Different patterns of short-term memory deficit in Alzheimer's disease, Parkinson's disease and subjective cognitive impairment.
It has recently been proposed that short-term memory (STM) binding deficits might be an important feature of Alzheimer's disease (AD), providing a potential avenue for earlier detection of this disorder. By contrast, work in Parkinson's disease (PD), using different tasks, has suggested that the STM impairment in this condition is characterised by increased random guessing, possibly due to fluctuating attention. In the present study, to establish whether a misbinding impairment is present in sporadic late-onset AD (LOAD) and increased guessing is a feature of PD, we compared the performance of these patient groups to two control populations: healthy age-matched controls and individuals with subjective cognitive impairment (SCI) with comparable recruitment history as patients. All participants performed a sensitive task of STM that required high resolution retention of object-location bindings. This paradigm also enabled us to explore the underlying sources of error contributing to impaired STM in patients with LOAD and PD using computational modelling of response error. Patients with LOAD performed significantly worse than other groups on this task. Importantly their impaired memory was associated with increased misbinding errors. This was in contrast to patients with PD who made significantly more guessing responses. These findings therefore provide additional support for the presence of two doubly dissociable signatures of STM deficit in AD and PD, with binding impairment in AD and increased random guessing characterising the STM deficit in PD. The task used to measure memory precision here provides an easy-to-administer assessment of STM that is sensitive to the different types of deficit in AD and PD and hence has the potential to inform clinical practice.


Human-in-the-loop Bayesian optimization of wearable device parameters.
The increasing capabilities of exoskeletons and powered prosthetics for walking assistance have paved the way for more sophisticated and individualized control strategies. In response to this opportunity, recent work on human-in-the-loop optimization has considered the problem of automatically tuning control parameters based on realtime physiological measurements. However, the common use of metabolic cost as a performance metric creates significant experimental challenges due to its long measurement times and low signal-to-noise ratio. We evaluate the use of Bayesian optimization-a family of sample-efficient, noise-tolerant, and global optimization methods-for quickly identifying near-optimal control parameters. To manage experimental complexity and provide comparisons against related work, we consider the task of minimizing metabolic cost by optimizing walking step frequencies in unaided human subjects. Compared to an existing approach based on gradient descent, Bayesian optimization identified a near-optimal step frequency with a faster time to convergence (12 minutes, p < 0.01), smaller inter-subject variability in convergence time (± 2 minutes, p < 0.01), and lower overall energy expenditure (p < 0.01).


Two candidate tumor suppressor genes, MEOX2 and SOSTDC1, identified in a 7p21 homozygous deletion region in a Wilms tumor.
A SNP-based array analysis of 100 Wilms tumors (WT) from 97 patients identified 7p alterations (hemizygous and homozygous deletions and uniparental disomy) in nine tumors. The homozygous deletion (HD) region of 7p21 found in one tumor partially overlapped with another HD region reported previously, and was narrowed down to a 2.1-Mb region. Based on an expression analysis of 10 genes located in the HD region in 3 WT lines and previous studies on tumorigenic roles of MEOX2 and SOSTDC1, we further analyzed these two genes. Sequencing showed no mutation in MEOX2, but two missense mutations (L50F and Q129L) in SOSTDC1 in four tumors; L50F in two tumors was of germline origin. Expression levels (0, 1+ and 2+) of MEOX2 were lower in four tumors with 7p alterations than in 18 tumors with no 7p alterations (P = 0.017), and those of SOSTDC1 tended to be lower in five tumors with 7p alterations or SOSTDC1 mutation than in 17 tumors with no 7p alterations or SOSTDC1 mutation (P = 0.056). There were no significant differences in clinical characteristics between nine patients with 7p alterations and 88 patients with no 7p alterations; however, there was a difference in the status of IGF2 (uniparental disomy, loss of imprinting, or retention of imprinting) between the two patient groups (P = 0.028). Losses of MEOX2 and SOSTDC1 may accelerate angiogenesis and augment signals in the Wnt pathway, respectively. Both genes may be prime candidates for 7p tumor suppressor genes, which may have a role in the progression of Wilms tumorigenesis.


Impact of Air Pollutants on Outpatient Visits for Acute Respiratory Outcomes.
The air pollution in China is a severe problem. The aim of our study was to investigate the impact of air pollutants on acute respiratory outcomes in outpatients. Outpatient data from 2 December 2013 to 1 December 2014 were collected, as well as air pollutant data including ozone (O₃), nitrogen dioxide (NO₂), carbon monoxide (CO), sulfur dioxide (SO₂), and particulate matter (PM2.5 and PM10). We screened six categories of acute respiratory outcomes and analyzed their associations with different air pollutant exposures, including upper respiratory tract infection (URTI), acute bronchitis (AB), community-acquired pneumonia (CAP), acute exacerbation of chronic obstructive pulmonary disease (AECOPD), acute exacerbation of asthma (AE-asthma), and acute exacerbation of bronchiectasis (AEBX). A case-crossover design with a bidirectional control sampling approach was used for statistical analysis. A total of 57,144 patients were enrolled for analysis. PM2.5, PM10, NO₂, SO₂, and CO exposures were positively associated with outpatient visits for URTI, AB, CAP, and AEBX. PM10, SO₂, and CO exposures were positively associated with outpatient visits for AECOPD. Exposure to O₃ was positively associated with outpatient visits for AE-asthma, but negatively associated with outpatient visits for URTI, CAP, and AEBX. In conclusion, air pollutants had acute effects on outpatient visits for acute respiratory outcomes, with specific outcomes associated with specific pollutants.


Consensus guidelines for newborn screening, diagnosis and treatment of infantile Krabbe disease.
Krabbe disease is a rare neurodegenerative genetic disorder caused by deficiency of galactocerebrosidase. Patients with the infantile form of Krabbe disease can be treated at a presymptomatic stage with human stem cell transplantation which improves survival and clinical outcomes. However, without a family history, most cases of infantile Krabbe disease present after onset of symptoms and are ineligible for transplantation. In 2006, New York began screening newborns for Krabbe disease to identify presymptomatic cases. To ensure that those identified with infantile disease received timely treatment, New York public health and medical systems took steps to accurately diagnose and rapidly refer infants for human stem cell transplantation within the first few weeks of life. After 11 years of active screening in New York and the introduction of Krabbe disease newborn screening in other states, new information has been gained which can inform the design of newborn screening programs to improve infantile Krabbe disease outcomes. Recent information relevant to Krabbe disease screening, diagnosis, and treatment were assessed by a diverse group of public health, medical, and advocacy professionals. Outcomes after newborn screening may improve if treatment for infantile disease is initiated before 30 days of life. Newer laboratory screening and diagnostic tools can improve the speed and specificity of diagnosis and help facilitate this early referral. Given the rarity of Krabbe disease, most recommendations were based on case series or expert opinion. This report updates recommendations for Krabbe disease newborn screening to improve the timeliness of diagnosis and treatment of infantile Krabbe disease. In the United States, several states have begun or are considering Krabbe disease newborn screening. These recommendations can guide public health laboratories on methodologies for screening and inform clinicians about the need to promptly diagnose and treat infantile Krabbe disease. The timing of the initial referral after newborn screening, the speed of diagnostic confirmation of infantile disease, and the transplantation center's experience and ability to rapidly respond to a suspected patient with newly diagnosed infantile Krabbe disease are critical for optimal outcomes.


Spectrocolorimetric control of ancient documents postablation with excimer lasers.
The application of excimer lasers in ablation, cleaning, and restoration for the recovery of paper and parchment manuscripts is a recently implemented technique. A report of the use of excimer lasers in a cleaning process by which mud was removed from Islamic papers and parchments is presented. It was found that, because of the close proximity of the binding energies of paper to paper and of paper to mud, it was difficult to maintain control of the ablation process. However, the substrate was not affected. Spectrocolorimetry was used as a technique to detect the effects of ablation on cleaned areas of the manuscripts in terms of change in color appearance and severity of aging postablation. The analysis was performed by comparison of treated and untreated areas. Mathematical modeling was developed to define a representative original color and a color-distribution parameter. Improvements in the measuring method were made to yield the required precision for evaluating differences in color produced by laser ablation and to follow the color evolution after ablation. Results show that the effects of restoration, aging, and the environmental conditions can be individually identified under certain conditions. The method has applications in other domains.


Examining the relationship between lifetime stressful life events and the onset of major depression in Chinese women.
In European and US studies, patients with major depressive disorder (MDD) report more stressful life events (SLEs) than controls, but this relationship has rarely been studied in Chinese populations. Sixteen lifetime SLEs were assessed at interview in two groups of Han Chinese women: 1970 clinically ascertained with recurrent MDD and 2597 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression. 60% of controls and 72% of cases reported at least one lifetime SLE. Fourteen of the sixteen SLEs occurred significantly more frequently in those with MDD (median odds ratio of 1.6). The three SLEs most strongly associated with risk for MDD (OR>3.0) preceded the onset of MDD the majority of the time: rape (82%), physical abuse (100%) and serious neglect (99%). Our results may apply to females only. SLEs were rated retrospectively and are subject to biases in recollection. We did not assess contextual information for each life event. More severe SLEs are more strongly associated with MDD. These results support the involvement of psychosocial adversity in the etiology of MDD in China.


Single-cell genomics-based analysis of virus-host interactions in marine surface bacterioplankton.
Viral infections dynamically alter the composition and metabolic potential of marine microbial communities and the evolutionary trajectories of host populations with resulting feedback on biogeochemical cycles. It is quite possible that all microbial populations in the ocean are impacted by viral infections. Our knowledge of virus-host relationships, however, has been limited to a minute fraction of cultivated host groups. Here, we utilized single-cell sequencing to obtain genomic blueprints of viruses inside or attached to individual bacterial and archaeal cells captured in their native environment, circumventing the need for host and virus cultivation. A combination of comparative genomics, metagenomic fragment recruitment, sequence anomalies and irregularities in sequence coverage depth and genome recovery were utilized to detect viruses and to decipher modes of virus-host interactions. Members of all three tailed phage families were identified in 20 out of 58 phylogenetically and geographically diverse single amplified genomes (SAGs) of marine bacteria and archaea. At least four phage-host interactions had the characteristics of late lytic infections, all of which were found in metabolically active cells. One virus had genetic potential for lysogeny. Our findings include first known viruses of Thaumarchaeota, Marinimicrobia, Verrucomicrobia and Gammaproteobacteria clusters SAR86 and SAR92. Viruses were also found in SAGs of Alphaproteobacteria and Bacteroidetes. A high fragment recruitment of viral metagenomic reads confirmed that most of the SAG-associated viruses are abundant in the ocean. Our study demonstrates that single-cell genomics, in conjunction with sequence-based computational tools, enable in situ, cultivation-independent insights into host-virus interactions in complex microbial communities.


Reduced expression of collagen VI alpha 3 (COL6A3) confers resistance to inflammation-induced MCP1 expression in adipocytes.
Collagen VI alpha 3 (COL6A3) is associated with insulin resistance and adipose tissue inflammation. In this study, the role of COL6A3 in human adipocyte function was characterized. Immortalized human preadipocyte cell lines stably expressing control or COL6A3 shRNA were used to study adipocyte function and inflammation. COL6A3 knockdown increased triglyceride content, lipolysis, insulin-induced Akt phosphorylation, and mRNA expression of key adipogenic genes (peroxisome proliferator-activated receptor-γ, glucose transporter, adiponectin, and fatty acid binding protein), indicating increased adipocyte function and insulin sensitivity. However, COL6A3 knockdown decreased basal adipocyte chemokine (C-C motif) ligand 2 [CCL2, monocyte chemoattractant protein (MCP1)] mRNA expression, reduced secreted protein levels, and abrogated tumor necrosis factor-α- and lipopolysaccharide-induced MCP1 mRNA expression. In addition, while control adipocytes co-cultured with THP1 macrophages showed a threefold increase in adipocyte MCP1 mRNA expression, in COL6A3 knockdown adipocytes MCP1 mRNA expression was unaltered by co-culturing. Lastly, in normal differentiated adipocytes, matrix metalloproteinase-11 treatment reduced expression of COL6A3 protein, MCP1 mRNA, MCP1 secretion, and abrogated tumor necrosis factor-α- and lipopolysaccharide-induced MCP1 mRNA expression and protein secretion. COL6A3 knockdown in adipocytes leads to the development of a unique state of inflammatory resistance via suppression of MCP1 induction.


Antifungal Activity of Apple Cider Vinegar on Candida Species Involved in Denture Stomatitis.
To evaluate the in vitro antifungal activity of apple cider vinegar on Candida spp. involved in denture stomatitis. The microdilution technique was used to determine the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of apple cider vinegar containing 4% maleic acid, and nystatin (control). Further tests of microbial kinetics and inhibition of adherence to acrylic resin were performed testing different concentrations (MIC, MICx2, MICx4) of the products at time intervals of 0, 30, 60, 120 and 180 minutes. A roughness meter was used to measure the changes in surface roughness; color change of the acrylic resin specimens exposed to the test products in different concentrations and time intervals were also evaluated. Apple cider vinegar (4%) showed MIC of 2500 μg/ml and MFC of 2500, 5000, and 10,000 μg/ml depending on the strain tested. Nystatin showed MIC of 3.125 μg/ml and strain-dependent MFC values ranging from 3.125 to 12.5 μg/ml. The microbial kinetic assay showed a statistical difference between apple cider vinegar and nystatin (p < 0.0001). After 30 minutes of exposure, apple cider vinegar showed fungicidal effect at MICx4, whereas nystatin maintained its fungistatic effect. Apple cider vinegar showed greater inhibition of adherence (p < 0.001) compared to control. Apple cider vinegar did not significantly alter the surface roughness of the acrylic resin specimens compared to nystatin (p > 0.05), and both had no influence on their color. Apple cider vinegar showed antifungal properties against Candida spp., thus representing a possible therapeutic alternative for patients with denture stomatitis.


[The role of Cd-binding proteins and phytochelatins in the formation of cadmium resistance in Nicotiana plumbaginifolia cell lines].
Nicotiana plumbaginifolia callus lines with the equal resistance to cadmium have been produced under different selective conditions--either without inhibition of the phytochelatin synthesis (line Cd-R) or in the presence of the inhibitor butionine sulfoximine (line Cd-Ri). The level of phytochelatin synthesis in the line Cd-R five-fold exceeded the control value and in the line Cd-Ri it was twice as much as in the control. It was shown that in the control line mainly three cadmium-binding proteins are expressed of the molecular weihgts 41, 34 and 19 kD. The common feature of the both resistant lines is the expression of the cadmium-binding proteins of 40, 37 and 19 kD. The resistant lines differ with respect to the synthesis of relatively low-molecular cadmium-binding proteins. The proteins of the molecular weights 12.5, 11.5 and 9 kD are expressed in the line Cd-R, while the proteins of 13 and 10 kD are expressed in the line Cd-Ri. It was supposed that both the phytochelatins and the Cd-binding proteins contribute to the resisitance of N. plumbaginifolia callus lines to cadmium and the lack of the phytochelatins can be equilibrated by the changes in the low-molecular Cd-binding protein synthesis.


Ophthalmic features of PLA2G6-related paediatric neurodegeneration with brain iron accumulation.
Neurodegeneration with brain iron accumulation (NBIA) refers to genetically heterogenous paediatric neurodegenerative disorders characterised by basal ganglia iron deposition. One major cause is recessive mutations in the PLA2G6 gene. While strabismus and optic nerve pallor have been reported for PLA2G6-related disease, the ophthalmic phenotype is not carefully defined. In this study we characterise the ophthalmic phenotype of PLA2G6-related NBIA. Prospective cohort study. The eight patients were 4-26 years old when examined. All had progressive cognitive and motor regression first noted between 9 months and 6 years of age that typically first manifested as difficulty walking (ataxia). Ophthalmic examination was sometimes limited by cognitive ability. Four of eight had exotropia, 7/7 bilateral supraduction defect, 5/7 poor convergence, 6/8 saccadic pursuit, 4/8 saccadic intrusions that resembled square-wave jerks, and 8/8 bilateral optic nerve head pallor. All patients lacked Bell phenomenon. Upgaze palsy, although not a previously reported finding, was confirmed in all patients (except in one for whom assessment could not be performed) and thus can be considered part of the phenotype in children and young adults. Other frequent findings not previously highlighted were abnormal convergence, saccadic pursuit, and saccadic intrusions. Optic nerve head pallor and strabismus, previously reported findings in the disease, were found in 100% and 50% of our cohort, respectively, and the strabismus in our series was always exotropia. Taken together, these clinical findings may be helpful in distinguishing PLA2G6-related neurodegeneration from the other major cause of NBIA, recessive PANK2 mutations.


Meat consumption and risk of incident dementia: cohort study of 493,888 UK Biobank participants.
Worldwide, the prevalence of dementia is increasing and diet as a modifiable factor could play a role. Meat consumption has been cross-sectionally associated with dementia risk, but specific amounts and types related to risk of incident dementia remain poorly understood. We aimed to investigate associations between meat consumption and risk of incident dementia in the UK Biobank cohort. Meat consumption was estimated using a short dietary questionnaire at recruitment and repeated 24-h dietary assessments. Incident all-cause dementia comprising Alzheimer disease (AD) and vascular dementia (VD) was identified by electronic linkages to hospital and mortality records. HRs for each meat type in relation to each dementia outcome were estimated in Cox proportional hazard models. Interactions between meat consumption and the apolipoprotein E (APOE) ε4 allele were additionally explored. Among 493,888 participants included, 2896 incident cases of all-cause dementia, 1006 cases of AD, and 490 cases of VD were identified, with mean ± SD follow-up of 8 ± 1.1 y. Each additional 25 g/day intake of processed meat was associated with increased risks of incident all-cause dementia (HR: 1.44; 95% CI: 1.24, 1.67; P-trend < 0.001) and AD (HR: 1.52; 95% CI: 1.18, 1.96; P-trend = 0.001). In contrast, a 50-g/d increment in unprocessed red meat intake was associated with reduced risks of all-cause dementia (HR: 0.81; 95% CI: 0.69, 0.95; P-trend = 0.011) and AD (HR: 0.70; 95% CI: 0.53, 0.92; P-trend = 0.009). The linear trend was not significant for unprocessed poultry and total meat. Regarding incident VD, there were no statistically significant linear trends identified, although for processed meat, higher consumption categories were associated with increased risks. The APOE ε4 allele increased dementia risk by 3 to 6 times but did not modify the associations with diet significantly. These findings highlight processed-meat consumption as a potential risk factor for incident dementia, independent of the APOE ε4 allele.


The role of the 5'-3' exoribonuclease XRNA in transcriptome-wide mRNA degradation.
The steady-state level of each mRNA in a cell is a balance between synthesis and degradation. Here, we use high-throughput RNA sequencing (RNASeq) to determine the relationship between mRNA degradation and mRNA abundance on a transcriptome-wide scale. The model organism used was the bloodstream form of Trypanosoma brucei, a protist that lacks regulation of RNA polymerase II initiation. The mRNA half-lives varied over two orders of magnitude, with a median half-life of 13 min for total (rRNA-depleted) mRNA. Data for poly(A)+ RNA yielded shorter half-lives than for total RNA, indicating that removal of the poly(A) tail was usually the first step in degradation. Depletion of the major 5'-3' exoribonuclease, XRNA, resulted in the stabilization of most mRNAs with half-lives under 30 min. Thus, on a transcriptome-wide scale, degradation of most mRNAs is initiated by deadenylation. Trypanosome mRNA levels are strongly influenced by gene copy number and mRNA half-life: Very abundant mRNAs that are required throughout the life-cycle may be encoded by multicopy genes and have intermediate-to-long half-lives; those encoding ribosomal proteins, with one to two gene copies, are exceptionally stable. Developmentally regulated transcripts with a lower abundance in the bloodstream forms than the procyclic forms had half-lives around the median, whereas those with a higher abundance in the bloodstream forms than the procyclic forms, such as those encoding glycolytic enzymes, had longer half-lives.


Automatic glomerular identification and quantification of histological phenotypes using image analysis and machine learning.
Current methods of scoring histological kidney samples, specifically glomeruli, do not allow for collection of quantitative data in a high-throughput and consistent manner. Neither untrained individuals nor computers are presently capable of identifying glomerular features, so expert pathologists must do the identification and score using a categorical matrix, complicating statistical analysis. Critical information regarding overall health and physiology is encoded in these samples. Rapid comprehensive histological scoring could be used, in combination with other physiological measures, to significantly advance renal research. Therefore, we used machine learning to develop a high-throughput method to automatically identify and collect quantitative data from glomeruli. Our method requires minimal human interaction between steps and provides quantifiable data independent of user bias. The method uses free existing software and is usable without extensive image analysis training. Validation of the classifier and feature scores in mice is highlighted in this work and shows the power of applying this method in murine research. Preliminary results indicate that the method can be applied to data sets from different species after training on relevant data, allowing for fast glomerular identification and quantitative measurements of glomerular features. Validation of the classifier and feature scores are highlighted in this work and show the power of applying this method. The resulting data are free from user bias. Continuous data, such that statistical analysis can be performed, allows for more precise and comprehensive interrogation of samples. These data can then be combined with other physiological data to broaden our overall understanding of renal function.


Efficacy of Individualized Homeopathic Medicines in Plantar Fasciitis: Double-blind, Randomized, Placebo-Controlled Clinical Trial.
Plantar fasciitis (PF) is a chronic degenerative condition causing marked thickening and fibrosis of the plantar fascia, and collagen necrosis, chondroid metaplasia and calcification. There is little convincing evidence in support of various approaches, including homeopathy, for treating PF. This study was undertaken to examine the efficacy of individualized homeopathic medicines (IHMs) compared with placebo in the treatment of PF. A double-blind, randomized, placebo-controlled trial was conducted at the outpatient departments of Mahesh Bhattacharyya Homoeopathic Medical College and Hospital, West Bengal, India. Patients were randomized to receive either IHMs or identical-looking placebo in the mutual context of conservative non-medicinal management. The Foot Function Index (FFI) questionnaire, as an outcome measure, was administered at baseline, and every month, up to 3 months. Group differences (unpaired t-tests) and effect sizes (Cohen's d) were calculated on an intention-to-treat sample. The sample was analyzed statistically after adjusting for baseline differences. The target sample size was 128; however, only 75 could be enrolled (IHMs: 37; Placebo: 38). Attrition rate was 9.3% (IHMs: 4, Placebo: 3). Differences between groups in total FFI% score favored IHMs against placebo at all the time points, with large effect sizes: month 1 (mean difference, -10.0; 95% confidence interval [CI], -15.7 to -4.2; p = 0.001; d = 0.8); month 2 (mean difference, -14.3; 95% CI, -20.4 to -8.2; p <0.001; d = 1.1); and month 3 (mean difference, -23.3; 95% CI, -30.5 to -16.2; p <0.001; d = 1.5). Similar significant results were also observed on three FFI sub-scales (pain%, disability%, and activity limitation%). Natrum muriaticum (n = 14; 18.7%) and Rhus toxicodendron and Ruta graveolens (n = 11 each; 14.7%) were the most frequently prescribed medicines. No harms, serious adverse events, or intercurrent illnesses were recorded in either of the groups. IHMs acted significantly better than placebo in the treatment of PF; however, the trial being underpowered, the results should be interpreted as preliminary only. Independent replications are warranted. CTRI/2018/10/016014.


Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring.
Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia.


Economic savings for scientific free and open source technology: A review.
Both the free and open source software (FOSS) as well as the distributed digital manufacturing of free and open source hardware (FOSH) has shown particular promise among scientists for developing custom scientific tools. Early research found substantial economic savings for these technologies, but as the open source design paradigm has grown by orders of magnitude it is possible that the savings observed in the early work was isolated to special cases. Today there are examples of open source technology for science in the vast majority of disciplines and several resources dedicated specifically to publishing them. Do the tremendous economic savings observed earlier hold today? To answer that question, this study evaluates free and open source technologies in the two repositories compared to proprietary functionally-equivalent tools as a function of their use of Arduino-based electronics, RepRap-class 3-D printing, as well as the combination of the two. The results of the review find overwhelming evidence for a wide range of scientific tools, that open source technologies provide economic savings of 87% compared to equivalent or lesser proprietary tools. These economic savings increased slightly to 89% for those that used Arduino technology and even more to 92% for those that used RepRap-class 3-D printing. Combining both Arduino and 3-D printing the savings averaged 94% for free and open source tools over commercial equivalents. The results provide strong evidence for financial support of open source hardware and software development for the sciences. Given the overwhelming economic advantages of free and open source technologies, it appears financially responsible to divert funding of proprietary scientific tools and their development in favor of FOSH. Policies were outlined that provide nations with a template for strategically harvesting the opportunities provided by the free and open source paradigm.


A 3-year old girl with seizures, hypokalemia and metabolic alkalosis.
A 3-year-old girl presented to the emergency department with seizures, low-grade fever and vomiting. She had tachycardia and a slow capillary refill. Blood pressure could not be measured. Because of suspected sepsis and/or meningo-encephalitis, broad spectrum antibiotics and antiviral medication were given together, along with volume expansion and anticonvulsive therapy. A few hours later, after a second seizure, the blood pressure was extremely high (156/116 mm Hg). The girl was treated with anticonvulsants and intravenous antihypertensive agents. MRI of the brain showed signs of posterior reversible encephalopathy syndrome. Cultures of blood and cerebrospinal fluid remained sterile. Further investigation into the cause of the malignant hypertension revealed hypokalemia, metabolic alkalosis and extremely high plasma renin activity, caused by a rare renal abnormality: bilateral renal segmental hypoplasia or Ask-Upmark kidneys.


Morphine withdrawal contributes to Th cell differentiation by biasing cells toward the Th2 lineage.
The consequences that drug withdrawal has on immune functioning has only recently been appreciated; however, given the wide variety of use and abuse of opiate analgesics, understanding the decrements to immune function that withdrawal from these drugs causes is of crucial importance. In previous work, we have demonstrated that morphine treatment contributes to immunosuppression by polarizing Th cells toward the Th2 lineage. In the current study, it was hypothesized that morphine withdrawal would result in Th2 differentiation and subsequent immune dysfunction. To address this hypothesis, mice were chronically treated with morphine for 72 h followed by a 24-h withdrawal period. It was determined that 24-h morphine withdrawal resulted in a decrease in IFN-gamma, the Th1 signature cytokine, whereas the Th2 cytokine, IL-4, was increased. In addition, Western blot and EMSA experiments revealed that morphine withdrawal-induced Th2 differentiation was mediated through the classical Th2 transcription factors Stat-6 and GATA-3. In addition, the consequence of morphine withdrawal in the presence of an immune stimulation was also examined by treating mice in vivo with LPS before morphine withdrawal. Following withdrawal, it was found that the Th1-polarizing cytokine IL-12 was significantly decreased, providing further support for the observation that withdrawal results in Th2 differentiation by possibly impacting the generation of an appropriate innate immune response which directs subsequent adaptive Th1/Th2 responses.


Testing the Implementation of a Pain Self-management Support Intervention for Oncology Patients in Clinical Practice: A Randomized Controlled Pilot Study (ANtiPain).
In oncology, pain control is a persistent problem. Significant barriers to cancer pain management are patient related. Pain self-management support interventions have shown to reduce pain intensity and patient-related barriers. Comparative effectiveness research is a suitable approach to test whether effects are sustained in clinical practice. In this pilot randomized controlled trial, the implementation of the ANtiPain intervention into clinical practice was tested to assess the effects on pain intensity, function-related outcomes, self-efficacy, and patient-related barriers to pain management to prepare a larger effectiveness trial. Within 14 months, 39 adult oncology patients with pain scores of 3 or higher on a 10-point numeric rating scale were recruited in an academic comprehensive cancer center in Southern Germany. Patients in the control group (n = 19) received standard care. Patients in the intervention group (n = 20) received ANtiPain, a cancer pain self-management support intervention based on 3 key strategies: provision of information, skill building, and nurse coaching. An intervention session was performed in-hospital. After discharge, follow-up was provided via telephone calls. Data were collected at baseline and 1 and 6 weeks after discharge. Effect sizes were calculated for all outcomes. Large effects were found for activity hindrance (Cohen d = 0.90), barriers (d = 0.91), and self-efficacy (d = 0.90). Small to moderate effects were found for average and worst pain (Cohen d = 0.17-0.45). Key findings of this study involved function-related outcomes and self-efficacy. Because these outcomes are particularly meaningful for patients, the integration of ANtiPain to routine clinical practice may be substantial. A larger study will be based on these findings.


Thorn-like ZnO/CNT composites via the hydrothermal method with different seed layer.
This paper studies the preparation of a zinc oxide (ZnO) seed layer deposited onto carbon nanotubes (CNTs) via RF sputtering, and the growth of ZnO/CNT composite via the hydrothermal method. The ZnO "thorns" have been successfully deposited on CNT "stems." The research focuses on the ZnO seed layer with different sputtering times and annealing processes. A scanning electron microscopy (SEM) investigation showed that the length and amount of ZnO thorns decreased with increased sputtering time of the seed layer. The x-ray diffraction (XRD) results showed that the ZnO crystalline structures improved after the seed layer, annealing at peaks of (100), (002), and (101). The results of Raman spectra showed that the ZnO seed layer deposited onto the CNTs, and the annealing, caused damage to the CNTs, reducing the IG/ID ratio from 0.9 to 0.5. Furthermore, the highest UV emission of thorn-like ZnO/CNTs occurred at a peak of 380 nm with seed layer deposition time of 2 min, after annealing.


Continuous ethanol production with a membrane bioreactor at high acetic Acid concentrations.
The release of inhibitory concentrations of acetic acid from lignocellulosic raw materials during hydrolysis is one of the main concerns for 2nd generation ethanol production. The undissociated form of acetic acid can enter the cell by diffusion through the plasma membrane and trigger several toxic effects, such as uncoupling and lowered intracellular pH. The effect of acetic acid on the ethanol production was investigated in continuous cultivations by adding medium containing 2.5 to 20.0 g·L-1 acetic acid at pH 5.0, at a dilution rate of 0.5 h-1. The cultivations were performed at both high (~25 g·L-1) and very high (100-200 g·L-1) yeast concentration by retaining the yeast cells inside the reactor by a cross-flow membrane in a membrane bioreactor. The yeast was able to steadily produce ethanol from 25 g·L-1 sucrose, at volumetric rates of 5-6 g·L-1·h-1 at acetic acid concentrations up to 15.0 g·L-1. However, the yeast continued to produce ethanol also at a concentration of 20 g·L-1 acetic acid but at a declining rate. The study thereby demonstrates the great potential of the membrane bioreactor for improving the robustness of the ethanol production based on lignocellulosic raw materials.


The glomerular basement membrane: not gone, just forgotten.
The glomerular capillaries function as the filtration barrier that retains albumin and other plasma proteins in the circulation. The unresolved question that has been asked for more than 50 years is, Which structural component of these capillaries constitutes the main molecular sieve that normally retains albumin and allows its passage in diseases associated with proteinuria? There is considerable evidence implicating both the glomerular basement membrane (GBM) and the epithelial filtration slits as the barrier. However, the prevailing point of view at present is that the slit diaphragms bridging the filtration slits are responsible for this important function, and evidence implicating the GBM is largely ignored or forgotten. In this issue of the JCI, Jarad et al. show that in laminin beta2-deficient (Lamb2-/-) mice, proteinuria can be directly attributed to the altered composition of the GBM (see the related article beginning on page 2272). Changes in the permeability of the GBM and its organization were primary to changes in the epithelium, as they preceded foot process effacement and loss of slit diaphragms.


Two models of the influenza A M2 channel domain: verification by comparison.
The influenza M2 protein is a simple membrane protein, containing a single transmembrane helix. It is representative of a very large family of single-transmembrane helix proteins. The functional protein is a tetramer, with the four transmembrane helices forming a proton-permeable channel across the bilayer. Two independently derived models of the M2 channel domain are compared, in order to assess the success of applying molecular modelling approaches to simple membrane proteins. The Calpha RSMD between the two models is 1.7 A. Both models are composed of a left-handed bundle of helices, with the helices tilted roughly 15 degrees relative to the (presumed) bilayer normal. The two models have similar pore radius profiles, with a pore cavity lined by the Ser31 and Gly34 residues and a pore constriction formed by the ring of His37 residues. Independent studies of M2 have converged on the same structural model for the channel domain. This model is in agreement with solid state NMR data. In particular, both model and NMR data indicate that the M2 helices are tilted relative to the bilayer normal and form a left-handed bundle. Such convergence suggests that, at least for simple membrane proteins, restraints-directed modelling might yield plausible models worthy of further computational and experimental investigation.


Evaluation of contrast nephropathy in percutaneous treatment of chronic total occlusions.
Contrast-induced nephropathy (CIN) is a leading cause of morbidity and mortality in patients undergoing percutaneous coronary intervention (PCI). Chronic total occlusions (CTO) are frequently observed among patients undergoing coronary angiography. A total of 128 CTO patients were included. Mehran score, lesion characteristics, interventional procedure, serological specimens and devices were recorded. The first group was administered with 1 ml · kg-1 · h-1 saline (0.9% NaCl) infusion that started 12 h before the procedure and continued 12 h post procedure as recommended by the guidelines. The second group was administered with saline infusion of 12 ml · kg-1 · h-1 only during CTO-PCI procedure, which is called as intensive infusion. CIN development was similar in two groups (four patients in standard hydration group and five patients in intensive hydration group). The amount of saline was significantly higher in the standard group (1,767 ± 192.2 vs. 1,043.6 ± 375; p < 0.001). Patients with higher creatinine levels prior to PCI had a higher rate of CIN development after procedure. Interestingly, age, left ventricular ejection fraction, and diabetes mellitus independently predicted CIN. Intensive hydration administration appears to be an effective and cost-effective method in CTO-PCI patients, especially in patients without left ventricular function failure.


Experiences of outreach workers in promoting smoking cessation to Bangladeshi and Pakistani men: longitudinal qualitative evaluation.
Despite having high smoking rates, there have been few tailored cessation programmes for male Bangladeshi and Pakistani smokers in the UK. We report on a qualitative evaluation of a community-based, outreach worker delivered, intervention that aimed to increase uptake of NHS smoking cessation services and tailor services to meet the needs of Bangladeshi and Pakistani men. This was a longitudinal, qualitative study, nested within a phase II cluster randomised controlled trial of a complex intervention. We explored the perspectives and experiences of five outreach workers, two stop smoking service managers and a specialist stop smoking advisor. Data were collected through focus group discussions, weekly diaries, observations of management meetings, shadowing of outreach workers, and one-to-one interviews with outreach workers and their managers. Analysis was undertaken using a modified Framework approach. Outreach workers promoted cessation services by word of mouth on the streets, in health service premises, in local businesses and at a wide range of community events. They emphasised the reasons for cessation, especially health effects, financial implications, and the impact of smoking on the family. Many smokers agreed to be referred to cessation services, but few attended, this in part being explained by concerns about the relative inflexibility of existing service provision. Although outreach workers successfully expanded service reach, they faced the challenges of perceived lack of awareness of the health risks associated with smoking in older smokers and apathy in younger smokers. These were compounded by perceptions of "lip service" being given to their role by community organisations and tensions both amongst the outreach workers and with the wider management team. Outreach workers expanded reach of the service through taking it to diverse locations of relevance to Pakistani and Bangladeshi communities. The optimum method of outreach to retain and treat Bangladeshi and Pakistani smokers effectively in cessation programmes needs further development.


Making sense of the challenge of smoking cessation during pregnancy: a phenomenographic approach.
In general, most women are familiar with the need to stop smoking when they are pregnant. In spite of this, many women find it difficult to stop. Using a phenomenographic approach, this study explored Swedish pregnant and post-pregnant women's ways of making sense of smoking during pregnancy. A total of 17 women who either smoked throughout pregnancy or stopped smoking during pregnancy were interviewed. Five different story types of how they are making sense of smoking during pregnancy were identified: smoking can be justified; will stop later; my smoking might hurt the baby; smoking is just given up; smoking must be taken charge of. Based on the study it is argued that the approach used in health education in relation to smoking cessation in antenatal care needs to move from information transfer and advice-giving to the creation of a dialogue. The starting point should be the woman's knowledge, concerns, rationalizations and prejudices. A model is suggested in which a woman may move in a space on three axes depending on life encounters, dialogue and reflections on meaning. The goal in health education would be to encourage movement along three axes: 'increase of self-efficacy towards control', 'increase awareness by reflection on meaning of the smoking issue' and 'avoidance of defense of the smoking behavior'.


SGLT2 Inhibition Increases Fasting Glucagon but Does Not Restore the Counterregulatory Hormone Response to Hypoglycemia in Participants With Type 1 Diabetes.
Individuals with type 1 diabetes have an impaired glucagon counterregulatory response to hypoglycemia. Sodium-glucose cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated whether SGLT inhibition restores the glucagon counterregulatory hormone response to hypoglycemia. Adults with type 1 diabetes (n = 22) were treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4 weeks in a randomized, double-blind, crossover study. After each treatment phase, participants underwent a hyperinsulinemic-hypoglycemic clamp. Basal glucagon concentrations were 32% higher following dapagliflozin versus placebo, with a median within-participant difference of 2.75 pg/mL (95% CI 1.38-12.6). However, increased basal glucagon levels did not correlate with decreased rates of hypoglycemia and thus do not appear to be protective in avoiding hypoglycemia. During hypoglycemic clamp, SGLT2 inhibition did not change counterregulatory hormone concentrations, time to recovery from hypoglycemia, hypoglycemia symptoms, or cognitive function. Thus, despite raising basal glucagon concentrations, SGLT inhibitor treatment did not restore the impaired glucagon response to hypoglycemia. We propose that clinical reduction in hypoglycemia associated with these agents is a result of changes in diabetes care (e.g., lower insulin doses or improved glycemic variability) as opposed to a direct, physiologic effect of these medications on α-cell function.


Maternal immunisation to improve the health of HIV-exposed infants.
HIV-exposed but uninfected (HEU) infants are at an increased risk of many infectious diseases that can contribute to the high mortality seen among HEU children. Maternal immunisation could be a promising strategy to reduce infections in HEU infants. However, very little research has explored the effect of HIV on the immunogenicity and effectiveness of vaccines given during pregnancy. We review the available evidence on maternal immunisation among women living with HIV (WLWH) for all vaccines recommended, considered, or being investigated for routine or risk-based use during pregnancy. Of the 11 vaccines included, only three have been investigated in WLWH. Available evidence suggests that maternal HIV infection limits the immunogenicity of several vaccines, leaving HEU infants more susceptible to infection during their first few months of life. Whether maternal immunisation reduces the infectious morbidity and mortality associated with infectious diseases in HEU children remains unknown. We conclude the Review by identifying future research priorities.


Fog-basking behaviour and water collection efficiency in Namib Desert Darkling beetles.
In the Namib Desert fog represents an alternative water source. This is utilised by Darkling beetles (Tenebrionidae) that employ different strategies for obtaining the fog water. Some dig trenches in the sand, while others use their own bodies as fog collectors assuming a characteristic fog-basking stance. Two beetle species from the genus Onymacris have been observed to fog-bask on the ridges of the sand dunes. These beetles all have smooth elytra surfaces, while another species with elytra covered in bumps is reported to have specialised adaptations facilitating water capture by fog-basking. To resolve if these other beetles also fog-bask, and if an elytra covered in bumps is a more efficient fog water collector than a smooth one, we examined four Namib Desert beetles; the smooth Onymacris unguicularis and O. laeviceps and the bumpy Stenocara gracilipes and Physasterna cribripes. Here we describe the beetles' fog-basking behaviour, the details of their elytra structures, and determine how efficient their dorsal surface areas are at harvesting water from fog. The beetles differ greatly in size. The largest P. cribripes has a dorsal surface area that is 1.39, 1.56, and 2.52 times larger than O. unguicularis, O. laeviceps, and S. gracilipes, respectively. In accordance with earlier reports, we found that the second largest O. unguicularis is the only one of the four beetles that assumes the head standing fog-basking behaviour, and that fog is necessary to trigger this behaviour. No differences were seen in the absolute amounts of fog water collected on the dorsal surface areas of the different beetles. However, data corrected according to the sizes of the beetles revealed differences. The better fog water harvesters were S. gracilipes and O. unguicularis while the large P. cribripes was the poorest. Examination of the elytra microstructures showed clear structural differences, but the elytra of all beetles were found to be completely hydrophobic. The differences in fog water harvesting efficiency by the dorsal surface areas of beetles with very different elytra surface structures were minor. We therefore conclude that the fog-basking behaviour itself is a more important factor than structural adaptations when O. unguicularis collect water from fog.


Predictors and outcomes of limited resection for early-stage non-small cell lung cancer.
Lobectomy is considered the standard treatment for early-stage non-small cell lung cancer (NSCLC); however, more limited resections are commonly performed. We examined patient and surgeon factors associated with limited resection and compared postoperative and long-term outcomes between sublobar and lobar resections. A population- and health system-based sample of patients newly diagnosed with stage I or II NSCLC between 2003 and 2005 in five geographically defined regions, five integrated health-care delivery systems, and 15 Veterans Affairs hospitals was observed for a median of 55 months, through May 31, 2010. Predictors of limited resection and postoperative outcomes were compared using unadjusted and propensity score-weighted analyses. All P values are from two-sided tests. One hundred fifty-five (23%) patients underwent limited resection and 524 (77%) underwent lobectomy. In adjusted analyses of patient-specific factors, smaller tumor size (P = .004), coverage by Medicare or Medicaid, no insurance or unknown insurance (P = .02), more severe lung disease (P < .001), and a history of stroke (P = .049) were associated with receipt of limited resection. In adjusted analyses of surgeon characteristics, thoracic surgery specialty (P = .02), non-fee-for-service compensation (P = .008), and National Cancer Institute cancer center designation (P = .006) were associated with higher odds of limited resection. Unadjusted 30-day mortality was higher with limited resection than with lobectomy (7.1% vs 1.9%, difference = 5.2%, 95% confidence interval [CI] = 1.5% to 10.8%, P = .003), and the adjusted difference was not statistically significant (6.5% vs 2.9%, difference = 3.6%, 95% CI = -.1% to 9.2%, P = .09). Postoperative complications did not differ by type of surgery (all P > .05). Over the course of the study, a non-statistically significant trend toward improved long-term survival was evident for lobectomy, compared with limited resection, in adjusted analyses (hazard ratio of death = 1.35 for limited resection, 95% CI = 0.99 to 1.84, P = .05). Evidence is statistically inconclusive but suggestive that lobectomy, compared with limited resection, is associated with increased long-term survival for early-stage lung cancer. Clinical, socioeconomic, and surgeon factors appear to be associated with the choice of surgical resection.


Beverage intake and risk of Crohn disease: A meta-analysis of 16 epidemiological studies.
Epidemiological studies were controversial in the association between beverage intake and risk of Crohn disease (CD). This study aimed to investigate the role of beverage intake in the development of CD. A systematic search was conducted in public databases to identify all relevant studies, and study-specific relative risks (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model. Sixteen studies were identified with a total of 130,431 participants and 1933 CD cases. No significant association was detected between alcohol intake and CD risk (RR for the highest vs the lowest consumption level: 0.85, 95% CI 0.68-1.08), and coffee intake and the risk (RR 0.82, 95% CI 0.46-1.46). High intake of soft drinks was associated with CD risk (RR 1.42, 95% CI 1.01-1.98), and tea intake was inversely associated with CD risk (RR 0.70, 95% CI 0.53-0.93). In conclusion, high intake of soft drinks might increase the risk of CD, whereas tea intake might decrease the risk.


Negative Epistasis between Sickle and Foetal Haemoglobin Suggests a Reduction in Protection against Malaria.
Haemoglobin variants, Sickle (HbS) and foetal (HbF) have been associated with malaria protection. This study explores epistatic interactions between HbS and HbF on malaria infection. The study was conducted between March 2004 and December 2013 within the sickle cell disease (SCD) programme at Muhimbili National Hospital, Tanzania. SCD status was categorized into HbAA, HbAS and HbSS using hemoglobin electrophoresis and High Performance Liquid Chromatography (HPLC). HbF levels were determined by HPLC. Malaria was diagnosed using rapid diagnostic test and/or blood film. Logistic regression and generalized estimating equations models were used to evaluate associations between SCD status, HbF and malaria. 2,049 individuals with age range 0-70 years, HbAA 311(15.2%), HbAS 241(11.8%) and HbSS 1,497(73.1%) were analysed. At enrolment, malaria prevalence was significantly higher in HbAA 13.2% compared to HbAS 1.24% and HbSS 1.34% (p<0.001). Mean HbF was lower in those with malaria compared to those without malaria in HbAA (0.43% vs 0.82%) but was the reverse in HbSS (8.10% vs 5.59%). An increase in HbF was associated with a decrease in risk of malaria OR=0.50 (95%CI: 0.28, 0.90; p=0.021) in HbAA, whereas for HbSS the risk of malaria increased OR=2.94 (1.44, 5.98; p=0.003). A similar pattern was seen during multiple visits; HbAA OR=0.52 (0.34, 0.80; p=0.003) vs HbSS OR=2.01 (1.27, 3.23; p=0.003). Higher prevalence of malaria in HbAA compared to HbAS and HbSS confirmed the protective effect of HbS. Lower prevalence of malaria in HbAA with high HbF supports a protective effect of HbF. However, in HbSS, the higher prevalence of malaria with high levels of HbF suggests loss of malaria protection. This is the first epidemiological study to suggest a negative epistasis between HbF and HbS on malaria.


Validation of the SYNTAX revascularization index to quantify reasonable level of incomplete revascularization after percutaneous coronary intervention.
Incomplete revascularization is common after percutaneous coronary intervention (PCI). Whether a "reasonable" degree of incomplete revascularization is associated with a similar favorable long-term prognosis compared with complete revascularization remains unknown. We sought to quantify the proportion of coronary artery disease burden treated by PCI and evaluate its impact on outcomes using a new prognostic instrument-the Synergy Between PCI with Taxus and Cardiac Surgery (SYNTAX) Revascularization Index (SRI). The baseline SYNTAX score (bSS), the residual SYNTAX score, and the delta SYNTAX score (ΔSS) were determined from 888 angiograms of patients enrolled in the prospective SYNTAX trial. The SRI was then calculated for each patient using the following formula: SRI = (ΔSS/bSS]) × 100. Outcomes were examined according to the proportion of revascularized myocardium (SRI = 100% [complete revascularization], 50% to <100%, and <50%). The Youden index for the SRI was computed to identify the best cutoff for 5-year all-cause mortality. The mean bSS was 28.4 ± 11.5, and after PCI, the mean ΔSS was 23.8 ± 10.9 and the mean residual SYNTAX score was 4.5 ± 6.9. The mean SRI was 85.3 ± 21.2% and was 100% in 385 patients (43.5%), <100% to 50% in 454 patients (51.1%), and <50% in 48 patients (5.4%). Five-year adverse outcomes, including death, were inversely proportional to the SRI. An SRI cutoff of <70% (present in 142 patients [16.0%] after PCI) had the best prognostic accuracy for prediction of death and, by multivariable analysis, was an independent predictor of 5-year mortality (hazard ratio [HR] 4.13, 95% confidence interval [CI] 2.79 to 6.11, p <0.0001). In conclusion, the SRI is a newly described method for quantifying the proportion of coronary artery disease burden treated by PCI. The SRI is a useful tool in assessing the degree of revascularization after PCI, with SRI ≥70% representing a "reasonable" goal for patients with complex coronary artery disease.


The association between persistent fetal occiput posterior position and perinatal outcomes: an example of propensity score and covariate distance matching.
In a retrospective cohort study of 18,880 full-term, cephalic singletons born in San Francisco, California, during 1976-2001, the authors used multivariable logistic regression (MVLR) and propensity score analysis (PSA) to examine the association between persistent fetal occiput posterior (OP) position and perinatal outcomes. The principles and applications of these techniques are compared and discussed. Pregnancies with OP positions at delivery were compared with those with occiput anterior positions. Perinatal outcomes were examined as adjusted odds ratios determined by MVLR and PSA and as risk differences determined by propensity score matched bootstrapping based on covariate distance. Persistent OP position was associated with operative delivery and maternal morbidity. The odds ratio estimates based on PSA were somewhat larger than those obtained with standard MVLR, and the confidence intervals were narrower. When statistical inference was evaluated with the permutation test, the results were more consistent with the PSA. These analyses demonstrate that PSA is likely to provide more precise estimates of exposure associations and more reliable statistical inferences than MVLR. The authors show that PSA can be extended with Mahalanobis distance matching to obtain estimates of risk difference between exposed and unexposed subjects that avoid violations of the experimental treatment assignment (positivity) assumption that is required for valid causal inference.


Cyanobacterial life at low O(2): community genomics and function reveal metabolic versatility and extremely low diversity in a Great Lakes sinkhole mat.
Cyanobacteria are renowned as the mediators of Earth's oxygenation. However, little is known about the cyanobacterial communities that flourished under the low-O(2) conditions that characterized most of their evolutionary history. Microbial mats in the submerged Middle Island Sinkhole of Lake Huron provide opportunities to investigate cyanobacteria under such persistent low-O(2) conditions. Here, venting groundwater rich in sulfate and low in O(2) supports a unique benthic ecosystem of purple-colored cyanobacterial mats. Beneath the mat is a layer of carbonate that is enriched in calcite and to a lesser extent dolomite. In situ benthic metabolism chambers revealed that the mats are net sinks for O(2), suggesting primary production mechanisms other than oxygenic photosynthesis. Indeed, (14)C-bicarbonate uptake studies of autotrophic production show variable contributions from oxygenic and anoxygenic photosynthesis and chemosynthesis, presumably because of supply of sulfide. These results suggest the presence of either facultatively anoxygenic cyanobacteria or a mix of oxygenic/anoxygenic types of cyanobacteria. Shotgun metagenomic sequencing revealed a remarkably low-diversity mat community dominated by just one genotype most closely related to the cyanobacterium Phormidium autumnale, for which an essentially complete genome was reconstructed. Also recovered were partial genomes from a second genotype of Phormidium and several Oscillatoria. Despite the taxonomic simplicity, diverse cyanobacterial genes putatively involved in sulfur oxidation were identified, suggesting a diversity of sulfide physiologies. The dominant Phormidium genome reflects versatile metabolism and physiology that is specialized for a communal lifestyle under fluctuating redox conditions and light availability. Overall, this study provides genomic and physiologic insights into low-O(2) cyanobacterial mat ecosystems that played crucial geobiological roles over long stretches of Earth history.


Optimization of biomass production of a mutant of Yarrowia lipolytica with an increased lipase activity using raw glycerol.
The yeast Yarrowia lipolytica accumulates oils and is able to produce extracellular lipases when growing in different carbon sources including glycerol, the principal by-product of the biodiesel industry. In this study, biomass production of a novel mutant strain of Y. lipolytica was statistically optimized by Response Surface Methodology in media containing biodiesel-derived glycerol as main carbon source. This strain exhibited distinctive morphological and fatty acid profile characteristics, and showed an increased extracellular lipase activity. An organic source of nitrogen and the addition of 1.0 g/l olive oil were necessary for significant lipase production. Plackett-Burman and Central Composite Statistical Designs were employed for screening and optimization of fermentation in shaken flasks cultures, and the maximum values obtained were 16.1 g/l for biomass and 12.2 Units/ml for lipase, respectively. Optimized batch bioprocess was thereafter scaled in aerated bioreactors and the values reached for lipase specific activity after 95 % of the glycerol had been consumed, were three-fold higher than those obtained in shaken flasks cultures. A sustainable bioprocess to obtain biomass and extracellular lipase activity was attained by maximizing the use of the by-products of biodiesel industry.


The Herbicide Glyphosate Negatively Affects Midgut Bacterial Communities and Survival of Honey Bee during Larvae Reared in Vitro.
Effects of glyphosate on survival, developmental rate, larval weight, and midgut bacterial diversity of Apis mellifera were tested in the laboratory. Larvae were reared in vitro and fed diet containing glyphosate 0.8, 4, and 20 mg/L. The dependent variables were compared with negative control and positive control (dimethoate 45 mg/L). Brood survival decreased in 4 or 20 mg/L glyphosate treatments but not in 0.8 mg/L, and larval weight decreased in 0.8 or 4 mg/L glyphosate treatments. Exposure to three concentrations did not affect the developmental rate. Furthermore, the intestinal bacterial communities were determined using high-throughput sequencing targeting the V3-V4 regions of the 16S rDNA. All core honey bee intestinal bacterial phyla such as Proteobacteria (30.86%), Firmicutes (13.82%), and Actinobacteria (11.88%) were detected, and significant changes were found in the species diversity and richness in 20 mg/L glyphosate group. Our results suggest that high concentrations of glyphosate are deleterious to immature bees.


Covariate-adjusted region-referenced generalized functional linear model for EEG data.
Electroencephalography (EEG) studies produce region-referenced functional data in the form of EEG signals recorded across electrodes on the scalp. It is of clinical interest to relate the highly structured EEG data to scalar outcomes such as diagnostic status. In our motivating study, resting-state EEG is collected on both typically developing (TD) children and children with autism spectrum disorder (ASD) aged 2 to 12 years old. The peak alpha frequency (PAF), defined as the location of a prominent peak in the alpha frequency band of the spectral density, is an important biomarker linked to neurodevelopment and is known to shift from lower to higher frequencies as children age. To retain the most amount of information from the data, we consider the oscillations in the spectral density within the alpha band, rather than just the peak location, as a functional predictor of diagnostic status (TD vs ASD), adjusted for chronological age. A covariate-adjusted region-referenced generalized functional linear model is proposed for modeling scalar outcomes from region-referenced functional predictors, which utilizes a tensor basis formed from one-dimensional discrete and continuous bases to estimate functional effects across a discrete regional domain while simultaneously adjusting for additional nonfunctional covariates, such as age. The proposed methodology provides novel insights into differences in neural development of TD and ASD children. The efficacy of the proposed methodology is investigated through extensive simulation studies.


Does Drain Position and Duration Influence Outcomes in Patients Undergoing Burr-Hole Evacuation of Chronic Subdural Hematoma? Lessons from a UK Multicenter Prospective Cohort Study.
Drain insertion following chronic subdural hematoma (CSDH) evacuation improves patient outcomes. To examine whether this is influenced by variation in drain location, positioning or duration of placement. We performed a subgroup analysis of a previously reported multicenter, prospective cohort study of CSDH patients performed between May 2013 and January 2014. Data were analyzed relating drain location (subdural or subgaleal), position (through a frontal or parietal burr hole), and duration of insertion, to outcomes in patients aged >16 yr undergoing burr-hole drainage of primary CSDH. Primary outcomes comprised modified Rankin scale (mRS) at discharge and symptomatic recurrence requiring redrainage within 60 d. A total of 577 patients were analyzed. The recurrence rate of 6.7% (12/160) in the frontal subdural drain group was comparable to 8.8% (30/343) in the parietal subdural drain group. Only 44/577 (7.6%) patients underwent subgaleal drain insertion. Recurrence rates were comparable between subdural (7.7%; 41/533) and subgaleal (9.1%; 4/44) groups (P = .95). We found no significant differences in discharge mRS between these groups. Recurrence rates were comparable between patients with postoperative drainage for 1 or 2 d, 6.4% and 8.4%, respectively (P = .44). There was no significant difference in mRS scores between these 2 groups (P = .56). Drain insertion after CSDH drainage is important, but position (subgaleal or subdural) and duration did not appear to influence recurrence rate or clinical outcomes. Similarly, drain location did not influence recurrence rate nor outcomes where both parietal and frontal burr holes were made. Further prospective cohort studies or randomized controlled trials could provide further clarification.


Major decline in malaria morbidity and mortality in the Union of Comoros between 2010 and 2014: The effect of a combination of prevention and control measures.
Malaria remains a public health challenge in sub-Saharan Africa. In response to this, many countries are working towards achieving the World Health Assembly and Roll Back Malaria Partnership target of a 75% decline in malaria incidence. To assess trends in malaria morbidity and mortality in the three islands of the Comoros Archipelago from 2010 to 2014. This was a retrospective study in which all confirmed malaria cases and deaths recorded between 2010 and 2014 were accessed from the national malaria control database. Trends and comparisons in malaria incidence and case fatality rates for all age groups, including under-5 children and pregnant women, were analysed using Microsoft Excel and SPSS version 16. A substantial decline in malaria incidence was observed for each island between 2010 and 2014; from 75.98 cases per 1 000 population in 2010 to 0.14 in 2014 in Moheli, 60.60 to 0.02 in Anjouan and 235.36 to 5.47 in Grand Comoro. Additionally, a general reduction in malaria case fatalities was observed. In Moheli, there were no case fatalities between 2010 and 2014, while there was a decline in the case fatality rate in Anjouan (from 1.20 fatalities per 1 000 cases to 0) and Grand Comoros (0.51 to 0). There were also significant differences (p<0.05) in malaria incidence and case fatalities between the three islands. A similar trend was observed for pregnant women and under-5 children. Our study indicates a significant decline in malaria morbidity and mortality in the islands of Moheli, Anjouan and Grand Comoro from 2010 to 2014. This considerable reduction is attributed to a combination of malaria prevention and control interventions implemented during the study period.


The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution.
The norepinephrine pathway is believed to modulate behavioral and physiological processes, such as mood, overall arousal, and attention. Furthermore, abnormalities in the pathway have been linked to numerous diseases, for example hypertension, depression, anxiety, Parkinson's disease, schizophrenia, Alzheimer's disease, attention deficit hyperactivity disorder, and cocaine dependence. We report the crystal structure of human dopamine β-hydroxylase, which is the enzyme converting dopamine to norepinephrine. The structure of the DOMON (dopamine β-monooxygenase N-terminal) domain, also found in >1600 other proteins, reveals a possible metal-binding site and a ligand-binding pocket. The catalytic core structure shows two different conformations: an open active site, as also seen in another member of this enzyme family [the peptidylglycine α-hydroxylating (and α-amidating) monooxygenase], and a closed active site structure, in which the two copper-binding sites are only 4 to 5 Å apart, in what might be a coupled binuclear copper site. The dimerization domain adopts a conformation that bears no resemblance to any other known protein structure. The structure provides new molecular insights into the numerous devastating disorders of both physiological and neurological origins associated with the dopamine system.


Proenkephalin products are stored in the sperm acrosome and may function in fertilization.
Previous studies have shown that spermatogenic cells are a major source of testicular RNA encoding the opioid peptide precursor proenkephalin, suggesting that proenkephalin-derived peptides may function as intratesticular paracrine factors produced by male germ cells. However, direct evidence for the production of proenkephalin by spermatogenic cells has been lacking. In this report, we have used polysome profile analysis, peptide quantitation, and immunocytochemistry to show that proenkephalin products are synthesized during spermatogenesis and are retained within spermatozoa of humans, hamsters, rats, and sheep. We further show that these peptides are stored in the sperm acrosome and are depleted from sperm following the acrosome reaction, an exocytotic event required for fertilization. Proenkephalin products thus may serve a dual function as sperm acrosomal factors released during the fertilization process as well as intratesticular regulators secreted by spermatogenic cells.


Pharmacokinetics of moxifloxacin in plasma and tissue of morbidly obese patients.
To assess the pharmacokinetics of moxifloxacin in morbidly obese patients. Twelve morbidly obese patients (2 male/10 female, age 25-61 years, weight 98-166 kg, body mass index 43.0-58.2 kg/m(2)) scheduled for gastric bypass surgery were treated with 400 mg of moxifloxacin orally once daily for 3 days and with 400 mg of moxifloxacin intravenously on day 4 (day of surgery). Pharmacokinetic analysis was performed on day 1 and day 4. Specimens of small intestine, greater omentum and subcutaneous adipose tissue were collected intraoperatively 1.8-3.7 h after moxifloxacin infusion. Moxifloxacin concentrations were determined by HPLC. The plasma pharmacokinetics (mean ± SD) was comparable to historical data in normal-weight subjects. Oral bioavailability was 79.6% ± 11.5%. After intravenous administration, plasma clearance was 9.6 ± 2.0 L/h, volume of distribution was 165 ± 30 L and area under the curve was 43.7 ± 11.8 mg·h/L. Linear regression analysis showed the volume of distribution to be better correlated with ideal body weight, lean body weight, fat-free mass or height (R(2) = 0.60-0.67, P = 0.001-0.003) than with total body weight (R(2) = 0.46, P = 0.015). Whereas mean tissue concentrations in small intestine (6.99 ± 2.34 mg/kg) were twice the concomitant plasma concentrations, the concentrations in greater omentum (0.801 ± 0.168 mg/kg) or subcutaneous fat (0.638 ± 0.180 mg/kg) were only one-quarter of those. The pharmacokinetics of moxifloxacin is not significantly affected by morbid obesity. No dose adjustment seems to be necessary in this particular population.


The impact of consultant delivered service in emergency medicine: the Wrexham Model.
Consultant based delivery of emergency service is perceived to add value. This study aims to demonstrate the impact of such a service model based on consultant working in a UK emergency department. This retrospective study was based on the emergency department of a district general hospital. Activity data was analysed for 2009. Workload and admission rates were compared between consultants, middle grade doctors and senior house officers (SHOs). Admission rates were compared against two similar departments. Data from night shifts allowed consultant activity to be contrasted with middle grades and SHOs. Time spent in the department, admission rates, patients who left without treatment, discharged outright and clinic returns were used for comparison. Consultants often saw more patients than SHOs or middle grade doctors. This was on top of their traditional duties of senior opinion. On comparison of activity at night shifts, they admitted fewer (25.2% vs 30.3%, p=0.026), had fewer leaving without treatment (1.6% vs 5.1%, p<0.001), discharged more outright (59.8% vs 47.5%, p<0.001), referred fewer to clinic (5.7% vs 6.6%, p=0.49) and had a faster turnaround time (p<0.001: Priority 2, 3 and 4) for every triage category. Some of the comparisons were clinically but not statistically significant. A consultant based service delivery offers many advantages. These cannot be matched by either junior or middle grades. This would be in addition to the consultants' supervisory role. Consultant expansion is urgently required to achieve this sustainably. A further study evaluating the cost benefits of this service model is now underway.


Subfrontal schwannoma without hyposmia--case report.
A 44-year-old man presented with a rare subfrontal schwannoma with headache. He had undergone radiation therapy for a pineal lesion 30 years previously, but the histology was not verified. On admission, neurological examination revealed no focal deficits including hyposmia. Computed tomography demonstrated a mass measuring 5 x 3 cm in the right anterior cranial fossa. Magnetic resonance imaging revealed a heterogeneously enhanced mass with multiple cysts. The tumor, which was clearly separable from the surrounding normal brain, was totally resected through a right frontal craniotomy. There was no adhesion between the tumor and the olfactory groove or cribriform plate. The frontal base dura was suspected to be the tumor attachment. The patient was discharged without hyposmia. Histological examination revealed a typical pattern of schwannoma consisting of Antoni type A and type B. Immunohistochemical staining was positive for S-100 protein but negative for epithelial membrane antigen. Subfrontal schwannoma not associated with the olfactory groove or cribriform plate is extremely rare. The operative findings and absence of hyposmia suggest that the meningeal branch of the trigeminal nerve was the origin of the tumor. However, the possibility of radiation-induced reactive Schwann cells cannot be excluded.


Seconds-resolved pharmacokinetic measurements of the chemotherapeutic irinotecan in situ in the living body.
The ability to measure drugs in the body rapidly and in real time would advance both our understanding of pharmacokinetics and our ability to optimally dose and deliver pharmacological therapies. To this end, we are developing electrochemical aptamer-based (E-AB) sensors, a seconds-resolved platform technology that, as critical for performing measurements in vivo, is reagentless, reversible, and selective enough to work when placed directly in bodily fluids. Here we describe the development of an E-AB sensor against irinotecan, a member of the camptothecin family of cancer chemotherapeutics, and its adaptation to in vivo sensing. To achieve this we first re-engineered (via truncation) a previously reported DNA aptamer against the camptothecins to support high-gain E-AB signaling. We then co-deposited the modified aptamer with an unstructured, redox-reporter-modified DNA sequence whose output was independent of target concentration, rendering the sensor's signal gain a sufficiently strong function of square-wave frequency to support kinetic-differential-measurement drift correction. The resultant, 200 μm-diameter, 3 mm-long sensor achieves 20 s-resolved, multi-hour measurements of plasma irinotecan when emplaced in the jugular veins of live rats, thus providing an unprecedentedly high-precision view into the pharmacokinetics of this class of chemotherapeutics.


Possible Role of Cyclic AMP Response Element Binding/Brain-Derived Neurotrophic Factor Signaling Pathway in Mediating the Pharmacological Effects of Duloxetine against Methamphetamine Use-Induced Cognitive Impairment and Withdrawal-Induced Anxiety and Depression in Rats.
Duloxetine is used for treating depression and anxiety. The current study evaluated the effects of duloxetine against methamphetamine withdrawal-induced anxiety, depression, and motor disturbances and methamphetamine use-induced cognitive impairments. Ninety-six adult male rats were used for two independent experiments. Each experiment consisted of Groups 1 and 2 which received normal saline (0.2 ml/rat) and methamphetamine (10 mg/kg) respectively, Groups 3, 4, and 5 received both methamphetamine and duloxetine at doses of 5, 10, and 15 mg/kg, respectively. Groups 6, 7, and 8 received 5, 10, and 15 mg/kg of duloxetine, respectively. All administrations were performed for 21 days. In experiment 1, elevated plus maze (EPM), open-field test (OFT), forced swim test (FST), and tail suspension test (TST) were used to examine anxiety and depression in animals during withdrawal period. In experiment 2, Morris water maze (MWM) test was used to assess the effect of methamphetamine use followed by duloxetine treatment, on learning and memory. In the experiments, the expression of cyclic AMP response element binding (CREB) and brain-derived neurotrophic factor (BDNF) proteins were evaluated using enzyme-linked immunosorbent assay. In the first experiment, duloxetine at all doses attenuated methamphetamine withdrawal induced-depression, anxiety, and motor disturbances in FST, OFT, EPM, and TST. In the second experiment, duloxetine at all doses attenuated methamphetamine use-induced cognitive impairment in MWM. In both experiments, duloxetine activated cAMP, CREB, and BDNF proteins' expression in methamphetamine-treated rats. Duloxetine can protect the brain against methamphetamine withdrawal-induced mood and motor disturbances and can also inhibit methamphetamine-induced cognitive impairment, possibly via cAMP/CREB/BDNF signaling pathway.


Prognostic influence of CDX2 expression in gastric carcinoma after surgery with a curative intent.
CDX2 is a specific transcription factor with a significant role in the early differentiation and maintenance of intestinal epithelial cells during gastrointestinal development and also as a tumor suppressor. The aim of this study was to assess the potential role of CDX2 expression as a prognostic predictor. ninety-two of 206 (44.6%) patients with gastric carcinoma that underwent a curative surgery and had immunohistochemical staining for CDX2 were enrolled into the study; 51.1% were female and the average age was 74.07 years. Overall, 56.5% of tumors were of the intestinal type, 33.7% were diffuse and 9.8% were mixed; 23.9% were T1/T2, 76.1% were T3/T4 and lymph node metastases (N+) were identified in 69.6% of cases; 13% (12) were clinical stage I, 40.2% (37) were stage II and 46.7% (43) were stage III. a total of 68.5% (63) expressed CDX2. Our study suggests that CDX2 expression (HR = 0.339, p = 0.024) represents an independent risk marker together with the Lauren type (HR = 3.471, p = 0.022). There was association between a milder clinical stage and CDX2 expression (stage I) (p = 0.046). A significant difference was found in overall survival that favored patients with positive CDX2 expression (85.7% vs 65.5%, p = 0.012). our results confirm that CDX2 expression in gastric carcinoma is associated with improved prognosis, although further studies are needed to draw definitive conclusions.


Inducible gene expression in trypanosomes mediated by a prokaryotic repressor.
An inducible expression system was developed for the protozoan parasite Trypanosoma brucei. Transgenic trypanosomes expressing the tetracycline repressor of Escherichia coli exhibited inducer (tetracycline)-dependent expression of chromosomally integrated reporter genes under the control of a procyclic acidic repetitive protein (PARP) promoter bearing a tet operator. Reporter expression could be controlled over a range of four orders of magnitude in response to tetracycline concentration, a degree of regulation that exceeds those exhibited by other eukaryotic repression-based systems. The tet repressor-controlled PARP promoter should be a valuable tool for the study of trypanosome biochemistry, pathogenicity, and cell and molecular biology.


Strain in southern california: measured uniaxial north-South regional contraction.
The plate tectonics model of the Pacific moving northwest relative to North America implies that the regional strain in California should be simple shear across a vertical plane striking N45 degrees W or equivalently equal parts of north-south contraction and east-west extension. Measurements of the strain accumulation at seven separate sites in southern California in the interval 1972 through 1978 indicate a remarkably consistent uniaxial north-south contraction of about 0.3 part per million per year; the expected east-west extension is absent. It is not clear whether the period from 1972 through 1978 is anomalous or whether the secular strain in southern California is indeed a uniaxial north-south contraction.


Dnt1 acts as a mitotic inhibitor of the spindle checkpoint protein dma1 in fission yeast.
The Schizosaccharomyces pombe checkpoint protein Dma1 couples mitotic progression with cytokinesis and is important in delaying mitotic exit and cytokinesis when kinetochores are not properly attached to the mitotic spindle. Dma1 is a ubiquitin ligase and potential functional relative of the human tumor suppressor Chfr. Dma1 delays mitotic exit and cytokinesis by ubiquitinating a scaffold protein (Sid4) of the septation initiation network, which, in turn, antagonizes the ability of the Polo-like kinase Plo1 to promote cell division. Here we identify Dnt1 as a Dma1-binding protein. Several lines of evidence indicate that Dnt1 inhibits Dma1 function during metaphase. First, Dnt1 interacts preferentially with Dma1 during metaphase. Second, Dma1 ubiquitin ligase activity and Sid4 ubiquitination are elevated in dnt1 cells. Third, the enhanced mitotic defects in dnt1Δ plo1 double mutants are partially rescued by deletion of dma1(+), suggesting that the defects in dnt1 plo1 double mutants are attributable to excess Dma1 activity. Taken together, these data show that Dnt1 acts to restrain Dma1 activity in early mitosis to allow normal mitotic progression.


Tanshinone IIA activates autophagy to reduce liver ischemia-reperfusion injury by MEK/ERK/mTOR pathway.
Autophagy is a highly conserved cell program in eukaryotic cells, which plays an important role for cells to deal with adverse external stimuli such as ischemia-reperfusion. Tanshinone IIA (TanIIA) is well known for its protective effect on myocardial disease, and it is know that it also could regulate autophagy in different cells. As this has not yet been shown for hepatocytes, using a mice liver ischemia-reperfusion model, we detected the role of TanIIA in regulating autophagy and the subsequent protective effects on hepatocytes. Our data showed that TanIIA pretreatment could significantly enhance autophagy by the MEK/ERK/mTOR pathway in hepatocytes after liver ischemia-reperfusion, and the enhanced autophagy decreased ROS generation by clearing damaged mitochondria, providing a protective effect on liver ischemia-reperfusion. This protective effect is manifested as reduced serum enzyme levels, reduced liver tissue damage, decreased inflammatory cell infiltration, decreased inflammatory cytokines and reduced hepatocyte apoptosis. In brief, moderate TanIIA utilization might be a potential treatment approach for clinically liver ischemia-reperfusion.


Suprascapular neuropathy in volleyball players.
Suprascapular nerve entrapment with isolated paralysis of the infraspinatus muscle is uncommon. However, this pathology has been reported in volleyball players. Despite a lack of scientific evidence, excessive strain on the nerve is often cited as a possible cause of this syndrome. Previous research has shown a close association between shoulder range of motion and strain on the suprascapular nerve. No clinical studies have so far been designed to examine the association between excessive shoulder mobility and the presence of this pathology. To study the possible association between the range of motion of the shoulder joint and the presence of suprascapular neuropathy by clinically examining the Belgian male volleyball team with respect to several parameters. An electromyographic investigation, a clinical shoulder examination, shoulder range of motion measurements, and an isokinetic concentric peak torque shoulder internal/external rotation strength test were performed in 16 professional players. The electrodiagnostic study showed a severe suprascapular neuropathy in four players which affected only the infraspinatus muscle. In each of these four players, suprascapular nerve entrapment was present on the dominant side. Except for the hypotrophy of the infraspinatus muscle, no significant differences between the affected and non-affected players were observed on clinical examination. Significant differences between the affected and non-affected players were found for range of motion measurements of external rotation, horizontal flexion and forward flexion, and for flexion of the shoulder girdle (protraction); all were found to be higher in the affected players than the non-affected players. This study suggests an association between increased range of motion of the shoulder joint and the presence of isolated paralysis of the infraspinatus muscle in volleyball players. However, the small number of patients in this study prevents definite conclusions from being drawn.


Overexpression of IRS2 in isolated pancreatic islets causes proliferation and protects human beta-cells from hyperglycemia-induced apoptosis.
Studies in vivo indicate that IRS2 plays an important role in maintaining functional beta-cell mass. To investigate if IRS2 autonomously affects beta-cells, we have studied proliferation, apoptosis, and beta-cell function in isolated rat and human islets after overexpression of IRS2 or IRS1. We found that beta-cell proliferation was significantly increased in rat islets overexpressing IRS2 while IRS1 was less effective. Moreover, proliferation of a beta-cell line, INS-1, was decreased after repression of Irs2 expression using RNA oligonucleotides. Overexpression of IRS2 in human islets significantly decreased apoptosis of beta-cells, induced by 33.3 mM D-glucose. However, IRS2 did not protect cultured rat islets against apoptosis in the presence of 0.5 mM palmitic acid. Overexpression of IRS2 in isolated rat islets significantly increased basal and D-glucose-stimulated insulin secretion as determined in perifusion experiments. Therefore, IRS2 is sufficient to induce proliferation in rat islets and to protect human beta-cells from D-glucose-induced apoptosis. In addition, IRS2 can improve beta-cell function. Our results indicate that IRS2 acts autonomously in beta-cells in maintenance and expansion of functional beta-cell mass in vivo.


Tetrameric complexes of human histocompatibility leukocyte antigen (HLA)-G bind to peripheral blood myelomonocytic cells.
The nonclassical MHC class I molecule human histocompatibility leukocyte antigen (HLA)-G is selectively expressed on fetal trophoblast tissue at the maternal-fetal interface in pregnancy. It has long been suggested that HLA-G may inhibit maternal natural killer (NK) cells through interaction with particular NK cell receptors (KIRs). To investigate interactions of HLA-G, we constructed phycoerythrin-labeled tetrameric complexes of HLA-G refolded with a self-peptide. These HLA-G tetramers failed to bind to NK cells and cells transfected with CD94/NKG2 and killer immunoglobulin-like NK receptors. In contrast, HLA-G tetramers did bind to peripheral blood monocytes, staining a CD16(+)CD14(mid) subset with greater intensity. On transfectants, HLA-G tetramers bound to inhibitory immunoglobulin-like transcript (ILT)2 and ILT4 receptors. However, staining in the presence of antibodies reactive with ILT receptors revealed that the interaction of HLA-G tetramers with blood monocytes was largely due to binding to ILT4. These results suggest that the primary role of HLA-G may be the modulation of myelomonocytic cell behavior in pregnancy.


Genomic Analysis of Shewanella sp. O23S-The Natural Host of the pSheB Plasmid Carrying Genes for Arsenic Resistance and Dissimilatory Reduction.
Shewanella sp. O23S is a dissimilatory arsenate reducing bacterial strain involved in arsenic transformations within the abandoned gold mine in Zloty Stok (SW Poland). Previous physiological studies revealed that O23S may not only release arsenic from minerals, but also facilitate its immobilization through co-precipitation with reduced sulfur species. Given these uncommon, complementary characteristics and the application potential of the strain in arsenic-removal technologies, its genome (~5.3 Mbp), consisting of a single chromosome, two large plasmids (pSheA and pSheB) and three small plasmid-like phages (pSheC-E) was sequenced and annotated. Genes encoding putative proteins involved in heavy metal transformations, antibiotic resistance and other phenotypic traits were identified. An in-depth comparative analysis of arsenic respiration (arr) and resistance (ars) genes and their genetic context was also performed, revealing that pSheB carries the only copy of the arr genes, and a complete ars operon. The plasmid pSheB is therefore a unique natural vector of these genes, providing the host cells arsenic respiration and resistance abilities. The functionality of the identified genes was determined based on the results of the previous and additional physiological studies, including: the assessment of heavy metal and antibiotic resistance under various conditions, adhesion-biofilm formation assay and BiologTM metabolic preferences test. This combined genetic and physiological approach shed a new light on the capabilities of O23S and their molecular basis, and helped to confirm the biosafety of the strain in relation to its application in bioremediation technologies.


COVID-19 and neurological disorders: are neurodegenerative or neuroimmunological diseases more vulnerable?
Neurological disorders and coronavirus 2019 (COVID-19) pandemic are two conditions with a recent well-documented association. Intriguing evidences showed that COVID-19 infection can modify clinical spectrum of manifested neurological disorders but also it plays a crucial role in the development of future diseases as long-tem consequences. In this viewpoint review, we aimed to assess the vulnerability to SARS-CoV-2 infection and development of COVID-19 among neurological disorders. With this in mind, we tested the hypothesis that age rather than neuropathology itself could be decisive in neurodegenerative diseases such as Parkinson's disease, whereas neuropathology rather than age may be critical in neuroimmunological diseases such as Multiple Sclerosis. Highlighting the role of potential susceptibility or protection factors from this disastrous infection, we also stratify the risk for future neurodegeneration.


Marginal Zinc Deficiency and Environmentally Relevant Concentrations of Arsenic Elicit Combined Effects on the Gut Microbiome.
Extensive research shows that dietary variation and toxicant exposure impact the gut microbiome, yielding effects on host physiology. However, prior work has mostly considered such exposure-microbiome interactions through the lens of single-factor exposures. In practice, humans exposed to toxicants vary in their dietary nutritional status, and this variation may impact subsequent exposure of the gut microbiome. For example, chronic arsenic exposure affects 200 million people globally and is often comorbid with zinc deficiency. Zinc deficiency can enhance arsenic toxicity, but it remains unknown how zinc status impacts the gut microbiome's response to arsenic exposure and whether this response links to host toxicity. Using 16S amplicon sequencing, we examined the combinatorial effects of exposure to environmentally relevant concentrations of arsenic on the composition of the microbiome in C57BL/6 mice fed diets varying in zinc concentration. Arsenic exposure and marginal zinc deficiency independently altered microbiome diversity. When combined, their effects on microbiome community structure were amplified. Generalized linear models identified microbial taxa whose relative abundance in the gut was perturbed by zinc deficiency, arsenic, or their interaction. Further, we correlated taxonomic abundances with host DNA damage, adiponectin expression, and plasma zinc concentration to identify taxa that may mediate host physiological responses to arsenic exposure or zinc deficiency. Arsenic exposure and zinc restriction also result in increased DNA damage and decreased plasma zinc. These physiological changes are associated with the relative abundance of several gut taxa. These data indicate that marginal zinc deficiency sensitizes the microbiome to arsenic exposure and that the microbiome associates with some toxicological effects of arsenic.IMPORTANCE Xenobiotic compounds, such as arsenic, have the potential to alter the composition and functioning of the gut microbiome. The gut microbiome may also interact with these compounds to mediate their impact on the host. However, little is known about how dietary variation may reshape how the microbiome responds to xenobiotic exposures or how these modified responses may in turn impact host physiology. Here, we investigated the combinatorial effects of marginal zinc deficiency and physiologically relevant concentrations of arsenic on the microbiome. Both zinc deficiency and arsenic exposure were individually associated with altered microbial diversity and when combined elicited synergistic effects. Microbial abundance also covaried with host physiological changes, indicating that the microbiome may contribute to or be influenced by these pathologies. Collectively, this work demonstrates that dietary zinc intake influences the sensitivity of the microbiome to subsequent arsenic exposure.