Profile of a pediatric rheumatology practice in Israel.
Several studies from Western countries have analyzed the profile of pediatric rheumatology practices. Due to differences in demography and health care systems the profile in Israel may differ from those countries. To describe the profile of a pediatric rheumatology practice in Israel. All new patients seen during the course of 2000 as part of my pediatric rheumatology practice in Northern Israel were registered at their initial encounter. Recorded were demographic data, referral patterns, diagnoses, and disease-related data. Diagnoses were grouped together by types of condition. 242 new patients were seen. 39% of the patients had a rheumatic condition, 39% had non-inflammatory conditions, 12% had periodic fever syndromes and for 10% no definitive diagnosis was determined. 14% had chronic rheumatic diseases. The time until diagnosis was significantly greater and more physicians were involved in the evaluation of periodic fever syndromes than in other disease groups. Seventeen (7%) patients had juvenile rheumatoid arthritis (JRA). The minimum estimated incidence of JRA was 8.8 per 100,000 children. Most patients seen did not have classic inflammatory rheumatic diseases, similar to data from other Western countries. Distinctive to Israel and the Middle East, periodic fever syndromes comprise a large proportion of the pediatric rheumatology practice. These syndromes are relatively difficult for community physicians to diagnose.


Prostate cancer with metastases to the kidney: a rare manifestation of a common disease.
A 66-year-old Caucasian man with a background of prostate cancer presented with a progressive history of nausea, reduced appetite, shortness of breath and a distended abdomen. Radiological imaging revealed a left-sided renal mass and gross ascites suggestive of metastatic renal cell carcinoma (RCC). Subsequent histological examination and immunostaining of renal mass biopsy revealed features characteristic of metastatic moderately differentiated to a focally poorly differentiated, large duct type of prostatic adenocarcinoma.


Development and Health of Adults Formerly Placed in Infant Care Institutions - Study Protocol of the LifeStories Project.
A growing volume of research from global data demonstrates that institutional care under conditions of deprivation is profoundly damaging to children, particularly during the critical early years of development. However, how these individuals develop over a life course remains unclear. This study uses data from a survey on the health and development of 420 children mostly under the age of three, placed in 12 infant care institutions between 1958 and 1961 in Zurich, Switzerland. The children exhibited significant delays in cognitive, social, and motor development in the first years of life. Moreover, a follow-up of a subsample of 143 children about 10 years later revealed persistent difficulties, including depression, school related-problems, and stereotypies. Between 2019 and 2021, these formerly institutionalized study participants were located through the Swiss population registry and invited to participate once again in the research project. Now in their early sixties, they are studied for their health, further development, and life-course trajectories. A mixed-methods approach using questionnaires, neuropsychological assessments, and narrative biographical interviews was implemented by a multidisciplinary team. Combining prospective and retrospective data with standardized quantitative and biographical qualitative data allows a rich reconstruction of life histories. The availability of a community sample from the same geographic location, the 1954-1961 cohort of the Zurich Longitudinal Studies, described in detail in a paper in this issue (Wehrle et al., 2020), enables comparison with an unaffected cohort. This article describes the study design and study participants in detail and discusses the potential and limitations of a comparison with a community sample. It outlines a set of challenges and solutions encountered in the process of a lifespan longitudinal study from early childhood into the cusp of old age with a potentially vulnerable sample and summarizes the lessons learned along the way.


Plasma adiponectin levels in high risk African-Americans with normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes.
We studied plasma adiponectin, insulin sensitivity, and insulin secretion before and after oral glucose challenge in normal glucose tolerant, impaired glucose tolerant, and type 2 diabetic first degree relatives of African-American patients with type 2 diabetes. We studied 19 subjects with normal glucose tolerance (NGT), 8 with impaired glucose tolerance (IGT), and 14 with type 2 diabetes. Serum glucose, insulin, C-peptide, and plasma adiponectin levels were measured before and 2 hours after oral glucose tolerance test. Homeostasis model assessment-insulin resistance index (HOMA-IR) and HOMA-beta cell function were calculated in each subject using HOMA. We empirically defined insulin sensitivity as HOMA-IR<2.68 and insulin resistance as HOMA-IR>2.68. Subjects with IGT and type 2 diabetes were more insulin resistant (as assessed by HOMA-IR) when compared with NGT subjects. Mean plasma fasting adiponectin levels were significantly lower in the type 2 diabetes group when compared with NGT and IGT groups. Plasma adiponectin levels were 2-fold greater (11.09+/-4.98 vs. 6.42+/-3.3811 microg/mL) in insulin-sensitive (HOMA-IR, 1.74+/-0.65) than in insulin-resistant (HOMA-IR, 5.12+/-2.14) NGT subjects. Mean plasma adiponectin levels were significantly lower in the glucose tolerant, insulin-resistant subjects than in the insulin sensitive NGT subjects and were comparable with those of the patients with newly diagnosed type 2 diabetes. We found significant inverse relationships of adiponectin with HOMA-IR (r=-0.502, p=0.046) and with HOMA-beta cell function (r=-0.498, p=0.042) but not with the percentage body fat (r=-0.368, p=0.063), serum glucose, BMI, age, and glycosylated hemoglobin A1C (%A1C). In summary, we found that plasma adiponectin levels were significantly lower in insulin-resistant, non-diabetic first degree relatives of African-American patients with type 2 diabetes and in those with newly diagnosed type 2 diabetes. We conclude that a decreased plasma adiponectin and insulin resistance coexist in a genetically prone subset of first degree African-American relatives before development of IGT and type 2 diabetes.


The Effect of Kangaroo Care on Paternal Attachment: A Randomized Controlled Study.
During the first interaction between the father and the infant, touch can be very important especially father-infant skin-to-skin contact. Few studies have focused on the effect of kangaroo care (KC) on paternal attachment. This randomized controlled study was conducted to determine the effect of KC on paternal attachment. A total of 90 fathers of healthy newborns, including 45 in the intervention group and 45 in the control group who met the inclusion criteria, were included randomly in the study. Data were collected using the Introductory Information Form at study admission and the Father-Infant Attachment Scale (FIAS) at 3 months of age. T test, Mann-Whitney U test, and Kruskal-Wallis test were used for statistical analysis. The mean FIAS scores for the intervention group (I) were higher than for the control group (C) (I: 80.57 ± 13.70; C: 56.76 ± 13.23) ( P < .05). Patience and tolerance (I: 13.70 ± 1.18; C: 11.57 ± 2.30), pleasure in interaction (I: 29.50 ± 2.86; C: 17.13 ± 5.93), and love and pride (I: 37.37 ± 2.85; C: 28.06 ± 5.82) mean scores for FIAS subdimensions in the intervention group were also higher than in the control group ( P < .05). Findings of this study demonstrate that KC has the potential to increase paternal attachment. Healthcare providers should provide discharge education for fathers on KC to increase father-infant attachment. There is a need for studies with larger samples in different cultures on the factors related to parents that affect father-infant attachment and evidence-based practices that increase attachment.


The human beta-defensins (-1, -2, -3, -4) and cathelicidin LL-37 induce IL-18 secretion through p38 and ERK MAPK activation in primary human keratinocytes.
In addition to its physical barrier against invading microorganisms, the skin produces antimicrobial peptides, human beta-defensins (hBDs) and cathelicidin LL-37, that participate in the innate host defense. Because IL-18 is produced by keratinocytes and involved in skin diseases in which hBDs and LL-37 are highly expressed, we hypothesized that these peptides would activate keratinocytes to secrete IL-18. We found that hBD-2, -3, and -4 and LL-37, but not hBD-1, activated normal human keratinocytes to secrete IL-18; this secretion reached peak strength at 3 h. In addition, the combination of peptides resulted in a synergistic effect on IL-18 secretion. We also revealed that hBD-2, -3, and -4 and LL-37 increased IL-18 mRNA expression, and that IL-18 secretion was more enhanced in keratinocytes differentiated in vitro with high Ca2+-containing medium. Furthermore, because IL-18 secretion induced by hBDs and LL-37 could not be suppressed by caspase-1 or caspase family inhibitors, and because these peptides failed to increase caspase-1 activity, we suggest that hBD- and LL-37-induced IL-18 secretion is probably via a caspase-1-independent pathway. To determine the molecular mechanism involved, we demonstrated that IL-18 secretion was through p38 and ERK1/2 MAPK pathways, because the inhibitors of p38 and ERK1/2, but not JNK, almost completely nullified IL-18 secretion. Moreover, hBD-2, -3, and -4 and LL-37 could induce the phosphorylation of p38 and ERK1/2, but not JNK. Thus, the ability of hBDs and LL-37 to induce IL-18 secretion by keratinocytes provides a new mechanism for these peptides in innate immunity and an understanding of their role in the pathogenesis of skin disorders.


[Actual strategies for preventing type-1 diabetes: international literature review].
The exact etiology and mechanisms that trigger the development of type 1 diabetes mellitus (DM1) are not conclusively studied. However, there is increasing scientific evidence that damage to pancreatic islet cells (β-cells) in genetically predisposed individuals is initiated by environmental factors. Currently, the main tactic of DM1 treatment at the stage of clinical manifestations is based on insulin replacement therapy. The introduction of modern insulin drugs and devices for its delivery, as well as continuous glucose monitoring systems into medical practice does not relieve patients from the need to take this hormone for life. Therefore, the development of methods to prevent DM1 remains the main task of diabetes research. The purpose of this article was to review current preventive strategies aimed at preventing or stopping the progression of DM1 in high-risk individuals. This article was prepared based on a review of current publications from the PubMed bibliographic database. The article discusses strategies targeting environmental triggers, methods to regulate the immune response using current cellular approaches and novel autoantigens, as well as off-target effects of the BCG vaccine and general principles of personalized prevention.


Water quality and health in a Sahelian semi-arid urban context: an integrated geographical approach in Nouakchott, Mauritania.
Access to sufficient quantities of safe drinking water is a human right. Moreover, access to clean water is of public health relevance, particularly in semi-arid and Sahelian cities due to the risks of water contamination and transmission of water-borne diseases. We conducted a study in Nouakchott, the capital of Mauritania, to deepen the understanding of diarrhoeal incidence in space and time. We used an integrated geographical approach, combining socio-environmental, microbiological and epidemiological data from various sources, including spatially explicit surveys, laboratory analysis of water samples and reported diarrhoeal episodes. A geospatial technique was applied to determine the environmental and microbiological risk factors that govern diarrhoeal transmission. Statistical and cartographic analyses revealed concentration of unimproved sources of drinking water in the most densely populated areas of the city, coupled with a daily water allocation below the recommended standard of 20 l per person. Bacteriological analysis indicated that 93% of the non-piped water sources supplied at water points were contaminated with 10-80 coliform bacteria per 100 ml. Diarrhoea was the second most important disease reported at health centres, accounting for 12.8% of health care service consultations on average. Diarrhoeal episodes were concentrated in municipalities with the largest number of contaminated water sources. Environmental factors (e.g. lack of improved water sources) and bacteriological aspects (e.g. water contamination with coliform bacteria) are the main drivers explaining the spatio-temporal distribution of diarrhoea. We conclude that integrating environmental, microbiological and epidemiological variables with statistical regression models facilitates risk profiling of diarrhoeal diseases. Modes of water supply and water contamination were the main drivers of diarrhoea in this semi-arid urban context of Nouakchott, and hence require a strategy to improve water quality at the various levels of the supply chain.


Respiratory health outcomes and air pollution in the Eastern Mediterranean Region: a systematic review.
Exposure to air pollution can cause detrimental health and be an economic burden. With newly developed equipment, monitoring of different air pollutants, identifying the sources, types of air pollutants and their corresponding concentrations, and applying mitigation intervention techniques became a crucial step in public health protection. Countries in the Eastern Mediterranean Region (EMR) are highly exposed to dust storms, have high levels of particulate matter (PM) concentrations, and have a unique climatic as well as topographic and socio-economic structure. This is the first study conducted to systemically and qualitatively assess the health impacts of air pollution in the EMR, identify susceptible populations, and ascertain research and knowledge gaps in the literature to better inform decisions by policy makers. We screened relevant papers and reports published between 2000 and 2014 in research databases. A total of 36 published studies met the inclusion criteria. A variety of indoor and outdoor exposures associated with various acute and chronic respiratory health outcomes were included. Respiratory health outcomes ranged in severity, from allergies and general respiratory complaints to lung cancer and mortality. Several adverse health outcomes were positively associated with various indoor/outdoor air pollutants throughout the EMR. However, epidemiological literature concerning the EMR is limited to a few studies in a few countries. More research is needed to elucidate the health outcomes of air pollution. Standardized reliable assessments on the national level for various air pollutants in different regions should be implemented and made publically available for researchers to utilize in their research. Moreover, advancing and utilizing more sound epidemiological designs and studies on the effect of air pollution on the respiratory health outcomes is needed to portray the actual situation in the region.


A nitrogen budget of the Changjiang river catchment.
Based on 1997-1998 field investigations in the Changjiang river mouth, rain sampling from the river's upper reaches to the mouth, historical data, and relevant literature, the various sources of Total Nitrogen (TN) and Dissolved Inorganic Nitrogen (DIN) in the Changjiang river catchment and N transport in the Changjiang river mouth were estimated. The export fluxes of various form of N were mainly controlled by the river runoff, and the export fluxes of NO3-N, DIN and TN in 1998 (an especially heavy flood year) were 1438 10(3) tonnes (t) yr(-1) or 795.1 kg km(-2) yr(-1), 1746 10(3) t yr(-1) or 965.4 kg km(-2) yr(-1) and 2849 10(3) t yr(-1) or 1575.3 kg km(-2) yr(-1), respectively. The TN and DIN in the Changjiang river came mainly from precipitation, agricultural nonpoint sources, N lost from fertilizer and soil, and point sources of industrial waste and residential sewage discharge, which were about 56.2% and 62.3%, 15.4% and 18.5%, 17.1% and 14.4%, respectively, of the N outflow at the Changjiang river mouth; maximum transport being in the middle reaches.


CCL25 and CCL28 promote alpha4 beta7-integrin-dependent adhesion of lymphocytes to MAdCAM-1 under shear flow.
Inflammatory bowel disease is characterized by the recruitment of lymphocytes to the gut via mucosal vessels. Chemokines are believed to trigger alpha(4)beta(1)- and alpha(4)beta(7)-integrin-mediated adhesion to vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on mucosal vessels, although the contribution of each pathway and the chemokines involved are not well characterized. These interactions occur under conditions of hemodynamic shear, which is critical in determining how lymphocytes integrate chemokine signals to promote transmigration. To define the role of specific chemokines in mediating lymphocyte adhesion to VCAM-1 and MAdCAM-1, we studied the ability of immobilized chemokines to activate adhesion of human lymphocytes in a flow-based adhesion assay. Adhesion to immobilized MAdCAM-1 was alpha(4)beta(7) dependent, with no contribution from alpha(4)beta(1), whereas alpha(4)beta(1) mediated rolling and static adhesion on VCAM-1. Immobilized CC-chemokine ligand (CCL) 25 and CCL28 were both able to trigger alpha(4)beta(7)-dependent lymphocyte arrest on MAdCAM-1 under shear, highlighting a potential role for these chemokines in the arrest of lymphocytes on postcapillary venules in the gut. Neither had any effect on adhesion to VCAM-1, suggesting that they selectively trigger alpha(4)beta(7)-mediated adhesion. Immobilized CCL21, CCL25, CCL28, and CXC-chemokine ligand (CXCL) 12 all converted rolling adhesion to static arrest on MAdCAM-1 by activating lymphocyte integrins, but only CCL21 and CXCL12 also triggered a motile phenotype characterized by lamelipodia and uropod formation. Thus alpha(4)beta(1)/VCAM-1 and alpha(4)beta(7)/MAdCAM-1 operate independently to support lymphocyte adhesion from flow, and chemokines may act in concert with one chemokine triggering integrin-mediated arrest and a second chemokine promoting motility and transendothelial migration.


Transport to the plasma membrane is regulated differently early and late in the cell cycle in Saccharomyces cerevisiae.
Traffic from the trans-Golgi network to the plasma membrane is thought to occur through at least two different independent pathways. The chitin synthase Chs3p requires the exomer complex and Arf1p to reach the bud neck of yeast cells in a cell-cycle-dependent manner, whereas the hexose transporter Hxt2p localizes over the entire plasma membrane independently of the exomer complex. Here, we conducted a visual screen for communalities and differences between the exomer-dependent and exomer-independent transport to the plasma membrane in Saccharomyces cerevisiae. We found that most of the components that are required for the fusion of transport vesicles with the plasma membrane, are involved in localization of both Chs3p and Hxt2p. However, the lethal giant larva homologue Sro7p is required primarily for the targeting of Chs3p, and not Hxt2p or other cargoes such as Itr1p, Cwp2p and Pma1p. Interestingly, this transport defect was more pronounced in large-budded cells just before cytokinesis than in small-budded cells. In addition, we found that the yeast Rab11 homologue Ypt31p determines the residence time of Chs3p in the bud neck of small-budded, but not large-budded, cells. We propose that transport to and from the bud neck is regulated differently in small- and large-budded cells, and differs early and late in the cell cycle.


Antarctic soft-bottom benthos in oligotrophic and eutrophic environments.
The benthos of the east and west sides of McMurdo Sound, Antarctica, is characterized by dramatically different infaunal assemblages. The eutrophic East Sound has higher infaunal densities than almost any other benthic assemblage in the world. In contrast, the oligotrophic West Sound, bathed by currents from beneath the Ross Ice Shelf, has patterns of mobile epifauna and low infauna density similar to bathyl deep-sea communities.


Long-term follow-up results of stepwise radical endoscopic resection for Barrett's esophagus with early neoplasia.
Stepwise radical endoscopic resection (SRER) has shown to be effective in eradicating Barrett's esophagus (BE) and its associated dysplasia. The aim of this study was to assess the long-term durability after successful SRER for early Barrett's neoplasia. Patients treated with SRER for BE ≤5 cm with high-grade dysplasia (HGD) or early cancer (EC) and who had reached complete eradication of intestinal metaplasia (CE-IM) and neoplasia (CE-neo) were included. Primary outcomes were recurrence of neoplasia (HGD/EC), recurrence of dysplasia (indefinite for dysplasia included), and recurrence of endoscopically visible BE. Secondary outcomes were buried Barrett's glands, IM in biopsy specimens obtained distal to a normal-appearing neo-squamocolumnar junction (neo-SCJ), need for retreatment, and sustained CE-IM and CE-neo at the last follow-up endoscopy. Seventy-three patients were included (64 men; mean age, 66 years; median BE, C2M3). Median follow-up was 76 months. Recurrence of neoplasia was observed in 1 patient (T1bN0M0) after 129 months of follow-up and was treated with curative surgery (annual incidence of .22% per patient-year of follow-up). In 4 patients, recurrence of dysplasia was found (.87% per patient-year of follow-up). Twelve patients had recurrent endoscopically visible BE after a median follow-up of 22 months (2.6% per patient-year of follow-up), mostly small islands or tongues. Five patients had a single finding of buried Barrett's glands (1.1% per patient-year of follow-up), and 27 patients (5.9% per patient-year of follow-up) showed IM in biopsy specimens just distal to the neo-SCJ, which was not reproduced in 56%. Retreatment was performed in 9 patients. CE-IM and CE-neo (excluding IM in the neo-SCJ) at the last follow-up endoscopy was seen in 95% and 97% of patients, respectively. This study presents the longest published follow-up data on SRER to date. The 6-year outcomes show that successful SRER is a durable treatment for BE ≤5 cm with HGD/EC.


[Cystic abnormalities of the pancreas: inflammatory pseudocyst or neoplasm].
A 79-year-old woman presented with complaints of upper abdominal pain, nausea and vomiting since a few days. Laboratory tests showed no abnormalities except for some indications of an inflammation. Based on the medical history, physical examination and findings from radiological examination, initially the diagnosis was 'chronic pancreatitis with formation ofa pseudocyst caused by alcohol abuse'. After one week the patient developed cholestatic liver function disorders with elevated serum pancreatic enzymes. A CT scan of the abdomen showed a dilated gallbladder and progression of the cystic lesion in the pancreatic head with compression of the distal common bile duct. An endoscopic retrograde cholangiopancreatography was performed and the findings fitted a diagnosis of an intraductal papillary mucinous neoplasm. Differentiation between an inflammatory or neoplastic origin of cystic lesions in the pancreas can be difficult. There is a risk ofmisdiagnosing a cystic neoplasm for a pseudocyst. This may lead to delays in making the correct diagnosis.


Profound morphine tolerance following high-dose methadone therapy.
Cross-tolerance among opioid analgesics may be a barrier to effective pain management. Although the exact mechanism is unknown, methadone continues to remain a viable option when other opioids have failed. Limited data are available regarding the impact of high-dose methadone on subsequent opioid analgesics. Conventional opioid doses may be insufficient for an analgesic effect in patients previously treated with methadone. A case of profound morphine tolerance following high-dose methadone therapy is described. The potential role of methadone-induced cross-tolerance is discussed.


Faster isosurface ray tracing using implicit KD-trees.
The visualization of high-quality isosurfaces at interactive rates is an important tool in many simulation and visualization applications. Today, isosurfaces are most often visualized by extracting a polygonal approximation that is then rendered via graphics hardware or by using a special variant of preintegrated volume rendering. However, these approaches have a number of limitations in terms of the quality of the isosurface, lack of performance for complex data sets, or supported shading models. An alternative isosurface rendering method that does not suffer from these limitations is to directly ray trace the isosurface. However, this approach has been much too slow for interactive applications unless massively parallel shared-memory supercomputers have been used. In this paper, we implement interactive isosurface ray tracing on commodity desktop PCs by building on recent advances in real-time ray tracing of polygonal scenes and using those to improve isosurface ray tracing performance as well. The high performance and scalability of our approach will be demonstrated with several practical examples, including the visualization of highly complex isosurface data sets, the interactive rendering of hybrid polygonal/isosurface scenes, including high-quality ray traced shading effects, and even interactive global illumination on isosurfaces.


A cluster of Shiga Toxin-producing Escherichia coli O157:H7 highlights raw pet food as an emerging potential source of infection in humans.
In August 2017, a cluster of four persons infected with genetically related strains of Shiga toxin-producing Escherichia coli (STEC) O157:H7 was identified. These strains possessed the Shiga toxin (stx) subtype stx2a, a toxin type known to be associated with severe clinical outcome. One person died after developing haemolytic uraemic syndrome. Interviews with cases revealed that three of the cases had been exposed to dogs fed on a raw meat-based diet (RMBD), specifically tripe. In two cases, the tripe had been purchased from the same supplier. Sampling and microbiological screening of raw pet food was undertaken and indicated the presence of STEC in the products. STEC was isolated from one sample of raw tripe but was different from the strain causing illness in humans. Nevertheless, the detection of STEC in the tripe provided evidence that raw pet food was a potential source of human STEC infection during this outbreak. This adds to the evidence of raw pet food as a risk factor for zoonotic transmission of gastrointestinal pathogens, which is widely accepted for Salmonella, Listeria and Campylobacter spp. Feeding RMBD to companion animals has recently increased in popularity due to the belief that they provide health benefits to animals. Although still rare, an increase in STEC cases reporting exposure to RMBDs was detected in 2017. There has also been an increased frequency of raw pet food incidents in 2017, suggesting an increasing trend in potential risk to humans from raw pet food. Recommendations to reduce the risk of infection included improved awareness of risk and promotion of good hygiene practices among the public when handling raw pet food.


Activin signaling targeted by insulin/dFOXO regulates aging and muscle proteostasis in Drosophila.
Reduced insulin/IGF signaling increases lifespan in many animals. To understand how insulin/IGF mediates lifespan in Drosophila, we performed chromatin immunoprecipitation-sequencing analysis with the insulin/IGF regulated transcription factor dFOXO in long-lived insulin/IGF signaling genotypes. Dawdle, an Activin ligand, is bound and repressed by dFOXO when reduced insulin/IGF extends lifespan. Reduced Activin signaling improves performance and protein homeostasis in muscles of aged flies. Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a) within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan. These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling.


A Case of Graves' Disease Accompanied with Acute Hepatitis A Virus Infection.
Concurrent presentation of acute hepatitis A virus (HAV) infection and Graves' disease has not been reported in literature worldwide. Although there is no well-established mechanism that explains the induction of Graves' disease by HAV to date, our case suggests that HAV infection may be responsible for inducing Graves' disease. A healthy 27-year-old female presented fever, palpitation, and diarrhea, and she was subsequently diagnosed as acute HAV infection. Concurrently, she showed hyperthyroidism, and the diagnosis was made as Graves' disease. She had never had symptoms that suggested hyperthyroidism, and previous thyroid function test was normal. Acute HAV infection was recovered by conservative management, however, thyroid dysfunction was maintained even after normalization of liver enzymes. Methimazole was used to treat Graves' disease. We report a case of concurrent acute HAV infection and Graves' disease in a patient without preexisting thyroid disease. This suggests that HAV infection may be a trigger for an autoimmune thyroid disease in susceptible individuals.


[Apparatus Aeltis-Synchro-02-"Yarilo" and vacuum laser therapeutic urologic massager AMVL 01-"Yarovit in the treatment of chronic prostatitis complicated with copulation disfunction].
There are three directions in pathogenetic treatment of chronic prostatitis (CP) which is conducted in parallel to etiotropic one (antimicrobial): general immunological; improving arterial inflow and venous outflow; creation of prostatic secretion outflow and that of seminal vesicles by means of contractions of the pelvic and perineal muscles, muscular fibers of the prostatic gland. The latter two directions can be managed with physiotherapy. It is proposed to use combination of drugs with physiotherapy conducted by means of the devices [see text].


Missing not at random models for latent growth curve analyses.
The past decade has seen a noticeable shift in missing data handling techniques that assume a missing at random (MAR) mechanism, where the propensity for missing data on an outcome is related to other analysis variables. Although MAR is often reasonable, there are situations where this assumption is unlikely to hold, leading to biased parameter estimates. One such example is a longitudinal study of substance use where participants with the highest frequency of use also have the highest likelihood of attrition, even after controlling for other correlates of missingness. There is a large body of literature on missing not at random (MNAR) analysis models for longitudinal data, particularly in the field of biostatistics. Because these methods allow for a relationship between the outcome variable and the propensity for missing data, they require a weaker assumption about the missing data mechanism. This article describes 2 classic MNAR modeling approaches for longitudinal data: the selection model and the pattern mixture model. To date, these models have been slow to migrate to the social sciences, in part because they required complicated custom computer programs. These models are now quite easy to estimate in popular structural equation modeling programs, particularly Mplus. The purpose of this article is to describe these MNAR modeling frameworks and to illustrate their application on a real data set. Despite their potential advantages, MNAR-based analyses are not without problems and also rely on untestable assumptions. This article offers practical advice for implementing and choosing among different longitudinal models.


Formulation, characteristics and antiatherogenic bioactivities of CD36-targeted epigallocatechin gallate (EGCG)-loaded nanoparticles.
Intimal macrophages are determinant cells for atherosclerotic lesion formation by releasing inflammatory factors and taking up oxidized low-density lipoprotein (oxLDL) via scavenger receptors, primarily the CD36 receptor. (-)-Epigallocatechin-3-gallate (EGCG) has a potential to decrease cholesterol accumulation and inflammatory responses in macrophages. We made EGCG-loaded nanoparticles (Enano) using phosphatidylcholine, kolliphor HS15, alpha-tocopherol acetate and EGCG. 1-(Palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine (KOdiA-PC), a CD36-targeted ligand found on oxLDL, was incorporated on the surface of Enano to make ligand-Enano (L-Enano). The objectives of this study are to deliver EGCG to macrophages via CD36-targeted L-Enano and to determine its antiatherogenic bioactivities. The optimized nanoparticles obtained in our study were spherical and around 108 nm in diameter, and had about 10% of EGCG loading capacity and 96% of EGCG encapsulation efficiency. Compared to Enano, CD36-targeted L-Enano had significantly higher binding affinity to and uptake by macrophages at the same pattern as oxLDL. CD36-targeted L-Enano dramatically improved EGCG stability, increased macrophage EGCG content, delivered EGCG to macrophage cytosol and avoided lysosomes. L-Enano significantly decreased macrophage mRNA levels and protein secretion of monocyte chemoattractant protein 1, but did not significantly change macrophage cholesterol content. The innovative CD36-targeted nanoparticles may facilitate targeted delivery of diagnostic, preventive and therapeutic compounds to intimal macrophages for the diagnosis, prevention and treatment of atherosclerosis with enhanced efficacy and decreased side effects.


New model for analysis of mucosal immunity: intestinal secretion of specific monoclonal immunoglobulin A from hybridoma tumors protects against Vibrio cholerae infection.
Secretory immunoglobulin A (sIgA) plays a role in defense against Vibrio cholerae and other microorganisms that infect mucosal surfaces, but it is not established whether sIgA alone can prevent disease. We report here a strategy for identifying the antigen specificities of monoclonal sIgA antibodies that are capable of providing such protection. IgA hybridomas were generated from Peyer's patch lymphocytes after oral immunization with V. cholerae Ogawa 395. A clone was selected that produced dimeric monoclonal IgA antibodies directed against an Ogawa-specific lipopolysaccharide carbohydrate antigen exposed on the bacterial surface. Hybridoma cells were used to produce subcutaneous "backpack" tumors in syngeneic mice, resulting in secretion of monoclonal sIgA onto mucosal surfaces. Neonatal mice bearing anti-lipopolysaccharide hybridoma backpack tumors were specifically protected against oral challenge with 100 50% lethal doses of virulent Ogawa 395 organisms. Thus, the IgA hybridoma backpack tumor method identifies protective epitopes in the mucosal system and demonstrates that a single monoclonal sIgA can be sufficient to protect against intestinal disease.


Finding the balance between surgery and medically-assisted reproduction in women with deep infiltrating endometriosis.
Deep infiltrating endometriosis (DIE) affects several anatomical locations including the bladder, torus uterinum, uterosacral ligament, rectovaginal septum and bowel. It is the most debilitating form of endometriosis and causes severe pain, digestive and urinary symptoms as well as infertility. Faced with an infertile woman suffering from DIE, the dilemma is whether to opt for first-line IVF treatment or for surgery. In the absence of high-level of evidence from randomized studies, several factors should be taken into account in the decision-making process. The main criterion is whether the patient wants in-vitro fertilization (IVF) treatment or not. Secondly, while previous reports have demonstrated the positive impact of surgery on pregnancy, they also underline the risk of severe complications requiring management in expert centers. Despite the availability of predictive models or scoring systems, the decision mainly boils down to the couple's characteristics. It seems logical to propose first-line IVF when spontaneous fertility is not possible due to associated male infertility or tubal obstruction; for women aged ≥35 years; or in women with diminished ovarian reserve. Conversely, first-line surgery could be the best option for women without these characteristics. However, this strategy is mainly based on low-level of evidence underlining the requiring of randomized trials.


Remodeling of glial coverage of glutamatergic synapses in the rat nucleus tractus solitarii after ozone inhalation.
Besides the well-described inflammatory and dysfunction effects on the respiratory tract, accumulating evidence indicates that ozone (O3 ) exposure also affects central nervous system functions. However, the mechanisms through which O3 exerts toxic effects on the brain remain poorly understood. We previously showed that O3 exposure caused a neuronal activation in regions of the rat nucleus tractus solitarii (NTS) overlapping terminal fields of vagal lung afferents. Knowing that O3 exposure can impact astrocytic protein expression, we decided to investigate whether it may induce astroglial cellular alterations in the NTS. Using electron microscopy and immunoblot techniques, we showed that in O3 -exposed animals, the astrocytic coverage of NTS glutamatergic synapses was 19% increased while the astrocyte volume fraction and membrane density were not modified. Moreover, the expression of glial fibrillary acidic protein and S100β, which are known to be increased in reactive astroglia, did not change. These results indicate that O3 inhalation induces a glial plasticity that is restricted to the peri-synaptic coverage without overall astroglial activation. Taken together, these findings, along with our previous observations, support the conclusion that O3 -induced pulmonary inflammation results in a specific activation of vagal lung afferents rather than non-specific overall brain alterations mediated by blood-borne agents. Exposure to ozone, a major atmospheric pollutant, induces an increase in the glial coverage of neurons that is restricted to peri-synaptic compartments. This observation does not support the view that the ozone-induced neuronal disorders are related to non-specific overall brain alterations. It rather argues for a specific activation of the vagus nerve in response to pulmonary inflammation.


Presynaptic and postjunctional muscarinic receptors in dog ileum: binding studies.
[3H]N-Methylscopolamine identified two distinct populations of muscarinic receptors in membranes derived from the longitudinal smooth muscle/myenteric plexus of dog ileum. In isolated axonal varicosities, the half-maximal saturation of binding sites occurred at 2.38 +/- 0.39 nM [3H]N-methylscopolamine, with maximal binding capacity 140 +/- 35 fmol/mg protein (mean +/- S.D., n = 8). In purified smooth muscle plasma membranes, the Kd value was 16 +/- 3 nM with Bmax 1960 +/- 494 fmol/mg. The displacement potencies of subtype-selective muscarinic antagonists in the fraction of axonal varicosities followed the order 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) methiodide much greater than pirenzepine = methoctramine greater than AF-DX 116 with pKi values 7.38, 5.67, 5.70 and 5.13, respectively. Both 4-DAMP methiodide and pirenzepine were approximately 4-fold less potent in displacing the ligand from the receptors in smooth muscle plasma membranes as compared to varicose receptors. The potency ratios of cardioselective antagonists methoctramine and AF-DX 116 on varicose and smooth muscle receptors were 1 and 1.7. It is concluded that presynaptic receptors located on isolated axonal varicosities have pharmacological properties similar to glandular (M3) subtype of muscarinic receptors. The binding properties of receptors present in smooth muscle plasma membranes were found incompatible with those of any of the M1, M2 or M3 subtypes.


Jupiter's Magnetosphere: Plasma Description from the Ulysses Flyby.
Plasma observations at Jupiter show that the outer regions of the Jovian magnetosphere are remarkably similar to those of Earth. Bow-shock precursor electrons and ions were detected in the upstream solar wind, as at Earth. Plasma changes across the bow shock and properties of the magnetosheath electrons were much like those at Earth, indicating that similar processes are operating. A boundary layer populated by a varying mixture of solar wind and magnetospheric plasmas was found inside the magnetopause, again as at Earth. In the middle magnetosphere, large electron density excursions were detected with a 10-hour periodicity as planetary rotation carried the tilted plasma sheet past Ulysses. Deep in the magnetosphere, Ulysses crossed a region, tentatively described as magnetically connected to the Jovian polar cap on one end and to the interplanetary magnetic field on the other. In the inner magnetosphere and lo torus, where corotation plays a dominant role, measurements could not be made because of extreme background rates from penetrating radiation belt particles.


Treating heart failure in older and oldest old patients.
Advanced age is a relevant risk factor for the heart failure (HF). The development of new pharmacological and non-pharmacological approaches has determined an improvement in survival of patients with HF, leading to the selection of an older and frailer population with HF. The clinical approach to such a complex population should require clear indications to assist physicians during their daily practice, but there is a huge lack of evidence regarding the treatment of HF in the oldest among the elderly patient population. In addition, the co-occurrence of specific conditions that are extremely prevalent in older individuals with HF, such as cognitive impairment, comorbidities, and polypharmacy, can further complicate the clinical man agement of this condition. Thus, a multidisciplinary approach with the goal of recognizing and treating conditions associated with HF may be necessary to improve the quality of care and to reduce expenditures. Several studies have assessed the effect of a comprehensive geriatric assessment and management on quality of care in HF patients, demonstrating a substantial improvement in patient outcomes and administration of the appropriate drug treatment.


Early onset of efficacy in patients with functional and motility-related gastrointestinal disorders : A noninterventional study with Iberogast®.
STW 5 (Iberogast®; Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany) contains nine plant extracts and possesses well-documented overall efficacy in functional gastrointestinal disorders (FGID). Little is known about the onset of symptom relief. Twenty-nine centers in Germany recruited 272 patients with established FGID. These patients were treated with STW 5 for approximately 3 weeks in this noninterventional study. Patients assessed the severity of their gastrointestinal complaints before and at defined times after the intake of STW 5 (10 cm visual analogue scale; VAS). Fifteen minutes after the first dose, the severity of gastrointestinal complaints had decreased by 1.4 cm (mean; initial mean: 5.2 of 10 cm). After 1 h, more than 90% of the maximum effect of 3.2 cm on the 10 cm VAS had been reached. Most patients with symptoms experienced a marked improvement within 5, 15 or 30 min of taking STW 5. Absolute improvements were larger in patients with more pronounced baseline complaints. Subgroups with upper (80% of the study population) and lower FGID (20%) did not present major differences. Neither did subgroups by age and duration of complaints. Treatment with STW 5 resulted in rapid improvement of symptoms.


An open, modular, and flexible micro X-ray computed tomography system for research.
In this paper, a modular and open micro X-ray Computed Tomography (μXRCT) system is presented, which was set up during the last years at the Institute of Applied Mechanics (CE) of the University of Stuttgart and earlier at the Institute of Computational Engineering of Ruhr-University Bochum. The system is characterized by its intrinsic flexibility resulting from the modular and open design on each level and the opportunity to implement advanced experimental in situ setups. On the one hand, the presented work is intended to support researchers interested in setting up an experimental XRCT system for the microstructural characterization of materials. On the other hand, it aims to support scientists confronted with the decision to set up a system on their own or to buy a commercial scanner. In addition to the presentation of the various hardware components and the applied modular software concept, the technical opportunities of the open and modular hard- and software design are demonstrated by implementing a simple and reliable method for the compensation of bad detector pixels to enhance the raw data quality of the projections. A detailed investigation of the performance of the presented system with regard to the achievable spatial resolution is presented. XRCT datasets of three different applications are finally shown and discussed, demonstrating the wide scope of options of the presented system.


Effectiveness of diabetes mellitus screening recommendations.
Screening guidelines proposed by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus have been endorsed by several medical societies. However, one-third of cases are undiagnosed, and complications at the time of diagnosis indicate that disease may have been present for several years before diagnosis. This study evaluates the effectiveness of the guidelines for detecting new cases of diabetes mellitus. By using a cross-sectional, representative sample of the United States (National Health and Nutritional Examination Survey, NHANES III), the guidelines are tested on adults, 20 years and older without a prior diagnosis of diabetes. Individuals are classified as nondiabetics (n = 6,241) or as having undiagnosed diabetes (n = 274) based on their blood glucose. Screening when one risk factor is present, as stated in the guidelines, has a true-positive rate of 100% and would require that 83% of the population be tested. Screening when two risk factors are present is more efficient, with a comparable true-positive rate (98%), but requires that only 59% of the population be tested. A notable finding is the earlier age of onset among minorities, which may be associated with other health disparities. Because diabetes occurs at younger ages in minorities, screening whites who are > or =40 and minorities > or =30 years of age has a high true-positive rate (95%) and also reduces testing (60%). The screening guidelines would be effective, if followed, and would essentially eliminate undiagnosed cases of diabetes.


Quality of life, dependency and mental health scales of interest to nutritional studies in the population.
Quality of life, dependency and mental health are multidimensional constructs that cannot be observed directly yet can be deduced in an indirect manner through indicators or profiles generated from questionnaires. These questionnaires are based on the validity of information transmitted by the respondents about perceptions, feelings and attitudes. For this reason, the information is difficult to contrast with and translate to a measuring system. The use of questionnaires or rapid quality of life and mental health evaluation scales involve a process directed towards an early identification of specific problems so as to establish medical treatment. This work will review the most commonly used scales or questionnaires in determining these variables and their relationship with the nutritional status of the population.


Molecularly Imprinted Artificial Biointerface for an Enzyme-Free Glucose Transistor.
A platform based on a highly selective and sensitive detection device functionalized with a well-designed artificial biointerface is required for versatile biosensors. We develop a molecularly imprinted polymer (MIP)-coated gate field-effect transistor (FET) biosensor for low-concentration glucose detection in biological fluid samples such as tears in an enzyme-free manner. The MIP includes glucose templates (GluMIP), in which glucose binds to vinylphenylboronic acid in the copolymerized membrane, resulting in the change in the density of molecular charges of the phenylboronic acid (PBA)/glucose complex. The FET biosensor can detect small biomolecules as long as biomolecular recognition events cause intrinsic changes in the density of molecular charges. As a result, the changes in the output voltage detected using the GluMIP-based FET sensor are fitted to the Langmuir adsorption isotherm equation at various concentrations of sugars, showing the low detection limit of 3 μM and the high sensitivity of 115 mV/decade from 100 μM to 4 mM glucose. On the basis of the equation, the stability constant ( Ka) of PBA with glucose is calculated and found to markedly increase to Ka = 1192 M-1, which is higher by a factor of a few hundreds than Ka = 4.6 M-1 obtained by nonelectrical detection methods. Moreover, the GluMIP-coated gate FET sensor shows an approximately 200-fold higher selectivity for glucose than for fructose. This is because glucose binds to PBA more selectively than fructose in the templates, resulting in the generation of negative charges. The electrical properties of the MIP-coated electrode are also evaluated by measuring capacitance. Our work suggests a new strategy of designing a platform based on the MIP-coated gate FET biosensor, which is suitable for a highly selective, sensitive, enzyme-free biosensing system.


Safety and outcomes following resection of colorectal liver metastases in the era of current perioperative chemotherapy.
Preoperative chemotherapy is increasingly utilized in the treatment of colorectal liver metastases (CRLM). Although this strategy may improve resectability, long-term advantages of preoperative chemotherapy for resectable CRLM are less clear. The objective of this study is to report safety and outcomes when perioperative chemotherapy is routinely added to surgery for CRLM. A retrospective review of patients undergoing liver resections for CRLM during 2003-2011 in single academic oncology center. Demographic data, tumor characteristics, chemotherapy, surgical details, complications and survival were analyzed. The study included 157 patients that underwent 168 liver operations. One hundred eighteen patients (70 %) underwent preoperative chemotherapy (75 % oxaliplatin-based). Preoperative portal vein embolization was utilized in 16 (10.1 %) patients. Overall survival (OS) was 89, 57, and 27 % at 1, 3, and 5 years, respectively (median survival-42.8 months). Eleven (7 %) patients had repeat resections for liver recurrence. Thirty-day mortality was 1.26 %, morbidity-24 % (6 %-liver related). Complications were not significantly different in patients that had preoperative chemotherapy. On a multivariate analysis advanced age and >3 lesions predicted poor OS, while advanced age, lesions >5 cm, synchronous lesions, margin-positivity and resection less than hepatectomy were associated with decreased DFS. Our results suggest that even with chemotherapy and resection only a subset of patients remain disease-free after 5 years. However, even in a high-risk patient with multiple lesions, preoperative chemotherapy can be administered safely without apparent increase in postoperative complications. Perioperative chemotherapy should be considered particularly in patients with multifocal or large lesions, synchronous disease and short disease-free interval.


Effect of methotrexate on embryonal implantation: an experimental rat model.
The aim of this study is to investigate the methotrexate (MTX) in rat embryonal implantation and its association with Glycodelin A (GdA) and Mucin-1 (MUC-1) expression. For this purpose, 32 pregnant rats were divided into four equal groups: non-pregnant rats in group I (n = 8, control) and pregnant rats in group III (n = 8) were injected intraperitoneal with single dose of normal saline, non-pregnant rats in group II (n = 8) and pregnant rats in group IV (n = 8) were given 0.2 mg i.m. injection of MTX before three months of pregnancy. The dams were killed on 5th day of gestation and uterine horn samples were removed. Following dissection and routine histological preparation, immunohistochemical analysis was carried out. During immunohistochemical examination of the tissue samples prepared from the control and experimental groups, a statistically significant difference was observed between the groups in the luminal-glandular-decidualized epithelium of the uterus with GdA and MUC-1. Finally, in light of our findings, MTX adversely affected the expression of two molecules in Wistar Albino rats embryonal implantation model.


Small molecules as modulators of the proteostasis machinery: Implication in cardiovascular diseases.
With the escalating prevalence of cardiovascular diseases, the substantial socioeconomic burden on healthcare systems is intensifying. Accumulating empirical evidence underscores the pivotal role of the proteostasis network in regulating cardiac homeostasis and function. Disruptions in proteostasis may contribute to the loss of protein function or the acquisition of toxic functions, which are intricately linked to the development of cardiovascular ailments such as atrial fibrillation, heart failure, atherosclerosis, and cardiac aging. It is widely acknowledged that the proteostasis network encompasses molecular chaperones, autophagy, and the ubiquitin proteasome system (UPS). Consequently, the proteostasis network emerges as an appealing target for therapeutic interventions in cardiovascular diseases. Numerous small molecules, acting as modulators of the proteostasis machinery, have exhibited therapeutic efficacy in managing cardiovascular diseases. This review centers on elucidating the role of the proteostasis network in various cardiovascular diseases and explores the potential of small molecules as therapeutic agents.


Inhibition of alloreactive cytotoxic T lymphocytes by peptides from the alpha 2 domain of HLA-A2.
Class I major histocompatibility complex (MHC) molecules function in the recognition of antigens by cytotoxic T lymphocytes (CTL). Although this biological role is firmly established and much has been learnt about their structure and polymorphic variation, little is known of the regions of class I molecules that are involved in functional interactions with components of the T-cell surface. Here we show that peptides derived from residues 98-113 of the alpha 2 domain of HLA-A2 specifically inhibit the recognition of target cells by many HLA-A2-specific CTL. In addition to identifying a region that is probably involved in binding the T-cell receptor these results raise the possibility that alloreactive CTL may recognize degraded fragments of class I histocompatibility antigens.


Setting up an acupuncture knee clinic under Practice Based Commissioning.
This paper outlines the setting up of a new service in primary care offering acupuncture to patients with severe osteoarthritis of the knee. The high volume clinic is funded under the Practice Based Commissioning initiative and is the first of its type in the UK. It appears to offer a model for similar services elsewhere.


AtCYP38 ensures early biogenesis, correct assembly and sustenance of photosystem II.
AtCYP38 is a thylakoid lumen protein comprising the immunophilin domain and the phosphatase inhibitor module. Here we show the association of AtCYP38 with the photosystem II (PSII) monomer complex and address its functional role using AtCYP38-deficient mutants. The dynamic greening process of etiolated leaves failed in the absence of AtCYP38, due to specific problems in the biogenesis of PSII complexes. Also the development of leaves under short-day conditions was severely disturbed. Detailed biophysical and biochemical analysis of mature AtCYP38-deficient plants from favorable growth conditions (long photoperiod) revealed: (i) intrinsic malfunction of PSII, which (ii) occurred on the donor side of PSII and (iii) was dependent on growing light intensity. AtCYP38 mutant plants also showed decreased accumulation of PSII, which was shown not to originate from impaired D1 synthesis or assembly of PSII monomers, dimers and supercomplexes as such but rather from the incorrect fine-tuning of the oxygen-evolving side of PSII. This, in turn, rendered PSII centers extremely susceptible to photoinhibition. AtCYP38 deficiency also drastically decreased the in vivo phosphorylation of PSII core proteins, probably related to the absence of the AtCYP38 phosphatase inhibitor domain. It is proposed that during PSII assembly AtCYP38 protein guides the proper folding of D1 (and CP43) into PSII, thereby enabling the correct assembly of the water-splitting Mn(4)-Ca cluster even with high turnover of PSII.


Complement activation during extracorporeal circulation. In vitro comparison of Duraflo II heparin-coated and uncoated oxygenator circuits.
The degree of complement activation during cardiopulmonary bypass is considered a valuable parameter of biocompatibility of the extracorporeal circuit. In an in vitro setting with a heart-lung machine primed with fresh whole blood and saline solution, the C3 activation products C3b, iC3b, and C3c and the terminal complement complex were measured in double-antibody enzyme immunosorbent assays. No differences were found between seven sets treated with Duraflo II heparin coating and seven uncoated sets after 2 hours of circulation. C3 activation products (expressed as median and 95% confidence intervals) increased from 4.5 AU (2.8 to 12.3 AU) to 16.5 AU (10.0 to 19.4 AU) in the uncoated sets (p = 0.02) and from 4.6 AU (2.2 to 5.8 AU) to 19.3 AU (3.5 to 27.1 AU) in the coated sets (p = 0.02). Terminal complement complex increased from 5.7 AU (2.7 to 11.3 AU) to 13.6 AU (8.2 to 17.8 AU) in the uncoated sets (p = 0.02) and from 7.9 AU (4.6 to 11.4 AU) to 17.3 AU (9.4 to 35.1 AU) in the coated sets (p = 0.02). A significant drop in thrombocyte levels was observed in both coated and uncoated sets. In a supplementary series, the sterilization process did not influence the results. Although Duraflo II heparin coating is considered highly effective in preventing coagulation, it did not prevent complement activation in the present in vitro study. We hypothesize that the mode by which the heparin molecule is bound to the surface may be essential to obtain effects on both coagulation and complement system.


DNA Polymerase θ: A Cancer Drug Target with Reverse Transcriptase Activity.
The emergence of precision medicine from the development of Poly (ADP-ribose) polymerase (PARP) inhibitors that preferentially kill cells defective in homologous recombination has sparked wide interest in identifying and characterizing additional DNA repair enzymes that are synthetic lethal with HR factors. DNA polymerase theta (Polθ) is a validated anti-cancer drug target that is synthetic lethal with HR factors and other DNA repair proteins and confers cellular resistance to various genotoxic cancer therapies. Since its initial characterization as a helicase-polymerase fusion protein in 2003, many exciting and unexpected activities of Polθ in microhomology-mediated end-joining (MMEJ) and translesion synthesis (TLS) have been discovered. Here, we provide a short review of Polθ's DNA repair activities and its potential as a drug target and highlight a recent report that reveals Polθ as a naturally occurring reverse transcriptase (RT) in mammalian cells.


Quantitative analysis of the IgG and IgG subclass immune responses to chromosomal Pseudomonas aeruginosa beta-lactamase in serum from patients with cystic fibrosis by western blotting and laser scanning densitometry.
Antibodies against chromosomal beta-lactamase of Pseudomonas aeruginosa (a beta ab) are markers of the development of resistance of P aeruginosa to beta-lactam antibiotics in patients with cystic fibrosis and chronic lung infection. The role of these antibodies in patients with chronic lung infection with P aeruginosa was further investigated by correlating the a beta ab IgG subclasses with pulmonary function in patients with cystic fibrosis. Immunoglobulin G (IgG) and IgG subclass a beta ab were investigated by western blotting and quantified by laser scanning densitometry. A longitudinal study on 43 consecutive patients with cystic fibrosis who developed chronic lung infection with P aeruginosa was performed. IgG subclass a beta ab appeared in all patients with chronic infection with P aeruginosa. Eleven years after the onset of infection all the patients had IgG1, 79% had IgG4, 56% IgG2, and only 16% of the patients had IgG3 a beta ab. The IgG1 and IgG4 a beta ab appeared first, and more than 50% of the patients were IgG1 and IgG4 a beta ab positive within 2-3 years of the onset of infection, but IgG2 positivity only appeared after seven years and IgG3 remained absent from most of the patients. The median a beta ab levels increased during chronic infection: 100-fold for IgG1, 22-fold for IgG2, and 45-fold for IgG4. A 16-fold increase in the IgG3 a beta ab levels was detected in the six patients who developed IgG3 a beta ab. In the first four years of the chronic infection the a beta ab titres were higher in patients with good lung function than in those with poor lung function. The association of a weak IgG3 and a strong IgG4 a beta ab response suggests that the contribution of a beta ab antibodies to lung diseases mediated by immune complexes might be less important than other antipseudomonal antibodies. A beneficial neutralising effect of the a beta ab antibodies on the antibiotic destroying enzymes may be an additional factor.


The current status of intraoperative iPTH assay in surgery for primary hyperparathyroidism.
Intraoperative intact parathyroid hormone (iPTH) monitoring has been accepted by many centers specializing in parathyroid surgery as a useful adjunct during surgery for primary hyperparathyroidism. This method can be utilized in three discreet modes of application: (I) to guide surgical decisions during parathyroidectomy in one of the following clinical contexts: (i) to confirm complete removal of all hyperfunctioning parathyroid tissue, which allows for termination of surgery with confidence that the hyperparathyroid state has been successfully corrected; (ii) to identify patients with additional hyperfunctioning parathyroid tissue following the incomplete removal of diseased parathyroid/s, which necessitates extended neck exploration in order to minimize the risk of operative failure; (II) to differentiate parathyroid from non-parathyroid tissue by iPTH measurement in the fine-needle aspiration washout; (III) to lateralize the side of the neck harboring hyperfunctioning parathyroid tissue by determination of jugular venous gradient in patients with negative or discordant preoperative imaging studies, in order to increase the number of patients eligible for unilateral neck exploration. There are many advantages of minimally invasive parathyroidectomy guided by intraoperative iPTH monitoring, including focused dissection in order to remove the image-indexed parathyroid adenoma with a similar or even higher operative success rate, lower prevalence of complications and shorter operative time when compared to conventional bilateral neck exploration. However, to achieve such excellent results, the surgeon needs to be aware of hormone dynamics during parathyroidectomy and carefully choose the protocol and interpretation criteria that best fit the individual practice. Understanding the nuances of intraoperative iPTH monitoring allows the surgeon for achieving intraoperative confidence in predicting operative success and preventing failure in cases of unsuspected multiglandular disease, while safely limiting neck exploration in the majority of patients with sporadic primary hyperparathyroidism. Thus, parathyroidectomy guided by intraoperative iPTH monitoring for the management of sporadic primary hyperparathyroidism is an ideal option for the treatment of this disease entity. However, the cost-benefit aspects of the standard application of this method still remain a matter of controversy.


[Ultrasound in diagnosis of traumatic intra-abdominal lesions. Value in primary diagnosis in the shock unit].
To evaluate sonography as a tool for initial diagnosis in emergency room patients with abdominal trauma. 174 cases of abdominal trauma were selected from 1837 emergency care patients. The initial sonographic findings were compared to CT-evaluation, operative and autopsy results, and both clinical and sonographic follow-up. In 31 cases initial sonographic findings were positive, leading to 6 laparotomies. In another 6 cases, changes of follow-up sonographic testing led to laparotomy. In 143 patients, the initial sonographic evaluation was negative. In this group, follow-up evaluation revealed changes in 16 cases leading to 3 laparotomies. In 8 patients with stab injuries, the negative sonographic study was confirmed by operative findings. Sonography is a well-tested diagnostic method in evaluating patients with abdominal trauma. Follow-up examinations-even with negative initial results-are needed. While the time interval between evaluations depends on the individual risk factors, hourly reevaluation is generally appropriate.


Mesozooplankton grazing on picocyanobacteria in the Baltic Sea as inferred from molecular diet analysis.
Our current knowledge on the microbial component of zooplankton diet is limited, and it is generally assumed that bacteria-sized prey is not directly consumed by most mesozooplankton grazers in the marine food webs. We questioned this assumption and conducted field and laboratory studies to examine picocyanobacteria contribution to the diets of Baltic Sea zooplankton, including copepods. First, qPCR targeting ITS-1 rDNA sequence of the picocyanobacteria Synechococcus spp. was used to examine picocyanobacterial DNA occurrence in the guts of Baltic zooplankton (copepods, cladocerans and rotifers). All field-collected zooplankton were found to consume picocyanobacteria in substantial quantities. In terms of Synechococcus quantity, the individual gut content was highest in cladocerans, whereas biomass-specific gut content was highest in rotifers and copepod nauplii. Moreover, the gut content in copepods was positively related to the picocyanobacteria abundance and negatively to the total phytoplankton abundance in the water column at the time of sampling. This indicates that increased availability of picocyanobacteria resulted in the increased intake of this prey and that copepods may rely more on picoplankton when food in the preferred size range declines. Second, a feeding experiments with a laboratory reared copepod Acartia tonsa fed a mixture of the picocyanobacterium Synechococcus bacillaris and microalga Rhodomonas salina confirmed that copepods ingested Synechococcus, even when the alternative food was plentiful. Finally, palatability of the picocyanobacteria for A. tonsa was demonstrated using uptake of (13)C by the copepods as a proxy for carbon uptake in feeding experiment with (13)C-labeled S. bacillaris. These findings suggest that, if abundant, picoplankton may become an important component of mesozooplankton diet, which needs to be accounted for in food web models and productivity assessments.


Sabotage at the Powerhouse? Unraveling the Molecular Target of 2-Isopropylbenzaldehyde Thiosemicarbazone, a Specific Inhibitor of Aflatoxin Biosynthesis and Sclerotia Development in Aspergillus flavus, Using Yeast as a Model System.
Amongst the various approaches to contain aflatoxin contamination of feed and food commodities, the use of inhibitors of fungal growth and/or toxin biosynthesis is showing great promise for the implementation or the replacement of conventional pesticide-based strategies. Several inhibition mechanisms were found taking place at different levels in the biology of the aflatoxin-producing fungal species such as Aspergillus flavus: compounds that influence aflatoxin production may block the biosynthetic pathway through the direct control of genes belonging to the aflatoxin gene cluster, or interfere with one or more of the several steps involved in the aflatoxin metabolism upstream. Recent findings pointed to mitochondrial functionality as one of the potential targets of some aflatoxin inhibitors. Additionally, we have recently reported that the effect of a compound belonging to the class of thiosemicarbazones might be related to the energy generation/carbon flow and redox homeostasis control by the fungal cell. Here, we report our investigation about a putative molecular target of the 3-isopropylbenzaldehyde thiosemicarbazone (mHtcum), using the yeast Saccharomyces cerevisiae as model system, to demonstrate how the compound can actually interfere with the mitochondrial respiratory chain.


Social Birth: Rites of Passage for the Newborn.
Rites of passage mark important changes during human life and, for the neonate, its transition from intrauterine life into society. Their original intent was to purify the body from blood and meconium. But the cleansing rites had a spiritual dimension from the very start. When the rites of Mesopotamian, Egyptian, Jewish, Greek, Roman, Hindu, Nordic, Muslim, Maya, and Christian cultures are briefly compared, they reveal a remarkable similarity. What most rites had in common was the cleansing of the body, or sprinkling it with water; special clothing; the exorcism of evil spirits; blessings and prayers for good spirits; and a name-giving ceremony and a feast for family, relatives, and friends. Before this rite, the infant's social existence was incomplete and it could easily be abandoned or killed, as was usual in cases of severe malformations. Infant baptism originated in the 4th century CE with the concept of original sin. Emergency baptism originated in the 12th century and had a profound influence on the development of obstetrics and neonatal care. Rites of passage defined, but also set an end to, the liminal status between life and death in a phase of high mortality and partial personhood, and granted the right to live for the infant.


The expression of an alcohol deprivation effect in the high-alcohol-drinking replicate rat lines is dependent on repeated deprivations.
The alcohol deprivation effect (ADE) is a temporary increase in the ratio of alcohol/total fluid intake and voluntary intake of ethanol (EtOH) solutions over baseline drinking conditions when EtOH access is reinstated after a period of alcohol deprivation. The ADE has been posited to be an animal model for alcohol craving. In the current study, we examined the effects of initial deprivation length and number of deprivation exposures on the ADE in the replicate lines of the high-alcohol-drinking (HAD) rats. Adult male HAD-1 and HAD-2 rats received 24 hr free-choice access to 10% (v/v) EtOH and water for 6 weeks. Rats were then assigned to groups deprived of EtOH for 0 (control), or 2 to 8 weeks. All deprived groups were then given 24 hr access to EtOH for 2 weeks before being deprived of EtOH for another 2 weeks. This cycle of 2 weeks of access and 2 weeks of deprivation was carried out for a total of four deprivations. After the initial EtOH deprivation period, EtOH consumption in HAD-1 and HAD-2 rats returned to baseline levels but failed to exhibit either an early onset ADE (initial 2 hr) or prolonged ADE (24 hr). An ADE was observed in two of the four deprived groups for the HAD-1 rats (2 week and 6 week groups) and in all deprived groups for the HAD-2 rats after a second deprivation, and in all deprived groups of both lines after a third deprivation. In the HAD-2 line, but not in the HAD-1 line, the duration of the ADE was prolonged into the second reinstatement day after the fourth deprivation. The expression of an ADE was observed only after repeated deprivation periods in the HAD lines. The duration of the ADE was prolonged in the HAD-2 line, but not in the HAD-1 line, with repeated deprivations, which suggests a dissociation between selection for alcohol preference and the effects of repeated deprivations on the duration of the ADE.


A dataset of proteomic changes during human heat stress and heat acclimation.
Hotter climates have important impacts on human health and performance. Yet, the cellular and molecular responses involved in human heat stress and acclimation remain understudied. This dataset includes physiological measurements and the plasma concentration of 2,938 proteins collected from 10 healthy adults, before and during passive heat stress that was performed both prior to and after a 7-day heat acclimation protocol. Physiological measurements included body temperatures, sweat rate, cutaneous vascular conductance, blood pressure, and skin sympathetic nerve activity. The proteomic dataset was generated using the Olink Explore 3072 assay, enabling a high-multiplex antibody-based assessment of protein changes based on proximity extension assay technology. The data need to be interpreted in the context of the moderate level of body hyperthermia attained and the specific demographic of young, healthy adults. We have made this dataset publicly available to facilitate research into the cellular and molecular mechanisms involved in human heat stress and acclimation, crucial for addressing the health and performance challenges posed by rising temperatures.


Contributions of an intensive HIV prevention programme in increasing HIV testing among men who have sex with men in Andhra Pradesh, India.
The objective of this study was to identify the factors associated with uptake of HIV testing and to assess their relative contributions in increasing HIV testing. Data are drawn from two rounds of cross-sectional Integrated Behavioural and Biological Assessment (IBBA) surveys of self-identified men who have sex with men (MSM) from Andhra Pradesh, India, recruited through probability-based sampling in 2005-2006 and 2009-2010 (IBBA1, n = 1621; IBBA2, n = 1608, respectively). Logistic regression model was used to assess the relationship between socio-demographic characteristics, sexual behaviours, programme exposure and HIV testing. Significant factors were further parsed using decomposition analysis to examine the contribution of different components of that factor towards the change in HIV testing. There was a significant increase in the proportion of MSM reporting HIV testing from IBBA1 to IBBA2. Higher literacy levels, being 25-34 years old, being a kothi (predominantly receptive), engaging in both commercial and non-commercial sexual relationships and intervention programme exposure contributed the most to the increase in HIV testing.


Linear growth deficit continues to accumulate beyond the first 1000 days in low- and middle-income countries: global evidence from 51 national surveys.
Growth faltering is usually assessed using height-for-age Z-scores (HAZs), which have been used for comparisons of children of different age and sex composition across populations. Because the SD (denominator) for calculating HAZ increases with age, the usefulness of HAZs to assess changes in height over time (across ages) is uncertain. We posited that population-level changes in height as populations age should be assessed using absolute height-for-age differences (HADs) and not HAZs. We used data from 51 nationwide surveys from low- and middle-income countries and graphed mean HAZs and HADs by age. We also calculated annual changes in HAZs and HADs and percentage of total height deficit accumulated annually from birth to age 60 mo using both approaches. Mean HAZ started at -0.4 Z-scores and dropped dramatically up to 24 mo, after which it stabilized and had no additional deterioration. Mean HAD started at -0.8 cm, with the most pronounced faltering occurring between 6 and 18 mo, similar to HAZ. However, in sharp contrast to HAZ, HAD curves had continued increases in the deficit of linear growth from 18 to 60 mo, with no indication of a leveling off. Globally, 70% of the absolute deficit accumulated in height (HAD) at 60 mo was found to be due to faltering during the first "1000 days" (conception to 24 mo), but 30% was due to continued increases in deficit from age 2 to 5 y. The use of HAZ masks these changes because of age-related changes in SD. Therefore, HAD, rather than HAZ, should be used to describe and compare changes in height as children age because detecting any deficit compared with expected changes in height as children grow is important and only HAD does this accurately at all ages. Our findings support the current global programmatic momentum to focus on the first 1000 d. Research is needed to better understand the dynamics and timing of linear growth faltering using indices and indicators that accurately reflect changes over ages and to identify cost-effective ways to prevent growth faltering and its consequences throughout the lifecycle.


Highly Cross-Linked Shape Memory Polymers with Tunable Oxidative and Hydrolytic Degradation Rates and Selected Products Based on Succinic Acid.
Minimally invasive medical devices are of great interest, with shape memory polymers (SMPs) representing one such possibility for producing these devices. Previous work with low density, highly porous SMPs has demonstrated oxidative degradation, while attempts to incorporate hydrolytic degradation have resulted in rapidly decreasing glass transition temperature (T g ), ultimately preventing strain fixity of the materials at clinically relevant temperatures. Through esterification of the amino alcohol triethanolamine, an alcohol containing network was synthesized and incorporated into SMPs. These ester networks were used to control the bulk morphology of the SMP, with the T g remaining above 37 °C when 50% of the alcohol was contributed by the ester network. This methodology also yielded SMPs that could degrade through both hydrolysis and oxidation; by oxidation, the SMPs degrade at a similar rate as the control materials (0.2%/day mass) for the first 30 days, at which point the rate changes to 3.5%/day until the samples become too fragile to examine at 80 days. By comparison, control materials have lost approximately 30% of mass by 140 days, at a constant rate of degradation, demonstrating that the ester SMPs are a promising material system for producing more rapidly degradable, soft, porous biomaterials.


Sexual pleasure and intimacy among men who engage in "bareback sex".
An ethnically diverse sample of 120 mostly gay-identified men who engaged in "bareback" intercourse was recruited via the Internet in New York City. By study design three quarters of participants were HIV-uninfected and engaged in condomless receptive anal intercourse. In the course of face-to-face in-depth interviews, participants were asked what led them to have their first bareback experience as well as to continue with the behavior. Qualitative analysis identified the pivotal role that sexual pleasure and intimacy have in this population and how drives for sexual satisfaction, adventure, intimacy, and love overpower health concerns and condom use recommendations. Men interested in bareback sex use a variety of defense mechanisms to account for, justify, and exonerate their behavior. HIV-prevention interventions have paid insufficient attention to libidinal drives, a crucial element of psychological functioning.


Immunotherapy in advanced non-small-cell lung cancer with EGFR mutations.
EGFR-tyrosine kinase inhibitors (EGFR-TKIs) had been regarded as the front-line treatment for advanced non-small-cell lung cancer (NSCLC) patients with EGFR mutations. However, resistance to EGFR-TKIs is inevitable, it remains a major challenge. Immune checkpoint inhibitors (ICIs) had shown superior clinical efficacy in many types of solid tumors, while it exhibited impaired overall efficacy in NSCLC with EGFR mutations. In this review, we will perform a meta-analysis to assess the relationship between the programmed death ligand 1 (PD-L1) expression and clinical benefit of EGFR-TKIs. We also overview the immunotherapy in advanced NSCLC patients with EGFR mutations to investigate the potential biomarkers predicting the ICIs efficiency, and the subgroups that could benefit from ICIs treatment.


Group I metabotropic glutamate receptor mediated dynamic immune dysfunction in children with fragile X syndrome.
Fragile X syndrome (FXS) is the leading cause of inheritable intellectual disability in male children, and is predominantly caused by a single gene mutation resulting in expanded trinucleotide CGG-repeats within the 5' untranslated region of the fragile X mental retardation (FMR1) gene. Reports have suggested the presence of immune dysregulation in FXS with evidence of altered plasma cytokine levels; however, no studies have directly assessed functional cellular immune responses in children with FXS. In order to ascertain if immune dysregulation is present in children with FXS, dynamic cellular responses to immune stimulation were examined. Peripheral blood mononuclear cells (PBMC) were from male children with FXS (n=27) and from male aged-matched typically developing (TD) controls (n=8). PBMC were cultured for 48 hours in media alone or with lipopolysaccharides (LPS; 1 μg/mL) to stimulate the innate immune response or with phytohemagglutinin (PHA; 8 μg/mL) to stimulate the adaptive T-cell response. Additionally, the group I mGluR agonist, DHPG, was added to cultures to ascertain the role of mGluR signaling in the immune response in subject with FXS. Supernatants were harvested and cytokine levels were assessed using Luminex multiplexing technology. Children with FXS displayed similar innate immune response following challenge with LPS alone when compared with TD controls; however, when LPS was added in the presence of a group I mGluR agonist, DHPG, increased immune response were observed in children with FXS for a number of pro-inflammatory cytokines including IL-6 (P=0.02), and IL-12p40 (P<0.01). Following PHA stimulation, with or without DHPG, no significant differences between subjects with FXS and TD were seen. In unstimulated cultures, subjects with FXS did not display altered dynamic immune response to LPS or PHA alone; however, subjects with FXS showed an altered response to co-current stimulation of LPS and DHPG, such that subjects with FXS failed to inhibit production of pro-inflammatory cytokines, suggesting a role of group I mGluR signaling in innate immune responses in FXS.


Diffuse Idiopathic Skeletal Hyperostosis in Smokers and Restrictive Spirometry Pattern: An Analysis of the COPDGene Cohort.
Diffuse idiopathic skeletal hyperostosis (DISH) is a condition characterized by bony proliferation at sites of tendinous and ligamentous insertions in the spine. Spinal mobility is reduced in DISH and may affect movement in the thorax, potentially leading to restrictive pulmonary function. This study investigated whether DISH is associated with restrictive spirometric pattern (RSP) in former and current smokers. Participants (n = 1784) with complete postbronchodilator spirometry who did not meet spirometric criteria for chronic obstructive pulmonary disease (COPD) at time of enrollment in the COPDGene study were included in this study. Subjects were classified as RSP if they had forced expiratory volume in 1 s(FEV1) to forced vital capacity (FVC) ratio > 0.7 with an FVC < 80%. Computed tomography (CT) scans were scored for the presence of DISH in accordance with the Resnick criteria. Chest CT measures of interstitial and alveolar lung disease, clinical symptoms, health surveys, and 6-min walking distance were recorded. Uni- and multivariable analyses were performed to test the association of DISH with RSP. DISH was present in 236 subjects (13.2%). RSP was twice as common in participants with DISH (n = 90/236, 38.1%) compared to those without DISH (n = 301/1548, 19.4%; p < 0.001). In multivariable analysis, DISH was significantly associated with RSP (OR 1.78; 95% CI 1.22-2.60; p = 0.003) after adjusting for potential confounders. The RSP group with and without DISH had significantly worse spirometry, dyspnea, St. George's Respiratory Questionnaire score, BODE index (Body mass index, airflow Obstruction, Dyspnea and Exercise capacity), and Medical Outcomes Study Short Form-36 questionnaire score. In heavy smokers with an FEV1/FVC ratio > 0.70, DISH is associated with RSP after adjustment for intrinsic and extrinsic causes of restrictive lung function. (Clinical trial registration number: NCT00608764.).


Antimicrobial behavior of polyelectrolyte-surfactant thin film assemblies.
Layer-by-layer (LbL) assembly, a technique that alternately deposites cationic and anionic materials, has proven to be a powerful technique for assembling thin films with a variety of properties and applications. The present work incorporates the antimicrobial agent cetyltrimethylammonium bromide (CTAB) in the cationic layer and uses poly(acrylic acid) (PAA) as the anionic layer. When the films are exposed to a humid environment, these agents diffuse out of the film, inhibiting bacterial growth in neighboring regions. Film growth, microstructure, and antimicrobial efficacy are studied here, with 10-bilayer films yielding thicknesses on the order of 2 microm. Various factors are shown to influence the antimicrobial efficacy including time, temperature, secondary ingredients, and number of bilayers. As more layers are deposited, antimicrobial efficacy is increased because more CTAB is able to diffuse throughout the film, and higher amounts of antimicrobials are released. Additionally, inclusion of the cationic poly(diallyldimethylammonium chloride) (PDDA) in the cationic layer in conjunction with CTAB increases film uniformity, and as a result, antimicrobial effectiveness is enhanced. These thin films provide the ability to render a surface antimicrobial and may be useful for bandages or sterilization of disposable objects (e.g., surgical marker).


Effects of truncation of the carboxy terminus of pseudorabies virus glycoprotein B on infectivity.
Glycoproteins homologous to the type I membrane glycoprotein B (gB) of herpes simplex virus 1 (HSV-1) are the most highly conserved glycoproteins within the family Herpesviridae and are present in members of each herpesvirus subfamily. In the alphaherpesvirus pseudorabies virus (PrV), gB is required for entry into target cells and for direct viral cell-to-cell spread. These processes, though related, appear to be distinct, and thus it was interesting to analyze whether they require different functions of gB. To this end, we established cell lines stably expressing different carboxy-terminally truncated versions of PrV gB by deleting either (i) one predicted intracytoplasmic alpha-helical domain encompassing putative YQRL and dileucine internalization signals, (ii) two predicted intracytoplasmic alpha-helical domains, (iii) the complete intracytoplasmic domain, or (iv) the intracytoplasmic domain and the transmembrane anchor region. Confocal laser scanning microscopy showed that gB derivatives lacking at least the last 29 amino acids (aa) localize close to the plasma membrane, while the full-length protein accumulates in intracellular aggregations. Trans-complementation studies with a gB-deleted PrV (PrV-gB(-)) demonstrated that the 29-aa truncated form lacking the putative internalization signals and the C-terminal alpha-helical domain (gB-008) was efficiently incorporated into PrV-gB(-) virions and efficiently complemented infectivity and cell-to-cell spread. Moreover, gB-008 exhibited an enhanced fusogenic activity. In contrast, gB proteins lacking both alpha-helical domains (gB-007), the complete intracytoplasmic domain, or the intracytoplasmic domain and transmembrane anchor were only inefficiently or not at all incorporated into PrV-gB(-) virions and did not complement infectivity. However, gB-007 was able to mediate cell-to-cell spread of PrV-gB(-). Similar phenotypes were observed when virus recombinants expressing gB-008 or gB-007, respectively, instead of wild-type gB were isolated and analyzed. Thus, our data show that internalization of gB is not required for gB incorporation into virions nor for its function in either entry or cell-to-cell spread. Moreover, they indicate different requirements for gB in these membrane fusion processes.


The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure.
Friedreich ataxia (FRDA), an autosomal recessive, neurodegenerative disease is the most common inherited ataxia. The vast majority of patients are homozygous for an abnormal expansion of a polymorphic GAA triplet repeat in the first intron of the X25 gene, which encodes a mitochondrial protein, frataxin. Cellular degeneration in FRDA may be caused by mitochondrial dysfunction, possibly due to abnormal iron accumulation, as observed in yeast cells deficient for a frataxin homologue. Using RNase protection assays, we have shown that patients homozygous for the expansion have a marked deficiency of mature X25 mRNA. The mechanism(s) by which the intronic GAA triplet expansion results in this reduction of X25 mRNA is presently unknown. No evidence was found for abnormal splicing of the expanded intron 1. Using cloned repeat sequences from FRDA patients, we show that the GAA repeat per se interferes with in vitro transcription in a length-dependent manner, with both prokaryotic and eukaryotic enzymes. This interference was most pronounced in the physiological orientation of transcription, when synthesis of the GAA-rich transcript was attempted. These results are consistent with the observed negative correlation between triplet-repeat length and the age at onset of disease. Using in vitro chemical probing strategies, we also show that the GAA triplet repeat adopts an unusual DNA structure, demonstrated by hyperreactivity to osmium tetroxide, hydroxylamine, and diethyl pyrocarbonate. These results raise the possibility that the GAA triplet-repeat expansion may result in an unusual yet stable DNA structure that interferes with transcription, ultimately leading to a cellular deficiency of frataxin.


Medicines reconciliation using a shared electronic health care record.
: This study aimed to evaluate the use of a shared electronic primary health care record (EHR) to assist with medicines reconciliation in the hospital from admission to discharge. : This is a prospective cross-sectional, comparison evaluation for 2 phases, in a short-term elderly admissions ward in the United Kingdom. In phase 1, full reconciliation of the medication history was attempted, using conventional methods, before accessing the EHR, and then the EHR was used to verify the reconciliation. In phase 2, the EHR was the initial method of retrieving the medication history-validated by conventional methods. : Where reconciliation was led by conventional methods, and before any access to the EHR was attempted, 28 (28%) of hospital prescriptions were found to contain errors. Of 99 prescriptions subsequently checked using the EHR, only 50 (50%) matched the EHR. Of the remainder, 25% of prescriptions contained errors when verified by the EHR. However, 26% of patients had an incorrect list of current medications on the EHR.Using the EHR as the primary method of reconciliation, 33 (32%) of 102 prescriptions matched the EHR. Of those that did not match, 39 (38%) of prescriptions were found to contain errors. Furthermore, 37 (36%) of patients had an incorrect list of current medications on the EHR.The most common error type on the discharge prescription was drug omission; and on the EHR, wrong drug. Common potentially serious errors were related to unidentified allergies and adverse drug reactions. : The EHR can reduce medication errors. However, the EHR should be seen as one of a range of information sources for reconciliation; the primary source being the patient or their carer. Both primary care and hospital clinicians should have read-and-write access to the EHR to reduce errors at care transitions. We recommend further evaluation studies.


Genomic landscape and chronological reconstruction of driver events in multiple myeloma.
The multiple myeloma (MM) genome is heterogeneous and evolves through preclinical and post-diagnosis phases. Here we report a catalog and hierarchy of driver lesions using sequences from 67 MM genomes serially collected from 30 patients together with public exome datasets. Bayesian clustering defines at least 7 genomic subgroups with distinct sets of co-operating events. Focusing on whole genome sequencing data, complex structural events emerge as major drivers, including chromothripsis and a novel replication-based mechanism of templated insertions, which typically occur early. Hyperdiploidy also occurs early, with individual trisomies often acquired in different chronological windows during evolution, and with a preferred order of acquisition. Conversely, positively selected point mutations, whole genome duplication and chromoplexy events occur in later disease phases. Thus, initiating driver events, drawn from a limited repertoire of structural and numerical chromosomal changes, shape preferred trajectories of evolution that are biologically relevant but heterogeneous across patients.


[Various problems of transformation of migraine].
Fifty-four patients aged 25 to 66 years suffering from hemicrania were examined. 21 patients showed certain changes in the clinical picture and course of hemicrania itself: enhancement of paroxysms or transformation of one form of hemicrania to the other one, more severe (e.g. a simple form transforms to an ophthalmic or an associated one). In 15 patients, ++vegeto-dystonic manifestations associated mostly with a significant reduction of migrainous paroxysms themselves and, more rarely, with their dramatic enhancement began with time to play the leading part in the disease clinical picture. Superimposition of essential hypertension or atherosclerosis was also coupled with changes in the course of hemicrania, in particular by an increase of the period of cephalgia and appearance of constant headaches.


cDNA clones encoding 1,3-beta-glucanase and a fimbrin-like cytoskeletal protein are induced by Al toxicity in wheat roots.
A cDNA library made from mRNA of Al-treated roots of an Al-sensitive wheat (Triticum aestivum cv Victory) cultivar was screened with a degenerate oligonucleotide probe derived from the partial amino acid sequence of the Al-induced protein TAI-18. Of seven clones that initially hybridized with the probe, one encoded a novel 1,3-beta-glucanase having a calculated molecular weight of 46.3 and an isoelectric point of 6.0. Like the A6 1,3-beta-glucanase gene products from Brassica napus and Arabidopsis thaliana, the predicted wheat protein had a C-terminal extension with three potential glycosylation sites. Northern analysis revealed that wheat 1,3-beta-glucanase mRNA was up-regulated in Al-intoxicated roots, with highest expression after 12 h. The antibody to A6 1,3-beta-glucanase from B. napus cross-reacted with a 56-kD protein that was induced after 24 h. A second partial cDNA clone showed similarity to genes encoding cytoskeletal fimbrin-like (actin-bundling) proteins. Although well studied in animals and fungi, fimbrins have not previously been described in plants. Fimbrin-like transcripts were up-regulated after 24 h of Al treatment in the Al-sensitive wheat cv Victory. In the Al-tolerant cv Atlas 66, fimbrin-like mRNA was up-regulated within 12 h by Al concentrations that did not inhibit root growth. Cellular stress associated with Al toxicity therefore causes up-regulation of a defense-related gene and a gene involved in the maintenance of cytoskeletal function.


Influence of sympathetic blockade on the acute hypertensive response to aortic constriction.
The objective of the present study was to determine the contribution of the sympathetic nervous system to the hypertensive response to acute (45-min) aortic coarctation in conscious intact or sinoaortic-denervated (SAD) rats. Rats were treated chronically (5 wk) with guanethidine (50 mg.kg-1.day-1 i.p.) to induce sympathetic nerve degeneration or acutely with the alpha 1-adrenergic receptor antagonist prazosin. (1 mg/kg i.v.). Aortic constriction elicited a prompt and sustained rise in mean carotid pressure that was significantly greater in SAD than in intact rats. The increase in pressure was associated with reflex bradycardia only in the intact rats, whereas the heart rate of SAD rats did not change. Guanethidine treatment did not affect the arterial pressure or heart rate responses to aortic coarctation of intact rats but blunted the hypertensive response of SAD rats to the same values exhibited by intact rats. Prazosin administered 10 min after the beginning of aortic coarctation reduced the hypertensive response of SAD rats to the same level as that of intact rats. In conclusion, the data obtained by means of the association of sinoaortic deafferentation with chronic sympathectomy with guanethidine or acute alpha 1-adrenergic receptor blockade with prazosin indicate that the greater hypertensive response of SAD rats involves a lack of suppression of the sympathetic activity in the maintenance of the rise in pressure elicited by aortic coarctation.