Diamino Allose Phosphates: Novel, Potent, and Highly Stable Toll-like Receptor 4 Agonists.

Most known synthetic toll-like receptor 4 (TLR4) agonists are carbohydrate-based lipid-A mimetics containing several fatty acyl chains, including a labile 3-O-acyl chain linked to the C-3 position of the non-reducing sugar known to undergo cleavage impacting stability and resulting in loss of activity. To overcome this inherent instability, we rationally designed a new class of chemically more stable synthetic TLR4 ligands that elicit robust innate and adaptive immune responses. This new class utilized a diamino allose phosphate (DAP) scaffold containing a nonhydrolyzable 3-amide bond instead of the classical 3-ester. Accordingly, the DAPs have significantly improved thermostability in aqueous formulations and potency relative to other known natural and synthetic TLR4 ligands. Furthermore, the DAP analogues function as potent vaccine adjuvants to enhance influenza-specific antibodies in mice and provide protection against lethal influenza virus challenges. This novel set of TLR4 ligands show promise as next-generation vaccine adjuvants and stand-alone immunomodulators.

Isolating the impact of antipsychotic medication on metabolic health: Secondary analysis of a randomized controlled trial of antipsychotic medication versus placebo in antipsychotic medication naïve first-episode psychosis (the STAGES study).

BACKGROUND: Cardiovascular and metabolic diseases are the leading contributors to the early mortality associated with psychotic disorders. To date, it has not been possible to disentangle the effect of medication and non-medication factors on the physical health of people with a first episode of psychosis (FEP). This study aimed to isolate the effects of antipsychotic medication on anthropometric measurements, fasting glucose and lipids. METHODS: This study utilized data from a triple-blind randomized placebo-controlled trial comparing two groups of antipsychotic-naïve young people with a FEP who were randomized to receive a second-generation antipsychotic medication (FEP-medication group) or placebo (FEP-placebo group) for 6 months. Twenty-seven control participants were also recruited. RESULTS: Eighty-one participants commenced the trial; 69.1% completed at least 3 months of the intervention and 33.3% completed the full 6 months. The FEP-placebo group gained a mean of 2.4 kg (±4.9) compared to 1.1 kg (±4.9) in the control participants (t = 0.76, p = .45). After controlling for multiple analyses, there was no difference in blood pressure, waist circumference or heart rate between the FEP-placebo group and controls. After 6 months, the FEP medication group had gained 4.1 kg (±4.5), higher than those receiving placebo but not statistically significant (t = 0.8, p = .44). There were no differences in fasting glucose or lipids between the FEP groups after 3 months. CONCLUSIONS: While limited by small numbers and high attrition, these findings indicate that some of the metabolic complications observed in psychotic disorders could be attributable to factors other than medication. This emphasizes the need to deliver physical health interventions early in the course of FEP.

Efficacy of synchronous telepsychology interventions for people with anxiety, depression, posttraumatic stress disorder, and adjustment disorder: A rapid evidence assessment.

Telepsychology holds promise as a treatment delivery method that may increase access to services as well as reduce barriers to treatment accessibility. The aim of this rapid evidence assessment was to assess the evidence for synchronous telepsychology interventions for 4 common mental health conditions (depression, anxiety, posttraumatic stress disorder, and adjustment disorder). Randomized controlled trials published between 2005 and 2016 that investigated synchronous telepsychology (i.e., telephone delivered, video teleconference delivered, or Internet delivered text based) were identified through literature searches. From an initial yield of 2,266 studies, 24 were included in the review. Ten studies investigated the effectiveness of telephone-delivered interventions, 11 investigated the effectiveness of video teleconference (VTC) interventions, 2 investigated Internet-delivered text-based interventions, and 2 were reviews of multiple telepsychology modalities. There was sufficient evidence to support VTC and telephone-delivered interventions for mental health conditions. The evidence for synchronous Internet-delivered text-based interventions was ranked as "unknown." Telephone-delivered and VTC-delivered psychological interventions provide a mode of treatment delivery that can potentially overcome barriers and increase access to psychological interventions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Dysregulation of Alveolar Macrophage PPARγ, NADPH Oxidases, and TGFß1 in Otherwise Healthy HIV-Infected Individuals.

Despite antiretroviral therapy (ART), respiratory infections increase mortality in individuals living with chronic human immunodeficiency virus (HIV) infection. In experimental and clinical studies of chronic HIV infection, alveolar macrophages (AMs) exhibit impaired phagocytosis and bacterial clearance. Peroxisome proliferator-activated receptor (PPAR)γ, NADPH oxidase (Nox) isoforms Nox1, Nox2, Nox4, and transforming growth factor-beta 1 (TGFß1) are critical mediators of AM oxidative stress and phagocytic dysfunction. Therefore, we hypothesized that HIV alters AM expression of these targets, resulting in chronic lung oxidative stress and subsequent immune dysfunction. A cross-sectional study of HIV-infected (n = 22) and HIV-uninfected (n = 6) subjects was conducted. Bronchoalveolar lavage (BAL) was performed, and AMs were isolated. Lung H2O2 generation was determined by measuring H2O2 in the BAL fluid. In AMs, PPARγ, Nox1, Nox2, Nox4, and TGFß1 mRNA (quantitative real-time polymerase chain reaction) and protein (fluorescent immunomicroscopy) levels were assessed. Compared with HIV-uninfected (control) subjects, HIV-infected subjects were relatively older and the majority were African American; ∼86% were on ART, and their median CD4 count was 445, with a median viral load of 0 log copies/ml. HIV infection was associated with increased H2O2 in the BAL, decreased AM mRNA and protein levels of PPARγ, and increased AM mRNA and protein levels of Nox1, Nox2, Nox4, and TGFß1. PPARγ attenuation and increases in Nox1, Nox2, Nox4, and TGFß1 contribute to AM oxidative stress and immune dysfunction in the AMs of otherwise healthy HIV-infected subjects. These findings provide novel insights into the molecular mechanisms by which HIV increases susceptibility to pulmonary infections.

Comparison of Glutathione, Cysteine, and Their Redox Potentials in the Plasma of Critically Ill and Healthy Children.

BACKGROUND: Oxidative stress is known to play a role in critical illness due to an imbalance in reactive oxygen species and reactive nitrogen species, and the body's ability to detoxify pro-oxidants using small molecule anti-oxidants and anti-oxidant enzymes. OBJECTIVE: To compare the concentrations of plasma redox metabolites and redox potentials for the Cys/CySS and GSH/GSSG thiol/disulfide pairs in critically ill children with healthy control children. METHODS: We performed a prospective clinical observational study of children ages ≤18 years and weight ≥6 kg, who were hospitalized between January 2010 and April 2012 in a 30-bed multidisciplinary medical-surgical pediatric intensive care unit (PICU). We measured the plasma concentrations of Cys, CySS, GSH, and GSSG within the first 24 h of PICU arrival, and we calculated the redox potential for the Cys/CySS (Eh Cys/CySS) and GSH/GSSG (Eh GSH/GSSG) thiol/disulfide pairs in the plasma of 61 critically ill children and 16 healthy control children. RESULTS: Critically ill children have less Cys (p = 0.009), less CySS (p = 0.011), less Total Cys ([Cys] + 2[CySS], p = 0.01), more GSSG (p < 0.001), and more oxidized Eh GSH/GSSG (p < 0.001) compared to healthy children. CONCLUSION: Our results demonstrate that in the presence of pediatric critical illness, the Total Cys/CySS thiol pool decreases while GSH is likely one component of the cellular redox system that reduces CySS back to Cys, thus maintaining Eh Cys/CySS. The Total Cys pool is more abundant than the Total GSH pool in the plasma of children. Further investigation is needed to elucidate the differences in redox potentials in subgroups of critically ill children, and to determine whether differences in redox metabolite concentrations and redox potentials correlate with severity of critical illness and clinical outcomes.

Exhaled breath condensate in intubated neonates--a window into the lung's glutathione status.

BACKGROUND: Analysis of exhaled breath condensates (EBC) is a non-invasive technique to evaluate biomarkers such as antioxidants in the pediatric population, but limited data exists of its use in intubated patients, particularly newborns. Currently, tracheal aspirate (TA) serves as the gold standard collection modality in critically ill newborns, but this method remains invasive. We tested the hypothesis that glutathione status would positively correlate between EBC and TA collections in intubated newborns in the Newborn Intensive Care Unit (NICU). We also hypothesized that these measurements would be associated with alveolar macrophage (AM) glutathione status in the newborn lung. METHODS: Reduced glutathione (rGSH), glutathione disulfide (GSSG), and total GSH (rGSH + (2 X GSSG)) were measured in sequential EBC and TA samples from 26 intubated newborns via high performance liquid chromatography (HPLC). Additionally, AM glutathione was evaluated via immunofluorescence. Pearson's correlation coefficient and associated 95% confidence intervals were used to quantify the associations between raw and urea-corrected concentrations in EBC and TA samples and AM staining. Statistical significance was defined as p ≤ 0.05 using two-tailed tests. The sample size was projected to allow for a correlation coefficient of 0.5, with 0.8 power and alpha of 0.05. RESULTS: EBC was obtainable from intubated newborns without adverse clinical events. EBC samples demonstrated moderate to strong positive correlations with TA samples in terms of rGSH, GSSG and total GSH. Positive correlations between the two sampling sites were observed in both raw and urea-corrected concentrations of rGSH, GSSG and total GSH. AM glutathione staining moderately correlated with GSSG and total GSH status in both the TA and EBC. CONCLUSIONS: GSH status in EBC samples of intubated newborns significantly correlated with the GSH status of the TA sample and was reflective of cellular GSH status in this cohort of neonatal patients. Non-invasive EBC sampling of intubated newborns holds promise for monitoring antioxidant status such as GSH in the premature lung. Further studies are necessary to evaluate the potential relationships between EBC biomarkers in the intubated premature newborn and respiratory morbidities.

In utero nicotine exposure promotes M2 activation in neonatal mouse alveolar macrophages.

BACKGROUND: Maternal smoking in utero has been associated with adverse health outcomes including lower respiratory tract infections in infants and children, but the mechanisms underlying these associations continue to be investigated. We hypothesized that nicotine plays a significant role in mediating the effects of maternal tobacco smoke on the function of the neonatal alveolar macrophage (AM), the resident immune cell in the neonatal lung. METHODS: Primary AMs were isolated at postnatal day 7 from a murine model of in utero nicotine exposure. The murine AM cell line MH-S was used for additional in vitro studies. RESULTS: In utero nicotine increased interleukin-13 and transforming growth factor-ß1 (TGFß1) in the neonatal lung. Nicotine-exposed AMs demonstrated increased TGFß1 and increased markers of alternative activation with diminished phagocytic function. However, AMs from mice deficient in the α7 nicotinic acetylcholine receptor (α7 nAChR) had less TGFß1, reduced alternative activation, and improved phagocytic functioning despite similar in utero nicotine exposure. CONCLUSION: In utero nicotine exposure, mediated in part via the α7 nAChR, may increase the risk of lower respiratory tract infections in neonates by changing the resting state of AM toward alternative activation. These findings have important implications for immune responses in the nicotine-exposed neonatal lung.

Characterisation of the prodrome to a first episode of psychotic mania: results of a retrospective study.

BACKGROUND: Little is known about the early phases of bipolar disorders (BPAD) and most of current knowledge derives from putative "high-risk" studies conducted in populations of bipolar off-spring; such information may therefore be relevant only to a sub-group of at-risk subjects. METHODS: Retrospective assessment of the phase preceding the emergence of mania and of premorbid characteristics of patients treated for a first episode of psychotic mania. The collected data was used mainly to generate hypotheses. RESULTS: Before onset of a first episode of psychotic mania, patients go through a phase of change from previous mental state where they present mood symptoms, sleep disruption and general functional decline. These clinical manifestations are however likely to have low specificity. However, their occurrence in patients presenting certain risk factors or markers of vulnerability that were identified at a relatively high prevalence in our sample, may be an indicator of impending first episode mania. LIMITATIONS: This is a retrospective study, in a small sample of patients presenting with psychotic mania. Criteria identified need therefore to be validated in larger prospective studies. CONCLUSIONS: Early identification of patients at risk to develop a first episode of psychotic mania is unlikely to be possible on the basis of symptoms alone. However, the occurrence of certain clinical characteristics in patients who have risk factors or markers of vulnerability to BPAD could be a sign of impending first episode mania.

The proximal prodrome to first episode mania--a new target for early intervention.

OBJECTIVE: Affective psychoses and bipolar disorders have been neglected in the development of early intervention strategies. This paper aims to gather current knowledge on the early phase of bipolar disorders in order to define new targets for early intervention. METHODS: Literature review based on the main computerized databases (MEDLINE, PUBMED and PSYCHLIT) and hand search of relevant literature. RESULTS: Based on current knowledge, it is likely that an approach aiming at the identification of impending first-episode mania is the most realistic and manageable strategy to promote earlier treatment. During the period preceding the onset of the first manic episode, patients go through a prodromal phase marked by the presence of mood fluctuation, sleep disturbance, and other symptoms such as irritability, anger, or functional impairment. Additionally, various risk factors and markers of vulnerability to bipolar disorders have been identified. CONCLUSIONS: In the few months preceding first-episode mania, patients go through a prodrome phase (proximal prodrome) that could become an important target for early intervention. However, considering the low specificity of the symptoms observed during this phase, criteria defining high-risk profiles to first-episode mania should also include certain risk factors or markers of vulnerability. While more research is needed in high-risk groups (e.g., bipolar offspring), retrospective studies conducted in first-episode mania cohorts could provide valuable information about this critical phase of the illness.

Medium term follow-up of a randomized controlled trial of interventions for young people at ultra high risk of psychosis.

Valid criteria to identify young people who are believed to be at ultra high risk (UHR) of developing a psychotic episode were developed over the last decade. The first randomized controlled trial of treatment in a UHR cohort indicated that specific pharmacotherapy and psychotherapy delayed onset of disorder, and possibly reduced incidence. This paper reports results of follow-up of that trial. 41 of the 59 (69.5%) participants in the original study agreed to follow-up. No differences were found in transition rate, level of symptomatology or functioning between participants who received a combination of psychological treatment and anti-psychotic medication compared to those who received supportive therapy alone. A significant proportion of both treatment groups reported moderate levels of psychiatric morbidity and a continuing need and desire for care at this follow-up. Low levels of hospitalisation were noted for those who did progress to psychosis. Conclusions that can be drawn from this exploratory study are limited by the relatively small number of participants in the original study and the failure to follow-up the entire cohort. Although participants may have been treated too briefly to result in enduring positive effects, there appear to have been some cost savings in inpatient mental health treatment required after the end of the trial for individuals in both treatment groups who developed psychosis.

The initial prodrome to bipolar affective disorder: prospective case studies.

BACKGROUND: The initial prodrome to bipolar disorder has received very little attention to date, with most of the available data only addressing the prodrome to relapse. This study presents several prospective case studies of the initial prodrome to bipolar affective disorder. METHODS: Three patients are presented who developed bipolar disorder during their treatment at the Personal Assessment and Crisis Evaluation Clinic (PACE). They were prospectively interviewed over a 12-month period using standard clinical research interviews. RESULTS: These patients met the criteria for bipolar disorder by the end of the treatment period. Depressive symptoms were the main reason for their first clinical presentation, with mania developing at a later date. Other comorbidities were observed before they were diagnosed with bipolar disorder. LIMITATIONS: The generalisability of our findings was constrained because of the small sample size. Furthermore, our findings are likely to be influenced by the intake criteria used at PACE, a clinic that primarily aims at identifying patients at risk of psychosis rather than bipolar disorder. CONCLUSION: Our study provides information about the initial prodrome to bipolar disorder, which has previously been neglected in research studies. We found there were no prodrome features that clearly distinguished between patients who go on to develop bipolar disorder and those who develop schizophrenia. We hope our prospective data will be the starting point for subsequent studies, with the aim of applying these findings to developing suitable preventative interventions for bipolar disorder.