Readiness of US General Surgery Residents for Independent Practice.
This study evaluates the current state of the General Surgery (GS) residency training model by investigating resident operative performance and autonomy. The American Board of Surgery has designated 132 procedures as being "Core" to the practice of GS. GS residents are expected to be able to safely and independently perform those procedures by the time they graduate. There is growing concern that not all residents achieve that standard. Lack of operative autonomy may play a role. Attendings in 14 General Surgery programs were trained to use a) the 5-level System for Improving and Measuring Procedural Learning (SIMPL) Performance scale to assess resident readiness for independent practice and b) the 4-level Zwisch scale to assess the level of guidance (ie, autonomy) they provided to residents during specific procedures. Ratings were collected immediately after cases that involved a categorical GS resident. Data were analyzed using descriptive statistics and supplemented with Bayesian ordinal model-based estimation. A total of 444 attending surgeons rated 536 categorical residents after 10,130 procedures. Performance: from the first to the last year of training, the proportion of Performance ratings for Core procedures (n = 6931) at "Practice Ready" or above increased from 12.3% to 77.1%. The predicted probability that a typical trainee would be rated as Competent after performing an average Core procedure on an average complexity patient during the last week of residency training is 90.5% (95% CI: 85.7%-94%). This falls to 84.6% for more complex patients and to less than 80% for more difficult Core procedures. Autonomy: for all procedures, the proportion of Zwisch ratings indicating meaningful autonomy ("Passive Help" or "Supervision Only") increased from 15.1% to 65.7% from the first to the last year of training. For the Core procedures performed by residents in their final 6 months of training (cholecystectomy, inguinal/femoral hernia repair, appendectomy, ventral hernia repair, and partial colectomy), the proportion of Zwisch ratings (n = 357) indicating near-independence ("Supervision Only") was 33.3%. US General Surgery residents are not universally ready to independently perform Core procedures by the time they complete residency training. Progressive resident autonomy is also limited. It is unknown if the amount of autonomy residents do achieve is sufficient to ensure readiness for the entire spectrum of independent practice.


Comparison between the LCx Probe system and the COBAS AMPLICOR system for detection of Chlamydia trachomatis and Neisseria gonorrhoeae infections in patients attending a clinic for treatment of sexually transmitted diseases in Amsterdam, The Netherlands.
Two assays for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae were compared: the LCx Probe system (the LCx system; Abbott Diagnostic Laboratories, North Chicago, Ill.) and the COBAS AMPLICOR C. trachomatis/N. gonorrhoeae system (the COBAS AMPLICOR system; Roche Diagnostic Systems, Branchburg, N.J.). Endocervical swab specimens, male urethral swab specimens, and female and male urine specimens were collected from 503 female and 498 male visitors attending a sexually transmitted diseases clinic in Amsterdam, The Netherlands. Prevalences for C. trachomatis were 12.5% (63 of 503) and 10.0% (50 of 498) in females and males, respectively. The prevalences for N. gonorrhoeae were 1.2% (6 of 503) and 4.2% (21 of 498) in females and males, respectively. Both assays showed high values for sensitivity and specificity with regard to the detection of C. trachomatis in endocervical swab specimens, male urethral swab specimens, and female and male urine specimens. The sensitivities for the LCx system were 92.1, 90.0, 88.9, and 94.0% for each type of specimen, respectively; and the sensitivies for the COBAS AMPLICOR system were 96.8, 98.0, 82.5, and 92.0% for each type of specimen, respectively. Specificities ranged between 98.4 and 100%. The sensitivity of the LCx system for the detection of N. gonorrhoeae was 100% for female cervical swab and urine specimens and male urethral swab specimens, while for male urine specimens the sensitivity was 95.2%; the specificity was 100% for all types of specimens. For the detection of N. gonorrhoeae by the COBAS AMPLICOR assay, the sensitivity for female cervical swab and male urethral swab specimens was 100%, that for female urine specimens was 66.7%, and that for male urine specimens was 95.2%. However, the predictive values of a positive test for female cervical swab specimens and urine specimens were 31.6 and 36.4%, respectively. Sequence analysis of the amplimers obtained by an in-house 16S rRNA PCR of the solely COBAS AMPLICOR system-positive swab specimens revealed neither N. gonorrhoeae nor other Neisseria spp. The COBAS AMPLICOR assay was considered not suitable for screening for infections with N. gonorrhoeae. If this assay is used for detection of N. gonorrhoeae, confirmation of positive results by a reliable test is mandatory.


Survival and prediction of successful ventilator weaning in COPD patients requiring mechanical ventilation for more than 21 days.
We studied survival and failure or success of weaning from mechanical ventilation (MV) in 42 consecutive chronic obstructive pulmonary disease (COPD) patients requiring prolonged MV (more than 21 days) after an episode of acute respiratory failure requiring admission to our Intermediate Intensive Care Unit (IICU). Parameters including arterial blood gases, pulmonary function tests, respiratory muscle force, neuromuscular drive, and nutritional status were recorded during a phase of clinical stability, in order to identify the features related to survival and weaning. All the patients were submitted to a comprehensive rehabilitation programme. Successful weaning from MV was defined as complete respiratory autonomy for at least 48 h. Twenty three patients were successfully weaned from MV after an average period of 44 days (Group A), requiring no further MV during their stay in hospital, whilst the remaining 19 patients were not able to be disconnected from the ventilator (Group B). The discriminant analysis showed that weaning from MV was significantly associated with arterial carbon dioxide tension (PaCO2), neuromuscular drive (P0.1), maximal inspiratory pressure (MIP), arterial oxygen tension (PaO2), the ratio of respiratory frequency to tidal volume (f/VT) and the serum protein level. Other pulmonary function tests (forced expiratory volume in one second (FEV1), FEV1/forced vital capacity (FVC), anthropometric data, nutritional status, number of pulmonary exacerbations during MV and evidence of cor pulmonale, were similar in the two groups. The discriminant equation considering PaCO2 and MIP could separate the two groups with an accuracy of 84%. The overall survival at 2 yrs was 40%; in Group B it was significantly lower than in Group A (22 vs 68%). Most of the deaths occurred within the first 120 days after intubation.(ABSTRACT TRUNCATED AT 250 WORDS)


The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013.
With recent improvements in vaccines and treatments against viral hepatitis, an improved understanding of the burden of viral hepatitis is needed to inform global intervention strategies. We used data from the Global Burden of Disease (GBD) Study to estimate morbidity and mortality for acute viral hepatitis, and for cirrhosis and liver cancer caused by viral hepatitis, by age, sex, and country from 1990 to 2013. We estimated mortality using natural history models for acute hepatitis infections and GBD's cause-of-death ensemble model for cirrhosis and liver cancer. We used meta-regression to estimate total cirrhosis and total liver cancer prevalence, as well as the proportion of cirrhosis and liver cancer attributable to each cause. We then estimated cause-specific prevalence as the product of the total prevalence and the proportion attributable to a specific cause. Disability-adjusted life-years (DALYs) were calculated as the sum of years of life lost (YLLs) and years lived with disability (YLDs). Between 1990 and 2013, global viral hepatitis deaths increased from 0·89 million (95% uncertainty interval [UI] 0·86-0·94) to 1·45 million (1·38-1·54); YLLs from 31·0 million (29·6-32·6) to 41·6 million (39·1-44·7); YLDs from 0·65 million (0·45-0·89) to 0·87 million (0·61-1·18); and DALYs from 31·7 million (30·2-33·3) to 42·5 million (39·9-45·6). In 2013, viral hepatitis was the seventh (95% UI seventh to eighth) leading cause of death worldwide, compared with tenth (tenth to 12th) in 1990. Viral hepatitis is a leading cause of death and disability worldwide. Unlike most communicable diseases, the absolute burden and relative rank of viral hepatitis increased between 1990 and 2013. The enormous health loss attributable to viral hepatitis, and the availability of effective vaccines and treatments, suggests an important opportunity to improve public health. Bill & Melinda Gates Foundation.


Oncocardiology-Past, Present, and Future: A Review.
Oncocardiology is a medical discipline that focuses on the identification, prevention, and treatment of cardiovascular complications related to cancer therapy. This discipline has gained interest from the cardiology community in recent years because of a remarkable increase in the number of cancer survivors and the proliferation of new cancer therapies causing cardiovascular complications, such as hypertension, heart failure, vascular complications, and cardiac arrhythmia. In this review, we provide historical perspectives, highlight new discoveries, and speculate on the opportunity created by merging the research interests and clinical practices of cardiology and oncology. The old paradigm of anthracycline cardiotoxic effects is replaced by new insights that anthracycline targets topoisomerase II β to cause DNA double-strand breaks and a profound change in the transcriptome leading to the generation of reactive oxygen species and the development of mitochondriopathy. Prevention of anthracycline cardiotoxic effects should be based on inhibiting or degrading topoisomerase II β. New challenges were posed by the introduction of trastuzumab and tyrosine kinase inhibitors that revolutionized cancer therapy. The on-target cardiotoxic effects of trastuzumab were owing to a prosurvival benefit of Her2 that binds to neuregulin, whereas the off-target effect of multitargeted tyrosine kinase inhibitors may be mediated by disruption of the vascular endothelial growth factor signaling pathway or the stress-induced angiogenesis. Sensitive imaging techniques, such as global strain, and biomarkers have allowed for early detection of cardiotoxic effects. Early treatment with heart failure medications may be beneficial in preventing the development of late cardiotoxic effects. Close collaboration between cardiologists and oncologists is required to meet the demand of an increasing number of cancer survivors. New insights based on mechanistic studies or genetic discoveries will pave the way for better prevention, diagnosis, and treatment of cancer therapy-induced cardiovascular complications.


Spatial mapping of phosphorus influx in bean root systems using digital autoradiography.
A novel technique was developed to spatially map the phosphorus net influx capacity in intact root systems. The method is based on digital autoradiography and permits the quantification of phosphorus influx at high spatial resolution (2 mm). Roots of 18-d-old common bean plants were exposed to (32)P-labelled orthophosphate, quickly frozen, excised, lyophilized, scanned, and exposed to a storage phosphor screen. Plots of (32)P content versus root length (distance from the root tip or from the base of the root) were obtained for three different root classes: basal, basal laterals, and taproot laterals. Radioactivity detected by filmless autoradiography correlated well (r(2)=0.99) with measurements made by scintillation counting. Basal roots absorbed 2.5 times and 1.9 times more phosphorus than the taproot lateral and basal lateral root classes, respectively, in the first 20 mm from the root apex. External phosphorus markedly affected influx: roots averaged 5, 16, and 34 pmol P min(-1) in the apical 20 mm when exposed to 1, 5, and 10 microM P solutions, respectively. The spatial pattern of phosphorus influx along the root axes of the different root classes was rather homogeneous when measured on a root surface area basis. Phosphorus influx in the older segments of basal roots (those next to the hypocotyl) did not differ from the newer segments close to the root apex. However, a heterogeneous pattern was detected for basal roots when measured on a length basis, indicating that both root class and diameter constitute main factors controlling the spatial pattern of net influx.


Can palliative care reduce futile treatment? A systematic review.
Palliative care interventions have the potential to lower health service costs by reducing the intensity of treatments intended to have curative effect while concentrating on quality of life and, in due course, quality of death. A patient receiving treatment inspired by curative intent during the end stage of their life is potentially exposed to medical futility. To conduct a systematic review of the evidence for palliative interventions reducing health service costs without impacting on quality of care. An electronic search of MEDLINE, EMBASE, AMED and CINAHL databases, augmented by hand-searching techniques, was performed. Only research where palliative care was the intervention or observation, and cost, together with either quality of life or patient satisfaction with care were outcome measures, was included in results. Of 1964 sources identified, only 12 measured both cost and an appropriate quality outcome. Evidence supported existing research that palliative care interventions generally reduce health service costs. Evidence of concurrent improvement in quality-of-life outcomes was limited; little available evidence derives from randomised trial designs. Small sample sizes and disparate outcome measures hamper statistical assessments. Evidence that palliative interventions cut costs, without reducing quality of life, by minimising futile medical acts is limited. Further research, including both observational studies and controlled trials, should be conducted to collect empirical data in this field. Future research should examine palliative interventions earlier in chronic progressive illness, and incorporate standardised outcome measures to allow meta-analysis.


Fluoride incorporation into apatite crystals delays amelogenin hydrolysis.
Enamel fluorosis has been related to an increase in the amount of amelogenin in fluorosed enamel compared with normal enamel in the maturation stage. In this study we tested the hypothesis that fluoride incorporated into carbonated apatite alters amelogenin hydrolysis. Recombinant human amelogenin (rh174) was allowed to bind to 0.15 mg of carbonated hydroxyapatite (CAP) or to fluoride-containing carbonated hydroxyapatite (F-CAP) synthesized to contain 100, 1,000, or 4,000 ppm F(-). After 3 h of digestion with recombinant human matrix metalloproteinase 20 (MMP20) or kallikrein-related peptidase 4 (KLK4), bound protein was characterized by reverse-phase high-performance liquid chromatography (HPLC). Proteolytic fragments of amelogenin formed after 24h of digestion with MMP20 of KLK 4 were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The hydrolysis, by both MMP20 and KLK4, of amelogenin bound to F100-CAP was significantly reduced in a dose-dependent manner compared with the hydrolysis of amelogenin bound to CAP. After 24 h of hydrolysis, a similar number of MMP20 cleavage sites was found for amelogenin bound to CAP and amelogenin bound to F100-CAP; however, 24 fewer KLK4 cleavage sites were identified for amelogenin bound to F100-CAP than for amelogenin bound to CAP. These results suggest that the reduced hydrolysis of amelogenins in fluorosed enamel may be partially caused by the increased fluoride content in fluoride-containing apatite, contributing to the hypomineralized enamel matrix phenotype observed in fluorosed enamel.


Colchicine-responsive chronic recurrent multifocal osteomyelitis associated with familial Mediterranean fever in the presence of MEFV mutation: A case report.
A 38-year-old female was referred with a history of fever, polyarthralgia, and bone pain. She was diagnosed with chronic recurrent multifocal osteomyelitis based on imaging and biopsy findings. Non-steroidal anti-inflammatory drugs and bisphosphonate caused no improvement. Then, she developed recurrent diarrhoea and abdominal pain. Genetic testing revealed MEFV mutation. Based on the symptoms and genetic mutation results that emerged during the course of these events, she was diagnosed with familial Mediterranean fever. All symptoms, including bone pain, improved with daily colchicine administration. This case was considered familial Mediterranean fever complicated with a clinical diagnosis of chronic recurrent multifocal osteomyelitis, which is included in the spectrum of pyrine autoinflammatory diseases. Considering this case, patients with chronic recurrent multifocal osteomyelitis with MEFV gene variants may respond to colchicine.


The pathology of unusual subtypes of prostate cancer.
There are some current literatures describing the morphologic change of prostate carcinoma variants. Some subtypes do not respond to hormone deprivation therapy, for example adenosquamous and squamous cell carcinoma (SQCC), basaloid and adenoid cystic carcinoma (ACC), small cell carcinoma (SmCC), sarcomatoid carcinoma, urothelial carcinoma; some are defined in special Gleason grade, some develop different prognosis. So, it is very important to identify these rare subtypes to avoid misdiagnosis. In this review, we aim to describe the typical clinicopathological features of the rare variants of prostate cancer, including prostate acinar adenocarcinoma morphologic variants.


Proteomics Analysis Reveals That Structural Proteins of the Virion Core and Involved in Gene Expression Are the Main Source for HLA Class II Ligands in Vaccinia Virus-Infected Cells.
Protective cellular and humoral immune responses require previous recognition of viral antigenic peptides complexed with human leukocyte antigen (HLA) class II molecules on the surface of the antigen presenting cells. The HLA class II-restricted immune response is important for the control and the clearance of poxvirus infection including vaccinia virus (VACV), the vaccine used in the worldwide eradication of smallpox. In this study, a mass spectrometry analysis was used to identify VACV ligands bound to HLA-DR and -DP class II molecules present on the surface of VACV-infected cells. Twenty-six naturally processed viral ligands among the tens of thousands of cell peptides bound to HLA class II proteins were identified. These viral ligands arose from 19 parental VACV proteins: A4, A5, A18, A35, A38, B5, B13, D1, D5, D7, D12, D13, E3, E8, H5, I2, I3, J2, and K2. The majority of these VACV proteins yielded one HLA ligand and were generated mainly, but not exclusively, by the classical HLA class II antigen processing pathway. Medium-sized and abundant proteins from the virion core and/or involved in the viral gene expression were the major source of VACV ligands bound to HLA-DR and -DP class II molecules. These findings will help to understand the effectiveness of current poxvirus-based vaccines and will be important in the design of new ones.


Architecture and evolution of a minute plant genome.
It has been argued that the evolution of plant genome size is principally unidirectional and increasing owing to the varied action of whole-genome duplications (WGDs) and mobile element proliferation. However, extreme genome size reductions have been reported in the angiosperm family tree. Here we report the sequence of the 82-megabase genome of the carnivorous bladderwort plant Utricularia gibba. Despite its tiny size, the U. gibba genome accommodates a typical number of genes for a plant, with the main difference from other plant genomes arising from a drastic reduction in non-genic DNA. Unexpectedly, we identified at least three rounds of WGD in U. gibba since common ancestry with tomato (Solanum) and grape (Vitis). The compressed architecture of the U. gibba genome indicates that a small fraction of intergenic DNA, with few or no active retrotransposons, is sufficient to regulate and integrate all the processes required for the development and reproduction of a complex organism.


A liposomal method for evaluation of inhibitors of H(+)-coupled multidrug transporters.
This paper describes a novel technique, Fluorosomes, applied to investigating the interaction of antimicrobials with proton driven microbial efflux transporters. These transporters remove toxic compounds from the cytoplasm, including antibiotics and are involved in antibiotic resistance. To assess transporter activity we developed a methodology to generate a proton gradient across Fluorosome membranes into which selected purified fully active efflux transporters were reconstituted. The interior of the Fluorosome particle (a unilamellar liposome) contains a fluorescent drug sensing probe whose fluorescence is quantitatively quenched by transporter substrates. Using an injecting fluorescence plate reader to initiate a proton gradient and to monitor subsequent fluorescence change, real time transport kinetics can be followed and transport inhibition characterized. Fluorosomes containing the Escherichia coli EmrE efflux pump demonstrated transport of two known EmrE substrates, ethidium and methyl viologen upon creation of a proton gradient. For Fluorosomes containing the inactive EmrE mutant, E14Q, no transport was observed. When the gradient was fully collapsed by the addition of nigericin, full inhibition of substrate transport was observed. The IC50 for nigericin inhibition of ethidium was shown to be 0.71 μM. We have for the first time prepared and validated a single bacterial efflux pump assay, Fluorosome-trans-EmrE, that faithfully mimics properties of the transporter in vivo. It is faster than whole cell screens, simple to use, amenable to robotics, and reports on very specific targets. We have demonstrated proof of principle with EmrE and have created the first of an intended series of proton driven Fluorosomes.


Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia.
Cytoarchitectural abnormalities have been reported in the cortex in schizophrenia. These suggest a developmental origin for this disorder. The Wnt signalling pathway is involved in the regulation of brain development; disruption of this pathway may lead to abnormal cortical development. In this study levels of three components of the Wnt signalling pathway; glycogen synthase kinase-3beta(GSK-3beta), beta-catenin and dishevelled-2 (Dvl-2) were determined in the prefrontal cortex of ten schizophrenic and ten control individuals using immunoblotting. GSK-3beta levels were significantly reduced in the schizophrenic group, while levels of beta-catenin and Dvl-2 did not differ between groups. This provides further evidence for an abnormality of the Wnt signalling pathway in schizophrenia.


German bike messengers' experiences and expressions of cycling anger.
Objective: The present study has 3 objectives: First, we wanted to examine whether the Cycling Anger Scale (CAS) applies to German professional bike messengers, because this scale was previously developed with nonprofessional cyclists in Germany. Second, we wanted to look at possible differences in cycling anger experience and expression between professional German bike messengers and nonprofessional German cyclists. Third, we explored whether cycling anger is somehow related to driving anger and general anger. Methods: We applied German versions of the CAS, the Driving Anger Scale (DAS), and the State-Trait Anger Expression Inventory (STAXI) to a sample of 123 professional German bike messengers. Then we compared their ratings with the results of 421 nonprofessional German cyclists. Results: Regarding our first objective, results indicate that the CAS model fit is better for nonprofessional than for professional cyclists. However, the CAS in a slightly modified version can be used for professional cyclists as well. As for our second objective, we show that professional cyclists experience significantly less cycling anger than nonprofessional cyclists. However, bike messengers report more frequent aggressive cycling behaviors when angry, indicating a weaker link between trait anger while cycling and aggressive behavior among professionals. Thirdly, we found relations between cycling anger, driving anger, and general anger. Conclusions: We conclude that the CAS in its slightly modified 13-item version with the established 4 subscales produces an acceptable model fit and can be applied to professional German bike messengers for further research purposes or applied issues; for example, traffic education or self-awareness in terms of accident prevention behaviors. In addition, for professional cyclists, less anger does not result in less aggressive cycling behaviors. Subsequent research should explore the role of anger in behavioral regulation of cyclists' unsafe cycling behaviors taking different levels of experience and professionalism into account in order to reduce adverse effects of anger on traffic safety.


Pancreatic glucoregulatory hormones in cirrhosis of the liver: portal vein concentrations during intravenous glucose tolerance test and in response to a meal.
We studied the relationship between the pancreatic glucoregulatory hormones, insulin and glucagon, and glucose intolerance through the response to food and intravenous glucose in 11 patients with verified hepatic cirrhosis. Blood samples were obtained from the portal vein and the superior vena cava. The results of the systemic vein hormone determinations were compared to results obtained from peripheral vein determination in 10 age-, sex- and weight-matched controls admitted to hospital for minor surgery and to results from ambulant, normal subjects. In the cirrhotics collateral shunting was elevated by transhepatic portography. The cirrhotics and the matched controls had similar glucagon levels and responses, but showed hyperresponsiveness to a meal compared to ambulant normal subjects. Compared to the matched controls the cirrhotics showed glucose tolerance and hyperinsulinism, but compared to normal subjects the hospitalized controls were also glucose intolerant and demonstrated hyperinsulinism. In the cirrhotics, the portal vein/vena cava ratio for insulin was negatively correlated to the degree of collateral shunting. No relationship was found between the degree of portosystemic shunting and fasting concentrations of glucagon and insulin, and the insulin response to glucose. The glucagon response to the meal, was correlated to severity of cirrhosis. The rate constant for glucose disappearance (K-value) was not related to the insulin response, to severity of disease or to degree of shunting. It was, however, correlated to the suppressibility of glucagon secretion as measured in the portal vein. Our results indicate that the glucoregulatory disturbances in compensated cirrhosis are partly caused by non-specific factors which are independent of cirrhosis; the portal-vein hormone responses, however, support the contention that glucagon secretion influences glucose tolerance in cirrhotics.


Microfabrication technologies in dielectrophoresis applications--a review.
DEP is an established technique for particle manipulation. Although first demonstrated in the 1950s, it was not until the development of miniaturization techniques in the 1990s that DEP became a popular research field. The 1990s saw an explosion of DEP publications using microfabricated metal electrode arrays to sort a wide variety of cells. The concurrent development of microfluidics enabled devices for flow management and better understanding of the interaction between hydrodynamic and electrokinetic forces. Starting in the 2000s, alternative techniques have arisen to overcome common problems in metal-electrode DEP, such as electrode fouling, and to increase the throughput of the system. Insulator-based DEP and light-induced DEP are the most significant examples. Most recently, new 3D techniques such as carbon-electrode DEP, contactless DEP, and the use of doped PDMS have further simplified the fabrication process. The constant desire of the community to develop practical solutions has led to devices which are more user friendly, less expensive, and are capable of higher throughput. The state-of-the-art of fabricating DEP devices is critically reviewed in this work. The focus is on how different fabrication techniques can boost the development of practical DEP devices to be used in different settings such as clinical cell sorting and infection diagnosis, industrial food safety, and enrichment of particle populations for drug development.


A new method for the rapid analysis of 1H-Pyrrole-2,5-diones (maleimides) in environmental samples by two-dimensional gas chromatography time-of-flight mass spectrometry.
Maleimides (1H-Pyrrole-2,5-diones) are monopyrrolic pigment derivatives with specific alkyl side chains that can be directly linked to their tetrapyrrole precursors, most notably chlorophylls and bacteriochlorophylls. These compounds can be used as palaeoenvironmental indicators such as algal productivity and redox conditions in ancient and modern aquatic systems. Here, we present a new method using two-dimensional gas chromatography time-of-flight mass spectrometry (GC × GC-ToF-MS), which enables the rapid analysis of maleimides in complex mixtures and different matrices (e.g. sediments and soils), therefore largely simplifying the previous intricate maleimide purification protocol. This method also reduces the potential for bias associated with partial losses due to low recovery and the high volatility of maleimides. The maleimide distributions and concentrations obtained by GC × GC-ToF-MS were reproducible and in agreement with the previously used purification procedure followed by analysis with traditional gas chromatography-mass spectrometry (GC-MS). The new method also resolved previously unrecognised, partial coelution of some maleimides with unknown compounds by quantification with the m/z 75 fragment ion. Furthermore, the higher sensitivity enabled the detection of previously unrecognised and preliminarily identified maleimides based on their relative retention times. The new, easier, rapid and more sensitive GC×GC-ToF-MS method greatly facilitates the analysis of maleimides in environmental samples to study tetrapyrrole degradation processes and will further the development of maleimides as biomarkers for palaeoenvironmental reconstructions.


Mitochondrial function and abnormalities implicated in the pathogenesis of ASD.
Mitochondria are the powerhouse that generate over 90% of the ATP produced in cells. In addition to its role in energy production, the mitochondrion also plays a major role in carbohydrate, fatty acid, amino acid and nucleotide metabolism, programmed cell death (apoptosis), generation of and protection against reactive oxygen species (ROS), immune response, regulation of intracellular calcium ion levels and even maintenance of gut microbiota. With its essential role in bio-energetic as well as non-energetic biological processes, it is not surprising that proper cellular, tissue and organ function is dependent upon proper mitochondrial function. Accordingly, mitochondrial dysfunction has been shown to be directly linked to a variety of medical disorders, particularly neuromuscular disorders and increasing evidence has linked mitochondrial dysfunction to neurodegenerative and neurodevelopmental disorders such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Rett Syndrome (RS) and Autism Spectrum Disorders (ASD). Over the last 40 years there has been a dramatic increase in the diagnosis of ASD and, more recently, an increasing body of evidence indicates that mitochondrial dysfunction plays an important role in ASD development. In this review, the latest evidence linking mitochondrial dysfunction and abnormalities in mitochondrial DNA (mtDNA) to the pathogenesis of autism will be presented. This review will also summarize the results of several recent `approaches used for improving mitochondrial function that may lead to new therapeutic approaches to managing and/or treating ASD.


Hyperbaric oxygenation for experimental bladder tumor. I. Tissue oxygen tension of the rabbit bladder during hyperbaric oxygenation.
Although considerable advances have been made in the application of hyperbaric oxygenation (HBO) on tumor treatment in the recent past, many difficulties persist due to conflicting results and the understanding of its mechanism. We tested whether HBO treatment in clinical use could really influence the tissue concentration of oxygen in bladder or circulatory condition in animals. Eleven rabbits were treated with 1-3 atmospheric absolute pressures under an environment of air saturating 30-35% of oxygen for 90 min. Ten control animals were placed in the same chamber without providing HBO treatment. The tissue oxygen pressure in trigone or dome of the in HBO-treated group was significantly higher than that of the control group. A similar tendency was also noted in the arterial oxygen concentration to a greater extent, while regional blood flow in the bladder, mean arterial blood pressure and plasma volume were not significantly changed following HBO treatment. The use of HBO appears to offer some possibilities for the treatment of bladder tumor in the future.


Eosinophil and T cell markers predict functional decline in COPD patients.
The major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, a single measurement of FEV1 cannot reliably predict subsequent decline. Recent studies indicate that T lymphocytes and eosinophils are important determinants of disease stability in COPD. We therefore measured cytokine levels in the lung lavage fluid and plasma of COPD patients in order to determine if the levels of T cell or eosinophil related cytokines were predictive of the future course of the disease. Baseline lung lavage and plasma samples were collected from COPD subjects with moderately severe airway obstruction and emphysematous changes on chest CT. The study participants were former smokers who had not had a disease exacerbation within the past six months or used steroids within the past two months. Those subjects who demonstrated stable disease over the following six months (DeltaFEV1 % predicted = 4.7 +/- 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (DeltaFEV1 % predicted = -16.0 +/- 6.0; N = 16) during the same time period and with normal controls (N = 11). Plasma and lung lavage cytokines were measured from clinical samples using the Luminex multiplex kit which enabled the simultaneous measurement of several T cell and eosinophil related cytokines. Stable COPD participants had significantly higher plasma IL-2 levels compared to participants with rapidly progressive COPD (p = 0.04). In contrast, plasma eotaxin-1 levels were significantly lower in stable COPD subjects compared to normal controls (p < 0.03). In addition, lung lavage eotaxin-1 levels were significantly higher in rapidly progressive COPD participants compared to both normal controls (p < 0.02) and stable COPD participants (p < 0.05). These findings indicate that IL-2 and eotaxin-1 levels may be important markers of disease stability in advanced emphysema patients. Prospective studies will need to confirm whether measuring IL-2 or eotaxin-1 can identify patients at risk for rapid disease progression.


Optimization and validation of a reversed-phase high performance liquid chromatography method for the measurement of bovine liver methylmalonyl-coenzyme a mutase activity.
Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses the interconversion of (2R)-methylmalonyl-CoA to succinyl-CoA. In humans, a deficit in activity of MCM, due to an impairment of intracellular formation of adenosylcobalamin and methylcobalamin results in a wide spectrum of clinical manifestations ranging from moderate to fatal. Consequently, MCM is the subject of abundant literature. However, there is a lack of consensus on the reliable method to monitor its activity. This metabolic pathway is highly solicited in ruminants because it is essential for the utilization of propionate formed during ruminal fermentation. In lactating dairy cows, propionate is the major substrate for glucose formation. In present study, a reversed-phase high performance liquid chromatography (RP-HPLC) was optimized and validated to evaluate MCM activity in bovine liver. The major aim of the study was to describe the conditions to optimize reproducibility of the method and to determine stability of the enzyme and its product during storage and processing of samples. Specificity of the method was good, as there was no interfering peak from liver extract at the retention times corresponding to methylmalonyl-CoA or succinyl-CoA. Repeatability of the method was improved as compared to previous RP-HPLC published data. Using 66 μg of protein, intra-assay coefficient of variation (CV) of specific activities, ranged from 0.90 to 8.05% and the CV inter-day was 7.40%. Storage and processing conditions (frozen homogenate of fresh tissue vs. fresh homogenate of tissue snapped in liquid nitrogen) did not alter the enzyme activity. The analyte was also stable in liver crude extract for three frozen/thawed cycles when stored at -20°C and thawed to room temperature. The improved method provides a way for studying the effects of stages of lactation, diet composition, and physiology in cattle on MCM activity over long periods of time, such as a complete lactation period. Interestingly, this sensitive and accurate method could benefit the study of the cobalamin status in experimental studies and clinical cases.


Conditions of transfer and quality of food.
Many factors contribute to the production of safe foods of animal origin. Initiatives for an integrated approach to food safety recognise the importance of optimising transportation conditions to ensure on-farm interventions are preserved. Physical, microbial, and environmental hazards during the transportation process may adversely affect the safety and quality of meat, poultry, and egg products. Additionally, the stress level in animals can be raised by transportation conditions, potentially causing increased pathogen shedding in carrier animals which exposes other animals to possible contamination. The physiological effects of stress on animals can reduce the quality of meat, poultry, and egg products produced by the animals, thus decreasing the economic value of the animal. Increased globalisation of markets provides an incentive for transportation standards of food animals within a country as well as transportation standards between countries.


Non-invasive beat to beat arterial blood pressure during non-REM sleep in obstructive sleep apnoea and snoring.
Obstructive sleep apnoea, and possibly snoring, are associated with a poorly understood increase in cardiovascular mortality which may be explained by their effects on systemic blood pressure during sleep. This study compares changes in mean blood pressure during obstructive sleep apnoea and snoring without apnoeas with those in matched control subjects during non-REM sleep. Eighteen men with obstructive sleep apnoea, 16 men who snored without apnoeas, and 34 control subjects matched for age, sex, obesity, smoking, and alcohol intake were studied. During polysomnography non-invasive mean blood pressure (Finapres) was recorded from each cardiac cycle during non-REM sleep and averaged over a 10 minute period. This was compared with the blood pressure during 10 minutes before sleep onset. The changes in the patients' sleeping blood pressure were compared with those in their individually matched control subjects. Compared with the control subjects the change in mean (SD) arterial blood pressure between being awake and asleep was higher during obstructive sleep apnoea (+6.5 (9) mm Hg v-2 (6.5), difference 8.5 (11)), and the rise from wakefulness to sleep in the obstructive sleep apnoea group was itself significant. The average mean arterial pressure was not raised in those who snored without apnoeas compared with either the control subjects or during wakefulness. Average mean arterial pressure is higher during obstructive sleep apnoea than it is during wakefulness, while normal subjects show a fall in blood pressure at sleep onset. This sleep related rise in blood pressure may contribute to the excess cardiovascular morbidity and mortality experienced by patients with this condition.


Does HIV infection favor the sexual transmission of hepatitis C?
There are widely discrepant findings on the sexual transmission of hepatitis C virus (HCV), commonly transmitted by the parenteral route. Coinfection with HCV is common in subjects infected with HIV. This case-control study evaluated the prevalence of anti-HCV in subjects with hetero- or homosexual contact and no history of intravenous drug abuse or blood transfusion, according to the presence or absence of HIV infection. In this case-control study, the cases considered were 106 consecutive patients who showed positive anti-HIV test results. For each case, two control subjects were selected who had been screened for HIV infection at the authors' center and found to have anti-HIV-negative test results, and who matched the case in terms age (+/- 5 years), gender, and risk factor for parenterally transmitted infections. The prevalence of subjects with positive test results for hepatitis B surface antigen (HBsAg) was similar between cases and control subjects (4.7% versus 2.4%). Positivity for anti-hepatitis B core antigen in connection with negative test results for HBsAg was observed more frequently in the 106 cases than in the 212 control subjects (33.9% versus 15.6%; P = 0.0003). Anti-HCV positivity was more frequent in the cases than in the control subjects (15.1% versus 5.2%; P = 0.005). In particular, among subjects who had hetero- or homosexual intercourse with a steady partner who had positive anti-HIV test results, anti-HCV positivity was observed in 18.7% of the 32 cases and 1.6% of the 64 control subjects (P = 0.008). This study demonstrated that in subjects who had only a sexual risk factor for parenterally transmitted infections, HIV may enhance the sexual transmission of HCV.


Optical imaging of periostin enables early endoscopic detection and characterization of esophageal cancer in mice.
Imaging strategies that detect early stage esophageal squamous cell carcinoma (ESCC) could improve clinical outcomes, when combined with endoscopic approaches. Periostin is an integrin-binding protein that is important in the tumor microenvironment. We created a fluorescent-labeled antibody that recognizes periostin and binds specifically to ESCC xenograft tumors in mice. In L2-cre;p120ctnLoxP/LoxP mice, which develop squamous cell cancers that resemble human ESCC, we visualized the probe in preneoplastic and neoplastic esophageal lesions using near-infrared fluorescent imaging with upper-gastrointestinal endoscopy. Periostin might be a biomarker of the esophageal tumor microenvironment that can be used to detect preneoplastic lesions.


Spinal radiosurgery--efficacy and safety after prior conventional radiotherapy.
Conventional external beam radiotherapy is a standard procedure for treatment of spinal metastases. In case of progression spinal cord tolerance limits further radiotherapy in pre-irradiated areas. Spinal stereotactic radiotherapy is a non-invasive option to re-treat pre-irradiated patients. Nevertheless, spinal radiosurgery results in relevant dose deposition within the myelon with potential toxicity. Aim of the study was to retrospectively analyse the efficacy and feasibility for salvage radiosurgery of spinal metastases. During a period of 4 years (2005-2009) 70 lesions in 54 patients were treated in 60 radiosurgery sessions and retrospectively analysed. Clinical (pain, sensory and motor deficit) and radiological (CT/MRI) follow-up data were collected prospectively after radiosurgery. Pain - as main symptom - was classified by the Visual Analogue Scale (VAS) score. Every patient received single session radiosurgery after having been treated first-line with conventionally fractionated radiotherapy. Kaplan-Meier method and life tables were used to analyse freedom from local failure and overall survival. At a median follow-up of 14.5 months the actuarial rates of freedom from local failure at 6/12/18 months were 93%, 88% and 85%, respectively. The median radiosurgery dose was 1 × 18 Gy (range 10-28 Gy) to the median 70% isodose. The VAS score of patients with pain (median 6) dropped significantly (median 4, p = 0.002). In 6 out of 7 patients worse sensory or motor deficit after SRS was caused by local or distant failures (diagnosed by CT/MRI). One patient with metastatic renal cell carcinoma developed a progressive complete paraparesis one year after the last treatment at lumbar level L3. Due to multiple surgery and radiosurgery treatments at the lumbar region and further local progression, the exact reason remained unclear. Apart from that, no CTC grade III or higher toxicity has been observed. By applying spinal radiosurgery relevant radiation doses can be limited to small parts of the myelon. This prevents myelopathic side effects and makes it an effective and safe treatment option for well-suited patients. Especially for previously irradiated patients with local failure or pain salvage SRS represents a valuable treatment option with high local control rates, low toxicity and significant pain reduction.


Current spectrum of causative pathogens in sepsis: A prospective nationwide cohort study in Japan.
There is no one-size-fits-all empiric antimicrobial therapy for sepsis because the pathogens vary according to the site of infection and have changed over time. Therefore, updating knowledge on the spectrum of pathogens is necessary for the rapid administration of appropriate antimicrobials. The aim of this study was to elucidate the current spectrum of pathogens and its variation by site of infection in sepsis. This was a prospective nationwide cohort study of consecutive adult patients with sepsis in 59 intensive care units in Japan. The spectrum of pathogens was evaluated in all patients and in subgroups by site of infection. Regression analyses were conducted to evaluate the associations between the pathogens and mortality. The study cohort comprised 1184 patients. The most common pathogen was Escherichia coli (21.5%), followed by Klebsiella pneumoniae (9.0%). However, the pattern varied widely by site of infection; for example, gram-positive bacteria were the dominant pathogen in bone/soft tissue infection (55.7%) and cardiovascular infection (52.6%), but were rarely identified in urinary tract infection (6.4%). In contrast, gram-negative bacteria were the predominant pathogens in abdominal infection (38.4%) and urinary tract infection (72.0%). The highest mortality of 47.5% was observed in patients infected with methicillin-resistant Staphylococcus aureus, which was significantly associated with an increased risk of death (odds ratio 1.88, 95% confidence interval 1.22-2.91). This study revealed the current spectrum of pathogens and its variation based on the site of infection, which is essential for empiric antimicrobial therapy against sepsis.


A systematic review of donor site aesthetic and complications after deep inferior epigastric perforator flap breast reconstruction.
The deep inferior epigastric perforator flap (DIEP) has gained widespread popularity in autologous breast reconstruction due to its natural aesthetic results and muscle-sparing design. However, donor site results regarding aesthetic outcome are often less favorable. Despite several studies on surgical technique and improvements of flap harvest, only a small number of studies addressing donor site aesthetic exist. A systematic review was performed on donor site aesthetic after DIEP flap harvest according to the PRISMA guidelines. Secondary interests were abdominal wall morbidity and complication rates in general. The following electronic databases were included to identify relevant studies: Medline, Embase, PubMed, Cochrane, and Web of Science. The search yielded 95 articles for full-text analysis, with only four key studies found on donor site aesthetic specifically. Regarding complication rates, the overall rate of abdominal hernia ranges from 0 to 7.1%. Abdominal bulging occurs in 2.3% to 33%. Besides abdominal wall integrity, wound dehiscence (12-39%), seroma (1-48%), hematoma (1-15%), infections (1-12%), fat necrosis (0-11%) and umbilical necrosis (2-3%) significantly impair donor site aesthetic. This systematic review reveals that the topic of donor site aesthetic and potential improvement of results has largely been neglected in the past decade. This study provides a thorough evaluation of potential problems that plastic surgeons may encounter and includes recommendations to improve results.


Control of supramolecular nanoassemblies by tuning the interactions of bent-shaped rod-coil molecules.
Rod-coil molecules 1a, 1b and 2a, 2b, consisting of biphenyl and phenyl units connected by an acetylene bond as the rod segment and oligo(ethylene glycol) (OEG) as the coil segment, were synthesized and characterized. Molecules 1a and 1b incorporate a butoxy group at the apex of their bent-shaped rigid building blocks, while both 1b and 2b contain a lateral methyl group between the rod and coil segments. The self-assembling behavior of these molecules was investigated using DSC, SAXS, CD, AFM, and TEM in bulk and aqueous solutions. In the bulk state, 1a self-assembles into oblique columnar structures, whereas 1b, incorporating butoxy and lateral methyl groups, self-assembles into three-dimensional body-centered tetragonal structures. Molecules 2a and 2b with no butoxy groups, and 2b incorporating a lateral methyl group, self-assemble into hexagonal perforated lamellar and oblique columnar structures, respectively. In dilute aqueous solutions, 1a assembles into tubular nanoassemblies, while 1b self-organizes into micelles and nanoparticles. On the other hand, 2a and 2b spontaneously aggregate into nanoribbons and nanofibers. Furthermore, CD experiments together with AFM investigations of 2b indicate the creation of self-organized helical fibers, implying that the lateral methyl group induces the helical stacking of the rod building block. These results reveal that the butoxy and lateral methyl groups between the rod and coil segments dramatically influence the creation of supramolecular nanostructures and morphologies.


Predicting in-hospital mortality and unanticipated admissions to the intensive care unit using routinely collected blood tests and vital signs: Development and validation of a multivariable model.
The National Early Warning System (NEWS) is based on vital signs; the Laboratory Decision Tree Early Warning Score (LDT-EWS) on laboratory test results. We aimed to develop and validate a new EWS (the LDTEWS:NEWS risk index) by combining the two and evaluating the discrimination of the primary outcome of unanticipated intensive care unit (ICU) admission or in-hospital mortality, within 24 h. We studied emergency medical admissions, aged 16 years or over, admitted to Oxford University Hospitals (OUH) and Portsmouth Hospitals (PH). Each admission had vital signs and laboratory tests measured within their hospital stay. We combined LDT-EWS and NEWS values using a linear time-decay weighting function imposed on the most recent blood tests. The LDTEWS:NEWS risk index was developed using data from 5 years of admissions to PH, and validated on a year of data from both PH and OUH. We tested the risk index's ability to discriminate the primary outcome using the c-statistic. The development cohort contained 97,933 admissions (median age = 73 years) of which 4723 (4.8%) resulted inhospital death and 1078 (1.1%) in unanticipated ICU admission. We validated the risk index using data from PH (n = 21,028) and OUH (n = 16,383). The risk index showed a higher discrimination in the validation sets (c-statistic value (95% CI)) (PH, 0.901 (0.898-0.905); OUH, 0.916 (0.911-0.921)), than NEWS alone (PH, 0.877 (0.873-0.882); OUH, 0.898 (0.893-0.904)). The LDTEWS:NEWS risk index increases the ability to identify patients at risk of deterioration, compared to NEWS alone.


Health visitors' awareness and perception of clinical genetic services.
A questionnaire was sent to 84 health visitors to assess their awareness and perception of genetic services and how they perceived their role in the referral of patients. The study showed that while health visitors had a reasonable knowledge of the more obvious aspects of genetic services, there were a number of areas in which they were unsure. The respondents did not identify themselves as prime initiators in the process of referring patients to a genetic service, although they appeared able to identify families on their caseloads for whom this service may be relevant. Health visitors viewed their own knowledge of genetics as poor, a factor which may account for the low referral rate initiated by this group of professionals. The respondents attached importance to genetic issues and 76 (95%) wished to be better informed about the subject. It is suggested that the inclusion of genetics as part of an in-service training programme might fulfil this need and lead to greater advocacy of genetic services among the families in their care. These findings are of interest in view of the proposals within the recent Royal College of Physicians report (Prenatal screening and genetic counselling) suggesting that community genetic services should make use of primary health care workers such as health visitors.


N-glycosylation state of TRPM8 protein revealed by terahertz spectroscopy and molecular modelling.
TRPM8 member of the TRP superfamily of membrane proteins participates to various cellular processes ranging from Ca2+ uptake and cold sensation to cellular proliferation and migration. TRPM8 is a large tetrameric protein with more than 70% of its residues located in the cytoplasm. TRPM8 is N-glycosylated, with a single site per subunit. This work focuses on the N-glycosylation of TRPM8 channel that was previously studied by our group in relation to proliferation and migration of tumoral cells. Here, experimental data performed with deglycosylating agents assess that the sole glycosylation site contains complex glycans with a molecular weight of 2.5 kDa. The glycosylation state of TRPM8 in cells untreated and treated with a deglycosylating agent was addressed with Terahertz (THz) spectroscopy. Results show a clear difference between cells comprising glycosylated and deglycosylated TRPM8, the first presenting an increased THz absorption. Human TRPM8 was modelled using as templates the available TRPM8 and other TRPM channels structures. Glycosylations were modelled by considering two glycan structures with molecular weight close to the experiment: shorter and branched at the first sugar unit (glc1) and longer and unbranched (glc2). Simulation of THz spectra based on the molecular dynamics of unglycosylated and the two glycosylated TRPM8 models in lipid membrane and solvation box showed that glycan structure strongly influences the THz spectrum of the channel and of other components from the simulation system. Only spectra of TRPM8 with glc1 glycans were in agreement with the experiment, leading to the validation of glc1 glycan structure.


A model of integrative care for low-back pain.
While previous studies focused on the effectiveness of individual complementary and alternative medical (CAM) therapies, the value of providing patients access to an integrated program involving multiple CAM and conventional therapies remains unknown. The objective of this study is to explore the feasibility and effects of a model of multidisciplinary integrative care for subacute low-back pain (LBP) in an academic teaching hospital. This was a pilot randomized trial comparing an individualized program of integrative care (IC) plus usual care to usual care (UC) alone for adults with LBP. Twenty (20) individuals with LPB of 3-12 weeks' duration were recruited from an occupational health clinic and community health center. Participants were randomized to 12 weeks of individualized IC plus usual care versus UC alone. IC was provided by a trained multidisciplinary team offering CAM therapies and conventional medical care. The outcome measures were symptoms (pain, bothersomeness), functional status (Roland-Morris score), SF-12, worry, and difficulty performing three self-selected activities. Over 12 weeks, participants in the IC group had a median of 12.0 visits (range 5-25). IC participants experienced significantly greater improvements at 12 weeks than those receiving UC alone in symptom bothersomeness (p=0.02) and pain (p=0.005), and showed greater improvement in functional status (p=0.08). Rates of improvement were greater for patients in IC than UC in functional status (p=0.02), bothersomeness (p=0.002), and pain scores (p=0.001). Secondary outcomes of self-selected most challenging activity, worry, and the SF-12 also showed improvement in the IC group at 12 weeks. These differences persisted at 26 weeks, but were no longer statistically significant. It was feasible for a multidisciplinary, outpatient IC team to deliver coordinated, individualized intervention to patients with subacute LBP. Results showed a promising trend for benefit of treating patients with persistent LBP with this IC model, and warrant evaluation in a full-scale study.


FMRI-based identity classification accuracy in left temporal and frontal regions predicts speaker recognition performance.
Speaker recognition is characterized by considerable inter-individual variability with poorly understood neural bases. This study was aimed at (1) clarifying the cerebral correlates of speaker recognition in humans, in particular the involvement of prefrontal areas, using multi voxel pattern analysis (MVPA) applied to fMRI data from a relatively large group of participants, and (2) at investigating the relationship across participants between fMRI-based classification and the group's variable behavioural performance at the speaker recognition task. A cohort of subjects (N = 40, 28 females) selected to present a wide distribution of voice recognition abilities underwent an fMRI speaker identification task during which they were asked to recognize three previously learned speakers with finger button presses. The results showed that speaker identity could be significantly decoded based on fMRI patterns in voice-sensitive regions including bilateral temporal voice areas (TVAs) along the superior temporal sulcus/gyrus but also in bilateral parietal and left inferior frontal regions. Furthermore, fMRI-based classification accuracy showed a significant correlation with individual behavioural performance in left anterior STG/STS and left inferior frontal gyrus. These results highlight the role of both temporal and extra-temporal regions in performing a speaker identity recognition task with motor responses.


Superfluid Density of Neutrons in the Inner Crust of Neutron Stars: New Life for Pulsar Glitch Models.
Calculations of the effects of band structure on the neutron superfluid density in the crust of neutron stars made under the assumption that the effects of pairing are small [N. Chamel, Phys. Rev. C 85, 035801 (2012)PRVCAN0556-2813] lead to moments of inertia of superfluid neutrons so small that the crust alone is insufficient to account for the magnitude of neutron star glitches. Inspired by earlier work on ultracold atomic gases in an optical lattice, we investigate fermions with attractive interactions in a periodic lattice in the mean-field approximation. The effects of band structure are suppressed when the pairing gap is of order or greater than the strength of the lattice potential. By applying the results to the inner crust of neutron stars, we conclude that the reduction of the neutron superfluid density is considerably less than previously estimated and, consequently, it is premature to rule out models of glitches based on neutron superfluidity in the crust.


The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration.
The intestinal crypt is a site of potential interactions between microbiota products, stem cells, and other cell types found in this niche, including Paneth cells, and thus offers a potential for commensal microbes to influence the host epithelium. However, the complexity of this microenvironment has been a challenge to deciphering the underlying mechanisms. We used in vitro cultured organoids of intestinal crypts from mice, reinforced with in vivo experiments, to examine the crypt-microbiota interface. We find that within the intestinal crypt, Lgr5(+) stem cells constitutively express the cytosolic innate immune sensor Nod2 at levels much higher than in Paneth cells. Nod2 stimulation by its bona fide agonist, muramyl-dipeptide (MDP), a peptidoglycan motif common to all bacteria, triggers stem cell survival, which leads to a strong cytoprotection against oxidative stress-mediated cell death. Thus, gut epithelial restitution is Nod2 dependent and triggered by the presence of microbiota-derived molecules.


Risk assessment for arsenic-contaminated groundwater along River Indus in Pakistan.
The study determined the risk zone and estimated the population at risk of adverse health effects for arsenic exposure along the bank of River Indus in Pakistan. A cross-sectional survey was conducted in 216 randomly selected villages of one of the districts along River Indus. Wells of ten households from each village were selected to measure arsenic levels. The location of wells was identified using global positioning system device, and spatial variations of the groundwater contamination were assessed using geographical information system tools. Using layers of contaminated drinking water wells according to arsenic levels and population with major landmarks, a risk zone and estimated population at risk were determined, which were exposed to arsenic level ≥10 µg/L. Drinking wells with arsenic levels of ≥10 µg/L were concentrated within 18 km near the river bank. Based on these estimates, a total of 13 million people were exposed to ≥10 µg/L arsenic concentration along the course of River Indus traversing through 27 districts in Pakistan. This information would help the researchers in designing health effect studies on arsenic and policy makers in allocating resources for designing focused interventions for arsenic mitigation in Pakistan. The study methods have implication on similar populations which are affected along rivers due to arsenic contamination.


Predictive Value of Breast MRI Background Parenchymal Enhancement for Neoadjuvant Treatment Response among HER2- Patients.
Women with advanced HER2- breast cancer have limited treatment options. Breast MRI functional tumor volume (FTV) is used to predict pathologic complete response (pCR) to improve treatment efficacy. In addition to FTV, background parenchymal enhancement (BPE) may predict response and was explored for HER2- patients in the I-SPY-2 TRIAL. Women with HER2- stage II or III breast cancer underwent prospective serial breast MRIs during four neoadjuvant chemotherapy timepoints. BPE was quantitatively calculated using whole-breast manual segmentation. Logistic regression models were systematically explored using pre-specified and optimized predictor selection based on BPE or combined with FTV. A total of 352 MRI examinations in 88 patients (29 with pCR, 59 non-pCR) were evaluated. Women with hormone receptor (HR)+HER2- cancers who achieved pCR demonstrated a significantly greater decrease in BPE from baseline to pre-surgery compared to non-pCR patients (odds ratio 0.64, 95% confidence interval (CI): 0.39-0.92, P = 0.04). The associated BPE area under the curve (AUC) was 0.77 (95% CI: 0.56-0.98), comparable to the range of FTV AUC estimates. Among multi-predictor models, the highest cross-validated AUC of 0.81 (95% CI: 0.73-0.90) was achieved with combined FTV+HR predictors, while adding BPE to FTV+HR models had an estimated AUC of 0.82 (95% CI: 0.74-0.92). Among women with HER2- cancer, BPE alone demonstrated association with pCR in women with HR+HER2- breast cancer, with similar diagnostic performance to FTV. BPE predictors remained significant in multivariate FTV models, but without added discrimination for pCR prediction. This may be due to small sample size limiting ability to create subtype-specific multivariate models.


Multiple cerebral infarctions from nonbacterial thrombotic endocarditis mimicking cerebral vasculitis.
Primary vasculitis of the central nervous system (PVCNS) is an uncommon disorder that can present with a variety of symptoms, making diagnosis and management difficult. We describe a case of cerebral infarction that occurred from nonbacterial thrombotic endocarditis (NBTE) and presented with clinical and radiologic imaging features that suggested PVCNS. The patient was a 58-year-old woman with left hemiparesis, aphasia, and episodic confusion. Magnetic resonance imaging of the brain demonstrated multifocal lesions consistent with infarction involving both cerebral hemispheres, and cerebral angiography showed changes consistent with vasculitis. Although brain biopsy findings were normal, the patient was treated for presumed vasculitis with cyclophosphamide and prednisone. Four months later respiratory failure secondary to polymicrobial pneumonia and adult respiratory distress syndrome developed, and she died. Autopsy revealed multiple infarcts in the heart, lungs, right kidney, spleen, and brain. Multiple thrombotic platelet-fibrin vegetations consistent with NBTE were found on all cardiac valves. Examination of the brain revealed no evidence of active or healed vasculitis. Cerebral angiography may show findings that suggest vasculitis, but it is not diagnostic, as several other conditions may cause similar changes. Nonbacterial thrombotic endocarditis may cause multiple cerebral infarctions and can be difficult to distinguish from vasculitis, as specific diagnostic tests for PVCNS are lacking.


Community Action for Health in India's National Rural Health Mission: One policy, many paths.
Community participation as a strategy for health system strengthening and accountability is an almost ubiquitous policy prescription. In 2005, with the election of a new Government in India, the National Rural Health Mission was launched. This was aimed at 'architectural correction' of the health care system, and enshrined 'communitization' as one of its pillars. The mission also provided unique policy spaces and opportunity structures that enabled civil society groups to attempt to bring on to the policy agenda as well as implement a more collective action and social justice based approach to community based accountability. Despite receiving a lot of support and funding from the central ministry in the pilot phase, the subsequent roll out of the process, led in the post-pilot phase by the individual state governments, showed very varied outcomes. This paper using both documentary and interview based data is the first study to document the roll out of this ambitious process. Looking critically at what varied and why, the paper attempts to derive lessons for future implementation of such contested concepts.


Can rheumatoid arthritis (RA) registries provide contextual safety data for modern RA clinical trials? The case for mortality and cardiovascular disease.
We implemented a novel method for providing contextual adverse event rates for a randomised controlled trial (RCT) programme through coordinated analyses of five RA registries, focusing here on cardiovascular disease (CVD) and mortality. Each participating registry (Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (East Europe, Latin America, India) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan)) defined a main cohort from January 2000 onwards. To address comparability and potential bias, we harmonised event definitions and defined several subcohorts for sensitivity analyses based on disease activity, treatment, calendar time, duration of follow-up and RCT exclusions. Rates were standardised for age, sex and, in one sensitivity analysis, also HAQ. The combined registry cohorts included 57 251 patients with RA (234 089 person-years)-24.5% men, mean (SD) baseline age 58.2 (13.8) and RA duration 8.2 (11.7) years. Standardised registry mortality rates (per 100 person-years) varied from 0.42 (CORRONA) to 0.80 (NOAR), with 0.60 for RCT patients. Myocardial infarction and major adverse cardiovascular events (MACE) rates ranged from 0.09 and 0.31 (IORRA) to 0.39 and 0.77 (SRR), with RCT rates intermediate (0.18 and 0.42), respectively. Additional subcohort analyses showed small and mostly consistent changes across registries, retaining reasonable consistency in rates across the Western registries. Additional standardisation for HAQ returned higher mortality and MACE registry rates. This coordinated approach to contextualising RA RCT safety data demonstrated reasonable differences and consistency in rates for mortality and CVD across registries, and comparable RCT rates, and may serve as a model method to supplement clinical trial analyses for drug development programmes.


Sociodemographic factors associated with obstacles to abortion care: findings from a survey of abortion patients in Mexico City.
First-trimester abortion was legalized in Mexico City in 2007, and services are now provided at public and private sites throughout the city. However, little is known about the obstacles women face when seeking abortion care. We surveyed women who obtained abortion services (n = 398) at three public sector facilities in Mexico City to identify the obstacles women faced when obtaining abortions. We used logistic regression to test whether obstacles varied by sociodemographic characteristics. Women with low education were more likely than high school-educated women to report difficulty getting appointments. Unmarried women and women with low education were more likely than married women or high school educated women to report difficulty getting time off work for appointments and arranging for transportation to the facility. Separated or divorced women were more likely than married women to report partner or other family member opposition to the abortion. Women who lived outside of Mexico City were more likely than Mexico City residents to report difficulty with transportation. Education, marital status, and place of residence were associated with the obstacles women reported. Strategies to improve access to care should be targeted to the groups at highest risk of experiencing obstacles: Women with primary education or lower, single women, separated/divorced women, and those residing outside of Mexico City.


Effects of exercise training and Mediterranean diet on vascular risk reduction in post-menopausal women.
This study tested the potential risk-reduction benefits of Mediterranean Diet (MD) and regular exercise training on microvascular activity and cardiorespiratory capacity in postmenopausal women. Fifteen sedentary postmenopausal participants (age = 54.6 ± 3.6) were randomised into either exercise training or exercise combined with following MD for eight-weeks, and were assessed for their cardiorespiratory capacity, and upper- and lower-limb endothelial cutaneous vascular conductance (CVC) test using Laser Doppler Fluximetry (LDF), coupled with measuring endothelium-dependent Acetylcholine Chloride (Ach) and -dependent Sodium Nitropurruside (SNP) vasodilators. Exercise training improved cardiorespiratory capacity as indicated by ventilatory threshold (11.5 ± 2.1 vs. 14.0 ± 3.0 ml·kg-1·min-1, p < 0.05) and improved the microcirculatory perfusion results of CVC for both vasodilators Ach (p < 0.001, d = 0.65) and SNP (p = 0.003, d = 0.53) in the lower-limb and ACh (p = 0.01, d = 0.41) and SNP (p = 0.03, d = 0.48) in the upper-limb, all (p < 0.05). However, combining exercise with MD showed a stronger improvement in Ach (p = 0.02, d = 0.36) of the lower limb, than in exercise alone group. The results suggest that regular moderate exercise improves microcirculatory vascular function and increases exercise tolerance, both are responsible for reducing cardiovascular risk in postmenopausal women. However, combining MD with exercise suggests additional microvascular vasodialiatory improvement, suggesting an effective strategy for further cardiovascular risk-reduction in this high-risk group.


Influence of Season and Soil Properties on Fungal Communities of Neighboring Climax Forests (Carpinus cordata and Fraxinus rhynchophylla).
Trees in forest ecosystems constantly interact with the soil fungal community, and this interaction plays a key role in nutrient cycling. The diversity of soil fungal communities is affected by both environmental factors and host tree species. We investigated the influence of both of these factors by examining the total fungal communities in the rhizospheric soil of climax tree species that have similar ecological roles (Carpinus cordata, an ectomycorrhizal [ECM] tree, and Fraxinus rhynchophylla, an arbuscular mycorrhizal [AM] tree) in temperate forests with continental climates of Mt. Jeombong, South Korea. Fungal communities were assessed by Illumina-MiSeq sequencing the internal transcribed spacer (ITS) region of environmental DNA, and comparing their environmental factors (season and soil properties). We found that soil fungi of the two forest types differed in terms of community structure and ecological guild composition. The total fungal community composition changed significantly with seasons and soil properties in the F. rhynchophylla forest, but not in the C. cordata forest. However, potassium and carbon were significantly correlated with fungal diversity in both forests, and a positive correlation was found only between symbiotrophs of C. cordata and the carbon to nitrogen (C/N) ratio. Thus, the effects of environmental factors on soil fungal communities depended on the host trees, but some factors were common in both forests. Our results indicate that individual tree species should be considered when anticipating how the fungal communities will respond to environmental change.


En face enhanced depth imaging optical coherence tomography of fibrovascular pigment epithelium detachment.
To analyze the internal structure of fibrovascular pigment epithelial detachment (FV-PED) due to AMD using en face enhanced depth imaging (EDI) spectral-domain optical coherence tomography (SD-OCT). Thirty-eight consecutive patients presenting with FV-PED due to AMD were enrolled in this study. Retinal images were automatically obtained with a spectral domain (SD) OCT instrument; the typical inverted 97 sections at 30-μm intervals, each comprised of nine averaged B-scans, were acquired in less than 60 seconds. The resultant images of en face cross-sections of the choroid (C-scans) were compared with indocyanine green angiography (ICGA) images, currently the only technique available for directly viewing occult choroidal neovascularization (CNV). Thirty-eight eyes of 38 consecutive patients (27 females and 11 males, mean age 76.7±3 years) were studied. In all 38 eyes, ICGA allowed visualization of the CNV within the FV-PED. In 30 eyes, en face EDI-OCT revealed what appeared to be the hyperreflective course of presumed CNV, which was located just beneath the detached retinal pigment epithelium; this was confirmed by comparative analysis of the extent of hyperreflective lesions on en face EDI-OCT images and that of the neovascular network on ICGA. An area of homogeneous hyporeflectivity, consistent with serous exudation, separated the CNV from the Bruch's membrane and the choroid. In the remaining eight eyes, en face EDI-OCT revealed homogenous hyperreflectivity, consistent with fibrous tissue that partially hid the neovascular network. Noninvasive en face EDI-OCT technique enables visualization and localization of the entire branching neovascular network of CNV within FV-PED without dye injection.


Phospholemman is a substrate for myotonic dystrophy protein kinase.
The genetic abnormality in myotonic muscular dystrophy, multiple CTG repeats lie upstream of a gene that encodes a novel protein kinase, myotonic dystrophy protein kinase (DMPK). Phospholemman (PLM), a major membrane substrate for phosphorylation by protein kinases A and C, induces Cl currents (I(Cl(PLM))) when expressed in Xenopus oocytes. To test the idea that PLM is a substrate for DMPK, we measured in vitro phosphorylation of purified PLM by DMPK. To assess the functional effects of PLM phosphorylation we compared I(Cl(PLM)) in Xenopus oocytes expressing PLM alone to currents in oocytes co-expressing DMPK, and examined the effect of DMPK on oocyte membrane PLM expression. We found that PLM is indeed a good substrate for DMPK in vitro. Co-expression of DMPK with PLM in oocytes resulted in a reduction in I(Cl(PLM)). This was most likely a specific effect of phosphorylation of PLM by DMPK, as the effect was not present in oocytes expressing a phos(-) PLM mutant in which all potential phosphorylation had been disabled by Ser --> Ala substitution. The biophysical characteristics of I(Cl(PLM)) were not changed by DMPK or by the phos(-) mutation. Co-expression of DMPK reduced the expression of PLM in oocyte membranes, suggesting a possible mechanism for the observed reduction in I(Cl(PLM)) amplitude. These data show that PLM is a substrate for phosphorylation by DMPK and provide functional evidence for modulation of PLM function by phosphorylation.


Association of catechol-O-methyltransferase (COMT) polymorphism and academic achievement in a Chinese cohort.
Catechol-O-methyltransferase (COMT) is a methylation enzyme that catalyzes the degradation pathway and inactivation of dopamine. It is accepted widely as being involved in the modulation of dopaminergic physiology and prefrontal cortex (PFC) function. The COMT Val158Met polymorphism is associated with variation in COMT activity. COMT 158Met allele may be advantageous for PFC-related cognitive abilities; however, it is also associated with increased anxiety, depression, and emotional vulnerability in response to stress or educational adversity. We hypothesized that the COMT polymorphism might be associated with academic performance. In this study, 779 Taiwanese tenth-grade volunteers were recruited. Scores from the Basic Competency Test (BCT), an annual national competitive entrance examination, were used to evaluate academic performance. The results indicated that students bearing homozygous for the Met allele tended to perform more poorly in all BCT subtests as compared to the other groups. In particular, the former performed significantly more poorly in the science and social science subtests. These findings provide evidence that affective factors might overwhelm cognitive abilities in high-stake tests like the BCT.


Association between cachexia, chemotherapy and outcomes in older cancer patients: A systematic review.
The aims of this systematic review were (i) to determine the prevalence of malnutrition and cachexia in older cancer patients in a chemotherapy setting, and (ii) to report the chemotherapy-related causes of malnutrition and (iii) the consequences of malnutrition on the outcomes of these patients. We searched MEDLINE for articles published in English or French between 2005 and 2016 and which reported retrospective or prospective, observational or interventional studies of the prevalence of malnutrition and its consequences in patients 65 years or older with solid tumors and chemotherapy-related causes of malnutrition. Malnutrition is prevalent up to 83% in older patients with cancer scheduled to receive chemotherapy. One third or more of patients were malnourished before receiving chemotherapy. A weight loss of 10% or more during the past three or six months was reported in 8%-40% of cancer patients, while a body mass index <21 kg/m2 was found in 10.7%-23%. Malnutrition was more prevalent in digestive (28%-75%) than in non-digestive cancers (8%-46.9%), and also in metastatic cancers (64%-76.5%). During the course of chemotherapy, weight loss was observed in 40%-91.6% of patients, depending on cancer location. The most frequently reported chemotherapy-related digestive symptoms likely to impair nutritional status were dry mouth, nausea, stomach pain, diarrhea and constipation. Low Mini-Nutritional-Assessment score was an independent predictor of early discontinuation of chemotherapy and increased the risk of mortality.


Predictors of Sexually Transmitted Infections among Female Sex Workers (FSWs) in a City of Northern India.
Sexually transmitted infections (STIs) and Reproductive tract infections RTIs are important public health problems in India. The prevalence of these infections is considerably higher among high risk groups (HRGs) ranging from 20-30%. It is high time that a study should be conducted to explore different factors and conditions responsible for the practice of unsafe sex among female sex workers (FSWs) in Uttar Pradesh (UP) and the impact of this on social life and health of FSWs. As Lucknow provides a comprehensive opportunity in terms of tourism, occupation, and economy, it becomes a potential hub for sex work. Studying FSW in Lucknow can thus be considered as a yardstick for the entire FSW population of UP population. The present study was thus planned with the objective of knowing the STI prevalence and its determinants among FSWs. A cross-sectional descriptive study was conducted on FSWs registered with Targeted Intervention-Non-government Organization (TI-NGO), registered with Uttar Pradesh State Acquired Immuno Deficiency Syndrome (AIDS) Control Society (UPSACS) of Lucknow city. Total 288 subjects were studied. The average age of FSWs was 31 years. FSWs were mostly Hindus and illiterate. The overall prevalence of STI as per Syndromic diagnosis was found to be 35.8%. However, the percentage of FSWs with STI was higher in street-based (50.6%) than home-based (29.8%). Majority (42.7%) of sex workers with STI had non-regular partners only while majority (52.4%) of sex workers without any STI had only regular partners. Condom usage with regular partners was poor. However, with the non-regular partners the condom usage was better. On multivariate analysis being single, having sex work as a sole means of earning, duration of sex work > 2 years, having pallor, and giving in to client's demand for unsafe sex were found to be significant in causing STI. Prevalence of STI among the female sex workers as per Syndromic diagnosis was found to be 35.8%. Unemployment, anemia, and having sex without condom for extra money, failure to persuade the client and not doing anything were found to be important predictors for presence of STI.


Nitrate causes deleterious effects on the behaviour and reproduction of the aquatic snail Potamopyrgus antipodarum (Hydrobiidae, Mollusca).
Nitrate (NO3 (-)) is present in aquatic ecosystems as a natural component of the nitrogen cycle. However, in the last decades, several human activities are the causes of the rising amounts of organic matter and inorganic nitrogen nutrients in aquatic ecosystems, causing notable increase of nitrate above background natural levels. In spite of the toxicity of nitrate to aquatic animals, there are relatively few studies on the chronic toxicity of this compound to invertebrates. The aim of our study is to assess the effect of chronic (35 days) exposure to nitrate on the behaviour (velocity of movement) and reproduction (number of newborns) of the aquatic snail Potamopyrgus antipodarum. Four actual concentrations of nitrate were used (21.4, 44.9, 81.8 and 156.1 mg N-NO3 (-)/L). In each treatment, 12 animals were individually monitored for velocity (weekly) and newborn production (every 3-4 days). Velocity was recorded using quantitative video monitoring. Our results showed that nitrate did not cause mortality, but it reduced the velocity of movement (at 44.9, 81.8 and 156.1 mg N-NO3 (-)/L) and number of live newborns (in all tested concentrations). Reproductive impairment was caused at realistic nitrate concentrations which is relevant to the risk assessment of this compound. Our study contributes to the knowledge of the chronic effects of nitrate on the behaviour and reproduction of an aquatic snail.


Generalization of motor learning depends on the history of prior action.
Generalization of motor learning refers to our ability to apply what has been learned in one context to other contexts. When generalization is beneficial, it is termed transfer, and when it is detrimental, it is termed interference. Insight into the mechanism of generalization may be acquired from understanding why training transfers in some contexts but not others. However, identifying relevant contextual cues has proven surprisingly difficult, perhaps because the search has mainly been for cues that are explicit. We hypothesized instead that a relevant contextual cue is an implicit memory of action with a particular body part. To test this hypothesis we considered a task in which participants learned to control motion of a cursor under visuomotor rotation in two contexts: by moving their hand through motion of their shoulder and elbow, or through motion of their wrist. Use of these contextual cues led to three observations: First, in naive participants, learning in the wrist context was much faster than in the arm context. Second, generalization was asymmetric so that arm training benefited subsequent wrist training, but not vice versa. Third, in people who had prior wrist training, generalization from the arm to the wrist was blocked. That is, prior wrist training appeared to prevent both the interference and transfer that subsequent arm training should have caused. To explain the data, we posited that the learner collected statistics of contextual history: all upper arm movements also move the hand, but occasionally we move our hands without moving the upper arm. In a Bayesian framework, history of limb segment use strongly affects parameter uncertainty, which is a measure of the covariance of the contextual cues. This simple Bayesian prior dictated a generalization pattern that largely reproduced all three findings. For motor learning, generalization depends on context, which is determined by the statistics of how we have previously used the various parts of our limbs.


Mitochondrial disease criteria: diagnostic applications in children.
Based on a previous prospective clinical and biochemical study, a consensus mitochondrial disease scoring system was established to facilitate the diagnosis in patients with a suspected mitochondrial disorder. To evaluate the specificity of the diagnostic system, we applied the mitochondrial disease score in 61 children with a multisystem disease and a suspected oxidative phosphorylation disorder who underwent a muscle biopsy and were consecutively diagnosed with a genetic mutation. We evaluated data of 44 children diagnosed with a disorder in oxidative phosphorylation, carrying a mutation in the mitochondrial or nuclear DNA. We compared them with 17 children who, based on the clinical and metabolic features, also had a muscle biopsy but were finally diagnosed with a nonmitochondrial multisystem disorder by further genetic analysis. All children with a genetically established diagnosis of a primary oxidative phosphorylation disorder had a mitochondrial disease score above 6 (probable mitochondrial disorder), and 73% of the children had a score above 8 (definite mitochondrial disorder) at evaluation of the muscle biopsy. In the nonmitochondrial multisystem disorder group, the score was significantly lower, and no patients reached a score comparable with a definite respiratory chain disorder. The mitochondrial disease criteria system has a high specificity to distinguish between mitochondrial and other multisystem disorders. The method could also be applied in children with a suspected mitochondrial disorder, prior to performing a muscle biopsy.


An interview with Mike Levine.
Mike Levine, director of the Lewis-Sigler Institute for Integrative Genomics at Princeton University, is a developmental biologist who has dedicated his career to understanding how gene expression is regulated during development. Some of his most significant research, such as the co-discovery of the homeobox genes and his work on even skipped stripe 2, was performed in Drosophila, but he has since branched out to Ciona intestinalis, which he is using as a model to understand how vertebrate features have evolved. We had a lively chat with Mike at this year's Society for Developmental Biology (SDB) meeting, where he was awarded the Edwin Grant Conklin Medal.


Relationship Between Physical Activity, Tic Severity and Quality of Life in Children with Tourette Syndrome.
To examine the relationship between physical activity, tic severity and quality of life (QoL) in children and adolescents with persistent tic disorder and Tourette Syndrome. Baseline data was examined from a larger randomized controlled trial (Clinicaltrials.gov NCT02153463). Physical activity was assessed via pedometers with daily step count recorded. Tic severity (assessed via Yale Global Tic Severity Scale or YGTSS) and QoL (assessed via PEDs QL 4.0) were compared between those more physically active (≥12,000 steps/day) and less physically active (<12,000 steps/day). Thirteen children participated; four had ≥12,000 steps/day and nine had <12,000 steps/day. The active group had a lower total tic severity (p = 0.02), and total YGTSS score (p=0.01). The vocal tic severity score was lower in the active group (p=0.02). Motor tic severity was not different amongst the two groups. For Peds QL scores, the active group performed better in physical functioning (p=0.01), social functioning (p=0.03), school functioning (p=0.02), psychosocial functioning (p=0.03) and total PEDs QL score (p=0.01). Higher physical activity levels are associated with lower vocal tic severity and improved aspects of quality of life. Further research is needed to determine the utility of physical activity as therapy for tics.


Short-term docosapentaenoic acid (22:5 n-3) supplementation increases tissue docosapentaenoic acid, DHA and EPA concentrations in rats.
The metabolic fate of dietary n-3 docosapentaenoic acid (DPA) in mammals is currently unknown. The aim of the present study was to determine the extent of conversion of dietary DPA to DHA and EPA in rats. Four groups of male weanling Sprague-Dawley rats (aged 5 weeks) were given 50 mg of DPA, EPA, DHA or oleic acid, daily for 7 d by gavage. At the end of the treatment period, the tissues were analysed for concentrations of long-chain PUFA. DPA supplementation led to significant increases in DPA concentration in all tissues, with largest increase being in adipose (5-fold) and smallest increase being in brain (1.1-fold). DPA supplementation significantly increased the concentration of DHA in liver and the concentration of EPA in liver, heart and skeletal muscle, presumably by the process of retroconversion. EPA supplementation significantly increased the concentration of EPA and DPA in liver, heart and skeletal muscle and the DHA concentration in liver. DHA supplementation elevated the DHA levels in all tissues and EPA levels in the liver. Adipose was the main tissue site for accumulation of DPA, EPA and DHA. These data suggest that dietary DPA can be converted to DHA in the liver, in a short-term study, and that in addition it is partly retroconverted to EPA in liver, adipose, heart and skeletal muscle. Future studies should examine the physiological effect of DPA in tissues such as liver and heart.


Evaluation of four techniques for injecting the trochanteric bursa of horses.
To describe the anatomic features of the equine trochanteric bursa and to evaluate 4 techniques for bursa centesis. Prospective, randomized design. Equine cadavers (n=2) and 20 live horses. The trochanteric bursae of 2 equine cadavers were injected with latex to identify the boundaries of the bursae. Four techniques for centesis of the trochanteric bursa were evaluated by attempting to inject dye into both trochanteric bursae of 20 live horses. Techniques included injection of the bursa with the limb-bearing weight and injection with the limb nonweight bearing and supported on a block, with or without ultrasonographic guidance of the needle. Ultrasonographic guidance of the needle was performed with or without the use of a guide channel attached to the ultrasound probe. Each of the 4 techniques was used to inject 10 bursae. The region of the bursa was dissected after horses were euthanatized to determine the location of the dye. The trochanteric bursa was most successfully injected with the limb positioned caudally with the foot on a block, even though topographic landmarks for centesis were more difficult to identify when the limb was in this position. The highest incidence of success was achieved when the needle was inserted using ultrasonographic guidance with the foot in a Hickman block. Positioning the limb caudally with the foot nonweight bearing and on a block facilitated centesis of the trochanteric bursa.


Impact of diagnostic misclassification on estimation of genetic correlations using genome-wide genotypes.
Disorders that share genetic risk factors often are placed in closely related diagnostic categories and treated similarly. Until recently, evidence for shared genetic etiology derived from classical research strategies--coaggregation in family and twin studies. Accumulating sufficient numbers of families was often problematic. However, in the era of genome-wide genotyping, we can now directly estimate the degree of sharing of genetic risk factors between disorders. This strategy is practical even for very rare disorders, where it is infeasible to ascertain informative families. Importantly, the estimates of genetic correlations from genome-wide genotypes are derived using such distant relatives that contamination by shared environmental factors seems unlikely. However, any method that seeks to quantify the shared etiology of disorders assumes they can be distinguished diagnostically from one another without error. Here we investigate the impact of misdiagnosis on estimates of genetic correlation both from traditional family data and from genome-wide genotypes of case-control samples from unrelated individuals. Our analyses show similar results for levels of misdiagnosis in both types of data. In both scenarios, genetic variances and heritabilities tend to be slightly underestimated but genetic correlations are overestimated, sometimes substantially so. For example, two genetically distinct but equally heritable disorders each with prevalence 1%, can generate false-positive estimates of genetic correlations of >0.2 in the presence of 10% reciprocal misdiagnosis. Strategies for minimizing the effects of misdiagnosis in cross-disorder genetic studies are discussed.


Understanding the Molecular Mechanisms Underpinning Gene by Environment Interactions in Psychiatric Disorders: The FKBP5 Model.
Epidemiologic and genetic studies suggest common environmental and genetic risk factors for a number of psychiatric disorders, including depression, bipolar disorder, and schizophrenia. Genetic and environmental factors, especially adverse life events, not only have main effects on disease development but also may interact to shape risk and resilience. Such gene by adversity interactions have been described for FKBP5, an endogenous regulator of the stress-neuroendocrine system, conferring risk for a number of psychiatric disorders. In this review, we present a molecular and cellular model of the consequences of FKBP5 by early adversity interactions. We illustrate how altered genetic and epigenetic regulation of FKBP5 may contribute to disease risk by covering evidence from clinical and preclinical studies of FKBP5 dysregulation, known cell-type and tissue-type expression patterns of FKBP5 in humans and animals, and the role of FKBP5 as a stress-responsive molecular hub modulating many cellular pathways. FKBP5 presents the possibility to better understand the molecular and cellular factors contributing to a disease-relevant gene by environment interaction, with implications for the development of biomarkers and interventions for psychiatric disorders.


Clinical group and modified TNM stage for rhabdomyosarcoma: A review from the Children's Oncology Group.
The Children's Oncology Group (COG) uses Clinical Group (CG) and modified Tumor Node Metastasis (TNM) stage to classify rhabdomyosarcoma (RMS). CG is based on surgicopathologic findings and is determined after the completion of initial surgical procedure(s) but prior to chemotherapy and/or radiation therapy. The modified TNM stage is based on clinical and radiographic findings and is assigned prior to any treatment. These systems have evolved over several decades. We review the history, evolution, and rationale behind the current CG and modified TNM classification systems used by COG for RMS. Data from the seven most recently completed and reported frontline COG trials (D9602, D9802, D9803, ARST0331, ARST0431, ARST0531, ARST08P1) were analyzed, and confirm that CG and modified TNM stage remain relevant and useful for predicting prognosis in RMS. We propose updates based on recent data and discuss factors warranting future study to further optimize these classification systems.