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1.
SLAS Discov ; : 2472555220920581, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32436764

RESUMO

Cytoplasmic dynein-1 (hereafter dynein) is a six-subunit motor complex that transports a variety of cellular components and pathogens along microtubules. Dynein's cellular functions are only partially understood, and potent and specific small-molecule inhibitors and activators of this motor would be valuable for addressing this issue. It has also been hypothesized that an inhibitor of dynein-based transport could be used in antiviral or antimitotic therapy, whereas an activator could alleviate age-related neurodegenerative diseases by enhancing microtubule-based transport in axons. Here, we present the first high-throughput screening (HTS) assay capable of identifying both activators and inhibitors of dynein-based transport. This project is also the first collaborative screening report from the Medical Research Council and AstraZeneca agreement to form the UK Centre for Lead Discovery. A cellular imaging assay was used, involving chemically controlled recruitment of activated dynein complexes to peroxisomes. Such a system has the potential to identify molecules that affect multiple aspects of dynein biology in vivo. Following optimization of key parameters, the assay was developed in a 384-well format with semiautomated liquid handling and image acquisition. Testing of more than 500,000 compounds identified both inhibitors and activators of dynein-based transport in multiple chemical series. Additional analysis indicated that many of the identified compounds do not affect the integrity of the microtubule cytoskeleton and are therefore candidates to directly target the transport machinery.

2.
J Hum Genet ; 65(5): 493-496, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32127623

RESUMO

Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare, recessively inherited neurological condition frequently involving insensitivity to pain. The subtype, HSAN2A, results from mutations in the gene WNK1. We identified a consanguineous Pakistani family with three affecteds showing symptoms of HSANII. We performed microarray genotyping, followed by homozygosity-by-descent (HBD) mapping, which indicated several significant HBD regions, including ~6 Mb towards the terminus of chromosome 12p, spanning WNK1. Simultaneously, we performed whole exome sequencing (WES) on one of the affected brothers, and identified a homozygous 1 bp insertion variant, Chr12:978101dupA, within exon 10. This variant, confirmed to segregate in the family, is predicted to truncate the protein (NM_213655.4:c.3464delinsAC; p.(Thr1155Asnfs*11) and lead to nonsense-mediated mRNA decay of the transcript. Previous studies of congenital pain insensitivity/HSANII in Pakistani families have identified mutations in SCN9A. Our study identified a previously unreported WNK1 mutation segregating with congenital pain insensitivity/HSANII in a Pakistani family.

3.
J Inorg Biochem ; 206: 111040, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32088595

RESUMO

Trivalent chromium has been proposed to be transported in vivo from the bloodstream to the tissues via endocytosis by transferrin (Tf), the major iron transport protein in the blood. While both Cr(III) binding and release from Tf have been proposed to be too slow to be physiologically relevant, recent kinetic studies under physiological conditions demonstrate that Cr(III) binding and release are sufficiently fast to occur during the time of the endocytosis cycle (circa 15 min). Consequently, the release of Cr(III) from human and bovine serum Tf has been examined under conditions mimicking an endosome during endocytosis. These studies have also found that Cr(III)2-Tf can exist in multiple conformations giving rise to different spectroscopic properties and different rates of Cr(III) release. Time-dependent spectroscopic studies of the binding and release of Cr(III) from human serum Tf have been used to identify three different conformations of Cr(III)2-Tf. The conformation of Cr(III)2-Tf used in most previous studies forms too slowly to be physiologically relevant and slowly releases Cr(III) in endosomal pH range. The conformation formed between 5 min to 60 min after the addition of Cr(III) to apoTf at pH 7.4 in 25 mM bicarbonate resembles the conformation of Cr(III)2-Tf in its complex with Tf receptor (TfR) and loses Cr(III) rapidly at endosomal pH, although not as fast as the Tf-TfR complex. The significance of these conformations and the potential role of Tf in detoxification of Cr(III) are described.

4.
J Am Soc Mass Spectrom ; 31(2): 308-318, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32031389

RESUMO

Addition of trivalent chromium, Cr(III), to solutions undergoing electrospray ionization (ESI) enhances protonation and leads to formation of [M + 2H]2+ for peptides that normally produce [M + H]+. This effect is explored using electronic structure calculations at the density functional theory (DFT) level to predict the energetics of various species that are potentially important to the mechanism. Gas- and solution-phase reaction free energies for glycine and its anion reacting with [Cr(III)(H2O)6]3+ and for dehydration of these species have been predicted, where glycine is used as a simple model for a peptide. For comparison, calculations were also performed with Fe(III), Al(III), Sc(III), Y(III), and La(III). Removal of water from these complexes, as would occur during the ESI desolvation process, results in species that are highly acidic. The calculated pKa of Cr(III) with a single solvation shell is -10.8, making [Cr(III)(H2O)6]3+ a superacid that is more acidic than sulfuric acid (pKa = -8.8). Binding to glycine requires removal of two aqua ligands, which gives [Cr(III)(H2O)4]3+ that has an extremely acidic pKa of -28.8. Removal of additional water further enhances acidity, reaching a pKa of -84.7 for [Cr(III)(H2O)]3+. A mechanism for enhanced protonation is proposed that incorporates computational and experiment results, as well as information on the known chemistry of Cr(III), which is substitutionally inert. The initial step involves binding of [Cr(III)(H2O)4]3+ to the deprotonated C-terminus of a peptide. As the drying process during ESI strips water from the complex, the resulting superacid transfers protons to the bound peptide, eventually leading to formation of [M + 2H]2+.

5.
J Hypertens ; 38(3): 420-425, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31584516

RESUMO

BACKGROUND: Visit-to-visit office blood pressure (BP) variability (BPV) has been associated with morbidity and mortality outcomes in several cardiovascular conditions. The aim of this study was to evaluate the association between BPV and outcomes in patients with heart failure and reduced ejection fraction and the effect of eplerenone on BPV. METHODS AND RESULTS: We evaluated the associations between BPV, calculated as SBP coefficient of variation (SBP-CoV = SD/mean × 100%), and the primary composite endpoint of cardiovascular mortality or heart failure hospitalization (HFH), and its components, in 2549 patients from the Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms trial. Lower SBP-CoV was independently associated with a higher risk of all the studied outcomes, while higher as well as lower SBP-CoV were associated with a higher risk of cardiovascular death. After a median follow-up period of 21 months the risk of the composite outcome of cardiovascular death or HFH was almost double in the lower SBP-CoV tertile as compared with the intermediate tertile [adjusted hazard ratio: 2.01, 95% confidence interval (1.62-2.51), P < 0.001]. The relationship between SBP-CoV and outcomes was not modified by eplerenone (P value for interaction = 0.48). An interaction was detected between mean SBP and SBP-CoV for the primary outcome (P = 0.048) and for HFH (P = 0.018). The effect modification was slight, but lower SBP-CoV was associated with worse outcomes in patients with both low and high SBP, while this interaction was less clear for patients with SBP in the 'normal' range. CONCLUSION: In our patients with heart failure and reduced ejection fraction and mild symptoms, both a lower and higher SBP-CoV were associated with worse outcomes. SBP-CoV did not modify the benefit of eplerenone. Further studies are warranted to clarify the role of BPV in heart failure. CLINICALTRIALS. GOV IDENTIFIER: NCT00232180.

6.
Chembiochem ; 21(5): 628-631, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31472032

RESUMO

Chromium(VI) is a carcinogen and mutagen, and its mechanisms of action are proposed to involve binding of its reduction product, chromium(III), to DNA. The manner in which chromium(III) binds DNA has not been established, particularly at a molecular level. Analysis of oligonucleotide duplex DNAs by NMR, EPR, and IR spectroscopies in the presence of chromium(III) allows the elucidation of the Cr binding site. The metal centers were found to interact exclusively with guanine N7 positions. No evidence of chromium interactions with other bases or backbone phosphates nor of Cr forming intra-strand crosslinks between neighboring guanine residues was observed.

7.
J Inorg Biochem ; 202: 110901, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669693

RESUMO

Transferrin, the major iron transport protein in the blood, apparently also transports trivalent chromium in vivo via endocytosis. Recent in vitro studies have, however, suggested that the release of chromic ions from serum transferrin is too slow to be biologically relevant. Consequently, the release of chromium(III) from human serum transferrin has been examined under conditions mimicking an endosome during endocytosis. At pH 4.5 and 5.5, the release of Cr(III) from transferrin occurs rapidly from the weak binding site. While appreciably slower, the release of Cr(III) from the tighter site in the presence of biological chelating agents is potentially sufficiently fast to be physiologically relevant. When Cr(III)-loaded transferrin is added to soluble transferrin receptor, the interaction with the receptor results in Cr(III) in both the weak and tight binding sites giving rise to an EPR signal similar to that of the weak binding site; concurrently, the loss of Cr(III) from both binding sites becomes rapid at acidic pH, more rapid than from either site in the absence of the receptor. Loss of Cr(III) from the transferrin-transferrin receptor complex, thus, is easily sufficiently rapid for transferrin to serve as the physiological transporter of Cr(III) from the bloodstream to the tissues. However, detailed studies of conformational changes of transferrin associated with the binding and release of chromium along with investigations of how and at what rate Cr(III) is transported from the endosome will be required before this question of whether transferrin transport Cr(III) in vivo can be definitively resolved.

8.
Epigenetics Chromatin ; 12(1): 63, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601272

RESUMO

BACKGROUND: MeCP2-a chromatin-binding protein associated with Rett syndrome-has two main isoforms, MeCP2-E1 and MeCP2-E2, differing in a few N-terminal amino acid residues. Previous studies have shown brain region-specific expression of these isoforms which, in addition to their different cellular localization and differential expression during brain development, suggest that they may also have non-overlapping molecular mechanisms. However, differential functions of MeCP2-E1 and E2 remain largely unexplored. RESULTS: Here, we show that the N-terminal domains (NTD) of MeCP2-E1 and E2 modulate the ability of the methyl-binding domain (MBD) to interact with DNA as well as influencing the turn-over rates, binding dynamics, response to neuronal depolarization, and circadian oscillations of the two isoforms. Our proteomics data indicate that both isoforms exhibit unique interacting protein partners. Moreover, genome-wide analysis using ChIP-seq provide evidence for a shared as well as a specific regulation of different sets of genes. CONCLUSIONS: Our study supports the idea that Rett syndrome might arise from simultaneous impairment of cellular processes involving non-overlapping functions of MECP2 isoforms. For instance, MeCP2-E1 mutations might impact stimuli-dependent chromatin regulation, while MeCP2-E2 mutations could result in aberrant ribosomal expression. Overall, our findings provide insight into the functional complexity of MeCP2 by dissecting differential aspects of its two isoforms.

9.
Curr Opin Clin Nutr Metab Care ; 22(6): 483-489, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31577642

RESUMO

PURPOSE OF REVIEW: Chromium(III) has been proposed to have a nutritional or pharmacological role in changing body composition and improving symptoms of insulin resistance, type 2 diabetes, and related conditions although the mode of action of Cr(III) at a molecular level has failed to be elucidated. This review details the current status of studies into Cr(III) supplementation. RECENT FINDINGS: Clinical trials, meta-analyses and systematic reviews have failed to demonstrate clinically significant effects from Cr(III) supplementation on body composition or symptoms of insulin resistance and related conditions in humans and farm animals. Although new Cr(III) supplements continue to appear in the scientific literature, studies have failed to elucidate the mechanism of chromium action at a molecular level. Conflicting results on a role of transferrin in Cr(III) transport and detoxification have appeared. SUMMARY: Cr(III) supplementation cannot currently be recommended in humans or farm animals. Further studies are required to probe the mechanism of Cr(III) action in increasing insulin sensitivity and glucose uptake in rodent models of insulin resistance and diabetes, with particular attention being turned to a potential role of transferrin in Cr(III) transport and detoxification.

10.
Hum Genet ; 138(10): 1183-1200, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31471722

RESUMO

The glutamate pyruvate transaminase 2 (GPT2) gene produces a nuclear-encoded mitochondrial enzyme that catalyzes the reversible transfer of an amino group from glutamate to pyruvate, generating alanine and alpha-ketoglutarate. Recessive mutations in GPT2 have been recently identified in a new syndrome involving intellectual and developmental disability (IDD), postnatal microcephaly, and spastic paraplegia. We have identified additional families with recessive GPT2 mutations and expanded the phenotype to include small stature. GPT2 loss-of-function mutations were identified in four families, nine patients total, including: a homozygous mutation in one child [c.775T>C (p.C259R)]; compound heterozygous mutations in two siblings [c.812A>C (p.N271T)/c.1432_1433delGT (p.V478Rfs*73)]; a novel homozygous, putative splicing mutation [c.1035C>T (p.G345=)]; and finally, a recurrent mutation, previously identified in a distinct family [c.1210C>T (p.R404*)]. All patients were diagnosed with IDD. A majority of patients had remarkably small stature throughout development, many < 1st percentile for height and weight. Given the potential biological function of GPT2 in cellular growth, this phenotype is strongly suggestive of a newly identified clinical susceptibility. Further, homozygous GPT2 mutations manifested in at least 2 of 176 families with IDD (approximately 1.1%) in a Pakistani cohort, thereby representing a relatively common cause of recessive IDD in this population, with recurrence of the p.R404* mutation in this population. Based on variants in the ExAC database, we estimated that approximately 1 in 248 individuals are carriers of moderately or severely deleterious variants in GPT2.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Genes Recessivos , Predisposição Genética para Doença , Mutação , Fenótipo , Transaminases/genética , Adolescente , Alelos , Substituição de Aminoácidos , Deficiências do Desenvolvimento/metabolismo , Ativação Enzimática , Éxons , Feminino , Frequência do Gene , Estudos de Associação Genética , Genética Populacional , Genótipo , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Imagem por Ressonância Magnética , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Modelos Moleculares , Linhagem , Conformação Proteica , Sítios de Splice de RNA , Análise de Sequência de DNA , Relação Estrutura-Atividade , Transaminases/química , Transaminases/metabolismo
11.
Am J Psychiatry ; 176(8): 651-660, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31164008

RESUMO

OBJECTIVE: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. METHODS: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. RESULTS: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%). CONCLUSIONS: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.


Assuntos
Transtorno Bipolar/genética , Transtorno Depressivo Maior/genética , Herança Multifatorial/genética , Esquizofrenia/genética , Tentativa de Suicídio , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Transtorno Depressivo Maior/psicologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fatores de Risco
12.
Psychiatry Res ; 278: 242-247, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31229838

RESUMO

Association of cannabis use with schizophrenia is a well-established finding. Its role in causation, however, is debated. Different studies have found that cannabis use impacts the outcome of schizophrenia and is associated with treatment non-adherence and a higher rate of relapses. In this paper, we investigated the impact of self-reported cannabis use on treatment response in a cohort of schizophrenia patients from Pakistan, a middle-income country. The data was collected from a psychiatric hospital in Khyber Pakhtunkhwa province of Pakistan where cannabis use is prevalent. Clinical evaluation and therapeutic response were established using the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impressions Scales-Severity (CGI-S) and Improvement (CGI-I) scale. Lack of response to adequate treatment with two trials of antipsychotics was classed as treatment resistance. We compared the treatment-resistant and treatment responsive groups for different variables including cannabis use, age at onset of illness, duration of untreated psychosis and consanguinity. We had data on 230 patients. More than ninety percent of our participants were men. The rate of treatment resistance was over 60%. Ongoing use of cannabis had an association with treatment resistance. We only included cases where treatment adherence was not a problem.

14.
Ann Hum Genet ; 83(4): 278-284, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30868578

RESUMO

Oculocutaneous albinism (OCA) is an autosomal-recessive disorder of a defective melanin pathway. The condition is characterized by hypopigmentation of hair, dermis, and ocular tissue. Genetic studies have reported seven nonsyndromic OCA genes, among which Pakistani OCA families mostly segregate TYR and OCA2 gene mutations. Here in the present study, we investigate the genetic factors of eight consanguineous OCA families from Pakistan. Genetic analysis was performed through single-nucleotide polymorphism (SNP) genotyping (for homozygosity mapping), whole exome sequencing (for mutation identification), Sanger sequencing (for validation and segregation analysis), and quantitative PCR (qPCR) (for copy number variant [CNV] validation). Genetic mapping in one family identified a novel homozygous deletion mutation of the entire TYRP1 gene, and a novel deletion of exon 19 in the OCA2 gene in two apparently unrelated families. In three further families, we identified homozygous mutations in TYR (NM_000372.4:c.1424G > A; p.Trp475*), NM_000372.4:c.895C > T; p.Arg299Cys), and SLC45A2 (NM_016180:c.1532C > T; p.Ala511Val). For the remaining two families, G and H, compound heterozygous TYR variants NM_000372.4:c.1037-7T > A, NM_000372.4:c.1255G > A (p.Gly419Arg), and NM_000372.4:c.1255G > A (p.Gly419Arg) and novel variant NM_000372.4:c.248T > G; (p.Val83Gly), respectively, were found. Our study further extends the evidence of TYR and OCA2 as genetic mutation hot spots in Pakistani families. Genetic screening of additional OCA cases may also contribute toward the development of Pakistani specific molecular diagnostic tests, genetic counseling, and personalized healthcare.

15.
Eur J Heart Fail ; 21(3): 345-351, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30768732

RESUMO

BACKGROUND: Current heart failure guidelines recommend target eplerenone dose of 50 mg/day. We have examined the effect of different eplerenone doses based on pre-specified renal function stratification in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). METHODS AND RESULTS: In EMPHASIS-HF, the target dose of eplerenone/placebo was stratified at randomization according to estimated glomerular filtration rate (eGFR): 50 mg/day if eGFR ≥ 50 mL/min/1.73 m2 and ≤ 25 mg/day if eGFR 30-49 mL/min/1.73 m2 . Patients remained within these dose ranges during the trial (as per stratification). The primary outcome was a composite of heart failure hospitalization or cardiovascular mortality. Eplerenone was superior to placebo within each respective eGFR stratum [eplerenone vs. placebo in the eGFR ≥ 50 mL/min/1.73 m2 stratum: hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.45-0.74; and eplerenone vs. placebo in the eGFR 30-49 mL/min/1.73 m2 stratum: HR 0.62, 95% CI 0.49-0.78; Pinteraction = 0.89]. Despite receiving lower eplerenone doses, patients in the eGFR 30-49 mL/min/1.73 m2 stratum more often had hyperkalaemia, renal failure events, and drug discontinuation. CONCLUSION: In EMPHASIS-HF the eplerenone dose was stratified according to renal function and the treatment effect was not influenced by renal function: 25 mg/day in patients with eGFR 30-49 mL/min/1.73 m2 was as effective as 50 mg/day in patients with eGFR > =50 mL/min/1.73 m2 . However, patients with impaired renal function experienced more adverse events, despite reveiving lower eplerenone doses. Current guidelines do not recommend tailoring the dose of eplereone according to renal function but the current data suggest they should.


Assuntos
Relação Dose-Resposta a Droga , Eplerenona , Taxa de Filtração Glomerular/efeitos dos fármacos , Insuficiência Cardíaca , Testes de Função Renal , Idoso , Disponibilidade Biológica , Monitoramento de Medicamentos/métodos , Eplerenona/administração & dosagem , Eplerenona/efeitos adversos , Eplerenona/farmacocinética , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Hospitalização/estatística & dados numéricos , Humanos , Testes de Função Renal/métodos , Testes de Função Renal/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Farmacovigilância , Resultado do Tratamento
16.
SAGE Open Med Case Rep ; 7: 2050313X19827743, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30800304

RESUMO

Revision total hip arthroplasty is a costly procedure accounting for approximately 14% of all hip arthroplasties. Compounding the cost considerations is the potential for serious injury to the patient when removing existing components. Such injury can result in not only increased morbidity but also dramatically increased costs. The use of computer-assisted navigation in revision total hip arthroplasty, while relatively uncommon, offers surgeons the ability to measure component position and orientation intraoperatively, thus allowing them the opportunity to modify their surgical plan, with the potential for decreasing both costs and iatrogenic injury. Here, we report a case of revision total hip arthroplasty where the use of computer-assisted navigation as a diagnostic tool allowed for intraoperative alterations in surgical plan and resulted in improved post-operative outcomes.

17.
Conserv Physiol ; 7(1): coy067, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30680216

RESUMO

Unmanned aircraft systems (UAS; i.e. 'drones') provide new opportunities for data collection in ecology, wildlife biology and conservation. Yet, several studies have documented behavioral or physiological responses to close-proximity UAS flights. We experimentally tested whether American black bears (Ursus americanus) habituate to repeated UAS exposure and whether tolerance levels persist during an extended period without UAS flights. Using implanted cardiac biologgers, we measured heart rate (HR) of five captive bears before and after the first of five flights each day. Spikes in HR, a measure of stress, diminished across the five flights within each day and over the course of 4 weeks of twice-weekly exposure. We halted flights for 118 days, and when we resumed, HR responses were similar to that at the end of the previous trials. Our findings highlight the capacity of a large mammal to become and remain habituated to a novel anthropogenic stimulus in a relatively short time (3-4 weeks). However, such habituation to mechanical noises may reduce their wariness of other human threats. Also, whereas cardiac effects diminished, frequent UAS disturbances may have other chronic physiological effects that were not measured. We caution that the rate of habituation may differ between wild and captive animals: while the captive bears displayed large initial spikes in HR change (albeit not as large as wild bears), these animals were accustomed to regular exposure to humans and mechanical noises that may have hastened habituation to the UAS.

18.
Clin Res Cardiol ; 108(7): 806-814, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30604047

RESUMO

BACKGROUND: Increased resting heart rate is a risk factor for cardiovascular mortality and morbidity. Mineralocorticoid receptor antagonists (MRAs) have been shown to improve cardiac sympathetic nerve activity, reduce heart rate and attenuate left ventricular remodelling. Whether or not the beneficial effects of MRA are affected by heart rate in heart failure patients with reduced ejection fraction (HFREF) is unclear. METHODS: We undertook a secondary analysis of data from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure study to assess if clinical outcomes, as well as the efficacy of eplerenone, varied according to heart rate at baseline. RESULTS: High resting heart rate of 80 bpm and above predisposed patients to greater risk of all outcomes in the trial, regardless of treatment allocation. The beneficial effects of eplerenone were observed across all categories of heart rate. Eplerenone reduced the risk of primary endpoint, the composite of cardiovascular death and hospitalisation for heart failure, by 30% (aHR 0.70; 95% CI 0.54-0.91) in subjects with heart rate ≥ 80 bpm, and by 48% (aHR 0.52; 95% CI 0.33-0.81) in subjects with heart rate ≤ 60 bpm. Eplerenone also reduced the risks of hospitalisation for heart failure, cardiovascular deaths and all-cause deaths independently of baseline heart rate. CONCLUSIONS: Baseline heart rate appears to be an important predictor of major clinical outcome events in patients with HFREF, as has been previously reported. The benefits of eplerenone were preserved across all categories of baseline heart rate, without observed heterogeneity in the responses.


Assuntos
Eplerenona/administração & dosagem , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Volume Sistólico/fisiologia , Relação Dose-Resposta a Droga , Europa (Continente)/epidemiologia , Feminino , Insuficiência Cardíaca Sistólica/mortalidade , Insuficiência Cardíaca Sistólica/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Fatores de Risco , Taxa de Sobrevida/tendências , Resultado do Tratamento , Estados Unidos/epidemiologia
19.
Biol Trace Elem Res ; 188(1): 99-126, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30430417

RESUMO

Chromium supplementation has been proposed to have beneficial effects in farm animals, particularly when under stress. The last two decades, in particular, have seen an emphasis on examining the effects of supplemental chromium on a variety of variables in chicks and chickens. Thus, given the recent approval of a Cr(III) compound for use in chicken feed in the United States and the recent surge in papers on the use of Cr in chicken feed, the need for a systematic review of studies utilizing chickens is extremely urgent and timely. With the exception of studies on cold-stressed laying hens, the results of studies of Cr supplementation of chickens, whether broilers or laying hens, were found to be too inconsistent for any firm conclusions to be drawn other than that Cr supplementation generally leads to accumulation of Cr in tissues. Few potential trends in terms or beneficial or deleterious effects from Cr supplementation were found regardless of strain of chicken, Cr source, Cr dose, duration of supplementation, or variable examined. Hence, in summary, no recommendation for the use of Cr as a supplement for the diet of chickens can be made at this time.


Assuntos
Galinhas/fisiologia , Cromo/farmacologia , Oligoelementos/farmacologia , Ração Animal , Animais , Cromo/química , Dieta/veterinária , Suplementos Nutricionais , Feminino , Oligoelementos/química
20.
Am J Med Genet B Neuropsychiatr Genet ; 180(1): 46-54, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30556376

RESUMO

Many genetic conditions can mimic mental health disorders, with psychiatric symptoms that are difficult to treat with standard psychotropic medications. This study tests the hypothesis that psychiatric populations are enriched for pathogenic variants associated with selected inborn errors of metabolism (IEMs). Using next-generation sequencing, 2046 psychiatric patients were screened for pathogenic variants in genes associated with four IEMs, Niemann-Pick disease type C (NPC), Wilson disease (WD), homocystinuria (HOM), and acute intermittent porphyria (AIP). Among the 2046 cases, carrier rates of 0.83, 0.98, and 0.20%, for NPC, WD and HOM, and affected rates of 0.10 and 0.24% for NPC and AIP were seen, respectively. An enrichment of known and predicted pathogenic variants in the genes associated with NPC and AIP was found in the psychiatric cohort and especially in schizophrenia patients. The results of this study support that pathogenic variants in genes associated with IEMs are enriched in psychiatric populations. Underlying undiagnosed IEMs could account for the psychiatric symptomatology in a subset of psychiatric patients. Further studies are warranted to investigate the possibility that carriers for IEMs may have an increased risk for psychiatric disorders, particularly in the context of poor treatment response.

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