Coverage of Adequately Iodized Salt Is Suboptimal and Rice Fortification Using Public Distribution Channels Could Reach Low-Income Households: Findings from a Cross-Sectional Survey of Anganwadi Center Catchment Areas in Telangana, India.
Food fortification is a cost-effective approach to prevent and control of micronutrient deficiencies in India. A cross-sectional survey of children 0-35 months of age residing in the catchment areas of anganwadi centers in the state of Telangana was conducted to assess the coverage of adequately iodized salt and the potential for rice fortification. Salt samples were collected and tested for iodine concentration using iodometric titration. Information on demographics, household rice consumption, and Telangana's rice sector was collected and interpreted. In households of selected children, 79% of salt samples were found to be adequately iodized. Salt brand and district were significant predictors of inadequately iodized salt. Daily rice consumption among children and women averaged 122 grams and 321 grams per day, respectively. Approximately 28% of households reported consuming rice produced themselves or purchased from a local farmer, 65% purchased rice from a market or shop, 6% got rice from a public distribution system site, and 2% obtained it from a rice mill. In the catchment areas of Telangana's anganwadi centers, there is significant variation in the coverage of adequately iodized salt by district. Future surveys in Telangana should measure the coverage of salt iodization in the general population using quantitative methods. Nonetheless, increasing the adequacy of iodization of smaller salt manufacturers would help achieve universal salt iodization in Telangana. Despite high consumption of rice, our findings suggest that large-scale market-based rice fortification is not feasible in Telangana due to a large proportion of households producing their own rice and highly fragmented rice distribution. Distributing fortified rice via Telangana's public distribution system may be a viable approach to target low-income households, but would only reach a small proportion of the population in Telangana.


A Rare Case of Extramedullary Plasmacytoma Presenting as Large Abdominal Mass.
A 79-year-old female with a past medical history of multiple myeloma, diabetes mellitus and chronic kidney disease presented to the hospital with generalized weakness. The patient was found to have a firm abdominal wall mass with no underlying skin changes or drainage on physical examination. Computerized tomography of the abdomen and pelvis without contrast revealed a large mass-like structure in the anterior abdominal wall in the subcutaneous region extending into the abdomen through the mesentery with juxtaposition and partial involvement of the left hepatic lobe and distal stomach. Solitary extramedullary plasmacytomas are extremely rare tumors that occur outside of the bone marrow in the absence of systemic involvement. This case reports details the finding of an extramedullary plasmacytomas, which accounts for less than 5% of plasma cell neoplasms.


Resting-state functional connectivity after concussion is associated with clinical recovery.
There has been a recent call for longitudinal imaging studies to better characterize the time course of physiological recovery following sport-related concussion (SRC) and its relationship with clinical recovery. To address this, we evaluated changes to resting-state functional connectivity (rs-FC) of the whole-brain network following SRC and explored associations between rs-FC and measures of clinical outcome. High school and collegiate football athletes were enrolled during preseason. Athletes that suffered SRC (N = 62) were assessed across the acute (within 48 hr) and sub-acute (days 8, 15, and 45) phases. Matched football athletes without concussion served as controls (N = 60) and participated in similar visits. Multi-band resting-state fMRI was used to assess whole-brain rs-FC at each visit using network-based statistic and average nodal strength from regions of interest defined using a common whole-brain parcellation. Concussed athletes had elevated symptoms, psychological distress, and oculomotor, balance, and memory deficits at 48 hr postconcussion relative to controls, with diminished yet significant elevations in symptoms and psychological distress at 8 days. Both rs-FC analyses showed that concussed athletes had a global increase in connectivity at 8 days postconcussion relative to controls, with no differences at the 48-hr, 15-day, or 45-day visits. Further analysis revealed the group effect at the 8-day visit was driven by the large minority of concussed athletes still symptomatic at their visit; asymptomatic concussed athletes did not differ from controls. Findings from this large-scale, prospective study suggest whole-brain rs-FC alterations following SRC are delayed in onset but associated with the presence of self-reported symptoms.


Evidence for restricted reactivity of ADAMDEC1 with protein substrates and endogenous inhibitors.
ADAMDEC1 is a proteolytically active metzincin metalloprotease displaying rare active site architecture with a zinc-binding Asp residue (Asp-362). We previously demonstrated that substitution of Asp-362 for a His residue, thereby reconstituting the canonical metzincin zinc-binding environment with three His zinc ligands, increases the proteolytic activity. The protease also has an atypically short domain structure with an odd number of Cys residues in the metalloprotease domain. Here, we investigated how these rare structural features in the ADAMDEC1 metalloprotease domain impact the proteolytic activity, the substrate specificity, and the effect of inhibitors. We identified carboxymethylated transferrin (Cm-Tf) as a new ADAMDEC1 substrate and determined the primary and secondary cleavage sites, which suggests a strong preference for Leu in the P1' position. Cys(392), present in humans but only partially conserved within sequenced ADAMDEC1 orthologs, was found to be unpaired, and substitution of Cys(392) for a Ser increased the reactivity with α2-macroglobulin but not with casein or Cm-Tf. Substitution of Asp(362) for His resulted in a general increase in proteolytic activity and a change in substrate specificity was observed with Cm-Tf. ADAMDEC1 was inhibited by the small molecule inhibitor batimastat but not by tissue inhibitor of metalloproteases (TIMP)-1, TIMP-2, or the N-terminal inhibitory domain of TIMP-3 (N-TIMP-3). However, N-TIMP-3 displayed profound inhibitory activity against the D362H variants with a reconstituted consensus metzincin zinc-binding environment. We hypothesize that these unique features of ADAMDEC1 may have evolved to escape from inhibition by endogenous metalloprotease inhibitors.


Cold Water Swimming Beneficially Modulates Insulin Sensitivity in Middle-Aged Individuals.
We determined whether cold water swimming for six consecutive months results in adaptive changes in body composition and insulin sensitivity. Thirty healthy subjects aged 50.2 ± 9.4 years were exposed to cold water at least twice a week. Body composition was determined and serum glucose and insulin served to calculate beta-cell function, insulin sensitivity, and resistance using HOMA2. Compared with control subjects, swimmers were overweight, and had greater percent body fat and beta cell function. Women had lower values of BMI, fat free mass, muscle mass, visceral adipose tissue level, and greater percent body fat than men. Increased insulin sensitivity and decreased insulin secretion and resistance from beginning to middle of swim season was observed in females and in lean subjects. Findings suggest that men and women differ in regard to body composition and response to repeated cold exposure. Cold water swimming may beneficially modulate insulin sensitivity in cold acclimated lean swimmers.


Effect of puberty on markers of glomerular hypertrophy and hypertension in IDDM.
Epidemiological data implicate puberty as a factor in the initiation of diabetic nephropathy. However, the mechanism remains unclear. We hypothesized that puberty would result in an increase in glomerular hypertrophy and hypertension; these two early concomitant events are seen as pivotal to the pathophysiology of diabetic nephropathy. We studied the effect of pubertal duration on three surrogate markers of glomerular hypertrophy/hypertension: kidney volume (KV), microalbuminuria (MA), and Na-Li countertransport (CT). We recruited 177 subjects (87 female and 90 male; aged 6.2-22.1 years) with IDDM of 5 to 10 years' duration (6.8 +/- 1.6 years) into three groups with different pubertal duration: prepubertal since IDDM diagnosis; prepubertal at diagnosis, now pubertal; or early puberty at diagnosis, now postpubertal. KV was measured by ultrasound and corrected for body surface area; MA was defined as urinary albumin excretion of 15-200 micrograms/min in two of three 24-h samples, and Na-Li CT was measured in erythrocytes. As pubertal duration increased, there was a disproportionate increase in mean KV (prepubertal, 247 +/- 6 [SE] ml/1.73 m2; pubertal, 282 +/- 7/1.73 m2; postpubertal, 295 +/- 7/1.73 m2, P = 0.001), prevalence of nephromegaly (KV > 300 ml/1.73 m2) (14, 31, and 45%, respectively, P = 0.001), and prevalence of MA (0, 9.7, and 20.5%, respectively, P = 0.003). Subjects with KV > 300 ml/1.73 m2 were eight times more likely to have MA than those with KV < 300 (odds ratio 8.1, 95% confidence interval 2.4-27.4, P = 0.0001). There was no effect of pubertal duration on Na-Li CT. Multiple regression with KV as the dependent variable found an association with pubertal duration, MA, Na-Li CT, and current HbA1c (P < 0.0001). Our findings indicate that pubertal duration is an important determinant of both KV and MA and suggest that nephromegaly precedes microalbuminuria. We postulate that these effects are attributable to the influence of the pubertal milieu on glomerular hypertrophy/hypertension.


Predictive oncology: a review of multidisciplinary, multiscale in silico modeling linking phenotype, morphology and growth.
Empirical evidence and theoretical studies suggest that the phenotype, i.e., cellular- and molecular-scale dynamics, including proliferation rate and adhesiveness due to microenvironmental factors and gene expression that govern tumor growth and invasiveness, also determine gross tumor-scale morphology. It has been difficult to quantify the relative effect of these links on disease progression and prognosis using conventional clinical and experimental methods and observables. As a result, successful individualized treatment of highly malignant and invasive cancers, such as glioblastoma, via surgical resection and chemotherapy cannot be offered and outcomes are generally poor. What is needed is a deterministic, quantifiable method to enable understanding of the connections between phenotype and tumor morphology. Here, we critically assess advantages and disadvantages of recent computational modeling efforts (e.g., continuum, discrete, and cellular automata models) that have pursued this understanding. Based on this assessment, we review a multiscale, i.e., from the molecular to the gross tumor scale, mathematical and computational "first-principle" approach based on mass conservation and other physical laws, such as employed in reaction-diffusion systems. Model variables describe known characteristics of tumor behavior, and parameters and functional relationships across scales are informed from in vitro, in vivo and ex vivo biology. We review the feasibility of this methodology that, once coupled to tumor imaging and tumor biopsy or cell culture data, should enable prediction of tumor growth and therapy outcome through quantification of the relation between the underlying dynamics and morphological characteristics. In particular, morphologic stability analysis of this mathematical model reveals that tumor cell patterning at the tumor-host interface is regulated by cell proliferation, adhesion and other phenotypic characteristics: histopathology information of tumor boundary can be inputted to the mathematical model and used as a phenotype-diagnostic tool to predict collective and individual tumor cell invasion of surrounding tissue. This approach further provides a means to deterministically test effects of novel and hypothetical therapy strategies on tumor behavior.


Tourism Labor, Embodied Suffering, and the Deportation Regime in the Dominican Republic.
In this article, we use syndemic theory to examine socio-structural factors that result in heightened vulnerability to HIV infection and drug addiction among Dominican deportees who survive post-deportation through informal tourism labor. Through an ongoing NIDA-funded ethnographic study of the syndemic of HIV and problematic drug use among men involved in tourism labor in the Dominican Republic, we argue that the legal and political-economic context of the global deportation regime contributes to structural vulnerabilities among deportees in the Dominican Republic, most of whom are men with histories of incarceration in the United States and/or Puerto Rico. While Dominican laws and institutional practices work conjointly with foreign policies to reconfigure non-criminal deportees as hardened criminals unworthy of full citizenship rights, the informal tourism economy provides one of the few absorption points for male deportee labor, linking the deportation regime directly to the Caribbean tourism industry.


Super-resolution imaging of light-matter interactions near single semiconductor nanowires.
Nanophotonics is becoming invaluable for an expanding range of applications, from controlling the spontaneous emission rate and the directionality of quantum emitters, to reducing material requirements of solar cells by an order of magnitude. These effects are highly dependent on the near field of the nanostructure, which constitutes the evanescent fields from propagating and resonant localized modes. Although the interactions between quantum emitters and nanophotonic structures are increasingly well understood theoretically, directly imaging these interactions experimentally remains challenging. Here we demonstrate a photoactivated localization microscopy-based technique to image emitter-nanostructure interactions. For a 75 nm diameter silicon nanowire, we directly observe a confluence of emission rate enhancement, directivity modification and guided mode excitation, with strong interaction at scales up to 13 times the nanowire diameter. Furthermore, through analytical modelling we distinguish the relative contribution of these effects, as well as their dependence on emitter orientation.


Relationship of preadmission variables and first- and second-year course performance to performance on the National Board of Osteopathic Medical Examiners' COMLEX-USA Level 1 examination.
The purpose of this study was to examine the relationship of performance on the Comprehensive Osteopathic Medical Licensing Examination (COMLEX-USA) Level 1 licensing examination to (1) academic performance during the first 2 years of the curriculum, and (2) preadmission grade point averages (GPAs) and Medical College Admission Test (MCAT) scores for one osteopathic medical school with the unique mission of providing osteopathic family physicians for West Virginia and rural Appalachia. Simple correlations were calculated for the 63 students at West Virginia School of Osteopathic Medicine who completed all requirements of the first 2 years of the curriculum in May 1998 and were first eligible for board exams in June 1998. These included 26 (41.3%) female students and 5 (7.9%) minority students. Students who had failed a year and/or a course but subsequently successfully completed the first 2 years of the curriculum in May 1998 were included in this study. Every student who qualified to take the June 1998 administration of COMLEX-USA Level 1 did so at that time. For the 55 academic or preadmissions variables of interest, correlation coefficients with COMLEX-USA Level 1 scores and significance levels were calculated using SPSS Base 9.0. The correlation of COMLEX-USA Level 1 performance with GPA for Phase I was 0.64; with GPA for Phase II, 0.67; and total GPA for the first 2 years, 0.70. Grades in most individual courses also correlated significantly with COMLEX-USA Level 1 performance. Given the special focus of this curriculum on the needs of the Appalachian region and use of clinical performance measures or participation measures in calculating academic GPAs, these correlations show a remarkable degree of agreement between these two sets of performance measures. Further research is needed to see if similar relationships exist for osteopathic medical schools with other missions and with other curriculum structures. Preadmissions GPAs and MCATs did not significantly relate to performance on COMLEX-USA Level 1.


Architectural diversity and elastic networks in hydrogen-bonded host frameworks: from molecular jaws to cylinders.
Guest-free guanidinium organomonosulfonates (GMS) and their inclusion compounds display a variety of lamellar crystalline architectures distinguished by different "up-down" projections of the organomonosulfonate residues on either side of a two-dimensional (2D) hydrogen-bonding network of complementary guanidinium ions (G) and sulfonate moieties (S), the so-called GS sheet. Using a combinatorial library of 24 GMS hosts and 26 guest molecules, a total of 304 inclusion compounds out of a possible 624 possible host-guest combinations were realized, revealing a remarkable capacity of the GMS hosts to form inclusion compounds despite the facile formation of the corresponding guest-free compounds and the absence of "predestined" inclusion cavities like those in related guanidinium organodisulfonate host frameworks. The GS sheets in the inclusion compounds behave as "molecular jaws" in which organomonosulfonate groups projecting from opposing sheets clamp down on the guest molecules, forming ordered interdigitated arrays of the host organic groups and guests. Both the guest-free and inclusion compounds display a variety of architectures that reveal the structural integrity of two-dimensional GS sheet and the unique ability of these hosts to conform to the steric demands of the organic guests. Certain GMS host-guest combinations prompt formation of tubular inclusion compounds in which the GS sheet curls into cylinders with retention of the 2D GS network. The cylinders assemble into hexagonal arrays through interdigitation of the organosulfonate residues that project from their outer surfaces, crystallizing in high-symmetry trigonal or hexagonal space groups. This unique example of network curvature and structural isomerism between lamellar and cylindrical structures, with retention of supramolecular connectivity, is reminiscent of the phase behavior observed in surfactant microstructures and block copolymers. The large number of host-guest combinations explored here permits grouping of the inclusion compound architectures according to the shape of the guests and the relative volumes of the organomonosulfonate groups, enabling more reliable structure prediction for this class of compounds than for molecular crystals in general.


The learning process of recently graduated nurses in professional situations--experiences of an introduction program.
An increased theoretical focus and decreased clinical training have resulted in sharp criticism from health care institutions of the content of the nursing education program. As a consequence of this criticism, employers offer introduction programs to recently graduated nurses after they have completed their nursing education. This study is part one of a larger research study. The aim of the present study was to analyze and describe how recently graduated nurses learn at the place of work and how they seek a meaning in their encounter with that environment. The research method was ethnographic, and the empirical material was based upon data from participant observations, interviews and field notes. The results disclosed that workplaces using the master-apprentice system as a model for supervising recently graduated nurses during the introduction program. The results also showed that the novices have acquired theoretical knowledge and know what action to take, but may have trouble assessing which part of their knowledge to use. The introduction program constitutes an obstacle in the professional development of the novices.


Biosynthesis of the blood group P antigen-like GalNAc beta 1-->3Gal beta 1-->4GlcNAc/Glc structure: a novel N-acetylgalactosaminyltransferase in human blood plasma.
Human blood group O plasma was found to contain an N-acetylgalactosaminyltransferase which catalyzes the transfer of N-acetylgalactosamine from UDP-GalNAc to Gal beta 1-->4Glc, Gal beta 1-->4GlcNAc, asialo-alpha 1-acid glycoprotein, and Gal beta 1-->4GlcNAc beta 1-->3Gal beta 1-->4Glc-ceramide, but not to Gal beta 1-->3GlcNAc. The enzyme required Mn2+ for its activity and showed a pH optimum at 7.0. The reaction products were readily hydrolyzed by beta-N-acetylhexosaminidase and released N-acetylgalactosamine. Apparent Km values for UDP-GalNAc, Mn2+, lactose, N-acetyllactosamine, and terminal N-acetyllactosaminyl residues of asialo-alpha 1-acid glycoprotein were 0.64, 0.28, 69, 20, and 1.5 mM, respectively. Studies on acceptor substrate competition indicated that all the acceptor substrates mentioned above compete for one enzyme, whereas the enzyme can be distinguished from an NeuAc alpha 2-->3Gal beta-1,4-N-acetylgalactosaminyltransferase, which also occurs in human plasma. The methylation study of the product formed by the transfer of N-acetylgalactosamine to lactose revealed that N-acetylgalactosamine had been transferred to the carbon-3 position of the beta-galactosyl residue. Although the GalNAc beta 1-->3Gal structure is known to have the blood group P antigen activity, human plasma showed no detectable activity of Gal alpha 1-->4Gal beta-1,3-N-acetylgalactosaminyltransferase, which is involved in the synthesis of the major P antigen-active glycolipid, GalNAc beta 1-->3Gal alpha 1-->4Gal beta 1-->4Glc-ceramide. Hence, the GalNAc beta 1-->3Gal beta 1-->4GlcNAc/Glc structure is synthesized by the novel Gal beta 1-->4GlcNAc/Glc beta-1,3-N-acetylgalactosaminyltransferase.


Children's First Experience of Taking Anabolic-Androgenic Steroids can Occur before Their 10th Birthday: A Systematic Review Identifying 9 Factors That Predicted Doping among Young People.
Taking performance-enhancing drugs (PEDs) can cause serious and irreversible health consequences, which can ultimately lead to premature death. Some young people may take PEDs without fully understanding the ramifications of their actions or based on the advice from others. The purpose of this systematic review was to identify the main factors that predicted doping among young people. The literature was systematically reviewed using search engines, manually searching specialist journals, and pearl growing. Fifty-two studies, which included 187,288 young people aged between 10 and 21 years of age, 883 parents of adolescent athletes, and 11 adult coaches, who were interviewed regarding young athletes, were included in this review. Nine factors predicted doping among young people: gender; age; sports participation; sport type; psychological variables; entourage; ethnicity; nutritional supplements; and health harming behaviors. In regards to psychological variables, 22 different constructs were associated with doping among young people. Some psychological constructs were negatively associated with doping (e.g., self-esteem, resisting social pressure, and perfectionist strivings), whereas other were positively associated with doping (e.g., suicide risk, anticipated regret, and aggression). Policy makers and National Anti-Doping Organizations could use these findings to help identify athletes who are more at risk of doping and then expose these individuals to anti-doping education. Based on the current findings, it also appears that education programs should commence at the onset of adolescence or even late childhood, due to the young age in which some individuals start doping.


Left ventricular dysfunction and associated cellular injury in rats exposed to chronic intermittent hypoxia.
Obstructive sleep apnea (OSA) increases cardiovascular morbidity and mortality. We have reported that chronic intermittent hypoxia (CIH), a direct consequence during OSA, leads to left ventricular (LV) remodeling and dysfunction in rats. The present study is to determine LV myocardial cellular injury that is possibly associated with LV global dysfunction. Fifty-six rats were exposed either to CIH (nadir O(2) 4-5%) or sham (handled normoxic controls, HC), 8 h/day for 6 wk. At the end of the exposure, we studied LV global function by cardiac catheterization, and LV myocardial cellular injury by in vitro analyses. Compared with HC, CIH animals demonstrated elevations in mean arterial pressure and LV end-diastolic pressure, but reductions in cardiac output (CIH 141.3 +/- 33.1 vs. HC 184.4 +/- 21.2 ml x min(-1) x kg(-1), P < 0.01), maximal rate of LV pressure rise in systole (+dP/dt), and maximal rate of LV pressure fall in diastole (-dP/dt). CIH led to significant cell injury in the left myocardium, including elevated LV myocyte size, measured by cell surface area (CIH 3,564 +/- 354 vs. HC 2,628 +/- 242 microm(2), P < 0.05) and cell length (CIH 148 +/- 23 vs. HC 115 +/- 16 microm, P < 0.05), elevated terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-stained positive cell number (CIH 98 +/- 45 vs. HC 15 +/- 13, P < 0.01), elevated caspase-3 activity (906 +/- 249 vs. 2,275 +/- 1,169 pmol x min(-1) x mg(-1), P < 0.05), and elevated expression of several remodeling gene markers, including c-fos, atrial natriuretic peptide, beta-myosin heavy chain, and myosin light chain-2. However, there was no difference between groups in sarcomere contractility of isolated LV myocytes, or in LV collagen deposition on trichrome-stained slices. In conclusion, CIH-mediated LV global dysfunction is associated with myocyte hypertrophy and apoptosis at the cellular level.


Mitogenic signaling of thrombin in mesangial cells: role of tyrosine phosphorylation.
Thrombin elicits multiple biological effects on a variety of cells. We have previously shown that thrombin is a potent mitogen for human glomerular mesangial cells. This mitogenic effect of thrombin is associated with activation of phospholipase C (PLC) and induction of platelet-derived growth factor (PDGF) gene expression. The thrombin receptor, which belongs to the guanine nucleotide binding protein (G protein)-coupled receptor family, has recently been shown to induce rapid tyrosine phosphorylation of cellular proteins. In the present study, we investigated the role of protein-tyrosine phosphorylation in mediating the cellular responses elicited by thrombin in human glomerular mesangial cells. Amino acid labeling followed by immunoprecipitation with phosphotyrosine antibodies demonstrate that thrombin stimulates tyrosine phosphorylation of a set of cellular proteins. Treatment of mesangial cells with thrombin followed by immunoblotting with phosphotyrosine antibodies showed three major bands of tyrosine-phosphorylated proteins approximately 130, 70, and 44-42 kDa. Phosphorylation of these proteins was inhibited by two tyrosine kinase inhibitors, herbimycin A and genistein. Both compounds inhibited DNA synthesis and PDGF B-chain gene expression but had no effect on inositol phosphates production or increases in cytosolic calcium in response to thrombin. These data demonstrate that protein-tyrosine phosphorylation is not required for thrombin-induced PLC activation with inositol phosphate formation and subsequent intracellular calcium release, but it is an absolute requirement for thrombin-induced DNA synthesis and PDGF B-chain gene expression.


Automatic clustering of docking poses in virtual screening process using self-organizing map.
Scoring functions provided by the docking software are still a major limiting factor in virtual screening (VS) process to classify compounds. Score analysis of the docking is not able to find out all active compounds. This is due to a bad estimation of the ligand binding energies. Making the assumption that active compounds should have specific contacts with their target to display activity, it would be possible to discriminate active compounds from inactive ones with careful analysis of interatomic contacts between the molecule and the target. However, compounds clustering is very tedious due to the large number of contacts extracted from the different conformations proposed by docking experiments. Structural analysis of docked structures is processed in three steps: (i) a Kohonen self-organizing map (SOM) training phase using drug-protein contact descriptors followed by (ii) an unsupervised cluster analysis and (iii) a Newick file generation for results visualization as a tree. The docking poses are then analysed and classified quickly and automatically by AuPosSOM (Automatic analysis of Poses using SOM). AuPosSOM can be integrated into strategies for VS currently employed. We demonstrate that it is possible to discriminate active compounds from inactive ones using only mean protein contacts' footprints calculation from the multiple conformations given by the docking software. Chemical structure of the compound and key binding residues information are not necessary to find out active molecules. Thus, contact-activity relationship can be employed as a new VS process. AuPosSOM is available at http://www.aupossom.com.


Effects of melatonin and tryptophan on healing of gastric and duodenal ulcers with Helicobacter pylori infection in humans.
Melatonin (MT) and its precursor L-tryptophan (TRP) are implicated in the protection of gastric mucosa against aspirin-induced lesions and in the acceleration of healing of idiopathic gastro-duodenal ulcers, but no information is available whether these agents are also effective in healing of gastroduodenal ulcers accompanied by Helicobacter pylori (H. pylori) infection. In this study three groups A, B and C, each including 7 H. pylori-positive patients with gastric ulcers and 7 H. pylori-positive patients with duodenal ulcers, aging 28-50 years, were randomly assigned for the treatment with omeprazole 20 mg twice daily combined with placebo (group A), MT administered in a dose of 5 mg twice daily (group B) or TRP applied in a dose of 250 mg twice daily (group C). All patients underwent routine endoscopy at day 0 during which the gastric mucosa was evaluated and gastric biopsies were taken for the presence of H. pylori and histopathological evaluation. The rate of ulcer healing was determined by gastroduodenoscopy at day 0, 7, 14 and 21 after the initiation of the therapy. Plasma MT, gastrin, ghrelin and leptin were measured by specific RIA. At day 21, all ulcers were healed in patients of groups B and C but only 3 out of 7 in group A of gastric ulcers and 3 out of 7 in duodenal ulcers. Initial plasma MT showed similar low levels in all three groups but it increased several folds above initial values in ulcer patients at day 7, 14 and 21. Plasma gastrin and leptin levels showed a significant rise over initial values in patients treated with omeprazole and placebo, MT or TRP while plasma ghrelin levels were not significantly affected by these treatments. We conclude that MT or TRP added to omeprazole treatment, significantly accelerates healing rate of H. pylori infected chronic gastroduodenal ulcers over that obtained with omeprazole alone and this likely depends upon the significant rise in plasma MT and possibly also in leptin levels, both hormones involved in the mechanism of gastroprotection and ulcer healing.


Therapeutic Modulation of Glutamate Receptors in Major Depressive Disorder.
Current pharmacotherapies for major depressive disorder (MDD) have a distinct lag of onset that can prolong distress and impairment for patients, and realworld effectiveness trials further suggest that antidepressant efficacy is limited in many patients. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms, e.g., receptor/reuptake agonists or antagonists with varying affinities for serotonin, norepinephrine, or dopamine. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, as well as in the development of novel therapeutics for this disorder. Since the rapid and robust antidepressant effects of the N-methyl-D-aspartate (NMDA) antagonist ketamine were first observed in 2000, other NMDA receptor antagonists have been studied in MDD. These have been associated with relatively modest antidepressant effects compared to ketamine, but some have shown more favorable characteristics with increased potential in clinical practice (for instance, oral administration, decreased dissociative and/or psychotomimetic effects, and reduced abuse/diversion liability). This article reviews the clinical evidence supporting the use of glutamate receptor modulators with direct affinity for cognate receptors: 1) non-competitive NMDA receptor antagonists (ketamine, memantine, dextromethorphan, AZD6765); 2) subunit (NR2B)-specific NMDA receptor antagonists (CP- 101,606/traxoprodil, MK-0657); 3) NMDA receptor glycine-site partial agonists (D-cycloserine, GLYX- 13); and 4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant). Several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy, but that have yet to be studied clinically, are also briefly discussed; these include α-amino-3-hydroxyl-5-methyl-4- isoxazoleproprionic acid (AMPA) agonists, mGluR2/3 negative allosteric modulators, and mGluR7 agonists.


Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2.
Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuropathies. Recently, three CMT1-associated point mutations (I43N, T51P, and I52T) were discovered in the abundant peripheral myelin protein P2. These mutations trigger abnormal myelin structure, leading to reduced nerve conduction velocity, muscle weakness, and distal limb atrophy. P2 is a myelin-specific protein expressed by Schwann cells that binds to fatty acids and membranes, contributing to peripheral myelin lipid homeostasis. We studied the molecular basis of the P2 patient mutations. None of the CMT1-associated mutations alter the overall folding of P2 in the crystal state. P2 disease variants show increased aggregation tendency and remarkably reduced stability, T51P being most severe. In addition, P2 disease mutations affect protein dynamics. Both fatty acid binding by P2 and the kinetics of its membrane interactions are affected by the mutations. Experiments and simulations suggest opening of the β barrel in T51P, possibly representing a general mechanism in fatty acid-binding proteins. Our findings demonstrate that altered biophysical properties and functional dynamics of P2 may cause myelin defects in CMT1 patients. At the molecular level, a few malformed hydrogen bonds lead to structural instability and misregulation of conformational changes related to ligand exchange and membrane binding.


Three-dimensional kinematics of the talocrural and subtalar joints during drop landing.
The bones and soft tissues of the foot act as a shock attenuator and the relative bony motions of the talocrural and subtalar joints are the subject of research interest for their roles in lower extremity pathology. Despite this interest, little information exists on the precise in vivo talocrural and subtalar joint kinematics during dynamic activities. Therefore, the purpose of this study was to quantify the three-dimensional kinematics of the talocrural and subtalar joints during landing by using single-plane fluoroscopic imaging and shape matching techniques. Three-dimensional bone positions for 6 subjects during landing from a 10 cm height were determined by using 3D-2D model-image registration techniques. The primary talocrural joint motion after toe contact was dorsiflexion with rotation ranges averaging 12° ± 7° dorsiflexion, 2° ± 2° eversion, and 3° ± 2° internal rotation. The subtalar joint exhibited similar patterns of increased dorsiflexion, eversion, and external rotation up to 150 ms after landing. The angular changes were 5° ± 3° dorsiflexion, 7° ± 3° eversion, and 6° ± 2° external rotation. This study contributes to the quantitative understanding of the function of the normal talocrural and subtalar joints and can be used for comparison with data obtained from injured feet.


Estimation of region of attraction for polynomial nonlinear systems: a numerical method.
This paper introduces a numerical method to estimate the region of attraction for polynomial nonlinear systems using sum of squares programming. This method computes a local Lyapunov function and an invariant set around a locally asymptotically stable equilibrium point. The invariant set is an estimation of the region of attraction for the equilibrium point. In order to enlarge the estimation, a subset of the invariant set defined by a shape factor is enlarged by solving a sum of squares optimization problem. In this paper, a new algorithm is proposed to select the shape factor based on the linearized dynamic model of the system. The shape factor is updated in each iteration using the computed local Lyapunov function from the previous iteration. The efficiency of the proposed method is shown by a few numerical examples.


Interferon-γ couples CD8+ T cell avidity and differentiation during infection.
Effective responses to intracellular pathogens are characterized by T cell clones with a broad affinity range for their cognate peptide and diverse functional phenotypes. How T cell clones are selected throughout the response to retain a breadth of avidities remains unclear. Here, we demonstrate that direct sensing of the cytokine IFN-γ by CD8+ T cells coordinates avidity and differentiation during infection. IFN-γ promotes the expansion of low-avidity T cells, allowing them to overcome the selective advantage of high-avidity T cells, whilst reinforcing high-avidity T cell entry into the memory pool, thus reducing the average avidity of the primary response and increasing that of the memory response. IFN-γ in this context is mainly provided by virtual memory T cells, an antigen-inexperienced subset with memory features. Overall, we propose that IFN-γ and virtual memory T cells fulfil a critical immunoregulatory role by enabling the coordination of T cell avidity and fate.


Transcriptome sequencing reveals thousands of novel long non-coding RNAs in B cell lymphoma.
Gene profiling of diffuse large B cell lymphoma (DLBCL) has revealed broad gene expression deregulation compared to normal B cells. While many studies have interrogated well known and annotated genes in DLBCL, none have yet performed a systematic analysis to uncover novel unannotated long non-coding RNAs (lncRNA) in DLBCL. In this study we sought to uncover these lncRNAs by examining RNA-seq data from primary DLBCL tumors and performed supporting analysis to identify potential role of these lncRNAs in DLBCL. We performed a systematic analysis of novel lncRNAs from the poly-adenylated transcriptome of 116 primary DLBCL samples. RNA-seq data were processed using de novo transcript assembly pipeline to discover novel lncRNAs in DLBCL. Systematic functional, mutational, cross-species, and co-expression analyses using numerous bioinformatics tools and statistical analysis were performed to characterize these novel lncRNAs. We identified 2,632 novel, multi-exonic lncRNAs expressed in more than one tumor, two-thirds of which are not expressed in normal B cells. Long read single molecule sequencing supports the splicing structure of many of these lncRNAs. More than one-third of novel lncRNAs are differentially expressed between the two major DLBCL subtypes, ABC and GCB. Novel lncRNAs are enriched at DLBCL super-enhancers, with a fraction of them conserved between human and dog lymphomas. We see transposable elements (TE) overlap in the exonic regions; particularly significant in the last exon of the novel lncRNAs suggest potential usage of cryptic TE polyadenylation signals. We identified highly co-expressed protein coding genes for at least 88 % of the novel lncRNAs. Functional enrichment analysis of co-expressed genes predicts a potential function for about half of novel lncRNAs. Finally, systematic structural analysis of candidate point mutations (SNVs) suggests that such mutations frequently stabilize lncRNA structures instead of destabilizing them. Discovery of these 2,632 novel lncRNAs in DLBCL significantly expands the lymphoma transcriptome and our analysis identifies potential roles of these lncRNAs in lymphomagenesis and/or tumor maintenance. For further studies, these novel lncRNAs also provide an abundant source of new targets for antisense oligonucleotide pharmacology, including shared targets between human and dog lymphomas.


Quality of life and health status of Indonesian women with breast cancer symptoms before the definitive diagnosis: A comparison with Indonesian women in general.
Breast cancer (BC) is prevalent in low and middle-income countries (LMICs) where the majority of cases are diagnosed in late stages. The aims of this study were: (1) to assess quality of life (QOL) and health status of Indonesian women with BC symptoms before definitive diagnosis; (2) to compare QOL and health status between women with BC symptoms before definitive diagnosis and Indonesian women in general; (3) to evaluate the association between demographic variables (age, residence, social economic status and education level) and QOL within the Indonesian women with BC symptoms before definitive diagnosis. We used WHOQOL-BREF to measure QOL and EQ-5D-5L for health status. Multivariate analysis of covariance (MANCOVA) was used to compare QOL and health status between women with BC symptoms and women from the general Indonesian population in order to control for confounders. Regression analyses were used for testing the association between the demographic variables, QOL, and health status. In comparison with the data from the women from the general population (n = 471), the women with BC symptoms (n = 132) reported lower QOL, especially in physical and psychological domains. They also reported more problems in all dimensions of health status. Higher education and monthly income were positively associated with QOL and health status among the women with BC symptoms. Before receiving a definitive diagnosis, women who visit hospitals with symptoms of BC, report a lower QOL and health status than women in general. Our results suggest that healthcare providers should provide targeted strategies for women with BC symptoms to improve their QOL.


Capitation combined with pay-for-performance improves antibiotic prescribing practices in rural China.
Pay-for-performance in health care holds promise as a policy lever to improve the quality and efficiency of care. Although the approach has become increasingly popular in developing countries in recent years, most policy designs do not permit the rigorous evaluation of its impact. Thus, evidence of its effect is limited. In collaboration with the government of Ningxia Province, a predominantly rural area in northwest China, we conducted a matched-pair cluster-randomized experiment between 2009 and 2012 to evaluate the effects of capitation with pay-for-performance on primary care providers' antibiotic prescribing practices, health spending, outpatient visit volume, and patient satisfaction. We found that the intervention led to a reduction of approximately 15 percent in antibiotic prescriptions and a small reduction in total spending per visit to village posts-essentially, community health clinics. We found no effect on other outcomes. Our results suggest that capitation with pay-for-performance can improve drug prescribing practices by reducing overprescribing and inappropriate prescribing. Our study also shows that rigorous evaluations of health system interventions are feasible when conducted in close collaboration with the government.


Polarization conversion by reflection in a thin-film grating.
A dielectric-film waveguide with a grating etched on its film-cover interface can be used as a polarization converter. The e wave can be converted into the h wave and vice versa if the guided wave is incident obliquely to the grating vector. The polarization converter is analyzed by use of a quasi-optic technique. A high degree of polarization-conversion efficiency is achieved by a suitable choice of the grating length. The Bragg angles of incidence and observation, the maximum polarization-conversion efficiency, and the frequency and the angular selectivity are all found to increase with an increase in the grating period. An illustrative numerical example is presented.


Short-term prophylaxis in hereditary angioedema due to deficiency of the C1-inhibitor--a long-term survey.
Hereditary angioedema is a potentially life-threatening disorder, because edema occurring in the mucosa of the upper airways can lead to suffocation. The management of HAE consists of avoiding the triggering factors, prophylaxis, and the acute treatment of edematous episodes. Medical procedures can also provoke edematous attacks, and therefore, short-term prophylaxis (STP) is recommended before such interventions. Our aim was to evaluate the efficacy and safety of STP administered before medical procedures. We conducted a retrospective analysis before and a prospective survey after establishing the diagnosis in a group of 137 (60 males, 77 females; 20 pediatric and 117 adult) patients with HAE. Both were implemented using questionnaires, patient diaries and hospital charts focusing on medical interventions provoking edematous attack, and the medicinal products (C1-INH concentrate, tranexamic acid, and danazol) administered for STP. Comparing surgical interventions performed without pre-event STP (in 39/89 patients before HAE was diagnosed), or after STP (in 3/55 cases after diagnosis), we found a significant (P < 0.0001, Fisher's exact test) reduction in the number of edematous episodes. Evaluating the efficacy of the drugs administered for STP revealed that C1-INH concentrate (Berinert(®) , CSL Behring, Marburg, Germany) was significantly (P = 0.0096, Fisher's exact test) superior to orally administered drugs in reducing the instances of postprocedural edema. None of the medicinal products caused adverse events potentially related to STP. STP reduces the number of postprocedural edematous episodes. C1-INH concentrate is safe and effective for prophylaxis. When this agent is not available, danazol is a potential alternative for prophylaxis before elective medical interventions.


What's your assessment?
The "What's Your Assessment?" series includes a short case presentation and differential diagnosis. It is followed by a discussion of the disease or condition and the rationale used in each step of the assessment.


Reliability and validity of the Japanese Migraine Disability Assessment (MIDAS) Questionnaire.
This study was designed to assess the test-retest reliability, internal consistency, and validity of a Japanese translation of the Migraine Disability Assessment (MIDAS) Questionnaire in a sample of Japanese patients with headache. Previous studies have demonstrated that the English-language version of the MIDAS Questionnaire is a reliable and valid instrument for the assessment of migraine-related disability. Any translations of the MIDAS Questionnaire must also be assessed for reliability and validity. Study participants were recruited from the patient population attending either the Neurology Department of Kitasato University or an affiliated clinic. Participants were eligible for study entry if they had 6 or more primary headaches per year. For reliability testing, participants completed the MIDAS Questionnaire on 2 occasions, exactly 2 weeks apart. To assess validity, patients were also invited to participate in a 90-day daily diary study. Composite measures from the 90-day diaries were compared to equivalent MIDAS measures (ie, 5 questions on headache-related disability and 1 question each on average pain intensity and headache frequency in the last 3 months) and to the total MIDAS score obtained from a third MIDAS Questionnaire completed at the end of this 90-day period. One hundred one patients between the ages of 21 and 77 years were recruited (81 women and 20 men). Ninety-nine patients (80 women and 19 men) participated in the diary study. At baseline, 46.5% of patients were MIDAS grade I or II (minimal, mild, or infrequent disability), 22.2% were MIDAS grade III (moderate disability), and 31.3% were MIDAS grade IV (severe disability). Test-retest Spearman correlations for the 5 disability questions and the questions on average pain intensity and headache frequency ranged from 0.59 to 0.80 (P<.0001). The test-retest Spearman correlation coefficient for the total MIDAS score was 0.83 (P<.0001). The degree to which individual MIDAS questions correlated with the diary-based measures ranged from 0.36 to 0.88. The correlation between the total MIDAS score and the equivalent diary-based measure was 0.66. In general, the mean and median values for the MIDAS items and total MIDAS score were similar to the means and medians for the diary-based measures. However, the mean MIDAS scores for the number of days on which headache was experienced and the number of missed workdays were significantly different compared to the diary-based estimates for these items (P<.05). In addition, the mean MIDAS score for the number of days of missed housework was significantly higher than the corresponding diary-based estimate (P<.01). The results from this study show that the Japanese translation of the MIDAS Questionnaire is comparable with the English-language version in terms of reliability and validity.


Outcomes and toxicity after salvage radiotherapy for vaginal relapse of endometrial cancer.
Studies of salvage radiotherapy in locally recurrent endometrial cancer remain limited. The aim of this study was to evaluate the efficacy of salvage radiotherapy for vaginal relapse of endometrial cancer and to explore prognostic factors associated with outcomes. We evaluated 30 patients treated with salvage external-beam radiotherapy and/or vaginal brachytherapy for vaginal relapses of endometrial cancer between 2009 and 2018. The inclusion criteria were: pathologically-confirmed recurrence; loco-regional relapse (in absence of distant metastases); and salvage treatment including external-beam radiotherapy and/or vaginal brachytherapy. Outcomes were evaluated via Kaplan-Meier, with the log-rank test employed to compare differences among various groups and identify prognostic factors. 30 patients developed vaginal recurrence at a median time of 20.6 months (range 2-219) post-hysterectomy. The most common site of recurrence was the vaginal apex (60%), followed by the distal vagina (10%). Salvage radiotherapy entailed combination external-beam radiotherapy and vaginal brachytherapy (n=24) or single modality treatment (n=6), along with concurrent chemotherapy in 20 cases. At a median follow-up of 4.4 years (range 0.1-130) post-radiotherapy, the 5 year rates of local control, regional control, metastasis-free interval, disease-free interval, and overall survival were 89%, 91.5%, 75.5%, 69%, and 83%, respectively. Factors associated with improved disease-free interval included: endometrioid histology (p=0.03), isolated vaginal relapse (p=0.003), late recurrence (>9 months) (p=0.007), and combined modality radiotherapy (p=0.001). The only factor associated with overall survival was isolated vaginal relapse (in the absence of other recurrent disease) (p=0.02). Regarding toxicity, 18% of patients experienced acute grade ≥3 events (most commonly gastrointestinal). The 5 year rates of rectal bleeding, small bowel obstruction, and pelvic fracture were 31%, 18%, and 13%, respectively. Salvage radiotherapy imparts excellent loco-regional control for vaginal relapses of endometrial cancer and should entail combination external-beam radiotherapy and vaginal brachytherapy. Patients should be closely monitored for late gastrointestinal toxicity following salvage radiotherapy.


In vitro assessment of reproductive toxicity of cigarette smoke and deleterious consequences of maternal exposure to its constituents.
Cigarette smoke is known to be a serious health risk factor and considered reproductively toxic. In the current study, we investigated whether constituents of cigarette smoke, pyrazine, 2-ethylpyridine, and 3-ethylpyridine, adversely affect reproductive functioning such as oocyte maturation and sperm capacitation. Our findings indicated that three smoke components were involved in retardation of oocyte maturation in a dose-dependent manner and the lowest-observed-adverse-effect level (LOAEL) was determined to be 10(-10)M. However, individual smoke components administrated at the LOAEL did not attenuate oocyte maturation, demonstrating that all three toxicants were equally required for the observed growth impairment. When exposed to all three components at 10(-10)M during in vitro capacitation, murine sperm lost forward progression and were unable to show adequate hyperactivation, which is indicative of the incompletion of the capacitation process. Only sperm administrated with 3-ethylpyridine alone showed significant reduction in capacitation status, suggesting the chemical is the one responsible for disrupting sperm capacitation. Taken together, this is the first report that documents the effect of cigarette smoke components on oocyte maturation and sperm capacitation. The present findings demonstrate the adverse effects of smoke constituents of mammalian reproduction and the differences in sensitivity to smoke components between male and female gametes. Since both processes take place in the female reproductive system, our data provide new insights into deleterious consequences of maternal exposure to cigarette smoke.


Epidemiologic characterization of human papillomavirus infection in rural Chaozhou, eastern Guangdong Province of China.
Human papilloma virus (HPV) infection was the main cause of cervical cancer. There were only a few reports and detailed data about epidemiological research of HPV infection in rural population of China. The cervical cells of rural Chaozhou women were collected, and multiplex real time PCR was firstly performed to detect high-risk HPV (HR-HPV) infection, which could detect 13 types of HR-HPV (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). Then, HPV-positive samples were typed by HPV GenoArray test. HR-HPV DNA was detected by multiplex real time-PCR in 3830 of 48559 cases (7.89%). There was a peak incidence in age of 55-60 years group, and a lower incidence in who lived in plain group compared with suburban, mountain and seashore group. 3380 cases of HPV positive sample were genotyped, 11.01% (372/3380) cases could not be classified, among the typed 3008 cases, 101 cases were identified without HR-HPV type infection, 2907 cases were infected with one HR-HPV type at least, the 6 most common HR-HPV types in descending order of infection, were type 52 (33.4%, 16 (20.95%), 58 (15.93%), 33 (9.94%), 68 (9.22%) and 18 (8.36%). The combined prevalence of HPV types 16 and 18 accounted for 28.52% of total infection. However, type 52 plus 58 presented 48.23% of total infection. 2209/2907 cases were infected with a single HPV type and 698/2907 cases were infected with multiple types, and multiple infection constituent ratio increased with age, with a peak incidence in age 55-60 years group. Our findings showed low prevalence of HPV vaccine types (16 and 18) and relatively high prevalence of HPV-52 and -58, support the hypothesis that the second-generation HPV vaccines including HPV-52 and -58 may offer higher protection for women in rural Guangdong Province.


Effect of combined application of methyl isothiocyanate and chloropicrin on their transformation.
Combining several soil fumigants to increase the broad spectrum of pest control is a common fumigation practice in current production agriculture. In this study, we investigated the effect of combined application of chloropicrin and methyl isothiocyanate (MITC) on their transformations and persistence in the environment. In aqueous solution, no direct reaction between MITC and chloropicrin occurred and relatively slow rates of hydrolysis of these compounds were observed in aquatic environments free of suspended solids. The transformation of chloropicrin, however, was accelerated in aqueous solution with MITC because of a reduction reaction with bisulfide (HS(-)), which is a by-product of MITC hydrolysis. In soil, when fumigants were applied simultaneously, the degradation of MITC was suppressed under the bi-fumigant application due to the inhibition of soil microbial activity and a possible abiotic competition with chloropicrin for a limited number of reaction sites on the surface of soil particles. However, the degradation rate of chloropicrin was significantly enhanced in the bi-fumigant soil system, which was primarily attributed to the reaction of chloropicrin and HS(-). Two sequential application approaches were developed to investigate the feasibility of the combined application of metam sodium (parent compound of MITC) and chloropicrin in soil and assess their potential effects on environmental fate. For both application sequences, the degradation of chloropicrin was accelerated and that of MITC, as a major breakdown product of metam sodium, was inhibited in soil.


Hepatitis B viral DNA is methylated in liver tissues.
The mechanisms that regulate hepatitis B virus (HBV) replication within the liver are poorly understood. Given that methylation of CpG islands regulates gene expression in human tissues, we sought to identify CpG islands in HBV-DNA and to determine if they are methylated in human tissues. In silico analysis demonstrated three CpG islands in HBV genotype A sequences, two of which were of particular interest because of their proximity to the HBV surface gene start codon (island 1) and to the enhancer 1/X gene promoter region (island 2). Human sera with intact virions that were largely unmethylated were used to transfect HepG2 cells and HBV-DNA became partially methylated at both islands 1 and 2 by day 6 following exposure of HepG2 to virus. Examination of three additional human sera and 10 liver tissues showed no methylation in sera but tissues showed methylation of island 1 in six of 10 cases and of island 2 in five of 10 cases. The cell line Hep3B, with integrated HBV, showed complete methylation of island 1 but no methylation of island 2. In conclusion, HBV-DNA can be methylated in human tissues and methylation may play an important role in regulation of HBV gene expression.


Cyclooxygenase-2 and hypoxia-regulated proteins are modulated by basic fibroblast growth factor in acute renal failure.
Acute renal failure (ARF) can be caused by injuries that induce tissue hypoxia, which in turn can trigger adaptive or inflammatory responses. We previously showed the participation of basic fibroblast growth factor (FGF-2) in renal repair. Based on this, the aim of this study was to analyze the effect of FGF-2 signaling pathway manipulation at hypoxia-induced protein levels, as well as in key proteins from the vasoactive systems of the kidney. We injected rat kidneys with FGF-2 recombinant protein (r-FGF) or FGF-2 receptor antisense oligonucleotide (FGFR2-ASO) after bilateral ischemia, and evaluated the presence of iNOS, EPO and HO-1, in representation of hypoxia-induced proteins, as well as COX-2, renin, kallikrein, and B2KR, in representation of the vasoactive systems of the kidney. A reduction in iNOS, HO-1, EPO, renin, kallikrein, B2KR, and in renal damage was observed in animals treated with r-FGF. The opposite effect was found with FGF-2 receptor down-regulation. In contrast, COX-2 protein levels were higher in kidneys treated with r-FGF and lower in those that received FGFR2-ASO, as compared to saline treated kidneys. These results suggest that the protective role of FGF-2 in the pathogenesis of ARF induced by I/R is a complex process, through which a differential regulation of metabolic pathways takes place.


The dynamic interplay between perceived true self-knowledge and decision satisfaction.
The present research used multiple methods to examine the hypothesis that perceived true self-knowledge and decision satisfaction are inextricably linked together by a widely held "true-self-as-guide" lay theory of decision making. Consistent with this proposition, Study 1 found that participants rated using the true self as a guide as more important for achieving personal satisfaction than a variety of other potential decision-making strategies. After establishing the prevalence of this lay theory, the remaining studies then focused on examining the proposed consequent relationship between perceived true self-knowledge and decision satisfaction. Consistent with hypotheses, 2 cross-sectional correlational studies (Studies 2 and 3) found a positive relationship between perceived true self-knowledge and decision satisfaction for different types of major decisions. Study 4 used daily diary methods to demonstrate that fluctuations in perceived true self-knowledge reliably covary with fluctuations in decision satisfaction. Finally, 2 studies directly examined the causal direction of this relationship through experimental manipulation and revealed that the relationship is truly bidirectional. More specifically, Study 5 showed that manipulating perceived knowledge of the true self (but not other self-concepts) directly affects decision satisfaction. Study 6 showed that this effect also works in reverse by manipulating feelings of decision satisfaction, which directly affected perceived knowledge of the true self (but not other self-concepts). Taken together, these studies suggest that people believe the true self should be used as a guide when making major life decisions and that this belief has observable consequences for the self and decision making.


Screening for risk of cardiovascular disease among officer grade bank employees of Gulbarga city.
The risk of cardiovascular disease was assessed among officer grade bank employees of Gulbarga city, as they face a large of amount of work related stress. (1) To assess the risk of cardiovascular disease among the study group. (2) To propose a similar population based heart disease screening strategy for other groups. Out of the 242 officers in 26 banks in Gulbarga city (nationalized and private), 59 officers were willing to be a part of the study. This population was initially screened by a self-assessment scale, consisting of 10 questions relating to past history, family history, and lifestyle practices. Scoring system was used for the analysis. The initial part of this cross-sectional study was conducted during April 2006. Forty nine officers who scored ≥3 were recruited for preliminary assessment, which consists of physical examination, Electrocardiogram (ECG) and some invasive investigations (fasting blood sugar and cholesterol). Those found at further risk, were recruited for detailed assessment. 15 officers who qualified were screened for specific cardiac markers using advanced investigations Lipoprotein (Lp) a, homocysteine, C reactive protein (CRP), lipid profile measurements, Treadmill test (TMT) / Echocardiogram (ECHO), and Glucose tolerance test (GTT). All the five officers who were found at the highest level of risk were referred to the tertiary health care centre. Microsoft excel was used to compute the frequencies and percentages. Among the 59 employees examined in the study, 49 were found to be at risk for cardiovascular diseases (comprising ~83% of the assessed population) and thus qualified to the second round of assessment. Only 31 officers underwent the second round of assessment, out of whom 15 (48.4%) were found to be at higher risk and thus were subjected to the third round. Only five officers (of the 15) underwent the third round of assessment and all were found to be utmost at risk for CVDs and were duly referred to a tertiary health care centre. The study shows the application of a risk assessment model, towards predicting the risk for cardiovascular diseases among a group of high risk population. Similar models could be used for the risk assessment of other population groups.


How reactants polarization can be used to change and unravel chemical reactivity.
This article presents theoretical methods for the description of the directional effect of reactant rotation on the reactivity of atom-diatom systems and suggests an experiment that could be used to test theoretical predictions. The theory can be used in conjunction with both quantum reactive scattering and quasiclassical trajectory calculations, and is stated in general terms, which allows it to deal with arbitrary reactant polarizations. The illustrative results obtained for the benchmark H + D2 reaction are also presented and show that under experimentally achievable conditions one can largely control reactive cross sections and product state distributions, while at the same time gaining valuable and at times surprising information on the reaction mechanism.


Photopolarimeter based on two gratings recorded in thin organic films.
A photopolarimeter based on two different kinds of diffraction gratings (a two-grating photopolarimeter) has been developed for real-time measurements of the four elements of the Stokes vector. The main elements of the device are a pure polarization grating and an ordinary transmission grating, both recorded by means of holographic techniques in thin films of organic materials. The first one consists of a diffraction grating recorded by two interfering opposite circularly polarized beams in a Langmuir-Blodgett film of an azo-compound material. The second component is a grating recorded by two interfering parallel circularly polarized beams in a thin film of a photosensitive polymer. Both gratings offer long time stability and good diffraction efficiency. Four photodiodes collect the first-order diffracted beams from these gratings, the output signals of which are read through an analog-to-digital converter by a PC. The optical alignment of the device is easy and the calibration is realized in a one-step procedure.


High-extinction-ratio micro polarizing beam splitter for short wavelength optical storage applications.
A surface-micromachined high-extinction-ratio polarizing beam splitter (PBS) using low absorptive silicon nitride layers for blue wavelength applications are demonstrated. The micro polarizing beam splitter consists of novel stack of two silicon nitride layers separated by an air gap. A PBS optimization model is established to achieve both high extinction-ratio and adequate process margin. The polarization extinction ratios of 25 dB for the reflected light and 15 dB for the transmitted light were experimentally achieved at lambda=405 nm. The fabrication of the PBS is compatible with other micro diffractive elements to build a micro optical bench, thus, feasible for short wavelength optical storage applications.


Reduced-Intensity Transplantation for Lymphomas Using Haploidentical Related Donors Versus HLA-Matched Sibling Donors: A Center for International Blood and Marrow Transplant Research Analysis.
Related donor haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplantation cyclophosphamide (PT-Cy) is increasingly used in patients lacking HLA-matched sibling donors (MSD). We compared outcomes after Haplo-HCT using PT-Cy with MSD-HCT in patients with lymphoma, using the Center for International Blood and Marrow Transplant Research registry. We evaluated 987 adult patients undergoing either Haplo-HCT (n = 180) or MSD-HCT (n = 807) following reduced-intensity conditioning regimens. The haploidentical group received graft-versus-host disease (GVHD) prophylaxis with PT-Cy with or without a calcineurin inhibitor and mycophenolate. The MSD group received calcineurin inhibitor-based GVHD prophylaxis. Median follow-up of survivors was 3 years. The 28-day neutrophil recovery was similar in the two groups (95% v 97%; P = .31). The 28-day platelet recovery was delayed in the haploidentical group compared with the MSD group (63% v 91%; P = .001). Cumulative incidence of grade II to IV acute GVHD at day 100 was similar between the two groups (27% v 25%; P = .84). Cumulative incidence of chronic GVHD at 1 year was significantly lower after Haplo-HCT (12% v 45%; P < .001), and this benefit was confirmed on multivariate analysis (relative risk, 0.21; 95% CI, 0.14 to 0.31; P < .001). For Haplo-HCT v MSD-HCT, 3-year rates of nonrelapse mortality (15% v 13%; P = .41), relapse/progression (37% v 40%; P = .51), progression-free survival (48% v 48%; P = .96), and overall survival (61% v 62%; P = .82) were similar. Multivariate analysis showed no significant difference between Haplo-HCT and MSD-HCT in terms of nonrelapse mortality (P = .06), progression/relapse (P = .10), progression-free survival (P = .83), and overall survival (P = .34). Haplo-HCT with PT-Cy provides survival outcomes comparable to MSD-HCT, with a significantly lower risk of chronic GVHD.


Variations in Multiple Syndromic Deafness Genes Mimic Non-syndromic Hearing Loss.
The genetics of both syndromic (SHL) and non-syndromic hearing loss (NSHL) is characterized by a high degree of genetic heterogeneity. We analyzed whole exome sequencing data of 102 unrelated probands with apparently NSHL without a causative variant in known NSHL genes. We detected five causative variants in different SHL genes (SOX10, MITF, PTPN11, CHD7, and KMT2D) in five (4.9%) probands. Clinical re-evaluation of these probands shows that some of them have subtle syndromic findings, while none of them meets clinical criteria for the diagnosis of the associated syndrome (Waardenburg (SOX10 and MITF), Kallmann (CHD7 and SOX10), Noonan/LEOPARD (PTPN11), CHARGE (CHD7), or Kabuki (KMT2D). This study demonstrates that individuals who are evaluated for NSHL can have pathogenic variants in SHL genes that are not usually considered for etiologic studies.


In vitro susceptibility of Plasmodium falciparum to chloroquine, amodiaquine, quinine, mefloquine, and sulfadoxine/pyrimethamine in Equatorial Guinea.
Between March 1990 and June 1992, a study was carried out in Equatorial Guinea on the in vitro response of Plasmodium falciparum to different antimalarial drugs. Field work for the study was conducted both in the country's island region as well as on the mainland, and resistant isolates were found to exhibit interregional differences. On the island of Bioko, 204 tests were performed with 16% (11 of 69) resistant to chloroquine, 9% (4 of 46) resistant to quinine, 14% (6 of 43) resistant to a combination of sulfadoxine/pyrimethamine, and 6.5% (3 of 46) resistant to amodiaquine. In the mainland area of Bata, the same antimalarial drugs and mefloquine were tested with the following results: 9% (5 of 58) resistant to chloroquine; 2% (1 of 58) resistant to amodiaquine, and 3% (2 of 58) resistant to a combination of sulfadoxine/pyrimethamine. No isolates resistant to quinine or mefloquine were found. Effective concentrations (EC50, EC90, and EC99) and regression lines (log dose/response) for each antimalarial drug were calculated to establish a surveillance system for antimalarial drug chemosensitivity in Equatorial Guinea. Finally, 12 isolates from 12 patients previously treated with chloroquine were studied to compare both tests (in vivo-in vitro) and obtain a correlation between the RII and RIII types of in vivo and in vitro resistances. No correlation for the RI type was found between the two methods.


Use of venous-thrombotic-embolic prophylaxis in patients undergoing surgery for renal tumors: a questionnaire survey in the Nordic countries (The NORENCA-2 study).
To examine the variation in venous thromboembolism prophylactic treatment (VTEP) among renal cancer patients undergoing surgery. An Internet-based questionnaire on renal tumor management before and after surgery was mailed to all Nordic departments of urology. The questions focused on the use of VTEP and were subdivided into different surgical modalities. Questionnaires were mailed to 91 institutions (response rate 53%). None of the centers used VTEP before surgery, unless the patient had a vena caval tumor thrombus. Overall, the VTEP utilized during hospitalization for patients undergoing renal surgery included early mobilization (45%), compression stockings (52%) and low-molecular-weight heparin (89%). In patients undergoing open radical Nx, 80% of institutions used VTEP during their hospitalization (23% compression stockings and 94% low-molecular-weight heparin). After leaving the hospital, the proportion and type of VTEP received varied considerably across institutions. The most common interval, used in 60% of the institutions, was for a period of 4 weeks. The restriction to the Nordic countries was a limitation and, therefore, may not reflect the practice patterns elsewhere. It is a survey study and, therefore, cannot measure the behaviors of those institutions that did not participate. We found variation in the type and duration of VTEP use for each type of local intervention for renal cancer. These widely disparate variations in care strongly argue for the establishment of national and international guidelines regarding VTEP in renal surgery.


NIDDM genes in mice: deleterious synergism by both parental genomes contributes to diabetogenic thresholds.
We used mouse genetics to model how polygenic thresholds for the transition from impaired glucose tolerance (IGT) to NIDDM are reached. NON/Lt and NZO/Hl are inbred mouse strains selected for IGT and polygenic obesity, respectively. Their F1 male progeny consistently developed NIDDM. Genetic analysis of F2 males from both cross directions identified an NON-derived diabetogenic locus, Nidd 1, on chromosome (Chr) 4 near the leptin receptor. This locus was associated with reduced plasma insulin, increased non-fasted blood glucose, and lower body weight. Another NON-derived diabetogenic locus on Chr 18 (Nidd2) that controls blood glucose was identified. An NZO-derived diabetogenic region on Chr 11 (Nidd3), possibly comprising two separate loci, reduced ability to sustain elevated plasma insulin and significantly reduced weight gain over time. Thus, the diabetogenic synergism between genetic loci from strains separately exhibiting subthreshold defects perturbing glucose homeostasis underscores the likely complexity of the inheritance of obesity-associated forms of NIDDM in humans.


Regulation of alpha- and beta-hemolysins by the sar locus of Staphylococcus aureus.
We recently identified a locus on the Staphylococcus aureus chromosome, designated sar, for staphylococcal accessory regulator, that is involved in the global regulation of extracellular and cell wall-associated proteins. Previous phenotypic and Southern blot analyses with Tn917 and agr probes indicated that this locus is distinct from agr, a previously described global regulator of exoproteins in S. aureus. To understand the mode of regulatory control of exoprotein synthesis by the sar locus, the sar genotype was transduced from the original sar mutant 11D2 into two prototypic S. aureus strains, RN6390 and RN450, with well-defined genetic backgrounds. An analysis of extracellular protein profiles by use of silver-stained sodium dodecyl sulfate gels revealed alterations in the pattern of exoprotein production in the late log-early stationary phase in the sar mutants in comparison with the corresponding parents. In addition, most of the phenotypic changes that occurred in the conversion from the sar+ genotype to the sar genotype in mutant 11D2 were also found in these mutants. Northern (RNA) blot analyses of two exoprotein transcripts (alpha- and beta-hemolysins) from strain RN6390 and its corresponding sar mutant revealed downregulation of these transcripts in the mutant. Serial studies of these hemolysin transcripts at various growth intervals demonstrated that the transcriptional regulation of the hemolysin genes by the sar locus began during the log phase and continued into the postexponential phase. These data suggested that the sar locus probably regulates exoprotein genes at the transcriptional level. This mode of regulation is similar to that of exoprotein target gene transcription by agr.


Active cortical networks promote shunting fast synaptic inhibition in vivo.
Fast synaptic inhibition determines neuronal response properties in the mammalian brain and is mediated by chloride-permeable ionotropic GABA-A receptors (GABAARs). Despite their fundamental role, it is still not known how GABAARs signal in the intact brain. Here, we use in vivo gramicidin recordings to investigate synaptic GABAAR signaling in mouse cortical pyramidal neurons under conditions that preserve native transmembrane chloride gradients. In anesthetized cortex, synaptic GABAARs exert classic hyperpolarizing effects. In contrast, GABAAR-mediated synaptic signaling in awake cortex is found to be predominantly shunting. This is due to more depolarized GABAAR equilibrium potentials (EGABAAR), which are shown to result from the high levels of synaptic activity that characterize awake cortical networks. Synaptic EGABAAR observed in awake cortex facilitates the desynchronizing effects of inhibitory inputs upon local networks, which increases the flexibility of spiking responses to external inputs. Our findings therefore suggest that GABAAR signaling adapts to optimize cortical functions.


Effect of incident light wavelength and corneal edema on light scattering and penetration: laboratory study of human corneas.
The outcome of ultrashort pulse laser surgery of the cornea is strongly influenced by the light scattering properties of the tissue, for which little data are available. The purpose of the present study is to provide quantitative values for light scattering and its relation to the degree of edema. An experimental optical measuring setup based on confocal geometry was used to measure the unscattered and scattered fractions of light transmitted by eye bank corneas presenting various degrees of edema. From these measurements, the effective light penetration depth in the cornea was calculated as a function of wavelength. Corneal transparency depends on the pathological state of the cornea and on wavelength. It may be predicted as a function of corneal thickness, ie, the degree of edema. In healthy and edematous cornea, the percentage of scattered light decreases with increasing wavelength. The total penetration depths at the wavelengths of ~1050 nm (which is used in typical clinical systems) and 1650 nm (which is recommended for future devices) are comparable; however, the former is limited by scattering, which degrades the laser beam quality, whereas the latter is only limited by optical absorption, which may be compensated for. The use of longer wavelengths should help improve the surgical outcome in ultrashort pulse laser surgery of the cornea when working on pathological tissue. A wavelength of approximately 1650 nm appears to be a good compromise, as it allows for reduced light scattering while keeping optical absorption reasonably low.


TopHap: Rapid inference of key phylogenetic structures from common haplotypes in large genome collections with limited diversity.
Building reliable phylogenies from very large collections of sequences with a limited number of phylogenetically informative sites is challenging because sequencing errors and recurrent/backward mutations interfere with the phylogenetic signal, confounding true evolutionary relationships. Massive global efforts of sequencing genomes and reconstructing the phylogeny of SARS-CoV-2 strains exemplify these difficulties since there are only hundreds of phylogenetically informative sites and millions of genomes. For such datasets, we set out to develop a method for building the phylogenetic tree of genomic haplotypes consisting of positions harboring common variants to improve the signal-to-noise ratio for more accurate phylogenetic inference of resolvable phylogenetic features. We present the TopHap approach that determines spatiotemporally common haplotypes of common variants and builds their phylogeny at a fraction of the computational time of traditional methods. To assess topological robustness, we develop a bootstrap resampling strategy that resamples genomes spatiotemporally. The application of TopHap to build a phylogeny of 68,057 genomes (68KG) produced an evolutionary tree of major SARS-CoV-2 haplotypes. This phylogeny is concordant with the mutation tree inferred using the co-occurrence pattern of mutations and recovers key phylogenetic relationships from more traditional analyses. We also evaluated alternative roots of the SARS-CoV-2 phylogeny and found that the earliest sampled genomes in 2019 likely evolved by four mutations of the most recent common ancestor of all SARS-CoV-2 genomes. An application of TopHap to more than 1 million genomes reconstructed the most comprehensive evolutionary relationships of major variants, which confirmed the 68KG phylogeny and provided evolutionary origins of major variants of concern. TopHap is available on the web at https://github.com/SayakaMiura/TopHap . firstname.lastname@example.com.


Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading.
Considerable difficulties persist amongst pathologists in agreeing on the presence and severity of gastric atrophy. An international group of pathologists pursued the following aims: (i) to generate an acceptable definition and a simple reproducible classification of gastric atrophy; and (ii) to develop guidelines for the recognition of atrophy useful for increasing agreement among observers. After redefining atrophy as the 'loss of appropriate glands' and examining histological samples from different gastric compartments, three categories were identified: (i) negative; (ii) indefinite; (iii) atrophy, with and without intestinalization. Atrophy was graded on a three-level scale. Interobserver reproducibility of the classification was tested by kappa statistics (general and weighted) in a series of 48 cases. The medians of the general agreement and weighted kappa values were 0.78 and 0.73, respectively. The weighted kappa coefficients, obtained by cross-tabulating the evaluation of each pathologist against all others, were, with only one exception, > 0.4 (moderate to excellent agreement). By using the definition of atrophy as the loss of appropriate glands and distinguishing the two main morphological entities of metaplastic and non-metaplastic types, a high level of agreement was achieved by a group of gastrointestinal pathologists trained in different cultural contexts.


Genomic and proteomic approaches highlight phagocytosis of living and apoptotic human cells by the parasite Entamoeba histolytica.
Phagocytosis plays a major role during the invasive process of the human intestine by the pathogenic amoeba E. histolytica. This parasite is the etiologic agent causing amoebic dysentery, a worldwide disease causing 50 million of clinical cases leading to about 100,000 deaths annually. The invasive process is characterized by a local acute inflammation and the destruction of the intestinal tissue at the invasion site. The recent sequencing of the E. histolytica genome has opened the way to large-scale approaches to study parasite virulence such as processes involved in human cell phagocytosis. In particular, two different studies have recently described the phagosome proteome, providing new insights into the process of phagocytosis by this pathogenic protozoan. It has been previously described that E. histolytica induces apoptosis and phagocytosis of the human target cells. Induction of apoptosis by the trophozoites is thought to be involved in the close regulation of the inflammatory response occurring during infection. Little is known about the molecular mechanisms responsible for induction of apoptosis or in the recognition of apoptotic cells by E. histolytica. In this review, we comment on the recent data we obtained after isolation of the early phagosomes and the identification of its associated proteins. We focus on the surface molecules potentially involved in human cell recognition. In particular, we propose several parasite molecules, potentially involved in the induction of apoptosis and/or the phagocytosis of human apoptotic cells.


An assessment of the subjectivity of sperm scoring.
Current histological investigation of vaginal swabs after alleged sexual assault includes the scoring of spermatozoa (0, + to ++++) and the recording of visible tails. It is a method that is universally employed. Despite this method being used for 40 years, there has never been a study investigating its suitability for forensic science. Here, we investigate the reproducibility and subjectivity of sperm scoring among different investigators. Dilutions of seminal fluid were randomly distributed onto 20 slides, stained with haematoxylin/eosin and assessed by 37 investigators, over 2 years. Slides were assessed for levels of spermatozoa and the presence of tails. Each slide was scored by a minimum of 25 investigators. On no slide was there a consensus between all scores. Standard deviation remained below 1, but relative standard deviation (RSD) ranged from 6 to 105% in a positive correlation as the average score decreased. Spermatozoa were not observed 56 times (9.6%) and 27 investigators (73%) did not observe spermatozoa on at least one slide. Spermatozoa with tails were observed on every slide by at least 10 examiners, but as the average score of the slide decreased, so did the observation of tails. The current sperm scoring method is highly subjective with a particularly high %RSD in slides with low overall sperm counts. Moreover, the recording of tails does not add value to the current technique of sperm scoring. Further research might improve the objectivity of sperm scoring and the reliability of recording of tails.


Charge separation and charge delocalization identified in long-living states of photoexcited DNA.
Base stacking in DNA is related to long-living excited states whose molecular nature is still under debate. To elucidate the molecular background we study well-defined oligonucleotides with natural bases, which allow selective UV excitation of one single base in the strand. IR probing in the picosecond regime enables us to dissect the contribution of different single bases to the excited state. All investigated oligonucleotides show long-living states on the 100-ps time scale, which are not observable in a mixture of single bases. The fraction of these states is well correlated with the stacking probabilities and reaches values up to 0.4. The long-living states show characteristic absorbance bands that can be assigned to charge-transfer states by comparing them to marker bands of radical cation and anion spectra. The charge separation is directed by the redox potential of the involved bases and thus controlled by the sequence. The spatial dimension of this charge separation was investigated in longer oligonucleotides, where bridging sequences separate the excited base from a sensor base with a characteristic marker band. After excitation we observe a bleach of all involved bases. The contribution of the sensor base is observable even if the bridge is composed of several bases. This result can be explained by a charge delocalization along a well-stacked domain in the strand. The presence of charged radicals in DNA strands after light absorption may cause reactions--oxidative or reductive damage--currently not considered in DNA photochemistry.


Use of alpha-blockers and the risk of hip/femur fractures.
To study the association between use of alpha-blockers and risk of hip/femur fractures. Population-based case-control study. General Practice Research Database. Cases were defined as men, aged 40 years and older with a first diagnosis for hip/femur fracture. Controls were matched 1 : 1 on gender, year of birth and general practitioner-practice. In all, 4571 cases and an equal number of controls were identified. Current use of alpha-blockers (prazosin, doxazosin, indoramin, terazosin, alfuzosin and tamsulosin) was compared with non-use of alpha-blockers. Current use of alpha-blockers on the index date was associated with an increased risk of hip/femur fracture [adjusted odds ratio (OR) 1.9, 95% confidence interval (CI): 1.1-3.0] in the overall analysis. The effect was particularly strong for first prescriptions within a treatment episode (adjusted OR 5.1, 95% CI: 1.0-31.7) and during the first month of treatment (adjusted OR 4.1, 95% CI: 0.7-23.9). Stratification according to indication of use showed that current use of alpha-blockers was not associated with hip/femur fracture in men with a diagnosis of benign prostatic hyperplasia (adjusted OR 1.0, 95% CI: 0.4-2.5), but was associated in men who used alpha-blockers for cardiovascular disease (adjusted OR 2.8, 95% CI: 1.4-5.4). Current use of alpha-blockers was associated with an increased risk of hip/femur fracture and with the start of a new treatment episode. The effect seemed to be confined to patients who used alpha-blockers for cardiovascular disease. Caution with respect to first-dose effects related to the initiation of a new episode of alpha-blocker treatment is advised.


Peptide-independent stabilization of MHC class I molecules breaches cellular quality control.
The intracellular trafficking of major histocompatibility complex class I (MHC-I) proteins is directed by three quality control mechanisms that test for their structural integrity, which is correlated to the binding of high-affinity antigenic peptide ligands. To investigate which molecular features of MHC-I these quality control mechanisms detect, we have followed the hypothesis that suboptimally loaded MHC-I molecules are characterized by their conformational mobility in the F-pocket region of the peptide-binding site. We have created a novel variant of an MHC-I protein, K(b)-Y84C, in which two α-helices in this region are linked by a disulfide bond that mimics the conformational and dynamic effects of bound high-affinity peptide. K(b)-Y84C shows a remarkable increase in the binding affinity to its light chain, beta-2 microglobulin (β2m), and bypasses all three cellular quality control steps. Our data demonstrate (1) that coupling between peptide and β2m binding to the MHC-I heavy chain is mediated by conformational dynamics; (2) that the folded conformation of MHC-I, supported by β2m, plays a decisive role in passing the ER-to-cell-surface transport quality controls; and (3) that β2m association is also tested by the cell surface quality control that leads to MHC-I endocytosis.


Inbreeding depression in a critically endangered carnivore.
Harmful effects arising from matings between relatives (inbreeding) is a long-standing observation that is well founded in theory. Empirical evidence for inbreeding depression in natural populations is however rare because of the challenges of assembling pedigrees supplemented with fitness traits. We examined the occurrence of inbreeding and subsequent inbreeding depression using a unique data set containing a genetically verified pedigree with individual fitness traits for a critically endangered arctic fox (Vulpes lagopus) population. The study covered nine years and was comprised of 33 litters with a total of 205 individuals. We recorded that the present population was founded by only five individuals. Over the study period, the population exhibited a tenfold increase in average inbreeding coefficient with a final level corresponding to half-sib matings. Inbreeding mainly occurred between cousins, but we also observed two cases of full-sib matings. The pedigree data demonstrated clear evidence of inbreeding depression on traditional fitness traits where inbred individuals displayed reduced survival and reproduction. Fitness traits were however differently affected by the fluctuating resource abundande. Inbred individuals born at low-quality years displayed reduced first-year survival, while inbred individuals born at high-quality years were less likely to reproduce. The documentation of inbreeding depression in fundamental fitness traits suggests that inbreeding depression can limit population recovery. Introducing new genetic material to promote a genetic rescue effect may thus be necessary for population long-term persistence.


Rubber contact mechanics: adhesion, friction and leakage of seals.
We study the adhesion, friction and leak rate of seals for four different elastomers: Acrylonitrile Butadiene Rubber (NBR), Ethylene Propylene Diene (EPDM), Polyepichlorohydrin (GECO) and Polydimethylsiloxane (PDMS). Adhesion between smooth clean glass balls and all the elastomers is studied both in the dry state and in water. In water, adhesion is observed for the NBR and PDMS elastomers, but not for the EPDM and GECO elastomers, which we attribute to the differences in surface energy and dewetting. The leakage of water is studied with rubber square-ring seals squeezed against sandblasted glass surfaces. Here we observe a strongly non-linear dependence of the leak rate on the water pressure ΔP for the elastomers exhibiting adhesion in water, while the leak rate depends nearly linearly on ΔP for the other elastomers. We attribute the non-linearity to some adhesion-related phenomena, such as dewetting or the (time-dependent) formation of gas bubbles, which blocks fluid flow channels. Finally, rubber friction is studied at low sliding speeds using smooth glass and sandblasted glass as substrates, both in the dry state and in water. The measured friction coefficients are compared to theory, and the origin of the frictional shear stress acting in the area of real contact is discussed. The NBR rubber, which exhibits the strongest adhesion both in the dry state and in water, also shows the highest friction both in the dry state and in water.


Two Distinct Patterns of Clostridium difficile Diversity Across Europe Indicating Contrasting Routes of Spread.
Rates of Clostridium difficile infection vary widely across Europe, as do prevalent ribotypes. The extent of Europe-wide diversity within each ribotype, however, is unknown. Inpatient diarrheal fecal samples submitted on a single day in summer and winter (2012-2013) to laboratories in 482 European hospitals were cultured for C. difficile, and isolates the 10 most prevalent ribotypes were whole-genome sequenced. Within each ribotype, country-based sequence clustering was assessed using the ratio of the median number of single-nucleotide polymorphisms between isolates within versus across different countries, using permutation tests. Time-scaled Bayesian phylogenies were used to reconstruct the historical location of each lineage. Sequenced isolates (n = 624) were from 19 countries. Five ribotypes had within-country clustering: ribotype 356, only in Italy; ribotype 018, predominantly in Italy; ribotype 176, with distinct Czech and German clades; ribotype 001/072, including distinct German, Slovakian, and Spanish clades; and ribotype 027, with multiple predominantly country-specific clades including in Hungary, Italy, Germany, Romania, and Poland. By contrast, we found no within-country clustering for ribotypes 078, 015, 002, 014, and 020, consistent with a Europe-wide distribution. Fluoroquinolone resistance was significantly more common in within-country clustered ribotypes (P = .009). Fluoroquinolone-resistant isolates were also more tightly clustered geographically with a median (interquartile range) of 43 (0-213) miles between each isolate and the most closely genetically related isolate, versus 421 (204-680) miles in nonresistant pairs (P < .001). Two distinct patterns of C. difficile ribotype spread were observed, consistent with either predominantly healthcare-associated acquisition or Europe-wide dissemination via other routes/sources, for example, the food chain.


Chronic pelvic abscedation after completion proctectomy in a rectal stump insufficiency; treatment with gracilis muscle flap following vacuum assisted closure therapy.
Presacral abscess formation due to rectal stump insufficiency following Hartmann procedure is very rare complication. If the abscess cavity is large, it might delay the reversal of the stoma and will probably result in a devastating future functioning of the neorectum. Moreover, very invasive treatments will be required in order to prevent severe septic complications. We present the case of a 58-year-old man with a past history of Hartmann procedure for a low rectal carcinoma who presented with rectal stump insufficiency and a large presacral abscess. Following extensive debridement and rectal stump resection, a vacuum-assisted closure (VAC) system was applied to the large abscess cavity to facilitate gracilis muscle flap reconstruction and to optimize wound healing. The satisfactory results showed in the present report led us to favor a combination of VAC therapy and a gracilis muscle flap in intrapelvic and perineal reconstruction in the case of large defects associated with high risks of septic complications.