Toronto, Ont.). Feb, 2012  |  Pubmed ID: 22328848

Platinum-based regimens represent the standard first-line treatment for non-small-cell lung cancer (nsclc). However, newer data have established a role for pemetrexed in the treatment of this disease. Such data suggest that histology represents a determining factor in the selection of treatment.

Role of Obesity, Metabolic Variables, and Diabetes in HIV-associated Neurocognitive Disorder

Neurology. Feb, 2012  |  Pubmed ID: 22330412

To evaluate relationships between HIV-associated neurocognitive disorder and metabolic variables in a subgroup of HIV+ participants examined in a prospective, observational, multicenter cohort study.

Antiangiogenic Therapy-evolving View Based on Clinical Trial Results

Nature Reviews. Clinical Oncology. Feb, 2012  |  Pubmed ID: 22330688

Antiangiogenic therapies that target VEGF or its receptors have become a mainstay of cancer therapy in multiple malignancies. However, the clinical efficacy of these agents is less than originally anticipated and, in most settings, requires the addition of cytotoxic chemotherapy suggesting that, as for other targeted therapies, VEGF inhibitors will require selection of patient subpopulations to achieve maximal clinical benefit. Without the identification and use of predictive biomarkers for VEGF-targeted agents, and other agents that target the vasculature, further improvements in current clinical outcomes are unlikely. Exciting new data presented in 2011 at the ESMO conference showed that retrospective evaluation of plasma concentrations of VEGF-A predicted progression-free survival and/or overall survival benefit from bevacizumab in phase III trials in certain tumour types; prospective evaluation of the assay is required. This endeavour should be followed by further biomarker research, requiring inter-laboratory collaboration and high-quality, adequately powered clinical trials.

New Advances in the In-vitro Culture of Dientamoeba Fragilis

Parasitology. Feb, 2012  |  Pubmed ID: 22336222

SUMMARYDientamoeba fragilis is an intestinal protozoan in humans that is commonly associated with diarrhoea and other gastrointestinal complaints. Studies conducted to investigate the biology of this parasite are limited by methods for in vitro cultivation. The objective of this study was to improve a biphasic culture medium, based on the Loeffler's slope, by further supplementation in order to increase the yield of trophozoites in culture. The current in vitro culture of D. fragilis is a xenic culture with a mix of bacteria. Three different liquid overlays were evaluated including Earle's balanced salt solution (EBSS), PBS and Dulbecco's modified PBS (DPBS), for their ability to support the in vitro growth of D. fragilis trophozoites. Out of these 3 overlays EBSS gave the highest increase in the trophozoite numbers. The effect of supplementation was analysed by supplementing EBSS with ascorbic acid, ferric ammonium citrate, L-cysteine, cholesterol and alpha-lipoic acid and quantification of in vitro growth by cell counts. A new liquid overlay is here described based upon EBSS supplemented with cholesterol and ferric ammonium citrate that, in conjunction with the Loeffler's slope, supports the growth of D. fragilis trophozoites in vitro. This modified overlay supported a 2-fold increase in the numbers of trophozoite in culture from all 4 D. fragilis isolates tested, when compared to a PBS overlay. These advances enable the harvest of a larger number of trophozoites needed for further studies on this parasite.

Melanoma In Situ Treated Successfully Using Imiquimod After Nonclearance with Surgery: Review of the Literature

Dermatologic Surgery : Official Publication for American Society for Dermatologic Surgery [et Al.]. Feb, 2012  |  Pubmed ID: 22338583

BACKGROUND: The standard of care for melanoma in situ (MIS) is surgical removal by surgical excision with a 5-mm margin or Mohs micrographic surgery, but as more and more MIS is diagnosed in the head and neck region, surgeries may not be an option for patients when the lesions are large or less well defined. In addition, when negative margins cannot be achieved without grossly disfiguring the patient or when patients have medical comorbidities that preclude a surgical option, other treatment modalities may be considered. Recently, topical treatment with an immunomodulator, imiquimod, has been proposed as an alternative treatment for MIS. OBJECTIVE: We report a case of MIS successfully treated with topical imiquimod cream. In addition, because there has not been any comprehensive review of the use of topical imiquimod on melanoma and MIS, we conducted an extensive literature search and reviewed the topic in detail. MATERIALS AND METHODS: Using the keywords "imiquimod," "melanoma," "melanoma-in-situ," and "lentigo maligna," we searched the literature using PubMed in an attempt to find all relevant articles on the use of imiquimod on MIS or melanoma. RESULTS: There were 46 reports involving 264 patients on the use of imiquimod on MIS or lentigo maligna. Twenty-three reports were published on the use of imiquimod on metastatic melanoma involving 55 patients, and two articles were on melanoma, with two patients in total. In addition, there were two articles on the use of imiquimod on dysplastic or atypical nevi with a total of 13 subjects. CONCLUSION: Imiquimod appears to be beneficial in the treatment of MIS and melanoma metastases when surgical options are not feasible. Imiquimod should not be used for removal of dysplastic or atypical nevi. The treatment regimens varied from study to study, and there are no randomized controlled trials in the literature. More studies are needed to develop a reliable and reproducible treatment regimen, to fully elucidate the role of imiquimod in the treatment of MIS and melanoma, and to determine the prognostic predictors for favorable responses to imiquimod.

How Much Does Intellectual Disability Really Cost? First Estimates for Australia

Journal of Intellectual & Developmental Disability. Mar, 2012  |  Pubmed ID: 22339044

Given the paucity of relevant data, this study estimates the cost of intellectual disability (ID) to families and the government in Australia.

Aptamer Sensor for Cocaine Using Minor Groove Binder Based Energy Transfer

Analytica Chimica Acta. Mar, 2012  |  Pubmed ID: 22340534

We report on an optical aptamer sensor for cocaine detection. The cocaine sensitive fluorescein isothiocyanate (FITC)-labeled aptamer underwent a conformational change from a partial single-stranded DNA with a short hairpin to a double-stranded T-junction in the presence of the target. The DNA minor groove binder Hoechst 33342 selectively bound to the double-stranded T-junction, bringing the dye within the Förster radius of FITC, and therefore initiating minor groove binder based energy transfer (MBET), and reporting on the presence of cocaine. The sensor showed a detection limit of 0.2 μM. The sensor was also implemented on a carboxy-functionalized polydimethylsiloxane (PDMS) surface by covalently immobilizing DNA aptamers. The ability of surface-bound cocaine detection is crucial for the development of microfluidic sensors.

Gamma Knife Stereotactic Radiosurgery As Salvage Therapy After Failure of Whole-Brain Radiotherapy in Patients with Small-Cell Lung Cancer

International Journal of Radiation Oncology, Biology, Physics. Feb, 2012  |  Pubmed ID: 22342297

PURPOSE: Radiosurgery has been successfully used in selected cases to avoid repeat whole-brain irradiation (WBI) in patients with multiple brain metastases of most solid tumor histological findings. Few data are available for the use of radiosurgery for small-cell lung cancer (SCLC). METHODS AND MATERIALS: Between November 1999 and June 2009, 51 patients with SCLC and previous WBI and new brain metastases were treated with GammaKnife stereotactic radiosurgery (GKSRS). A median dose of 18 Gy (range, 10-24 Gy) was prescribed to the margin of each metastasis. Patients were followed with serial imaging. Patient electronic records were reviewed to determine disease-related factors and clinical outcomes after GKSRS. Local and distant brain failure rates, overall survival, and likelihood of neurologic death were determined based on imaging results. The Kaplan-Meier method was used to determine survival and local and distant brain control. Cox proportional hazard regression was performed to determine strength of association between disease-related factors and survival. RESULTS: Median survival time for the entire cohort was 5.9 months. Local control rates at 1 and 2 years were 57% and 34%, respectively. Distant brain failure rates at 1 and 2 years were 58% and 75%, respectively. Fifty-three percent of patients ultimately died of neurologic death. On multivariate analysis, patients with stable (hazard ratio [HR] = 2.89) or progressive (HR = 6.98) extracranial disease (ECD) had worse overall survival than patients without evidence of ECD (p = 0.00002). Concurrent chemotherapy improved local control (HR = 89; p = 0.006). CONCLUSIONS: GKSRS represents a feasible salvage option in patients with SCLC and brain metastases for whom previous WBI has failed. The status of patients' ECD is a dominant factor predictive of overall survival. Local control may be inferior to that seen with other cancer histological results, although the use of concurrent chemotherapy may help to improve this.

An Empirical Model of Water Quality for Use in Rapid Management Strategy Evaluation in Southeast Queensland, Australia

Marine Pollution Bulletin. Apr, 2012  |  Pubmed ID: 22342574

Simulation models have been widely adopted in fisheries for management strategy evaluation (MSE). However, in catchment management of water quality, MSE is hampered by the complexity of both decision space and the hydrological process models. Empirical models based on monitoring data provide a feasible alternative to process models; they run much faster and, by conditioning on data, they can simulate realistic responses to management actions. Using 10years of water quality indicators from Queensland, Australia, we built an empirical model suitable for rapid MSE that reproduces the water quality variables' mean and covariance structure, adjusts the expected indicators through local management effects, and propagates effects downstream by capturing inter-site regression relationships. Empirical models enable managers to search the space of possible strategies using rapid assessment. They provide not only realistic responses in water quality indicators but also variability in those indicators, allowing managers to assess strategies in an uncertain world.

The One-Year Attributable Cost of Poststroke Aphasia

Stroke; a Journal of Cerebral Circulation. Feb, 2012  |  Pubmed ID: 22343643

BACKGROUND AND PURPOSE: Little is known about the contribution of aphasia to the cost of care for patients who experience stroke. METHODS: We retrospectively examined a cohort of South Carolina Medicare beneficiaries who experienced ischemic stroke in 2004 to determine the attributable cost of aphasia. Univariate analyses were used to compare demographic, comorbidity, and severity differences between individuals with poststroke aphasia and those without aphasia. Differences in payments by Medicare because of stroke were examined using a gamma-distributed generalized linear multivariate model. RESULTS: Three thousand, two hundred Medicare beneficiaries experienced ischemic stroke in South Carolina in 2004, and 398 beneficiaries had poststroke aphasia. Patients with aphasia experienced longer length of stays, greater morbidity, and greater mortality than did those without aphasia. In adjusted models that controlled for relevant covariates, the attributable 1-year cost of aphasia was estimated at $1703. CONCLUSIONS: Aphasia adds to the cost of stroke-related care, above the cost of stroke alone.

A Regulatory Network for Coordinated Flower Maturation

PLoS Genetics. Feb, 2012  |  Pubmed ID: 22346763

For self-pollinating plants to reproduce, male and female organ development must be coordinated as flowers mature. The Arabidopsis transcription factors AUXIN RESPONSE FACTOR 6 (ARF6) and ARF8 regulate this complex process by promoting petal expansion, stamen filament elongation, anther dehiscence, and gynoecium maturation, thereby ensuring that pollen released from the anthers is deposited on the stigma of a receptive gynoecium. ARF6 and ARF8 induce jasmonate production, which in turn triggers expression of MYB21 and MYB24, encoding R2R3 MYB transcription factors that promote petal and stamen growth. To understand the dynamics of this flower maturation regulatory network, we have characterized morphological, chemical, and global gene expression phenotypes of arf, myb, and jasmonate pathway mutant flowers. We found that MYB21 and MYB24 promoted not only petal and stamen development but also gynoecium growth. As well as regulating reproductive competence, both the ARF and MYB factors promoted nectary development or function and volatile sesquiterpene production, which may attract insect pollinators and/or repel pathogens. Mutants lacking jasmonate synthesis or response had decreased MYB21 expression and stamen and petal growth at the stage when flowers normally open, but had increased MYB21 expression in petals of older flowers, resulting in renewed and persistent petal expansion at later stages. Both auxin response and jasmonate synthesis promoted positive feedbacks that may ensure rapid petal and stamen growth as flowers open. MYB21 also fed back negatively on expression of jasmonate biosynthesis pathway genes to decrease flower jasmonate level, which correlated with termination of growth after flowers have opened. These dynamic feedbacks may promote timely, coordinated, and transient growth of flower organs.

Bis(η-naphthalene)-molybdenum(0)

Acta Crystallographica. Section E, Structure Reports Online. Feb, 2012  |  Pubmed ID: 22346882

The title compound, [Mo(C(10)H(8))(2)], was prepared from the naphthalene radical anion and MoCl(4)(thf)(2) (thf is tetra-hydro-furan). In the crystal, the mol-ecule is located on an inversion center. The Mo atom is equally disordered over two positions; the range of Mo-C distances is 2.2244 (19)-2.3400 (17) Å for both components of the disorder.