Curcumin exerts neuroprotective effects against homocysteine intracerebroventricular injection-induced cognitive impairment and oxidative stress in rat brain.
Aging is the major risk factor for neurodegenerative diseases and oxidative stress and is involved in their pathophysiology. Oxidative stress can induce neuronal damage and modulate intracellular signaling, ultimately leading to neuronal death by apoptosis or necrosis. In this study we investigated the neuroprotective properties of the natural polyphenolic antioxidant compound, curcumin, against homocysteine (Hcy) neurotoxicity. Curcumin (5, 15, or 45 mg/kg) was injected intraperitoneally once daily for a period of 10 days beginning 5 days prior to Hcy (0.2 micromol/microl) intracerebroventricular injection in rats. Biochemical and behavioral studies, including passive avoidance learning and locomotor activity tests, were evaluated 24 hours after the last injection of curcumin or vehicle. Results indicated that Hcy induces lipid peroxidation and increases malondialdehyde (MDA) and superoxide anion (SOA) levels in whole rat brain. In addition, Hcy impaired memory retention in the passive avoidance learning test. However, curcumin treatment significantly decreased MDA and SOA levels and improved learning and memory in rats. These results suggest that Hcy may induce lipid peroxidation in rat brain and that polyphenol treatment (curcumin) improves learning and memory deficits by protecting the nervous system against oxidative stress.


Investigation of genetic variants, birthweight and hypothalamic-pituitary-adrenal axis function suggests a genetic variant in the SERPINA6 gene is associated with corticosteroid binding globulin in the western Australia pregnancy cohort (Raine) study.
The hypothalamic-pituitary-adrenal (HPA) axis regulates stress responses and HPA dysfunction has been associated with several chronic diseases. Low birthweight may be associated with HPA dysfunction in later life, yet human studies are inconclusive. The primary study aim was to identify genetic variants associated with HPA axis function. A secondary aim was to evaluate if these variants modify the association between birthweight and HPA axis function in adolescents. Morning fasted blood samples were collected from children of the Western Australia Pregnancy Cohort (Raine) at age 17 (n = 1077). Basal HPA axis function was assessed by total cortisol, corticosteroid binding globulin (CBG), and adrenocorticotropic hormone (ACTH). The associations between 124 tag single nucleotide polymorphisms (SNPs) within 16 HPA pathway candidate genes and each hormone were evaluated using multivariate linear regression and penalized linear regression analysis using the HyperLasso method. The penalized regression analysis revealed one candidate gene SNP, rs11621961 in the CBG encoding gene (SERPINA6), significantly associated with total cortisol and CBG. No other candidate gene SNPs were significant after applying the penalty or adjusting for multiple comparisons; however, several SNPs approached significance. For example, rs907621 (p = 0.002) and rs3846326 (p = 0.003) in the mineralocorticoid receptor gene (NR3C2) were associated with ACTH and SERPINA6 SNPs rs941601 (p = 0.004) and rs11622665 (p = 0.008), were associated with CBG. To further investigate our findings for SERPINA6, rare and common SNPs in the gene were imputed from the 1,000 genomes data and 8 SNPs across the gene were significantly associated with CBG levels after adjustment for multiple comparisons. Birthweight was not associated with any HPA outcome, and none of the gene-birthweight interactions were significant after adjustment for multiple comparisons. Our study suggests that genetic variation in the SERPINA6 gene may be associated with altered CBG levels during adolescence. Replication of these findings is required.


Iron storage disorders in captive wild mammals: the comparative evidence.
Excessive burden of iron, or iron storage disease (ISD), has been reported in a large variety of captive mammal species, including browsing rhinoceroses; tapirs; fruit bats; lemurs; marmosets and some other primates; sugar gliders; hyraxes; some rodents and lagomorphs; dolphins; and some carnivores; including procyonids and pinnipeds. This report collates the comparative evidence for species' susceptibility, recognizing that the data for mammal species are limited. Differences reported in the occurrence of ISD between facilities, or within facilities over periods that span management changes, have been reported in individual cases but are underused in ISD research. Given the species composition, the hypothesis that evolutionary adaptations to the iron content and availability in the natural diet determine a species' susceptibility to ISD (in the face of deviating iron content and availability in diets offered in captivity) seems plausible in many cases. But exceptions, and additional species putatively susceptible based on this rationale, should be investigated. Whereas screening for ISD should be routine in zoo animal necropsy, screening of live individuals may be implemented for valuable species, to decide on therapeutic measures such as chelator application or phlebotomy. Whatever the reasons for ISD susceptibility, reducing dietary iron levels to maintenance requirements of the species in question seems to be a logical, preventive measure.


Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia.
Early results of the fludarabine, cyclophosphamide, and rituximab (FCR) regimen in 224 patients showed that it was highly active as initial therapy of chronic lymphocytic leukemia. In this report, we present the final results of all 300 study patients at a median follow up of 6 years. The overall response rate was 95%, with complete remission in 72%, nodular partial remission in 10%, partial remission due to cytopenia in 7%, and partial remission due to residual disease in 6%. Two patients (< 1%) died within 3 months of starting therapy. Six-year overall and failure-free survival were 77% and 51%, respectively. Median time to progression was 80 months. Pretreatment characteristics independently associated with inferior response were age 70 years or older, beta2-microglobulin twice the upper limit of normal (2N) or more, white cell count 150 x 10(9)/L or more, abnormal chromosome 17, and lactate dehydrogenase 2N or more. No pretreatment characteristic was independently associated with decreased complete remission duration. The risk of late infection was 10% and 4% for the first and second years of remission, respectively, and less than 1.5% per year for the third year onward. In a multivariate analysis of patients receiving fludarabine-based therapy at our center, FCR therapy emerged as the strongest independent determinant of survival.


Multisensory decision-making in rats and humans.
We report a novel multisensory decision task designed to encourage subjects to combine information across both time and sensory modalities. We presented subjects, humans and rats, with multisensory event streams, consisting of a series of brief auditory and/or visual events. Subjects made judgments about whether the event rate of these streams was high or low. We have three main findings. First, we report that subjects can combine multisensory information over time to improve judgments about whether a fluctuating rate is high or low. Importantly, the improvement we observed was frequently close to, or better than, the statistically optimal prediction. Second, we found that subjects showed a clear multisensory enhancement both when the inputs in each modality were redundant and when they provided independent evidence about the rate. This latter finding suggests a model where event rates are estimated separately for each modality and fused at a later stage. Finally, because a similar multisensory enhancement was observed in both humans and rats, we conclude that the ability to optimally exploit sequentially presented multisensory information is not restricted to a particular species.


Tumor suppressor PAX6 functions as androgen receptor co-repressor to inhibit prostate cancer growth.
PAX6, a transcription factor, has currently been suggested to function as a tumor suppressor in glioblastoma and to act as an early differentiation marker for neuroendocrine cells. The androgen receptor (AR) plays a pivotal role in prostate cancer development and progression due to its transcriptional activity in regulating genes involved in cell growth, differentiation, and apoptosis. To determine the role of PAX6 in prostate cancer, we investigated whether PAX6 interacts with AR to affect prostate cancer development. We used immunostaining, RT-PCR, and Western blotting assays to show the expression status of PAX6 in prostate tissue and human prostate cancer cell lines. The role of PAX6 in cell growth and colony regeneration potential of LNCaP cells were evaluated by MTT assay and soft agar assay with PAX6-overexpressed LNCaP cells. Mammalian two-hybrid and co-immunoprecipitation (Co-IP) assays were used to demonstrate the interaction between PAX6 and AR. Reporter gene and Q-RT-PCR assays were performed to determine the effects of PAX6 on the function of AR. In prostate cancer tissues, PAX6 expression was stronger in normal epithelial cells than cancer cells, and decreased in LNCaP cells compared to that of DU145 and PC3 cells. Enforced expression of PAX6 suppressed the cell growth of LNCaP cells and also inhibited the colony formation of LNCaP cells. PAX 6 interacted with AR and repressed its transcriptional activity. PAX6 overexpression decreased the expression of androgen target gene PSA in LNCaP cells. In this study, we found that PAX6 may act as a prostate cancer repressor by interacting with AR and repressing the transcriptional activity and target gene expression of AR to regulate cell growth and regeneration.


2-Phenylquinoline S. aureus NorA Efflux Pump Inhibitors: Evaluation of the Importance of Methoxy Group Introduction.
Antimicrobial resistance (AMR) represents a hot topic in drug discovery. Besides the identification of new antibiotics, the use of nonantibiotic molecules to block resistance mechanisms is a powerful alternative. Bacterial efflux pumps exert an early step in AMR development by allowing bacteria to grow at subinhibitorial drug concentrations. Thus, efflux pump inhibitors (EPIs) offer a great opportunity to fight AMR. Given our experience in developing Staphylococcus aureus NorA EPIs, in this work, starting from the 2-phenylquinoline hit 1, we planned the introduction of methoxy groups on the basis of their presence in known NorA EPIs. Among the 35 different synthesized derivatives, compounds 3b and 7d exhibited the best NorA inhibition activity by restoring at very low concentrations ciprofloxacin MICs against resistant S. aureus strains. Interestingly, both compounds displayed EPI activities at nontoxic concentrations for human cells as well as highlighted promising results by preliminary pharmacokinetic studies.


Understanding the relationship between costs and the modified Rankin Scale: A systematic review, multidisciplinary consensus and recommendations for future studies.
Cost-of-illness studies often describe a single aggregate cost of a disease state. This approach is less helpful for a condition with a spectrum of outcomes like stroke. The modified Rankin Scale is the most commonly used outcome measure for stroke. We sought to describe the existing evidence on the costs of stroke according to individual modified Rankin Scale categories. This may be useful in future cost effectiveness modelling studies of interventions where cost data have not been collected, but disability outcome is known. Systematic review of the published literature, searching electronic databases between 2004 and 2015 using validated search filters. Results were screened to identify studies presenting costs by individual modified Rankin Scale categories. Of 17,782 unique identified articles, 13 matched all inclusion criteria. In only four of these studies were costs reported by modified Rankin Scale categories. Most studies included direct medical costs only. Societal costs were assessed in two studies. Overall, studies had a high methodological and reporting quality. The heterogeneity in costing methods used in the identified studies prevented meaningful comparison of the reported cost data. Despite this limitation, the costs consistently increased with greater severity (increasing modified Rankin Scale score). Few cost studies of stroke include information based on stroke recovery measured by individual modified Rankin Scale categories and the existing data are limited. To reliably capture this information, future studies are needed that preferably apply standardised costing methods to promote greater potential for use in cost-effectiveness analyses whereby direct collection of patient-level resource use has not been possible.


Winter forest soil respiration controlled by climate and microbial community composition.
Most terrestrial carbon sequestration at mid-latitudes in the Northern Hemisphere occurs in seasonal, montane forest ecosystems. Winter respiratory carbon dioxide losses from these ecosystems are high, and over half of the carbon assimilated by photosynthesis in the summer can be lost the following winter. The amount of winter carbon dioxide loss is potentially susceptible to changes in the depth of the snowpack; a shallower snowpack has less insulation potential, causing colder soil temperatures and potentially lower soil respiration rates. Recent climate analyses have shown widespread declines in the winter snowpack of mountain ecosystems in the western USA and Europe that are coupled to positive temperature anomalies. Here we study the effect of changes in snow cover on soil carbon cycling within the context of natural climate variation. We use a six-year record of net ecosystem carbon dioxide exchange in a subalpine forest to show that years with a reduced winter snowpack are accompanied by significantly lower rates of soil respiration. Furthermore, we show that the cause of the high sensitivity of soil respiration rate to changes in snow depth is a unique soil microbial community that exhibits exponential growth and high rates of substrate utilization at the cold temperatures that exist beneath the snow. Our observations suggest that a warmer climate may change soil carbon sequestration rates in forest ecosystems owing to changes in the depth of the insulating snow cover.


A Rare Case of Colonic Metastases From Tonsillar Carcinoma: Case Report and Review of Literature.
The incidence of tonsillar cancer has increased by four times in the United States over the last few decades likely due to recent increase in human papilloma virus (HPV) infections. The stage of the tumor predicts likelihood of metastasis, with advanced stages associated with higher chances of metastasis. The squamous cell carcinomas (SCCs) of the head and neck commonly metastasize to the lung, bone and liver in descending order. Tonsillar cancer rarely involves the small bowel and our review of the literature did not reveal any reported case of metastasis to the colon/large bowel. Our patient had locally metastatic tonsillar cancer, treated with partial pharyngectomy and selective neck dissection but later developed several bone and colonic metastases concurrently, likely secondary to hematogeneous dissemination after a few months of therapy. To the best of our knowledge, large bowel metastasis from head and neck SCC has never been reported in the literature. In these patients presenting with atypical gastrointestinal symptoms, a high index of suspicion should be maintained to determine the extent of metastasis and identify other metastatic sites.


Enhancement of Cancer-Specific Protoporphyrin IX Fluorescence by Targeting Oncogenic Ras/MEK Pathway.
Protoporphyrin IX (PpIX) is an endogenous fluorescent molecule that selectively accumulates in cancer cells treated with the heme precursor 5-aminolevulinic acid (5-ALA). This cancer-specific accumulation of PpIX is used to distinguish tumor from normal tissues in fluorescence-guided surgery (FGS) and to destroy cancer cells by photodynamic therapy (PDT). In this study, we demonstrate that oncogenic Ras/mitogen-activated protein kinase kinase (MEK) pathway can modulate PpIX accumulation in cancer cells. Methods: To identify Ras downstream elements involved in PpIX accumulation, chemical inhibitors were used. To demonstrate the increase of PpIX accumulation by MEK inhibition, different human normal and cancer cell lines, BALB/c mice bearing mammary 4T1 tumors and athymic nude mice bearing human tumors were used. To identify the mechanisms of PpIX regulation by MEK, biochemical and molecular biological experiments were conducted. Results: Inhibition of one of the Ras downstream elements, MEK, promoted PpIX accumulation in cancer cells treated with 5-ALA, while inhibitors against other Ras downstream elements did not. Increased PpIX accumulation with MEK inhibition was observed in different types of human cancer cell lines, but not in normal cell lines. We identified two independent cellular mechanisms that underlie this effect in cancer cells. MEK inhibition reduced PpIX efflux from cancer cells by decreasing the expression level of ATP binding cassette subfamily B member 1 (ABCB1) transporter. In addition, the activity of ferrochelatase (FECH), the enzyme responsible for converting PpIX to heme, was reduced by MEK inhibition. Finally, we found that in vivo treatment with MEK inhibitors increased PpIX accumulation (2.2- to 2.4-fold) within mammary 4T1 tumors in BALB/c mice injected with 5-ALA without any change in normal organs. Similar results were also observed in a human tumor xenograft model. Conclusion: Our study demonstrates that inhibition of oncogenic Ras/MEK significantly enhances PpIX accumulation in vitro and in vivo in a cancer-specific manner. Thus, suppressing the Ras/MEK pathway may be a viable strategy to selectively intensify PpIX fluorescence in cancer cells and improve its clinical applications in FGS.


Increase in fat oxidation on a high-fat diet is accompanied by an increase in triglyceride-derived fatty acid oxidation.
The aim of this study is to investigate the mechanism behind the slow increase in fat oxidation on a high-fat diet. Therefore, we determined 24-h substrate oxidation using respiration chambers and the rate of appearance and oxidation of plasma-derived fatty acids in seven healthy nonobese men (age 23 +/- 2 years, height 1.85 +/- 0.03 m, weight 70.4 +/- 2.3 kg, % body fat 13 +/- 1). Before testing, they consumed a low-fat diet (30% fat, 55% carbohydrate) at home for 3 days. Measurements were performed after 1 day consumption of either a low-fat diet (LF), a high-fat diet (HF1, 60% fat, 25% carbohydrate), or a high-fat diet preceded by a glycogen-lowering exercise test (HF1+EX), and after 7 days on a high-fat diet (HF7). After an overnight fast, an infusion of [U-13C]palmitate (0.00806 micromol x min(-1) x kg(-1)) was started and continued for 2 h at rest followed by 1 h of exercise at 50% of maximal power output (Wmax). Whole-body fat oxidation was measured using indirect calorimetry, and plasma-derived fatty acid oxidation was evaluated by measuring breath 13CO2 enrichment and corrected with the acetate recovery factor. Twenty-four-hour fat oxidation gradually increased on the high-fat diet. Both at rest and during exercise, there was no change in rate of appearance of fatty acids and plasma-derived fatty acid oxidation. Triglyceride-derived fatty acid oxidation tended to be higher after 7 days of high-fat diet at rest (P < 0.07). This difference was significant during exercise (P < 0.05). In conclusion, the results from this study suggest that triglyceride-derived fatty acid oxidation (VLDL or intramuscular triglycerides) plays a role in the increase in fat oxidation on a high-fat diet, but plasma-derived fatty acids remain the major source for fat oxidation.


Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber).
The naked mole-rat (NMR, Heterocephalus glaber) is a long-lived mammal in which spontaneous cancer has not been observed. To investigate possible mechanisms for cancer resistance in this species, we studied the properties of skin fibroblasts from the NMR following transduction with oncogenes that cause cells of other mammalian species to form malignant tumors. Naked mole-rat fibroblasts were transduced with a retrovirus encoding SV40 large T antigen and oncogenic Ras(G12V). Following transplantation of transduced cells into immunodeficient mice, cells rapidly entered crisis, as evidenced by the presence of anaphase bridges, giant cells with enlarged nuclei, multinucleated cells, and cells with large number of chromosomes or abnormal chromatin material. In contrast, similarly transduced mouse and rat fibroblasts formed tumors that grew rapidly without crisis. Crisis was also observed after > 40 population doublings in SV40 TAg/Ras-expressing NMR cells in culture. Crisis in culture was prevented by additional infection of the cells with a retrovirus encoding hTERT (telomerase reverse transcriptase). SV40 TAg/Ras/hTERT-expressing NMR cells formed tumors that grew rapidly in immunodeficient mice without evidence of crisis. Crisis could also be induced in SV40 TAg/Ras-expressing NMR cells by loss of anchorage, but after hTERT transduction, cells were able to proliferate normally following loss of anchorage. Thus, rapid crisis is a response of oncogene-expressing NMR cells to growth in an in vivo environment, which requires anchorage independence, and hTERT permits cells to avoid crisis and to achieve malignant tumor growth. The unique reaction of NMR cells to oncogene expression may form part of the cancer resistance of this species.


Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction.
Results of well-controlled prospective clinical trials showed the efficacy of lipid-lowering therapies in the reduction of cardiovascular (CV) events in western populations, but they were not reported with a Chinese population. This multicenter study was conducted to determine the effects of Xuezhikang (XZK), a partially purified extract of red yeast rice, on lipoprotein and CV end points in Chinese patients who experienced a previous myocardial infarction. Nearly 5,000 of these patients with average low-density lipoprotein cholesterol levels at baseline were randomly assigned either to placebo or to XZK daily for an average of 4.5 years. The primary end point was a major coronary event that included nonfatal myocardial infarction and death from coronary heart disease. Frequencies of the primary end point were 10.4% in the placebo group and 5.7% in the XZK-treated group, with absolute and relative decreases of 4.7% and 45%, respectively. Treatment with XZK also significantly decreased CV and total mortality by 30% and 33%, the need for coronary revascularization by 1/3, and lowered total and low-density lipoprotein cholesterol and triglycerides, but raised high-density lipoprotein cholesterol levels. In conclusion, long-term therapy with XZK significantly decreased the recurrence of coronary events and the occurrence of new CV events and deaths, improved lipoprotein regulation, and was safe and well tolerated.


Genetic variation of the Toll-like receptors in a Swedish allergic rhinitis case population.
Variation in the 10 toll-like receptor (TLR) genes has been significantly associated with allergic rhinitis (AR) in several candidate gene studies and three large genome-wide association studies. These have all investigated common variants, but no investigations for rare variants (MAF ≤ 1%) have been made in AR. The present study aims to describe the genetic variation of the promoter and coding sequences of the 10 TLR genes in 288 AR patients. Sanger sequencing and Ion Torrent next-generation sequencing was used to identify polymorphisms in a Swedish AR population and these were subsequently compared and evaluated using 1000Genomes and Exome Aggregation Consortium (ExAC) data. The overall level of genetic variation was clearly different among the 10 TLR genes. The TLR10-TLR1-TLR6 locus was the most variable, while the TLR7-TLR8 locus was consistently showing a much lower level of variation. The AR patients had a total of 37 promoter polymorphisms with 14 rare (MAF ≤ 1%) and 14 AR-specific polymorphisms. These numbers were highly similar when comparing the AR and the European part of the 1000Genomes populations, with the exception of TLR10 where a significant (P = 0.00009) accumulation of polymorphisms were identified. The coding sequences had a total of 119 polymorphisms, 68 were rare and 43 were not present in the European part of the 1000Genomes population. Comparing the numbers of rare and AR-specific SNPs in the patients with the European part of the 1000Genomes population it was seen that the numbers were quite similar both for individual genes and for the sum of all 10 genes. However, TLR1, TLR5, TLR7 and TLR9 showed a significant excess of rare variants in the AR population when compared to the non-Finnish European part of ExAC. In particular the TLR1 S324* nonsense mutation was clearly overrepresented in the AR population. Most TLR genes showed a similar level of variation between AR patients and public databases, but a significant excess of rare variants in AR patients were detected in TLR1, TLR5, TLR7, TLR9 and TLR10. This further emphasizes the frequently reproduced TLR10-TLR1-TLR6 locus as being involved in the pathogenesis of allergic rhinitis.


Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis.
The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) has anticolorectal cancer activity in vitro and in preclinical models. The present study tested whether a novel, enteric-coated formulation of EPA, as the free fatty acid (EPA-FFA), has chemopreventative efficacy in patients with familial adenomatous polyposis (FAP), in a randomised, double-blind, placebo-controlled trial. Patients undergoing endoscopic surveillance of their retained rectum postcolectomy were randomised to EPA-FFA (SLA Pharma) 2 g daily or placebo for 6 months. The number and size of polyps in an area of mucosa defined by a tattoo were determined before and after intervention. Global rectal polyp burden was scored (-1, 0, +1) by examination of video endoscopy records. Mucosal fatty acid content was measured by gas chromatography-mass spectrometry. 55 patients with FAP were evaluated by an intention-to-treat analysis (EPA-FFA 28, placebo 27). Treatment with EPA-FFA for 6 months was associated with a mean 22.4% (95% CI 5.1% to 39.6%) reduction in polyp number (p=0.012) and a 29.8% (3.6% to 56.1%) decrease in the sum of polyp diameters (p=0.027). Global polyp burden worsened over 6 months in the placebo group (-0.34) unlike the EPA-FFA group (+0.09, difference 0.42 (0.10-0.75), p=0.011). EPA-FFA treatment led to a mean 2.6-fold increase in mucosal EPA levels (p=0.018 compared with placebo). EPA-FFA was well tolerated with an incidence of adverse events similar to placebo. EPA-FFA has chemopreventative efficacy in FAP, to a degree similar to that previously observed with selective cyclo-oxygenase-2 inhibitors. EPA holds promise as a colorectal cancer chemoprevention agent with a favourable safety profile.


Association between mass media and body weight concern among Jordanian adolescents' residents of Amman: the role of gender and obesity.
Body image in the mass media promotes an unrealistic picture of body shape that leads to body dissatisfaction among adolescentsQuery. Therefore, the study presented in this paper aimed to assess the association between mass media and adolescents' weight concerns and perceptions of body weight and shape. A cross-sectional survey was conducted on school adolescents aged between 15 and 18 years during the academic year 2013-2014. Multistage stratified sampling method was used. The number of participants in the study was 795 students: 400 boys and 395 girls. All participants have a common behavior in rarely reading magazines, but they spend more than 2 h in watching television or less than 3 h using the internet. However, most of obese/non-obese adolescents, boys or girls, have shown high influence (p < 0.05) of reading magazines on the subject of dieting to lose weight. While obese students read more magazines on dieting to lose weight, other mass media did not show the same results on weight concerns and body shape among Jordanian adolescents.


HIV infection in older adults in sub-Saharan Africa: extrapolating prevalence from existing data.
To quantify the number of cases and prevalence of human immunodeficiency virus (HIV) infection among older adults in sub-Saharan Africa. We reviewed data from Demographic and Health Surveys (DHS). Although in these surveys all female respondents are < 50 years of age, 18 of the surveys contained data on HIV infection among men aged ≥ 50 years. To estimate the percentage of older adults (i.e. people ≥ 50 years of age) who were positive for HIV (HIV+), we extrapolated from data from the Joint United Nations Programme on HIV/AIDS on the estimated number of people living with HIV and on HIV infection prevalence among adults aged 15-49 years. In 2007, approximately 3 million people aged ≥ 50 years were living with HIV in sub-Saharan Africa. The prevalence of HIV infection in this group was 4.0%, compared with 5.0% among those aged 15-49 years. Of the approximately 21 million people in sub-Saharan Africa aged ≥ 15 years that were HIV+, 14.3% were ≥ 50 years old. To better reflect the longer survival of people living with HIV and the ageing of the HIV+ population, indicators of the prevalence of HIV infection should be expanded to include people > 49 years of age. Little is known about comorbidity and sexual behaviour among HIV+ older adults or about the biological and cultural factors that increase the risk of transmission. HIV services need to be better targeted to respond to the growing needs of older adults living with HIV.


[Effects of DNA quality on the measurement of telomere length].
Existing evidence on the association of telomere length with life expectancy and the risk of various age related diseases is discordant. This inconsistency in the data may be due to methodological factors, e.g., the differences in the techniques for measuring telomere length, cell harvesting, DNA isolation, and material. One of the general requirements to experiments concerned with the measurement of telomere length is the high quality of DNA samples under study. The current review considers the most common errors during the measurement of telomere length associated with the improper quality of the biological material.


Dopamine D1 and D2 mediation of the discriminative stimulus properties of d-amphetamine and cocaine.
Evidence suggests that stimulants such as d-amphetamine and cocaine act presynaptically by increasing the amount of dopamine (DA) available to stimulate postsynaptic DA receptors. Since two subpopulations of DA receptors (D1 and D2) exist, we investigated the role of both of these receptor subtypes in mediating the internal "state" produced by these stimulants. Two groups of rats (N = 8/group) were trained to discriminate intraperitoneal (IP) injections of either d-amphetamine (1 mg/kg) or cocaine (10 mg/kg) from saline in a two-lever, water-reinforced, drug discrimination task. After stable performance was established (i.e., more than 85% correct under each training condition), substitution and combination tests were conducted with selective D1 and D2 agonists and antagonists. The D2 agonist quinpirole (0.0313-0.125 mg/kg) mimicked both stimulant cues while the D1 agonist SKF 38393 (5-20 mg/kg) substituted partially for cocaine but not d-amphetamine. Combination tests with DA antagonists indicated that both the D1 antagonist SCH 23390 (0.0063-0.25 mg/kg) and the D2 antagonist haloperidol (0.125-0.5 mg/kg) attenuated the effects of both stimulants; in addition, the substitution of cocaine (20 mg/kg) for d-amphetamine was blocked by both DA antagonists. The ability of both D1 and D2 antagonists to attenuate the stimulus effects of d-amphetamine and cocaine raises the possibility that a synergistic ("enabling") interaction between D1 and D2 receptors may modulate stimulant cues.


Progressive exercise compared with best-practice advice, with or without corticosteroid injection, for rotator cuff disorders: the GRASP factorial RCT.
Rotator cuff-related shoulder pain is very common, but there is uncertainty regarding which modes of exercise delivery are optimal and the long-term benefits of corticosteroid injections. To assess the clinical effectiveness and cost-effectiveness of progressive exercise compared with best-practice physiotherapy advice, with or without corticosteroid injection, in adults with a rotator cuff disorder. This was a pragmatic multicentre superiority randomised controlled trial (with a 2 × 2 factorial design). Twenty NHS primary care-based musculoskeletal and related physiotherapy services. Adults aged ≥ 18 years with a new episode of rotator cuff-related shoulder pain in the previous 6 months. A total of 708 participants were randomised (March 2017-May 2019) by a centralised computer-generated 1 : 1 : 1 : 1 allocation ratio to one of four interventions: (1) progressive exercise (n = 174) (six or fewer physiotherapy sessions), (2) best-practice advice (n = 174) (one physiotherapy session), (3) corticosteroid injection then progressive exercise (n = 182) (six or fewer physiotherapy sessions) or (4) corticosteroid injection then best-practice advice (n = 178) (one physiotherapy session). The primary outcome was Shoulder Pain and Disability Index (SPADI) score over 12 months. Secondary outcomes included SPADI subdomains, the EuroQol 5 Dimensions, five-level version, sleep disturbance, fear avoidance, pain self-efficacy, return to activity, Global Impression of Treatment and health resource use. Outcomes were collected by postal questionnaires at 8 weeks and at 6 and 12 months. A within-trial economic evaluation was also conducted. The primary analysis was intention to treat. Participants had a mean age of 55.5 (standard deviation 13.1) years and 49.3% were female. The mean baseline SPADI score was 54.1 (standard deviation 18.5). Follow-up rates were 91% at 8 weeks and 87% at 6 and 12 months. There was an overall improvement in SPADI score from baseline in each group over time. Over 12 months, there was no evidence of a difference in the SPADI scores between the progressive exercise intervention and the best-practice advice intervention in shoulder pain and function (adjusted mean difference between groups over 12 months -0.66, 99% confidence interval -4.52 to 3.20). There was also no difference in SPADI scores between the progressive exercise intervention and best-practice advice intervention when analysed at the 8-week and 6- and 12-month time points. Injection resulted in improvement in shoulder pain and function at 8 weeks compared with no injection (adjusted mean difference -5.64, 99% confidence interval -9.93 to -1.35), but not when analysed over 12 months (adjusted mean difference -1.11, 99% confidence interval -4.47 to 2.26), or at 6 and 12 months. There were no serious adverse events. In the base-case analysis, adding injection to best-practice advice gained 0.021 quality-adjusted life-years (p = 0.184) and increased the cost by £10 per participant (p = 0.747). Progressive exercise alone was £52 (p = 0.247) more expensive per participant than best-practice advice, and gained 0.019 QALYs (p = 0.220). At a ceiling ratio of £20,000 per quality-adjusted life-year, injection plus best-practice advice had a 54.93% probability of being the most cost-effective treatment. Participants and physiotherapists were not blinded to group allocation. Twelve-month follow-up may be insufficient for identifying all safety concerns. Progressive exercise was not superior to a best-practice advice session with a physiotherapist. Subacromial corticosteroid injection improved shoulder pain and function, but provided only modest short-term benefit. Best-practice advice in combination with corticosteroid injection was expected to be most cost-effective, although there was substantial uncertainty. Longer-term follow-up, including any serious adverse effects of corticosteroid injection. Current Controlled Trials ISRCTN16539266 and EudraCT 2016-002991-28. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 48. See the NIHR Journals Library website for further project information.


Can social interaction constitute social cognition?
An important shift is taking place in social cognition research, away from a focus on the individual mind and toward embodied and participatory aspects of social understanding. Empirical results already imply that social cognition is not reducible to the workings of individual cognitive mechanisms. To galvanize this interactive turn, we provide an operational definition of social interaction and distinguish the different explanatory roles - contextual, enabling and constitutive - it can play in social cognition. We show that interactive processes are more than a context for social cognition: they can complement and even replace individual mechanisms. This new explanatory power of social interaction can push the field forward by expanding the possibilities of scientific explanation beyond the individual.


Ethylene biosynthesis in detached young persimmon fruit is initiated in calyx and modulated by water loss from the fruit.
Persimmon (Diospyros kaki Thunb.) fruit are usually classified as climacteric fruit; however, unlike typical climacteric fruits, persimmon fruit exhibit a unique characteristic in that the younger the stage of fruit detached, the greater the level of ethylene produced. To investigate ethylene induction mechanisms in detached young persimmon fruit, we cloned three cDNAs encoding 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (DK-ACS1, 2, and -3) and two encoding ACC oxidase (DK-ACO1 and -2) genes involved in ethylene biosynthesis, and we analyzed their expression in various fruit tissues. Ethylene production was induced within a few days of detachment in all fruit tissues tested, accompanied by temporally and spatially coordinated expression of all the DK-ACS and DK-ACO genes. In all tissues except the calyx, treatment with 1-methylcyclopropene, an inhibitor of ethylene action, suppressed ethylene production and ethylene biosynthesis-related gene expression. In the calyx, one ACC synthase gene (DK-ACS2) exhibited increased mRNA accumulation accompanied by a large quantity of ethylene production, and treatment of the fruit with 1-methylcyclopropene did not prevent either the accumulation of DK-ACS2 transcripts or ethylene induction. Furthermore, the alleviation of water loss from the fruit significantly delayed the onset of ethylene production and the expression of DK-ACS2 in the calyx. These results indicate that ethylene biosynthesis in detached young persimmon fruit is initially induced in calyx and is modulated by water loss through transcriptional activation of DK-ACS2. The ethylene produced in the calyx subsequently diffuses to other fruit tissues and acts as a secondary signal that stimulates autocatalytic ethylene biosynthesis in these tissues, leading to a burst of ethylene production.


Biosynthesis and organizing action of neurosteroids in the developing Purkinje cell.
Probing undiscovered neurosubstances that play important roles in the regulation of cerebellar function is essential for the progress of our understanding of the cerebellum. New findings over the past decade have established that the cerebellum as well as other brain regions synthesizes steroids de novo from cholesterol through mechanisms at least partly independent of peripheral steroidogenic glands. Such steroids synthesized de novo in the brain are called neurosteroids. Recently the Purkinje cell, a cerebellar neuron, has been identified as a major site for neurosteroid formation in the brain. This is the first demonstration of de novo neuronal neurosteroidogenesis in the brain. In mammals, the Purkinje cell actively synthesizes progesterone de novo from cholesterol during neonatal life, when cerebellar cortical formation occurs. 3alpha,5alpha-Tetrahydroprogesterone (allopregnanolone) is metabolized from progesterone in the neonatal cerebellum. Estrogen formation in the Purkinje cell may also occur in the neonate. Subsequently, recent studies on mammals using the Purkinje cell have demonstrated organizing actions of neurosteroids. Both progesterone and estradiol promote dendritic growth, spinogenesis and synaptogenesis via each cognate nuclear receptor in Purkinje neurons. Allopregnanolone is also involved in Purkinje and granule cell survival. Thus the Purkinje cell serves as an excellent cellular model for understanding the formation of cerebellar neuronal circuit in relation to organizing actions of neurosteroids.


The dual developmental origin of spinal cerebrospinal fluid-contacting neurons gives rise to distinct functional subtypes.
Chemical and mechanical cues from the cerebrospinal fluid (CSF) can affect the development and function of the central nervous system (CNS). How such cues are detected and relayed to the CNS remains elusive. Cerebrospinal fluid-contacting neurons (CSF-cNs) situated at the interface between the CSF and the CNS are ideally located to convey such information to local networks. In the spinal cord, these GABAergic neurons expressing the PKD2L1 channel extend an apical extension into the CSF and an ascending axon in the spinal cord. In zebrafish and mouse spinal CSF-cNs originate from two distinct progenitor domains characterized by distinct cascades of transcription factors. Here we ask whether these neurons with different developmental origins differentiate into cells types with different functional properties. We show in zebrafish larva that the expression of specific markers, the morphology of the apical extension and axonal projections, as well as the neuronal targets contacted by CSF-cN axons, distinguish the two CSF-cN subtypes. Altogether our study demonstrates that the developmental origins of spinal CSF-cNs give rise to two distinct functional populations of sensory neurons. This work opens novel avenues to understand how these subtypes may carry distinct functions related to development of the spinal cord, locomotion and posture.


Quasars and gravitational lenses.
Despite the expenditure of large amounts of telescope time and other resources, most of the fundamental questions concerning quasi-stellar objects (quasars) remain unanswered. A complex phenomenology of radio, infrared, optical, and x-ray properties has accumulated but has not yielded even a satisfactory classification system. The large red shifts (distances) of quasars make them very valuable tools for studying cosmology and the properties of intervening matter in the Universe through observations of absorption lines and gravitational lenses.


The hyper-fluorescent trichome phenotype of the brt1 mutant of Arabidopsis is the result of a defect in a sinapic acid: UDPG glucosyltransferase.
Sinapoylmalate is a major phenylpropanoid that is accumulated in Arabidopsis. Its presence causes the adaxial surface of leaves to fluoresce blue under UV light, and mutations that lead to lower levels of sinapoylmalate decrease UV-induced leaf fluorescence. The Arabidopsis bright trichomes 1 (brt1) mutant was first identified in a screen for mutants that exhibit a reduced epidermal fluorescence phenotype; however, subsequent examination of the mutant revealed that its trichomes are hyper-fluorescent. The results from genetic mapping and complementation analyses showed that BRT1 (At3g21560) encodes UGT84A2, a glucosyltransferase previously shown to be capable of using sinapic acid as a substrate. Residual levels of sinapoylmalate and sinapic acid:UDP-glucose glucosyltransferase activity in brt1 leaves suggest that BRT1 is one member of a family of partially redundant glycosyltransferases that function in Arabidopsis sinapate ester biosynthesis. RT-PCR analysis showed that BRT1 is expressed through all stages of plant life cycle, a result consistent with the impact of the brt1 mutation on both leaf sinapoylmalate levels and seed sinapoylcholine content. Finally, the compound accumulated in brt1 trichomes was identified as a sinapic acid-derived polyketide, indicating that when sinapic acid glycosylation is reduced, a portion of it is instead activated to its CoA thioester, which then serves as a substrate for chalcone synthase.


B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial.
Epidemiological studies suggest that raised plasma concentrations of total homocysteine might be a risk factor for major vascular events. Whether lowering total homocysteine with B vitamins prevents major vascular events in patients with previous stroke or transient ischaemic attack is unknown. We aimed to assess whether the addition of once-daily supplements of B vitamins to usual medical care would lower total homocysteine and reduce the combined incidence of non-fatal stroke, non-fatal myocardial infarction, and death attributable to vascular causes in patients with recent stroke or transient ischaemic attack of the brain or eye. In this randomised, double-blind, parallel, placebo-controlled trial, we assigned patients with recent stroke or transient ischaemic attack (within the past 7 months) from 123 medical centres in 20 countries to receive one tablet daily of placebo or B vitamins (2 mg folic acid, 25 mg vitamin B6, and 0.5 mg vitamin B12). Patients were randomly allocated by means of a central 24-h telephone service or an interactive website, and allocation was by use of random permuted blocks stratified by hospital. Participants, clinicians, carers, and investigators who assessed outcomes were masked to the assigned intervention. The primary endpoint was the composite of stroke, myocardial infarction, or vascular death. All patients randomly allocated to a group were included in the analysis of the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT00097669, and Current Controlled Trials, ISRCTN74743444. Between Nov 19, 1998, and Dec 31, 2008, 8164 patients were randomly assigned to receive B vitamins (n=4089) or placebo (n=4075). Patients were followed up for a median duration of 3.4 years (IQR 2.0-5.5). 616 (15%) patients assigned to B vitamins and 678 (17%) assigned to placebo reached the primary endpoint (risk ratio [RR] 0.91, 95% CI 0.82 to 1.00, p=0.05; absolute risk reduction 1.56%, -0.01 to 3.16). There were no unexpected serious adverse reactions and no significant differences in common adverse effects between the treatment groups. Daily administration of folic acid, vitamin B6, and vitamin B12 to patients with recent stroke or transient ischaemic attack was safe but did not seem to be more effective than placebo in reducing the incidence of major vascular events. These results do not support the use of B vitamins to prevent recurrent stroke. The results of ongoing trials and an individual patient data meta-analysis will add statistical power and precision to present estimates of the effect of B vitamins. Australia National Health and Medical Research Council, UK Medical Research Council, Singapore Biomedical Research Council, Singapore National Medical Research Council, Australia National Heart Foundation, Royal Perth Hospital Medical Research Foundation, and Health Department of Western Australia.


U-statistics-based tests for multiple genes in genetic association studies.
As our understanding of biological pathways and the genes that regulate these pathways increases, consideration of these biological pathways has become an increasingly important part of genetic and molecular epidemiology. Pathway-based genetic association studies often involve genotyping of variants in genes acting in certain biological pathways. Such pathway-based genetic association studies can potentially capture the highly heterogeneous nature of many complex traits, with multiple causative loci and multiple alleles at some of the causative loci. In this paper, we develop two nonparametric test statistics that consider simultaneously the effects of multiple markers. Our approach, which is based on data-adaptive U-statistics, can handle both qualitative data such as case-control data and quantitative continuous phenotype data. Simulations demonstrate that our proposed methods are more powerful than standard methods, especially when there are multiple risk loci each with small genetic effects. When the number of disease-predisposing genes is small, the data-adaptive weighting of the U-statistics over all the markers produces similar power to commonly used single marker tests. We further illustrate the potential merits of our proposed tests in the analysis of a data set from a pathway-based candidate gene association study of breast cancer and hormone metabolism pathways. Finally, potential applications of the proposed tests to genome-wide association studies are also discussed.


Pediatric Lower Extremity Lawn Mower Injuries and Reconstruction: Retrospective 10-Year Review at a Level 1 Trauma Center.
From 2004 to 2013, there were 9341 lawn mower injuries in children under 20 years old. The incidence of lawn mower injuries in children has not decreased since 1990 despite implementation of various different prevention strategies. In this report, the authors review the results of pediatric lawn mower-related lower-extremity injuries treated at a tertiary care referral center as well as review the overall literature. A retrospective review was performed at a level 1 trauma center over a 10-year period (2005-2015). Patients younger than 18 years who presented to the emergency room with lower extremity lawn mower injuries were included. Of the 27 patients with lower-extremity lawn mower injuries during this period, the mean age at injury was 5.5 years and Injury Severity Score was 7.2. Most (85%) patients were boys and the predominant type of mower causing injury was a riding lawn mower (96%). Injury occurred in patients who were bystanders in 78%, passengers in 11%, and operators in 11%. Mean length of stay was 12.2 days, and mean time to reconstruction was 7.9 days. Mean number of surgical procedures per patient was 4.1. Amputations occurred in 15 (56%) cases with the most common level of amputation being distal to the metatarsophalangeal joint (67%). Reconstructive procedures ranged from direct closure (41%) to free tissue transfer (7%). Major complications included infection (7%), wound dehiscence (11%), and delayed wound healing (15%). Mean follow up was 23.6 months and 100% of the patients were ambulatory after injury. The subgroup of patients with the most severe injuries, highest number of amputations, and need for overall surgical procedures were patients aged 2 to 5 years. A review of the literature also showed consistent findings. This study demonstrates the danger and morbidity that lawn mowers present to the pediatric population, particularly children aged 2 to 5 years. Every rung of the so-called reconstructive ladder is used in caring for these children. Increased public awareness is insufficient to decrease the incidence of these injuries. These products should have additional warning labels and meet updated changes to the design of lawn mowers to prevent these mutilating injuries successfully.


Protective immunity against Helicobacter is characterized by a unique transcriptional signature.
Immunization with a whole-cell sonicate vaccine of Helicobacter felis in conjunction with cholera toxin as a mucosal adjuvant induces long-term protective immunity in a majority of laboratory mice. We have combined gene expression profiling and immunohistochemical analysis on a set of immunized animals to better understand the mechanism of protection. The stomachs of protected animals exhibited a strikingly different transcriptional profile compared with those of nonprotected or control mice, indicating that vaccination targets the appropriate site and leaves a molecular signature. Among the genes whose up-regulation is significantly correlated with protection are a number of adipocyte-specific factors. These include the fat-cell-specific cytokines adipsin, resistin, and adiponectin and the adipocyte surface marker CD36. Interestingly, potentially protective T and B lymphocytes can be found embedded in the adipose tissue surrounding protected stomachs but never in control or unprotected stomachs. Adipsin-specific immunohistochemical staining of protected stomach sections further revealed molecular cross-talk between adjacent lymphoid and adipose cell populations. We propose a mechanism of protection that involves the effector responses of either or both lymphocyte subclasses as well as the previously unappreciated paracrine functions of adipose tissue surrounding the resident lymphocytes.


Telephone-based low intensity therapy after crisis presentations to the emergency department is associated with improved outcomes.
In Australia there is an overwhelming need to provide effective treatment to patients presenting to the Emergency Department (ED) in mental health crisis. We adapted Improving Access to Psychological Therapies service model (IAPT) from the National Health Service (NHS) method for the large scale delivery of psychological therapies throughout the United Kingdom to an Australian ED setting. This telephone-based low intensity therapy was provided to people presenting in crisis to the EDs with combinations of anxiety, depression, substance use, and suicidal thinking. This uncontrolled study utilised session-by-session, before-and-after measures of anxiety and depression via Patient Health Questionnaire (PHQ-9) and Generalised Anxiety Disorder-7 (GAD-7). Of 347 eligible post-crisis ED referred patients, 291 (83.9%) engaged with the IAPT team. Most patients (65%) had attended the ED previously on an average of 3.9 (SD = 6.0) occasions. Two hundred and forty one patients received an average of 4.1 (SD = 2.3) contacts of low-intensity psychological therapies including 1.2 (SD = 1.7) community outreach visits between 20th Oct 2011 and 31st Dec 2012. Treated patients reported clinically significant improvements in anxiety, depression and suicidal ideation. Uncontrolled effect sizes were moderate for anxiety (0.6) and depression (0.6). The Australian ED IAPT program demonstrated that the UK IAPT program could be adapted for emergency mental health patients and be associated with similar clinical benefits as the original program. The Flinders Medical Centre IAPT program received Emergency Department project funding from the Australian Commonwealth Government through the Council of Australian Governments (COAG) and the South Australian Government initiative, Every Patient Every Service (EPES).


PLGA-based nanofibers with a biomimetic polynoradrenaline sheath for rapid in vivo sampling of tetrodotoxin and sulfonamides in pufferfish.
Nanomaterials have shown great potential for application in microextraction due to their distinguishing nanoscale architectures and superior physicochemical properties. Herein, novel poly(lactic-co-glycolic acid) (PLGA) solid-phase microextraction (SPME) fibers, which were incorporated with a self-assembled graphene oxide (GO)-coated γ-Al2O3 composite (Al2O3@GO), were fabricated on stainless steel wires via an electrospinning method. The as-spun nanofibers were further sheathed through the self-polymerization of noradrenaline (NA), an agonist found in oysters, to provide a compatible biointerface and antifouling capacity. Acting as the coating substrate of the as-prepared fibers, PLGA is known for its prominent biocompatibility and biodegradability, while the adsorptive Al2O3@GO particles helped to increase their loading capacity. The modified PLGA-based electrospun nanofibers exhibited much higher extraction efficiency compared with the thicker polydimethylsiloxane (PDMS) coatings (165 μm) and polyacrylate (PA) coatings (85 μm). Due to the fine biointerface of the PLGA-based nanofibers, a rapid extraction equilibrium was observed and sampling with the custom-made Al2O3@GO-PLGA@PNA fibers could be accomplished within 15 min. The fibers were then successfully employed for simultaneous in vivo sampling of tetrodotoxin (TTX) and sulfonamides (SAs) in the dorsal-epaxial muscle of living pufferfish (Takifugu obscurus), and satisfactory sensitivities with limits of detection (LODs) in the range of 0.52-2.30 ng g-1 and comparable accuracies to the conventional liquid extraction (LE) method were achieved. In vivo sampling of target pharmaceuticals with the modified nanofibers showed their feasibility for further metabolomics and pharmacokinetics studies in biotissues.


Antibiotics in Canadian poultry productions and anticipated alternatives.
The use of antibiotics in food-producing animals has significantly increased animal health by lowering mortality and the incidence of diseases. Antibiotics also have largely contributed to increase productivity of farms. However, antibiotic usage in general and relevance of non-therapeutic antibiotics (growth promoters) in feed need to be reevaluated especially because bacterial pathogens of humans and animals have developed and shared a variety of antibiotic resistance mechanisms that can easily be spread within microbial communities. In Canada, poultry production involves more than 2600 regulated chicken producers who have access to several antibiotics approved as feed additives for poultry. Feed recipes and mixtures vary greatly geographically and from one farm to another, making links between use of a specific antibiotic feed additive and production yields or selection of specific antibiotic-resistant bacteria difficult to establish. Many on-farm studies have revealed the widespread presence of antibiotic-resistant bacteria in broiler chickens. While some reports linked the presence of antibiotic-resistant organisms to the use of feed supplemented with antibiotics, no recent studies could clearly demonstrate the benefit of antimicrobial growth promoters on performance and production yields. With modern biosecurity and hygienic practices, there is a genuine concern that intensive utilization of antibiotics or use of antimicrobial growth promoters in feed might no longer be useful. Public pressure and concerns about food and environmental safety (antibiotic residues, antibiotic-resistant pathogens) have driven researchers to actively look for alternatives to antibiotics. Some of the alternatives include pre- and probiotics, organic acids and essential oils. We will describe here the properties of some bioactive molecules, like those found in cranberry, which have shown interesting polyvalent antibacterial and immuno-stimulatory activities.


Regulation of human metabolism by hypoxia-inducible factor.
The hypoxia-inducible factor (HIF) family of transcription factors directs a coordinated cellular response to hypoxia that includes the transcriptional regulation of a number of metabolic enzymes. Chuvash polycythemia (CP) is an autosomal recessive human disorder in which the regulatory degradation of HIF is impaired, resulting in elevated levels of HIF at normal oxygen tensions. Apart from the polycythemia, CP patients have marked abnormalities of cardiopulmonary function. No studies of integrated metabolic function have been reported. Here we describe the response of these patients to a series of metabolic stresses: exercise of a large muscle mass on a cycle ergometer, exercise of a small muscle mass (calf muscle) which allowed noninvasive in vivo assessments of muscle metabolism using (31)P magnetic resonance spectroscopy, and a standard meal tolerance test. During exercise, CP patients had early and marked phosphocreatine depletion and acidosis in skeletal muscle, greater accumulation of lactate in blood, and reduced maximum exercise capacities. Muscle biopsy specimens from CP patients showed elevated levels of transcript for pyruvate dehydrogenase kinase, phosphofructokinase, and muscle pyruvate kinase. In cell culture, a range of experimental manipulations have been used to study the effects of HIF on cellular metabolism. However, these approaches provide no potential to investigate integrated responses at the level of the whole organism. Although CP is relatively subtle disorder, our study now reveals a striking regulatory role for HIF on metabolism during exercise in humans. These findings have significant implications for the development of therapeutic approaches targeting the HIF pathway.


Control of a visual keyboard using an electrocorticographic brain-computer interface.
Brain-computer interfaces (BCIs) are devices that enable severely disabled people to communicate and interact with their environments using their brain waves. Most studies investigating BCI in humans have used scalp EEG as the source of electrical signals and focused on motor control of prostheses or computer cursors on a screen. The authors hypothesize that the use of brain signals obtained directly from the cortical surface will more effectively control a communication/spelling task compared to scalp EEG. A total of 6 patients with medically intractable epilepsy were tested for the ability to control a visual keyboard using electrocorticographic (ECOG) signals. ECOG data collected during a P300 visual task paradigm were preprocessed and used to train a linear classifier to subsequently predict the intended target letters. The classifier was able to predict the intended target character at or near 100% accuracy using fewer than 15 stimulation sequences in 5 of the 6 people tested. ECOG data from electrodes outside the language cortex contributed to the classifier and enabled participants to write words on a visual keyboard. This is a novel finding because previous invasive BCI research in humans used signals exclusively from the motor cortex to control a computer cursor or prosthetic device. These results demonstrate that ECOG signals from electrodes both overlying and outside the language cortex can reliably control a visual keyboard to generate language output without voice or limb movements.


Milk helps build strong teeth and promotes oral health.
A great deal of research into the benefits of milk consumption has gone largely under the radar for many decades. There is a wealth of studies both in the United States and abroad to suggest that milk consumption is largely anti-cariogenic when combined with a typical routine of oral hygiene. This effect can be mostly attributed to several factors: tooth remineralization, inhibition of bacterial colonization, and biofilm inhibition. These abilities have been studied in detail and are likely due to numerous proteins found in milk. An attractive feature of milk from the community health perspective is its widespread consumption throughout the world. For this reason, studies have been initiated to investigate the possibilities of using milk to deliver fluoride and antibacterial antibodies to high-risk populations worldwide. This review will focus on the various components of milk, which promote oral health, and will also discuss common approaches to improve upon the oral health benefits of milk consumption.


Care of infants with hypoplastic left heart syndrome.
Hypoplastic left heart syndrome (HLHS) is a common congenital heart defect that is universally fatal without surgical intervention. Two distinctly different surgical options, heart transplantation and reconstruction surgery, have been successful in treating infants with HLHS. This article reviews the anatomy and pathophysiology of HLHS. Preoperative care of infants with HLHS is discussed. The care required by infants with HLHS after heart transplantation is the same as that required by other infants who need heart transplant and has been reported. The primary focus of this report is postoperative care after staged reconstructive surgery for infants with HLHS.


DNA testing for malignant hyperthermia: the reality and the dream.
The advent of the polymerase chain reaction and the availability of data from various global human genome projects should make it possible, using a DNA sample isolated from white blood cells, to diagnose rapidly and accurately almost any monogenic condition resulting from single nucleotide changes. DNA-based diagnosis for malignant hyperthermia (MH) is an attractive proposition, because it could replace the invasive and morbid caffeine-halothane/in vitro contracture tests of skeletal muscle biopsy tissue. Moreover, MH is preventable if an accurate diagnosis of susceptibility can be made before general anesthesia, the most common trigger of an MH episode. Diagnosis of MH using DNA was suggested as early as 1990 when the skeletal muscle ryanodine receptor gene (RYR1), and a single point mutation therein, was linked to MH susceptibility. In 1994, a single point mutation in the α 1 subunit of the dihydropyridine receptor gene (CACNA1S) was identified and also subsequently shown to be causative of MH. In the succeeding years, the number of identified mutations in RYR1 has grown, as has the number of potential susceptibility loci, although no other gene has yet been definitively associated with MH. In addition, it has become clear that MH is associated with either of these 2 genes (RYR1 and CACNA1S) in only 50% to 70% of affected families. While DNA testing for MH susceptibility has now become widespread, it still does not replace the in vitro contracture tests. Whole exome sequence analysis makes it potentially possible to identify all variants within human coding regions, but the complexity of the genome, the heterogeneity of MH, the limitations of bioinformatic tools, and the lack of precise genotype/phenotype correlations are all confounding factors. In addition, the requirement for demonstration of causality, by in vitro functional analysis, of any familial mutation currently precludes DNA-based diagnosis as the sole test for MH susceptibility. Nevertheless, familial DNA testing for MH susceptibility is now widespread although limited to a positive diagnosis and to those few mutations that have been functionally characterized. Identification of new susceptibility genes remains elusive. When new genes are identified, it will be the role of the biochemists, physiologists, and biophysicists to devise functional assays in appropriate systems. This will remain the bottleneck unless high throughput platforms can be designed for functional work. Analysis of entire genomes from several individuals simultaneously is a reality. DNA testing for MH, based on current criteria, remains the dream.


Predicting treatment related imaging changes (TRICs) after radiosurgery for brain metastases using treatment dose and conformality metrics.
Treatment-related imaging changes (TRICs) after stereotactic radiosurgery (SRS) involves the benign transient enlargement of radiographic lesions after treatment. Identifying the radiation dose volumes and conformality metrics associated with TRICs for different post-treatment periods would be helpful and improve clinical decision making. 367 metastases in 113 patients were treated using Gamma Knife SRS between 1/1/2007-12/31/2009. Each metastasis was measured at each imaging follow-up to detect TRICs (defined as ≥ 20% increase in volume). Fluctuations in small volume lesions (less than 108 mm3) were ignored given widely variable conformity indices (CI) for small volumes. The Karolinska Adverse Radiation Effect (KARE) factor, Paddick's CI, Shaw's CI, tumor volume (TV), 10 Gy (V10) and 12 Gy (V12) volumes, and prescription isodose volume (PIV) were calculated. From 0-6 months, all measures correlated with the incidence of TRICs (p<.001), except KARE, which was inversely correlated. During the 6-12 month period all measures except KARE were still correlated. Beyond 12 months, no correlation was found between any of the measures and the development of TRICs. All metrics except KARE were associated with TRICs from 0-12 months only. Additional patient and treatment factors may become dominant at greater times after SRS.


Is red cell distribution width a marker for the presence and poor prognosis of cardiovascular disease?
Red cell distribution width (RDW) is an indices heterogeneity of cell size in the peripheral blood and has been shown to be an independent correlate of adverse outcomes in healthy subjects and in some cardiac conditions. Additionally, RDW is associated with both the presence and the complexity of vascular disease. In this review we investigate the importance of RDW in vascular disease in the light of recent information.


Abrogation of MRL/lpr lupus nephritis by dietary flaxseed.
A diet supplemented with flaxseed, rich in alpha-linolenic acid and plant lignans (the latter, potent platelet-activating factor receptor antagonists), was tested in a murine model of lupus nephritis. MRL/lpr female mice (n = 25) were fed 15% flaxseed diet for 14 weeks commencing at 10 weeks of age. As controls, 30 MRL/lpr mice received a standard rodent diet without flaxseed. Isotope-glomerular filtration rate (14C-inulin clearance) was measured at 9, 16, and 24 weeks of age. Proteinuria was assessed at 2-week intervals. Spleen lymphocyte proliferation, quantitated by DNA analysis, was evaluated using flow cytometry at 9, 13, 19, and 21 weeks of age. Mortality was recorded throughout the study. Glomerular filtration rate at 16 weeks was greater in flaxseed-fed mice (0.15 +/- 0.03 mL/min) compared with controls (0.06 +/- 0.04 mL/min; P = 0.01). The onset of proteinuria (Albustix, Ames Division, Miles Laboratories, Rexdale, Ontario, Canada; > or = 2+) was delayed by 4 weeks in the flax-treated mice. The percentage of flaxseed-fed mice with proteinuria was lower than the control mice up to 21 weeks of age (39% v 58%; P = 0.01). Spleen lymphocyte proliferation (percentage of cells in S-phase) at 13 weeks of age was significantly higher in the control group (22.9 +/- 5.0, P = 0.01) but not in the flaxseed group (17.2 +/- 4.9) compared with baseline (9 weeks of age) values (13.0 +/- 3.5). Mortality was lower in the flaxseed-fed mice versus the control mice (assessed by Mantel-Haenszel (log-rank) test; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Left ventricular performance assessed by echocardiographic automated border detection and arterial pressure.
Automated echocardiographic measures of left ventricular (LV) cavity area are closely correlated with changes in volume and can be coupled with LV pressure (PLV) to construct pressure-area loops in real time. The objective was to rapidly estimate LV contractility from end-systolic relationships of cavity area (as a surrogate for LV volume) and central arterial pressure (Pa) (as a surrogate for PLV) in a canine model using automated algorithms. In eight anesthetized mongrel dogs, we simultaneously measured PLV, LV area, and Pa (fluid-filled catheter). End-systolic pressure-area relationships in terms of pressure-area elastance (E'es)] from pressure-area loops during inferior vena caval occlusions were determined during basal conditions (control), dobutamine infusion (5-10 micrograms.mg-1.min-1), and after bolus propranolol (2 mg/kg) with both PLV and Pa by semiautomated and automated iterative regression methods. E'es increased during dobutamine infusion and decreased after propranolol infusion in all animals and with all iterative methods. Estimates of Ees from Pa were closely correlated with E'es from PLV by both the semiautomated and automated methods (r = 0.93; P < 0.01). The relationship between E'es obtained from Pn for the two methods was also closely correlated. Although the automated methods displayed larger differences from the semiautomated iterative technique by Bland-Altman analysis, the change in E'es with all techniques during dobutamine infusion and after propranolol infusion was of similar magnitude and direction among the three techniques. Greater variability with the dobutamine runs was partially due to abnormally conducted ventricular beats that minimized the number of consecutive beats that could be used for these analyses. We conclude that on-line Pa recordings from fluid-filled catheters can be used with echocardiographic automated border detection to rapidly calculate E'es as a means to estimate LV contractility.


Longitudinal study of intestinal Entamoeba histolytica infections in asymptomatic adult carriers.
To gain insight into the dynamics of intestinal Entamoeba histolytica infection, a longitudinal study was performed over an observation period of 15 months with a group of 383 randomly selected adult individuals (mean age, 38.5 years) living in an area of amebiasis endemicity in central Vietnam. Ameba infection was diagnosed by using species-specific PCR and DNA extracted directly from fecal samples. The results indicated an E. histolytica prevalence of 11.2% and an annual new infection rate of 4.1% in the study population. Follow-up of the 43 individuals who were E. histolytica positive at enrollment suggested a regular exponential decline in infection of about 3% per month and a mean half-life of infection of more than 15 months. However, the reinfection rate for this group of participants was 2.7 times higher than that predicted for the study population as a whole. Both the reappearance of the parasite after successful treatment of E. histolytica infection and changes in "genetic fingerprints" of parasites during the course of infection revealed an annual new infection rate of about 11.5%. Thus, the mean half-life of E. histolytica infection was calculated to be 12.9 months (95% confidence interval, 10.2 to 15.6 months). Notably, none of the participants developed symptoms compatible with invasive intestinal amebiasis, and only one of the subjects developed an amebic liver abscess during the observation period.


GPRC5B activates obesity-associated inflammatory signaling in adipocytes.
A genome-wide association study identified a strong correlation between body mass index and the presence of a 21-kb copy number variation upstream of the human GPRC5B gene; however, the functional role of GPRC5B in obesity remains unknown. We report that GPRC5B-deficient mice were protected from diet-induced obesity and insulin resistance because of reduced inflammation in their white adipose tissue. GPRC5B is a lipid raft-associated transmembrane protein that contains multiple phosphorylated residues in its carboxyl terminus. Phosphorylation of GPRC5B by the tyrosine kinase Fyn and the subsequent direct interaction with Fyn through the Fyn Src homology 2 (SH2) domain were critical for the initiation and progression of inflammatory signaling in adipose tissue. We demonstrated that a GPRC5B mutant lacking the direct binding site for Fyn failed to activate a positive feedback loop of nuclear factor κB-inhibitor of κB kinase ε signaling. These findings suggest that GPRC5B may be a major node in adipose signaling systems linking diet-induced obesity to type 2 diabetes and may open new avenues for therapeutic approaches to diabetic progression.


Use of diabetes data management software reports by health care providers, patients with diabetes, and caregivers improves accuracy and efficiency of data analysis and interpretation compared with traditional logbook data: first results of the Accu-Chek Connect Reports Utility and Efficiency Study (ACCRUES).
We assessed users' proficiency and efficiency in identifying and interpreting self-monitored blood glucose (SMBG), insulin, and carbohydrate intake data using data management software reports compared with standard logbooks. This prospective, self-controlled, randomized study enrolled insulin-treated patients with diabetes (PWDs) (continuous subcutaneous insulin infusion [CSII] and multiple daily insulin injection [MDI] therapy), patient caregivers [CGVs]) and health care providers (HCPs) who were naïve to diabetes data management computer software. Six paired clinical cases (3 CSII, 3 MDI) and associated multiple-choice questions/answers were reviewed by diabetes specialists and presented to participants via a web portal in both software report (SR) and traditional logbook (TL) formats. Participant response time and accuracy were documented and assessed. Participants completed a preference questionnaire at study completion. All participants (54 PWDs, 24 CGVs, 33 HCPs) completed the cases. Participants achieved greater accuracy (assessed by percentage of accurate answers) using the SR versus TL formats: PWDs, 80.3 (13.2)% versus 63.7 (15.0)%, P < .0001; CGVs, 84.6 (8.9)% versus 63.6 (14.4)%, P < .0001; HCPs, 89.5 (8.0)% versus 66.4 (12.3)%, P < .0001. Participants spent less time (minutes) with each case using the SR versus TL formats: PWDs, 8.6 (4.3) versus 19.9 (12.2), P < .0001; CGVs, 7.0 (3.5) versus 15.5 (11.8), P = .0005; HCPs, 6.7 (2.9) versus 16.0 (12.0), P < .0001. The majority of participants preferred using the software reports versus logbook data. Use of the Accu-Chek Connect Online software reports enabled PWDs, CGVs, and HCPs, naïve to diabetes data management software, to identify and utilize key diabetes information with significantly greater accuracy and efficiency compared with traditional logbook information. Use of SRs was preferred over logbooks.


Overcoming the limitations of fine needle aspiration biopsy: detection of lateral neck node metastasis in papillary thyroid carcinoma.
Ultrasound (US) and US-guided fine needle aspiration biopsies (FNAB) are considered the modalities of choice for assessing lymph nodes suspected of containing metastases, but the sensitivity of FNAB varies and is specific to the operator. We analyzed the risk of FNAB providing false negative results of lateral neck node metastasis, and evaluated diagnostic accuracy of FNAB, in patients with papillary thyroid cancer. FNAB was performed in 242 patients suspected of having lateral neck node metastasis on preoperative imaging. Thyroglobulin in the fine-needle aspirate washout (FNA wash-out Tg) and computed tomography enhancement (Hounsfield units) were measured. Patients with negative results on FNAB were examined by intraoperative frozen section. The false negative and true negative groups were compared. Of the 242 patients, 130 were confirmed as having lateral neck node metastases. In 74 patients, the metastasis was identified by FNAB. False positive results were observed in 2 patients (0.8%) and false negatives in 58 (44.6%). Risk analysis showed that patient age <45 years (p=0.006), tumor size >1 cm (p=0.008) and elevated FNA wash-out Tg (p=0.004) were significantly associated with false negative results on FNAB. The accuracy of FNAB increased significantly when combined with FNA wash-out Tg (p=0.003). To reduce the false negative rate of FNAB, patient age (<45 years), tumor size (>1 cm) and FNA wash-out Tg (>34.8 ng/mL) should be considered in preoperative planning. Accuracy may be improved by combining the results of FNAB and FNA wash-out Tg.


Comparative genomics reveals evidence of marine adaptation in Salinispora species.
Actinobacteria represent a consistent component of most marine bacterial communities yet little is known about the mechanisms by which these Gram-positive bacteria adapt to life in the marine environment. Here we employed a phylogenomic approach to identify marine adaptation genes in marine Actinobacteria. The focus was on the obligate marine actinomycete genus Salinispora and the identification of marine adaptation genes that have been acquired from other marine bacteria. Functional annotation, comparative genomics, and evidence of a shared evolutionary history with bacteria from hyperosmotic environments were used to identify a pool of more than 50 marine adaptation genes. An Actinobacterial species tree was used to infer the likelihood of gene gain or loss in accounting for the distribution of each gene. Acquired marine adaptation genes were associated with electron transport, sodium and ABC transporters, and channels and pores. In addition, the loss of a mechanosensitive channel gene appears to have played a major role in the inability of Salinispora strains to grow following transfer to low osmotic strength media. The marine Actinobacteria for which genome sequences are available are broadly distributed throughout the Actinobacterial phylogenetic tree and closely related to non-marine forms suggesting they have been independently introduced relatively recently into the marine environment. It appears that the acquisition of transporters in Salinispora spp. represents a major marine adaptation while gene loss is proposed to play a role in the inability of this genus to survive outside of the marine environment. This study reveals fundamental differences between marine adaptations in Gram-positive and Gram-negative bacteria and no common genetic basis for marine adaptation among the Actinobacteria analyzed.


Honeybee-collected pollen from five Portuguese Natural Parks: palynological origin, phenolic content, antioxidant properties and antimicrobial activity.
The aim of this study was to determine the palynological origin, phenolic content, antioxidant and antimicrobial properties of pollen from five Portuguese Natural-Parks [Parque Nacional Peneda Gerês (PNPG); Parque Natural do Montesinho (PNM); Parque Natural do Alvão (PNA); Parque Natural da Serra da Estrela (PNSE) and Parque Natural do Douro Internacional (PNDI)]. Eight families were found in the mixture of bee pollen: Rosaceae, Cistaceae, Boraginaceae, Asteraceae, Fagaceae, Ericaeae, Myrtaceae and Fabaceae. The phenolic compounds content, determined by the Folin-Ciocalteu method, varied between 10.5 and 16.8 mg of gallic acid equivalents/g of extract (mg GAE/g) found in bee pollen from PNM and PNDI, respectively. The free radical scavenging measured showed the highest effective extract - PNM with EC(50) 2.16, followed by PND with 2.24 mg/mL. In the β-carotene bleaching assay the same behaviour as in the DPPH method was verified. We also verified that the presence of pollen differentially affected the growth of bacteria Gram-positive, Gram-negative and yeasts under study, depending this on the microorganism and the pollen used. This is an important study since, as far we know, it is the first time that Portuguese bee pollen from Natural Parks was studied, and their characterization can increase their economic value.


Non-malarial febrile illness: a systematic review of published aetiological studies and case reports from Southern Asia and South-eastern Asia, 1980-2015.
In the absence of definitive diagnosis, healthcare providers are likely to prescribe empirical antibacterials to those who test negative for malaria. This problem is of critical importance in Southern Asia (SA) and South-eastern Asia (SEA) where high levels of antimicrobial consumption and high prevalence of antimicrobial resistance have been reported. To improve management and guide further diagnostic test development, better understanding is needed of the true causative agents of fever and their geographical variability. We conducted a systematic review of published literature (1980-2015) to characterise the spectrum of pathogens causing non-malarial febrile illness in SA and SEA. We searched six databases in English and French languages: MEDLINE, EMBASE, Global Health (CABI) database, WHO Global Health Library, PASCAL, and Bulletin de la Société Française de Parasitologie (BDSP). Selection criteria included reporting on an infection or infections with a confirmed diagnosis, defined as pathogens detected in or cultured from samples from normally sterile sites, or serological evidence of current or past infection. A total of 29,558 records from 19 countries in SA and SEA were screened, of which 2410 (8.1%) met the selection criteria. Bacterial aetiologies were reported in 1235 (51.2%) articles, viral in 846 (35.1%), parasitic in 132 (5.5%), and fungal in 54 (2.2%), and 143 (6.0%) articles reported more than one pathogen group. In descending order of frequency, Salmonella Typhi, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and coagulase negative Staphylococcus were the commonly reported bacteria, while dengue virus, chikungunya virus, Japanese encephalitis virus, hepatitis B virus, and hepatitis C virus were common viral pathogens reported. Reports of rarely reported or emerging pathogens included a case report of Borrelia burgdorferi (Lyme disease) in India in 2010 and reports of Nipah virus in Singapore and India. This review summarises the reported non-malaria pathogens that may cause febrile illness in SA and SEA. The findings emphasise the need of standardising the reporting of aetiological studies to develop effective, evidence-based fever management and improved surveillance. Research and development of diagnostic tools would benefit from up-to-date epidemiological reporting of the regional diversities of non-malaria fever aetiologies. PROSPERO registration, CRD42016049281.


Meta gene set enrichment analyses link miR-137-regulated pathways with schizophrenia risk.
A single nucleotide polymorphism (SNP) within MIR137, the host gene for miR-137, has been identified repeatedly as a risk factor for schizophrenia. Previous genetic pathway analyses suggest that potential targets of this microRNA (miRNA) are also highly enriched in schizophrenia-relevant biological pathways, including those involved in nervous system development and function. In this study, we evaluated the schizophrenia risk of miR-137 target genes within these pathways. Gene set enrichment analysis of pathway-specific miR-137 targets was performed using the stage 1 (21,856 subjects) schizophrenia genome wide association study data from the Psychiatric Genomics Consortium and a small independent replication cohort (244 subjects) from the Mind Clinical Imaging Consortium and Northwestern University. Gene sets of potential miR-137 targets were enriched with variants associated with schizophrenia risk, including target sets involved in axonal guidance signaling, Ephrin receptor signaling, long-term potentiation, PKA signaling, and Sertoli cell junction signaling. The schizophrenia-risk association of SNPs in PKA signaling targets was replicated in the second independent cohort. These results suggest that these biological pathways may be involved in the mechanisms by which this MIR137 variant enhances schizophrenia risk. SNPs in targets and the miRNA host gene may collectively lead to dysregulation of target expression and aberrant functioning of such implicated pathways. Pathway-guided gene set enrichment analyses should be useful in evaluating the impact of other miRNAs and target genes in different diseases.


Homeostatically Maintained Resting Naive CD4+ T Cells Resist Latent HIV Reactivation.
Homeostatic proliferation (HSP) is a major mechanism by which long-lived naïve and memory CD4+ T cells are maintained in vivo and suggested to contribute to the persistence of the latent HIV-1 reservoir. However, while many in vitro latency models rely on CD4+ T cells that were initially differentiated via T-cell receptor (TCR) stimulation into memory/effector cells, latent infection of naïve resting CD4+ T cells maintained under HSP conditions has not been fully addressed. Here, we describe an in vitro HSP culture system utilizing the cytokines IL-7 and IL-15 that allows studying latency in naïve resting CD4+ T cells. CD4+ T cells isolated from several healthy donors were infected with HIV pseudotypes expressing GFP and cultured under HSP conditions or TCR conditions as control. Cell proliferation, phenotype, and GFP expression were analyzed by flow cytometry. RNA expression was quantified by qRT-PCR. Under HSP culture conditions, latently HIV-1 infected naïve cells are in part maintained in the non-dividing (= resting) state. Although a few HIV-1 provirus+ cells were present in these resting GFP negative cells, the estimated level of GFP transcripts per infected cell seems to indicate a block at the post-transcriptional level. Interestingly, neither TCR nor the prototypic HDAC inhibitor SAHA were able to reactivate HIV-1 provirus from these cells. This lack of reactivation was not due to methylation of the HIV LTR. These results point to a mechanism of HIV control in HSP-cultured resting naïve CD4+ T cells that may be distinct from that in TCR-stimulated memory/effector T cells.


Voice-Hearing and Personification: Characterizing Social Qualities of Auditory Verbal Hallucinations in Early Psychosis.
Recent therapeutic approaches to auditory verbal hallucinations (AVH) exploit the person-like qualities of voices. Little is known, however, about how, why, and when AVH become personified. We aimed to investigate personification in individuals' early voice-hearing experiences. We invited Early Intervention in Psychosis (EIP) service users aged 16-65 to participate in a semistructured interview on AVH phenomenology. Forty voice-hearers (M = 114.13 days in EIP) were recruited through 2 National Health Service trusts in northern England. We used content and thematic analysis to code the interviews and then statistically examined key associations with personification. Some participants had heard voices intermittently for multiple years prior to clinical involvement (M = 74.38 months), although distressing voice onset was typically more recent (median = 12 months). Participants reported a range of negative emotions (predominantly fear, 60%, 24/40, and anxiety, 62.5%, 26/40), visual hallucinations (75%, 30/40), bodily states (65%, 25/40), and "felt presences" (52.5%, 21/40) in relation to voices. Complex personification, reported by a sizeable minority (16/40, 40%), was associated with experiencing voices as conversational (odds ratio [OR] = 2.56) and companionable (OR = 3.19) but not as commanding or trauma-related. Neither age of AVH onset nor time since onset related to personification. Our findings highlight significant personification of AVH even at first clinical presentation. Personified voices appear to be distinguished less by their intrinsic properties, commanding qualities, or connection with trauma than by their affordances for conversation and companionship.


Differential effects of Foxp2 disruption in distinct motor circuits.
Disruptions of the FOXP2 gene cause a speech and language disorder involving difficulties in sequencing orofacial movements. FOXP2 is expressed in cortico-striatal and cortico-cerebellar circuits important for fine motor skills, and affected individuals show abnormalities in these brain regions. We selectively disrupted Foxp2 in the cerebellar Purkinje cells, striatum or cortex of mice and assessed the effects on skilled motor behaviour using an operant lever-pressing task. Foxp2 loss in each region impacted behaviour differently, with striatal and Purkinje cell disruptions affecting the variability and the speed of lever-press sequences, respectively. Mice lacking Foxp2 in Purkinje cells showed a prominent phenotype involving slowed lever pressing as well as deficits in skilled locomotion. In vivo recordings from Purkinje cells uncovered an increased simple spike firing rate and decreased modulation of firing during limb movements. This was caused by increased intrinsic excitability rather than changes in excitatory or inhibitory inputs. Our findings show that Foxp2 can modulate different aspects of motor behaviour in distinct brain regions, and uncover an unknown role for Foxp2 in the modulation of Purkinje cell activity that severely impacts skilled movements.


Organ transplantation in Italy: analysis of donors and recipients.
The Istituto Superiore di Sanità (The Italian National Institute of Health) has been collecting information regarding organ donation and transplantation in Italy. Herein we describe organ procurement and transplant activity in Italy in the years 1992 1997 and show some of the characteristics regarding both donors and transplanted patients who received kidneys, hearts, livers and lungs. Although transplantation in Italy has been very difficult because of shortage of organ donors, national rates have been improving year after year. The present situation should ameliorate further to enable Italy to reach the same level of other advanced European countries.


Protocol for Pertussis Immunisation and Food Allergy (PIFA): a case-control study of the association between pertussis vaccination in infancy and the risk of IgE-mediated food allergy among Australian children.
Atopic diseases, including food allergy, have become a predominant cause of chronic illness among children in developed countries. In Australia, a rise in hospitalisations among infants coded as anaphylaxis to foods coincided with the replacement of whole-cell pertussis (wP) vaccine with subunit acellular pertussis (aP) vaccine on the national immunisation schedule in the late 1990s. Atopy is characterised by a tendency to mount T helper type 2 (Th2) responses to otherwise innocuous environmental antigens. Compared with infants who receive aP as their first pertussis vaccine, those who receive wP appear less likely to mount Th2 immune responses to either vaccine or extraneous antigens. We therefore speculate that removal of wP from the vaccine schedule contributed to the observed rise in IgE-mediated food allergy among Australian infants. This is a retrospective individually matched case-control study among a cohort of Australian children born from 1997 to 1999, the period of transition from wP to aP vaccines; we include in the cohort children listed on Australia's comprehensive population-based immunisation register as having received a first dose of either pertussis vaccine by 16 weeks old. 500 cohort children diagnosed as having IgE-mediated food allergy at specialist allergy clinics will be included as cases. Controls matched to each case by date and jurisdiction of birth and regional socioeconomic index will be sampled from the immunisation register. Conditional logistic regression will be used to estimate OR (±95% CI) of receipt of wP (vs aP) as the first vaccine dose among cases compared with controls. The study is approved by all relevant human research ethics committees: Western Australia Child and Adolescent Health Services (2015052EP), Women's and Children's Hospital (HREC/15/WCHN/162), Royal Children's Hospital (35230A) and Sydney Children's Hospital Network (HREC/15/SCHN/405). Outcomes will be disseminated through publication and scientific presentation. NCT02490007.


Comparison of comorbid conditions between open-angle glaucoma patients and a control cohort: a case-control study.
To determine the prevalence of selected comorbidities in patients with open-angle glaucoma (OAG) and whether these comorbidities are more prevalent among individuals with OAG than those without OAG. A retrospective, nationwide, case-control study using an administrative database. The study group comprised 76,673 OAG patients. The comparison group comprised 230,019 subjects matched to the study cohort. Data were collected retrospectively from the Taiwan National Health Insurance Research Database. The study cohort comprised all patients with a diagnosis of OAG (International Classification of Diseases, 9th Revision, Clinical Modification codes 365.1-365.11) in 2005 (n = 76,673). The comparison cohort comprised randomly selected patients (3 for every 1 OAG patient; n = 230,019) matched with the study group in terms of age, gender, urbanization level, and monthly income. In total, 31 medical comorbidities were selected based mainly on the Elixhauser Comorbidity Index. Separate conditional logistic regression analyses were used to estimate the adjusted odds ratio for each of the medical comorbidities between patients with and without OAG. The prevalences of selected comorbidities. More than half (50.5%) of the OAG patients had hypertension, and more than 30% had hyperlipidemia or diabetes (30.5% and 30.2%, respectively). The prevalences of 28 of 31 comorbidities were significantly higher for OAG patients than subjects without glaucoma after adjusting for age, gender, urbanization level, and monthly income. The adjusted odds ratio was more than 1.50 for hypertension, hyperlipidemia, systemic lupus erythematosus, diabetes, hypothyroidism, fluid and electrolyte disorders, depression, and psychosis. Among the studied comorbidities, the prevalence difference of the OAG group minus the control group was 3% or higher for hypertension, hyperlipidemia, stroke, diabetes, liver disease, and peptic ulcer. Open-angle glaucoma patients are significantly more likely to have comorbidities, many of which can be life threatening or can affect the quality of life appreciably. The author(s) have no proprietary or commercial interest in any materials discussedin this article


On agent-based modeling and computational social science.
In the first part of the paper, the field of agent-based modeling (ABM) is discussed focusing on the role of generative theories, aiming at explaining phenomena by growing them. After a brief analysis of the major strengths of the field some crucial weaknesses are analyzed. In particular, the generative power of ABM is found to have been underexploited, as the pressure for simple recipes has prevailed and shadowed the application of rich cognitive models. In the second part of the paper, the renewal of interest for Computational Social Science (CSS) is focused upon, and several of its variants, such as deductive, generative, and complex CSS, are identified and described. In the concluding remarks, an interdisciplinary variant, which takes after ABM, reconciling it with the quantitative one, is proposed as a fundamental requirement for a new program of the CSS.