Association between Low Testosterone Levels and Sarcopenia in Cirrhosis: A Cross-sectional Study.
Sarcopenia is an independent predictor of mortality in cirrhosis. Hypogonadism is common in cirrhosis and has been associated with sarcopenia in non-cirrhotic chronic liver disease populations. The aim of this study is to investigate if sarcopenia is associated with low testosterone levels in patients with cirrhosis. This is a retrospective analysis of prospectively collected data of 211 cirrhotic patients undergoing evaluation for liver transplantation. Sarcopenia was defined by computed tomography (CT) scan using specific cutoffs of the 3rd lumbar vertebra skeletal muscle index (L3 SMI). Morning testosterone levels were obtained in all patients. Of the 211 patients, sarcopenia was noted in 94 (45%). Testosterone levels were lower in sarcopenic patients (10.7 ± 1.1 vs. 13.7 ± 1.4 nmol/L, p = 0.03) and hypotestosteronemia was more frequent in them too (34 vs. 16%, p = 0.004). In males, those with sarcopenia had lower testosterone levels (14.6 ± 1.4 vs. 21.9 ± 1.8, p = 0.002), and the corresponding frequency of hypotestosteronemia (42 vs. 19%, p = 0.006) was also higher. There were no significant differences in female patients. There was a weak correlation between L3 SMI and testosterone levels (r 0.37, p < 0.001). On multivariable regression analysis including sex, body mass index (BMI), hypotestosteronemia, MELD and etiology of cirrhosis, only hypotestosteronemia (RR 2.76, p = 0.005) and BMI (RR 0.88, p < 0.001) were independently associated with sarcopenia. Low testosterone levels are associated with sarcopenia in male cirrhotic patients. The potential therapeutic effect of testosterone to reverse sarcopenia in these patients warrants evaluation in future trials.


Distal ureterectomy techniques in laparoscopic and robot-assisted nephroureterectomy: Updated review.
Controversies exist about the best method for managing the distal ureter during the laparoscopic (LNU) and robot-assisted nephroureterectomy (RANU). Therefore, PubMed, Scopus and Web of Science databases were searched in order to identify articles describing the management of distal ureter during LNU or RANU in patients suffering from upper urinary tract urothelial cell carcinoma. Forty seven articles were selected for their relevance to the subject of this review. The approaches that are usually performed regarding the distal ureter management are open excision, transurethral resection of ureteral orifice (Pluck Technique), ureteric intussusception and pure LNU or pure RANU. Pure LNU and RANU with complete laparoscopic dissection and suture reconstruction of ureter and bladder cuff seems to be better tolerated than open nephroureterectomy providing equal efficacy, without deteriorating the oncological outcome, however evidence is poor. Transurethral resection of the ureteric orifice and the bladder cuff after occlusion of the ureter with a balloon catheter seems to be an attractive alternative option for low stage, low grade tumors of the renal pelvis and the proximal ureter, while stapling technique is correlated with the increased risk of positive surgical margins. The open resection of the distal ureter in continuity with the bladder cuff is considered the most reliable approach, preferred in our practice as well, however the existing data are based on retrospective and non-randomized studies.


High doses of biotin in chronic progressive multiple sclerosis: a pilot study.
No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis. The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS. Uncontrolled, non-blinded proof of concept study 23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures. In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment׳s onset. These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going.


Preventing adolescent drug use: long-term results of a junior high program.
Although several studies have reported short-term gains for drug-use prevention programs targeted at young adolescents, few have assessed the long-term effects of such programs. Such information is essential for judging how long prevention benefits last. This paper reports results over a 6-year period for a multisite randomized trial that achieved reductions in drug use during the junior high school years. The 11-lesson curriculum, which was tested in 30 schools in eight highly diverse West Coast communities, focused on helping 7th and 8th grade students develop the motivation and skills to resist drugs. Schools were randomly assigned to treatment and control conditions. About 4000 students were assessed in grade 7 and six times thereafter through grade 12. Program effects were adjusted for pretest covariates and school effects. Once the lessons stopped, the program's effects on drug use stopped. Effects on cognitive risk factors persisted for a longer time (many through grade 10), but were not sufficient to produce corresponding reductions in use. It is unlikely that early prevention gains can be maintained without additional prevention efforts during high school. Future research is needed to develop and test such efforts.


Randomized clinical trials in orthopaedic surgery: strategies to improve quantity and quality.
Randomized clinical trials (RCTs) generally provide the highest quality and least biased evidence for treatment effectiveness. Relatively few high-quality RCTs have been published in the orthopaedic literature. Barriers to increasing the quantity of trials include the orthopaedic culture, patient preferences, and the availability of treatment outside trials. Challenges to conducting better quality trials include sample size, random allocation, and blinding. Undertaking more high-quality trials can improve the evidence available for determining treatment effectiveness, resulting in better patient care.


SMART MOVE - a smartphone-based intervention to promote physical activity in primary care: study protocol for a randomized controlled trial.
Sedentary lifestyles are now becoming a major concern for governments of developed and developing countries with physical inactivity related to increased all-cause mortality, lower quality of life, and increased risk of obesity, diabetes, hypertension and many other chronic diseases. The powerful onboard computing capacity of smartphones, along with the unique relationship individuals have with their mobile phones, suggests that mobile devices have the potential to influence behavior. However, no previous trials have been conducted using smartphone technology to promote physical activity. This project has the potential to provide robust evidence in this area of innovation. The aim of this study is to evaluate the effectiveness of a smartphone application as an intervention to promote physical activity in primary care. A two-group, parallel randomized controlled trial (RCT) with a main outcome measure of mean difference in daily step count between baseline and follow up over eight weeks. A minimum of 80 active android smartphone users over 16 years of age who are able to undertake moderate physical activity are randomly assigned to the intervention group (n = 40) or to a control group (n = 40) for an eight week period. After randomization, all participants will complete a baseline period of one week during which a baseline mean daily step count will be established. The intervention group will be instructed in the usability features of the smartphone application, will be encouraged to try to achieve 10,000 steps per day as an exercise goal and will be given an exercise promotion leaflet. The control group will be encouraged to try to walk an additional 30 minutes per day along with their normal activity (the equivalent of 10,000 steps) as an exercise goal and will be given an exercise promotion leaflet. The primary outcome is mean difference in daily step count between baseline and follow-up. Secondary outcomes are systolic and diastolic blood pressure, resting heart rate, mental health score using HADS and quality of life score using Euroqol. Randomization and allocation to the intervention and groups will be carried out by an independent researcher, ensuring the allocation sequence is concealed from the study researchers until the interventions are assigned. The primary analysis is based on mean daily step count, comparing the mean difference in daily step count between the baseline and the trial periods in the intervention and control groups at follow up.


Quality of life improves within 30 days of surgery for Crohn's disease.
The effect of surgery on quality of life (QOL) in the early postoperative period is important in Crohn's disease because of the multiple surgical procedures that patients undergo and the acute QOL benefits that might occur as a result of modifications of medical treatment. Earlier studies of the effect of surgery on QOL have been retrospective and assessed changes 3 to 24 months after surgery. This study prospectively assesses the effect of surgery on QOL in the early postoperative period. Patients requiring surgical management of sequelae of Crohn's disease were obtained from a prospectively entered database including data on QOL. Preoperative and 30-day postoperative QOL were determined in 82 patients using Cleveland Global Quality of Life (CGQL) scores (range from 0 [worst] to 10 [best possible] QOL). Preoperative and postoperative scores were compared using a paired t-test to determine the significance of any change in QOL after surgery. The effect of other variables on change in QOL after surgery was assessed using the t-test or analysis of variance. Multifactor analysis of variance was used to assess the effect of several independent variables. Eighty-two patients (41 women) of 142 patients who had had surgery (58%) had complete preoperative and 30-day postoperative scores. The incidence of complications was 23% (11% were major). There was a significant improvement in QOL 30 days after surgery as measured by CGQL (0.6 +/- 0.2 preoperative to 0.7 +/- 0.2 postoperative; mean +/- SD; p < 0.001). The mean preoperative CGQL was 0.56 +/- 0.24 and the mean improvement was 0.11 +/- 0.20 toward a better QOL. Female patients (p < 0.05) and those who did not develop complications within 30 days of surgery (p < 0.05) had a significantly greater improvement in CGQL after surgery than other groups. No other factor was predictive of improved outcomes. QOL as measured by CGQL improves early after surgery (30 days postoperatively). Improvement in CGQL is greater in female patients and patients who do not develop complications in the postoperative period. It is not affected by other patient characteristics, nature of disease, indication, or procedure performed. Most patients who undergo surgery for Crohn's disease feel that surgery has helped them and would undergo surgery again.


Influence of PEG chain on the complement activation suppression and longevity in vivo prolongation of the PCL biomedical nanoparticles.
The process of opsonization is the major biological barrier to the injectable polymeric nanoparticles (NPs). Complement protein is one kind of opsonins and it can be activated potentially by the negative charged particles. The fragment C3b generated by complement activation could subsequently induce the opsonization on the NPs surface. The aim of our work was to examine the relationship between the hydrophilic poly(ethylene glycol) (PEG) chain on the surface of NPs and particles longevity in vivo from the biological point of view such as complement activation (C3 cleavage) as well as uptake by macrophages. The studies showed that the introduction of PEG chains led to slightly smaller NPs with lower polydispersities than those prepared from naked poly(epsilon-caprolactone) (PCL) and enhanced the zeta potential of NPs from -27.17 mV to -6.046 mV. It was also found that PEG hydrophilic chain could decrease the C3 cleavage and remarkably suppress opsonization and phagocytosis subsequently. In biodistribution investigations in vivo, as a control, PCL NPs were present in MPS tissues in the first 5 min followed by metabolism elimination rapidly, whereas the PEGylated NPs had more particles blood retention in vivo after injection. In fact, in present work, it has been convinced that these results in vivo could be predicted by the in vitro fluorescent phagocytosis model and the extent of complement activation in advance.


Neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and SLC25A13 mutations among Thai infants.
The most common causes of cholestatic jaundice are biliary atresia and idiopathic neonatal hepatitis (INH). Specific disorders underlying INH, such as various infectious and metabolic causes, including neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) especially, in East Asian populations are increasingly being identified. Since most NICCD infants recovered from liver disease by 1 year of age, they often are misdiagnosed with INH, leading to difficulty in determining the true prevalence of NICCD. Mutation(s) of human SLC25A13 gene encoding a mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), can lead to AGC2 deficiency, resulting in NICCD and an adult-onset fatal disease namely citrullinemia type II (CTLN2). To study the prevalence of NICCD and SLC25A13 mutations in Thai infants, and to compare manifestations of NICCD and non-NICCD, infants with idiopathic cholestatic jaundice or INH were enrolled. Clinical and biochemical data were reviewed. Urine organic acid and plasma amino acids profiles were analyzed. PCR-sequencing of all 18 exons of SLC25A13 and gap PCR for the mutations IVS16ins3kb and Ex16+74_IVS17-32del516 were performed. mRNA were analyzed in selected cases with possible splicing error. Five out of 39 (12.8%) unrelated infants enrolled in the study were found to have NICCD, of which three had homozygous 851del4 (GTATdel) and two compound heterozygous 851del4/IVS16ins3kb and 851del4/1638ins23, respectively. Two missense mutations (p.M1? and p.R605Q) of unknown functional significance were identified. At the initial presentation, NICCD patients had higher levels of alkaline phosphatase (ALP) and alpha-fetoprotein (AFP) and lower level of alanine aminotransferase (ALT) than those in non-NICCD patients (p< 0.05). NICCD patients showed higher citrulline level and threonine/serine ratio than non-NICCD infants (p< 0.05). Fatty liver was found in 2 NICCD patients. Jaundice resolved in all NICCD and in 87.5% of non-NICCD infants at the median age of 9.5 and 4.0 months, respectively. NICCD should be considered in infants with idiopathic cholestasis. The preliminary estimated prevalence of NICCD was calculated to be 1/48,228 with carrier rate of 1/110 among Thai infants. However, this number may be underestimated and required further analysis with mutation screening in larger control population to establish the true prevalence of NICCD and AGC2 deficiency.


Role of protein kinase C in interleukin 1, anti-T3, and mitogenic lectin-induced interleukin 2 secretion.
Activation of T-lymphocytes by antigen, mitogenic lectins, or antibodies against the T-cell receptor complex, particularly in the presence of IL1, induces the secretion of the T-cell growth factor IL2. IL2 then has a major role in regulating the duration and magnitude of the immune response. Interaction of antigen, antibodies against the T-cell receptor complex, or mitogenic lectins with T-lymphocytes also induces hydrolysis of membrane phospholipids, leading to the production of diacylglycerol, an activator of the Ca2+- and phospholipid-dependent phosphotransferase, protein kinase C (PKC). Phorbol esters, potent activators of PKC, augment secretion of the T-cell growth factor, interleukin 2 (IL2). Activation of PKC may therefore serve as an important early event in the production and secretion of IL2. We have determined whether IL2 secretion can be induced in the murine cell T-lymphocyte line LBRM 331A5, where PKC is inhibited by staurosporine or sphingosine or in cells where PKC is depleted by prolonged incubation with high concentrations of phorbol esters. In cells in which PKC was either inhibited or depleted, antibodies against the T3 portion of the T-cell receptor complex and the mitogenic lectin phytohemagglutinin (PHA) still triggered IL2 secretion. In addition, the monokine IL1 augmented this IL2 secretion irrespective of whether PKC was inhibited or depleted. These data indicate that activation of PKC is not an obligatory step for IL2 secretion in LBRM 331A5 murine T-lymphocytes.


Micronutrients versus standard medication management in autism: a naturalistic case-control study.
Autism spectrum disorder (ASD) is often accompanied by self-injurious behavior (SIB), aggression, and tantrums, symptoms that have reportedly improved with micronutrient (vitamins and minerals) treatment. The current study took advantage of naturally occurring differences in parental preferences for treatment approaches. The micronutrient group asked for treatment without pharmaceuticals (n = 44, aged 2-28 years at entry [M = 8.39 +/- 5.58]). Their records were matched with those of 44 similar children whose families requested conventional treatment (medication group). Both groups improved on both the Childhood Autism Rating Scale and the Childhood Psychiatric Rating Scale (all p values <0.0001). Both groups also exhibited significant decreases in total Aberrant Behavior Checklist scores, but the micronutrient group's improvement was significantly greater (p < 0.0001). SIB Intensity was lower in the micronutrient group at the end of the study (p = 0.005), and improvement on the Clinical Global Impressions scale was greater for the micronutrient group (p = 0.0029). It is difficult to determine whether the observed changes were exerted through improvement in mood disorder or through an independent effect on autistic disorder. There were some advantages to treatment with micronutrients-lower activity level, less social withdrawal, less anger, better spontaneity with the examiner, less irritability, lower intensity SIB, markedly fewer adverse events, and less weight gain. Advantages of medication management were insurance coverage, fewer pills, and less frequent dosing.


Enhanced neurocognitive functioning and positive temperament in twins discordant for bipolar disorder.
Based on evidence linking creativity and bipolar disorder, a model has been proposed whereby factors influencing liability to bipolar disorder confer certain traits with positive effects on reproductive fitness. The authors tested this model by examining key traits known to be associated with evolutionary fitness, namely, temperament and neurocognition, in individuals carrying liability for bipolar disorder. Schizophrenia probands and their co-twins were included as psychiatric controls. Twin pairs discordant for bipolar disorder and schizophrenia and control pairs were identified through the Swedish Twin Registry. The authors administered a neuropsychological test battery and temperament questionnaires to samples of bipolar probands, bipolar co-twins, schizophrenia probands, schizophrenia co-twins, and controls. Multivariate mixed-model analyses of variance were conducted to compare groups on temperament and neurocognitive scores. Bipolar co-twins showed elevated scores on a "positivity" temperament scale compared with controls and bipolar probands, while bipolar probands scored higher on a "negativity" scale compared with their co-twins and controls, who did not differ. Additionally, bipolar co-twins showed superior performance compared with controls on tests of verbal learning and fluency, while bipolar probands showed performance decrements across all neurocognitive domains. In contrast, schizophrenia co-twins showed attenuated impairments in positivity and overall neurocognitive functioning relative to their ill proband counterparts. These findings suggest that supra-normal levels of sociability and verbal functioning may be associated with liability for bipolar disorder. These effects were specific to liability for bipolar disorder and did not apply to schizophrenia. Such benefits may provide a partial explanation for the persistence of bipolar illness in the population.


Maternal vitamin D status determines bone variables in the newborn.
Vitamin D regulates 3% of the human genome, including effects on bone health throughout life. Maternal vitamin D status may program neonatal skeletal development. The objective here was to determine the association of mothers' vitamin D status with bone variables of their newborns. In a birth hospital, pregnant women (n = 125) participated in a cross-sectional study with a longitudinal follow-up of the pregnancy. The mean (sd) values for age, body mass index before pregnancy, pregnancy weight gain, and total vitamin D intake in mothers were 31 (4) yr, 23.5 (3.7) kg/m(2), 13.1 (4.3) kg, and 14.3 (5.8) microg, respectively. All newborns were full-term, 99% were appropriate for gestational age, and 53% were boys. Blood samples were collected from mothers during the first trimester and 2 d postpartum and from umbilical cords at birth for analysis of serum 25-hydroxyvitamin D (S-25-OHD), PTH, and bone remodeling markers. Bone variables were measured by pQCT at the 20% site of the newborn tibia on an average of 10 (11) d postpartum. Bone contour was analyzed with a single threshold of 180 mg/mm(3) for the detection of total bone mineral density (BMD), bone mineral content (BMC), and cross-sectional area (CSA). Mean S-25-OHD was 41.0 (13.6), 45.1 (11.9), and 50.7 (14.9) nmol/liter during the first trimester, postpartum, and in the umbilical cord, respectively. The median value of the individual means for first trimester and the 2-d postpartum S-25-OHD was 42.6 nmol/liter, which was used as cutoff to define two equal-sized groups. Groups are called below median and above median in the text. Newborns below median were heavier (P = 0.05), and 60% were boys. Tibia bone mineral content was 0.047 (95% confidence interval, 0.011-0.082) g/cm higher (P = 0.01), and cross-sectional area was 12.3 (95% confidence interval, 2.0-22.6) mm(2) larger (P = 0.02), but no difference in bone mineral density was observed, above median compared with below median group. These results were adjusted for newborn Z-score birth weight, maternal height, and newborn age at the measurement. A positive, significant correlation was observed between remodeling markers in mothers at different time points and above median group in the cord. Although the mean total intake of vitamin D among mothers met current Nordic recommendations, 71% of women and 15% of newborns were vitamin D deficient during the pregnancy. Our results suggest that maternal vitamin D status affects bone mineral accrual during the intrauterine period and influences bone size. More efforts should be made to revise current nutrition recommendations for pregnant women that may have permanent effects on the well-being of children.


Willingness-to-pay for community-based insurance in Burkina Faso.
To study the willingness-to-pay (WTP) for a proposed community-based health insurance (CBI) scheme in order to provide information about the relationship between the premium that is required to cover the costs of the scheme and expected insurance enrollment levels. In addition, factors that influence WTP were to be identified. Data were collected from a household survey using a two-stage cluster sampling approach, with each household having the same probability of being selected. Interviews were conducted with 2414 individuals and 705 household heads. The take-it-or-leave-it (TIOLI) and the bidding game were used to elicit WTP. The average individual was willing to pay 2384 (elicited by the TIOLI) or 3191 (elicited by the bidding game) CFA (3.17 US dollars or 4.25 US dollars) to join CBI for him/herself. The head of household agreed to pay from 6448 (elicited by the TIOLI) or 9769 (elicited by the bidding game) CFA (8.6 US dollars or 13.03 US dollars) to join the health insurance scheme for his/her household. These results were influenced by household and individual ability-to-pay, household and individual characteristics, such as age, sex and education. The two methods yielded similar patterns of estimated WTP, in that higher WTP was obtained for higher income level, higher previous medical expenditure, higher education, younger people and males. A starting point bias was found in the case of the bidding game. Both TIOLI and bidding game methods can elicit a value of WTP for CBI. The value elicited by the bidding game is higher than by the TIOLI, but the two approaches yielded similar patterns of estimated WTP. WTP information can be used for setting insurance premium. When setting the premiums, it is important to consider differences between the real market and the theoretical one, and between the WTP and the cost of benefits package. The beneficiaries of CBI should be enrolled at the level of households or villages in order to protect vulnerable groups such as women, elders and the poor.


Management of obesity.
A modern approach to obesity acknowledges the multifactorial determinants of weight gain and the health benefits to be derived from weight loss. Foundational to any weight loss effort is lifestyle change, diet, and increased physical activity. The approach should be a high quality diet to which patients will adhere accompanied by an exercise prescription describing frequency, intensity, type, and time with a minimum of 150 min moderate weekly activity. For patients who struggle with weight loss and who would receive health benefit from weight loss, management of medications that are contributing to weight gain and use of approved medications for chronic weight management along with lifestyle changes are appropriate. Medications approved in the USA or European Union are orlistat, naltrexone/bupropion, and liraglutide; in the USA, lorcaserin and phentermine/topiramate are also available. Surgical management (gastric banding, sleeve gastrectomy, and Roux-en Y gastric bypass) can produce remarkable health improvement and reduce mortality for patients with severe obesity.


Chemical structure of wood charcoal by infrared spectroscopy and multivariate analysis.
In this work, the effect of temperature on charcoal structure and chemical composition is investigated for four tree species. Wood charcoal carbonized at various temperatures is analyzed by mid infrared spectroscopy coupled with multivariate analysis and by thermogravimetric analysis to characterize the chemical composition during the carbonization process. The multivariate models of charcoal were able to distinguish between species and wood thermal treatments, revealing that the characteristics of the wood charcoal depend not only on the wood species, but also on the carbonization temperature. This work demonstrates the potential of mid infrared spectroscopy in the whiskey industry, from the identification and classification of the wood species for the mellowing process to the chemical characterization of the barrels after the toasting and charring process.


Spreading Patterns of NDM-Producing Enterobacteriaceae in Clinical and Environmental Settings in Yangon, Myanmar.
The spread of carbapenemase-producing Enterobacteriaceae (CPE), contributing to widespread carbapenem resistance, has become a global concern. However, the specific dissemination patterns of carbapenemase genes have not been intensively investigated in developing countries, including Myanmar, where NDM-type carbapenemases are spreading in clinical settings. In the present study, we phenotypically and genetically characterized 91 CPE isolates obtained from clinical (n = 77) and environmental (n = 14) samples in Yangon, Myanmar. We determined the dissemination of plasmids harboring genes encoding NDM-1 and its variants using whole-genome sequencing and plasmid analysis. IncFII plasmids harboring blaNDM-5 and IncX3 plasmids harboring blaNDM-4 or blaNDM-7 were the most prevalent plasmid types identified among the isolates. The IncFII plasmids were predominantly carried by clinical isolates of Escherichia coli, and their clonal expansion was observed within the same ward of a hospital. In contrast, the IncX3 plasmids were found in phylogenetically divergent isolates from clinical and environmental samples classified into nine species, suggesting widespread dissemination of plasmids via horizontal transfer. Half of the environmental isolates were found to possess IncX3 plasmids, and this type of plasmid was confirmed to transfer more effectively to recipient organisms at a relatively low temperature (25°C) compared to the IncFII plasmid. Moreover, various other plasmid types were identified harboring blaNDM-1, including IncFIB, IncFII, IncL/M, and IncA/C2, among clinical isolates of Klebsiella pneumoniae or Enterobacter cloacae complex. Overall, our results highlight three distinct patterns of the dissemination of blaNDM-harboring plasmids among CPE isolates in Myanmar, contributing to a better understanding of their molecular epidemiology and dissemination in a setting of endemicity.


MTADV 5-MER peptide suppresses chronic inflammations as well as autoimmune pathologies and unveils a new potential target-Serum Amyloid A.
Despite the existence of potent anti-inflammatory biological drugs e.g., anti-TNF and anti IL-6 receptor antibodies, for treating chronic inflammatory and autoimmune diseases, these are costly and not specific. Cheaper oral available drugs remain an unmet need. Expression of the acute phase protein Serum Amyloid A (SAA) is dependent on release of pro-inflammatory cytokines IL-1, IL-6 and TNF-α during inflammation. Conversely, SAA induces pro-inflammatory cytokine secretion, including Th17, leading to a pathogenic vicious cycle and chronic inflammation. 5- MER peptide (5-MP) MTADV (methionine-threonine-alanine-aspartic acid-valine), also called Amilo-5MER, was originally derived from a sequence of a pro-inflammatory CD44 variant isolated from synovial fluid of a Rheumatoid Arthritis (RA) patient. This human peptide displays an efficient anti-inflammatory effects to ameliorate pathology and clinical symptoms in mouse models of RA, Inflammatory Bowel Disease (IBD) and Multiple Sclerosis (MS). Bioinformatics and qRT-PCR revealed that 5-MP, administrated to encephalomyelytic mice, up-regulates genes contributing to chronic inflammation resistance. Mass spectrometry of proteins that were pulled down from an RA synovial cell extract with biotinylated 5-MP, showed that it binds SAA. 5-MP disrupted SAA assembly, which is correlated with its pro-inflammatory activity. The peptide MTADV (but not scrambled TMVAD) significantly inhibited the release of pro-inflammatory cytokines IL-6 and IL-1β from SAA-activated human fibroblasts, THP-1 monocytes and peripheral blood mononuclear cells. 5-MP suppresses the pro-inflammatory IL-6 release from SAA-activated cells, but not from non-activated cells. 5-MP could not display therapeutic activity in rats, which are SAA deficient, but does inhibit inflammations in animal models of IBD and MS, both are SAA-dependent, as shown by others in SAA knockout mice. In conclusion, 5-MP suppresses chronic inflammation in animal models of RA, IBD and MS, which are SAA-dependent, but not in animal models, which are SAA-independent.


Brain Glucose Metabolism, Cognition, and Cardiorespiratory Fitness Following Exercise Training in Adults at Risk for Alzheimer's Disease.
Aerobic exercise has been associated with reduced burden of brain and cognitive changes related to Alzheimer's disease (AD). However, it is unknown whether exercise training in asymptomatic individuals harboring risk for AD improves outcomes associated with AD. We investigated the effect of 26 weeks of supervised aerobic treadmill exercise training on brain glucose metabolism and cognition among 23 late-middle-aged adults from a cohort enriched with familial and genetic risk of AD. They were randomized to Usual Physical Activity (PA) or Enhanced PA conditions. Usual PA received instruction about maintaining an active lifestyle. Enhanced PA completed a progressive exercise training program consisting of 3 sessions of treadmill walking per week for 26 weeks. By week seven, participants exercised at 70- 80% heart rate reserve for 50 minutes per session to achieve 150 minutes of moderate intensity activity per week in accordance with public health guidelines. Before and after the intervention, participants completed a graded treadmill test to assess VO2peak as a measure of cardiorespiratory fitness (CRF), wore an accelerometer to measure free-living PA, underwent 18F-fluorodeoxyglucose positron emission tomography imaging to assess brain glucose metabolism, and a neuropsychological battery to assess episodic memory and executive function. VO2peak increased, sedentary behavior decreased, and moderate-to-vigorous PA increased significantly in the Enhanced PA group as compared to Usual PA. Glucose metabolism in the posterior cingulate cortex (PCC) did not change significantly in Enhanced PA relative to Usual PA. However, change in PCC glucose metabolism correlated positively with change in VO2peak. Executive function, but not episodic memory, was significantly improved after Enhanced PA relative to Usual PA. Improvement in executive function correlated with increased VO2peak. Favorable CRF adaptation after 26 weeks of aerobic exercise training was associated with improvements in PCC glucose metabolism and executive function, important markers of AD.


Diagnostic value of sonography in patients with suspected carpal tunnel syndrome: a prospective study.
To determine the diagnostic value of sonography in patients with suspected carpal tunnel syndrome (CTS). We conducted a prospective study of 110 wrists in 74 consecutive patients with suspected CTS who had been referred to a tertiary care center. We determined the largest cross-sectional area of the median nerve at the carpal tunnel. Because of the lack of a universally accepted reference standard, we first examined the association of sonography with nerve conduction. Then, we compared sonography with a reference standard based on the combination of nerve conduction studies and signs and symptoms. Sonography and reference standard tests were performed independently and interpreted under blinded conditions. Based on a fitted receiver operating characteristic curve, we estimated likelihood ratios (LRs) and posttest probabilities for different cutoffs. There was a high concordance between sonography and nerve conduction. Based on the combined reference standard, a cutoff of 10 mm(2) resulted in approximately equal sensitivity and specificity, but only moderate LRs. A cutoff of <8 mm(2) had satisfactory power to rule out CTS: the fitted-negative LR was 0.13. Conversely, a cutoff of > or =12 mm(2) had excellent power to rule in CTS, with a fitted-positive LR of 19.9. For nerves > or =12 mm(2) and a pretest probability of 70% expected in patients with suspected CTS in tertiary care, we found a posttest probability of CTS of 98%. Depending on setting and purpose, different cutoff values for the largest cross-sectional area may be used to accurately rule in or rule out CTS. Using sonography as a first-line test may cost-effectively reduce the number of nerve conduction studies in patients with suspected CTS. A large-scale, randomized controlled trial is required to determine the effects of sonography on clinical outcomes, the number of nerve conduction studies performed, and the total cost.


Bone morphogenetic proteins (BMP) -4, -6, and -7 potently suppress basal and luteinizing hormone-induced androgen production by bovine theca interna cells in primary culture: could ovarian hyperandrogenic dysfunction be caused by a defect in thecal BMP signaling?
We reported recently that bovine theca interna cells in primary culture express several type-I and type-II receptors for bone morphogenetic proteins (BMPs). The same cells express at least two potential ligands for these receptors (BMP-4 and -7), whereas bovine granulosa cells and oocytes express BMP-6. Therefore, BMPs of intrafollicular origin may exert autocrine/paracrine actions to modulate theca cell function. Here we report that BMP-4, -6, and -7 potently suppress both basal (P < 0.0001; respective IC(50) values, 0.78, 0.30, and 1.50 ng/ml) and LH-induced (P < 0.0001; respective IC(50) values, 5.00, 0.55, and 4.55 ng/ml) androgen production by bovine theca cells while having only a moderate effect on progesterone production and cell number. Semiquantitative RT-PCR showed that all three BMPs markedly reduced steady-state levels of mRNA for P450c17. Levels of mRNA encoding steroidogenic acute regulatory protein, P450scc, and 3beta-hydroxy- steroid dehydrogenase were also reduced but to a much lesser extent. Immunocytochemistry confirmed a marked reduction in cellular content of P450c17 protein after BMP treatment (P < 0.001). Exposure to BMPs led to cellular accumulation of phosphorylated Smad1, but not Smad2, confirming that the receptors signal via a Smad1 pathway. The specificity of the BMP response was further explored by coincubating cells with BMPs and several potential BMP antagonists, chordin, gremlin, and follistatin. Gremlin and chordin were found to be effective antagonists of BMP-4 and -7, respectively, and the observation that both antagonists enhanced (P < 0.01) androgen production in the absence of exogenous BMP suggests an autocrine/paracrine role for theca-derived BMP-4 and -7 in modulating androgen production. Collectively, these data indicate that an intrafollicular BMP signaling pathway contributes to the negative regulation of thecal androgen production and that ovarian hyperandrogenic dysfunction could be a result of a defective autoregulatory pathway involving thecal BMP signaling.


cgmisc: enhanced genome-wide association analyses and visualization.
High-throughput genotyping and sequencing technologies facilitate studies of complex genetic traits and provide new research opportunities. The increasing popularity of genome-wide association studies (GWAS) leads to the discovery of new associated loci and a better understanding of the genetic architecture underlying not only diseases, but also other monogenic and complex phenotypes. Several softwares are available for performing GWAS analyses, R environment being one of them. We present cgmisc, an R package that enables enhanced data analysis and visualization of results from GWAS. The package contains several utilities and modules that complement and enhance the functionality of the existing software. It also provides several tools for advanced visualization of genomic data and utilizes the power of the R language to aid in preparation of publication-quality figures. Some of the package functions are specific for the domestic dog (Canis familiaris) data. The package is operating system-independent and is available from: https://github.com/cgmisc-team/cgmisc firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


Spatial aggregation of aquatic habitats affects oviposition patterns in Aedes mosquitoes.
Colonization, including oviposition, is an important driver of population and community dynamics both within and across habitat patches. Most research has focused on the roles of habitat availability or quality on colonization and its outcomes. However, the spatial distribution of habitats also likely affects these processes. We conducted field experiments in Georgia, USA, using clustered and dispersed arrays of equal numbers of oviposition patches to investigate how patch aggregation influenced oviposition by Aedes mosquitoes. We tested the effects of aggregation on: (1) the total number of eggs an array received, (2) the proportion of patches within an array that received eggs, and (3) the number of eggs per colonized patch. We compared results to predictions from three models (Field of Dreams, Propagule Redirection, and Excess Attraction), which vary in the degree to which arrays attract colonists and apportion those colonists among patches. Clustered arrays received 22% more eggs than dispersed arrays, with clustered patches significantly more likely to receive eggs. At the species level, A. albopictus responded more to clustering than did A. triseriatus. These results are inconsistent with Propagule Redirection, but support the Excess Attraction and Field of Dreams models. Although clustered arrays occupied a relatively small area, they attracted at least as many ovipositing mosquitoes as did dispersed arrays. However, the number of eggs per colonized patch did not differ between clustered and dispersed arrays. Therefore, density dependence among larvae, and hence the production of adult mosquitoes on a per-patch basis, should be similar in dispersed and clustered landscapes.


Thermal and laser properties of Nd:Lu₃Sc₁.₅Ga₃.₅O₁₂ for high power dual-wavelength laser.
We measured the thermal properties of Nd:Lu₃Sc₁.₅Ga₃.₅O₁₂ (Nd:LuSGG) crystal, including the thermal expansion coefficient, specific heat, and thermal diffusion coefficient. The calculated thermal conductivity is 4.4 W/mK at room temperature. A high-power continuous-wave and passively Q-switched Nd:LuSGG laser was also demonstrated. Continuous-wave output power of 6.96 W is obtained which is the highest power with this material. For the first time to our knowledge, the passively Q-switched Nd:LuSGG laser is reported with the shortest pulse width, largest pulse energy, and highest peak power are achieved to be 5.1 ns, 62.5 μJ, and 12 kW, respectively. By spectral analysis, it has been found that the Nd:LuSGG laser was located at 1059 nm under low pump power, and became dual-wavelength at 1061.5 and 1059 nm when the incident pump power is over 2.27 W. The generating mechanism of dual-wavelength laser is also discussed.


Alignment-Based Prediction of Sites of Metabolism.
Prediction of metabolically labile atom positions in a molecule (sites of metabolism) is a key component of the simulation of xenobiotic metabolism as a whole, providing crucial information for the development of safe and effective drugs. In 2008, an exploratory study was published in which sites of metabolism were derived based on molecular shape- and chemical feature-based alignment to a molecule whose site of metabolism (SoM) had been determined by experiments. We present a detailed analysis of the breadth of applicability of alignment-based SoM prediction, including transfer of the approach from a structure- to ligand-based method and extension of the applicability of the models from cytochrome P450 2C9 to all cytochrome P450 isozymes involved in drug metabolism. We evaluate the effect of molecular similarity of the query and reference molecules on the ability of this approach to accurately predict SoMs. In addition, we combine the alignment-based method with a leading chemical reactivity model to take reactivity into account. The combined model yielded superior performance in comparison to the alignment-based approach and the reactivity models with an average area under the receiver operating characteristic curve of 0.85 in cross-validation experiments. In particular, early enrichment was improved, as evidenced by higher BEDROC scores (mean BEDROC = 0.59 for α = 20.0, mean BEDROC = 0.73 for α = 80.5).


Effects of salinity on the characteristics of biomass and membrane fouling in membrane bioreactors.
This study investigated the effects of high salinity on the performance and membrane fouling of membrane bioreactor (MBR) with saline wastewater. Synthetic wastewaters containing 5-20 g/L salts (NaCl) were treated in identical lab-scale (7 L) MBRs monitoring removals of dissolved organic carbon (DOC) and ammonia. Increase in salt concentrations did not significantly change the removal efficiency of DOC in the MBRs. However, the ammonia removals decreased from 87% to 46% with increasing salt concentrations. PCR-DGGE analysis indicated changes in the microbial communities' composition due to high salinity; and the changes in microbial composition in turn have affected the performance of the MBRs. Membrane fouling was accelerated by the increased pore blocking resistance at higher salt concentrations. Analysis results of physicochemical and biological characteristics of biomass (EPS, floc size, zeta potential) verified the impacts of high salinity on the increased membrane fouling.


Determination of the foveal cone spacing by ocular speckle interferometry: limiting factors and acuity predictions.
We have developed a high-resolution imaging technique, based on speckle interferometry, for the objective determination of the cone spacing in the living human fovea. The spatial resolution attained with this technique is theoretically diffraction limited by the pupil size. However, the highest frequency that we measure varies greatly among subjects, especially for fully dilated pupils. We have conducted several experiments (determination of the cutoff frequency of ocular speckle interferometry, the double-pass modulation transfer function, and the Stiles-Crawford effect) that indicate that, as expected, the resolution is not limited by the incoherent modulation transfer function. We found, though, a high correlation between the cutoff frequency and the width of the eye's Stiles-Crawford function. This implies that the resolution depends on the structural properties of the cone mosaic itself. In addition, we have compared the Nyquist frequency of the cone mosaic, determined objectively by our technique, with the grating visual acuity measured in the same eyes at the same foveal eccentricities. For our subjects, visual resolution nearly matches the Nyquist frequency within the fovea, except at the foveal center, where the optical transfer function of the eye attenuates the contrast of frequencies close to the Nyquist limit to a value below threshold.


Sedative Effects of Latexes Obtained from Some Lactuca L. Species Growing in Turkey.
Lactuca L. species belong to the Asteraceae family and these plants are traditionally used for therapeutic purposes around the world. The dried milky latex of L. serriola is known as "lettuce oil" and is used as a sedative in Turkey. This study aimed to evaluate the sedative effects and analyze the chemical compositions of latexes obtained from some Lactuca species growing in Turkey. The sedative effects were evaluated through various behavioral tests on mice. For this purpose, latexes were obtained from L. glareosa Boiss., L. viminea (L.) J. Presl and C. P, L. mulgedioides (Vis and Panćić) Boiss. and Kotschy ex. Boiss., L. saligna L., and L. serriola L. The latex from L. saligna showed the highest sedative effects, whilst L. serriola and L. viminea latexes also displayed significant sedative effects compared to the control group at a dose of 100 mg/kg. However, the latexes from L. glareosa and L. mulqedioides did not exhibit any sedative effects on mice. Characteristic sesquiterpene lactones (lactucin, lactucopicrin, 11,13β-dihydrolactucin, and 11,13β-dihydrolactucopicrin) were determined qualitatively and quantitatively by high-performance liquid chromatography (HPLC). Lactucin was identified as the main component.


Prevalence and risk factors of toxoplasmosis among adults in a small Brazilian city.
The prevalence of Toxoplasma gondii infection varies markedly among different populations, especially depending on factors related to socioeconomic development and eating habits. Cássia dos Coqueiros is a small city in Brazil with rural characteristics and increased risk factors traditionally associated with T. gondii infection. We carried out a cross-sectional study involving 970 inhabitants aged 18 years or more, selected from patients of the local health unit and home visits in urban and rural areas. Each participant completed a survey with questions regarding demographic, socioeconomic, and risk factors for toxoplasmosis. Blood samples from participants were tested for presence of IgG and IgM antibodies against T. gondii using a chemiluminescent microparticle immunoassay. The prevalence of IgG and IgM antibodies was 62.3% and 2.5%, respectively. Variables that proved to be independent predictors of infection were age, low levels of education, and previous diagnosis of toxoplasmosis. The high prevalence of toxoplasmosis serological markers in this adult population highlights the need to promote preventive practices, especially those directed toward women of childbearing age, in this part of Brazil.


Measuring the quality of life of youth with facial differences.
To describe the Facial Differences Module of the Youth Quality of Life Instruments (YQOL-FD) and present results evaluating domain structure, internal consistency, reproducibility, validity, and respondent burden. A multisite observational study of youth aged 11 to 18 years with acquired or congenital facial differences. Three hundred seven youth recruited through clinics at four U.S. sites and one U.K. site. Eligible youth were aged 11 to 18 years, had a noticeable facial difference, could read at the fifth-grade level, and, for youth with facial burns, were at least 2 years posttrauma. Included were the newly developed YQOL-FD, the generic Youth Quality of Life Instrument, the Children's Depression Inventory, and demographics. Principal components analysis showed five significant factors that closely matched the domain structure hypothesized a priori. Domain scores of the YQOL-FD showed acceptable internal consistency and reproducibility. Scores were more strongly correlated with the Children's Depression Inventory score than with self-rating of health as predicted. All domain scores showed adequate discrimination among levels of general quality of life (Wilks lambda = 0.84, p = .001). The median time to complete the module was 10 minutes. The YQOL Facial Differences Module augmented information obtained from the generic YQOL measure by addressing specific concerns. The module was well received by youth and showed acceptable measurement properties for evaluating the perceived quality-of-life status of youth facial differences. Future use in longitudinal studies and clinical trials is anticipated to evaluate the ability to detect change.


Overcoming trastuzumab resistance in HER2-overexpressing breast cancer cells by using a novel celecoxib-derived phosphoinositide-dependent kinase-1 inhibitor.
Although trastuzumab has been successfully used in patients with HER2-overexpressing metastatic breast cancer, resistance is a common problem that ultimately culminates in treatment failure. In light of the importance of Akt signaling in trastuzumab's antitumor action, we hypothesized that concurrent inhibition of Akt could enhance trastuzumab sensitivity and moreover reverse the resistant phenotype in HER2-positive breast cancer cells. Based on our finding that celecoxib mediates antitumor effects through the inhibition of phosphoinositide-dependent kinase-1 (PDK-1)/Akt signaling independently of cyclooxygenase-2 (COX-2), we used celecoxib as a scaffold to develop a COX-2-inactive PDK-1 inhibitor, 2-amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012). Here, we investigated the effect of OSU-03012 on trastuzumab-mediated apoptosis in four breast cancer cell lines with different HER2 expression and trastuzumab-resistance status, including MDA-MB-231, BT474, SKBR3, and insulin-like growth factor-I receptor-overexpressing SKBR3 (SKBR3/IGF-IR). Effects of trastuzumab and OSU-03012, individually or in combination, on cell viability and changes in pertinent biomarkers including HER2 expression, phosphorylation of Akt, p27(kip1), and the PDK-1 substrate p70(S6K) were assessed. OSU-03012 alone was able to trigger apoptosis in all cell lines with equal potency (IC(50) = 3-4 microM), suggesting no cross-resistance with trastuzumab. Medium dose-effect analysis indicates that OSU-03012 potentiated trastuzumab's antiproliferative effect in HER2-positive cells, especially in SKBR3/IGF-IR cells, through the down-regulation of PDK-1/Akt signaling. This synergy, however, was not observed in HER2-negative MDA-MB-231 cells. This combination treatment represents a novel strategy to increase the efficacy of trastuzumab and to overcome trastuzumab resistance in the treatment of HER2-positive breast cancer.


Long-term follow-up after tight control of blood pressure in type 2 diabetes.
Post-trial monitoring of patients in the United Kingdom Prospective Diabetes Study (UKPDS) examined whether risk reductions for microvascular and macrovascular disease, achieved with the use of improved blood-pressure control during the trial, would be sustained. Among 5102 UKPDS patients with newly diagnosed type 2 diabetes mellitus, we randomly assigned, over a 4-year period beginning in 1987, 1148 patients with hypertension to tight or less-tight blood-pressure control regimens. The 884 patients who underwent post-trial monitoring were asked to attend annual UKPDS clinics for the first 5 years, but no attempt was made to maintain their previously assigned therapies. Annual questionnaires completed by patients and general practitioners were used to follow patients who were unable to attend the clinic in years 1 through 5, and questionnaires were used for all patients in years 6 to 10. Seven prespecified aggregate clinical end points were examined on an intention-to-treat basis, according to the previous randomization categories. Differences in blood pressure between the two groups during the trial disappeared within 2 years after termination of the trial. Significant relative risk reductions found during the trial for any diabetes-related end point, diabetes-related death, microvascular disease, and stroke in the group receiving tight, as compared with less tight, blood-pressure control were not sustained during the post-trial follow-up. No risk reductions were seen during or after the trial for myocardial infarction or death from any cause, but a risk reduction for peripheral vascular disease associated with tight blood-pressure control became significant (P=0.02). The benefits of previously improved blood-pressure control were not sustained when between-group differences in blood pressure were lost. Early improvement in blood-pressure control in patients with both type 2 diabetes and hypertension was associated with a reduced risk of complications, but it appears that good blood-pressure control must be continued if the benefits are to be maintained. (UKPDS 81; Current Controlled Trials number, ISRCTN75451837.)


Inducing an interpretation bias changes self-imagery: a preliminary investigation.
Prior work suggests that variations in self-imagery can influence the emotional interpretations people make about social situations. The current experiment investigated the converse possibility: that inducing an inferential bias can change the content of self-related images. The effects of repeated practice in accessing either negative or positive social outcomes was tested by having participants report on self-images generated during subsequent experience with ambiguous social situations. Participants and independent judges rated the content of participants' self-images as being more negative after prior practice in accessing negative rather than positive social outcomes. Furthermore, participants who practiced accessing negative outcomes rated their anticipated anxiety in an imagined stressful social situation as being greater, and their expected social performance as poorer than participants in the positive outcome group. Groups did not differ in state anxiety levels when making their ratings, so it is unlikely that any observed differences between groups can be attributed to mood effects. We suggest that this finding is consistent with the hypothesis that inferential biases and content of self-images can interact with each other and may together serve to maintain social anxiety.


Whole genome sequence and comparative analysis of Borrelia burgdorferi MM1.
Lyme disease is caused by spirochaetes of the Borrelia burgdorferi sensu lato genospecies. Complete genome assemblies are available for fewer than ten strains of Borrelia burgdorferi sensu stricto, the primary cause of Lyme disease in North America. MM1 is a sensu stricto strain originally isolated in the midwestern United States. Aside from a small number of genes, the complete genome sequence of this strain has not been reported. Here we present the complete genome sequence of MM1 in relation to other sensu stricto strains and in terms of its Multi Locus Sequence Typing. Our results indicate that MM1 is a new sequence type which contains a conserved main chromosome and 15 plasmids. Our results include the first contiguous 28.5 kb assembly of lp28-8, a linear plasmid carrying the vls antigenic variation system, from a Borrelia burgdorferi sensu stricto strain.


A role for MHC class I down-regulation in NK cell lysis of herpes virus-infected cells.
NK cells represent an efficient first line of defense against virus infection, preceding the generation of adaptive T cell responses. However, the NK cell receptors involved in the recognition of virus-infected cells remain ill defined. We studied the in vitro response of isolated human NK cell clones to cells infected by the herpes viruses, herpes simplex virus (HSV) and human cytomegalovirus (HCMV). Both HSV and HCMV were found to induce NK cell cytotoxicity by down-regulating HLA-C molecules engaged in the triggering of killer inhibitory receptors (KIR). This conclusion was further substantiated by the finding that expression of viral genes known to interfere with MHC class I expression, such as the TAP inhibitor ICP47 of HSV and the MHC class I-destroying US11 protein of HCMV, was sufficient to trigger the cytotoxicity of NK cell clones expressing an inhibitory KIR for HLA-C. These results show for the first time that MHC class I down-regulation could render cells infected with herpes viruses susceptible to NK cell killing, thus demonstrating a role for KIR in the recognition of virally infected cells.


The efficacy of an integrated risk reduction intervention for HIV-positive women with child sexual abuse histories.
Child sexual abuse (CSA) is associated with HIV risk behaviors [Bensley, L., Van Eenwyk, J., and Simmons, K. W., 2003.] and more prevalent among women living with HIV than in the general population [Koenig, L. J., and Clark, H., 2004]. This randomized Phase~I clinical trial tested the impact of a culturally congruent psychoeducational intervention designed to reduce sexual risks and increase HIV medication adherence for HIV-positive women with CSA histories. An ethnically diverse sample of 147 women were randomized to two conditions: an 11-session Enhanced Sexual Health Intervention (ESHI) or an attention control. Results based on "intent to treat'' analyses of pre-post changes are reported here. Additional analyses explored whether the observed effects might depend on "intervention dose,'' i.e., number of sessions attended. Women in the ESHI condition reported greater sexual risk reduction than women in the control condition. Although there were no differences between women in the ESHI and control groups on medication adherence, women in the ESHI condition who attended 8 or more sessions reported greater medication adherence at posttest than control women. The findings provide initial support for this culturally and gender-congruent psychoeducational intervention for HIV-positive women with CSA, and highlight the importance of addressing the effects of CSA on sexual risk reduction and medication adherence in preventive interventions for women.


Expression of human cytochromes P450 1A1 and P450 1A2 as fused enzymes with yeast NADPH-cytochrome P450 oxidoreductase in transgenic tobacco plants.
Among 11 isoforms of the human cytochrome P450 enzymes metabolizing xenobiotics, CYP 1A1 and CYP 1A2 were major P450 species in the metabolism of the herbicides chlortoluron and atrazine in a yeast expression system. CYP1A2 was more active in the metabolism of both herbicides than CYP1A1. The fused enzymes of CYP1A1 and CYP1A2 with yeast NADPH-cytochrome P450 oxidoreductase were functionally active in the microsomal fraction of the yeast Saccharomyces cerevisiae and showed increased specific activity towards 7-ethoxyresorufin as compared to CYP1A1 and CYP1A2 alone. Then, both fused enzymes were each expressed in the microsomes of tobacco (Nicotiana tabacum cv. Samsun NN) plants. The transgenic plants expressing the CYP1A2 fusion enzyme had higher resistance to the herbicide chlortoluron than the plants expressing the CYP1A1 fusion enzyme did. The transgenic plants expressing the CYP1A2 fused enzyme metabolized chlortoluron to a larger extent to its non-phytotoxic metabolites through N-demethylation and ring-methyl hydroxylation as compared to the plants expressing the CYP1A1 fused enzyme. Thus, the possibility of increasing the herbicide resistance in the transgenic plants by the selection of P450 species and the fusion with P450 reductase is discussed.


Barriers and facilitators to physical activity in second-generation British Indian women: A qualitative study.
To understand the barriers to and motivations for physical activity among second-generation British Indian women. Approximately 50% of British South Asians are UK-born, and this group is increasing as the second-generation also have children. Previous research into the barriers to and facilitators for physical activity has focused on migrant, first-generation populations. Qualitative research is needed to understand a) how we might further reduce the gap in physical activity levels between White British women and British Indian women and b) the different approaches that may be required for different generations. Applying a socioecological model to take into account the wider social and physical contexts, we conducted semi-structured interviews with 28 Indian women living in Manchester, England. Interviews with first-generation British Indian women were also included to provide a comparator. Interviews were audio-recorded, transcribed, thematically coded and analysed using a grounded theory approach. Ways of socialising, concerns over appearance while being physically active, safety concerns and prioritising educational attainment in adolescence were all described as barriers to physical activity in second-generation British Indian women. Facilitators for physical activity included acknowledging the importance of taking time out for oneself; religious beliefs and religious groups promoting activity; being prompted by family illness; positive messages in both the media and while at school, and having local facilities to use. Barriers to physical activity in second-generation Indian women were very similar to those already reported for White British women. Public health measures aimed at women in the general population may also positively affect second-generation Indian women. First-generation Indian women, second-generation children and Muslim women may respond better to culturally tailored interventions.


A survey of Type III restriction-modification systems reveals numerous, novel epigenetic regulators controlling phase-variable regulons; phasevarions.
Many bacteria utilize simple DNA sequence repeats as a mechanism to randomly switch genes on and off. This process is called phase variation. Several phase-variable N6-adenine DNA-methyltransferases from Type III restriction-modification systems have been reported in bacterial pathogens. Random switching of DNA methyltransferases changes the global DNA methylation pattern, leading to changes in gene expression. These epigenetic regulatory systems are called phasevarions - phase-variable regulons. The extent of these phase-variable genes in the bacterial kingdom is unknown. Here, we interrogated a database of restriction-modification systems, REBASE, by searching for all simple DNA sequence repeats in mod genes that encode Type III N6-adenine DNA-methyltransferases. We report that 17.4% of Type III mod genes (662/3805) contain simple sequence repeats. Of these, only one-fifth have been previously identified. The newly discovered examples are widely distributed and include many examples in opportunistic pathogens as well as in environmental species. In many cases, multiple phasevarions exist in one genome, with examples of up to 4 independent phasevarions in some species. We found several new types of phase-variable mod genes, including the first example of a phase-variable methyltransferase in pathogenic Escherichia coli. Phasevarions are a common epigenetic regulation contingency strategy used by both pathogenic and non-pathogenic bacteria.


Mitral regurgitation surgery in heart failure due to ischemic cardiomyopathy: a 24-year experience.
The long-term benefits of mitral regurgitation (MR) surgery in ischemic cardiomyopathy (ICM) are controversial. Herein are reported the results and trends of this surgical approach over the past 24-year period. Patients were identified in refractory heart failure due to ICM with NYHA functional class III/IV symptoms, left ventricular ejection fraction < or =35% and MR who underwent mitral surgery between 1979 and 2002. The early and late outcomes were analyzed and compared for the different surgical eras classified as early (1979 to 1986), middle (1987 to 1994), and late (1995 to 2002). Mitral repair (70%) and replacement (30%) were performed with coronary artery bypass grafting (CABG) (85%) and tricuspid valve repair (7%) in 179 patients (mean age 68 +/- 9 years). The overall one- and five-year survival rates were 84% and 51%, respectively, and the corresponding freedom from recurrent MR after repair 86% and 55%. An increasing number of patients underwent surgery from the early to the late era. Whereas patients more frequently presented with cardiomegaly and renal failure during the early era, they were older, more often had prior CABG, concurrent tricuspid regurgitation and underwent mitral repair during the late era. A progressive improvement was observed in operative mortality from the early to late eras (24%, 11% and 5%, respectively; p = 0.009), and also for the one-and five-year survivals (68%, 85% and 89%; 46%, 43% and 57%, respectively; p = 0.06). Preoperative renal failure and concomitant tricuspid valve repair were predictors of late mortality. During the past 24 years, operative results for the surgical correction of MR in patients with heart failure due to ICM have steadily improved. Currently, while the early and mid-term survival are satisfactory the long-term survival is limited, especially when heart failure is complicated by renal failure and severe tricuspid regurgitation.


Distributed virtual experiments in water quality management.
Since the complexity of virtual experiments (VEs) and their underlying models is constantly increasing, computational performance of monolithic software solutions is rapidly becoming insufficient. Examples of VEs are probabilistic design, model calibration, optimal experimental design and scenario analysis. In order to tackle this computational bottleneck, a framework for the distributed execution of VEs on a potentially heterogeneous pool of work nodes has been implemented. This framework was named WDVE (WEST distributed virtual experimentation) and is built on top of technologies such as C++, XML and SOAP. It was designed for stability, expandability, performance, platform-independence and ease of use. Complex VEs are most often composed of mutually independent sub-experiments, which can be run concurrently. With WDVE, a complex VE that is executed on a so-called Master machine will therefore attempt to execute its sub-experiments on Slave machines that have previously registered with the Master. The process of submitting requests for the execution of sub-experiments is transparent and involves the transfer of a description of the experiment to be executed, and the resources that are needed for the execution (i.e., model and input data). WDVE is in many ways similar to the Grid Computing paradigm, which is currently receiving widespread attention. However, WDVE is more geared towards application within the scope of water quality management.


Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.
In the United States, colorectal cancer (CRC) is the third most common cancer diagnosed among men and women and the second leading cause of death from cancer. CRC largely can be prevented by the detection and removal of adenomatous polyps, and survival is significantly better when CRC is diagnosed while still localized. In 2006 to 2007, the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology came together to develop consensus guidelines for the detection of adenomatous polyps and CRC in asymptomatic average-risk adults. In this update of each organization's guidelines, screening tests are grouped into those that primarily detect cancer early and those that can detect cancer early and also can detect adenomatous polyps, thus providing a greater potential for prevention through polypectomy. When possible, clinicians should make patients aware of the full range of screening options, but at a minimum they should be prepared to offer patients a choice between a screening test that primarily is effective at early cancer detection and a screening test that is effective at both early cancer detection and cancer prevention through the detection and removal of polyps. It is the strong opinion of these 3 organizations that colon cancer prevention should be the primary goal of screening.


Global analysis of Smad2/3-dependent TGF-beta signaling in living mice reveals prominent tissue-specific responses to injury.
Smad2 and Smad3 (Smad2/3) proteins are key signaling molecules for TGF-beta and some related family members regulating the transcription of several hundred genes. TGF-beta have key roles in development, tissue homeostasis, and the pathogenesis of many human diseases, including cancer, fibrotic disorders, developmental defects, and neurodegeneration. To study the temporal and spatial patterns of Smad2/3-dependent signaling in normal and pathological conditions in the living organism, we engineered transgenic mice with a Smad-responsive luciferase reporter construct (SBE-luc mice). Using bioluminescent imaging, we assessed Smad2/3 signaling activity noninvasively in living mice. At baseline, this activity was highest in brain, intestine, heart, and skin, and correlated with biochemical measurements of reporter activity. Primary astrocytes cultured from SBE-luc mice showed specific activation of the reporter in response to Smad2/3-activating TGF-beta family members. Treatment of mice with the endotoxin LPS resulted in a fast and vigorous, but transient activation of the reporter in the intestine. Although the response was similarly rapid in brain, it remained increased, indicating important but different cellular responses to endotoxin challenge in these organs. Traumatic brain injury with a needle stab resulted in local activation of Smad2/3-dependent genes and a severalfold increase in bioluminescence in living mice. SBE-luc mice can therefore be used to study temporal, tissue-specific activation of Smad2/3-dependent signaling in living mice in normal or pathological conditions as well as for the identification of endogenous or synthetic modulators of this pathway.


A novel allelopathic substance, 13-epi-orthosiphol N, in Orthosiphon stamineus.
Orthosiphon stamineus (Java tea) has been widely used as traditional herb and several bioactive compounds against animal cells have been isolated. However, no bioactive compound against plants has been reported. Therefore, we investigated possible allelopathic properties and substances in O. stamineus. Aqueous methanol extracts of O. stamineus inhibited root and hypocotyl growth of cress (Lepidium sativum) and lettuce (Lactuca sativa) seedlings. Increasing the extract concentration increased the inhibition, which suggests that O. stamineus may have allelopathic properties. When the extract was divided into an ethyl acetate and an aqueous fraction, the ethyl acetate fraction showed the stronger inhibitory effect. Thus, the ethyl acetate phase was further purified, and the main allelopathic substance was isolated and identified as 13-epi-orthosiphol N, a novel compound, by spectral data. 13-epi-Orthosiphol N inhibited root and hypocotyl growth of cress and lettuce at concentrations greater than 10 μmol/L. The concentrations required for 50% inhibition ranged from 41 to 102 μmol/L. These results suggest that 13-epi-orthosiphol N may be an allelochemical and main contributor to the growth inhibitory effect of O. stamineus and may have potential as a template for the development of new plant control substances.


Detection of titanium oxide in the atmosphere of a hot Jupiter.
As an exoplanet transits its host star, some of the light from the star is absorbed by the atoms and molecules in the planet's atmosphere, causing the planet to seem bigger; plotting the planet's observed size as a function of the wavelength of the light produces a transmission spectrum. Measuring the tiny variations in the transmission spectrum, together with atmospheric modelling, then gives clues to the properties of the exoplanet's atmosphere. Chemical species composed of light elements-such as hydrogen, oxygen, carbon, sodium and potassium-have in this way been detected in the atmospheres of several hot giant exoplanets, but molecules composed of heavier elements have thus far proved elusive. Nonetheless, it has been predicted that metal oxides such as titanium oxide (TiO) and vanadium oxide occur in the observable regions of the very hottest exoplanetary atmospheres, causing thermal inversions on the dayside. Here we report the detection of TiO in the atmosphere of the hot-Jupiter planet WASP-19b. Our combined spectrum, with its wide spectral coverage, reveals the presence of TiO (to a confidence level of 7.7σ), a strongly scattering haze (7.4σ) and sodium (3.4σ), and confirms the presence of water (7.9σ) in the atmosphere.


Methamphetamine reduces LTP and increases baseline synaptic transmission in the CA1 region of mouse hippocampus.
Methamphetamine (METH) is an addictive psychostimulant whose societal impact is on the rise. Emerging evidence suggests that psychostimulants alter synaptic plasticity in the brain--which may partly account for their adverse effects. While it is known that METH increases the extracellular concentration of monoamines dopamine, serotonin, and norepinephrine, it is not clear how METH alters glutamatergic transmission. Within this context, the aim of the present study was to investigate the effects of acute and systemic METH on basal synaptic transmission and long-term potentiation (LTP; an activity-induced increase in synaptic efficacy) in CA1 sub-field in the hippocampus. Both the acute ex vivo application of METH to hippocampal slices and systemic administration of METH decreased LTP. Interestingly, the acute ex vivo application of METH at a concentration of 30 or 60 microM increased baseline synaptic transmission as well as decreased LTP. Pretreatment with eticlopride (D2-like receptor antagonist) did not alter the effects of METH on synaptic transmission or LTP. In contrast, pretreatment with D1/D5 dopamine receptor antagonist SCH23390 or 5-HT1A receptor antagonist NAN-190 abrogated the effect of METH on synaptic transmission. Furthermore, METH did not increase baseline synaptic transmission in D1 dopamine receptor haploinsufficient mice. Our findings suggest that METH affects excitatory synaptic transmission via activation of dopamine and serotonin receptor systems in the hippocampus. This modulation may contribute to synaptic maladaption induced by METH addiction and/or METH-mediated cognitive dysfunction.


Analysis of auditory evoked potentials by magnitude-squared coherence.
Evoked potentials are usually analyzed in the time domain (voltage versus time). The most familiar frequency-domain measure, the power spectral density function, displays power as a function of frequency but doesn't distinguish signal power from noise power. The coherence function estimates, for each frequency, the ratio of signal power to total (signal plus noise) power and, thus, indicates the degree to which system output (scalp potential) is determined by input (acoustic stimulus). Coherence ranges from 0 to 1; values above specified critical values can be accepted as demonstrating statistically significant system response. In this paper, we present coherence analysis of human scalp responses to clicks and amplitude-modulated tones. In both cases, this analytic method provides insight into the spectral character of the response (for example, assisting in specifying desirable filter characteristics). Threshold sensitivity is also improved: statistically significant responses can be detected at lower intensity by coherence analysis than by inspection of time-domain waveforms.


Development of a Protein-based Human Identification Capability from a Single Hair.
Shed human hair (lacking root nuclear DNA) frequently contributes important information to forensic investigations involving human identification. Detection of genetic variation observed in amino acid sequences of hair proteins provides a new suite of identity markers that augment microscopic hair analysis and mitochondrial DNA sequencing. In this study, a new method that completely dissolves single hairs using a combination of heat, ultrasonication, and surfactants was developed. Dissolved proteins were digested and genetically variant peptide (GVP) profiles were obtained for single hairs (25 mm) via high-resolution nanoflow liquid chromatography-based mass spectrometry and a novel exome-driven bioinformatic approach. Overall, 6519 unique peptides were identified and a total of 57 GVPs were confirmed. Random match probabilities ranged between 2.6 × 10-2 and 6.0 × 10-9 . The new bioinformatic strategy and ability to analyze GVPs in forensically relevant samples sizes demonstrate applicability of this approach to distinguish individuals in forensic contexts.


Prevention of infections associated with combat-related eye, maxillofacial, and neck injuries.
The percentage of combat wounds involving the eyes, maxillofacial, and neck regions reported in the literature is increasing, representing 36% of all combat-related injuries at the start of the Iraq War. Recent meta-analysis of 21st century eye, maxillofacial, and neck injuries described combat injury incidences of 8% to 20% for the face, 2% to 11% for the neck, and 0.5% to 13% for the eye and periocular structures. This article reviews recent data from military and civilian studies to support evidence-based recommendations for the prevention of infections associated with combat-related eye, maxillofacial, and neck injuries. The major emphasis of this review is on recent developments in surgical practice as new antimicrobial studies were not performed. Further studies of bacterial infection epidemiology and postinjury antimicrobial use in combat-related injuries to the eyes, maxillofacial, and neck region are needed to improve evidence-based medicine recommendations. This evidence-based medicine review was produced to support the Guidelines for the Prevention of Infections associated with Combat-related Injuries: 2011 Update contained in this supplement of Journal of Trauma.


Mothers' views of the health visiting service in the UK: a web-based survey.
User and client views are an important source of information for providers and commissioners of public services. This paper reports on a user-led UK wide survey of mothers' views about sources of support and experiences accessing the health visiting service. Netmums, a family of websites run by local mothers, undertook the survey following concerns that the health visiting service was proving increasingly difficult to access. 4,665 mothers responded to questions about a) who they would seek help from, b) views of the local health visiting service and c) perceived change in it over the past two years. The results show that the majority of respondents rate their service as quite or very good, valuing most the characteristics of a) expertise in child health development and parenting and b) time and willingness to listen on the part of health visitors. In all areas but one, the service was seen as changing for the worse. Following the re-affirmation of a need for a universal health visiting service to be able to pick up families in need, the challenge is now to design local services that have sufficient resources so that mothers can maintain relationships and confidently access the services when they need them.


Generation and characterization of murine monoclonal antibodies reactive against N-terminal and other regions of HIV-1 reverse transcriptase.
We produced a series of monoclonal antibodies against the human immunodeficiency virus (HIV-1) reverse transcriptase by immunizing mice with either purified recombinant HIV-1 p66 protein or with recombinant vaccinia virus which expresses HIV-1 pol sequences. The antibodies generated were specific for the reverse transcriptase protein, and recognized only the p51 and p66 subunits of the enzyme in each of the HIV-1 viral lysates and lysates of HIV-1 infected cells. The antibodies did not cross-react with HIV-2 reverse transcriptase. Most important, several of the antibodies are unique, in that they are the first that can bind to sites close to the N-terminal. This latter region has been suggested to form part of the polymerase domain of the reverse transcriptase. None of the antibodies could neutralize either the RNA-dependent DNA polymerase or RNase H activities of either p66 or p51/66 proteins. The binding patterns of these various antibodies to p66 and p51/66 were dependent on each of three independent variables: the source of antigen amployed, the individual specificity of the antibody, and the method employed to detect reactivity. These monoclonal antibodies provide useful reagents for the study of reverse transcriptase native structure-function relationships.


Chromosomal amplification is associated with cisplatin resistance of human male germ cell tumors.
Chemotherapy resistance of tumors is an important biological and clinical problem. Studies from many tumor types have indicated that resistance may be based on multiple genetic pathways. Human male germa cell tumors (GCTs) are an especially good model system to study the genetic basis of tumor sensitivity and resistance to chemotherapy. GCTs are exquisitely sensitive to treatment with DNA-damaging drugs such as cisplatin, rarely exhibit TP53 gene mutations, express normal p53 protein, and undergo p53-mediated apoptosis upon drug treatment. A small proportion of tumors (20-30% of metastatic lesions) escape the apoptotic response and result in treatment resistance. We have recently shown (J. Houldsworth, et al., Oncogene, 16: 2345-2359, 1998) that in a subset of such tumors, resistance is linked to TP53 gene mutations. In a further search for genetic mechanisms underlying resistance, we subjected a panel of 17 tumors from relapse-free patients (sensitive) and 17 chemotherapy-resistant tumors to comparative genomic hybridization analysis to identify possible amplified regions (implying amplified/overexpressed genes) associated with resistance. With the exception of 12p11.2-12, high level amplification was not detected in any of the sensitive tumors. We have identified eight amplified regions (1q31-32, 2p23-24, 7q21, 7q31, 9q22, 9q32-34, 15q23-24, and 20q11.2-12) in five resistant tumors, which suggests that chromosomal and, hence, gene amplification may comprise a pathway to drug resistance. Identification of amplified/overexpressed genes at these sites may elucidate new genetic pathways of chemotherapy resistance in GCTs and possibly also in other tumors.


Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia.
The efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (Covid-19) pneumonia are unclear. We randomly assigned, in a 1:1 ratio, hospitalized adults with Covid-19 pneumonia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed. A total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P = 0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group. Among patients hospitalized with Covid-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo. (Funded by Pfizer; STOP-COVID ClinicalTrials.gov number, NCT04469114.).


Characterization of the localization and function of NECAP 1 in neurons.
NECAPs (adaptin ear-binding clathrin-associated protein) are a new family of clathrin accessory proteins identified through a proteomic analysis of clathrin-coated vesicles (CCVs) from the brain. One member of this family, NECAP 1, is found primarily in tissues from the central nervous system and has been shown to be complexed tightly with a substantial portion of adaptor protein-2 (AP-2) in brain extracts. However, the function and intracellular location of this protein is unknown. In this study, we find that endogenous and epitope-tagged NECAP 1 co-localizes well with clathrin and AP-2 in punctate structures, many of which also contain the presynaptic markers synaptophysin, synaptotagmin or synaptic vesicle protein 2 (SV2). NECAP 1 was also detected by western blot in synaptic vesicle preparations. Overexpression of a truncation mutant of NECAP 1 (BC-NECAP 1) in neurons inhibited transferrin endocytosis but not epidermal growth factor (EGF) endocytosis, and this inhibition was dependent on an AP-2-binding WVQF motif. Moreover, overexpression of BC-NECAP 1 results in inhibition of synaptotagmin endocytosis both in unstimulated neurons and in neurons stimulated with potassium chloride. This inhibition was abrogated by truncation of the WVQF domain. We conclude from these observations that NECAP 1 plays a role in clathrin-mediated neuronal endocytosis, including a role in presynaptic endocytosis.


Extended microsatellite analysis in microsatellite stable, MSH2 and MLH1 mutation-negative HNPCC patients: genetic reclassification and correlation with clinical features.
Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder predisposing to predominantly colorectal cancer (CRC) and endometrial cancer frequently due to germline mutations in DNA mismatch repair (MMR) genes, mainly MLH1, MSH2 and also MSH6 in families seen to demonstrate an excess of endometrial cancer. As a consequence, tumors in HNPCC reveal alterations in the length of simple repetitive genomic sequences like poly-A, poly-T, CA or GT repeats (microsatellites) in at least 90% of the cases. The study cohort consisted of 25 HNPCC index patients (19 Amsterdam positive, 6 Bethesda positive) who revealed a microsatellite stable (MSS)--or low instable (MSI-L)--tumor phenotype with negative mutation analysis for the MMR genes MLH1 and MSH2. An extended marker panel (BAT40, D10S197, D13S153, D18S58, MYCL1) was analyzed for the tumors of these patients with regard to three aspects. First, to reconfirm the MSI-L phenotype found by the standard panel; second, to find minor MSIs which might point towards an MSH6 mutation, and third, to reconfirm the MSS status of hereditary tumors. The reconfirmation of the MSS status of tumors not caused by mutations in the MMR genes should allow one to define another entity of hereditary CRC. Their clinical features were compared with those of 150 patients with sporadic CRCs. In this way, 17 MSS and 8 MSI-L tumors were reclassified as 5 MSS, 18 MSI-L and even 2 MSI-H (high instability) tumors, the last being seen to demonstrate at least 4 instable markers out of 10. Among all family members, 87 malignancies were documented. The mean age of onset for CRCs was the lowest in the MSI-H-phenotyped patients with 40.5 +/- 4.9 years (vs. 47.0 +/- 14.6 and 49.8 +/- 11.9 years in MSI-L- and MSS-phenotyped patients, respectively). The percentage of CRC was the highest in families with MSS-phenotyped tumors (88%), followed by MSI-L-phenotyped (78%) and then by MSI-H-phenotyped (67%) tumors. MSS tumors were preferentially localized in the distal colon supposing a similar biologic behavior like sporadic CRC. MSH6 mutation analysis for the MSI-L and MSI-H patients revealed one truncating mutation for a patient initially with an MSS tumor, which was reclassified as MSI-L by analyzing the extended marker panel. Extended microsatellite analysis serves to evaluate the sensitivity of the reference panel for HNPCC detection and permits phenotype confirmation or upgrading. Additionally, it confirms the MSS status of hereditary CRCs not caused by the common mutations in the MMR genes and provides hints to another entity of hereditary CRC.


Molecular detection and identification of Bartonella species in rat fleas from northeastern Thailand.
The presence of Bartonella species in Xenopsylla cheopis fleas collected from Rattus spp. (R. exulans, R. norvegicus, and R. rattus) in Khon Kaen Province, Thailand was investigated. One hundred ninety-three fleas obtained from 62 rats, were screened by polymerase chain reaction using primers specific for the 16S-23S intergenic spacer region, and the presence of Bartonella DNA was confirmed by using the citrate synthase gene. Bartonella DNA was detected in 59.1% (114 of 193) of fleas examined. Sequencing demonstrated the presence of Bartonella spp. similar to B. elizabethae, B. rattimassiliensis, B. rochalimae, and B. tribocorum in the samples tested with a cutoff for sequence similarity ≥ 96% and 4 clustered together with the closest match with B. grahamii (95.5% identity). If X. cheopis proves to be a competent vector of these species, our results suggest that humans and animals residing in this area may be at risk for infection by several zoonotic Bartonella species.


Magnetic resonance diffusion tensor imaging of the optic nerves to guide treatment of pediatric suprasellar tumors.
As a preoperative planning tool, conventional magnetic resonance (MR) imaging may have limited value in differentiating tumors from white matter tracts. MR diffusion tensor imaging (MRDTI) has become a useful tool for evaluating white matter tracts in relation to surrounding structures and has been used in surgical planning for brain tumors involving white matter. We investigated the use of DTI of the optic nerves in surgical planning for pediatric suprasellar tumors. We present findings in 10 pediatric control patients and 2 cases of pediatric suprasellar tumors in which a routine 6-direction DTI of the brain was performed at 3 T. Postprocessing permitted the study of the diffusion tensor parameters, as well as the tractography, of the optic nerves. The control patients demonstrated the optimization of the technique and permitted the quantitation of fractional anisotropy and apparent diffusion coefficient values. The tumor cases demonstrated the utility of optic nerve DTI to differentiate between optic nerves and suprasellar/chiasmatic brain tumors. A routine 6-direction DTI of the pediatric brain at 3 T permits a detailed DTI study of the optic nerves. Optic nerve tractography can be used to aid in the evaluation and treatment of pediatric brain tumors in the area of the optic chiasm.


Single-shot soft x-ray laser linewidth measurement using a grating interferometer.
The linewidth of a 14.7 nm wavelength Ni-like Pd soft x-ray laser was measured in a single shot using a soft x-ray diffraction grating interferometer. The instrument uses the time delay introduced by the gratings across the beam to measure the temporal coherence. The spectral linewidth of the 4d1S0-4p1P1 Ni-like Pd lasing line was measured to be Δλ/λ=3×10(-5) from the Fourier transform of the fringe visibility. This single shot linewidth measurement technique provides a rapid and accurate way to determine the temporal coherence of soft x-ray lasers that can contribute to the development of femtosecond plasma-based soft x-ray lasers.


First Report of Neofusicoccum parvum Causing Rachis Necrosis of Mango (Mangifera indica) in Puerto Rico.
Mango is an important tropical fruit crop in Puerto Rico that has been grown in the island for centuries. One of the major disease issues in mango production is rotting of the rachis (main axis stem of the inflorescence). During a disease survey from 2008 to 2010, rachis and flower necrosis were observed at the Mango Germplasm Collection of the University of Puerto Rico's Experiment Station in Juana Diaz. Diseased inflorescences from cultivars Haden and Irwin were disinfested with 70% ethanol, followed by 0.5% sodium hypochlorite, rinsed with sterile, deionized, double-distilled water, and transferred to acidified potato dextrose agar (APDA). Two isolates, 91LY and K15C, of Neofusicoccum parvum (Pennycook & Samuels) Crous, Slippers & A.J.L. were purified and identified morphologically using taxonomic keys (1,4) and DNA sequence comparisons. In APDA, colonies of N. parvum were whitish grey with aerial mycelia turning dark gray with age. Pycnidia were uni- or multilocular and dark brown to black in color. Conidiogenous cells were hyaline and holoblastic. Conidia were hyaline, ellipsoid, smooth, and one-celled with sub-obtuse apex and truncate base. Conidia (n = 50) were 16.75 μm long by 5.5 μm wide. PCR amplification of three genes was used to support morphological identification. DNA analysis of ITS1-5.8S-ITS2 region, and fragments of both β-tubulin and elongation factor 1-alpha (EF1-α) genes were sequenced and compared using BLASTn with other sequences of N. parvum submitted to the NCBI GenBank. Accession numbers of gene sequences of N. parvum submitted to GenBank were: KC631661 and KC631662 for ITS region; KC631653 and KC631654 for β-tubulin; and KC631657 and KC631658 for EF1-α. For all genes used, sequences were 99 to 100% identical to ex-type specimen CMW9081 of N. parvum reported in GenBank. Pathogenicity tests were conducted on mango trees using six random healthy non-detached mango inflorescences for both Haden and Irwin cultivars and for both isolates. Inflorescences were inoculated with 5-mm mycelial disks from 8-day-old pure cultures grown in APDA and kept in a humid chamber using plastic bags for 8 days under field temperature, light, and other environmental conditions. Untreated controls were inoculated with APDA disks only. The test was repeated twice. For both cultivars, at 8 days after inoculation, isolates of N. parvum caused rachis necrosis ranging from 20 to 35 mm in rachis length. On cultivar Irwin, inflorescences turned brown and the necrosis was extended from the rachis to the flowers. On cultivar Haden, inflorescences turned brown and only rachis necrosis was observed. Untreated controls showed no symptoms and no fungi were reisolated from tissue. N. parvum was reisolated from diseased inflorescences, fulfilling Koch's postulates. Worldwide, N. parvum has been associated with stem-end rot, branch dieback, blossom blight, and cankers on mango (2,3). To our knowledge, this is the first report of N. parvum causing rachis necrosis on mango in Puerto Rico. References: (1) A. J. L. Phillips. Key to the various lineages in "Botryosphaeria" Version 01 2007. Retrieved from http://www.crem.fct.unl.pt/botryosphaeria_site/key.htm , 6 August 2013. (2) G. I. Johnson et al. Ann. Appl. Biol. 120:225, 1992. (3) B. Slippers et al. Mycologia 97:99, 2005. (4) P. W. Crous et al. Stud. Mycol. 55:235, 2006.