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1.
Sci Rep ; 9(1): 1448, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30723302

RESUMO

The cerebellar cortex is involved in the control of diverse motor and non-motor functions. Its principal circuit elements are the Purkinje cells that integrate incoming excitatory and local inhibitory inputs and provide the sole output of the cerebellar cortex. However, the transcriptional control of circuit assembly in the cerebellar cortex is not well understood. Here, we show that NeuroD2, a neuronal basic helix-loop-helix (bHLH) transcription factor, promotes the postnatal survival of both granule cells and molecular layer interneurons (basket and stellate cells). However, while NeuroD2 is not essential for the integration of surviving granule cells into the excitatory circuit, it is required for the terminal differentiation of basket cells. Axons of surviving NeuroD2-deficient basket cells follow irregular trajectories and their inhibitory terminals are virtually absent from Purkinje cells in Neurod2 mutants. As a result inhibitory, but not excitatory, input to Purkinje cells is strongly reduced in the absence of NeuroD2. Together, we conclude that NeuroD2 is necessary to instruct a terminal differentiation program in basket cells that regulates targeted axon growth and inhibitory synapse formation. An imbalance of excitation and inhibition in the cerebellar cortex affecting Purkinje cell output may underlay impaired adaptive motor learning observed in Neurod2 mutants.

2.
Nat Commun ; 9(1): 666, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29445168

RESUMO

Efficient sunlight harvesting and re-directioning onto small areas has great potential for more widespread use of precious high-performance photovoltaics but so far intrinsic solar concentrator loss mechanisms outweighed the benefits. Here we present an antenna concept allowing high light absorption without high reabsorption or escape-cone losses. An excess of randomly oriented pigments collects light from any direction and funnels the energy to individual acceptors all having identical orientations and emitting ~90% of photons into angles suitable for total internal reflection waveguiding to desired energy converters (funneling diffuse-light re-directioning, FunDiLight). This is achieved using distinct molecules that align efficiently within stretched polymers together with others staying randomly orientated. Emission quantum efficiencies can be >80% and single-foil reabsorption <0.5%. Efficient donor-pool energy funneling, dipole re-orientation, and ~1.5-2 nm nearest donor-acceptor transfer occurs within hundreds to ~20 ps. Single-molecule 3D-polarization experiments confirm nearly parallel emitters. Stacked pigment selection may allow coverage of the entire solar spectrum.

3.
Nat Neurosci ; 20(1): 10-15, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27775720

RESUMO

The molecular trigger of CNS myelination is unknown. By targeting Pten in cerebellar granule cells and activating the AKT1-mTOR pathway, we increased the caliber of normally unmyelinated axons and the expression of numerous genes encoding regulatory proteins. This led to the expansion of genetically wild-type oligodendrocyte progenitor cells, oligodendrocyte differentiation and de novo myelination of parallel fibers. Thus, a neuronal program dependent on the phosphoinositide PI(3,4,5)P3 is sufficient to trigger all steps of myelination.


Assuntos
Axônios/metabolismo , Bainha de Mielina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Oligodendroglia/citologia , Fosfatidilinositóis/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Camundongos Transgênicos
4.
Eur Heart J ; 37(27): 2105-14, 2016 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-27130705

RESUMO

AIMS: To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus. METHODS AND RESULTS: Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: NCT01807221). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7-10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.5→5, 5→10, 7.5→15, 10→20, and 15→20 mg finerenone groups, respectively (P = 0.42-0.88). Except for the 2.5→5 mg finerenone group, the composite clinical endpoint occurred numerically less frequently in finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 10→20 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups. CONCLUSION: Finerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the finerenone 10→20 mg group should be further explored in a large outcomes trial.


Assuntos
Insuficiência Cardíaca , Idoso , Doença Crônica , Diabetes Mellitus , Método Duplo-Cego , Eplerenona , Humanos , Antagonistas de Receptores de Mineralocorticoides , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Insuficiência Renal Crônica , Espironolactona/análogos & derivados
5.
JAMA ; 314(9): 884-94, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26325557

RESUMO

IMPORTANCE: Steroidal mineralocorticoid receptor antagonists, when added to a renin-angiotensin system blocker, further reduce proteinuria in patients with chronic kidney disease but may be underused because of a high risk of adverse events. OBJECTIVE: To evaluate the safety and efficacy of different oral doses of the nonsteroidal mineralocorticoid receptor antagonist finerenone, given for 90 days to patients with diabetes and high or very high albuminuria who are receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled, parallel-group study conducted at 148 sites in 23 countries. Patients were recruited from June 2013 to February 2014 and the study was completed in August 2014. Of 1501 screened patients, 823 were randomized and 821 received study drug. INTERVENTIONS: Participants were randomly assigned to receive oral, once-daily finerenone (1.25 mg/d, n = 96; 2.5 mg/d, n = 92; 5 mg/d, n = 100; 7.5 mg/d, n = 97; 10 mg/d, n = 98; 15 mg/d, n = 125; and 25 mg/d, n = 119) or matching placebo (n = 94) for 90 days. MAIN OUTCOMES AND MEASURES: The primary outcome was the ratio of the urinary albumin-creatinine ratio (UACR) at day 90 vs at baseline. Safety end points were changes from baseline in serum potassium and estimated glomerular filtration rate. RESULTS: The mean age of the participants was 64.2 years; 78% were male. At baseline, 36.7% of patients treated had very high albuminuria (UACR ≥300 mg/g) and 40.0% had an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or lower. Finerenone demonstrated a dose-dependent reduction in UACR. The primary outcome, the placebo-corrected mean ratio of the UACR at day 90 relative to baseline, was reduced in the finerenone 7.5-, 10-, 15-, and 20-mg/d groups (for 7.5 mg/d, 0.79 [90% CI, 0.68-0.91; P = .004]; for 10 mg/d, 0.76 [90% CI, 0.65-0.88; P = .001]; for 15 mg/d, 0.67 [90% CI, 0.58-0.77; P<.001]; for 20 mg/d, 0.62 [90% CI, 0.54-0.72; P < .001]). The prespecified secondary outcome of hyperkalemia leading to discontinuation was not observed in the placebo and finerenone 10-mg/d groups; incidences in the finerenone 7.5-, 15-, and 20-mg/d groups were 2.1%, 3.2%, and 1.7%, respectively. There were no differences in the incidence of the prespecified secondary outcome of an estimated glomerular filtration rate decrease of 30% or more or in incidences of adverse events and serious adverse events between the placebo and finerenone groups. CONCLUSIONS AND RELEVANCE: Among patients with diabetic nephropathy, most receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, the addition of finerenone compared with placebo resulted in improvement in the urinary albumin-creatinine ratio. Further trials are needed to compare finerenone with other active medications. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT1874431.


Assuntos
Albuminúria/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Naftiridinas/administração & dosagem , Administração Oral , Idoso , Análise de Variância , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Creatinina/urina , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/urina , Nefropatias Diabéticas/etnologia , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/urina , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hiperpotassemia/induzido quimicamente , Hiperpotassemia/epidemiologia , Incidência , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Naftiridinas/efeitos adversos , Potássio/sangue
6.
Adv Hematol ; 2015: 431268, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26356675

RESUMO

Objectives. Prophylaxis regimens for severe hemophilia A allowing more flexible dosing while maintaining efficacy may improve adherence and decrease the cost of prophylaxis. Here, we compared the clinical effectiveness of once- or twice-weekly versus ≥3-times-weekly prophylaxis with sucrose-formulated recombinant factor VIII (rFVIII-FS) in a "real-world" practice setting. Methods. Data from 3 postmarketing studies were pooled. Patients with severe hemophilia A receiving ≥1 prophylaxis infusion/wk of rFVIII-FS for ≥80% of a prophylaxis observation period (≥5 months) were included. Patients were categorized based on physician-assigned treatment regimens of 1-2 prophylaxis injections/wk (n = 63) or ≥3 prophylaxis injections/wk (n = 76). Descriptive statistics were determined for annualized bleeding rates (ABRs). Results. Median (quartile 1; quartile 3) ABR for all bleeds was 2.0 (0; 4.0) in the 1-2 prophylaxis injections/wk group and 3.9 (1.5; 9.3) in the ≥3 prophylaxis injections/wk group. Median ABRs for joint, spontaneous, and trauma-related bleeds were numerically lower with 1-2 prophylaxis injections/wk. As an estimate of prophylaxis success, 63% (≥3 prophylaxis injections/wk) to 84% of patients (1-2 prophylaxis injections/wk) had ≤4 annualized joint bleeds. Conclusions. Dosing flexibility and successful prophylaxis with rFVIII-FS were demonstrated. Very good bleeding control was achieved with both once-twice-weekly and ≥3-times-weekly prophylaxis dosing regimens.

7.
Eur J Heart Fail ; 17(2): 224-32, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25678098

RESUMO

AIMS: To investigate the safety and potential efficacy of the novel non-steroidal mineralocorticoid receptor antagonist finerenone in patients with worsening chronic heart failure and reduced left ventricular ejection fraction (HFrEF) and at high risk of hyperkalaemia and worsening renal dysfunction. METHODS AND RESULTS: The MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF; NCT01807221) is a multicentre, randomized, double-blind, active-comparator-controlled, six-parallel-group, phase 2b dose-finding study. In total, 1060 patients with HFrEF and concomitant type 2 diabetes mellitus and/or chronic kidney disease (CKD) will be randomized within 7 days of emergency presentation to hospital for worsening chronic HF to receive finerenone (one of five doses in the range 2.5-20.0 mg once daily) or eplerenone (25 mg every second day to 50 mg once daily for 90 days). The primary objective is to investigate the safety and potential efficacy (measured as the percentage of individuals with a decrease in plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP] of more than 30% relative to baseline at day 90 ± 2) of different oral doses of finerenone compared with eplerenone. Other objectives are to assess the effects of finerenone on a composite clinical endpoint (death from any cause, cardiovascular hospitalizations, or emergency presentations for worsening chronic HF), and on changes in health-related quality of life from baseline. CONCLUSIONS: ARTS-HF is the first phase 2b clinical trial to investigate the effects of finerenone on plasma NT-proBNP in a high-risk population of patients who have worsening chronic HF with type 2 diabetes mellitus and/or CKD presenting at the emergency department.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Naftiridinas/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Espironolactona/análogos & derivados , Comorbidade , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Eplerenona , Insuficiência Cardíaca/sangue , Humanos , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Naftiridinas/efeitos adversos , Natriuréticos/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Insuficiência Renal Crônica/sangue , Espironolactona/efeitos adversos , Espironolactona/uso terapêutico
8.
Am J Nephrol ; 40(6): 572-81, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25591469

RESUMO

BACKGROUND/AIMS: Finerenone decreases albuminuria in patients having heart failure with reduced ejection fraction and mild-to-moderate (stage 2-3) chronic kidney disease. The MinerAlocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN; NCT01874431) is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2b study. ARTS-DN investigated whether the mineralocorticoid receptor antagonist finerenone reduces albuminuria without causing major alterations in serum potassium levels in patients with type 2 diabetes mellitus and a clinical diagnosis of DN who were receiving a renin-angiotensin-system (RAS) inhibitor. METHODS: Patients were randomized to oral finerenone 1.25-20 mg or placebo once daily. The primary objectives were to assess the ratio of the urinary albumin-to-creatinine ratio at day 90 to that at baseline in patients receiving finerenone, and to compare it with that in the placebo group. Additional exploratory analyses included evaluating changes from baseline in serum potassium levels, efficacy and safety biomarkers, and health-related quality of life. RESULTS: Of 1,501 patients screened, 821 (the sample population) received at least one dose of finerenone/placebo. Baseline characteristics included: male, 77.8%; white, 84.2%; very high albuminuria (formerly macroalbuminuria), 38.4%; high albuminuria (formerly microalbuminuria), 60.3%; median (range) estimated glomerular filtration rate, 66.3 (24.5-130.7) ml/min/1.73 m(2); and systolic blood pressure (mean ± standard deviation), 138.1 ± 14.4 mm Hg. There was a history of cardiovascular disease in 39.6%, diabetic neuropathy in 20.0%, and diabetic retinopathy in 19.9% of patients. CONCLUSION: ARTS-DN is the first phase 2b trial of finerenone in combination with a RAS inhibitor in patients with type 2 diabetes mellitus and a clinical diagnosis of DN.


Assuntos
Albuminúria/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Naftiridinas/administração & dosagem , Idoso , Albuminúria/urina , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Creatinina/urina , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/urina , Método Duplo-Cego , Hipertensão Pulmonar Primária Familiar/complicações , Hipertensão Pulmonar Primária Familiar/tratamento farmacológico , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Naftiridinas/efeitos adversos , Potássio/sangue
9.
J Neurosci ; 33(2): 641-51, 2013 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-23303943

RESUMO

Establishment of long-range fiber tracts by neocortical projection neurons is fundamental for higher brain functions. The molecular control of axon tract formation, however, is still poorly understood. Here, we have identified basic helix-loop-helix (bHLH) transcription factors Neurod2 and Neurod6 as key regulators of fasciculation and targeted axogenesis in the mouse neocortex. In Neurod2/6 double-mutant mice, callosal axons lack expression of the cell adhesion molecule Contactin2, defasciculate in the subventricular zone, and fail to grow toward the midline without forming Probst bundles. Instead, mutant axons overexpress Robo1 and follow random trajectories into the ipsilateral cortex. In contrast to long-range axogenesis, generation and maintenance of pyramidal neurons and initial axon outgrowth are grossly normal, suggesting that these processes are under distinct transcriptional control. Our findings define a new stage in corpus callosum development and demonstrate that neocortical projection neurons require transcriptional specification by neuronal bHLH proteins to execute an intrinsic program of remote connectivity.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Córtex Cerebral/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Vias Neurais/fisiologia , Neurônios/fisiologia , Neuropeptídeos/fisiologia , Animais , Animais Recém-Nascidos/fisiologia , Axônios/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Contactina 2/genética , Contactina 2/fisiologia , Corpo Caloso/citologia , Corpo Caloso/crescimento & desenvolvimento , Corpo Caloso/fisiologia , Eletroporação , Embrião de Mamíferos/citologia , Embrião de Mamíferos/fisiologia , Genótipo , Glutamatos/fisiologia , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Hibridização In Situ , Microdissecção e Captura a Laser , Camundongos , Fibras Nervosas/fisiologia , Proteínas do Tecido Nervoso/genética , Vias Neurais/citologia , Vias Neurais/crescimento & desenvolvimento , Neurogênese/fisiologia , Reação em Cadeia da Polimerase , Receptores Imunológicos/genética , Receptores Imunológicos/fisiologia , Sinapses/fisiologia
10.
EMBO Mol Med ; 4(6): 486-99, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22488882

RESUMO

'Tomacula' and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the molecular mechanisms of tomacula formation have remained obscure. We hypothesized that they are caused by uncontrolled, excessive myelin membrane growth, a process, which is regulated in normal development by neuregulin-1/ErbB2, PI3 Kinase signalling and ERK/MAPK signalling. Here, we demonstrate by targeted disruption of Pten in Schwann cells that hyperactivation of the endogenous PI3 Kinase pathway causes focal hypermyelination, myelin outfoldings and tomacula, even when induced in adult animals by tamoxifen, and is associated with progressive peripheral neuropathy. Activated AKT kinase is associated with PtdIns(3,4,5)P(3) at paranodal loops and Schmidt-Lanterman incisures. This striking myelin pathology, with features of human CMT type 4B1 and HNPP, is dependent on AKT/mTOR signalling, as evidenced by a significant amelioration of the pathology in mice treated with rapamycin. We suggest that regions of non-compact myelin are under lifelong protection by PTEN against abnormal membrane outgrowth, and that dysregulated phosphoinositide levels play a critical role in the pathology of tomaculous neuropathies.


Assuntos
Artrogripose/patologia , Técnicas de Inativação de Genes , Neuropatia Hereditária Motora e Sensorial/patologia , Bainha de Mielina/patologia , PTEN Fosfo-Hidrolase/deficiência , Animais , Linhagem Celular , Modelos Animais de Doenças , Camundongos , Células de Schwann/química , Células de Schwann/citologia
11.
Genesis ; 42(4): 247-52, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16028233

RESUMO

NeuroD/Beta2 is a basic helix-loop-helix (bHLH) transcription factor with important functions during development of the pancreas and the nervous system. NeuroD null mutant mice die perinatally due to diabetes caused by impaired differentiation of pancreatic endocrine cells. Additionally, null mutants display severe defects in the formation of cerebellar and hippocampal granule cells, inner ear sensory neurons, and retinal photoreceptor cells. For spatio-temporally restricted inactivation of the NeuroD gene, we generated conditional mouse mutants by flanking the NeuroD coding region with loxP sites. Homozygous NeuroD(loxP) mutant mice are fully viable and express normal levels of NeuroD mRNA and protein. Breeding NeuroD(loxP) mice to Tg(malpha6-Cre)B1LFR mice that express Cre recombinase under control of the GABA(A) receptor alpha6 subunit promoter resulted in efficient inactivation of the NeuroD gene in post-migratory cerebellar granule cells and a subset of brainstem nuclei. The NeuroD(loxP) mouse mutant will be a valuable tool to study the developmental and adult function of NeuroD in nervous system and pancreas.


Assuntos
Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica no Desenvolvimento , Sequências Hélice-Alça-Hélice/genética , Camundongos Mutantes Neurológicos/genética , Proteínas do Tecido Nervoso/genética , Transativadores/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular/genética , Sistema Nervoso Central/citologia , Sistema Nervoso Central/crescimento & desenvolvimento , Proteínas da Matriz Extracelular/biossíntese , Proteínas da Matriz Extracelular/genética , Técnicas de Transferência de Genes , Genótipo , Imuno-Histoquímica , Integrases/biossíntese , Integrases/genética , Camundongos , Modelos Animais , Pâncreas/citologia , Pâncreas/crescimento & desenvolvimento , Proteína-Lisina 6-Oxidase/biossíntese , Proteína-Lisina 6-Oxidase/genética
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