Correlation between throat-related symptoms and histological examination in adults with chronic tonsillitis.
The aim of the study was to evaluate correlations between throat-related symptoms and histological findings in adults with chronic tonsillitis. A prospective cohort study was carried out. Throat-related symptoms (complaints, tonsillitis rate, and pharyngeal findings) of 81 adults with histologically proven chronic tonsillitis followed by tonsillectomy were analyzed. Four types of histological changes in removed tonsils were determined: (1) pure hyperplasia, (2) chronic inflammation, (3) chronic inflammation with hyperplasia, (4) chronic inflammation with scarring/fibrosis. The power of correlation was tested using the Pearson contingency coefficient (CC). Recurrent throat infections were the most common complaint (74.1%). The mean tonsillitis rate was 3.6 (SD 1.9) episodes per year. Tonsillar cryptic debris (61.7%) and hyperemia of the anterior pillars (59.3%) were the most common pharyngeal findings. Chronic inflammation with hyperplasia was predominant (38.3%) histological type of chronic tonsillitis. The statistically significant correlations between histological type and combination of tonsillitis rate ≥3 times per year with cryptic debris (CC=0.346; P=0.010) and cryptic debris alone (CC=0.294; P=0.051) were detected. Assessment of throat-related symptoms is complementary to histological examination in adults with chronic tonsillitis.


Extreme evolutionary disparities seen in positive selection across seven complex diseases.
Positive selection is known to occur when the environment that an organism inhabits is suddenly altered, as is the case across recent human history. Genome-wide association studies (GWASs) have successfully illuminated disease-associated variation. However, whether human evolution is heading towards or away from disease susceptibility in general remains an open question. The genetic-basis of common complex disease may partially be caused by positive selection events, which simultaneously increased fitness and susceptibility to disease. We analyze seven diseases studied by the Wellcome Trust Case Control Consortium to compare evidence for selection at every locus associated with disease. We take a large set of the most strongly associated SNPs in each GWA study in order to capture more hidden associations at the cost of introducing false positives into our analysis. We then search for signs of positive selection in this inclusive set of SNPs. There are striking differences between the seven studied diseases. We find alleles increasing susceptibility to Type 1 Diabetes (T1D), Rheumatoid Arthritis (RA), and Crohn's Disease (CD) underwent recent positive selection. There is more selection in alleles increasing, rather than decreasing, susceptibility to T1D. In the 80 SNPs most associated with T1D (p-value <7.01 x 10(-5)) showing strong signs of positive selection, 58 alleles associated with disease susceptibility show signs of positive selection, while only 22 associated with disease protection show signs of positive selection. Alleles increasing susceptibility to RA are under selection as well. In contrast, selection in SNPs associated with CD favors protective alleles. These results inform the current understanding of disease etiology, shed light on potential benefits associated with the genetic-basis of disease, and aid in the efforts to identify causal genetic factors underlying complex disease.


The Primary Causes of Muscle Dysfunction Associated with the Point Mutations in Tpm3.12; Conformational Analysis of Mutant Proteins as a Tool for Classification of Myopathies.
Point mutations in genes encoding isoforms of skeletal muscle tropomyosin may cause nemaline myopathy, cap myopathy (Cap), congenital fiber-type disproportion (CFTD), and distal arthrogryposis. The molecular mechanisms of muscle dysfunction in these diseases remain unclear. We studied the effect of the E173A, R90P, E150A, and A155T myopathy-causing substitutions in γ-tropomyosin (Tpm3.12) on the position of tropomyosin in thin filaments, and the conformational state of actin monomers and myosin heads at different stages of the ATPase cycle using polarized fluorescence microscopy. The E173A, R90P, and E150A mutations produced abnormally large displacement of tropomyosin to the inner domains of actin and an increase in the number of myosin heads in strong-binding state at low and high Ca2+, which is characteristic of CFTD. On the contrary, the A155T mutation caused a decrease in the amount of such heads at high Ca2+ which is typical for mutations associated with Cap. An increase in the number of the myosin heads in strong-binding state at low Ca2+ was observed for all mutations associated with high Ca2+-sensitivity. Comparison between the typical conformational changes in mutant proteins associated with different myopathies observed with α-, β-, and γ-tropomyosins demonstrated the possibility of using such changes as tests for identifying the diseases.


Impaired tumor growth and angiogenesis in mice heterozygous for Vegfr2 (Flk1).
VEGF signaling through its tyrosine kinase receptor, VEGFR2 (FLK1), is critical for tumor angiogenesis. Previous studies have identified a critical gene dosage effect of VegfA in embryonic development and vessel homeostasis, neovascularization, and tumor growth, and potent inhibitors of VEGFR2 have been used to treat a variety of cancers. Inhibition of FGFR signaling has also been considered as an antiangiogenic approach to treat a variety of cancers. Inhibition of VEGFR2 with neutralizing antibodies or with pharmacological inhibitors of the VEGFR tyrosine kinase domain has at least short-term efficacy with some cancers; however, also affects vessel homeostasis, leading to adverse complications. We investigate gene dosage effects of Vegfr2, Fgfr1, and Fgfr2 in three independent mouse models of tumorigenesis: two-stage skin chemical carcinogenesis, and sub-cutaneous transplantation of B16F0 melanoma and Lewis Lung Carcinoma (LLC). Mice heterozygous for Vegfr2 display profound defects in supporting tumor growth and angiogenesis. Unexpectedly, additional deletion of endothelial Fgfr1 and Fgfr2 in Vegfr2 heterozygous mice shows similar tumor growth and angiogenesis as the Vegfr2 heterozygous mice. Notably, hematopoietic deletion of two alleles of Vegfr2 had minimal impact on tumor growth, with little effect on angiogenesis, reinforcing the importance of endothelial Vegfr2 heterozygosity. These studies reveal previously unrecognized Vegfr2 gene dosage effects in tumor angiogenesis and a lack of synergy between VEGFR2 and endothelial FGFR1/2 signaling during tumor growth.


Reemergence of Human African Trypanosomiasis Caused by Trypanosoma brucei rhodesiense, Ethiopia.
We report 4 cases of human African trypanosomiasis that occurred in Ethiopia in 2022, thirty years after the last previously reported case in the country. Two of 4 patients died before medicine became available. We identified the infecting parasite as Trypanosoma brucei rhodesiense. Those cases imply human African trypanosomiasis has reemerged.


Mindful Parenting, Caregiver Distress, and Conduct Problems in Children With Autism.
Children with autism may display an externalizing problem behavior, which are associated with increased parenting stress and depression in caregivers. Mindful parenting is defined as having a non-judgmental moment-to-moment awareness during caregiver-child interactions. The extant literature is mixed, with some reporting that associations between child problem behavior and parenting stress and depression vary by level of mindful parenting, while others have not found these relations. We sought to extend these explorations. Participants who were caregivers of 75 children with autism spectrum disorder (ASD) ages 5-10, in the Pacific Northwestern region of the United States. Child conduct problems, parenting stress and caregiver depression, and mindful parenting were measured using caregiver-reported measures. Child conduct problems, parenting stress, and caregiver depression, and mindful parenting were all significantly correlated. The association between child conduct problems and parenting stress was significant for caregivers with high and low levels of mindful parenting. In contrast, the association between child conduct problems and caregiver depression was significant only for caregivers with low levels of mindful parenting. Our results suggest that mindful parenting may be a promising protective factor for the well-being of caregivers of children with autism. Implications are discussed.


Automatic tunable and reconfigurable fiberoptic microwave filters based on a broadband optical source sliced by uniform fiber Bragg gratings.
We demonstrate an automatic tunable transversal notch filter based on uniform fiber Bragg gratings and a broadband optical source. High tunability can be performed by stretching the fiber with the gratings written in series. Also, high sidelobe supression can be achieved by introducing tunable attenuators in a parallel configuration of the gratings.


Plastome Evolution and Phylogeny of Orchidaceae, With 24 New Sequences.
In order to understand the evolution of the orchid plastome, we annotated and compared 124 complete plastomes of Orchidaceae representing all the major lineages in their structures, gene contents, gene rearrangements, and IR contractions/expansions. Forty-two of these plastomes were generated from the corresponding author's laboratory, and 24 plastomes-including nine genera (Amitostigma, Bulbophyllum, Dactylorhiza, Dipodium, Galearis, Gymnadenia, Hetaeria, Oreorchis, and Sedirea)-are new in this study. All orchid plastomes, except Aphyllorchis montana, Epipogium aphyllum, and Gastrodia elata, have a quadripartite structure consisting of a large single copy (LSC), two inverted repeats (IRs), and a small single copy (SSC) region. The IR region was completely lost in the A. montana and G. elata plastomes. The SSC is lost in the E. aphyllum plastome. The smallest plastome size was 19,047 bp, in E. roseum, and the largest plastome size was 178,131 bp, in Cypripedium formosanum. The small plastome sizes are primarily the result of gene losses associated with mycoheterotrophic habitats, while the large plastome sizes are due to the expansion of noncoding regions. The minimal number of common genes among orchid plastomes to maintain minimal plastome activity was 15, including the three subunits of rpl (14, 16, and 36), seven subunits of rps (2, 3, 4, 7, 8, 11, and 14), three subunits of rrn (5, 16, and 23), trnC-GCA, and clpP genes. Three stages of gene loss were observed among the orchid plastomes. The first was ndh gene loss, which is widespread in Apostasioideae, Vanilloideae, Cypripedioideae, and Epidendroideae, but rare in the Orchidoideae. The second stage was the loss of photosynthetic genes (atp, pet, psa, and psb) and rpo gene subunits, which are restricted to Aphyllorchis, Hetaeria, Hexalectris, and some species of Corallorhiza and Neottia. The third stage was gene loss related to prokaryotic gene expression (rpl, rps, trn, and others), which was observed in Epipogium, Gastrodia, Lecanorchis, and Rhizanthella. In addition, an intermediate stage between the second and third stage was observed in Cyrtosia (Vanilloideae). The majority of intron losses are associated with the loss of their corresponding genes. In some orchid taxa, however, introns have been lost in rpl16, rps16, and clpP(2) without their corresponding gene being lost. A total of 104 gene rearrangements were counted when comparing 116 orchid plastomes. Among them, many were concentrated near the IRa/b-SSC junction area. The plastome phylogeny of 124 orchid species confirmed the relationship of {Apostasioideae [Vanilloideae (Cypripedioideae (Orchidoideae, Epidendroideae))]} at the subfamily level and the phylogenetic relationships of 17 tribes were also established. Molecular clock analysis based on the whole plastome sequences suggested that Orchidaceae diverged from its sister family 99.2 mya, and the estimated divergence times of five subfamilies are as follows: Apostasioideae (79.91 mya), Vanilloideae (69.84 mya), Cypripedioideae (64.97 mya), Orchidoideae (59.16 mya), and Epidendroideae (59.16 mya). We also released the first nuclear ribosomal (nr) DNA unit (18S-ITS1-5.8S-ITS2-28S-NTS-ETS) sequences for the 42 species of Orchidaceae. Finally, the phylogenetic tree based on the nrDNA unit sequences is compared to the tree based on the 42 identical plastome sequences, and the differences between the two datasets are discussed in this paper.


Chain dynamics of poly(ethylene-alt-propylene) melts by means of coarse-grained simulations based on atomistic molecular dynamics.
We present coarse-grained molecular dynamics simulations of poly(ethylene-alt-propylene) (PEP) melts, ranging in chain length from about N(e) (the entanglement length) to N=6N(e). The coarse-grained parameters, potential of mean force and bare friction, were determined from fully atomistic molecular dynamics simulations carried out on a PEP cell containing 12 chains of 80 monomers each and subjected to periodic boundary conditions. These atomistic simulations were previously validated by means of extensive neutron scattering measurements. Uncrossability constrains were also introduced in the coarse-grained model to prevent unphysical bond crossing. The coarse-grained simulations were carried out at 492 K and focus on chain dynamics. The results obtained were analyzed in terms of Rouse coordinates and Rouse correlators. We observe deviations from Rouse behavior for all chain lengths investigated, even when the chain stiffness is incorporated in the Rouse model. These deviations become more important as the chain length increases. The general scenario emerging from the results obtained is that the deviations from Rouse-like behavior are due to correlations among the forces acting upon a chain bead, which seem to be related with the constraint of uncrossability among the chains. As consequence, nonexponentiality of the Rouse correlators and mode- and time-dependent friction are observed. It seems that, in the molecular weight explored, these effects still give not raise to reptation behavior but to a crossover regime between Rouse and reptation. On the other hand, the results obtained are in qualitative agreement with those expected from the so-called generalized Rouse models, based on memory function formalisms.


Health-related quality of life in old age: a comparison between rural areas in Bangladesh and Vietnam.
This study compares health-related quality of life (HRQoL) and its determinants among older people (≥60 years) in rural Bangladesh and Vietnam. Cross-sectional studies among older people were conducted in Bangladesh (n = 1031) and Vietnam (n = 870). Data on HRQoL were collected using an instrument that includes 24 items distributed into 6 dimensions. Older people in Vietnam reported more favorable HRQoL outcomes than those in Bangladesh, reporting better HRQoL on physical, psychological, social, and financial dimensions. Hierarchical linear regression analyses show that advanced age, being a woman, belonging to a poor household, and reporting poor health were significantly associated with lower HRQoL scores in both Bangladesh and Vietnam. In Bangladesh, being illiterate was additionally associated with lower HRQoL scores. The results of this explorative study underline the importance of a cross-cultural understanding of HRQoL of older people and the influence of the socioecological context.


Bonum vinum laetificat cor hominum.
Beneficial effects of wine consumption on health have been suspected since the antiquity. Recent epidemiological studies show that coronary heart disease mortality markedly decreases from northern to southern Europe and is lower in Mediterranean than in other developed countries. Because wine is a component of the Mediterranean diet, it has been suggested that moderate wine especially red wine consumption may produce additional beneficial effects on cardiovascular morbidity and mortality compared to consuming the same quantity of alcohol in other beverages. Polyphenols are good candidates to explain the putative cardiovascular protective effect of wine, because they are abundant in wine especially red wine, and possess antioxidant and superoxide ion scavenging properties. Because it is readily accessible from blood and produces cardioprotective agents like nitric oxide (NO) the endothelial cell may be a privileged target for wine polyphenols. Polyphenols from red wine can prevent oxidation of low density lipoproteins (LDL). As oxidized LDL inhibit agonist-activated NO release from endothelial cells and subsequent endothelium-dependent relaxation of arteries, wine polyphenols might prevent LDL-induced alterations of endothelial function. Furthermore some wine polyphenols contained in oligomeric condensed tannins- and anthocyaninsD enriched fractions can act directly on endothelial cells to cause calcium-dependent release of NO. The latter effect is independent from superoxide scavenging and antioxidant properties of the polyphenols, and it is produced by compounds with specific structures only. Thus, decreased oxidation of LDL and enhanced release of NO from endothelium caused by polyphenols from red wine may result in cardiovascular protection. However further studies are required to demonstrate whether or not these effects are involved in the putative protective effect of wine on cardiovascular morbidity and mortality.


Chromosomal-Level Assembly of the Asian Seabass Genome Using Long Sequence Reads and Multi-layered Scaffolding.
We report here the ~670 Mb genome assembly of the Asian seabass (Lates calcarifer), a tropical marine teleost. We used long-read sequencing augmented by transcriptomics, optical and genetic mapping along with shared synteny from closely related fish species to derive a chromosome-level assembly with a contig N50 size over 1 Mb and scaffold N50 size over 25 Mb that span ~90% of the genome. The population structure of L. calcarifer species complex was analyzed by re-sequencing 61 individuals representing various regions across the species' native range. SNP analyses identified high levels of genetic diversity and confirmed earlier indications of a population stratification comprising three clades with signs of admixture apparent in the South-East Asian population. The quality of the Asian seabass genome assembly far exceeds that of any other fish species, and will serve as a new standard for fish genomics.


The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.
Cirrhosis and other chronic liver diseases (collectively referred to as cirrhosis in this paper) are a major cause of morbidity and mortality globally, although the burden and underlying causes differ across locations and demographic groups. We report on results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 on the burden of cirrhosis and its trends since 1990, by cause, sex, and age, for 195 countries and territories. We used data from vital registrations, vital registration samples, and verbal autopsies to estimate mortality. We modelled prevalence of total, compensated, and decompensated cirrhosis on the basis of hospital and claims data. Disability-adjusted life-years (DALYs) were calculated as the sum of years of life lost due to premature death and years lived with disability. Estimates are presented as numbers and age-standardised or age-specific rates per 100 000 population, with 95% uncertainty intervals (UIs). All estimates are presented for five causes of cirrhosis: hepatitis B, hepatitis C, alcohol-related liver disease, non-alcoholic steatohepatitis (NASH), and other causes. We compared mortality, prevalence, and DALY estimates with those expected according to the Socio-demographic Index (SDI) as a proxy for the development status of regions and countries. In 2017, cirrhosis caused more than 1·32 million (95% UI 1·27-1·45) deaths (440 000 [416 000-518 000; 33·3%] in females and 883 000 [838 000-967 000; 66·7%] in males) globally, compared with less than 899 000 (829 000-948 000) deaths in 1990. Deaths due to cirrhosis constituted 2·4% (2·3-2·6) of total deaths globally in 2017 compared with 1·9% (1·8-2·0) in 1990. Despite an increase in the number of deaths, the age-standardised death rate decreased from 21·0 (19·2-22·3) per 100 000 population in 1990 to 16·5 (15·8-18·1) per 100 000 population in 2017. Sub-Saharan Africa had the highest age-standardised death rate among GBD super-regions for all years of the study period (32·2 [25·8-38·6] deaths per 100 000 population in 2017), and the high-income super-region had the lowest (10·1 [9·8-10·5] deaths per 100 000 population in 2017). The age-standardised death rate decreased or remained constant from 1990 to 2017 in all GBD regions except eastern Europe and central Asia, where the age-standardised death rate increased, primarily due to increases in alcohol-related liver disease prevalence. At the national level, the age-standardised death rate of cirrhosis was lowest in Singapore in 2017 (3·7 [3·3-4·0] per 100 000 in 2017) and highest in Egypt in all years since 1990 (103·3 [64·4-133·4] per 100 000 in 2017). There were 10·6 million (10·3-10·9) prevalent cases of decompensated cirrhosis and 112 million (107-119) prevalent cases of compensated cirrhosis globally in 2017. There was a significant increase in age-standardised prevalence rate of decompensated cirrhosis between 1990 and 2017. Cirrhosis caused by NASH had a steady age-standardised death rate throughout the study period, whereas the other four causes showed declines in age-standardised death rate. The age-standardised prevalence of compensated and decompensated cirrhosis due to NASH increased more than for any other cause of cirrhosis (by 33·2% for compensated cirrhosis and 54·8% for decompensated cirrhosis) over the study period. From 1990 to 2017, the number of prevalent cases more than doubled for compensated cirrhosis due to NASH and more than tripled for decompensated cirrhosis due to NASH. In 2017, age-standardised death and DALY rates were lower among countries and territories with higher SDI. Cirrhosis imposes a substantial health burden on many countries and this burden has increased at the global level since 1990, partly due to population growth and ageing. Although the age-standardised death and DALY rates of cirrhosis decreased from 1990 to 2017, numbers of deaths and DALYs and the proportion of all global deaths due to cirrhosis increased. Despite the availability of effective interventions for the prevention and treatment of hepatitis B and C, they were still the main causes of cirrhosis burden worldwide, particularly in low-income countries. The impact of hepatitis B and C is expected to be attenuated and overtaken by that of NASH in the near future. Cost-effective interventions are required to continue the prevention and treatment of viral hepatitis, and to achieve early diagnosis and prevention of cirrhosis due to alcohol-related liver disease and NASH. Bill & Melinda Gates Foundation.


Degradation of HMG-CoA reductase-induced membranes in the fission yeast, Schizosaccharomyces pombe.
Elevated levels of certain membrane proteins, including the sterol biosynthetic enzyme HMG-CoA reductase, induce proliferation of the endoplasmic reticulum. When the amounts of these proteins return to basal levels, the proliferated membranes are degraded, but the molecular details of this degradation remain unknown. We have examined the degradation of HMG-CoA reductase-induced membranes in the fission yeast, Schizosaccharomyces pombe. In this yeast, increased levels of the Saccharomyces cerevisiae HMG-CoA reductase isozyme encoded by HMG1 induced several types of membranes, including karmellae, which formed a cap of stacked membranes that partially surrounded the nucleus. When expression of HMG1 was repressed, the karmellae detached from the nucleus and formed concentric, multilayered membrane whorls that were then degraded. During the degradation process, CDCFDA-stained compartments distinct from preexisting vacuoles formed within the interior of the whorls. In addition to these compartments, particles that contained neutral lipids also formed within the whorl. As the thickness of the whorl decreased, the lipid particle became larger. When degradation was complete, only the lipid particle remained. Cycloheximide treatment did not prevent the formation of whorls. Thus, new protein synthesis was not needed for the initial stages of karmellae degradation. On the contrary, cycloheximide promoted the detachment of karmellae to form whorls, suggesting that a short lived protein may be involved in maintaining karmellae integrity. Taken together, these results demonstrate that karmellae membranes differentiated into self-degradative organelles. This process may be a common pathway by which ER membranes are turned over in cells.


White matter changes after stroke in type 2 diabetic rats measured by diffusion magnetic resonance imaging.
Diffusion-related magnetic resonance imaging parametric maps may be employed to characterize white matter of brain. We hypothesize that entropy of diffusion anisotropy may be most effective for detecting therapeutic effects of bone marrow stromal cell treatment of ischemia in type 2 diabetes mellitus rats. Type 2 diabetes mellitus was induced in adult male Wistar rats. These rats were then subjected to 2 h of middle cerebral artery occlusion, and received bone marrow stromal cell (5 × 106, n = 8) or an equal volume of saline (n = 8) via tail vein injection at three days after middle cerebral artery occlusion. Magnetic resonance imaging was performed on day one and then weekly for five weeks post middle cerebral artery occlusion. The diffusion metrics complementarily permitted characterization of axons and axonal myelination. All six magnetic resonance imaging diffusion metrics, confirmed by histological measures, demonstrated that bone marrow stromal cell treatment significantly (p < 0.05) improved magnetic resonance imaging diffusion indices of white matter in type 2 diabetes mellitus rats after middle cerebral artery occlusion compared with the saline-treated rats. Superior to the fractional anisotropy metric that provided measures related to organization of neuronal fiber bundles, the entropy metric can also identify microstructures and low-density axonal fibers of cerebral tissue after stroke in type 2 diabetes mellitus rats.


A meta-analysis of the dark side of the American dream: Evidence for the universal wellness costs of prioritizing extrinsic over intrinsic goals.
Self-determination theory holds that the intrinsic and extrinsic content of people's aspirations differentially affect their wellness. An evidence base spanning nearly 30 years indicates that focusing on intrinsic goals (such as for growth, relationships, community giving, and health) promotes well-being, whereas a focus on extrinsic goals (such as for wealth, fame, and beauty) deters well-being. Yet, the evidence base contains exceptions, and some authors have argued that focusing on extrinsic goals may not be universally detrimental. We conducted a systematic review and used multilevel meta-analytic structural equation modeling to evaluate the links between intrinsic and extrinsic aspirations with indices of well-being and ill-being. Across 92 reports (105 studies), 1,808 effects, and a total sample of N = 70,110, we found that intrinsic aspirations were linked positively with well-being, r = 0.24 [95% CI 0.22, 0.27], and negatively with ill-being, r = -0.11 [-0.14, -0.08]. When the variety of extrinsic aspiration scoring methods were combined, the link with well-being was not statistically significant, r = 0.02 [-0.02, 0.06]. However, when extrinsic aspirations were evaluated in terms of their predominance in the overall pattern of aspiring the effect was universally detrimental, linking negatively to well-being, r = -0.22 [-0.32, -0.11], and positively to ill-being, r = 0.23 [0.17, 0.30]. Meta-analytic conclusions about the associations between goal types and wellness are important because they inform how individuals could shape aspirations to support their own happiness and how groups and institutions can frame goals such that their pursuit is for the common good. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Analysis of EMG signals of patients with essential tremor focusing on the change of tremor frequency.
Essential tremor is a disorder that causes involuntary oscillations in patients while engaging in actions or while maintaining a posture. ET patients have serious difficulties in performing activities of daily living such as eating food, drinking water, and writing. We have thus been developing an EMG-controlled exoskeletal robot to suppress tremors. The EMG signal of ET patients involves a mix of voluntary movement and tremor signals. To control the exoskeletal robot accurately, tremor signals must be removed from the patient's EMG signal. To date, we have been developing a filter to remove tremor signals from the patient's EMG. The design of this filter was based on the hypothesis that the rectified tremor signals are able to be approximated by a powered sine wave. This filter was found to have a large effect on removing tremor signals. However, tremor signals are generated both while performing voluntary movement and while maintaining a posture, and the filter was attenuating both signals. To control this robot accurately, the signal generated while performing voluntary movement is expected not to be attenuated. To accomplish this, we try to use a parameter that reflects a state of the patient's movement, performing a voluntary movement or maintaining a posture, as a switch to activate the powered sine filter. This paper provides an analysis of the favorable parameters. We focus on two parameters: the peak-to-peak interval of the rectified EMG signal, and the interval of the flat and low amplitude area of the rectified EMG signal. Through evaluation, it is affirmed that both parameters change with the state of the patient's movement. However, the latter parameter is superior to the former in terms of variability, which indicates that the interval of the flat and low amplitude area of the rectified EMG signal is a more favorable parameter to promote control of the exoskeletal robot. As a future work, we will mount the parameter to the algorithm and evaluate the robotic system.


Heat intolerance: predisposing factor or residual injury?
Great individual variability exists in the ability to sustain heat stress. Some individuals are more susceptible to heat than others. Those individuals, among the young active population (athletes, military recruits, laborers), are at risk to contract exertional heat stroke. Low tolerance to heat results from either functional factors, or from congenital or acquired disturbances. In most cases heat intolerance can be foreseen. Cases of dehydration, overweight, low physical fitness, lack of acclimatization, febrile or infectious diseases, and skin disorders should be regarded a priori as predisposing factors for heat intolerance. Special attention should be paid to subjects with previous heat stroke episodes since it might reflect an underlying cause for heat susceptibility. The heat tolerance of these subjects should be tested 8-12 wk postepisode to detect a possible residual injury in the ability to thermoregulate adequately in the heat.


Diffuse optical spectroscopic imaging of subcutaneous adipose tissue metabolic changes during weight loss.
Changes in subcutaneous adipose tissue (AT) structure and metabolism have been shown to correlate with the development of obesity and related metabolic disorders. Measurements of AT physiology could provide new insight into metabolic disease progression and response to therapy. An emerging functional imaging technology, diffuse optical spectroscopic imaging (DOSI), was used to obtain quantitative measures of near infrared (NIR) AT optical and physiological properties. Ten overweight or obese adults were assessed during 3 months on calorie-restricted diets. DOSI-derived tissue concentrations of hemoglobin, water and lipid and the wavelength-dependent scattering amplitude (A) and slope (b) obtained from 30 abdominal locations and three time points (T0, T6, T12) were calculated and analyzed using linear mixed-effects models and were also used to form 3D surface images. Subjects lost a mean of 11.7±3.4% of starting weight, while significant changes in A (+0.23±0.04 mm(-1), adj. P<0.001),b (-0.17±0.04, adj. P<0.001), tissue water fraction (+7.2±1.1%, adj. P<0.001) and deoxyhemoglobin (1.1±0.3 μM, adj. P<0.001) were observed using mixed-effect model analysis. Optical scattering signals reveal alterations in tissue structure that possibly correlate with reductions in adipose cell volume, while water and hemoglobin dynamics suggest improved AT perfusion and oxygen extraction. These results suggest that DOSI measurements of NIR optical and physiological properties could be used to enhance understanding of the role of AT in metabolic disorders and provide new strategies for diagnostic monitoring of obesity and weight loss.


Making the professionalism curriculum for undergraduate medical education more relevant.
This study was an assessment of the professionalism curriculum at a community-based medical school from the perspective of undergraduate medical students. The goal of this study was to ascertain the perspectives of faculty and students on their interpretations of professionalism and its role in medical education to improve and expand existing professionalism curricula. An online survey was created and sent to all students (n = 245) and selected faculty (n = 41). The survey utilized multiple choice and open-ended questions to allow responders to provide their insights on the definition of professionalism and detail how professionalism is taught and evaluated at their institution. A content analysis was conducted to categorize open-ended responses and the resulting themes were further examined using SPSS 20.0 for Windows (IBM Corp., Armonk, NY) frequency analyses. Students and faculty respondents were similar in their definitions of medical professionalism and their perceptions of teaching methods. Role modeling was the most common and preferred method of professionalism education. Responses to whether evaluations of professional behavior were effective suggested both students and faculty are unclear about current professionalism assessments. This study showed that a cohesive standardized definition of professionalism is needed, as well as clearer guidelines on how professionalism is assessed.


Reduction of Prep1 levels affects differentiation of normal and malignant B cells and accelerates Myc driven lymphomagenesis.
The Prep1 homeodomain transcription factor has recently been recognized as a tumor suppressor. Among other features, haploinsufficiency of Prep1 is able to strongly accelerate the B-lymphomagenesis in EμMyc mice. Now we report that this occurs concomitantly with a change in the type of B-cell lymphomas generated by the Myc oncogene. Indeed, the tumors generated in the EμMyc-Prep1(+/-) mice are much more immature, being mostly made up of Pro-B or Pre-B cells, while those in the EμMyc-Prep1(+/+) mice are more differentiated being invariably IgM(+). Moreover, we show that Prep1 is in fact required for the differentiation of Pro-B and Pre-B cells into IgM(+) lymphocytes and/or their proliferation, thus showing also how a normal function of Prep1 affects EμMyc lymphomagenesis. Finally, we show that the haploinsufficiency of Prep1 is accompanied with a major decrease of Myc-induced apoptosis and that the haploinsufficieny is sufficient for all these effects because the second allele of Prep1 is not lost even at late stages. Therefore, the tumor-suppressive activity of Prep1 is intertwined with both the interference with Myc-induced apoptosis as well as with natural developmental functions of the protein.


The enemy within: Targeting host-parasite interaction for antileishmanial drug discovery.
The state of antileishmanial chemotherapy is strongly compromised by the emergence of drug-resistant Leishmania. The evolution of drug-resistant phenotypes has been linked to the parasites' intrinsic genome instability, with frequent gene and chromosome amplifications causing fitness gains that are directly selected by environmental factors, including the presence of antileishmanial drugs. Thus, even though the unique eukaryotic biology of Leishmania and its dependence on parasite-specific virulence factors provide valid opportunities for chemotherapeutical intervention, all strategies that target the parasite in a direct fashion are likely prone to select for resistance. Here, we review the current state of antileishmanial chemotherapy and discuss the limitations of ongoing drug discovery efforts. We finally propose new strategies that target Leishmania viability indirectly via mechanisms of host-parasite interaction, including parasite-released ectokinases and host epigenetic regulation, which modulate host cell signaling and transcriptional regulation, respectively, to establish permissive conditions for intracellular Leishmania survival.


Adaptive equipment used in the rehabilitation of hip arthroplasty patients.
In this paper an occupational therapy program involved in the acute rehabilitation of patients with total hip replacement and total surface replacement is described. The goal of the program is to help patients achieve independence in activities of daily living by the conclusion of their 2-week hospitalization, while complying with the physical limitations imposed by the surgical protocol. The program consists of instruction in the use of selected adaptive equipment, in activities of daily living, and in environmental modifications. The findings of a retrospective patient survey are included. Specifically, the majority of the patients surveyed were found to be independent in essential activities of daily living by the time they were discharged from the hospital, and that use of the adaptive equipment was very high.


Weak Interactions between Salmonella enterica FlhB and Other Flagellar Export Apparatus Proteins Govern Type III Secretion Dynamics.
The bacterial flagellum contains its own type III secretion apparatus that coordinates protein export with assembly at the distal end. While many interactions among export apparatus proteins have been reported, few have been examined with respect to the differential affinities and dynamic relationships that must govern the mechanism of export. FlhB, an integral membrane protein, plays critical roles in both export and the substrate specificity switching that occurs upon hook completion. Reported herein is the quantitative characterization of interactions between the cytoplasmic domain of FlhB (FlhBC) and other export apparatus proteins including FliK, FlhAC and FliI. FliK and FlhAC bound with micromolar affinity. KD for FliI binding in the absence of ATP was 84 nM. ATP-induced oligomerization of FliI induced kinetic changes, stimulating fast-on, fast-off binding and lowering affinity. Full length FlhB purified under solubilizing, nondenaturing conditions formed a stable dimer via its transmembrane domain and stably bound FliH. Together, the present results support the previously hypothesized central role of FlhB and elucidate the dynamics of protein-protein interactions in type III secretion.


Multivariate phenotype analysis enables genome-wide inference of mammalian gene function.
The function of the majority of genes in the human and mouse genomes is unknown. Investigating and illuminating this dark genome is a major challenge for the biomedical sciences. The International Mouse Phenotyping Consortium (IMPC) is addressing this through the generation and broad-based phenotyping of a knockout (KO) mouse line for every protein-coding gene, producing a multidimensional data set that underlies a genome-wide annotation map from genes to phenotypes. Here, we develop a multivariate (MV) statistical approach and apply it to IMPC data comprising 148 phenotypes measured across 4,548 KO lines. There are 4,256 (1.4% of 302,997 observed data measurements) hits called by the univariate (UV) model analysing each phenotype separately, compared to 31,843 (10.5%) hits in the observed data results of the MV model, corresponding to an estimated 7.5-fold increase in power of the MV model relative to the UV model. One key property of the data set is its 55.0% rate of missingness, resulting from quality control filters and incomplete measurement of some KO lines. This raises the question of whether it is possible to infer perturbations at phenotype-gene pairs at which data are not available, i.e., to infer some in vivo effects using statistical analysis rather than experimentation. We demonstrate that, even at missing phenotypes, the MV model can detect perturbations with power comparable to the single-phenotype analysis, thereby filling in the complete gene-phenotype map with good sensitivity. A factor analysis of the MV model's fitted covariance structure identifies 20 clusters of phenotypes, with each cluster tending to be perturbed collectively. These factors cumulatively explain 75% of the KO-induced variation in the data and facilitate biological interpretation of perturbations. We also demonstrate that the MV approach strengthens the correspondence between IMPC phenotypes and existing gene annotation databases. Analysis of a subset of KO lines measured in replicate across multiple laboratories confirms that the MV model increases power with high replicability.


The aged face: the facial manifestations of aging.
Traditionally, cosmetic maxillofacial surgery designed to rejuvenate "the aged face" has been reserved for the elderly. However, any patient with facial manifestations that reflect, but are not limited to, an increased chronologic age is a candidate for esthetic maxillofacial surgery. In this text, the aged face refers to any facial manifestations that are perceived as indices of advanced age beyond an individual's chronologic or desired age. This paper presents a brief outline of the specific facial features that account for the aged face and describes surgical correction.


Cholesteatoma of the maxillary sinus.
Cholesteatoma of the maxillary sinus is a rare condition, but it should be considered in the differential diagnosis of any slowly expanding lesion of the maxillary sinus. Because the keratinizing squamous epithelium continues to desquamate and expand, thereby causing erosion of the surrounding structures, the cholesteatoma sac must be removed completely. We describe a case of cholesteatoma of the maxillary sinus in an 18-year-old woman.


Unveiling the controversy on egg freezing in The Netherlands: A Q-methodology study on women's viewpoints.
Preserving the option to conceive through egg freezing (oocyte cryopreservation) is surrounded by value conflicts and diverse viewpoints, particularly when non-medical or so-called 'social' reasons are involved. The debate is controversial and shaped by normative perceptions of the life course, including concepts regarding reproductive ageing, gender, motherhood and biomedicalization. To unravel the controversy and systematically identify the variety of viewpoints on egg freezing, a Q-methodology study was conducted in The Netherlands between December 2018 and October 2019. Thirty-four women of reproductive age participated in the study. They ranked 40 statements according to their level of agreement, and explained their ranking during follow-up interviews. Data were analysed using by-person factor analysis and interpreted using both quantitative and qualitative data. Four viewpoints, of which the fourth was bipolar, were identified: (1) cautious about egg freezing technology; (2) my body, my choice; (3) egg freezing is unnatural; and (4) have children and have them early. The distinct viewpoints illustrate different prioritizations of values and normative dimensions of biomedical innovations. By knowing more about the prevalent opinions on egg freezing and the surrounding controversy, policy makers and practitioners can make better informed decisions in terms of promoting and providing patient-centred infertility care. The findings furthermore stimulate continuing scholarly work on egg freezing and other innovations in reproductive medicine which may continue to disrupt normative standards.


Behavioral Inflexibility Across Two Neurogenetic Conditions: Down Syndrome and Fragile X Syndrome.
Behavioral inflexibility (BI) has been highlighted to occur across genetic and neurodevelopmental disorders. This study characterized BI in two common neurogenetic conditions: Fragile X syndrome (FXS) and Down syndrome (DS). Caregivers of children with FXS (N = 56; with ASD = 28; FXS only = 28) and DS (N = 146) completed the Behavioral Inflexibility Scale (BIS) via an online survey. Total BIS scores were higher in FXS+ASD than both FXS only and DS (p <.001). Most endorsed items were similar across the three groups, but scores were higher in the FXS+ASD group. In all groups, BI associated with other clinical variables (receptive behaviors, anxiety, social communication). The current data suggest that BI is variable across neurogenetic conditions and higher in individuals with comorbid ASD.


Dropshaft cascades in urban drainage systems.
Dropshaft cascades are typical elements of sewer systems in steep urban catchment basins. The design of a dropshaft cascade, which is generally addressed as an optimization problem, also needs to consider the subsequent effects induced on the flow by the different elements of the cascade. Experimental research has been performed at the hydraulic engineering laboratory of the University of Cassino and Southern Lazio in order to investigate the basic flow patterns in a dropshaft cascade, with particular reference to energy dissipation and air entrainment. This research has shown that, regarding these aspects, a dropshaft cascade proved to be a more efficient solution of the single drop manhole with the same total drop height.


In vitro insulin secretion by pancreatic tissue from infants with diazoxide-resistant congenital hyperinsulinism deviates from model predictions.
Congenital hyperinsulinism (CHI) is the major cause of persistent neonatal hypoglycemia. CHI most often occurs due to mutations in the ABCC8 (which encodes sulfonylurea receptor 1) or KCNJ11 (which encodes the potassium channel Kir6.2) gene, which result in a lack of functional KATP channels in pancreatic β cells. Diffuse forms of CHI (DiCHI), in which all β cells are abnormal, often require subtotal pancreatectomy, whereas focal forms (FoCHI), which are characterized by localized hyperplasia of abnormal β cells, can be cured by resection of the lesion. Here, we characterized the in vitro kinetics of insulin secretion by pancreatic fragments from 6 DiCHI patients and by focal lesion and normal adjacent pancreas from 18 FoCHI patients. Responses of normal pancreas were similar to those reported for islets from adult organ donors. Compared with normal pancreas, basal insulin secretion was elevated in both FoCHI and DiCHI tissue. Affected tissues were heterogeneous in their secretory responses, with increased glucose levels often producing a rapid increase in insulin secretion that could be followed by a paradoxical decrease below prestimulatory levels. The KATP channel blocker tolbutamide was consistently ineffective in stimulating insulin secretion; conversely, the KATP channel activator diazoxide often caused an unanticipated increase in insulin secretion. These observed alterations in secretory behavior were similar in focal lesion and DiCHI tissue, and independent of the specific mutation in ABCC8 or KCNJ11. They cannot be explained by classic models of β cell function. Our results provide insight into the excessive and sometimes paradoxical changes in insulin secretion observed in CHI patients with inactivating mutations of KATP channels.


Atrial embolism caused by portal vein embolization: Treatment by percutaneous withdrawal and stenting.
Hepatectomy remains the only curative treatment for many primary and secondary liver cancers. Portal vein embolization (PVE) has been used to increase the volume of the future liver remnant and thus lower the risk of small-for-size syndrome and postoperative liver failure. This technique has proven its safety, with a low post-procedure morbidity rate. Here, we describe a very rare case in which a young patient suffered a glue embolism to the right atrial cavity following PVE in preparation for a major hepatectomy for colorectal metastasis. The foreign body was withdrawn from the heart with a femoral, percutaneous device and trapped against the wall of the femoral vein with a self-expanding metal stent. Our report shows that this previously unknown complication of PVE can be resolved without recourse to sternotomy and open heart surgery.


The Malaria Cell Atlas: Single parasite transcriptomes across the complete Plasmodium life cycle.
Malaria parasites adopt a remarkable variety of morphological life stages as they transition through multiple mammalian host and mosquito vector environments. We profiled the single-cell transcriptomes of thousands of individual parasites, deriving the first high-resolution transcriptional atlas of the entire Plasmodium berghei life cycle. We then used our atlas to precisely define developmental stages of single cells from three different human malaria parasite species, including parasites isolated directly from infected individuals. The Malaria Cell Atlas provides both a comprehensive view of gene usage in a eukaryotic parasite and an open-access reference dataset for the study of malaria parasites.


Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus.
Siderophore-antibiotic drug conjugates are considered potent tools to deliver and potentiate the antibacterial activity of antibiotics, but only few have seen preclinical and clinical success. Here, we introduce the gallium(iii) complex of a ciprofloxacin-functionalized linear desferrichrome, Galbofloxacin, with a cleavable serine linker as a potent therapeutic for S. aureus bacterial infections. We employed characterization using in vitro inhibitory assays, radiochemical, tracer-based uptake and pharmacokinetic assessment of our lead compound, culminating in in vivo efficacy studies in a soft tissue model of infection. Galbofloxacin exhibits a minimum inhibitory concentration of (MIC98) 93 nM in wt S. aureus, exceeding the potency of the parent antibiotic ciprofloxacin (0.9 μM). Galbofloxacin is a protease substrate that can release the antibiotic payload in the bacterial cytoplasm. Radiochemical experiments with wt bacterial strains reveal that 67Galbofloxacin is taken up efficiently using siderophore mediated, active uptake. Biodistribution of 67Galbofloxacin in a mouse model of intramuscular S. aureus infection revealed renal clearance and enhanced uptake in infected muscle when compared to 67Ga-citrate, which showed no selectivity. A subsequent in vivo drug therapy study reveals efficient reduction in S. aureus infection burden and sustained survival with Galbofloxacin for 7 days. Ciprofloxacin had no treatment efficacy at identical molecular dose (9.3 μmol kg-1) and resulted in death of all study animals in <24 hours. Taken together, the favorable bacterial growth inhibitory, pharmacokinetic and in vivo efficacy properties qualify Galbofloxacin as the first rationally designed Ga-coordination complex for the management of S. aureus bacterial infections.


Contribution of modifiable risk factors for hypertension and type-2 diabetes in Peruvian resource-limited settings.
It is important to understand the local burden of non-communicable diseases including within-country heterogeneity. The aim of this study was to characterise hypertension and type-2 diabetes profiles across different Peruvian geographical settings emphasising the assessment of modifiable risk factors. Analysis of the CRONICAS Cohort Study baseline assessment was conducted. Cardiometabolic outcomes were blood pressure categories (hypertension, prehypertension, normal) and glucose metabolism disorder status (diabetes, prediabetes, normal). Exposures were study setting and six modifiable factors (smoking, alcohol drinking, leisure time and transport-related physical activity levels, TV watching, fruit/vegetables intake and obesity). Poisson regression models were used to report prevalence ratios (PR). Population attributable risks (PAR) were also estimated. Data from 3238 participants, 48.3% male, mean age 45.3 years, were analysed. Age-standardised (WHO population) prevalence of prehypertension and hypertension was 24% and 16%, whereas for prediabetes and type-2 diabetes it was 18% and 6%, respectively. Outcomes varied according to study setting (p<0.001). In multivariable model, hypertension was higher among daily smokers (PR 1.76), heavy alcohol drinkers (PR 1.61) and the obese (PR 2.06); whereas only obesity (PR 2.26) increased the prevalence of diabetes. PAR showed that obesity was an important determinant for hypertension (15.7%) and type-2 diabetes (23.9%). There is an evident heterogeneity in the prevalence of and risk factors for hypertension and diabetes within Peru. Prehypertension and prediabetes are highly prevalent across settings. Our results emphasise the need of understanding the epidemiology of cardiometabolic conditions to appropriately implement interventions to tackle the burden of non-communicable diseases.


Feasibility of multimodal multiphoton microscopy to facilitate surgical margin assessment in pancreatic cancer.
Pancreatic cancer is a common cancer with poor odds of survival for the patient, with surgical resection offering the only hope of cure. Current surgical practice is time-consuming and, due to time constraints, does not sample the whole cut surface sufficiently to check for remaining cancer. Although microscopy with hematoxylin and eosin (H&E) stain is the gold standard for microscopic evaluation, multiphoton microscopy (MPM) has emerged as an alternative tool for imaging tissue architecture and cellular morphology without labels. We explored the use of multimodal MPM for the label-free identification of normal and cancerous tissue of the pancreas in a mouse model by comparing the images to H&E microscopy. Our early studies indicate that MPM using second-harmonic generation, third-harmonic generation, and multiphoton excitation of endogenous fluorescent proteins can each contribute to the label-free analysis of the pancreatic surgical margin.


Intra-assay reliability and robustness of QuantiFERON(R)-TB Gold In-Tube test in Zambia.
Interferon-gamma (IFN-gamma) release assays (IGRAs), such as the QuantiFERON-TB Gold In-Tube test (QFT-GIT), are becoming a preferred method for diagnosis of tuberculosis (TB) infection in many industrialised countries. However, data on the effectiveness of IGRAs in high TB-HIV (human immunodeficiency virus) endemic and resource-limited settings, such as Zambia, are limited. To determine the intra-assay reliability and robustness of QFT-GIT in a field setting in Zambia. During July-October 2007, 109 adult smear-positive TB patients were recruited to determine QFT-GIT reliability and the effect of a 24-h delay in incubation. Two simulated laboratory experiments were also performed using 9-14 volunteers, to explore the effect of power outages during incubation and storage temperature of collection tubes on IFN-gamma responses. QFT-GIT intra-assay concordance was 91.7% (kappa = 0.8). Discordance was observed for nine patients, of whom six were HIV-positive. There was evidence of an association between HIV status and discordant results (OR 1.98, 95%CI 1.06-3.67, P = 0.03). A 24-h delay in incubation changed results for 25 of the 109 (22.9%) patients. Power outages that altered incubation time reduced IFN-gamma responses. Although QFT-GIT seems reliable in this setting, we have identified operational factors that affect its robustness. These factors may influence the effectiveness of this test in similar resource-limited settings.


Investigation of the effects of an ultraviolet germicidal irradiation system on concentrations of aerosolized surrogates for common veterinary pathogens.
To determine whether exposure to UV germicidal irradiation (UVGI) reduces concentrations of viable aerosolized microorganisms (attenuated strains of common veterinary pathogens) in a simulated heating, ventilation, and air conditioning (HVAC) system. 42 air samples seeded with bacteriophage MS2 or attenuated strains of Bordetella bronchiseptica, feline calicivirus, feline herpesvirus-1, canine parvovirus, or canine distemper virus (6/microorganism) or with no microorganisms added (6). A simulated HVAC unit was built that included a nebulizer to aerosolize microorganisms suspended in phosphate-buffered water, a fan to produce airflow, 2 UVGI bulb systems, and an impinger for air sampling. Ten-minute trials (3 with UVGI, 3 without UVGI, and 1 negative control) were conducted for each microorganism. Impingers collected microorganisms into phosphate-buffered water for subsequent quantification with culture-based assays. Results for samples yielding no target microorganisms were recorded as the assay's lower limit of detection. Statistical analysis was not performed. The UVGI treatment resulted in subjectively lower concentrations of viable MS2, B bronchiseptica, and canine distemper virus (arithmetic mean ± SD log10 microorganism reduction, 2.57 ± 0.47, ≥ 3.45 ± 0.24, and ≥ 1.50 ± 0.25, respectively) collected from air. Feline herpesvirus-1 was detected in only 1 sample without and no samples with UVGI treatment. Feline calicivirus and canine parvovirus were not detectable in any collected samples. Results for some surrogates of veterinary pathogens suggested a potential benefit to supplementing manual disinfection practices with UVGI-based air cleaning systems in animal care environments. Further research is needed to investigate the utility of UVGI in operating HVAC systems.


New model of action for mood stabilizers: phosphoproteome from rat pre-frontal cortex synaptoneurosomal preparations.
Mitochondrial short and long-range movements are necessary to generate the energy needed for synaptic signaling and plasticity. Therefore, an effective mechanism to transport and anchor mitochondria to pre- and post-synaptic terminals is as important as functional mitochondria in neuronal firing. Mitochondrial movement range is regulated by phosphorylation of cytoskeletal and motor proteins in addition to changes in mitochondrial membrane potential. Movement direction is regulated by serotonin and dopamine levels. However, data on mitochondrial movement defects and their involvement in defective signaling and neuroplasticity in relationship with mood disorders is scarce. We have previously reported the effects of lithium, valproate and a new antipsychotic, paliperidone on protein expression levels at the synaptic level. Mitochondrial function defects have recently been implicated in schizophrenia and bipolar disorder. We postulate that mood stabilizer treatment has a profound effect on mitochondrial function, synaptic plasticity, mitochondrial migration and direction of movement. Synaptoneurosomal preparations from rat pre-frontal cortex were obtained after 28 daily intraperitoneal injections of lithium, valproate and paliperidone. Phosphorylated proteins were identified using 2D-DIGE and nano LC-ESI tandem mass spectrometry. Lithium, valproate and paliperidone had a substantial and common effect on the phosphorylation state of specific actin, tubulin and myosin isoforms as well as other proteins associated with neurofilaments. Furthermore, different subunits from complex III and V of the electron transfer chain were heavily phosphorylated by treatment with these drugs indicating selective phosphorylation. Mood stabilizers have an effect on mitochondrial function, mitochondrial movement and the direction of this movement. The implications of these findings will contribute to novel insights regarding clinical treatment and the mode of action of these drugs.


Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets.
Dedifferentiated liposarcoma (DDLS) is a rare but aggressive cancer with high recurrence and low response rates to targeted therapies. Increasing treatment efficacy may require combinations of targeted agents that counteract the effects of multiple abnormalities. To identify a possible multicomponent therapy, we performed a combinatorial drug screen in a DDLS-derived cell line and identified cyclin-dependent kinase 4 (CDK4) and insulin-like growth factor 1 receptor (IGF1R) as synergistic drug targets. We measured the phosphorylation of multiple proteins and cell viability in response to systematic drug combinations and derived computational models of the signaling network. These models predict that the observed synergy in reducing cell viability with CDK4 and IGF1R inhibitors depends on the activity of the AKT pathway. Experiments confirmed that combined inhibition of CDK4 and IGF1R cooperatively suppresses the activation of proteins within the AKT pathway. Consistent with these findings, synergistic reductions in cell viability were also found when combining CDK4 inhibition with inhibition of either AKT or epidermal growth factor receptor (EGFR), another receptor similar to IGF1R that activates AKT. Thus, network models derived from context-specific proteomic measurements of systematically perturbed cancer cells may reveal cancer-specific signaling mechanisms and aid in the design of effective combination therapies.


Acyloxyacyl hydrolase is a host determinant of gut microbiome-mediated pelvic pain.
Dysbiosis of gut microbiota is associated with many pathologies, yet host factors modulating microbiota remain unclear. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition of chronic pelvic pain often with comorbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in patients with IC/BPS. We identified the locus encoding acyloxyacyl hydrolase, Aoah, as a modulator of pelvic pain severity in a murine IC/BPS model. AOAH-deficient mice spontaneously develop rodent correlates of pelvic pain, increased responses to induced pelvic pain models, voiding dysfunction, and anxious/depressive behaviors. Here, we report that AOAH-deficient mice exhibit dysbiosis of gastrointestinal (GI) microbiota. AOAH-deficient mice exhibit an enlarged cecum, a phenotype long associated with germ-free rodents, and a "leaky gut" phenotype. AOAH-deficient ceca showed altered gene expression consistent with inflammation, Wnt signaling, and urologic disease. 16S sequencing of stool revealed altered microbiota in AOAH-deficient mice, and GC-MS identified altered metabolomes. Cohousing AOAH-deficient mice with wild-type mice resulted in converged microbiota and altered predicted metagenomes. Cohousing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAH-deficient mice with stool slurry of wild-type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAH-deficient mice. Oral gavage of AOAH-deficient mice with anaerobes cultured from IC/BPS stool resulted in exacerbation of pelvic allodynia. Together, these data indicate that AOAH is a host determinant of normal gut microbiota, and dysbiosis associated with AOAH deficiency contributes to pelvic pain. These findings suggest that the gut microbiome is a potential therapeutic target for IC/BPS.


Thrombolysis for acute ischaemic stroke.
Most strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with thrombolytic drugs can restore blood flow before major brain damage has occurred and improve recovery after stroke in some people. Thrombolytic drugs, however, can also cause serious bleeding in the brain, which can be fatal. One drug, recombinant tissue plasminogen activator (rt-PA), is licensed for use in selected patients within 4.5 hours of stroke in Europe and within three hours in the USA. There is an upper age limit of 80 years in some countries, and a limitation to mainly non-severe stroke in others. Forty per cent more data are available since this review was last updated in 2009. To determine whether, and in what circumstances, thrombolytic therapy might be an effective and safe treatment for acute ischaemic stroke. We searched the Cochrane Stroke Group Trials Register (last searched November 2013), MEDLINE (1966 to November 2013) and EMBASE (1980 to November 2013). We also handsearched conference proceedings and journals, searched reference lists and contacted pharmaceutical companies and trialists. Randomised trials of any thrombolytic agent compared with control in people with definite ischaemic stroke. Two review authors applied the inclusion criteria, extracted data and assessed trial quality. We verified the extracted data with investigators of all major trials, obtaining additional unpublished data if available. We included 27 trials, involving 10,187 participants, testing urokinase, streptokinase, rt-PA, recombinant pro-urokinase or desmoteplase. Four trials used intra-arterial administration, while the rest used the intravenous route. Most data come from trials that started treatment up to six hours after stroke. About 44% of the trials (about 70% of the participants) were testing intravenous rt-PA. In earlier studies very few of the participants (0.5%) were aged over 80 years; in this update, 16% of participants are over 80 years of age due to the inclusion of IST-3 (53% of participants in this trial were aged over 80 years). Trials published more recently utilised computerised randomisation, so there are less likely to be baseline imbalances than in previous versions of the review. More than 50% of trials fulfilled criteria for high-grade concealment; there were few losses to follow-up for the main outcomes.Thrombolytic therapy, mostly administered up to six hours after ischaemic stroke, significantly reduced the proportion of participants who were dead or dependent (modified Rankin 3 to 6) at three to six months after stroke (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.78 to 0.93). Thrombolytic therapy increased the risk of symptomatic intracranial haemorrhage (OR 3.75, 95% CI 3.11 to 4.51), early death (OR 1.69, 95% CI 1.44 to 1.98; 13 trials, 7458 participants) and death by three to six months after stroke (OR 1.18, 95% CI 1.06 to 1.30). Early death after thrombolysis was mostly attributable to intracranial haemorrhage. Treatment within three hours of stroke was more effective in reducing death or dependency (OR 0.66, 95% CI 0.56 to 0.79) without any increase in death (OR 0.99, 95% CI 0.82 to 1.21; 11 trials, 2187 participants). There was heterogeneity between the trials. Contemporaneous antithrombotic drugs increased the risk of death. Trials testing rt-PA showed a significant reduction in death or dependency with treatment up to six hours (OR 0.84, 95% CI 0.77 to 0.93, P = 0.0006; 8 trials, 6729 participants) with significant heterogeneity; treatment within three hours was more beneficial (OR 0.65, 95% CI 0.54 to 0.80, P < 0.0001; 6 trials, 1779 participants) without heterogeneity. Participants aged over 80 years benefited equally to those aged under 80 years, particularly if treated within three hours of stroke. Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up (except for trials testing rt-PA, which had no effect on death at final follow-up). Further trials are needed to identify the latest time window, whether people with mild stroke benefit from thrombolysis, to find ways of reducing symptomatic intracranial haemorrhage and deaths, and to identify the environment in which thrombolysis may best be given in routine practice.


Comparison of the effect of honey and miconazole against Candida albicans in vitro.
One of the most common causes of vaginitis is candidiasis. The aim of this study is to compare the effect of honey and miconazole against Candida albicans, in vitro. The different W/V concentrations of honey were prepared at 20, 40, 60, 80, and 95% and different dilutions of miconazole were prepared in 0.05, 5, and 50 μg/ml. A microdilution of 100/000 cells per ml of a two-day old culture of Candida albicans was prepared in normal saline, after culturing the strain of PTCC 5027 in RPMI 1640 medium. Ten microliters of this dilution was added to 1 ml of the RPMI 1640 medium containing different concentrations of honey and to 1 ml of the RPMI 1640 medium containing different dilutions of miconazole. The cultures were incubated at 35°C for 12, 24, and 48 hours. The growth rate of Candida albicans was determined in the cultures. The results indicated that the honey prevented the growth of C. albicans greatly only at an 80% concentration, whereas, miconazole inhibited it completely. As Candida albicans is a normal vaginal flora, the inhibitory effect of honey without the fungicide effect is a very good trend in the treatment of vaginal candidiasis.


GRAP repair: single-stage reconstruction of hypospadias as an out-patient procedure.
A novel repair of the distal urethra with glanular and preputial reconstruction is described for distal penile hypospadias; 52 consecutive patients underwent this procedure without catheter splintage or urinary diversion. All voided without problems on the day of operation; 44 (85%) were treated as day cases, while the remaining 8 boys stayed in hospital for at least 1 night post-operatively for reasons not associated with the operation. Follow-up was complete and ranged from 15 to 30 months (mean 18). There was no evidence of meatal stenosis, phimosis or urethral stricture; 26 boys (50%) had associated chordee pre-operatively which was incompletely corrected in 2 (8%). These have a minor degree of chordee of glans on penile shaft and neither has required further treatment. Four boys (8%) developed partial wound breakdown which necessitated reconstruction in 2 and both of these have now been treated successfully. Functional and cosmetic results are excellent.


Autosomal recessive hydrotic ectodermal dysplasia.
First cousins, a male and a female, with a new type of hidrotic ectodermal dysplasia are described. They were each the result of first cousin marriage from the Egyptian Karaite community. They both had partial adontia, conical peg-shaped teeth, fine hair that did not grow long, normal sweating, eversion of lips, and pronounced facial similarity. The male had cleft lip on the right side while the female had a branchial cyst on the left side of the neck. The parents of both the cases were completely normal. The patients had distinct clinical similarity to the condition described by Witkop (1965) as 'Autosomal dominant dysplasia of nails and hypodontia' but the nails were less affected and the mode of inheritance was completely different.


Effects of behavioral and pharmacological therapies on peer reinforcement of deviancy in children with ADHD-only, ADHD and conduct problems, and controls.
This study compared the unique and combined effects of evidence-based treatments for ADHD-stimulant medication and behavior modification-on children's rates of reinforcement for deviant peer behavior (RDPB). Using a within-subjects design, 222 elementary school-age children attending a summer treatment program, including 151 children with ADHD (127 male), with and without comorbid conduct problems, and 71 control children (57 male), received varying combinations of behavior modification (no, low-intensity, and high-intensity) and methylphenidate (placebo, 0.15 mg/kg, 0.30 mg/kg, and 0.60 mg/kg). RDPB was measured through direct observation and compared across all behavior modification and medication conditions. Children with ADHD reinforced the deviant behavior of their peers at a significantly higher rate than control children in the absence of either intervention. However, that difference largely disappeared in the presence of both behavior modification and medication. Both low and high-intensity behavior modification, as well as medium (0.30 mg/kg) and high (0.60 mg/kg) doses of methylphenidate, significantly reduced the rate of ADHD children's RDPB to levels similar to the control group. Results indicate that although untreated children with ADHD do engage in RDPB at a greater rate than their non-ADHD peers, existing evidence-based interventions can substantially decrease the presence of RDPB, thereby limiting potential iatrogenic effects in group-based treatment settings.


The dynamic behavior of the early dental caries lesion in caries-active adults and implications.
To describe the full range of behavior of the visible, noncavitated, early caries lesion in caries-active adults with substantial fluoride exposure, and to consider implications. The data were from the Xylitol for Adult Caries Trial (X-ACT) collected annually for 33 months using condensed ICDAS caries threshold criteria. Individual tooth surfaces having a noncavitated caries lesion were included, and the patterns of transition to each subsequent annual clinical examination to sound, noncavitated or cavitated, filled or crowned were determined. The resulting sets of patterns for an individual tooth surface, looking forward from its first appearance as a noncavitated lesion, were combined into one of four behavior profiles classified as reversing, stable, oscillating, or continuously progressing, or were excluded if not part of the caries continuum. The distributions of profile types were assessed using the Rao-Scott chi-square test, which adjusts for clustering of tooth surfaces within teeth. Inter- and intra-examiner kappa scores demonstrated acceptable calibration at baseline and annually. 8084 tooth surfaces from 543 subjects were included. The distribution of profile types differed significantly between coronal and root surfaces. Overall, two-thirds of all coronal noncavitated lesions were first seen at baseline, half reversed, over a fifth were stable, 15% oscillated, and only 8.3% progressed to cavitation, filled, or crowned in 33 months or less (6.3% consistently Progressed plus 2.0% inconsistently, a subset of oscillating, which oscillated before progressing to cavitation). Approximal, smooth, and occlusal coronal surfaces each were significantly different in their individual distributions of profile types. Xylitol showed no significant and consistent effect on this distribution by tooth surface type. This was in keeping with the X-ACT's lack of effect of xylitol at the noncavitated plus cavitated lesion thresholds combined. This study demonstrated the full dynamic range of early caries lesion behavior. The great majority were not progressive, and few (8.3%) became cavitated over 33 months in caries-active adults using fluorides. Important caries management implications favoring recorded longitudinal monitoring, prevention of active risks, and minimal restoration only after direct visual determination of cavitation are discussed.


The SMARCA2/4 ATPase Domain Surpasses the Bromodomain as a Drug Target in SWI/SNF-Mutant Cancers: Insights from cDNA Rescue and PFI-3 Inhibitor Studies.
The SWI/SNF multisubunit complex modulates chromatin structure through the activity of two mutually exclusive catalytic subunits, SMARCA2 and SMARCA4, which both contain a bromodomain and an ATPase domain. Using RNAi, cancer-specific vulnerabilities have been identified in SWI/SNF-mutant tumors, including SMARCA4-deficient lung cancer; however, the contribution of conserved, druggable protein domains to this anticancer phenotype is unknown. Here, we functionally deconstruct the SMARCA2/4 paralog dependence of cancer cells using bioinformatics, genetic, and pharmacologic tools. We evaluate a selective SMARCA2/4 bromodomain inhibitor (PFI-3) and characterize its activity in chromatin-binding and cell-functional assays focusing on cells with altered SWI/SNF complex (e.g., lung, synovial sarcoma, leukemia, and rhabdoid tumors). We demonstrate that PFI-3 is a potent, cell-permeable probe capable of displacing ectopically expressed, GFP-tagged SMARCA2-bromodomain from chromatin, yet contrary to target knockdown, the inhibitor fails to display an antiproliferative phenotype. Mechanistically, the lack of pharmacologic efficacy is reconciled by the failure of bromodomain inhibition to displace endogenous, full-length SMARCA2 from chromatin as determined by in situ cell extraction, chromatin immunoprecipitation, and target gene expression studies. Furthermore, using inducible RNAi and cDNA complementation (bromodomain- and ATPase-dead constructs), we unequivocally identify the ATPase domain, and not the bromodomain of SMARCA2, as the relevant therapeutic target with the catalytic activity suppressing defined transcriptional programs. Taken together, our complementary genetic and pharmacologic studies exemplify a general strategy for multidomain protein drug-target validation and in case of SMARCA2/4 highlight the potential for drugging the more challenging helicase/ATPase domain to deliver on the promise of synthetic-lethality therapy.


Interaction of the Anti-Proliferative GPER Inverse Agonist ERα17p with the Breast Cancer Cell Plasma Membrane: From Biophysics to Biology.
The peptide ERα17p, which corresponds to the 295-311 fragment of the hinge/AF2 domains of the human estrogen receptor α (ERα), exerts apoptosis in breast cancer cells through a mechanism involving the G protein-coupled estrogen-dependent receptor GPER. Besides this receptor-mediated mechanism, we have detected a direct interaction (Kd value in the micromolar range) of this peptide with lipid vesicles mimicking the plasma membrane of eukaryotes. The reversible and not reversible pools of interacting peptide may correspond to soluble and aggregated membrane-interacting peptide populations, respectively. By using circular dichroism (CD) spectroscopy, we have shown that the interaction of the peptide with this membrane model was associated with its folding into β sheet. A slight leakage of the 5(6)-fluorescein was also observed, indicating lipid bilayer permeability. When the peptide was incubated with living breast cancer cells at the active concentration of 10 μM, aggregates were detected at the plasma membrane under the form of spheres. This insoluble pool of peptide, which seems to result from a fibrillation process, is internalized in micrometric vacuoles under the form of fibrils, without evidence of cytotoxicity, at least at the microscopic level. This study provides new information on the interaction of ERα17p with breast cancer cell membranes as well as on its mechanism of action, with respect to direct membrane effects.


Fixed-target protein serial microcrystallography with an x-ray free electron laser.
We present results from experiments at the Linac Coherent Light Source (LCLS) demonstrating that serial femtosecond crystallography (SFX) can be performed to high resolution (~2.5 Å) using protein microcrystals deposited on an ultra-thin silicon nitride membrane and embedded in a preservation medium at room temperature. Data can be acquired at a high acquisition rate using x-ray free electron laser sources to overcome radiation damage, while sample consumption is dramatically reduced compared to flowing jet methods. We achieved a peak data acquisition rate of 10 Hz with a hit rate of ~38%, indicating that a complete data set could be acquired in about one 12-hour LCLS shift using the setup described here, or in even less time using hardware optimized for fixed target SFX. This demonstration opens the door to ultra low sample consumption SFX using the technique of diffraction-before-destruction on proteins that exist in only small quantities and/or do not produce the copious quantities of microcrystals required for flowing jet methods.


Architectural and functional heterogeneity of hematopoietic stem/progenitor cells in non-del(5q) myelodysplastic syndromes.
Myelodysplastic syndromes (MDSs) are hematopoietic stem cell disorders in which recurrent mutations define clonal hematopoiesis. The origin of the phenotypic diversity of non-del(5q) MDS remains unclear. Here, we investigated the clonal architecture of the CD34+CD38- hematopoietic stem/progenitor cell (HSPC) compartment and interrogated dominant clones for MDS-initiating cells. We found that clones mainly accumulate mutations in a linear succession with retention of a dominant subclone. The clone detected in the long-term culture-initiating cell compartment that reconstitutes short-term human hematopoiesis in xenotransplantation models is usually the dominant clone, which gives rise to the myeloid and to a lesser extent to the lymphoid lineage. The pattern of mutations may differ between common myeloid progenitors (CMPs), granulomonocytic progenitors (GMPs), and megakaryocytic-erythroid progenitors (MEPs). Rare STAG2 mutations can amplify at the level of GMPs, from which it may drive the transformation to acute myeloid leukemia. We report that major truncating BCOR gene mutation affecting HSPC and CMP was beneath the threshold of detection in GMP or MEP. Consistently, BCOR knock-down (KD) in normal CD34+ progenitors modifies their granulocytic and erythroid differentiation. Clonal architecture of the HSPC compartment and mutations selected during differentiation contribute to the phenotypic heterogeneity of MDS. Defining the hierarchy of driver mutations provides insights into the process of transformation and may guide the search for novel therapeutic strategies.


Platelet aggregation in experimental diabetes and experimental galactosemia.
Platelet aggregation and related plasma factors have been studied in experimentally diabetic dogs, experimentally galactosemic dogs, and in normal dogs. Platelet aggregation, when induced in vitro by ADP (up to 22 microM) or collagen (up to 4 micrograms/ml), was not significantly different from normal in the diabetic or galactosemic dogs. Plasma (platelet-deficient) from the diabetic or galactosemic dogs did not enhance ADP-induced aggregation of normal canine platelets. Fibrinogen concentration in blood tended to be elevated in hyperglycemic diabetic dogs, and was significantly correlated with the levels of HbA1 and blood glucose, whereas galactosemic animals had normal fibrinogen concentrations. The quantity of 6-keto prostaglandin F1 alpha released from aortas of diabetic dogs was less than that released from aortas of normal dogs. Since alloxan-diabetic dogs and galactosemic dogs develop microaneurysms, occluded capillaries, and other retinal lesions characteristic of diabetic retinopathy in human patients, these studies suggest that retinopathy can develop in the absence of extraordinary in vitro platelet aggregation.


A new species of eagle ray Aetobatus narutobiei from the Northwest Pacific: an example of the critical role taxonomy plays in fisheries and ecological sciences.
Recent taxonomic and molecular work on the eagle rays (Family Myliobatidae) revealed a cryptic species in the northwest Pacific. This species is formally described as Aetobatus narutobiei sp. nov. and compared to its congeners. Aetobatus narutobiei is found in eastern Vietnam, Hong Kong, China, Korea and southern Japan. It was previously considered to be conspecific with Aetobatus flagellum, but these species differ in size, structure of the NADH2 and CO1 genes, some morphological and meristic characters and colouration. Aetobatus narutobiei is particularly abundant in Ariake Bay in southern Japan where it is considered a pest species that predates heavily on farmed bivalve stocks and is culled annually as part of a 'predator control' program. The discovery of A. narutobiei highlights the paucity of detailed taxonomic research on this group of rays. This discovery impacts on current conservation assessments of A. flagellum and these need to be revised based on the findings of this study.


Interleukin-6 Is an Early Plasma Marker of Severe Postoperative Complications in Thoracic Surgery: Exploratory Results From a Substudy of a Randomized Controlled Multicenter Trial.
Postoperative complications in surgery are a significant burden, not only for the patients but also economically. While several predicting factors have already been identified, it is still not well known if increased levels of inflammatory markers in the immediate perioperative phase correlate with a higher incidence of postoperative complications. This study aimed to evaluate which patient characteristics and intraoperative parameters correlate with increased plasma values of monocyte chemoattractant protein 1 (MCP-1) and interleukin 6 (IL-6) of thoracic surgery patients. A second goal was to explore whether MCP-1 and IL-6 are associated with the incidence of postoperative complications. We hypothesized that there is a positive association between inflammatory markers and the occurrence of complications within 6 months after surgery. This is a substudy of a recent randomized controlled trial, which defined the effect of desflurane versus propofol anesthesia on morbidity and mortality in patients undergoing thoracic surgery. MCP-1 and IL-6 were determined in plasma obtained before and 30 minutes after 1-lung ventilation, 6 hours after surgery, and on postoperative days 1 and 2. Complications were recorded for 6 months. Mixed linear models were used to examine factors associated with MCP-1 and IL-6 levels. Logistic regression models and receiver operating characteristic curves were used to determine the association between MCP-1 and IL-6 and postoperative complications. In the original study, 460 patients were included, MCP-1 and IL-6 levels were determined in 428 patients. MCP-1 was positively associated with the duration of surgery (P = .016), whereas IL-6 levels increased with both the length (P < .001) and invasiveness of lung surgery (thoracoscopic wedge resection or lobectomy versus open lobectomy, P = .005; thoracoscopic wedge resection or lobectomy versus pneumonectomy, P = .021). In an exploratory approach, elevated IL-6 plasma peaks were associated with the occurrence of severe complications defined as Clavien-Dindo score grade ≥IVa during the postoperative phase up to 6 months after thoracic surgery (P = .006). In summary, this substudy reveals factors, which correlate with high MCP-1 and IL-6 values. Moreover, higher IL-6 seems to be associated with postoperative severe complications. Perioperative IL-6 monitoring might be helpful for risk estimation in the perioperative setting of patients after lung surgery.


Behavioral patterns of bats at a wind turbine confirm seasonality of fatality risk.
Bat fatalities at wind energy facilities in North America are predominantly comprised of migratory, tree-dependent species, but it is unclear why these bats are at higher risk. Factors influencing bat susceptibility to wind turbines might be revealed by temporal patterns in their behaviors around these dynamic landscape structures. In northern temperate zones, fatalities occur mostly from July through October, but whether this reflects seasonally variable behaviors, passage of migrants, or some combination of factors remains unknown. In this study, we examined video imagery spanning one year in the state of Colorado in the United States, to characterize patterns of seasonal and nightly variability in bat behavior at a wind turbine. We detected bats on 177 of 306 nights representing approximately 3,800 hr of video and > 2,000 discrete bat events. We observed bats approaching the turbine throughout the night across all months during which bats were observed. Two distinct seasonal peaks of bat activity occurred in July and September, representing 30% and 42% increases in discrete bat events from the preceding months June and August, respectively. Bats exhibited behaviors around the turbine that increased in both diversity and duration in July and September. The peaks in bat events were reflected in chasing and turbine approach behaviors. Many of the bat events involved multiple approaches to the turbine, including when bats were displaced through the air by moving blades. The seasonal and nightly patterns we observed were consistent with the possibility that wind turbines invoke investigative behaviors in bats in late summer and autumn coincident with migration and that bats may return and fly close to wind turbines even after experiencing potentially disruptive stimuli like moving blades. Our results point to the need for a deeper understanding of the seasonality, drivers, and characteristics of bat movement across spatial scales.


The first case of benign multicystic mesothelioma presenting as a splenic mass.
Multicystic mesothelioma (MM) is a relatively rare tumour arising in the pelvic peritoneum of the tuboovarian region of young woman. Exceptionally, MM occurs on the serosal surfaces of various organs including kidney, bladder, lymph nodes, and liver. We report here the first case of MM wherein a 58-year-old woman with a previous history of endometriosis of the right ovary presented with a large multicystic mass of the spleen. The diagnosis of MM was made on a surgical specimen after splenectomy. A histopathologic examination is always necessary for the diagnosis of MM which should be differentiated from other lesions particularly from cystic lymphangioma. At one year follow-up, the patient had no evidence of recurrence. Despite the high frequency of local recurrences, MM is a benign lesion and 'en bloc' surgical excision with prolonged follow-ups is the treatment of choice.


A Systematic Review of the Incidence, Risk Factors and Case Fatality Rates of Invasive Nontyphoidal Salmonella (iNTS) Disease in Africa (1966 to 2014).
This study systematically reviews the literature on the occurrence, incidence and case fatality rate (CFR) of invasive nontyphoidal Salmonella (iNTS) disease in Africa from 1966 to 2014. Data on the burden of iNTS disease in Africa are sparse and generally have not been aggregated, making it difficult to describe the epidemiology that is needed to inform the development and implementation of effective prevention and control policies. This study involved a comprehensive search of PubMed and Embase databases. It documents the geographical spread of iNTS disease over time in Africa, and describes its reported incidence, risk factors and CFR. We found that Nontyphoidal Salmonella (NTS) have been reported as a cause of bacteraemia in 33 out of 54 African countries, spanning the five geographical regions of Africa, and especially in sub-Saharan Africa since 1966. Our review indicates that NTS have been responsible for up to 39% of community acquired blood stream infections in sub-Saharan Africa with an average CFR of 19%. Salmonella Typhimurium and Enteritidis are the major serovars implicated and together have been responsible for 91%% of the cases of iNTS disease, (where serotype was determined), reported in Africa. The study confirms that iNTS disease is more prevalent amongst Human Immunodeficiency Virus (HIV)-infected individuals, infants, and young children with malaria, anaemia and malnutrition. In conclusion, iNTS disease is a substantial cause of community-acquired bacteraemia in Africa. Given the high morbidity and mortality of iNTS disease in Africa, it is important to develop effective prevention and control strategies including vaccination.


Significant neurological presentations in commando trained personnel: case studies and consideration of differential diagnosis.
A 27-year-old Royal Marine presented to his sickbay following two episodes of sudden onset visual disturbance. A subsequent MRI Scan demonstrated ischaemic changes in the territory of his right posterior cerebral artery. Transthoracic echocardiography was normal but a bubble contrast study was strongly positive indicating the presence of a relatively large patent foramen ovale (PFO). He underwent endovascular closure of his patent foramen ovale and was subsequently upgraded back to full duties. A 35-year-old Army Sergeant presented with sudden onset collapse, right sided weakness, dysarthria and confusion. He was airlifted to a Host Nation hospital and following a normal CT head underwent thrombolysis in the Emergency Department. This was unsuccessful but a CT guided embolectomy led to complete resolution of symptoms. Subsequent transthoracic echo revealed a PFO. He underwent endovascular closure and has since been returned to full duties. The incidence of PFO is common affecting 27% of the population but the incidence of ischaemic stroke in young adults (aged 15-45 years old) is rare. This maybe linked to the size of the PFOs in symptomatic individuals. These case reports emphasise the requirement for further investigation of individuals presenting with collapse and persisting neurology. Differential diagnosis and initial management for primary care and pre-hospital clinicians is also reviewed.


Fabrication of Defect-Free P84® Polyimide Hollow Fiber for Gas Separation: Pathway to Formation of Optimized Structure.
The elimination of the additional defect healing post-treatment step in asymmetric hollow fiber manufacturing would result in a significant reduction in membrane production cost. However, obtaining integrally skinned polymeric asymmetric hollow fiber membranes with an ultrathin and defect-free selective layer is quite challenging. In this study, P84® asymmetric hollow fiber membranes with a highly thin (~56 nm) defect-free skin were successfully fabricated by fine tuning the dope composition and spinning parameters using volatile additive (tetrahydrofuran, THF) as key parameters. An extensive experimental and theoretical study of the influence of volatile THF addition on the solubility parameter of the N-methylpyrrolidone/THF solvent mixture was performed. Although THF itself is not a solvent for P84®, in a mixture with a good solvent for the polymer, like N-Methyl-2-pyrrolidone (NMP), it can be dissolved at high THF concentrations (NMP/THF ratio > 0.52). The as-spun fibers had a reproducible ideal CO2/N2 selectivity of 40, and a CO2 permeance of 23 GPU at 35 °C. The fiber production can be scaled-up with retention of the selectivity.


Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners' Oral Contraception Study.
To see if the mortality risk among women who have used oral contraceptives differs from that of never users. Prospective cohort study started in 1968 with mortality data supplied by participating general practitioners, National Health Service central registries, or both. 1400 general practices throughout the United Kingdom. 46 112 women observed for up to 39 years, resulting in 378 006 woman years of observation among never users of oral contraception and 819 175 among ever users. Directly standardised adjusted relative risks between never and ever users for all cause and cause specific mortality. 1747 deaths occurred in never users of oral contraception and 2864 in ever users. Compared with never users, ever users of oral contraception had a significantly lower rate of death from any cause (adjusted relative risk 0.88, 95% confidence interval 0.82 to 0.93). They also had significantly lower rates of death from all cancers; large bowel/rectum, uterine body, and ovarian cancer; main gynaecological cancers combined; all circulatory disease; ischaemic heart disease; and all other diseases. They had higher rates of violent deaths. No association between overall mortality and duration of oral contraceptive use was observed, although some disease specific relations were apparent. An increased relative risk of death from any cause between ever users and never users was observed in women aged under 45 years who had stopped using oral contraceptives 5-9 years previously but not in those with more distant use. The estimated absolute reduction in all cause mortality among ever users of oral contraception was 52 per 100 000 woman years. Oral contraception was not associated with an increased long term risk of death in this large UK cohort; indeed, a net benefit was apparent. The balance of risks and benefits, however, may vary globally, depending on patterns of oral contraception usage and background risk of disease.


Simultaneous detection of electronic structure changes from two elements of a bifunctional catalyst using wavelength-dispersive X-ray emission spectroscopy and in situ electrochemistry.
Multielectron catalytic reactions, such as water oxidation, nitrogen reduction, or hydrogen production in enzymes and inorganic catalysts often involve multimetallic clusters. In these systems, the reaction takes place between metals or metals and ligands to facilitate charge transfer, bond formation/breaking, substrate binding, and release of products. In this study, we present a method to detect X-ray emission signals from multiple elements simultaneously, which allows for the study of charge transfer and the sequential chemistry occurring between elements. Kβ X-ray emission spectroscopy (XES) probes charge and spin states of metals as well as their ligand environment. A wavelength-dispersive spectrometer based on the von Hamos geometry was used to disperse Kβ signals of multiple elements onto a position detector, enabling an XES spectrum to be measured in a single-shot mode. This overcomes the scanning needs of the scanning spectrometers, providing data free from temporal and normalization errors and therefore ideal to follow sequential chemistry at multiple sites. We have applied this method to study MnOx-based bifunctional electrocatalysts for the oxygen evolution reaction (OER) and the oxygen reduction reaction (ORR). In particular, we investigated the effects of adding a secondary element, Ni, to form MnNiOx and its impact on the chemical states and catalytic activity, by tracking the redox characteristics of each element upon sweeping the electrode potential. The detection scheme we describe here is general and can be applied to time-resolved studies of materials consisting of multiple elements, to follow the dynamics of catalytic and electron transfer reactions.