Variations in Host Preference among and within Populations of Heterodera trifolii and Related Species.
Seven populations of Heterodera trifolii from Arkansas, Kentucky, Pennsylvania, and Australia plus 3 or 4 single-cyst isolates (SCI) from each population were tested for reproduction on seven species of plants to compare the host preferences among and within populations. Common lespedeza, Kummerowia striata cv. Kobe, was a good host for all populations and isolates. Therefore, a plant was considered to be a host if the number of females produced on it was 10% or more of the number on Kobe. All seven populations reproduced on Trifolium repens and T. pratense. None reproduced on Beta vulgaris or Glycine max. One single-cyst isolate from the Australian population produced a few females on T. pratense. The Australian population maintained on carnation, Dianthus caryophyllus, produced females on carnation but not on curly dock, Rumex crispus. However, its subpopulation maintained on T. repens produced females on R. crispus but not on carnation. Four of the other six populations produced females on R. crispus, and four produced females on carnation. Differences in host range were observed among seven of the mother populations and their SCI, and among isolates within each population. Five host range patterns were found in populations and SCI of H. trifolii. Significant quantitative differences occurred among populations in the numbers of females on most hosts, between isolates and their original populations, and among isolates from the same population. SCI selected from white clover produced fewer females on a series of test hosts and had host ranges the same as or narrower than those of the original populations. However, SCI selected from Kobe lespedeza had more females on some hosts and had host ranges the same as or wider than those of the original populations. The host ranges of all populations and SCI of H. trifolii were different from those of populations and SCI of race 3 of H. glycines and H. lespedezae.


Moderate alcohol consumption increases cholesterol efflux mediated by ABCA1.
Moderate alcohol consumption increases HDL cholesterol, which is involved in reverse cholesterol transport (RCT). The aim of this study was to investigate the effect of moderate alcohol consumption on cholesterol efflux, using J774 mouse macrophages and Fu5AH cells, and on other parameters in the RCT pathway. Twenty-three healthy men (45-65 years) participated in a randomized, partially diet-controlled, crossover trial. They consumed four glasses of whisky (40 g of alcohol) or water daily for 17 days. After 17 days of whisky consumption, serum capacity to induce ABCA1-dependent cholesterol efflux from J774 mouse macrophages was increased by 17.5% (P = 0.027) compared with water consumption. Plasma capacity to induce cholesterol efflux from Fu5AH cells increased by 4.6% (P = 0.002). Prebeta-HDL, apolipoprotein A-I (apoA-I), and lipoprotein A-I:A-II also increased by 31.6, 6.2, and 5.7% (P < 0.05), respectively, after whisky consumption compared with water consumption. Changes of cAMP-stimulated cholesterol efflux correlated (r = 0.65, P < 0.05) with changes of apoA-I but not with changes of prebeta-HDL (r = 0.30, P = 0.18). Cholesterol efflux capacities from serum of lean men were higher than those from overweight men. In conclusion, this study shows that moderate alcohol consumption increases the capacity of serum to induce cholesterol efflux from J774 mouse macrophages, which may be mediated by ABCA1.


High-density lipoproteins retard the progression of atherosclerosis and favorably remodel lesions without suppressing indices of inflammation or oxidation.
Protective properties of high-density lipoproteins (HDL) may include reverse cholesterol transport and suppression of oxidation and inflammation. These were investigated in vivo, as were the effects of HDL on the characteristics of atherosclerotic lesions. Male apolipoprotein E knockout (apoE-/-) and apoE-/- mice expressing human apolipoprotein AI (hAI/apoE-/-) were studied up to 20 weeks after commencing a high-fat diet. Plasma HDL cholesterol was twice as high in hAI/apoE-/- mice. Over time, aortic root lesion area remained less in hAI/apoE-/- mice, although plaques became complex. In advanced lesions, plaque lipid was higher in apoE-/- mice, whereas plaque collagen and alpha actin were increased in hAI/apoE-/- mice. In nonlesional aorta, mRNA abundance for pro-inflammatory proteins (vascular cell adhesion molecule [VCAM]-1, intercellular adhesion molecule-1 [ICAM-1], monocyte chemoattractant protein-1 [MCP-1]) increased between 4 and 16 weeks in apoE-/- (but not wild-type) mice, and were not reduced by elevated HDL. Autoantibodies to malondialdehyde low-density lipoprotein (LDL) increased progressively in apoE-/- mice, with similar results in hAI/apoE-/- mice. HDL retarded plaque size progression despite greatly elevated plasma cholesterol. This effect was over a wide range of lesion severity. Expression of hAI reduced plaque lipid and increased the proportion of plaque occupied by collagen and smooth muscle cells, but did not affect indicators of inflammation or LDL oxidation.


Predicting invasion success in complex ecological networks.
A central and perhaps insurmountable challenge of invasion ecology is to predict which combinations of species and habitats most effectively promote and prevent biological invasions. Here, we integrate models of network structure and nonlinear population dynamics to search for potential generalities among trophic factors that may drive invasion success and failure. We simulate invasions where 100 different species attempt to invade 150 different food webs with 15-26 species and a wide range (0.06-0.32) of connectance. These simulations yield 11 438 invasion attempts by non-basal species, 47 per cent of which are successful. At the time of introduction, whether or not the invader is a generalist best predicts final invasion success; however, once the invader establishes itself, it is best distinguished from unsuccessful invaders by occupying a lower trophic position and being relatively invulnerable to predation. In general, variables that reflect the interaction between an invading species and its new community, such as generality and trophic position, best predict invasion success; however, for some trophic categories of invaders, fundamental species traits, such as having the centre of the feeding range low on the theoretical niche axis (for non-omnivorous and omnivorous herbivores), or the topology of the food web (for tertiary carnivores), best predict invasion success. Across all invasion scenarios, a discriminant analysis model predicted successful and failed invasions with 76.5 per cent accuracy for properties at the time of introduction or 100 per cent accuracy for properties at the time of establishment. More generally, our results suggest that tackling the challenge of predicting the properties of species and habitats that promote or inhibit invasions from food web perspective may aid ecologists in identifying rules that govern invasions in natural ecosystems.


Performance comparison of multi-label learning algorithms on clinical data for chronic diseases.
We are motivated by the issue of classifying diseases of chronically ill patients to assist physicians in their everyday work. Our goal is to provide a performance comparison of state-of-the-art multi-label learning algorithms for the analysis of multivariate sequential clinical data from medical records of patients affected by chronic diseases. As a matter of fact, the multi-label learning approach appears to be a good candidate for modeling overlapped medical conditions, specific to chronically ill patients. With the availability of such comparison study, the evaluation of new algorithms should be enhanced. According to the method, we choose a summary statistics approach for the processing of the sequential clinical data, so that the extracted features maintain an interpretable link to their corresponding medical records. The publicly available MIMIC-II dataset, which contains more than 19,000 patients with chronic diseases, is used in this study. For the comparison we selected the following multi-label algorithms: ML-kNN, AdaBoostMH, binary relevance, classifier chains, HOMER and RAkEL. Regarding the results, binary relevance approaches, despite their elementary design and their independence assumption concerning the chronic illnesses, perform optimally in most scenarios, in particular for the detection of relevant diseases. In addition, binary relevance approaches scale up to large dataset and are easy to learn. However, the RAkEL algorithm, despite its scalability problems when it is confronted to large dataset, performs well in the scenario which consists of the ranking of the labels according to the dominant disease of the patient.


Emerging technologies to measure neighborhood conditions in public health: implications for interventions and next steps.
Adverse neighborhood conditions play an important role beyond individual characteristics. There is increasing interest in identifying specific characteristics of the social and built environments adversely affecting health outcomes. Most research has assessed aspects of such exposures via self-reported instruments or census data. Potential threats in the local environment may be subject to short-term changes that can only be measured with more nimble technology. The advent of new technologies may offer new opportunities to obtain geospatial data about neighborhoods that may circumvent the limitations of traditional data sources. This overview describes the utility, validity and reliability of selected emerging technologies to measure neighborhood conditions for public health applications. It also describes next steps for future research and opportunities for interventions. The paper presents an overview of the literature on measurement of the built and social environment in public health (Google Street View, webcams, crowdsourcing, remote sensing, social media, unmanned aerial vehicles, and lifespace) and location-based interventions. Emerging technologies such as Google Street View, social media, drones, webcams, and crowdsourcing may serve as effective and inexpensive tools to measure the ever-changing environment. Georeferenced social media responses may help identify where to target intervention activities, but also to passively evaluate their effectiveness. Future studies should measure exposure across key time points during the life-course as part of the exposome paradigm and integrate various types of data sources to measure environmental contexts. By harnessing these technologies, public health research can not only monitor populations and the environment, but intervene using novel strategies to improve the public health.


Specific linkages among luteinizing hormone, follicle-stimulating hormone, and testosterone release in the peripheral blood and human spermatic vein: evidence for both positive (feed-forward) and negative (feedback) within-axis regulation.
We have investigated possible (negative) feedback and (positive) feed-forward activity within the human male gonadotropic axis by measuring serum concentrations of LH, FSH, and testosterone in blood sampled frequently and for a prolonged interval (every 20 min for 19 h) simultaneously from the peripheral circulation and the left spermatic vein. Cross-correlation analysis with time lag was used to evaluate relationships among serial serum LH, FSH, and/or testosterone concentrations over time (i.e. consistency or dissociation of trends in concentrations). Separately, Cluster analysis was applied to identify discrete LH, FSH, and testosterone pulses, which were cataloged for possible peak coincidence. The hypergeometric probability distribution was then used to test the null hypothesis that LH, FSH, and testosterone pulses are randomly associated. Cross-correlation analysis revealed: 1) peripheral blood LH and testosterone concentrations correlate positively at lags of 40-120 min with LH increases preceding testosterone increases, viz., feed-forward (P < 0.001); 2) LH and FSH concentrations in peripheral blood are positively correlated in simultaneous blood samples, as well as when FSH lags LH by 20 min (P < 0.01); 3) unexpectedly, LH and FSH concentrations in peripheral blood are inversely related at a lag of 80-100 min (P = 0.002) and 0.004, respectively) where LH lags FSH; 4) LH and testosterone concentrations in the spermatic vein show strongly positive correlations at lags of 80, 100, and 120 min (P = 0.002, 0.004, and 0.021, respectively); 5) spermatic vein testosterone concentrations correlate negatively with peripheral blood LH concentrations 20 or 40 min later (P = 0.012 and 0.05, respectively), which indicates autonegative feedback; and 6) in contrast, testosterone levels in the spermatic vein correlate negatively with FSH values in the periphery 100 and 120 min later (P < 0.01), indicating more delayed negative feedback of testosterone on serum FSH concentrations. Discrete pulse coincidence analysis disclosed: 1) a total of 30 testosterone pulses in the spermatic vein and 25 testosterone pulses in peripheral blood, with 28 LH and 29 FSH pulses in the periphery; 2) individual LH and FSH peak concordance was significantly nonrandom for FSH pulse maxima lagging LH pulse maxima by 20 min (P < 0.05 vs. randomness), with 6 observed coincidences vs. 2.9 +/- 1.5 (SD) expected; 3) peripheral LH pulses and spermatic vein testosterone pulses were strongly nonrandomly coupled at an 80-min lag, with 8 events observed vs. 3.0 +/- 1.5 events expected (P = 0.004); and 4) LH peaks in peripheral blood followed testosterone peaks in the spermatic vein by 40 min in a nonrandom manner, specifically, n = 11 observed vs. 3.0 +/- 1.5 expected (P < 0.001), indicating possible LH escape from testosterone's negative feedback. In summary, physiological regulation of the human male LH, FSH, and testosterone axis comprises multidirectional interactions, consisting of both (positive) feed-forward and (negative) feedback coupling. Based on a concept of network integration, we propose that age and other pathophysiological factors might modulate and/or disrupt these dynamic within-axis multihormonal linkages.


Roles of alpha and beta carbonic anhydrases of Helicobacter pylori in the urease-dependent response to acidity and in colonization of the murine gastric mucosa.
Carbon dioxide occupies a central position in the physiology of Helicobacter pylori owing to its capnophilic nature, the large amounts of carbon dioxide produced by urease-mediated urea hydrolysis, and the constant bicarbonate supply in the stomach. Carbonic anhydrases (CA) catalyze the interconversion of carbon dioxide and bicarbonate and are involved in functions such as CO(2) transport or trapping and pH homeostasis. H. pylori encodes a periplasmic alpha-CA (alpha-CA-HP) and a cytoplasmic beta-CA (beta-CA-HP). Single CA inactivation and double CA inactivation were obtained for five genetic backgrounds, indicating that H. pylori CA are not essential for growth in vitro. Bicarbonate-carbon dioxide exchange rates were measured by nuclear magnetic resonance spectroscopy using lysates of parental strains and CA mutants. Only the mutants defective in the alpha-CA-HP enzyme showed strongly reduced exchange rates. In H. pylori, urease activity is essential for acid resistance in the gastric environment. Urease activity measured using crude cell extracts was not modified by the absence of CA. With intact CA mutant cells incubated in acidic conditions (pH 2.2) in the presence of urea there was a delay in the increase in the pH of the incubation medium, a phenotype most pronounced in the absence of H. pylori alpha-CA. This correlated with a delay in acid activation of the urease as measured by slower ammonia production in whole cells. The role of CA in vivo was examined using the mouse model of infection with two mouse-adapted H. pylori strains, SS1 and X47-2AL. Compared to colonization by the wild-type strain, colonization by X47-2AL single and double CA mutants was strongly reduced. Colonization by SS1 CA mutants was not significantly different from colonization by wild-type strain SS1. However, when mice were infected by SS1 Delta(beta-CA-HP) or by a SS1 double CA mutant, the inflammation scores of the mouse gastric mucosa were strongly reduced. In conclusion, CA contribute to the urease-dependent response to acidity of H. pylori and are required for high-grade inflammation and efficient colonization by some strains.


Radiation-induced lymphoid tumors and radiation lethality are inhibited by combined treatment with small doses of zinc aspartate and WR 2721.
Combined small doses of zinc aspartate and WR 2721 provided additive protection against radiation lethality in mice. Survival obtained with a small dose of WR 2721 which was ineffective alone could be enhanced to 83% by combining the drug with zinc aspartate, which on its own also displayed no effect. The survival of 25% provided by a higher dose of WR 2721 was increased significantly by adding zinc aspartate. Additivity was also tested in a model of radiation carcinogenesis. For this purpose, lethality and occurrence of lymphoid tumors induced by fractionated total-body irradiation were studied in C57B1/6 mice treated with zinc aspartate and WR 2721. In order to reveal additive effects, both agents were used at sub-optimal dosages. In mice subjected to 5 daily exposures of 1.9 Gy, the combination of zinc aspartate and WR 2721 was effective and enhanced the survival to 83% as compared with 25% afforded by WR 2721 alone (p < 0.005). Similarly, histological assessment of organ involvement with lymphoma revealed that zinc aspartate and WR 2721 alone did not bring about a significant reduction of lymphoma incidence. On the other hand, the combined agents diminished organ involvement with lymphoma to 9.1% as against 90% in the controls (p < 0.0005) and 62.5% with WR 2721 alone (p < 0.025). Thus, combined treatment with zinc aspartate and WR 2721 also inhibited radiation-induced lymphoid tumors.


Front-line immunosuppressive treatment of acquired aplastic anemia.
In this article, front-line immunosuppressive therapy (IST) for acquired plastic anemia (AA) is illustrated and discussed. Also second-line and salvage options are briefly illustrated. First-line IST should consist of horse anti-thymocyte globulin (ATG) and CsA that has been shown to result in response rates between 60 and 80%. CsA should be given for 12 months until transfusion independence is achieved and then tapered very slowly in the presence of a CR. Patients with a partial response are usually continued on CsA. Tight monitoring of the blood count during CsA tapering is necessary to identify early loss of response. G-CSF 5 μg/kg/day s.c. in the first 30 days has been shown to reduce infections and hospitalization and to identify early responders, as those who achieve neutrophils count of0.5 × 10(9)/L by day +30. This schedule is recommended in the first month of therapy. Afterward, G-CSF can be considered in neutropenic febrile episodes. Patients not achieving transfusion independence after a first course of IST may be considered for second-line IST, or for an allogeneic hematopoietic SCT depending on patient age, ongoing infection, neutrophil count and transfusion requirements. Third-line IST is rarely given, but some options are discussed.


Generation of human induced pluripotent stem cells from urine samples.
Human induced pluripotent stem cells (iPSCs) have been generated with varied efficiencies from multiple tissues. Yet, acquiring donor cells is, in most instances, an invasive procedure that requires laborious isolation. Here we present a detailed protocol for generating human iPSCs from exfoliated renal epithelial cells present in urine. This method is advantageous in many circumstances, as the isolation of urinary cells is simple (30 ml of urine are sufficient), cost-effective and universal (can be applied to any age, gender and race). Moreover, the entire procedure is reasonably quick--around 2 weeks for the urinary cell culture and 3-4 weeks for the reprogramming--and the yield of iPSC colonies is generally high--up to 4% using retroviral delivery of exogenous factors. Urinary iPSCs (UiPSCs) also show excellent differentiation potential, and thus represent a good choice for producing pluripotent cells from normal individuals or patients with genetic diseases, including those affecting the kidney.


Policy interventions to promote healthy eating: a review of what works, what does not, and what is promising.
Unhealthy diets can lead to various diseases, which in turn can translate into a bigger burden for the state in the form of health services and lost production. Obesity alone has enormous costs and claims thousands of lives every year. Although diet quality in the European Union has improved across countries, it still falls well short of conformity with the World Health Organization dietary guidelines. In this review, we classify types of policy interventions addressing healthy eating and identify through a literature review what specific policy interventions are better suited to improve diets. Policy interventions are classified into two broad categories: information measures and measures targeting the market environment. Using this classification, we summarize a number of previous systematic reviews, academic papers, and institutional reports and draw some conclusions about their effectiveness. Of the information measures, policy interventions aimed at reducing or banning unhealthy food advertisements generally have had a weak positive effect on improving diets, while public information campaigns have been successful in raising awareness of unhealthy eating but have failed to translate the message into action. Nutritional labeling allows for informed choice. However, informed choice is not necessarily healthier; knowing or being able to read and interpret nutritional labeling on food purchased does not necessarily result in consumption of healthier foods. Interventions targeting the market environment, such as fiscal measures and nutrient, food, and diet standards, are rarer and generally more effective, though more intrusive. Overall, we conclude that measures to support informed choice have a mixed and limited record of success. On the other hand, measures to target the market environment are more intrusive but may be more effective.


Computational crystallization.
Crystallization is a key step in macromolecular structure determination by crystallography. While a robust theoretical treatment of the process is available, due to the complexity of the system, the experimental process is still largely one of trial and error. In this article, efforts in the field are discussed together with a theoretical underpinning using a solubility phase diagram. Prior knowledge has been used to develop tools that computationally predict the crystallization outcome and define mutational approaches that enhance the likelihood of crystallization. For the most part these tools are based on binary outcomes (crystal or no crystal), and the full information contained in an assembly of crystallization screening experiments is lost. The potential of this additional information is illustrated by examples where new biological knowledge can be obtained and where a target can be sub-categorized to predict which class of reagents provides the crystallization driving force. Computational analysis of crystallization requires complete and correctly formatted data. While massive crystallization screening efforts are under way, the data available from many of these studies are sparse. The potential for this data and the steps needed to realize this potential are discussed.


Urinary Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (uTWEAK) and Urinary Monocyte Chemo-attractant Protein-1 (uMCP-1): Promising Biomarkers of Lupus Nephritis Activity?
There is no single biomarker to detect lupus nephritis (LN) activity. Renal biopsy is still the gold standard method but it is invasive and mainly used in the initial assessment of the patients. Urinary tumor necrosis factor-like weak inducer of apoptosis (uTWEAK) and urinary monocyte chemo-attractant protein-1 (uMCP-1) can be secreted in the urine of active LN. The aim of the study is to assess the potential role of uTWEAK and uMCP-1 in lupus patients and to determine their correlation with disease activity. This is a case-control study conducted on a total of 114 subjects; 92 systemic lupus erythematosus (SLE) patients and 22 healthy volunteers. The patients were recruited from the rheumatology unit at the internal medicine department, Tanta University Hospital, Tanta, Egypt. The patients and controls were subjected to full history taking, complete clinical examination, routine laboratory tests, uTWEAK and uMCP-1 measurement, assessment of the disease activity using SLE Disease Activity Index (SLEDAI), and renal SLEDAI (rSLEDAI) scores. uTWEAK and uMCP-1 levels were higher in SLE with active nephritis group than those of other SLE groups and controls. There was a significant positive correlation between uTWEAK and uMCP-1 levels in lupus patients with proteinuria, anti-dsDNA, SLEDAI and r-SLEDAI and a negative correlation with C3 and C4. TWEAK showed a sensitivity of 80.43% and 100% and specificity of 50% and 100% in detecting lupus activity and LN activity, respectively. Furthermore, uMCP-1 showed a sensitivity of 82.6% and 100% and specificity of 50% and 100% in detecting lupus activity and LN activity, respectively. uTWEAK and uMCP-1 are new, easily obtained, accurate markers with high sensitivity and specificity in the detection of LN activity.


Association between parent-adolescent communication about sex-related topics and HIV testing, United States. 2006-2013.
Adolescents need information about sex-related topics in order to reduce risk behavior and engage in healthy sexual decision-making. Parents have the potential to be an important source of this information. Using the 2006-2010 and 2011-2013 National Survey of Family Growth, we examined associations between parent-adolescent communication before age 18 about sex-related topics and HIV testing among respondents aged 18-24 that ever had sexual intercourse (women = 3893; men = 3359). Analyses showed that for both men and women, discussing how to prevent HIV/AIDS and how to use a condom with a parent before age 18 were positively associated with HIV testing. Among women only, discussions about methods of birth control, where to get birth control, and STDs were positively associated with HIV testing. Developing strategies and interventions to facilitate parent-adolescent communication about sex-related topics, particularly HIV prevention and condom use, may be important to increase HIV testing among young women and men.


A Data-Driven Space-Time-Parameter Reduced-Order Model with Manifold Learning for Coupled Problems: Application to Deformable Capsules Flowing in Microchannels.
An innovative data-driven model-order reduction technique is proposed to model dilute micrometric or nanometric suspensions of microcapsules, i.e., microdrops protected in a thin hyperelastic membrane, which are used in Healthcare as innovative drug vehicles. We consider a microcapsule flowing in a similar-size microfluidic channel and vary systematically the governing parameter, namely the capillary number, ratio of the viscous to elastic forces, and the confinement ratio, ratio of the capsule to tube size. The resulting space-time-parameter problem is solved using two global POD reduced bases, determined in the offline stage for the space and parameter variables, respectively. A suitable low-order spatial reduced basis is then computed in the online stage for any new parameter instance. The time evolution of the capsule dynamics is achieved by identifying the nonlinear low-order manifold of the reduced variables; for that, a point cloud of reduced data is computed and a diffuse approximation method is used. Numerical comparisons between the full-order fluid-structure interaction model and the reduced-order one confirm both accuracy and stability of the reduction technique over the whole admissible parameter domain. We believe that such an approach can be applied to a broad range of coupled problems especially involving quasistatic models of structural mechanics.


Study protocol: home-based telehealth stroke care: a randomized trial for veterans.
Stroke is one of the most disabling and costly impairments of adulthood in the United States. Stroke patients clearly benefit from intensive inpatient care, but due to the high cost, there is considerable interest in implementing interventions to reduce hospital lengths of stay. Early discharge rehabilitation programs require coordinated, well-organized home-based rehabilitation, yet lack of sufficient information about the home setting impedes successful rehabilitation. This trial examines a multifaceted telerehabilitation (TR) intervention that uses telehealth technology to simultaneously evaluate the home environment, assess the patient's mobility skills, initiate rehabilitative treatment, prescribe exercises tailored for stroke patients and provide periodic goal oriented reassessment, feedback and encouragement. We describe an ongoing Phase II, 2-arm, 3-site randomized controlled trial (RCT) that determines primarily the effect of TR on physical function and secondarily the effect on disability, falls-related self-efficacy, and patient satisfaction. Fifty participants with a diagnosis of ischemic or hemorrhagic stroke will be randomly assigned to one of two groups: (a) TR; or (b) Usual Care. The TR intervention uses a combination of three videotaped visits and five telephone calls, an in-home messaging device, and additional telephonic contact as needed over a 3-month study period, to provide a progressive rehabilitative intervention with a treatment goal of safe functional mobility of the individual within an accessible home environment. Dependent variables will be measured at baseline, 3-, and 6-months and analyzed with a linear mixed-effects model across all time points. For patients recovering from stroke, the use of TR to provide home assessments and follow-up training in prescribed equipment has the potential to effectively supplement existing home health services, assist transition to home and increase efficiency. This may be particularly relevant when patients live in remote locations, as is the case for many veterans. Clinical Trials.gov Identifier: NCT00384748.


The 67gallium-transferrin pulmonary leak index in patients at risk for the acute respiratory distress syndrome.
To determine the occurrence and clinical importance of increased pulmonary microvascular permeability in patients at risk for acute respiratory distress syndrome (ARDS). Prospective, cohort study. Medical and surgical intensive care unit (ICU) and department of nuclear medicine of a university hospital. Thirteen consecutive patients at risk for ARDS with sepsis (n = 4), multiple trauma (n = 3), hemorrhagic pancreatitis (n = 5), and near-drowning (n = 1), admitted into the ICU. All patients were intubated and mechanically ventilated in the course of the study. None. The 67gallium-transferrin pulmonary leak index (PLI) (upper limit of normal in patients scheduled for major surgery 14.7 x 10(-3)/min) was measured within 24 hrs of admission. In addition, radiographic, gas exchange, and ventilatory variables allowing calculation of the Lung Injury Score, were obtained on the day of the PLI (day 0) and from days 1 to 7. Patients were followed until discharge or death in the ICU. No patient developed ARDS (Lung Injury Score of >2.5 in the absence of congestive heart failure) and all but four patients survived. The PLI (median [range]) was 18.5 (7.0 to 81.9) x 10(-3)/min and was supranormal in 8 of 13 patients (p < .001 vs. normal). The PLI correlated with the Simplified Acute Physiology Score (SAPS) II (r[s] = .79, p < .01) and was higher in nonsurvivors than in survivors (p < .05), with a tendency for a higher SAPS II in the nonsurvivors. On day 0, the chest radiographic score of alveolar abnormalities was 0 (0 to 4), indicating absence of radiographic abnormalities in most patients. Also, on day 0, the median PaO2/FIO2 ratio was 257 (range 119 to 460). The Lung Injury Score on day 0 was 1.0 (0 to 2.0), which is consistent with mild acute lung injury in all but one patient. In the course of time, the oxygenation ratio was lower and the Lung Injury Score was higher in nonsurvivors than in survivors, particularly for the Lung Injury Score on days 1 and 2. The PLI correlated directly with the Lung Injury Score on days 0 and 1. On day 0, the PLI correlated inversely with the oxygenation ratio. On the last evaluable day of the first ICU week, the PLI correlated directly with the Lung Injury Score and the positive end-expiratory pressure level. The duration of mechanical ventilation tended to be longer in patients with a supranormal PLI. In this small population, 61% of patients at risk for ARDS and with only mild respiratory changes exhibited increased microvascular permeability in the lungs at ICU admission. Increased permeability may be an early marker of acute lung injury and its clinical features, and may be associated with a relatively complicated respiratory course during the first week after admission, even in the absence of progression to ARDS. Finally, increased pulmonary microvascular permeability may be associated with severe underlying disease and ultimate mortality in the ICU.


Bronchoscopic management of patients with symptomatic airway stenosis and prognostic factors for survival.
Interventional bronchoscopy is effective in the management of patients with symptomatic airway obstruction for both malignant and benign conditions. The main aim of this study is to report our experience with emergency interventional bronchoscopy in patients with symptomatic airway obstruction and identify prognostic factors for survival. This is a retrospective observational study of patients undergoing emergency interventional bronchoscopy over a 4-year period. Survival times were analyzed separately for patients with benign and malignant airway obstruction by the Kaplan-Meier method. Between June 2009 and July 2013, 168 emergency interventional bronchoscopies were performed in 112 patients for airway obstruction. The median age was 63 years (range, 20 to 86), and 91 patients (54%) patients were female. Seventy-two cases (43%) had airway obstruction due to malignant disease. There were 3 in-hospital deaths (2.7%). Median survival of the study population was 5.6 months (range, 0 to 51) with a median follow-up of 7.3 months (range, 0 to 51). Median survival for patients with malignant airway obstruction was 3.5 months (range, 0 to 21), and 9.8 months (range, 0.1 to 51) for those with benign disease. Airway intervention facilitated palliative chemotherapy in 32 patients (44%) of those with malignant airway obstruction. At multivariate analysis in patients with malignant airway obstruction, presence of stridor (hazard ratio 1.919, 95% confidence interval: 1.082 to 3.404, p = 0.026) and not receiving postprocedure chemotherapy (hazard ratio 2.05, 95% confidence interval: 1.156 to 3.636, p = 0.014) were independent prognostic factors for death. Emergency interventional bronchoscopy for airway obstruction is safe, relieved symptoms, and facilitated palliative chemotherapy, which improved survival.


Thromboprophylaxis in Head and Neck Microvascular Reconstruction.
Head and neck patients undergoing microvascular reconstruction are at high risk for thromboembolism. While the prevention of thromboembolism has become an essential aspect of care, within the field of microsurgery, concern for anastomotic complications have hindered the creation of an accepted regimen. The aim of this review was to evaluate the risks and benefits of prophylactic agents for thromboprophylaxis. A literature search was conducted in MEDLINE, Cochrane Library, and PubMed/NCBI databases. Articles discussing thromboprophylaxis in otolaryngology, head and neck surgery, or microvascular reconstruction were considered in the review from the past 30 years. The majority of patients undergoing microvascular surgery have multiple risk factors for thrombus formation. Several consensus guidelines exist for the prophylaxis in patients who are critically ill, undergoing surgery, or with malignancy. Significant evidence supports the routine use of mechanical means, such as early mobilization and pneumatic compression along with subcutaneous heparin. Low-molecular-weight heparin is also frequently utilized, although results are largely divided. Data on aspirin remain equivocal. Studies on microvascular failure and flap loss have demonstrated little to no association with chemoprophylaxis. The evidence for postoperative thromboprophylaxis regimens in patients undergoing head and neck free tissue transfer is variable. Multiple studies have supported the use of unfractionated heparin or low-molecular-weight heparin. There appears to be an expert consensus for the combined use of mechanical prophylactic methods and chemical prophylaxis. Prospective randomized trials are required to validate the most effective combination of chemoprophylaxis agents.


Histamine-4 receptor antagonist JNJ7777120 inhibits pro-inflammatory microglia and prevents the progression of Parkinson-like pathology and behaviour in a rat model.
The activation of microglial cells is presumed to play a key role in the pathogenesis of Parkinson's disease (PD). The activity of microglia is regulated by the histamine-4 receptor (H4R), thus providing a novel target that may prevent the progression of PD. However, this putative mechanism has so far not been validated. In our previous study, we found that mRNA expression of H4R was upregulated in PD patients. In the present study, we validated this possible mechanism using the rotenone-induced PD rat model, in which mRNA expression levels of H4R-, and microglial markers were significantly increased in the ventral midbrain. Inhibition of H4R in rotenone-induced PD rat model by infusion of the specific H4R antagonist JNJ7777120 into the lateral ventricle resulted in blockade of microglial activation. In addition, pharmacological targeting of H4R in rotenone-lesioned rats resulted in reduced apomorphine-induced rotational behaviour, prevention of dopaminergic neuron degeneration and associated decreases in striatal dopamine levels. These changes were accompanied by a reduction of Lewy body-like neuropathology. Our results provide first proof of the efficacy of an H4R antagonist in a commonly used PD rat model, and proposes the H4R as a promising target to clinically tackle microglial activation and thereby the progression of PD.


COMT polymorphism regulates the hippocampal subfield volumes in first-episode, drug-naive patients with major depressive disorder.
Purpose: Compared with healthy subjects (HS), patients with major depressive disorder (MDD) exhibit volume differences that affect the volume changes in several areas such as the limbic, cortical, subcortical, and white matter. Catechol-O-methyltransferase (COMT) is a methylation enzyme that catalyzes endogenous catecholamines. The Val158Met polymorphism of COMT has been reported to affect the dopamine (DA) levels, which plays an important role in psychiatric diseases. However, the relationships among both DA levels, COMT genotype, and brain morphology are complicated and controversial. In previous studies that investigated the hippocampal subfields, the greatest brain abnormalities in MDD patients were observed in Cornu Ammonis (CA)1 and the subiculum, followed by that in CA2-3. We have prospectively demonstrated the relationship between the single-nucleotide polymorphism of the Val158Met COMT gene (rs4680) and the hippocampal subfields in drug-naive MDD patients. Patients and methods: In this study, we compared 27 MDD patients and 42 HS who were divided into groups based on their COMT genotype. The effects of the diagnosis, genotype, and genotype-diagnosis interaction related to CA1 and the subiculum volumes, as well as the whole-brain cortical thickness, were evaluated by performing a FreeSurfer statistical analysis of high-resolution magnetic resonance imaging (MRI) findings. Results: The results revealed that there was a statistically significant interaction between the effects of diagnosis and genotype on the right subiculum (a component of the hippocampus). Conclusion: This Val158Met COMT polymorphism may influence the subiculum volume in drug-naive, first-episode MDD patients.


Degree of Trauma Differs for Major Osteoporotic Fracture Events in Older Men Versus Older Women.
To examine the degree of trauma in major osteoporotic fractures (MOF) in men versus women, we used data from 15,698 adults aged ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) study (5994 men) and the Study of Osteoporotic Fractures (SOF) (9704 women). Participants were contacted tri-annually to ascertain incident fractures, which were confirmed by radiographic reports and coded according to degree of self-reported trauma. Trauma was classified as low (fall from ≤ standing height; fall on stairs, steps, or curb; minimal trauma other than fall [coughing, turning over]); moderate (collisions with objects during normal activity without associated fall); or high (fall from > standing height; severe trauma [motor vehicle accident, assault]). MOF included hip, clinical vertebral, wrist, and humerus fractures. Mean fracture follow-up was 9.1 years in SOF and 8.7 years in MrOS. A total of 14.6% of the MOF in men versus 6.3% of the MOF in women were classified as high trauma (p < 0.001); men versus women more often experienced fractures resulting from severe trauma as well as from fall > standing height. High-trauma fractures were more significantly common in men versus women at the hip (p = 0.002) and wrist (p < 0.001) but not at the spine or humerus. Among participants with MOF, the odds ratio of a fracture related to high-trauma fracture among men versus women was 3.12 (95% confidence interval [CI] 1.70-5.71) after adjustment for traditional risk factors. Findings were similar in analyses limited to participants with hip fractures (odds ratio [OR] = 3.34, 95% CI 1.04-10.67) and those with wrist fracture (OR = 5.68, 95% CI 2.03-15.85). Among community-dwelling older adults, MOF are more likely to be related to high trauma in men than in women. These findings are not explained by sex differences in conventional risk factors and may reflect a greater propensity among men to engage in risky behavior. © 2015 American Society for Bone and Mineral Research.


A feasibility study of mindfulness-based cognitive therapy for individuals with borderline personality disorder.
Mindfulness-based cognitive therapy (MBCT) was originally developed to prevent relapse in recurrent depression. More recently it has been applied to individuals at high risk of suicide or currently suffering with anxiety and depression. The aim of this study was to consider the feasibility of MBCT for individuals with a diagnosis of borderline personality disorder (BPD). The design of the study was a repeated measures, quasi-experimental design employing within-subject and between-subject comparisons of a sample of participants with BPD. Based on previous studies and theoretical models of the effect of mindfulness and of cognitive therapy, pre- and post-group measures of mindfulness, depression, anxiety, dissociation, impulsivity, experiential avoidance, and attention were obtained. Participants attended an 8-week adapted MBCT (MBCT-a) group intervention. A total of 22 participants were assessed pre- and post-intervention and were subsequently divided for analysis into two groups: treatment completers (N= 16) and non-completers (number of sessions attended < 4; N= 6). The study found that MBCT-a is acceptable to individuals with BPD. Using intention to treat analyses, only attentional control improved. However, post hoc analyses of treatment improvers (N= 9) identified changes in mindfulness and somatoform dissociation. A dose-effect analysis suggested a weak improvement in mindfulness, experiential avoidance, state anxiety, and somatoform dissociation. This study suggests that further exploration of MBCT for use with individuals with BPD is merited. The study lends tentative support for attentional and avoidance models of the effects of mindfulness.


Mechanisms of disease: Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 as a novel treatment for the metabolic syndrome.
The magnitude of the obesity and metabolic syndrome epidemic has heightened the need for the development of new and effective treatments. Although circulating cortisol concentrations are not elevated in obesity or in the metabolic syndrome, decreasing the tissue-specific generation of cortisol through inhibition of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been postulated as a therapeutic strategy. Observations in cohorts of obese patients, in comparison with those with type 2 diabetes, have suggested that the ability to decrease tissue-specific cortisol production might represent a protective mechanism to improve insulin sensitivity and prevent diabetes. In rodents, pharmacologic exploitation of this mechanism, through the development of inhibitors selective for 11beta-HSD1 (in preference to the type 2 isoform), dramatically improves insulin sensitivity. Here we review the published data and the rationale for treatment in humans, as well as discussing potential problems and adverse effects of future selective 11beta-HSD1 inhibitors.


Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: the RENAAL study.
Diabetic nephropathy is the most important cause of ESRD. The aim of this study was to develop a risk score from risk predictors for ESRD, with and without death, in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and to compare ability of the ESRD risk score and its components to predict ESRD. The risk score was developed from coefficients of independent risk factors from multivariate analysis of baseline variables and equals (1.96 x log [urinary albumin:creatinine ratio]) - (0.78 serum albumin [g/dl]) + (1.28 x serum creatinine [mg/dl]) - (0.11 x hemoglobin [g/dl]). It was robust with respect to severity of nephropathy, gender, race, and treatment group. The risk score for ESRD or death was comparable. The four risk predictors for progression of kidney disease were independent of therapy. For combined treatment groups, the hazard ratio between the fourth and first quartiles of the ESRD risk score was 49.0, as compared with the corresponding hazard ratios for each component: 14.7 for urinary albumin:creatinine ratio, 9.2 for serum creatinine, 5.5 for hemoglobin, and 10.2 for serum albumin. The RENAAL risk scores for ESRD with or without death emphasize the importance of identification of level of albuminuria, serum albumin, serum creatinine, and hemoglobin to predict development of ESRD in patients with type 2 diabetes and nephropathy. Although albuminuria is a strong risk factor for ESRD, the contribution of serum albumin, serum creatinine, and hemoglobin level further enhances prediction of ESRD. Future trials with a similar patient population and outcomes measures should consider adjusting analyses for baseline risk factors.


Medical Nutrition Education, Training, and Competencies to Advance Guideline-Based Diet Counseling by Physicians: A Science Advisory From the American Heart Association.
Growing scientific evidence of the benefits of heart-healthy dietary patterns and of the massive public health and economic burdens attributed to obesity and poor diet quality have triggered national calls to increase diet counseling in outpatients with atherosclerotic cardiovascular disease or risk factors. However, despite evidence that physicians are willing to undertake this task and are viewed as credible sources of diet information, they engage patients in diet counseling at less than desirable rates and cite insufficient knowledge and training as barriers. These data align with evidence of large and persistent gaps in medical nutrition education and training in the United States. Now, major reforms in undergraduate and graduate medical education designed to incorporate advances in the science of learning and to better prepare physicians for 21st century healthcare delivery are providing a new impetus and novel ways to expand medical nutrition education and training. This science advisory reviews gaps in undergraduate and graduate medical education in nutrition in the United States, summarizes reforms that support and facilitate more robust nutrition education and training, and outlines new opportunities for accomplishing this goal via multidimensional curricula, pedagogies, technologies, and competency-based assessments. Real-world examples of efforts to improve undergraduate and graduate medical education in nutrition by integrating formal learning with practical, experiential, inquiry-driven, interprofessional, and population health management activities are provided. The authors conclude that enhancing physician education and training in nutrition, as well as increasing collaborative nutrition care delivery by 21st century health systems, will reduce the health and economic burdens from atherosclerotic cardiovascular disease to a degree not previously realized.


Central sensitization syndrome and the initial evaluation of a patient with fibromyalgia: a review.
In both primary care and consultative practices, patients presenting with fibromyalgia (FM) often have other medically unexplained somatic symptoms and are ultimately diagnosed as having central sensitization (CS). Central sensitization encompasses many disorders where the central nervous system amplifies sensory input across many organ systems and results in myriad symptoms. A pragmatic approach to evaluate FM and related symptoms, including a focused review of medical records, interviewing techniques, and observations, is offered here, giving valuable tools for identifying and addressing the most relevant symptoms. At the time of the clinical evaluation, early consideration of CS may improve the efficiency of the visit, reduce excessive testing, and help in discerning between typical and atypical cases so as to avoid an inaccurate diagnosis. Discussion of pain and neurophysiology and sensitization often proves helpful.


Liver transplant recipients older than 60 years have lower survival and higher incidence of malignancy.
Older age is not considered a contraindication for liver transplantation, but age-related morbidity may be a cause of mortality. Survival and the incidence of the main post-transplant complications were assessed in 111 adult liver transplant recipients. They were divided in two groups according to their age (patients younger than 60 years, n=54; patients older than 60 years, n=57) and both groups were compared. Older patients were more frequently transplanted for hepatitis C (p= 0.03) and hepatocellular carcinoma (p= 0.05) and their liver disease was less advanced (Child-Pugh and MELD scores were significantly lower; p=0.004 and p=0.05, respectively). After transplantation, older patients had a significantly lower survival (p=0.02). Higher age was independently associated with mortality (hazard ratio for each 10-year increase: 2.1; 95% confidence interval: 1.1- 4.0; p=0.02). The incidence of de novo neoplasia and nonskin neoplasia were higher in older patients (p=0.02 and p =0.007, respectively). Malignancy was the cause of death in one patient younger than 60 years and in 12 patients older than 60 years (p =0.002). In multivariate analysis, a higher age and smoking were independently associated with a higher risk of dying of de novo neoplasia. In conclusion, older liver transplant recipients have a significantly lower survival than younger patients. Malignancy is responsible for this decreased survival.


Drug-repositioning screening identified piperlongumine as a direct STAT3 inhibitor with potent activity against breast cancer.
Signal transducer and activator of transcription (STAT) 3 regulates many cardinal features of cancer including cancer cell growth, apoptosis resistance, DNA damage response, metastasis, immune escape, tumor angiogenesis, the Warburg effect and oncogene addiction and has been validated as a drug target for cancer therapy. Several strategies have been used to identify agents that target Stat3 in breast cancer but none has yet entered into clinical use. We used a high-throughput fluorescence microscopy search strategy to identify compounds in a drug-repositioning library (Prestwick library) that block ligand-induced nuclear translocation of Stat3 and identified piperlongumine (PL), a natural product isolated from the fruit of the pepper Piper longum. PL inhibited Stat3 nuclear translocation, inhibited ligand-induced and constitutive Stat3 phosphorylation, and modulated expression of multiple Stat3-regulated genes. Surface plasmon resonance assay revealed that PL directly inhibited binding of Stat3 to its phosphotyrosyl peptide ligand. Phosphoprotein antibody array analysis revealed that PL does not modulate kinases known to activate Stat3 such as Janus kinases, Src kinase family members or receptor tyrosine kinases. PL inhibited anchorage-independent and anchorage-dependent growth of multiple breast cancer cell lines having increased pStat3 or total Stat3, and induced apoptosis. PL also inhibited mammosphere formation by tumor cells from patient-derived xenografts. PL's antitumorigenic function was causally linked to its Stat3-inhibitory effect. PL was non-toxic in mice up to a dose of 30 mg/kg/day for 14 days and caused regression of breast cancer cell line xenografts in nude mice. Thus, PL represents a promising new agent for rapid entry into the clinic for use in treating breast cancer, as well as other cancers in which Stat3 has a role.


Bud23 methylates G1575 of 18S rRNA and is required for efficient nuclear export of pre-40S subunits.
BUD23 was identified from a bioinformatics analysis of Saccharomyces cerevisiae genes involved in ribosome biogenesis. Deletion of BUD23 leads to severely impaired growth, reduced levels of the small (40S) ribosomal subunit, and a block in processing 20S rRNA to 18S rRNA, a late step in 40S maturation. Bud23 belongs to the S-adenosylmethionine-dependent Rossmann-fold methyltransferase superfamily and is related to small-molecule methyltransferases. Nevertheless, we considered that Bud23 methylates rRNA. Methylation of G1575 is the only mapped modification for which the methylase has not been assigned. Here, we show that this modification is lost in bud23 mutants. The nuclear accumulation of the small-subunit reporters Rps2-green fluorescent protein (GFP) and Rps3-GFP, as well as the rRNA processing intermediate, the 5' internal transcribed spacer 1, indicate that bud23 mutants are defective for small-subunit export. Mutations in Bud23 that inactivated its methyltransferase activity complemented a bud23Delta mutant. In addition, mutant ribosomes in which G1575 was changed to adenosine supported growth comparable to that of cells with wild-type ribosomes. Thus, Bud23 protein, but not its methyltransferase activity, is important for biogenesis and export of the 40S subunit in yeast.


RNAi-mediated suppression of the mitochondrial iron chaperone, frataxin, in Drosophila.
The mitochondrial iron chaperone, frataxin, plays a critical role in cellular iron homeostasis and the synthesis and regeneration of Fe-S centers. Genetic insufficiency for frataxin is associated with Friedreich's Ataxia in humans and confers loss of function of Fe-containing proteins including components of the respiratory chain and mitochondrial and cytosolic aconitases. Here, we report the use of RNA-interference (RNAi) to suppress frataxin in the multicellular eukaryote, Drosophila. Phenotypically, suppression of the Drosophila frataxin homologue (dfh) confers distinct phenotypes in larvae and adults, leading to giant long-lived larvae and to conditional short-lived adults. Deficiency of the DFH protein results in diminished activities of numerous heme- and iron-sulfur-containing enzymes, loss of intracellular iron homeostasis and increased susceptibility to iron toxicity. In parallel with the differential larval and adult phenotypes, our results indicate that dfh silencing differentially dysregulates ferritin expression in adults but not in larvae. Moreover, silencing of dfh in the peripheral nervous system, a specific focus of Friedreich's pathology, permits normal larval development but imposes a marked reduction in adult lifespan. In contrast, dfh silencing in motorneurons has no deleterious effect in either larvae or adults. Finally, overexpression of Sod1, Sod2 or Cat does not suppress the failure of DFH-deficient animals to successfully complete eclosion, suggesting a minimal role of oxidative stress in this phenotype. The robust developmental, biochemical and tissue-specific phenotypes conferred by DFH deficiency in Drosophila provide a platform for identifying genetic, nutritional and environmental factors, which ameliorate the symptoms arising from frataxin deficiency.


The association of increased levels of intermediate-density lipoproteins with smoking and with coronary artery disease.
Studies were undertaken to determine whether there is an association between elevated levels of intermediate-density lipoproteins (IDL) (Sf 12-60 lipoproteins) and coronary artery disease. Forty-five to sixty-five-year-old men with objectively documented coronary artery disease (n = 58) who were free of known risk factors (diabetes, hypertension, obesity, hyperuricemia, and hypercholesterolemia) were compared with similar men who were free of coronary artery disease (n = 52). Smokers could not be excluded. The coronary artery disease group had a higher rate of cigarette smoking (NS, due to large variations); higher concentrations of triglycerides in their plasma (p = .003) and higher levels of very low-density lipoproteins (VLDL) (p = .007), IDL (p = .016), and low-density lipoproteins (LDL) (p = .04); as well as somewhat lower levels of high-density lipoprotein (HDL) cholesterol (p = .04). Chi-squared analysis demonstrated a strong association between coronary artery disease and IDL apolipoprotein (apo) B (p = .006), coronary artery disease and IDL triglyceride (p = .032), and coronary artery disease and IDL apo B times IDL triglyceride (p = .006) when the top quintile of the population was compared with the bottom quintile for each of these variables. Stepwise logistic regression analysis resulted in rejection of an association between coronary artery disease and HDL cholesterol, plasma triglyceride, VLDL triglyceride, or LDL triglyceride. However, it did show that coronary artery disease was most strongly associated with smoking and that the second strongest association was with IDL.(ABSTRACT TRUNCATED AT 250 WORDS)


Inferring transmission trees to guide targeting of interventions against visceral leishmaniasis and post-kala-azar dermal leishmaniasis.
Understanding of spatiotemporal transmission of infectious diseases has improved significantly in recent years. Advances in Bayesian inference methods for individual-level geo-located epidemiological data have enabled reconstruction of transmission trees and quantification of disease spread in space and time, while accounting for uncertainty in missing data. However, these methods have rarely been applied to endemic diseases or ones in which asymptomatic infection plays a role, for which additional estimation methods are required. Here, we develop such methods to analyze longitudinal incidence data on visceral leishmaniasis (VL) and its sequela, post-kala-azar dermal leishmaniasis (PKDL), in a highly endemic community in Bangladesh. Incorporating recent data on VL and PKDL infectiousness, we show that while VL cases drive transmission when incidence is high, the contribution of PKDL increases significantly as VL incidence declines (reaching 55% in this setting). Transmission is highly focal: 85% of mean distances from inferred infectors to their secondary VL cases were <300 m, and estimated average times from infector onset to secondary case infection were <4 mo for 88% of VL infectors, but up to 2.9 y for PKDL infectors. Estimated numbers of secondary cases per VL and PKDL case varied from 0 to 6 and were strongly correlated with the infector's duration of symptoms. Counterfactual simulations suggest that prevention of PKDL could have reduced overall VL incidence by up to 25%. These results highlight the need for prompt detection and treatment of PKDL to achieve VL elimination in the Indian subcontinent and provide quantitative estimates to guide spatiotemporally targeted interventions against VL.


Potassium is critical for the Ni(II)-responsive DNA-binding activity of Escherichia coli NikR.
The Escherichia coli NikR transcription factor is a Ni(II)-dependent repressor that regulates the production of a nickel ion transporter. The X-ray crystal structure of the Ni(II)-NikR-DNA bound complex revealed a K(+)-binding site positioned at the interface of the metal- and DNA-binding domains, but the significance of the potassium was unclear. Mutation of one of the K(+) ligands impairs the affinity and specificity of DNA binding in the presence of either stoichiometric or excess Ni(II). Removal of K(+) abrogates Ni(II)-responsive DNA binding completely while the addition of K(+) restores this activity. Furthermore, the observed K(+) dependence can be relieved by replacing the K(+) ligand Asp34 with an arginine. These mutagenesis and cation exchange experiments reveal that K(+) is a critical structural component for the activation of Ni(II)-responsive DNA binding by NikR.


Transcranial electrical stimulation nomenclature.
Transcranial electrical stimulation (tES) aims to alter brain function non-invasively by applying current to electrodes on the scalp. Decades of research and technological advancement are associated with a growing diversity of tES methods and the associated nomenclature for describing these methods. Whether intended to produce a specific response so the brain can be studied or lead to a more enduring change in behavior (e.g. for treatment), the motivations for using tES have themselves influenced the evolution of nomenclature, leading to some scientific, clinical, and public confusion. This ambiguity arises from (i) the infinite parameter space available in designing tES methods of application and (ii) varied naming conventions based upon the intended effects and/or methods of application. Here, we compile a cohesive nomenclature for contemporary tES technologies that respects existing and historical norms, while incorporating insight and classifications based on state-of-the-art findings. We consolidate and clarify existing terminology conventions, but do not aim to create new nomenclature. The presented nomenclature aims to balance adopting broad definitions that encourage flexibility and innovation in research approaches, against classification specificity that minimizes ambiguity about protocols but can hinder progress. Constructive research around tES classification, such as transcranial direct current stimulation (tDCS), should allow some variations in protocol but also distinguish from approaches that bear so little resemblance that their safety and efficacy should not be compared directly. The proposed framework includes terms in contemporary use across peer-reviewed publications, including relatively new nomenclature introduced in the past decade, such as transcranial alternating current stimulation (tACS) and transcranial pulsed current stimulation (tPCS), as well as terms with long historical use such as electroconvulsive therapy (ECT). We also define commonly used terms-of-the-trade including electrode, lead, anode, and cathode, whose prior use, in varied contexts, can also be a source of confusion. This comprehensive clarification of nomenclature and associated preliminary proposals for standardized terminology can support the development of consensus on efficacy, safety, and regulatory standards.


Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications.
Endogenous cannabinoids (ECs) are lipid-signaling molecules that specifically bind to cannabinoid receptor types 1 and 2 (CB1R and CB2R) and are highly expressed in central and many peripheral tissues under pathological conditions. Activation of hepatic CB1R is associated with obesity, insulin resistance, and impaired metabolic function, owing to increased energy intake and storage, impaired glucose and lipid metabolism, and enhanced oxidative stress and inflammatory responses. Additionally, blocking peripheral CB1R improves insulin sensitivity and glucose metabolism and also reduces hepatic steatosis and body weight in obese mice. Thus, targeting EC receptors, especially CB1R, may provide a potential therapeutic strategy against obesity and insulin resistance. There are many CB1R antagonists, including inverse agonists and natural compounds that target CB1R and can reduce body weight, adiposity, and hepatic steatosis, and those that improve insulin sensitivity and reverse leptin resistance. Recently, the use of CB1R antagonists was suspended due to adverse central effects, and this caused a major setback in the development of CB1R antagonists. Recent studies, however, have focused on development of antagonists lacking adverse effects. In this review, we detail the important role of CB1R in hepatic insulin resistance and the possible underlying mechanisms, and the therapeutic potential of CB1R targeting is also discussed.


Management of delayed cerebral ischemia after subarachnoid hemorrhage.
For patients who survive the initial bleeding event of a ruptured brain aneurysm, delayed cerebral ischemia (DCI) is one of the most important causes of mortality and poor neurological outcome. New insights in the last decade have led to an important paradigm shift in the understanding of DCI pathogenesis. Large-vessel cerebral vasospasm has been challenged as the sole causal mechanism; new hypotheses now focus on the early brain injury, microcirculatory dysfunction, impaired autoregulation, and spreading depolarization. Prevention of DCI primarily relies on nimodipine administration and optimization of blood volume and cardiac performance. Neurological monitoring is essential for early DCI detection and intervention. Serial clinical examination combined with intermittent transcranial Doppler ultrasonography and CT angiography (with or without perfusion) is the most commonly used monitoring paradigm, and usually suffices in good grade patients. By contrast, poor grade patients (WFNS grades 4 and 5) require more advanced monitoring because stupor and coma reduce sensitivity to the effects of ischemia. Greater reliance on CT perfusion imaging, continuous electroencephalography, and invasive brain multimodality monitoring are potential strategies to improve situational awareness as it relates to detecting DCI. Pharmacologically-induced hypertension combined with volume is the established first-line therapy for DCI; a good clinical response with reversal of the presenting deficit occurs in 70 % of patients. Medically refractory DCI, defined as failure to respond adequately to these measures, should trigger step-wise escalation of rescue therapy. Level 1 rescue therapy consists of cardiac output optimization, hemoglobin optimization, and endovascular intervention, including angioplasty and intra-arterial vasodilator infusion. In highly refractory cases, level 2 rescue therapies are also considered, none of which have been validated. This review provides an overview of current state-of-the-art care for DCI management.


Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks.
Antiretroviral tolerability is a critical factor contributing to treatment outcome. The T-20 Versus Optimized Background Regimen Only (TORO) studies assessed the safety and efficacy of enfuvirtide in treatment-experienced HIV-1-infected patients. A total of 997 patients were randomized at a 2:1 ratio to an optimized background antiretroviral regimen plus enfuvirtide (n = 663) or an optimized background regimen alone (control group; n = 334). Control patients could switch to enfuvirtide on virologic failure. In total, 26.5% of patients randomized to enfuvirtide and 36.6% to the control group discontinued study treatment before week 48; the percentage of patients withdrawn for safety reasons (including adverse events [AEs], deaths, and laboratory abnormalities) was 14.0% in the enfuvirtide group and 11.6% in the control group. Injection site reactions (ISRs) occurred in 98% of enfuvirtide patients and led to treatment discontinuation in 4.4%. Treatment-related (defined as possibly, probably, or remotely) AE rates per 100 patient-years were lower with enfuvirtide (96.2) than in the control group (149.9); diarrhea, nausea, and fatigue, the most frequently reported AEs, were significantly less frequent with enfuvirtide than in the control group. Pneumonia was significantly more frequent in patients treated with enfuvirtide (6.7 vs. 0.6 events per 100 patient-years), although the incidence was within expected ranges for this population. Lymphadenopathy was also higher in enfuvirtide-treated patients (7.1 vs. 1.2 events per 100 patient-years) for control patients. The addition of enfuvirtide to an optimized background regimen does not exacerbate AEs commonly associated with antiretrovirals. ISRs limited treatment in <5% of patients.


[Minimally invasive technique for mitral valve repair--the importance of intraoperative transesophageal echocardiography].
A 65-year-old male with mitral regurgitation was scheduled for the mitral valve repair by means of minimally invasive technique. The technique, which requires a 10-cm right parasternal incision, offers minimal discomfort, less postoperative pain, quick functional recovery and excellent cosmetic healing. However, the intraoperative monitoring by the transesophageal echocardiography was required to evaluate the mitral valve function and to confirm the complete removal of air from the apex of the left ventricle and right upper pulmonary vein due to the small operative field. In addition, the monitoring of the short-axis view of the left ventricle makes it possible to evaluate and to confirm the preload and the left ventricular contractility. We considered that the transesophageal echocardiography is essential and useful for the minimally invasive mitral valve repair.


Cardiovascular disease contributes to Alzheimer's disease: evidence from large-scale genome-wide association studies.
Alzheimer's disease (AD) is the most common and complex neurodegenerative disease in the elderly individuals. Recently, genome-wide association studies (GWAS) have been used to investigate AD pathogenesis. These GWAS have yielded important new insights into the genetic mechanisms of AD. However, these newly identified AD susceptibility loci exert only very small risk effects and cannot fully explain the underlying AD genetic risk. We hypothesize that combining the findings from different AD GWAS may have greater power than genetic analysis alone. To identify new AD risk factors, we integrated findings from 3 previous large-scale AD GWAS (n = 14,138) using a gene-based meta-analysis and subsequently conducted a pathway analysis using the kyoto encyclopedia of genes and genomes and gene ontology databases. Interestingly, we not only confirmed previous findings, but also highlighted, for the first time, the involvement of cardiovascular disease-related pathways in AD. Our results provided the clues as to the link between these diseases using pathway analysis methods. We believe that these findings will be very useful for future genetic studies of AD.


Characterization of a highly polymorphic region 5' to JH in the human immunoglobulin heavy chain.
A cloned DNA segment 1.25 kilobases (kb) upstream from the joining segments of the human heavy chain immunoglobulin gene revealed extensive polymorphic variation at this locus, and the polymorphic pattern was stably transmitted to the next generation. Genomic restriction analysis showed that the polymorphism was caused by insertions/deletions within an MspI/BamHI fragment. Sequencing of one allele, 848 base pairs (bp) long, revealed eleven 50-base-pair tandem repeats. A second allele, 648 bp long, was cloned from a human genomic cosmid library, sequenced, and found to contain four fewer repeats than the first allele. A survey of 186 chromosomes from unrelated individuals of primarily northern European descent revealed at least six alleles.


Knee laxity after staircase exercise predicts radiographic disease progression in medial compartment knee osteoarthritis.
To evaluate whether increased laxity of the knee during daily physical activities such as stair climbing is associated with progression of knee joint osteoarthritis (OA). During the years 2001-2003, 136 patients with bilateral primary medial compartment knee joint OA were enrolled in this prospective study. Baseline data collected were body mass index (BMI), muscle power, radiographic joint space width, mechanical axis on standing radiography, and anteroposterior (AP) knee laxity before and after physical exercise. After 8 years of followup, 84 patients were reexamined to assess radiographic changes. Radiographic disease progression was defined as progression of >1 grade on the Kellgren/Lawrence scale. AP knee laxity increased significantly after stair climbing. Patients with OA progression and those without progression did not differ significantly in age, sex, baseline quadriceps muscle strength, mechanical axis, joint space width, and AP knee laxity before exercise. The 2 groups of patients did, however, differ significantly in baseline BMI and change in AP knee laxity due to exercise. The risk of progression of knee OA increased 4.15-fold with each millimeter of increase in the change in AP knee laxity due to exercise and 1.24-fold with each point increase in the BMI. Our results indicate that patients with OA progression have significantly greater changes in knee joint laxity during physical activities and a higher BMI than patients without OA progression. These findings suggest that larger changes in knee laxity during repetitive physical activities and a higher BMI play significant roles in the progression of knee OA.


Microtubule and chromatin behavior follow MAP kinase activity but not MPF activity during meiosis in mouse oocytes.
Oocyte meiotic maturation is triggered by different stimuli (hormones, unknown signals through cell interactions) in different species. These stimuli indirectly lead to the activation of a major cell cycle regulating activity, the maturation promoting factor (MPF). Other factors, such as the product of the proto-oncogene c-mos or enzymes of the MAP kinase family, are also involved in the process of maturation. MAP kinase activation occurs during meiotic maturation in oocytes from different species with different kinetics. The relationships between MPF activation and MAP kinase activation have been well studied in species such as clam and Xenopus. In this paper, we study the precise timing of MAP kinase activation (as measured by phosphorylation of exogenous myelin basic protein and shifts in mobility of ERK 1 and ERK 2) versus MPF activation (as measured by phosphorylation of exogenous histone H1) during mouse oocyte maturation and, in parallel, morphological events such as changes in microtubule organization and chromatin condensation. We observed that MAP kinase activation was delayed after MPF activation and that this activity persisted throughout maturation whereas MPF activity dropped between the two meiotic metaphases. After parthenogenetic activation of ovulated eggs, MAP kinase inactivation was very slow compared to MPF inactivation. During the first mitotic cell cycle, a rise in myelin basic protein kinase activity at M-phase was observed but it was not related to MAP kinase activation. Furthermore, microtubules and chromatin remained in a metaphase-like state during the complete period of maturation (including the period between the two meiotic metaphases) and a few hours after activation.(ABSTRACT TRUNCATED AT 250 WORDS)


High STAP1 expression in DUX4-rearranged cases is not suitable as therapeutic target in pediatric B-cell precursor acute lymphoblastic leukemia.
Approximately 25% of the pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases are genetically unclassified. More thorough elucidation of the pathobiology of these genetically unclassified ('B-other') cases may identify novel treatment options. We analyzed gene expression profiles of 572 pediatric BCP-ALL cases, representing all major ALL subtypes. High expression of STAP1, an adaptor protein downstream of the B-cell receptor (BCR), was identified in BCR-ABL1-like and non-BCR-ABL1-like B-other cases. Limma analysis revealed an association between high expression of STAP1 and BCR signaling genes. However, STAP1 expression and pre-BCR signaling were not causally related: cytoplasmic Igμ levels were not abnormal in cases with high levels of STAP1 and stimulation of pre-BCR signaling did not induce STAP1 expression. To elucidate the role of STAP1 in BCP-ALL survival, expression was silenced in two human BCP-ALL cell lines. Knockdown of STAP1 did not reduce the proliferation rate or viability of these cells, suggesting that STAP1 is not a likely candidate for precision medicines. Moreover, high expression of STAP1 was not predictive for an unfavorable prognosis of BCR-ABL1-like and non-BCR-ABL1-like B-other cases. Remarkably, DUX4-rearrangements and intragenic ERG deletions, were enriched in cases harboring high expression of STAP1.


Quantifying culture gaps between physicians and managers in Dutch hospitals: a survey.
The demands in hospitals for safety and quality, combined with limitations in financing health care require effective cooperation between physicians and managers. The complex relationship between both groups has been described in literature. We aim to add a perspective to literature, by developing a questionnaire which provides an opportunity to quantitatively report and elaborate on the size and content of differences between physicians and managers. Insight gained from use of the questionnaire might enable us to reflect on these differences and could provide practical tools to improve cooperation between physicians and managers, with an aim to enhance hospital performance. The CG-Questionnaire was developed by adjusting, pre-testing, and shortening Kralewski's questionnaire, and appeared suitable to measure culture gaps. It was shortened by exploratory factor analysis, using principal-axis factoring extraction with Varimax rotation. The CG-Questionnaire was sent to all physicians and managers within 37 Dutch general hospitals. ANOVA and paired sample T-tests were used to determine significant differences between perceptions of daily work practices based in both professional cultures; culture gaps. The size and content of culture gaps were determined with descriptive statistics. The total response (27%) consisted of 929 physicians and 310 managers. The Cronbachs alpha's were 0.70 - 0.79. Statistical analyses showed many differences; culture gaps were found in the present situation; they were even larger in the preferred situation. Differences between both groups can be classified into three categories: (1) culture gaps in the present situation and not in the preferred, (2) culture gaps in the preferred situation and not in the present, and (3) culture gaps in both situations. With data from the CG-Questionnaire it is now possible to measure the size and content of culture gaps between physicians and managers in hospitals. Results gained with the CG-Questionnaire enables hospitals to reflect on these differences. Combining the results, we distinguished three categories of increasing complexity. We linked these three categories to three methods from intergroup literature (enhanced information, contact and ultimately meta cognition) which could help to improve the cooperation between physicians and managers.


Genetic connectivity in the Florida reef system: comparative phylogeography of commensal invertebrates with contrasting reproductive strategies.
Effective spatial management of coral reefs including design of marine protected areas requires an understanding of interpopulation genetic connectivity. We assessed gene flow along 355 km of the Florida reef system and between Florida and Belize in three commensal invertebrates occupying the same host sponge (Callyspongia vaginalis) but displaying contrasting reproductive dispersal strategies: the broadcast-spawning brittle star Ophiothrix lineata and two brooding amphipods Leucothoe kensleyi and Leucothoe ashleyae. Multiple analytical approaches to sequence variation in the mitochondrial COI gene demonstrated a high degree of overall connectivity for all three species along the Florida reef system. Ophiothrix lineata showed significant genetic structuring between Florida and Belize, and a pattern of isolation by distance but no significant genetic structuring along the Florida coastline. Bayesian estimates of migration detected a strong southerly dispersal bias for O. lineata along the Florida reef system, contrary to the general assumption of northerly gene flow in this region based on the direction of the Florida Current. Both amphipods, despite direct development, also showed high gene flow along the Florida reef system. Multiple inferences of long-distance dispersal from a nested clade analysis support the hypothesis that amphipod transport, possibly in detached sponge fragments, could generate the high levels of overall gene flow observed. However, this transport mechanism appears much less effective across deep water as connectivity between Florida and Belize (1072 km) is highly restricted.


Inhibition of arginase ameliorates experimental ulcerative colitis in mice.
Nitric oxide (NO) is produced from the conversion of L-arginine by NO synthase (NOS) and regulates a variety of processes in the gastrointestinal tract. Considering the increased activity of arginase in colitis tissue, it is speculated that arginase could inhibit NO synthesis by competing for the same L-arginine substrate, resulting in the exacerbation of colitis. We examined the role of arginase and its relationship to NO metabolism in dextran sulfate sodium (DSS)-induced colitis. Experimental colitis was induced in mice by administration of 2.5% DSS in drinking water for 8 days. Treatment for arginase inhibition was done by once daily intraperitoneal injection of N(ω)-hydroxy-nor- arginine (nor-NOHA). On day 8, we evaluated clinical parameters (body weight, disease activity index, and colon length), histological features, the activity and expression of arginase, L-arginine content, the expression of NO synthase (NOS), and the concentration of NO end-product (NOx: nitrite + nitrate). Administration of nor-NOHA improved the worsened clinical parameters and histological features in DSS-induced colitis. Treatment with nor-NOHA attenuated the increased activity of arginase, upregulation of arginase Ι at both mRNA and protein levels, and decreased the content of L-arginine in colonic tissue in the DSS-treated mice. Conversely, despite the decreased expression of NOS2 mRNA, the decreased concentration of NOx in colonic tissues was restored to almost normal levels. The consumption of L-arginine by arginase could lead to decreased production of NO from NOS, contributing to the pathogenesis of the colonic inflammation; thus, arginase inhibition might be effective for improving colitis.


Associations between single-nucleotide polymorphisms of ADIPOQ, serum adiponectin and increased type 2 diabetes mellitus risk in Bahraini individuals.
This study aimed to estimate the frequency of the SNPs (+45T>G and +276G>T) genotypes and investigate the association between the two SNPs and adiponectin concentration, metabolic parameters and risk of T2DM in the Bahraini population. We genotyped the two ADIPOQ SNPs in 140 unrelated T2DM patients and 66 nondiabetic controls using the polymerase chain reaction-restriction fragment length polymorphism assay. Lipid profile was measured by enzymatic methods. Total serum adiponectin levels were measured by immunoassay. T2DM patients had reduced adiponectin levels compared with controls. +45T>G was more prevalent in patients than controls. The rare G allele of +45T>G occurred more frequently than the common T allele in T2DM patients compared with controls, and was associated with lower serum adiponectin levels. There was no significant difference in allele and genotype frequencies of +276G>T between type T2DM patients and controls. There was no association between both SNPs and metabolic parameters.


Time-resolved M(2) of nanosecond pulses from a Q-switched variable-reflectivity-mirror Nd:YAG laser.
Time-resolved M(2) numerical computation and experimental measurements of nanosecond pulses from a Q-switched variable-reflectivity-mirror Nd:YAG laser are presented for the first time to our knowledge. The beam quality parameter is seen to vary approximately from 1 at the beginning to 2 at the end of a high-energy pulse, with a value of 1.35 at the peak of the pulse, which also corresponds to the M(2) obtained from the time-averaged detection of the pulse profile.


Differentiation of IKA in amphibian spinal neurons.
We have examined the development of an inactivating outward current in embryonic amphibian neurons differentiating in culture. On the basis of ionic selectivity, voltage dependence of activation and inactivation and pharmacological sensitivity, it is similar to A currents described in other neurons. In these embryonic neurons the A current appears later than other voltage-dependent currents studied previously. Furthermore, its maturation extends to times later than those required for the differentiation of another potassium current, the voltage-dependent delayed rectifier. These changes in A current are consistent with parallel changes in the action potential and excitability of the developing neurons.


Flexible-dose fesoterodine in elderly adults with overactive bladder: results of the randomized, double-blind, placebo-controlled study of fesoterodine in an aging population trial.
To assess the efficacy and safety of flexible-dose fesoterodine in elderly adults with overactive bladder (OAB). Twelve-week, randomized, double-blind, placebo-controlled trial. Sixty-one outpatient clinics in Europe, Israel, and Turkey. Seven hundred ninety-four individuals aged 65 and older (47% male) with OAB symptoms for 3 months or longer, mean of eight or more micturitions and three or more urgency episodes per 24 hours, at least some moderate problems on Patient Perception of Bladder Condition (PPBC), and Mini-Mental State Examination (MMSE) score of 20 or greater. Participants were randomized to fesoterodine or placebo for 12 weeks, with stratification according to age (>75 vs ≤ 75) and dosing time (morning vs evening). Participants receiving fesoterodine started on 4 mg and could increase to 8 mg at week 4 or 8 and de-escalate to 4 mg at week 8 (sham escalation for placebo). Changes from baseline in bladder-diary variables (primary endpoint, urgency episodes) and patient-reported outcomes including OAB Questionnaire, Treatment Benefit Scale (TBS), PPBC, Urgency Perception Scale (UPS), and OAB Satisfaction Questionnaire (OAB-S); all observed or reported adverse events. By week 8, 64% of fesoterodine-treated and 71% of placebo-treated participants opted for dose escalation. At week 12, the fesoterodine group had statistically significantly greater improvement than the placebo group in urgency episodes, micturitions, nocturnal micturitions, incontinence pad use, and OAB Questionnaire scores but not urgency urinary incontinence episodes. Responder rates on TBS, PPBC, UPS, and OAB-S were statistically significantly higher with fesoterodine. Improvements in most diary variables and participant-reported outcomes were greater with fesoterodine than placebo in participants in both age groups and when administered in the morning and evening. Rates of dry mouth and constipation were 34% and 9% with fesoterodine and 5% and 3% with placebo, respectively. Rates of adverse events and discontinuations were generally similar in participants in both age groups. There was no change in MMSE score. Fesoterodine was associated with significantly greater improvements in most diary variables and participant-reported outcomes than placebo and was generally well tolerated in older people.


Female-biased sex ratios in urban centers create a "fertility trap" in post-war Finland.
Because sex ratios are a key factor regulating mating success and subsequent fitness both across and within species, there is widespread interest in how population-wide sex ratio imbalances affect marriage markets and the formation of families in human societies. Although most modern cities have more women than men and suffer from low fertility rates, the effects of female-biased sex ratios have garnered less attention than male-biased ratios. Here, we analyze how sex ratios are linked to marriages, reproductive histories, dispersal, and urbanization by taking advantage of a natural experiment in which an entire population was forcibly displaced during World War II to other local Finnish populations of varying sizes and sex ratios. Using a discrete time-event generalized linear mixed-effects model, and including factors that change across time, such as annual sex ratio, we show how sex ratios, reproduction, and migration are connected in a female-dominated environment. Young childless women migrated toward urban centers where work was available to women, and away from male-biased rural areas. In such areas where there were more females, women were less likely to start reproduction. Despite this constraint, women showed little flexibility in mate choice, with no evidence for an increase in partner age difference in female-biased areas. We propose that together these behaviors and conditions combine to generate an "urban fertility trap" which may have important consequences for our understanding of the fertility dynamics of today including the current fertility decline across the developed world.


The psychological impact of anal cancer screening on HIV-infected men.
Anal cancer rates are increasing in HIV-infected men. Screening programmes similar to prostate and cervical cancer have been recommended to reduce morbidity and mortality. Research shows that screening processes have psychological consequences that need to be considered. Limited investigation of the psychological impact of anal cancer screening has been conducted. A prospective longitudinal survey of 291 men was conducted at three time points over 14 weeks at a public HIV clinic in Sydney, Australia. Self-report questionnaires measuring worry, distress, depression, anxiety, stress and health-related quality of life (SF-12) were collected. Those who had a biopsy recommended were significantly more worried about anal cancer, rated their anal health worse and were less optimistic about their future health than the control group who needed no further medical investigation. The group receiving high grade histology results remained worried about anal cancer at time 3. We found no evidence that general anxiety, depression or quality of life was significantly affected by the process. Anal cancer specific worry increases throughout the screening process. Clear communication prior to procedures about the procedure itself, potential adverse events, the recovery process and non-technical explanations of results should be implemented in anal screening programmes.


Effect of investment in malaria control on child mortality in sub-Saharan Africa in 2002-2008.
Around 8.8 million children under-five die each year, mostly due to infectious diseases, including malaria that accounts for 16% of deaths in Africa, but the impact of international financing of malaria control on under-five mortality in sub-Saharan Africa has not been examined. We combined multiple data sources and used panel data regression analysis to study the relationship among investment, service delivery/intervention coverage, and impact on child health by observing changes in 34 sub-Saharan African countries over 2002-2008. We used Lives Saved Tool to estimate the number of lives saved from coverage increase of insecticide-treated nets (ITNs)/indoor residual spraying (IRS). As an indicator of outcome, we also used under-five mortality rate. Global Fund investments comprised more than 70% of the Official Development Assistance (ODA) for malaria control in 34 countries. Each $1 million ODA for malaria enabled distribution of 50,478 ITNs [95%CI: 37,774-63,182] in the disbursement year. 1,000 additional ITNs distributed saved 0.625 lives [95%CI: 0.369-0.881]. Cumulatively Global Fund investments that increased ITN/IRS coverage in 2002-2008 prevented an estimated 240,000 deaths. Countries with higher malaria burden received less ODA disbursement per person-at-risk compared to lower-burden countries ($3.90 vs. $7.05). Increased ITN/IRS coverage in high-burden countries led to 3,575 lives saved per 1 million children, as compared with 914 lives in lower-burden countries. Impact of ITN/IRS coverage on under-five mortality was significant among major child health interventions such as immunisation showing that 10% increase in households with ITN/IRS would reduce 1.5 [95%CI: 0.3-2.8] child deaths per 1000 live births. Along with other key child survival interventions, increased ITNs/IRS coverage has significantly contributed to child mortality reduction since 2002. ITN/IRS scale-up can be more efficiently prioritized to countries where malaria is a major cause of child deaths to save greater number of lives with available resources.


Resilience to Discrimination and Rejection Among Young Sexual Minority Males and Transgender Females: A Qualitative Study on Coping With Minority Stress.
Sexual minority and transgender status is associated with mental health disparities, which have been empirically and theoretically linked to stressors related to social stigma. Despite exposure to these unique stressors, many sexual minority and transgender individuals will not experience mental health disorders in their lifetime. Little is known about the specific processes that sexual minority and transgender youth use to maintain their wellbeing in the presence of discrimination and rejection. Semistructured interviews were conducted with 10 sexual minority males and transgender females aged 18-22 years, who currently met criteria for an operationalized definition of resilience to depression and anxiety. Data were analyzed qualitatively, yielding information related to a wide variety of problem-solving, support-seeking, and accommodative coping strategies employed by youth in the face of social stigma. Results are discussed in light of their clinical implications.


A missense mutation in the LIM2 gene is associated with autosomal recessive presenile cataract in an inbred Iraqi Jewish family.
In an inbred Iraqi Jewish family, we have studied three siblings with presenile cataract first noticed between the ages of 20 and 51 years and segregating in an autosomal recessive mode. Using microsatellite repeat markers in close proximity to 25 genes and loci previously associated with congenital cataracts in humans and mice, we identified five markers on chromosome 19q that cosegregated with the disease. Sequencing of LIM2, one of two candidate genes in this region, revealed a homozygous T-->G change resulting in a phenylalanine-to-valine substitution at position 105 of the protein. To our knowledge, this constitutes the first report, in humans, of cataract formation associated with a mutation in LIM2. Studies of late-onset single-gene cataracts may provide insight into the pathogenesis of the more common age-related cataracts.


Comparison of two different matrix band systems in restoring two surface cavities in posterior teeth done by senior undergraduate students at Qassim University, Saudi Arabia: A randomized controlled clinical trial.
Dental students commonly face the problem of overhanging proximal margins and unsatisfactory proximal contact points (PCPs) while restoring Class II cavities in posterior teeth. Various matrix band systems are used in dental clinics to avoid such problems. The aim of this study is to compare the effects of two matrix band systems, circumferential matrix system and sectional matrix system on the PCPs and contours when restoring Class II cavities in posterior teeth. This was a randomized controlled clinical trial done at College of Dentistry, Qassim University, Saudi Arabia. Total 1200 Class II cavities in teeth were selected for this study. Treatment was done by senior undergraduate students. Cavities were randomly divided into two groups. Group 1: Total 600 cavities were restored using circumferential band system. Group 2: Total 600 cavities were restored using sectional band system. Teeth were restored either with the composite or the amalgam restoration. Contact points were evaluated. The presence or absence of proximal overhangs was assessed. Overhanging margins were categorized as positive overhangs, negative overhangs, and absent overhangs. To identify the relationship between matrix band systems and other factors, Chi-square tests (χ2-tests) and Z-tests were used. Pearson correlation coefficient was computed and logistic regression analysis was carried out to assess variables that can affect proximal margins and contact points of final restorations. All optimum contacts 389 (100%) were found in restorations done using sectional band system. A highly significant association was found between open contact points and negative overhanging margins with the use of circumferential matrix band system (P < 0.00). Sectional matrix band system has been found superior to circumferential matrix band system.


Visual loss resulting from immunosuppressive therapy in patients with syphilitic uveitis.
Permanent visual loss can be caused by improper use of immunosuppressive therapy in cases of uveitis without differential diagnosis of syphilitic uveitis. We present four cases of syphilitic uveitis that were incorrectly diagnosed as being secondary to rheumatic diseases and were subsequently treated with immunosuppressive therapy, leading to permanent visual loss. These cases highlight the importance of ruling out syphilis in the differential diagnosis of inflammatory ocular diseases before starting use of immunosuppressive therapy.