Sex differences in the presentation, treatment and outcomes of patients with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal semi-dominant lipid metabolism disorder characterized by extremely high low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease. The objective of this study was to investigate sex-differences in the treatment and outcomes of patients with HoFH. METHODS: We examined clinical characteristics, lipid-lowering therapy (LLT), and cardiovascular events using descriptive statistics of patients in the Canadian HoFH registry. Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, non-fatal myocardial infarction, and stroke. Sex differences between continuous and categorical variables were analyzed using Mann-Whitney U test and Fisher's Exact test, respectively. RESULTS: This study included 48 patients (27 (56%) female). The median age at diagnosis in females was 14.0 (interquartile range (IQR) 9.0-30.0) and in males was 8.0 (IQR 2.0-23.0) (p = 0.07). Baseline clinical characteristics were comparable between both sexes. The median baseline LDL-C was 12.7 mmol/L (10.0-18.3) in females and 15.3 (10.5-20.0) in males (p = 0.51). Follow up LDL-C levels were 7.6 mmol/L (IQR 4.8-11.0) in females and 6.3 (IQR 4.6-7.5) in males (p = 0.1). Most patients were taking 3 or more LLTs, with comparable proportions in both sexes (p = 0.26). Apheresis was similar in both sexes, 14 (51.8%) vs. 10 (47.6%) (p = 0.2). Over a mean of 10 years of follow-up, MACE occurred in 3 females (11.1%) and 4 males (19.1%) (p = 0.2). CONCLUSION: Lipid levels and treatment were similar between sexes. MACE occurred in similar proportions between sexes, indicating that HoFH offsets the inherently lower cardiovascular risk in pre-menopausal females. Further investigation into sex-differences in HoFH in larger sample sizes is warranted.

Piloting Safety and Stabilization: A Multi-component Trauma Intervention to Improve HIV Viral Suppression, Retention in Care, and Post-traumatic Stress Disorder in a Southern United States HIV Service Organization.

In this observational study, we assessed the extent to which a community-created pilot intervention, providing trauma-informed care for persons with HIV (PWH), affected HIV care retention and viral suppression among PWH attending an HIV Services Organization in the Southern US. PWH with trauma exposure and/or trauma symptoms (N = 166) were offered a screening and referral to treatment (SBIRT) session. Per self-selection, 30 opted-out, 29 received SBIRT-Only, 25 received SBIRT-only but reported receiving other behavioral health care elsewhere, and 82 participated in the Safety and Stabilization (S&S) Intervention. Estimates from multivariable logistic regression analyses indicated S&S Intervention participants had increased retention in HIV care (adjusted odds ratio [aOR] 5.46, 95% CI 1.70-17.50) and viral suppression (aOR 17.74, 95% CI 1.83-172), compared to opt-out participants. Some evidence suggested that PTSD symptoms decreased for intervention participants. A randomized controlled trial is needed to confirm findings.

Consistent predictors of microbial community composition across spatial scales in grasslands reveal low context-dependency.

Environmental circumstances shaping soil microbial communities have been studied extensively. However, due to disparate study designs, it has been difficult to resolve whether a globally consistent set of predictors exists, or context-dependency prevails. Here, we used a network of 18 grassland sites (11 of those containing regional plant productivity gradients) to examine (i) if similar abiotic or biotic factors predict both large-scale (across sites) and regional-scale (within sites) patterns in bacterial and fungal community composition, and (ii) if microbial community composition differs consistently at two levels of regional plant productivity (low vs. high). Our results revealed that bacteria were associated with particular soil properties (such as base saturation) and both bacteria and fungi were associated with plant community composition across sites and within the majority of sites. Moreover, a discernible microbial community signal emerged, clearly distinguishing high and low-productivity soils across different grasslands independent of their location in the world. Hence, regional productivity differences may be typified by characteristic soil microbial communities across the grassland biome. These results could encourage future research aiming to predict the general effects of global changes on soil microbial community composition in grasslands and to discriminate fertile from infertile systems using generally applicable microbial indicators.

Process Mapping to inform implementation of Trauma-Informed Care for youth aged 14-24 with HIV in the Southern United States.

Background: Trauma-Informed Care (TIC) is an evidence-based approach for improving health outcomes by providing systematic, trauma- sensitive and -responsive care. Because TIC adoption varies by setting and population, Implementation Science (IS) is particularly well-suited to guide roll-out efforts. Process Mapping (PM) is an IS model for creating shared visual depictions of systems as they are to identify rate-limiting steps of intervention adoption, but guidance on how to apply PM to guide TIC adoption is lacking. Authors of this study aimed to develop a novel method for conducting TIC-focused PM. Methods: A real-life TIC implementation study is presented to show how TIC-focused PM was conducted in the case example of a pediatric HIV clinic in a Southern urban area with a high burden of psychological trauma among youth with HIV. A five-phase PM model was applied to evince clinic standards of care, including Preparation, planning and process identification; Data and information gathering; Map generation; Analysis; and Taking it forward. Practices and conditions from four TIC domains were assessed, including Trauma responsive services; Practices of inclusivity, safety, and wellness; Training and sustaining trauma responsiveness; and Cultural responsiveness. Results: The TIC-focused PM method indicated the case clinic provided limited and non-systematic patient trauma screening, assessment, and interventions; limited efforts to promote professional quality of life and elicit and integrate patient experiences and preferences for care; no ongoing efforts to train and prepare workforce for trauma- sensitive or -responsive care; and no clinic-specific efforts to promote diversity, equity, and inclusion for patients and personnel. Conclusion: Principles and constructs of resilience-focused TIC were synthesized with a five-phase PM model to generate a baseline depiction of TIC in a pediatric HIV clinic. Results will inform the implementation of TIC in the clinic. Future champions may follow the TIC-focused PM model to guide context-tailored TIC adoption.

Relationship between the concentration of ergothioneine in plasma and the likelihood of developing pre-eclampsia.

Ergothioneine, an antioxidant nutraceutical mainly at present derived from the dietary intake of mushrooms, has been suggested as a preventive for pre-eclampsia (PE). We analysed early pregnancy samples from a cohort of 432 first time mothers as part of the Screening for Endpoints in Pregnancy (SCOPE, European branch) project to determine the concentration of ergothioneine in their plasma. There was a weak association between the ergothioneine levels and maternal age but none for BMI. Of these 432 women, 97 went on to develop pre-term (23) or term (74) PE. If a threshold was set at the 90th percentile of the reference range in the control population (≥462 ng/ml), only one of these 97 women (1%) developed PE, versus 96/397 (24.2%) whose ergothioneine level was below this threshold. One possible interpretation of these findings, consistent with previous experiments in a reduced uterine perfusion model in rats, is that ergothioneine may indeed prove protective against PE in humans. An intervention study of some kind now seems warranted.

Docetaxel as a Model Compound to Promote HDL (High-Density Lipoprotein) Biogenesis and Reduce Atherosclerosis.

The recent identification of the cell-surface protein DSC1 (desmocollin 1) as a negative regulator of HDL (high-density lipoprotein) biogenesis has attracted us to revisit the old HDL biogenesis hypothesis: HDL biogenesis reduces atherosclerosis. The location and function of DSC1 suggest that DSC1 is a druggable target for the promotion of HDL biogenesis, and the discovery of docetaxel as a potent inhibitor of the DSC1 sequestration of apolipoprotein A-I has provided us with new opportunities to test this hypothesis. The FDA-approved chemotherapy drug docetaxel promotes HDL biogenesis at low-nanomolar concentrations that are far lower than used in chemotherapy. Docetaxel has also been shown to inhibit atherogenic proliferation of vascular smooth muscle cells. In accordance with these atheroprotective effects of docetaxel, animal studies have shown that docetaxel reduces dyslipidemia-induced atherosclerosis. In the absence of HDL-directed therapies for atherosclerosis, DSC1 constitutes an important new target for the promotion of HDL biogenesis, and the DSC1-targeting compound docetaxel serves as a model compound to prove the hypothesis. In this brief review, we discuss opportunities, challenges, and future directions for using docetaxel in the prevention and treatment of atherosclerosis.

First-trimester preterm preeclampsia prediction with metabolite biomarkers: differential prediction according to maternal body mass index.

BACKGROUND: Prediction of preeclampsia risk is key to informing effective maternal care. Current screening for preeclampsia at 11 to 13 weeks of gestation using maternal demographic characteristics and medical history with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor can identify approximately 75% of women who develop preterm preeclampsia with delivery at <37 weeks of gestation. Further improvements to preeclampsia screening tests will likely require integrating additional biomarkers. Recent research suggests the existence of distinct maternal risk profiles. Therefore, biomarker evaluation should account for the possibility that a biomarker only predicts preeclampsia in a specific maternal phenotype. OBJECTIVE: This study aimed to verify metabolite biomarkers as preterm preeclampsia predictors early in pregnancy in all women and across body mass index groups. STUDY DESIGN: Observational case-control study drawn from a large prospective study on the early prediction of pregnancy complications in women attending their routine first hospital visit at King's College Hospital, London, United Kingdom, in 2010 to 2015. Pregnant women underwent a complete first-trimester assessment, including the collection of blood samples for biobanking. In 11- to 13-week plasma samples of 2501 singleton pregnancies, the levels of preselected metabolites implicated in the prediction of pregnancy complications were analyzed using a targeted liquid chromatography-mass spectrometry method, yielding high-quality quantification data on 50 metabolites. The ratios of amino acid levels involved in arginine biosynthesis and nitric oxide synthase pathways were added to the list of biomarkers. Placental growth factor and pregnancy-associated plasma protein A were also available for all study subjects, serving as comparator risk predictors. Data on 1635 control and 106 pregnancies complicated by preterm preeclampsia were considered for this analysis, normalized using multiples of medians. Prediction analyses were performed across the following patient strata: all subjects and the body mass index classes of <25, 25 to <30, and ≥30 kg/m2. Adjusted median levels were compared between cases and controls and between each body mass index class group. Odds ratios and 95% confidence intervals were calculated at the mean ±1 standard deviation to gauge clinical prediction merits. RESULTS: The levels of 13 metabolites were associated with preterm preeclampsia in the entire study population (P<.05) with particularly significant (P<.01) associations found for 6 of them, namely, 2-hydroxy-(2/3)-methylbutyric acid, 25-hydroxyvitamin D3, 2-hydroxybutyric acid, alanine, dodecanoylcarnitine, and 1-(1Z-octadecenyl)-2-oleoyl-sn-glycero-3-phosphocholine. Fold changes in 7 amino acid ratios, all involving glutamine or ornithine, were also significantly different between cases and controls (P<.01). The predictive performance of some metabolites and ratios differed according to body mass index classification; for example, ornithine (P<.001) and several ornithine-related ratios (P<.0001 to P<.01) were only strongly associated with preterm preeclampsia in the body mass index of <25 kg/m2 group, whereas dodecanoylcarnitine and 3 glutamine ratios were particularly predictive in the body mass index of ≥30 kg/m2 group (P<.01). CONCLUSION: Single metabolites and ratios of amino acids related to arginine bioavailability and nitric oxide synthase pathways were associated with preterm preeclampsia risk at 11 to 13 weeks of gestation. Differential prediction was observed according to body mass index classes, supporting the existence of distinct maternal risk profiles. Future studies in preeclampsia prediction should account for the possibility of different maternal risk profiles to improve etiologic and prognostic understanding and, ultimately, clinical utility of screening tests.

Correlates of Safety Strategy Use Among South African Women Living With HIV and at Risk of Intimate Partner Violence.

Intimate partner violence (IPV) and HIV are correlated and endemic in South Africa. However, safety strategy use to prevent IPV among HIV-positive women is understudied. This study assesses correlates of specific safety strategy use among 166 Black South African women recently experiencing IPV and testing positive for HIV. Associations were observed between consultation with formal (i.e., counselors, clergy, IPV specialists) and informal networks (i.e., friends/family) and participant language (isiZulu, isiXhosa, Sesotho, and English), past year IPV, and engaging in HIV care. Future HIV-IPV programs should consider how characteristics of different IPV safety strategies may influence strategy uptake and ultimately HIV care.

The organizational trauma resilience assessment: Methods and psychometric properties.

OBJECTIVE: Despite many strengths of trauma-informed care (TIC), critics argue TIC is necessary but alone insufficient, can be deficit focused, lacks construct operationalization, and requires greater inclusion of resilience theory. We sought to address these critiques by creating an assessment tool through an iterative and community-engaged process. METHOD: We collected cross-sectional data between May and June 2019 with a convenience sample from 12 sites across the United States (N = 861). Data were analyzed through application of classical test theory and item response theory, using principal components analysis. RESULTS: The final 40-item Organizational Trauma Resilience Assessment (OTRA) is sufficiently unidimensional and has a five-factor solution with strong validity and reliability. CONCLUSION: We believe this instrument marks the first of its kind to synthesize tenets of organizational resilience with TIC principles. Creation of the OTRA progresses the TIC knowledge base and is a cost-effective and valid method for evaluating organizational culture of trauma resilience. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Effects of rainfall, temperature and photoperiod on the phenology of ephemeral resources for selected bushveld woody plant species in southern Africa.

Variability of ephemeral resources provided by woody plants is related to fluctuating environmental conditions, specifically the predominant climate variables temperature and rainfall. Photoperiod has less impact but also plays a role in the onset of resource pulses. In the seasonally affected bushveld of southern Africa, declining resources could have dire consequences to various animals that depend on these resources. Understanding the impact that rainfall, temperature and photoperiod has on woody plant resources allows managers of natural areas to plan for times when resources are scarce. Using a series of General Linear Models, this baseline study investigates the effects that these variables have on flower production, numbers of new fruit/pods and numbers of new leaves for 113 tagged trees from 26 woody plant species. Leads, lags and coincidental relationships observed between environmental predictor and phenological response variables were explored using time-series cross-correlations and concomitant correlograms. Model results indicated that temperature was the predominant indicator for flowering, with initial flowering starting when temperatures increase in September. A significant lead was observed between flowering and rainfall, suggesting that flower numbers increase approximately one month before rainfall increases. Temperature had the biggest effect on the number of species with new fruits and pods. Significant lags were observed between new fruits and pods and all environmental variables investigated, indicating that these resources depend on rainfall, temperature and photoperiod to reach their full potential. Photoperiod, temperature and the interaction between these variables had a noticeable effect on the number of species with new leaves. Peaks in species with new leaves coincide with peaks in rainfall, temperature and photoperiod. No leading or lagging indicators were observed between new leaves and the environmental variables investigated. In areas containing wildlife populations, recommendations are to undertake regular monitoring of climatic variables investigated, and the ephemeral resources on woody plant species.

Placenta Accreta Spectrum.

Placenta accreta spectrum is a term used to describe abnormal adherence and abnormal invasion of the placenta into the uterine wall during pregnancy. The incidence of placenta accreta spectrum has steadily increased over the last 40 years and is most notably linked to rising cesarean birth rates. This condition is associated with increased maternal morbidity and mortality because of the high risk of severe hemorrhage and likely need for hysterectomy at the time of birth. Early diagnosis of abnormal placentation is preferable in order to coordinate birth planning with a interprofessional collaborative team within a high-level perinatal care center. This article describes the case of a woman diagnosed with placenta accreta spectrum and the clinical course of her pregnancy and birth.

Prediction of preeclampsia risk in first time pregnant women: Metabolite biomarkers for a clinical test.

Preeclampsia remains a leading cause of maternal and perinatal morbidity and mortality. Accurate prediction of preeclampsia risk would enable more effective, risk-based prenatal care pathways. Current risk assessment algorithms depend on clinical risk factors largely unavailable for first-time pregnant women. Delivering accurate preeclampsia risk assessment to this cohort of women, therefore requires for novel biomarkers. Here, we evaluated the relevance of metabolite biomarker candidates for their selection into a prototype rapid, quantitative Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS) based clinical screening assay. First, a library of targeted LC-MS/MS assays for metabolite biomarker candidates was developed, using a medium-throughput translational metabolomics workflow, to verify biomarker potential in the Screening-for-Pregnancy-Endpoints (SCOPE, European branch) study. A variable pre-selection step was followed by the development of multivariable prediction models for pre-defined clinical use cases, i.e., prediction of preterm preeclampsia risk and of any preeclampsia risk. Within a large set of metabolite biomarker candidates, we confirmed the potential of dilinoleoyl-glycerol and heptadecanoyl-2-hydroxy-sn-glycero-3-phosphocholine to effectively complement Placental Growth Factor, an established preeclampsia biomarker, for the prediction of preeclampsia risk in first-time pregnancies without overt risk factors. These metabolites will be considered for integration in a prototype rapid, quantitative LC-MS/MS assay, and subsequent validation in an independent cohort.

Lomitapide for treatment of homozygous familial hypercholesterolemia: The Québec experience.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (HoFH) is an orphan disease, most often caused by bi-allelic mutations of the LDLR gene. Patients with HoFH have elevated LDL-C levels >13 mmol/L, tendinous xanthomata and severe, premature atherosclerotic cardiovascular disease (ASCVD). Untreated, most HoFH patients die of ASCVD in youth. New therapeutic modalities include lomitapide, an inhibitor of microsomal triglyceride transfer protein that lowers hepatic LDL-C production. We have recently identified 79 Canadian patients with HoFH. Here, we describe our experience with lomitapide in the province of Quebec, a geographic area known to have a high prevalence of HoFH. METHODS: This is a retrospective case series of 12 HoFH patients followed at three lipidology centers in the province of Quebec. RESULTS: Mean age of the patients was 44 ± 18 years; age at time of HoFH diagnosis ranged from 2 to 59 years. All patients were on a statin and ezetimibe 10 mg/day and five patients were treated with LDL apheresis. Treatment with lomitapide reduced LDL-C levels by 38% (intention-to-treat). Intolerable gastrointestinal side effects were observed in 3/12 patients and were the main reason for treatment discontinuation. Three patients tolerated lomitapide at doses ranging between 5 and 30 mg/day without major side effects. Downwards drug titration was necessary in the 6 remaining patients because of gastrointestinal side effects (n = 5) and elevated liver enzymes (n = 1), and 2 of them finally discontinued treatment. CONCLUSIONS: Lomitapide may be used to further decrease LDL-C in HoFH patients; gastrointestinal side effects and hepatic toxicity may limit adherence.

Evaluating teen driving knowledge and behaviors following educational outreach.

BACKGROUND: Teen driving educational events are an effective strategy to increase adolescent drivers' awareness of safe driving practices. The objectives of this study were to evaluate changing rates of self-reported driving practices and knowledge of the state Graduated Driver Licensing laws (GDL) by teens over a nine-year period in a single state. METHODS: This was a prospective observational study of high school students ages 14 to 19 years old. Paper surveys were sent to the high schools participating in teen driving educational events (9 schools in 2009 and 4 schools in 2018). Students in those schools completed surveys prior to the events. Students completing the anonymous survey were invited to the event. Questions evaluated awareness of state GDL and safe and risky driving behaviors. Statistical comparisons of survey answers from 2009 to 2018 were analyzed using the z test of proportions (2 tailed, alpha 0.05). RESULTS: A total of 397 students participated in 2018 with ages ranging from 14 to 19 years. Racial distribution was 81% white, 14% black, and there were 57% female participants. Only 69% (n = 273) reported "always" wearing their seatbelt. When asked about high risk behaviors, 78% (n = 309) of adolescents reported they personally "never" text while driving; 97% (385); never drive after drinking, and 87% (n = 344) never ride with someone who has been drinking. Compared to 2009 participants (1304 students, 9 schools from central part of state), the students in 2018 (4 schools scattered across state) reported wearing seatbelts "always" (n = 69% vs 39%; p < 0.001); "never texting while driving" (78% vs 33%; p < 0.001); and "never drinking and driving" (97% vs 88%; p < 0.001). No significant difference in rates of students having taken a driving education class nor driving over speed limit were reported. CONCLUSION: Results are encouraging that participants in 2018 report more use of seatbelts, less texting while driving, less drinking while driving and lower numbers of being in MVC than in 2009. However, rates of high-risk driving behaviors are still concerning.

Impact of Seriphium plumosum densification on Mesic Highveld Grassland biodiversity in South Africa.

Mesic Highveld Grassland is important for biodiversity conservation, but is threatened by bush densification from Seriphium plumosum. This indigenous densifier spreads rapidly and outcompetes other herbaceous species, changing the species composition and structure of grasslands. This study looks at three different densities of S. plumosum and how these affect grassland biodiversity within Telperion, Mpumalanga, South Africa. An intermediate density of S. plumosum (1500 individuals (ind) ha-1) resulted in the highest plant species diversity (H = 2.26), a low density (24 ind ha-1) was moderately diverse (H = 1.96) and a high density (9500 ind ha-1) was least diverse (H = 1.78). There were differences between the three densities in terms of plant species diversity, with the intermediate density being significantly more diverse (p < 0.01) than both the low and high densities. Findings indicate that there was a significant difference between the sites in terms of ecological successional status (p < 0.01). The presence of S. plumosum at low densities can be considered an integral part of the environment. It is important that in areas where S. plumosum occurs, it should be monitored. If this species is not in balance within its environment and it starts becoming dense, it will negatively affect the biodiversity, species composition and structure of the habitat.

Climate induced stress and mortality in vervet monkeys.

As the effects of global climate change become more apparent, animal species will become increasingly affected by extreme climate and its effect on the environment. There is a pressing need to understand animal physiological and behavioural responses to climatic stressors. We used the reactive scope model as a framework to investigate the influence of drought conditions on vervet monkey (Chlorocebus pygerythrus) behaviour, physiological stress and survival across 2.5 years in South Africa. Data were collected on climatic, environmental and behavioural variables and physiological stress via faecal glucocorticoid metabolites (fGCMs). There was a meaningful interaction between water availability and resource abundance: when food availability was high but standing water was unavailable, fGCM concentrations were higher compared to when food was abundant and water was available. Vervet monkeys adapted their behaviour during a drought period by spending a greater proportion of time resting at the expense of feeding, moving and social behaviour. As food availability decreased, vervet mortality increased. Peak mortality occurred when food availability was at its lowest and there was no standing water. A survival analysis revealed that higher fGCM concentrations were associated with an increased probability of mortality. Our results suggest that with continued climate change, the increasing prevalence of drought will negatively affect vervet abundance and distribution in our population. Our study contributes to knowledge of the limits and scope of behavioural and physiological plasticity among vervet monkeys in the face of rapid environmental change.

Home range utilization by chacma baboon (Papio ursinus) troops on Suikerbosrand Nature Reserve, South Africa.

Rapid urbanization coupled with decreasing areas of natural habitat are causing baboon populations to become scattered and isolated, often resulting in increased levels of human-baboon conflict. To implement baboon-human conflict management strategies, it is essential to formulate realistic conservation policies that deal with all stakeholder concerns and ensure the conservation of viable baboon populations. A study was initiated in response to complaints of perceived excessive baboon numbers and associated lack of food resources on Suikerbosrand Nature Reserve in South Africa. Data obtained from GPS tracking collars fitted to one baboon from each of 10 identified troops were analyzed to determine home range size and utilization. The spatial representation of home ranges generated from this study will allow reserve management to identify areas of potential high and low human-baboon conflict and will contribute to the development of a formal baboon management plan to reduce human-baboon conflict on and around the reserve. Home ranges were unevenly distributed and had a mean size of 26.72 km2 ± 13.91 SD in the cold/dry season and 26.54 km2 ± 12.76 SD in the warm/wet season. Troop home ranges overlapped to some degree and five troops utilized areas outside the reserve. Although no significant relationship between troop size and home range was found, there was a positive relationship between troop size and daily distance travelled. All troops had significantly longer mean daily distances during the warm/wet season than during the cold/dry season (P ≤ 0.02).

Ionic Liquid-Liquid Chromatography: A New General Purpose Separation Methodology.

Ionic liquids can form biphasic solvent systems with many organic solvents and water, and these solvent systems can be used in liquid-liquid separations and countercurrent chromatography. The wide range of ionic liquids that can by synthesised, with specifically tailored properties, represents a new philosophy for the separation of organic, inorganic and bio-based materials. A customised countercurrent chromatograph has been designed and constructed specifically to allow the more viscous character of ionic liquid-based solvent systems to be used in a wide variety of separations (including transition metal salts, arenes, alkenes, alkanes, bio-oils and sugars).

Relative expression of the p75 neurotrophin receptor, tyrosine receptor kinase A, and insulin receptor in SH-SY5Y neuroblastoma cells and hippocampi from Alzheimer's disease patients.

We have previously shown in SH-SY5Y human neuroblastoma cells that the expressions of basal (75 kDa) and high molecular weight (HMW; 85 kDa) isoforms of the p75 neurotrophic receptor (p75NTR) are stimulated by amyloid-ß peptide1-42 oligomers (AßOs) via the insulin-like growth factor-1 receptor (IGF-1R). On the other hand, it is known that AßOs inhibit insulin receptor (IR) signaling. The purpose of the present study was to determine the involvement of IR signaling in the regulation of p75 neurotrophin receptor (p75NTR) protein isoform expression in cultured SH-SY5Y cells and in hippocampi from late-stage human Alzheimer's disease (AD) brains. Interestingly, insulin induced the expression of basal and HMW p75NTR isoforms in SH-SY5Y cells, suggesting the presence of cross-talk between the IR and IGF-1R for the regulation of p75NTR expression. Reducing IR signaling with an IR kinase inhibitor (AG 1024) or IR-targeted siRNAs increased HMW p75NTR expression and reduced tyrosine receptor kinase-A (Trk-A) expression as well as postsynaptic density protein 95 (PSD95) expression in SH-SY5Y cells. Both basal and HMW p75NTR isoforms were increased in the hippocampi of post-mortem late-stage human AD brains (relative to non-AD brains), and the protein expression of HMW p75NTR was negatively associated with Trk-A expression, PSD95 expression, and IR expression. Thus, increased p75NTR expression, specifically an increased p75NTR-to-Trk-A ratio, is likely to play a role in synaptic loss and neuronal cell death in late-stage AD. Collectively, these findings suggest that increased expression of the p75NTR due to IR signaling inhibition by AßOs might be involved in the pathology of AD.

Presence of a Prophage Determines Temperature-Dependent Capsule Production in Streptococcus pyogenes.

A hyaluronic acid capsule is a major virulence factor in the pathogenesis of Streptococcus pyogenes. It acts as an anti-phagocytic agent and adhesin to keratinocytes. The expression of the capsule is primarily regulated at the transcriptional level by the two-component regulatory system CovRS, in which CovR acts as a transcriptional repressor. The covRS genes are frequently mutated in many invasive strains, and a subset of the invasive CovRS mutants does not produce a detectable level of the capsule at 37 °C, but produces a significant amount of the capsule at sub-body temperatures. Here, we report that a prophage has a crucial role in this capsule thermoregulation. Passaging CovR-null strains showing capsule thermoregulation using a lab medium produced spontaneous mutants producing a significant amount of the capsule regardless of incubation temperature and this phenotypic change was caused by curing of a particular prophage. The lab strain HSC5 contains three prophages on the chromosome, and only ΦHSC5.3 was cured in all spontaneous mutants. This result indicates that the prophage ΦHSC5.3 plays a crucial role in capsule thermoregulation, most likely by repressing capsule production at 37 °C.