Residual beta-cell function and metabolic stability in insulin-dependent diabetes mellitus.
Using the modified sensitive method of measurement of urinary C-peptide immunoreactivity (CPR) excretion, we studied whether positive correlation between residual beta-cell function and metabolic consequence is present in insulin-dependent diabetes mellitus (IDDM) or not. After urinary CPR excretions were measured for 3 days in 40 IDDM, they were divided to three groups: group A, urinary CPR excretion less than 1 microgram/day (n = 16); group B, 1-4 micrograms/day (n = 15); group C, greater than or equal to 4 micrograms/day (n = 9). All subjects were treated with intensive insulin therapy for 1-2 months, and 1) fasting blood glucose (FBS) for one week, 2) 24-hr urinary sugar excretion (US) for one week, 3) M-value for daily variation of blood glucose, and 4) hemoglobin A1 (HbA1) were measured before and after intensive insulin treatment. And, we calculated mean and standard deviation (S.D.) of FBS and US. After intensive insulin therapy, a significant difference of the S.D. of FBS was seen between group A and group B (p less than 0.01). And, a significant difference of M-value was found between group A and group B (p less than 0.05). As significant differences were observed between group A and group B, which could not be divided into two groups by conventional CPR measurement, it seems likely that metabolic stability in IDDM mainly result from minimal remaining residual beta-cell function.


Feasibility of intravenous administration of landiolol hydrochloride for multislice computed tomography coronary angiography: initial experience.
The feasibility of using landiolol hydrochloride in multislice computed tomography (MSCT) coronary angiography (CAG) was investigated in the present study. Landiolol hydrochloride was continuously administered intravenously to 145 patients before starting MSCT CAG. Hemodynamic changes [blood pressure (BP), heart rate (HR)], adverse effects, image quality using a 5-point scale, and accuracy of detecting significant stenoses (>or=50% reduction in lumen diameter) were evaluated. HR was significantly reduced during injection, and quickly recovered after cessation of administration, of landiolol hydrochloride. Neither significant changes in BP nor adverse effects occurred. Among visible segments, 1,869 (94%) displayed an excellent (83%) or good (11%) image quality. Diagnostic accuracy was evaluated in 39 of 145 patients who underwent invasive CAG within 3 weeks after MSCT. The sensitivity, specificity, positive predictive value, and negative predictive value of MSCT CAG for detection of significant stenoses in assessable segments were excellent (per artery: 94%, 98%, 92%, and 100%; per segment: 92%, 98%, 94%, and 96%, respectively). Intravenous administration of landiolol hydrochloride reduces HR without a significant reduction in BP, which enables favorable image quality and diagnostic accuracy without adverse effects, making this agent feasible as a premedication for MSCT CAG.


Musical literacy shifts asymmetries in the ventral visual cortex.
The acquisition of literacy has a profound impact on the functional specialization and lateralization of the visual cortex. Due to the overall lateralization of the language network, specialization for printed words develops in the left occipitotemporal cortex, allegedly inducing a secondary shift of visual face processing to the right, in literate as compared to illiterate subjects. Applying the same logic to the acquisition of high-level musical literacy, we predicted that, in musicians as compared to non-musicians, occipitotemporal activations should show a leftward shift for music reading, and an additional rightward push for face perception. To test these predictions, professional musicians and non-musicians viewed pictures of musical notation, faces, words, tools and houses in the MRI, and laterality was assessed in the ventral stream combining ROI and voxel-based approaches. The results supported both predictions, and allowed to locate the leftward shift to the inferior temporal gyrus and the rightward shift to the fusiform cortex. Moreover, these laterality shifts generalized to categories other than music and faces. Finally, correlation measures across subjects did not support a causal link between the leftward and rightward shifts. Thus the acquisition of an additional perceptual expertise extensively modifies the laterality pattern in the visual system.


Issues relating to the inclusion of high-dose chemotherapy in breast cancer treatment guidelines.
The development of guidelines for the use of high-dose chemotherapy in the treatment of breast cancer is a challenging task. The absence of large amounts of data from prospective, randomized, phase III clinical trials, and the variability of patient populations and treatment strategies in phase II studies mean that these guidelines have to be developed in the absence of conclusive clinical data. Nonetheless, the available information suggests strategies for incorporating this therapy into the care of certain patients with breast cancer.


Reference Genomes from Distantly Related Species Can Be Used for Discovery of Single Nucleotide Polymorphisms to Inform Conservation Management.
Threatened species recovery programmes benefit from incorporating genomic data into conservation management strategies to enhance species recovery. However, a lack of readily available genomic resources, including conspecific reference genomes, often limits the inclusion of genomic data. Here, we investigate the utility of closely related high-quality reference genomes for single nucleotide polymorphism (SNP) discovery using the critically endangered kakī/black stilt (Himantopus novaezelandiae) and four Charadriiform reference genomes as proof of concept. We compare diversity estimates (i.e., nucleotide diversity, individual heterozygosity, and relatedness) based on kakī SNPs discovered from genotyping-by-sequencing and whole genome resequencing reads mapped to conordinal (killdeer, Charadrius vociferus), confamilial (pied avocet, Recurvirostra avosetta), congeneric (pied stilt, Himantopus himantopus) and conspecific reference genomes. Results indicate that diversity estimates calculated from SNPs discovered using closely related reference genomes correlate significantly with estimates calculated from SNPs discovered using a conspecific genome. Congeneric and confamilial references provide higher correlations and more similar measures of nucleotide diversity, individual heterozygosity, and relatedness. While conspecific genomes may be necessary to address other questions in conservation, SNP discovery using high-quality reference genomes of closely related species is a cost-effective approach for estimating diversity measures in threatened species.


Virus-derived gene expression and RNA interference vector for grapevine.
The improvement of the agricultural and wine-making qualities of the grapevine (Vitis vinifera) is hampered by adherence to traditional varieties, the recalcitrance of this plant to genetic modifications, and public resistance to genetically modified organism (GMO) technologies. To address these challenges, we developed an RNA virus-based vector for the introduction of desired traits into grapevine without heritable modifications to the genome. This vector expresses recombinant proteins in the phloem tissue that is involved in sugar transport throughout the plant, from leaves to roots to berries. Furthermore, the vector provides a powerful RNA interference (RNAi) capability of regulating the expression of endogenous genes via virus-induced gene-silencing (VIGS) technology. Additional advantages of this vector include superb genetic capacity and stability, as well as the swiftness of technology implementation. The most significant applications of the viral vector include functional genomics of the grapevine and disease control via RNAi-enabled vaccination against pathogens or invertebrate pests.


Molecularly imprinted solid phase extraction for simultaneous determination of Δ9-tetrahydrocannabinol and its main metabolites by gas chromatography-mass spectrometry in urine samples.
In presented paper analytical method based on solid-phase extraction using molecularly imprinted polymer and gas chromatography-mass spectrometry has been developed and validated for the confirmation of THC, THC-OH and THC-COOH in urine samples. Non-covalent molecularly imprinted polymers of THC-OH were prepared using different functional monomers (methacrylic acid, 4-vinylpyridine, and 2-hydroxyethyl methacrylate), ethylene glycol dimethacrylate as a cross-linker and 2,2'-azobis-isobutyronitrile as an initiator of radical polymerization. Analytes were extracted from urine samples using prepared polymer sorbent with highest binding selectivity and capability. Before extraction, urine samples were hydrolyzed with alkaline. Elution was performed with chloroform:ethyl acetate (60:40, v/v). Dry extracts were silylated with BSTFA+1% TMCS. Detection and quantification were performed using gas chromatography-mass spectrometry in single ion recording mode. The developed method was linear over the range from LOQ to 150 ng mL(-1) for all three analytes. For THC, THC-OH and THC-COOH LOD was 2.5, 1 and 1 ng mL(-1), and LOQ was 3, 2 and 2 ng mL(-1), respectively. The precision, accuracy, recovery and matrix effect were investigated at 5, 25 and 50 ng mL(-1). In the investigated concentration range recoveries were 71.9% for THC, 78.6% for THC-OH and 75.2% for THC-COOH. Matrix effect was not significant (<10%) for all analytes in the concentration range from 5 ng mL(-1) to 50 ng mL(-1). Extraction recovery on non-imprinted polymer was relatively high indicating high non-specific binding. Optimized and validated method was applied to 15 post-mortem urine samples.


[Democratic management and new craft: concepts to rethink integration between autonomy and responsibility in health work].
This article analyses tensions between the dominant management rationality and health work. By means of philosophical concepts and bibliography revision it was found that clinical and public health practices are structured as praxis, a term defined by Aristotle. It does not work automatically, depending on a human being to reflect and decide in most situations, making mediation between established knowledge and singular context. So, it is recommended the adoption of a management model that enables and favors the combination of professional autonomy and sanitary responsibility.


Iterative cluster-NMA: A tool for generating conformational transitions in proteins.
Computational models provide insight into the structure-function relationship in proteins. These approaches, especially those based on normal mode analysis, can identify the accessible motion space around a given equilibrium structure. The large magnitude, collective motions identified by these methods are often well aligned with the general direction of the expected conformational transitions. However, these motions cannot realistically be extrapolated beyond the local neighborhood of the starting conformation. In this article, the iterative cluster-NMA (icNMA) method is presented for traversing the energy landscape from a starting conformation to a desired goal conformation. This is accomplished by allowing the evolving geometry of the intermediate structures to define the local accessible motion space, and thus produce an appropriate displacement. Following the derivation of the icNMA method, a set of sample simulations are performed to probe the robustness of the model. A detailed analysis of beta1,4-galactosyltransferase-T1 is also given, to highlight many of the capabilities of icNMA. Remarkably, during the transition, a helix is seen to be extended by an additional turn, emphasizing a new unknown role for secondary structures to absorb slack during transitions. The transition pathway for adenylate kinase, which has been frequently studied in the literature, is also discussed.


Percutaneous venting gastrostomy/gastrojejunostomy for malignant bowel obstruction: a qualitative study.
Malignant bowel obstruction (MBO) is a complication of advanced malignancy and is associated with a short prognosis. MBO can infrequently be reversed by surgery or stenting. The focus of treatment is usually symptomatic management, of which percutaneous venting gastrostomy/gastrojejunostomy (PVG) is one consideration. There is little data considering the impact of PVG on quality of life; we therefore aimed to explore this. We identified patients with a PVG inserted for MBO and those who consented to participate were interviewed. The interviews were audio recorded, transcribed and analysed using Framework. Alongside patient interviews, a data collection tool was designed and used to record patient demographics and medical information, enabling us to contextualise individual patients' experiences. 11 patients were interviewed and 10 patients' data were analysed (1 patient withdrew). No patients regretted having a PVG and many benefitted symptomatically and psychosocially. Challenges encountered included practical issues, pain and PVG tube complications. The analysis provided a detailed insight into the impact of PVG insertion and demonstrated that each patient's experience is shaped by a complex interplay of individual factors, thereby highlighting the need to improve referral criteria and individualise patient selection. Other service improvements include enhancing information provision for patients and training for healthcare professionals, thus aiming to mitigate the challenges experienced. Our study is the first in-depth exploration of patients' experiences of PVG at a tertiary cancer centre. Ensuring that the insights from this study are fed back to guide future service provision is critical in enhancing future patient experiences.


Independent Validation of Genomic Prediction in Strawberry Over Multiple Cycles.
The University of Florida strawberry (Fragaria × ananassa) breeding program has implemented genomic prediction (GP) as a tool for choosing outstanding parents for crosses over the last five seasons. This has allowed the use of some parents 1 year earlier than with traditional methods, thus reducing the duration of the breeding cycle. However, as the number of breeding cycles increases over time, greater knowledge is needed on how multiple cycles can be used in the practical implementation of GP in strawberry breeding. Advanced selections and cultivars totaling 1,558 unique individuals were tested in field trials for yield and fruit quality traits over five consecutive years and genotyped for 9,908 SNP markers. Prediction of breeding values was carried out using Bayes B models. Independent validation was carried out using separate trials/years as training (TRN) and testing (TST) populations. Single-trial predictive abilities for five polygenic traits averaged 0.35, which was reduced to 0.24 when individuals common across trials were excluded, emphasizing the importance of relatedness among training and testing populations. Training populations including up to four previous breeding cycles increased predictive abilities, likely due to increases in both training population size and relatedness. Predictive ability was also strongly influenced by heritability, but less so by changes in linkage disequilibrium and effective population size. Genotype by year interactions were minimal. A strategy for practical implementation of GP in strawberry breeding is outlined that uses multiple cycles to predict parental performance and accounts for traits not included in GP models when constructing crosses. Given the importance of relatedness to the success of GP in strawberry, future work could focus on the optimization of relatedness in the design of TRN and TST populations to increase predictive ability in the short-term without compromising long-term genetic gains.


Divergent chemokine receptor expression and the consequence for human IgG4 B cell responses.
IgG4 antibodies are unique to humans. IgG4 is associated with tolerance during immunotherapy in allergy, but also with pathology, as in pemphigus vulgaris and IgG4-related disease. Its induction is largely restricted to nonmicrobial antigens, and requires repeated or prolonged antigenic stimulation, for reasons poorly understood. An important aspect in generating high-affinity IgG antibodies is chemokine receptor-mediated migration of B cells into appropriate niches, such as germinal centers. Here, we show that compared to IgG1 B cells, circulating IgG4 B cells express lower levels of CXCR3, CXCR4, CXCR5, CCR6, and CCR7, chemokine receptors involved in GC reactions and generation of long-lived plasma cells. This phenotype was recapitulated by in vitro priming of naive B cells with an IgG4-inducing combination of TFH /TH2 cytokines. Consistent with these observations, we found a low abundance of IgG4 B cells in secondary lymphoid tissues in vivo, and the IgG4 antibody response is substantially more short-lived compared to other IgG subclasses in patient groups undergoing CD20+ B cell depletion therapy with rituximab. These results prompt the hypothesis that factors needed to form IgG4 B cells restrain at the same time the induction of a robust migratory phenotype that could support a long-lived IgG4 antibody response.


BAR proteins in cancer and blood disorders.
Remodeling of the membrane and cytoskeleton is involved in a wide range of normal and pathologic cellular function. These are complex, highly-coordinated biochemical and biophysical processes involving dozens of proteins. Serving as a scaffold for a variety of proteins and possessing a domain that interacts with plasma membranes, the BAR family of proteins contribute to a range of cellular functions characterized by membrane and cytoskeletal remodeling. There are several subgroups of BAR proteins: BAR, N-BAR, I-BAR, and F-BAR. They differ in their ability to induce angles of membrane curvature and in their recruitment of effector proteins. Evidence is accumulating that BAR proteins contribute to cancer cell invasion, T cell trafficking, phagocytosis, and platelet production. In this review, we discuss the physiological function of BAR proteins and discuss how they contribute to blood and cancer disorders.


Mesenchymal stem cells for acute lung injury: preclinical evidence.
Several experimental studies have suggested that mesenchymal stem cells may have value for the treatment of clinical disorders, including myocardial infarction, diabetes, acute renal failure, sepsis, and acute lung injury. In preclinical studies, mesenchymal stem cells have been effective in reducing lung injury from endotoxin, live bacteria, bleomycin, and hyperoxia. In some studies, the cultured medium from mesenchymal stem cells has been as effective as the mesenchymal stem cells themselves. Several paracrine mediators that can mediate the effect of mesenchymal stem cells have been identified, including interleukin-10, interleukin-1ra, keratinocyte growth factor, and prostaglandin E2. Further preclinical studies are needed, as is planning for clinical trials for acute lung injury.


Binge-Watching and Mental Health Problems: A Systematic Review and Meta-Analysis.
Binge-watching, the viewing of online videos or streamed content, may be associated with different types of mental health problems. The present study aimed to investigate the associations between binge-watching and five mental health concerns including depression, loneliness, sleep problems, anxiety, and stress. Academic databases of PubMed, Scopus, Web of Science, ProQuest, PsycINFO, and Psych Articles were systematically searched through February of 2022. The Newcastle-Ottawa Scale was used to assess the methodological quality. A meta-analysis was performed on Fisher's z values as effect sizes, using a random effect model. Publication bias, small study effect, and moderators in this association were assessed. Binge-watching was significantly associated with the five types of mental health concerns with the most robust correlations found with stress (0.32) and anxiety (0.25). Stronger associations between binge-watching and two types of mental health problems (depression and sleep problems) were found during the COVID-19 pandemic than before the pandemic. Moreover, stronger associations between binge-watching and two types of mental health problems (stress and sleep problems) were found in developing countries than in developed countries. The associations between binge-watching and mental health concerns were significant and positive. Programs and interventions to reduce binge-watching should be considered and tested.


Whole-transcriptome analysis reveals virulence-specific pathogen-host interactions at the placenta in bovine neosporosis.
Research on bovine neosporosis has achieved relevant milestones, but the mechanisms underlying the occurrence of foetal death or protection against foetal death remain unclear. In a recent study, placentas from heifers challenged with the high-virulence isolate Nc-Spain7 exhibited focal necrosis and inflammatory infiltrates as soon as 10 days post-infection (dpi), although parasite detection was minimal. These lesions were more frequent at 20 dpi, coinciding with higher rates of parasite detection and the occurrence of foetal death in some animals. In contrast, such lesions were not observed in placentas from animals infected with the low-virulence isolate Nc-Spain1H, where the parasite was detected only in placenta from one animal at 20 dpi. This work aimed to study which mechanisms are triggered in the placentas (caruncles and cotyledons) of these pregnant heifers at early stages of infection (10 and 20 dpi) through whole-transcriptome analysis. In caruncles, infection with the high-virulence isolate provoked a strong proinflammatory response at 10 dpi. This effect was not observed in heifers infected with the low-virulence isolate, where IL-6/JAK/STAT3 signalling and TNF-alpha signalling via NF-κB pathways were down-regulated. Interestingly, the expression of E2F target genes, related to restraining the inflammatory response, was higher in these animals. At 20 dpi, more pronounced proinflammatory gene signatures were detectable in heifers infected with the high-virulence isolate, being more intense in heifers carrying dead fetuses. However, the low-virulence isolate continued without activating the proinflammatory response. In cotyledons, the response to infection with the high-virulence isolate was similar to that observed in caruncles; however, the low-virulence isolate induced mild proinflammatory signals at 20 dpi. Finally, a deconvolutional analysis of gene signatures from both placentome tissues revealed a markedly higher fraction of activated natural killers, M1 macrophages and CD8+ T cells for the high-virulence isolate. Therefore, our transcriptomic analysis supports the hypothesis that an intense immune response probably triggered by parasite multiplication could be a key contributor to abortion. Further studies are required to determine the parasite effectors that govern the distinct interactions of high- and low-virulence isolates with the host, which could help elucidate the molecular processes underlying the pathogenesis of neosporosis in cattle.


Nail gun injuries treated in U.S emergency departments, 2006-2011: not just a worker safety issue.
Nail guns increase productivity in residential building but with a corresponding increase in worker injuries. They are also easily accessible, at low cost, to consumers. Data from the occupational supplement to the National Electronic Injury Surveillance System (NEISS-Work) were used to calculate national estimates of work-related injuries from nail guns between 2006 and 2011. These were compared to estimates of consumer injuries obtained through online access to the Consumer Product Safety Commission's (CPSC) NEISS data. Approximately 25,000 ED-treated work-related and consumer nail gun injuries were estimated each year. During the construction economy collapse, injuries among workers declined markedly, closely following patterns of reduced residential employment. Reduction in consumer injuries was much more modest. Current nail gun injury patterns suggest marked blurring of work and home exposures. A united effort of CPSC, NIOSH, and OSHA is warranted to address these preventable injuries.


The role of the use of different host plants in the maintenance of the inversion polymorphism in the cactophilic Drosophila buzzatii.
Inversion polymorphisms often have been associated with fitness variation. Cactophilic Drosophila buzzatii has been used widely for the study of the maintenance of chromosomal variation. The purpose of this paper is to address the relative importance of variable selection regimes associated with the use of three different host cacti and antagonistic pleiotropy in the maintenance of chromosomal variation. Using homokaryotypic stocks derived from several lines homozygous for four second-chromosome arrangements, we show that inversions significantly affect first-instar larva to adult viability (VT), developmental time (DT) and adult thorax length (TL). We also show that the effects of inversions on DT and VT are dependent on the cactus rearing media. The effects of polymorphic gene arrangements on life-history traits suggest the existence of trade-offs between early and late fitness components. The dosage of arrangement 2st, the ancestral gene order, was negatively correlated with DT and TL, whereas flies carrying the derived arrangements 2j and 2jq7 had longer DTs and larger TLs. Arrangements 2st and 2jq7 increased viability, at least in one of the cactus media tested. Our results suggest that environmental heterogeneity, as represented by the use of different cactus hosts and the trade-off between DT and TL, may be involved in the maintenance of the polymorphism. In addition, our data suggest that the chromosomal phylogeny may be decoupled from the evolution of the genes affecting life-history traits linked to the inversion system.


Drug transporters and blood--testis barrier function.
The blood--testis barrier (BTB) creates an immunological barrier that segregates the seminiferous epithelium into the basal and apical compartment. Thus, meiosis I/II and post-meiotic germ cell development take place in a specialized microenvironment in the apical compartment behind the BTB and these events are being shielded from the host immune system. If unwanted drugs and/or chemicals enter the apical compartment from the microvessels in the interstitium via the basal compartment, efflux pumps (e.g. P-glycoprotein) located in Sertoli cells and/or spermatids can actively transport these molecules out of the apical compartment. However, the mechanism(s) by which influx pumps regulate the entry of drugs/chemicals into the apical compartment is not known. In this study, a solute carrier (SLC) transporter organic anion transporting polypeptide 3 (Oatp3, Slco1a5) was shown to be an integrated component of the N-cadherin-based adhesion complex at the BTB. However, a knockdown of Oatp3 alone or in combination with three other major Sertoli cell drug influx pumps, namely Slc22a5, Slco6b1, and Slco6c1, by RNAi using corresponding specific siRNA duplexes failed to perturb the Sertoli cell tight junction (TJ) permeability barrier function. Yet, the transport of [(3)H]adjudin, a potential male contraceptive that is considered a toxicant to spermatogenesis, across the BTB was impeded following the knockdown of either Oatp3 or all the four SLC transporters. In short, even though drug transporters (e.g. influx pumps) are integrated components of the adhesion protein complexes at the BTB, they are not involved in regulating the Sertoli cell TJ permeability barrier function, instead they are only involved in the transport of drugs, such as adjudin, across the immunological barrier at the BTB.


High-frequency, scaled graphene transistors on diamond-like carbon.
Owing to its high carrier mobility and saturation velocity, graphene has attracted enormous attention in recent years. In particular, high-performance graphene transistors for radio-frequency (r.f.) applications are of great interest. Synthesis of large-scale graphene sheets of high quality and at low cost has been demonstrated using chemical vapour deposition (CVD) methods. However, very few studies have been performed on the scaling behaviour of transistors made from CVD graphene for r.f. applications, which hold great potential for commercialization. Here we report the systematic study of top-gated CVD-graphene r.f. transistors with gate lengths scaled down to 40 nm, the shortest gate length demonstrated on graphene r.f. devices. The CVD graphene was grown on copper film and transferred to a wafer of diamond-like carbon. Cut-off frequencies as high as 155 GHz have been obtained for the 40-nm transistors, and the cut-off frequency was found to scale as 1/(gate length). Furthermore, we studied graphene r.f. transistors at cryogenic temperatures. Unlike conventional semiconductor devices where low-temperature performance is hampered by carrier freeze-out effects, the r.f. performance of our graphene devices exhibits little temperature dependence down to 4.3 K, providing a much larger operation window than is available for conventional devices.


The impact of medication adherence on clinical outcomes of coronary artery disease: A meta-analysis.
Background Long-term use of evidence-based medications is recommended by international guidelines for the management of stable coronary artery disease, however, non-adherence to medications is common. This meta-analysis aims to systematically evaluate the impact of medication adherence on clinical outcomes in patients with stable coronary artery disease. Methods Articles from January 1960-December 2015 were retrieved from the MEDLINE and EMBASE databases without any language restriction. A meta-analysis was performed to investigate the risk ratios of all-cause mortality, cardiovascular mortality, and myocardial infarction/hospitalization between groups with good medication adherence and poor medication adherence. Studies were independently reviewed by two investigators. Data from eligible studies were extracted, and the meta-analysis was performed using R Version 3.1.0 software. Results A total of 10 studies were included in the analysis, with a total of 106,002 coronary artery disease patients. The results showed that good adherence to evidence-based medication regimens, including β-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, antiplatelet drugs, and statins, was related to a lower risk of all-cause mortality(risk ratio 0.56; 95% confidence interval: 0.45-0.69), cardiovascular mortality(risk ratio 0.66; 95% confidence interval: 0.51-0.87), and cardiovascular hospitalization/myocardial infarction(risk ratio 0.61; 95% confidence interval: 0.45-0.82). Conclusions This meta-analysis confirms the significant impact of good medication adherence on clinical outcomes in patients with stable coronary artery disease. More strategy and planning are needed to improve medication adherence.


Genetic Atrial Cardiomyopathies: Common Features, Specific Differences, and Broader Relevance to Understanding Atrial Cardiomyopathy.
Atrial cardiomyopathy is a condition that causes electrical and contractile dysfunction of the atria, often along with structural and functional changes. Atrial cardiomyopathy most commonly occurs in conjunction with ventricular dysfunction, in which case it is difficult to discern the atrial features that are secondary to ventricular dysfunction from those that arise as a result of primary atrial abnormalities. Isolated atrial cardiomyopathy (atrial-selective cardiomyopathy; atrial-selective cardiomyopathy [ASCM], with minimal or no ventricular function disturbance) is relatively uncommon and has most frequently been reported in association with deleterious rare genetic variants. The genes involved can affect proteins responsible for various biological functions, not necessarily limited to the heart but also involving extracardiac tissues. Atrial enlargement and atrial fibrillation are common complications of ASCM and are often the predominant clinical features. Despite progress in identifying disease-causing rare variants, an overarching understanding and approach to the molecular pathogenesis, phenotypic spectrum, and treatment of genetic ASCM is still lacking. In this review, we aim to analyze the literature relevant to genetic ASCM to understand the key features of this rather rare condition, as well as, to identify distinct characteristics of ASCM and its arrhythmic complications that are related to specific genotypes. We outline the insights that have been gained using basic research models of genetic ASCM in vitro and in vivo and correlate these with patient outcomes. Finally, we provide suggestions for the future investigation of patients with genetic ASCM and improvements to basic scientific models and systems. Overall, a better understanding of the genetic underpinnings of ASCM will not only provide a better understanding of this condition but also promises to clarify our appreciation of the more commonly occurring forms of atrial cardiomyopathy associated with ventricular dysfunction.


Bats perceptually weight prey cues across sensory systems when hunting in noise.
Anthropogenic noise can interfere with environmental information processing and thereby reduce survival and reproduction. Receivers of signals and cues in particular depend on perceptual strategies to adjust to noisy conditions. We found that predators that hunt using prey sounds can reduce the negative impact of noise by making use of prey cues conveyed through additional sensory systems. In the presence of masking noise, but not in its absence, frog-eating bats preferred and were faster in attacking a robotic frog emitting multiple sensory cues. The behavioral changes induced by masking noise were accompanied by an increase in active localization through echolocation. Our findings help to reveal how animals can adapt to anthropogenic noise and have implications for the role of sensory ecology in driving species interactions.


The high light-inducible polypeptides in Synechocystis PCC6803. Expression and function in high light.
There are five Synechocystis PCC6803 genes encoding polypeptides with similarity to the Lhc polypeptides of plants. Four of the polypeptides, designated HliA-D (Dolganov, N. A. M., Bhaya, D., and Grossman, A. R. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 636-640) (corresponding to ScpC, ScpD, ScpB, and ScpE in Funk, C., and Vermaas, W. (1999) Biochemistry 38, 9397-9404) contain a single transmembrane domain. The fifth polypeptide (HemH) represents a fusion between a ferrochelatase and an Hli-like polypeptide. By using an epitope tag to identify specifically the different Hli polypeptides, the accumulation of each (excluding HemH) was examined under various environmental conditions. The levels of all of the Hli polypeptides were elevated in high light and during nitrogen limitation, whereas HliA, HliB, and HliC also accumulated to high levels following exposure to sulfur deprivation and low temperature. The temporal pattern of accumulation was significantly different among the different Hli polypeptides. HliC rapidly accumulated in high light, and its level remained high for at least 24 h. HliA and HliB also accumulated rapidly, but their levels began to decline 9-12 h following the imposition of high light. HliD was transiently expressed in high light and was not detected 24 h after the initiation of high light exposure. These results demonstrate that there is specificity to the accumulation of the Hli polypeptides under a diverse range of environmental conditions. Furthermore, mutants for the individual and combinations of the hli genes were evaluated for their fitness to grow in high light. Although all of the mutants grew as fast as wild-type cells in low light, strains inactivated for hliA or hliC/hliD were unable to compete with wild-type cells during co-cultivation in high light. A mutant lacking all four hli genes gradually lost its photosynthesis capacity and died in high light. Hence, the Hli polypeptides are critical for survival when Synechocystis PCC6803 is absorbing excess excitation energy and may allow the cells to cope more effectively with the production of reactive oxygen species.


Near-infrared frequency-domain optical spectroscopy and magnetic resonance imaging: a combined approach to studying cerebral maturation in neonatal rabbits.
The neonatal rabbit brain shows prolonged postnatal development both structurally and physiologically. We use noninvasive near-IR frequency-domain optical spectroscopy (NIRS) and magnetic resonance imaging (MRI) to follow early developmental changes in cerebral oxygenation and anatomy, respectively. Four groups of animals are measured: NIRS in normals, MRI in normals, and both NIRS and MRI with hypoxia-ischemia (HI) (diffusion MRI staging). NIRS and/or MRI are performed from P3 (postnatal day=P) up to P76. NIRS is performed on awake animals with a frequency-domain tissue photometer. Absolute values of oxyhemoglobin concentration ([HbO2]), deoxyhemoglobin concentration ([HbR]), total hemoglobin concentration (HbT), and hemoglobin saturation (StO2) are calculated. The brains of all animals appeared to be maturing as shown in the diffusion tensor MRI. Mean optical coefficients (reduced scattering) remained unchanged in all animals throughout. StO2 increased in all animals (40% at P9 to 65% at P43) and there are no differences between normal, HI controls, and HI brains. The measured increase in StO2 is in agreement with the reported increase in blood flow during the first 2 months of life in rabbits. HbT, which reflects blood volume, peaked at postnatal day P17, as expected since the capillary density increases up to P17 when the microvasculature matures.


Age-associated pharmacodynamic changes.
Many pharmacodynamic changes with age have been identified. Quite likely, they, in concert with age-associated pharmacokinetic changes and multiple drug use, are responsible for altered drug action in the elderly and an increasing incidence of adverse drug reactions with age. The pharmacodynamic changes, which can result in altered action of important drugs, can lead to major adverse clinical outcomes if not recognized, particularly in those drugs which affect the heart and the central nervous system.


Effects of folic acid supplementation on serum homocysteine levels, lipid profiles, and vascular parameters in post-menopausal Korean women with type 2 diabetes mellitus.
Complications of diabetes, such as cardiovascular disease, are associated with increased mortality among type 2 diabetes mellitus patients. Homocysteine has been recently identified as a predictor of cardiovascular disease-related complications in diabetes. We investigated whether or not supplementation with folic acid tablets can lower homocysteine levels and improve parameters related with vascular complications. We conducted a non-randomized 8-week trial involving postmenopausal diabetic women (n = 25) supplemented with 800 µg of folic acid (400 µg twice a day) daily. Subjects' serum levels of folate, homocysteine, and vitamin B12 were measured, along with vascular function and brachial-ankle pulse wave velocity. Folic acid supplementation significantly increased serum folate levels (P < 0.0001), reduced homocysteine levels (P < 0.0001), and increased vitamin B12 levels (P = 0.0063). There were significant decreases in low-density lipoprotein cholesterol levels as well as the ratios of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol and total cholesterol to high-density lipoprotein cholesterol. Brachial-ankle pulse wave velocities were not altered by supplementation. Changes in serum vitamin B12 after folic acid supplementation were negatively correlated with changes in brachial-ankle pulse wave velocity. In this study on postmenopausal Korean women with type 2 diabetes mellitus, folic acid supplementation reduced serum homocysteine levels, increased serum folate and vitamin B12 levels, and lowered lipid parameters.


Enhancing the monitoring of fallen stock at different hierarchical administrative levels: an illustration on dairy cattle from regions with distinct husbandry, demographical and climate traits.
The automated collection of non-specific data from livestock, combined with techniques for data mining and time series analyses, facilitates the development of animal health syndromic surveillance (AHSyS). An example of AHSyS approach relates to the monitoring of bovine fallen stock. In order to enhance part of the machinery of a complete syndromic surveillance system, the present work developed a novel approach for modelling in near real time multiple mortality patterns at different hierarchical administrative levels. To illustrate its functionality, this system was applied to mortality data in dairy cattle collected across two Spanish regions with distinct demographical, husbandry, and climate conditions. The process analyzed the patterns of weekly counts of fallen dairy cattle at different hierarchical administrative levels across two regions between Jan-2006 and Dec-2013 and predicted their respective expected counts between Jan-2014 and Jun- 2015. By comparing predicted to observed data, those counts of fallen dairy cattle that exceeded the upper limits of a conventional 95% predicted interval were identified as mortality peaks. This work proposes a dynamic system that combines hierarchical time series and autoregressive integrated moving average models (ARIMA). These ARIMA models also include trend and seasonality for describing profiles of weekly mortality and detecting aberrations at the region, province, and county levels (spatial aggregations). Software that fitted the model parameters was built using the R statistical packages. The work builds a novel tool to monitor fallen stock data for different geographical aggregations and can serve as a means of generating early warning signals of a health problem. This approach can be adapted to other types of animal health data that share similar hierarchical structures.


Activated WNK3 induced by intracerebral hemorrhage deteriorates brain injury maybe via WNK3/SPAK/NKCC1 pathway.
Intracerebral hemorrhage (ICH) is the common brain diseases in middle-aged and elderly people, with high disability and/or mortality rate, and is a serious public health concern. Both WNK3 kinase and the WNK3/SPAK/NKCC1 signaling pathway play an integral role in maintaining normal cell homeostasis. However, their role and underlying mechanisms in ICH-induced secondary brain injury (SBI) have yet to be elucidated. We established an ICH model using male Sprague-Dawley (SD) rats by injecting autologous arterial blood into the unilateral basal ganglia. To establish ICH model in vitro, oxyhemoglobin (OxyHb; 20 μM) and neurons were cultured for 6 h at 37 °C, 5% CO2 atmosphere. To investigate the role of WNK3 and the WNK3/SPAK/NKCC1 signaling pathway in SBI, after genetic interventions, rotation and water maze test, brain edema and neuroinflammation were detected, and terminal-deoxynucleoitidyl transferase mediated dUTP nick end labeling (TUNEL), Fluoro-Jade C (FJC), and Nissl staining were performed. Our data showed that WNK3 expression in brain tissue were upregulated after ICH induction. In addition, silencing of WNK3 reduced neuronal apoptosis, and inflammatory responses in rats that underwent ICH. Inhibition of WNK3 expression reduced the damaged blood-brain barrier (BBB), alleviated the impaired degree of cerebral edema, and improved disruptive neurobehavioral cognition caused by ICH. Moreover, overexpression of WNK3 had the opposite effects. Finally, WNK3/SPAK/NKCC1 signaling pathway may be involved in the above-mentioned processes. In conclusion, our findings showed that WNK3 and WNK3/SPAK/NKCC1 signaling pathway play a vital biological function in ICH-induced SBI. Depletion of WNK3 attenuated brain injury after ICH both in vivo and in vitro. Thus, WNK3 and WNK3/SPAK/NKCC1 signaling pathway are potential targets for treating SBI after ICH.


Synthetic hydrogel platform for three-dimensional culture of embryonic stem cell-derived motor neurons.
Culturing mammalian neurons in three-dimensional (3D) microenvironments that more closely recapitulate critical biochemical and biophysical aspects of the developing or adult central nervous system (CNS) milieu remains a significant challenge in neurobiological studies and in regenerative medicine. Here, we aimed to exploit recent advances in poly(ethylene glycol) (PEG) hydrogel chemistries to define a synthetic niche capable of supporting the culture and axonal outgrowth of both aggregated and dissociated mouse embryonic stem cell-derived motor neurons (ESMNs). Using thiol-ene click chemistry to create peptide crosslinked PEG hydrogels, we identified a hydrogel formulation that promotes neuronal survival and axon outgrowth through cell-extracellular matrix interactions, such as those between the laminin-derived peptide YIGSR and its integrin, and that allows neurons to remodel their extracellular environment through matrix metalloproteinase (MMP)-mediated polymer network degradation. Our results demonstrate a 3D platform for culture of both aggregated and single mammalian motor nerve cells that not only permits cell survival over more than a week of culture, but also allows for the robust extension of motor axons. In addition, the optical transparency of the hydrogel allows simultaneous imaging of live cell functions, and as such, this material system should prove useful for studying fundamental aspects of neuronal development.


Intraobserver repeatability and interobserver reproducibility in musculoskeletal ultrasound imaging measurements.
To assess the repeatability and reproducibility of ultrasonographic measurements at the anterior surface of the femoral neck and iliofemoral ligament and on a human tissue-mimicking phantom. Two independent investigators studied 22 consecutive hips. One investigator had previous experience in musculoskeletal ultrasonography (US). The other investigator had undergone a short course in hip sonography (only 3 hours). Both investigators were blinded to their own and each other's results. On the phantom both observers had taken 10 vertical measurements at 6 cm deep where two objects were placed at 2 cm from each other. Calculation of measurement errors, percent errors and the Bland-Altman graphic technique were used for analysis of data. After 132 examinations the first investigator's within-subject standard deviation was 0.4 mm. The intraobserver error was 4.75%. The second investigator's within-subject standard deviation was 0.6 mm and his intraobserver error was 7.00%. The interobserver error was 10.91%. After 20 phantom examinations the first investigators's intraobserver error was 1.11% and the second investigator's intraobserver error was 1.47%. An inexperienced musculoskeletal sonographer can achieve an acceptable performance if given appropriate training.


A review on production of polyhydroxyalkanoate (PHA) biopolyesters by thermophilic microbes using waste feedstocks.
Polyhydroxyalkanoates (PHAs) are produced by numerous microbes as a subcellular energy source. Despite of their diverse applications, exorbitant production cost limits their commercial synthesis. Apart from various cost determining factors such as cost-effective feedstocks or economic recovery methods, the use of appropriate bacteria holds the key to reduce the fermentation economics. Extremophiles, especially thermophilic PHA producers, could make the bioprocess economically viable by reducing the production cost in several aspects. Using variety of waste feedstocks as carbon substrates could open the way for the valorisation of industrial waste streams and cost-effective PHA production. Therefore, the article critically reviews the current knowledge of the synthesis of PHA polyesters in thermophilic conditions. Additionally, it summarises several studies on thermophilic PHA producing bacteria grown on various waste substrates. To conclude, the paper focuses on screening and recovery methods as well as technical challenges in thermophilic PHA production.


Platelet distribution width (PDW) is increased in vaso-occlusive crisis in sickle cell disease.
Considering the multigenic and multifactorial nature of the disease, we argue that a generalized bone marrow hyperplasia-and not merely erythroid hyperplasia-will occur in sickle cell disease. Consequently, we expect the hematological parameters to depict erythroid, myeloid as well as megakaryocyte hyperplasia. In the light of this expectation, we hypothesized that platelet distribution width (PDW) will increase in sickle cell disease. Here, we report the results from a cross-sectional study of 216 children admitted with complaints suggestive of vaso-occlusive crisis. We observed a strong association between PDW and sickle cell disease as compared to children who had HbAA genotype. Our findings bridge previous inconsistencies relating to the role of platelets in sickle cell disease. Implications of this finding are discussed.


Prevalence and unmet need for diabetes care across the care continuum in a national sample of South African adults: Evidence from the SANHANES-1, 2011-2012.
South Africa faces an epidemic of chronic non-communicable diseases (NCDs), yet national surveillance is limited due to the lack of recent data. We used data from the first comprehensive national survey on NCDs-the South African National Health and Nutrition Examination Survey (SANHANES-1 (2011-2012))-to evaluate the prevalence of and health system response to diabetes through a diabetes care cascade. We defined diabetes as a Hemoglobin A1c equal to or above 6.5% or currently on treatment for diabetes. We constructed a diabetes care cascade by categorizing the population with diabetes into those who were unscreened, screened but undiagnosed, diagnosed but untreated, treated but uncontrolled, and treated and controlled. We then used multivariable logistic regression models to explore factors associated with diagnosed and undiagnosed diabetes. The age-standardized prevalence of diabetes in South Africans aged 15+ was 10.1%. Prevalence rates were higher among the non-white population and among women. Among individuals with diabetes, a total of 45.4% were unscreened, 14.7% were screened but undiagnosed, 2.3% were diagnosed but untreated, 18.1% were treated but uncontrolled, and 19.4% were treated and controlled, suggesting that 80.6% of the diabetic population had unmet need for care. The diabetes care cascade revealed significant losses from lack of screening, between screening and diagnosis, and between treatment and control. These results point to significant unmet need for diabetes care in South Africa. Additionally, this analysis provides a benchmark for evaluating efforts to manage the rising burden of diabetes in South Africa.


Violence in lesbian and gay relationships: theory, prevalence, and correlational factors.
This article reviews and critiques the existing empirical literature examining interpersonal violence in lesbian and gay relationships. Studies assessing psychological, physical, and nonconsenting sexual forms of violence in intimate, same-sex relationships are reviewed, and their findings are integrated with what is known about partner abuse in heterosexual relationships. Nineteen studies are described and categorized according to the specific questions being addressed. This body of literature suggests that prevalence rates of same-sex partner abuse are high and its correlates show many similarities to those identified in incidents of heterosexual partner abuse. This article addresses the need for substantially increased efforts in this field of study in terms of well-controlled and theory-driven research design. In terms of other implications of this body of literature, the high prevalence rate of partner abuse among lesbian and gay populations needs to be recognized by providers of both physical and mental health services who potentially treat victims, so that they can more accurately identify appropriate interventions. More research is warranted, not only in the general area of lesbian and gay partner abuse, but in examining various treatment modalities and their effectiveness in helping perpetrators to end the cycle of violence.


[Clinical information, informed consent and medical deontology. A recent relationship].
In Spain, the right to clinical information and informed consent as a practical expression of the principle of autonomy, are legal conquests achieved in the late twentieth century. From the law they have been transferred to the codes of medical deontology. The aim of this work is to study the pace of this transfer. Historical review of the different codes of medical deontology in Spain since the Civil War, seeking the presence of these ideas in them. Until code of medical deontology of 1979, the idea of clinical information did not appear in the contemporary deontological norm, and the rules on consent did so in very restricted cases. As of that date, their appearance is progressive in the successive codes. Currently, both concepts are fully developed in Spanish deontological regulations. Medical Deontology has take on the ideas of patient information and informed consent. This has been a long process which have brought considerable changes the deontological orientations of the traditional form of doctor-patient relationship. In these aspects, medical deontology has drifted, from emphasizing the prudence of the doctor, to emphasize the duty to inform and give ample space to the patient's decisions, which he recognizes as an autonomous and reflective moral agent, capable of taking his own decisions about your health.


Apoptosis-associated speck-like protein containing a caspase recruitment domain is a regulator of procaspase-1 activation.
Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)/target of methylation-induced silencing/PYCARD represents one of only two proteins encoded in the human genome that contains a caspase recruitment domain (CARD) together with a pyrin, AIM, ASC, and death domain-like (PAAD)/PYRIN/DAPIN domain. CARDs regulate caspase family proteases. We show here that ASC binds by its CARD to procaspase-1 and to adapter proteins involved in caspase-1 activation, thereby regulating cytokine pro-IL-1beta activation by this protease in THP-1 monocytes. ASC enhances IL-1beta secretion into the cell culture supernatants, at low concentrations, while suppressing at high concentrations. When expressed in HEK293 cells, ASC interferes with Cardiak/Rip2/Rick-mediated oligomerization of procaspase-1 and suppresses activation this protease, as measured by protease activity assays. Moreover, ASC also recruits procaspase-1 into ASC-formed cytosolic specks, separating it from Cardiak. We also show that expression of the PAAD/PYRIN family proteins pyrin or cryopyrin/PYPAF1/NALP3 individually inhibits IL-1beta secretion but that coexpression of ASC with these proteins results in enhanced IL-1beta secretion. However, expression of ASC uniformly interferes with caspase-1 activation and IL-1beta secretion induced by proinflammatory stimuli such as LPS and TNF, suggesting pathway competition. Moreover, LPS and TNF induce increases in ASC mRNA and protein expression in cells of myeloid/monocytic origin, revealing another level of cross-talk of cytokine-signaling pathways with the ASC-controlled pathway. Thus, our results suggest a complex interplay of the bipartite adapter protein ASC with PAAD/PYRIN family proteins, LPS (Toll family receptors), and TNF in the regulation of procaspase-1 activation, cytokine production, and control of inflammatory responses.


Cyclic AMP phosphodiesterase in diabetes. Effect of glyburide.
Low-Michaelis constant cAMP phosphodiesterase (PDE; EC3.1.4.C) activity is inhibited in tissues of rats with type I ketosis-prone diabetes and is restored to normal by insulin treatment. To determine whether the oral hypoglycemic agent glyburide affected tissue cAMP PDE activity in non-insulin-dependent oral agent-treatable diabetes, cAMP PDE activity was measured in the liver and fat of animals rendered diabetic by low-dose streptozocin (STZ-DM) and treated for 3 wk with oral glyburide (360 micrograms/kg). The results were compared with PDE activity in the liver and fat of untreated STZ-DM and normal control rats. At the time of death, low-Km cAMP PDE activity [as maximum velocity (Vmax)] in STZ-DM rats was decreased to 66% of control values in the liver and to 65% in fat (P less than .001). PDE activity was restored toward normal by glyburide treatment: 91% in the liver (P less than .01) and 80% in fat (P less than .05). Calmodulin and calmodulin-like activity (PDE-activator activity) in the liver and fat was decreased in diabetes and restored toward normal after glyburide treatment (P less than .05). These data demonstrate that oral agents as well as insulin can restore the activity of cAMP PDE in the low-dose STZ-DM model, which is in some ways similar to type II diabetes.


Two-dimensional tortuosity of the superficial femoral artery in early atherosclerosis.
Tortuosity of an artery can disturb fluid mechanics and cause flow separation, which might in turn promote atherogenesis. This study discusses theoretically several quantitative measures of arterial tortuosity and curvature in two dimensions and tests them with computations from digitized femoral arteriograms. When reproducibility, sensitivity to scaling and computational procedure, and agreement between the measures were all taken into account, the total curvature and distance factor were considered the most suitable measures. Significant correlations were found between tortuosity and atherosclerosis measures, but the interpretation of this finding is not straightforward.


Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization.
Noxious input can sensitize pain (nociceptive) circuits within the spinal cord, inducing a lasting increase in spinal cord neural excitability (central sensitization) that is thought to contribute to chronic pain. The development of spinally-mediated central sensitization is regulated by descending fibers and GABAergic interneurons. The current study provides evidence that spinal cord injury (SCI) transforms how GABA affects nociceptive transmission within the spinal cord, recapitulating an earlier developmental state wherein GABA has an excitatory effect. In spinally transected rats, noxious electrical stimulation and inflammation induce enhanced mechanical reactivity (EMR), a behavioral index of nociceptive sensitization. Pretreatment with the GABAA receptor antagonist bicuculline blocked these effects. Peripheral application of an irritant (capsaicin) also induced EMR. Both the induction and maintenance of this effect were blocked by bicuculline. Cellular indices of central sensitization [c-fos expression and ERK phosphorylation (pERK)] were also attenuated. In intact (sham operated) rats, bicuculline had the opposite effect. Pretreatment with a GABA agonist (muscimol) attenuated nociceptive sensitization in intact, but not spinally injured, rats. The effect of SCI on GABA function was linked to a reduction in the Cl- transporter, KCC2, leading to a reduction in intracellular Cl- that would attenuate GABA-mediated inhibition. Pharmacologically blocking the KCC2 channel (with i.t. DIOA) in intact rats mimicked the effect of SCI. Conversely, a pharmacological treatment (bumetanide) that should increase intracellular Cl- levels blocked the effect of SCI. The results suggest that GABAergic neurons drive, rather than inhibit, the development of nociceptive sensitization after spinal injury.


Traumatic encephalopathy.
Traumatic brain injury is the leading cause of death and disability among young adults. Clinical evaluation is of limited value in the assessment of patients with traumatic brain injury and is often inaccurate in determining the extent of brain damage. Neurophysiological techniques and neuroimaging can provide valuable prognostic information and are useful in monitoring for seizures and other causes of secondary brain damage and in tracking the effects of therapy. More recently, cognitive electrophysiology and functional magnetic resonance imaging have shown that many patients clinically deemed to be in vegetative or in minimally conscious states are, in fact, aware. This opens new frontiers for further research into establishing communication with otherwise unresponsive patients.


Production of drug metabolites by immobilised Cunninghamella elegans: from screening to scale up.
Cunninghamella elegans is a fungus that has been used extensively as a microbial model of mammalian drug metabolism, whilst its potential as a biocatalyst for the preparative production of human drug metabolites has been often proposed, little effort has been made to enable this. Here, we describe a workflow for the application of C. elegans for the production of drug metabolites, starting from well-plate screening assays leading to the preparative production of drug metabolites using fungus immobilised either in alginate or as a biofilm. Using 12- and 96-well plates, the simultaneous screening of several drug biotransformations was achieved. To scale up the biotransformation, both modes of immobilisation enabled semi-continuous production of hydroxylated drug metabolites through repeated addition of drug and rejuvenation of the fungus. It was possible to improve the productivity in the biofilm culture for the production of 4'-hydroxydiclofenac from 1 mg/l h to over 4 mg/l h by reducing the incubation time for biotransformation and the number of rejuvenation steps.


Effect of dehydration, haemorrhage and oviposition on serum concentrations of vasotocin, mesotocin and prolactin in the chicken.
Serum concentrations of arginine vasotocin (AVT), mesotocin and prolactin were determined by radioimmunoassay in Rhode Island Red chickens during and after dehydration, haemorrhage and oviposition. During dehydration increased circulating levels of AVT, mesotocin and prolactin were found. As water deprivation proceeded, marked differences were observed. After an initial rise in serum AVT, mesotocin and prolactin levels during mild and moderate dehydration, concentrations of both AVT and prolactin tended to normalize during continued water deprivation, while those of mesotocin remained high throughout the whole dehydration experiment with the highest at the end of the water-deprivation period. Removal of 5 ml blood at intervals of 10 min during six consecutive time-periods did not affect serum osmolality and circulating levels of AVT and prolactin, but slightly increased mesotocin. These results suggest an osmoregulatory role for AVT and prolactin, whereas mesotocin may be involved in volume control. Finally, 1 min after oviposition, control values of 19.5 +/- 3.4 pmol AVT/1 (n = 9) were raised more than sevenfold to 142.9 +/- 12.5 pmol/l (n = 11). Thereafter, a decline occurred with a half-life for AVT of 13 min with raised serum levels up to 31 min after oviposition. In contrast, the serum concentrations of mesotocin and prolactin remained unaffected by oviposition.


Mobilization of naturally occurring perchlorate related to land-use change in the southern High Plains, Texas.
Perchlorate (Cl4-) reservoirs that accumulated in semiarid unsaturated zones, similar to chloride (Cl-), can contaminate underlying aquifers if they are mobilized. The purpose of this study was to evaluate Cl)4- mobilization related to land-use change from natural to agricultural ecosystems in the southern High Plains (SHP, USA), where large ClO4- concentrations (< or =60 microg/L) are found in the underlying Ogallala aquifer. Boreholes were drilled and sampled beneath natural ecosystems (3 boreholes) and beneath nonirrigated (rainfed, 7 boreholes) agricultural ecosystems. Large ClO4- reservoirs (361-934 g ClO4-/ha; peaks 47-111 gamma ClO4-/L pore water), that accumulated for up to approximately 30,000 yr under natural ecosystems, are being displaced to depths of 2.2 to >9.2 m in sampled boreholes under rainfed agriculture by increased drainage/recharge. High correlations between ClO4- and Cl- under natural areas (r = 0.81) and rainfed agricultural areas (r = 0.88) indicate that accumulation and mobilization of ClO4- can be predicted from Cl- data. Minimal analysis of ClO4- (e.g., two points, minimum and maximum Cl- concentrations in each profile) can be used to predict ClO4- inventories to within 9% of estimates based on detailed sampling. A pooled linear regression model based on all data in this study (99 points) predicts ClO4- inventories to within 19% of measured inventories. Continued mobilization of pre-existing unsaturated zone ClO4- reservoirs (361-934 g/ha) could increase the current groundwater ClO4- values by a further 8-21 microg/L in the SHP.


Capturing the Resistome: a Targeted Capture Method To Reveal Antibiotic Resistance Determinants in Metagenomes.
Identification of the nucleotide sequences encoding antibiotic resistance elements and determination of their association with antibiotic resistance are critical to improve surveillance and monitor trends in antibiotic resistance. Current methods to study antibiotic resistance in various environments rely on extensive deep sequencing or laborious culturing of fastidious organisms, both of which are heavily time-consuming operations. An accurate and sensitive method to identify both rare and common resistance elements in complex metagenomic samples is needed. Referencing the sequences in the Comprehensive Antibiotic Resistance Database, we designed a set of 37,826 probes to specifically target over 2,000 nucleotide sequences associated with antibiotic resistance in clinically relevant bacteria. Testing of this probe set on DNA libraries generated from multidrug-resistant bacteria to selectively capture resistance genes reproducibly produced higher numbers of reads on target at a greater length of coverage than shotgun sequencing. We also identified additional resistance gene sequences from human gut microbiome samples that sequencing alone was not able to detect. Our method to capture the resistome enables a sensitive means of gene detection in diverse environments where genes encoding antibiotic resistance represent less than 0.1% of the metagenome.


Markers of inflammation, proteolysis, and apoptosis in ESRD.
Hemodialysis (HD) is associated with protein catabolism and augmented apoptosis. Although the effect of metabolic acidosis and inflammatory cytokines on activation of the ubiquitin-proteasome pathway and branched-chain keto acid dehydrogenase (BCKAD) is well known, the effect of HD on these pathways remains unexplored. Twelve patients with end-stage renal disease were studied before and during HD. Eight controls also were studied. Plasma levels of complement components and cytokines, interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were measured. Messenger RNA (mRNA) levels of caspase-3, a mediator of apoptosis; ubiquitin, a marker of proteolysis; and BCKAD-E2, an enzyme regulating branched-chain amino acid oxidation, were estimated in skeletal muscle biopsy specimens by means of reverse-transcriptase polymerase chain reaction. Annexin-V expression was quantified by DNA array. Before the study, participants were placed on a 1.2-g/kg/d protein diet, and metabolic acidosis was corrected. During HD, plasma IL-6 levels increased from 7.54 +/- 2.24 to 27.86 +/- 4.94 pg/dL (P < 0.001). Complement component, IL-1, and TNF-alpha levels did not change significantly during HD. mRNA levels of caspase-3 (0.50 +/- 0.01 versus 0.81 +/- 0.04), annexin-V (0.94 +/- 0.06 versus 1.48 +/- 0.05; P < 0.001), ubiquitin (1.10 +/- 0.03 versus 1.44 +/- 0.03), and BCKAD-E2 (0.47 +/- 0.01 versus 0.81 +/- 0.04) increased in muscle during HD compared with pre-HD values (P < 0.001). mRNA levels of ubiquitin (0.62 +/- 0.03) and BCKAD-E2 (0.58 +/- 0.02) were greater in controls than pre-HD values (P < 0.05). There were significant positive correlations between plasma IL-6 levels and expression of caspase-3, ubiquitin, and BCKAD-E2 genes. HD causes activation of cytokines, which may mediate the increase in gene expression of caspase-3, ubiquitin, and BCKAD-E2 in skeletal muscles.


Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis.
p38-Alpha mitogen-activated protein kinase (p38-MAPK) is a tumor suppressor often mutated in human cancers, but its specific role in colorectal cancer is not completely understood. Previous studies have found that p38-MAPK activity inhibits epithelial proliferation and promotes apoptosis in the intestine. Therefore, we sought to test the hypothesis that intestinal disruption of p38-MAPK would lead to increased tumorigenesis in the colon. p38-MAPK was deleted in mice within the intestinal epithelium using a tamoxifen-inducible Cre system under control of the villin promoter [villin-Cre ERT2(+), MAPK14(f/f)]. An azoxymethane and dextran sodium sulfate protocol was used to drive intestinal tumor development. Tumor measurements were made using computer software from photographs of excised colon specimens. The number of mice that developed tumors was not statistically different when comparing wild-type mice (7/14) to inducible, intestine epithelial-deleted p38-MAPK (9/11) mice after azoxymethane/dextran sodium sulfate treatment (P = .21). However, the epithelial-deleted p38-MAPK mice developed significantly more tumors (3.7 vs 1.1; P = .008) and nearly 4 times the total tumor burden as wild-type mice (17.4 vs 4.8 mm(2); P = .03). Wild-type and epithelial-deleted p38-MAPK groups demonstrated a similar degree of colon inflammation. Deletion of p38-MAPK within the colonic mucosa leads to a hyperplastic state promoting greater tumor development. Because the severity of colitis was not augmented in mice with p38-MAPK deficiency, tumor development is likely mediated by impaired cell cycle regulation within the colonic epithelium. Manipulation of p38-MAPK activity may provide a novel treatment and/or prevention strategy in the management of colorectal cancer, particularly in the setting of inflammatory bowel disease.


Dynamic Patterns of Testosterone Levels in Individuals and Risk of Prostate Cancer among Hypogonadal Men: A Longitudinal Study.
We investigated whether dynamic patterns of testosterone levels contribute to risk of prostate cancer. We used data on 376 untreated men with hypogonadism (testosterone 12.1 nmol/l or less) recruited from a urology office in Germany. Age at study entry served as a surrogate for age at the first detection of testosterone below 12.1 nmol/l. We derived 3 indicators, including the coefficient of variation, the ratio of the largest decline relative to the mean and the median of maximum declines, to measure the dynamic patterns of testosterone in an individual. Our findings suggest that the later that testosterone dropped below 12.1 nmol/l in a man, the less the lifetime risk of prostate cancer in that individual (HR 0.68, 95% CI 0.57-0.82). Further declines or dynamic variations of testosterone were associated with increased risk of prostate cancer (high vs low coefficient of variation HR 4.88, 95% CI 1.97-12.08, high vs low ratio of largest decline relative to mean HR 8.45, 95% CI 2.82-25.37 and high vs low median of maximum declines HR 2.70, 95% CI 1.15-6.35). To our knowledge this study is the first to provide evidence of the association between dynamic patterns of testosterone and prostate cancer development. This may have substantial clinical impacts on prostate cancer prevention.


[Daily blood pressure profile in patients with hypertensive encephalopathy].
The purpose of the study was to study daily variations of blood pressure (BP) in patients with hypertensive encephalopathy (HE). Daily BP monitoring (DBPM) was made in 100 patients with different stages of HE. In HE, a proportion of patients from a non-dippers group substantially increased. An excessive nocturnal reduction in systolic BP (SBP) was more common. A dippers group was predominant in the controls. The daily index for SBP significantly decreased in patients with stage I HE; that for diastolic BP (DBP) reduced in those with stages I-II HE. The morning increase rate (MIC) of BP was studied. MIC of SBP was higher in patients with HE, which was most commonly observed in the non-dippers group. There was a more significant reduction in DBP in combination with high MIC in 10% of the examinees.


PHARMACOKINETICS OF CEFTIOFUR CRYSTALLINE FREE ACID STERILE SUSPENSION IN GREEN IGUANAS ( IGUANA IGUANA) AFTER SINGLE INTRAMUSCULAR ADMINISTRATION.
The objective of this study was to establish the pharmacokinetic parameters of ceftiofur crystalline free acid (CCFA) for a single intramuscular injection in green iguanas ( Iguana iguana). Six green iguanas received an injection of 5 mg/kg CCFA into the triceps muscle. Using high-performance liquid chromatography, concentrations of ceftiofur free acid equivalents in plasma samples collected at predetermined time points were evaluated up to 21 days following drug administration. Noncompartmental pharmacokinetic analysis was applied to the data. The observed maximum plasma concentration (Cmax obs) was 2.765 ± 0.864 μg/mL, and the time of observed maximum concentration (Tmax obs) was 6.1 ± 9.2 hr. The area under the curve (0 to infinity) was 239.3 ± 121.1 μg·hr/mL. No significant adverse drug reactions were clinically observed, and no visible injection site reactions were noted. Minimum inhibitory concentrations of bacterial isolates from iguanas were used to establish a target plasma concentration of 2.0 μg/mL. Based on the results from this study, a potential dosing interval for ceftiofur crystalline free acid administered at 5 mg/kg intramuscularly for iguanas maintained at a temperature of 30°C would be 24 hr based on a target plasma concentration of 2 μg/mL; however, multidose studies still need to be performed.


Do the transtheoretical processes of change predict transitions in stages of change for fruit intake?
In a longitudinal study, it is examined whether the transtheoretical processes of change do predict stage transitions in fruit intake. A random sample of an existing Internet research panel resulted in a cohort of 735 adults, who were examined three times with electronic questionnaires assessing stages of change, processes of change, and fruit intake. Cross-sectional differences were found for the processes of change between precontemplation and all further stages. Experiential as well as behavioral processes increased from precontemplation to action with similar patterns. Both experiential and behavioral processes predicted forward transition out of precontemplation and forward transition into action, whereas only behavioral processes predicted forward transition out of contemplation. The results indicate that the transtheoretical processes of change predict stage transitions for fruit intake, but that the pattern of relevant processes for fruit intake is not as straightforward as outlined by the transtheoretical model of behavior change.


Naringenin-induced migration of embrynoic trophectoderm cells is mediated via PI3K/AKT and ERK1/2 MAPK signaling cascades.
For successful pregnancy, a well-coordinated network of growth factors, nutrients and hormones is required for fetal-maternal interactions. Naringenin, as a weak phytoestrogen, improves diabetes, inflammation, neuronal diseases, cardiovascular diseases and cancers. However, the role of naringenin in migration mechanism(s) of peri-implantation conceptuses is unknown. Therefore, in the present study, we determined the effects of naringenin on migration of porcine trophectoderm (pTr) cells, which is a known in vitro model for research on trophectoderm cell biology and placental-fetal developmental biology, in order to assess intracellular signal transduction pathways activated by naringenin. Migration of pTr cells increased in a dose-dependent manner in response to naringenin. Also, naringenin activated the phosphorylation of AKT and ERK1/2 proteins in a dose-dependent manner and those proteins were abundant mainly in the cytoplasm of naringenin-treated pTr cells. Within 30 min after treatment with 20 μM naringenin, the abundance of phosphorylated EKR1/2, P70S6K, P90RSK and S6K proteins increased, and then returned to basal levels by 120 min whereas the abundance of AKT increased gradually to 120 min post-treatment. However, the phosphorylation of AKT, P70S6K, P90RSK and S6K was reduced in naringenin-induced pTr cells pre-treated with a PI3K inhibitor (LY294002). Also, a MEK1/2 inhibitor (U0126) significantly decreased naringenin-induced phosphorylation of ERK1/2, P70S6K and S6K proteins in pTr cells. Moreover, the naringenin-stimulated migration of pTr cells was suppressed by LY294002 and U0126. Collectively, results of the present study suggest that naringenin supports migration of pTr cells through PI3K/AKT and ERK1/2 MAPK signaling pathways crucial for orchestrating conceptus-uterine interactions.


Repeated analyses of national clinical audit reports demonstrate improvements in feedback methods.
There is growing interest in the impact of national clinical audit programmes on the quality of healthcare. There is also an evolving evidence-base for enhancing the design and delivery of audit and feedback. We assessed the extent to which a sample of UK national clinical audit feedback reports met a set of good practice criteria over three time points. We undertook three cross-sectional content analyses. We developed good practice criteria for the content and delivery of feedback based upon evidence, behavioural theory and expert opinion. We applied these to a feedback reports from 23 national audits listed on the Healthcare Quality Improvement Partnership (HQIP) website in November 2015. We repeated our assessments in January 2017 for 20 repeat feedback reports, after HQIP had published reporting guidance for national audits, and in August 2019 for a further 14 repeat feedback reports. We verified our assessments, where possible, with audit leads. Feedback reports consistently included strengths at baseline, including past or planned repeated audit cycles (21; 91%), stating the importance of the topic in relation to patient care (22; 93%), using multi-modal data presentation (23; 100%), and summarising key findings (23; 100%). We observed improvements over subsequent assessments, so that by 2019, at least 13 out of 14 (93%) feedback reports presented easily identifiable key findings and recommendations, linked recommendations to audit standards, and proposed easily identifiable action plans. Whilst the use of regional comparators did not improve, audit leads highlighted that programmes now provide local data via additional means. The main shortcoming was the time lag between data collection and feedback; none of the 14 reports assessed in 2019 presented performance data less than 6 months old. Audit leads highlighted that some of these data might be available via programme websites. We identified increased adherence to good practice in feedback by national clinical audit programmes that may enhance their impact on service delivery and outcomes. There is scope for improvement, especially in the recency of performance data. With further refinements, a criterion-based assessment offers an efficient means of monitoring the quality of national clinical audit feedback reports.


The myostatin null mutation and clenbuterol administration elicit additive effects in mice.
In mice, the myostatin (Mstn) null mutation and treatment with clenbuterol both increase muscle growth and decrease fat mass. Our objective was to determine whether mechanistic overlap exists by administering clenbuterol to Mstn null mice. Male Mstn null and wild-type mice of similar genetic backgrounds received either 0 (control) or 20 p.p.m. clenbuterol in tap water free choice for 14 days. Several traits were measured to estimate muscle and fat growth. The Mstn null mutation resulted in increased body and empty carcass weight, increased muscle weights and decreased fat pad weights. Fat content was reduced and protein content was increased in the empty carcasses of Mstn null mice. Similarly, treatment with clenbuterol resulted in increased body and empty carcass weight, increased muscle weights and reduced fat pad weights. Fat content of empty carcasses and viscera was reduced and protein content of empty carcasses was increased with clenbuterol treatment. A significant interaction of genotype and clenbuterol treatment would indicate an altered responsiveness of Mstn null mice to clenbuterol. However, only the weight of gastrocnemius muscles exhibited a significant (P = 0.01) interaction of genotype and clenbuterol treatment, indicating that Mstn null mice were less responsive to clenbuterol compared with wild-type mice. Thus, for all other traits, the impact of Mstn null mutation and clenbuterol treatment was completely additive. These data suggest that disruption of Mstn function does not alter the response of mice to β-adrenergic agonists.


Abdominal Organ Location, Morphology, and Rib Coverage for the 5(th), 50(th), and 95(th) Percentile Males and Females in the Supine and Seated Posture using Multi-Modality Imaging.
The purpose of this study was to use data from a multi-modality image set of males and females representing the 5(th), 50(th), and 95(th) percentile (n=6) to examine abdominal organ location, morphology, and rib coverage variations between supine and seated postures. Medical images were acquired from volunteers in three image modalities including Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and upright MRI (uMRI). A manual and semi-automated segmentation method was used to acquire data and a registration technique was employed to conduct a comparative analysis between abdominal organs (liver, spleen, and kidneys) in both postures. Location of abdominal organs, defined by center of gravity movement, varied between postures and was found to be significant (p=0.002 to p=0.04) in multiple directions for each organ. In addition, morphology changes, including compression and expansion, were seen in each organ as a result of postural changes. Rib coverage, defined as the projected area of the ribs onto the abdominal organs, was measured in frontal, lateral, and posterior projections, and also varied between postures. A significant change in rib coverage between postures was measured for the spleen and right kidney (p=0.03 and p=0.02). The results indicate that posture affects the location, morphology and rib coverage area of abdominal organs and these implications should be noted in computational modeling efforts focused on a seated posture.


Atherosclerotic vascular disease rather than metabolic syndrome predicts ischemic stroke in diabetic patients.
The purpose of this study was to evaluate the effect of metabolic syndrome on ischemic stroke in Chinese subjects with type 2 diabetes. Anthropometric parameters (waist circumference and body mass index), blood pressure, and plasma biochemical (lipid and glycemic profiles) were collected. Subjects with type 2 diabetes were categorized by the criteria of the updated Adult Treatment Panel III (ATP III) with the modified definitions of obesity in Asians. Transcranial Doppler was performed to define middle cerebral artery stenosis. Of 2,197 patients (age 55.4 +/- 11.3 years; male 40.8%; median follow-up period 8.7 years, interquartile range 7.8-9.5 years) without symptoms of cerebrovascular disease, evidence of middle cerebral artery stenosis was identified in 272 subjects (12.4%). According to NCEP ATP III criteria, 1,324 (60.3%) patients had MetS at baseline. Ischemic stroke occurred in 184 (8.4%, 184/2197) patients during follow-up. Patients with incident stroke had a higher prevalence of MetS compared with those without stroke (p = 0.004), and the number of components of MetS was also significantly increased in patients with stroke (p = 0.001). Cox regression demonstrated that MetS was not associated with incident stroke. In Chinese type 2 diabetic patients, metabolic syndrome does affect stroke occurrence with a higher stroke incidence among those with metabolic syndrome, but stroke occurrence seems to be better explained by other vascular risk factors than by metabolic syndrome.


Chloroplast-expressed MSI-99 in tobacco improves disease resistance and displays inhibitory effect against rice blast fungus.
Rice blast is a major destructive fungal disease that poses a serious threat to rice production and the improvement of blast resistance is critical to rice breeding. The antimicrobial peptide MSI-99 has been suggested as an antimicrobial peptide conferring resistance to bacterial and fungal diseases. Here, a vector harboring the MSI-99 gene was constructed and introduced into the tobacco chloroplast genome via particle bombardment. Transformed plants were obtained and verified to be homoplastomic by PCR and Southern hybridization. In planta assays demonstrated that the transgenic tobacco plants displayed an enhanced resistance to the fungal disease. The evaluation of the antimicrobial activity revealed that the crude protein extracts from the transgenic plants manifested an antimicrobial activity against E. coli, even after incubation at 120 °C for 20 min, indicating significant heat stability of MSI-99. More importantly, the MSI-99-containing protein extracts were firstly proved in vitro and in vivo to display significant suppressive effects on two rice blast isolates. These findings provide a strong basis for the development of new biopesticides to combat rice blast.


Characteristics of impaired endothelium-dependent relaxation of rat aorta after streptozotocin-induced diabetes.
To study whether impaired endothelium-dependent relaxation (EDR) in early diabetic mellitus in response to different receptor-mediated and nonreceptor-mediated vasodilators ran parallel and its possible mechanism. Isometric tension recording in aortic rings from streptozotocin (Str)-induced diabetic and age-matched nondiabetic rats. EDR induced by receptor agonist acetylcholine (ACh), histamine (His) or bradykinin (BK) were all significantly reduced in diabetic rings compared with control rings, whereas nonreceptor agonist calcimycin-induced EDR was well reserved in diabetic rings [IC50 control: (0.13 +/- 0.07) mumol.L-1 diabetic: (0.14 +/- 0.06) mumol.L-1, P > 0.05, n = 7]. Cyclopiazonic acid (CPA) which also is a nonreceptor mediated endothelium-dependent vasorelaxant and cells' capacitative Ca2+ entry stimulant, failed to trigger EDR in diabetic rings. Pretreatment with N omega-nitro-L-arginine methylester (L-NAME, 0.3 mmol.L-1) not only abolished all of the EDR elicited by above mentioned vasodilators in either of diabetic or control rings, but also leveled responses triggered by each of the agonists between diabetic and control rings. Upon the maximal EDR induced by ACh (1 mol.L-1) or CPA (3 mumol.L-1) in phenylephrine (1 mumol.L-1) precontracted rings, calcimycin (1 mumol.L-1) further relaxed diabetic rings, but contracted control preparations. When endothelium was denuded, relaxation evoked by sodium nitroprusside and contractions triggered by CPA or His were all identical between diabetic and control rings. Receptor agonists but not nonreceptor agonists-induced EDR are commonly impaired in 4-wk Str-induced diabetic rat aorta, and this defective effect is attributable to the low formation of EDRF/NO which is related to impaired capacitative Ca2+ entry pathway in endothelium.


Catalytic activation of carbon-fluorine bonds by a soluble transition metal complex.
Homogeneous catalytic activation of the strong carbon-fluorine bonds under mild conditions was achieved with the use of rhodium complexes as catalysts. The catalytic reactions between polyfluorobenzenes and hydrosilanes result in substitution of fluorine atoms by hydrogen atoms and are chemo- and regioselective. With individual stoichiometric steps observed and combined, and with intermediates isolated and fully characterized (including crystal structures), these systems demonstrate the effectiveness of a rational approach to catalytic design.


Bright light therapy for seasonal affective disorder in Israel (latitude 32.6 degrees N): a single case placebo-controlled study.
We describe a patient diagnosed as having seasonal affective disorder (SAD, winter depression), an unlikely condition in Israel (latitude 32.6 degrees N), a country with relatively minor daylight photoperiodic changes between seasons. Case report. A 46-year-old woman with a clinical picture of depression (Diagnostic and Statistical Manual of Mental Disorders diagnostic criteria for 'major depression with seasonal pattern') reacted positively to 3 weeks of daily bright light therapy of 10,000 lux/wide spectrum. She was asked to wear dark sunglasses during placebo sessions to accommodate an A-B-C single-case-design. The intervention resulted in an improvement of 74-80% in the Hamilton anxiety and depression scales (clinician-rated) and the Beck depression inventory, similar to results obtained in high latitude regions. The depression and anxiety levels returned close to baseline levels following 1 week of the placebo intervention. Seasonal affective disorder is apparently not limited to certain latitudes. The effect of light therapy was short-lived after discontinuation of the treatment, with rapid relapse occurring in the placebo phase.


A case study evaluating the portability of an executable computable phenotype algorithm across multiple institutions and electronic health record environments.
Electronic health record (EHR) algorithms for defining patient cohorts are commonly shared as free-text descriptions that require human intervention both to interpret and implement. We developed the Phenotype Execution and Modeling Architecture (PhEMA, http://projectphema.org) to author and execute standardized computable phenotype algorithms. With PhEMA, we converted an algorithm for benign prostatic hyperplasia, developed for the electronic Medical Records and Genomics network (eMERGE), into a standards-based computable format. Eight sites (7 within eMERGE) received the computable algorithm, and 6 successfully executed it against local data warehouses and/or i2b2 instances. Blinded random chart review of cases selected by the computable algorithm shows PPV ≥90%, and 3 out of 5 sites had >90% overlap of selected cases when comparing the computable algorithm to their original eMERGE implementation. This case study demonstrates potential use of PhEMA computable representations to automate phenotyping across different EHR systems, but also highlights some ongoing challenges.


Regulation of GRP1-catalyzed ADP ribosylation factor guanine nucleotide exchange by phosphatidylinositol 3,4,5-trisphosphate.
Cellular levels of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) are rapidly elevated in response to activation of growth factor receptor tyrosine kinases. This polyphosphoinositide binds the pleckstrin homology (PH) domain of GRP1, a protein that also contains 200 residues with high sequence similarity to a segment of the yeast Sec7 protein that functions as an ADP ribosylation exchange factor (ARF) (Klarlund, J., Guilherme, A., Holik, J. J., Virbasius, J. V., Chawla, A., and Czech, M. P. (1997) Science 275, 1927-1930). Here we show that dioctanoyl PtdIns(3,4,5)P3 binds the PH domain of GRP1 with a Kd = 0.5 microM, an affinity 2 orders of magnitude greater than dioctanoyl-PtdIns(4,5)P2. Further, the Sec7 domain of GRP1 is found to catalyze guanine nucleotide exchange of ARF1 and -5 but not ARF6. Importantly, PtdIns(3,4,5)P3, but not PtdIns(4,5)P2, markedly enhances the ARF exchange activity of GRP1 in a reaction mixture containing dimyristoylphosphatidylcholine micelles, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid, and a low concentration of sodium cholate. PtdIns(3,4,5)P3-mediated ARF nucleotide exchange through GRP1 is selectively blocked by 100 microM inositol 1,3,4,5-tetrakisphosphate, which also binds the PH domain of GRP1. Taken together, these data are consistent with the hypothesis that selective recruitment of GRP1 to PtdIns(3,4,5)P3 in membranes activates ARF1 and -5, known regulators of intracellular membrane trafficking.


Blunt trauma in intoxicated patients: is computed tomography of the abdomen always necessary?
Physical examination to detect abdominal injuries has been considered unreliable in alcohol-intoxicated trauma patients. Computed tomography (CT) plays the primary role in these abdominal evaluations. We reviewed medical records of all blunt trauma patients admitted to our trauma service from January 1, 1992, to March 31, 1998. Study patients had a blood alcohol level > or =80 mg/dL, Glasgow Coma Scale (GCS) score of 15, and unremarkable abdominal examination. Of 324 patients studied, 317 (98%) had CT scans negative for abdominal injury. Abdominal injuries were identified in 7 patients (2%), with only 2 (0.6%) requiring abdominal exploration. A significant association was found between major chest injury and abdominal injury. The incidence of abdominal injury in intoxicated, hemodynamically stable, blunt trauma patients with a normal abdominal examination and normal mentation is low. Physical examination and attention to clinical risk factors allow accurate abdominal evaluation without CT.


Controlled release of ethacrynic acid from poly(lactide-co-glycolide) films for glaucoma treatment.
Ethacrynic acid (ECA) is a potential glaucoma drug that can reduce intraocular pressure. However, conventional methods of ECA administration may cause toxicity to normal eye tissues and are inconvenient to patients. Therefore, we developed and characterized an ECA loaded poly(lactide-co-glycolide) (PLGA) copolymer film, and quantified the therapeutic efficacy of the film implanted in the rabbit eye. In the aqueous medium, the release of ECA from the PLGA50:50 film was time dependent and more than 90% of ECA was released within a week. This release profile was consistent with the kinetics of water uptake and microstructural changes of PLGA50:50 films as revealed by an electron microscopy examination. ECA release and PLGA degradation caused a gradual pH decrease in the release medium. The total pH decrease was 0.4 unit in 3 days. We also observed that the initial rate of ECA release was positively correlated with the weight ratio of ECA versus PLGA and inversely correlated with the molar ratio of lactide versus glycolide in PLGA films. At the end of a 3-day incubation, the cumulative release of ECA from PLGA50:50, PLGA85:15 and PLGA100:00 films were 78.8%, 9.35% and 3.60%, respectively. When the PLGA50:50 film loaded with ECA was implanted into the sclera of rabbit eyes, the intraocular pressure was significantly reduced and the reduction was maintained for at least 10 days. These data indicate that PLGA films have a potential to be used as a controlled ECA release device for glaucoma treatment.


Population attributable fractions of risk factors for hepatocellular carcinoma in the United States.
Hepatocellular carcinoma (HCC) incidence has been increasing in the United States for several decades; and, as the incidence of hepatitis C virus (HCV) infection declines and the prevalence of metabolic disorders rises, the proportion of HCC attributable to various risk factors may be changing. Data from the Surveillance, Epidemiology, and End Results-Medicare linkage were used to calculate population attributable fractions (PAFs) for each risk factor over time. Patients with HCC (n = 10,708) who were diagnosed during the years 2000 through 2011 were compared with a 5% random sample of cancer-free controls (n = 332,107) residing in the Surveillance, Epidemiology, and End Results areas. Adjusted odds ratios (ORs) and PAFs were calculated for HCV, hepatitis B virus (HBV), metabolic disorders, alcohol-related disorders, smoking, and genetic disorders. Overall, the PAF was greatest for metabolic disorders (32%), followed by HCV (20.5%), alcohol (13.4%), smoking (9%), HBV (4.3%), and genetic disorders (1.5%). The PAF for all factors combined was 59.5%. PAFs differed by race/ethnicity and sex. Metabolic disorders had the largest PAF among Hispanics (PAF, 39.3%; 95% confidence interval [CI], 31.9%-46.7%) and whites (PAF, 34.8%; 95% CI, 33.1%-36.5%), whereas HCV had the largest PAF among blacks (PAF, 36.1%; 95% CI, 31.8%-40.4%) and Asians (PAF, 29.7%; 95% CI, 25.9%-33.4%). Between 2000 and 2011, the PAF of metabolic disorders increased from 25.8% (95% CI, 22.8%-28.9%) to 36% (95% CI, 33.6%-38.5%). In contrast, the PAFs of alcohol-related disorders and HCV remained stable. Among US Medicare recipients, metabolic disorders contribute more to the burden of HCC than any other risk factor, and the fraction of HCC caused by metabolic disorders has increased in the last decade. Cancer 2016;122:1757-65. Published 2016. This article is a U.S. Government work and is in the public domain in the USA..


[The ocular components in anisometropia].
To asses the correlation between ocular components (axial length, anterior segment length, corneal power, vitreous length and equivalent power of the eye) and refractive error in eyes with higher and lower ametropia of subjects with anisometropia. An analytical survey was carried out in 68 patients with anisometropia of two or more diopters, assisted at the Ophthalmological Clinic from "Hospital das Clínicas da Faculdade de Medicina" of São Paulo University. All participants were submitted to ophthalmologic examination which included objective and subjective cycloplegic refratometry, keratometry and ultrasonic biometry. No significant difference between measures of ocular components of the eyes with higher and lower ametropias was observed. The eyes with lower ametropia presented the same significant correlations observed in emmetropic eyes: of refraction with anterior segment length and axial length, and of the axial length with corneal power and vitreous length. The eyes with higher ametropia presented significant correlation of refraction with the axial length and of the axial length with vitreous length. Furthermore, we observed in both eyes, significant correlation of the power of the crystalline lens with the anterior chamber depth. The eyes with lower ametropia presented correlations more frequently observed in emmetropia. The eyes with higher ametropia did not present the same correlations observed in emmetropic eyes.