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1.
Toxicol Pathol ; : 192623319879091, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645209

RESUMO

The effects of particulate matter (PM) on cardiopulmonary health have been studied extensively over the past three decades. Particulate matter is the primary criteria air pollutant most commonly associated with adverse health effects on the cardiovascular and respiratory systems. The mechanisms by which PM exerts its effects are thought to be due to a variety of factors which may include, but are not limited to, concentration, duration of exposure, and age of exposed persons. Adverse effects of PM are strongly driven by their physicochemical properties, sites of deposition, and interactions with cells of the respiratory and cardiovascular systems. The direct translocation of particles, as well as neural and local inflammatory events, are primary drivers for the observed cardiopulmonary health effects. In this review, toxicological studies in animals, and clinical and epidemiological studies in humans are examined to demonstrate the importance of using all three approaches to better define potential mechanisms driving health outcomes upon exposure to airborne PM of diverse physicochemical compositions.

2.
Lancet ; 393(10189): 2416-2427, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31104833

RESUMO

BACKGROUND: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia. METHODS: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. FINDINGS: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved. INTERPRETATION: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. FUNDING: Ultragenyx Pharmaceutical and Kyowa Kirin International.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Estatura , Criança , Desenvolvimento Infantil , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Feminino , Humanos , Lactente , Masculino , Índice de Gravidade de Doença , Resultado do Tratamento
3.
Bone ; 122: 76-81, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30772600

RESUMO

The Rickets Severity Score (RSS) was used to evaluate X-linked hypophosphatemic rickets (XLH), a genetic disorder mediated by increased circulating FGF23. The reliability of the RSS was assessed using data from a randomized, phase 2 clinical trial that evaluated the effects of burosumab, a fully human anti-FGF23 monoclonal antibody, in 52 children with XLH ages 5 to 12 years. Bilateral knee and wrist radiographs were obtained at baseline, week 40, and week 64. We evaluated the relationships of the RSS to the Radiographic Global Impression of Change (RGI-C), serum alkaline phosphatase (ALP), height Z-score, 6-minute walk test (6MWT) percent predicted, and the Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI). The RSS showed moderate-to-substantial inter-rater reliability (weighted kappa, 0.45-0.65; Pearson correlation coefficient (r), 0.83-0.89) and substantial intra-rater reliability (weighted Kappa, 0.66; r = 0.91). Baseline RSS correlated with serum ALP (r = 0.47). Baseline RSS identified two subgroups (higher [RSS ≥1.5] and lower RSS [RSS <1.5]) that discriminated between subjects with greater and lesser rachitic disease. Higher RSS was associated with more severe clinical features, including impaired growth (Z-score, -2.12 vs -1.44) and walking ability (6MWT percent predicted, 77% vs 86%), more severe self-reported pain (29.9 [more severe] vs 45.3 [less severe]) and less physical function (29.6 [more severe] vs 40.9 [less severe]). During burosumab treatment, greater reductions in RSS corresponded to higher RGI-C global scores (r = -0.65). Improvements in RSS correlated with decreased serum ALP (r = 0.47). These results show the reliability of the RSS in XLH, and demonstrate that higher RSS values are associated with greater biochemical, clinical, and functional impairments in children with XLH.

4.
J Inherit Metab Dis ; 42(1): 169-177, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30740733

RESUMO

Long-chain fatty acid oxidation disorders (LC-FAOD) are rare disorders characterized by acute crises of energy metabolism and severe energy deficiency that may present with cardiomyopathy, hypoglycemia, and/or rhabdomyolysis, which can lead to frequent hospitalizations and early death. An open-label Phase 2 study evaluated the efficacy of UX007, an investigational odd-carbon medium-chain triglyceride, in 29 subjects with severe LC-FAOD. UX007 was administered over 78 weeks at a target dose of 25-35% total daily caloric intake (mean 27.5%). The frequency and duration of major clinical events (hospitalizations, emergency room visits, and emergency home interventions due to rhabdomyolysis, hypoglycemia, and cardiomyopathy) occurring during 78 weeks of UX007 treatment was compared with the frequency and duration of events captured retrospectively from medical records for 78 weeks before UX007 initiation. The mean annualized event rates decreased from 1.69 to 0.88 events/year following UX007 initiation (p = 0.021; 48.1% reduction). The mean annualized duration rate decreased from 5.96 to 2.96 days/year (p = 0.028; 50.3% reduction). Hospitalizations due to rhabdomyolysis, the most common event, decreased from 1.03 to 0.63 events/year (p = 0.104; 38.7% reduction). Initiation of UX007 eliminated hypoglycemia events leading to hospitalization (from 11 pre-UX007 hospitalizations, 0.30 events/year vs. 0; p = 0.067) and intensive care unit (ICU) care (from 2 pre-UX007 ICU admissions, 0.05 events/year vs. 0; p = 0.161) and reduced cardiomyopathy events (3 events vs. 1 event; 0.07 to 0.02 events/year; 69.7% decrease). The majority of treatment-related adverse events (AEs) were mild to moderate gastrointestinal symptoms, including diarrhea, vomiting, and abdominal or gastrointestinal pain, which can be managed with smaller, frequent doses mixed with food.

5.
Value Health ; 21(8): 973-983, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30098676

RESUMO

BACKGROUND: X-linked hypophosphatemia (XLH) is a rare genetic disorder characterized by renal phosphate wasting and defective bone mineralization. Symptoms include bone pain, joint pain, stiffness, and fatigue. Published evidence regarding the patient experience of XLH is sparse and no XLH-specific outcome measures have been validated. OBJECTIVES: To understand the symptoms, impacts, and patient experience of XLH and to evaluate the face and content validity of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) and the Brief Pain Inventory Short Form (BPI-SF) for use as end points in XLH clinical trials. METHODS: Face-to-face, qualitative, semistructured interviews were conducted with 18 adults with XLH in the United States using concept elicitation and cognitive debriefing techniques. Open-ended questioning elicited spontaneous concepts focusing on XLH-associated symptoms and functional limitations. Cognitive debriefing of the WOMAC® and BPI-SF assessed the relevance and patient understanding of item wording, recall period, and response options. RESULTS: Various distinct symptom concepts were elicited including pain symptoms, dental symptoms, sensory symptoms, tiredness/fatigue symptoms, and musculoskeletal symptoms. Participants reported experiencing significant bone and joint pain, stiffness, mobility limitations, and an impact on their ability to work. Cognitive interviewing found both instruments to be relevant and well understood by most patients. CONCLUSIONS: The interviews generated rich, qualitative insights into the patient experience of XLH. Cognitive debriefing of the BPI-SF and WOMAC® supported their value as XLH clinical trial end points. Future research will assess the psychometric properties of these instruments for use in the XLH population.


Assuntos
Raquitismo Hipofosfatêmico Familiar/psicologia , Satisfação do Paciente , Adulto , Feminino , Humanos , Entrevistas como Assunto/métodos , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Psicometria/instrumentação , Psicometria/métodos , Pesquisa Qualitativa , Índice de Gravidade de Doença
6.
J Inherit Metab Dis ; 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29987492

RESUMO

Long-chain fatty acid oxidation disorders (LC-FAOD) are rare disorders characterized by acute crises of energy metabolism and severe energy deficiency that may present with cardiomyopathy, hypoglycemia, and/or rhabdomyolysis, which can lead to frequent hospitalizations and early death. An open-label Phase 2 study evaluated the efficacy of UX007, an investigational odd-carbon medium-chain triglyceride, in 29 subjects with severe LC-FAOD. UX007 was administered over 78 weeks at a target dose of 25-35% total daily caloric intake (mean 27.5%). The frequency and duration of major clinical events (hospitalizations, emergency room visits, and emergency home interventions due to rhabdomyolysis, hypoglycemia, and cardiomyopathy) occurring during 78 weeks of UX007 treatment was compared with the frequency and duration of events captured retrospectively from medical records for 78 weeks before UX007 initiation. The mean annualized event rates decreased from 1.69 to 0.88 events/year following UX007 initiation (p = 0.021; 48.1% reduction). The mean annualized duration rate decreased from 5.96 to 2.96 days/year (p = 0.028; 50.3% reduction). Hospitalizations due to rhabdomyolysis, the most common event, decreased from 1.03 to 0.63 events/year (p = 0.104; 38.7% reduction). Initiation of UX007 eliminated hypoglycemia events leading to hospitalization (from 11 pre-UX007 hospitalizations, 0.30 events/year vs. 0; p = 0.067) and intensive care unit (ICU) care (from 2 pre-UX007 ICU admissions, 0.05 events/year vs. 0; p = 0.161) and reduced cardiomyopathy events (3 events vs. 1 event; 0.07 to 0.02 events/year; 69.7% decrease). The majority of treatment-related adverse events (AEs) were mild to moderate gastrointestinal symptoms, including diarrhea, vomiting, and abdominal or gastrointestinal pain, which can be managed with smaller, frequent doses mixed with food.

7.
Cell Rep ; 24(2): 355-365, 2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-29996097

RESUMO

Down syndrome (DS) is a genetic disorder that causes cognitive impairment. The staggering effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of DS pathophysiology. We examined the neuron-astrocyte interplay in a fully recapitulated HSA21 trisomy cellular model differentiated from DS-patient-derived induced pluripotent stem cells (iPSCs). By combining calcium imaging with genetic approaches, we discovered the functional defects of DS astroglia and their effects on neuronal excitability. Compared with control isogenic astroglia, DS astroglia exhibited more-frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. Furthermore, suppressed neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine-mediated signaling or genetically by knockdown of inositol triphosphate (IP3) receptors or S100B, a calcium binding protein coded on HSA21. Our results suggest a mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability.

8.
J Bone Miner Res ; 33(8): 1383-1393, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29947083

RESUMO

In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n = 68) or placebo (n = 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean ± standard error [SE] difference, -8.1 ± 3.24; p = 0.012). Reductions in WOMAC physical function subscale (-4.9 ± 2.48; p = 0.048) and Brief Pain Inventory worst pain (-0.5 ± 0.28; p = 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

9.
N Engl J Med ; 378(21): 1987-1998, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29791829

RESUMO

BACKGROUND: X-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia. METHODS: In an open-label, phase 2 trial, we randomly assigned 52 children with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient-reported outcomes and the incidence of adverse events. RESULTS: The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P<0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both groups, the mean serum alkaline phosphatase level decreased from 459 U per liter at baseline to 369 U per liter at week 64. The mean standing-height z score increased in both groups, with greater improvement seen at all time points with every-2-week dosing (an increase from baseline of 0.19 at week 64) than with every-4-week dosing (an increase from baseline of 0.12 at week 64). Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity. CONCLUSIONS: In children with X-linked hypophosphatemia, treatment with burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets. (Funded by Ultragenyx Pharmaceutical and Kyowa Hakko Kirin; ClinicalTrials.gov number, NCT02163577 ; EudraCT number, 2014-000406-35 ).


Assuntos
Anticorpos Monoclonais/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Fosfatase Alcalina/sangue , Criança , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/metabolismo , Raquitismo Hipofosfatêmico Familiar/fisiopatologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Crescimento/efeitos dos fármacos , Humanos , Túbulos Renais/metabolismo , Articulação do Joelho/diagnóstico por imagem , Masculino , Manejo da Dor , Fósforo/sangue , Radiografia , Índice de Gravidade de Doença
10.
EMBO J ; 37(1): 122-138, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29118000

RESUMO

Postsynaptic density protein-95 (PSD-95) localizes AMPA-type glutamate receptors (AMPARs) to postsynaptic sites of glutamatergic synapses. Its postsynaptic displacement is necessary for loss of AMPARs during homeostatic scaling down of synapses. Here, we demonstrate that upon Ca2+ influx, Ca2+/calmodulin (Ca2+/CaM) binding to the N-terminus of PSD-95 mediates postsynaptic loss of PSD-95 and AMPARs during homeostatic scaling down. Our NMR structural analysis identified E17 within the PSD-95 N-terminus as important for binding to Ca2+/CaM by interacting with R126 on CaM. Mutating E17 to R prevented homeostatic scaling down in primary hippocampal neurons, which is rescued via charge inversion by ectopic expression of CaMR126E, as determined by analysis of miniature excitatory postsynaptic currents. Accordingly, increased binding of Ca2+/CaM to PSD-95 induced by a chronic increase in Ca2+ influx is a critical molecular event in homeostatic downscaling of glutamatergic synaptic transmission.


Assuntos
Sinalização do Cálcio , Calmodulina/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Sinapses/fisiologia , Animais , Calmodulina/química , Calmodulina/genética , Células Cultivadas , Proteína 4 Homóloga a Disks-Large/química , Proteína 4 Homóloga a Disks-Large/genética , Ácido Glutâmico/metabolismo , Hipocampo/citologia , Lipoilação , Modelos Moleculares , Neurônios/citologia , Ligação Proteica , Conformação Proteica , Ratos , Receptores de Glutamato/metabolismo , Transmissão Sináptica , Xenopus laevis/crescimento & desenvolvimento , Xenopus laevis/metabolismo
11.
Neurobiol Dis ; 109(Pt A): 25-32, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28927958

RESUMO

Rett syndrome (RTT) is a devastating neurodevelopmental disorder caused by loss-of-function mutations in the X-linked methyl-CpG binding protein 2 (Mecp2) gene. GABAergic dysfunction has been implicated contributing to the respiratory dysfunction, one major clinical feature of RTT. The nucleus tractus solitarius (NTS) is the first central site integrating respiratory sensory information that can change the nature of the reflex output. We hypothesized that deficiency in Mecp2 gene reduces GABAergic neurotransmission in the NTS. Using whole-cell patch-clamp recordings in NTS slices, we measured spontaneous inhibitory postsynaptic currents (sIPSCs), miniature IPSCs (mIPSCs), NTS-evoked IPSCs (eIPSCs), and GABAA receptor (GABAA-R) agonist-induced responses. Compared to those from wild-type mice, NTS neurons from Mecp2-null mice had significantly (p<0.05) reduced sIPSC amplitude, sIPSC frequency, and mIPSC amplitude but not mIPSC frequency. Mecp2-null mice also had decreased eIPSC amplitude with no change in paired-pulse ratio. The data suggest reduced synaptic receptor-mediated phasic GABA transmission in Mecp2-null mice. In contrast, muscimol (GABAA-R agonist, 0.3-100µM) and THIP (selective extrasynaptic GABAA-R agonist, 5µM) induced significantly greater current response in Mecp2-null mice, suggesting increased extrasynaptic receptors. Using qPCR, we found a 2.5 fold increase in the delta subunit of the GABAA-Rs in the NTS in Mecp2-null mice, consistent with increased extrasynaptic receptors. As the NTS was recently found required for respiratory pathology in RTT, our results provide a mechanism for NTS dysfunction which involves shifting the balance of synaptic/extrasynaptic receptors in favor of extrasynaptic site, providing a target for boosting GABAergic inhibition in RTT.


Assuntos
Potenciais Pós-Sinápticos Inibidores , Proteína 2 de Ligação a Metil-CpG/fisiologia , Neurônios/fisiologia , Síndrome de Rett/fisiopatologia , Núcleo Solitário/fisiologia , Transmissão Sináptica , Ácido gama-Aminobutírico/fisiologia , Animais , Modelos Animais de Doenças , Agonistas de Receptores de GABA-A , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Potenciais Pós-Sinápticos em Miniatura , Neurônios/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores de GABA-A/administração & dosagem , Receptores de GABA-A/fisiologia , Síndrome de Rett/metabolismo , Núcleo Solitário/metabolismo
12.
Environ Health Perspect ; 126(12): 127001, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30675795

RESUMO

BACKGROUND: Epidemiological evidence suggests that a majority of deaths attributed to secondhand smoke (SHS) exposure are cardiovascular related. However, to our knowledge, the impact of SHS on cardiac electrophysiology, [Formula: see text] handling, and arrhythmia risk has not been studied. OBJECTIVES: The purpose of this study was to investigate the impact of an environmentally relevant concentration of SHS on cardiac electrophysiology and indicators of arrhythmia. METHODS: Male C57BL/6 mice were exposed to SHS [total suspended particles (THS): [Formula: see text], nicotine: [Formula: see text], carbon monoxide: [Formula: see text], or filtered air (FA) for 4, 8, or 12 wk ([Formula: see text]]. Hearts were excised and Langendorff perfused for dual optical mapping with voltage- and [Formula: see text]-sensitive dyes. RESULTS: At slow pacing rates, SHS exposure did not alter baseline electrophysiological parameters. With increasing pacing frequency, action potential duration (APD), and intracellular [Formula: see text] alternans magnitude progressively increased in all groups. At 4 and 8 wk, there were no statistical differences in APD or [Formula: see text] alternans magnitude between SHS and FA groups. At 12 wk, both APD and [Formula: see text] alternans magnitude were significantly increased in the SHS compared to FA group ([Formula: see text]). SHS exposure did not impact the time constant of [Formula: see text] transient decay ([Formula: see text]) at any exposure time point. At 12 wk exposure, the recovery of [Formula: see text] transient amplitude with premature stimuli was slightly (but nonsignificantly) delayed in SHS compared to FA hearts, suggesting that [Formula: see text] release via ryanodine receptors may be impaired. CONCLUSIONS: In male mice, chronic exposure to SHS at levels relevant to social situations in humans increased their susceptibility to cardiac alternans, a known precursor to ventricular arrhythmia. https://doi.org/10.1289/EHP3664.


Assuntos
Arritmias Cardíacas/fisiopatologia , Coração/fisiopatologia , Poluição por Fumaça de Tabaco/efeitos adversos , Potenciais de Ação , Animais , Cálcio/metabolismo , Monóxido de Carbono/toxicidade , Estimulação Cardíaca Artificial , Eletrocardiografia , Masculino , Camundongos Endogâmicos C57BL , Nicotina/toxicidade , Material Particulado/toxicidade , Perfusão , Fibrilação Ventricular/metabolismo , Fibrilação Ventricular/fisiopatologia , Imagens com Corantes Sensíveis à Voltagem
13.
Schizophr Res ; 182: 90-97, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27789188

RESUMO

OBJECTIVE: To determine the safety and efficacy of AMG 747, an oral inhibitor of glycine transporter type-1 (GlyT1), as an add-on to antipsychotic therapy in clinically stable people with schizophrenia with enduring negative symptoms. METHOD: Analysis of pooled data from two phase 2 studies. Adults diagnosed with schizophrenia stabilized on antipsychotic medication randomized (2:2:2:3) to orally receive daily AMG 747 (5mg, 15mg, or 40mg) or placebo. Primary endpoint was Negative Symptom Assessment (NSA)-16 total score change from baseline to week 12. RESULTS: Studies were terminated early after a report of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) in one participant (40-mg AMG 747). At termination, 232 participants had enrolled and 153 completed 12weeks of treatment. At week 12, change from baseline NSA-16 total score showed no differences between groups. Mean decrease in Positive and Negative Syndrome Scale (PANSS) Negative Symptom Factor Score (NSFS) and NSA-16 global score were greater with 15-mg AMG 747 than placebo (p<0.05). Changes in PANSS-Positive Symptom Factor Scale were not significantly different for any group. Changes in patient-reported outcomes (Sheehan Disability Scale and Quality of Life Enjoyment and Satisfaction Questionnaire) showed trends consistent with greater efficacy of 15-mg AMG 747 compared with placebo (p≤0.1). Adverse event rates were similar among all groups, with no clear differences observed. CONCLUSIONS: Significant treatment effects of 15-mg AMG 747, but not higher or lower doses, were observed on secondary endpoints but not on the primary outcome. These results replicate previous reports of an inverted-U dose response curve and suggest further evaluation of GlyT1 inhibitors in schizophrenia negative symptoms is warranted. TRIAL REGISTRATION: Clinicaltrials.govNCT01568216 (https://clinicaltrials.gov/ct2/show/NCT01568216) and NCT01568229 (https://clinicaltrials.gov/ct2/show/NCT01568229?term=NCT01568229&rank=1); EudraCT number 2011-004844-23 and 2011-004845-42.


Assuntos
Antipsicóticos/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Piperazinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Adolescente , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Adulto Jovem
14.
PLoS One ; 9(9): e108021, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25229608

RESUMO

Perampanel is an aryl substituted 2-pyridone AMPA receptor antagonist that was recently approved as a treatment for epilepsy. The drug potently inhibits AMPA receptor responses but the mode of block has not been characterized. Here the action of perampanel on AMPA receptors was investigated by whole-cell voltage-clamp recording in cultured rat hippocampal neurons. Perampanel caused a slow (τ∼1 s at 3 µM), concentration-dependent inhibition of AMPA receptor currents evoked by AMPA and kainate. The rates of block and unblock of AMPA receptor currents were 1.5×105 M-1 s-1 and 0.58 s-1, respectively. Perampanel did not affect NMDA receptor currents. The extent of block of non-desensitizing kainate-evoked currents (IC50, 0.56 µM) was similar at all kainate concentrations (3-100 µM), demonstrating a noncompetitive blocking action. Parampanel did not alter the trajectory of AMPA evoked currents indicating that it does not influence AMPA receptor desensitization. Perampanel is a selective negative allosteric AMPA receptor antagonist of high-affinity and slow blocking kinetics.


Assuntos
Fenômenos Eletrofisiológicos/efeitos dos fármacos , Hipocampo/citologia , Hipocampo/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Piridonas/farmacologia , Receptores de AMPA/metabolismo , Animais , Células Cultivadas , Feminino , Ácido Caínico/farmacologia , Cinética , Gravidez , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/antagonistas & inibidores
15.
Eur Neuropsychopharmacol ; 24(10): 1615-21, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25172269

RESUMO

BACKGROUND: Persistent negative symptoms are an important area of clinical research. However, there is limited consensus on how to define positive and negative symptom severity thresholds for inclusion in clinical trials. From the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) dataset we evaluated the performance of varying baseline negative and positive symptom thresholds on baseline symptom severity, change from baseline, and negative symptom variance attributable to positive symptom change. METHODS: In CATIE, we first identified the group of subjects lacking an exacerbation prior to study enrollment. Six subsets with varying baseline positive and negative symptom thresholds were then identified. Baseline characteristics were summarized; negative and positive symptom change from baseline through month 3 was calculated both as crude change and change adjusted for corresponding baseline scores. Sensitivity analyses and correlations were calculated to assess the extent to which negative symptom variance was attributable to positive symptom change. RESULTS: More restrictive baseline symptom severity thresholds yielded a considerably smaller sample size and higher negative and lower positive symptoms at baseline. Unadjusted negative symptom change was greater with more restrictive criteria; when adjusted for baseline severity the magnitude of change was comparable across subsets. The amount of variance in negative symptom change attributed to positive symptom change was also comparable across subsets. CONCLUSIONS: The use of restrictive positive and negative symptom thresholds yields a marked decrease in eligible sample size with no clear improvement in adjusted negative symptom change or amount of variance associated with positive symptom change.


Assuntos
Pesquisa Biomédica/métodos , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Adulto , Antipsicóticos/uso terapêutico , Ensaios Clínicos como Assunto , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Esquizofrenia/tratamento farmacológico , Sensibilidade e Especificidade
16.
J Formos Med Assoc ; 113(6): 334-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24650494

RESUMO

Osteoporosis is a prevalent health concern among older adults and is associated with an increased risk of falls that incur fracture, injury, or mortality. Identifying the risk factors of falls within this population is essential for the development of effective regimes for fall prevention. Studies have shown that muscle quality and good posture alignments are critical for balance control in elderly individuals. People with osteoporosis often have muscle weakness and increased spine kyphosis leading to vertebral fractures and poor balance control, or even falls. Therefore, improving muscle quality, strengthening weak muscles, and correcting postural alignment are essential elements for the prevention of falls and fractures in older adults with osteoporosis. This review reports the necessary information regarding the critical factors of balance control in older adults with osteoporosis, as well as testing the clinical innovations of exercise training to improve the long-term prognosis of osteoporosis in this vulnerable population.


Assuntos
Osteoporose/fisiopatologia , Equilíbrio Postural , Acidentes por Quedas/prevenção & controle , Idoso , Exercício , Humanos , Força Muscular , Osteoporose/epidemiologia , Sarcopenia/epidemiologia , Sarcopenia/fisiopatologia
17.
Circ Res ; 114(4): 607-15, 2014 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-24323672

RESUMO

RATIONALE: Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca(2+)-activated K(+) (BKCa) channel function. The scaffolding protein A-kinase anchoring protein 150 (AKAP150) is a key regulator of calcineurin (CaN), a phosphatase known to modulate the expression of the regulatory BKCa ß1 subunit. Whether AKAP150 mediates BKCa channel suppression during hyperglycemia and diabetes mellitus is unknown. OBJECTIVE: To test the hypothesis that AKAP150-dependent CaN signaling mediates BKCa ß1 downregulation and impaired vascular BKCa channel function during hyperglycemia and diabetes mellitus. METHODS AND RESULTS: We found that AKAP150 is an important determinant of BKCa channel remodeling, CaN/nuclear factor of activated T-cells c3 (NFATc3) activation, and resistance artery constriction in hyperglycemic animals on high-fat diet. Genetic ablation of AKAP150 protected against these alterations, including augmented vasoconstriction. d-glucose-dependent suppression of BKCa channel ß1 subunits required Ca(2+) influx via voltage-gated L-type Ca(2+) channels and mobilization of a CaN/NFATc3 signaling pathway. Remarkably, high-fat diet mice expressing a mutant AKAP150 unable to anchor CaN resisted activation of NFATc3 and downregulation of BKCa ß1 subunits and attenuated high-fat diet-induced elevation in arterial blood pressure. CONCLUSIONS: Our results support a model whereby subcellular anchoring of CaN by AKAP150 is a key molecular determinant of vascular BKCa channel remodeling, which contributes to vasoconstriction during diabetes mellitus.


Assuntos
Proteínas de Ancoragem à Quinase A/metabolismo , Diabetes Mellitus Experimental/metabolismo , Hiperglicemia/metabolismo , Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Vasoconstrição/fisiologia , Proteínas de Ancoragem à Quinase A/genética , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/fisiopatologia , Gorduras na Dieta/farmacologia , Técnicas de Introdução de Genes , Hiperglicemia/genética , Hiperglicemia/fisiopatologia , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Fatores de Transcrição NFATC/metabolismo , Peptídeos/farmacologia , Transdução de Sinais/fisiologia , Toxinas Biológicas/farmacologia , Vasoconstrição/efeitos dos fármacos
18.
Am J Physiol Regul Integr Comp Physiol ; 305(10): R1153-62, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24068050

RESUMO

We previously described synaptic currents between baroreceptor fibers and second-order neurons in the nucleus tractus solitarius (NTS) that were larger in Syrian hamsters than in rats. This suggested that although electrical activity throughout the hamster brain decreased as brain temperature declined, the greater synaptic input to its NTS would support continued operation of cardiorespiratory reflexes at low body temperatures. Here, we focused on properties that would protect these neurons against potential damage from the larger synaptic inputs, testing the hypotheses that hamster NTS neurons exhibit: 1) intrinsic N-methyl-D-aspartate receptor (NMDAR) properties that limit Ca(2+) influx to a greater degree than do rat NTS neurons and 2) properties that reduce gating signals to NMDARs to a greater degree than in rat NTS neurons. Whole cell patch-clamp recordings on anatomically identified second-order NTS baroreceptive neurons showed that NMDAR-mediated synaptic currents between sensory fibers and second-order NTS neurons were larger in hamsters than in rats at 33°C and 15°C, with no difference in their permeability to Ca(2+). However, at 15°C, but not at 33°C, non-NMDAR currents evoked by glutamate released from baroreceptor fibers had significantly shorter durations in hamsters than in rats. Thus, hamster NMDARs did not exhibit lower Ca(2+) influx than did rats (negating hypothesis 1), but they did exhibit significant differences in non-NMDAR neuronal properties at low temperature (consistent with hypothesis 2). The latter (shorter duration of non-NMDAR currents) would likely limit NMDAR coincidence gating and may help protect hamster NTS neurons, enabling them to contribute to signal processing at low body temperatures.


Assuntos
Temperatura Baixa , Hibernação/fisiologia , Pressorreceptores/fisiologia , Transdução de Sinais/fisiologia , Núcleo Solitário/fisiologia , Animais , Regulação da Temperatura Corporal/fisiologia , Cricetinae , Regulação da Expressão Gênica/fisiologia , Masculino , Potenciais da Membrana/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleo Solitário/citologia
19.
Am J Physiol Regul Integr Comp Physiol ; 305(7): R759-68, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23904107

RESUMO

Hibernating mammals undergo torpor during which blood pressure (BP), heart rate (HR), metabolic rate, and core temperature (TC) dramatically decrease, conserving energy. While the cardiovascular system remains functional, temporal changes in BP, HR, and baroreceptor-HR reflex sensitivity (BRS) over complete hibernation bouts and their relation to TC are unknown. We implanted BP/temperature telemetry transmitters into Syrian hamsters to test three hypotheses: H-1) BP, HR, and BRS decrease concurrently during entry into hibernation and increase concurrently during arousal; H-2) these changes occur before changes in TC; and H-3) the pattern of changes is consistent over successive bouts. We found: 1) upon hibernation entry, BP and HR declined before TC and BRS, suggesting baroreflex control of HR continues to regulate BP as the BP set point decreases; 2) during the later phase of entry, BRS decreased rapidly whereas BP and TC fell gradually, suggesting the importance of TC in further BP declines; 3) during torpor, BP slowly increased (but remained relatively low) without changes in HR or BRS or increased TC, suggesting minimal baroreflex or temperature influence; 4) during arousal, increased TC and BRS significantly lagged increases in BP and HR, consistent with establishment of tissue perfusion before increased TC/metabolism; and 5) the temporal pattern of these changes was similar over successive bouts in all hamsters. These results negate H-1, support H-2 with respect to BP and HR, support H-3, and indicate that the baroreflex contributes to cardiovascular regulation over a hibernation bout, albeit operating in a fundamentally different manner during entry vs. arousal.


Assuntos
Barorreflexo , Pressão Sanguínea , Regulação da Temperatura Corporal , Frequência Cardíaca , Hibernação , Animais , Nível de Alerta , Monitorização Ambulatorial da Pressão Arterial , Cricetinae , Eletrocardiografia Ambulatorial , Metabolismo Energético , Feminino , Masculino , Mesocricetus , Telemetria , Fatores de Tempo
20.
Am J Kidney Dis ; 61(2): 238-46, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23159232

RESUMO

BACKGROUND: Sparse data are available about the natural history of hemoglobin (Hb) level trends in contemporary patients with anemia, chronic kidney disease (CKD), and type 2 diabetes mellitus. We intended to describe Hb level trends over time with no or minimal administration of erythropoiesis-stimulating agents. STUDY DESIGN: Prospective clinical trial cohort. SETTING & PARTICIPANTS: 2,019 individuals with type 2 diabetes, moderate anemia, and CKD from the placebo arm of the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) followed up for 2.3 years with an average of 32 monthly Hb level determinations per patient. Darbepoetin alfa was administered only if Hb level decreased to <9 g/dL. OUTCOMES & MEASUREMENTS: Number of protocol-directed doses of darbepoetin alfa received due to an Hb level decrease to <9 g/dL. RESULTS: 1,106 (55%) placebo patients consistently maintained an Hb level ≥9 g/dL and received no protocol-directed darbepoetin alfa. The other patients received 1 (16%), 2-4 (16%), or 5 or more (13%) doses of darbepoetin alfa. Those who received no darbepoetin alfa doses had higher baseline Hb levels, higher estimated glomerular filtration rates (eGFRs), less proteinuria, and lower ferritin and transferrin saturation values. On average, Hb levels were stable or increased in all groups. Compared with individuals who received no darbepoetin alfa, those who received 5 or more doses were more likely to receive intravenous iron therapy and blood transfusions and progress to renal replacement therapy, but were not at higher risk of death. The strongest predictors of requiring 5 or more doses of darbepoetin alfa were lower baseline Hb level, lower eGFR, and higher proteinuria level. LIMITATIONS: Post hoc analysis of a clinical trial of a specific population with diabetes, anemia, and non-dialysis-dependent CKD. CONCLUSIONS: In the TREAT placebo arm, Hb levels were stable with no or minimal protocol-directed darbepoetin alfa during 2.3 years of follow-up. Most patients with moderate anemia, non-dialysis-dependent CKD, and type 2 diabetes are able to maintain a stable Hb level without implementing long-term erythropoiesis-stimulating agent therapy.


Assuntos
Anemia/sangue , Anemia/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Eritropoetina/análogos & derivados , Hematínicos/farmacologia , Hematínicos/uso terapêutico , Hemoglobinas/análise , Insuficiência Renal Crônica/sangue , Idoso , Darbepoetina alfa , Método Duplo-Cego , Eritropoetina/farmacologia , Eritropoetina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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