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Patients with glutaric aciduria type 1, without early diagnosis and initiation of preventive treatment, often develop movement disorders and various degrees of motor disability due to striatal area-specific damage induced by an acute episode of metabolic decompensation. The neuroimaging phenotype of patients with glutaric aciduria type 1 includes characteristic cyst-like bilateral enlargement of the Sylvian fissures and anterior subarachnoid spaces and signal abnormalities including supratentorial white matter and deep gray matter structure T2 hyperintensities, frequently associated with restricted diffusion. In this retrospective study, we add to the neuroimaging spectrum of glutaric aciduria type 1, a novel imaging finding present regardless of a previous metabolic crisis: the enlargement of the optic chiasm associated with signal abnormalities in the anterior intracranial visual structures observed in 6 of 10 patients. These optic pathway abnormalities are suggested as useful diagnostic clues for glutaric aciduria type 1, and possible pathophysiologic mechanisms are discussed.
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Erros Inatos do Metabolismo dos Aminoácidos , Pessoas com Deficiência , Transtornos Motores , Encefalopatias Metabólicas , Glutaril-CoA Desidrogenase/deficiência , Humanos , Imageamento por Ressonância Magnética , Quiasma Óptico/diagnóstico por imagem , Estudos RetrospectivosRESUMO
INTRODUCTION: Mitochondrial trifunctional protein deficiency (MTPD) is a long-chain fatty acid oxidation disorder characterized by co-existence of rhabdomyolysis episodes and peripheral neuropathy. Two phenotypes are described: generalized mitochondrial trifunctional protein deficiency (gMTPD) and isolated long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency (iLCHADD) that is always associated with the c.1528G>C mutation. Peripheral neuropathy of MTPD is commonly described in children as axonal, length-dependent and sensorimotor. OBJECTIVES: To report clinical and electrophysiological features of four independent adult MTPD patients with peripheral neuropathy. RESULTS: Onset of the disease was characterized in all patients by rhabdomyolysis episodes occurring during childhood preceded by severe hypoglycemic episodes in three patients. Peripheral nerve involvement manifesting as sensory ataxia appeared later, during adolescence or adulthood. In all cases, electroneuromyogram showed no length-dependent sensory potentials decrease characteristic of sensory neuronopathy ("ganglionopathy"). All patients harbored at least one c.1528G>C mutation. DISCUSSION: We describe MTPD as a newly hereditary etiology of sensory neuronopathy in adults, specifically in patients with c.1528G>C mutation. MTPD should be screened for by performing plasma acylcarnitines in patients with chronic sensory neuronopathy and additional suggestive features such as exercise intolerance or retinopathy.
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Cardiomiopatias/complicações , Cardiomiopatias/diagnóstico , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/diagnóstico , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/diagnóstico , Proteína Mitocondrial Trifuncional/deficiência , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/etiologia , Rabdomiólise/complicações , Rabdomiólise/diagnóstico , Adulto , Fatores Etários , Cardiomiopatias/patologia , Feminino , Humanos , Erros Inatos do Metabolismo Lipídico/patologia , Masculino , Pessoa de Meia-Idade , Miopatias Mitocondriais/patologia , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso Periférico/patologia , Fenótipo , Rabdomiólise/patologia , Adulto JovemRESUMO
Inherited metabolic diseases (IMD) form a heterogeneous group of genetic disorders that surface primarily during childhood and result in significant morbidity and mortality. A prevalence of 1 in 2500-5000 live births is often reported. The transfer of adolescents from pediatric care to adult health facilities is often difficult for patients and their families and can lead to a breakdown in medical follow-up and therefore serious complications. Existing recommendations for the successful transition of patients with chronic disorders do not specifically address patients with IMDs associated with dietary treatment. Here, the French network for rare inherited metabolic diseases (G2M) presents its reflections and recommendations for a successful transition. Preparations for the transfer must be made well in advance. The transfer must aim for adolescents gaining autonomy by making them responsible and providing them with the knowledge that will enable them to manage their care themselves, know how to react appropriately if there is any change in their condition, and move comfortably within the adult healthcare system. This requires the active participation of the patient, his or her family, and pediatric and adult care teams. It involves multidisciplinary management plus the production and maintenance of an educational therapy program. Finally, the identification of physicians and dietitians trained in IMDs, relevant subspecialists, and even expert patients could improve the continuum of complete and appropriate care for these patients within adult medicine.
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Cdc42, a Rho family small GTPase, regulates cytoskeleton organization, vesicle trafficking, and other cellular processes in development and homeostasis. However, Cdc42's roles in prenatal tooth development remain elusive. Here, we investigated Cdc42 functions in mouse enamel organ. Cdc42 showed highly dynamic temporospatial patterns in the developing enamel organ, with robust expression in the outer enamel epithelium, stellate reticulum (SR), and stratum intermedium layers. Strikingly, epithelium-specific Cdc42 deletion resulted in cystic lesions in the enamel organ. Cystic lesions were first noted at embryonic day 15.5 and progressively enlarged during gestation. At birth, cystic lesions occupied the bulk of the entire enamel organ, with intracystic erythrocyte accumulation. Ameloblast differentiation was retarded upon epithelial Cdc42 deletion. Apoptosis occurred in the Cdc42 mutant enamel organ prior to and synchronously with cystogenesis. Transmission electron microscopy examination showed disrupted actin assemblies, aberrant desmosomes, and significantly fewer cell junctions in the SR cells of Cdc42 mutants than littermate controls. Autophagosomes were present in the SR cells of Cdc42 mutants relative to the virtual absence of autophagosome in the SR cells of littermate controls. Epithelium-specific Cdc42 deletion attenuated Wnt/ß-catenin and Shh signaling in dental epithelium and induced aberrant Sox2 expression in the secondary enamel knot. These findings suggest that excessive cell death and disrupted cell-cell connections may be among multiple factors responsible for the observed cystic lesions in Cdc42 mutant enamel organs. Taken together, Cdc42 exerts multidimensional and pivotal roles in enamel organ development and is particularly required for cell survival and tooth morphogenesis.
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Cistos/embriologia , Órgão do Esmalte/embriologia , Epitélio/embriologia , Proteínas rho de Ligação ao GTP/metabolismo , Actinas/metabolismo , Ameloblastos/metabolismo , Animais , Apoptose , Autofagossomos/metabolismo , Western Blotting , Diferenciação Celular , Proteínas do Citoesqueleto , Marcação In Situ das Extremidades Cortadas , Junções Intercelulares/metabolismo , Camundongos , Microscopia Eletrônica de Transmissão , Reação em Cadeia da Polimerase em Tempo RealRESUMO
WHAT IS KNOWN ON THE SUBJECT?: The psychometrics of the CUB measure have been tested within an inpatient psychiatric setting. Results show that the CUB has two factors that reflect patients' approach and avoidance of dimensions of the treatment milieu, and that an increase of approach and decrease of avoidance are correlated with discharge. No empirical research has examined the validity of the CUB in a day hospital programme. WHAT THIS ARTICLE ADDS TO EXISTING KNOWLEDGE?: This study was the first to address the validity of this questionnaire within a psychiatric day hospital setting. This now allows other mental health service providers to use this questionnaire following administration of patient engagement interventions (such as behavioural activation), which are routinely used within this type of a setting. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Our results can enable healthcare providers to employ an effective and psychometrically validated tool in a day hospital setting to measure treatment outcomes and provide reflections of patients' approach behaviours and avoidance behaviours. ABSTRACT: Introduction We evaluated the Checklist of Unit Behaviours (CUBs) questionnaire in a novel mental health setting: a day hospital within a large acute care general hospital. No empirical evidence exists, as of yet, to look at the validity of this measure in this type of a treatment setting. The CUB measures two factors, avoidance or approach, of the patients' engagement with the treatment milieu within the previous 24 hr. Aim A confirmatory factor analysis (CFA) was conducted to validate the CUB's original two factor structure in an outpatient day programme. Methods Psychiatric outpatients (n = 163) completed the CUB daily while participating in a day hospital programme in Toronto, Canada. Results A CFA was used to confirm the CUB factors but resulted in a poor fitting model for our sample, χ2 (103) = 278.59, p < .001, CFI = 0.80, RMSEA = 0.10, SRMR = 0.10. Questions 5, 8 and 10 had higher loadings on a third factor revealed through exploratory factor analysis. We believe this factor, "Group Engagement," reflects the construct of group-related issues. Discussion The CUB was a practical and useful tool in our psychiatric day hospital setting at a large acute care general hospital. Implications for practice Our analysis identified group engagement, a critical variable in day programmes, as patients have autonomy regarding staying or leaving the programme.
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Lista de Checagem/normas , Transtornos Mentais/psicologia , Ambulatório Hospitalar , Pacientes Ambulatoriais/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Psicometria/normas , Adulto , Idoso , Canadá , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários/normas , Adulto JovemRESUMO
BACKGROUND: Nociceptin in the peripheral circulation has been proposed to have an immunoregulatory role with regards to inflammation and pain. However, the mechanisms involved in its regulation are still not clear. The aim of this study was to investigate signalling pathways contributing to the regulation of the expression of nociceptin under inflammatory conditions. METHODS: Mono Mac 6 cells (MM6) were cultured with or without phorbol-12-myristate-13-acetate (PMA). Prepronociceptin (ppNOC) mRNA was detected by RT-qPCR and extracellular nociceptin by fluorescent-enzyme immunoassay. Intracellular nociceptin and phosphorylated kinases were measured using flow cytometry. To evaluate the contribution of various signalling pathways to the regulation of ppNOC mRNA and nociceptin protein, cells were pre-treated with specific kinase inhibitors before co-culturing with PMA. RESULTS: ppNOC mRNA was expressed in untreated MM6 at low concentrations. Exposure of cells to PMA upregulated ppNOC after nine h compared with controls without PMA (median normalized ratio with IQR: 0.18 (0.15-0.26) vs. 0 (0-0.02), P<0.01). Inhibition of mitogen-activated protein kinases specific for signal transduction reversed the PMA effects (all P<0.001). Induction of nociceptin protein concentrations in PMA stimulated MM6 was prevented predominantly by identity of ERK inhibitor (P<0.05). CONCLUSIONS: Upregulation of nociceptin expression by PMA in MM6 cells involves several pathways. Underlying mechanisms involved in nociceptin expression may lead to new insights in the treatment of pain and inflammatory diseases.
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Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Peptídeos Opioides/biossíntese , Inibidores de Proteínas Quinases/farmacologia , Acetato de Tetradecanoilforbol/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Relação Dose-Resposta a Droga , Humanos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , NociceptinaRESUMO
Lysinuric protein intolerance (LPI) is a rare autosomal recessive metabolic disorder, caused by defective transport of cationic amino acids at the basolateral membrane of epithelial cells, typically in intestines and kidneys. The SLC7A7 gene, mutated in LPI patients, encodes the light subunit (y+LAT1) of a member of the heterodimeric amino acid transporter family.The diagnosis of LPI is difficult due to unspecific clinical features: protein intolerance, failure to thrive and vomiting after weaning. Later on, patients may present delayed growth osteoporosis, hepatosplenomegaly, muscle hypotonia and life-threatening complications such as alveolar proteinosis, haemophagocytic lymphohistiocytosis and macrophage activation syndrome. Renal involvement is also a serious complication with tubular and more rarely, glomerular lesions that may lead to end-stage kidney disease (ESKD). We report six cases of LPI followed in three different French paediatric centres who presented LPI-related nephropathy during childhood. Four of them developed chronic kidney disease during follow-up, including one with ESKD. Five developed chronic tubulopathies and one a chronic glomerulonephritis. A histological pattern of membranoproliferative glomerulonephritis was first associated with a polyclonal immunoglobulin deposition, treated by immunosuppressive therapy. He then required a second kidney biopsy after a relapse of the nephrotic syndrome; the immunoglobulin deposition was then monoclonal (IgG1 kappa). This is the first observation of an evolution from a polyclonal to a monotypic immune glomerulonephritis. Immune dysfunction potentially attributable to nitric oxide overproduction secondary to arginine intracellular trapping is a debated complication in LPI. Our results suggest all LPI patients should be monitored for renal disease regularly.
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The neural cell adhesion molecule (NCAM) is a glycoprotein implicated in cell-cell adhesion, neurite outgrowth and synaptic plasticity. Polysialic acid (polySia) is mainly attached to NCAM (polySia-NCAM) and has an essential role in regulating NCAM-dependent developmental processes that require plasticity, that is, cell migration, axon guidance and synapse formation. Post-mortem and genetic evidence suggests that dysregulation of polySia-NCAM is involved in schizophrenia (SZ). We enrolled 45 patients diagnosed with SZ and 45 healthy individuals who were submitted to polySia-NCAM peripheral quantification, cognitive and psychopathological assessment and structural neuroimaging (brain volumes and diffusion tensor imaging). PolySia-NCAM serum levels were increased in SZ patients, independently of antipsychotic treatment, and were associated with negative symptoms, blunted affect and declarative memory impairment. The increased polySia-NCAM levels were associated with decreased volume in the left prefrontal cortex, namely Brodmann area 46, in patients and increased volume in the same brain area of healthy individuals. As this brain region is involved in the pathophysiology of SZ and its associated phenomenology, the data indicate that polySia-NCAM deserves further scrutiny because of its possible role in early neurodevelopmental mechanisms of the disorder.
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Encéfalo/patologia , Transtornos Cognitivos/complicações , Moléculas de Adesão de Célula Nervosa/sangue , Esquizofrenia/complicações , Ácidos Siálicos/sangue , Adulto , Mapeamento Encefálico , Movimento Celular/genética , Transtornos Cognitivos/sangue , Transtornos Cognitivos/genética , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Moléculas de Adesão de Célula Nervosa/genética , Plasticidade Neuronal/genética , Tamanho do Órgão , Esquizofrenia/sangue , Esquizofrenia/genética , Ácidos Siálicos/genéticaRESUMO
The present study investigated maternal emotion regulation as mediating the association between maternal posttraumatic stress symptoms and children's emotional dysregulation in a community sample of 431 Israeli mothers and children exposed to trauma. Little is known about the specific pathways through which maternal posttraumatic symptoms and deficits in emotion regulation contribute to emotional dysregulation. Inspired by the intergenerational process of relational posttraumatic stress disorder (PTSD), in which posttraumatic distress is transmitted from mothers to children, we suggest an analogous concept of relational emotion regulation, by which maternal emotion regulation problems may contribute to child emotion regulation deficits. Child emotion regulation problems were measured using the Child Behavior Checklist-Dysregulation Profile (CBCL-DP; T.M. Achenbach & I. Rescorla, 2000), which is comprised of three subscales of the CBCL: Attention, Aggression, and Anxiety/Depression. Maternal PTSD symptoms were assessed by the Posttraumatic Diagnostic Scale (E.B. Foa, L. Cashman, L. Jaycox, & K. Perry, 1997) and maternal emotion regulation by the Difficulties in Emotion Regulation Scale (K.L. Gratz & L. Roemer, 2004). Results showed that the child's emotion regulation problems were associated with both maternal posttraumatic symptoms and maternal emotion dysregulation. Further, maternal emotion regulation mediated the association between maternal posttraumatic symptoms and the child's regulation deficits. These findings highlight the central role of mothers' emotion regulation skills in the aftermath of trauma as it relates to children's emotion regulation skills. The degree of mothers' regulatory skills in the context of posttraumatic stress symptoms reflects a key process through which the intergenerational transmission of trauma may occur. Study results have critical implications for planning and developing clinical interventions geared toward the treatment of families in the aftermath of trauma and, in particular, the enhancement of mothers' emotion regulation skills after trauma.
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Emoções , Mães/psicologia , Psicologia da Criança , Transtornos de Estresse Pós-Traumáticos , Criança , Transtornos do Comportamento Infantil , Pré-Escolar , Feminino , Humanos , Entrevistas como Assunto , Israel , Relações Mãe-Filho , ViolênciaRESUMO
New American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for the classification of rheumatoid arthritis (RA) have recently been proposed. The aim of this cohort study was to examine whether fulfilling these 2010 ACR/EULAR criteria at the first visit has an impact on the clinical course and on the radiographic progression of the disease. For this observational cohort study, we included patients from the Swiss RA registry SCQM with early RA or undifferentiated arthritis (UA, disease duration ≤1 year), as defined by the treating rheumatologist, who had not received any previous disease modifying anti-rheumatic drugs (DMARDs). Patients were categorized into two groups depending on whether or not they fulfilled the 2010 ACR/EULAR criteria (≥6 points vs <6 points) at the first visit. The primary outcome measures were the evolution of the DAS 28 and of radiographic erosions as measured by the Ratingen score over time. Of the 592 patients fulfilling the inclusion criteria, 352 satisfied the 2010 ACR/EULAR criteria at baseline, whereas 240 were not classifiable as definite RA. The ACR/EULAR criteria scores correlated with disease activity at disease onset (R (2) = 0.31). DMARD treatment was subsequently initiated in all patients, mostly with methotrexate (MTX). There were no significant differences in the therapeutic strategies between patients fulfilling or not fulfilling the classification criteria. Six months after inclusion, patients fulfilling the ACR/EULAR criteria developed a 39.1 % reduction of DAS 28 scores, as compared to a 33.6 % reduction in patients not fulfilling the ACR/EULAR criteria (p = 0.0002), independently of their respective treatment strategy. Importantly, the DAS 28 scores were higher in those patients fulfilling the ACR/EULAR criteria (ACR/EULAR positive patients) throughout the observation, as compared to patients not fulfilling those (ACR/EULAR negative patients). Average radiographic progression was higher among ACR/EULAR positive than negative patients (progression of Ratingen score/year 0.50 vs 0.32, resp., p = 0.03) after 3 years of follow-up. Among early RA/UA patients, a score of the 2010 ACR/EULAR criteria sufficient to classify RA selects patients with worse clinical outcome and more radiographic progression.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Adulto , Idoso , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Radiografia , Reumatologia , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Transcobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy- or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.
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Transcobalaminas/deficiência , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Hidroxocobalamina/uso terapêutico , Lactente , Recém-Nascido , Masculino , Mutação , Resultado do Tratamento , Vitamina B 12/uso terapêuticoRESUMO
UNLABELLED: Sjögren-Larsson syndrome (SLS) is a neurocutaneous autosomal recessive disease caused by fatty aldehyde dehydrogenase (FADH) deficiency. This enzyme is involved in the biosynthesis pathways of some fatty acids, phytanic acid, and leukotrienes. The main features of the disease are its association with congenital ichthyosis, mental retardation, and spastic tetraplegia. METHODS: We report on the diagnostic and therapeutic management of 2 cases of SLS. RESULTS: The diagnosis of SLS was suspected in the first patient at 2 years of age before the clinical triad appeared and confirmed at 4 years of age by the culture of fibroblasts and the peak of lipids on 1.3 ppm spectroscopy. After 3 months of treatment with zileuton, an inhibitor of leukotriene synthesis, moderate clinical efficacy for pruritus and ichthyosis was observed. The second patient was diagnosed at 1 year of age with the association of psychomotor retardation and congenital ichthyosis, in accordance with acute Guillain-Barré syndrome. Diagnosis was confirmed with enzymology, and cerebral spectro-MRI featured an abnormal lipidic peak. Zileuton therapy was initiated at the time of diagnosis and was effective for pruritus after 6 months of treatment. CONCLUSION: We report 2 cases of SLS with delayed diagnosis, due to non neonatal symptoms. Treatment with zileuton shows partial efficacy especially in pruritus. The uncommon association of this rare dysmyelinating disease with Guillain-Barré syndrome in the second patient is discussed.
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Síndrome de Sjogren-Larsson , Feminino , Humanos , Lactente , Masculino , Síndrome de Sjogren-Larsson/diagnósticoRESUMO
Pneumatosis intestinalis (PI) occurs when gastrointestinal (GI) wall disruption, increased wall permeability or necrosis leads to wall infiltration by gas. It is associated with a spectrum of causal factors, including GI disease in allogeneic blood and marrow transplant patients. Traditionally, PI has been managed surgically with high morbidity and mortality. We describe our experience managing allogeneic blood and marrow transplant patients with PI. From January 1998 to May 2008, 320 patients underwent allogeneic blood and marrow transplant of whom 10 were identified with PI. PI diagnosis was established by computed tomography scan (n=7), plain film (n=2) or colonoscopy (n=1). A total of 9 of 10 patients had ongoing GI GvHD or received recent treatment for GI GvHD. Before April 2002, two patients underwent subtotal colectomy with ileostomy (n=1) and sigmoid colectomy with colostomy (n=1). One patient was managed with bowel rest and total parental nutrition (TPN) only. These three patients died 0.4, 1.1 and 3.9 years after PI diagnosis owing to GI GvHD (n=2) and surgical complications (n=1). Seven patients, diagnosed after September 2006, were treated with GI rest, TPN and antibiotics. PI treated with GI rest, TPN and antibiotics will resolve without surgical intervention. AlloBMT-associated PI is often a non-critical finding that does not represent true GI tract ischemia and/or GI tract perforation.
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Transplante de Medula Óssea/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pneumatose Cistoide Intestinal/terapia , Adulto , Antibacterianos , Gerenciamento Clínico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nutrição Parenteral , Pneumatose Cistoide Intestinal/etiologia , Estudos Retrospectivos , Transplante Homólogo , Resultado do TratamentoAssuntos
Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Erros Inatos do Metabolismo/diagnóstico , Encefalopatias Metabólicas/diagnóstico , Encefalopatias Metabólicas/genética , Criança , Transtornos do Comportamento Infantil/diagnóstico , Transtornos do Comportamento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Diagnóstico Diferencial , Predisposição Genética para Doença/genética , Humanos , Lactente , Erros Inatos do Metabolismo/genética , Fenótipo , Fatores de RiscoRESUMO
OBJECTIVES: To assess the ability of efficacy measures that incorporate onset or sustainability to detect treatment effect or reflect patient satisfaction, using exploratory analyses of data from the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate Responders) trial. METHODS: 218 abatacept- and 99 placebo-treated patients were evaluated. Reporting methods included time to onset (first American College of Rheumatology [ACR] 50 response/Low Disease Activity State [LDAS; DAS28 < or =3.2]) and sustainability of ACR50/LDAS, both assessed according to discriminatory capacity (number of patients needed to study [NNS]) and patient satisfaction with treatment. RESULTS: Efficacy measures incorporating elements of sustainability or onset decreased discriminatory capacity, while sustainability, but not onset of action, was important in reflecting patient satisfaction. CONCLUSIONS: Optimal assessment methods depend on whether the outcome of interest is ability to detect treatment effects or to reflect patient satisfaction. Sustainability of response (and possibly, at a lower magnitude, fast onset of action) may be important when evaluating patient satisfaction with RA therapies in patients who have previously failed anti-TNF therapy.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/fisiopatologia , Imunoconjugados/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Abatacepte , Bases de Dados Factuais , Humanos , Placebos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Índice de Gravidade de Doença , Falha de TratamentoAssuntos
Antirreumáticos/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Abatacepte , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais Murinos , Humanos , Imunoconjugados/uso terapêutico , Rituximab , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Diabetes mellitus is occasionally observed in patients with skeletal muscle respiratory chain deficiency, suggesting that skeletal muscle mitochondrial dysfunction might play a pathogenic role in type 2 diabetes (T2D). In support of this hypothesis, decreased muscle mitochondrial activity has been reported in T2D patients and in mouse models of diabetes. However, recent work by several groups suggests that decreased muscle mitochondrial function may be a consequence rather than a cause of diabetes, since decreased mitochondrial function in mice affords protection from diabetes and obesity. We review the data on this controversial but important issue of potential links between mitochondrial dysfunction and diabetes.
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Diabetes Mellitus Tipo 2/etiologia , Mitocôndrias Musculares/fisiologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Células Secretoras de Insulina/fisiologia , Camundongos , Mitocôndrias Musculares/metabolismo , Doenças Mitocondriais/complicações , Modelos Biológicos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Transdução de Sinais/fisiologiaRESUMO
UNLABELLED: Hyperargininaemia is a rare inborn error of metabolism due to a defect in the final step of the urea cycle. Infantile onset is the most common presentation with recurrent vomiting and psychomotor delay associated with spastic paraparesis; chronic hyperammonaemia is often overlooked. Neonatal and early-onset presentations are very uncommon and their clinical course not well-described. We report on a 3-week-old hyperargininaemic girl who presented with neurological deterioration associated with liver failure and 47-day ammonia intoxication before diagnosis could be made and treatment started. Despite appropriate but delayed treatment, our patient exhibited severe psychomotor delay at age 1 year. CONCLUSION: Early identification and management of this rare but potentially treatable affection is crucial as delayed management may result in poor neurological outcome.