Experimental studies of paranoid thinking in clinical and nonclinical populations: a systematic review and meta-analysis.

Paranoia is common in clinical and nonclinical populations, consistent with continuum models of psychosis. A number of experimental studies have been conducted that attempt to induce, manipulate or measure paranoid thinking in both clinical and nonclinical populations, which is important to understand causal mechanisms and advance psychological interventions. Our aim was to conduct a systematic review and meta-analysis of experimental studies (non-sleep, non-drug paradigms) on psychometrically assessed paranoia in clinical and nonclinical populations. The review was conducted using PRISMA guidelines. Six databases (PsycINFO, PubMed, EMBASE, Web of Science, Medline and AMED) were searched for peer-reviewed experimental studies using within and between-subject designs to investigate paranoia in clinical and nonclinical populations. Effect sizes for each study were calculated using Hedge's g and were integrated using a random effect meta-analysis model. Thirty studies were included in the review (total n = 3898), which used 13 experimental paradigms to induce paranoia; 10 studies set out to explicitly induce paranoia, and 20 studies induced a range of other states. Effect sizes for individual studies ranged from 0.03 to 1.55. Meta-analysis found a significant summary effect of 0.51 [95% confidence interval 0.37-0.66, p < 0.001], indicating a medium effect of experimental paradigms on paranoia. Paranoia can be induced and investigated using a wide range of experimental paradigms, which can inform decision-making about which paradigms to use in future studies, and is consistent with cognitive, continuum and evolutionary models of paranoia.

Canine and feline P-glycoprotein deficiency: What we know and where we need to go.

In 2001 the molecular genetic basis of so-called "ivermectin sensitivity" in herding breed dogs was determined to be a P-glycoprotein deficiency caused by a genetic variant of the MDR1 (ABCB1) gene often called "the MDR1 mutation." We have learned a great deal about P-glycoprotein's role in drug disposition since that discovery, namely that P-glycoprotein transports many more drugs than just macrocyclic lactones that P-glycoprotein mediated drug transport is present in more places than just the blood brain barrier, that some cats have a genetic variant of MDR1 that results in P-glycoprotein deficiency, that P-glycoprotein dysfunction can occur as a result of drug-drug interactions in any dog or cat, and that the concept of P-glycoprotein "inhibitors" versus P-glycoprotein substrates is somewhat arbitrary and artificial. This paper will review these discoveries and discuss how they impact drug selection and dosing in dogs and cats with genetically mediated P-glycoprotein deficiency or P-glycoprotein dysfunction resulting from drug-drug interactions.

Facilitators and Barriers to the Implementation of a School-Based Intervention for Anxiety.

School-based cognitive behavioural interventions for anxiety are found to be effective, but there is a lack of research on their implementation in real world settings. The current study aims to explore the facilitators and barriers to the implementation of a school-based intervention for anxiety through a qualitative process evaluation. Evaluation of the implementation of Let's Introduce Anxiety Management (LIAM), a six-session school-based cognitive behavioural intervention, was conducted. LIAM was implemented by non-mental health professionals trained and coached on the model. Semi-structured interviews with stakeholders (N = 15) were analysed with grounded theory and framework analysis. Forty-one practitioners were trained and coached on LIAM, with thirty-five children and young people receiving the intervention. Facilitators (e.g. systemic collaboration, self-efficacy and an enabling context) and barriers (e.g. the exclusivity of the intervention and a lack of systemic understanding) to implementation emerged as themes. Implementing school-based interventions is complex and requires the involvement of multiple stakeholders.

Dystrophin and mini-dystrophin quantification by mass spectrometry in skeletal muscle for gene therapy development in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disorder caused by mutations in the DMD gene, leading to severe reduction or absence of the protein dystrophin. Gene therapy strategies that aim to increase expression of a functional dystrophin protein (mini-dystrophin) are under investigation. The ability to accurately quantify dystrophin/mini-dystrophin is essential in assessing the level of gene transduction. We demonstrated the validation and application of a novel peptide immunoaffinity liquid chromatography-tandem mass spectrometry (IA-LC-MS/MS) assay. Data showed that dystrophin expression in Becker muscular dystrophy and DMD tissues, normalized against the mean of non-dystrophic control tissues (n = 20), was 4-84.5% (mean 32%, n = 20) and 0.4-24.1% (mean 5%, n = 20), respectively. In a DMD rat model, biceps femoris tissue from dystrophin-deficient rats treated with AAV9.hCK.Hopti-Dys3978.spA, an adeno-associated virus vector containing a mini-dystrophin transgene, showed a dose-dependent increase in mini-dystrophin expression at 6 months post-dose, exceeding wildtype dystrophin levels at high doses. Validation data showed that inter- and intra-assay precision were ≤20% (≤25% at the lower limit of quantification [LLOQ]) and inter- and intra-run relative error was within ±20% (±25% at LLOQ). IA-LC-MS/MS accurately quantifies dystrophin/mini-dystrophin in human and preclinical species with sufficient sensitivity for immediate application in preclinical/clinical trials.

PDE10A Inhibition Reduces the Manifestation of Pathology in DMD Zebrafish and Represses the Genetic Modifier PITPNA.

Duchenne muscular dystrophy (DMD) is a severe genetic disorder caused by mutations in the DMD gene. Absence of dystrophin protein leads to progressive degradation of skeletal and cardiac function and leads to premature death. Over the years, zebrafish have been increasingly used for studying DMD and are a powerful tool for drug discovery and therapeutic development. In our study, a birefringence screening assay led to identification of phosphodiesterase 10A (PDE10A) inhibitors that reduced the manifestation of dystrophic muscle phenotype in dystrophin-deficient sapje-like zebrafish larvae. PDE10A has been validated as a therapeutic target by pde10a morpholino-mediated reduction in muscle pathology and improvement in locomotion, muscle, and vascular function as well as long-term survival in sapje-like larvae. PDE10A inhibition in zebrafish and DMD patient-derived myoblasts were also associated with reduction of PITPNA expression that has been previously identified as a protective genetic modifier in two exceptional dystrophin-deficient golden retriever muscular dystrophy (GRMD) dogs that escaped the dystrophic phenotype. The combination of a phenotypic assay and relevant functional assessments in the sapje-like zebrafish enhances the potential for the prospective discovery of DMD therapeutics. Indeed, our results suggest a new application for a PDE10A inhibitor as a potential DMD therapeutic to be investigated in a mouse model of DMD.

A novel transdermal ketoprofen formulation for analgesia in cattle.

Ketoprofen is registered in many countries for injectable administration in cattle. Because it is soluble in a wide range of excipients, development of a novel transdermal (TD) ketoprofen formulation was pursued to provide a convenient and pain-free route of administration in cattle. One hundred and six excipient combinations were screened using in vitro techniques (Franz diffusion cells), with a 20%(w/v) ketoprofen formulation dissolved in a combination of 45%:45%(v/v) ethanol and isopropyl myristate (IPM) and 10%(v/v) eucalyptus oil achieving maximal penetration of ketoprofen through bovine skin. A bioavailability study was then conducted using a randomized cross-over design (n = 12), including IV, IM (both 3 mg/kg) and TD (10 mg/kg) ketoprofen formulations administered with a one-week washout period between administrations. The IV and IM formulation pharmacokinetic results were as expected. The CMAX , Tmax and AUC0-Last were significantly higher (arithmetic mean ± SD) after TD administration (20.0 ± 6.5 µg/ml, 115 ± 17 min and 3940 ± 1324 µg*min/ml, respectively), compared to IM (11.0 ± 4.0 µg/ml, 74 ± 43 min and 2376 ± 738 µg*min/ml, respectively), although there were no significant differences for T½ß . However, dose corrected values CMAX and AUCinf were significantly higher for IM compared to TD. The arithmetic mean bioavailability (F) of the transdermal formulation was 50%. The plasma concentration of the TD formulation at a dose of 10 mg/kg was similar to the IM formulation at 3 mg/kg by 30 min post-dosing with an arithmetic mean ± SD of 7.97 ± 4.38 vs. 8.02 ± 3.55 µg/ml, respectively. The TD formulation was generally well tolerated by cattle, although some local irritation along the site of application was noted after 12 h of exposure during the bioavailability study. Results indicate that this novel TD formulation provides a substantial improvement in administration convenience, may improve animal welfare and end-user safety through needle-free administration, and achieves similar plasma pharmacokinetics to the IM product when administered at 10 mg/kg.

Myostatin inhibition promotes fast fibre hypertrophy but causes loss of AMP-activated protein kinase signalling and poor exercise tolerance in a model of limb-girdle muscular dystrophy R1/2A.

KEY POINTS: Limb-girdle muscular dystrophy R1 (LGMD R1) is caused by mutations in the CAPN3 gene and is characterized by progressive muscle loss, impaired mitochondrial function and reductions in the slow oxidative gene expression programme. Myostatin is a negative regulator of muscle growth, and its inhibition improves the phenotype in several muscle wasting disorders. The effect of genetic and pharmacological inhibition of myostatin signalling on the disease phenotype in a mouse model of LGMD R1 (CAPN3 knockout mouse-C3KO) was studied. Inhibition of myostatin signalling in C3KO muscles resulted in significant muscle hypertrophy; however, there were no improvements in muscle strength and exacerbation of exercise intolerance concomitant with further reduction of muscle oxidative capacity was observed. Inhibition of myostatin signalling is unlikely to be a valid therapeutic strategy for LGMD R1. ABSTRACT: Limb-girdle muscular dystrophy R1 (LGMD R1) is caused by mutations in the CAPN3 gene and is characterized by progressive muscle loss, impaired mitochondrial function and reductions in the slow oxidative gene expression programme. There are currently no therapies available to patients. We sought to determine if induction of muscle growth, through myostatin inhibition, represents a viable therapeutic strategy for this disease. Myostatin is a negative regulator of muscle growth, and its inhibition improves the phenotype in several muscle wasting disorders. However, the effect of myostatin depends on the genetic and pathophysiological context and may not be efficacious in all contexts. We found that genetic inhibition of myostatin through overexpression of follistatin (an endogenous inhibitor of myostatin) in our LGMD R1 model (C3KO) resulted in 1.5- to 2-fold increase of muscle mass for the majority of limb muscles. However, muscle strength was not improved and exercise intolerance was exacerbated. Pharmacological inhibition of myostatin, using an anti-myostatin antibody, resulted in statistically significant increases in muscle mass; however, functional testing did not reveal changes in muscle strength nor endurance in treated C3KO mice. Histochemical and biochemical evaluation of follistatin overexpressing mice revealed a reduction in the percentage of oxidative fibres and decreased activation of AMP-activated protein kinase signalling in transgenics compared to C3KO muscles. Our data suggest that muscle hypertrophy, induced by myostatin inhibition, leads to loss of oxidative capacity, which further compromises metabolically impaired C3KO muscles and thus is unlikely to be a valid strategy for treatment of LGMD R1.

Myostatin inhibition using mRK35 produces skeletal muscle growth and tubular aggregate formation in wild type and TgACTA1D286G nemaline myopathy mice.

Nemaline myopathy (NM) is a heterogeneous congenital skeletal muscle disease with cytoplasmic rod-like structures (nemaline bodies) in muscle tissue. While weakness in NM is related to contractile abnormalities, myofiber smallness is an additional abnormality in NM that may be treatable. We evaluated the effects of mRK35 (a myostatin inhibitor developed by Pfizer) treatment in the TgACTA1D286G mouse model of NM. mRK35 induced skeletal muscle growth that led to significant increases in animal bodyweight, forelimb grip strength and muscle fiber force, although it should be noted that animal weight and forelimb grip strength in untreated TgACTA1D286G mice was not different from controls. Treatment was also associated with an increase in the number of tubular aggregates found in skeletal muscle. These findings suggest that myostatin inhibition may be useful in promoting muscle growth and strength in Acta1-mutant muscle, while also further establishing the relationship between low levels of myostatin and tubular aggregate formation.

In vitro efficacy of cefovecin against anaerobic bacteria isolated from subgingival plaque of dogs and cats with periodontal disease.

Periodontal disease is a common disease of dogs and cats often requiring antimicrobial treatment as an adjunct to mechanical debridement. However, correct compliance with oral antimicrobial therapy in companion animals is often difficult. Cefovecin is a recently introduced veterinary cephalosporin that has demonstrated prolonged concentrations in extracellular fluid, allowing for dosing intervals of up to 14 days. Subgingival samples were collected from the oral cavity of 29 dogs and eight cats exhibiting grade 2 or grade 3 periodontal disease. Samples were cultivated on Wilkin Chalgrens agar and incubated in an anaerobic chamber for seven days. Selected anaerobic bacteria were isolated and identified to species level using 16S rRNA gene sequence analysis. Minimum inhibitory concentrations were determined for cefovecin and six additional antimicrobials using the agar dilution methodology recommended by the Clinical and Laboratory Standards Institute. The 65 clinical isolates were identified as Porphyromonas gulae (n = 45), Porphyromonas crevioricanis (n = 12), Porphyromonas macacae (n = 1), Porphyromonas cangingivalis (n = 1) Fusobacterium nucleatum (n = 2), Fusobacterium russii (n = 1) and Solobacterium moorei (n = 3). This is the first report of S. moorei being isolated from companion animals with periodontal disease. All isolates were highly susceptible to cefovecin, with a MIC90 of ≤0.125 µg/ml. Conversely, different resistance rates to ampicillin, amoxicillin and erythromycin between isolates were detected. Cefovecin is thus shown to be effective in vitro against anaerobic bacteria isolated from dogs and cats with periodontal disease.

Evaluation of an AAV9-mini-dystrophin gene therapy candidate in a rat model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by loss-of-function mutations in the dystrophin gene and is characterized by muscle wasting and early mortality. Adeno-associated virus-mediated gene therapy is being investigated as a treatment for DMD. In the nonclinical study documented here, we determined the effective dose of fordadistrogene movaparvovec, a clinical candidate adeno-associated virus serotype 9 vector carrying a human mini-dystrophin transgene, after single intravenous injection in a dystrophin-deficient (DMDmdx) rat model of DMD. Overall, we found that transduction efficiency, number of muscle fibers expressing the human mini-dystrophin polypeptide, improvement of the skeletal and cardiac muscle tissue architecture, correction of muscle strength and fatigability, and improvement of diastolic and systolic cardiac function were directly correlated with the amount of vector administered. The effective dose was then tested in older DMDmdx rats with a more dystrophic phenotype similar to the pathology observed in older patients with DMD. Except for a less complete rescue of muscle function in the oldest cohort, fordadistrogene movaparvovec was also found to be therapeutically effective in older DMDmdx rats, suggesting that this product may be appropriate for evaluation in patients with DMD at all stages of disease.

Osteogenic effects of a potent Src-over-Abl-selective kinase inhibitor in the mouse.

Src-null mice have higher bone mass because of decreased bone resorption and increased bone formation, whereas Abl-null mice are osteopenic, because of decreased bone formation. Compound I, a potent inhibitor of Src in an isolated enzyme assay (IC(50) 0.55 nM) and a Src-dependent cell growth assay, with lower activity on equivalent Abl-based assays, potently, but biphasically, accelerated differentiation of human mesenchymal stem cells to an osteoblast phenotype (1-10 nM). Compound I (≥0.1 nM) also activated osteoblasts and induced bone formation in isolated neonatal mouse calvariae. Compound I required higher concentrations (100 nM) to inhibit differentiation and activity of osteoclasts. Transcriptional profiling (TxP) of calvaria treated with 1 µM compound I revealed down-regulation of osteoclastic genes and up-regulation of matrix genes and genes associated with the osteoblast phenotype, confirming compound I's dual effects on bone resorption and formation. In addition, calvarial TxP implicated calcitonin-related polypeptide, ß (ß-CGRP) as a potential mediator of compound I's osteogenic effect. In vivo, compound I (1 mg/kg s.c.) increased vertebral trabecular bone volume 21% (microcomputed tomography) in intact female mice. Increased trabecular volume was also detected histologically in a separate bone, the femur, particularly in the secondary spongiosa (100% increase), which underwent a 171% increase in bone formation rate, a 73% increase in mineralizing surface, and a 59% increase in mineral apposition rate. Similar effects were observed in ovariectomized mice with established osteopenia. We conclude that the Src inhibitor compound I is osteogenic, presumably because of its potent stimulation of osteoblast differentiation and activation, possibly mediated by ß-CGRP.

CRISPR-mediated correction of skeletal muscle Ca2+ handling in a novel DMD patient-derived pluripotent stem cell model.

Mutations in the dystrophin gene cause the most common and currently incurable Duchenne muscular dystrophy (DMD) characterized by progressive muscle wasting. Although abnormal Ca2+ handling is a pathological feature of DMD, mechanisms underlying defective Ca2+ homeostasis remain unclear. Here we generate a novel DMD patient-derived pluripotent stem cell (PSC) model of skeletal muscle with an isogenic control using clustered regularly interspaced short palindromic repeat (CRISPR)-mediated precise gene correction. Transcriptome analysis identifies dysregulated gene sets in the absence of dystrophin, including genes involved in Ca2+ handling, excitation-contraction coupling and muscle contraction. Specifically, analysis of intracellular Ca2+ transients and mathematical modeling of Ca2+ dynamics reveal significantly reduced cytosolic Ca2+ clearance rates in DMD-PSC derived myotubes. Pharmacological assays demonstrate Ca2+ flux in myotubes is determined by both intracellular and extracellular sources. DMD-PSC derived myotubes display significantly reduced velocity of contractility. Compared with a non-isogenic wildtype PSC line, these pathophysiological defects could be rescued by CRISPR-mediated precise gene correction. Our study provides new insights into abnormal Ca2+ homeostasis in DMD and suggests that Ca2+ signaling pathways amenable to pharmacological modulation are potential therapeutic targets. Importantly, we have established a human physiology-relevant in vitro model enabling rapid pre-clinical testing of potential therapies for DMD.

DUX4 expression activates JNK and p38 MAP kinases in myoblasts.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by misexpression of the DUX4 transcription factor in skeletal muscle that results in transcriptional alterations, abnormal phenotypes and cell death. To gain insight into the kinetics of DUX4-induced stresses, we activated DUX4 expression in myoblasts and performed longitudinal RNA sequencing paired with proteomics and phosphoproteomics. This analysis revealed changes in cellular physiology upon DUX4 activation, including DNA damage and altered mRNA splicing. Phosphoproteomic analysis uncovered rapid widespread changes in protein phosphorylation following DUX4 induction, indicating that alterations in kinase signaling might play a role in DUX4-mediated stress and cell death. Indeed, we demonstrate that two stress-responsive MAP kinase pathways, JNK and p38, are activated in response to DUX4 expression. Inhibition of each of these pathways ameliorated DUX4-mediated cell death in myoblasts. These findings uncover that the JNK pathway is involved in DUX4-mediated cell death and provide additional insights into the role of the p38 pathway, a clinical target for the treatment of FSHD.

Distinct protein degradation profiles are induced by different disuse models of skeletal muscle atrophy.

Skeletal muscle atrophy can be a consequence of many diseases, environmental insults, inactivity, age, and injury. Atrophy is characterized by active degradation, removal of contractile proteins, and a reduction in muscle fiber size. Animal models have been extensively used to identify pathways that lead to atrophic conditions. We used genome-wide expression profiling analyses and quantitative PCR to identify the molecular changes that occur in two clinically relevant mouse models of muscle atrophy: hindlimb casting and Achilles tendon laceration (tenotomy). Gastrocnemius muscle samples were collected 2, 7, and 14 days after casting or injury. The total amount of muscle loss, as measured by wet weight and muscle fiber size, was equivalent between models on day 14, although tenotomy resulted in a more rapid induction of muscle atrophy. Furthermore, tenotomy resulted in the regulation of significantly more mRNA transcripts then did casting. Analysis of the regulated genes and pathways suggest that the mechanisms of atrophy are distinct between these models. The degradation following casting was ubiquitin-proteasome mediated, while degradation following tenotomy was lysosomal and matrix-metalloproteinase mediated, suggesting a possible role for autophagy. These data suggest that there are multiple mechanisms leading to muscle atrophy and that specific therapeutic agents may be necessary to combat atrophy resulting from different conditions.

p38 MAPKs - roles in skeletal muscle physiology, disease mechanisms, and as potential therapeutic targets.

p38 MAPKs play a central role in orchestrating the cellular response to stress and inflammation and in the regulation of myogenesis. Potent inhibitors of p38 MAPKs have been pursued as potential therapies for several disease indications due to their antiinflammatory properties, although none have been approved to date. Here, we provide a brief overview of p38 MAPKs, including their role in regulating myogenesis and their association with disease progression. Finally, we discuss targeting p38 MAPKs as a therapeutic approach for treating facioscapulohumeral muscular dystrophy and other muscular dystrophies by addressing multiple pathological mechanisms in skeletal muscle.

In vitro invasiveness and antimicrobial resistance of Salmonella enterica subspecies isolated from wild and captive reptiles.

Reptiles are carriers of Salmonella and can intermittently shed bacteria in their faeces. Contact with snakes and lizards is a source of human salmonellosis. Here, two populations of reptiles, wild and captive were surveyed for Salmonella. One hundred thirty wild-caught reptiles were sampled for Salmonella including 2 turtle, 9 snake and 31 lizard species. Fifty-two of 130 (40%) animals were Salmonella positive: one of 5 (20%) turtles, 7 of 14 (50%) snakes and 44 of 111 (39.6%) lizards. One hundred twenty-two reptiles were sampled from a zoo collection including 1 turtle, 6 tortoise, 9 lizard, 14 snake and 1 crocodile species. Forty-two of 122 (34.4%) captive reptiles sampled were Salmonella positive. Salmonella was most commonly isolated from lizards and snakes. Fifteen serotypes were identified from zoo and 19 from wild-caught reptiles and most were members of subspecies enterica (I), salamae (II), arizonae (IIIa) or diarizonae (IIIb). Antimicrobial susceptibility testing was conducted on all Salmonella isolates; only two exhibited resistance, a Salmonella subsp. (II) ser. 21:z10 :z6 (Wandsbek) isolate cultured from a wild-caught reptile and a Salmonella Typhimurium DT120 isolated from a captive snake. The invasive capacity of reptile-associated Salmonella strains into cultured human intestinal epithelial (Caco2) and mouse macrophages cell lines (J774A.1) was also investigated. All isolates were invasive into both cell lines. Significant (P ≤ 0.001) variability in invasiveness into polarized Caco2 cells was observed. Salmonella Eastbourne exhibited the highest invasiveness into Caco2 cells and Salmonella Chester the lowest, with mean per cent recoveries of 19.99 ± 0.32 and 1.23 ± 0.30, respectively. Invasion into J774A.1 macrophages was also variable but was not significant. Salmonella subsp. II ser. 17:g,t:- (Bleadon) exhibited the highest invasiveness into J774A.1 with a mean per cent recovery of 10.19 ± 0.19. Thus, reptile-associated Salmonellae are likely to have different capacities to cause disease in humans.

Are inflammatory and coagulation biomarkers related to sleep characteristics in mid-life women?: Study of Women's Health across the Nation sleep study.

STUDY OBJECTIVES: Inflammation and pro-coagulation biomarkers may be a link between sleep characteristics and risk for cardiometabolic disorders. We tested the hypothesis that worse sleep characteristics would be associated with C-reactive protein (CRP), fibrinogen, factor VIIc, and plasminogen activator inhibitor (PAI)-1 in a multi-ethnic subsample of mid-life women enrolled in the Study of Women's Health across the Nation. DESIGN: Cross-sectional. MEASUREMENTS AND RESULTS: African American, Chinese, and Caucasian women (N=340) participated in 3 days of in-home polysomnographic (PSG) monitoring and had measures of inflammation and coagulation. Regression analyses revealed that each of the biomarkers were associated with indicators of sleep disordered breathing after adjusting for age, duration between sleep study and blood draw, site, menopausal status, ethnicity, residualized body mass index, smoking status, and medications that affect sleep or biomarkers. Among African American women, those who had higher levels of CRP had shorter PSG-sleep duration and those who had higher levels of fibrinogen had less efficient sleep in multivariate models. CONCLUSIONS: These results suggest that inflammation and pro-coagulation processes may be an important pathway connecting sleep disordered breathing and cardiometabolic disorders in women of these ethnic groups and that inflammation may be a particularly important pathway in African Americans.

Serum glutamate dehydrogenase activity enables early detection of liver injury in subjects with underlying muscle impairments.

Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury. Since ALT and AST lack liver specificity, the diagnosis of the onset of hepatocellular injury in patients with underlying muscle impairments is severely limited. Thus, we evaluated the potential of glutamate dehydrogenase (GLDH) as a liver specific alternative biomarker of hepatocellular injury. In our study, serum GLDH in subjects with Duchene muscular dystrophy (DMD) was equivalent to serum GLDH in age matched healthy subjects, while serum ALT was increased 20-fold in DMD subjects. Furthermore, serum GLDH in 131 subjects with variety of muscle impairments was similar to serum GLDH of healthy subjects while serum ALT corelated with serum creatine kinase, a widely accepted biomarker of muscle impairment. In addition, significant elevations of ALT, AST, and CK were observed in a case of a patient with rhabdomyolysis, while serum GLDH stayed within the normal range until the onset of hypoxia-induced liver injury. In a mouse model of DMD (DMDmdx), serum GLDH but not serum ALT clearly correlated with the degree of acetaminophen-induced liver injury. Taken together, our data support the utility of serum GLDH as a liver-specific biomarker of liver injury that has a potential to improve diagnosis of hepatocellular injury in patients with underlying muscle impairments. In drug development, GLDH may have utility as a biomarker of drug induced liver injury in clinical trials of new therapies to treat muscle diseases such as DMD.

SURVEILLANCE FOR CHLAMYDIA SPP. WITH MULTILOCUS SEQUENCE TYPING ANALYSIS IN WILD AND CAPTIVE BIRDS IN VICTORIA, AUSTRALIA.

Chlamydia psittaci typically infects birds and can cause outbreaks of avian chlamydiosis, but it also has the potential to cause zoonotic disease (psittacosis) in humans. To better understand the epidemiology of C. psittaci in Victoria, Australia, we conducted opportunistic sampling of more than 400 wild and captive birds presented to the Australian Wildlife Health Centre at Zoos Victoria's Healesville Sanctuary for veterinary care between December 2014 and December 2015. Samples were screened for the presence of chlamydial DNA using quantitative PCR, and positive samples were subjected to multilocus sequence typing analysis. The results showed a significantly higher prevalence of infection in captive birds (8%; 9/113) compared to wild birds (0.7%; 2/299). Multilocus sequence typing analysis revealed that C. psittaci sequence type 24 was detected in both wild and captive birds in the local region, while C. psittaci sequence type 27 was detected for the first time in an Australian avian host. The generally low prevalence of C. psittaci detection points to a generally low zoonotic risk to veterinary and support staff, although this risk may be higher when handling captive birds, where the prevalence of C. psittaci infection was almost 10-fold higher. Even with low rates of C. psittaci detection, appropriate hygiene and biosecurity practices are recommended due to the serious human health implications of infection with this pathogen.

Race and financial strain are independent correlates of sleep in midlife women: the SWAN sleep study.

STUDY OBJECTIVES: To examine racial differences in sleep in a large cohort of midlife women and to evaluate whether indices of socioeconomic status (SES) are associated with racial differences in sleep. DESIGN: Cross-sectional study. SETTING: Participants' homes. PARTICIPANTS: Caucasian (n=171), African American (n=138) and Chinese women (n=59). INTERVENTIONS: None. MEASUREMENTS: Sleep quality was assessed with the Pittsburgh Sleep Quality Index. Polysomnographically assessed sleep duration, continuity, architecture, and NREM electroencephalograhic (EEG) power were calculated over multiple nights. Sleep disordered breathing and periodic leg movements were measured on a separate night. Linear regression analysis was used to model the independent and synergistic effects of race and SES on sleep after adjusting for other factors that impact sleep in midlife women. Indices of SES were self-reported educational attainment and financial strain. RESULTS: Sleep was worse in African American women than Caucasian participants as measured by self-report, visual sleep stage scoring, and NREM EEG power. Slow wave sleep differences were also observed between Chinese and Caucasian participants. Racial differences persisted after adjustment for indices of SES. Although educational attainment was unrelated to sleep, financial strain was associated with decreased sleep quality and lower sleep efficiency. Financial strain-by-race interactions were not statistically significant, suggesting that financial strain has additive effects on sleep, independent of race. CONCLUSIONS: Independent relationships between race and financial strain with sleep were observed despite statistical adjustment for other factors that might account for these relationships. Results do not suggest that assessed indices of SES moderate the race-sleep relationship, perhaps due to too few women of low SES in the study.