[Clinical manifestations of thyroid ophthalmopathy].
Ophthalmopathy is a common manifestation of autoimmune thyroid disease. Periorbital swelling, eyelid lag, exophthalmos, and impaired vision may occur. From 25% to 50% of patients with Graves' hyperthyroidism will have some features of ophthalmopathy. All of the clinically significant eye symptoms and findings among patients with Graves' ophthalmopathy can be traced to one of two phenomena: swelling in the retrobulbar space due to deposition of glycosaminoglycans (GAG) or restriction of extraocular muscle motion, which is attributed to initial swelling and later fibrosis. Patients with Graves' eye disease typically complain of ocular or periocular pain, lacrimation, photophobia, blurred vision, diplopia, or impaired perception of colour. On examination, they exhibit orbital congestion, proptosis, optic neuropathy, restricted gaze, divergent visual axis, corneal exposure, lid retraction, and periorbital edema. This paper describes the main clinical features of Graves' ophthalmopathy, in order to establish measurable and reproducible classifications that can be used in the surgery setting to record changes and to guide and assess therapy. Finally, we recommend the use of objective measurements for proptosis, extraocular movements, corneal alterations, and the optic nerve, using the clinical activity scale or a recorded change in objective measurements to document disease activity, and lastly, documenting the patients' perception of their disease status.


Influence of context and behavior on stimulus reconstruction from neural activity in primary auditory cortex.
Population responses of cortical neurons encode considerable details about sensory stimuli, and the encoded information is likely to change with stimulus context and behavioral conditions. The details of encoding are difficult to discern across large sets of single neuron data because of the complexity of naturally occurring stimulus features and cortical receptive fields. To overcome this problem, we used the method of stimulus reconstruction to study how complex sounds are encoded in primary auditory cortex (AI). This method uses a linear spectro-temporal model to map neural population responses to an estimate of the stimulus spectrogram, thereby enabling a direct comparison between the original stimulus and its reconstruction. By assessing the fidelity of such reconstructions from responses to modulated noise stimuli, we estimated the range over which AI neurons can faithfully encode spectro-temporal features. For stimuli containing statistical regularities (typical of those found in complex natural sounds), we found that knowledge of these regularities substantially improves reconstruction accuracy over reconstructions that do not take advantage of this prior knowledge. Finally, contrasting stimulus reconstructions under different behavioral states showed a novel view of the rapid changes in spectro-temporal response properties induced by attentional and motivational state.


DNA self-recognition in the structure of Pot1 bound to telomeric single-stranded DNA.
Telomeres, specialized protein-DNA complexes that cap the ends of linear chromosomes, are essential for protecting chromosomes from degradation and end-to-end fusions. The Pot1 (protection of telomeres 1) protein is a widely distributed eukaryotic end-capping protein, having been identified in fission yeast, microsporidia, plants and animals. Schizosaccharomyces pombe Pot1p is essential for telomere maintenance, and human POT1 has been implicated in telomerase regulation. Pot1 binds telomeric single-stranded DNA (ssDNA) with exceptionally high sequence specificity, the molecular basis of which has been unknown. Here we describe the 1.9-A-resolution crystal structure of the amino-terminal DNA-binding domain of S. pombe Pot1p complexed with ssDNA. The protein adopts an oligonucleotide/oligosaccharide-binding (OB) fold with two loops that protrude to form a clamp for ssDNA binding. The structure explains the sequence specificity of binding: in the context of the Pot1 protein, DNA self-recognition involving base-stacking and unusual G-T base pairs compacts the DNA. Any sequence change disrupts the ability of the DNA to form this structure, preventing it from contacting the array of protein hydrogen-bonding groups. The structure also explains how Pot1p avoids binding the vast excess of RNA in the nucleus.


Common single-nucleotide polymorphisms in the estrogen receptor β promoter are associated with colorectal cancer survival in postmenopausal women.
Loss of estrogen receptor β (ERβ) expression in the gut is associated with colorectal cancer (CRC) initiation and progression. Germline single-nucleotide polymorphisms (SNP) in genes for the sex-steroid hormone receptors are not strongly associated with CRC risk; however, these SNPs have not previously been evaluated in relation to survival after diagnosis. We enrolled 729 women, ages 50 to 74, diagnosed with invasive CRC between 1997 and 2002 in 13 counties covered by the Seattle-Puget Sound Surveillance Epidemiology and End Results cancer registry. Participants provided germline DNA. We selected 99 tag-SNPs for the androgen receptor (AR), ERα (ESR1), ERβ (ESR2), and progesterone receptor (PGR) genes. Mortality outcomes were ascertained from the National Death Index. During a median of 6.6 years of follow-up, 244 deaths occurred (161 from CRC). We identified 20 SNPs (12 of ESR2 and 8 of PGR) for replication in 1,729 women diagnosed with incident invasive CRC (555 deaths; 405 from CRC) from three prospective cohort studies that participate in the Genetics and Epidemiology of Colorectal Cancer Consortium. Three correlated SNPs in the promoter of ESR2 (rs2987983, rs3020443, and rs2978381) were statistically significant predictors of CRC-specific and overall survival. Minor alleles of each were associated with improved survival [for rs2987983, CRC-specific HR, 0.77; 95% confidence interval (CI), 0.60-0.99 in the initial study, and HR, 0.79; CI, 0.64-0.98 in replication]. No associations were noted for SNPs of AR, ESR1, or PGR. SNPs in the promoter of ESR2 may be important to pathways related to the association between ERβ and tumor progression and metastasis.


Quantifying periodicity in omics data.
Oscillations play a significant role in biological systems, with many examples in the fast, ultradian, circadian, circalunar, and yearly time domains. However, determining periodicity in such data can be problematic. There are a number of computational methods to identify the periodic components in large datasets, such as signal-to-noise based Fourier decomposition, Fisher's g-test and autocorrelation. However, the available methods assume a sinusoidal model and do not attempt to quantify the waveform shape and the presence of multiple periodicities, which provide vital clues in determining the underlying dynamics. Here, we developed a Fourier based measure that generates a de-noised waveform from multiple significant frequencies. This waveform is then correlated with the raw data from the respiratory oscillation found in yeast, to provide oscillation statistics including waveform metrics and multi-periods. The method is compared and contrasted to commonly used statistics. Moreover, we show the utility of the program in the analysis of noisy datasets and other high-throughput analyses, such as metabolomics and flow cytometry, respectively.


The experiences of parents of children with mental disability regarding access to mental health care.
The aim of this qualitative study was to describe the problems that parents or caregivers of children with mental health disabilities and disorders in Namibia experience when accessing healthcare resources for their children. Data was collected through focus group discussions with the participants and individual interviews with the key informants. Overall, a total of 41 people provided information for this study. Thematic data analysis was used to assess the data. The main barriers experienced by the parents were poor service provision, transport and money, whilst access to education services facilitated access to healthcare services. The challenges go beyond commonly-reported problems such as sub-optimal service provision and include the basic challenge of lack of transportation to reach healthcare services. Many of the barriers identified in this study have been related to general problems with the healthcare system in Namibia. Therefore there is a need to address general concerns about healthcare provision as well as improve specific services for children with mental health disabilities and disorders in Namibia.


Cesarean delivery for suspected fetal distress among preterm parturients.
Among preterm parturients (< 37 weeks) who underwent cesarean delivery for suspected fetal distress, to determine the factors associated with decision-incision time (DIT) of < or = 30 minutes and to assess if umbilical arterial pH < 7.10 is more common with DIT < or = 30 or > 30 minutes. The peripartum course of all patients who had cesareans for suspected fetal distress over three years was reviewed. The inclusion criteria were reliable gestational age < 37 weeks and a single indication for cesarean delivery, suspected fetal distress. Twenty antepartum and intrapartum factors were used in a univariate analysis. The mean DIT among the 84 parturients was 30.5 +/- 21.2 minutes, and 63% of patients had surgery started within 30 minutes. The incidence of pH < 7.10 was 20%. Multivariate analysis indicated that the two factors significantly associated with prolonged time to surgery were tachycardia with decreased variability (odds ratio [OR] 5.9, 95% confidence interval [CI] 1.6-21.6) and use of spinal anesthesia (OR 6.2, 95% CI 1.1-35.0). Though none of the 20 variables had significant univariate associations with neonatal acidosis at alpha = .05, those with P < .20 were considered in multiple logistic regression analysis. None of the 20 factors were associated with pH < 7.10, including DIT of > or = 30 minutes (OR 0.26, 95% CI 0.06-1.03). DIT is likely to be > 30 minutes if cesarean delivery is due to decreased fetal heart variability or if spinal anesthesia is utilized; neonatal acidosis, however, is not significantly associated with a prolonged interval.


The interleukin-6 family cytokine interleukin-11 regulates homeostatic epithelial cell turnover and promotes gastric tumor development.
Gastric cancer is the second most common cause of cancer-related mortality worldwide, mainly as a result of late-stage detection. Interleukin (IL)-11 is a multifunctional cytokine reported to be up-regulated in human gastric cancer. We investigated the importance of IL-11 in gastric cancer progression by examining its role in a variety of mouse gastric tumor models, as well as in nonneoplastic and tumor tissues taken from gastric cancer patients. We then determined the transcriptional and translational outcomes of IL-11 overexpression in normal gastric mucosa and identified a novel gene signature important early in the progression toward gastric tumorigenesis. IL-11 was up-regulated significantly in 4 diverse mouse models of gastric pathology as well as in human biopsy specimens adjacent to and within gastric cancer. Removal of IL-11 co-receptor alpha significantly reduced HKbeta-/- mouse fundic hyperplasia and ablated gp130(757F/F) mouse tumorigenesis. Exogenous IL-11 but not IL-6 activated oncogenic signal transducer and activator of transcription-3, and altered expression of novel proliferative and cytoprotective genes RegIII-beta, RegIII-gamma, gremlin-1, clusterin, and growth arrest specific-1 in wild-type gastric mucosa, a gene signature common in gp130(757F/F) and HKbeta-/- tumors as well as nonneoplastic mucosa of gastric cancer patients. One week of chronic IL-11 administration in wild-type mice sustained the gene signature, causing pretumorigenic changes in both antrum and fundus. Increased gastric IL-11 alters expression of proliferative and cytoprotective genes and promotes pretumorigenic cellular changes.


Differential trajectory of functional recovery and determinants for first time stroke survivors by using a LCGA approach: a hospital based analysis over a 1-year period.
Functional outcome and the risk factors for stroke survivors have explored in previous study. However, a comprehensive understanding of the patterns and critical risk factors of functional recovery is limited. To explore the trajectory groups and determinants of functional recovery for ischemic stroke patients during 1 year after stroke. Longitudinal study. Inpatient. First-time stroke patients. A total of 367 first-time ischemic stroke patients from the Stroke Registry in the Chang Gung Hospital (SRICH) database were analyzed in this study. Study variables comprised demographic and disease characteristics, laboratory data, and functional outcome. The Latent Class Growth Analysis (LCGA) was used to identify various trajectory clusters and multinomial logistic regression was used to identify the predictors of functional recovery. Five trajectory clusters of functional recovery were identified using the Barthel Index. Among five clusters of functional recovery, nearly 18% of first-ever ischemic stroke patients maintained functional dependence, whereas 82% of stroke patients demonstrated functional recovery; and the significant recovery time totaled three months after the stroke. Determinants for various trajectory clusters of functional recovery were body mass index and serum albumin level, especially a higher serum albumin concentration predicted a more favorable functional recovery. Our findings suggest that diverse functional recovery clusters persisted and serum albumin concentration at admission was a critical assessment factor. CLINICAL REHABILITATION: Such information could be useful for identifying the different rehabilitation needs of varying trajectory groups and for effectively improving functional ability among the ischemic stroke population.


Does Emotional Arousal Influence Swearing Fluency?
This study assessed the effect of experimentally manipulated emotional arousal on swearing fluency. We hypothesised that swear word generation would be increased with raised emotional arousal. The emotional arousal of 60 participants was manipulated by having them play a first-person shooter video game or, as a control, a golf video game, in a randomised order. A behavioural measure of swearing fluency based on the Controlled Oral Word Association Test was employed. Successful experimental manipulation was indicated by raised State Hostility Questionnaire scores after playing the shooter game. Swearing fluency was significantly greater after playing the shooter game compared with the golf game. Validity of the swearing fluency task was demonstrated via positive correlations with self-reported swearing fluency and daily swearing frequency. In certain instances swearing may represent a form of emotional expression. This finding will inform debates around the acceptability of using taboo language.


The longitudinal relationship between control over working hours and depressive symptoms: Results from SLOSH, a population-based cohort study.
Psychosocial work factors can affect depressive moods, but research is inconclusive if flexibility to self-determine working hours (work-time control, WTC) is associated with depressive symptoms over time. We investigated if either sub-dimension of WTC, control over daily hours and control over time off, was related to depressive symptoms over time and examined causal, reversed-causal, and reciprocal pathways. The study was based on four waves of the Swedish Longitudinal Occupational Survey of Health which is a follow-up of representative samples of the Swedish working population. WTC was measured using a 5-item index. Depressive symptoms were assessed with a brief subscale of the Symptom Checklist. Latent growth curve models and cross-lagged panel models were tested. Best fit was found for a model with correlated intercepts (control over daily hours) and both correlated intercepts and slopes (control over time off) between WTC and depressive symptoms, with stronger associations for control over time off. Causal models estimating impacts from WTC to subsequent depressive symptoms were best fitting, with a standardised coefficient between -0.023 and -0.048. Results were mainly based on self-report data and mean age in the study sample was relatively high. Higher WTC was related to fewer depressive symptoms over time albeit small effects. Giving workers control over working hours - especially over taking breaks and vacation - may improve working conditions and buffer against developing depression, potentially by enabling workers to recover more easily and promoting work-life balance.


Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus.
Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.


Profound biopterin oxidation and protein tyrosine nitration in tissues of ApoE-null mice on an atherogenic diet: contribution of inducible nitric oxide synthase.
Diminished nitric oxide (NO) bioactivity and enhanced peroxynitrite formation have been implicated as major contributors to atherosclerotic vascular dysfunctions. Hallmark reactions of peroxynitrite include the accumulation of 3-nitrotyrosine (3-NT) in proteins and oxidation of the NO synthase (NOS) cofactor, tetrahydrobiopterin (BH(4)). The present study sought to 1) quantify the extent to which 3-NT accumulates and BH(4) becomes oxidized in organs of apolipoprotein E-deficient (ApoE(-/-)) atherosclerotic mice and 2) determine the specific contribution of inducible NOS (iNOS) to these processes. Whereas protein 3-NT and oxidized BH(4) were undetected or near the detection limit in heart, lung, and kidney of 3-wk-old ApoE(-/-) mice or ApoE(-/-) mice fed a regular chow diet for 24 wk, robust accumulation was evident after 24 wk on a Western (atherogenic) diet. Since 3-NT accumulation was diminished 3- to 20-fold in heart, lung, and liver in ApoE(-/-) mice missing iNOS, iNOS-derived species are involved in this reaction. In contrast, iNOS-derived species did not contribute to elevated protein 3-NT formation in kidney or brain. iNOS deletion also afforded marked protection against BH(4) oxidation in heart, lung, and kidney of atherogenic ApoE(-/-) mice but not in brain or liver. These findings demonstrate that iNOS-derived species are increased during atherogenesis in ApoE(-/-) mice and that these species differentially contribute to protein 3-NT accumulation and BH(4) oxidation in a tissue-selective manner. Since BH(4) oxidation can switch the predominant NOS product from NO to superoxide, we predict that progressive NOS uncoupling is likely to drive atherogenic vascular dysfunctions.


Unraveling the ECM-Immune Cell Crosstalk in Skin Diseases.
The extracellular matrix (ECM) is a complex network of proteins and proteoglycans secreted by keratinocytes, fibroblasts and immune cells. The function of the skin ECM has expanded from being a scaffold that provides structural integrity, to a more dynamic entity that is constantly remodeled to maintain tissue homeostasis. The ECM functions as ligands for cell surface receptors such as integrins, dystroglycans, and toll-like receptors (TLRs) and regulate cellular signaling and immune cell dynamics. The ECM also acts as a sink for growth factors and cytokines, providing critical cues during epithelial morphogenesis. Dysregulation in the organization and deposition of ECMs lead to a plethora of pathophysiological conditions that are exacerbated by aberrant ECM-immune cell interactions. In this review, we focus on the interplay between ECM and immune cells in the context of skin diseases and also discuss state of the art therapies that target the key molecular players involved.


Low-dose developmental bisphenol A exposure alters fatty acid metabolism in Fischer 344 rat offspring.
Bisphenol A (BPA) is an endocrine disruptor and also a suggested obesogen and metabolism-disrupting chemical. Accumulating data indicates that the fatty acid (FA) profile and their ratios in plasma and other metabolic tissues are associated with metabolic disorders. Stearoyl-CoA desaturase 1 (SCD-1) is a key regulator of lipid metabolism and its activity can be estimated by dividing the FA product by its precursor measured in blood or other tissues. The primary aim of this study was to investigate the effect of low-dose developmental BPA exposure on tissue-specific FA composition including estimated SCD-1 activity, studied in 5- and 52-week (wk)-old Fischer 344 (F344) rat offspring. Pregnant F344 rats were exposed to BPA via their drinking water corresponding to 0: [CTRL], 0.5: [BPA0.5], or 50 µg/kg BW/day: [BPA50], from gestational day 3.5 until postnatal day 22. BPA0.5 increased SCD-16 (estimated as the 16:1n-7/16:0 ratio) and SCD-18 (estimated as the 18:1n-9/18:0 ratio) indices in inguinal white adipose tissue triglycerides (iWAT-TG) and in plasma cholesterol esters (PL-CE), respectively, in 5-wk-old male offspring. In addition, BPA0.5 altered the FA composition in male offspring, e.g. by decreasing levels of the essential polyunsaturated FA linoleic acid (18:2n-6) in iWAT-and liver-TG. No differences were observed regarding the studied FAs in 52-wk-old offspring, although a slightly increased BW was observed in 52-wk-old female offspring. Low-dose developmental BPA exposure increased SCD-16 in iWAT-TG and SCD-18 in PL-CE of male offspring, which may reflect higher SCD-1 activity in these tissues. Altered desaturation activity and signs of altered FA composition are novel findings that may indicate insulin resistance in the rat offspring. These aforementioned results, together with the observed increased BW, adds to previously published data demonstrating that BPA can act as a metabolism disrupting chemical.


Interpersonal conflict and referrals to counseling among married soldiers following return from deployment.
Deployment represents a significant potential strain on military families. The impact of postdeployment stresses may be increased if family coping resources are diminished by returning service members' physical injuries, mental health issues, or substance abuse. This article examines the health and mental health correlates of self-reported concerns regarding interpersonal conflict among married soldiers following return from deployment and the likelihood that soldiers acknowledging such concerns are referred to counseling services. Among 20,166 married Army soldiers completing Post-Deployment Health Reassessments, 18% reported having experienced serious interpersonal conflict with their spouse, family members, close friends, or coworkers. Results indicate that interpersonal conflict was more common among those who reported health problems, depression, post-traumatic stress disorder, and alcohol abuse. Among soldiers reporting interpersonal conflict and not already receiving services, 11% were referred to service. Findings support the need to communicate with soldiers and their spouses about the availability of services following return from deployment and to continue efforts to reduce stigma associated with seeking treatment.


Fertility of frozen sex-sorted sperm at 4 × 106 sperm per dose in lactating dairy cows in seasonal-calving pasture-based herds.
The objective was to evaluate the reproductive performance of frozen sex-sorted sperm at 4 × 106 sperm per dose (SexedULTRA 4M, Sexing Technologies, Navasota, TX) relative to frozen conventional sperm in seasonal-calving pasture-based dairy cows. Semen from Holstein-Friesian (n = 8) and Jersey (n = 2) bulls was used. Four of the Holstein bulls used were resident at or near a sex-sorting laboratory (Cogent, UK, or ST Benelux, the Netherlands). The remaining 6 bulls were located at studs in Ireland. For these 6 bulls, ejaculates were collected, diluted with transport medium, and couriered to Cogent in parcel shippers. Transit time from ejaculation to arrival at the sorting laboratory was 6 to 7 h. For all bulls, ejaculates were split and processed to provide frozen conventional sperm (CONV) at 15 × 106 sperm per straw and frozen sex-sorted (SS) sperm at 4 × 106 sperm per straw and used to inseminate lactating dairy cows after spontaneous estrus. Pregnancy diagnosis was performed by ultrasound scanning (n = 7,246 records available for analysis). Generalized linear mixed models were used to examine effects on pregnancy per AI (P/AI) at first artificial insemination, with sperm treatment (CONV vs. SS), bull (n = 10), and treatment × bull interaction as the fixed effects, and herd (n = 142) as a random effect. Overall, P/AI was greater for cows inseminated with CONV than for those inseminated with SS (59.9% vs. 45.5%; 76.0% relative to CONV). This study was not designed to compare resident bulls vs. shipped ejaculates, but the magnitude of the difference between P/AI achieved by CONV and SS was apparently less for resident bulls (60.3% vs. 50.2%) than for shipped ejaculates (58.6% vs. 40.7%). We discovered a treatment × bull interaction for shipped ejaculates (P/AI ranged from 45 to 86% relative to CONV) but not for the resident bulls (P/AI ranged from 81 to 87% relative to CONV). Relative P/AI of SS compared with CONV was greater in cows with high or average fertility potential (76.1% and 78.3%, respectively) than in cows with low fertility potential (58.1%). In 33.1% of the enrolled herds, the P/AI achieved with SS was 90% or more of the P/AI achieved with CONV; this was mainly explained by herds in which SS performed exceptionally well but CONV performed poorly. In conclusion, SS had lower overall P/AI compared with CONV; however, P/AI achieved with SS was dependent on the bull, fertility potential of the cow, and herd. Strategies to improve the P/AI with SS in seasonal-calving pasture-based lactating dairy cows require further research.


A novel biomimetic treatment for an improved osteointegration of titanium.
Direct osteointegration of titanium and titanium alloys implants is one of the main goals of biomaterials research for dental and orthopedic applications. Chemical, mechanical or biological treatments are investigated searching for fast and durable implant to bone bonding. The aim of the present work is to assess the in vitro mineralisation capabilities and to investigate the mechanical and physico-chemical properties of a new biomimetic treatment on titanium. The new surface treatment was obtained using Anodic Spark Deposition technique, and consists of a first ASD treatment performed in solutions containing phosphate ions followed by a second ASD treatment in a solution rich in calcium ions. The resulting surface is finally treated by alkali etching. The physio-chemical and mechanical properties of this material are analyzed and the mineralization potential is considered by surface analysis after soaking it in different solutions of simulated body fluid (SBF). The developed biomimetic treatment was then compared to other treatments from the literature. The proposed treatment was found to possess a very high mineralization capaci-ty, that makes its application very interesting in terms of speed and strength of direct implant osteointegration. (Journal of Ap-plied Biomaterials & Biomechanics 2003; 1: 33-42).


A Decade of Gabapentinoid Misuse: An Analysis of the European Medicines Agency's 'Suspected Adverse Drug Reactions' Database.
The gabapentinoids pregabalin and gabapentin are being increasingly prescribed for a range of clinical conditions. Recently, although gabapentinoids at therapeutic dosages may present with low addictive liability levels, cases of misuse and rising numbers of related fatalities have been reported. The aim of the study was to identify and assess cases of gabapentinoid misuse or dependence as reported to the European Medicines Agency's EudraVigilance database, to identify the magnitude of this problem and the characteristics of these reactions. All spontaneous reports of both gabapentin- (2004-2015) and pregabalin- (2006-2015) related misuse/abuse/dependence were retrieved. A descriptive analysis by source, sex, age, and type of report was performed. From the EudraVigilance database 7639 (6.6 % of a total of 115,616) and 4301 (4.8 % of 90,166) adverse drug reaction reports of misuse/abuse/dependence were, respectively, associated with pregabalin and gabapentin, with an overall reporting frequency increasing over time. For both molecules, subjects typically involved were female adults. A total of 27 and 86 fatalities, respectively, associated with pregabalin and gabapentin, and mostly in combination with opioids, were identified. Analysis of proportional reporting ratios for drug abuse/dependence/intentional product misuse values seem to indicate that these adverse drug reactions were more frequently reported for pregabalin (1.25, 1.39, and 1.58, respectively) compared with gabapentin. Despite data collection/methodological approach limitations, the present data seem to suggest that gabapentinoid misuse may be a cause for concern, especially in patients with a history of substance misuse. Hence, healthcare professionals should be vigilant when prescribing these molecules.


Determination of Common Adulterants in Herbal Medicine and Food Samples using Core-shell Column Coupled to Tandem Mass Spectrometry.
High-performance liquid chromatography coupled to tandem mass spectrometry was used to develop and validate a rapid method to qualitatively and quantitatively analyse 18 common adulterants in herbal medicine and food samples. Initially, the mobile phase composition was optimized in three different columns: core-shell, monolithic and standard 3.5-µm-particle-size columns. The results show that the core-shell column provides the best separation. Moreover, the tandem mass spectrometry was optimized. The linear range for all adulterants was 0.5-500 μg mL-1. Finally, the samples that were supplied by the Public Authority of Customer Protection, Ministry of Health, and those collected from the local market were analysed. The results indicate that 7 of 33 analysed samples contained adulterants. The adulterated samples mainly contain sildenafil, tadalafil or vardenafil. The concentrations of these three adulterants in the samples were 0.18-39 wt%. This study is the first report in the Sultanate of Oman about adulteration in herbal medicine and food samples. The results clearly raise some concern and require proper plan of action to increase public awareness about this serious issue.


Negative impact of prolonged cold storage time before machine perfusion preservation in donation after circulatory death kidney transplantation.
Kidney grafts are often preserved initially in static cold storage (CS) and subsequently on hypothermic machine perfusion (MP). However, the impact of CS/MP time on transplant outcome remains unclear. We evaluated the effect of prolonged CS/MP time in a single-center retrospective cohort of 59 donation after circulatory death (DCD) and 177 matched donation after brain death (DBD) kidney-alone transplant recipients. With mean overall CS/MP times of 6.0 h/30.0 h, overall incidence of delayed graft function (DGF) was higher in DCD transplants (30.5%) than DBD transplants (7.3%, P < 0.0001). In logistic regression, DCD recipient (P < 0.0001), longer CS time (P = 0.0002), male recipient (P = 0.02), and longer MP time (P = 0.08) were associated with higher DGF incidence. In evaluating the joint effects of donor type (DBD vs. DCD), CS time (<6 vs. ≥6 h), and MP time (<36 vs. ≥36 h) on DGF incidence, one clearly sees an unfavorable effect of MP time ≥36 h (P = 0.003) across each donor type and CS time stratum, whereas the unfavorable effect of CS time ≥6 h (P = 0.01) is primarily seen among DCD recipients. Prolonged cold ischemia time had no unfavorable effect on renal function or graft survival at 12mo post-transplant. Long CS/MP time detrimentally affects early DCD/DBD kidney transplant outcome when grafts were mainly preserved by MP; prolonged CS time before MP has a particularly negative impact in DCD kidney transplantation.


Managing migraine headaches experienced by patients who self-report with menstrually related migraine: a prospective, placebo-controlled study with oral sumatriptan.
The objective was to evaluate the efficacy and tolerability of oral sumatriptan (100 mg) in patients who self-reported with menstrually related migraine. A prospective, multicentre, randomised, double-blind, placebo-controlled, two-group crossover study was carried out in 20 UK primary and secondary care surgeries. Of 115 patients with a self-reported history of menstrually related migraine that entered the study, 93 patients completed it. Patients treated all migraine attacks for 2 months with sumatriptan (100 mg) and for 2 months with placebo. The primary endpoint was the proportion of patients reporting headache relief at 4 hours for the first treated attack. Only 11% of patients fulfilled the protocol definition of menstrually related migraine. Patients reported a variable pattern of migraine attacks occurring inside and outside the menstrual window. For the first attack, significantly more patients receiving sumatriptan than placebo reported headache relief for attacks occurring inside (67% vs. 33%, p=0.007) and outside (79% vs. 31%, p<0.001) the menstrual period. Sumatriptan was generally well tolerated. Oral sumatriptan (100 mg) is an effective and well tolerated acute treatment for patients who report menstrually related migraine.


Optimal Dose of Perineural Dexamethasone to Prolong Analgesia After Brachial Plexus Blockade: A Systematic Review and Meta-analysis.
Perineural dexamethasone has gained popularity in regional anesthesia to prolong analgesia duration. However, uncertainty remains regarding the optimal perineural dose. Clarification of this characteristic is of significant importance as the administration of dexamethasone may lead to dose-dependent complications. The objective of this meta-analysis was to define the optimal perineural dexamethasone dose to prolong analgesia after brachial plexus blockade for adult patients undergoing upper limb surgery. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines and searched databases including MEDLINE, PubMed, and EMBASE until January 2017, without language restriction. Only trials comparing perineural dexamethasone and local anesthetics with local anesthetics alone for brachial plexus blocks were included in the present meta-analysis. The Cochrane Collaboration's Risk of Bias Tool was used to assess the methodological quality of each trial and meta-analyses were performed following a random effects model. The primary outcome was duration of analgesia for each type of local anesthetic (short-/intermediate-acting and long-acting local anesthetics). A meta-regression followed by a subgroup analysis were performed to assess the impact of different perineural dexamethasone doses on duration of analgesia; for the latter analysis, trials were grouped in low (1-4 mg) and moderate (5-10 mg) dexamethasone doses. Secondary outcomes included the rate of neurologic complication and resting pain scores and morphine consumption within the first 24 hours. Thirty-three controlled trials, including 2138 patients, were identified. The meta-regression revealed a ceiling effect with a perineural dexamethasone dose of 4 mg when combined with short-/intermediate-acting (8 trials; 366 participants) or long-acting local anesthetics (23 trials; 1869 participants). This finding was confirmed by subgroup analyses comparing low and moderate dexamethasone doses. With short-/intermediate-acting local anesthetics, the mean difference (95% confidence interval) of analgesia duration with low and moderate doses was 277 (234-322) minutes and 229 (161-297) minutes, respectively. With long-acting local anesthetics, the mean differences with low and moderate doses were 505 (342-669) minutes and 509 (443-575) minutes. Perineural dexamethasone did not increase the rate of neurologic complications (risk ratio [95% confidence interval], 1.40 [0.54-3.63]). The Grades of Recommendation, Assessment, Development, and Evaluation quality of evidence for the primary and secondary outcomes were very low, due mainly to limitations, inconsistency, indirectness, and publication bias. There is currently very low quality evidence that 4 mg of perineural dexamethasone represents a ceiling dose that prolongs analgesia duration by a mean period of 6 and 8 hours when combined with short-/intermediate- or long-acting local anesthetics, respectively. Additional data are needed to explore the threshold for this effect, particularly with doses below 4 mg. The risk of neurologic complications is probably not increased (very low evidence).


The prognostic implication and potential role of BRAF mutation in the decision to perform elective neck dissection for thyroid cancer.
The BRAF V600E mutation is the most common genetic change in patients with papillary thyroid cancer (PTC). Many studies have shown that detection of the BRAF V600E mutation is useful for confirming or establishing the preoperative diagnosis of PTC. Moreover, the mutation is associated with aggressive tumor characteristics or poor prognostic factors in most. However, whether preoperative detection of this mutation changes the treatment strategy or surgical extent, including prophylactic central neck dissection (CND), remains controversial. In this paper, we review the currently available literature regarding the potential role of the BRAF V600E mutation in the decision to perform elective neck dissection for PTC.


Comparative analysis of outcome measures used in examining neurodevelopmental effects of early childhood anesthesia exposure.
Immature animals exposed to anesthesia display apoptotic neurodegeneration and neurobehavioral deficits. The safety of anesthetic agents in children has been evaluated using a variety of neurodevelopmental outcome measures with varied results. The authors used data from the Western Australian Pregnancy Cohort (Raine) Study to examine the association between exposure to anesthesia in children younger than 3 yr of age and three types of outcomes at age of 10 yr: neuropsychological testing, International Classification of Diseases, 9th Revision, Clinical Modification-coded clinical disorders, and academic achievement. The authors' primary analysis was restricted to children with data for all outcomes and covariates from the total cohort of 2,868 children born from 1989 to 1992. The authors used a modified multivariable Poisson regression model to determine the adjusted association of anesthesia exposure with outcomes. Of 781 children studied, 112 had anesthesia exposure. The incidence of deficit ranged from 5.1 to 7.8% in neuropsychological tests, 14.6 to 29.5% in International Classification of Diseases, 9th Revision, Clinical Modification-coded outcomes, and 4.2 to 11.8% in academic achievement tests. Compared with unexposed peers, exposed children had an increased risk of deficit in neuropsychological language assessments (Clinical Evaluation of Language Fundamentals Total Score: adjusted risk ratio, 2.47; 95% CI, 1.41 to 4.33, Clinical Evaluation of Language Fundamentals Receptive Language Score: adjusted risk ratio, 2.23; 95% CI, 1.19 to 4.18, and Clinical Evaluation of Language Fundamentals Expressive Language Score: adjusted risk ratio, 2.00; 95% CI, 1.08 to 3.68) and International Classification of Diseases, 9th Revision, Clinical Modification-coded language and cognitive disorders (adjusted risk ratio, 1.57; 95% CI, 1.18 to 2.10), but not academic achievement scores. When assessing cognition in children with early exposure to anesthesia, the results may depend on the outcome measure used. Neuropsychological and International Classification of Diseases, 9th Revision, Clinical Modification-coded clinical outcomes showed an increased risk of deficit in exposed children compared with that in unexposed children, whereas academic achievement scores did not. This may explain some of the variation in the literature and underscores the importance of the outcome measures when interpreting studies of cognitive function.


Technoeconomic analysis of semicontinuous bioreactor production of biopharmaceuticals in transgenic rice cell suspension cultures.
Biopharmaceutical protein production using transgenic plant cell bioreactor processes offers advantages over microbial and mammalian cell culture platforms in its ability to produce complex biologics with simple chemically defined media and reduced biosafety concerns. A disadvantage of plant cells from a traditional batch bioprocessing perspective is their slow growth rate which has motivated us to develop semicontinuous and/or perfusion processes. Although the economic benefits of plant cell culture bioprocesses are often mentioned in the literature, to our knowledge no rigorous technoeconomic models or analyses have been published. Here we present technoeconomic models in SuperPro Designer® for the large-scale production of recombinant butyrylcholinesterase (BChE), a prophylactic/therapeutic bioscavenger against organophosphate nerve agent poisoning, in inducible transgenic rice cell suspension cultures. The base facility designed to produce 25 kg BChE per year utilizing two-stage semicontinuous bioreactor operation manufactures a single 400 mg dose of BChE for $263. Semicontinuous operation scenarios result in 4-11% reduction over traditional two-stage batch operation scenarios. In addition to providing a simulation tool that will be useful to the plant-made pharmaceutical community, the model also provides a computational framework that can be used for other semicontinuous or batch bioreactor-based processes.


Asymmetric responses of primary productivity to precipitation extremes: A synthesis of grassland precipitation manipulation experiments.
Climatic changes are altering Earth's hydrological cycle, resulting in altered precipitation amounts, increased interannual variability of precipitation, and more frequent extreme precipitation events. These trends will likely continue into the future, having substantial impacts on net primary productivity (NPP) and associated ecosystem services such as food production and carbon sequestration. Frequently, experimental manipulations of precipitation have linked altered precipitation regimes to changes in NPP. Yet, findings have been diverse and substantial uncertainty still surrounds generalities describing patterns of ecosystem sensitivity to altered precipitation. Additionally, we do not know whether previously observed correlations between NPP and precipitation remain accurate when precipitation changes become extreme. We synthesized results from 83 case studies of experimental precipitation manipulations in grasslands worldwide. We used meta-analytical techniques to search for generalities and asymmetries of aboveground NPP (ANPP) and belowground NPP (BNPP) responses to both the direction and magnitude of precipitation change. Sensitivity (i.e., productivity response standardized by the amount of precipitation change) of BNPP was similar under precipitation additions and reductions, but ANPP was more sensitive to precipitation additions than reductions; this was especially evident in drier ecosystems. Additionally, overall relationships between the magnitude of productivity responses and the magnitude of precipitation change were saturating in form. The saturating form of this relationship was likely driven by ANPP responses to very extreme precipitation increases, although there were limited studies imposing extreme precipitation change, and there was considerable variation among experiments. This highlights the importance of incorporating gradients of manipulations, ranging from extreme drought to extreme precipitation increases into future climate change experiments. Additionally, policy and land management decisions related to global change scenarios should consider how ANPP and BNPP responses may differ, and that ecosystem responses to extreme events might not be predicted from relationships found under moderate environmental changes.


ATR-Chk1-APC/CCdh1-dependent stabilization of Cdc7-ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress.
Cdc7 kinase regulates DNA replication. However, its role in DNA repair and recombination is poorly understood. Here we describe a pathway that stabilizes the human Cdc7-ASK (activator of S-phase kinase; also called Dbf4), its regulation, and its function in cellular responses to compromised DNA replication. Stalled DNA replication evoked stabilization of the Cdc7-ASK (Dbf4) complex in a manner dependent on ATR-Chk1-mediated checkpoint signaling and its interplay with the anaphase-promoting complex/cyclosome(Cdh1) (APC/C(Cdh1)) ubiquitin ligase. Mechanistically, Chk1 kinase inactivates APC/C(Cdh1) through degradation of Cdh1 upon replication block, thereby stabilizing APC/C(Cdh1) substrates, including Cdc7-ASK (Dbf4). Furthermore, motif C of ASK (Dbf4) interacts with the N-terminal region of RAD18 ubiquitin ligase, and this interaction is required for chromatin binding of RAD18. Impaired interaction of ASK (Dbf4) with RAD18 disables foci formation by RAD18 and hinders chromatin loading of translesion DNA polymerase η. These findings define a novel mechanism that orchestrates replication checkpoint signaling and ubiquitin-proteasome machinery with the DNA damage bypass pathway to guard against replication collapse under conditions of replication stress.


Lenalidomide monotherapy and in combination with cytarabine, daunorubicin and etoposide for high-risk myelodysplasia and acute myeloid leukaemia with chromosome 5 abnormalities.
Patients with high risk myelodysplasia (HR-MDS) and acute myeloid leukaemia (AML) with chromosomal changes involving deletion of the long arm of chromosome 5 (del5q), especially with complex karyotype, rarely have a durable response to combination chemotherapy. In the subgroup with monosomal karyotype there are no long term survivors (Fang et al., 2011) [1]. Recent experience indicates that the incidence of del5q in AML is ~20-30%, with only 20-25% of patients achieving complete remission (CR) (Farag et al., 2006) [2]. Additionally, therapy has significant toxicity, with induction death rates ~20% even in younger patients (Juliusson et al., 2009) [3]. This lack of efficacy provides the clinical rationale for combination/sequential therapy with Lenalidomide and combination chemotherapy. Dose dependent haematological toxicity is the major safety concern with such a combination protocol. Therefore we conducted a phase 2 study, AML Len5 (ISRCTN58492795), to assess safety, tolerability and efficacy of lenalidomide monotherapy, followed by lenalidomide with intensive chemotherapy in patients with primary/relapsed/refractory high risk MDS or AML with abnormalities of chromosome 5.


Effects of maternal vitamin B12 supplementation on early infant neurocognitive outcomes: a randomized controlled clinical trial.
Maternal nutritional status during pregnancy impacts fetal brain development. Vitamin B12 plays a vital role in neuronal development. However, findings from studies on the association between maternal B12 status and child cognitive functions have been inconsistent. We performed a randomized, placebo-controlled clinical trial of oral B12 supplementation (50 µg) beginning at <14 weeks of gestation through a 6-week post-partum. In the present study, we report the effects of maternal B12 supplementation on cognitive development in infants at 9 months of age on Bayley Scales of Infant Development-III (BSID-III). One hundred eighty-three pregnant women received vitamin B12, and 183 received placebo. Nine-month BSID-III development score was available in 178 infants. There were no significant differences in maternal sociodemographic characteristics and baseline biochemical measures between infants who underwent BSID-III evaluation and infants who were not evaluated. There were no significant differences in any of the subscales of BSID-III between infants born to mothers who received B12 supplementation (n = 78) vs. placebo (n = 100). On multiple regression analysis, elevated maternal total homocysteine (tHcy) levels adjusted for treatment group, birthweight, parity, income and home environment at second trimester of pregnancy were significantly negatively associated with expressive language (β = 3.13 points, P < 0.001), and in third trimester of pregnancy with expressive language (β = -2.29 points, P < 0.001) and fine motor (β = -1.41 points, P = 0.005) domains of BSID-III. While no significant effects of maternal B12 supplementation were seen on cognitive development in infants at 9 months of age, elevated maternal tHcy levels were associated with poorer cognitive performance in some of the subdomains of BSID-III. In pregnant women with elevated tHcy levels and or B12 deficiencies, it may be worthwhile to study the impact of longer term maternal supplementation on infant cognitive outcomes.


Continuous support for women during childbirth.
Historically, women have been attended and supported by other women during labour. However, in hospitals worldwide, continuous support during labour has become the exception rather than the routine. Primary: to assess the effects of continuous, one-to-one intrapartum support compared with usual care. Secondary: to determine whether the effects of continuous support are influenced by: (1) routine practices and policies; (2) the provider's relationship to the hospital and to the woman; and (3) timing of onset. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2012). All published and unpublished randomised controlled trials comparing continuous support during labour with usual care. We used standard methods of The Cochrane Collaboration Pregnancy and Childbirth Group. Two review authors independently evaluated methodological quality and extracted the data. We sought additional information from the trial authors. We used random-effects analyses for comparisons in which high heterogeneity was present, and we reported results using the average risk ratio (RR) for categorical data and mean difference (MD) for continuous data. Twenty-two trials involving 15,288 women met inclusion criteria and provided usable outcome data. Results are of random-effects analyses, unless otherwise noted. Women allocated to continuous support were more likely to have a spontaneous vaginal birth (RR 1.08, 95% confidence interval (CI) 1.04 to 1.12) and less likely to have intrapartum analgesia (RR 0.90, 95% CI 0.84 to 0.96) or to report dissatisfaction (RR 0.69, 95% CI 0.59 to 0.79). In addition, their labours were shorter (MD -0.58 hours, 95% CI -0.85 to -0.31), they were less likely to have a caesarean (RR 0.78, 95% CI 0.67 to 0.91) or instrumental vaginal birth (fixed-effect, RR 0.90, 95% CI 0.85 to 0.96), regional analgesia (RR 0.93, 95% CI 0.88 to 0.99), or a baby with a low five-minute Apgar score (fixed-effect, RR 0.69, 95% CI 0.50 to 0.95). There was no apparent impact on other intrapartum interventions, maternal or neonatal complications, or breastfeeding. Subgroup analyses suggested that continuous support was most effective when the provider was neither part of the hospital staff nor the woman's social network, and in settings in which epidural analgesia was not routinely available. No conclusions could be drawn about the timing of onset of continuous support. Continuous support during labour has clinically meaningful benefits for women and infants and no known harm. All women should have support throughout labour and birth.


A novel aqueous micellar two-phase system composed of surfactant and sorbitol for purification of pectinase enzyme from Psidium guajava and recycling phase components.
A novel aqueous two-phase system composed of a surfactant and sorbitol was employed for the first time to purify pectinase from Psidium guajava. The influences of different parameters, including the type and concentration of the surfactant and the concentration and composition of the surfactant/sorbitol ratio, on the partitioning behavior and recovery of pectinase were investigated. Moreover, the effects of system pH and the crude load on purification fold and the yield of purified pectinase were studied. The experimental results indicated that the pectinase was partitioned into surfactant-rich top phase, and the impurities were partitioned into the sorbitol-rich bottom phase with the novel method involving an ATPS composed of 26% (w/w) Triton X-100 and 23% (w/w) sorbitol at 54.2% of the TLL crude load of 20% (w/w) at pH 6.0. The enzyme was successfully recovered by this method with a high purification factor of 15.2 and a yield of 98.3%, whereas the phase components were also recovered and recycled at rates above 96%. This study demonstrated that this novel ATPS method can be used as an efficient and economical alternative to the traditional ATPS for the purification and recovery of the valuable enzyme.


Health effects of fluoride pollution caused by coal burning.
Recently a huge amount of fluoride in coal has been released into indoor environments by the combustion of coal and fluoride pollution seems to be increasing in some rural areas in China. Combustion of coal and coal bricks is the primary source of gaseous and aerosol fluoride and these forms of fluoride can easily enter exposed food products and the human respiratory tract. Major human fluoride exposure was caused by consumption of fluoride contaminated food, such as corn, chilies and potatoes. For each diagnostic syndrome of dental fluorosis, a log-normal distribution was observed on the logarithm of urinary fluoride concentration in students in China. Urinary fluoride content was found to be a primary health indicator of the prevalence of dental fluorosis in the community. In the fluorosis areas, osteosclerosis in skeletal fluorosis patients was observed with a high prevalence. A biochemical marker of bone resorption, urinary deoxypyridinoline content was much higher in residents in China than in residents in Japan. It was suggested that bone resorption was stimulated to a greater extent in residents in China and fluoride may stimulate both bone resorption and bone formation. Renal function especially glomerular filtration rate was very sensitive to fluoride exposure. Inorganic phosphate concentrations in urine were significantly lower in the residents in fluorosis areas in China than in non-fluorosis area in China and Japan. Since airborne fluoride from the combustion of coal pollutes extensively both the living environment and food, it is necessary to reduce fluoride pollution caused by coal burning.


Dark Classics in Chemical Neuroscience: Mescaline.
Archeological studies in the United States, Mexico, and Peru suggest that mescaline, as a cactus constituent, has been used for more than 6000 years. Although it is a widespread cactus alkaloid, it is present in high concentrations in few species, notably the North American peyote ( Lophophora williamsii) and the South American wachuma ( Trichocereus pachanoi, T. peruvianus, and T. bridgesii). Spanish 16th century chroniclers considered these cacti "diabolic", leading to their prohibition, but their use persisted to our days and has been spreading for the last 150 years. In the late 1800s, peyote attracted scientific attention; mescaline was isolated, and its role in the psychedelic effects of peyote tops or "mescal buttons" was demonstrated. Its structure was established by synthesis in 1929, and alternative routes were developed, providing larger amounts for pharmacological and biosynthetic research. Although its effects are attributed mainly to its action as a 5-HT2A serotonin receptor agonist, mescaline binds in a similar concentration range to 5-HT1A and α2A receptors. It is largely excreted unchanged in human urine, and its metabolic products are apparently unrelated to its psychedelic properties. Its low potency is probably responsible for its relative neglect by recreational substance users, as the successful search for structure-activity relationships in the hallucinogen field focused largely on finding more potent analogues. Renewed interest in the possible therapeutic applications of psychedelic drugs may hopefully lead to novel insights regarding the commonalities and differences between the actions of individual classic hallucinogens.


Domestication effects on behavioural synchronization and individual distances in chickens (Gallus gallus).
Behavioural synchrony (allelomimetic behaviour), and inter-individual distances are aspects of social and anti-predator strategies which may have been affected by domestication. Chickens are known to adjust synchronization and inter-individual distances depending on behaviour. We hypothesized that White Leghorn (WL) chickens would show less synchronized behaviour than the ancestor, the red jungle fowl (RJF). Sixty birds, 15 female and 15 male WL and the same number of RJF (28 weeks old) were studied in groups of three in furnished pens (1 m×2 m) for 24 consecutive hours per group, following 24 h of habituation. Video tapes covering 4 h per group (dawn, 9-10 am, 1-2 pm and dusk) were analysed. Red junglefowl perched significantly more, but there were no breed effects on the frequency or daily rhythm of any other activities, or on average inter-individual distances. Red junglefowl were more synchronized during perching and a tendency for the same was found for social behaviour. After performance of the two most synchronized behaviours, perching and comfort behaviour, individual distance increased more for RJF than WL. According to this study domestication of chickens appears not to have significantly altered the relative frequencies of different activities or average inter-individual distances, but have caused some changes in behavioural synchronization and maintenance of activity-specific inter-individual distances in chickens. The changes may indicate an adaptive response to captivity and domestication.


ATLS(R) and damage control in spine trauma.
Substantial inflammatory disturbances following major trauma have been found throughout the posttraumatic course of polytraumatized patients, which was confirmed in experimental models of trauma and in vitro settings. As a consequence, the principle of damage control surgery (DCS) has developed over the last two decades and has been successfully introduced in the treatment of severely injured patients. The aim of damage control surgery and orthopaedics (DCO) is to limit additional iatrogenic trauma in the vulnerable phase following major injury. Considering traumatic brain and acute lung injury, implants for quick stabilization like external fixators as well as decided surgical approaches with minimized potential for additional surgery-related impairment of the patient's immunologic state have been developed and used widely. It is obvious, that a similar approach should be undertaken in the case of spinal trauma in the polytraumatized patient. Yet, few data on damage control spine surgery are published to so far, controlled trials are missing and spinal injury is addressed only secondarily in the broadly used ATLS(R) polytrauma algorithm. This article reviews the literature on spine trauma assessment and treatment in the polytrauma setting, gives hints on how to assess the spine trauma patient regarding to the ATLS(R) protocol and recommendations on therapeutic strategies in spinal injury in the polytraumatized patient.


Effects of platelet-derived growth factor and epidermal growth factor on antigen-induced proliferation of human T-cell lines.
When the serum content of tissue culture medium is reduced from 10% to 1%, the capacity of T cells to proliferate in response to antigen within that medium is dramatically reduced. Physiological concentrations of platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) are able to partially replace the requirement for serum, in that they are able to increase antigen-driven T-cell proliferation at a serum concentration of 1%. Neither growth factor is mitogenic for T cells in the absence of antigen, and neither is able to act synergistically with T-cell growth factor (TCGF) or IL-2) in the absence of antigen. Antigen-presenting cells (APC) pulsed with antigen in the presence of PDGF or EGF are able to stimulate antigen-specific T-cell proliferation to a greater extent than antigen-presenting cells pulsed in the absence of exogenous PDGF or EGF. Both growth factors increase the expression of MHC Class II antigens on antigen-presenting cells.


Common bile duct injuries during laparoscopic cholecystectomy that result in litigation.
Iatrogenic common bile duct injury is the worst complication of laparoscopic cholecystectomy. The goal of this study is to increase awareness of the problem and educate surgeons about the consequences of these injuries. A total of 46 bile duct injuries were analyzed by review of medical records, cholangiograms, videotapes, and surgeon statements. All cases were involved in malpractice litigation. All types of injuries were represented. There were 15 transections, 11 excisions, 6 lacerations, 8 clip impingements, 3 burns, 2 bile leaks, and 1 cystic duct leak. In all, 72% of these injuries occurred in elective cases in which there was no acute inflammation. Cholangiograms were performed in 16 cases, but they were misinterpreted in 11 of them. Injury type and severity was similar in patients with and without cholangiography. A total of 80% of these injuries were not detected at the initial surgery. The average delay in diagnosis was 10 days. Complications were worse in patients with delayed diagnosis. Primary surgeons had less successful outcomes from repairs than referral surgeons (27% versus 79%). In 86% of cases, litigation was resolved in favor of plaintiffs by settlement or verdicts. The average award was $214,000. Factors that predispose to lawsuits include treatment failures in immediately recognized injuries, complications that result from delays in diagnosis, and misinterpretation of abnormal cholangiograms. Injury prevention can be improved by increased awareness of common mistakes,. Improved cholangiographic technique and interpretation should decrease injury severity, delays in diagnosis, and subsequent morbidity.


"I am not telling. The mobile is telling": Factors influencing the outcomes of a community health worker mHealth intervention in India.
Improving maternal health outcomes remains a priority in Low and Middle Income Countries. With the rapid proliferation of mobile health technologies, there is an increased interest in understanding how these technologies can effectively improve maternal health outcomes particularly maternal health seeking knowledge and behaviors. However, few studies present clear explanations of the program developers' rationale (theory of change) and contextual factors that could influence program outcomes. This mixed-methods study assesses Mobile for Mothers, a community health workers (CHW) utilized maternal mHealth intervention. We present the program developers' rationale and utilize it as a framework to guide our study that aimed to identify intervention-related and contextual factors, which influence the observed outcomes of a CHW, utilized mHealth intervention. Quantitative methods (a questionnaire with 740 women who received the intervention and survey of 57 CHWs who utilized the intervention) and qualitative methods (12 interviews and 4 group discussions with CHWs and 20 interviews and 5 group discussions with pregnant and lactating women and 15 interviews and 2 group discussions with men) were conducted. These were used to understand how the mHealth intervention was implemented and to gain insight into contextual factors that potentially influenced the observed intervention outcomes. Results were grouped following three categories: (1) perceptions and experiences of CHWs utilizing the mHealth technology; (2) CHW-related outcomes; and (3) contextual factors that influence maternal health-seeking behavior. The overall response of CHWs and community members to the intervention was positive. However, contextual factors like the relationship between the CHWs and their respective communities, the pregnant women's decision-making power and lack of access due to financial influenced the observed outcomes. Mobile health applications are promising interventions for improving the performance of CHWs and health-seeking behavior of pregnant women. However, the contextual factors play a crucial role in intervention outcomes and need to be explicated by program developers during intervention design and implementation.


Ethics of palliative care in late-stage cancer management and end-of-life issues in a depressed economy.
The Hippocratic Oath has often been referred to as the ethical foundation of medical practice with the key restriction "cause no harm" which is also the principle of benevolence in bioethics. In medical profession, the Oath still exemplifies the key virtues of a doctor in its emphasis on the obligations toward the well-being of the individual patient. In management of end-stage cancer in a depressed economy such as Nigeria, we frequently encounter a wide range of ethical issues that arise in the provision of palliative care mostly due to the prevailing economic situation and cultural setting. Since most of these patients came from a lower economic class of the society, with little or no formal education and lived at a subsistence level, they often find it difficult to provide the medications needed. In a poor setting where health inequity is rife, and ignorance and poverty are commonplace, a good understanding of medical ethics with a good model of health care system will contribute to the health professional's decision-making that will be in the best interest of the patients. Physicians must protect the lives of their patients and should never hasten their death. In end-stage cancer management, we have to relieve suffering and pains, promote palliative care, and give psychological support but never abandoning the patient or initiate terminating their life. This presentation is a clinical analysis of the ethical issues regarding the management of end-stage cancer patients in a poor economy with a critical overview of end-of-life issues in African perspective.


The rs1447295 at 8q24 is a risk variant for prostate cancer in Taiwanese men.
To determine the association of a common variant, rs1447295, at the 8q24 region with prostate cancer (PCa) risk in Taiwanese men. Common variants at the 8q24 region have been shown to be associated with PCa risk. The variant rs1447295 has shown the strongest association. Most of the studies have been performed in European and American populations. This case-control study comprised 340 PCa patients and 337 controls. Genotyping was performed for rs14417295 to test for the association between its risk allele and PCa. Its association with disease stage, Gleason score, PSA level, and disease aggressiveness was also determined. The A allele of rs1447295 was significantly associated with increased PCa risk (odds ratio = 1.49, 95% CI = 1.12-1.99). When compared with controls, the risk allele A was more frequent in PCa patients of both stages I+II (P = .028) and stages III+IV (P = .023), in patients of all Gleason scores (P < .05 in all subgroups), in patients with PSA levels >20 ng/mL (P = .001), and in patients with aggressive disease (P = .005). This study confirmed that the A allele of rs1447295 is associated with a high risk of PCa in Taiwanese men.


Unitary response of mouse olfactory receptor neurons.
The sense of smell begins with odorant molecules binding to membrane receptors on the cilia of olfactory receptor neurons (ORNs), thereby activating a G protein, G(olf), and the downstream effector enzyme, an adenylyl cyclase (ACIII). Recently, we have found in amphibian ORNs that an odorant-binding event has a low probability of activating sensory transduction at all; even when successful, the resulting unitary response apparently involves a single active Gα(olf)-ACIII molecular complex. This low amplification is in contrast to rod phototransduction in vision, the best-quantified G-protein signaling pathway, where each photoisomerized rhodopsin molecule is well known to produce substantial amplification by activating many G-protein, and hence effector-enzyme, molecules. We have now carried out similar experiments on mouse ORNs, which offer, additionally, the advantage of genetics. Indeed, we found the same low probability of transduction, based on the unitary olfactory response having a fairly constant amplitude and similar kinetics across different odorants and randomly encountered ORNs. Also, consistent with our picture, the unitary response of Gα(olf)(+/-) ORNs was similar to WT in amplitude, although their Gα(olf)-protein expression was only half of normal. Finally, from the action potential firing, we estimated that ≤19 odorant-binding events successfully triggering transduction in a WT mouse ORN will lead to signaling to the brain.


The Association between Serum LDL Cholesterol and Genetic Variation in Chromosomal Locus 1p13.3 among Coronary Artery Disease Patients.
Several polymorphisms of a locus on chromosome 1p13.3 have a significant effect on low-density lipoprotein cholesterol (LDL-C), atherosclerosis, and acute coronary syndrome (ACS). We aimed to investigate the association between rs599839, rs646776, and rs4970834 of locus 1p13.3 and serum LDL-C and severity of coronary artery stenosis in ACS patients. Genotyping of the rs599839, rs646776, and rs4970834 polymorphisms was performed on Arab patients undergoing coronary angiography for ACS. Patients were divided into group A (ACS with insignificant stenosis (<50%)) and group B (with significant stenosis (≥ 50%)). Patients carrying the minor G allele in rs599839 had significantly lower mean of LDL-C (2.58 versus 3.44 mM, P = 0.026) than homozygous A allele carriers (GG versus AA). Carriers of minor C allele in rs64776 had significantly higher mean of HDL-C (2.16 versus 1.36 mM, P = 0.004) than carriers of the T alleles (AA versus GG). The odd ratio and 95% confidence interval for dominant model for G allele carriers of rs599839 were 0.51 (0.30-0.92), P = 0.038, among patients with significant stenosis. Polymorphisms rs646776 and rs599839 of locus 1p13.3 were significantly associated with LDL-C and other lipid parameters. In addition, the G-allele carriers of variant rs599839 had a significant protective effect against the atherosclerosis.


WHO study on Prevention of REcurrences of Myocardial Infarction and StrokE (WHO-PREMISE).
To determine the extent of secondary prevention of coronary heart disease (CHD) and cerebrovascular disease (CVD) in low- and middle-income countries. A descriptive cross-sectional survey of a sample of 10 000 CHD (85.2%) and CVD (14.8%) patients (6252 men; 3748 women) was conducted over 6 months in geographically defined areas. The mean age was 59.2 years (standard deviation (SD), 10.8). Consecutive patients were recruited from a stratified random sample of primary, secondary and tertiary care facilities in defined areas in 10 countries (Brazil, Egypt, India, Indonesia, Islamic Republic of Iran, Pakistan, Russian Federation, Sri Lanka, Tunisia and Turkey). The main outcome measures were levels of lifestyle and physiological risk factors, and the use of drugs for secondary prevention of CHD and CVD. Approximately 82%, 89% and 77% of patients were aware of the cardiovascular benefits of quitting smoking, a heart-healthy diet and regular physical activity, respectively. About half (52.5%) engaged in less than 30 minutes of physical activity per day, 35% did not follow a heart-healthy diet and 12.5 % were current tobacco users. Blood pressure had been measured in 93.8% (range 71-100%), blood cholesterol in 85.5% (range 29-97%) and blood sugar in 75.5% (range 65-99%) in the preceding 12 months. The proportions who had received medications among CHD and CVD patients were: aspirin, 81.2%, 70.6%; beta-blockers, 48.1%, 22.8%; angiotensin-converting enzyme inhibitor, 39.8%, 37.8%; statins, 29.8%, 14.1%, respectively. About one-fifth of patients with CHD had undergone revascularization. A significant proportion of patients did not receive appropriate medications. About 47% of patients had at least two or more modifiable risk factors (smoking, physical inactivity, hypertension, diabetes or hypercholesterolaemia). There are considerable missed opportunities for prevention of recurrences in those with established CVD in low- and middle-income countries.


Near infrared frequency comb vernier spectrometer for broadband trace gas detection.
We present a femtosecond frequency comb vernier spectrometer in the near infrared with a femtosecond Er doped fiber laser, a scanning high-finesse cavity and an InGaAs camera. By utilizing the properties of a frequency comb and a scanning high-finesse cavity such a spectrometer provides broad spectral bandwidth, high spectral resolution, and high detection sensitivity on a short time scale. We achieved an absorption sensitivity of ~8 × 10(-8) cm(-1)Hz(-1/2), corresponding to a detection limit of ~70 ppbv for acetylene, with a resolution of ~1.1 GHz in single images taken in 0.5 seconds and covering a frequency range of ~5 THz. Such measurements have broad applications for sensing greenhouse gases in this fingerprint near infrared region with a simple apparatus.


Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells.
Malignant mesothelioma (MM) is poorly responsive to systemic cytotoxic chemotherapy and invariably fatal. Here we describe a screen of 94 drugs in 15 exome-sequenced MM lines and the discovery of a subset defined by loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1) that demonstrate heightened sensitivity to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand). This association is observed across human early passage MM cultures, mouse xenografts and human tumour explants. We demonstrate that BAP1 deubiquitinase activity and its association with ASXL1 to form the Polycomb repressive deubiquitinase complex (PR-DUB) impacts TRAIL sensitivity implicating transcriptional modulation as an underlying mechanism. Death receptor agonists are well-tolerated anti-cancer agents demonstrating limited therapeutic benefit in trials without a targeting biomarker. We identify BAP1 loss-of-function mutations, which are frequent in MM, as a potential genomic stratification tool for TRAIL sensitivity with immediate and actionable therapeutic implications.


Racial/Ethnic Differences in Use of Health Care Services for Diabetes Management.
Research demonstrates consistent racial/ethnic disparities in access to and use of health care services for a variety of chronic conditions. Yet we know little about whether these disparities exist for use of health care services for diabetes management. Racial/ethnic minorities disproportionately suffer from diabetes, complications from diabetes, and diabetes-related mortality. Proper diabetes management can reduce the risk of complications and premature mortality. Using a large national data set (N = 37,705) of White, Black, Hispanic, Asian, and Native American U.S. adults aged 65 years and older who have been diagnosed with diabetes, we examine three specific types of health care provider (HCP) use for diabetes management: number of times seen by a health care professional for diabetes, number of times feet have been checked by a health care professional, and number of visits for a glycosylated hemoglobin check. We found that net of controls for a variety of demographic and socioeconomic characteristics, Blacks and Hispanics had significantly more visits to a HCP for their diabetes and significantly more glycosylated hemoglobin checks than Whites, and Blacks and Native Americans had significantly more HCP feet checks than Whites. Our results suggest that the reduced access to health care services traditionally found among racial/ethnic minorities does not hold for access to health care services for diabetes management, where racial/ethnic minority diabetics are actually more likely to use care than are White diabetics. Future research should examine whether higher use of health care services for diabetes among racial/ethnic minorities is due to greater disease severity among racial/ethnic minorities than among non-Hispanic Whites.


Lactobacillus rhamnosus from human breast milk shows therapeutic function against foodborne infection by multi-drug resistant Escherichia coli in mice.
The emergence of multi-drug resistant (MDR) pathogens greatly challenges the development of new drugs. Probiotics with the ability to inhibit MDR pathogens offer advantages over chemical antibiotics and drugs due to increased safety and fewer side effects. This study reports that Lactobacillus rhamnosus SHA113 (isolated from breast milk) significantly inhibited MDR Escherichia coli both in vitro and in vivo. MDR E. coli caused more severe inflammatory effects. TNF-α and IL-6 levels increased, while the IL-10 content decreased in serum. MDR E. coli caused disturbance in the gut microbial balance, increased the total coliform, decreased lactic acid bacteria in feces, decreased Firmicutes, and increased both Bacteroidetes and Proteobacteria. At the end of the curing treatment, ampicillin (AMP) treatment significantly reduced lactic acid bacteria compared to total coliform in feces and exacerbated the increase of Proteobacteria caused by MDR E. coli. L. rhamnosus SHA113 treatment resulted in a more significant and faster decrease of total coliform in feces and a significant decrease of Proteobacteria in the gut microbiota. The increase of total coliform in feces (caused by MDR E. coli infection) was positively correlated with IL-6 and TNF-α and negatively correlated with IL-10 in serum. However, the increase of lactic acid bacteria in feces (caused by L. rhamnosus SHA113 treatment) was negatively correlated with serum TNF-α, indicating that SHA113 exerted anti-inflammatory effects. These results suggest that L. rhamnosus SHA113 has great potential for inhibiting infections by MDR E. coli and for regulating the gut flora balance.


Impact of PD-L1 Expression in Patients with Surgically Resected Non-Small-Cell Lung Cancer.
Immunotherapy can become a crucial therapeutic option to improve the prognosis of patients with non-small-cell lung cancer (NSCLC). Here, we evaluated the impact of programmed cell death ligand-1 (PD-L1) expression in surgically resected NSCLCs. We estimated PD-L1 expression in 229 consecutive NSCLC specimens using rabbit polyclonal antibodies to human PD-L1 in a SP263 immunohistochemical assay and evaluated PD-L1 expression for potential associations with clinicopathological parameters and survival time. PD-L1 expression was significantly higher in tumors from men or current smokers. Squamous cell carcinoma histology was independently associated with high PD-L1 expression according to multivariate analysis (p = 0.015). The 5-year survival rate of patients was 70%, and the difference in the 5-year survival rate according to PD-L1 expression was not statistically significant (high expression group [67%] vs. low expression group [68%]); however, the squamous cell carcinoma group exhibited significantly lower 5-year survival rates as compared to the non-squamous cell carcinoma group (53 and 71%, respectively; p = 0.026). Here, we revealed high PD-L1 expression and poor prognosis observed in patients with surgically resected squamous NSCLC as compared with non-squamous NSCLC. Our results support the identification of patient subsets that most likely respond to anti-PD-1 therapy as the first step in precision medicine.


Proliferative activity of cyst epithelium in human renal cystic diseases.
Increased proliferative activity of the renal tubular epithelium is thought to be a prerequisite for renal cyst formation by many investigators. However, in humans, the exact in vivo proliferation rate of epithelial cells lining these cysts is not known. In this study, which used immunohistochemical methods with an antibody to proliferating cell nuclear antigen (PCNA), the proliferation index (PI) (percentage of PCNA positive cell nuclei among epithelial cells lining the renal cysts) was determined in 10 cases of autosomal dominant polycystic kidney disease (ADPKD), 8 cases of autosomal recessive polycystic kidney disease (ARPKD), and 8 cases of acquired cystic kidney disease (ACKD). Cysts with proximal and distal nephron phenotype and cysts with markedly thickened basement membranes, as well as cysts lined by atrophic (flattened), "regular" (cuboidal or cylindrical), and hyperplastic epithelium, were evaluated separately. The overall PI of cyst epithelium (excluding hyperplastic cysts) was 2.58 in ADPKD, was 10.5 in ARPKD, and was 3.61 in ACKD. Overall, there were only minor differences in the PI between the various types of cysts. Cysts with hyperplastic epithelium in ACKD (unlike in ADPKD) showed a high PI (9.1). For comparison, the PI of two renal cell carcinomas occurring in two ACKD cases was also determined (13.70 and 8.67%). The PI of tubular epithelium in normal kidneys was only 0.22 to 0.33%, depending on the tubule segment. In contrast, in polycystic kidneys, those noncystic segments of the nephron from which the cysts are thought to originate (distal nephron (specifically collecting duct)) in ARPKD, primarily distal in ADPKD, proximal and distal in ACKD, had PI values similar to those of the cyst epithelium.(ABSTRACT TRUNCATED AT 400 WORDS)


Geographic barriers to achieving universal health coverage: evidence from rural Madagascar.
Poor geographic access can persist even when affordable and well-functioning health systems are in place, limiting efforts for universal health coverage (UHC). It is unclear how to balance support for health facilities and community health workers in UHC national strategies. The goal of this study was to evaluate how a health system strengthening (HSS) intervention aimed towards UHC affected the geographic access to primary care in a rural district of Madagascar. For this, we collected the fokontany of residence (lowest administrative unit) from nearly 300 000 outpatient consultations occurring in facilities of Ifanadiana district in 2014-2017 and in the subset of community sites supported by the HSS intervention. Distance from patients to facilities was accurately estimated following a full mapping of the district's footpaths and residential areas. We modelled per capita utilization for each fokontany through interrupted time-series analyses with control groups, accounting for non-linear relationships with distance and travel time among other factors, and we predicted facility utilization across the district under a scenario with and without HSS. Finally, we compared geographic trends in primary care when combining utilization at health facilities and community sites. We find that facility-based interventions similar to those in UHC strategies achieved high utilization rates of 1-3 consultations per person year only among populations living in close proximity to facilities. We predict that scaling only facility-based HSS programmes would result in large gaps in access, with over 75% of the population unable to reach one consultation per person year. Community health delivery, available only for children under 5 years, provided major improvements in service utilization regardless of their distance from facilities, contributing to 90% of primary care consultations in remote populations. Our results reveal the geographic limits of current UHC strategies and highlight the need to invest on professionalized community health programmes with larger scopes of service.


Plk1 self-organization and priming phosphorylation of HsCYK-4 at the spindle midzone regulate the onset of division in human cells.
Animal cells initiate cytokinesis in parallel with anaphase onset, when an actomyosin ring assembles and constricts through localized activation of the small GTPase RhoA, giving rise to a cleavage furrow. Furrow formation relies on positional cues provided by anaphase spindle microtubules (MTs), but how such cues are generated remains unclear. Using chemical genetics to achieve both temporal and spatial control, we show that the self-organized delivery of Polo-like kinase 1 (Plk1) to the midzone and its local phosphorylation of a MT-bound substrate are critical for generating this furrow-inducing signal. When Plk1 was active but unable to target itself to this equatorial landmark, both cortical RhoA recruitment and furrow induction failed to occur, thus recapitulating the effects of anaphase-specific Plk1 inhibition. Using tandem mass spectrometry and phosphospecific antibodies, we found that Plk1 binds and directly phosphorylates the HsCYK-4 subunit of centralspindlin (also known as MgcRacGAP) at the midzone. At serine 157, this modification creates a major docking site for the tandem BRCT repeats of the Rho GTP exchange factor Ect2. Cells expressing only a nonphosphorylatable form of HsCYK-4 failed to localize Ect2 at the midzone and were severely impaired in cleavage furrow formation, implying that HsCYK-4 is Plk1's rate-limiting target upstream of RhoA. Conversely, tethering an inhibitor-resistant allele of Plk1 to HsCYK-4 allowed furrows to form despite global inhibition of all other Plk1 molecules in the cell. Our findings illuminate two key mechanisms governing the initiation of cytokinesis in human cells and illustrate the power of chemical genetics to probe such regulation both in time and space.


Insights into the isothiourea-catalyzed asymmetric [4 + 2] annulation of phenylacetic acid with alkylidene pyrazolone.
A density functional theory (DFT) study was performed to explore the possible reaction mechanisms and the origin of stereoselectivity for the isothiourea-catalyzed [4 + 2] annulation reaction of in situ activated phenylacetic acid with alkylidene pyrazolone. The computed results reveal that the reaction contains several steps, including complexation of isothiourea with substrate, dissociation of the t-BuCO2- group, α-C-H deprotonation of the acyl ammonium intermediate, stepwise [4 + 2] cycloaddition processes, and the dissociation of isothiourea. The C-C bond formation involved in the [4 + 2] cycloaddition process was identified as the stereoselectivity-determining step, in which the two chiral carbon centers emerge. The pathway associated with the RR configurational isomer is calculated to be most energetically favorable, which is consistent with the experimental observations. The origin of stereoselectivity was further studied through analyses of distortion/interaction and non-covalent interaction (NCI), and the role of isothiourea was discovered by the analyses of the global reaction index (GRI) and Parr functions. By analyzing the activity of different isothiourea catalysts, it was found that a stronger nucleophilicity of the center N atom of the isothiourea catalysts would result in a lower energy barrier of the reaction. The novel insights obtained in the present study would be useful for the rational design of more efficient catalysts for this kind of reaction.


Genome sequence and characterization of the bcs clusters for the production of nanocellulose from the low pH resistant strain Komagataeibacter medellinensis ID13488.
Komagataeibacter medellinensis ID13488 (formerly Gluconacetobacter medellinensis ID13488) is able to produce crystalline bacterial cellulose (BC) under high acidic growth conditions. These abilities make this strain desirable for industrial BC production from acidic residues (e.g. wastes generated from cider production). To explore the molecular bases of the BC biosynthesis in this bacterium, the genome has been sequenced revealing a sequence of 3.4 Mb containing three putative plasmids of 38.1 kb (pKM01), 4.3 kb (pKM02) and 3.3 Kb (pKM03). Genome comparison analyses of K. medellinensis ID13488 with other cellulose-producing related strains resulted in the identification of the bcs genes involved in the cellulose biosynthesis. Genes arrangement and composition of four bcs clusters (bcs1, bcs2, bcs3 and bcs4) was studied by RT-PCR, and their organization in four operons transcribed as four independent polycistronic mRNAs was determined. qRT-PCR experiments demonstrated that mostly bcs1 and bcs4 are expressed under BC production conditions, suggesting that these operons direct the synthesis of BC. Genomic differences with the close related strain K. medellinensis NBRC 3288 unable to produce BC were also described and discussed.


The Effect of Functional Hearing and Hearing Aid Usage on Verbal Reasoning in a Large Community-Dwelling Population.
Verbal reasoning performance is an indicator of the ability to think constructively in everyday life and relies on both crystallized and fluid intelligence. This study aimed to determine the effect of functional hearing on verbal reasoning when controlling for age, gender, and education. In addition, the study investigated whether hearing aid usage mitigated the effect and examined different routes from hearing to verbal reasoning. Cross-sectional data on 40- to 70-year-old community-dwelling participants from the UK Biobank resource were accessed. Data consisted of behavioral and subjective measures of functional hearing, assessments of numerical and linguistic verbal reasoning, measures of executive function, and demographic and lifestyle information. Data on 119,093 participants who had completed hearing and verbal reasoning tests were submitted to multiple regression analyses, and data on 61,688 of these participants, who had completed additional cognitive tests and provided relevant lifestyle information, were submitted to structural equation modeling. Poorer performance on the behavioral measure of functional hearing was significantly associated with poorer verbal reasoning in both the numerical and linguistic domains (p < 0.001). There was no association between the subjective measure of functional hearing and verbal reasoning. Functional hearing significantly interacted with education (p < 0.002), showing a trend for functional hearing to have a greater impact on verbal reasoning among those with a higher level of formal education. Among those with poor hearing, hearing aid usage had a significant positive, but not necessarily causal, effect on both numerical and linguistic verbal reasoning (p < 0.005). The estimated effect of hearing aid usage was less than the effect of poor functional hearing. Structural equation modeling analyses confirmed that controlling for education reduced the effect of functional hearing on verbal reasoning and showed that controlling for executive function eliminated the effect. However, when computer usage was controlled for, the eliminating effect of executive function was weakened. Poor functional hearing was associated with poor verbal reasoning in a 40- to 70-year-old community-dwelling population after controlling for age, gender, and education. The effect of functional hearing on verbal reasoning was significantly reduced among hearing aid users and completely overcome by good executive function skills, which may be enhanced by playing computer games.


Spinning-induced rhabdomyolysis: A case report and review of literature.
Rhabdomyolysis is a condition of skeletal muscle breakdown in which muscle injury causes a release of myoglobin and the muscle enzymes creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and transaminases. Exertional rhabdomyolysis, which is precipitated by exercise or exertion, ranges from mild muscle injury with negligible symptoms or systemic effects to fulminant cases. Herein, we report a 26-year-old female patient who was admitted to our Physical Medicine and Rehabilitation outpatient clinics with severe bilateral thigh pain persisting for 5 days after participating in a spinning class and diagnosed with exertional rhabdomyolysis. Timely diagnosis and treatment prevented the potentially life-threatening consequences. We assume that it is essential to raise the awareness of this phenomenon not only by physicians but also by the community, since regular exercise and being physically active are increasingly encouraged in modern life.


Characterization of the Mechanical Strength, Resorption Properties, and Histologic Characteristics of a Fully Absorbable Material (Poly-4-hydroxybutyrate-PHASIX Mesh) in a Porcine Model of Hernia Repair.
Purpose. Poly-4-hydroxybutyrate (P4HB) is a naturally derived, absorbable polymer. P4HB has been manufactured into PHASIX Mesh and P4HB Plug designs for soft tissue repair. The objective of this study was to evaluate mechanical strength, resorption properties, and histologic characteristics in a porcine model. Methods. Bilateral defects were created in the abdominal wall of n = 20 Yucatan minipigs and repaired in a bridged fashion with PHASIX Mesh or P4HB Plug fixated with SorbaFix or permanent suture, respectively. Mechanical strength, resorption properties, and histologic characteristics were evaluated at 6, 12, 26, and 52 weeks (n = 5 each). Results. PHASIX Mesh and P4HB Plug repairs exhibited similar burst strength, stiffness, and molecular weight at all time points, with no significant differences detected between the two devices (P > 0.05). PHASIX Mesh and P4HB Plug repairs also demonstrated significantly greater burst strength and stiffness than native abdominal wall at all time points (P < 0.05), and material resorption increased significantly over time (P < 0.001). Inflammatory infiltrates were mononuclear, and both devices exhibited mild to moderate granulation tissue/vascularization. Conclusions. PHASIX Mesh and P4HB Plug demonstrated significant mechanical strength compared to native abdominal wall, despite significant material resorption over time. Histological assessment revealed a comparable mild inflammatory response and mild to moderate granulation tissue/vascularization.


Integrating ergonomics in design processes: a case study within an engineering consultancy firm.
This paper reports on a case study within an engineering consultancy firm, where engineering designers and ergonomists were working together on the design of a new hospital sterile processing plant. The objective of the paper is to gain a better understanding of the premises for integrating ergonomics into engineering design processes and how different factors either promote or limit the integration. Based on a grounded theory approach a model illustrating these factors is developed and different hypotheses about how these factors either promote and/or limit the integration of ergonomics into design processes is presented along with the model.


Identification and characterization of genes involved in the carcinogenesis of human squamous cell cervical carcinoma.
We utilized RT-PCR differential display and cDNA microarrays to identify cellular genes involved in the multi-step carcinogenesis of squamous cell cervical carcinoma. Thirty-eight cervical cancer patients in various stages of the disease and 5 non-cervical cancer patients were studied. Twenty-five cDNA clones were identified and these were subsequently demonstrated to be consistently over-expressed in squamous cell cervical carcinoma biopsies of various FIGO stages. To further evaluate the possible role that these genes may play in the progression of disease, we performed Northern blot analysis and RNA-RNA in situ hybridization studies using cervical cancer biopsies of various FIGO stages. Of particular interest are the 2 clones G32C4B and G30CC that have been identified to be the NADH dehydrogenase 4 gene and the gene that encodes ribosomal protein S12 respectively when compared to sequences available in the GenBank database. Increased expression of these 2 genes were detected in the matched normal tissues collected together with the late FIGO stages of cervical cancer biopsies. In comparison, upregulation of these 2 genes was not detected in cervical squamous epithelium collected from patients admitted for surgery for non-malignant conditions, suggesting that expression of these 2 genes may have altered in the adjacent histopathologically "normal" cervical squamous epithelial tissue from cervical cancer patients. The ribosomal protein S12 and the NADH dehydrogenase 4 genes may therefore be potentially useful as early pre-transformation diagnostic markers for human cervical cancer.


Gendered contexts: variation in suicidal ideation by female and male youth across U.S. states.
We use data from the National Longitudinal Study of Adolescent Health (13,186 respondents in 30 states) to develop a unique state-level measure of the gendered context in order to examine the influence of gender normative attitudes and behaviors on state rates of suicidal ideation and individual-level suicidal ideation for female and male youth (ages 13 to 22). The findings demonstrate the negative consequences for youth, especially females who report feminine-typical traits, who live in contexts defined by restrictive gender norms at both the ecological and individual levels. This study points to the importance of fatalistic suicide for female youth and suggests possible mechanisms to explain this association.