RESUMO
OBJECTIVES: In Parkinson's disease, Pisa syndrom (PS) has been associated with disease stage and severity, combined treatment with levodopa and dopamine agonists, gait disorders, and comorbidities. Some forms of PS are potentially reversible; nevertheless, little is known about the impact of this syndrome on survival. DESIGN: Prospective study with a median follow-up of 2 years. SETTING AND PARTICIPANTS: Patients with Parkinson's disease, age 65 years and older (N = 189), attending a geriatric day hospital. MEASUREMENTS: According to established criteria, PS was diagnosed in the presence of at least 10° lateral flexion of the trunk reducible by passive mobilization or supine positioning. Cox regression was adopted to assess the association of PS with all-cause mortality. RESULTS: PS was diagnosed in 40 patients (21%); over the follow-up, 21 (11%) subjects died. In Cox regression, PS was associated with higher mortality [hazard ratio (HR) 4.10; 95% confidence interval (CI) = 1.36-12.38], after adjusting; other variables associated with mortality were age (HR = 1.19, 95% CI = 1.08-1.32), beta blockers (HR = 4.35, 95% CI = 1.23-15.39), and albumin levels (HR = 0.05, 95% CI = 0.01-0.33). The association of PS with mortality remained significant also after adjusting for variables associated with this syndrome (HR = 4.04, 95% CI = 1.33-12.25). CONCLUSIONS/IMPLICATIONS: PS represents a risk factor for earlier mortality in Parkinson's disease; further studies are needed to ascertain the underlying causes and whether treatment of this condition might improve survival.
Assuntos
Antiparkinsonianos/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/mortalidade , Equilíbrio Postural/efeitos dos fármacos , Curvaturas da Coluna Vertebral/induzido quimicamente , Idoso , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Fatores de Risco , SíndromeRESUMO
Mutations of EXOSC3 have been linked to the rare neurological disorder known as Pontocerebellar Hypoplasia type 1B (PCH1B). EXOSC3 is one of three putative RNA-binding structural cap proteins that guide RNA into the RNA exosome, the cellular machinery that degrades RNA. Using RNAcompete, we identified a G-rich RNA motif binding to EXOSC3. Surface plasmon resonance (SPR) and microscale thermophoresis (MST) indicated an affinity in the low micromolar range of EXOSC3 for long and short G-rich RNA sequences. Although several PCH1B-causing mutations in EXOSC3 did not engage a specific RNA motif as shown by RNAcompete, they exhibited lower binding affinity to G-rich RNA as demonstrated by MST. To test the hypothesis that modification of the RNA-protein interface in EXOSC3 mutants may be phenocopied by small molecules, we performed an in-silico screen of 50â¯000 small molecules and used enzyme-linked immunosorbant assays (ELISAs) and MST to assess the ability of the molecules to inhibit RNA-binding by EXOSC3. We identified a small molecule, EXOSC3-RNA disrupting (ERD) compound 3 (ERD03), which ( i) bound specifically to EXOSC3 in saturation transfer difference nuclear magnetic resonance (STD-NMR), ( ii) disrupted the EXOSC3-RNA interaction in a concentration-dependent manner, and ( iii) produced a PCH1B-like phenotype with a 50% reduction in the cerebellum and an abnormally curved spine in zebrafish embryos. This compound also induced modification of zebrafish RNA expression levels similar to that observed with a morpholino against EXOSC3. To our knowledge, this is the first example of a small molecule obtained by rational design that models the abnormal developmental effects of a neurodegenerative disease in a whole organism.
Assuntos
Modelos Animais de Doenças , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Isoquinolinas/farmacologia , Isoquinolinas/toxicidade , Atrofias Olivopontocerebelares/genética , Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , Peixe-Zebra/anormalidades , Animais , Atrofia , Cerebelo/patologia , Regulação para Baixo , Complexo Multienzimático de Ribonucleases do Exossomo/química , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Técnicas de Silenciamento de Genes , Humanos , Isoquinolinas/metabolismo , Simulação de Acoplamento Molecular , Mutação , Atrofias Olivopontocerebelares/induzido quimicamente , Atrofias Olivopontocerebelares/patologia , Fenótipo , Ligação Proteica , Domínios Proteicos , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Curvaturas da Coluna Vertebral/induzido quimicamente , Transcriptoma/efeitos dos fármacos , Regulação para CimaRESUMO
OBJECTIVE: The aim of this study was to evaluate the relationship between antiparkinsonian treatments, especially dopamine agonist (DAs) and the development of postural disorders in patients with Parkinson's disease (PD). METHODS: We performed an exploratory case-control study. Cases were PD patients with camptocormia, Pisa syndrome, or anterocollis. Control subjects were PD patients without postural disorders matched by sex and age. Demographic and clinical data including pharmacologic treatments history were collected retrospectively. Characteristics of cases and control subjects were compared using parametric and nonparametric tests accordingly, and logistic regression models were used to analyze correlations. RESULTS: We included 63 patients with PD and postural disorders and 63 control subjects. Cases were more exposed to DAs (74.60% vs 58.73%, P = 0.05) and amantadine (30.16% vs 7.94%, P < 0.05) than control subjects. Cases showed longer disease duration (7.63 ± 7.83 vs 4.27 ± 3.87 years, P < 0.05), higher Hoehn and Yahr stage (2.83 ± 0.80 vs 2.15 ± 0.73, P < 0.05), higher Movement Disorder Society Unified Parkinson's Disease Rating Scale part III score (29.61 ± 1.39 vs 20.76 ± 10.94, P = 0.05), and more dyslipidemia (28.57% vs 12.70%, P < 0.05) than control subjects, as well as lower prevalence of depression (46.03% vs 28.57%, P < 0.05). We found no clinical predictors for the development of postural disorders after multivariable adjusted regression. CONCLUSIONS: Our results suggest a possible association between the use of DAs and amantadine and the development of postural disorders in PD and suggest potential risk factors including advanced disease and more severe motor symptoms. These results support the need of a cautious use of these medications in patients with advanced disease due to the possibility of increasing the risk-benefit ratio.
Assuntos
Antiparkinsonianos/efeitos adversos , Atrofia Muscular Espinal/induzido quimicamente , Pescoço/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Postura , Curvaturas da Coluna Vertebral/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Avaliação da Deficiência , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Postura/fisiologia , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Tronco/fisiopatologiaRESUMO
Camptocormia, a condition that involves the abnormal flexion of the trunk and results in a forward-bending posture, is relatively common during the course of Parkinson disease (PD). Despite this, there is ongoing controversy concerning its mechanisms and no consensus regarding the underlying etiology. This report demonstrates a case in which a dopaminergic agonist (DA) was implicated in the onset of camptocormia episodes in a non-PD patient who developed camptocormia after the start of DA treatment. Over a course of 8 years, the patient experienced intermittent camptocormia, which resulted in multiple falls. After cessation of the DA, the patient showed decreased camptocormia symptoms. This case report suggests that clinicians should consider the possibility of DA-induced camptocormia in patients with PD and non-PD patients receiving DA treatments, and serves to caution clinicians regarding the administration of DAs.
Assuntos
Agonistas de Dopamina/efeitos adversos , Indóis/efeitos adversos , Atrofia Muscular Espinal/induzido quimicamente , Curvaturas da Coluna Vertebral/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Agonistas de Dopamina/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Indóis/uso terapêutico , Atrofia Muscular Espinal/metabolismo , Curvaturas da Coluna Vertebral/metabolismo , Tremor/tratamento farmacológicoRESUMO
The escalating demand for fipronil by the increasing insects' resistance to synthetic pyrethroids placed a burden on aquatic vertebrates. Although awareness regarding the toxicity of fipronil to fish is arising, the integral alteration caused by fipronil remains unexplored. Here, we investigated on the development toxicity of fipronil and the metabolic physiology perturbation at 120h post fertilization through GC-MS metabolomics on zebrafish embryo. We observed that fipronil dose-dependently induced malformations including uninflated swim bladder and bent spine. Further, the "omic" technique hit 26 differential metabolites after exposure to fipronil and five significant signaling pathways. We speculated that changes in primary bile acid synthesis pathway and the content of saturated fatty acid in the chemical-related group indicated the liver toxicity. Pathway of Aminoacyl-tRNA biosynthesis changed by fipronil may relate to the macromolecular synthesis. Concurrently, methane metabolism pathway was also identified while the role in zebrafish needs further determination. Overall, this study revealed several new signaling pathways in fipronil-treated zebrafish embryo/larval.
Assuntos
Embrião não Mamífero/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Pirazóis/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Sacos Aéreos/anormalidades , Sacos Aéreos/efeitos dos fármacos , Sacos Aéreos/embriologia , Animais , Relação Dose-Resposta a Droga , Embrião não Mamífero/anormalidades , Embrião não Mamífero/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Larva , Metabolômica , Atrofia Muscular Espinal/induzido quimicamente , Atrofia Muscular Espinal/embriologia , Curvaturas da Coluna Vertebral/induzido quimicamente , Curvaturas da Coluna Vertebral/embriologia , Peixe-Zebra/embriologiaAssuntos
Antipsicóticos/efeitos adversos , Benzodiazepinas/efeitos adversos , Atrofia Muscular Espinal/induzido quimicamente , Atrofia Muscular Espinal/diagnóstico , Curvaturas da Coluna Vertebral/induzido quimicamente , Curvaturas da Coluna Vertebral/diagnóstico , Adulto , Humanos , Masculino , Olanzapina , Esquizofrenia Paranoide/diagnóstico , Esquizofrenia Paranoide/tratamento farmacológicoRESUMO
In recent years, the management of Parkinson's disease (PD) has come a long way, leading to an increase in therapeutic options that now include oral and transdermal drug delivery, infusion as well as surgical treatments. Nonetheless, in the evolution of this complex neurodegenerative disorder, several symptoms remain refractory to dopaminergic therapy. It is our aim to review the literature to date and to bring them into focus, as well as emphasizing on pathophysiological mechanisms, profile of risk factors in their development, and therapeutic options. We will focus on freezing of gait, camptocormia, dysphagia and dysphonia, as well as cognitive impairment and dementia because they represent the far end of therapy-resistant symptoms, encompassing poor health-related quality of life and often a more reserved prognosis with either a rapid evolution of the disease, and/or merely a more severe clinical picture. Pathophysiological mechanisms and brain neurotransmitter abnormalities behind these symptoms seem to overlap to some extent, and a better understanding of these correlations is desirable. We believe that further research is paramount to expand our knowledge of the dopamine-resistant symptoms and, consequently, to develop specific therapeutic strategies.
Assuntos
Antiparasitários/efeitos adversos , Resistência a Medicamentos/fisiologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Transtornos Cognitivos/induzido quimicamente , Transtornos de Deglutição/induzido quimicamente , Disfonia/induzido quimicamente , Transtornos Neurológicos da Marcha/induzido quimicamente , Humanos , Atrofia Muscular Espinal/induzido quimicamente , Transtornos de Sensação/induzido quimicamente , Curvaturas da Coluna Vertebral/induzido quimicamenteAssuntos
Inibidores da Captação Adrenérgica/efeitos adversos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Atrofia Muscular Espinal/induzido quimicamente , Propilaminas/efeitos adversos , Curvaturas da Coluna Vertebral/induzido quimicamente , Inibidores da Captação Adrenérgica/uso terapêutico , Cloridrato de Atomoxetina , Criança , Seguimentos , Humanos , Masculino , Propilaminas/uso terapêuticoRESUMO
Perfluorooctane sulphonate (PFOS) is one of the most commonly detected perfluorinated alkylated substances in the aquatic environment due to its persistence and the degradation of less stable compounds to PFOS. PFOS is known to cause developmental effects in fish. The main effect of PFOS in zebrafish larvae is an uninflated swim bladder. As no previous studies have focused on the effect of PFOS on zebrafish swim bladder inflation, the exact mechanisms leading to this effect are currently unknown. The objective of this study was to determine the exposure windows during early zebrafish development that are sensitive to PFOS exposure and result in impaired swim bladder inflation in order to specify the mechanisms by which this effect might be caused. Seven different time windows of exposure (1-48, 1-72, 1-120, 1-144, 48-144, 72-144, 120-144h post fertilization (hpf)) were tested based on the different developmental stages of the swim bladder. These seven time windows were tested for four concentrations corresponding to the EC-values of 1, 10, 80 and 95% impaired swim bladder inflation (EC1=0.70 mg L(-1), EC10=1.14 mg L(-1), EC80=3.07 mg L(-1) and EC95=4.28 mg L(-1)). At 6 days post fertilization, effects on survival, hatching, swim bladder inflation and size, larval length and swimming performance were assessed. For 0.70 mg L(-1), no significant effects were found for the tested parameters while 1.14 mg L(-1) resulted in a reduction of larval length. For 3.07 and 4.28 mg L(-1), the number of larvae affected and the severity of effects caused by PFOS were dependent on the time window of exposure. Exposure for 3 days or more resulted in significant reductions of swim bladder size, larval length and swimming speed with increasing severity of effects when the duration of exposure was longer, suggesting a possible effect of accumulated dose. Larvae that were only exposed early (1-48 hpf) or late (120-144 hpf) during development showed no effects on the studied endpoints. The results demonstrate that PFOS does not affect the budding phase, and does not cause deflation of already inflated swim bladders. PFOS clearly affects processes that take place during the inflation phase and might also have an effect on the formation of the tissue layers forming the swim bladder.
Assuntos
Sacos Aéreos/efeitos dos fármacos , Ácidos Alcanossulfônicos/toxicidade , Fluorocarbonos/toxicidade , Natação , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/fisiologia , Animais , Tamanho Corporal/efeitos dos fármacos , Larva/efeitos dos fármacos , Curvaturas da Coluna Vertebral/induzido quimicamente , Coluna Vertebral/efeitos dos fármacos , Fatores de TempoAssuntos
Antipsicóticos/efeitos adversos , Distonia/induzido quimicamente , Atrofia Muscular Espinal/induzido quimicamente , Curvaturas da Coluna Vertebral/induzido quimicamente , Adulto , Antipsicóticos/uso terapêutico , Deficiências do Desenvolvimento/tratamento farmacológico , Feminino , Humanos , Masculino , Postura , SíndromeAssuntos
Antiparkinsonianos/efeitos adversos , Benzotiazóis/efeitos adversos , Atrofia Muscular Espinal/induzido quimicamente , Atrofia Muscular Espinal/diagnóstico , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/tratamento farmacológico , Curvaturas da Coluna Vertebral/induzido quimicamente , Curvaturas da Coluna Vertebral/diagnóstico , Idoso , Erros de Diagnóstico , Feminino , Humanos , Pramipexol , Doenças Vasculares/diagnóstico , Doenças Vasculares/tratamento farmacológicoRESUMO
SUMMARY: Eighty children with nephrotic syndrome underwent lumbar spine densitometry and vertebral morphometry soon after glucocorticoid initiation. We found an inverse relationship between glucocorticoid exposure and spine areal bone mineral density (BMD) Z-score and a low rate of vertebral deformities (8%). INTRODUCTION: Vertebral fractures are an under-recognized complication of childhood glucocorticoid-treated illnesses. Our goal was to study the relationships among glucocorticoid exposure, lumbar spine areal BMD (LS BMD), and vertebral shape in glucocorticoid-treated children with new-onset nephrotic syndrome. METHODS: Lateral thoracolumbar spine radiography and LS BMD were performed in 80 children with nephrotic syndrome (median age 4.4 years; 46 boys) within the first 37 days of glucocorticoid therapy. Genant semiquantitative grading was used as the primary method for vertebral morphometry; the algorithm-based qualitative (ABQ) method was used for secondary vertebral deformity analysis. RESULTS: Six of the 78 children with usable radiographs (8%; 95% confidence interval 4 to 16%) manifested a single Genant grade 1 deformity each. All deformities were mild anterior wedging (two at each of T6, T7, and T8). Four of the 78 children (5%; 95% confidence interval 2 to 13%) showed one ABQ sign of fracture each (loss of endplate parallelism; two children at T6 and two at T8). Two of the children with ABQ signs also had a Genant grade 1 deformity in the same vertebral body. None of the children with a Genant or ABQ deformity reported back pain. An inverse relationship was identified between LS BMD Z-score and glucocorticoid exposure. CONCLUSIONS: Although we identified an inverse relationship between steroid exposure and LS BMD soon after glucocorticoid initiation for childhood nephrotic syndrome, there was only a low rate of vertebral deformities. The clinical significance of these findings requires further study.
Assuntos
Glucocorticoides/efeitos adversos , Síndrome Nefrótica/tratamento farmacológico , Curvaturas da Coluna Vertebral/induzido quimicamente , Absorciometria de Fóton/métodos , Adolescente , Antropometria/métodos , Dor nas Costas/induzido quimicamente , Densidade Óssea/efeitos dos fármacos , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Lactente , Vértebras Lombares/fisiopatologia , Masculino , Síndrome Nefrótica/fisiopatologia , Curvaturas da Coluna Vertebral/diagnóstico por imagem , Curvaturas da Coluna Vertebral/fisiopatologia , Fraturas da Coluna Vertebral/induzido quimicamente , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/fisiopatologia , Vértebras Torácicas/diagnóstico por imagemRESUMO
Ciguatoxins are lipophilic polyether toxins which concentrate in the viscera and flesh of coral reef associated finfish (Hessel et al., 1960). In this study, we quantify the adverse effects of ciguatoxin on fish embryos by microinjection into the egg yolk of medaka (Oryzias latipis) embryos. Embryos microinjected with 0.1-0.9 pg/egg (ppb) of ciguatoxin exhibit cardiovascular, muscular, and skeletal abnormalities and those injected with higher levels (1.0-9.0 pg/egg) exhibit significantly reduced hatching success. The sensitivity of embryonic fish to direct oocyte exposure indicates that maternal transfer of low levels of ciguatoxin may represent an unrecognized threat to the reproductive success of reef fish and a previously undetected ecological consequence of proliferation of ciguatoxin-producing algae in reef systems increasingly impacted by human perturbations.