Laminin-411 is a vascular ligand for MCAM and facilitates TH17 cell entry into the CNS.
TH17 cells enter tissues to facilitate pathogenic autoimmune responses, including multiple sclerosis (MS). However, the adhesion molecules involved in the unique migratory capacity of TH17 cells, into both inflamed and uninflamed tissues remain unclear. Herein, we characterize MCAM (CD146) as an adhesion molecule that defines human TH17 cells in the circulation; following in vitro restimulation of human memory T cells, nearly all of the capacity to secrete IL-17 is contained within the population of cells expressing MCAM. Furthermore, we identify the MCAM ligand as laminin 411, an isoform of laminin expressed within the vascular endothelial basement membranes under inflammatory as well as homeotstatic conditions. Purified MCAM-Fc binds to laminin 411 with an affinity of 27 nM, and recognizes vascular basement membranes in mouse and human tissue. MCAM-Fc binding was undetectable in tissue from mice with targeted deletion of laminin 411, indicating that laminin 411 is a major tissue ligand for MCAM. An anti-MCAM monoclonal antibody, selected for inhibition of laminin binding, as well as soluble MCAM-Fc, inhibited T cell adhesion to laminin 411 in vitro. When administered in vivo, the antibody reduced TH17 cell infiltration into the CNS and ameliorated disease in an animal model of MS. Our data suggest that MCAM and laminin 411 interact to facilitate TH17 cell entry into tissues and promote inflammation.


N-arginine dibasic convertase (nardilysin) isoforms are soluble dibasic-specific metalloendopeptidases that localize in the cytoplasm and at the cell surface.
N-arginine (R) dibasic (NRD) convertase (nardilysin; EC 220.127.116.11), a metalloendopeptidase of the M16 family, specifically cleaves peptide substrates at the N-terminus of arginines in dibasic motifs in vitro. In rat testis, the enzyme localizes within the cytoplasm of spermatids and associates with microtubules of the manchette and axoneme. NRD1 and NRD2 convertases, two NRD convertase isoforms, differ by the absence (isoform 1) or presence (isoform 2) of a 68-amino acid insertion close to the active site. In this study, we overexpressed both isoforms, either by vaccinia virus infection of BSC40 cells or transfection of COS-7 cells. The partially purified enzymes exhibit very similar biochemical and enzymic properties. Microsequencing revealed that NRD convertase is N-terminally processed. Results of immunocytofluorescence, immunoelectron microscopy and subcellular fractionation studies argue in favour of a primary cytosolic localization of both peptidases. Although the putative signal peptide did not direct NRD convertase into microsomes in an in vitro translation assay, biotinylation experiments clearly showed the presence of both isoforms at the cell surface. In conclusion, although most known processing events at pairs of basic residues are achieved by proprotein convertases within the secretory pathway, NRD convertase may fulfil a similar function in the cytoplasm and/or at the cell surface.


Assessment of detection limits of fiber-optic distributed temperature sensing for detection of illicit connections.
Distributed temperature sensing (DTS) with fiber-optic cables is a powerful tool to detect illicit connections in storm sewer systems. High-frequency temperature measurements along the in-sewer cable create a detailed representation of temperature anomalies due to illicit discharges. The detection limits of the monitoring equipment itself are well-known, but there is little information available on detection limits for the discovery of illicit connections, as in mixing of sewers, and attenuation also plays an important role. This paper describes the results of full-scale experiments aiming to quantify the detection limits for illicit connections under various sewer conditions. Based on the results, a new monitoring set-up for (partially) filled sewer conduits has been proposed.


Waldian t tests: Sequential Bayesian t tests with controlled error probabilities.
Bayesian t tests have become increasingly popular alternatives to null-hypothesis significance testing (NHST) in psychological research. In contrast to NHST, they allow for the quantification of evidence in favor of the null hypothesis and for optional stopping. A major drawback of Bayesian t tests, however, is that error probabilities of statistical decisions remain uncontrolled. Previous approaches in the literature to remedy this problem require time-consuming simulations to calibrate decision thresholds. In this article, we propose a sequential probability ratio test that combines Bayesian t tests with simple decision criteria developed by Abraham Wald in 1947. We discuss this sequential procedure, which we call Waldian t test, in the context of three recently proposed specifications of Bayesian t tests. Waldian t tests preserve the key idea of Bayesian t tests by assuming a distribution for the effect size under the alternative hypothesis. At the same time, they control expected frequentist error probabilities, with the nominal Type I and Type II error probabilities serving as upper bounds to the actual expected error rates under the specified statistical models. Thus, Waldian t tests are fully justified from both a Bayesian and a frequentist point of view. We highlight the relationship between Bayesian and frequentist error probabilities and critically discuss the implications of conventional stopping criteria for sequential Bayesian t tests. Finally, we provide a user-friendly web application that implements the proposed procedure for interested researchers. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Creep evaluation of (orthotic) cast materials during simulated clubfoot correction.
The Ponseti method is a widely accepted and highly successful conservative treatment of pediatric clubfoot that relies on weekly manipulations and cast applications. However, the material behavior of the cast in the Ponseti technique has not been investigated. The current study sought to characterize the ability of two standard casting materials to maintain the Ponseti corrected foot position by evaluating creep response. A dynamic cast testing device (DCTD) was built to simulate a typical pediatric clubfoot. Semi-rigid fiberglass and rigid fiberglass casting materials were applied to the device, and the rotational creep was measured at various constant torques. The movement was measured using a 3D motion capture system. A 2-way ANOVA was performed on the creep displacement data at a significance level of 0.05. Among cast materials, the rotational creep displacement was found to be significantly different (p-values ≪ 0.001). The most creep displacement occurs in the semi-rigid fiberglass (approximately 1.0 degrees), then the rigid fiberglass (approximately 0.4 degrees). There was no effect of torque magnitude on the creep displacement. All materials maintained the corrected position with minimal change in position over time.


Dickkopf-1 regulates gastrulation movements by coordinated modulation of Wnt/beta catenin and Wnt/PCP activities, through interaction with the Dally-like homolog Knypek.
Dickkopf-1 (Dkk1) is a secreted protein that negatively modulates the Wnt/beta catenin pathway. Lack of Dkk1 function affects head formation in frog and mice, supporting the idea that Dkk1 acts as a "head inducer" during gastrulation. We show here that lack of Dkk1 function accelerates internalization and rostral progression of the mesendoderm and that gain of function slows down both internalization and convergence extension, indicating a novel role for Dkk1 in modulating these movements. The motility phenotype found in the morphants is not observed in embryos in which the Wnt/beta catenin pathway is overactivated, and that dominant-negative Wnt proteins are not able to rescue the gastrulation movement defect induced by absence of Dkk1. These data strongly suggest that Dkk1 is acting in a beta catenin independent fashion when modulating gastrulation movements. We demonstrate that the glypican 4/6 homolog Knypek (Kny) binds to Dkk1 and that they are able to functionally interact in vivo. Moreover, Dkk1 regulation of gastrulation movements is kny dependent. Kny is a component of the Wnt/planar cell polarity (PCP) pathway. We found that indeed Dkk1 is able to activate this pathway in both Xenopus and zebrafish. Furthermore, concomitant alteration of the beta catenin and PCP activities is able to mimic the morphant accelerated cell motility phenotype. Our data therefore indicate that Dkk1 regulates gastrulation movement through interaction with LRP5/6 and Kny and coordinated modulations of Wnt/beta catenin and Wnt/PCP pathways.


Adaptation and Validation of the Instrument Treatment Outcomes Profile to the Chilean Population.
This study aims to psychometrically validate the Chilean version of the treatment outcomes profile (TOP), an instrument that can be used by treatment centers to monitor the results of drug and alcohol treatments. Specifically, this study is interested in evaluating the inter-rater reliability, concurrent validity, change sensitivity and discriminant and construct validity of this instrument. The TOP was modified to reflect the Chilean context and then applied in three successive stages: an initial application at the beginning of treatment, a retest after 1week, and a follow up after a month. The sample was composed of 411 users of different types of drugs who were in treatment centers in the three largest regions of the country. The TOP reliability was greater than .75 for most items. Regarding concurrent validity, all the coefficients were in the expected direction and statistically significant. Change over time, as measured by Cohen's d statistic and the Reliable Change Index, was significant for most items. Users in treatment for less than 3months showed higher alcohol consumption (odds ratio [OR]=1.07; 95% confidence interval [95% CI]: 1.01-1.13), poorer psychological health (OR=0.94; 95% CI: 0.87-1.00), fewer days worked (0.56; 0.95-0.99) and poorer housing conditions (OR=2.76; 95% CI: 1.22-6.23) than did their counterparts who had more than 3months of treatment. Researchers extracted six components with eigenvalues greater than one, accounting for 69.0% of the total variance. In general, the Chilean TOP is a reliable and valid mechanism to monitor outcomes of people treated for problems with drug and alcohol abuse in Chile, but further validation work is required in some dimensions.


Autophagy: a two-edged sword in diabetes mellitus.
A fragility fracture is a serious complication in patients with diabetes mellitus as a result of hyperglycaemia, insulin resistance and the production of AGEs (advanced glycation end-products). In their paper published in the Biochemical Journal, Bartolomé et al. identified a role for autophagy in the differentiation, function and survival of osteoblastic cells in a high-glucose environment, and they also demonstrated that osteoblastic cell survival was limited by chemical and genetic inhibition of autophagy. These novel findings show the possibility of investigating a therapeutic strategy of maintaining autophagy in osteoblasts to lead to the prevention of diabetes-related osteopaenia. Autophagy is one of the common functions for maintaining cellular health, and the regulation of autophagy that is perturbed by diabetes mellitus may induce improvement of cellular functions not only for diabetes-related osteopaenia, but also for other systemic complications. However, systemic activation of autophagy may not always induce beneficial effects for non-targeted healthy cells, and autophagy should be controlled at a proper level at each disease stage in each target organ.


Immune enhancement effects and extraction optimization of polysaccharides from Citrus aurantium L. var. amara Engl.
The crude polysaccharides of Citrus aurantium L. var. amara Engl (CAVAPs) were extracted and their bioactivities including DPPH radical scavenging activity, cytotoxicity to human breast cancer cells, MCF-7, as well as lung cancer cells, HCC827, and their immune-enhancement activity were evaluated. Results showed that CAVAPs exhibited better immunoenhancement activity compared to the DPPH radical scavenging and anticancer activities. Subsequently, the immune enhancement activity of CAVAPs on RAW264.7 cells was further observed and the results displayed that CAVAPs could significantly stimulate the production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in RAW264.7 cells, and promote the mRNA expression levels of inducible nitric oxide synthase (iNOS), TNF-α, interleukin-1 beta (IL-1β), and IL-6. Furthermore, western blot analysis demonstrated that the phosphorylated extracellular signal-regulated kinase (ERK), phosphorylated c-Jun N-terminal kinase (JNK), phosphorylated p38 and phosphorylated p65 were all remarkably increased in CAVAP-treated RAW264.7 cells. All these results indicated that CAVAPs might activate macrophages through the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathway. Additionally, a three-level-three-factor Box-Behnken design (BBD) was performed to optimize the extraction process of CAVAPs for the purpose of application and further research. The maximum extraction yield reached 4.49 ± 0.25%.


The COVID-19 pandemic will have a long-lasting impact on the quality of cirrhosis care.
The coronavirus disease 2019 (COVID-19) pandemic has shattered the meticulously developed processes by which we delivered quality care for patients with cirrhosis. Care has been transformed by the crisis, but enduring lessons have been learned. In this article, we review how COVID-19 will impact cirrhosis care. We describe how this impact unfolds over 3 waves; i) an intense period with prioritized high-acuity care with delayed elective procedures and routine care during physical distancing, ii) a challenging 'return to normal' following the end of physical distancing, with increased emergent decompensations, morbidity, and systems of care overwhelmed by the backlog of deferred care, and iii) a protracted period of suboptimal outcomes characterized by missed diagnoses, progressive disease and loss to follow-up. We outline the concrete steps required to preserve the quality of care provided to patients with cirrhosis. This includes an intensification of the preventative care provided to patients with compensated cirrhosis, proactive chronic disease management, robust telehealth programs, and a reorganization of care delivery to provide a full service of care with flexible clinical staffing. Managing the pandemic of a serious chronic disease in the midst of a global infectious pandemic is challenging. It is incumbent upon the entire healthcare establishment to be strong enough to weather the storm. Change is needed.


A new oral testosterone undecanoate formulation.
Testosterone undecanoate has been available on the market for more than 20 years. This testosterone ester is used worldwide for oral treatment of male hypogonadism. So far, testosterone undecanoate has been dissolved in oleic acid, leading to inconvenient storage conditions. It will now be available in a new formulation with castor oil and propylene glycol laurate instead of oleic acid, thus improving storage conditions markedly (stable at room temperature for approximately 3 years). Pharmacokinetic and pharmacodynamic studies have demonstrated bioequivalence of the old and the new formulation of testosterone undecanoate. Therefore, the results of studies that were performed with the old formulation can be transferred to the clinical use of the new formulation. Controlled studies have shown its efficacy in the treatment of symptoms associated with reduced serum testosterone levels. In these cases testosterone undecanoate improves bone mineral density, quality of life, muscle mass, libido and mood. Further studies will help evaluate the efficacy and safety of the new formulation in the treatment of elderly men with late-onset hypogonadism.


[Investigation of Ca2+ -induced changes of membrane potential of smooth muscle mitochondria using flow cytometric analysis].
Using flow cytometric analysis and potential-sensitive fluorescent dye TMRM Ca2+ -induced changes of membrane potential of isolated smooth muscle mitochondria were studied. It was shown, that Ca2+ (100 microM) addition to the incubation medium induced mitochondrial membrane depolarization that probably could be explained by Ca2+/H+ -exchanger activation which functioning lead to membrane potential dissipation. In the case of ruthenium red (10 microM) preliminary presence in incubation medium, Ca2+ (100 microM) addition did not lead to membrane potential dissipation. Hence, membrane potential dissipation was caused by an increase of matrix Ca2+ concentration. In the presence of Mg2+ (3 mM) and ATP (3 mM), Ca2+ addition did not cause depolarization. It was supposed that in this case ATP synthase acted in the opposite direction as H+ -pump and prevented from mitochondrial membrane potential dissipation. Thus, the flow cytometry method allows to register membrane potential of isolated smooth muscle mitochondria and also to test the effectors, capable to modulate this parameter.


Noncharged and Charged Monodendronised Perylene Bisimides as Highly Fluorescent Labels and their Bioconjugates.
A series of water-soluble, hydroxylated and sulphated, polyglycerol (PG) dendronised, monofunctional perylene bisimides (PBIs) were synthesised in three generations. Their photophysical properties were determined by absorption and emission spectroscopy and their suitability as potential biolabels examined by biological in vitro studies after bioconjugation. It could be shown that the photophysical properties of the PBI labels can be improved by increasing the sterical demand and ionic charge of the attached dendron. Thereby, charged labels show superior suppression of aggregation over charge neutral labels owing to electrostatic repulsion forces on the PG-dendron. The ionic charges also enabled a reduction in dendron generation while retaining the labels' outstanding fluorescence quantum yields (FQYs) up to 100 %. These core-unsubstituted perylene derivatives were successfully applied as fluorescent labels upon bioconjugation to the therapeutic antibody cetuximab. The dye-antibody conjugates showed a strongly enhanced aggregation tendency compared to the corresponding free dyes. Biological evaluation by receptor-binding, cellular uptake, and cytotoxicity studies revealed that labelling did not affect the antibody's function, which renders the noncharged and charged dendronised PBIs suitable candidates as fluorescent labels in biological imaging.


Forecasting smog-related health hazard based on social media and physical sensor.
Smog disasters are becoming more and more frequent and may cause severe consequences on the environment and public health, especially in urban areas. Social media as a real-time urban data source has become an increasingly effective channel to observe people׳s reactions on smog-related health hazard. It can be used to capture possible smog-related public health disasters in its early stage. We then propose a predictive analytic approach that utilizes both social media and physical sensor data to forecast the next day smog-related health hazard. First, we model smog-related health hazards and smog severity through mining raw microblogging text and network information diffusion data. Second, we developed an artificial neural network (ANN)-based model to forecast smog-related health hazard with the current health hazard and smog severity observations. We evaluate the performance of the approach with other alternative machine learning methods. To the best of our knowledge, we are the first to integrate social media and physical sensor data for smog-related health hazard forecasting. The empirical findings can help researchers to better understand the non-linear relationships between the current smog observations and the next day health hazard. In addition, this forecasting approach can provide decision support for smog-related health hazard management through functions like early warning.


Development of a swine model of secondary liver tumor from a genetically induced swine fibroblast cell line.
Metastatic disease is the most common liver tumor. Although alternative therapies have been developed for non-surgical candidates, those therapies lacked ideal testing prior to clinical application because of a paucity of large animal models. The purpose of the present study was to develop a model for secondary liver tumor in a large animal. Fibroblasts were isolated from swine ear lobules and then transfected with amphotrophic retroviruses encoding human or murine genetic material (hTERT, p53(DD), cyclinD-1, CDK4(R24C), Myc (T58A), Ras(G12V)). Transformed cell lines were finally inoculated subcutaneously (s.c.) into: 1) immunodeficient mice (nude), 2) immunocompetent mice (wild type), 3) immunosuppressed swine (under tacrolimus or corticosteroids), 4) immunocompetent swine, and 5) into the liver and portal circulation of swine under steroid-based immunosuppression. In the murine model, tumor growth was evident in 100% of the nude mice (n=5), with a peak size of 20 mm (15.22+/-4.5 mm; mean+/-SD) at the time of sacrifice (3 weeks). Tumor growth was evident in 71% of the wild mice (n=21), with a peak size of 7.8 mm (4.19+/-1.1 mm) by the third week of growth. In the swine model, tumor growth was evident in 75% (3/4 ears; n=2) of swine under tacrolimus-based immunosuppression versus 50% of swine under steroids-based immunosuppression (n=2). Tumor growth was slow in two animals, while in one animal the tumor was larger with a peak growth of 42 mm at 3 weeks. The tumor pattern in the ear lobules was characterized by slow growth, with a peak size of 6-8 mm in the immunocompetent swine at 3 weeks. All tumors were shown to be malignant by histology. In contrast, inoculums of the transformed fibroblast cell line in swine livers showed no evidence of tumor growth at 3 weeks. Development of a transformed swine fibroblast cell line was successful, resulting in an in vivo malignant tumor. Cell line inoculums had tumorigenic properties in nude mice, wild-type mice, and immunosuppressed swine, as judged by uncontrolled cell growth, invasion of surrounding tissue, neoangiogenesis, and invasion of normal vasculature, resulting in the formation of tumor nodules. Such properties were not observed in swine upon inoculation into the liver/portal circulation.


Identification of genes and pathways potentially related to PHF20 by gene expression profile analysis of glioblastoma U87 cell line.
Glioblastoma is the most common and aggressive brain tumor associated with a poor prognosis. Plant homeodomain finger protein 20 (PHF20) is highly expressed in primary human gliomas and its expression is associated with tumor grade. However, the molecular mechanism by which PHF20 regulates glioblastoma remains poorly understood. Genome wide gene expression analysis was performed to identify differentially expressed genes (DEGs) in U87 cells with PHF20 gene knockdown. Gene ontology (GO) and pathway enrichment analyses were performed to investigate the functions and pathways of DEGs. Pathway-net and signal-net analyses were conducted to identify the key genes and pathways related to PHF20. Expression of 540 genes, including FEN1 and CCL3, were significantly altered upon PHF20 gene silencing. GO analysis results showed that DEGs were significantly enriched in small molecule metabolic and apoptotic processes. Pathway analysis indicated that DEGs were mainly involved in cancer and metabolic pathways. The MAPK, apoptosis and p53 signaling pathways were identified as the hub pathways in the pathway network, while PLCB1, NRAS and PIK3 s were hub genes in the signaling network. Our findings indicated that PHF20 is a pivotal upstream regulator. It affects the occurrence and development of glioma by regulating a series of tumor-related genes, such as FEN1, CCL3, PLCB1, NRAS and PIK3s, and activation of apoptosis signaling pathways. Therefore, PHF20 might be a novel biomarker for early diagnosis, and a potential target for glioblastoma therapies.


[Cross-correlational analysis of the neuronal connections of the cerebellum in the waking rabbit].
The methods of cross-interval and crosscorrelation analysis were used to study interneuronal connections in cerebellar vermis in awake rabbit. Crosscorrelation, or spike-triggering method, complemented the analysis of cross-intervals which estimated the neuronal interaction comparing spike sequences as point processes. Among 16 neuronal pairs recorded intra- or extracellularly 10 pairs were considered as interconnected. Inhibitory interconnections dominated. The inhibitory neuronal interconnections were revealed in pairs with complex spikes. Neurons which constituted pairs with reciprocal excitatory-inhibitory interaction fired only simple spikes. The variability and plasticity of common inputs to Purkinje cells were seemingly lower than those of direct connections which probably transmitted the output signals of Purkinje cells.


[Why has malaria not been rooted in present-day Russia?].
At present, a favorable malaria situation that contributes to the elimination of local vivax malaria transmission has established in Russia by 2010 due to the following factors: 1) a considerable reduction in the number of imported cases ofvivax malaria from endemic CIS countries; 2) a low malariogenic potential of the territory of the Moscow region where the basic importation of malaria occurs; 3) a higher awareness about the prevention of malaria in the population; 4) medical workers' alertness and timely detection of patients with malaria; 5) failure for sporadic cases of vivax malaria to be rooted in the urban area due to episodic carriage of various pathogenic phenotypes.


New understanding and treatments for osteoporosis.
To summarize promising areas of investigation in osteoporosis and to stimulate further research in this area, as discussed in a recent international conference. Over the recent years, there has been an improvement in the knowledge of molecular pathways involved in bone formation and resorption with the development of new drugs to treat osteoporosis. Intact parathyroid hormone, teriparatide, and anti-sclerostin monoclonal antibody are anabolic drugs, whereas denosumab and odanacatib are anti-resorptive drugs with more reversible effects as compared to bisphosphonates. Anabolic and anti-resorptive agents have different effects on bone, and research in this area includes the efficacy of combination and sequential therapies with them. New insights in the molecular pathways of bone remodeling have clarified the mechanisms responsible for skeletal fragility in several forms of secondary osteoporosis, such as that occurring in type 2 diabetes, following drug exposure and systemic inflammatory diseases. Future research is needed to address the efficacy of anti-osteoporotic drugs in these more recently recognized conditions of skeletal fragility. Osteoporosis continues to be an important field of biomedical research.


Metal-induced specific and nonspecific oligonucleotide folding studied by FRET and related biophysical and bioanalytical implications.
Metal induced nucleic acid folding has been extensively studied with ribozymes, DNAzymes, tRNA and riboswitches. These RNA/DNA molecules usually have a high content of double-stranded regions to support a rigid scaffold. On the other hand, such rigid structural features are not available for many in vitro selected or rationally designed DNA aptamers; they adopt flexible random coil structures in the absence of target molecules. Upon target binding, these aptamers adaptively fold into a compact structure with a reduced end-to-end distance, making fluorescence resonance energy transfer (FRET) a popular signaling mechanism. However, nonspecific folding induced by mono- or divalent metal ions can also reduce the end-to-end distance and thus lead to false positive results. In this study we used a FRET pair labeled Hg(II) binding DNA and monitored metal-induced folding in the presence of various cations. While nonspecific electrostatically mediated folding can be very significant, at each tested salt condition, Hg(II) induced folding was still observed with a similar sensitivity. We also studied the biophysical meaning of the acceptor/donor fluorescence ratio that allowed us to explain the experimental observations. Potential solutions for this ionic strength problem have been discussed. For example, probes designed to signal the formation of double-stranded DNA showed a lower dependency on ionic strength.


Individual and mixture toxicity of three pesticides; atrazine, chlorpyrifos, and chlorothalonil to the marine phytoplankton species Dunaliella tertiolecta.
This study analyzed the toxicity of three pesticides (the herbicide atrazine, the insecticide chlorpyrifos and the fungicide chlorothalonil) individually, and in two mixtures (atrazine and chlorpyrifos; atrazine and chlorothalonil) to the marine phytoplankton species Dunaliella tertiolecta (Chlorophyta). A standard 96 h static algal bioassay was used to determine pesticide effects on the population growth rate of D. tertiolecta. Mixture toxicity was assessed using the additive index approach. Atrazine and chlorothalonil concentrations > or = 25 microg/L and 33.3 microg/L, respectively, caused significant decreases in D. tertiolecta population growth rate. At much higher concentrations (> or = 400 microg/L) chlorpyrifos also elicited a significant effect on D. tertiolecta population growth rate, but toxicity would not be expected at typical environmental concentrations. The population growth rate EC50 values determined for D. tertiolecta were 64 microg/L for chlorothalonil, 69 microg/L for atrazine, and 769 microg/L for chlorpyrifos. Atrazine and chlorpyrifos in mixture displayed additive toxicity, whereas atrazine and chlorothalonil in mixture had a synergistic effect. The toxicity of atrazine and chlorothalonil combined was approximately 2 times greater than that of the individual chemicals. Therefore, decreases in phytoplankton populations resulting from pesticide exposure could occur at lower than expected concentrations in aquatic systems where atrazine and chlorothalonil are present in mixture. Detrimental effects on phytoplankton population growth rate could impact nutrient cycling rates and food availability to higher trophic levels. Characterizing the toxicity of chemical mixtures likely to be encountered in the environment may benefit the pesticide registration and regulation process.


Loss-of-function mutations affecting a specific Glycine max R2R3 MYB transcription factor result in brown hilum and brown seed coats.
Although modern soybean cultivars feature yellow seed coats, with the only color variation found at the hila, the ancestral condition is black seed coats. Both seed coat and hila coloration are due to the presence of phenylpropanoid pathway derivatives, principally anthocyanins. The genetics of soybean seed coat and hilum coloration were first investigated during the resurgence of genetics during the 1920s, following the rediscovery of Mendel's work. Despite the inclusion of this phenotypic marker into the extensive genetic maps developed for soybean over the last twenty years, the genetic basis behind the phenomenon of brown seed coats (the R locus) has remained undetermined until now. In order to identify the gene responsible for the r gene effect (brown hilum or seed coat color), we utilized bulk segregant analysis and identified recombinant lines derived from a population segregating for two phenotypically distinct alleles of the R locus. Fine mapping was accelerated through use of a novel, bioinformatically determined set of Simple Sequence Repeat (SSR) markers which allowed us to delimit the genomic region containing the r gene to less than 200 kbp, despite the use of a mapping population of only 100 F6 lines. Candidate gene analysis identified a loss of function mutation affecting a seed coat-specific expressed R2R3 MYB transcription factor gene (Glyma09g36990) as a strong candidate for the brown hilum phenotype. We observed a near perfect correlation between the mRNA expression levels of the functional R gene candidate and an UDP-glucose:flavonoid 3-O-glucosyltransferase (UF3GT) gene, which is responsible for the final step in anthocyanin biosynthesis. In contrast, when a null allele of Glyma09g36990 is expressed no upregulation of the UF3GT gene was found. We discovered an allelic series of four loss of function mutations affecting our R locus gene candidate. The presence of any one of these mutations was perfectly correlated with the brown seed coat/hilum phenotype in a broadly distributed survey of soybean cultivars, barring the presence of the epistatic dominant I allele or gray pubescence, both of which can mask the effect of the r allele, resulting in yellow or buff hila. These findings strongly suggest that loss of function for one particular seed coat-expressed R2R3 MYB gene is responsible for the brown seed coat/hilum phenotype in soybean.


Optimization of exogenous carbohydrases supplemented in broiler diets using in vitro simulated gastrointestinal digestion and response surface methodology.
The present study aimed to explore the optimal zymogram of combination of 6 carbohydrases (glucoamylase, pullulanase, maltase, thermostable α-amylase, medium temperature α-amylase, and cold-active α-amylase) supplemented in corn-soybean based diet of broilers aged 1 to 3 wk for the maximum starch digestibility, by using in vitro simulated gastrointestinal digestion and response surface method. The third generation of simulated monogastric animal digestion system was used for in vitro digestion experiment. By using single factor completely random design, the optimal supplement levels of single carbohydras were determined by the reducing sugar release amount and improved dry matter digestibility, which were the parameters representing the starch digestibility of the diet. Additionally, Box-Behnken response surface method was used to predict the optimal combination of 6 carbohydrases. The results showed that the optimistic zymogram of 6 carbohydrases in corn-soybean based diet for broilers aged 1 to 3 wk were 297.39 U/g glucoamylase, 549.72 U/g pullulanase, 3.01 U/g maltase, 1,455.73 U/g thermostable α-amylase, 278.64 U/g medium temperature α-amylase, and 1,985.97 U/g cold-active α-amylase, and the associated reduced sugar release amount and improved dry matter digestibility were 215.98 mg/g, and 6.23%, respectively. Furthermore, we conducted in vitro digestion experiments with diets supplemented with the predicted optimistic zymogram and found that the experimental reduced sugar release amount and improved dry matter digestibility were 219.26 mg/g and 6.31% respectively, whose errors to the predicted optimistic reducing sugar release amount and the improved dry matter digestibility were 1.05% and 1.02%. To sum up, the predicted optimal zymogram of 6 carbohydrases in the present study were capable to improve the starch digestibility in diet for broilers aged 1 to 3 wk, which were represented by increased reduced sugar release amount and improved dry matter digestibility.


Parvovirus-associated cerebellar hypoplasia and hydrocephalus in day old broiler chickens.
Cerebellar hypoplasia and hydrocephalus were identified in day old broiler chickens showing nervous signs, impaired mobility, and diarrhea. At postmortem examination, brains of chickens were misshapen and cerebellums were smaller than normal. Microscopically, cerebellar folia were reduced in size and irregularly shaped, and the ventricles were widely distended. Affected cerebellums had focal areas along the base of folia where the internal granular cell layer had been lost, and Purkinje cells were disorganized and located within the molecular layer. Parvovirus DNA was detected by polymerase chain reaction in three of nine brains with oligonucleotide primers designed for amplification of chicken and turkey parvoviruses. On the basis of phylogenetic analyses, the detected virus was most closely related to chicken parvoviruses. These findings suggest that a chicken parvovirus might cause a neurologic disease of young chickens characterized by cerebellar hypoplasia and hydrocephalus; however, its role as the cause of the disease remains to be confirmed.


Dufour's gland secretion, sterility and foraging behavior: correlated behavior traits in bumblebee workers.
Bombus terrestris colonies go through two major phases: the "pre-competition phase" in which the queen is the sole reproducer and aggression is rare, and the "competition phase" in which workers aggressively compete over reproduction. Conflicts over reproduction are partially regulated by a group of octyl esters that are produced in Dufour's gland of reproductively subordinate workers and protect them from being aggressed. However, workers possess octyl esters even before overt aggression occurs, raising the question of why produce the ester-signal before it is functionally necessary? In most insect societies, foragers show reduced aggression and low dominance rank. We hypothesize that ester production in B. terrestris is not only correlated with sterility but also with foraging, signaling cooperative behavior by subordinate workers. Such a signal helps to maintain social organization, reduce the cost of fights between reproductives and helpers, and increase colony productivity, enabling subordinates to gain greater inclusive fitness. We demonstrate that foragers produce larger amounts of esters compared to non-foragers, and that their amounts positively correlate with foraging efforts. We further suggest that task performance, potential fecundity, and aggression are interlinked, and that worker-worker interactions are involved in regulating foraging behavior. B. terrestris, being an intermediate phase between primitive and derived eusocial insects, provides an excellent model for understanding the evolution of early phases of eusociality. Our results, combined with those in primitively eusocial wasps, suggest that at early stages of social evolution, reproduction was regulated by a "primordial division of labor", that comprised foragers and reproducers, which further evolved to a more complex division of labor, a hallmark of eusociality.


Detection and inhibition of lipid-derived radicals in low-density lipoprotein.
Oxidized low density lipoprotein (Ox-LDL) is implicated in a variety of oxidative diseases. To clarify the mechanisms involved and facilitate the investigation of therapeutics, we previously developed a detection method for lipid-derived radicals using the fluorescent probe 2,2,6-trimethyl-6-pentyl-4-(4-nitrobenzo[1,2,5]oxadiazol-7-ylamino)piperidine-1-oxyl (NBD-Pen). In this study, NBD-Pen was used to detect lipid-derived radicals in Ox-LDL from in vitro and in vivo samples using an iron overloaded mouse model. By following the timeline of lipid radical generation using this method, the iron overloaded mice could be successfully treated with the antioxidant Trolox, resulting in successful lowering of the plasma lipid peroxidation, aspartate transaminase and alanine transaminase levels. Furthermore, using a combination therapy of the chelating agent deferoxamine (DFX) and Trolox, liver injury and oxidative stress markers were also reduced in iron overloaded mice. The NBD-Pen method is highly sensitive as well as selective and is suitable for targeting minimally modified LDL compared with other existing methods.


Superior X-ray Radiation Shielding Effectiveness of Biocompatible Polyaniline Reinforced with Hybrid Graphene Oxide-Iron Tungsten Nitride Flakes.
X-ray radiation is a harmful carcinogenic electromagnetic source that can adversely affect the health of living species and deteriorate the DNA of cells, thus it's vital to protect vulnerable sources from them. To address this flaw, the conductive polymeric structure of polyaniline (PANi) was reinforced with diverse filler loadings (i.e., 25 wt % and 50 wt %) of hybrid graphene oxide-iron tungsten nitride (ITN) flakes toward attenuation of X-ray beams and inhabitation of microorganisms' growth. Primary characterizations confirmed the successful decoration of graphene oxide (GO) with interconnected and highly dense structure of iron tungsten nitride with a density of about 24.21 g.cm⁻3 and reinforcement of PANi with GO-ITN. Additionally, the outcome of evaluations showed the superior performance of developed shields, where a shield with 1.2 mm thickness containing 50 wt % GO-ITN showed 131.73 % increase in the electrical conductivity (compared with neat PANi) along with 78.07%, 57.12%, and 44.99% decrease in the amplitude of the total irradiated X-ray waves at 30, 40, and 60 kVp tube voltages, respectively, compared with control X-ray dosage. More importantly, the developed shields not only showed non-toxic nature and improved the viability of cells, but also completely removed the selected microorganisms at a concentration of 1000 µg.mL-1.


Clues to unraveling the coral species problem: distinguishing species from geographic variation in Porites across the Pacific with molecular markers and microskeletal traits.
Morphological variation in the geographically widespread coral Porites lobata can make it difficult to distinguish from other massive congeneric species. This morphological variation could be attributed to geographic variability, phenotypic plasticity, or a combination of such factors. We examined genetic and microscopic morphological variability in P. lobata samples from the Galápagos, Easter Island, Tahiti, Fiji, Rarotonga, and Australia. Panamanian P. evermanni specimens were used as a previously established distinct outgroup against which to test genetic and morphological methods of discrimination. We employed a molecular analysis of variance (AMOVA) based on ribosomal internal transcribed spacer region (ITS) sequence, principal component analysis (PCA) of skeletal landmarks, and Mantel tests to compare genetic and morphological variation. Both genetic and morphometric methods clearly distinguished P. lobata and P. evermanni, while significant genetic and morphological variance was attributed to differences among geographic regions for P. lobata. Mantel tests indicate a correlation between genetic and morphological variation for P. lobata across the Pacific. Here we highlight landmark morphometric measures that correlate well with genetic differences, showing promise for resolving species of Porites, one of the most ubiquitous yet challenging to identify architects of coral reefs.


Serum uric acid: a risk factor and a target for treatment?
Serum uric acid was first noted to be associated with increased BP by Frederick Mohamed in the 1870s. Although the link was rediscovered periodically over the years, it generally was dismissed as a surrogate marker for decreased renal function that led to increased uric acid and increased risk for hypertension and cardiovascular (CV) disease. Recently, however, several lines of evidence suggest that increased serum uric acid may be a significant modifiable risk factor. Increased serum uric acid is associated with increased risk for future hypertension in several large longitudinal clinical trials as well as an independent risk factor for poor CV prognosis. Animal model experiments demonstrate that increased serum uric acid causes increased BP that initially is reversible but becomes irreversible, salt sensitive, and uric acid independent over time. The mechanisms include the direct action of uric acid on smooth muscle and vascular endothelial cells. Finally, in adolescents with new-onset essential hypertension, the prevalence of elevated serum uric acid is >90%, and preliminary clinical trial evidence suggests that agents that lower serum uric acid may lower BP in this select population. Although the investigations are still preliminary, serum uric acid represents a possible new and intriguing target for the reduction of morbidity and mortality associated with hypertension and CV disease.


Apoptosis signals in atopy and asthma measured with cDNA arrays.
A variety of studies have stressed the importance of the control of inflammatory cell longevity and the balance of pro-survival and pro-apoptotic signalling. Recently, asthma was found to be associated with reduced apoptosis of inflammatory cells in lung tissue. The aim of the study was to investigate the systemic activation of apoptosis pathways using cDNA array technology in atopy and asthma. Eighteen atopic asthmatics (AA), eight atopic non-asthmatic (AN) and 14 healthy control subjects (C) were included in the study. Peripheral blood mononuclear cells were separated with gradient centrifugation, mRNA purified and the reverse-transcribed probes hybridized to cDNA arrays. The signals were compared by standardizing to the 100 most expressed genes and group differences assessed with the Mann-Whitney U-test. We found a concerted up-regulation of several pro-survival cytokines and growth factors in AN and AA. FAS and FASL were not differentially expressed, but FAST kinase was over-expressed in AN and AA. The tumour necrosis factor pathway was activated in AN and AA with increased cytokine and receptor levels and increased TRAF2, an intracellular signalling product. There were indications of a down-regulated p53 system. In contrast, the Bcl-2 family of genes showed a net pro-apoptotic profile in AN and AA. The group of caspases showed a constant gene expression pattern in all groups. In conclusion, significant differences in the expression of apoptosis-related genes were found in peripheral blood of atopic individuals with and without asthma. cDNA array technology proved to be useful and may be complementary to DNA-based studies in order to analyse interactive and multidimensional pathways as shown here for apoptosis.


Measurement properties of the NIH Stroke Scale during acute rehabilitation.
The scale of stroke impairment characteristics by Brott and associates, the National Institutes of Health (NIH) Stroke Scale, has been used widely in various studies of stroke outcome; however, the measurement properties of the items applied to patients during medical rehabilitation have not been evaluated thoroughly. This study evaluated the extent to which scale items cohere to define a unidimensional construct and have a useful range for application to patients during medical rehabilitation. Rating scale (or Rasch) analysis of the 15 NIH Stroke Scale items was conducted using the BIGSTEPS computer program to evaluate (1) the range of impairment assessed by the items, (2) the items' coherence with an underlying construct of impairment, and (3) range of impairment measured in rehabilitation patients. We sought to maximize the range of impairment measured by conducting analyses recursively; at each subsequent step, the worst fitting item was deleted or rescored. The sample comprised 1291 admission and discharge records from 693 rehabilitation inpatients with stroke. Thirteen items arrayed the sample across a sufficient range of impairment. The limb ataxia item fit poorly and was deleted; lower ratings for this item were associated with higher scores on the total scale. Pupillary response was also deleted because ratings reflected poor congruence with the total score. Best language was rescored because intermediate ratings were inconsistently related to the total score. Patients with hemorrhagic strokes had poorer fitting measures than did patients with ischemic strokes. The items in a revised NIH Stroke Scale worked well together to define the severity of impairment resulting from stroke that is observed during medical rehabilitation. Directions regarding limb ataxia should be modified to indicate untestability due to hemiplegia.


Effects of antibiotics and metals on lung and intestinal microbiome dysbiosis after sub-chronic lower-level exposure of air pollution in ageing rats.
We investigated the effects of antibiotics, drugs, and metals on lung and intestinal microbiomes after sub-chronic exposure of low-level air pollution in ageing rats. Male 1.5-year-old Fischer 344 ageing rats were exposed to low-level traffic-related air pollution via whole-body exposure system for 3 months with/without high-efficiency particulate air (HEPA) filtration (gaseous vs. particulate matter with aerodynamic diameter of ≤2.5 µm (PM2.5) pollution). Lung functions, antibiotics, drugs, and metals in lungs were examined and linked to lung and fecal microbiome analyses by high-throughput sequencing analysis of 16 s ribosomal (r)DNA. Rats were exposed to 8.7 μg/m3 PM2.5, 10.1 ppb NO2, 1.6 ppb SO2, and 23.9 ppb O3 in average during the study period. Air pollution exposure decreased forced vital capacity (FVC), peak expiratory flow (PEF), forced expiratory volume in 20 ms (FEV20), and FEF at 25∼75% of FVC (FEF25-75). Air pollution exposure increased antibiotics and drugs (benzotriazole, methamphetamine, methyl-1 H-benzotriazole, ketamine, ampicillin, ciprofloxacin, pentoxifylline, erythromycin, clarithromycin, ceftriaxone, penicillin G, and penicillin V) and altered metals (V, Cr, Cu, Zn, and Ba) levels in lungs. Fusobacteria and Verrucomicrobia at phylum level were increased in lung microbiome by air pollution, whereas increased alpha diversity, Bacteroidetes and Proteobacteria and decreased Firmicutes at phylum level were occurred in intestinal microbiome. Lung function decline was correlated with increasing antibiotics, drugs, and metals in lungs as well as lung and intestinal microbiome dysbiosis. The antibiotics, drugs, and Cr, Co, Ca, and Cu levels in lung were correlated with lung and intestinal microbiome dysbiosis. The lung microbiome was correlated with intestinal microbiome at several phylum and family levels after air pollution exposure. Our results revealed that antibiotics, drugs, and metals in the lung caused lung and intestinal microbiome dysbiosis in ageing rats exposed to air pollution, which may lead to lung function decline.


Intra-individual comparison of different contrast media concentrations (300 mg, 370 mg and 400 mg iodine) in MDCT.
To compare intra-individual contrast enhancement in multi-detector-row computed tomography (MDCT) using contrast media (CM) containing 300, 370 and 400 mg iodine per ml (mgI/ml). Six pigs underwent repeated chest MDCT using three different CM (iopromide 300, iopromide 370, iomeprol 400). An identical iodine delivery (IDR) rate of 1.5 gI/s and a constant total iodine dose of 300 mg/kg body weight were used. Dynamic CT were acquired at the level of the pulmonary artery, and the ascending and descending aorta. After the time enhancement curves were computed, the pulmonary and aortic peak enhancement, time to peak and plateau time above 300 HU were calculated. Intra-individual peak contrast enhancement was significantly higher for the 300 mgI/ml contrast medium compared with the 370 and 400 mgI/ml media: pulmonary trunk 595 HU vs 516 HU (p = 0.0093) vs 472 HU (p = 0.0005), and aorta 505 HU vs 454 HU (p = 0.0008) vs 439 HU (p = 0.0001), respectively. Comparison of time to peaks showed no significant difference. Plateau times were significantly longer for the 300 mgI/ml than for the 370 and 400 mgI/ml CM at all anatomical sites. Given normalised IDR and total iodine burden, the use of CM with a standard concentration with 300 mg iodine/ml provides improved contrast enhancement compared with highly concentrated CM in the chest.


Decoupling diffusional from dimensional control of signaling in 3D culture reveals a role for myosin in tubulogenesis.
We present a novel microfabricated platform to culture cells within arrays of micrometer-scale three-dimensional (3D) extracellular matrix scaffolds (microgels). These microscale cultures eliminate diffusion barriers that are intrinsic to traditional 3D culture systems (macrogels) and enable uniform cytokine stimulation of the entire culture population, as well as allow immunolabeling, imaging and population-based biochemical assays across the relatively coplanar microgels. Examining early signaling associated with hepatocyte growth factor (HGF)-mediated scattering and tubulogenesis of MDCK cells revealed that 3D culture modulates cellular responses both through dimensionality and altered stimulation rates. Comparing responses in 2D culture, microgels and macrogels demonstrated that HGF-induced ERK signaling was driven by the dynamics of stimulation and not by whether cells were in a 2D or 3D environment, and that this ERK signaling was equally important for HGF-induced cell scattering on 2D substrates and tubulogenesis in 3D. By contrast, we discovered a specific HGF-induced increase in myosin expression leading to sustained downregulation of myosin activity that occurred only within 3D contexts and was required for 3D tubulogenesis but not 2D scattering. Interestingly, although absent in cells on collagen-coated plates, downregulation of myosin activity also occurred for cells on collagen gels, but was transient and mediated by a combination of myosin dephosphorylation and enhanced myosin expression. Furthermore, upregulating myosin activity via siRNA targeted to a myosin phosphatase did not attenuate scattering in 2D but did inhibit tubulogenesis in 3D. Together, these results demonstrate that cellular responses to soluble cues in 3D culture are regulated by both rates of stimulation and by matrix dimensionality, and highlight the importance of decoupling these effects to identify early signals relevant to cellular function in 3D environments.


The integration of the applied Thai traditional medicine into hospitals of the current health delivery system: the development of an administrative/management model.
Develop a model of administration/management of district/general hospitals in the Ministry of Public Health of Thailand to enable the medical services of Applied Thai Traditional Medicine to be integrated into the current Modern Medical (Health) System. A prospective study of the various services of Applied Thai Traditional Medicine in relation to the needs of other related services of the hospitals and the health needs of the population of Huay Ploo District Hospital of Nakhon Pathom Province. The collection of data of services covered 12 months to enable the comparisons of changes that occurred during the period. The study was both quantitative and quantitative measures. There is a statistical difference in all aspects compared of the opinions of personnel related to the services of Thai Traditional Medicine before and after the interventions in the areas of knowledge, attitude, beliefs, and the support of the services rendered by Thai Traditional Medicine. The present study showed that more system diseases was seen before than after the interventions whereas the most common incidence of diseases was in the musculo-skeletal system when compared to those found in other systems. After the interventions, the patients' preferences in the methods of treatment were mixed, with several methods of treatment preferred and with the tendency to resort to Thai Traditional Medicine more than before the interventions. This was believed to be the result of changes in the hospital i.e. personnel from all service units after answering the questionnaires and voiced opinions were found to require more relevant competencies and in need of support from their superiors. The personnel surveyed wished that the planning and policies'goals succeed with efficiency The Administrators outlined the plan and strategies to move forward. With cooperation to solve problems, should any occur and with mutual role and coordination of personnel and services, the way towards solving problems should be beneficial as all sides participated in the undertakings. The management/administration of Government district/general hospitals under the Ministry of Public Heath aiming for an integration of all services of Applied Thai Traditional Medicine into services of Modern Medicine in Government Hospitals at the mentioned level was feasible and this undertaking would comply with the National Health Policy and WHO Guidelines. The present research study proposed that the Hospital uses health care services as a 'principal core' and other related sectors acted as supporting/promoting/and facilitating the principal core towards the best practice in health/medical care. The researchers wished to label the development of this model as "Huay Ploo Model", which will be a landmark. In addition, the Ministry may want to pursue a similar model as the administrative structures of all hospitals under the Ministry, under the Thai civil service system. The researchers also proposed the set-up of a Centre for Training and Learning within the hospital. It was also suggested that the Hospital should hold regular academic meetings of various forms to strengthen the knowledge, skill, and overall capacity of its personnel.


Intraparotid facial nerve schwannoma: a report of five cases and an analysis of MR imaging results.
We present five cases of intraparotid facial nerve schwannoma. In four of the five cases, tumors arising from the main facial nerve trunk were centered just below the skull base near the stylomastoid foramen and had a small cranial extension into the lower facial nerve canal. In three cases, each tumor had higher signal intensity around the periphery on T2-weighted images (target sign). These findings may be highly suggestive of an intraparotid facial nerve schwannoma.


Biomedical applications of graphene.
Graphene exhibits unique 2-D structure and exceptional phyiscal and chemical properties that lead to many potential applications. Among various applications, biomedical applications of graphene have attracted ever-increasing interests over the last three years. In this review, we present an overview of current advances in applications of graphene in biomedicine with focus on drug delivery, cancer therapy and biological imaging, together with a brief discussion on the challenges and perspectives for future research in this field.


Factors affecting protein thiol reactivity and specificity in peroxide reduction.
Protein thiol reactivity generally involves the nucleophilic attack of the thiolate on an electrophile. A low pK(a) means higher availability of the thiolate at neutral pH but often a lower nucleophilicity. Protein structural factors contribute to increasing the reactivity of the thiol in very specific reactions, but these factors do not provide an indiscriminate augmentation in general reactivity. Notably, reduction of hydroperoxides by the catalytic cysteine of peroxiredoxins can achieve extraordinary reaction rates relative to free cysteine. The discussion of this catalytic efficiency has centered in the stabilization of the thiolate as a way to increase nucleophilicity. Such stabilization originates from electrostatic and polar interactions of the catalytic cysteine with the protein environment. We propose that the set of interactions is better described as a means of stabilizing the anionic transition state of the reaction. The enhanced acidity of the critical cysteine is concurrent but not the cause of catalytic efficiency. Protein stabilization of the transition state is achieved by (a) a relatively static charge distribution around the cysteine that includes a conserved arginine and the N-terminus of an α-helix providing a cationic environment that stabilizes the reacting thiolate, the transition state, and also the anionic leaving group; (b) a dynamic set of polar interactions that stabilize the thiolate in the resting enzyme and contribute to restraining its reactivity in the absence of substrate; but upon peroxide binding these active/binding site groups switch interactions from thiolate to peroxide oxygens, simultaneously increasing the nucleophilicity of the attacking sulfur and facilitating the correct positioning of the substrate. The switching of polar interaction provides further acceleration and, importantly, confers specificity to the thiol reactivity. The extraordinary thiol reactivity and specificity toward H(2)O(2) combined with their ubiquity and abundance place peroxiredoxins, along with glutathione peroxidases, as obligate hydroperoxide cellular sensors.


Reduction in central line-associated bloodstream infections by implementation of a postinsertion care bundle.
Central line-associated bloodstream infections (CLABSIs) cause substantial morbidity and incur excess costs. The use of a central line insertion bundle has been shown to reduce the incidence of CLABSI. Postinsertion care has been included in some studies of CLABSI, but this has not been studied independently of other interventions. Surveillance for CLABSI was conducted by trained infection preventionists using National Health Safety Network case definitions and device-day measurement methods. During the intervention period, nursing staff used a postinsertion care bundle consisting of daily inspection of the insertion site; site care if the dressing was wet, soiled, or had not been changed for 7 days; documentation of ongoing need for the catheter; proper application of a chlorohexidine gluconate-impregnated sponge at the insertion site; performance of hand hygiene before handling the intravenous system; and application of an alcohol scrub to the infusion hub for 15 seconds before each entry. During the preintervention period, there were 4415 documented catheter-days and 25 CLABSIs, for an incidence density of 5.7 CLABSIs per 1000 catheter-days. After implementation of the interventions, there were 2825 catheter-days and 3 CLABSIs, for an incidence density of 1.1 per 1000 catheter-days. The relative risk for a CLABSI occurring during the postintervention period compared with the preintervention period was 0.19 (95% confidence interval, 0.06-0.63; P = .004). This study demonstrates that implementation of a central venous catheter postinsertion care bundle was associated with a significant reduction in CLABSI in a setting where compliance with the central line insertion bundle was already high.


[Chloroquine neuromyopathies: 4 cases during antimalarial prevention].
Four cases of chloroquine neuropathy presented two points of particular interest: 1) these were all young women with strictly prophylactic doses of chloroquine (100 mg/24 h); two patients showed pronounced loss of weight; 2) signs of myogenic lesions were apparent in only one patient whereas clinical and electric signs of neurogenic involvement were observed in all 4 cases. Biopsy in 3 patients (muscle in one and muscle and nerve in two) failed to show characteristic vacuoles; in one case mild segmental demyelinization was present. A favorable course was obtained in all cases after discontinuation of chloroquine, with dramatic recovery from the motor deficit. Pharmacokinetic studies in 1 patient showed abnormally high chloroquine levels at initial assay with slow elimination after its discontinuation.


Evaluating patient anxiety levels during contact lens fitting.
Patient anxiety has been shown to be detrimental to many aspects of primary healthcare consultations. However, to date, the subject has received minimal attention within optometric practice. Therefore, the purpose of this study was to evaluate patient anxiety during a commonly conducted type of optometric examination, namely a contact lens fit. Forty participants (15 male, 25 female; mean age 28.3 +/- 9.5) underwent a full contact lens fitting consultation. Skin conductance was recorded continuously to measure participant arousal; the physiological correlate of anxiety. A short form of the Speilberger state anxiety scale was also completed by participants before and after the contact lens fit. Skin conductance analysis identified arousal levels peak during history and symptoms, contact lens insertion and removal and practitioner advice. The Wilcoxen test identified a significant reduction in participant anxiety measured with the shortened Speilberger state anxiety scale after the consultation. Patient arousal levels fluctuate in a characteristic way throughout the contact lens fitting examination. Peak arousal levels occur during periods of 'communicative interaction' between the patient and the optometrist. Since anxiety is associated with poor attention, this suggests that optometrists should not assume that patients remember what they are told during the consultation. Furthermore, patient anxiety is significantly reduced after the examination, which may indicate that patient anxiety is moderated by experience.


Predictors and Outcomes of Healthcare-Associated Infections among Patients with COVID-19 Admitted to Intensive Care Units in Punjab, Pakistan; Findings and Implications.
Healthcare-associated infections (HAIs) have a considerable impact on morbidity, mortality and costs. The COVID-19 pandemic resulted in an appreciable number of hospitalized patients being admitted to intensive care units (ICUs) globally with a greater risk of HAIs. Consequently, there is a need to evaluate predictors and outcomes of HAIs among COVID-19 patients admitted to ICUs. A retrospective study of patients with COVID-19 admitted to ICUs of three tertiary care hospitals in the Punjab province over a five-month period in 2021 was undertaken to ascertain predictors and outcomes of HAIs. Of the 4534 hospitalized COVID-19 patients, 678 were admitted to ICUs, of which 636 patients fulfilled the inclusion criteria. Overall, 67 HAIs were identified among the admitted patients. Ventilator-associated lower respiratory tract infections and catheter-related urinary tract infections were the most frequent HAIs. A significantly higher number of patients who developed HAIs were on anticoagulants (p = 0.003), antithrombotic agents (p < 0.001), antivirals (p < 0.001) and IL-6 inhibiting agents (p < 0.001). Secondary infections were significantly higher in patients who were on invasive mechanical ventilation (p < 0.001), had central venous access (p = 0.023), and urinary catheters (p < 0.001). The mortality rate was significantly higher in those with secondary infections (25.8% vs. 1.2%, p < 0.001). Our study concluded that COVID-19 patients admitted to ICUs have a high prevalence of HAIs associated with greater mortality. Key factors need to be addressed to reduce HAIs.


The soluble pool of beta 2-microglobulin free HLA class I alpha-chains. Qualitative and quantitative characterization.
Previous studies have demonstrated that HLA class I heterodimers are present in plasma and cell culture supernatants. They can be precipitated by mAb the binding of which is dependent on the proper association of the polymorphic alpha-chain with beta 2-microglobulin (beta 2-m). The molecular mass of the alpha-chain ranges from 45 to 35 kDa with a number of intermediate products. We report on the identification of 35-kDa soluble beta 2-m free HLA class I H chains immunoprecipitated by mAb LA45 from cell culture media of activated B and T cells. Furthermore, a peptide-based competitive immunosorbent assay was established to determine the amounts of soluble HLA class I alpha-chains. By means of this assay, we formally proved the specificity of mAb LA45 for a linear epitope on HLA class I H chains centered on residues arginine-asparagine at positions 62 and 63 of the alpha 1-domain. PHA or rIL-2 were identified as efficient stimuli for PBMC leading to the generation of soluble beta 2-m free HLA class I H chains. Testing of cell lines representing distinct stages of hematopoietic differentiation demonstrated a significant correlation between cell surface expression of beta 2-m free HLA class I H chains and amounts of soluble LA45 reactive molecules. However, three of six human T lymphotropic virus type I transfected cell lines, although expressing beta 2-m free H chains, do not generate soluble molecules. Finally, human sera were found to contain considerable amounts of beta 2-m free HLA class I H chains. The average amount of these molecules in sera of individuals with one positive LA45 allele was determined to be 46.9 +/- 38.6 nM/liter.


Iontophoresis-Assisted Corneal Collagen Cross-Linking with Epithelial Debridement: Preliminary Results.
Purpose. To report the early outcomes of iontophoresis-assisted corneal collagen cross-linking procedure with epithelial debridement (I-SCXL). Methods. Twenty eyes of twenty patients with progressive keratoconus were included in this prospective clinical study. Best spectacle corrected visual acuity (BSCVA), sphere and cylinder refraction, corneal topography, Scheimpflug tomography, aberrometry, anterior segment optical coherence tomography (AS-OCT), and endothelial cell count were assessed at baseline and at 1, 3, and 6 months of follow-up. The parameters considered to establish keratoconus progression were always proven with differential maps as change in curvature in the cone area of at least 1 diopter obtained with an instantaneous map. Results. Functional parameters showed a significant improvement (p < 0.05) of BSCVA after 3 and 6 months of follow-up. Morphological parameters indicated stabilization of the corneal ectasia during the follow-up; however, a positive trend was noted with a mean flattening of 1.73 D. Minimum pachymetry values showed thinning that remained constant after the treatment. The demarcation line was clearly visible in all patients, reaching a depth of 308.2 ± 37.74 μm. None of the patients had continuous progression of keratoconus or had to repeat cross-linking procedures. Endothelial cell counts did not change significantly (p > 0.05). Conclusion. The early results indicate that the I-SCXL may be able to reduce the treatment time and improve the riboflavin diffusion.


Utility of Cardiopulmonary Exercise Testing in Chronic Obstructive Pulmonary Disease: A Review.
Chronic obstructive pulmonary disease (COPD) is a disease defined by airflow obstruction with a high morbidity and mortality and significant economic burden. Although pulmonary function testing is the cornerstone in diagnosis of COPD, it cannot fully characterize disease severity or cause of dyspnea because of disease heterogeneity and variable related and comorbid conditions affecting cardiac, vascular, and musculoskeletal systems. Cardiopulmonary exercise testing (CPET) is a valuable tool for assessing physical function in a wide range of clinical conditions, including COPD. Familiarity with measurements made during CPET and its potential to aid in clinical decision-making related to COPD can thus be useful to clinicians caring for this population. This review highlights pulmonary and extrapulmonary impairments that can contribute to exercise limitation in COPD. Key elements of CPET are identified with an emphasis on measurements most relevant to COPD. Finally, clinical applications of CPET demonstrated to be of value in the COPD setting are identified. These include quantifying functional capacity, differentiating among potential causes of symptoms and limitation, prognostication and risk assessment for operative procedures, and guiding exercise prescription.


Health-care workers: source, vector, or victim of MRSA?
There is ongoing controversy about the role of health-care workers in transmission of meticillin-resistant Staphylococcus aureus (MRSA). We did a search of the literature from January, 1980, to March, 2006, to determine the likelihood of MRSA colonisation and infection in health-care workers and to assess their role in MRSA transmission. In 127 investigations, the average MRSA carriage rate among 33 318 screened health-care workers was 4.6%; 5.1% had clinical infections. Risk factors included chronic skin diseases, poor hygiene practices, and having worked in countries with endemic MRSA. Both transiently and persistently colonised health-care workers were responsible for several MRSA clusters. Transmission from personnel to patients was likely in 63 (93%) of 68 studies that undertook genotyping. MRSA eradication was achieved in 449 (88%) of 510 health-care workers. Subclinical infections and colonisation of extranasal sites were associated with persistent carriage. We discuss advantages and disadvantages of screening and eradication policies for MRSA control and give recommendations for the management of colonised health-care workers in different settings.


A method for the study of swimming stress and stress-induced antinociception in preweanling rats.
Stress-induced antinociception (SIA) which is well characterized in the adult rat can also be observed in young rats, and, by varying swimming times, it can be dissociated into opioid and nonopioid forms. However, swimming ability in the rat does not fully develop until the third postnatal week and this has precluded the study of swim SIA in neonates. We report here the development of a harness device to aid swimming in young rats which we have successfully employed down to the age of 2 days without distress to the animals. Further we have also shown the development of the opioid form of swim SIA in the rat using this device. Swim SIA is absent at days 2 and 5, but at postnatal day 10 a small level of SIA is evident which is reversed by naloxone (10 mg/kg). Swim SIA develops rapidly thereafter, and the adult profile is observed by day 25.


Health-related quality of life predicts outcomes but is not affected by peritoneal clearance: The ADEMEX trial.
We hypothesized that increasing small solute clearance in peritoneal dialysis (PD) would lead to improvements in patient health-related quality of life (HRQOL). Patients were randomized to a control group [standard 4 x 2 L continuous ambulatory peritoneal dialysis (CAPD)] and an intervention group (CAPD with a target creatinine clearance >/=60 L/week/1.73 m(2)). The Kidney Disease Quality of Life Short Form was obtained at baseline and at 6, 12, and 24 months. Physical (PCS), mental (MCS), and kidney disease component summary (KDCS) scores were computed. The two groups were comparable at baseline with respect to HRQOL. Baseline variables highly predictive of better QOL included absence of diabetes, younger age, higher starting GFR, and serum albumin. Baseline values of QOL were highly predictive of survival and hospitalizations. An unadjusted comparison revealed that patients in the intervention group had significantly higher PCS and KDCS scores at six months. However, there were no significant differences between the intervention and control patients at 12 or 24 months. When similar analyses were carried out adjusting for different patterns of patient dropout, there were no significant differences between the two groups at any time point in terms of PCS, MCS, and KDCS scores. We found no evidence of a long-term benefit in HRQOL of CAPD patients by increasing peritoneal small-solute clearances when HRQOL parameters were adjusted for patient dropout. Measures of HRQOL have a significant predictive value for patient survival and hospitalizations.


Epidemiology of pre-pregnancy body mass index (BMI) among mothers in Abu Dhabi, the United Arab Emirates.
Pre-pregnancy obesity is a risk factor for several health problems such as gestational diabetes, preeclampsia, labor induction, postpartum hemorrhage, and neonatal hypoglycemia. Being underweight is a risk factor for fetal growth restriction. Despite the negative impact of abnormal pre-pregnancy body mass index (BMI) (over and underweight) on pregnancy outcomes, a limited amount of studies has been conducted on the prevalence of pre-pregnancy over and underweight and associated factors in the United Arab Emirates (UAE). Thus, the aim of this study was to investigate the prevalence and factors associated with underweight, overweight, and obesity among mothers with children under the age of 2 years in Abu Dhabi, the UAE. A cross-sectional multicenter study was conducted in 2017 and included data from seven government health care centers in Abu Dhabi. Maternal pre-pregnancy BMI was calculated as the weight in kilograms (kg) divided by the square of the height in meters (m), (kg/m2). A total of 1,622 mother-child pairs were included in this study. Out of the 1,622 mothers, 43 (2.7%) were underweight, 1,068 (65.8%) were normal weight, 412 (25.4%) were overweight, and 99 (6.1%) were obese. Mothers with advanced maternal age (AMA) (≥35 years) were more likely to be overweight, odds ratio [OR] = 1.93, (95% confidence interval [CI] 1.52-2.3), p ≤ 0.001, and obese OR = 2.15 (95% CI 1.32-3.39), p = 0.001. Mothers with lower family income were more likely to be obese OR = 2.72 (95% CI 1.44-5.93), p = 0.002. Mothers with high parity (≥2) were more likely to be overweight OR = 1.91 (95% CI 1.49-2.50), p ≤ 0.001; obese OR = 1.76 (95% CI 1.06-2.92), p = 0.024; and less likely to be underweight OR = 0.52 (95% CI 0.27-0.94), p = 0.037. Obese mothers were more likely to deliver via cesarean section (CS) OR = 1.95 (95% CI 1.27-2.96), p = 0.002. This study provides valuable baseline information on the epidemiology of pre-pregnancy BMI in the UAE. The sociodemographic factors identified in the study can be used to target at-risk women. The study findings can also be used to develop contextualized strategies to prevent and manage complications associated with abnormal pre-pregnancy BMI in Emirati women.


A robust association test for detecting genetic variants with heterogeneous effects.
One common strategy for detecting disease-associated genetic markers is to compare the genotype distributions between cases and controls, where cases have been diagnosed as having the disease condition. In a study of a complex disease with a heterogeneous etiology, the sampled case group most likely consists of people having different disease subtypes. If we conduct an association test by treating all cases as a single group, we maximize our chance of finding genetic risk factors with a homogeneous effect, regardless of the underlying disease etiology. However, this strategy might diminish the power for detecting risk factors whose effect size varies by disease subtype. We propose a robust statistical procedure to identify genetic risk factors that have either a uniform effect for all disease subtypes or heterogeneous effects across different subtypes, in situations where the subtypes are not predefined but can be characterized roughly by a set of clinical and/or pathologic markers. We demonstrate the advantage of the new procedure through numeric simulation studies and an application to a breast cancer study.


[Comparative analysis of evolution of Eigen's hypercycles and microbial populations in open systems].
The models of evolution of Eigen's hypercycles and microbial populations were compared. It has been proved that both above mentioned model descriptions of evolution completely coincide for the case of support constant organization (1). It has been shown that in the case of constant flows (2) for the Eigen's model it is necessary to take into account the dynamics of concentration of energy monomers. The experimental results of microevolution of microbial populations for conditions 1 and 2 are presented.


[Study of cross reactions between group A streptococcal antigens and cardiac interstitial connective tissue fibroblasts of different species of mammals].
It has been revealed by indirect immunofluorescence that sera of rabbits immunized with group A streptococcal non-type-specific antigens and F (ab')2 fragments of IgG obtained from these sera intensively react with fibroblasts of interstitial connective tissue (ICT) of the myocardium of humans and different mammalian species with the exception of rabbits. Negative or weak reactions with the same sera and F (ab')2 fragments were observed with fibroblasts of ICT of nonimmunized rabbits. Myocardial ICT of immunized animals showed bound immunoglobulins. This model can be used for making clear the reason for presence in sera of rheumatic patients circulating antibodies only to heterologous but not to homologous ICT of the myocardium regardless of the revealing bound immunoglobulins in the ICT of these patients.


The prognostic value of 18F-FDG PET/CT for hepatocellular carcinoma treated with transarterial chemoembolization (TACE).
18F-Fluoro-deoxyglucose (FDG) PET/CT can be used to monitor the biological behavior of hepatocellular carcinoma (HCC). Baseline PET/CT has prognostic value in HCC patients, but there is litter knowledge of the PET/CT changes after treatment. We evaluated 27 HCC patients treated with transarterial chemoembolization (TACE) from June 2011 to July 2012, and we investigated the prognostic value of PET/CT. Patients were followed up with regular clinical and laboratory examinations and contrast-enhanced spiral computed tomography (CT). Furthermore, PET/CT assessments were collected and analyzed before (range 1~15 d) and after the first month of TACE (range, 27~45 d). We tested the prognostic value of the tumor standardized uptake value (TSUV) and normal liver SUV(LSUV) according to the VOI (volume of interest). The SUVs were used to assess the relationship between the treatment response and survival. To assess their prognostic value, we evaluated the areas under the receiver operating characteristic (ROC) curves of different SUVs for predicting survival. Finally, the median overall survival (OS) and time to progression (TTP) for 27 patients were 15.4 months (95%CI, 3.3-27.5 months) and 11.4 months (95%CI, 6.7-16.1 months), respectively. The ΔTSUVmax%, based on the VOI, had the highest discriminative prognostic value and the cutoff PET/CT response was 0.1 with a sensitivity of 100% and a specificity of 95.2%. The OS was significantly better in the PET/CT response group than in the PET/CT non-response group (p=0.025). In conclusion, an early interim PET/CT after TACE may have prognostic value for HCC patients treated with TACE, and the ΔTSUVmax% may help in determining the HCCs viability in patients with high baseline and follow-up18F-FDG uptake.


Long-term effects of combined neonatal and adolescent stress on brain-derived neurotrophic factor and dopamine receptor expression in the rat forebrain.
Altered brain-derived neurotrophic factor (BDNF) signalling and dopaminergic neurotransmission have been shown in the forebrain in schizophrenia. The 'two hit' hypothesis proposes that two major disruptions during development are involved in the pathophysiology of this illness. We therefore used a 'two hit' rat model of combined neonatal and young-adult stress to assess effects on BDNF signalling and dopamine receptor expression. Wistar rats were exposed to neonatal maternal separation (MS) stress and/or adolescent/young-adult corticosterone (CORT) treatment. At adulthood the medial prefrontal cortex (mPFC), caudate putamen (CPu) and nucleus accumbens (NAc) were analysed by qPCR and Western blot. The 'two hit' combination of MS and CORT treatment caused significant increases in BDNF mRNA and protein levels in the mPFC of male, but not female rats. BDNF mRNA expression was unchanged in the CPu but was significantly reduced by CORT in the NAc. DR3 and DR2 mRNA were significantly up-regulated in the mPFC of two-hit rats and a positive correlation was found between BDNF and DR3 expression in male, but not female rats. DR2 and DR3 expression were significantly increased following CORT treatment in the NAc and a significant negative correlation between BDNF and DR3 and DR2 mRNA levels was found. Our data demonstrate male-specific two-hit effects of developmental stress on BDNF and DR3 expression in the mPFC. Furthermore, following chronic adolescent CORT treatment, the relationship between BDNF and dopamine receptor expression was significantly altered in the NAc. These results elucidate the long-term effects of 'two hit' developmental stress on behaviour.


Antacids in the treatment of acute alcohol-induced pancreatitis.
Antacids were given to a group of 18 patients who had acute alcoholic pancreatitis and the results were compared with those in a similar group of 15 patients who did not receive antacid therapy. There was no statistical difference in the course of the illness between the two groups as regards duration of abdominal pain, epigastric tenderness, hospital stay or time taken for the patient to resume a normal diet.


Comparative activity of the penem antibiotic Sch 34343 against gram-negative and gram-positive bacteria with special reference to multiresistant strains.
A new penem antibiotic, Sch 34343, was shown to be active against a large number of Gram-positive bacteria. The drug inhibited penicillinase-positive and -negative staphylococci equally well, being five times more active than cefamandole and ten times more active than methicillin. Most methicillin-resistant staphylococci were inhibited by concentrations between 0.25 and 4 mg/l, but a small group of highly resistant strains were observed. Sch 34343 was eight times less active than ampicillin and penicillin G, but as active as piperacillin against enterococci. The drug showed excellent activity against various streptococci. Sch 34343 was as bactericidal as flucloxacillin, ampicillin and penicillin G against staphylococci, enterococci and streptococci, respectively, in killing kinetic tests. Enterobacteriaceae susceptible to third-generation cephalosporins were approximately five times less susceptible to Sch 34343, but MICs were far below the susceptibility breakpoint. Sch 34343 was equally active against Citrobacter and Enterobacter strains that were highly resistant to third-generation cephalosporins and to aztreonam. Together with thienamycin, this drug seems to be a good alternative for the treatment of infections caused by bacteria resistant to third-generation cephalosporins and to aztreonam.


Study of Antimicrobial Utilization and Cost of Therapy in Medicine Intensive Care Unit of a Tertiary Care Hospital in Eastern India.
High utilization of antimicrobial agent (AMA) and inappropriate usage in an intensive care unit (ICU) intensifies resistant organism, morbidity, mortality, and treatment cost. Prescription audit and active feedback are a proven method to check the irrational prescription. To analyze and compare the utilization of drugs, the World Health Organization (WHO) proposed daily defined dose (DDD)/100 patient days and days of therapy (DOT)/100 patient days to measure utilization of AMAs. Data of AMAs utilization are required for planning an antibiotic policy and for follow-up of intervention strategies. A prospective observational study was conducted for 1 year from July 2018 to June 2019 and the data obtained from ICU of a tertiary care hospital. The demographic data, the disease data, and the utilization of different classes of AMAs [WHO-Anatomical Therapeutic Chemical (ATC) classification] as well as their cost were recorded. Total number of patient days, DDD, DDD/100 patient days, and DOT/100 patient days were calculated as proposed by the WHO. Statistical analysis was performed using statistical software SPSS version 25.0. The descriptive analysis was performed using summary statistics median [interquartile range (IQR)]. A total 939 patients were included, out of them 332 (35.4%) were female. The median age of the total patients was 58 (45-70). The median length of stay in ICU was 3 days. Mortality rate during our study period was 38.6%. The highly utilized AMAs in our study was ceftriaxone (36.95 DDD/100 patient days) followed by piperacillin/tazobactam (31.57), meropenem (26.4), doxycycline (21.53), and polymyxin B (21.38). The association between APACHE II and SOFA score with use of restricted antibiotics found to be statistical significant (p value 0.018 and 0.000, respectively). The cost of antibiotics per patient and patient days were $449.97 and $93.77, respectively, while median value of total cost was $2,343.26. Ceftriaxone was the highest utilized AMA. The risk of receiving restricted antibiotics intensified with increasing prevalence of multidrug resistance bacteria and associated comorbidities. High treatment cost is responsible for higher utilization of restricted antibiotics in ICU. Patra SK, Mishra SB, Rath A, Samal S, Iqbal SN. Study of Antimicrobial Utilization and Cost of Therapy in Medicine Intensive Care Unit of a Tertiary Care Hospital in Eastern India. Indian J Crit Care Med 2020;24(10):938-942.


Vascular Origins of BOLD and CBV fMRI Signals: Statistical Mapping and Histological Sections Compared.
Comparison of 3T blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) activation maps to histological sections enables the spatial discrimination of functional magnetic resonance imaging (fMRI) signal changes into different vascular compartments. We use a standard gradient echo-echo planar imaging technique to measure BOLD signal changes in the somatosensory cortex in response to whisker stimulation. Corresponding changes in CBV were estimated following the infusion of a super-paramagnetic contrast agent. We imaged in a tangential imaging plane that covered the cortical surface. Images were associated with post mortem histological sections showing both the surface vasculature and cytochrome oxidase stained whisker barrel cortex. We found a significant BOLD signal change in the large draining veins which occurred in the absence of a corresponding CBV change. Results suggest that in the venous drainage system, ~3mm distant from the area of activity, there is a robust change in blood oxygen saturation with little or no volume change. CBV changes are localised over the somatosensory barrel cortex and overlying arterial supply, supporting the theory that CBV changes are greater in the arterial than in the venous vasculature. This work investigating BOLD signal and underlying hemodynamics provides more information on the vascular origins of these important neuroimaging signals.


Effect of a physical phase plate on contrast transfer in an aberration-corrected transmission electron microscope.
In this theoretical study we analyze contrast transfer of weak-phase objects in a transmission electron microscope, which is equipped with an aberration corrector (C(s)-corrector) in the imaging lens system and a physical phase plate in the back focal plane of the objective lens. For a phase shift of pi/2 between scattered and unscattered electrons induced by a physical phase plate, the sine-type phase contrast transfer function is converted into a cosine-type function. Optimal imaging conditions could theoretically be achieved if the phase shifts caused by the objective lens defocus and lens aberrations would be equal to zero. In reality this situation is difficult to realize because of residual aberrations and varying, non-zero local defocus values, which in general result from an uneven sample surface topography. We explore the conditions--i.e. range of C(s)-values and defocus--for most favourable contrast transfer as a function of the information limit, which is only limited by the effect of partial coherence of the electron wave in C(s)-corrected transmission electron microscopes. Under high-resolution operation conditions we find that a physical phase plate improves strongly low- and medium-resolution object contrast, while improving tolerance to defocus and C(s)-variations, compared to a microscope without a phase plate.


Microbiota and the gut-brain axis.
Changes in gut microbiota can modulate the peripheral and central nervous systems, resulting in altered brain functioning, and suggesting the existence of a microbiota gut-brain axis. Diet can also change the profile of gut microbiota and, thereby, behavior. Effects of bacteria on the nervous system cannot be disassociated from effects on the immune system since the two are in constant bidirectional communication. While the composition of the gut microbiota varies greatly among individuals, alterations to the balance and content of common gut microbes may affect the production of molecules such as neurotransmitters, e.g., gamma amino butyric acid, and the products of fermentation, e.g., the short chain fatty acids butyrate, propionate, and acetate. Short chain fatty acids, which are pleomorphic, especially butyrate, positively influence host metabolism by promoting glucose and energy homeostasis, regulating immune responses and epithelial cell growth, and promoting the functioning of the central and peripheral nervous systems. In the future, the composition, diversity, and function of specific probiotics, coupled with similar, more detailed knowledge about gut microbiota, will potentially help in developing more effective diet- and drug-based therapies.


Diagnosis of histoplasmosis in immunosuppressed patients.
To define the most appropriate studies for making a diagnosis of histoplasmosis in immunosuppressed patients. As is true of all fungal infections in immunosuppressed patients, heightened awareness of the epidemiology and clinical manifestations of histoplasmosis is essential in making an early diagnosis. Increasingly, Histoplasma antigen detection is used to help establish a diagnosis of histoplasmosis. Most of the reported data are on patients with AIDS, but limited data suggest the usefulness of this assay in other immunosuppressed patients as well. False positive reactions occur with other fungal infections, especially blastomycosis, and patients who have histoplasmosis may have a false positive serum Aspergillus galactomannan assay. The identification of the yeast phase of Histoplasma capsulatum in tissue biopsy samples and, uncommonly, in circulating blood phagocytes is also helpful in establishing a diagnosis quickly. PCR techniques have yet to prove useful for the rapid diagnosis of histoplasmosis, and serology is often negative in immunosuppressed patients. Culture remains definitive and should always be performed to confirm the results of the rapid diagnostic studies. Rapid techniques, mostly antigen detection in serum and urine and histopathological identification of Histoplasma capsulatum in tissues, are the most important rapid diagnostic tests for histoplasmosis in immunosuppressed patients.


Diabetes and driving.
The principal safety concern for driving for people treated with insulin or insulin secretagogues is hypoglycaemia, which impairs driving performance. Other complications, such as those causing visual impairment and peripheral neuropathy, are also relevant to medical fitness to drive. Case control studies have suggested that drivers with diabetes pose a modestly increased but acceptable and measurable risk of motor vehicle accidents compared to non-diabetic drivers, but many studies are limited and of poor quality. Factors which have been shown to increase driving risk include previous episodes of severe hypoglycaemia, previous hypoglycaemia while driving, strict glycaemic control (lower HbA1c) and absence of blood glucose monitoring before driving. Impaired awareness of hypoglycaemia may be counteracted by frequent blood glucose testing. The European Union Third directive on driving (2006) has necessitated changes in statutory regulations for driving licences for people with diabetes in all European States, including the UK. Stricter criteria have been introduced for Group 1 vehicle licences while those for Group 2 licences have been relaxed. Insulin-treated drivers can now apply to drive Group 2 vehicles, but in the UK must meet very strict criteria and be assessed by an independent specialist to be issued with a 1-year licence.


Volumetric modulated arc therapy for carotid sparing in the management of early glottic cancer.
Radiotherapy of the neck is known to cause carotid artery stenosis. We compared the carotid artery dose received between volumetric modulated arc therapy (VMAT) and conventional fixed-field intensity-modulated radiotherapy (IMRT) plans in patients with early glottic cancer. Twenty-one early glottic cancer patients who previously underwent definitive radiotherapy were selected for this study. For each patient, double arc VMAT, 8-field IMRT, 3-dimensional conformal radiotherapy (3DCRT), and lateral parallel-opposed photon field radiotherapy (LPRT) plans were created. The 3DCRT plan was generated using lateral parallel-opposed photon fields plus an anterior photon field. VMAT and IMRT treatment plan optimization was performed under standardized conditions to obtain adequate target volume coverage and spare the carotid artery. Dose-volume specifications for the VMAT, IMRT, 3DCRT, and LPRT plans were calculated with radiotherapy planning system. Monitor units (MUs) and delivery time were measured to evaluate treatment efficiency. Target volume coverage and homogeneity results were comparable between VMAT and IMRT; however, VMAT was superior to IMRT for carotid artery dose sparing. The mean dose to the carotid arteries in double arc VMAT was reduced by 6.8% compared to fixed-field IMRT (p < 0.001). The MUs for VMAT and IMRT were not significantly different (p = 0.089). VMAT allowed an approximately two-fold reduction in treatment delivery time in comparison to IMRT (3 to 5 minutes vs. 5 to 10 minutes). VMAT resulted in a lower carotid artery dose compared to conventional fixed-field IMRT, and maintained good target coverage in patients with early glottic cancer.


Coffee, tea, and cocoa and risk of stroke.
Current evidence from experimental studies in animals and humans along with findings from prospective studies indicates beneficial effects of green and black tea as well as chocolate on cardiovascular health, and that tea and chocolate consumption may reduce the risk of stroke. The strongest evidence exists for beneficial effects of tea and cocoa on endothelial function, total and LDL cholesterol (tea only), and insulin sensitivity (cocoa only). The majority of prospective studies have reported a weak inverse association between moderate consumption of coffee and risk of stroke. However, there are yet no clear biological mechanisms whereby coffee might provide cardiovascular health benefits. Awaiting the results from further long-term RCTs and prospective studies, moderate consumption of filtered coffee, tea, and dark chocolate seems prudent.