Degenerative lumbar spinal stenosis: correlation with Oswestry Disability Index and MR imaging.
Because neither the degree of constriction of the spinal canal considered to be symptomatic for lumbar spinal stenosis nor the relationship between the clinical appearance and the degree of a radiologically verified constriction is clear, a correlation of patient's disability level and radiographic constriction of the lumbar spinal canal is of interest. The aim of this study was to establish a relationship between the degree of radiologically established anatomical stenosis and the severity of self-assessed Oswestry Disability Index in patients undergoing surgery for degenerative lumbar spinal stenosis. Sixty-three consecutive patients with degenerative lumbar spinal stenosis who were scheduled for elective surgery were enrolled in the study. All patients underwent preoperative magnetic resonance imaging and completed a self-assessment Oswestry Disability Index questionnaire. Quantitative image evaluation for lumbar spinal stenosis included the dural sac cross-sectional area, and qualitative evaluation of the lateral recess and foraminal stenosis were also performed. Every patient subsequently answered the national translation of the Oswestry Disability Index questionnaire and the percentage disability was calculated. Statistical analysis of the data was performed to seek a relationship between radiological stenosis and percentage disability recorded by the Oswestry Disability Index. Upon radiological assessment, 27 of the 63 patients evaluated had severe and 33 patients had moderate central dural sac stenosis; 11 had grade 3 and 27 had grade 2 nerve root compromise in the lateral recess; 22 had grade 3 and 37 had grade 2 foraminal stenosis. On the basis of the percentage disability score, of the 63 patients, 10 patients demonstrated mild disability, 13 patients moderate disability, 25 patients severe disability, 12 patients were crippled and three patients were bedridden. Radiologically, eight patients with severe central stenosis and nine patients with moderate lateral stenosis demonstrated only minimal disability on percentage Oswestry Disability Index scores. Statistical evaluation of central and lateral radiological stenosis versus Oswestry Disability Index percentage scores showed no significant correlation. In conclusion, lumbar spinal stenosis remains a clinico-radiological syndrome, and both the clinical picture and the magnetic resonance imaging findings are important when evaluating and discussing surgery with patients having this diagnosis. MR imaging has to be used to determine the levels to be decompressed.


Different Clinical Contexts of Use of Blood Neurofilament Light Chain Protein in the Spectrum of Neurodegenerative Diseases.
One of the most pressing challenges in the clinical research of neurodegenerative diseases (NDDs) is the validation and standardization of pathophysiological biomarkers for different contexts of use (CoUs), such as early detection, diagnosis, prognosis, and prediction of treatment response. Neurofilament light chain (NFL) concentration is a particularly promising candidate, an indicator of axonal degeneration, which can be analyzed in peripheral blood with advanced ultrasensitive methods. Serum/plasma NFL concentration is closely correlated with cerebrospinal fluid NFL and directly reflects neurodegeneration within the central nervous system. Here, we provide an update on the feasible CoU of blood NFL in NDDs and translate recent findings to potentially valuable clinical practice applications. As NFL is not a disease-specific biomarker, however, blood NFL is an easily accessible biomarker with promising different clinical applications for several NDDs: (1) early detection and diagnosis (i.e., amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, atypical parkinsonisms, sporadic late-onset ataxias), (2) prognosis (Huntington's disease and Parkinson's disease), and (3) prediction of time to symptom onset (presymptomatic mutation carriers in genetic Alzheimer's disease and spinocerebellar ataxia type 3).


Stem cells repurpose proliferation to contain a breach in their niche barrier.
Adult stem cells are responsible for life-long tissue maintenance. They reside in and interact with specialized tissue microenvironments (niches). Using murine hair follicle as a model, we show that when junctional perturbations in the niche disrupt barrier function, adjacent stem cells dramatically change their transcriptome independent of bacterial invasion and become capable of directly signaling to and recruiting immune cells. Additionally, these stem cells elevate cell cycle transcripts which reduce their quiescence threshold, enabling them to selectively proliferate within this microenvironment of immune distress cues. However, rather than mobilizing to fuel new tissue regeneration, these ectopically proliferative stem cells remain within their niche to contain the breach. Together, our findings expose a potential communication relay system that operates from the niche to the stem cells to the immune system and back. The repurposing of proliferation by these stem cells patch the breached barrier, stoke the immune response and restore niche integrity.


Analysis of multimask fabrication errors for diffractive optical elements.
As design algorithms for diffractive optical elements improve, the limiting factor becomes the fabrication process. It is hoped a better understanding of fabrication errors will allow elements with greater tolerance to be designed. This is important for high-power laser fiber coupling, where hot spots lead to failure. We model seven different fan-out gratings applying misetch, misalignment, and feature rounding. Our main findings are that misetch can lead to improved results, misalignment is strongly asymmetric, and both the pi and pi/2 masks can dominate misalignment. Rounding has a r(2) dependence and potentially can be incorporated into the design stage. Finally we present some experimental data for misalignment.


Pharmacologic interventions for treating phantom limb pain.
This is an updated version of the original Cochrane review published in Issue 12, 2011. Phantom limb pain (PLP) is pain that arises in the missing limb after amputation and can be severe, intractable, and disabling. Various medications have been studied in the treatment of phantom pain. There is currently uncertainty in the optimal pharmacologic management of PLP. This review aimed to summarise the evidence of effectiveness of pharmacologic interventions in treating PLP. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), MEDLINE, and Embase for relevant studies. We ran the searches for the original review in September 2011 and subsequent searches for this update up to April 2016. We sought additional studies from clinical trials databases and reference lists of retrieved papers. We included randomised and quasi-randomised trials studying the effectiveness of pharmacologic interventions compared with placebo, another active treatment, or no treatment, in established PLP. We considered the following outcomes: change in pain intensity, function, sleep, depression or mood, quality of life, adverse events, treatment satisfaction, and withdrawals from the study. We independently assessed issues of study quality and extracted efficacy and adverse event data. Due to the wide variability in the studies, we did not perform a meta-analysis for all the interventions and outcomes, but attempted to pool the results of some studies where possible. We prepared a qualitative description and narrative summary of results. We assessed clinical heterogeneity by making qualitative comparisons of the populations, interventions, outcomes/outcome measures, and methods. We added only one new study with 14 participants to this updated review. We included a 14 studies (10 with low risk of bias and 4 with unclear risk of bias overall) with a total of 269 participants. We added another drug class, botulinum neurotoxins (BoNTs), in particular botulinum toxin A (BoNT/A), to the group of medications reviewed previously. Our primary outcome was change in pain intensity. Most studies did not report our secondary outcomes of sleep, depression or mood, quality of life, treatment satisfaction, or withdrawals from the study.BoNT/A did not improve phantom limb pain intensity during the six months of follow-up compared with lidocaine/methylprednisolone.Compared with placebo, morphine (oral and intravenous) was effective in decreasing pain intensity in the short term with reported adverse events being constipation, sedation, tiredness, dizziness, sweating, voiding difficulty, vertigo, itching, and respiratory problems.The N-methyl D-aspartate (NMDA) receptor antagonists ketamine (versus placebo; versus calcitonin) and dextromethorphan (versus placebo), but not memantine, had analgesic effects. The adverse events of ketamine were more serious than placebo and calcitonin and included loss of consciousness, sedation, hallucinations, hearing and position impairment, and insobriety.The results for gabapentin in terms of pain relief were conflicting, but combining the results favoured treatment group (gabapentin) over control group (placebo) (mean difference -1.16, 95% confidence interval -1.94 to -0.38; 2 studies). However, gabapentin did not improve function, depression score, or sleep quality. Adverse events experienced were somnolence, dizziness, headache, and nausea.Compared with an active control benztropine mesylate, amitriptyline was not effective in PLP, with dry mouth and dizziness as the most frequent adverse events based on one study.The findings for calcitonin (versus placebo; versus ketamine) and local anaesthetics (versus placebo) were variable. Adverse events of calcitonin were headache, vertigo, drowsiness, nausea, vomiting, and hot and cold flushes. Most of the studies were limited by their small sample sizes. Since the last version of this review, we identified another study that added another form of medical therapy, BoNTs, specifically BoNT/A, to the list of pharmacologic interventions being reviewed for clinical efficacy in phantom limb pain. However, the results of this study did not substantially change the main conclusions. The short- and long-term effectiveness of BoNT/A, opioids, NMDA receptor antagonists, anticonvulsants, antidepressants, calcitonins, and local anaesthetics for clinically relevant outcomes including pain, function, mood, sleep, quality of life, treatment satisfaction, and adverse events remain unclear. Based on a small study, BoNT/A (versus lidocaine/methylprednisolone) does not decrease phantom limb pain. Morphine, gabapentin, and ketamine demonstrate favourable short-term analgesic efficacy compared with placebo. Memantine and amitriptyline may not be effective for PLP. However, results must be interpreted with caution, as they were based mostly on a small number of studies with limited sample sizes that varied considerably and also lacked long-term efficacy and safety outcomes. The direction of efficacy of calcitonin, local anaesthetics, and dextromethorphan needs further clarification. Overall, the efficacy evidence for the reviewed medications is thus far inconclusive. Larger and more rigorous randomised controlled trials are needed for us to reach more definitive conclusions about which medications would be useful for clinical practice.


MOTHER-OF-FT-AND-TFL1 regulates the seed oil and protein content in soybean.
Soybean is a major crop that produces valuable seed oil and protein for global consumption. Seed oil and protein are regulated by complex quantitative trait loci (QTLs) and have undergone intensive selections during the domestication of soybean. It is essential to identify the major genetic components and understand their mechanism behind seed oil and protein in soybean. We report that MOTHER-OF-FT-AND-TFL1 (GmMFT) is the gene of a classical QTL that has been reported to regulate seed oil and protein content in many studies. Mutation of MFT decreased seeds oil content and weight in both Arabidopsis and soybean, whereas increased expression of GmMFT enhanced seeds oil content and weight. Haplotype analysis showed that GmMFT has undergone selection, which resulted in the extended haplotype homozygosity in the cultivated soybean and the enriching of the oil-favorable allele in modern soybean cultivars. This work unraveled the GmMFT-mediated mechanism regulating seed oil and protein content and seed weight, and revealed a previously unknown function of MFT that provides new insights into targeted soybean improvement and breeding.


Saponin from sea cucumber exhibited more significant effects than ginsenoside on ameliorating high fat diet-induced obesity in C57BL/6 mice.
Obesity and its comorbidities are considered to be a severe public health problem. Many natural compounds found in food have been proved to ameliorate the metabolic abnormalities induced by obesity. The purpose of this study was to compare the effects of saponin from sea cucumber (SSC) and ginsenoside (SG) on improving the lipid metabolism in C57BL/6 mice fed with a high fat diet. The mice were randomly divided into six groups including a low fat diet group (LF), a high fat diet group (HF), and four dietary intervention groups. The administration of SSC for 8 weeks exhibited a more significant reduction in HF induced fat mass, weight gain, lipid levels in the liver and serum, and serum glucose and insulin levels than SG. Further research indicated that SSC ameliorated high fat diet-induced obesity in C57BL/6 mice mainly through inhibiting lipid synthesis and accelerating lipid β-oxidation and glycolysis in the liver. These results suggested that saponin from sea cucumber might be applied as a food supplement and/or functional ingredient to relieve metabolic disorders induced by obesity.


Estimation of genetic parameters for milk and fat yields of dairy cattle in Spain and the United States.
Interaction of genotype with environment was studied with 10,780 Spanish production records (daughters of 210 Holstein-Friesian bulls) and two subsets of United States data (800,821 records with 1170 sires and 762,152 records with 1186 sires). Only 74 bulls had daughter records in both Spanish and United States data. Genetic and phenotypic (co)variances and correlations and heritability for milk and fat yields were estimated both within country and between countries with countries considered as separate traits (joint analysis). (Co)variance components were estimated with a REML procedure. Heritability estimates for milk and fat in the Spanish population (.16 and .14, within country; .12 and .09, joint) were smaller than for United States data (means of .33 and .31, within country; .26 and .24, joint). Genetic and phenotypic correlations between milk and fat within country were higher for Spain (.94 and .91) than for United States data (means of .66 and .81). Genetic correlation between countries averaged .81 for milk and .50 for fat. Rankings of bulls for milk yield are expected to be similar in Spain and the United States, although a scaling effect on predicted values is expected from different genetic variances in each country. Ranking of bulls for fat yield may be quite different.


Why residents of Dutch deprived neighbourhoods are less likely to be heavy drinkers: the role of individual and contextual characteristics.
Earlier research has shown that residents of Dutch deprived neighbourhoods drink less alcohol than people in other areas. We aimed to assess the role of individual and neighbourhood characteristics in a cross-sectional, nationwide, multilevel study. Individual data of 30,117 Dutch adults, living in 1722 neighbourhoods across the Netherlands, were obtained from the 2004 to 2009 national health survey (POLS). Chronic heavy alcohol consumption was measured as ≥14 drinks/week for women and ≥21 for men, and episodic heavy drinking as ≥6 drinks/day at least once a week. Neighbourhood deprivation was dichotomous; deprived districts as selected by the Dutch government versus other areas. Multilevel logistic regression models of the association between deprivation and heavy drinking were corrected for age, gender, household composition, population density and potential predictors ethnicity, socioeconomic status (education, income), neighbourhood-level social cohesion and percentage Muslims. The prevalence of heavy drinking was lower in deprived neighbourhoods than in the rest of the Netherlands. This association was found for both chronic and episodic heavy drinking (OR=0.58 (0.47 to 0.72) and OR=0.57 (0.45 to 0.72), respectively). Adding ethnicity to the model reduced these associations by approximately one half. Socioeconomic composition did not contribute to the relationship. The proportion of Muslims explained a small part, while social cohesion explained even less of the association. Stronger associations were observed for women and older adults than for men and younger adults. The lower prevalence of heavy drinking occurring in deprived areas is largely explained by the ethnicity of neighbourhood residents.


Pleiotropy of the serotonin transporter gene for seasonality and neuroticism.
Pleiotropy refers to the ability of a single gene to influence multiple traits. A polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) has previously been found to be associated both with the personality trait of neuroticism and with seasonal changes in mood and behavior, or seasonality. Hypothesizing that the contribution of the serotonin transporter gene to seasonality is specific, i.e. independent of neuroticism, we measured 5-HTTLPR genotypes and both psychological traits in 236 healthy volunteers. The results indicated that the 5-HTTLPR contributions to variation in the two traits are largely independent; approximately three-quarters of the effect of the gene on seasonality are not related to its effects on neuroticism. Moreover, the gene has a larger effect on the covariation between neuroticism and seasonality than it does on either trait alone. Sibling-pair analysis confirmed that the effects of the 5-HTTLPR are due to genetic pleiotropy rather than population stratification.


A cloud based tool for knowledge exchange on local scale flood risk.
There is an emerging and urgent need for new approaches for the management of environmental challenges such as flood hazard in the broad context of sustainability. This requires a new way of working which bridges disciplines and organisations, and that breaks down science-culture boundaries. With this, there is growing recognition that the appropriate involvement of local communities in catchment management decisions can result in multiple benefits. However, new tools are required to connect organisations and communities. The growth of cloud based technologies offers a novel way to facilitate this process of exchange of information in environmental science and management; however, stakeholders need to be engaged with as part of the development process from the beginning rather than being presented with a final product at the end. Here we present the development of a pilot Local Environmental Virtual Observatory Flooding Tool. The aim was to develop a cloud based learning platform for stakeholders, bringing together fragmented data, models and visualisation tools that will enable these stakeholders to make scientifically informed environmental management decisions at the local scale. It has been developed by engaging with different stakeholder groups in three catchment case studies in the UK and a panel of national experts in relevant topic areas. However, these case study catchments are typical of many northern latitude catchments. The tool was designed to communicate flood risk in locally impacted communities whilst engaging with landowners/farmers about the risk of runoff from the farmed landscape. It has been developed iteratively to reflect the needs, interests and capabilities of a wide range of stakeholders. The pilot tool combines cloud based services, local catchment datasets, a hydrological model and bespoke visualisation tools to explore real time hydrometric data and the impact of flood risk caused by future land use changes. The novel aspects of the pilot tool are; the co-evolution of tools on a cloud based platform with stakeholders, policy and scientists; encouraging different science disciplines to work together; a wealth of information that is accessible and understandable to a range of stakeholders; and provides a framework for how to approach the development of such a cloud based tool in the future. Above all, stakeholders saw the tool and the potential of cloud technologies as an effective means to taking a whole systems approach to solving environmental issues. This sense of community ownership is essential in order to facilitate future appropriate and acceptable land use management decisions to be co-developed by local catchment communities. The development processes and the resulting pilot tool could be applied to local catchments globally to facilitate bottom up catchment management approaches.


Sex and gender differences in travel-associated disease.
No systematic studies exist on sex and gender differences across a broad range of travel-associated diseases. Travel and tropical medicine GeoSentinel clinics worldwide contributed prospective, standardized data on 58,908 patients with travel-associated illness to a central database from 1 March 1997 through 31 October 2007. We evaluated sex and gender differences in health outcomes and in demographic characteristics. Statistical significance for crude analysis of dichotomous variables was determined using chi2 tests with calculation of odds ratios (ORs) and 95% confidence intervals (CIs). The main outcome measure was proportionate morbidity of specific diagnoses in men and women. The analyses were adjusted for age, travel duration, pretravel encounter, reason for travel, and geographical region visited. We found statistically significant (P < .001) differences in morbidity by sex. Women are proportionately more likely than men to present with acute diarrhea (OR, 1.13; 95% CI, 1.09-1.38), chronic diarrhea (OR, 1.28; 95% CI, 1.19-1.37), irritable bowel syndrome (OR, 1.39; 95% CI, 1.24-1.57), upper respiratory tract infection (OR, 1.23; 95% CI, 1.14-1.33); urinary tract infection (OR, 4.01; 95% CI, 3.34-4.71), psychological stressors (OR, 1.3; 95% CI, 1.14-1.48), oral and dental conditions, or adverse reactions to medication. Women are proportionately less likely to have febrile illnesses (OR, 0.15; 95% CI, 0.10-0.21); vector-borne diseases, such as malaria (OR, 0.46; 95% CI, 0.41-0.51), leishmaniasis, or rickettsioses (OR, 0.57; 95% CI, 0.43-0.74); sexually transmitted infections (OR, 0.68; 95% CI 0.58-0.81); viral hepatitis (OR, 0.34; 95% CI, 0.21-0.54); or noninfectious problems, including cardiovascular disease, acute mountain sickness, and frostbite. Women are statistically significantly more likely to obtain pretravel advice (OR, 1.28; 95% CI, 1.23-1.32), and ill female travelers are less likely than ill male travelers to be hospitalized (OR, 0.45; 95% CI, 0.42-0.49). Men and women present with different profiles of travel-related morbidity. Preventive travel medicine and future travel medicine research need to address gender-specific intervention strategies and differential susceptibility to disease.


Phenotypic correlates of hybridisation between red and sika deer (genus Cervus).
1. Hybridisation with an invasive species has the potential to alter the phenotype and hence the ecology of a native counterpart. 2. Here data from populations of native red deer Cervus elaphus and invasive sika deer Cervus nippon in Scotland is used to assess the extent to which hybridisation between them is causing phenotypic change. This is done by regression of phenotypic traits against genetic hybrid scores. 3. Hybridisation is causing increases in the body weight of sika-like deer and decreases in the body weight of red-like females. Hybridisation is causing increases in jaw length and increases in incisor arcade breadth in sika-like females. Hybridisation is also causing decreases in incisor arcade breadth in red-like females. 4. There is currently no evidence that hybridisation is causing changes in the kidney fat weight or pregnancy rates of either population. 5. Increased phenotypic similarity between the two species is likely to lead to further hybridisation. The ecological consequences of this are difficult to predict.


Effects of d-myo-inositol-1,2,6-trisphosphate on neuropeptide Y-induced potentiation of various vasoconstrictor agents in the rat.
The adrenergic cotransmitter neuropeptide Y (NPY) induces vascular smooth muscle contraction by occupying postsynaptic Y1 receptors and by enhancing the vasoconstriction induced by a series of other pressor agents. In particular, NPY modulates the blood pressure response to alpha-1 adrenergic agonists and angiotensin II. The inositol phosphate derivative, d-myo-inositol-1,2,6-trisphosphate (PP56), is a novel NPY antagonist which within a defined dose range selectively blocks the effects of exogenously administered NPY in vivo. In the pithed animal as well as in the freely moving Sprague-Dawley rat, an i.v. bolus administration of PP56 (2 mg/kg) followed by an infusion (20 mg/kg/hr for 30 min) inhibited the approximate 50% increase in mean arterial blood pressure induced by a continuous infusion of NPY (2 micrograms/kg/min for 10 min). Furthermore, PP56 treatment completely inhibited the enhancement induced by NPY (0.1 microgram/min for 50 min or 2 micrograms/kg/min for 10 min) of the pressor responses to preganglionic sympathetic nerve stimulation (in the pithed rat) and to i.v. bolus injections of noradrenaline (20 ng), the indirect sympathomimetic tyramine (40 micrograms) as well as to angiotensin II (10 ng). These results show that PP56, representing a new class of synthetic nonpeptide drugs, is capable of antagonizing the vascular smooth muscle contractile as well as the potentiating effects of NPY in vivo in the pithed as well as the conscious rat.


Neuroprotective Methodologies of Co-Enzyme Q10 Mediated Brain Hemorrhagic Treatment: Clinical and Pre-Clinical Findings.
Cerebral brain hemorrhage is associated with the highest mortality and morbidity despite only constituting approximately 10-15% of all strokes classified into intracerebral and intraventricular hemorrhage where most of the patients suffer from impairment in memory, weakness or paralysis in arms or legs, headache, fatigue, gait abnormality and cognitive dysfunctions. Understanding molecular pathology and finding the worsening cause of hemorrhage will lead to explore the therapeutic interventions that could prevent and cure the disease. Mitochondrial ETC-complexes dysfunction has been found to increase neuroinflammatory cytokines, oxidative free radicals, excitotoxicity, neurotransmitter and energy imbalance that are the key neuropathological hallmarks of cerebral hemorrhage. Coenzyme Q10 (CoQ10), as a part of the mitochondrial respiratory chain can effectively restore these neuronal dysfunctions by preventing the opening of mitochondrial membrane transition pore, thereby counteracting cell death events as well as exerts an anti-inflammatory effect by influencing the expression of NF-kB1 dependent genes thus preventing the neuroinflammation and energy restoration. Due to behavior and biochemical heterogeneity in post cerebral brain hemorrhagic pattern different preclinical autologous blood injection models are required to precisely investigate the forthcoming therapeutic strategies. Despite emerging pre-clinical research and resultant large clinical trials for promising symptomatic treatments, there are very less pharmacological interventions demonstrated to improve post operative condition of patients where intensive care is required. Therefore, in current review, we explore the disease pattern, clinical and pre-clinical interventions under investigation and neuroprotective methodologies of CoQ10 precursors to ameliorate post brain hemorrhagic conditions.


A Genomic Perspective Across Earth's Microbiomes Reveals That Genome Size in Archaea and Bacteria Is Linked to Ecosystem Type and Trophic Strategy.
Our view of genome size in Archaea and Bacteria has remained skewed as the data has been dominated by genomes of microorganisms that have been cultivated under laboratory settings. However, the continuous effort to catalog Earth's microbiomes, specifically propelled by recent extensive work on uncultivated microorganisms, provides an opportunity to revise our perspective on genome size distribution. We present a meta-analysis that includes 26,101 representative genomes from 3 published genomic databases; metagenomic assembled genomes (MAGs) from GEMs and stratfreshDB, and isolates from GTDB. Aquatic and host-associated microbial genomes present on average the smallest estimated genome sizes (3.1 and 3.0 Mbp, respectively). These are followed by terrestrial microbial genomes (average 3.7 Mbp), and genomes from isolated microorganisms (average 4.3 Mbp). On the one hand, aquatic and host-associated ecosystems present smaller genomes sizes in genera of phyla with genome sizes above 3 Mbp. On the other hand, estimated genome size in phyla with genomes under 3 Mbp showed no difference between ecosystems. Moreover, we observed that when using 95% average nucleotide identity (ANI) as an estimator for genetic units, only 3% of MAGs cluster together with genomes from isolated microorganisms. Although there are potential methodological limitations when assembling and binning MAGs, we found that in genome clusters containing both environmental MAGs and isolate genomes, MAGs were estimated only an average 3.7% smaller than isolate genomes. Even when assembly and binning methods introduce biases, estimated genome size of MAGs and isolates are very similar. Finally, to better understand the ecological drivers of genome size, we discuss on the known and the overlooked factors that influence genome size in different ecosystems, phylogenetic groups, and trophic strategies.


A standardized method to determine the concentration of extracellular vesicles using tunable resistive pulse sensing.
Understanding the pathogenic role of extracellular vesicles (EVs) in disease and their potential diagnostic and therapeutic utility is extremely reliant on in-depth quantification, measurement and identification of EV sub-populations. Quantification of EVs has presented several challenges, predominantly due to the small size of vesicles such as exosomes and the availability of various technologies to measure nanosized particles, each technology having its own limitations. A standardized methodology to measure the concentration of extracellular vesicles (EVs) has been developed and tested. The method is based on measuring the EV concentration as a function of a defined size range. Blood plasma EVs are isolated and purified using size exclusion columns (qEV) and consecutively measured with tunable resistive pulse sensing (TRPS). Six independent research groups measured liposome and EV samples with the aim to evaluate the developed methodology. Each group measured identical samples using up to 5 nanopores with 3 repeat measurements per pore. Descriptive statistics and unsupervised multivariate data analysis with principal component analysis (PCA) were used to evaluate reproducibility across the groups and to explore and visualise possible patterns and outliers in EV and liposome data sets. PCA revealed good reproducibility within and between laboratories, with few minor outlying samples. Measured mean liposome (not filtered with qEV) and EV (filtered with qEV) concentrations had coefficients of variance of 23.9% and 52.5%, respectively. The increased variance of the EV concentration measurements could be attributed to the use of qEVs and the polydisperse nature of EVs. The results of this study demonstrate the feasibility of this standardized methodology to facilitate comparable and reproducible EV concentration measurements.


Defining reliable disability outcomes in multiple sclerosis.
Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events.


A systematic review of barriers to data sharing in public health.
In the current information age, the use of data has become essential for decision making in public health at the local, national, and global level. Despite a global commitment to the use and sharing of public health data, this can be challenging in reality. No systematic framework or global operational guidelines have been created for data sharing in public health. Barriers at different levels have limited data sharing but have only been anecdotally discussed or in the context of specific case studies. Incomplete systematic evidence on the scope and variety of these barriers has limited opportunities to maximize the value and use of public health data for science and policy. We conducted a systematic literature review of potential barriers to public health data sharing. Documents that described barriers to sharing of routinely collected public health data were eligible for inclusion and reviewed independently by a team of experts. We grouped identified barriers in a taxonomy for a focused international dialogue on solutions. Twenty potential barriers were identified and classified in six categories: technical, motivational, economic, political, legal and ethical. The first three categories are deeply rooted in well-known challenges of health information systems for which structural solutions have yet to be found; the last three have solutions that lie in an international dialogue aimed at generating consensus on policies and instruments for data sharing. The simultaneous effect of multiple interacting barriers ranging from technical to intangible issues has greatly complicated advances in public health data sharing. A systematic framework of barriers to data sharing in public health will be essential to accelerate the use of valuable information for the global good.


Phylogeography of a pan-Atlantic abyssal protobranch bivalve: implications for evolution in the Deep Atlantic.
The deep sea is a vast and essentially continuous environment with few obvious barriers to gene flow. How populations diverge and new species form in this remote ecosystem is poorly understood. Phylogeographical analyses have begun to provide some insight into evolutionary processes at bathyal depths (<3000 m), but much less is known about evolution in the more extensive abyssal regions (>3000 m). Here, we quantify geographical and bathymetric patterns of genetic variation (16S rRNA mitochondrial gene) in the protobranch bivalve Ledella ultima, which is one of the most abundant abyssal protobranchs in the Atlantic with a broad bathymetric and geographical distribution. We found virtually no genetic divergence within basins and only modest divergence among eight Atlantic basins. Levels of population divergence among basins were related to geographical distance and were greater in the South Atlantic than in the North Atlantic. Ocean-wide patterns of genetic variation indicate basin-wide divergence that exceeds what others have found for abyssal organisms, but considerably less than bathyal protobranchs across similar geographical scales. Populations on either side of the Mid-Atlantic Ridge in the North Atlantic differed, suggesting the Ridge might impede gene flow at abyssal depths. Our results indicate that abyssal populations might be quite large (cosmopolitan), exhibit only modest genetic structure and probably provide little potential for the formation of new species.


How does endothelial cell injury start? The role of endothelin in systemic sclerosis.
A considerable amount of research time has been invested in studies aimed at elucidating pathogenic processes in systemic sclerosis (SSc). Despite this, major challenges for biomedical science remain, such as identification of the key factors that determine susceptibility to SSc, and elucidation of the precise nature of the initiating event that causes endothelial cell injury and ultimately brings about the biological cascade(s) that lead to the pathologic vascular changes. Involved factors are likely to include genetic perturbations, environmental cues, tissue injury, infection and hypoxia/oxidative stress. As important as determining the initiating events are the identification and characterization of key factors that are functionally important in driving vascular disease progression, because these factors are potential targets for therapeutic intervention. This article reviews the role of endothelin as an example of a pleiotropic mediator with effects on various aspects of SSc pathogenesis, such as inflammation, vasculopathy and tissue remodelling.


XRK3F2 Inhibition of p62-ZZ Domain Signaling Rescues Myeloma-Induced GFI1-Driven Epigenetic Repression of the Runx2 Gene in Pre-osteoblasts to Overcome Differentiation Suppression.
Multiple myeloma bone disease (MMBD) is characterized by non-healing lytic bone lesions that persist even after a patient has achieved a hematologic remission. We previously reported that p62 (sequestosome-1) in bone marrow stromal cells (BMSC) is critical for the formation of MM-induced signaling complexes that mediate OB suppression. Importantly, XRK3F2, an inhibitor of the p62-ZZ domain, blunted MM-induced Runx2 suppression in vitro, and induced new bone formation and remodeling in the presence of tumor in vivo. Additionally, we reported that MM cells induce the formation of repressive chromatin on the Runx2 gene in BMSC via direct binding of the transcriptional repressor GFI1, which recruits the histone modifiers, histone deacetylase 1 (HDAC1) and Enhancer of zeste homolog 2 (EZH2). In this study we investigated the mechanism by which blocking p62-ZZ domain-dependent signaling prevents MM-induced suppression of Runx2 in BMSC. XRK3F2 prevented MM-induced upregulation of Gfi1 and repression of the Runx2 gene when present in MM-preOB co-cultures. We also show that p62-ZZ-domain blocking by XRK3F2 also prevented MM conditioned media and TNF plus IL7-mediated Gfi1 mRNA upregulation and the concomitant Runx2 repression, indicating that XRK3F2's prevention of p62-ZZ domain signaling within preOB is involved in the response. Chromatin immunoprecipitation (ChIP) analyses revealed that XRK3F2 decreased MM-induced GFI1 occupancy at the Runx2-P1 promoter and prevented recruitment of HDAC1, thus preserving the transcriptionally permissive chromatin mark H3K9ac on Runx2 and allowing osteogenic differentiation. Furthermore, treatment of MM-exposed preOB with XRK3F2 after MM removal decreased GFI1 enrichment at Runx2-P1 and rescued MM-induced suppression of Runx2 mRNA and its downstream osteogenic gene targets together with increased osteogenic differentiation. Further, primary BMSC (hBMSC) from MM patients (MM-hBMSC) had little ability to increase H3K9ac on the Runx2 promoter in osteogenic conditions when compared to hBMSC from healthy donors (HD). XRK3F2 treatment enriched Runx2 gene H3K9ac levels in MM-hBMSC to the level observed in HD-hBMSC, but did not alter HD-hBMSC H3K9ac. Importantly, XRK3F2 treatment of long-term MM-hBMSC cultures rescued osteogenic differentiation and mineralization. Our data show that blocking p62-ZZ domain-dependent signaling with XRK3F2 can reverse epigenetic-based mechanisms of MM-induced Runx2 suppression and promote osteogenic differentiation.


Anatomic distribution of venous thrombosis in patients with antiphospholipid antibody: imaging findings.
Antiphospholipid antibodies are immunoglobulins that cross-react with phospholipid within cell membranes. These antibodies have been associated with a hypercoagulable state manifested by early stroke, frequent arterial and venous thromboses, recurrent fetal loss, thrombocytopenia, and livedo reticularis (antiphospholipid syndrome). The purpose of this study was to determine the anatomic distribution of venous thrombosis in patients with antiphospholipid antibodies as seen on imaging examinations. We retrospectively reviewed the laboratory results of patients tested for antiphospholipid antibodies at a tertiary referral center during the period January 1992 to April 1994. This review revealed 228 patients with antiphospholipid antibodies. We excluded patients with systemic lupus erythematosus or any other medical condition associated with a hypercoagulable state and patients over 65 years old. Thirty-one of the remaining 73 patients had undergone imaging studies of the CNS or non-CNS venous system. Radiologic studies (contrast angiography or venography, MR angiography or venography, or Doppler sonography) were examined for the presence of venous thrombosis. Nineteen patients--11 men and eight women, 18-62 years old (average age, 38 years)--with venous thromboses were identified. Twelve patients had non-CNS thrombosis alone, three had CNS thrombosis alone, and four had both CNS and non-CNS thromboses. Locations of non-CNS thromboses included deep veins of the legs (nine occurrences), pulmonary vessels (five), and large veins in the thorax or abdomen (six). Three of these patients had documented thromboses at other sites. Twelve patients had recurrent thrombotic events (six with multiple recurrences), including five with arterial thromboses and two with both venous and arterial thromboses and stroke. Among patients with CNS involvement, five had documented thromboses (four dural sinus, one arterial) and two had arterial distribution strokes demonstrated by CT. Two patients with only non-CNS thromboses had either seizures or migraines. Deep veins of the leg were the most common site of venous thrombosis. The thoracic and abdominal venous system and the dural sinuses--unusual sites of thrombosis in the general population--are other common sites. Antiphospholipid antibodies should be suspected when thromboses are found in these locations in the absence of other known risk factors, or when found in combination with arterial thromboses or CNS ischemic disease in young or middle-aged patients.


2013: Signaling breakthroughs of the year.
The editorial staff and distinguished scientists in the field of cell signaling nominated diverse research as advances for 2013. Breakthroughs in understanding how spatial and temporal signals control cellular behavior ranged from filtering high-frequency stimuli to interpreting circadian inputs. This year's nominations also highlight the importance of understanding cell signaling in the context of physiology and disease, such as links between the nervous system and cancer. Furthermore, the application of new techniques to study cell signaling--such as optogenetics, DNA editing with CRISPR-Cas9, and sequencing untranslated regions of transcripts--continues to expand the realm and impact of signaling research.


User-defined local stimulation of live tissue through a movable microfluidic port.
Many in vivo tissue responses begin locally, yet most in vitro stimuli are delivered globally. Microfluidics has a unique ability to provide focal stimulation to tissue samples with precise control over fluid location, flow rate, and composition. However, previous devices utilizing fixed ports beneath the tissue required manual alignment of the tissue over the ports, increasing the risk of mechanical damage. Here we present a novel microfluidic device that allows the user to define the location of fluid delivery to a living tissue slice without manipulating the tissue itself. The device utilized a two-component SlipChip design to create a mobile port beneath the tissue slice. A culture chamber perforated by an array of ports housed a tissue slice and was separated by a layer of fluorocarbon oil from a single delivery port, fed by a microfluidic channel in the movable layer below. We derived and validated a physical model, based on interfacial tension and flow resistance, to predict the conditions under which fluid delivery occurred without leakage into the gap between layers. Aqueous solution was delivered reproducibly to samples of tissue and gel, and the width of the delivery region was controlled primarily by convection. Tissue slice viability was not affected by stimulation on the device. As a proof-of-principle, we showed that live slices of lymph node tissue could be sequentially targeted for precise stimulation. In the future this device may serve as a platform to study the effects of fluid flow in tissues and to perform local drug screening.


Adjusting Challenge-Skill Balance to Improve Quality of Life in Older Adults: A Randomized Controlled Trial.
We sought to investigate whether occupational therapy that includes adjusting the challenge-skill balance improves health-related quality of life (HRQOL) for older adults in comparison with standard occupational therapy. In this single-blind, randomized controlled trial, 56 older adults were assigned to two groups that received 10 sessions of occupational therapy with and without adjustment of challenge-skill balance. The primary outcome was change in HRQOL after 10 sessions of occupational therapy. Significant differences were observed in HRQOL using the EuroQol-5 Dimension score (p = .022, d = 0.76) and the eight-item Short-Form Health Survey scores for general health (p = .001, d = 0.99) and in flow experience using the Flow State Scale for Occupational Tasks (p = .008, d = 0.82). Assessment and adjustment of the challenge-skill balance of activities may effectively improve older adults' HRQOL.


High temporal resolution decoding of object position and category.
We effortlessly and seemingly instantaneously recognize thousands of objects, although we rarely--if ever--see the same image of an object twice. The retinal image of an object can vary by context, size, viewpoint, illumination, and location. The present study examined how the visual system abstracts object category across variations in retinal location. In three experiments, participants viewed images of objects presented to different retinal locations while brain activity was recorded using magnetoencephalography (MEG). A pattern classifier was trained to recover the stimulus position (Experiments 1, 2, and 3) and category (Experiment 3) from the recordings. Using this decoding approach, we show that an object's location in the visual field can be recovered in high temporal resolution (5 ms) and with sufficient fidelity to capture topographic organization in visual areas. Experiment 3 showed that an object's category could be recovered from the recordings as early as 135 ms after the onset of the stimulus and that category decoding generalized across retinal location (i.e., position invariance). Our experiments thus show that the visual system rapidly constructs a category representation for objects that is invariant to position.


Ability of Functional Performance Tests to Identify Individuals With Chronic Ankle Instability: A Systematic Review With Meta-Analysis.
The purpose of this systematic review with meta-analysis was to determine the effectiveness of functional performance tests (FPTs) in differentiating between individuals with chronic ankle instability (CAI) and healthy controls. The National Library of Medicine Catalog (PubMed), the Cumulative Index for Nursing and Allied Health Literature (CINAHL), and the SPORTDiscus, from inception to June 2017 were searched. Search terms consisted of: "Functional Performance Test*" OR "Dynamic Balance Test*" OR "Postural Stability Test*" OR "Star Excursion Balance Test*" OR "Hop Test*" AND "Ankle Instability" OR "Ankle Sprain." Included articles assessed differences in FPTs in patients with CAI compared with a control group. Included studies were assessed for methodological quality and level of evidence. Individual and mean effect sizes were also calculated for FPTs from the included articles. Twenty-nine studies met the criteria and were analyzed. The most common FPTs were timed-hop tests, side-hop, multiple-hop test, single-hop for distance, foot-lift test, and the Star Excursion Balance Tests (SEBTs). The side-hop (g = -1.056, P = 0.009, n = 7), timed-hop tests (g = -0.958, P = 0.002, n = 9), multiple-hop test (g = 1.399, P < 0.001, n = 3), and foot-lift tests (g = -0.761, P = 0.020, n = 3) demonstrated the best utility with large mean effect sizes, whereas the SEBT anteromedial (g = 0.326, P = 0.022, n = 7), medial (g = 0.369, P = 0.006, n = 7), and posteromedial (g = 0.374, P < 0.001, n = 13) directions had moderate effects. The side-hop, timed-hopping, multiple-hop, and foot-lift seem the best FPTs to evaluate individuals with CAI. There was a large degree of heterogeneity and inconsistent reporting, potentially limiting the clinical implementation of these FPTs. These tests are cheap, effective, alternatives compared with instrumented measures.


Rapid assessment of a helpdesk service supporting severe acute respiratory syndrome patients and their relatives.
To contain severe acute respiratory syndrome, the Hong Kong Hospital Authority set a policy that stipulated there should be no visitors to hospital wards. A helpdesk service was established with the goal of providing immediate emotional and communication support to relatives while severe acute respiratory syndrome patients were isolated during the acute phase of the illness. This study describes the results of a rapid assessment of the effectiveness of a helpdesk service designed to meet the immediate needs of relatives of severe acute respiratory syndrome patients in Hong Kong. Survey. Eighty-three respondents, representing about 46.3% of relatives (179), attending the helpdesk on the day of the study were recruited. Service evaluation data was collected using a self-administered questionnaire completed by respondents. Nearly 100% of respondents who used the service found the delivery service with on-site counselling useful for alleviating their anxiety. However, about half of these relatives complained of insufficient information regarding the patient's condition and progress. The majority of respondents were satisfied with the service. In describing the most important traits of the service providers, caring and enthusiasm were mentioned most frequently by respondents who stated that they were very satisfied with the service. The results support the value of the service, and demonstrate that the service is effective in meeting relatives' immediate needs. These needs include information, aid in fulfilling their role as caretaker for the patient (delivering prepared soup) and psychological support. The results suggest that facilitation of visitation of patients by relatives via video conferencing and education of the public on the nature and course of severe acute respiratory syndrome to reduce the social stigma of having a potentially life-threatening disease should be introduced in Hong Kong. The results highlight important attributes that helpers (nurses) should have in order to alleviate the suffering of severe acute respiratory syndrome patients and their relatives.


Choriocarcinoma in Women: Analysis of a Case Series With Genotyping.
Choriocarcinoma is an uncommon malignant neoplasm, which can be either gestational or nongestational in origin. Distinction of these subtypes has prognostic and therapeutic implications. Twenty-two tumors were genotyped using polymerase chain reaction amplification of 15 short tandem repeat loci and the amelogenin locus (XY determination). DNA patterns from tumor and maternal tissue, as well as villous tissue from any available prior or concurrent gestation, were compared, to determine gestational versus nongestational nature (containing vs. lacking a paternal chromosome complement, respectively) and the relationship between the tumor and any prior or concurrent gestation. Nineteen tumors were gestational. Of these, 14 were purely androgenetic/homozygous XX: 6 uterine tumors with a concurrent or prior genetically related complete hydatidiform mole (CHM), 4 uterine tumors without an accompanying villous component, 1 uterine cornual tumor separate from a genetically distinct second trimester intrauterine placenta, 1 ectopic ovarian tumor separate from a genetically distinct third trimester intrauterine placenta, and 2 ectopic fallopian tube tumors. Five gestational tumors were biparental: 3 (2 XX, 1 XY) intraplacental choriocarcinomas genetically related to the placenta and 2 uterine tumors without accompanying placental tissue after term deliveries (1 XX 4 weeks postpartum and 1 XYY with allelic imbalances 1 year postpartum; prior placentas not available for analysis). Three tumors were nongestational: all XX with allelic imbalances; 2 ovarian, 1 pelvic. Gestational choriocarcinoma can be androgenetic or biparental. Most are androgenetic/homozygous XX, often associated with a genetically related concurrent or prior CHM, and thus of molar-associated type. These findings support that homozygous XX CHMs are associated with some risk of significant gestational trophoblastic disease. Intraplacental choriocarcinomas are biparental and genetically related to the placenta. Biparental choriocarcinoma detected in a postpartum uterine sample is consistent with undetected intraplacental choriocarcinoma. Eutopic or ectopic androgenetic choriocarcinoma separate from a concurrent intrauterine placenta is not derived from intraplacental tumor and is consistent with either a form of dispermic twin gestation (molar-type choriocarcinoma and coexistent nonmolar fetus) or origin from an antecedent molar pregnancy. While fallopian tube tumors are usually gestational, tumors in other sites (ovary, pelvis) can be nongestational and should not be assumed to be metastatic from a regressed or occult intrauterine or intraplacental gestational tumor.


Nutrition for the pediatric surgical patient: approach in the peri-operative period.
Nutrition is essential for maintenance of physiologic homeostasis and growth. Hypermetabolic states lead to a depletion of body stores, with decreased immunocompetence and increased morbidity and mortality. The purpose of this paper is to provide an update regarding the provision of appropriate nutrition for the pediatric surgical patient, emphasizing the preoperative and postoperative periods. Modern nutritional support for the surgical patient comprises numerous stages, including assessment of nutritional status, nutritional requirements, and nutritional therapy. Nutritional assessment is performed utilizing the clinical history, clinical examination, anthropometry, and biochemical evaluation. Anthropometric parameters include body weight, height, arm and head circumference, and skinfold thickness measurements. The biochemical evaluation is conducted using determinations of plasma levels of proteins, including album, pre-albumin, transferrin, and retinol-binding protein. These parameters are subject to error and are influenced by the rapid changes in body composition in the peri-operative period. Nutritional therapy includes enteral and/or parenteral nutrition. Enteral feeding is the first choice for nutritional therapy. If enteral feeding is not indicated, parenteral nutrition must be utilized. In all cases, an individualized, adequate diet (enteral formula or parenteral solution) is obligatory to decrease the occurrence of overfeeding and its undesirable consequences.


Transcriptional regulation of neutrophil differentiation and function during inflammation.
Neutrophils are the most abundant leukocytes in innate immunity where they elicit powerful effector functions to eliminate invading pathogens and modulate the adaptive as well as the innate immune response. Neutrophil function must be tightly regulated during inflammation and infection to avoid additional tissue damage. Increasing evidence suggests that transcription factors (TFs) function as key regulators to modulate transcriptional output, thereby controlling cell fate decision and the inflammatory responses. However, the molecular mechanisms underlying neutrophil differentiation and function during inflammation remain largely uncharacterized. Here, we provide a comprehensive overview of TFs known to be crucial for neutrophil maturation and in the signaling pathways that control neutrophil differentiation and activation. We also outline how emerging genomic and single-cell technologies may facilitate further discovery of neutrophil transcriptional regulators.


Dantrolene mediates vasorelaxation in cerebral vasoconstriction: a case series.
Cerebral vasoconstriction syndromes such as vasospasm after subarachnoid hemorrhage (SAH) and trauma, or Call-Fleming syndrome are difficult to treat, and can lead to substantial disability and death. Dantrolene, a ryanodine receptor antagonist, inhibits intracellular calcium release from the sarco-endoplasmic reticulum. We examined the effect of dantrolene on middle cerebral artery (MCA) blood flow velocities as measured by transcranial Doppler (TCD). Three consecutive patients with elevated MCA TCD velocities receiving dantrolene (2.5 mg/kg i.v. q6h) were retrospectively reviewed. Average MCA peak systolic, mean flow velocities, and the pulsatility index (PI) before and after the dantrolene infusion were compared within patients. Systemic physiological parameters (blood pressure, heart rate, central venous pressure, intracranial pressure, body temperature, and cooling water temperature) were retrospectively collected 6 h before and after the dantrolene infusion. MCA peak systolic velocities (mean +/- SE) for the three patients were 297 +/- 3, 248 +/- 8, and 268 +/- 19 cm/s before dantrolene and 159 +/- 9, 169 +/- 8, and 216 +/- 12 cm/s after dantrolene. Average mean flow velocities showed the same trend. Interestingly, the PI increased slightly from 0.6, 0.52, and 0.67 before dantrolene, to 1.17, 0.71, and 0.77 after dantrolene. Systemic physiological parameters remained stable in all three patients. Dantrolene attenuated cerebral vasoconstriction as measured by TCD without altering systemic physiological parameters. This suggests that intracellular calcium release from ryanodine channels in smooth muscle might play a role in vasospasm. A prospective study is underway to test this hypothesis.


Intraoperative subcortical electrical mapping of optic radiations in awake surgery for glioma involving visual pathways.
Preservation of the visual field in glioma surgery, especially avoidance of hemianopia, is crucial for patients' quality of life, particularly for driving. Recent studies used tractography or cortical occipital stimulation to try to avoid visual deficit. However, optic radiations have not been directly mapped intraoperatively. The authors present, for the first time to their knowledge, a consecutive series of awake surgeries for cerebral glioma with intrasurgical identification and preservation of visual pathways using subcortical electrical mapping. Fourteen patients underwent awake resection of a glioma (1 WHO Grade I, 11 WHO Grade II, 2 WHO Grade III) involving the optic radiations. The patients had no presurgical visual field deficit. Intraoperatively, a picture-naming task was used, with presentation of 2 objects situated diagonally on a screen divided into 4 quadrants. An image was presented in the quadrant to be saved and another image was presented in the opposite quadrant. Direct subcortical electrostimulation was repeatedly performed without the patient's knowledge, until optic radiations were identified (transient visual disturbances). All patients underwent an objective visual field assessment 3 months after surgery. All patients experienced visual symptoms during stimulation. These disturbances led the authors to stop the tumor resection at that level. Postoperatively, only 1 patient had a permanent hemianopia, despite an expected quadrantanopia in 12 cases. The mean extent of resection was 93.6% (range 85%-100%). Online identification of optic radiations by direct subcortical electrostimulation is a reliable and effective method to avoid permanent hemianopia in surgery for gliomas involving visual pathways.


Amplification of ehrlichial DNA from dogs 34 months after infection with Ehrlichia canis.
In order to determine whether dogs in the subclinical phase of canine monocytic ehrlichiosis (CME) are carriers of Ehrlichia canis and to determine the significance of persistent indirect immunofluorescent anti-E. canis antibody titers during this phase, PCR was performed with blood, bone marrow, and splenic aspirates collected 34 months postinoculation from six clinically healthy beagle dogs experimentally infected with E. canis. At least one of the three samples (spleen, bone marrow, and blood) from four of the six dogs was PCR positive. The spleens of all four of these dogs were PCR positive, and the bone marrow and blood of two of the four dogs were PCR positive. Indirect immunofluorescent-antibody titers increased progressively during the first 5 months postinfection, remained high for an additional period of more than 11 months, and declined thereafter, suggesting that the dogs were recovering from the disease. Five of the dogs remained seropositive 34 months postinfection. The data obtained in this study demonstrate for the first time that clinically healthy dogs in the subclinical phase of CME are carriers of the rickettsia. It was shown that dogs can harbor E. canis for years without developing the chronic clinical disease and that dogs can eliminate the parasite and recover from CME without medical treatment. Our findings suggest that the spleen is the organ most likely to harbor E. canis parasites during the subclinical phase and the last organ to accommodate the parasite before elimination. It was concluded that PCR of DNA extracted from splenic aspirates is a reliable method for determining the carrier state of CME.


Resting and sensitized T lymphocytes exhibit distinct stimulatory (antigen-presenting cell) requirements for growth and lymphokine release.
Previous studies have shown that unprimed or resting T lymphocytes will grow and release lymphokines when stimulated by dendritic cells (DC). We now have examined the stimulatory requirements for antigen-primed or blast-transformed T cells. The latter were derived from dendritic/T cell clusters that developed during the primary mixed leukocyte reaction (MLR). The specificity of the blasts was established by a binding assay in which most T cells aggregated small B lymphocytes of the appropriate haplotype within 2 h at 4 or 37 degrees C. Since unprimed T cells did not aggregate allogeneic B cells, we suggest that DC induce T lymphocytes to express additional functioning receptors for antigen. Lyt-2-T blasts did not grow or release interleukin 2 or B cell helper factors unless rechallenged with specific alloantigen, whereupon growth (generation time of 14-18 h) and lymphokine release rapidly resumed. The blasts could be stimulated by allogeneic macrophages, B cells, and B lymphoblasts, whereas the primary MLR was initiated primarily by DC. responsiveness appeared restricted to the I region of the major histocompatibility complex, and varied directly with the level of Ia antigens on the stimulator cells. The interaction of B cells and T blasts was bidirectional. The T blasts would grow and form B cell helper factors, while the B cells grew and secreted antibody. However, the efficacy of T cell-mediated antibody formation was enhanced some 10-fold by the addition of specific antigen. Therefore, responses of resting helper T cells, then, are initiated by antigen plus DC. Once sensitized, T blasts interact independently with antigen presented by other leukocytes.


Protease-resistant modified human β-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis model.
GM2 gangliosidoses, including Tay-Sachs and Sandhoff diseases, are neurodegenerative lysosomal storage diseases that are caused by deficiency of β-hexosaminidase A, which comprises an αβ heterodimer. There are no effective treatments for these diseases; however, various strategies aimed at restoring β-hexosaminidase A have been explored. Here, we produced a modified human hexosaminidase subunit β (HexB), which we have termed mod2B, composed of homodimeric β subunits that contain amino acid sequences from the α subunit that confer GM2 ganglioside-degrading activity and protease resistance. We also developed fluorescent probes that allow visualization of endocytosis of mod2B via mannose 6-phosphate receptors and delivery of mod2B to lysosomes in GM2 gangliosidosis models. In addition, we applied imaging mass spectrometry to monitor efficacy of this approach in Sandhoff disease model mice. Following i.c.v. administration, mod2B was widely distributed and reduced accumulation of GM2, asialo-GM2, and bis(monoacylglycero)phosphate in brain regions including the hypothalamus, hippocampus, and cerebellum. Moreover, mod2B administration markedly improved motor dysfunction and a prolonged lifespan in Sandhoff disease mice. Together, the results of our study indicate that mod2B has potential for intracerebrospinal fluid enzyme replacement therapy and should be further explored as a gene therapy for GM2 gangliosidoses.


Crystal structures of an enantioselective fab-fragment in free and complex forms.
Enantioselective antibodies can separate the enantiomers of a chiral compound in a highly specific manner. We have recently reported the cloning and applications of a recombinant Fab-fragment, ENA11His, in the enantioseparation of a drug candidate, finrozole, which contains two chiral centers. Here, the crystal structures of this enantioselective antibody Fab-fragment are determined in the absence of the hapten at a resolution of 2.75 A, and in the presence of the hapten at 2.05 A resolution. The conformation of the protein was found to be similar in both free and complex forms. The hapten molecule was tightly bound in a deep cleft between the light and heavy chains of the Fab-fragment. The complex structure also allowed us to describe the molecular basis for enantioselectivity and to deduce the absolute configurations of all the four different stereoisomers (a-d) of finrozole. The ENA11His antibody fragment selectively binds the SR (a) enantiomer from the racemic mixture of a and d-enantiomers, thus allowing separation from the pharmacologically most active RS enantiomer (d). In particular, Asp95 and Asn35 of the H-chain in the ENA11 His antibody seem to provide this specificity through hydrogen bonding.


Changes in the Brain-Derived Neurotrophic Factor Are Associated with Improvements in Diabetes Risk Factors after Exercise Training in Adolescents with Obesity: The HEARTY Randomized Controlled Trial.
Obesity in youth increases the risk of type 2 diabetes (T2D), and both are risk factors for neurocognitive deficits. Exercise attenuates the risk of obesity and T2D while improving cognitive function. In adults, these benefits are associated with the actions of the brain-derived neurotrophic factor (BDNF), a protein critical in modulating neuroplasticity, glucose regulation, fat oxidation, and appetite regulation in adults. However, little research exists in youth. This study examined the associations between changes in diabetes risk factors and changes in BDNF levels after 6 months of exercise training in adolescents with obesity. The sample consisted of 202 postpubertal adolescents with obesity (70% females) aged 14-18 years who were randomized to 6 months of aerobic and/or resistance training or nonexercise control. All participants received a healthy eating plan designed to induce a 250/kcal deficit per day. Resting serum BDNF levels and diabetes risk factors, such as fasting glucose, insulin, homeostasis model assessment (HOMA-B-beta cell insulin secretory capacity) and (HOMA-IS-insulin sensitivity), and hemoglobin A1c (HbA1c), were measured after an overnight fast at baseline and 6 months. There were no significant intergroup differences on changes in BDNF or diabetes risk factors. In the exercise group, increases in BDNF were associated with reductions in fasting glucose (β = -6.57, SE = 3.37, p = 0.05) and increases in HOMA-B (β = 0.093, SE = 0.03, p = 0.004) after controlling for confounders. No associations were found between changes in diabetes risk factors and BDNF in controls. In conclusion, exercise-induced reductions in some diabetes risk factors were associated with increases in BDNF in adolescents with obesity, suggesting that exercise training may be an effective strategy to promote metabolic health and increases in BDNF, a protein favoring neuroplasticity. This trial is registered with ClinicalTrials.gov NCT00195858, September 12, 2005 (funded by the Canadian Institutes of Health Research).


Geometrical interpretation of gaussian beam optics.
The relationship between conventional optics and Gaussian beam optics is discussed. Geometrical concepts such as image and object planes, pupil plane, F-number, resolution, and depth of field are discussed for Gaussian beams and are given a precise meaning in terms of the Gaussian beam parameters. The approach is useful in the design of laser scanning systems and holographic optical memory systems.


Deep brain stimulation entrains local neuronal firing in human globus pallidus internus.
Deep brain stimulation (DBS) in the internal segment of the globus pallidus (GPi) relieves the motor symptoms of Parkinson's disease, yet the mechanism of action remains uncertain. To address the question of how therapeutic stimulation changes neuronal firing in the human brain, we studied the effects of GPi stimulation on local neurons in unanesthetized patients. Eleven patients with idiopathic Parkinson's disease consented to participate in neuronal recordings during stimulator implantation surgery. A recording microelectrode and a DBS macroelectrode were advanced through the GPi in parallel until a single neuron was isolated. After a baseline period, stimulation was initiated with varying voltages and different stimulation sites. The intra-operative stimulation parameters (1-8 V, 88-180 Hz, 0.1-ms pulses) were comparable with the postoperative DBS settings. Stimulation in the GPi did not silence local neuronal activity uniformly, but instead loosely entrained firing and decreased net activity in a voltage-dependent fashion. Most neurons had decreased activity during stimulation, although some increased or did not change firing rate. Thirty-three of 45 neurons displayed complex patterns of entrainment during stimulation, and burst-firing was decreased consistently after stimulation. Recorded spike trains from patients were used as input into a model of a thalamocortical relay neuron. Only spike trains that occurred during therapeutically relevant voltages significantly reduced transmission error, an effect attributable to changes in firing patterns. These data indicate that DBS in the human GPi does not silence neuronal activity, but instead disrupts the pathological firing patterns through loose entrainment of neuronal activity.


Visual signal detection in structured backgrounds. IV. Figures of merit for model performance in multiple-alternative forced-choice detection tasks with correlated responses.
Many investigators are currently developing models to predict human performance in detecting a signal embedded in complex backgrounds. A common figure of merit for model performance is d', an index of detectability that can be mathematically related to the proportion correct (Pc) when the responses of the model are Gaussian distributed and statistically independent. However, in many multiple-alternative forced-choice (MAFC) detection tasks, the target appears in one of M different locations within an image. If the image contains slow spatially varying luminance changes (low-pass noise), the pixel luminance values at the possible signal locations are correlated and therefore the model/human responses to the different locations might also be correlated. We investigate the effect of response correlations on model performance and compare different figures of merit for these conditions. Our results show that use of the standard d' index of detectability assuming statistical independence can lead to erroneous underestimates of Pc and misleading comparisons of models. We introduce a novel figure of merit d'(r) that takes into account response correlations and can be used to accurately estimate Pc. Furthermore, we show that d'(r) can be readily related to the standard index of detectability d' by d'(r) = d'/square root of (1 - r), where r is the correlation between the responses in any MAFC detection task. We illustrate the use of the theory by computing figures of merit for two linear models detecting a signal in one of four locations within medical image backgrounds.


Effects of metformin on burn-induced hepatic endoplasmic reticulum stress in male rats.
Severe burn injury causes hepatic dysfunction that results in major metabolic derangements including insulin resistance and hyperglycemia and is associated with hepatic endoplasmic reticulum (ER) stress. We have recently shown that insulin reduces ER stress and improves liver function and morphology; however, it is not clear whether these changes are directly insulin mediated or are due to glucose alterations. Metformin is an antidiabetic agent that decreases hyperglycemia by different pathways than insulin; therefore, we asked whether metformin affects postburn ER stress and hepatic metabolism. The aim of the present study is to determine the effects of metformin on postburn hepatic ER stress and metabolic markers. Male rats were randomized to sham, burn injury and burn injury plus metformin and were sacrificed at various time points. Outcomes measured were hepatic damage, function, metabolism and ER stress. Burn-induced decrease in albumin mRNA and increase in alanine transaminase (p < 0.01 versus sham) were not normalized by metformin treatment. In addition, ER stress markers were similarly increased in burn injury with or without metformin compared with sham (p < 0.05). We also found that gluconeogenesis and fatty acid metabolism gene expressions were upregulated with or without metformin compared with sham (p < 0.05). Our results indicate that, whereas thermal injury results in hepatic ER stress, metformin does not ameliorate postburn stress responses by correcting hepatic ER stress.


Addressing Iron and Zinc Micronutrient Malnutrition Through Nutrigenomics in Pearl Millet: Advances and Prospects.
Iron (Fe) and zinc (Zn) micronutrient deficiencies are significant health concerns, particularly among the underprivileged and resource-poor people in the semi-arid tropics globally. Pearl millet is regarded as a climate-smart crop with low water and energy footprints. It thrives well under adverse agro-ecologies such as high temperatures and limited rainfall. Pearl millet is regarded as a nutri-cereal owing to health-promoting traits such as high grain Fe and Zn content, metabolizable energy, high antioxidant and polyphenols, high proportion of slowly digestible starches, dietary fibers, and favorable essential amino acid profile compared to many cereals. Higher genetic variability for grain Fe and Zn content has facilitated considerable progress in mapping and mining QTLs, alleles and genes underlying micronutrient metabolism. This has been made possible by developing efficient genetic and genomic resources in pearl millet over the last decade. These include genetic stocks such as bi-parental RIL mapping populations, association mapping panels, chromosome segment substitution lines (CSSLs) and TILLING populations. On the genomics side, considerable progress has been made in generating genomic markers, such as SSR marker repository development. This was followed by the development of a next-generation sequencing-based genome-wide SNP repository. The circa 1,000 genomes re-sequencing project played a significant role. A high-quality reference genome was made available by re-sequencing of world diversity panel, mapping population parents and hybrid parental lines. This mini-review attempts to provide information on the current developments on mapping Fe and Zn content in pearl millet and future outlook.


Carbon monoxide poisoning associated with water pipe smoking.
The water pipe is a means of tobacco consumption widespread in Turkey and Arab countries. We present two patients brought to our emergency department due to a syncopal attack secondary to carbon monoxide toxicity following water pipe use. This rare form of poisoning should be borne in mind by emergency physicians as a differential diagnosis in water pipe smokers. Water pipes should be used where there is adequate ventilation.


Intrinsic GTPase activity of a bacterial twin-arginine translocation proofreading chaperone induced by domain swapping.
The bacterial twin-arginine translocation (Tat) system is a protein targeting pathway dedicated to the transport of folded proteins across the cytoplasmic membrane. Proteins transported on the Tat pathway are synthesised as precursors with N-terminal signal peptides containing a conserved amino acid motif. In Escherichia coli, many Tat substrates contain prosthetic groups and undergo cytoplasmic assembly processes prior to the translocation event. A pre-export 'Tat proofreading' process, mediated by signal peptide-binding chaperones, is considered to prevent premature export of some Tat-targeted proteins until all other assembly processes are complete. TorD is a paradigm Tat proofreading chaperone and co-ordinates the maturation and export of the periplasmic respiratory enzyme trimethylamine N-oxide reductase (TorA). Although it is well established that TorD binds directly to the TorA signal peptide, the mechanism of regulation or control of binding is not understood. Previous structural analyses of TorD homologues showed that these proteins can exist as monomeric and domain-swapped dimeric forms. In the present study, we demonstrate that isolated recombinant TorD exhibits a magnesium-dependent GTP hydrolytic activity, despite the absence of classical nucleotide-binding motifs in the protein. TorD GTPase activity is shown to be present only in the domain-swapped homodimeric form of the protein, thus defining a biochemical role for the oligomerisation. Site-directed mutagenesis identified one TorD side-chain (D68) that was important in substrate selectivity. A D68W variant TorD protein was found to exhibit an ATPase activity not observed for native TorD, and an in vivo assay established that this variant was defective in the Tat proofreading process.


Opioid Prescribing Recommendations After Mohs Micrographic Surgery and Reconstruction: A Delphi Consensus.
Prescription opioids play a large role in the opioid epidemic. Even short-term prescriptions provided postoperatively can lead to dependence. To provide opioid prescription recommendations after Mohs micrographic surgery (MMS) and reconstruction. This was a multi-institutional Delphi consensus study consisting of a panel of members of the American College of Mohs Surgery from various practice settings. Participants were first asked to describe scenarios in which they prescribe opioids at various frequencies. These scenarios then underwent 2 Delphi ratings rounds that aimed to identify situations in which opioid prescriptions should, or should not, be routinely prescribed. Consensus was set at ≥80% agreement. Prescription recommendations were then distributed to the panelists for feedback and approval. Twenty-three Mohs surgeons participated in the study. There was no scenario in which consensus was met to routinely provide an opioid prescription. However, there were several scenarios in which consensus were met to not routinely prescribe an opioid. Opioids should not be routinely prescribed to every patient undergoing MMS. Prescription recommendations for opioids after MMS and reconstruction may decrease the exposure to these drugs and help combat the opioid epidemic.


US Department of Education data on "autism" are not reliable for tracking autism prevalence.
Many autism advocacy groups use the data collected by the US Department of Education (USDE) to show a rapidly increasing prevalence of autism. Closer examination of these data to follow each birth-year cohort reveals anomalies within the USDE data on autism. The USDE data show not only a rise in overall autism prevalence with time but also a significant and nearly linear rise in autism prevalence within a birth-year cohort as it ages, with significant numbers of new cases as late as 17 years of age. In addition, an unexpected reduction in the rise of autism prevalence occurs in most cohorts at 12 years of age, the age when most children would be entering middle school. These anomalies point to internal problems in the USDE data that make them unsuitable for tracking autism prevalence.


IL-1beta decreases the elastic modulus of human tenocytes.
Cellular responses to mechanical stimuli are regulated by interactions with the extracellular matrix, which, in turn, are strongly influenced by the degree of cell stiffness (Young's modulus). It was hypothesized that a more elastic cell could better withstand the rigors of remodeling and mechanical loading. It was further hypothesized that interleukin-1beta (IL-1beta) would modulate intracellular cytoskeleton polymerization and regulate cell stiffness. The purpose of this study was to investigate the utility of IL-1beta to alter the Young's modulus of human tenocytes. Young's modulus is the ratio of the stress to the strain, E = stress/strain = (F/A)/(deltaL/L0), where L0 is the equilibrium length, deltaL is the length change under the applied stress, F is the force applied, and A is the area over which the force is applied. Human tenocytes were incubated with 100 pM recombinant human IL-1beta for 5 days. The Young's modulus was reduced by 27-63%. Actin filaments were disrupted in >75% of IL-1beta-treated cells, resulting in a stellate shape. In contrast, immunostaining of alpha-tubulin showed increased intensity in IL-1beta-treated tenocytes. Human tenocytes in IL-1beta-treated bioartificial tendons were more tolerant to mechanical loading than were untreated counterparts. These results indicate that IL-1beta reduced the Young's modulus of human tenocytes by disrupting the cytoskeleton and/or downregulating the expression of actin and upregulating the expression of tubulins. The reduction in cell modulus may help cells to survive excessive mechanical loading that may occur in damaged or healing tendons.


Revelation of Potent Epitopes Present in Unannotated ORF Antigens of SARS-CoV-2 for Epitope-Based Polyvalent Vaccine Design Using Immunoinformatics Approach.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) kills thousands of people worldwide every day, thus necessitating rapid development of countermeasures. Immunoinformatics analyses carried out here in search of immunodominant regions in recently identified SARS-CoV-2 unannotated open reading frames (uORFs) have identified eight linear B-cell, one conformational B-cell, 10 CD4+ T-cell, and 12 CD8+ T-cell promising epitopes. Among them, ORF9b B-cell and T-cell epitopes are the most promising followed by M.ext and ORF3c epitopes. ORF9b40-48 (CD8+ T-cell epitope) is found to be highly immunogenic and antigenic with the highest allele coverage. Furthermore, it has overlap with four potent CD4+ T-cell epitopes. Structure-based B-cell epitope prediction has identified ORF9b61-68 to be immunodominant, which partially overlaps with one of the linear B-cell epitopes (ORF9b65-69). ORF3c CD4+ T-cell epitopes (ORF3c2-16, ORF3c3-17, and ORF3c4-18) and linear B-cell epitope (ORF3c14-22) have also been identified as the candidate epitopes. Similarly, M.ext and 7a.iORF1 (overlap with M and ORF7a) proteins have promising immunogenic regions. By considering the level of antigen expression, four ORF9b and five M.ext epitopes are finally shortlisted as potent epitopes. Mutation analysis has further revealed that the shortlisted potent uORF epitopes are resistant to recurrent mutations. Additionally, four N-protein (expressed by canonical ORF) epitopes are found to be potent. Thus, SARS-CoV-2 uORF B-cell and T-cell epitopes identified here along with canonical ORF epitopes may aid in the design of a promising epitope-based polyvalent vaccine (when connected through appropriate linkers) against SARS-CoV-2. Such a vaccine can act as a bulwark against SARS-CoV-2, especially in the scenario of emergence of variants with recurring mutations in the spike protein.


Candidate genes for the hypoxic tumor phenotype.
In this study, we have analyzed changes induced by hypoxia at the transcriptional level of genes that could be responsible for a more aggressive phenotype. Using a series of DNA array membranes, we identified a group of hypoxia-induced genes that included plasminogen activator inhibitor-1 (PAI-1), insulin-like growth factor-binding protein 3 (IGFBP-3), endothelin-2, low-density lipoprotein receptor-related protein (LRP), BCL2-interacting killer (BIK), migration-inhibitory factor (MIF), matrix metalloproteinase-13 (MMP-13), fibroblast growth factor-3 (FGF-3), GADD45, and vascular endothelial growth factor (VEGF). The induction of each gene was confirmed by Northern blot analysis in two different squamous cell carcinoma-derived cell lines. We also analyzed the kinetics of PAI-1 induction by hypoxia in more detail because it is a secreted protein that may serve as a useful molecular marker of hypoxia. On exposure to hypoxia, there was a gradual increase in PAI-1 mRNA between 2 and 24 h of hypoxia followed by a rapid decay after 2 h of reoxygenation. PAI-1 levels were also measured in the serum of a small group of head and neck cancer patients and were found to correlate with the degree of tumor hypoxia found in these patients.


NCCN Guidelines Insights: Multiple Myeloma, Version 3.2018.
The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, evaluation, treatment, including supportive-care, and follow-up for patients with myeloma. These NCCN Guidelines Insights highlight the important updates/changes specific to the myeloma therapy options in the 2018 version of the NCCN Guidelines.


Geranium macrorrhizum L. (Geraniaceae) essential oil: a potent agent against Bacillus subtilis.
The volatile hydrodistilled compounds from aerial parts and rhizomes of the ethnopharmacologically highly valued plant species Geranium macrorrhizum L. were screened for their antimicrobial activity in disc-diffusion and microdilution assays. The assays pointed out to a very high and selective activity of the oils against Bacillus subtilis with minimum inhibitory concentrations (MIC) of 0.4-1.0 μg/ml. This prompted us to perform detailed compositional analyses of the oils. GC and GC/MS analyses allowed the identification of 283 constituents. The oils consisted mainly of sesquiterpenoids, the main ones being germacrone (49.7% in the oil from aerial parts) and δ-guaiene (49.2% in rhizome oil). Significant qualitative and quantitative compositional differences in the oils from the two plant parts were observed. Further antimicrobial testing enabled us to determine that germacrone, the major constituent of the oil from aerial parts, was not the sole agent responsible for the observed activity.


Acute Management of Open Fractures: An Evidence-Based Review.
Open fractures are complex injuries associated with high morbidity and mortality. Despite advances made in fracture care and infection prevention, open fractures remain a therapeutic challenge with varying levels of evidence to support some of the most commonly used practices. Additionally, a significant number of studies on this topic have focused on open tibial fractures. A systematic approach to evaluation and management should begin as soon as immediate life-threatening conditions have been stabilized. The Gustilo classification is arguably the most widely used method for characterizing open fractures. A first-generation cephalosporin should be administered as soon as possible. The optimal duration of antibiotics has not been well defined, but they should be continued for 24 hours. There is inconclusive evidence to support either extending the duration or broadening the antibiotic prophylaxis for type Gustilo type III wounds. Urgent surgical irrigation and debridement remains the mainstay of infection eradication, although questions persist regarding the optimal irrigation solution, volume, and delivery pressure. Wound sampling has a poor predictive value in determining subsequent infections. Early wound closure is recommended to minimize the risk of infection and cannot be substituted by negative-pressure wound therapy. Antibiotic-impregnated devices can be important adjuncts to systemic antibiotics in highly contaminated or comminuted injuries. Multiple fixation techniques are available, each having advantages and disadvantages. It is extremely important to maintain a high index of suspicion for compartment syndrome, especially in the setting of high-energy trauma.


Perineural dexamethasone added to local anesthesia for brachial plexus block improves pain but delays block onset and motor blockade recovery.
Multiple studies have shown that perineural dexamethasone improves postoperative analgesia. However, some studies have shown minimal benefit, and have raised concerns regarding adverse physio-chemical effects of perineural dexamethasone. Furthermore, there is a paucity of studies wherein control (IV) dexamethasone was considered. The purpose of this meta-analysis was to evaluate the effectiveness of different concentrations of perineural dexamethasone injection on postoperative analgesia, as well as complications from its use for brachial plexus blocks. A systematic literature search was conducted using the Cochrane Central Registry of Controlled Trials, PubMed, and Scopus. Trials comparing control and local dexamethasone-treated groups, and those which reported duration of analgesia and/or pain scores/opioid consumptions were selected. Meta-analysis was performed using the Review Manager (RevMan) software 5.1. Fourteen studies consisting of a total of 1,022 patients were included. Perineural dexamethasone significantly prolonged the duration of postoperative analgesia in patients receiving both low-dose (4 - 5 mg) [SMD 2.41 (95% CI: 1.47, 3.35 P = 0<0.00001) I² = 82%], and higher-doses (8 - 10 mg) [SMD 4.46 (95% CI 3.54, 5.38 P < 0.00001) I² = 94%]. However, the duration of motor block was also prolonged [SMD 2.52 (95% CI: 1.06, 3.98 P = 0.0007) I² = 97%] and dexamethasone delayed latency of onset of sensory [SMD -0.49 (95% CI: -0.89, -0.09 P = 0.02) I² = 76%] and motor [SMD -0.56 (95% CI: -1.13, 0.00 P = 0.05) I² = 87%] blocks. Postoperative pain scores were improved at both 24 hours [SMD -1.46 (95% CI: -2.43, -0.50 P = 0.003) I² = 95%] and 48 hours [SMD -1.20 (95% CI: -2.26, -0.13 P = 0.03) I² = 95%] in dexamethasone-treated groups, whereas opioid consumption was reduced only at 48 hours [SMD -2.97 (95% CI: -4.17, -1.76 P < 0.00001) I² = 88%]. Complications were comparable between control and dexamethasone-adjuvant groups, except for the excessively prolonged nerve block that was observed predominantly in the dexamethasone-adjuvant group. The limitations include different definitions used for the measurements of certain parameters such as the duration of analgesia and duration of motor block, number of studies assessing certain parameters having high heterogeneity, and varying types of local anesthetics used in various studies. Perineural dexamethasone addition to local anesthetic solutions significantly improved postoperative pain in brachial plexus block without increasing complications. However, perineural adjuvant dexamethasone delayed the onset of sensory and motor block, and prolonged the duration of motor block. Smaller doses of dexamethasone (4 - 5 mg) were as effective as higher doses (8 - 10 mg).


Factors associated with disclosure of medical errors by housestaff.
Attributes of the organisational culture of residency training programmes may impact patient safety. Training environments are complex, composed of clinical teams, residency programmes, and clinical units. We examined the relationship between residents' perceptions of their training environment and disclosure of or apology for their worst error. Anonymous, self-administered surveys were distributed to Medicine and Surgery residents at Boston Medical Center in 2005. Surveys asked residents to describe their worst medical error, and to answer selected questions from validated surveys measuring elements of working environments that promote learning from error. Subscales measured the microenvironments of the clinical team, residency programme, and clinical unit. Univariate and bivariate statistical analyses examined relationships between trainee characteristics, their perceived learning environment(s), and their responses to the error. Out of 109 surveys distributed to residents, 99 surveys were returned (91% overall response rate), two incomplete surveys were excluded, leaving 97: 61% internal medicine, 39% surgery, 59% male residents. While 31% reported apologising for the situation associated with the error, only 17% reported disclosing the error to patients and/or family. More male residents disclosed the error than female residents (p=0.04). Surgery residents scored higher on the subscales of safety culture pertaining to the residency programme (p=0.02) and managerial commitment to safety (p=0.05). Our Medical Culture Summary score was positively associated with disclosure (p=0.04) and apology (p=0.05). Factors in the learning environments of residents are associated with responses to medical errors. Organisational safety culture can be measured, and used to evaluate environmental attributes of clinical training that are associated with disclosure of, and apology for, medical error.


Opposite effects of lipopolysaccharide and dextran sulfate on membrane phospholipid metabolism of murine B lymphocytes.
The metabolism of [3H]inositol- and [14C]arachidonate-labeled phospholipids of B lymphocytes from normal (C3H/HePAS) and endotoxin-hyporesponsive (C3H/HeJ) mice, after incubation with two B cell mitogens, lipopolysaccharide (LPS) and dextran sulfate (DxS) was examined. The early effects of the two mitogens on the biosynthesis of phosphoinositides were different. DxS enhanced the levels of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate in C3H/HeJ and C3H/HePAS cells, whereas LPS did not modify the levels of these components. When mixed with DxS, LPS reduced the effects of this stimulant. Analysis of the metabolism of fatty acids gave opposite results. Incorporation of arachidonate in all phospholipids, and particularly in phosphatidic acid, was inhibited in the two cell types after incubation with DxS, but was enhanced in C3H/HePAS and remained unchanged in C3H/HeJ cells after incubation with LPS. This activation of acyltransferases by LPS in B lymphocytes from endotoxin-responsive mice was inhibited when DxS was added in the stimulating mixture. The outcome of these opposite biochemical effects of LPS and DxS on the mitogenic responses of B cells was also examined. Preincubation with DxS for a 15-min period blocked the mitogenic effect of LPS in C3H/HePAS cells, whereas preincubation with LPS blocked the mitogenic effect of DxS in C3H/HeJ cells. Early changes in phospholipid metabolism induced by the two stimulants are therefore correlated with their late mitogenic effect.