Medication class enrichment analysis: a novel algorithm to analyze multiple pharmacologic exposures simultaneously using electronic health record data.
Observational studies analyzing multiple exposures simultaneously have been limited by difficulty distinguishing relevant results from chance associations due to poor specificity. Set-based methods have been successfully used in genomics to improve signal-to-noise ratio. We present and demonstrate medication class enrichment analysis (MCEA), a signal-to-noise enhancement algorithm for observational data inspired by set-based methods. We used The Health Improvement Network database to study medications associated with Clostridium difficile infection (CDI). We performed case-control studies for each medication in The Health Improvement Network to obtain odds ratios (ORs) for association with CDI. We then calculated the association of each pharmacologic class with CDI using logistic regression and MCEA. We also performed simulation studies in which we assessed the sensitivity and specificity of logistic regression compared to MCEA for ORs 0.1-2.0. When analyzing pharmacologic classes using logistic regression, 47 of 110 pharmacologic classes were identified as associated with CDI. When analyzing pharmacologic classes using MCEA, only fluoroquinolones, a class of antibiotics with biologically confirmed causation, and heparin products were associated with CDI. In simulation, MCEA had superior specificity compared to logistic regression across all tested effect sizes and equal or better sensitivity for all effect sizes besides those close to null. Although these results demonstrate the promise of MCEA, additional studies that include inpatient administered medications are necessary for validation of the algorithm. In clinical and simulation studies, MCEA demonstrated superior sensitivity and specificity for identifying pharmacologic classes associated with CDI compared to logistic regression.


Diagnostic challenges in multiple system atrophy.
Multiple system atrophy is a progressive neurodegenerative disorder that is characterized by autonomic failure, cerebellar ataxia and parkinsonism syndrome in various combinations. In spite of the presence of well-established clinical criteria for multiple system atrophy, ante-mortem diagnosis is difficult. In our case report, we present a 78-year-old female patient who presented with early progressive aphasia and severe autonomic dysfunction. Two years after appearance of the first symptoms, she fulfilled all the major criteria for probable multiple system atrophy with rapid progression. In addition, brain magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography findings were more typical for progressive supranuclear palsy. Clinically differentiating multiple system atrophy from progressive supranuclear palsy and other similar neurodegenerative disorders may be challenging in all stages of the disease, especially with atypical disease presentation.


Relationship of Theiler's murine encephalomyelitis viruses to the cardiovirus genus of picornaviruses.
Sequence analysis of VP1 in the DA strain of Theiler's murine encephalomyelitis viruses (TMEV) showed that 13 of the first 23 N-terminal amino acids were identical to those in the corresponding protein of encephalomyocarditis virus. There was little similarity to the corresponding VP1 sequences of poliovirus types 1, 2 and 3, coxsackievirus B3, human rhinoviruses 2 and 14, human hepatitis A virus or foot-and-mouth disease virus. These results, as well as serological relationships detected by immunoblotting, suggest that the TMEV are more closely related to the cardioviruses than to the enteroviruses with which they are presently classified. This newly recognized relationship suggests potential for recombinant infectious cDNA studies between TMEV and cardioviruses.


Microchimerism in the human brain: more questions than answers.
Recently, our group reported the presence of microchimerism (Mc) in the human brain by performing quantitative PCR on female human brain tissues to amplify male DNA. We found brain Mc to be relatively frequent in humans and widely distributed in this organ. Our data also suggested a lower prevalence of brain Mc in women without Alzheimer disease than women without neurological disease. Altogether, these findings suggest that Mc could sometimes influence health and disease of the brain. As further research will be required to clarify this issue, here we discuss some of the questions that could be addressed to improve our understanding.


Interaction of poly-L-lysine with chromatin. Inhibition of in situ RNA synthesis mediated by Escherichia coli RNA polymerase.
RNA polymerase from Escherichia coli was used in conjunction with labeled nucleosides as an autoradiographic reagent to study the availability of template in the chromatin of fixed nuclei and chromosomes Sequential treatments of the tissues with acid and poly-L-lysine were used to compare the effect of these treatments on the availability of template with the previously reported effects on the in situ priming for Escherichia coli DNA polymerase Acid treatment was found to increase the in situ activity of both enzymes, while poly-L-lysine strongly inhibited the in situ reactions mediated by RNA and DNA polymerases. When the DNA polymerase reaction was previously carried out on alcohol-fixed chicken blood smears, leukocyte nuclei primed extensively for DNA synthesis. In contrast, we did not detect incorporation into intact nuclei of any cell type in alcohol-fixed blood smears that were treated with RNA polymerase.


Torsion-vibration coupling in methanol: the adiabatic approximation and intramolecular vibrational redistribution scaling.
The four-dimensional model Hamiltonian of Wang and Perry [J. Chem. Phys. 109, 10795 (1998)] is used to compare the approximate adiabatic separation of the torsion and CH stretches in methanol to an exact solution of the same Hamiltonian. The adiabatic approximation accounts for the pattern of the energy levels in the lowest torsional states, including the inverted tunneling splittings, but does not account for the pattern of systematic two- and four-fold near degeneracies at high torsional excitation. In the adiabatic basis, the nonadiabatic couplings mix the torsional and vibrational degrees of freedom and hence are a source for intramolecular vibrational redistribution (IVR). These IVR matrix elements are found to decrease by only a factor of 2 or 3 with each higher coupling order, in agreement with the results of Pearman and Gruebele [Z. Phys. Chem. Munich 214, 1439 (2000)]. This gentle scaling behavior, which contrasts with a steeper falloff with coupling order in more rigid molecules, points to a more important role for direct high-order couplings in torsional molecules. In this model, the scaling behavior derives from a single coupling term that is low order in the torsional angular momentum in combination with one-dimensional torsional functions that include contributions from many torsional angular momenta.


Increase of circulating gamma/delta T lymphocytes in the peripheral blood of patients affected by active inflammatory bowel disease.
In order to study the role of gamma/delta T cells in the pathogenesis of inflammatory bowel disease (IBD) in humans, we measured the percentage of these cells in the peripheral blood, assessed the ratio of the non-disulphide-linked (delta TCS1) type of T cell receptor (TCR) in the total gamma/delta T cells, studied the co-expression of gamma/delta TCR and accessory molecules CD8 and CD16, and compared these data with both the type and the activity of the disease. Percentage levels and absolute numbers of gamma/delta+ T cells were higher in active patients than in controls (P < 0.05), mainly as a result of an increase of V delta 1+ (delta TCS1) T cell subset (P < 0.05). This trend was strongly retained independently of disease activity and clinical picture. An increased percentage of TCR delta 1+/CD16+ cells was observed in our patients compared with controls (P < 0.05). In contrast, no difference was observed as far as the TCR delta 1+/CD8+ cells were concerned. These results suggest that IBD is associated with an expansion of gamma/delta T cells in peripheral blood, which may play a role in the pathogenesis of these disorders.


Prior human polyomavirus and papillomavirus infection and incident lung cancer: a nested case-control study.
To test whether infection with select human polyomaviruses (HPyV) and human papillomaviruses (HPV) is associated with incident lung cancer. We performed a nested case-control study, testing serum from the carotene and retinol efficacy trial, conducted 1985-2005, for antibodies to Merkel cell (MCV), KI (KIV), and WU (WUV) HPyVs as well as to six high-risk and two low-risk HPV types. Incident lung cancer cases (n = 200) were frequency-matched with controls (n = 200) on age, enrollment and blood draw dates, intervention arm assignment, and the number of serum freeze/thaw cycles. Sera were tested using multiplex liquid bead microarray antibody assays. We used logistic regression to assess the association between HPyV and HPV antibodies and lung cancer. There was no evidence of a positive association between levels of MCV, KIV, or WUV antibodies and incident lung cancer (p corrected >0.10 for all trend tests; odds ratio (OR) range 0.72-1.09, p corrected >0.10 for all). There was also no evidence for a positive association between HPV 16 or 18 infection and incident lung cancer (p corrected ≥0.10 for all trend tests; OR range 0.25-2.54, p > 0.05 for all OR > 1), but the number of persons with serologic evidence of these infections was small. Prior infection with any of several types of HPyV or HPV was not associated with subsequent diagnosis of lung cancer. Infection with these viruses likely does not influence a person's risk of lung cancer in Western smoking populations.


Preventive interventions to reduce the burden of rheumatic heart disease in populations at risk: a systematic review protocol.
Rheumatic heart disease is preventable, yet associated with significant health burden, mostly in low-resourced settings. It is prevalent among children and young adults living in impoverished areas. Primordial, primary, and secondary preventive measures have been recommended through health interventions and comprehensive programmes, although most implemented interventions are the high-resourced settings. The proposed review aims to synthesise the evidence of prevention effectiveness of implemented health interventions for the prevention of rheumatic heart disease. This article describes a protocol for a systematic review. A predefined search strategy will be used to search for relevant literature published from the year 2000 to present. Electronic databases Medline, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials will be searched for the studies, as well as reference lists of relevant studies included. Risk of bias and quality appraisal will be done for the included studies using ROBINS-I tool and Cochrane tool for assessing risk of bias in randomised control trials. Findings will be analysed in subgroups based on the level of intervention and prevention strategy implemented. We will present the findings in descriptive formats with tables and flow diagrams. This review will provide evidence on the prevention effectiveness of interventions or strategies implemented for the prevention of RHD. The findings of this will be significant for policy, practice, and research in countries planning to implement interventions. PROSPERO ID: CRD42020170503.


Relationships between fear of falling, balance confidence, and control of balance, gait, and reactive stepping in individuals with sub-acute stroke.
Fear of falling is common in individuals with stroke; however, the associations between fear of falling, balance confidence, and the control of balance and gait are not well understood for this population. This study aimed to determine whether, at the time of admission to in-patient rehabilitation, specific features of balance and gait differed between individuals with stroke who did and did not report fear of falling, and whether these features were related to balance confidence. Individuals with stroke entering in-patient rehabilitation were asked if they were afraid of falling, and completed the Activities-Specific Balance Confidence Scale. Participants performed quiet standing, gait, and reactive stepping tasks, and specific measures were extracted for each (quiet standing: centre of pressure amplitude, between-limb synchronization, and Romberg quotients; gait: walking velocity, double support time, and variability measures; reactive stepping: number of steps, frequency of grasp reactions, and frequency of assists). No significant differences were identified between individuals with and without fear of falling. Balance confidence was negatively related to centre of pressure amplitude, double support time, and step time variability, and positively related to walking velocity. Low balance confidence was related to poor quiet standing balance control and cautious behavior when walking in individuals with sub-acute stroke. While the causal relationship between balance confidence and the control of balance and gait is unclear from the current work, these findings suggest there may be a role for interventions to increase balance confidence among individuals with stroke, in order to improve functional mobility.


Iodide uptake by forest soils is principally related to the activity of extracellular oxidases.
129I is a nuclear fission decay product of concern because of its long half-life (16 Ma) and propensity to bioaccumulate. Microorganisms impact iodine mobility in soil systems by promoting iodination (covalent binding) of soil organic matter through processes that are not fully understood. Here, we examined iodide uptake by soils collected at two depths (0-10 and 10-20 cm) from 5 deciduous and coniferous forests in Japan and the United States. Autoclaved soils, and soils amended with an enzyme inhibitor (sodium azide) or an antibacterial agent (bronopol), bound significantly less 125I tracer (93%, 81%, 61% decrease, respectively) than the untreated control soils, confirming a microbial role in soil iodide uptake. Correlation analyses identified the strongest significant correlation between 125I uptake and three explanatory variables, actinobacteria soil biomass (p = 6.04E-04, 1.35E-02 for Kendall-Tau and regression analysis, respectively), soil nitrogen content (p = 4.86E-04, 4.24E-03), and soil oxidase enzyme activity at pH 7.0 using the substrate L-DOPA (p = 2.83E-03, 4.33E-04) and at pH 5.5 using the ABTS (p = 5.09E-03, 3.14E-03). Together, the results suggest that extracellular oxidases, primarily of bacterial origin, are the primary catalyst for soil iodination in aerobic, surface soils of deciduous and coniferous forests, and that soil N content may be indicative of the availability of binding sites for reactive iodine species.


Expression characteristics and interaction networks of microRNAs in spleen tissues of grass carp (Ctenopharyngodon idella).
The spleen is an important immune organ in fish. MicroRNAs (miRNAs) have been shown to play an important role in the regulation of immune function. However, miRNA expression profiles and their interaction networks associated with the postnatal late development of spleen tissue are still poorly understood in fish. The grass carp (Ctenopharyngodon idella) is an important economic aquaculture species in China. Here, two small RNA libraries were constructed from the spleen tissue of healthy grass carp at one-year-old and three-year-old. A total of 324 known conserved miRNAs and 9 novel miRNAs were identified by using bioinformatic analysis. Family analysis showed that 23 families such as let-7, mir-1, mir-10, mir-124, mir-8, mir-7, mir-9, and mir-153 were highly conserved between vertebrates and invertebrates. In addition, 14 families such as mir-459, mir-430, mir-462, mir-7147, mir-2187, and mir-722 were present only in fish. Expression analysis showed that the expression patterns of miRNAs in the spleen of one-year-old and three-year-old grass carp were highly consistent, and the percentage of miRNAs with TPM > 100 was above 39%. Twenty significant differentially expressed (SDE) miRNAs were identified. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that these SDE miRNAs were primarily involved in erythrocyte differentiation, lymphoid organ development, immune response, lipid metabolic process, the B cell receptor signaling pathway, the T cell receptor signaling pathway, and the PPAR signaling pathway. In addition, the following miRNA-mRNA interaction networks were constructed: immune and hematopoietic, cell proliferation and differentiation, and lipid metabolism. This study determined the miRNA transcriptome as well as miRNA-mRNA interaction networks in normal spleen tissue during the late development stages of grass carp. The results expand the number of known miRNAs in grass carp and are a valuable resource for better understanding the molecular biology of the spleen development in grass carp.


Experimental warming decreases arbuscular mycorrhizal fungal colonization in prairie plants along a Mediterranean climate gradient.
Arbuscular mycorrhizal fungi (AMF) provide numerous services to their plant symbionts. Understanding climate change effects on AMF, and the resulting plant responses, is crucial for predicting ecosystem responses at regional and global scales. We investigated how the effects of climate change on AMF-plant symbioses are mediated by soil water availability, soil nutrient availability, and vegetation dynamics. We used a combination of a greenhouse experiment and a manipulative climate change experiment embedded within a Mediterranean climate gradient in the Pacific Northwest, USA to examine this question. Structural equation modeling (SEM) was used to determine the direct and indirect effects of experimental warming on AMF colonization. Warming directly decreased AMF colonization across plant species and across the climate gradient of the study region. Other positive and negative indirect effects of warming, mediated by soil water availability, soil nutrient availability, and vegetation dynamics, canceled each other out. A warming-induced decrease in AMF colonization would likely have substantial consequences for plant communities and ecosystem function. Moreover, predicted increases in more intense droughts and heavier rains for this region could shift the balance among indirect causal pathways, and either exacerbate or mitigate the negative, direct effect of increased temperature on AMF colonization.


Correction: A new AIE multi-block polyurethane copolymer material for subcellular microfilament imaging in living cells.
Correction for 'A new AIE multi-block polyurethane copolymer material for subcellular microfilament imaging in living cells' by Yu-qing Niu et al., Chem. Commun., 2017, DOI: .


Correlation of anemia and clinical outcomes in heart failure at Rajavithi Hospital.
Anemia is one of the precipitating factors leading to congestive heart failure. Although much data indicate that anemia is associated with worsening clinical outcomes in heart failure patients, only few studies have been conducted on the subjects in Thailand. Hence, the researchers decided to study about this issue. The present study aimed to evaluate whether anemia could have adverse effects on mortality and morbidity rates in patients with a diagnosis of heart failure. A retrospective cross-sectional study was performed by collecting data from medical records of patients who were admitted in Rajavithi Hospital due to congestive heart failure from January 1, 2011 to December 31, 2012. Those data showed a total 486 patients with congestive heart failure treated during the period. Of the 486 patients, 18 were excluded on the basis of selection criteria, a total of 468. These selected patients were divided in two groups, one group of congestive heart failure patients with anemia (n = 221) and another group of congestive heart failure patients without anemia (n = 247). The study showed that the mortality rate in patients with the anemia group was 8.6%, whereas among nonanemic patients no deaths were reported (0%) [p-value <0.0001]. Patients with anemia had a higher incidence of no restoration of spontaneous circulation after Cardiopulmonary resuscitation (3.62%) than nonanemic patients (0%) [p-value = 0.002]. No difference was observed in the use of inotropic drugs between the two groups [p-value = 0.078]. The patients with anemia (14.75±20.31 days) had a longer duration of hospital admission than nonanemic patients (7.12±8.57 days) [p-value <0.0001]. Anemia was associated with increased morbidity and mortality rate among heart failure patients. The mortality rate tended to increases in correlation with the severity of the anemia. Moreover blood transfusion after congestive heart failure occurrence may not reduce the mortality rate.


Effect of tube current modulation for dose estimation using a simulation tool on body CT examination.
The purpose of this study was to evaluate the effect of tube current modulation for dose estimation of a body computed tomography (CT) examination using a simulation tool. The authors also compared longitudinal variations in tube current values between iterative reconstruction (IR) and filtered back-projection (FBP) reconstruction algorithms. One hundred patients underwent body CT examinations. The tube current values around 10 organ regions were recorded longitudinally from tube current information. The organ and effective doses were simulated by average tube current values and longitudinal modulated tube current values. The organ doses for the bladder and breast estimated by longitudinal modulated tube current values were 20 % higher and 25 % lower than those estimated using the average tube current values, respectively. The differences in effective doses were small (mean, 0.7 mSv). The longitudinal variations in tube current values were almost the same for the IR and FBP algorithms.


Technical note: In vitro total gas and methane production measurements from closed or vented rumen batch culture systems.
This study compared measured gas production (GP) and computed CH4 production values provided by closed or vented bottles connected to gas collection bags. Two forages and 3 concentrates were incubated. Two incubations were conducted, where the 5 feeds were tested in 3 replicates in closed or vented bottles, plus 4 blanks, for a total of 64 bottles. Half of the bottles were not vented, and the others were vented at a fixed pressure (6.8 kPa) and gas was collected into one gas collection bag connected to each bottle. Each bottle (317 mL) was filled with 0.4000 ± 0.0010 g of feed sample and 60 mL of buffered rumen fluid (headspace volume = 257 mL) and incubated at 39.0°C for 24 h. At 24 h, gas samples were collected from the headspace of closed bottles or from headspace and bags of vented bottles and analyzed for CH4 concentration. Volumes of GP at 24 h were corrected for the gas dissolved in the fermentation fluid, according to Henry's law of gas solubility. Methane concentration (mL/100mL of GP) was measured and CH4 production (mL/g of incubated DM) was computed using corrected or uncorrected GP values. Data were analyzed for the effect of venting technique (T), feed (F), interaction between venting technique and feed (T × F), and incubation run as a random factor. Closed bottles provided lower uncorrected GP (-18%) compared with vented bottles, especially for concentrates. Correction for dissolved gas reduced but did not remove differences between techniques, and closed bottles (+25 mL of gas/g of incubated DM) had a greater magnitude of variation than did vented bottles (+1 mL of gas/g of incubated DM). Feeds differed in uncorrected and corrected GP, but the ranking was the same for the 2 techniques. The T × F interaction influenced uncorrected GP values, but this effect disappeared after correction. Closed bottles provided uncorrected CH4 concentrations 23% greater than that of vented bottles. Correction reduced but did not remove this difference. Methane concentration was influenced by feed but not by the T × F interaction. Corrected CH4 production was influenced by feed, but not by venting technique or the T × F interaction. Closed bottles provide good measurements of CH4 production but not of GP. Venting of bottles at low pressure permits a reliable evaluation of total GP and CH4 production.


Nutritional regulation of postruminal digestive enzymes in ruminants.
Nutritional regulation of digestive enzymes has received limited study in ruminants. Comparable studies with nonruminants report adaptations occurring in pancreatic and mucosal enzyme concentrations and synthesis in response to increased consumption of carbohydrate, lipid, or protein. Adaptations in carbohydrases apparently are mediated through changes in blood glucose and insulin, and changes in lipase are mediated through changes in circulating beta-hydroxybutyrate. Increased synthesis and secretion of pancreatic proteases apparently are mediated directly through luminal effects of protein, possibly through a messenger peptide. Available information for ruminants suggests that pancreatic alpha-amylase concentration increases with increased energy intake, but not with increased carbohydrate intake, independent of energy. This result may indicate an adaptation mechanism similar to that of nonruminants, one that is mediated through increased glucose turnover, not intestinal carbohydrate supply alone. Increased intake of energy or increased intestinal supply of carbohydrates results in little or no increase in mucosal carbohydrases in the ruminant. Comparable data for effects of changing intestinal supply of protein are limited to the developing ruminant. Experiments involving lipid feeding are not available, but duodenal lipid infusion decreases pancreatic lipase secretion. Ruminant data are inadequate to predict accurately an adaptive response to feeding any diet.


Mesenchymal stem cells in immune-mediated bone marrow failure syndromes.
Immune-mediated bone marrow failure syndromes (BMFS) are characterized by ineffective marrow haemopoiesis and subsequent peripheral cytopenias. Ineffective haemopoiesis is the result of a complex marrow deregulation including genetic, epigenetic, and immune-mediated alterations in haemopoietic stem/progenitor cells, as well as abnormal haemopoietic-to-stromal cell interactions, with abnormal release of haemopoietic growth factors, chemokines, and inhibitors. Mesenchymal stem/stromal cells (MSCs) and their progeny (i.e., osteoblasts, adipocytes, and reticular cells) are considered as key cellular components of the bone marrow haemopoietic niche. MSCs may interfere with haemopoietic as well as immune regulation. Evidence suggests that bone marrow MSCs may be involved in immune-mediated BMFS underlying pathophysiology, harboring either native abnormalities and/or secondary defects, caused by exposure to activated marrow components. This review summarizes previous as well as more recent information related to the biologic/functional characteristics of bone marrow MSCs in myelodysplastic syndromes, acquired aplastic anemia, and chronic idiopathic neutropenia.


Experimental band compression factor of a neutral compound under high pressure gradient elution.
To measure the gradient compression factor for a low molecular weight compound (caffeine, MW=194 g/L), 1 microL samples of solution were injected into a 2.1 mm x 100 mm column packed with bridged ethylsiloxane BEH-silica. These samples were successively run under isocratic and gradient elution modes. Both chromatograms were recorded with either a low (<250 bar) or a high pressure drop (>650 bar), corresponding to flow rates of 0.10 and 0.35 mL/min, respectively. Caffeine was eluted with a mixture of methanol and water at room temperature. The efficiency and the retention factors of caffeine on the BEH-C(18)column were measured as a function of the mobile phase composition under isocratic conditions. During the gradient elution, the methanol concentration was increased from 10 to 25% (v/v). The experimental compression factors measured are in excellent agreement with those predicted with an equation previously derived, which is valid at low flow rates and for smooth gradients. The negative relative difference observed between experimental and theoretical values at high flow rates originates from the compressibility of the eluent. Using a high gradient steepness to perform fast gradient elution limits the degree of band compression that can be achieved, even when the radial temperature gradient across the column is as small as 0.2K.


Supplementation of serum albumin is associated with improved pulmonary function: NHANES 2013-2014.
Background: The serum albumin level is reflective of the function of multiple organs, such as the liver and kidneys. However, the association between serum albumin and pulmonary function is unclear; therefore, this study aimed to determine the relationship between pulmonary function and serum albumin, including the threshold of serum albumin at the changes of the pulmonary function in the total population and in different strata of population. Methods: In this cross-sectional study, We examined the relationship between serum albumin and two independent indicators of pulmonary function: forced vital capacity (FVC) and forced expiratory volume in one second (FEV 1), using data from National Health and Nutrition Examination Survey (NHANES 2013-2014) (n = 3286). We used univariate analysis, stratified analysis, and multiple regression equation analysis to examine the correlation between serum albumin levels and FVC and FEV 1, and performed smoothed curve fitting, threshold effect, and saturation effect analysis (for stratification) to determine the threshold serum albumin level at which FVC and FEV 1 begin to change. Results: The adjusted smoothed curve fit plot showed a linear relationship between serum albu-min levels and FVC: for every 1 g/dl increase in the serum albumin level, FVC increased by 80.40 ml (11.18, 149.61). Serum albumin and FEV 1 showed a non-linear relationship. When serum al-bumin reached the inflection point (3.8 g/dl), FEV 1 increased with increasing serum albumin and the correlation coefficient β was 205.55 (140.15, 270.95). Conclusion: Serum albumin is a core indicator of liver function, and abnormal liver function has a direct impact on pulmonary function. In the total population, serum albumin levels were linearly and positively correlated with FVC. Above 3.6 g/dl, serum albumin was positively correlated with FEV 1. Based on the total population and different population strata, this study revealed a positive association between the serum albumin level and pulmonary function, and identified the threshold of serum albumin when Indicators of pulmonary function tests starts to rise, providing a new early warning indicator for people at high risk of pulmonary insufficiency and has positive implications for the prevention of combined respiratory failure in patients with liver insufficiency.


Research on highly sensitive optomagnetic sensor for rapid detection of inflammation.
C-reactive protein (CRP) is used to evaluate the evolution of infections and sepsis in critically ill patients. For POCT testing, biosensor-based detection techniques offer quick and convenient application. A prototype three dimensional chip was fabricated based on a new optomagnetic method to achieve the rapid detection of CRP. This work investigates a new technology for the quick quantitative detection of the C-reactive protein (CRP) by total internal reflection magnetic imaging (TIRMI) on a three dimensional optomagnetic sensor. Transparent glass and hydrophilic plastic film with channels were used to construct the three dimensional sensor. The magnetic nanoparticles and immunological reagent were immobilized on the reaction area of the sensor. Samples were detected using total internal reflection magnetic spot imaging (TIRMI) based on a sandwich magnetic immunoassay by one-step assay. The developed 3D biosensor-TIRMI method showed a wide dynamic linear range (0.2-200 ng/ml) and quick detection (5 min) with low-sample volume (10 μL). We have presented a three dimensional optical protein chip that fulfills the demanding for point-of-care diagnostics in terms of ease-of-use (one step assay), miniaturization, assay time. This approach shows great promise for application in clinical investigations of biological samples.


Prototyping and Simulation of Robot Group Intelligence using Kohonen Networks.
Intelligent agents such as robots can form ad hoc networks and replace human being in many dangerous scenarios such as a complicated disaster relief site. This project prototypes and builds a computer simulator to simulate robot kinetics, unsupervised learning using Kohonen networks, as well as group intelligence when an ad hoc network is formed. Each robot is modeled using an object with a simple set of attributes and methods that define its internal states and possible actions it may take under certain circumstances. As the result, simple, reliable, and affordable robots can be deployed to form the network. The simulator simulates a group of robots as an unsupervised learning unit and tests the learning results under scenarios with different complexities. The simulation results show that a group of robots could demonstrate highly collaborative behavior on a complex terrain. This study could potentially provide a software simulation platform for testing individual and group capability of robots before the design process and manufacturing of robots. Therefore, results of the project have the potential to reduce the cost and improve the efficiency of robot design and building.


Lichen conservation in heavily managed boreal forests.
Lichens are an important component of the boreal forest, where they are long lived, tend to accumulate in older stands, and are a major food source for the threatened woodland caribou (Rangifer tarandus caribou). To be fully sustainable, silvicultural practices in the boreal forest must include the conservation of ecological integrity. Dominant forest management practices, however, have short-term negative effects on lichen diversity, particularly the application of herbicides. To better understand the long-term effects of forest management, we examined lichen regeneration in 35 mixed black spruce (Picea mariana) and jack pine (Pinus banksiana) forest stands across northern Ontario to determine recovery following logging and postharvest silvicultural practices. Our forest stands were 25-40 years old and had undergone 3 common sivilcultural treatments that included harvested and planted; harvested, planted, and treated with N-[phosphonomethyl] glycine (glyphosate); and harvested, planted, and treated with 2,4-dichlorophenoxyacetic acid (2,4-D). Forest stands with herbicide treatments had lower lichen biomass and higher beta and gamma diversity than planted stands that were not treated chemically or control stands. In northwestern Ontario, planted stands that were not treated chemically had significantly greater (p < 0.05) alpha diversity than stands treated with herbicides or control stands. Our results show that common silvicultural practices do not emulate natural disturbances caused by wildfires in the boreal forest for the lichen community. We suggest a reduction in the amount of chemical application be considered in areas where lichen biomass is likely to be high and where the recovery of woodland caribou is an objective.


Helicobacter pylori CagA protein activates Akt and attenuates chemotherapeutics-induced apoptosis in gastric cancer cells.
Infection with cagA-positive Helicobacter pylori is associated with a higher risk of gastric cancer. The cagA gene product, CagA, is translocated into gastric epithelial cells and perturbs host cellular biological functions. Etoposide, a topoisomerase II inhibitor widely used to couple DNA damage to apoptosis, is a common cytotoxic agent used for advanced gastric cancer. We investigate the effect of CagA on etoposide-induced apoptosis in gastric cancer cells to elucidate whether CagA play a role in gastric carcinogenesis via impairing DNA damage-dependent apoptosis. AGS cell lines stably expressing CagA isolated from H. pylori 26695 strain were established. In the presence of etoposide, viability of parental AGS cells was decreased in a time-and dose-dependent manner, whereas CagA-expressing AGS cells were less susceptible to etoposide induced cell-killing effect. Suppression of etoposide-induced apoptosis was shown in CagA-expressing but not in parental AGS cells by DNA fragmentation, cell cycle, and annexin-V assays. This inhibitory effect of etoposide-induced apoptosis conferred by CagA was also demonstrated in SCM1 and MKN45 gastric cancer cell lines, with two additional chemotherapeutics, 5-FU and cisplatin. The effect of Akt activation on inhibition of etoposide-induced cytotoxicity by CagA was also evaluated. CagA expression and etoposide administration activate Akt in a dose-dependent manner. Enhancement of etoposide cytotoxicity by a PI-3-kinase inhibitor, LY294002, was evident in parental but was attenuated in CagA-expressing AGS cells. CagA may activate Akt, either in the absence or presence of etoposide, potentially contributing to gastric carcinogenesis associated with H. pylori infection and therapeutic resistance by impairing DNA damage-dependent apoptosis.


Effect of soil treatment with the organophosphorus insecticide Profenfos on the fungal flora and some microbial activities.
Tests were conducted to determine the effects of Profenfos [(0-(4-bromo-2-chlorophenyl) 0-ethyl S-n-propyl-phosphorothioat] on fungal populations and some activities in soil. Profenfos (at 5.4 micrograms active ingredient/g dry soil), has a significant adverse effect on the count of total fungi after 2, 4 and 6 weeks after treatment. This effect was completely alleviated after longer incubation. Incorporation of this insecticide into the agar medium inhibited the total count of soil fungi at 6.4 and 38.4 micrograms ml-1. Initial activation followed by a decrease in CO2 output occurred in soil treated with 5.4 micrograms a.i./g. The two doses of Profenfos accelerated urease activity for 6 weeks after soil treatment, but inhibited the enzyme activity after longer periods. An inhibitory effect on nitrate reductase activity was observed with some insecticide treatments in the early stages of incubation followed by an activation in certain cases.


Evidence from a meta-analysis: is nivolumabneurotoxic in cancer patients?
The aim of this study was to summarize the findings of previous studies focusing on whether the risks of certain neurotoxicities are correlated to the programmed death 1 (PD-1) inhibitor nivolumab versus other chemotherapy or immunotherapy drugs. Six eligible studies, including 3,023 patients, were considered in the meta-analysis. The risk ratios (RRs) of fatigue, headache, dysgeusia, vertigo, paresthesia, anxiety or malaise and peripheral neuropathy were 0.908 (95% confidence interval [95% CI]: 0.724, 1.138; P=0.402), 0.841 (95% CI: 0.606, 1.168; P=0.302), 0.423 (95% CI: 0.132, 1.357; P=0.148), 0.762 (95% CI: 0.475, 1.223; P=0.261), 0.411 (95% CI: 0.232, 0.730; P=0.002), 1.049 (95% CI: 0.094, 11.752; P=0.969) and 0.192 (95% CI: 0.039, 0.935; P=0.041), respectively. Our analysis supported that the PD-1 inhibitor nivolumab did not cause increased or decreased risks of fatigue, headache, dysgeusia, vertigo and anxiety or malaise and was associated with decreased risks of paresthesia and peripheral neuropathy as compared with controls. These outcomes indicated that although clinicians should be attentive of the side effects of nivolumab, in terms of nervous system side effects, nivolumab is generally safe.


Redox Chemistry and Reversible Structural Changes in Rhombohedral VO2F Cathode during Li Intercalation.
Metal oxyfluorides are currently attracting much attention for next-generation rechargeable batteries because of their high theoretical capacity and resulting high energy density. Rhombohedral VO2F is promising because it allows two-electron transfer during electrochemical lithium cycling, with a theoretical capacity of 526 mAh g-1. However, the chemical changes it undergoes during operation are not clearly understood. In this work, a combination of synchrotron X-ray and neutron diffraction was employed to accurately describe the crystal structure of both pristine and lithiated VO2F, using samples with high crystallinity to overcome challenges in previous studies. The mechanism and reversibility of the lithium insertion was monitored in real time by high angular synchrotron diffraction measurements, performed in operando on a lithium battery in the high-voltage range: 3.9-2.3 V vs Li+/Li. Insertion of up to one lithium ion proceeds through a solid-solution reaction, while Rietveld refinements of neutron powder diffraction data revealed that the lithiated states adopt the noncentrosymmetric R3c framework, uncovering an octahedral Li-(O/F)6 coordination with reasonable Li-O/F bond lengths. This work further evaluates the redox changes of VO2F upon Li intercalation. By a comparison of changes in electronic states of all the elements in the compound, it clarifies the critical role of both anions, O and F, in the charge compensation through their covalent interactions with the 3d states of V. The clear evidence of participation of F challenges existing assumptions that its high electronegativity renders this anion largely a spectator in the redox reaction.


Fat metabolism in higher plants. XXXIV. Development of fatty acid synthetase as a function of protein synthesis in aging potato tuber slices.
Experiments with inhibitors of protein synthesis (actinomycin D, puromycin, actidione) showed that the increase and the change in fatty acid synthetase activity, observed during the aging of potato disks, were accompanied by and related to a temporary rise in the rate of protein and RNA synthesis. These results concur with the earlier suggestion by Click and Hackett that the aging process involves a type of derepression. A possible course of events during aging, and possible derepression mechanisms are suggested and discussed.


Relationship between tooth type and material used in the construction of endocrowns and fracture force values: a systematic review.
The aim of this study was to summarize the results of the endocrown (EC) studies that compared tooth preparation designs, tooth types, and ceramic material types in relation to fracture force values. A full literature search was conducted in Web of Science, PubMed/Medline, EMBASE, Scopus, Cochrane Library, Google Scholar, and ProQuest electronic databases. The following keywords: Endocrown [(molar(s)) or (premolar(s) or (posterior teeth)] and Ceramic materials as (Lithium disilicate glass-ceramic; Zirconia; Lava Ultimate) and (fracture strength) or (fatigue) were used. Articles were manually searched utilizing their reference lists. Study selection was not restricted or limited to the time of publication, type of tested tooth, ceramic material, and EC design. A total of 34 laboratory studies published between 2008 and 2023 were included in this systemic review. Twelve studies were published in the last 3 years, the mandibular molar was examined by 14 studies, and premolars in both arches were investigated, followed by premolars in both arches. Lithium disilicate glass-ceramic (LDGC) was the most used material for EC testing, followed by LAVA Ultimate and zirconia materials. The EC design with a 2 mm extension inside the pulp (14 studies) was the most used. Fracture forces of maxillary molars or premolars were nearly equal and lower than those of mandibular molars. Differences among the fracture forces of the tested ceramic materials were marginal. EC with 2 mm deep inside the pulp showed the highest fracture force. Mandibular EC molars showed the highest fracture forces, followed by maxillary premolars and molars. No differences among the EC materials in the 2- and 4-mm pulpal extension designs were found, which had higher fracture forces than other designs.


The predictive value of plasma biomarkers in discharged heart failure patients: the role of plasma BNP.
To date, heart failure (HF) prognosis is still difficult: symptoms and signs are often non-specific, and poor sensitive indicators for HF severity. Brain natriuretic peptide (BNP) is now included in the current guidelines for HF diagnosis, management and risk assessment because of its high specificity and sensibility. BNP became a first-line exam in HF patients' evaluation at hospital admission together with clinical and chest X-ray. In discharged patients, the prognostic role of BNP is associated with decongestion and its significant reduction compared to admission level appears one of the best outcome predictors. In fact BNP measurement could identify patients with increased risk of adverse events and left ventricular remodeling. Although a single BNP value assay and the absolute value during hospitalization is related to the prognosis, especially at discharge. On the other hand, hormone levels could be influenced by several factors (i.e., renal dysfunction, anemia, age, liver insufficiency, Body Mass Index) independently from systemic and pulmonary congestion. Therefore, a new approach which considers a multimodality strategy including BNP assay among the traditional clinical examination and imaging studies should be routinely encouraged to better define cardiac dysfunction's etiology and severity, as well as to recognize patients at risk of adverse outcome.


Multilocus evidence for globally distributed cryptic species and distinct populations across ocean gyres in a mesopelagic copepod.
Zooplanktonic taxa have a greater number of distinct populations and species than might be predicted based on their large population sizes and open-ocean habitat, which lacks obvious physical barriers to dispersal and gene flow. To gain insight into the evolutionary mechanisms driving genetic diversification in zooplankton, we developed eight microsatellite markers to examine the population structure of an abundant, globally distributed mesopelagic copepod, Haloptilus longicornis, at 18 sample sites across the Atlantic and Pacific Oceans (n = 761). When comparing our microsatellite results with those of a prior study that used a mtDNA marker (mtCOII, n = 1059, 43 sample sites), we unexpectedly found evidence for the presence of a cryptic species pair. These species were globally distributed and apparently sympatric, and were separated by relatively weak genetic divergence (reciprocally monophyletic mtCOII lineages 1.6% divergent; microsatellite FST ranging from 0.28 to 0.88 across loci, P < 0.00001). Using both mtDNA and microsatellite data for the most common of the two species (n = 669 for microsatellites, n = 572 for mtDNA), we also found evidence for allopatric barriers to gene flow within species, with distinct populations separated by continental landmasses and equatorial waters in both the Atlantic and Pacific Ocean basins. Our study shows that oceanic barriers to gene flow can act as a mechanism promoting allopatric diversification in holoplanktonic taxa, despite the high potential dispersal abilities and pelagic habitat for these species.


A tunable ratchet driving human RNA polymerase II translocation adjusted by accurately templated nucleoside triphosphates loaded at downstream sites and by elongation factors.
When nucleoside triphosphate (NTP) substrates and alpha-amanitin are added to a human RNA polymerase II elongation complex simultaneously, the reaction becomes stalled in the core of the bond synthesis mechanism. The mode of stalling is influenced by NTP substrates at the active site and at downstream sites and by transcription factor IIF (TFIIF) and TFIIS. NTP substrates templated at i+2, i+3, and i+4 downstream DNA sites can reverse the previously stable binding of an NTP loaded at the i+1 substrate site. Deoxy-(d)NTPs and NDPs (nucleoside diphosphates) do not substitute for NTPs at the i+2 and i+3 positions (considered together) or the i+4, i+5, and i+6 positions (considered together). The mode of stalling is altered by changing the number of downstream template sites that are accurately occupied by NTPs and by changing NTP concentration. In the presence of the translocation blocker alpha-amanitin, a steady state condition is established in which RNA polymerase II stably loads an NTP substrate at i+1 and forms a phosphodiester bond but cannot rapidly complete bond synthesis by releasing pyrophosphate. These observations support a role for incoming NTP substrates in stimulating translocation; results appear inconsistent with the secondary pore being the sole route of NTP entry for human RNA polymerase II, and results indicate mechanisms of dynamic error avoidance and error correction during rapid RNA synthesis.


Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174.
Losartan is metabolised to its active metabolite E-3174 by CYP2C9 and CYP3A4 in vitro. Itraconazole is an inhibitor of CYP3A4, whereas fluconazole affects CYP2C9 more than CYP3A4. We wanted to study the possible interaction of these antimycotics with losartan in healthy volunteers. A randomised, double-blind, three-phase crossover study design was used. Eleven healthy volunteers ingested orally, once a day for 4 days, either itraconazole 200 mg, fluconazole (400 mg on day 1 and 200 mg on days 2-4) or placebo (control). On day 4, a single 50-mg oral dose of losartan was ingested. Plasma concentrations of losartan, E-3174, itraconazole, hydroxy-itraconazole and fluconazole were determined over 24 h. The blood pressure and heart rate were also recorded over 24 h. The mean peak plasma concentration (Cmax) and area under the curve [AUC(0-infinity)] of E-3174 were significantly decreased by fluconazole to 30% and to 47% of their control values, respectively, and the t1/2 was increased to 167%. Fluconazole caused only a nonsignificant increase (23-41%) in the AUC and t1/2 of the unchanged losartan. Itraconazole had no significant effect on the pharmacokinetic variables of losartan or E-3174. The ratio AUC(0-infinity)(E-3174)/AUC(0-infinity)losartan was 60% smaller during the fluconazole than during the placebo and itraconazole phases. No clinically significant changes in the effects of losartan on blood pressure and heart rate were observed between fluconazole, itraconazole and placebo phases. Fluconazole but not itraconazole interacts with losartan by inhibiting its metabolism to the active metabolite E-3174. This implicates that, in man, CYP2C9 is a major enzyme for the formation of E-3174 from losartan. The clinical significance of the fluconazole losartan interaction is unclear, but the possibility of a decreased therapeutic effect of losartan should be kept in mind.


Normal postprandial lipemia and chylomicron clearance in offspring of parents with early coronary artery disease.
To assess the importance of postprandial lipemia and delayed chylomicron clearance as early atherogenic risk factors, 60 male offspring of parents with early coronary artery disease (CAD) and 41 controls were administered a fat-rich meal containing vitamin A. There were no significant differences between CAD-positive (CAD+) offspring and CAD-negative controls for areas under the postprandial curves for triglyceride and plasma, chylomicron, and chylomicron remnant retinyl palmitate. Older CAD+ offspring, aged 31-45 yr, had significantly increased very low density lipoprotein (VLDL) cholesterol, VLDL triglyceride, VLDL apoprotein B, and areas under postprandial curves for triglyceride and plasma, chylomicron, and chylomicron remnant retinyl palmitate than younger CAD+ offspring, aged 15-30 yr. Correcting for waist/hip ratio eliminated significant differences between the two groups for VLDL and areas under the triglyceride and chylomicron remnant curves, but this was not the case for the insulin sensitivity index. We conclude that neither increased postprandial lipemia nor abnormalities of chylomicron clearance are important early atherogenic risk factors in this population. An increase in age is associated with increased VLDL and postprandial lipemia and decreased chylomicron remnant clearance. This is due mainly to an increase in the waist/hip ratio and not to a change in insulin sensitivity.


Ab initio/density functional theory and multichannel RRKM study for the ClO + CH2O reaction.
The potential energy surface for the CH(2)O + ClO reaction was calculated at the QCISD(T)/6-311G(2d,2p)//B3LYP/6-311G(d,p) level of theory. The rate constants for the lower barrier reaction channels producing HOCl + HCO, H atom, OCH(2)OCl, cis-HC(O)OCl and trans-HC(O)OCl have been calculated by TST and multichannel RRKM theory. Over the temperature range of 200-2000 K, the overall rate constants were k(200-2000K) = 1.19 x 10(-13)T(0.79) exp(-3000.00/T). At 250 K, the calculated overall rate constant was 5.80 x 10(-17) cm(3) molecule(-1) s(-1), which was in good agreement with the experimental upper limit data. The calculated results demonstrated that the formation of HOCl + HCO was the dominant reaction channel and was exothermic by 9.7 kcal/mol with a barrier of 5.0 kcal/mol. When it retrograded to the reactants CH(2)O + ClO, an energy barrier of 14.7 kcal/mol is required. Furthermore, when HOCl decomposed into H + ClO, the energy required was 93.3 kcal/mol. These results suggest that the decomposition in both the forward and backward directions for HOCl would be difficult in the ground electronic state.


Assessing the Value of Nusinersen for Spinal Muscular Atrophy: A Comparative Analysis of Reimbursement Submission and Appraisal in European Countries.
Background: Nusinersen is an orphan drug intended for the treatment of spinal muscular atrophy (SMA), a severe genetic neuromuscular disorder. Considering the very high costs of orphan drugs and the expected market entry of cell and gene therapies, there is increased interest in the use of health technology assessment (HTA) for orphan drugs. This study explores the role of the economic evaluation and budget impact analysis on the reimbursement of nusinersen. Methods: Appraisal reports for nusinersen were retrieved from reimbursement and HTA agencies in Belgium, Canada, France, England and Wales, Germany, Italy, Ireland, Scotland, Sweden, the Netherlands, and the United States. Detailed information was extracted on the economic evaluation, the budget impact, the overall reimbursement decision, and the managed entry agreement (MEA). Costs were adjusted for inflation and currency. Results: Overall, the reports included limited data on budget impact, excluding information on the sources of data for cost and patient estimates. Only three jurisdictions reported on total budget impact, estimated between 30 and 40 million euros per year. For early-onset SMA, the incremental cost-effectiveness threshold (ICER) ranged from €464,891 to €6,399,097 per quality-adjusted life year (QALY) gained for nusinersen versus standard of care. For later-onset SMA, the ICER varied from €493,756 to €10,611,936 per QALY. Although none of the jurisdictions found nusinersen to be cost-effective, reimbursement was granted in each jurisdiction. Remarkably, only four reports included arguments in favor of reimbursement. However, the majority of the jurisdictions set up an MEA, which may have promoted a positive reimbursement decision. Conclusion: There is a need for more transparency on the appraisal process and conditions included in the MEA. Additionally, by considering all relevant criteria explicitly during the appraisal process, decision-makers are in a better position to justify their allocation of funds among the rising number of orphan drugs that are coming to the market in the near future.


[Fluoroethylthyrosine 18F PET in the detection of brain tumours].
PET with fluoroethylthyrosine (FET), amino-acid analogue, has been performed in Germany since the beginning of the decade for molecular and metabolic imaging of brain tumours, since FDG, the glucose analogue which is the reference tracer for clinical PET, has this drawback to be taken-up intensely by cerebral cortex. We report on our preliminary results on the comparison of PET/CT with FET and FDG in 10 evaluable patients presenting with a brain lesion either at diagnosis or after treatment. In an attempt to optimise specificity, FET PET/CT has been acquired as a static image 1h after injection, while the most current practice is a dynamic 40 min acquisition starting at FET injection. With our acquisition protocol, diagnostic performance of FET was 88% sensitivity and 80% accuracy vs 13% and 30% respectively for FDG. FET is a radiopharmaceutical with clinical usefulness for the diagnosis, delineation and monitoring of brain tumours. Association with FDG allows identification of high-grade lesions or components, but it could be avoided providing that acquisition and quantification procedures of FET PET/CT would have been better optimised and standardised.


Identification of predictive circulating biomarkers of bevacizumab-containing regimen efficacy in pre-treated metastatic colorectal cancer patients.
To identify whether circulating levels of angiogenesis-related factors may be predictive of bevacizumab efficacy in pre-treated metastatic colorectal cancer (mCRC) patients. Pre-treatment serum levels of 24 cytokines were measured using a multiplex bead assay (MBA) in 32 pre-treated mCRC patients treated with irinotecan plus bevacizumab-based salvage therapy. Macrophage-derived chemokine (MDC), interleukins (ILs) 8 and 6 levels were also validated by enzyme-linked immunosorbent assay (ELISA) at different time points during therapy. Higher epidermal growth factor (EGF) and MDC baseline levels (2.2- and 1.4-fold, respectively) and lower IL-10, IL-6 and IL-8 levels (0.2-, 0.6-, and 0.6-fold, respectively, P<0.05) were observed in patients responding to therapy. Baseline levels of these five serum factors compose a risk signature that may define the subset of patients most likely to benefit from bevacizumab-based therapy in terms of response rate and survival times. A positive correlation was found between MBA and ELISA results (P<0.01). Treatment exposure increased MDC and had opposite effects on IL-8 levels, which were decreased (P<0.05). This study suggests that a set of inflammatory and angiogenesis-related serum markers may be associated with the efficacy of bevacizumab-containing regimen.


Urinary retention and catheter use among U.S. female Medicare beneficiaries: Prevalence and risk factors.
To identify the prevalence of and risk factors for urinary retention and catheterization among female Medicare beneficiaries. We identified women with a diagnosis of urinary retention in a 5% sample of Medicare claims in 2012. Women were categorized into three groups based on the occurrence and duration of urinary catheterization within a 1 year period: 1) no catheterization; 2) short-term catheterization (ie, one or more catheterizations in less than 30 days); and 3) chronic catheterization (catheterizations in multiple 30 day periods within 1 year). We then identified a group of age-matched controls without catheterization or a diagnosis of urinary retention in 2012. Clinical and demographic data were collected for each patient, and risk factors for retention and catheterization were compared across groups. We assessed factors associated with urinary retention using multivariable logistic regression. We estimated the rate of retention to be 1532 per 100 000 U.S. female Medicare beneficiaries in 2012, with rates of short term and chronic catheterization estimated to be 160 and 108 per 100 000 women, respectively. Prior diagnoses of neurologic condition, urinary tract infection, and pelvic organ prolapse were positively associated with retention and catheterization in multivariable analyses. We estimated the prevalence of urinary retention diagnoses among female Medicare beneficiaries to be 1532 per 100 000 women. Retention and catheterization were significantly associated with comorbid disease, with the strongest associations identified with a concomitant diagnosis of neurologic condition, UTI, and POP.


NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies.
The NLRP3 inflammasome is one of the NOD-like receptor family members with the most functional characterization and acts as a key player in innate immune system, participating in several physiological processes including, among others, the modulation of the immune system response and the coordination of host defences. Activation of the inflammasome is a crucial signaling mechanism that promotes both an acute and a chronic inflammatory response, which can accelerate the production of pro-inflammatory cytokines, mainly Interleukin (IL)-1β and IL-18, leading to an exacerbated inflammatory network. Cryopyrin associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder, clinically characterized by cutaneous and systemic, musculoskeletal, and central nervous system inflammation. Gain-of-function mutations in NLRP3 gene are causative of signs and inflammatory symptoms in CAPS patients, in which an abnormal activation of the NLRP3 inflammasome, resulting in an inappropriate release of IL-1β and gasdermin-D-dependent pyroptosis, has been demonstrated both in in vitro and in ex vivo studies. During recent years, two new hereditary NLRP3-related disorders have been described, deafness autosomal dominant 34 (DFN34) and keratitis fugax hereditaria (KFH), with an exclusive cochlear- and anterior eye- restricted autoinflammation, respectively, and caused by mutations in NLRP3 gene, thus expanding the clinical and genetic spectrum of NLRP3-associated autoinflammatory diseases. Several crucial mechanisms involved in the control of activation and regulation of the NLRP3 inflammasome have been identified and researchers took advantage of this to develop novel target therapies with a significant improvement of clinical signs and symptoms of NLRP3-associated diseases. This review provides a broad overview of NLRP3 inflammasome biology with particular emphasis on CAPS, whose clinical, genetic, and therapeutic aspects will be explored in depth. The latest evidence on two "new" diseases, DFN34 and KFH, caused by mutations in NLRP3 is also described.


Bacterial meningitis in children in southern Ghana.
One hundred and three children (1% of seriously ill children referred to the Korle Bu Teaching Hospital in Accra) were admitted with bacterial meningitis over a 17 month period. 43 of these children had been ill for more than 4 days before arrival at our centre. The main causative organisms were S. pneumoniae (47.9%), Neisseria meningitides (38.4%) and Haemophilus influenzae (9.6%). All bacterial isolates were highly sensitive to ceftriaxone. Resistance to penicillin and chloramphenicol was however present in 5-17% of isolates. All cerebrospinal fluid samples were sterilised within 48 hours of antibiotic treatment. Case fatality rate was 22% with the majority of deaths occurring within hours of admission and closely related to S. pneumoniae infection. Neurological complications occurred in 22%; mild diarrhoea in 33% and secondary fever in 14.8% of survivors. No significant difference was noted among the three treatment regimens of ceftriaxone alone, penicillin plus chloramphenicol, and ceftriaxone alone for 48 hours followed by penicillin/chloramphenicol combination. Our overall outcome would have been better if patients had been started on appropriate antibiotic treatment within the earlier hours of the infection. Furthermore, the latter generation cephalosporins, including ceftriaxone, must be given consideration as antibiotics of first choice world wide.


Bivalent Inhibitors of c-Src Tyrosine Kinase That Bind a Regulatory Domain.
We have developed a general methodology to produce bivalent kinase inhibitors for c-Src that interact with the SH2 and ATP binding pockets. Our approach led to a highly selective bivalent inhibitor of c-Src. We demonstrate impressive selectivity for c-Src over homologous kinases. Exploration of the unexpected high level of selectivity yielded insight into the inherent flexibility of homologous kinases. Finally, we demonstrate that our methodology is modular and both the ATP-competitive fragment and conjugation chemistry can be swapped.


Did the 2011 AAP recommendations on youth HIV testing change practice? Trends from a large urban adolescent program.
The purpose of this study was to determine whether there is adherence to the October 2011 American Academy of Pediatrics (AAP) recommendations for HIV screening in a large urban adolescent program with availability of a publicly funded program providing free, confidential, sexually transmitted infection (STI) and HIV counseling and testing (then rapid or third generation HIV testing), nested in the same adolescent clinic. We conducted a retrospective chart review of HIV screening trends among 13- to 24-year-old patients tested for HIV during periods of January 2010 to June 2011 (18 months pre-AAP recommendations period) and July 2011 to December 2012 (18-month period, which included 15 months after the AAP recommendations). During the period of January 2010 to June 2011, there were 22 tests/1,000 medical visits (N = 824 of 37,520 medical visits), and during the period of July 2011 to December 2012, there were 27 tests/1,000 medical visits (N = 1,068 of 38,763 medical visits) (p < 0.0001, odds ratio [OR] 1.26). The number of 13- to 18-year-old patients screened in the pre-AAP period was 150, compared to 297 in the second 18-month period (X 2 = 43.3, df = 1, p < 0.0001). A summative risk profile score of 0-9 was created in the form of a continuous variable, with a risk score of 0 for those with no risk factor identified and 1 point for each risk behavior identified. The proportion of HIV test clients with zero-specified risk (a risk score of "0") increased from 2010 to 2012. Release of the 2011 AAP HIV testing guidelines was associated with a modest increase in HIV screening and a shift toward testing younger people and away from risk-based screening.


Facilitation of instrumental behavior by a Pavlovian appetitive conditioned stimulus.
Three experiments examined appetitive Pavlovian-instrumental interactions by presenting separately trained conditioned stimuli (CSs) during reinforced instrumental responding in rabbits. Intra-oral reinforcement was used to minimize interference from peripheral responses such as magazine approach. In experiment 1, the rabbits were first trained to perform an instrumental head-raising response for sucrose reward. A conditioned jaw movement response was then established to a 2-sec CS by pairing it with sucrose; a control stimulus was unpaired with sucrose. Instrumental responding maintained by a variable-interval 40-sec schedule was enhanced during 10-sec presentations of the paired, but not the unpaired, CS. Responding on a variable-ratio 15 schedule was unaffected except on trials on which the pre-CS baseline response rate was low; in such cases the paired CS caused a long-lasting acceleration of responding. Noncontingent presentation of the sucrose reinforcer itself briefly suppressed responding but had no long-term effect. In Experiment 2, a CS that had been conditioned at a 10-sec duration produced the same pattern of effects as in the first study, indicating that facilitation resulted from CS presentation rather than from the frustrative effects of non-reinforcement of the CS. In Experiment 3 an inhibitory CS blocked facilitation by the excitatory CS but did not itself affect instrumental responding. These results support the view that Pavlovian processes play a positive role in instrumental performance and suggest that previous findings of suppression by a short-duration CS reflect peripheral interference. The dependence of facilitation on the baseline level of responding is discussed in terms of associative and motivational theories of Pavlovian mediation.


Establishing a Virus-Induced Gene Silencing System in Lycoris chinensis.
Lycoris is an important plant with both medicinal and ornamental values. However, it does not have an efficient genetic transformation system, which makes it difficult to study gene function of the genus. Virus-induced gene silencing (VIGS) is an effective technique for studying gene functions in plants. In this study, we develop an efficient virus-induced gene-silencing (VIGS) system using the leaf tip needle injection method. The widely used TRV vector is constructed, and the Cloroplastos Alterados 1 (CLA1) and Phytoene Desaturase (PDS) genes are selected as visual indicators in the VIGS system. As a result, it is observed that leaves infected with TRV-LcCLA1 and TRV-LcPDS both show a yellowing phenotype (loss of green), and the chlorosis range of TRV-LcCLA1 was larger and deeper than that of TRV-LcPDS. qRT-PCR results show that the expression levels of LcCLA1 and LcPDS are significantly reduced, and the silencing efficiency of LcCLA1 is higher than that of LcPDS. These results indicate that the VIGS system of L. chinensis was preliminarily established, and LcCLA1 is more suitable as a gene-silencing indicator. For the monocotyledonous plant leaves with a waxy surface, the leaf tip injection method greatly improves the infiltration efficiency. The newly established VIGS system will contribute to gene functional research in Lycoris species.


Cortisol as a biomarker of stress in term human labor: physiological and methodological issues.
Literature on the use of plasma cortisol to quantify psychophysiological stress in humans is extensive. However, in parturition at term gestation, the use of cortisol as a biomarker of stress is particularly complex. Plasma cortisol levels increase as labor progresses. This increase seems to be important for maintenance of maternal/fetal well-being and facilitation of normal labor progress. Unique physiological and methodological issues involved in the use of cortisol as a biomarker of stress in labor present challenges for researchers. This review examines these issues, suggests mixed methods and within-subject repeated measures designs, and offers recommendations for assay procedures for parturient sampling. Documentation of clinical interventions and delivery outcomes may elucidate relationships among psychophysiological stressors, cortisol, and normal labor progress. With attention to these methodological issues, analysis of plasma cortisol may lead to clinical interventions that support normal labor physiology.


Cardiac pacing in paediatric patients with congenital heart defects: transvenous or epicardial?
Cardiac pacing is a difficult technique in children, particularly in patients with congenital heart defects (CHDs). Few studies to date have addressed this topic. We performed a retrospective analysis of the results of a single centre. Between 1982 and 2008, 287 patients with CHD, median age of 5 years (25-75%, 1-11) underwent cardiac pacing for sinus node dysfunction (SND) and atrioventricular block (AVB); 97% of patients underwent at least one heart surgery. Endocardial systems (Endo) were implanted in 117 patients, epicardial systems (Epi) in 170, with 595 leads (228 Endo, 367 Epi). Endocardial systems showed a significantly older age group with more frequent SND; Epi a younger age group, with more frequent AVB, greater number of surgical interventions. Perioperative complications were mortality 0.6% (Epi), pericardial effusion 0.6% (Epi), and haemothorax 3.4% (Endo). The median follow-up is 5 (2-10) years: the pacing system failed in 29% of patients, 13% Endo, and 40% Epi (P < 0.0001). Multivariate analysis showed a significantly higher risk of failure for Epi, a lower implant age, greater the number of leads implanted. The risk of malfunction of the leads increases significantly for Epi and the younger age when implanted. The steroid-eluting leads have a lower risk of malfunction (P = 0.05), steroid-eluting Endo leads provide significantly better outcomes than Epi. Cardiac pacing in paediatric patients with CHD shows satisfactory results in the long term. Endocardial systems show significantly better results than Epi systems. A younger age when implanted is a risk factor for complications at follow-up.


Observations following Corynebacterium parvum administration to patients with advanced malignancy. a phase I study.
There has been increasing interest regarding the use of Corynebacterium parvum (CP) with other modalities in the management of primary cancer. Due to the paucity of specific information available relative to CP toxicity, a Phase I study was carried out in patients with advanced disease. The purpose of the investigation was not to evaluate the effect of CP on tumor growth. from 273 injections of CP in 40 patients it was observed that following intravenous (i.v.) infusion of CP: a) a febrile response and chills of considerable severity occured in almost all patients and did not appreciably diminish in intensity following repetitive administrations; b) nausea, vomiting, headache, and confusion were not infrequent; c) a "flu-like" syndrome lasting 24 to 48 hours occurred following almost all courses of CP; d) blood pressure elevations occurred on occasion and were related to the severity of other-side-effects; hyper- or hypo- tension was not a problem; e) ther were no anaphalactic reactions. Pretreatment with a single administration of 100 mg of hydrocortisone prior to CP infusion markedly and in some instances dramatically diminished the toxicity and made acceptable the use of i.v. CP on an outpatient basis. The use of i.v. CP in patients with cerebral metasteses may be hazardous. Subcutaneously administered CP resulted in a significant number of undesirable local reactions. Evaluation of delayed cutaneous hypersensitivity response, immunoglobulins, complement, and E- and EAC-rosette-forming cells during CP administration failed to demonstrate significant change from injection values. Results were similar whether hydrocortisone pretreatment was or was not employed. From the standpoint of toxicity it now seems appropriate to use i.v. CP, particularly following pretreatment with hydrocortisone, in a controlled clinical trial to evaluate its therapeutic effectiveness in the management of primary cancer.


A natural history of athleticism and cardiovascular health.
Epidemiologic studies in Olympic year 1984 suggest that personal athleticism alters trends in life-style and coronary heart disease. Analysis of 572 first attacks among 16,936 Harvard alumni, 1962 to 1972, and 1,413 total deaths, 1962 to 1978, shows that habitual postcollege exercise, not student sports play, predicts low coronary heart disease risk. Sedentary alumni, even ex-varsity athletes, have high risk. Sedentary students becoming physically active alumni acquire low risk. Exercise benefit is independent of contrary life-style elements--smoking, obesity, weight gain, hypertension, and adverse parental disease history--in affecting coronary heart disease incidence. Hypertension is clinically the strongest predictor of coronary attack, but inadequate exercise is strongest on a community basis. Exercise level is inversely related to total, cardiovascular, and respiratory mortality but less related to cancer or unnatural deaths. The current exercise revolution may improve life-style, cardiovascular health, and longevity.


Genetic, acclimatizational and anthropometric factors in hand cooling among North and South Chinese.
The left hands of unacclimatized North Chinese (N=16) and South Chinese (N=13) were exposed to 5 degrees C water for 30 minutes followed by a 10 minute recovery period. Significant differences independent of body composition were found between the two samples on mean 30 minute temperature during immersion, time and temperature of the onset of initial CIVD (cold-induced vasodilation) at 0.01, 0.05 and 0.10 levels respectively. The result suggests the presence of a genetic component in the cold responses of Continental Asian populations and the possibility of the presence of a clinal distribution of cold response in Asia.


Phylogenetic Analysis of Allotetraploid Species Using Polarized Genomic Sequences.
Phylogenetic analysis of polyploid hybrid species has long posed a formidable challenge as it requires the ability to distinguish between alleles of different ancestral origins in order to disentangle their individual evolutionary history. This problem has been previously addressed by conceiving phylogenies as reticulate networks, using a two-step phasing strategy that first identifies and segregates homoeologous loci and then, during a second phasing step, assigns each gene copy to one of the subgenomes of an allopolyploid species. Here, we propose an alternative approach, one that preserves the core idea behind phasing-to produce separate nucleotide sequences that capture the reticulate evolutionary history of a polyploid-while vastly simplifying its implementation by reducing a complex multistage procedure to a single phasing step. While most current methods used for phylogenetic reconstruction of polyploid species require sequencing reads to be pre-phased using experimental or computational methods-usually an expensive, complex, and/or time-consuming endeavor-phasing executed using our algorithm is performed directly on the multiple-sequence alignment (MSA), a key change that allows for the simultaneous segregation and sorting of gene copies. We introduce the concept of genomic polarization that, when applied to an allopolyploid species, produces nucleotide sequences that capture the fraction of a polyploid genome that deviates from that of a reference sequence, usually one of the other species present in the MSA. We show that if the reference sequence is one of the parental species, the polarized polyploid sequence has a close resemblance (high pairwise sequence identity) to the second parental species. This knowledge is harnessed to build a new heuristic algorithm where, by replacing the allopolyploid genomic sequence in the MSA by its polarized version, it is possible to identify the phylogenetic position of the polyploid's ancestral parents in an iterative process. The proposed methodology can be used with long-read and short-read high-throughput sequencing data and requires only one representative individual for each species to be included in the phylogenetic analysis. In its current form, it can be used in the analysis of phylogenies containing tetraploid and diploid species. We test the newly developed method extensively using simulated data in order to evaluate its accuracy. We show empirically that the use of polarized genomic sequences allows for the correct identification of both parental species of an allotetraploid with up to 97% certainty in phylogenies with moderate levels of incomplete lineage sorting (ILS) and 87% in phylogenies containing high levels of ILS. We then apply the polarization protocol to reconstruct the reticulate histories of Arabidopsis kamchatica and Arabidopsis suecica, two allopolyploids whose ancestry has been well documented. [Allopolyploidy; Arabidopsis; genomic polarization; homoeologs; incomplete lineage sorting; phasing; polyploid phylogenetics; reticulate evolution.].


The relationship of caries with oral hygiene status and extra-oral risk factors.
Dental caries is a lifetime disease, with highest priority risk group between 11-14 years of age group. Environmental factors such as culture, socioeconomic status, life style and dietary pattern can have a greater impact on caries-resistance or development. The present study was performed to evaluate the relationship between dental caries, oral hygiene status and risk factors among students. Oral examination was performed in 242 adolescent between 11 and 14 years to check decayed, missing and filled teeth (DMFT) index and simplified oral hygiene (OHI-S) score. A questionnaire was distributed to gather data concerning external modifying risk factors such as socioeconomic status, oral hygiene practices and snacking habits. Average DMFT was found, 3.27 and OHI-S score was fair in majority of students. DMFT in 67.77% of students fell between 0 and 3. The prevalence of caries is significantly higher in female students as compared to their male counterparts. The major component of the DMFT was the untreated decay (D) in both genders. Half of the students claimed to be familiar with the benefits of fluoride and use toothbrush before bedtime. 16.1% of the subjects were aware of a bad-breath problem. Caries experience was significantly inversely related to socio-economic status whereas strongly correlated with frequency of sugar intake and frequency of snacking in between meals. No relationship was found between OHI-S and DMFT.


Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease.
We sought to examine the pathogenic role of excessive VEGF-A expression in podocytes, since it has been reported that diabetic nephropathy and other glomerular diseases are associated with increased VEGF-A expression. The induction of podocyte-specific VEGF164 overexpression in adult transgenic mice led to proteinuria, glomerulomegaly, glomerular basement membrane thickening, mesangial expansion, loss of slit diaphragms, and podocyte effacement. When doxycycline-mediated VEGF164 was stopped, these abnormalities reversed. These findings were associated with reversible downregulation of metalloproteinase 9 and nephrin expression. Using transmission electron microscopy, we established that VEGF-A receptor-2 (VEGFR2) was expressed in podocytes and glomerular endothelial cells. We also found that VEGF164 induced VEGFR2 phosphorylation in podocytes. Further, we were able to co-immunoprecipitate VEGFR2 and nephrin using whole kidney lysates, confirming interaction in vivo. This implies that autocrine and paracrine VEGF-A signaling through VEGFR2 occurs in podocytes and may mediate the glomerular phenotype caused by VEGF164 overexpression. Thus, we suggest that podocyte VEGF164 overexpression in adult mice is sufficient to induce glomerular filtration barrier structural and functional abnormalities similar to those present in murine diabetic nephropathy.


ClaID: a Rapid Method of Clade-Level Identification of the Multidrug Resistant Human Fungal Pathogen Candida auris.
Candida auris, the multidrug-resistant human fungal pathogen, emerged as four major distinct geographical clades (clade 1-clade 4) in the past decade. Though isolates of the same species, C. auris clinical strains exhibit clade-specific properties associated with virulence and drug resistance. In this study, we report the identification of unique DNA sequence junctions by mapping clade-specific regions through comparative analysis of whole-genome sequences of strains belonging to different clades. These unique DNA sequence stretches are used to identify C. auris isolates at the clade level in subsequent in silico and experimental analyses. We develop a colony PCR-based clade-identification system (ClaID), which is rapid and specific. In summary, we demonstrate a proof-of-concept for using unique DNA sequence junctions conserved in a clade-specific manner for the rapid identification of each of the four major clades of C. auris. IMPORTANCE C. auris was first isolated in Japan in 2009 as an antifungal drug-susceptible pathogen causing localized infections. Within a decade, it simultaneously evolved in different parts of the world as distinct clades exhibiting resistance to antifungal drugs at varying levels. Recent studies hinted the mixing of isolates belonging to different geographical clades in a single location, suggesting that the area of isolation alone may not indicate the clade status of an isolate. In this study, we compared the genomes of representative strains of the four major clades to identify clade-specific sequences, which were then used to design clade-specific primers. We propose the utilization of whole genome sequence data to extract clade-specific sequences for clade-typing. The colony PCR-based method employed can rapidly distinguish between the four major clades of C. auris, with scope for expanding the panel by adding more primer pairs.


Human absorption of crude coal tar products.
Five normal adult volunteers without cutaneous disease applied 2% crude coal tar to the skin for eight-hour periods on two consecutive days. Blood extracts subjected to gas chromatography and mass spectrometry yielded evidence of absorption in all five volunteers. Phenanthrene, anthracene, pyrene, and fluoranthene, found in four of our volunteers, have been shown to be tumor initiators or cocarcinogens.


A mechanochromic donor-acceptor torsional spring.
Mechanochromic polymers are intriguing materials that allow to sense force of specimens under load. Most mechanochromic systems rely on covalent bond scission and hence are two-state systems with optically distinct "on" and "off" states where correlating force with wavelength is usually not possible. Translating force of different magnitude with gradually different wavelength of absorption or emission would open up new possibilities to map and understand force distributions in polymeric materials. Here, we present a mechanochromic donor-acceptor (DA) torsional spring that undergoes force-induced planarization during uniaxial elongation leading to red-shifted absorption and emission spectra. The DA spring is based on ortho-substituted diketopyrrolopyrrole (o-DPP). Covalent incorporation of o-DPP into a rigid yet ductile polyphenylene matrix allows to transduce sufficiently large stress to the DA spring. The mechanically induced deflection from equilibrium geometry of the DA spring is theoretically predicted, in agreement with experiments, and is fully reversible upon stress release.


Clinical and radiological outcome after arthroscopic rotator cuff repair using PEEK-CF anchors.
The goal of this study was to evaluate the clinical and radiological outcome after arthroscopic rotator cuff repair using new carbonfiber reinforced polyetheretherketone (CF-PEEK) suture anchors. One hundred (n=100) patients with rotator cuff tears were enrolled at seven French hospitals between July 2019 and June 2020. Pain levels, Constant score and Subjective Shoulder Value (SSV) were taken preoperatively and 6 months postoperatively. Ultrasonography (US) was performed at 6 months postoperatively to evaluate tendon healing using the Sugaya classification. Statistical analysis was done with the Student t test with 95% confidence intervals. One hundred patients of the 100 patients were followed at 6 months. The mean SSV and Constant score improved from 40,1% preoperatively to 78% at 6 months (p<0.0001) and from 43 points preoperatively to 65 points at 6 months (p<0.0001), respectively. The mean level of pain, as measured with the visual analogue scale, decreased from 5,9 to 1,6 (p<0.001). There were no postoperative complications that resulted in revision surgery. The study showed good results at 6 months follow-up using carbonfiber reinforced PEEK anchors with improved Constant and SSV scores as well as a high ultrasonographic tendon healing rate, making PEEK CF anchors safe to use, comparable to commonly used anchors. IV.


Selenium speciation in Agaricus bisporus and Lentinula edodes mushroom proteins using multi-dimensional chromatography coupled to inductively coupled plasma mass spectrometry.
In this study, selenium species from Se containing proteins in mushrooms (Agaricus bisporus and Lentinula edodes) were investigated with size-exclusion liquid chromatography coupled to UV and inductively coupled plasma mass spectrometry (ICP-MS). Different protein extraction protocols were investigated. Variability of the fractionation patterns with three extraction media (0.1M NaOH, 30 mM Tris-HCl, and enzymatic digestions) was evaluated for both mushroom types. A 24 h Tris-HCl extraction followed by acetone addition was found to be optimal for protein precipitation. Presumably protein bound selenoamino acids were released using enzymes (proteinase K, protease XIV and trypsin). The selenium speciation of the proteolytic extract of the water soluble proteins fraction was carried out by using reversed-phase ion-pairing high performance liquid chromatography (RP-HPIPC) coupled on-line to ICP-MS for selenium specific detection. Selenocystine, selenomethionine, methylselenocysteine and inorganic selenium were established in both samples utilizing retention time standards and standard additions to the sample.


Effect of Tongxinluo on Nephrin Expression via Inhibition of Notch1/Snail Pathway in Diabetic Rats.
Podocyte injury is an important mechanism of diabetic nephropathy (DN). Accumulating evidence suggests that nephrin expression is decreased in podocyte in DN. Moreover, it has been demonstrated that tongxinluo (TXL) can ameliorate renal structure disruption and dysfunction in DN. However, the effect of TXL on podocyte injury in DN and its molecular mechanism is unclear. In order to explore the effect of TXL on podocyte injury and its molecular mechanism in DN, our in vivo and in vitro studies were performed. Our results showed that TXL increased nephrin expression in diabetic rats and in high glucose cultured podocyte. Meanwhile, TXL decreased ICN1 (the intracellular domain of notch), HES1, and snail expression in podocyte in vivo and in vitro. More importantly, we found that TXL protected podocyte from injury in DN. The results demonstrated that TXL inhibited the activation of notch1/snail pathway and increased nephrin expression, which may be a mechanism of protecting effect on podocyte injury in DN.


Natriuretic efficiency of frusemide as a consequence of drug input rate.
The aim of the present study was to investigate the influence of the rate of delivery of frusemide to its site of action on the effect and efficiency of the drug. Frusemide 30 mg was administered as a bolus dose, a slow-rate infusion and a bolus dose in combination with 2 g of probenecid in a three way cross-over design to seven healthy volunteers. Urinary volume and contents of frusemide and sodium were measured in samples collected over 10 h. Total natriuretic response was 40% higher (P < 0.001) after the infusion and 20% higher (P < 0.05) after the combined treatment with probenecid, as compared with the bolus dose. Total natriuretic efficiency did not differ between the infusion (0.013 mmol microg(-1)) and the combined treatment with probenecid (0.015 mmol microg(-1)), but was significantly higher as compared with the bolus dose (0.009 mmol microg(-1)). Natriuretic effect data were modeled according to the sigmoid Emax model and the frusemide excretion rate with maximum efficiency (ER(effmax)) was calculated from the estimated parameters. For both the frusemide infusion and the combined treatment with probenecid, the time course of delivery of frusemide into the urine consistently approached ER(effmax) more closely than was the case for the bolus dose. The natriuretic effect vs frusemide excretion rate curves were shifted to the right, and the estimated values of the sigmoid Emax model were higher for EC50 and lower for the slope factor after the bolus dose, which may indicate tolerance development for this treatment. Slowing the delivery of frusemide to the site of action increased the efficiency of the drug, leading to an increased natriuretic response.


Antepartum diagnosis of arthrogryposis associated with trisomy 18.
The discovery of a fetal abnormality during ultrasonography is a widely acknowledged indication for genetic amniocentesis. We present a case in which the early diagnosis of severe arthrogryposis led to the diagnosis of trisomy 18.


Targeting metastatic melanoma.
New medications and combination treatment strategies for patients with metastatic melanoma are discussed. Bcl-2 is an inhibitor of apoptosis that is overexpressed in approximately 80% of melanoma cell lines and is believed to contribute to the development of resistance to cytotoxic chemotherapy in patients with melanoma. Oblimersen, an antisense oligonucleotide that stops the translation of Bcl-2 mRNA to protein, significantly improved progression-free survival when administered in combination with dacarbazine. Overall survival was significantly improved in patients with low levels of serum lactate dehydrogenase (LDH), but not in patients with elevated LDH. RAF proteins are a family of serine/threonine kinases that regulate many aspects of cellular function. RAF mutations occur in 70% of melanoma cell lines. Although RAF kinases are thought to be important in the pathogenesis of melanoma, RAF inhibition with sorafenib has not significantly improved survival in patients with advanced disease. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a naturally occurring inhibitor of T-cell function that prevents the complete activation of T cells upon exposure to antigens by antigen-presenting cells. Two monoclonal antibodies to CTLA-4 (tremelimumab and ipilimumab) have been developed to promote T-cell activation in melanoma and other types of cancer. Phase I and phase II clinical trials of these agents in patients with metastatic melanoma have demonstrated promising effects on tumor progression, with objective response rates of approximately 20% and sustained responses in some patients. Several vaccines have been developed to stimulate immune system responses against melanoma. Despite promising early findings with polyvalent melanoma vaccine and with vaccine containing heat shock proteins, results with these agents in larger clinical trials have been disappointing. Ongoing clinical trials continue to evaluate these and other novel approaches to the treatment of metastatic melanoma.


[Pay attention to the detection and evaluation of CD30 in pathological diagnosis of lymphoma].
CD30 is a transmembrane glycoprotein of tumor necrosis factor receptor family, which is expressed differently in various lymphomas. It has specific effects on the proliferation and function of tumor cells. However, the significance of CD30 expression has not been fully recognized by clinicians and pathologists, and the detection and evaluation of CD30 have not been standardized. The role of CD30 in the diagnosis of lymphoma, detection methods and reporting standards are summarized in the paper to improve the understanding of CD30.


Therapeutic hypothermia and outcome in hyponatraemic encephalopathy secondary to maternal water intoxication.
Misguided encouragement to consume large volumes of water during labour for pain relief results in dilutional hyponatraemia in mothers and their babies presenting with neurological dysfunction. We report three babies who were encephalopathic with seizures in the background of hyponatraemia secondary to maternal ingestion of large volumes of water and mild perinatal asphyxia. All babies underwent therapeutic hypothermia in addition to sodium supplementation with fluid restriction. Their neurodevelopment was appropriate for age. This case series highlights the dilemma that could arise with hyponatraemic encephalopathy and mild perinatal asphyxia in the first 6 hours of life, which is the window of opportunity for therapeutic hypothermia for hypoxic-ischaemic encephalopathy. It is important to educate pregnant mothers in labour on the adverse effects of excessive fluid ingestion.


Intrasellar arachnoid cysts.
To evaluate the clinical, endocrinological, and radiological presentation of nine cases of surgically verified intrasellar arachnoid cysts and to discuss the physiopathological mechanisms of formation of these cysts. Among 1540 patients presenting with pituitary lesions, nine presented with an intrasellar arachnoid cyst. Their charts were retrospectively reviewed. Presenting symptoms included headache (n = 2), visual symptoms (n = 3), menstrual irregularities (n = 2), rapid weight gain (n = 1), vertigo (n = 1), and/or confusion (n = 1). Two cysts were discovered incidentally. T1-weighted magnetic resonance imaging scans showed an intrasellar cystic lesion in all cases, with a huge suprasellar extension in six cases. The cyst was of the same intensity as the cerebrospinal fluid (CSF) in only two patients. A transsphenoidal approach allowed the transdural aspiration of fluid and injection of a water-soluble contrast agent under mild pressure. In three patients, the contrast infiltrated along the pituitary stalk toward the subarachnoid spaces; in the other patients, it remained in the intrasellar compartment. Cyst membranes were removed as completely as possible with fenestration toward the subarachnoid spaces in communicating cysts. In spite of tight packing of the sella and sphenoid sinus, CSF fistulae requiring reoperation developed in two patients. The clinical picture of an intrasellar arachnoid cyst resembles that of a nonfunctional pituitary adenoma. Magnetic resonance imaging scans typically show a cystic intrasellar lesion with suprasellar extension, containing isointense or, more often, hyperintense fluid on T1-weighted sequences. In spite of the risk of CSF fistulae, the preferred surgical approach is transsphenoidal. A physiopathological mechanism is proposed according to anatomic variations of the sellar diaphragma allowing penetration of subarachnoid spaces into the sellar compartment and their enlargement by a ball-valve mechanism.