Genetic control of neuronal migrations in human cortical development.
The early steps in corticogenesis are decisive for the correct unfolding of neurogenesis, neuronal migration and differentiation under tight genetic control. In this monograph, we outline the main events in human preplate formation, the gradual transformation of the preplate into the cortical plate, and the establishment of the transient compartments of the foetal cortical wall. The main neuronal populations of the embryonic and fetal cortex are presented according to their timetable of appearance and the expression of developmentally relevant gene products, with the main focus on members of the Reelin-Dab1 signalling pathway, LIS1 and Doublecortin, all of which are crucial for cortical migration. The often significant developmental differences between the lissencephalic rodent brain, which has become the prevailing model of corticogenesis, and the highly differentiated, gyrated human brain are pointed out and discussed.


Scoping review of priority setting of research topics for musculoskeletal conditions.
Describe research methods used in priority-setting exercises for musculoskeletal conditions and synthesise the priorities identified. Scoping review. Studies that elicited the research priorities of patients/consumers, clinicians, researchers, policy-makers and/or funders for any musculoskeletal condition were included. We searched MEDLINE and EMBASE from inception to November 2017 and the James Lind Alliance top 10 priorities, Cochrane Priority Setting Methods Group, and Cochrane Musculoskeletal and Back Groups review priority lists. The reported methods and research topics/questions identified were extracted, and a descriptive synthesis conducted. Forty-nine articles fulfilled our inclusion criteria. Methodologies and stakeholders varied widely (26 included a mix of clinicians, consumers and others, 16 included only clinicians, 6 included only consumers or patients and in 1 participants were unclear). Only two (4%) reported any explicit inclusion criteria for priorities. We identified 294 broad research priorities from 37 articles and 246 specific research questions from 17 articles, although only four (24%) of the latter listed questions in an actionable format. Research priorities for osteoarthritis were identified most often (n=7), followed by rheumatoid arthritis (n=4), osteoporosis (n=4) and back pain (n=4). Nearly half of both broad and specific research priorities were focused on treatment interventions (n=116 and 111, respectively), while few were economic (n=8, 2.7% broad and n=1, 0.4% specific), implementation (n=6, 2% broad and n=4, 1.6% specific) or health services and systems research (n=15, 5.1% broad and n=9, 3.7% specific) priorities. While many research priority-setting studies in the musculoskeletal field have been performed, methodological limitations and lack of actionable research questions limit their usefulness. Future studies should ensure they conform to good priority-setting practice to ensure that the generated priorities are of maximum value. CRD42017059250.


Collagen density and alignment in responsive and resistant trastuzumab-treated breast cancer xenografts.
Tumor collagen characteristics influence tumor malignancy, invasion, and metastasis. This study investigates the effects of trastuzumab (Tz) on the collagen of Tz-responsive (BT474) and Tz-resistant (HR6) breast cancer xenografts. Collagen content was assessed by in vivo second harmonic generation (SHG) imaging and histological trichrome staining of tumor sections. Collagen SHG imaging of control BT474 and HR6 tumors demonstrated increased collagen density after 14 days of treatment (p < 0.05). Trichrome staining revealed decreased collagen in Tz-treated BT474 and HR6 tumors at 2, 5, and 14 days of treatment, suggesting that Tz affects the tumor microenvironment independent of epithelial cell response. Additionally, collagen alignment analysis revealed significantly less aligned collagen in the Tz-treated BT474 tumors at day 14 compared with control BT474 tumors. There was no correlation between SHG endpoints (collagen density and alignment) and trichrome staining (p > 0.05), consistent with the physically distinctive nature of these measurements. There was also no correlation between tumor size and collagen endpoints (p > 0.05). These results identify changes within the collagen compartment of the tumor microenvironment following Tz treatment, which are independent from the tumor cell response to Tz, and demonstrate that intravital collagen SHG imaging is capable of measuring dynamic changes in tumor microenvironment following treatment that complements trichrome staining.


Association between visceral and subcutaneous adiposity and clinicopathological outcomes in non-metastatic clear cell renal cell carcinoma.
Visceral adiposity has been inconsistently associated with clinicopathologic features and outcomes of clear cell renal cell carcinoma (ccRCC); however, most studies were conducted in non-Western populations. We evaluated the associations between visceral and subcutaneous adiposity and clinicopathological characteristics of non-metastatic ccRCC patients in a Western population. The medical records of 220 surgically treated ccRCC patients with documented preoperative body mass index (BMI) and computed tomography (CT) scans were retrospectively reviewed. Nineteen patients with stage IV disease were excluded. Visceral (VFA) and subcutaneous fat area (SFA) were computed from pre-operative CT scans. Correlations between obesity measures were assessed with Pearson correlation. Associations between obesity measures and pathologic features were evaluated using logistic regression models adjusted for sex. Overall survival (OS) probabilities were estimated using Cox regression analysis. The log-rank test was used for group comparisons. The study cohort comprised 150 men and 51 women. Women had higher SFA (p = 0.01) but lower VFA (p < 0.001) than men. BMI was highly correlated with SFA (r = 0.804) and moderately correlated with VFA (r = 0.542). SFA and VFA were weakly correlated (r = 0.367). An increased BMI was associated with a better OS (p = 0.028). When adjusting for sex, neither SFA nor VFA was significantly associated with tumour grade, stage, or OS. Consistent with prior reports, our study suggests that increased BMI is associated with a better OS for patient with nonmetastatic ccRCC. Despite the high correlation between SFA and BMI, neither SFA nor VFA were significantly associated with tumour stage, grade, or OS in the current study; however, further studies in larger cohorts are required to validate this finding.


Does this patient have an exudative pleural effusion? The Rational Clinical Examination systematic review.
Thoracentesis is performed to identify the cause of a pleural effusion. Although generally safe, thoracentesis may be complicated by transient hypoxemia, bleeding, patient discomfort, reexpansion pulmonary edema, and pneumothorax. To identify the best means for differentiating between transudative and exudative effusions and also to identify thoracentesis techniques for minimizing the risk of complications by performing a systematic review the evidence. We searched The Cochrane Library, MEDLINE, and Embase from inception to February 2014 to identify relevant studies. We included randomized and observational studies of adult patients undergoing thoracentesis that examined diagnostic tests for differentiating exudates from transudates and evaluated thoracentesis techniques associated with a successful procedure with minimal complications. Two investigators independently appraised study quality and extracted data from studies of laboratory diagnosis of pleural effusion for calculation of likelihood ratios (LRs; n = 48 studies) and factors affecting adverse event rates (n = 37 studies). The diagnosis of an exudate was most accurate if cholesterol in the pleural fluid was greater than 55 mg/dL (LR range, 7.1-250), lactate dehydrogenase (LDH) was greater than 200 U/L (LR, 18; 95% CI, 6.8-46), or the ratio of pleural fluid cholesterol to serum cholesterol was greater than 0.3 (LR, 14; 95% CI, 5.5-38). A diagnosis of exudate was less likely when all Light's criteria (a ratio of pleural fluid protein to serum protein >0.5, a ratio of pleural fluid LDH to serum LDH >0.6, or pleural fluid LDH >two-thirds the upper limit of normal for serum LDH) were absent (LR, 0.04; 95% CI, 0.02-0.11). The most common complication of thoracentesis was pneumothorax, which occurred in 6.0% of cases (95% CI, 4.0%-7.0%). Chest tube placement was required in 2.0% of procedures (95% CI, 0.99%-2.9%) in which a patient was determined to have radiographic evidence of a pneumothorax. With ultrasound, a radiologist's marking the needle insertion site was not associated with decreased pneumothorax events (skin marking vs no skin marking odds ratio [OR], 0.37; 95% CI, 0.08-1.7). Use of ultrasound by any experienced practitioner also was not associated with decreased pneumothorax events (OR, 0.55; 95% CI, 0.06-5.3). Light's criteria, cholesterol and pleural fluid LDH levels, and the pleural fluid cholesterol-to-serum ratio are the most accurate diagnostic indicators for pleural exudates. Ultrasound skin marking by a radiologist or ultrasound-guided thoracentesis were not associated with a decrease in pneumothorax events.


Noninvasive positive-pressure ventilation as a weaning strategy for intubated adults with respiratory failure.
Noninvasive positive-pressure ventilation (NPPV) provides ventilatory support without the need for an invasive airway. Interest has emerged in using NPPV to facilitate earlier removal of an endotracheal tube and to decrease complications associated with prolonged intubation. We evaluated studies in which invasively ventilated adults with respiratory failure of any cause (chronic obstructive pulmonary disease (COPD), non-COPD, postoperative, nonoperative) were weaned by means of early extubation followed by immediate application of NPPV or continued IPPV weaning. The primary objective was to determine whether the noninvasive positive-pressure ventilation (NPPV) strategy reduced all-cause mortality compared with invasive positive-pressure ventilation (IPPV) weaning. Secondary objectives were to ascertain differences between strategies in proportions of weaning failure and ventilator-associated pneumonia (VAP), intensive care unit (ICU) and hospital length of stay (LOS), total duration of mechanical ventilation, duration of mechanical support related to weaning, duration of endotracheal mechanical ventilation (ETMV), frequency of adverse events (related to weaning) and overall quality of life. We planned sensitivity and subgroup analyses to assess (1) the influence on mortality and VAP of excluding quasi-randomized trials, and (2) effects on mortality and weaning failure associated with different causes of respiratory failure (COPD vs. mixed populations). We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 5, 2013), MEDLINE (January 1966 to May 2013), EMBASE (January 1980 to May 2013), proceedings from four conferences, trial registration websites and personal files; we contacted authors to identify trials comparing NPPV versus conventional IPPV weaning. Randomized and quasi-randomized trials comparing early extubation with immediate application of NPPV versus IPPV weaning in intubated adults with respiratory failure. Two review authors independently assessed trial quality and abstracted data according to prespecified criteria. Sensitivity and subgroup analyses assessed (1) the impact of excluding quasi-randomized trials, and (2) the effects on selected outcomes noted with different causes of respiratory failure. We identified 16 trials, predominantly of moderate to good quality, involving 994 participants, most with chronic obstructive pulmonary disease (COPD). Compared with IPPV weaning, NPPV weaning significantly decreased mortality. The benefits for mortality were significantly greater in trials enrolling exclusively participants with COPD (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.24 to 0.56) versus mixed populations (RR 0.81, 95% CI 0.47 to 1.40). NPPV significantly reduced weaning failure (RR 0.63, 95% CI 0.42 to 0.96) and ventilator-associated pneumonia (RR 0.25, 95% CI 0.15 to 0.43); shortened length of stay in an intensive care unit (mean difference (MD) -5.59 days, 95% CI -7.90 to -3.28) and in hospital (MD -6.04 days, 95% CI -9.22 to -2.87); and decreased the total duration of ventilation (MD -5.64 days, 95% CI -9.50 to -1.77) and the duration of endotracheal mechanical ventilation (MD - 7.44 days, 95% CI -10.34 to -4.55) amidst significant heterogeneity. Noninvasive weaning also significantly reduced tracheostomy (RR 0.19, 95% CI 0.08 to 0.47) and reintubation (RR 0.65, 95% CI 0.44 to 0.97) rates. Noninvasive weaning had no effect on the duration of ventilation related to weaning. Exclusion of a single quasi-randomized trial did not alter these results. Subgroup analyses suggest that the benefits for mortality were significantly greater in trials enrolling exclusively participants with COPD versus mixed populations. Summary estimates from 16 trials of moderate to good quality that included predominantly participants with COPD suggest that a weaning strategy that includes NPPV may reduce rates of mortality and ventilator-associated pneumonia without increasing the risk of weaning failure or reintubation.


The effect of a nanothickness coating on rough titanium substrate in the osteogenic properties of human bone cells.
This study evaluated the effect of a bioactive ceramic coating, in the nanothickness range, onto a moderately rough surface on the osteogenic behavior of human bone cells. The cells were harvested from the mandibular mental region and were cultured over Ti-6Al-4V disks of different surfaces: as-machined (M), alumina-blasted/acid etched (AB/AE), and alumina-blasted/acid-etched + 300-500 nm thickness amorphous Ca- and P-based coating obtained by ion beam-assisted deposition (Nano). The culture was then evaluated regarding cell viability, adhesion, morphology, immunolocalization of osteopontin (OPN) and alkaline phosphatase (ALP). The results showed that the surface treatment did not interfere with cell viability. At 1 day, AB/AE and Nano showed higher adhesion than the M surface (p < 0.001). Higher adhesion was observed for the M than the Nano surface at 7 days (p < 0.005). The percentage of cells showing intracellular labeling for OPN at day 1 was significantly higher for the Nano compared to M surface (p < 0.03). The percentage of ALP intracellular labeling at 7 days was significantly higher for the AB/AE compared to the M surface (p < 0.0065); no differences were detected at 14 days. Our results suggest that the presence of a thin bioactive ceramic coating on a rough substrate did not favor the events related to in vitro osteogenesis. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.


Blood Pressure Variability and Cognitive Function Among Older African Americans: Introducing a New Blood Pressure Variability Measure.
Although blood pressure (BP) variability has been reported to be associated with cognitive impairment, whether this relationship affects African Americans has been unclear. We sought correlations between systolic and diastolic BP variability and cognitive function in community-dwelling older African Americans, and introduced a new BP variability measure that can be applied to BP data collected in clinical practice. We assessed cognitive function in 94 cognitively normal older African Americans using the Mini-Mental State Examination (MMSE) and the Computer Assessment of Mild Cognitive Impairment (CAMCI). We used BP measurements taken at the patients' three most recent primary care clinic visits to generate three traditional BP variability indices, range, standard deviation, and coefficient of variation, plus a new index, random slope, which accounts for unequal BP measurement intervals within and across patients. MMSE scores did not correlate with any of the BP variability indices. Patients with greater diastolic BP variability were less accurate on the CAMCI verbal memory and incidental memory tasks. Results were similar across the four BP variability indices. In a sample of cognitively intact older African American adults, BP variability did not correlate with global cognitive function, as measured by the MMSE. However, higher diastolic BP variability correlated with poorer verbal and incidental memory. By accounting for differences in BP measurement intervals, our new BP variability index may help alert primary care physicians to patients at particular risk for cognitive decline.


Dual-Use Nano-Neurotechnology: An assessment of the implications of trends in science and technology.
The chemical and biological nonproliferation regime stands at a watershed moment, when failure seems a real possibility. After the unsuccessful outcome of the 2016 Eighth Review Conference, the future of the Biological and Toxin Weapons Convention is uncertain. As the Chemical Weapons Convention (CWC) approaches its Fourth Review Conference in 2018, it has almost completed removing the huge stocks of chemical weapons, but it now faces the difficult organizational task of moving its focus to preventing the reemergence of chemical weapons at a time when the international security situation appears to be increasingly more difficult and dangerous. In this article, we assess the current and near-term state (5-10 years) and impact of three related areas of science and technology that could be of dual-use concern: targeted delivery of agents to the central nervous system (CNS), particularly by means of nanotechnology; direct impact of nanomaterials on synaptic functions in the CNS; and neuronal circuits in the brain that might be targeted by those with hostile intent. We attempt to assess the implications of our findings, particularly for the consideration of the problem of state-level interest in so-called nonlethal incapacitating chemical agents for law enforcement at the CWC Review Conference in 2018, but also more generally for the longer-term future of the chemical and biological nonproliferation regime.


MRG1 expression in fibroblasts is regulated by Sp1/Sp3 and an Ets transcription factor.
MRG1 (melanocyte-specific gene 1 (MSG1)-related gene), a ubiquitously expressed transcription factor that interacts with p300/CBP, TATA-binding protein and Lhx2, is the founding member of a new family of transcription factors. Initial characterization of this newly discovered transcription factor has underscored its potential involvement in many important cellular processes through transcriptional modulation. We previously demonstrated that MRG1 can be induced by various biological stimuli (Sun, H. B., Zhu, Y. X., Yin, T., Sledge, G., and Yang, Y. C. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 13555-13560). As a first step in understanding its role in different biological processes, we investigated mechanisms that regulate transcription of the mouse MRG1 gene in fibroblasts. Transient transfection of Rat1 fibroblast cells with sequential 5'-deletions of mouse MRG1 promoter-luciferase fusion constructs indicated that the -104 to +121 region contains the full promoter activity. Deletion and site-directed mutations within this region revealed that the Ets-1 site at -97 to -94 and the Sp1 site at -51 to -46 are critical for MRG1 expression in fibroblasts. Gel mobility shift and supershift assays performed with Rat1 nuclear extracts identified nucleoprotein complexes binding to the Ets-1 site and the Sp1 site. In Drosophila SL2 cells, which lack the Sp and Ets family of transcription factors, expression of Sp1, Sp3, and Ets-1 or Elf-1 functionally stimulated MRG1 promoter activity in a synergistic manner. These results suggest that multiple transcription factors acting in synergy are responsible for MRG1 expression and the responsiveness of cells to different biological stimuli.


Highly reflective Bragg gratings in slightly etched step-index polymer optical fiber.
During the past few years, a strong progress has been made in the photo-writing of fiber Bragg gratings (FBGs) in polymer optical fibers (POFs), animated by the constant wish to enhance the grating reflectivity and improve the sensing performances. In this paper, we report the photo-inscription of highly reflective gratings in step-index POFs, obtained thanks to a slight etching of the cladding. We demonstrate that a cladding diameter decrease of ~12% is an ideal trade-off to produce highly reflective gratings with enhanced axial strain sensitivity, while keeping almost intact their mechanical resistance. For this, we make use of Trans-4-stilbenemethanol-doped photosensitive step-index poly(methyl methacrylate) (PMMA) POFs. FBGs are inscribed at ~1550 nm by the scanning phase mask technique in POFs of different external diameters. Reflectivity reaching 97% is achieved for 6 mm long FBGs, compared to 25% for non-etched POFs. We also report that a cladding decrease enhances the FBG axial tension while keeping unchanged temperature and surrounding refractive index sensitivities. Finally and for the first time, a measurement is conducted in transmission with polarized light, showing that a photo-induced birefringence of 7 × 10(-6) is generated (one order of magnitude higher than the intrinsic fiber birefringence), which is similar to the one generated in silica fiber using ultra-violet laser.


The influence of stress and social support on depressive symptoms in mothers with young children.
Limited research has examined the associations of stress, social support, and depression among mothers with young children over time. Longitudinal studies are needed to identify risk and protective factors for maternal depression given that depression can be cyclical and may affect women through the early years of their children's development. This study examined the relationships among stress, social support, and depressive symptoms in a national sample of low-income urban American women with young children. A secondary data analysis of the Fragile Families and Child Wellbeing Study, a national longitudinal panel study of nearly 5000 births across 20 cities with populations of 200,000 or more in the United States, was conducted. The analytic sample included all mothers (N = 3675) who completed assessments at baseline through year 5 of the study between 1998 and 2005. Multivariate models using generalized estimating equations were used to estimate the probability of being depressed as a function of stress-related risk factors, social support factors, and sociodemographic variables. The rate of depression each year ranged from 15% to 21%. The results suggest that stress related to economic hardship, parenting, and poor physical health increases the risk of depression among low-income urban mothers with young children. Instrumental and partner support were found to be potential protective factors in reducing the negative effects of stress, but only to a certain degree. Future efforts are needed to strengthen social support and mitigate chronic stressors that contribute to mental health problems in low-income communities.


Latitudinal variability in the seroprevalence of antibodies against Toxoplasma gondii in non-migrant and Arctic migratory geese.
Toxoplasma gondii is an intracellular coccidian parasite found worldwide and is known to infect virtually all warm-blooded animals. It requires a cat (family Felidae) to complete its full life cycle. Despite the absence of wild felids on the Arctic archipelago of Svalbard, T. gondii has been found in resident predators such as the arctic fox and polar bear. It has therefore been suggested that T. gondii may enter this ecosystem via migratory birds. The objective of this study was to identify locations where goose populations may become infected with T. gondii, and to investigate the dynamics of T. gondii specific antibodies. Single blood samples of both adults and juveniles were collected from selected goose species (Anser anser, A. brachyrhynchus, Branta canadensis, B. leucopsis) at Arctic brood-rearing areas in Russia and on Svalbard, and temperate wintering grounds in the Netherlands and Denmark (migratory populations) as well as temperate brood-rearing grounds (the Netherlands, non-migratory populations). A modified agglutination test was used on serum, for detection of antibodies against T. gondii. Occasional repeated annual sampling of individual adults was performed to determine the antibody dynamics. Adults were found seropositive at all locations (Arctic and temperate, brood-rearing and wintering grounds) with low seroprevalence in brood-rearing birds on temperate grounds. As no juvenile geese were found seropositive at any brood-rearing location, but nine month old geese were found seropositive during spring migration we conclude that geese, irrespective of species and migration, encounter T. gondii infection in wintering areas. In re-sampled birds on Svalbard significant seroreversion was observed, with 42% of seropositive adults showing no detectable antibodies after 12 months, while the proportion of seroconversion was only 3%. Modelled variation of seroprevalence with field data on antibody longevity and parasite transmission suggests seroprevalence of a population within a range of 5.2-19.9%, in line with measured values. The high occurrence of seroreversion compared to the low occurrence of seroconversion hampers analysis of species- or site-specific patterns, but explains the absence of an increase in seroprevalence with age and the observed variation in antibody titre. These findings imply that even though infection rate is low, adults introduce T. gondii to the high Arctic ecosystem following infection in temperate regions.


Bile: miRNA pattern and protein-based biomarkers may predict acute cellular rejection after liver transplantation.
Bile rather than blood depicts the local inflammation in the liver and may improve prediction and diagnosis of acute cellular rejection (ACR) after liver transplantation (OLT). Secretome and miRNAs were analyzed during the first two weeks and on clinical suspicion of ACR in the bile of 45 OLT recipients. Levels of CD44, CXCL9, miR-122, miR-133a, miR-148a and miR-194 were significantly higher in bile of patients who developed ACR within the first 6 months after OLT and during ACR. Analysis of secretome and miRNA in bile could improve our understanding of the local inflammatory process during rejection.


Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2.
Metanephric mesenchyme gives rise to both the epithelial cells of the nephron and the stromal cells of the mature kidney. The function of the stroma. in kidney morphogenesis is poorly understood. We have generated mice with a null mutation in the Winged Helix (WH) transcription factor BF-2 to examine its function during development. BF-2 expression within the developing kidney is restricted to the stromal cell lineage. Homozygotes die within the first 24 hr after birth with abnormal kidneys. Mutant kidneys are small, fused longitudinally, and rotated 90 degrees ventrally. Histological examination reveals a smaller collecting system, numerous large condensations of mesenchyme, and a decrease in the number of nephrons. Using molecular markers we show that induction and condensation of the nephrogenic mesenchyme occurs normally in mutant. The disruption of BF-2 reduces the rate of differentiation of the condensed mesenchyme into tubular epithelium, as well as the rate of growth and branching of the ureter and collecting system. Our findings demonstrate that BF-2 and stromal cells have essential functions during kidney morphogenesis. Furthermore, they suggest that BF-2 controls the production, by the stroma, of signals or factors that are required for the normal transition of induced mesenchyme into tubular epithelium and full growth and branching of the collecting system.


Multimodal evaluation of xenograft tumors in mice with an in-vivo stereo imaging system and small-animal PET/CT.
In small-animal studies, calipers are the standard method used for measurement of external tumor size. However, as tumors are not usually prolate spheroids, this may lead to inaccuracies in the data. Also, correlations vary according to the kind and size of tumors. Tumors were generated by transplanting B16 mouse melanoma cells into the back of Balb/c nude mice. True volumes were measured by calipers, an in-vivo stereo imaging system, and as a standard uptake value (SUV) by (18)F-fluorodeoxyglucose ([(18)F]FDG)-PET. Correlations between measurements were analyzed. Correlation with the true volume was higher for measurements using the in-vivo stereo imaging system (r = 0.876) than with calipers (r = 0.744). Measurement of melanoma volume has a larger measuring error when performed using a caliper compared with measurements performed by stereo imaging when the volume of the melanoma is small. Correlation of the volume and PET-SUV by a caliper is low as the size of the melanoma increases. This same relationship exists with the comparison of stereo imaging and PET-SUV. The correlation between the SUV of [(18)F]FDG-PET and tumor volume with the melanoma is expected to be important in related future studies.


Autonomic nervous system monitoring in intensive care as a prognostic tool. Systematic review.
To present a systematic review of the use of autonomic nervous system monitoring as a prognostic tool in intensive care units by assessing heart rate variability. Literature review of studies published until July 2016 listed in PubMed/Medline and conducted in intensive care units, on autonomic nervous system monitoring, via analysis of heart rate variability as a prognostic tool (mortality study). The following English terms were entered in the search field: ("autonomic nervous system" OR "heart rate variability") AND ("intensive care" OR "critical care" OR "emergency care" OR "ICU") AND ("prognosis" OR "prognoses" OR "mortality"). There was an increased likelihood of death in patients who had a decrease in heart rate variability as analyzed via heart rate variance, cardiac uncoupling, heart rate volatility, integer heart rate variability, standard deviation of NN intervals, root mean square of successive differences, total power, low frequency, very low frequency, low frequency/high frequency ratio, ratio of short-term to long-term fractal exponents, Shannon entropy, multiscale entropy and approximate entropy. In patients admitted to intensive care units, regardless of the pathology, heart rate variability varies inversely with clinical severity and prognosis.


Estimating 'net' HIV-related mortality and the importance of background mortality rates.
To estimate mortality directly attributable to HIV in HIV-infected adults in low and middle income countries and discuss appropriate methodology. : Illustrative analysis of pooled data from six studies across sub-Saharan Africa and Thailand with data on individuals with known dates of seroconversion to HIV. Five of the studies also had data from HIV-negative subjects and one had verbal autopsies. Data for HIV-negative cohorts were weighted by the initial age and sex distribution of the seroconverters. Using the survival of the HIV-negative group to represent the background mortality, net survival from HIV was calculated for the seroconverters using competing risk methods. Mortality from all causes and 'net' mortality were modelled using piecewise exponential regression. Alternative approaches are explored in the dataset without information on mortality of uninfected individuals. The overall effect of the net mortality adjustment was to increase survivorship proportionately by 2 to 5% at 6 years post-infection. The increase ranged from 2% at ages 15-24 to 22% in those 55 and over. Mortality rate ratios between sites were similar to corresponding ratios for all-cause mortality. Differences between HIV mortality in different populations and age groups are not explained by differences in background mortality, although this does appear to contribute to the excess at older ages. In the absence of data from uninfected individuals in the same population, model life tables can be used to calculate background rates.


Age-related effects in the neocortical organization of chimpanzees: gray and white matter volume, cortical thickness, and gyrification.
Among primates, humans exhibit the most profound degree of age-related brain volumetric decline in particular regions, such as the hippocampus and the frontal lobe. Recent studies have shown that our closest living relatives, the chimpanzees, experience little to no volumetric decline in gray and white matter over the adult lifespan. However, these previous studies were limited with a small sample of chimpanzees of the most advanced ages. In the present study, we sought to further test for potential age-related decline in cortical organization in chimpanzees by expanding the sample size of aged chimpanzees. We used the BrainVisa software to measure total brain volume, gray and white matter volumes, gray matter thickness, and gyrification index in a cross-sectional sample of 219 captive chimpanzees (8-53 years old), with 38 subjects being 40 or more years of age. Mean depth and cortical fold opening of 11 major sulci of the chimpanzee brains were also measured. We found that chimpanzees showed increased gyrification with age and a cubic relationship between age and white matter volume. For the association between age and sulcus depth and width, the results were mostly non-significant with the exception of one negative correlation between age and the fronto-orbital sulcus. In short, results showed that chimpanzees exhibit few age-related changes in global cortical organization, sulcus folding and sulcus width. These findings support previous studies and the theory that the age-related changes in the human brain is due to an extended lifespan.


A Better Way to Attend: Attention with Trees for Video Question Answering.
We propose a new attention model for video question answering. The main idea of the attention models is to locate on the most informative parts of the visual data. The attention mechanisms are quite popular these days. However, most existing visual attention mechanisms regard the question as a whole. They ignore the word-level semantics where each word can have different attentions and some words need no attention. Neither do they consider the semantic structure of the sentences. Although the Extended Soft Attention (E-SA) model for video question answering leverages the word-level attention, it performs poorly on long question sentences. In this paper, we propose the heterogeneous tree-structured memory network (HTreeMN) for video question answering. Our proposed approach is based upon the syntax parse trees of the question sentences. The HTreeMN treats the words differently where the visual words are processed with an attention module and the verbal ones not. It also utilizes the semantic structure of the sentences by combining the neighbors based on the recursive structure of the parse trees. The understandings of the words and the videos are propagated and merged from leaves to the root. Furthermore, we build a hierarchical attention mechanism to distill the attended features. We evaluate our approach on two datasets. The experimental results show the superiority of our HTreeMN model over the other attention models especially on complex questions.


Clean versus sterile technique for common joint injections: a review from the physiatry perspective.
Preparation of the skin prior to joint injection varies widely among disciplines and across regional borders. This is likely due to the paucity of literature on the most effective and efficient methods of preparation. There is no standard definition of clean technique prior to joint injection. Review of the available literature suggests that alcohol is effective preparation for the skin prior to most procedures. Surveys of current clinical practice demonstrate that the use of gloves may be favored, but no conclusions can be drawn in regards to whether sterile gloves are required. Clean technique should be defined as use of non-sterile gloves and agents such as alcohol or soap prior to injection. Significant cost savings may be achieved with the consistent use of clean technique for preparation of the skin prior to joint injection. Further study should address the incidence of iatrogenic bacterial arthritis following clean technique versus sterile technique for joint injection.


The process of setting micronutrient recommendations: a cross-European comparison of nutrition-related scientific advisory bodies.
To examine the workings of the nutrition-related scientific advisory bodies in Europe, paying particular attention to the internal and external contexts within which they operate. Desk research based on two data collection strategies: a questionnaire completed by key informants in the field of micronutrient recommendations and a case study that focused on mandatory folic acid (FA) fortification. Questionnaire-based data were collected across thirty-five European countries. The FA fortification case study was conducted in the UK, Norway, Denmark, Germany, Spain, Czech Republic and Hungary. Varied bodies are responsible for setting micronutrient recommendations, each with different statutory and legal models of operation. Transparency is highest where there are standing scientific advisory committees (SAC). Where the standing SAC is created, the range of expertise and the terms of reference for the SAC are determined by the government. Where there is no dedicated SAC, the impetus for the development of micronutrient recommendations and the associated policies comes from interested specialists in the area. This is typically linked with an ad hoc selection of a problem area to consider, lack of openness and transparency in the decisions and over-reliance on international recommendations. Even when there is consensus about the science behind micronutrient recommendations, there is a range of other influences that will affect decisions about the policy approaches to nutrition-related public health. This indicates the need to document the evidence that is drawn upon in the decisions about nutrition policy related to micronutrient intake.


Physician-community health worker partnering to support diabetes self-management in primary care.
The role of community health workers (CHWs) has expanded from outreach and education to working within a clinical team in a primary care setting. To improve self-management among patients with type 2 diabetes incorporating CHWs as members of a clinical team. A cohort of 114 patients with type 2 diabetes enrolled in 2007 participated in a teambased self-management intervention with followup in 2008. The study assessed whether significant changes occurred in clinical, patient satisfaction and activation measures after the intervention compared with baseline. The programme was located at St Luke's Health Care Center in San Francisco, California, in an ethnically diverse neighbourhood serving predominantly low-income Latino patients. Clinical outcomes measured included glycosylated haemoglobin (HbA1c), low-density lipoprotein (LDL), blood pressure and total cholesterol. A Patient Activation Measure (PAM) assessed self-management. Both provider and patient experiences with the programme were also assessed using a patient telephone satisfaction survey and provider focus group. The majority of patients were Latino Spanish speaking women on public insurance. Thirty-one patients participated in a telephone satisfaction survey. Six providers participated in a focus group to assess satisfaction with care. HealthFirst had a positive impact, improving HbA1c among high-risk patients with type 2 diabetes (HbA1c≥ 9.0) and maintaining glycaemic control among patients with controlled glycaemic level at baseline (HbA1c<7.0). In addition, LDL, total cholesterol and self-management outcomes significantly improved. Ninety-seven percent of patients were satisfied with the CHWs' support. Overall, providers' comfort level in referring patients to CHWs was very high. Physician-CHW partnership had a positive impact on patients' self-management skills and clinical outcomes. Patients and physicians also had higher satisfaction with overall care. With appropriate training, CHWs can collaborate as team members with primary care providers and with non-medical providers to improve the quality of care.


Investigating the surface expression of the renal type IIa Na+/Pi-cotransporter in Xenopus laevis oocytes.
We have combined a functional assay, surface labeling and immunocytochemical methods to compare total and surface-exposed renal type IIa Na+/Pi cotransporter protein. The wild-type type cotransporter (NaPi-IIa) and its functionally comparable cysteine mutant S460C were expressed in Xenopus oocytes. S460C contains a novel cysteine residue that, when modified by preincubation with methanethiosulfonate reagents, leads to complete suppression of cotransport function. This allowed surface labeling of the S460C using MTSEA-Biotin and confirmation by electrophysiology on the same cell. Protein was analyzed by Western blotting before and after streptavidin precipitation and by immunocytochemistry and immunogold electronmicroscopy. MTSEA-Biotin treatment resulted in a complete inhibition of S460C-mediated Na+/Pi-cotransport activity, which indicated that all transporters at the surface were biotinylated. After biotinylation, only a small fraction of total S460C protein was precipitated by streptavidin compared with the total amount of S460C protein detected in the lysate. Light- and electron-microscopy analysis of oocytes showed a large amount of WT and S460C transporter protein beneath the oocyte membrane. These data indicate that the apparent weak labeling efficiencies of surface-biotinylation-based assays of membrane proteins heterologously expressed in oocytes can be related to diminished incorporation of the protein in the oolemma.


Alterations in locomotor activity after microinjections of GBR-12909, selective dopamine antagonists or neurotensin into the medial prefrontal cortex.
It has been postulated that increased dopamine (DA) activity in the medial prefrontal cortex (mPFC) exerts an inhibitory influence over DA release in the nucleus accumbens and, thus, also over locomotor activity. Experiments were designed to examine the role of mPFC DA and neurotensin (NT), a neuropeptide which interacts with DA, in spontaneous locomotor activity. LS/IBG mice were injected bilaterally with either GBR-12909, a selective DA uptake blocker, the DA D1 receptor antagonist R-(+)-SCH-23390, the DA D2 receptor antagonist epidepride, NT or a combination of drugs. GBR-12909 produced a U-shaped dose-response curve with a maximum inhibition of 47% of control. Postmortem tissue levels of DA, 5-hydroxytryptamine, norepinephrine and their major metabolites were determined after microinjections of GBR-12909. Tissue levels of these compounds were not significantly affected by GBR-12909. However, the ratios of homovanilic acid/DA and homovanilic acid + 3,4-dihyroxyphenylacetic acid/DA were significantly decreased, whereas the 5-hydroxyindoleacetic acid/5-hydroxytryptamine ratio was not affected by GBR-12909, suggesting a selective effect on DAergic processes. By itself, R-(+)-SCH-23390 had no effect on locomotor activity except at a very high dose which caused locomotor inhibition (49% of control). Epidepride caused a dose-dependent inhibition of locomotor activity with a maximum inhibition of 49% of control. When coinjected with an inhibitory dose of GBR-12909, both epidepride and R-(+)-SCH-23390 attenuated the GBR-12909 effect in a dose-dependent manner. A broad range of doses of NT was found to have no consistent effect on locomotor activity. However, when coinjected with an inhibitory dose of GBR-12909, NT attenuated the GBR-12909-induced inhibition in a dose-dependent manner. The results suggest that stimulation of DA receptors in the mPFC, both DA D1 and DA D2 receptors mediates locomotor inhibition. Furthermore, stimulation of NT receptors appears to antagonize the effects of DA.


The biology of mammalian parenting and its effect on offspring social development.
Parents know the transformative nature of having and caring for a child. Among many mammals, giving birth leads from an aversion to infant stimuli to irresistible attraction. Here, we review the biological mechanisms governing this shift in parental motivation in mammals. Estrogen and progesterone prepare the uterus for embryo implantation and placental development. Prolactin stimulates milk production, whereas oxytocin initiates labor and triggers milk ejection during nursing. These same molecules, interacting with dopamine, also activate specific neural pathways to motivate parents to nurture, bond with, and protect their offspring. Parenting in turn shapes the neural development of the infant social brain. Recent work suggests that many of the principles governing parental behavior and its effect on infant development are conserved from rodent to humans.


Distinct roles of the anterior cingulate and prefrontal cortex in the acquisition and performance of a cognitive skill.
The purpose of the present work is to study the functional roles of two predefined regions of interest: one in the left anterior cingulate cortex (ACC) that seems to reflect goal-relevant control demand, and one in the left prefrontal cortex (PFC) that reflects memory retrieval demand. Two slow event-related brain imaging experiments were conducted, adapting a cognitive skill acquisition paradigm. Experiment 1 found that both left ACC and left PFC activity increased parametrically with task difficulty. Using a slight modification of the same basic paradigm, Experiment 2 attempted to decouple retrieval and control demands over the course of learning. Participants were imaged early in training and again several days later, after substantial additional training in the task. There was a clear dissociation between activity in the left PFC and the left ACC. Although the PFC region showed a substantial decrease in activity over the course of learning, reflecting greater ease of retrieval, the ACC showed the opposite pattern of results with significantly greater activity after training, reflecting increased control demand. Moreover, the increased response in the ACC occurred when errors and latencies were smallest.


Mechanisms of IR amplification in radical cation polarons.
Break down of the Born-Oppenheimer approximation is caused by mixing of electronic and vibrational transitions in the radical cations of some conjugated polymers, resulting in unusually intense vibrational bands known as infrared active vibrations (IRAVs). Here, we investigate the mechanism of this amplification, and show that it provides insights into intramolecular charge migration. Spectroelectrochemical time-resolved infrared (TRIR) and two-dimensional infrared (2D-IR) spectroscopies were used to investigate the radical cations of two butadiyne-linked conjugated porphyrin oligomers, a linear dimer and a cyclic hexamer. The 2D-IR spectra reveal strong coupling between all the IRAVs and the electronic π-π* polaron band. Intramolecular vibrational energy redistribution (IVR) and vibrational relaxation occur within ∼0.1-7 ps. TRIR spectra show that the transient ground state bleach (GSB) and excited state absorption (ESA) signals have anisotropies of 0.31 ± 0.07 and 0.08 ± 0.04 for the linear dimer and cyclic hexamer cations, respectively. The small TRIR anisotropy for the cyclic hexamer radical cation indicates that the vibrationally excited polaron migrates round the nanoring on a time scale faster than the measurement, i.e. within 0.5 ps, at 298 K. Density functional theory (DFT) calculations qualitatively reproduce the emergence of the IRAVs. The first singlet (S1) excited states of the neutral porphyrin oligomers exhibit similar IRAVs to the radical cations, implying that the excitons have similar electronic structures to polarons. Our results show that IRAVs originate from the strong coupling of charge redistribution to nuclear motion, and from the similar energies of electronic and vibrational transitions.


Identification of microRNA precursors using reduced and hybrid features.
MicroRNAs (also called miRNAs) are a group of short non-coding RNA molecules. They play a vital role in the gene expression of transcriptional and post-transcriptional processes. However, abnormality of their expression has been observed in cancer, heart diseases and nervous system disorders. Therefore for basic research and microRNA based therapy, it is imperative to separate real pre-miRNAs from false ones (hairpin sequences similar to pre-miRNA stem loops). Different conservation and machine learning methods have been applied for the identification of miRNAs. However, machine learning algorithms have gained more popularity than conservative based algorithms in terms of sensitivity and overall performance. Due to the avalanche of RNA sequences discovered in a post-genomic age, it is necessary to construct a predictor for the identification of pre-microRNAs in humans. We have developed a predictor called MicroR-Pred in which the RNA sequences are formulated by a hybrid feature vector. The novelty of the new predictor is in the use of the partial least squares technique followed by the Random Forest and SVM (Support Vector Machine) algorithms for dimension reduction and classification. The performance of the MicroR-Pred model is quite promising compared to other state-of-the-art miRNA predictors. It has achieved 88.40% and 93.90% accuracies for RF and SVM.


Potential roles of gut microbiome and metabolites in modulating ALS in mice.
Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.


Assessment of urine-concentrating ability in man: effect of fludrocortisone and urea in enhancing response to vasopressin.
1. Healthy subjects, given a long-acting preparation of vasopressin intramuscularly, excreted a significantly less concentrated urine than when subjected to fluid deprivation for 28 h. 2. When fludrocortisone, a potent mineralocorticoid, was given in addition to vasopressin the urine was not significantly less concentrated than after fluid deprivation. 3. Oral urea-loading also enhanced the urine-concentrating power of vasopressin but its effect was less marked than that of fludrocortisone. Oral urea did not increase further the urine concentration achieved by combined fludrocortisone and vasopressin. 4. Renal concentrating power was assessed in fourteen patients with renal disease and impaired concentrating ability. Fludrocortisone significantly enhanced the urine concentration achieved by vasopressin alone and the resultant urine was not significantly less concentrated than that achieved by fluid deprivation. 5. The action of fludrocortisone in enhancing the urine-concentrating effect of vasopressin is similar to that of aldosterone and is probably due to the increased sequestration of solute in the renal medulla, caused by increased reabsorption of sodium chloride in the ascending limb of the loop of Henle. 6. In the clinical assessment of renal concentrating power, the combined use of fludrocortisone and vasopressin has potential advantages over established methods.


The relationship between fat, oil and grease (FOG) deposits in building drainage systems and FOG disposal patterns.
Fat, oil and grease (FOG) deposits are an important contributor to blockages in building drainage systems. Such blockages bring undesirable financial, health and environmental costs, and thereby burden society. It is unclear to what extent the behavior of inhabitants, and more precisely domestic FOG disposal, affects the occurrence of FOG blockages. For this study, samples of FOG blockages were collected from building drainage systems (kitchen drains and lateral house connections) and analyzed. The results showed that the deposits were calcium salts of fatty acids. Dissimilarities between the network locations demonstrate that, even at short distance, in-sewer transformation processes occur. Surveys were conducted to reveal information about FOG disposal patterns. Three households showed a clear link between the type of cooking oils used and the type of deposits collected.


Readability and usefulness of the clinical microsystem assessment tool.
Using an instrument such as the Clinical Microsystem Assessment Tool (CMAT) to examine microsystem performance can provide valuable guidance for the development of quality and safety initiatives within the microsystem. However, instruments developed for this purpose must take into account diverse literacy levels. Perceptions of health care professionals of the usefulness and readability of the CMAT were examined. Readability was determined with the Flesch Reading Ease scale, in which the CMAT was rated as "very difficult" to read, and a Simple Measure of Gobbledygook analysis revealed that 14.71 years of education would be needed to understand the content. Although the majority of the participating health care professionals identified the tool as useful, the high level of reading ability required to understand the content may create limitations for use, given the educational diversity of the health care workforce.


Paucity of clinical disease despite serological autoimmunity and kidney pathology in lupus-prone New Zealand mixed 2328 mice deficient in BAFF.
Constitutive overexpression of B cell-activating factor belonging to the TNF family (BAFF) promotes development of systemic lupus erythematosus (SLE), and treatment of SLE mice with BAFF antagonists ameliorates disease. To determine whether SLE can develop de novo in BAFF-deficient hosts, BAFF-deficient New Zealand Mixed (NZM) 2328 (NZM.Baff(-/-)) mice were generated. In NZM.Baff(-/-) mice, spleen B cells (including CD5(+) B1a and CD5(-) B1b B cells), germinal centers, Ig-secreting cells, and T cells were reduced in comparison to NZM.Baff(+/+) mice. Serum total Ig and autoantibody levels were reduced at 4-6 mo but approached wild-type levels with increasing age, indicating that autoreactive B cells can survive and secrete autoantibodies despite the complete absence of BAFF. At least some of these autoantibodies are nephrophilic in that glomerular deposition of total IgG and IgG1 (but not of IgG2a, IgG2b, or C3) was substantial in NZM.Baff(-/-) mice by 12-13 mo of age. Despite proliferative glomerulonephritis, highlighted by widespread glomerular hyaline thrombi, being common among NZM.Baff(-/-) mice by 6-7 mo of age, severe proteinuria and mortality were greatly attenuated. These results demonstrate that the lifelong absence of BAFF does not protect NZM 2328 mice from serological autoimmunity and renal pathology. Nevertheless, the character of the renal pathology is altered, and the mice are largely spared from clinically overt disease (severe proteinuria and premature death). These observations may have profound ramifications for the use of BAFF antagonists in human SLE and related diseases.


Genetic variants in the prediction of rheumatoid arthritis.
To determine whether the currently known genetic risk factors for rheumatoid arthritis (RA) improve the prediction of the development of RA compared to prediction using clinical risk factors alone in patients with undifferentiated arthritis (UA). Five hundred and seventy early UA-patients included in the Leiden Early Arthritis Clinic cohort, previously used to derive a clinical prediction rule, were used to explore the additional value of genetic variants. The following genetic variants were assessed HLA-DRB1 shared epitope (SE) alleles, rs2476601 (PTPN22), rs108184088 (TRAF1-C5), rs7574865 (STAT4), rs3087243 (CTLA4), rs4810485 (CD40), rs1678542 (KIF5A-PIP4K2C), rs2812378 (CCL21), rs42041 (CDK6), rs4750316 (PRKCQ), rs6684865 (MMEL1-TNFRSF14), rs2004640 (IRF5), rs6920220 and rs10499194 (TNFAIP3-OLIG3), interactions between HLA-SE alleles and rs2476601 (PTPN22) and between HLA-SE alleles and smoking. The area under the receiver operator curve (AUC) was used as measure of the discriminative ability of the models. The AUC of a model consisting of genetic variants only was low, 0.536 (95% CI 0.48 to 0.59). The AUC of the model including genetic and clinical risk factors was not superior over the AUC of the clinical prediction rule (0.889, 95% CI 0.86 to 0.95 and 0.884, 95% CI 0.86 to 0.92). In a population at risk, information on currently known genetic risk factors for RA does not improve prediction of risk for RA compared to a prediction rule based on common clinical risk factors alone.


Epithelial cytoprotection sustains ectopic expression of tissue-restricted antigens in the thymus during murine acute GVHD.
Development of acute graft-versus-host disease (aGVHD) predisposes to chronic GVHD with autoimmune manifestations. A characteristic of experimental aGVHD is the de novo generation of autoreactive T cells. Central tolerance is dependent on the intrathymic expression of tissue-restricted peripheral self-antigens (TRA), which is in mature medullary thymic epithelial cells (mTEC(high)) partly controlled by the autoimmune regulator (Aire). Because TECs are targets of donor T-cell alloimmunity, we tested whether murine aGVHD interfered with the capacity of recipient Aire(+)mTEC(high) to sustain TRA diversity. We report that aGVHD weakens the platform for central tolerance induction because individual TRAs are purged from the total repertoire secondary to a decline in the Aire(+)mTEC(high) cell pool. Peritransplant administration of an epithelial cytoprotective agent, fibroblast growth factor-7, maintained a stable pool of Aire(+)mTEC(high), with an improved TRA transcriptome despite aGVHD. Taken together, our data provide a mechanism for how autoimmunity may develop in the context of antecedent alloimmunity.


Exploring a communication curriculum through a focus on social accountability: A case study at a South African medical school.
Good communication is integral to social accountability, and training is included in medical curricula internationally. In KwaZulu-Natal, training is conducted in English, in spite of most public sector patients being mother tongue isiZulu speakers. Communication challenges with patients are common, but good communication and African language teaching are not emphasised in teaching. This study explored communication training and how it related to social accountability at a single institution in KwaZulu-Natal. This exploratory, qualitative case study design at the medical school explored participants' perceptions about communication and social accountability and reviewed relevant educational documentation for evidence. Purposive sampling was used to select medical students, educators and stakeholders from the educational and service platforms. Focus group discussions and semi-structured interviews were conducted. The data were thematically analysed with reference to Boelen's social obligation scale for medical schools. Good communication was valued, but often poorly role-modelled. Participants agreed that communication and isiZulu teaching were insufficiently supported to respond adequately to the needs of local communities. Social accountability was not well understood by students, while medical school educators and other stakeholders indicated that, despite aspirations, this goal had not yet been achieved. Learning isiZulu language and culture in an integrated manner in both preclinical and clinical phases would improve communication with patients, contribute to socially responsive health care, and better address health care needs. Incorporating a social accountability framework in curriculum review would highlight the importance of measuring health outcomes and community impacts, and so enhance the educational mission of the medical school.


Spinal cord injury and aging: challenges and recommendations for future research.
Population aging, caused by reductions in fertility and increasing longevity, varies by country and is anticipated to continue and to reach global proportions during the 21st century. Although the effects of population aging have been well documented for decades, the impact of aging on people with spinal cord injury (SCI) has not received similar attention. It is reasonable to expect that population aging features such as the increasing mean age of the population, share of the population in the oldest age groups, and life expectancy would be reflected in SCI population demographics. Although the mean age and share of the SCI population older than 65 yrs are increasing, data from the National Spinal Cord Injury Statistical Center suggest that life expectancy increases in the SCI population have not kept the same pace as those without SCI in the last 15 yrs. The reasons for this disparity are likely multifactorial and include the changing demographics of the SCI population with more older people being injured; susceptibility of people with SCI to numerous medical conditions that impart a health hazard; risky behaviors leading to a disproportionate percentage of deaths as a result of preventable causes, including septicemia; changes in the delivery of health services during the first year after injury when the greatest resources are available; and other unknown factors. The purposes of this paper are (1) to define and differentiate general population aging and aging in people with SCI, (2) to briefly present the state of the science on health conditions in those aging with SCI, and finally, (3) to present recommendations for future research in the area of aging with SCI.


Efficient total nitrogen removal in an ammonia gas biofilter through high-rate OLAND.
Ammonia gas is conventionally treated in nitrifying biofilters; however, addition of organic carbon to perform post-denitrification is required to obtain total nitrogen removal. Oxygen-limited autotrophic nitrification/denitrification (OLAND), applied in full-scale for wastewater treatment, can offer a cost-effective alternative for gas treatment. In this study, the OLAND application thus was broadened toward ammonia loaded gaseous streams. A down flow, oxygen-saturated biofilter (height of 1.5 m; diameter of 0.11 m) was fed with an ammonia gas stream (248 ± 10 ppmv) at a loading rate of 0.86 ± 0.04 kg N m(-3) biofilter d(-1) and an empty bed residence time of 14 s. After 45 days of operation a stable nitrogen removal rate of 0.67 ± 0.06 kg N m(-3) biofilter d(-1), an ammonia removal efficiency of 99%, a removal of 75-80% of the total nitrogen, and negligible NO/N(2)O productions were obtained at water flow rates of 1.3 ± 0.4 m(3) m(-2) biofilter section d(-1). Profile measurements revealed that 91% of the total nitrogen activity was taking place in the top 36% of the filter. This study demonstrated for the first time highly effective and sustainable autotrophic ammonia removal in a gas biofilter and therefore shows the appealing potential of the OLAND process to treat ammonia containing gaseous streams.


Hearing impairment in persons with the hemoglobin SC genotype.
The hemoglobin (Hb) SC genotype is seen in persons who have inherited the gene for hemoglobin S from one parent and the gene for hemoglobin C from the other. Some people with this genotype develop Hb SC disease, a variant of sickle cell disease. Hb SC disease, a compound heterozygous condition, is the most common of the hemoglobinopathies and the least severe, although it is still serious. One of the documented complications of the presence of the Hb SC genotype is sensorineural hearing loss (SNHL). We conducted a prospective case-control study of 43 subjects, aged 15 to 65 years, who had the Hb SC genotype to determine the incidence of SNHL and to determine if the hearing loss in these subjects was correlated with sex or age. Our control group was made up of 100 generally healthy, sex- and age-matched subjects with the normal Hb AA genotype. SNHL was defined as a loss of more than 25 dB HL at two or more frequencies in the same ear or at one or more frequencies in both ears. We found that SNHL was present in 12 of the 43 subjects (27.9%) in the Hb SC group (17 of 86 ears [19.8%]) and in 17 of the 100 subjects (17.0%) in the Hb AA group (21 of 200 ears [10.5%]; the difference between the two groups was not statistically significant (chi(2) = 1.589; p = 0.105). We found that in the Hb SC group, SNHL was more common among females than males (38.5 vs. 11.8%), although the difference was not quite significant statistically (chi(2) = 2.435; p = 0.056); in the Hb AA group, the incidence was fairly equal-15.4 and 18.8%, respectively (chi(2) = 0.033; p = 0.427). Therefore, we conclude that the hearing loss in the subjects of this study was not correlated with the presence of the Hb SC genotype in either sex. In terms of age, SNHL was significantly more common in subjects aged 41 to 65 years than in those aged 15 to 40 years in both genotype groups. In the Hb SC group, SNHL was present in 4 of the 33 younger subjects (12.1%) and in 8 of the 10 older subjects (80.0%) (chi(2) = 14.354; p < 0.001). In the Hb AA group, the corresponding figures were 7 of 85 (8.2%) and 10 of 15 (66.7%) (chi(2) = 26.840; p < 0.001). Therefore, we conclude that the hearing loss in the subjects of this study was a function of age and was not associated with the presence of the Hb SC genotype.


Assessing normal growth of hepatic hemangiomas during long-term follow-up.
Few long-term data describe the natural history of hepatic hemangiomas. Because these lesions are frequently imaged repetitively on studies performed for other indications, health care professionals are commonly confronted with the problem of a growing hemangioma. Because the rate and magnitude of normal growth is not well characterized, it is difficult to recognize lesions growing at an abnormal rate, which may require further evaluation or intervention. To establish quantitatively the expected growth rate of hepatic hemangiomas and to define a measure of hemangioma growth that could be used clinically to help identify hemangiomas for which growth is more than expected. Retrospective cohort study at an academic hospital tertiary referral center evaluating the growth rate of hepatic hemangiomas on cross-sectional imaging studies during a 10-year period (1997-2007). The mean (SD) follow-up time was 3.7 (1.9) years. The radiology information system was searched in a 10-year period for hemangioma. Patients with hepatic hemangiomas that were 1 cm or larger as seen on cross-sectional imaging (computed tomography or magnetic resonance imaging), and 1 year or more apart were selected. Images with the longest interval between studies were selected for further review. Each study was rereviewed for diagnostic confirmation and to ensure consistency in measurement technique. Lesions were remeasured in 3 dimensions, and volumes were calculated using 3-dimensional software. Primary outcomes include the fraction of hepatic hemangiomas that demonstrated growth during long-term follow-up and the annual growth rate of those lesions. A total of 163 hemangiomas were identified in 123 patients. The mean (SD) initial size was 3.2 (3.1) cm. During follow-up, 39.3% of hemangiomas grew 5% or more in mean linear dimension. The mean (SD) annual linear growth rate was 0.03 (0.21) cm for all lesions and 0.19 (0.23) cm for those that grew 5% or more. By volume, 44.7% of lesions grew 5% or more. The mean (SD) annual volumetric growth rate was 2.8% (21.0%) for all lesions and 17.7% (22.8%) in those that grew 5% or more. The initial size predicted the growth in linear dimension and volume (P < .001). There was no significant change in growth rate over time, indicating uniform growth (R = 0.00843; P = .92). Nearly 40% of hepatic hemangiomas grow over time. Although the overall rate of growth is slow, hemangiomas that exhibit growth do so at a modest rate (2 mm/y in linear dimension and 17.4% per year in volume). Further research is needed to determine how patients with more rapidly growing hemangiomas should be treated.


Transmission of hepatitis B virus infection in Gambian families revealed by phylogenetic analysis.
Transmission of hepatitis B virus (HBV) in Africa occurs horizontally, with most people becoming infected between the ages of 1 and 5 years. The index cases in such events have been assumed to come from within the family unit or from sources outside the immediate family, such as other families or inhabitants of the same compound or village. Here, we define these routes of transmission by phylogenetic tree analysis of sequences from the entire pre-core/core region of the virus, in Gambian chronic carriers. Amplification by polymerase chain reaction of serum extracted HBV-DNA was followed by direct sequencing of the target region. Following editing and alignment of these sequences, phylogenetic tree analysis was performed using the neighbour-joining and maximum-likelihood methods. Despite the overall conserved nature of the sequences of the pre-core/core region from 142 chronic carriers, distinct clusters were easily defined at the family and village level, but not on a wider geographical separation. Phylogenetic tree analysis of sequences obtained from family members provided strong evidence of intrafamilial transmission of HBV in at least two-thirds of the families studied from Gambia.


Development of tailored SPION-PNIPAM nanoparticles by ATRP for dually responsive doxorubicin delivery and MR imaging.
Biocompatible, colloidally stable and ultra-small Fe3O4 nanoparticles (SPIONs) coated with poly(N-isopropylacrylamide) (PNIPAM) were synthesized via surface-initiated ATRP (atom transfer radical polymerization) to prevent excessive aggregation of magnetic cores and interparticle crosslinking, and to provide control over polymer content. These SPION-PNIPAM nanoparticles (NPs) have a hydrodynamic size between 8 and 60 nm depending on the PNIPAM content, and hence are ultrasmall in size and have an LCST around 38 °C. They had a high drug-loading capacity reaching 9.6 wt% doxorubicin in the final composition. The Dox release studies revealed pH and temperature-dependent release, which was not reported for PNIPAM before. Release of Dox under physiological conditions was below 20%, but around 90% at 42 °C and pH 5. This dually responsive nature is very advantageous to increase the drug efficacy and reduce side-effects, simultaneously. The cytocompatability of the SPION-PNIPAM NPs and the influence of Dox delivery to cells were investigated via in vitro cell viability, apoptosis, DNA-damage and confocal microscopy studies. The NPs were shown to be highly cytocompatible and induce significant cell death due to Dox when loaded with the drug. Besides, it was seen that the polymeric content can be used as an additional factor in tuning the release kinetics. Lastly, these nanoparticles reduced the signal intensity significantly in the T2 mode, acting as a potential SPION-based contrast agent. Overall, here, we demonstrate the design of small, smart theranostic nanoparticles with high drug-loading capacity and pH-dependent temperature-sensitive release characteristics with the ability to generate contrast in MRI.


Association between copper excess, zinc deficiency, and TP53 mutations in esophageal squamous cell carcinoma from Kashmir Valley, India--a high risk area.
Trace element deficiency or excess is implicated in the development or progression in some cancers. Here we report the elevated level of copper and low level of zinc in the plasma of esophageal cancer patients in Kashmir India--a high incidence area. The average level of copper was significantly higher (P < 0.0001) for patients than for controls, with a mean concentration of 169 microg/dl and 149 microg/dl for patients and controls, respectively. The control group consisted of 55 healthy individuals matched for age, sex, and place of residence of the patients. In contrast, the average level of zinc in patients was significantly lower than in controls (P < 0.0001), with a mean concentration of 86.8 microg/dl and 96.1 microg/dl for patients and controls, respectively. The levels of both copper and zinc showed significant differences based on gender and age in patients as compared to controls. Similarly, smokers depicted a significant increase in serum copper (N = 39, P = 0.002) and a decrease in serum zinc approaching level of significance in the patient group as compared to controls. The copper and zinc levels were significantly altered in patients (N = 40) when compared to controls as a function of snuff consumption. The differences in the levels of copper and zinc showed significant association with the consumption of local salted tea up to 1,500 ml per day, but the changes were insignificant beyond that. Patients with poorly differentiated tumors (N = 7) had a higher copper concentration than those with moderately or well-differentiated tumors (P < 0.0001). To validate the general notion that imbalance in copper and zinc levels may lead to higher prevalence of TP53 mutations, we compared the 3 variables, and no association was found between copper concentration and TP53 mutation status; but patients with TP53 mutant tumor had lower zinc levels than those with no mutation. In conclusion, our results point toward a role of the trace element imbalance in the esophageal tumorigenesis in high-risk Kashmiri population exposed to a range of nitroso compounds or their precursors. Further prospective cohort studies are warranted to determine whether change in the plasma zinc and copper homeostasis may represent an independent risk factor for this malignancy as well as a possible target for preventive intervention.


A Multivariate Timeseries Modeling Approach to Severity of Illness Assessment and Forecasting in ICU with Sparse, Heterogeneous Clinical Data.
The ability to determine patient acuity (or severity of illness) has immediate practical use for clinicians. We evaluate the use of multivariate timeseries modeling with the multi-task Gaussian process (GP) models using noisy, incomplete, sparse, heterogeneous and unevenly-sampled clinical data, including both physiological signals and clinical notes. The learned multi-task GP (MTGP) hyperparameters are then used to assess and forecast patient acuity. Experiments were conducted with two real clinical data sets acquired from ICU patients: firstly, estimating cerebrovascular pressure reactivity, an important indicator of secondary damage for traumatic brain injury patients, by learning the interactions between intracranial pressure and mean arterial blood pressure signals, and secondly, mortality prediction using clinical progress notes. In both cases, MTGPs provided improved results: an MTGP model provided better results than single-task GP models for signal interpolation and forecasting (0.91 vs 0.69 RMSE), and the use of MTGP hyperparameters obtained improved results when used as additional classification features (0.812 vs 0.788 AUC).


Impact of antidepressants on cytokine production of depressed patients in vitro.
The interplay between immune and nervous systems plays a pivotal role in the pathophysiology of depression. In depressive episodes, patients show increased production of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α. There is limited information on the effect of antidepressant drugs on cytokines, most studies report on a limited sample of cytokines and none have reported effects on IL-22. We systematically investigated the effect of three antidepressant drugs, citalopram, escitalopram and mirtazapine, on secretion of cytokines IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in a whole blood assay in vitro, using murine anti-human CD3 monoclonal antibody OKT3, and 5C3 monoclonal antibody against CD40, to stimulate T and B cells respectively. Citalopram increased production of IL-1β, IL-6, TNF-α and IL-22. Mirtazapine increased IL-1β, TNF-α and IL-22. Escitalopram decreased IL-17 levels. The influence of antidepressants on IL-2 and IL-4 levels was not significant for all three drugs. Compared to escitalopram, citalopram led to higher levels of IL-1β, IL-6, IL-17 and IL-22; and mirtazapine to higher levels of IL-1β, IL-17, IL-22 and TNF-α. Mirtazapine and citalopram increased IL-22 production. The differing profile of cytokine production may relate to differences in therapeutic effects, risk of relapse and side effects.


Predicting precision grip grasp locations on three-dimensional objects.
We rarely experience difficulty picking up objects, yet of all potential contact points on the surface, only a small proportion yield effective grasps. Here, we present extensive behavioral data alongside a normative model that correctly predicts human precision grasping of unfamiliar 3D objects. We tracked participants' forefinger and thumb as they picked up objects of 10 wood and brass cubes configured to tease apart effects of shape, weight, orientation, and mass distribution. Grasps were highly systematic and consistent across repetitions and participants. We employed these data to construct a model which combines five cost functions related to force closure, torque, natural grasp axis, grasp aperture, and visibility. Even without free parameters, the model predicts individual grasps almost as well as different individuals predict one another's, but fitting weights reveals the relative importance of the different constraints. The model also accurately predicts human grasps on novel 3D-printed objects with more naturalistic geometries and is robust to perturbations in its key parameters. Together, the findings provide a unified account of how we successfully grasp objects of different 3D shape, orientation, mass, and mass distribution.


Pooling strategies to reduce the cost of HIV-1 RNA load monitoring in a resource-limited setting.
Quantitative human immunodeficiency virus (HIV) RNA load testing surpasses CD4 cell count and clinical monitoring in detecting antiretroviral therapy (ART) failure; however, its cost can be prohibitive. Recently, the use of pooling strategies with a clinically appropriate viral load threshold was shown to be accurate and efficient for monitoring when the prevalence of virologic failure is low. We used laboratory request form information to identify specimens with a low pretest probability of virologic failure. Patients aged ≥15 years who were receiving first-line ART had individual viral load results available were eligible. Blood plasma, dried blood spots, and dried plasma spots were evaluated. Two pooling strategies were compared: minipools of 5 samples and a 10 ×10 matrix platform (liquid plasma specimens only). A deconvolution algorithm was used to identify specimens(s) with detectable viral loads. The virologic failure rate in the study sample was <10%. Specimens included were liquid plasma specimens tested in minipools(n = 400), of which 300 were available for testing by matrix, and specimens tested with minipools only: dried blood spots (n = 100) and dried plasma spots (n = 185). Pooling methods resulted in 30.5%-60% fewer HIV RNA tests required to screen the study sample. For plasma pooling, the matrix strategy had the better efficiency, but minipools of 5 dried blood spots had the best efficiency overall and were accurate at a >95% negative predictive value with minimal technical requirements. In resource-constrained settings, a combination of preselection of patients with low pretest probability of virologic failure and pooled testing can reduce the cost of virologic monitoring without compromising accuracy.


Daytime mechanical ventilation in chronic respiratory insufficiency.
Chronic respiratory insufficiency (CRI) is associated with nocturnal hypoventilation. Treatment with noninvasive mechanical ventilation (NIMV) performed overnight relieves symptoms of hypoventilation and improves daytime blood gases in CRI. In order to test whether the efficacy of NIMV depends on it being applied during sleep, we conducted a prospective case-controlled study comparing daytime mechanical ventilation (dMV) in awake patients with nocturnal mechanical ventilation (nMV) given in equal quantities. We enrolled 34 clinically stable patients (age 56.1+/-12.1 yrs, 20 females, 14 males) with CRI due to restrictive lung and chest wall disorders and neuromuscular disease. Using a prospective case-control design, matched subjects were allocated alternately to dMV and nMV. After 1 month of NIMV there was considerable symptomatic improvement in both dMV and nMV patients. There were no significant differences between groups in the improvement in daytime arterial carbon dioxide tension (Pa,CO2) (dMV from 7.5+/-0.6 to 5.7+/-0.6 kPa; nMV from 7.2+/-0.5 to 5.8+/-0.5 kPa, p<0.0001) and during the unassisted spontaneous night-time ventilation in terms of transcutaneous Pa,CO2 (dMV from 8.4+/-1.2 to 6.6+/-0.7 kPa; nMV from 8.2+/-1.2 to 6.8+/-0.5 kPa, p<0.0001). We conclude that in many respects, when compared to nocturnal mechanical ventilation, daytime mechanical ventilation in awake patients is equally effective at reversing chronic respiratory insufficiency. Since long-term safety issues were not addressed in this study, we recommend that nocturnal mechanical ventilation should remain the modality of choice for noninvasive mechanical ventilation.


Extending the treatment options in alcohol dependence: a randomized controlled study of as-needed nalmefene.
There is a large treatment gap in alcohol dependence, and current treatments are only moderately effective in preventing relapse. New treatment modalities, allowing for reduction of alcohol consumption as a treatment goal are needed. This study evaluated the efficacy of as-needed use of the opioid system modulator nalmefene in reducing alcohol consumption in patients with alcohol dependence. Six hundred and four patients (placebo = 298; nalmefene = 306),≥18 years of age, with a diagnosis of alcohol dependence,≥6 heavy drinking days, and average alcohol consumption≥World Health Organization medium drinking risk level in the 4 weeks preceding screening, were randomized (1:1) to 24 weeks of as-needed placebo or nalmefene 18 mg. Patients taking placebo (n = 289) and patients taking nalmefene (n = 290) were included in the efficacy analyses. At Month 6, there was a significant effect of nalmefene compared with placebo in reducing the number of heavy drinking days (-2.3 days [95% confidence interval:-3.8 to-.8]; p = .0021) and total alcohol consumption (-11.0 g/day [95% confidence interval:-16.8 to-5.1]; p = .0003). Improvements in Clinical Global Impression and liver enzymes were larger in the nalmefene group compared with placebo at Week 24. Adverse events (most mild or moderate) and dropouts due to adverse events were more common with nalmefene than placebo. The number of patients with serious adverse events was similar in the two groups. Nalmefene provides clinical benefit, constitutes a potential new pharmacological treatment paradigm in terms of the treatment goal and dosing regimen, and provides a method to address the unmet medical need in patients with alcohol dependence that need to reduce their alcohol consumption.


A JUN N-terminal kinase inhibitor induces ectodomain shedding of the cancer-associated membrane protease Prss14/epithin via protein kinase CβII.
Serine protease 14 (Prss14)/epithin is a transmembrane serine protease that plays essential roles in tumor progression and metastasis and therefore is a promising target for managing cancer. Prss14/epithin shedding may underlie its activity in cancer and worsen outcomes; accordingly, a detailed understanding of the molecular mechanisms in Prss14/epithin shedding may inform the design of future cancer therapies. On the basis of our previous observation that an activator of PKC, phorbol 12-myristate 13-acetate (PMA), induces Prss14/epithin shedding, here we further investigated the intracellular signaling pathway involved in this process. While using mitogen-activated protein kinase inhibitors to investigate possible effectors of downstream PKC signaling, we unexpectedly found that an inhibitor of c-Jun N-terminal kinase (JNK), SP600125, induces Prss14/epithin shedding even in the absence of PMA. SP600125-induced shedding, like that stimulated by PMA, was mediated by tumor necrosis factor-α-converting enzyme. In contrast, a JNK activator, anisomycin, partially abolished the effects of SP600125 on Prss14/epithin shedding. Moreover, the results from loss-of-function experiments with specific inhibitors, short hairpin RNA-mediated knockdown, and overexpression of dominant-negative PKCβII variants indicated that PKCβII is a major player in JNK inhibition- and PMA-mediated Prss14/epithin shedding. SP600125 increased phosphorylation of PKCβII and tumor necrosis factor-α-converting enzyme and induced their translocation into the plasma membrane. Finally, in vitro cell invasion experiments and bioinformatics analysis of data in The Cancer Genome Atlas breast cancer database revealed that JNK and PKCβII are important for Prss14/epithin-mediated cancer progression. These results provide important information regarding strategies against tumor metastasis.


A systematic review of outcome following synchronous carotid endarterectomy and coronary artery bypass: influence of surgical and patient variables.
Outcomes after synchronous carotid endarterectomy (CEA) plus coronary artery bypass (CABG) relative to surgical and patient based variables. Systematic review of 94 published series (7863 synchronous procedures). 11.5% of patients died or suffered a stroke/myocardial infarction in the peri-operative period (95% CI 10.1-12.9). The risk of death/stroke appeared to significantly diminish in studies published between 1993-2002, compared with 1972-1992 (7.2% (95% CI 6.5-9.1) versus 10.7% (95% CI 8.9-12.5), p = 0.03). However, increasing operative experience was not associated with significantly lower risks of death/stroke; (1-49 cases (9.6% (95% CI 7.5-11.8); 50-99 cases (9.1% (95% CI 6.4-11.8); 100+ cases (8.4% (95% CI 6.9-10.1) (p = 0.64)). Patients with severe bilateral carotid disease were significantly more likely to suffer death and/or stroke compared to patients with unilateral disease (odds ratio 2.5, 95% CI 1.4-5.0, p = 0.001). Similarly, patients with a prior history of stroke/transient ischaemic attack (TIA) were significantly more likely to suffer a further stroke than asymptomatic patients (odds ratio 1.8, 95% CI 1.1-2.8, p = 0.008). There was no difference in the risk of death/stroke relative to the timing of CEA (pre- versus on-cardiopulmonary bypass), but recent small studies indicate that improved outcomes might be achieved by performing CABG 'off-bypass'. Synchronous CEA + CABG is associated with a not insignificant cardiovascular risk. No comparable information is available for similar patients undergoing CABG without prophylactic CEA.


Substrate conformational dynamics facilitate structure-specific recognition of gapped DNA by DNA polymerase.
DNA-binding proteins utilise different recognition mechanisms to locate their DNA targets; some proteins recognise specific DNA sequences, while others interact with specific DNA structures. While sequence-specific DNA binding has been studied extensively, structure-specific recognition mechanisms remain unclear. Here, we study structure-specific DNA recognition by examining the structure and dynamics of DNA polymerase I Klenow Fragment (Pol) substrates both alone and in DNA-Pol complexes. Using a docking approach based on a network of 73 distances collected using single-molecule FRET, we determined a novel solution structure of the single-nucleotide-gapped DNA-Pol binary complex. The structure resembled existing crystal structures with regards to the downstream primer-template DNA substrate, and revealed a previously unobserved sharp bend (∼120°) in the DNA substrate; this pronounced bend was present in living cells. MD simulations and single-molecule assays also revealed that 4-5 nt of downstream gap-proximal DNA are unwound in the binary complex. Further, experiments and coarse-grained modelling showed the substrate alone frequently adopts bent conformations with 1-2 nt fraying around the gap, suggesting a mechanism wherein Pol recognises a pre-bent, partially-melted conformation of gapped DNA. We propose a general mechanism for substrate recognition by structure-specific enzymes driven by protein sensing of the conformational dynamics of their DNA substrates.


Biologic therapies for refractory juvenile dermatomyositis: five years of experience of the Childhood Arthritis and Rheumatology Research Alliance in North America.
The prognosis of children with juvenile dermatomyositis (JDM) has improved remarkably since the 1960's with the use of corticosteroid and immunosuppressive therapy. Yet there remain a minority of children who have refractory disease. Since 2003 the sporadic use of biologics (genetically-engineered proteins that usually are derived from human genes) for inflammatory myositis has been reported. In 2011-2016 we investigated our collective experience of biologics in JDM through the Childhood Arthritis and Rheumatology Research Alliance (CARRA). The JDM biologic study group developed a survey on the CARRA member experience using biologics for Juvenile DM utilizing Delphi consensus methods in 2011-2012. The survey was completed online by the CARRA members interested in JDM in 2012. A second survey was similarly developed that provided more opportunity to describe their experiences with biologics in JDM in detail and was completed by CARRA members in Feb 2013. During three CARRA meetings in 2013-2015, nominal group techniques were used for achieving consensus on the current choices of biologic drugs. A final survey was performed at the 2016 CARRA meeting. One hundred and five of a potential 231 pediatric rheumatologists (42%) responded to the first survey in 2012. Thirty-five of 90 had never used a biologic for Juvenile DM at that time. Fifty-five of 91 (denominators vary) had used biologics for JDM in their practice with 32%, 5%, and 4% using rituximab, etanercept, and infliximab, respectively, and 17% having used more than one of the three drugs. Ten percent used a biologic as monotherapy, 19% a biologic in combination with methotrexate (mtx), 52% a biologic in combination with mtx and corticosteroids, 42% a combination of a biologic, mtx, corticosteroids (steroids), and an immunosuppressive drug, and 43% a combination of a biologic, IVIG and mtx. The results of the second survey supported these findings in considerably more detail with multiple combinations of drugs used with biologics and supported the use of rituximab, abatacept, anti-TNFα drugs, and tocilizumab in that order. One hundred percent recommended that CARRA continue studying biologics for JDM. The CARRA meeting survey in 2016 again supported the study and use of these four biologic drug groups. Our CARRA JDM biologic work group developed and performed three surveys demonstrating that pediatric rheumatologists in North America have been using multiple biologics for refractory JDM in numerous scenarios from 2011 to 2016. These survey results and our consensus meetings determined our choice of four biologic therapies (rituximab, abatacept, tocilizumab and anti-TNFα drugs) to consider for refractory JDM treatment when indicated and to evaluate for comparative effectiveness and safety in the future. Significance and Innovations This is the first report that provides a substantial clinical experience of a large group of pediatric rheumatologists with biologics for refractory JDM over five years. This experience with biologic therapies for refractory JDM may aid pediatric rheumatologists in the current treatment of these children and form a basis for further clinical research into the comparative effectiveness and safety of biologics for refractory JDM.


Multiple roles of motor imagery during action observation.
Over the last 20 years, the topics of action observation (AO) and motor imagery (MI) have been largely studied in isolation from each other, despite the early integrative account by Jeannerod (1994, 2001). Recent neuroimaging studies demonstrate enhanced cortical activity when AO and MI are performed concurrently ("AO+MI"), compared to either AO or MI performed in isolation. These results indicate the potentially beneficial effects of AO+MI, and they also demonstrate that the underlying neurocognitive processes are partly shared. We separately review the evidence for MI and AO as forms of motor simulation, and present two quantitative literature analyses that indeed indicate rather little overlap between the two bodies of research. We then propose a spectrum of concurrent AO+MI states, from congruent AO+MI where the contents of AO and MI widely overlap, over coordinative AO+MI, where observed and imagined action are different but can be coordinated with each other, to cases of conflicting AO+MI. We believe that an integrative account of AO and MI is theoretically attractive, that it should generate novel experimental approaches, and that it can also stimulate a wide range of applications in sport, occupational therapy, and neurorehabilitation.


Intestinal permeability in allergic rats: nerve involvement in antigen-induced changes.
In vivo uptake of the probe 51Cr-labeled EDTA from the jejunum of egg albumin (EA)-sensitized rats was compared with controls at baseline and after intraluminal antigen challenge. Probe recovery in blood was 60-80% greater in sensitized animals during the baseline period, suggesting that sensitization resulted in increased intestinal permeability. Sensitized, but not control, rats demonstrated a 15-fold increase in 51Cr-EDTA uptake after intraluminal antigen; no change occurred with an unrelated protein. Macromolecular recovery was also enhanced in sensitized animals, since serum levels of immunoreactive EA were elevated 14-fold compared with controls. Antigen challenge was accompanied by biochemical (protease release) and morphological (reduced numbers) evidence of mast cell degranulation in sensitized rats. The neurotoxin tetrodotoxin (applied directly to ligated jejunal segments) inhibited EA-induced uptake of 51Cr-EDTA and antigen. In isolated jejunum from sensitized rats, tetrodotoxin reduced secretory responses to luminal, but not serosal, antigen. These results indicate that neural factors may influence the uptake of molecules from the gut lumen during intestinal anaphylaxis.


ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR PROLIFERATIVE DIABETIC RETINOPATHY: A Systematic Review and Meta-Analysis.
To systematically review and perform meta-analysis on the available randomized controlled trial data for anti-vascular endothelial growth factor (anti-VEGF) agents in the management of proliferative diabetic retinopathy and its complications. The authors identified randomized controlled trials using anti-VEGF agents, either as stand-alone therapy or combined with other interventions, in the management of proliferative diabetic retinopathy. The primary outcome measures were change in best-corrected visual acuity and (in the context of vitrectomy) duration of surgery and postoperative vitreous hemorrhage. Secondary outcomes were change in central retinal thickness and (in the context of vitrectomy) intraoperative variables suggestive of complex surgery (retinal breaks, intraoperative bleeding, and endodiathermy applications). The quality of evidence for all outcomes was appraised using the GRADE criteria. Twenty-two studies involving 1,397 subjects met the criteria for inclusion in this study. One study compared intravitreal ranibizumab with saline, one compared intravitreal pegaptanib to pan-retinal photocoagulation (PRP), one compared intravitreal bevacizumab to PRP, 3 compared combined intravitreal ranibizumab/PRP to PRP, 5 compared combined intravitreal bevacizumab/PRP to PRP alone, and 11 compared combined intravitreal bevacizumab/PPV to PPV alone. When used in conjunction with PRP, there is a high-quality evidence to suggest that intravitreal ranibizumab is associated with superior visual acuity and central retinal thickness outcomes at 3 months to 4 months. In the context of PPV, there is moderate quality evidence to suggest that preoperative intravitreal bevacizumab results in a significant reduction in the duration of surgery, fewer retinal breaks, less intraoperative bleeding, and fewer endodiathermy applications. Although there is evidence to suggest occurrence of early postoperative vitreous hemorrhage is reduced, the quality of evidence in support of this finding is low. The use of anti-VEGF agents before PRP results in superior functional and structural outcomes at 3 months to 4 months. The use of anti-VEGF agents before PPV results in decreased duration of surgery, fewer breaks, and less intra-operative bleeding. Although there is evidence for a decreased incidence of early postoperative vitreous hemorrhage, the quality of evidence is low. The available data therefore support the use of anti-VEGF agents as adjuncts to PRP and PPV in patients with complicated proliferative diabetic retinopathy primarily as a means of facilitating, and potentially minimizing the iatrogenic damage resulting from, these procedures.