Comparison of Transcriptomic Changes in Survivors of Exertional Heat Illness with Malignant Hyperthermia Susceptible Patients.

Exertional heat illness (EHI) is an occupational health hazard for athletes and military personnel-characterised by the inability to thermoregulate during exercise. The ability to thermoregulate can be studied using a standardised heat tolerance test (HTT) developed by The Institute of Naval Medicine. In this study, we investigated whole blood gene expression (at baseline, 2 h post-HTT and 24 h post-HTT) in male subjects with either a history of EHI or known susceptibility to malignant hyperthermia (MHS): a pharmacogenetic condition with similar clinical phenotype. Compared to healthy controls at baseline, 291 genes were differentially expressed in the EHI cohort, with functional enrichment in inflammatory response genes (up to a four-fold increase). In contrast, the MHS cohort featured 1019 differentially expressed genes with significant down-regulation of genes associated with oxidative phosphorylation (OXPHOS). A number of differentially expressed genes in the inflammation and OXPHOS pathways overlapped between the EHI and MHS subjects, indicating a common underlying pathophysiology. Transcriptome profiles between subjects who passed and failed the HTT (based on whether they achieved a plateau in core temperature or not, respectively) were not discernable at baseline, and HTT was shown to elevate inflammatory response gene expression across all clinical phenotypes.

Prevalence of Metabolic Syndrome and Insulin Resistance in Adult Patients with Acne: Association with Traditional Cardiovascular Risk Factors and Acne Severity.

Introduction: Acne is a chronic inflammatory disease that affects the pilosebaceous unit, and there are conflicting evidences regarding its association with metabolic syndrome (MS) and insulin resistance (IR). Methods: A cross-sectional study was performed with 162 acne patients, over 20 years of age, matched for age and sex with 78 healthy controls without acne. The measured parameters included waist circumference (WC), body mass index (BMI), systolic blood pressure, diastolic blood pressure, fasting blood glucose, fasting insulin, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol. Acne severity was determined according to the Global Acne Grading System. The criteria used for the diagnosis of MS were those of the Harmonizing the Metabolic Syndrome Statement, adjusted for South Americans, and the IR was calculated using the HOMA-IR. Results: The prevalence of MS was significantly higher in cases, compared to controls (12.3% vs. 2.6%, P = 0.014), as was the prevalence of IR (11.7% vs. 3.8%, P = 0.047). In addition, MS and IR showed a positive correlation with the degree of acne severity (P = 0.011 and P = 0.021, respectively). HDL levels were significantly lower in cases (P = 0.012) and showed an association with acne severity (P = 0.038). In the logistic regression model, the risk factor that independently influenced both MS and IR in patients with acne was the WC (P = 0.001). Conclusions: Adults with acne, especially the most severe cases, are significantly more likely to have MS, IR, and lower HDL levels, compared to controls without acne.

Investigating the genetic susceptibility to exertional heat illness.

BACKGROUND: We aimed to identify rare (minor allele frequency ≤1%), potentially pathogenic non-synonymous variants in a well-characterised cohort with a clinical history of exertional heat illness (EHI) or exertional rhabdomyolysis (ER). The genetic link between malignant hyperthermia (MH) and EHI was investigated due to their phenotypic overlap. METHODS: The coding regions of 38 genes relating to skeletal muscle calcium homeostasis or exercise intolerance were sequenced in 64 patients (mostly military personnel) with a history of EHI, or ER and who were phenotyped using skeletal muscle in vitro contracture tests. We assessed the pathogenicity of variants using prevalence data, in silico analysis, phenotype and segregation evidence and by review of the literature. RESULTS: We found 51 non-polymorphic, potentially pathogenic variants in 20 genes in 38 patients. Our data indicate that RYR1 p.T3711M (previously shown to be likely pathogenic for MH susceptibility) and RYR1 p.I3253T are likely pathogenic for EHI. PYGM p.A193S was found in 3 patients with EHI, which is significantly greater than the control prevalence (p=0.000025). We report the second case of EHI in which a missense variant at CACNA1S p.R498 has been found. Combinations of rare variants in the same or different genes are implicated in EHI. CONCLUSION: We confirm a role of RYR1 in the heritability of EHI as well as ER but highlight the likely genetic heterogeneity of these complex conditions. We propose defects, or combinations of defects, in skeletal muscle calcium homeostasis, oxidative metabolism and membrane excitability are associated with EHI.

Thermoregulation and markers of muscle breakdown in malignant hyperthermia susceptible volunteers during an acute heat tolerance test.

OBJECTIVES: The study was undertaken to compare the thermal and biochemical responses to a heat tolerance test (HTT) of malignant hyperthermia (MH) susceptible individuals, volunteers who have suffered heat illness (HI) and control volunteers. METHODS: Three groups of male volunteers (n=6 in each group) were recruited to the study: MHS - civilian volunteers previously diagnosed as MH susceptible; EHI - military volunteers with a history of exertional HI; CON - military volunteers with no history of HI or MH. For the HTT, volunteers walked on a treadmill at 60% maximal oxygen uptake in a hot environment. Measurements were made of core and skin temperatures, heat flow, whole body sweat rate and serum lactate, creatine kinase and myoglobin concentrations. RESULTS: There were no differences in deep body temperature, oxygen uptake or serum lactate and creatine kinase concentrations between the three groups. One MHS volunteer and two EHI volunteers failed to achieve thermal balance with rectal temperature continuing to rise throughout the test and reaching 39.5°C, the rectal temperatures of the other volunteers plateaued at a mean (SD) of 38.7 (0.4)°C demonstrating thermal tolerance on this test. Serum myoglobin concentration and the increase in serum myoglobin was higher in MHS than EHI and CON Post HHT (P<0.05). CONCLUSION: MH susceptibility does not always predispose an individual to heat intolerance during an acute HTT, but does appear to increase muscle breakdown. The inclusion of serum myoglobin measurements to a HTT may help to distinguish patients that are potentially MHS, and who otherwise demonstrate thermal tolerance.

An evaluation of a collaborative course for child and adolescent mental health professionals.

There is a considerable gap between the offer and the demand for mental health treatment of children and adolescents, especially in low- and middle-income countries (LMICs). Permanent education in these countries is a promising and needed strategy to reduce this gap. This study was designed to evaluate the perceived impact of an educational intervention for child and adolescent mental health professionals in Brazil, the Child and Adolescent Mental Health Specialization Course (CESMIA). The intervention consisted of a 360-hour interprofessional postgraduation course. The CESMIA offered lectures and small-group case discussions for exchanging their experiences in dealing with the patients. The students were placed in these groups according to their professions in order to ensure a proportional distribution of healthcare professionals in each group. The evaluation employed a quasi-experimental design by the use of a knowledge, attitude, and practice (KAP) survey. The 39 participants reported significant improvement in all KAP dimensions. More specifically, the data indicated a 17% improvement for attitudes, a 9.4% increase for knowledge, and a 14% improvement for the practice dimensions. The CESMIA appeared to improve the level of knowledge of participants and their attitudes and actions towards patients, which reinforces the relevance of similar courses.

Data on inflammasome gene polymorphisms of patients with sporadic malignant melanoma in a Brazilian cohort.

This article presents data related to our another article entitled, Genotyping and differential expression analysis of inflammasome genes in sporadic malignant melanoma reveal novel contribution of CARD8, IL1B and IL18 in melanoma susceptibility and progression (W.C. Silva, T.M. Oshiro, D.C. Sá, D.D.G.S. Franco, C. Festa Neto, A. Pontillo, 2016) [2]. Data presented here refers to the distribution of selected inflammasome SNPs in a Brazilian case/control cohort. We have identified 4 inflammasome related Single Nucleotide Polymorphisms (SNPs) for CARD8 (rs6509365); IL1B (rs1143643) and IL18 (rs5744256 and rs1834481) related to melanoma susceptibility/protection. This data can serve as a potential prognostic marker in sporadic malignant melanoma.

Inflammasomes and dermatology.

Inflammasomes are intracellular multiprotein complexes that comprise part of the innate immune response. Since their definition, inflammasome disorders have been linked to an increasing number of diseases. Autoinflammatory diseases refer to disorders in which local factors lead to the activation of innate immune cells, causing tissue damage when in the absence of autoantigens and autoantibodies. Skin symptoms include the main features of monogenic inflammasomopathies, such as Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF), Schnitzler Syndrome, Hyper-IgD Syndrome (HIDS), PAPA Syndrome, and Deficiency of IL-1 Receptor Antagonist (DIRA). Concepts from other pathologies have also been reviewed in recent years, such as psoriasis, after the recognition of a combined contribution of innate and adaptive immunity in its pathogenesis. Inflammasomes are also involved in the response to various infections, malignancies, such as melanoma, autoimmune diseases, including vitiligo and lupus erythematosus, atopic and contact dermatitis, acne, hidradenitis suppurativa, among others. Inhibition of the inflammasome pathway may be a target for future therapies, as already occurs in the handling of CAPS, through the introduction of IL-1 inhibitors. This study presents a literature review focusing on the participation of inflammasomes in skin diseases.

Genotyping and differential expression analysis of inflammasome genes in sporadic malignant melanoma reveal novel contribution of CARD8, IL1B and IL18 in melanoma susceptibility and progression.

Sporadic melanoma malignancy is correlated with constitutive secretion of IL-1ß in transformed melanocytes suggesting the involvement of inflammasome in melanoma. Common variants in inflammasome genes are known to affect IL-1ß expression. To investigate the contribution of inflammasome genetics in melanoma development and progression and to identify a potential prognostic marker, the distribution of selected inflammasome SNPs was analysed in a Brazilian case/control cohort of sporadic malignant melanoma (SMM) and then the expression of inflammasome components was evaluated in melanoma biopsies. Allele and gene-specific Taqman assays were implied for genotyping of case/control DNA samples and for relative expression analysis in skin biopsies respectively. CARD8 rs6509365 was found to be significantly more common in healthy volunteers than in SMM patients suggesting a protection effect of this variant towards melanoma development. Accordingly, CARD8 expression was found to be reduced in nevus compared to melanoma biopsies. Upon stratification, NLRP1 rs11651270 and CARD8 rs2043211 were found associated with nodular melanoma; IL1B rs1143643 to a lower value of Breslow index; IL18 rs5744256 to melanoma development in sun sensitive individuals. As expected, IL1B expression was up-regulated in tumour biopsies especially in metastatic samples, whereas IL18 was down-regulated compared to nevus. Our results demonstrated for the first time the contribution of inflammasome genes CARD8, IL1B and IL18 in SMM.

Inflammasomes and dermatology

Abstract: Inflammasomes are intracellular multiprotein complexes that comprise part of the innate immune response. Since their definition, inflammasome disorders have been linked to an increasing number of diseases. Autoinflammatory diseases refer to disorders in which local factors lead to the activation of innate immune cells, causing tissue damage when in the absence of autoantigens and autoantibodies. Skin symptoms include the main features of monogenic inflammasomopathies, such as Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF), Schnitzler Syndrome, Hyper-IgD Syndrome (HIDS), PAPA Syndrome, and Deficiency of IL-1 Receptor Antagonist (DIRA). Concepts from other pathologies have also been reviewed in recent years, such as psoriasis, after the recognition of a combined contribution of innate and adaptive immunity in its pathogenesis. Inflammasomes are also involved in the response to various infections, malignancies, such as melanoma, autoimmune diseases, including vitiligo and lupus erythematosus, atopic and contact dermatitis, acne, hidradenitis suppurativa, among others. Inhibition of the inflammasome pathway may be a target for future therapies, as already occurs in the handling of CAPS, through the introduction of IL-1 inhibitors. This study presents a literature review focusing on the participation of inflammasomes in skin diseases.

Custo econômico e social do transtorno obsessivo-compulsivo e outros transtornos mentais na infância / Cost-effective programs of treatment of the childhood with mental disorders and obsessive-compulsive disorder

Os transtornos mentais na infância são prevalentes e causam prejuízo para o indivíduo, família e sociedade. Informações acerca do custo dos transtornos mentais na infância são úteis para o planejamento do sistema de saúde, para auxiliar tomadas de decisão de gestores acerca de investimentos na área e para determinação de prioridades no orçamento público. No entanto, não há dados sobre o custo dos transtornos mentais na infância no Brasil. Já dados sobre o custo dos transtornos mentais na infância em nível subclínico são inexistentes na literatura nacional e internacional. Os objetivos centrais da presente tese de doutorado, dividida em Estudo I e Estudo 11, foram: estimar a média do custo do transtorno mental na infância em níveis subclínico e clínico, e estimar o custo total destes para o Brasil. O Estudo I teve como desfecho clínico qualquer diagnóstico de transtorno mental na infância; o Estudo 11, o transtorno obsessivo- compulsivo na infância (TOC), ambos em nível subclínico e clínico. A presente pesquisa é uma avaliação econômica de custo de doença de transtornos mentais na infância com utilização de método bottom-up retrospectivo. Foi baseada em dados de prevalência de um estudo populacional transversal de 2.512 estudantes de escolas públicas de Porto Alegre e São Paulo, selecionados por meio de duas técnicas: a) seleção aleatória de crianças e b) seleção de crianças com alto fiSCO para desenvolvimento de transtornos mentais (baseado no histórico psiquiátrico familiar). Para avaliação de transtornos mentais na infância, foi utilizado o instrumento Development and Well Being Assesment (DAWBA). Os custos de doença foram estimados a partir dos seguintes componentes: tratamentos em saúde mental (uso de medicamentos, psicoterapia, hospitalização), uso de serviços sociais (assistência social, conselho tutelar, medidas socioeducativas) e problemas escolares (suspensão, abandono e repetência escolar). A amostra final foi de 2.512 crianças, de 6-14 anos de...

Child mental disorders are prevalent and impairing, negatively impacting families and society. lnformation on child mental disorders costs is important to plan the health system and to show policy makers how plan and prioritize budgets. However, there are no child mental disorders cost studies in Brazil. The main objectives of the present thesis were to estimate the mean costs of subthreshold and clinical mental disorders in children living in Brazil and to estimate its national costs. Outcome of Study I was any child mental disorder, outcome of Study II was child obsessive-compulsive disorder (OCD), both subthreshold and clinical. The present study it is cost-of-illness study of child mental disorders using a retrospective bottom-up methods, based on prevalence data from a cross-sectional study of children registered at public schools in Porto Alegre and Sao Paulo. A total of 8,012 families were interviewed, providing information about 9,937 children. From this pool, two subgroups were further investigated using random- selection (n=958) and high-risk group selection procedure (n=I,514), resulting in a total sample of 2,512 subjects 6-14 years old. Mental disorder assessment was made using the Development and Well-Being Assessment (DAWBA). The cost of child mental disorders was estimated from the following components: use of mental health services, social services and school problems. Costs were estimated for each child and the economic impact at the national levei was calculated. Study I results: subthreshold and clinical disorder showed lifetime mean total cost of $1,750.86 and $3,141.21, respectively. The national lifetime cost estimate of clinical mental disorders in Brazil was $11.65 billion, whereas for subthreshold mental disorder it was $19.92 billion (alI values in PPP, purchasing power parity). Study 11: subthreshold and clínical OCD showed lifetime mean total cost of $1,651.81 and $3,293.38, respectively. The national lifetime cost estimate of...

Rebreather Unit to Prolong Underwater Survival Time.

INTRODUCTION: This study investigated whether the timing of activation affects the utility of an emergency underwater rebreather unit (RBU) when submerged in cold water. METHOD: On two successive occasions, 16 male UK Royal Marines were submerged in stirred water at 12.2°C for up to 78 s. The subjects were lowered (taking 18 s) into the water in a seated position and were instructed to take a large breath in, activate the unit, breath-hold for as long as possible, exhale into the unit, and breathe normally to and from the unit for the remainder of submersion. On one occasion the subjects were instructed to activate the RBU when the water reached chest height (Condition-1) and, on the other, prior to the feet entering the water (Condition-2). Measurements were made of the duration of breath-hold, rebreathing and submersion, exhaled oxygen and carbon dioxide concentrations, skin temperature, and heart rate. RESULTS: In 16 of the 32 submersions, the breath-hold was released before the subject became fully submerged and in 8 submersions the subject requested early withdrawal from the water. Mean (SD) breath-hold duration was 14.0 (13.8) s and the duration of rebreathing was 45.9 (21.9) s. The duration of breath-hold once completely submerged was longer in Condition-1 (9.1 s) than Condition-2 (4.1 s). CONCLUSIONS: The study indicates the RBU should be activated just before the mouth becomes submerged rather than before entering the water, and that the RBU will prolong underwater stay time, thereby increasing survival prospects. House CM, Shaw AM, Roiz de Sa DG. Rebreather unit to prolong underwater stay time, thereby increasing survival prospects.

Temporal trends in infective endocarditis epidemiology from 2007 to 2013 in Olmsted County, MN.

BACKGROUND: The aim of this study is to determine if there have been contemporary shifts in infective endocarditis (IE) epidemiology in our local population; an analysis of cases from 2007 to 2013 was conducted. METHODS: This is a population-based review of all adults (≥18 years) residing in Olmsted County, MN, with definite or possible IE using the Rochester Epidemiology Project from January 1, 2007, to December 31, 2013. RESULTS: We identified 51 cases of IE in Olmsted County, MN, between 2007 and 2013. Median age of IE cases was 68.8 years (interquartile range 55.6-76.5), and 41% were females. Age- and sex-adjusted incidence of IE was 7.4 (95% CI 5.3-9.4) cases per 100,000 person-years. From a multivariable Poisson regression model, incidence of IE did not change significantly during the study period (P = .222) but was significantly higher in males and those of older age (P < .001). The annual incidences (per 100,000 person-years) were 2.5 for Staphylococcus aureus, 1.1 for viridans group streptococci, 1.6 for Enterococcus species, and 0.8 for coagulase-negative staphylococci. Only 19.6% (10/51) of Olmsted County patients underwent valve surgery between 2007 and 2013 as compared with 44.4% (197/444) of non-Olmsted County patients treated at Mayo Clinic Rochester. CONCLUSION: In this population-based study, no significant change in the overall incidence of IE in Olmsted County, MN, between 2007 and 2013 was seen, and it was similar to that seen between 1970 and 2006. Male gender and older age were associated with increased IE risk. With a lesser extent of cases attributable to viridans group streptococcal IE compared with previous years, S aureus was the predominant pathogen in IE cases during 2007 to 2013. The relatively low valve surgery rate was disparate from that reported from large, tertiary care centers (including our own) with non-population-based cohorts, which are subject to referral bias and can influence the expected characterization of IE.

Incidence of Infective Endocarditis Due to Viridans Group Streptococci Before and After the 2007 American Heart Association's Prevention Guidelines: An Extended Evaluation of the Olmsted County, Minnesota, Population and Nationwide Inpatient Sample.

OBJECTIVE: To determine whether the incidence of infective endocarditis (IE) due to viridans group streptococci (VGS) increased after the publication of the 2007 American Heart Association (AHA) IE prevention guidelines. PATIENTS AND METHODS: We performed a population-based survey of all adults (18 years and older) residing in Olmsted County, Minnesota, from January 1, 1999, through December 31, 2013, to identify definite or possible cases of VGS-IE using the Rochester Epidemiology Project. The National (Nationwide) Inpatient Sample hospital discharge database was examined to determine the number of VGS-IE cases in the United States between 2000 and 2011. RESULTS: Rates of incidence (per 100,000 person-years) during the intervals of 1999-2002, 2003-2006, 2007-2010, and 2011-2013 were 3.6 (95% CI, 1.3-5.9), 2.7 (95% CI, 0.9-4.4), 0.7 (95% CI, 0.0-1.6), and 1.5 (95% CI, 0.2-2.9), respectively, reflecting an overall significant decrease (P=.03 from Poisson regression). Likewise, nationwide estimates of hospital discharges with a VGS-IE diagnosis trended downward during 2000-2011, with a mean number per year of 15,853 and 16,157 for 2000-2003 and 2004-2007, respectively, decreasing to 14,231 in 2008-2011 (P=.05 from linear regression using weighted least squares method). CONCLUSION: Despite major reductions in the number of indications for antibiotic prophylaxis for invasive dental procedures espoused by the 2007 AHA IE prevention guidelines, both local and national data indicate that the incidence of VGS-IE has not increased.

Association of Mitral Valve Prolapse With Infective Endocarditis Due to Viridans Group Streptococci.

Although patients with certain cardiac valve abnormalities have increased risk of infective endocarditis (IE), it is unknown whether these abnormalities are associated with specific pathogens in IE cases. We report a strong association between mitral valve prolapse and viridans group streptococcal IE in a population-based cohort from Olmsted County, Minnesota.