School-based education programmes for the prevention of child sexual abuse.
Child sexual abuse is a significant global problem in both magnitude and sequelae. The most widely used primary prevention strategy has been the provision of school-based education programmes. Although programmes have been taught in schools since the 1980s, their effectiveness requires ongoing scrutiny. To systematically assess evidence of the effectiveness of school-based education programmes for the prevention of child sexual abuse. Specifically, to assess whether: programmes are effective in improving students' protective behaviours and knowledge about sexual abuse prevention; behaviours and skills are retained over time; and participation results in disclosures of sexual abuse, produces harms, or both. In September 2014, we searched CENTRAL, Ovid MEDLINE, EMBASE and 11 other databases. We also searched two trials registers and screened the reference lists of previous reviews for additional trials. We selected randomised controlled trials (RCTs), cluster-RCTs, and quasi-RCTs of school-based education interventions for the prevention of child sexual abuse compared with another intervention or no intervention. Two review authors independently assessed the eligibility of trials for inclusion, extracted data, and assessed risk of bias. We summarised data for six outcomes: protective behaviours; knowledge of sexual abuse or sexual abuse prevention concepts; retention of protective behaviours over time; retention of knowledge over time; harm; and disclosures of sexual abuse. This is an update of a Cochrane Review that included 15 trials (up to August 2006). We identified 10 additional trials for the period to September 2014. We excluded one trial from the original review. Therefore, this update includes a total of 24 trials (5802 participants). We conducted several meta-analyses. More than half of the trials in each meta-analysis contained unit of analysis errors.1. Meta-analysis of two trials (n = 102) evaluating protective behaviours favoured intervention (odds ratio (OR) 5.71, 95% confidence interval (CI) 1.98 to 16.51), with borderline low to moderate heterogeneity (Chi² = 1.37, df = 1, P value = 0.24, I² = 27%, Tau² = 0.16). The results did not change when we made adjustments using intraclass correlation coefficients (ICCs) to correct errors made in studies where data were analysed without accounting for the clustering of students in classes or schools.2. Meta-analysis of 18 trials (n = 4657) evaluating questionnaire-based knowledge favoured intervention (standardised mean difference (SMD) 0.61, 95% CI 0.45 to 0.78), but there was substantial heterogeneity (Chi² = 104.76, df = 17, P value < 0.00001, I² = 84%, Tau² = 0.10). The results did not change when adjusted for clustering (ICC: 0.1 SMD 0.66, 95% CI 0.51 to 0.81; ICC: 0.2 SMD 0.63, 95% CI 0.50 to 0.77).3. Meta-analysis of 11 trials (n =1688) evaluating vignette-based knowledge favoured intervention (SMD 0.45, 95% CI 0.24 to 0.65), but there was substantial heterogeneity (Chi² = 34.25, df = 10, P value < 0.0002, I² = 71%, Tau² = 0.08). The results did not change when adjusted for clustering (ICC: 0.1 SMD 0.53, 95% CI 0.32 to 0.74; ICC: 0.2 SMD 0.60, 95% CI 0.31 to 0.89).4. We included four trials in the meta-analysis for retention of knowledge over time. The effect of intervention seemed to persist beyond the immediate assessment (SMD 0.78, 95% CI 0.38 to 1.17; I² = 84%, Tau² = 0.13, P value = 0.0003; n = 956) to six months (SMD 0.69, 95% CI 0.51 to 0.87; I² = 25%; Tau² = 0.01, P value = 0.26; n = 929). The results did not change when adjustments were made using ICCs.5. We included three studies in the meta-analysis for adverse effects (harm) manifesting as child anxiety or fear. The results showed no increase or decrease in anxiety or fear in intervention participants (SMD -0.08, 95% CI -0.22 to 0.07; n = 795) and there was no heterogeneity (I² = 0%, P value = 0.79; n=795). The results did not change when adjustments were made using ICCs.6. We included three studies (n = 1788) in the meta-analysis for disclosure of previous or current sexual abuse. The results favoured intervention (OR 3.56, 95% CI 1.13 to 11.24), with no heterogeneity (I² = 0%, P value = 0.84). However, adjusting for the effect of clustering had the effect of widening the confidence intervals around the OR (ICC: 0.1 OR 3.04, 95% CI 0.75 to 12.33; ICC: 0.2 OR 2.95, 95% CI 0.69 to 12.61).Insufficient information was provided in the included studies to conduct planned subgroup analyses and there were insufficient studies to conduct meaningful analyses.The quality of evidence for all outcomes included in the meta-analyses was moderate owing to unclear risk of selection bias across most studies, high or unclear risk of detection bias across over half of included studies, and high or unclear risk of attrition bias across most studies. The results should be interpreted cautiously. The studies included in this review show evidence of improvements in protective behaviours and knowledge among children exposed to school-based programmes, regardless of the type of programme. The results might have differed had the true ICCs or cluster-adjusted results been available. There is evidence that children's knowledge does not deteriorate over time, although this requires further research with longer-term follow-up. Programme participation does not generate increased or decreased child anxiety or fear, however there is a need for ongoing monitoring of both positive and negative short- and long-term effects. The results show that programme participation may increase the odds of disclosure, however there is a need for more programme evaluations to routinely collect such data. Further investigation of the moderators of programme effects is required along with longitudinal or data linkage studies that can assess actual prevention of child sexual abuse.


Inducible deletion of epidermal Dicer and Drosha reveals multiple functions for miRNAs in postnatal skin.
MicroRNAs (miRNAs) regulate the expression of many mammalian genes and play key roles in embryonic hair follicle development; however, little is known of their functions in postnatal hair growth. We compared the effects of deleting the essential miRNA biogenesis enzymes Drosha and Dicer in mouse skin epithelial cells at successive postnatal time points. Deletion of either Drosha or Dicer during an established growth phase (anagen) caused failure of hair follicles to enter a normal catagen regression phase, eventual follicular degradation and stem cell loss. Deletion of Drosha or Dicer in resting phase follicles did not affect follicular structure or epithelial stem cell maintenance, and stimulation of anagen by hair plucking caused follicular proliferation and formation of a primitive transient amplifying matrix population. However, mutant matrix cells exhibited apoptosis and DNA damage and hair follicles rapidly degraded. Hair follicle defects at early time points post-deletion occurred in the absence of inflammation, but a dermal inflammatory response and hyperproliferation of interfollicular epidermis accompanied subsequent hair follicle degradation. These data reveal multiple functions for Drosha and Dicer in suppressing DNA damage in rapidly proliferating follicular matrix cells, facilitating catagen and maintaining follicular structures and their associated stem cells. Although Drosha and Dicer each possess independent non-miRNA-related functions, the similarity in phenotypes of the inducible epidermal Drosha and Dicer mutants indicates that these defects result primarily from failure of miRNA processing. Consistent with this, Dicer deletion resulted in the upregulation of multiple direct targets of the highly expressed epithelial miRNA miR-205.


Translation of clinical prediction rules for febrile children to primary care practice: an observational cohort study.
Clinical prediction rules (CPRs) to identify children with serious infections lack validation in low-prevalence populations, which hampers their implementation in primary care practice. To evaluate the diagnostic value of published CPRs for febrile children in primary care. Observational cohort study among febrile children (<16 years) who consulted five GP cooperatives (GPCs) in the Netherlands. Alarm signs of serious infection and clinical management were extracted from routine clinical practice data and manually recoded with a structured electronic data-entry program. Eight CPRs were selected from literature. CPR-variables were matched with alarm signs and CPRs were applied to the GPC-population. 'Referral to emergency department (ED)' was used as a proxy outcome measure for 'serious infection'. CPR performance was assessed by calibration analyses, sensitivity, specificity, and area under the ROC-curve (ROC-area). A total of 9794 GPC-contacts were eligible, 54% male, median age 2.3 years (interquartile range 1.0-4.6 years) and 8.1% referred to ED. Frequencies of CPR-variables varied from 0.5% (cyanosis, drowsy) to 25% (temperature ≥40°C). Alarm signs frequently included in CPRs were 'ill appearance', 'inconsolable', and 'abnormal circulatory or respiratory signs'. The height of the CPR's predicted risks generally corresponded with being (or not being) referred to the ED in practice. However, calibration-slopes indicated that three CPRs underestimated the risk of serious infection in the GPC-population. Sensitivities ranged from 42% to 54%, specificities from 68% to 89%. ROC-areas ranged from 0.52 to 0.81, with best performance of CPRs for children aged <3 months. Published CPRs performed moderately well in the primary out-of-hours care population. Advice is given on how to improve translation of CPRs to primary care practice.


Vehicles driven by teenagers in their first year of licensure.
to determine access to vehicles, vehicle ownership and its correlates, and types of vehicles driven by teenagers during their first year of licensure. About 3,500 Connecticut teenagers and their parents recruited at DMV offices participated in a study aimed at persuading parents to impose and maintain driving restrictions on their sons and daughters. Telephone interviews with teens and parents, which included questions on vehicles driven, were conducted upon licensure and at intervals throughout the year. The majority of both male and female teens owned vehicles immediately upon licensure. Family income and number of vehicles in the family were associated with early ownership. A year later 74% owned vehicles. Small cars, which provide inferior crash protection, were the most popular vehicle; the percent driving small cars increased from 36% to 42% over the year. About 25% were driving SUVs, pickups, or sports cars, which may increase crash risk for young beginners. One year after licensure, only 35% of teens were driving midsize or large passenger cars, the types of vehicles recommended for them, and about one-third of these vehicles were 10 or more years old. Owners were more likely than non-owners to drive older and smaller vehicles, to drive more miles, do more risky driving, and to have more traffic violations and crashes. Many teenagers in Connecticut were driving vehicles that rank low in crash protection or may increase crash risk. Attention to the young driver problem has been focused primarily on managing driving risks through graduated licensing systems. More attention needs to be given to the vehicles teens drive, and how decisions about vehicle type and ownership are made. Parents exert control over what vehicles their sons and daughters drive, and may benefit from information on how to make choices that better balance cost, safety, and other factors that go into these decisions.


Dependence of surface aging on DNA topography investigated in attractive bimodal atomic force microscopy.
Here we employ bimodal atomic force microscopy (AFM) to investigate the relevance of the aging of the surface and accumulation of adsorbates on the resolved topography of biomolecules. We produce raw bimodal images and a set of contrast channels derived from these to show that the imaging of DNA molecules on hydrophilic model substrates such as mica should be performed immediately after the sample is prepared. Days after preparation, i.e. 48 hours, the adsorbates shield the forces arising from the true substrate and molecule and the molecule might become "invisible" in the images. We employ dsDNA molecules on mica as a model system since the nominal height of dsDNA is comparable to the height of the adsorbed films. With this set up, the molecules can fully disappear under attractive imaging due to the shielding effects of the adsorbates. We further transform the images obtained immediately after cleaving the mica surface and show that the data are then suitable to be transformed into more physically meaningful maps such as Hamaker maps.


Functional corneal endothelium derived from corneal stroma stem cells of neural crest origin by retinoic acid and Wnt/β-catenin signaling.
Corneal endothelial dysfunction remains a major indication for corneal transplantation. Both corneal endothelial cells and stromal cells originate from the neural crest, but have distinct phenotypes and function in the adult cornea. We previously reported that stem cells isolated from the adult corneal stroma [cornea-derived precursors (COPs)] show characteristics of multipotent neural crest-derived stem cells. In this study, we report the induction of functional tissue-engineered corneal endothelium (TECE) from mouse and human COPs. TECE was engineered from Wnt1-Cre/Floxed EGFP mouse COPs in a medium containing retinoic acid and glycogen synthase kinase (GSK) 3β inhibitor (activator of Wnt/β-catenin signaling). The expression levels of major markers characterizing corneal endothelial function (Atp1a1, Slc4a4, Car2, Col4a2, Col8a2, and Cdh2) were significantly upregulated. Both retinoic acid and GSK 3β inhibitor upregulated the expression of Pitx2, a homeobox gene involved in the development of the anterior segment of the eye. GSK 3β inhibitor increased Atp1a1 expression and Na,K-ATPase pump activity of TECE, which was significantly higher than COPs or control 3T3 cells, and 2.6-fold higher than cultured mouse corneal endothelial cells. Mouse TECE transplanted into rabbit corneas maintained transparency and corneal thickness, whereas control corneas without TECE showed marked edema and increased corneal thickness. Furthermore, we successfully induced TECE from human COPs, and human TECE transplanted into rabbit corneas also maintained corneal transparency and thickness. This protocol enables efficient production of corneal endothelium from corneal stromal stem cells by direct induction, which may lead to a novel stem cell therapy for corneal endothelial dysfunction.


Stiffness Effects in Rocker-Soled Shoes: Biomechanical Implications.
Rocker-soled shoes provide a way to reduce the possible concentration of stress, as well as change movement patterns, during gait. This study attempts to examine how plantar force and spatio-temporal variables are affected by two rocker designs, one with softer and one with denser sole materials, by comparing them with the barefoot condition and with flat-soled shoes. Eleven subjects' gait parameters during walking and jogging were recorded. Our results showed that compared with barefoot walking, plantar forces were higher for flat shoes while lower for both types of rocker shoes, the softer-material rocker being the lowest. The plantar force of flat shoes is greater than the vertical ground reaction force, while that of both rocker shoes is much less, 13.87-30.55% body weight. However, as locomotion speed increased to jogging, for all shoe types, except at the second peak plantar force of the denser sole material rocker shoes, plantar forces were greater than for bare feet. More interestingly, because the transmission of force was faster while jogging, greater plantar force was seen in the rocker-soled shoes with softer material than with denser material; results for higher-speed shock absorption in rocker-soled shoes with softer material were thus not as good. In general, the rolling phenomena along the bottom surface of the rocker shoes, as well as an increase in the duration of simultaneous curve rolling and ankle rotation, could contribute to the reduction of plantar force for both rocker designs. The possible mechanism is the conversion of vertical kinetic energy into rotational kinetic energy. To conclude, since plantar force is related to foot-ground interface and deceleration methods, rocker-design shoes could achieve desired plantar force reduction through certain rolling phenomena, shoe-sole stiffness levels, and locomotion speeds.


An FMRI study of saccadic and smooth-pursuit eye movement control in patients with age-related macular degeneration.
To compare the cortical networks that underlie oculomotor function in patients with age-related macular degeneration (AMD) with those in normally sighted control subjects, using functional magnetic resonance imaging (fMRI). Six patients with bilateral geographic retinal atrophy due to AMD (age range, 55-83 years) were recruited for the study. The visual acuities of the patients ranged from 20/76 (0.58 logMAR) to 20/360 (1.26 logMAR). An additional six younger (age range, 22-31 years) and six older (age range, 54-78 years) normally sighted individuals were recruited as control subjects. fMRI data were acquired on a 3.0-Tesla, scanner while subjects performed visually guided saccade (VGS) and smooth-pursuit (SmP) tasks. Contrasts between VGS and fixation on a stationary target identified a network of activation that included the frontal eye fields (FEFs), supplementary eye fields (SMA/SEFs), prefrontal cortex (PFC), intraparietal sulci (IPS), and the areas of the visual cortex (MT/V5, V2/V3, and V1) in control subjects and patients. A similar network was identified for comparisons between SmP and periods of fixation. Marked variability was observed in the performance of both tasks across all patients. For both tasks, the patients generally showed increased PFC and IPS activation, with decreased activation in visual cortex compared with the control subjects. The patients showed significantly increased activation of the FEFs and SMA/SEFs in the SmP task, compared with the control subjects. These data suggest that performance of both eye movement tasks required greater involvement of the cortical regions generally implicated in attention and effort in patients with AMD.


Role of the C-terminal domain of Thermus thermophilus trehalose synthase in the thermophilicity, thermostability, and efficient production of trehalose.
Trehalose synthase (TS) from Thermus thermophilus (TtTS) is a thermostable enzyme that catalyzes the conversion of maltose into trehalose by intramolecular transglucosylation. It has a relatively higher thermophilicity and thermostability and a better conversion ratio for trehalose production than other known TSs from different sources at present. By amino acid sequences and the schematic motif alignment of trehalose synthase-related enzymes, it was found that TtTS (965 amino acid residues) contains a particular C-terminal fragment that is not found in most other TSs. To verify the function of this fragment, C-terminal deletion and enzyme fusion were respectively performed to explain the important role this fragment plays in the formation of trehalose. First, the C terminus (TtTSDeltaN, 415 amino acid residues) of TtTS is deleted to construct a TtTSDeltaC containing 550 amino acids. Furthermore, a novel cold-active TS was cloned and purified from Deinococcus radiodurans (DrTS, 552 amino acid residues) and then a fusion protein was created with TtTSDeltaN at the C terminus of DrTS (DrTS-TtTSDeltaN). It was found that the recombinant TtTStriangle upC enzyme had a lower thermostability and a higher byproduct than TtTS in catalyzing the conversion of maltose into trehalose. On the other hand, the recombinant DrTS-TtTSDeltaN enzyme had a higher thermostability and a lower byproduct than DrTS in their reactions. The above-mentioned results allowed the inference that the C terminus of TtTS plays a key role in maintaining its thermostability and hence in modulating the side reaction to reduce glucose production at a high temperature. A new, simple, and fast method to improve thermophilicity by fusing this fragment with particular conformation to a thermolabile enzyme is offered.


Nutritional regulation of renal lipogenic factor expression in mice: comparison to regulation in the liver and skeletal muscle.
Regulation of lipogenesis by pathophysiological factors in the liver and skeletal muscle is well understood; however, regulation in the kidney is still unclear. To elucidate nutritional regulation of lipogenic factors in the kidney, we measured the renal expression of lipogenic transcriptional factors and enzymes during fasting and refeeding in chow-fed and high-fat-fed mice. We also examined the regulatory effect of the liver X receptor (LXR) on the expression of lipogenic factors. The renal gene expression of sterol regulatory element-binding protein (SREBP)-1c and fatty acid synthase (FAS) was reduced by fasting for 48 h and restored by refeeding, whereas the mRNA levels of forkhead box O (FOXO)1/3 were increased by fasting and restored by refeeding. Accordingly, protein levels of SREBP-1, FAS, and phosphorylated FOXO1/3 were reduced by fasting and restored by refeeding. The patterns of lipogenic factors expression in the kidney were similar to those in the liver and skeletal muscle. However, this phasic regulation of renal lipogenic gene expression was blunted in diet-induced obese mice. LXR agonist TO901317 increased the lipogenic gene expression and the protein levels of SREBP-1 precursor and FAS but not nuclear SREBP-1. Moreover, increases in insulin-induced gene mRNA and nuclear carbohydrate-responsive element binding protein (ChREBP) levels were observed in the TO901317-treated mice. These results suggest that the kidney shows flexible suppression and restoration of lipogenic factors following fasting and refeeding in lean mice, but this is blunted in obese mice. LXR is involved in the renal expression of lipogenic enzymes, and ChREBP may mediate the response.


Teaching the Emergency Department Patient Experience: Needs Assessment from the CORD-EM Task Force.
Since the creation of Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) patient satisfaction (PS) scores, patient experience (PE) has become a metric that can profoundly affect the fiscal balance of hospital systems, reputation of entire departments and welfare of individual physicians. While government and hospital mandates demonstrate the prominence of PE as a quality measure, no such mandate exists for its education. The objective of this study was to determine the education and evaluation landscape for PE in categorical emergency medicine (EM) residencies. This was a prospective survey analysis of the Council of Emergency Medicine Residency Directors (CORD) membership. Program directors (PDs), assistant PDs and core faculty who are part of the CORD listserv were sent an email link to a brief, anonymous electronic survey. Respondents were asked their position in the residency, the name of their department, and questions regarding the presence and types of PS evaluative data and PE education they provide. We obtained 168 responses from 139 individual residencies, representing 72% of all categorical EM residencies. This survey found that only 27% of responding residencies provide PS data to their residents. Of those programs, 61% offer simulation scores, 39% provide third-party attending data on cases with resident participation, 37% provide third-party acquired data specifically about residents and 37% provide internally acquired quantitative data. Only 35% of residencies reported having any organized PE curricula. Of the programs that provide an organized PE curriculum, most offer multiple modalities; 96% provide didactic lectures, 49% small group sessions, 47% simulation sessions and 27% specifically use standardized patient encounters in their simulation sessions. The majority of categorical EM residencies do not provide either PS data or any organized PE curriculum. Those that do use a heterogeneous set of data collection modalities and educational techniques. American Osteopathic Association and Accreditation Council for Graduate Medical Education residencies show no significant differences in their resident PS data provision or formal curricula. Further work is needed to improve education given the high stakes of PS scores in the emergency physician's career.


Global identification of hnRNP A1 binding sites for SSO-based splicing modulation.
Many pathogenic genetic variants have been shown to disrupt mRNA splicing. Besides splice mutations in the well-conserved splice sites, mutations in splicing regulatory elements (SREs) may deregulate splicing and cause disease. A promising therapeutic approach is to compensate for this deregulation by blocking other SREs with splice-switching oligonucleotides (SSOs). However, the location and sequence of most SREs are not well known. Here, we used individual-nucleotide resolution crosslinking immunoprecipitation (iCLIP) to establish an in vivo binding map for the key splicing regulatory factor hnRNP A1 and to generate an hnRNP A1 consensus binding motif. We find that hnRNP A1 binding in proximal introns may be important for repressing exons. We show that inclusion of the alternative cassette exon 3 in SKA2 can be significantly increased by SSO-based treatment which blocks an iCLIP-identified hnRNP A1 binding site immediately downstream of the 5' splice site. Because pseudoexons are well suited as models for constitutive exons which have been inactivated by pathogenic mutations in SREs, we used a pseudoexon in MTRR as a model and showed that an iCLIP-identified hnRNP A1 binding site downstream of the 5' splice site can be blocked by SSOs to activate the exon. The hnRNP A1 binding map can be used to identify potential targets for SSO-based therapy. Moreover, together with the hnRNP A1 consensus binding motif, the binding map may be used to predict whether disease-associated mutations and SNPs affect hnRNP A1 binding and eventually mRNA splicing.


Histone deacetylase activity is necessary for left-right patterning during vertebrate development.
Consistent asymmetry of the left-right (LR) axis is a crucial aspect of vertebrate embryogenesis. Asymmetric gene expression of the TGFβ superfamily member Nodal related 1 (Nr1) in the left lateral mesoderm plate is a highly conserved step regulating the situs of the heart and viscera. In Xenopus, movement of maternal serotonin (5HT) through gap-junctional paths at cleavage stages dictates asymmetry upstream of Nr1. However, the mechanisms linking earlier biophysical asymmetries with this transcriptional control point are not known. To understand how an early physiological gradient is transduced into a late, stable pattern of Nr1 expression we investigated epigenetic regulation during LR patterning. Embryos injected with mRNA encoding a dominant-negative of Histone Deacetylase (HDAC) lacked Nr1 expression and exhibited randomized sidedness of the heart and viscera (heterotaxia) at stage 45. Timing analysis using pharmacological blockade of HDACs implicated cleavage stages as the active period. Inhibition during these early stages was correlated with an absence of Nr1 expression at stage 21, high levels of heterotaxia at stage 45, and the deposition of the epigenetic marker H3K4me2 on the Nr1 gene. To link the epigenetic machinery to the 5HT signaling pathway, we performed a high-throughput proteomic screen for novel cytoplasmic 5HT partners associated with the epigenetic machinery. The data identified the known HDAC partner protein Mad3 as a 5HT-binding regulator. While Mad3 overexpression led to an absence of Nr1 transcription and randomized the LR axis, a mutant form of Mad3 lacking 5HT binding sites was not able to induce heterotaxia, showing that Mad3's biological activity is dependent on 5HT binding. HDAC activity is a new LR determinant controlling the epigenetic state of Nr1 from early developmental stages. The HDAC binding partner Mad3 may be a new serotonin-dependent regulator of asymmetry linking early physiological asymmetries to stable changes in gene expression during organogenesis.


Diosmin ameliorates intestinal injury induced by hepatic ischemia reperfusion in rats.
Hepatic ischemia-reperfusion causes histologic injury to the intestinal mucosa. We investigated the effects of diosmin, a phelobotrophic drug with antioxidant and antiinflammatory effects, on intestinal injury in the experimental liver ischemia-reperfusion model. Fourty rats were divided into four groups: sham group (Group 1), control group (Group 2), perop diosmin group (50 mg/kg) treatment group (Group 3) and preop 10-day diosmin (50 mg/kg) treatment group (Group 4). Ischemia-reperfusion model was carried out by clamping the hepatic pedicle for 60 min and then reperfusing the liver for 90 min. At the end of procedures, blood and ileum tissue samples were obtained for biochemical and histopathological assessments. According to the results of liver function tests (AST, ALT and LDH) there was a significant difference between the control and other groups (p < 0.001 for all). According to the plasma and ileum oxidative stress parameters (MDA, GSH-Px and XO), there was a significant difference between the control and other groups (p < 0.05 for all). Histopathologically; the specimens in Group 2 showed specific morphological abnormalities (the epithelial lining of the apical surface of villi was degenerated and desquamated to the lumen). Group 3 and 4 showed ileal histomorphology similar to the sham group. Pathological scores were significantly different between Group 2 and other groups. Diosmin can be administered for protection from destructive effects of hepatic ischemia-reperfusion injury on intestine in both emergent and elective hepatic surgical operations in which the possible ischemic periods are expected (Tab. 4, Fig. 1, Ref. 39).


First and second cattle passage of transmissible mink encephalopathy by intracerebral inoculation.
To compare clinicopathologic findings of transmissible mink encephalopathy (TME) with other transmissible spongiform encephalopathies (TSE, prion diseases) that have been shown to be experimentally transmissible to cattle (sheep scrapie and chronic wasting disease [CWD]), two groups of calves (n = 4 each) were intracerebrally inoculated with TME agents from two different sources (mink with TME and a steer with TME). Two uninoculated calves served as controls. Within 15.3 months postinoculation, all animals from both inoculated groups developed clinical signs of central nervous system (CNS) abnormality; their CNS tissues had microscopic spongiform encephalopathy (SE); and abnormal prion protein (PrP(res)) as detected in their CNS tissues by immunohistochemistry (IHC) and Western blot (WB) techniques. These findings demonstrate that intracerebrally inoculated cattle not only amplify TME PrP(res) but also develop clinical CNS signs and extensive lesions of SE. The latter has not been shown with other TSE agents (scrapie and CWD) similarly inoculated into cattle. The findings also suggest that the diagnostic techniques currently used for confirmation of bovine spongiform encephalopathy (BSE) would detect TME in cattle should it occur naturally. However, it would be a diagnostic challenge to differentiate TME in cattle from BSE by clinical signs, neuropathology, or the presence of PrP(res) by IHC and WB.


Complementary and alternative medicine use in oncology: a questionnaire survey of patients and health care professionals.
We aimed to investigate the prevalence and predictors of Complementary and Alternative Medicine (CAM) use among cancer patients and non-cancer volunteers, and to assess the knowledge of and attitudes toward CAM use in oncology among health care professionals. This is a cross-sectional questionnaire survey conducted in a single institution in Ireland. Survey was performed in outpatient and inpatient settings involving cancer patients and non-cancer volunteers. Clinicians and allied health care professionals were asked to complete a different questionnaire. In 676 participants including 219 cancer patients; 301 non-cancer volunteers and 156 health care professionals, the overall prevalence of CAM use was 32.5% (29.1%, 30.9% and 39.7% respectively in the three study cohorts). Female gender (p < 0.001), younger age (p = 0.004), higher educational background (p < 0.001), higher annual household income (p = 0.001), private health insurance (p = 0.001) and non-Christian (p < 0.001) were factors associated with more likely CAM use. Multivariate analysis identified female gender (p < 0.001), non-Christian (p = 0.001) and private health insurance (p = 0.015) as independent predictors of CAM use. Most health care professionals thought they did not have adequate knowledge (58.8%) nor were up to date with the best evidence (79.2%) on CAM use in oncology. Health care professionals who used CAM were more likely to recommend it to patients (p < 0.001). This study demonstrates a similarly high prevalence of CAM use among oncology health care professionals, cancer and non cancer patients. Patients are more likely to disclose CAM usage if they are specifically asked. Health care professionals are interested to learn more about various CAM therapies and have poor evidence-based knowledge on specific oncology treatments. There is a need for further training to meet to the escalation of CAM use among patients and to raise awareness of potential benefits and risks associated with these therapies.


Tracking circadian rhythms of bone mineral deposition in murine calvarial organ cultures.
Osteoblasts, which orchestrate the deposition of small apatite crystals through the expression of nucleating proteins, have been shown to also express clock genes associated with the circadian signaling pathway. We hypothesized that protein-mediated bone mineralization may be linked to circadian oscillator mechanisms functioning in peripheral bone tissue. In this study, Per1 expression in ex vivo neonatal murine calvaria organ cultures was monitored for 6 days using a Per1-luciferase transgene as a bioluminescent indicator of clock function. Fluctuations in Per1 expression had a period of 25 ± 4 hours (n = 14) with early expression at CT09:59 ± 03:37 (CT = circadian time). We also established the kinetics of mineral deposition in developing bone by using noninvasive Raman microscopy to track mineral accumulation in calvarial tissue. The content and quality of newly deposited mineral was continually examined at the interparietal bone/fontanel boundary for a period of 6 days with 1-hour temporal resolution. Using this approach, mineralization over time exhibited bursts of mineral deposition followed by little or no deposition, which was recurrent with a periodicity of 26.8 ± 9.6 hours. As many as six near-daily mineralization events were observed in the calvaria before deposition ceased. Earliest mineralization events occurred at CT16:51 ± 03:45, which is 6 hours behind Per1 expression. These findings are consistent with the hypothesis that mineralization in developing bone tissue is regulated by a local circadian oscillator mechanism.


Malignant gliomas can be converted to non‑proliferating glial cells by treatment with a combination of small molecules.
Gliomas, the most highly malignant central nervous system tumors, are associated with an extremely poor patient survival rate. Given that gliomas are derived from mutations in glial precursor cells, a considerable number of them strongly react with glial precursor cell‑specific markers. Thus, we investigated whether malignant gliomas can be converted to glial cells through the regulation of endogenous gene expression implicated in glial precursor cells. In the present study, we used three small‑molecule compounds, [cyclic adenosine monophosphate (cAMP) enhancer, a mammalian target of rapamycin (mTOR) inhibitor, and a bromodomain and extra‑terminal motif (BET) inhibitor] for glial reprogramming. Small‑molecule‑induced gliomas (SMiGs) were not only transformed into exhibiting a glial‑specific morphology, but also showed positive reactions with glial‑specific markers such as glial fibrillary acidic protein (GFAP), 2',3'‑cyclic nucleotide 3'‑phosphohydrolase (CNP) and anti‑oligodendrocyte (RIP). A microarray analysis indicated that SMiGs exhibited a marked increase in specific gene levels, whereas that of a malignant cancer‑specific gene was greatly decreased. Moreover, proliferation of the cells was markedly suppressed after the conversion of malignant glioma cells into glial cells. Our findings confirmed that malignant gliomas can be reprogrammed to non‑proliferating glial cells, using a combination of small molecules, and their proliferation can be regulated by their differentiation. We suggest that our small‑molecule combination (with forskolin, rapamycin and I‑BET151) may be the next generation of anticancer agents that act by reprogramming malignant gliomas to differentiate into glial cells.


Vitamin B12 and folate status of older New Zealand women.
The primary aim of this study was to assess the biochemical vitamin B12 and folate status of a representative group of elderly women (70-80 y) living in Dunedin, New Zealand. A second aim was to determine the prevalence of hyperhomocysteinaemia and to explore the determinants of homocysteine (hcy) concentration in this population. A cross-sectional study was carried out between June and August of 2000. Two hundred and fifty women were randomly selected from the 1998 electoral roll. Fasting blood samples were analysed for folate, vitamin B12, total hcy, creatinine, and haematological parameters. Of the women selected, 87 did not respond, 37 were not traceable, 23 were not eligible or had died, and 103 agreed to participate. The overall response rate was 46%. Based on a cut-off of 150 pmol/L for serum B12, 13% of participants would be classified as having sub-optimal vitamin B12 status. Of the women, 3 and 5%, respectively, had low serum (< 6.6 nmol/L) and erythrocyte folate (< 317 nmol/L) concentrations. No participant had megaloblastic anaemia. The prevalence of hyperhomocysteinaemia (> 15 mumol/L) in this population was 18%. Hyperhomocysteinaemia in this group may be partly explained by renal insufficiency because there was a significant association between serum creatinine and plasma hcy (P < 0.001). Blood folate levels but not serum B12 were significantly inversely associated with hcy. In conclusion, there was a moderately high prevalence of hyperhomocysteinaemia and suboptimal plasma vitamin B12 concentrations but not low blood folate concentrations in this elderly female population.


Stinging insect hypersensitivity: a practice parameter update 2011.
These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing "Stinging insect hypersensitivity: a practice parameter update II." Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or the ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. These parameters are not designed for use by pharmaceutical companies in drug promotion. The Joint Task Force understands that the cost of diagnostic tests and therapeutic agents is an important concern that may appropriately influence the work-up and treatment chosen for a given patient. The Joint Task Force recognizes that the emphasis of our primary recommendations regarding a medication may vary, for example, depending on third party payer issues and product patent expiration dates. However, since a given test or agent's cost is so widely variable, and there is a paucity of pharmacoeconomic data, the Joint Task Force generally does not consider cost when formulating Practice Parameter recommendations. In extraordinary circumstances, when the cost benefit of an intervention is prohibitive as supported by pharmacoeconomic data, commentary may be provided.


Risk factors for substances use and misuse among young people in France: What can we learn from the Substance Use Risk Profile Scale?
The prevention of addictions in young people is a challenge for Mental and Public Health policies, and requires specific risk-screening tools. Specific personality traits, as assessed using the Substance Use Risk Profile Scale (SURPS), could play a key role in the onset and escalation of substance use. This study aimed to examine (1) measurement invariance across age and gender (2) the effects of age and gender on associations between SURPS scores and the most frequently-consumed substances. Analyses were based on the responses from 5069 participants (aged 14-20 years) from the 2011 ESPAD-France dataset. Substance-use outcomes were experimentation and current frequency of alcohol, tobacco and cannabis use, and drunkenness. Our approach, consisting in analysing measurement and structural invariance and interaction terms, established the stability of (i) SURPS profiles, and (ii) relationships between these scores and substance experimentation and use over a developmental period ranging from mid-adolescence to early adulthood. Measurement invariance across genders was also confirmed despite the absence of scalar invariance for 2 items. Significant interactions between gender and SURPS factors were established, highlighting differential vulnerability, especially concerning Hopelessness and experimentation of alcohol and drunkenness, or Impulsivity and tobacco experimentation. Finally, Anxiety Sensitivity could be protective against substance use, especially for cannabis in girls. Our results suggest the relevance of the SURPS to assess vulnerability towards drug use, and underline the need to consider gender differences in addiction risks.


Immediate mobilization after coronary angiography or percutaneous coronary intervention following hemostasis with the AngioSeal vascular closure device (the MOBS study).
In patients undergoing coronary angiography or percutaneous coronary intervention (PCI), the standard post procedure regime includes immobilization and bed rest despite the use of vascular closure devices. In the Mobilization after Coronary Angiography or Percutaneous Coronary Intervention (MOBS) study we compared bleeding complications after cardiac catheterization with femoral artery access after mobilization immediately off the angiographic table or standard care with1 hour (MOBS I after a diagnostic angiogram) or 2 hours of bed rest before mobilization (MOBS II after PCI). Bleeding complications were defined as major (requiring surgery of the femoral artery, transfusion or increased hospital stay) and minor (hematoma <5 × 5 cm(2), oozing from the puncture site or minor bleeding that could be compressed manually). In the MOBS I cohort (100 patients were mobilized immediately and 100 patients followed standard care) no major bleeding complications were seen. In the immediate mobilization group 2.0% experienced minor bleeding compared to 4.0% in the standard care group (p=0.41). In the MOBS II cohort after PCI (158 patients were mobilized immediately and 161 patients followed standard care), major bleeding complication rates did not differ significantly between the two groups: immediate mobilization group 26.6% vs. standard care group 28.0%, p=0.78. The majority of bleeding complications were due to oozing: immediate mobilization group 22.8% vs. standard care group 20.5%, p=0.62. Immediate mobilization after a coronary angiogram or PCI with the femoral access site closed by the closure device AngioSeal was not associated with increased bleeding risk compared to standard care with bed rest.


Linking microcircuit dysfunction to cognitive impairment: effects of disinhibition associated with schizophrenia in a cortical working memory model.
Excitation-inhibition balance (E/I balance) is a fundamental property of cortical microcircuitry. Disruption of E/I balance in prefrontal cortex is hypothesized to underlie cognitive deficits observed in neuropsychiatric illnesses such as schizophrenia. To elucidate the link between these phenomena, we incorporated synaptic disinhibition, via N-methyl-D-aspartate receptor perturbation on interneurons, into a network model of spatial working memory (WM). At the neural level, disinhibition broadens the tuning of WM-related, stimulus-selective persistent activity patterns. The model predicts that this change at the neural level leads to 2 primary behavioral deficits: 1) increased behavioral variability that degrades the precision of stored information and 2) decreased ability to filter out distractors during WM maintenance. We specifically tested the main model prediction, broadened WM representation under disinhibition, using behavioral data from human subjects performing a spatial WM task combined with ketamine infusion, a pharmacological model of schizophrenia hypothesized to induce disinhibition. Ketamine increased errors in a pattern predicted by the model. Finally, as proof-of-principle, we demonstrate that WM deteriorations in the model can be ameliorated by compensations that restore E/I balance. Our findings identify specific ways by which cortical disinhibition affects WM, suggesting new experimental designs for probing the brain mechanisms of WM deficits in schizophrenia.


The role of the pulvinar in resolving competition between memory and visual selection: a functional connectivity study.
Memory and attention interact. Information held in working memory (WM) can bias visual selection toward matching stimuli in a subsequent search display, while a search target that is different from the memory stimulus can interfere with its subsequent recognition. In recent fMRI studies, the pulvinar has been consistently shown to have an enhanced response when an item in WM matches a search target and a reduced response when the WM item matches a distracter in search. Here we used Granger causality analysis to help understand the role of the pulvinar in resolving competition between memory and selection processes. Across three experiments the results showed increased coupling between the pulvinar and the ipsilateral superior frontal gyrus, contralateral temporal-parietal junction (TPJ) and calcarine sulcus when a visual search distracter matched the item held in memory. This connection pattern suggests that the pulvinar suppresses visual responses to the target when a contralateral distracter contains information held in working memory. We propose that this suppression acts to protect the memory item from interference arising from information associated with the search target. Consistent with this proposal we showed that the strength of the thalamus-to-visual connection predicted performance on a subsequent memory test. The data therefore suggest that the thalamus modulates bottom up processing in sensory cortex to minimize interference to WM content.


Recognition of achiral and chiral ammonium salts by neutral ditopic receptors based on chiral salen-UO2 macrocycles.
A mononuclear (M20) and a dinuclear (M40) uranyl chiral macrocyclic complex, incorporating both a salen unit containing two phenyl rings linked to a chiral diimine bridge and the (R)-BINOL unit, behaves as an efficient ditopic receptor for achiral and chiral quaternary ammonium salts. Binding affinities in chloroform solution have been measured for 1:1 complexes of many quaternary salts encompassing tetramethylammonium (TMA), tetraethylammonium (TEA), tetrabutylammonium (TBA), and acetylcholine (ACh), as well as trimethylanilinium (TriMAn), benzyltrimethylammonium (BnTriMA), (alpha-methylbenzyl)trimethylammonium and pyrrolidinium cations. The anion of the salt is bound by the hard Lewis acidic uranyl site, with an increasing binding efficiency on increasing the anion hardness (I(-) < Br(-) < Cl(-)), whereas CH-pi or pi-pi attractions by binapthyl moiety, or the salicylaldehyde unit, or the phenyl rings of diimine bridge ensure the recognition of the cation partner. Optimized structures of receptor-anion-cation ternary complexes obtained by MM calculations are supported by 2D-ROESY NMR measurements.


Achievable information rates calculation for optical OFDM few-mode fiber long-haul transmission systems.
We propose a method to estimate the lower bound of achievable information rates (AIRs) of high speed orthogonal frequency-division multiplexing (OFDM) in spatial division multiplexing (SDM) optical long-haul transmission systems. The estimation of AIR is based on the forward recursion of multidimensional super-symbol efficient sliding-window Bahl-Cocke-Jelinek-Raviv (BCJR) algorithm. We consider most of the degradations of fiber links including nonlinear effects in few-mode fiber (FMF). This method does not consider the SDM as a simple multiplexer of independent data streams, but provides a super-symbol version for AIR calculation over spatial channels. This super-symbol version of AIR calculation algorithm, in principle, can be used for arbitrary multiple-input-multiple-output (MIMO)-SDM system with channel memory consideration. We illustrate this method by performing Monte Carlo simulations in a complete FMF model. Both channel model and algorithm for calculation of the AIRs are described in details. We also compare the AIRs results for QPSK/16QAM in both single mode fiber (SMF)- and FMF-based optical OFDM transmission.


Irony comprehension and theory of mind deficits in patients with Parkinson's disease.
Many individuals with Parkinson's disease (PD) are known to have difficulties in understanding pragmatic aspects of language. In the present study, a group of eleven non-demented PD patients and eleven healthy control (HC) participants were tested on their ability to interpret communicative intentions underlying verbal irony and lies, as well as on their ability to infer first- and second-order mental states (i.e., theory of mind). Following Winner et al. (1998), participants answered different types of questions about the events which unfolded in stories which ended in either an ironic statement or a lie. Results showed that PD patients were significantly less accurate than HC participants in assigning second-order beliefs during the story comprehension task, suggesting that the ability to make a second-order mental state attribution declines in PD. The PD patients were also less able to distinguish whether the final statement of a story should be interpreted as a joke or a lie, suggesting a failure in pragmatic interpretation abilities. The implications of frontal lobe dysfunction in PD as a source of difficulties with working memory, mental state attributions, and pragmatic language deficits are discussed in the context of these findings.


Acute regulation of pancreatic islet microcirculation and glycaemia by telmisartan and ramipril: discordant effects between normal and type 2 diabetic rats.
Diabetic patients are often treated with an ACEi (angiotensin-converting enzyme inhibitor) or angiotensin receptor antagonist against hypertension or albuminuria. These drugs also have a positive impact on glucose tolerance, but the mechanism for this remains elusive. Hypothesizing a positive non-additive effect, we studied whether the angiotensin receptor antagonist telmisartan or the ACEi ramipril acutely influence insulin secretion and glycaemia in vivo in healthy and Type 2 diabetic rats through effects on islet blood perfusion. Telmisartan and ramipril were injected intravenously into anaesthetized non-diabetic Wistar rats or Type 2 diabetic GK (Goto-Kakizaki) rats. In non-diabetic Wistar rats, neither whole PBF (pancreatic blood flow) nor IBF (islet blood flow) were significantly influenced by telmisartan and ramipril, alone or in combination. Renal blood flow was enhanced significantly by telmisartan and ramipril when used in combination, whereas ABF (adrenal blood flow) was not affected by any of the drugs. Telmisartan and ramipril both significantly increased serum insulin levels, but did not influence glycaemia. In Type 2 diabetic GK rats, both whole PBF and IBF were significantly decreased by telmisartan and ramipril, but only when used in combination. Renal blood flow was enhanced significantly by telmisartan and ramipril alone, but not when used in combination, whereas ABF was not affected by any of the drugs. Telmisartan and ramipril both significantly decreased serum insulin levels, and non-additively elevated blood glucose levels. In conclusion, the present study suggests that a local pancreatic RAS (renin-angiotensin system), sensitive to acute administration of telmisartan and ramipril, controls pancreatic IBF and insulin secretion and thereby has an impact on glucose tolerance. Our findings indicate unexpected significant differences in the effects of these agents on islet microcirculation, in vivo insulin secretion and glycaemia between healthy and Type 2 diabetic rats.


Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas.
Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas. Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria. A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival. Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth.


Easy, reproducible extraperitoneal pelvic access for robot - assisted radical prostatectomy.
Robot - assisted radical prostatectomy is commonly performed transperitoneally (tRARP), although the extraperitoneal (eRARP) approach is a safe and effective alternative that may be preferred in certain situations. We developed a novel method of direct access into the space of Retzius with a visual obturator port (VisiportTM) for laparoscopic or robotic prostatectomy. We present an instructional video of extraperitoneal pelvic access for eRARP with both internal and external camera views. The patient is first placed in lithotomy and 15° Trendelenburg position. The camera is inserted infraumbilically and angled caudally. The pre-peritoneal space is accessed through the anterior rectus fascia using a VisiportTM (Covidien, $ 60 www.esutures.com), and the working space is developed with a kidney - shaped balloon OMSPDBS2TM (Covidien, $ 49 www.esutures.com). After the space is insufflated, subsequent trocars are angled in extraperitoneally under direct vision. The average time from incision to final port placement after a learning curve of about 50 cases is 8 minutes (IQR 7-10). We have performed over 1.000 cases using this technique and eRARP has become our procedure of choice. Our last 500 + cases were performed robotically. Approximately 10% of the time peritoneotomies were noted, but rarely did these require conversion to tRARP. There have been no bowel or other abdominal organ injuries, major vascular or other complications in any of these cases.


Education for health professionals in the emerging market economies: a literature review.
Along with economic growth and social reforms, the emerging market economies (EMEs) are undergoing restructuring of their health care systems. There is now an increased focus on disease prevention and primary care, along with a patient-centred approach to health care delivery. However, these changes need to be complemented by alterations in the health care education system. A review of the published literature, limited to the last 10 years, was conducted to include recent updates on medical and nursing education. This was done by systematically searching appropriate databases using keywords. This review covers only the common issues related to education and training in EMEs. Issues identified included: the mismatch between the health needs of the population and education curricula; outdated curricula and teaching methods; growing numbers of medical schools; the quality of education, and inadequate career guidance for students to help them make decisions about choosing a health profession as a career and, later, about choosing a field of specialisation. The literature provides evidence of innovative approaches adopted in several EMEs, which include: outcome-based education; community-oriented medical education; problem-based learning; initiatives to improve quality, and initiatives to resolve the shortage of skilled educators for medical and nursing schools. The health care systems in EMEs are undergoing changes imposed by economic, political and social transition. Reforms in health systems will need to be complemented by educational reforms. Education systems require to be updated through needs-based comprehensive curriculum design and innovative teaching methods. The challenges imposed by the growth in the number of public and private institutions and the need for a standardised accreditation system for quality assurance demand attention. The profiles of both family medicine and community health care will need to be raised and their status enhanced to attract high-calibre students to these specialties.


K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current.
In mammalian cardiac cells, a variety of transient or sustained K+ currents contribute to the repolarization of action potentials. There are two main components of the delayed-rectifier sustained K+ current, I(Kr) (rapid) and I(Ks), (slow). I(Kr) is the product of the gene HERG, which is altered in the long-QT syndrome, LQT2. A channel with properties similar to those of the I(Ks) channel is produced when the cardiac protein IsK is expressed in Xenopus oocytes. However, it is a small protein with a very unusual structure for a cation channel. The LQT1 gene is another gene associated with the LQT syndrome, a disorder that causes sudden death from ventricular arrhythmias. Here we report the cloning of the full-length mouse K(V)LQT1 complementary DNA and show that K(V)LQT1 associates with IsK to form the channel underlying the I(Ks) cardiac current, which is a target of class-III anti-arrhythmic drugs and is involved in the LQT1 syndrome.


Harderian gland: influence on pineal hydroxyindole-O-methyltransferase activity in neonatal rats.
A circadian rhythm has been found in hydroxyindole-O-methyltransferase activity of the pineal gland of blinded 12-day-old rats. Five additional hours of lighting can partly prevent the nocturnal increase in pineal hydroxyindole-O-methyltransferase activity in such rats. Removal of the Harderian gland abolishes this response to light in 12-day-old blinded animals, giving further support to the suggestion that this gland may function as an extraretinal photosensitive organ influencing the pineal gland in blinded suckling rats.


Possible Interaction Between Cigarette Smoking and HLA-DRB1 Variation in the Risk of Follicular Lymphoma.
Follicular lymphoma (FL) risk is strongly associated with germline genetic variation in human leukocyte antigen (HLA) class II. Cigarette smoking has been suggested to increase FL risk, primarily among women. We hypothesized that amino acids in HLA-antigen D-related β1 subunit (DRB1) interact with smoking in FL risk, as shown for rheumatoid arthritis. We analyzed 373 patients with FL and 818 controls from 2 population-based case-control studies in Sweden and Denmark (1999-2003). Haplotypes in HLA-DRB1 were imputed at amino acid positions 11, 13, 28, 30, and 70-74 (shared epitope). We estimated the relative risk of FL as odds ratios with 95% confidence intervals for different smoking status/haplotype combinations. Interaction was defined as departure from additivity of effects and quantified by the attributable proportion (AP). Relative to never-smokers carrying no shared epitope alleles, smoking was associated with the risk of FL among all subjects (for former smokers, odds ratio (OR) = 2.20, 95% confidence interval (CI): 1.10, 4.41; ORcurrent = 3.56, 95% CI: 1.60, 7.92) and women (ORformer = 2.95, 95% CI: 1.18, 7.37; ORcurrent = 5.63, 95% CI: 2.07, 15.3) carrying 2 shared epitope alleles but not among those carrying zero or 1 shared epitope allele. Smoking and shared epitope status interacted significantly as measured by AP (overall, AP = 0.6, 95% CI: 0.15, 1.0; for women, AP = 0.5, 95% CI: 0.005, 1.0). These results suggest a possible interaction between smoking and HLA-DRB1-associated antigen presentation in FL risk and provide a model to further unravel FL etiology.


Muscle activation during maximal voluntary eccentric and concentric knee extension.
The aim of this investigation was to study the relationships among movement velocity, torque output and electromyographic (EMG) activity of the knee extensor muscles under eccentric and concentric loading. Fourteen male subjects performed maximal voluntary eccentric and concentric constant-velocity knee extensions at 45, 90, 180 and 360 degrees.s-1. Myoelectric signals were recorded, using surface electrodes, from the vastus medialis, vastus lateralis and rectus femoris muscles. For comparison, torque and full-wave rectified EMG signals were amplitude-averaged through the central half (30 degrees-70 degrees) of the range of motion. For each test velocity, eccentric torque was greater than concentric torque (range of mean differences: 20%-146%, P less than 0.05). In contrast, EMG activity for all muscles was lower under eccentric loading than velocity-matched concentric loading (7%-31%, P less than 0.05). Neither torque output nor EMG activity for the three muscles changed across eccentric test velocities (P greater than 0.05). While concentric torque increased with decreasing velocity, EMG activity for all muscles decreased with decreasing velocity (P less than 0.05). These data suggest that under certain high-tension loading conditions (especially during eccentric muscle actions), the neural drive to the agonist muscles was reduced, despite maximal voluntary effort. This may protect the musculoskeletal system from an injury that could result if the muscle was to become fully activated under these conditions.


Infection After Unicompartmental Knee Arthroplasty: A High Risk of Subsequent Complications.
Unicompartmental knee arthroplasty restores function and improves pain in appropriately selected patients. Scant evidence exists regarding the treatment of periprosthetic joint infection (PJI) after unicompartmental knee arthroplasty (UKA). (1) What was the overall survivorship free from reinfection? (2) What is the survivorship free of all-cause revision? (3) What are the Knee Society scores (KSS) and complications after surgical treatment of UKA PJI? This retrospective study with data drawn from a longitudinally maintained institutional registry identified 15 UKA PJIs between 1992 and 2014. The median age at PJI diagnosis was 58 years (range, 41-82 years), nine of 15 were men, and the median body mass index was 29 kg/m (range, 23-36 kg/m). Ten patients (10 of 15) satisfied major Musculoskeletal Infection Society diagnostic criteria. There were five patients (five of 15) with early postoperative infections, five (five of 15) with acute hematogenous infections, and five (five of 15) with chronic PJIs. Two-stage exchange was performed in four patients with PJIs (four of 15), and débridement, antibiotics, and implant retention (DAIR) was performed in 11 patients (11 of 15) with PJIs. We performed Kaplan-Meier survivorship analysis for reinfection and revision procedures. Thirteen patients had a minimum of 2 years' followup and were included in the clinical analysis. Median followup was 4 years (range, 2-6 years). We calculated KSS. Infection-free survivorship was 71% at 5 years (95% confidence interval [CI], 46%-96%). Treatment success was higher for patients undergoing two-stage exchange (100% at 5 years; 95% CI, 100%-100%) versus DAIR (61% at 5 years; 95% CI, 31%-92%). Four of 11 patients undergoing DAIR had developed a reinfection at final followup. Survivorship free of any revision was 49% at 5 years (95% CI, 19%-79%). One patient from the two-stage exchange cohort underwent femoral component revision for aseptic loosening 5 years after PJI treatment, and two patients from the DAIR group were converted to TKA for disease progression at a mean of 4 years. In patients with a minimum of 2 years' followup, median KSS improved from 73 (range, 50-93) before index UKA to 94 (range, 55-100; p = 0.016). Treatment of UKA PJI with DAIR was associated with a lower infection-free survivorship at 5 years compared with two-stage exchange with conversion to TKA. Among those patients who were infection-free, a number needed reoperations for disease progression (in the DAIR group) or component loosening (in both groups). UKA PJI results in substantial morbidity, and patients with these infections should be followed closely for aseptic causes of failure in addition to infection recurrence. Level IV, therapeutic study.


Preface: Special Topic on Single-Molecule Biophysics.
Single-molecule measurements are now almost routinely used to study biological systems and processes. The scope of this special topic emphasizes the physics side of single-molecule observations, with the goal of highlighting new developments in physical techniques as well as conceptual insights that single-molecule measurements bring to biophysics. This issue also comprises recent advances in theoretical physical models of single-molecule phenomena, interpretation of single-molecule signals, and fundamental areas of statistical mechanics that are related to single-molecule observations. A particular goal is to illustrate the increasing synergy between theory, simulation, and experiment in single-molecule biophysics.


Variability in potentially preventable hospitalisations: an observational study of clinical practice patterns of general practitioners and care outcomes in the Basque Country (Spain).
To explain the variability in the frequency of potentially preventable hospitalisations (ambulatory care sensitive conditions, ACSCs) based on factors at multiple levels (individual, health professional, health centre and health district), and specifically using resource efficiency indicators for general practitioners (GPs). Cross-sectional study. We analysed primary care electronic health records and hospital discharge data using multilevel mixed models. Primary care network of the Basque Health Service (Spain). All the residents in the Basque Country ≥14 years of age, covered by the public healthcare system (n=1,959,682), and all the GPs (n=1193) and health centres (n=130). Individuals admitted for ACSCs, over a 12- month period. Admissions for ACSCs were less frequent among patients who were female, middle-aged or from the highest socioeconomic classes. The health centre variables considered and GP list size were not found to be significant. After adjusting for the variables studied including morbidity, the risk of hospital admission was higher among individuals under the care of GPs with greater than expected numbers of patient visits and prescribing costs (OR=1.27 (95% CI 1.18 to 1.37); 1.16 (1.08 to 1.25)), and who make fewer referrals than the mean among their colleagues (OR=1.33 (1.22 to 1.44)). When assessing activities and procedure indicators in primary care, we should also define outcome-based criteria. Specifically, GPs who are repeatedly visited by their patients, have higher prescribing costs and are more reluctant to refer patients to specialists obtain poorer outcomes.


Acute Garcinia mangostana (mangosteen) supplementation does not alleviate physical fatigue during exercise: a randomized, double-blind, placebo-controlled, crossover trial.
The purple mangosteen (Garcinia mangostana), known as the "queen of fruit," is widely consumed and unique not only because of its outstanding appearance and flavor but also its remarkable and diverse pharmacological effects. The aim of the present study is to evaluate the effect of acute mangosteen supplementation on physical fatigue during exercise. A randomized, double-blind, placebo-controlled, crossover study was carried out by 12 healthy adults. The participants were randomly assigned to receive acute oral administration of either 250 mL of the mangosteen-based juice (supplementation treatment; 305 mg of α-mangostin and 278 mg of hydroxycitric acid) or a placebo (control treatment) 1 h before cycle ergometer exercise. Time to exhaustion, heart rate, Borg Rating of Perceived Exertion score, blood biochemical markers (namely ammonia, cortisol, creatine kinase, aspartate aminotransferase, alanine aminotransferase, glucose, and lactate), muscle dynamic stiffness, and Profile of Mood States (POMS) were evaluated and recorded. The results showed all parameters we examined were significantly altered by the exercise challenge, which demonstrated they directly reflected the condition of fatigue. However, there were no differences between the two treatments besides a positive impact on the POMS examination. The occurrence of physical fatigue depends on multiple underlying mechanisms. We concluded that acute mangosteen supplementation had no impact on alleviating physical fatigue during exercise.


Oridonin confers protection against arsenic-induced toxicity through activation of the Nrf2-mediated defensive response.
Groundwater contaminated with arsenic imposes a big challenge to human health worldwide. Using natural compounds to subvert the detrimental effects of arsenic represents an attractive strategy. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical regulator of the cellular antioxidant response and xenobiotic metabolism. Recently, activation of the Nrf2 signaling pathway has been reported to confer protection against arsenic-induced toxicity in a cell culture model. The goal of the present work was to identify a potent Nrf2 activator from plants as a chemopreventive compound and to demonstrate the efficacy of the compound in battling arsenic-induced toxicity. Oridonin activated the Nrf2 signaling pathway at a low subtoxic dose and was able to stabilize Nrf2 by blocking Nrf2 ubiquitination and degradation, leading to accumulation of the Nrf2 protein and activation of the Nrf2-dependent cytoprotective response. Pretreatment of UROtsa cells with 1.4 muM oridonin significantly enhanced the cellular redox capacity, reduced formation of reactive oxygen species (ROS), and improved cell survival after arsenic challenge. We identified oridonin as representing a novel class of Nrf2 activators and illustrated the mechanism by which the Nrf2 pathway is activated. Furthermore, we demonstrated the feasibility of using natural compounds targeting Nrf2 as a therapeutic approach to protect humans from various environmental insults that may occur daily.


Phyto-oestrogens, their mechanism of action: current evidence for a role in breast and prostate cancer.
The incidence of hormone-dependent cancers, such as those of the breast and prostate, is much lower in Eastern countries such as China and Japan in comparison with the Western world. Diet is believed to have a major effect on disease risk and one group of compounds, the phyto-oestrogens, which are consumed in large amounts in Asian populations, have been implicated in cancer protection. This view follows the finding that plasma and urinary levels of phyto-oestrogens are much higher in areas where cancer incidence is low in comparison with areas of high cancer incidence. The phyto-oestrogens are comprised of two main groups; the isoflavones and lignans. Of the isoflavones, genistein and daidzein have been the most widely studied. These compounds have been shown to possess anticancer properties; however their precise mechanism of action remains to be elucidated. In comparison, few studies have investigated the effects of lignans in breast and prostate cancer. In vitro studies have shown that genistein exerts biphasic effects on cancer cell growth, stimulating growth at low concentrations (<10 microm) and inhibiting growth at high concentrations (>10 microm), which suggests that low phyto-oestrogen levels may stimulate cancer growth in vivo. Plasma phyto-oestrogen concentrations of >10 microm cannot be achieved by dietary intake and therefore the timing of exposure to phyto-oestrogens may be of the utmost importance in determining their chemopreventive effects. The present paper reviews the effects of phyto-oestrogens on breast and prostate cancer in vivo and in vitro and discusses possible mechanisms of action via which these compounds may exert their effects.


Gill transcriptome response to changes in environmental calcium in the green spotted puffer fish.
Calcium ion is tightly regulated in body fluids and for euryhaline fish, which are exposed to rapid changes in environmental [Ca2+], homeostasis is especially challenging. The gill is the main organ of active calcium uptake and therefore plays a crucial role in the maintenance of calcium ion homeostasis. To study the molecular basis of the short-term responses to changing calcium availability, the whole gill transcriptome obtained by Super Serial Analysis of Gene Expression (SuperSAGE) of the euryhaline teleost green spotted puffer fish, Tetraodon nigroviridis, exposed to water with altered [Ca2+] was analysed. Transfer of T. nigroviridis from 10 ppt water salinity containing 2.9 mM Ca2+ to high (10 mM Ca2+ ) and low (0.01 mM Ca2+) calcium water of similar salinity for 2-12 h resulted in 1,339 differentially expressed SuperSAGE tags (26-bp transcript identifiers) in gills. Of these 869 tags (65%) were mapped to T. nigroviridis cDNAs or genomic DNA and 497 (57%) were assigned to known proteins. Thirteen percent of the genes matched multiple tags indicating alternative RNA transcripts. The main enriched gene ontology groups belong to Ca2+ signaling/homeostasis but also muscle contraction, cytoskeleton, energy production/homeostasis and tissue remodeling. K-means clustering identified co-expressed transcripts with distinct patterns in response to water [Ca2+] and exposure time. The generated transcript expression patterns provide a framework of novel water calcium-responsive genes in the gill during the initial response after transfer to different [Ca2+]. This molecular response entails initial perception of alterations, activation of signaling networks and effectors and suggests active remodeling of cytoskeletal proteins during the initial acclimation process. Genes related to energy production and energy homeostasis are also up-regulated, probably reflecting the increased energetic needs of the acclimation response. This study is the first genome-wide transcriptome analysis of fish gills and is an important resource for future research on the short-term mechanisms involved in the gill acclimation responses to environmental Ca2+ changes and osmoregulation.


Phosphorus in Phoenix: a budget and spatial representation of phosphorus in an urban ecosystem.
As urban environments dominate the landscape, we need to examine how limiting nutrients such as phosphorus (P) cycle in these novel ecosystems. Sustainable management of P resources is necessary to ensure global food security and to minimize freshwater pollution. We used a spatially explicit budget to quantify the pools and fluxes of P in the Greater Phoenix Area in Arizona, USA, using the boundaries of the Central Arizona-Phoenix Long-Term Ecological Research site. Inputs were dominated by direct imports of food and fertilizer for local agriculture, while most outputs were small, including water, crops, and material destined for recycling. Internally, fluxes were dominated by transfers of food and feed from local agriculture and the recycling of human and animal excretion. Spatial correction of P dynamics across the city showed that human density and associated infrastructure, especially asphalt, dominated the distribution of P pools across the landscape. Phosphorus fluxes were dominated by agricultural production, with agricultural soils accumulating P. Human features (infrastructure, technology, and waste management decisions) and biophysical characteristics (soil properties, water fluxes, and storage) mediated P dynamics in Phoenix. P cycling was most notably affected by water management practices that conserve and recycle water, preventing the loss of waterborne P from the ecosystem. P is not intentionally managed, and as a result, changes in land use and demographics, particularly increased urbanization and declining agriculture, may lead to increased losses of P from this system. We suggest that city managers should minimize cross-boundary fluxes of P to the city. Reduced P fluxes may be accomplished through more efficient recycling of waste, therefore decreasing dependence on external nonrenewable P resources and minimizing aquatic pollution. Our spatial approach and consideration of both pools and fluxes across a heterogeneous urban ecosystem increases the utility of nutrient budgets for city managers. Our budget explicitly links processes that affect P cycling across space with the management of other resources (e.g., water). A holistic management strategy that deliberately couples the management of P and other resources should be a priority for cities in achieving urban sustainability.


The Beneficial Effects of a Polysaccharide from Moringa oleifera Leaf on Gut Microecology in Mice.
Moringa oleifera is a natural plant with high nutritional and pharmacological value. Leaves of M. oleifera contain a variety of active substances. In our previous research, we had obtained a polysaccharide separated from M. oleifera leaf, namely MOs-2-a (1.35 × 104 Da). In this study, this polysaccharide was administrated daily to 6 week-old ICR mice for 4 weeks. Then, the body weight, immunity, intestinal digestion, and intestinal microenvironment of Institute of Cancer Research (ICR) mice were investigated. After 4 weeks of feeding intervention with the polysaccharide, the immune and intestinal digestive ability of the ICR mice were significant as shown by the organ index, digestive enzymes, and reduction of serum tumor necrosis factor-alpha and diamine oxidase levels. The polysaccharide could regulate the microbial composition of the intestinal tract in mice by increasing the bacteria that have been reported for antiobesity effects, short chain fatty acid production, and lactic acid production. These findings indicate that the polysaccharide of M. oleifera leaf might be a promising prebiotic that exhibits health promotion effects.


Controlling macro- and mesostructures with hierarchical porosity through combined hard and soft templating.
Rigid, porous objects and surfactants serve as powerful templates for the formation of mesoporous and macroporous materials. When both types of template are combined in a single synthesis, materials with intricate architectures and hierarchical porosity can be obtained. In this tutorial review, we explain how to conduct syntheses with both soft and hard templates; moreover, we describe methods to control the final structure present in the templated material. Much of the foundation for multiple templating lies in the study of materials made with only one type of template. To establish a foundation in this area, a description of hard and soft templating is given, delving into the templates available and the steps required for effective templating. This leads into an extended discussion about materials templated with both hard and soft templates. Through the use of recent examples in the literature, we aim to show the diversity of structures possible through multiple templating and the advantages these structures can provide for a wide range of applications. An emphasis is placed on how various factors-such as the type of template, type of precursor, heat-treatment temperature, confinement within a small space, and template-template interactions-impact morphology.


Effects of groundwater development on uranium: Central Valley, California, USA.
Uranium (U) concentrations in groundwater in several parts of the eastern San Joaquin Valley, California, have exceeded federal and state drinking water standards during the last 20 years. The San Joaquin Valley is located within the Central Valley of California and is one of the most productive agricultural areas in the world. Increased irrigation and pumping associated with agricultural and urban development during the last 100 years have changed the chemistry and magnitude of groundwater recharge, and increased the rate of downward groundwater movement. Strong correlations between U and bicarbonate suggest that U is leached from shallow sediments by high bicarbonate water, consistent with findings of previous work in Modesto, California. Summer irrigation of crops in agricultural areas and, to lesser extent, of landscape plants and grasses in urban areas, has increased Pco(2) concentrations in the soil zone and caused higher temperature and salinity of groundwater recharge. Coupled with groundwater pumping, this process, as evidenced by increasing bicarbonate concentrations in groundwater over the last 100 years, has caused shallow, young groundwater with high U concentrations to migrate to deeper parts of the groundwater system that are tapped by public-supply wells. Continued downward migration of U-affected groundwater and expansion of urban centers into agricultural areas will likely be associated with increased U concentrations in public-supply wells. The results from this study illustrate the potential long-term effects of groundwater development and irrigation-supported agriculture on water quality in arid and semiarid regions around the world.


Direct anterior approach versus posterior approach in primary total hip replacement: comparison of minimum 2-year outcomes.
The direct anterior approach (DAA) has gained popularity in recent years for total hip arthroplasty (THA). Several authors reported significantly better early outcomes when compared to the posterior approach (PA). Nevertheless, controversy exists regarding longer-term benefits of the DAA. Data was prospectively collected and retrospectively reviewed for primary THAs conducted between July 2008 and July 2016. Patients who underwent DAA and PA with minimum 2-year follow-up for Harris Hip Score (HHS), Forgotten Joint Score-12 (FJS-12), Veteran RAND 12 Mental (VR-12 Mental), Veteran RAND 12 Physical (VR-12 Physical), 12-Item Short Form Survey Mental (SF-12 Mental), 12-Item Short Form Survey Physical (SF-12 Physical), visual analogue scale, and patient satisfaction were included. Propensity score matching was performed on the DAA and PA cohorts (1:1) based on the following variables: age, sex, body mass index, and laterality. 205 DAA hips were satisfactorily matched to 205 PA hips. The DAA group had higher scores at final follow-up for VR-12 Mental (p = 0.0145), VR-12 Physical (p = 0.0236), SF-12 Mental (p = 0.0393), and SF-12 Physical (p = 0.0391). The DAA and PA groups had comparable HHS (p = 0.0737) and FJS-12 (p = 0.2900). Although the DAA and PA groups had different follow-up periods, both the DAA and PA groups reported favourable outcomes at minimum 2-year follow-up. While both groups achieved comparable scores for the majority of PROs including VAS and patient satisfaction, the DAA group achieved superior quality of life outcomes when compared with a propensity score matched group of PA surgeries.


A predictive enrichment procedure to identify potential responders to a new therapy for randomized, comparative controlled clinical studies.
To evaluate a new therapy versus a control via a randomized, comparative clinical study or a series of trials, due to heterogeneity of the study patient population, a pre-specified, predictive enrichment procedure may be implemented to identify an "enrichable" subpopulation. For patients in this subpopulation, the therapy is expected to have a desirable overall risk-benefit profile. To develop and validate such a "therapy-diagnostic co-development" strategy, a three-step procedure may be conducted with three independent data sets from a series of similar studies or a single trial. At the first stage, we create various candidate scoring systems based on the baseline information of the patients via, for example, parametric models using the first data set. Each individual score reflects an anticipated average treatment difference for future patients who share similar baseline profiles. A large score indicates that these patients tend to benefit from the new therapy. At the second step, a potentially promising, enrichable subgroup is identified using the totality of evidence from these scoring systems. At the final stage, we validate such a selection via two-sample inference procedures for assessing the treatment effectiveness statistically and clinically with the third data set, the so-called holdout sample. When the study size is not large, one may combine the first two steps using a "cross-training-evaluation" process. Comprehensive numerical studies are conducted to investigate the operational characteristics of the proposed method. The entire enrichment procedure is illustrated with the data from a cardiovascular trial to evaluate a beta-blocker versus a placebo for treating chronic heart failure patients.


The effects of diosgenin in the regulation of renal proximal tubular fibrosis.
Fibrosis is the important pathway for end-stage renal failure. Glucose has been demonstrated to be the most important fibrogenesis-inducing agent according to previous studies. Despite diosgenin has been demonstrated to be anti-inflammatory, the possible role in fibrosis regulation of diosgenin remain to be investigated. In this study, renal proximal tubular epithelial cells (designated as HK-2) were treated with high concentration of glucose (HG, 27.5mM) to determine whether diosgenin (0.1, 1 and 10 μM) has the effects to regulate renal cellular fibrosis. We found that 10 μM of diosgenin exert optimal inhibitory effects on high glucose-induced fibronectin expression in HK-2 cells. In addition, diosgenin markedly inhibited HG-induced increase in α-smooth muscle actin (α-SMA) and HG-induced decrease in E-cadherin. In addition, diosgenin antagonizes high glucose-induced epithelial-to-mesenchymal transition (EMT) signals partly by enhancing the catabolism of Snail in renal cells. Collectively, these data suggest that diosgenin has the potential to inhibit high glucose-induced renal tubular fibrosis possibly through EMT pathway.


In situ detection of autoreactive CD4 T cells in brain and heart using major histocompatibility complex class II dextramers.
This report demonstrates the use of major histocompatibility complex (MHC) class II dextramers for detection of autoreactive CD4 T cells in situ in myelin proteolipid protein (PLP) 139-151-induced experimental autoimmune encephalomyelitis (EAE) in SJL mice and cardiac myosin heavy chain-α (Myhc) 334-352-induced experimental autoimmune myocarditis (EAM) in A/J mice. Two sets of cocktails of dextramer reagents were used, where dextramers(+) cells were analyzed by laser scanning confocal microscope (LSCM): EAE, IA(s)/PLP 139-151 dextramers (specific)/anti-CD4 and IA(s)/Theiler's murine encephalomyelitis virus (TMEV) 70-86 dextramers (control)/anti-CD4; and EAM, IA(k)/Myhc 334-352 dextramers/anti-CD4 and IA(k)/bovine ribonuclease (RNase) 43-56 dextramers (control)/anti-CD4. LSCM analysis of brain sections obtained from EAE mice showed the presence of cells positive for CD4 and PLP 139-151 dextramers, but not TMEV 70-86 dextramers suggesting that the staining obtained with PLP 139-151 dextramers was specific. Likewise, heart sections prepared from EAM mice also revealed the presence of Myhc 334-352, but not RNase 43-56-dextramer(+) cells as expected. Further, a comprehensive method has also been devised to quantitatively analyze the frequencies of antigen-specific CD4 T cells in the 'Z' serial images.


Depression, anxiety and perceived stress in women with and without PCOS: a community-based study.
Polycystic ovary syndrome (PCOS) is associated with increased psychological distress in clinical populations. We aimed to assess depression, anxiety and perceived stress in women with and without PCOS in a large community-based sample and investigate the role of stress in contributing to and mediating the relationship between PCOS, depression and anxiety. A cross-sectional analysis was performed from the Australian Longitudinal Study of Women's Health (ALWSH) comparing women with (n = 478) or without (n = 8134) a self-reported diagnosis of PCOS. Main outcome measures were depression, anxiety and perceived stress measured using validated scales. The χ2 and t tests were used to assess differences between groups. Univariable and multivariable regression were performed to determine factors contributing to each outcome. Women reporting PCOS, compared with women not reporting PCOS, reported higher prevalence of depression (27.3% v. 18.8%), anxiety symptoms (50% v. 39.2%) and greater score for perceived stress (1.01 ± 0.03 v. 0.88 ± 0.01). After adjusting for body mass index, infertility and socio-demographic factors, women with PCOS were still more likely to be depressed, anxious and to have a higher level of perceived stress. There was a high-level mediation effect of stress between PCOS and both depression and anxiety. Compared with women not reporting PCOS, women reporting PCOS have increased depression, anxiety and perceived stress. Stress may play a role in the association between PCOS, depression and anxiety. Further studies should consider assessment and management of stress in PCOS as it may be relevant for understanding the aetiology and treatment of psychological distress.


An electrically powered total artificial heart. Over 1 year survival in the calf.
An electric motor driven orthotopic artificial heart was implanted in a 110 kg female Holstein calf as part of a series of 12 such implants intended to demonstrate the in vivo durability and compatibility of the device. The device uses pusher plates set into motion by a reversing brushless DC motor and roller screw to alternately eject two cylindrical sac type blood pumps. The pumps use Bjork-Shiley Delrindisc convexo-concave or monostrut valves. The left pump provides an 88-90 ml dynamic stroke volume. Woven Dacron grafts and polyurethane coated Dacron/Lycra cuffs are used to attach the device to the major arteries and atria, respectively. A polyurethane conduit and anchoring skin button bring motor wires percutaneously to an extracorporeal controller. The controller provides balanced cardiac output sensitive to atrial or aortic pressures, without operator intervention. The system is hermetically sealed and uses a simple compliance sac to maintain thoracic pressure between the pumps. The calf recovered uneventfully from surgery and thrived thereafter. She was killed on the 388th post-operative day because of worsening cardiac insufficiency. The previous three operative survivors in this series lived 131, 134, and 204 days. These results indicate the device's good potential for durability and body compatibility.


Effect of dietary Maitake (Grifola frondosa) mushrooms on plasma cholesterol and hepatic gene expression in cholesterol-fed mice.
To investigate the effects of dietary Grifola frondosa on cholesterol, normal mice were fed a diet containing 1% cholesterol (HC group) or 1% cholesterol and 10% freeze-dried G. frondosa powder (HC+G group) for 4 weeks and hepatic and plasma lipid levels were compared with those of a cholesterol-free diet-fed mice (N group). Hepatic total cholesterol (TC), triacylglycerol contents were considerably increased and plasma TC / phospholipid (PL) was also increased significantly in the HC group compared with the N group. However, plasma TC content decreased in the HC+G group compared with the HC group. To characterize the mechanisms responsible for lowered plasma cholesterol in G. frondosa-supplemented mice, hepatic gene expression was profiled using DNA microarray and gene ontology. Genome analyses revealed that de novo cholesterol synthesis genes were suppressed following cholesterol intake. However, expression of bile acid biosynthesis and low-density lipoprotein receptor genes showed little change. Scarb1, Abcg5, and Abcg8, involved in cholesterol transport and excretion, were slightly upregulated in the HC+G group compared with the HC group. These data indicate the plasma cholesterol-lowering effect of G. frondosa. Moreover, fatty acid (FA) β-oxidation was promoted via adipocytokine signaling pathways, and Saa, encodes serum amyloid A related to arteriosclerosis, was suppressed in the HC+G group.


Oral health and HIV.
Most oral health problems can be found in people who are either HIV positive or negative. Yet there are some important differences. A few conditions are seen almost exclusively in people with HIV, while some that are found in both populations are more problematic for people with HIV, especially those with advanced disease. A diminished immune system can alter the course of oral disease and require more aggressive treatment to prevent minor troubles from escalating into major health problems. Over 30 different oral manifestations of HIV disease have been reported since the beginning of the AIDS epidemic. This article will address several of the most common of these oral health issues. As with any health condition faced by HIV positive people, early identification and treatment should be emphasized. In many cases, referral to a dentist should be made as soon as possible.


The Association between Frailty and All-Cause Mortality in Community-Dwelling Older Individuals: An Umbrella Review.
Frailty is associated with multiple adverse health outcomes, including mortality. Several methods have been used to characterize frailty, each based on different frailty scales. These include scales based on phenotype, multidomain, and deficit accumulations. Several systematic reviews have examined the association between frailty and mortality; however, it is unclear whether these different frailty scales similarly predict mortality. This umbrella review aims to examine the association between frailty assessed by different frailty scales and all-cause mortality among community-dwelling older adults. A protocol was registered at PROSPERO, and it was conducted following the PRISMA statement. MEDLINE, Embase, PubMed, Cochrane Database of Systematic Reviews, Joanna Briggs Institute (JBI) EBP database, and Web of Science database was searched. Methodological quality was assessed using the JBI critical appraisal checklist and online AMSTAR-2 critical appraisal checklist. For eligible studies, essential information was extracted and synthesized qualitatively. Five systematic reviews were included, with a total of 434,115 participants. Three systematic reviews focused on single frailty scales; one evaluated Fried's physical frailty phenotype and its modifications; another focused on the deficit accumulation frailty index. The third evaluated the FRAIL (Fatigue, Resistance, Ambulation, Illness, and Loss of weight) scale. The two other systematic reviews determined the association between frailty and mortality using different frailty scales. All of the systematic reviews found that frailty was significantly associated with all-cause mortality. This umbrella review demonstrates that frailty is a significant predictor of all-cause mortality, irrespective of the specific frailty scale.