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Cardiac hypertrophy (CH) is an adaptive response to maintain cardiac function; however, persistent stress responses lead to contractile dysfunction and heart failure. Although inflammation is involved in these processes, the mechanisms that control cardiac inflammation and hypertrophy still need to be clarified. The NLRP3 inflammasome is a cytosolic multiprotein complex that mediates IL-1ß production. The priming step of NLRP3 is essential for increasing the expression of its components and occurs following NF-κB activation. Hyperthyroidism triggers CH, which can progress to maladaptive CH and even heart failure. We have shown in a previous study that thyroid hormone (TH)-induced CH is linked to the upregulation of S100A8, leading to NF-κB activation. Therefore, we aimed to investigate whether the NLRP3 inflammasome is involved in TH-induced CH and its potential role in CH pathophysiology. Hyperthyroidism was induced in NLRP3 knockout (NLRP3-KO), Caspase-1-KO and Wild Type (WT) male mice of the C57Bl/6J strain, aged 8-12 weeks, by triiodothyronine (7 µg/100 g BW, i.p.) administered daily for 14 days. Morphological and cardiac functional analysis besides molecular assays showed, for the first time, that TH-induced CH is accompanied by reduced NLRP3 expression in the heart and that it occurs independently of the NLRP3 inflammasome and caspase 1-related pathways. However, NLRP3 is important for the maintenance of basal cardiac function since NLRP3-KO mice had impaired diastolic function and reduced heart rate, ejection fraction, and fractional shortening compared with WT mice.

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BACKGROUND: Antibiotic misuse is a key contributor to antimicrobial resistance and a concern in long-term aged care facilities (LTCFs). Our objectives were to: i) summarise key indicators of systemic antibiotic use and appropriateness of use, and ii) examine temporal and regional variations in antibiotic use, in LTCFs (PROSPERO registration CRD42018107125). METHODS & FINDINGS: Medline and EMBASE were searched for studies published between 1990-2021 reporting antibiotic use rates in LTCFs. Random effects meta-analysis provided pooled estimates of antibiotic use rates (percentage of residents on an antibiotic on a single day [point prevalence] and over 12 months [period prevalence]; percentage of appropriate prescriptions). Meta-regression examined associations between antibiotic use, year of measurement and region. A total of 90 articles representing 78 studies from 39 countries with data between 1985-2019 were included. Pooled estimates of point prevalence and 12-month period prevalence were 5.2% (95% CI: 3.3-7.9; n = 523,171) and 62.0% (95% CI: 54.0-69.3; n = 946,127), respectively. Point prevalence varied significantly between regions (Q = 224.1, df = 7, p<0.001), and ranged from 2.4% (95% CI: 1.9-2.7) in Eastern Europe to 9.0% in the British Isles (95% CI: 7.6-10.5) and Northern Europe (95% CI: 7.7-10.5). Twelve-month period prevalence varied significantly between regions (Q = 15.1, df = 3, p = 0.002) and ranged from 53.9% (95% CI: 48.3-59.4) in the British Isles to 68.3% (95% CI: 63.6-72.7) in Australia. Meta-regression found no association between year of measurement and antibiotic use prevalence. The pooled estimate of the percentage of appropriate antibiotic prescriptions was 28.5% (95% CI: 10.3-58.0; n = 17,245) as assessed by the McGeer criteria. Year of measurement was associated with decreasing appropriateness of antibiotic use over time (OR:0.78, 95% CI: 0.67-0.91). The most frequently used antibiotic classes were penicillins (n = 44 studies), cephalosporins (n = 36), sulphonamides/trimethoprim (n = 31), and quinolones (n = 28). CONCLUSIONS: Coordinated efforts focusing on LTCFs are required to address antibiotic misuse in LTCFs. Our analysis provides overall baseline and regional estimates for future monitoring of antibiotic use in LTCFs.

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OBJECTIVES: There are high levels of inappropriate antibiotic use in long-term care facilities (LTCFs). Our objective was to examine evidence of the effectiveness of interventions designed to reduce antibiotic use and/or inappropriate use in LTCFs. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase and CINAHL from 1997 until November 2018. ELIGIBILITY CRITERIA: Controlled and uncontrolled studies in LTCFs measuring intervention effects on rates of overall antibiotic use and/or appropriateness of use were included. Secondary outcomes were intervention implementation barriers from process evaluations. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently applied the Cochrane Effective Practice and Organisation of Care group's resources to classify interventions and assess risk of bias. Meta-analyses used random effects models to pool results. RESULTS: Of include studies (n=19), 10 had a control group and 17 had a high risk of bias. All interventions had multiple components. Eight studies (with high risk of bias) showed positive impacts on outcomes and included one of the following interventions: audit and feedback, introduction of care pathways or an infectious disease team. Meta-analyses on change in the percentage of residents on antibiotics (pooled relative risk (RR) (three studies, 6862 residents): 0.85, 95% CI: 0.61 to 1.18), appropriateness of decision to treat with antibiotics (pooled RR (three studies, 993 antibiotic orders): 1.10, 95% CI: 0.64 to 1.91) and appropriateness of antibiotic selection for respiratory tract infections (pooled RR (three studies, 292 orders): 1.15, 95% CI: 0.95 to 1.40), showed no significant intervention effects. However, meta-analyses only included results from intervention groups since most studies lacked a control group. Insufficient data prevented meta-analysis on other outcomes. Process evaluations (n=7) noted poor intervention adoption, low physician engagement and high staff turnover as barriers. CONCLUSIONS: There is insufficient evidence that interventions employed to date are effective at improving antibiotic use in LTCFs. Future studies should use rigorous study designs and tailor intervention implementation to the setting.

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Migraine is a brain disorder characterized by a piercing headache which affects one side of the head, located mainly at the temples and in the area around the eye. Migraine imparts substantial suffering to the family in addition to the sufferer, particularly as it affects three times more women than men and is most prevalent between the ages of 25 and 45, the years of child rearing. Migraine typically occurs in individuals with a genetic predisposition and is aggravated by specific environmental triggers. Attempts to study the biochemistry of migraine began as early as the 1960s and were primarily directed at serotonin metabolism after an increase of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin was observed in urine of migraineurs. Genetic and biochemical studies have primarily focused on the neurotransmitter serotonin, considering receptor binding, transport and synthesis of serotonin and have investigated serotonergic mediators including enzymes, receptors as well as intermediary metabolites. These studies have been mainly assayed in blood, CSF and urine as the most accessible fluids. More recently PET imaging technology integrated with a metabolomics and a systems biology platform are being applied to study serotonergic biology. The general trend observed is that migraine patients have alterations of neurotransmitter metabolism detected in biological fluids with different biochemistry from controls, however the interpretation of the biological significance of these peripheral changes is unresolved. In this review we present the biology of the serotonergic system and metabolic routes for serotonin and discuss results of biochemical studies with regard to alterations in serotonin in brain, cerebrospinal fluid, saliva, platelets, plasma and urine of migraine patients.

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Migraine is a complex polygenic disorder that continues to be a great source of morbidity in the developed world with a prevalence of 12% in the Caucasian population. Genetic and pharmacological studies have implicated the glutamate pathway in migraine pathophysiology. Glutamate profoundly impacts brain circuits that regulate core symptom domains in a range of neuropsychiatric conditions and thus remains a "hot" target for drug discovery. Glutamate has been implicated in cortical spreading depression (CSD), the phenomenon responsible for migraine with aura and in animal models carrying FHM mutations. Genotyping case-control studies have shown an association between glutamate receptor genes, namely, GRIA1 and GRIA3 with migraine with indirect supporting evidence from GWAS. New evidence localizes PRRT2 at glutamatergic synapses and shows it affects glutamate signalling and glutamate receptor activity via interactions with GRIA1. Glutamate-system defects have also been recently implicated in a novel FHM2 ATP1A2 disease-mutation mouse model. Adding to the growing evidence neurophysiological findings support a role for glutamate in cortical excitability. In addition to the existence of multiple genes to choreograph the functions of fast-signalling glutamatergic neurons, glutamate receptor diversity and regulation is further increased by the post-translational mechanisms of RNA editing and miRNAs. Ongoing genetic studies, GWAS and meta-analysis implicate neurogenic mechanisms in migraine pathology and the first genome-wide associated locus for migraine on chromosome X. Finally, in addition to glutamate modulating therapies, the kynurenine pathway has emerged as a candidate for involvement in migraine pathophysiology. In this review we discuss recent genetic evidence and glutamate modulating therapies that bear on the hypothesis that a glutamatergic mechanism may be involved in migraine susceptibility.

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BACKGROUND: Migraine causes crippling attacks of severe head pain along with associated nausea, vomiting, photophobia and/or phonophobia. The aim of this study was to investigate single nucleotide polymorphisms (SNPs) in the adenosine deaminase, RNA-specific, B1 (ADARB1) and adenosine deaminase, RNA specific, B2 (ADARB2) genes in an Australian case-control Caucasian population for association with migraine. Both candidate genes are highly expressed in the central nervous system and fit criteria for migraine neuropathology. SNPs in the ADARB2 gene were previously found to be positively associated with migraine in a pedigree-based genome wide association study using the genetic isolate of Norfolk Island, Australia. The ADARB1 gene was also chosen for investigation due to its important function in editing neurotransmitter receptor transcripts. METHODS: Four SNPs in ADARB1 and nine in ADARB2 were selected by inspecting blocks of linkage disequilibrium in Haploview for genotyping using either TaqMan or Sequenom assays. These SNPs were genotyped in two-hundred and ninety one patients who satisfied the International Classification of Headache Disorders-II 2004 diagnostic criteria for migraine, and three-hundred and fourteen controls, and PLINK was used for association testing. RESULTS: Chi-square analysis found no significant association between any of the SNPs tested in the ADARB1 and ADARB2 genes in this study and the occurrence of migraine. CONCLUSIONS: In contrast to findings that SNPs in the ADARB2 gene were positively associated with migraine in the Norfolk Island population, we find no evidence to support the involvement of RNA editing genes in migraine susceptibility in an Australian Caucasian population.

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BACKGROUND: Migraine is a brain disorder affecting ∼12% of the Caucasian population. Genes involved in neurological, vascular, and hormonal pathways have all been implicated in predisposing individuals to developing migraine. The migraineur presents with disabling head pain and varying symptoms of nausea, emesis, photophobia, phonophobia, and occasionally visual sensory disturbances. Biochemical and genetic studies have demonstrated dysfunction of neurotransmitters: serotonin, dopamine, and glutamate in migraine susceptibility. Glutamate mediates the transmission of excitatory signals in the mammalian central nervous system that affect normal brain function including cognition, memory and learning. The aim of this study was to investigate polymorphisms in the GRIA2 and GRIA4 genes, which encode subunits of the ionotropic AMPA receptor for association in an Australian Caucasian population. METHODS: Genotypes for each polymorphism were determined using high resolution melt analysis and the RFLP method. RESULTS: Statistical analysis showed no association between migraine and the GRIA2 and GRIA4 polymorphisms investigated. CONCLUSIONS: Although the results of this study showed no significant association between the tested GRIA gene variants and migraine in our Australian Caucasian population further investigation of other components of the glutamatergic system may help to elucidate if there is a relationship between glutamatergic dysfunction and migraine.

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Migraine is a neurological disorder that affects the central nervous system causing painful attacks of headache. A genetic vulnerability and exposure to environmental triggers can influence the migraine phenotype. Migraine interferes in many facets of people's daily life including employment commitments and their ability to look after their families resulting in a reduced quality of life. Identification of the biological processes that underlie this relatively common affliction has been difficult because migraine does not have any clearly identifiable pathology or structural lesion detectable by current medical technology. Theories to explain the symptoms of migraine have focused on the physiological mechanisms involved in the various phases of headache and include the vascular and neurogenic theories. In relation to migraine pathophysiology the trigeminovascular system and cortical spreading depression have also been implicated with supporting evidence from imaging studies and animal models. The objective of current research is to better understand the pathways and mechanisms involved in causing pain and headache to be able to target interventions. The genetic component of migraine has been teased apart using linkage studies and both candidate gene and genome-wide association studies, in family and case-control cohorts. Genomic regions that increase individual risk to migraine have been identified in neurological, vascular and hormonal pathways. This review discusses knowledge of the pathophysiology and genetic basis of migraine with the latest scientific evidence from genetic studies.

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Multiple sclerosis (MS) is a chronic neurological disease characterized by central nervous system (CNS) inflammation and demyelination. The C677T substitution variant in the methylenetetrahydrofolate reductase (MTHFR) gene has been associated with increased levels of circulating homocysteine and is a mild risk factor for vascular disease. Higher blood levels of homocysteine have also been reported in MS. Thus, the C677T mutation of the MTHFR gene may influence MS susceptibility. Noradrenaline, a neurotransmitter believed to play an immunosupressive role in neuroinflammatory disorders, is catabolized by catechol-O-methyl transferase (COMT). The COMT G158A substitution results in a three- to four-fold decreased activity of the COMT enzyme, which may influence CNS synaptic catecholamine breakdown and could also play a role in MS inflammation. We tested DNA from Australian MS patients and unaffected control subjects, matched for gender, age and ethnicity. Specifically, we genotyped the MTHFR C677T and the COMT G158A mutations. Genotype distributions showed that the homozygous mutant MTHFR genotype (T/T) and the COMT (H/H) genotype were slightly over-represented in the MS group (16% versus 11% and 24% versus 19%, respectively), but both variations failed to reach statistical significance (P=0.15 and P=0.32, respectively). Hence, results from the present study do not support a major role for either functional gene mutation in MS susceptibility.

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