RESUMO
Sporadic inclusion body myositis (sIBM) is an insidious late-onset progressive myopathy that typically affects patients over the age of 50. Clinically, patients develop a characteristic pattern of weakness that affects the forearm flexors and knee extensors. Muscle biopsy, often utilized in the diagnosis, demonstrates a chronic myopathy with mixed pathologies harbouring intramyofiber protein inclusions and endomysial inflammation. The co-existence of these pathologic features (that is, inflammation and protein aggregation) has divided the field of sIBM research into two opposing (albeit slowly unifying) camps regarding disease pathogenesis. The present review explores the recent evidence supporting these distinct pathogenic mechanisms. Future therapies that are designed to target both aspects of sIBM pathologies will likely be necessary to treat sIBM.
Assuntos
Miosite de Corpos de Inclusão/patologia , HumanosRESUMO
The proper targeting and clustering of neurotransmitter receptors at appropriate postsynaptic sites are principal requirements for the formation of functional synapses. Recently, new studies have begun to elucidate the mechanisms underlying the targeting and clustering of glutamate receptors at excitatory synapses in the brain. Members of the SAP90/PSD-95 family of proteins have emerged as potential regulators of glutamate-receptor membrane distribution. Further, targeting motifs within glutamate receptor subunits have been identified. These findings provide important clues in the effort to understand the molecular features of synaptic organization.
Assuntos
Compartimento Celular , Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Transporte Biológico , Modelos BiológicosRESUMO
The levels of selected neuroregulatory proteins that inhibit or promote apoptotic cell death were measured in the striatum of piglets subjected to precisely controlled 1 h hypoxic insult followed by 0, 2 and 4 h recovery and compared to sham operated animals. The anti-apoptotic proteins: there were increases in Survivin at 0 (157%, P = 0.031) and 4 h (171%, P = 0.033), in Bcl-XL at 0 (138%, P = 0.028) and 4 h (143%, P = 0.007), in VEGF at 4 h (185%, P = 0.019) and Hsp27 at 2 h (144%, P = 0.05) and 4 h (143%, P = 0.05). The pro-apoptotic proteins: caspases-1 and 7 increased at 4 h (135%, P = 0.05) and (129%, P = 0.038), respectively. Bim increased after 4 h (115%, P = 0.028), Apoptosis Inducing Factor after 2 h (127%, P = 0.048) and Calpain after 4 h (143% of control, P = 0.04). Hypoxia causes increase in levels of both anti- and pro-apoptotic proteins. Their relative activity determines the outcome in terms of cell damage and neuronal deficit.
Assuntos
Animais Recém-Nascidos , Corpo Estriado/metabolismo , Hipóxia/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Corpo Estriado/patologia , Hipóxia/patologia , SuínosRESUMO
Responses of selected neuroregulatory proteins that promote (Caspase 3 and Bax) or inhibit (Bcl-2, high Bcl-2/Bax ratio) apoptotic cell death were measured in the brain of piglets subjected to precisely controlled hypoxic and ischemic insults: 1 h hypoxia (decreasing FiO2 from 21 to 6%) or ischemia (ligation of carotid arteries and hemorrhage), followed by 0, 2 and 4 h recovery with 21% FiO2. Protein expression was measured in cortex, hippocampus and striatum by Western blot. There were no significant differences in expression of Caspase-3 between sham operated, hypoxic and ischemic groups. There were significant regional differences in expression of Bcl-2 and Bax in response to hypoxia and ischemia. The changes in Bcl-2/Bax ratio were similar for hypoxia and ischemia except for striatum at zero time recovery, with ischemia giving lower ratios than hypoxia. The Bcl-2/Bax ratio was also lower for the striatum than for the other regions of the brain, suggesting this region is the more susceptible to apoptotic injury.
Assuntos
Animais Recém-Nascidos , Apoptose/fisiologia , Isquemia Encefálica/fisiopatologia , Hipóxia Encefálica/fisiopatologia , Animais , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Caspase 3/metabolismo , Hipocampo/metabolismo , Hipóxia Encefálica/metabolismo , Oxigênio/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Suínos , Proteína X Associada a bcl-2/metabolismoRESUMO
BACKGROUND: Interstitial lung disease-associated antisynthetase syndrome (AS-ILD) carries significant morbidity and mortality. Corticosteroids and immunosuppressive drugs are the mainstay of treatment. Human immunoglobulin (IVIg), an immunomodulator without immunosuppressive properties, is effective in myositis but the evidence supporting its use in ILD is scarce. OBJECTIVE: To describe clinical outcomes of AS-ILD patients receiving IVIg. METHODS: Retrospective analysis of AS-ILD patients. Linear mixed models using restricted maximum likelihood estimation was used to estimate the change in lung function and corticosteroid dose over time. RESULTS: Data from 17 patients was analyzed. Median follow-up was 24.6 months. Fourteen patients had refractory disease. The mean percent-predicted forced vital capacity (FVC%) (pâ¯=â¯0.048) and percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (pâ¯=â¯0.0223) increased over time, while the mean prednisone dose (pâ¯<â¯0.001) decreased over time. Seven patients achieved a >10% increase in FVC%, including two who used IVIg as initial treatment. Five patients showed a >10% increase in DLCO% and TLC%. Nine (53%) patients experienced side effects. CONCLUSIONS: IVIg may be a useful complementary therapy in active progressive AS-ILD but is associated with potential side effects. Fssssurther investigation is required to determine the value of IVIg as an initial treatment in AS-ILD.
Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Doenças Pulmonares Intersticiais/terapia , Miosite/terapia , Administração Intravenosa , Corticosteroides/uso terapêutico , Adulto , Idoso , Monóxido de Carbono/metabolismo , Feminino , Seguimentos , Humanos , Imunoglobulinas Intravenosas/efeitos adversos , Imunossupressores/uso terapêutico , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/mortalidade , Masculino , Pessoa de Meia-Idade , Miosite/complicações , Miosite/mortalidade , Prednisona/uso terapêutico , Capacidade de Difusão Pulmonar/efeitos dos fármacos , Estudos Retrospectivos , Resultado do Tratamento , Capacidade Vital/efeitos dos fármacosRESUMO
We have characterized the phosphorylation of the glutamate receptor subunit GluR1, using biochemical and electrophysiological techniques. GluR1 is phosphorylated on multiple sites that are all located on the C-terminus of the protein. Cyclic AMP-dependent protein kinase specifically phosphorylates SER-845 of GluR1 in transfected HEK cells and in neurons in culture. Phosphorylation of this residue results in a 40% potentiation of the peak current through GluR1 homomeric channels. In addition, protein kinase C specifically phosphorylates Ser-831 of GluR1 in HEK-293 cells and in cultured neurons. These results are consistent with the recently proposed transmembrane topology models of glutamate receptors, in which the C-terminus is intracellular. In addition, the modulation of GluR1 by PKA phosphorylation of Ser-845 suggests that phosphorylation of this residue may underlie the PKA-induced potentiation of AMPA receptors in neurons.
Assuntos
Potenciais da Membrana/fisiologia , Receptores de AMPA/metabolismo , Sequência de Aminoácidos , Células Cultivadas , Expressão Gênica , Humanos , Dados de Sequência Molecular , FosforilaçãoRESUMO
The purpose of this study was to assess the utility and validity of using customized heterochromatic flicker photometry (cHFP) to measure macular pigment optical density (MPOD) in patients with intermediate stages of age-related macular degeneration (AMD). The measurement procedure was optimized to accommodate individual differences in temporal vision related to age, disease, or other factors. The validity criteria were based on the similarity of the spectral absorption curves to ex vivo curves of lutein and zeaxanthin and the similarity of spatial density profiles to those measured in subjects without retinal disease. Macular pigment optical density (MPOD) spatial profiles were measured with an LED-based macular densitometer; spectral absorption curves were measured with a 3-channel Maxwellian view system including a monochromator. All patients were characterized via clinical exams and all but 2 subjects from whom data were obtained had masked grading of color fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. Most of the patients were in AREDS category 2 (27%) or 3 (57%). Patients with visual acuity as poor as 20/80 were included, and could perform the task as long as they could see the stimulus. Eighty-one percent of the patients screened were able to perform the cHFP task, and data were obtained from 30 AMD patients. Spatial profiles of MPOD were measured in 19 subjects who could see the stimulus at all tested loci. These profiles were highly similar to those that have been measured with HFP in subjects without retinal disease. The average shape of the spectral absorption curves for the AMD subjects corresponded well to an ex vivo template. These data support both the utility and validity of the cHFP method for measuring MPOD in subjects with intermediate stages of AMD. The ability to measure the retinal response to nutritional intervention is of practical importance for monitoring patients being supplemented with lutein and zeaxanthin in hopes of retarding visual loss and/or disease progression.
Assuntos
Fusão Flicker , Macula Lutea/química , Degeneração Macular/metabolismo , Pigmentos da Retina/análise , Idoso , Idoso de 80 Anos ou mais , Cor de Olho , Feminino , Humanos , Degeneração Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fotometria/métodos , Psicofísica , Acuidade VisualRESUMO
BACKGROUND: Nitric oxide is a messenger molecule of the nervous system, which is produced by the enzyme nitric oxide synthase, which may regulate cyclic guanosine monophosphate levels and which has been implicated in the control of neurotransmitter release. PC-12 pheochromocytoma cells differentiate to form neuronal cells in culture when they are exposed to nerve growth factor. The levels of cyclic guanosine monophosphate in the cells and their ability to release acetylcholine in response to K(+)-depolarization are both maximal after eight days of treatment with nerve growth factor. We set out to assess a possible role for nitric oxide in the processes that occur in differentiating PC-12 cells. RESULTS: Nitric oxide synthase is first evident in differentiating PC-12 cells eight days after beginning treatment with nerve growth factor, coinciding with the marked increase in K(+)-depolarization-induced release of acetylcholine. The release of both acetylcholine and dopamine in response to K(+)-depolarization is blocked by inhibitors of nitric oxide synthase and by hemoglobin, which binds nitric oxide. Providing l-arginine, a precursor required for nitric oxide synthesis, reverses the effects of the inhibitors. In synaptosomal preparations from the corpus striatum, inhibitors of nitric oxide synthase prevent the release of glutamate in response to the glutamate derivative N-methyl-d-aspartate but not in response to K(+)-depolarization. CONCLUSION: Nitric oxide may mediate the release of acetylcholine and dopamine in response to K(+)-depolarization in PC-12 cells and the release of glutamate in response to N-methyl-d-aspartate in striatal synaptosomes. Nitric oxide synthase expression is induced after eight days of treating PC-12 cells with nerve growth factor, coinciding with a marked enhancement of the release of neurotransmitters in response to K(+)-depolarization.
RESUMO
BACKGROUND: The new antiglaucoma drug, dorzolamide, mainly evokes local side effects like eye burning, pruritus, blurred sight and a foreign-body sensation. A clinical study was conducted to determine it dorzolamide has any influence on corneal sensitivity. SUBJECTS AND METHODS: We examined three different groups of substances. We used sodium chloride solution 0.9% and the local anesthetic oxybuprocaine 0.4% as control groups, each in two subgroups aged 23-40 years or 60-86 years. Corneal sensitivity was measured in the corneal center with Draeger's electronic optic aesthesiometer. We took the measurements directly before and 1,5,10,15 and 20 min after applying one eye drop. RESULTS: The control groups with sodium chloride solution showed no significant (P > 0.05) corneal hyposensitivity. The local anesthetic caused corneal asensitivity (P < 0.05) until the 10-min measurement. Twenty minutes after giving the anesthetic, with 12.10(-5) N corneal sensitivity nearly reached the starting value. At this time corneal sensitivity in the older subgroup was still decreased with 627.10(-5) N. In the younger subgroup dorzolamide only caused slight, but significant (P < 0.05), hyposensitivity of the cornea 1 and 5 min after application of the eye drop. CONCLUSION: Although dorzolamide decreases corneal sensitivity only a little, people with glaucoma using contact lenses should not insert them until at least 15 min after applying the dorzolamide.
Assuntos
Anti-Hipertensivos/farmacologia , Córnea/inervação , Limiar da Dor/efeitos dos fármacos , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anestésicos Locais/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas , Procaína/análogos & derivados , Procaína/farmacologiaRESUMO
BACKGROUND: Interstitial lung disease (ILD) is a common extramuscular manifestation of the idiopathic inflammatory myopathies (IIMs), dermatomyositis (DM) and polymyositis (PM). Patients with antisynthetase antibodies (ASA) demonstrate some or all of the features of the antisynthetase syndrome including IIM and ILD. It has been hypothesized that the clinical expression of antisynthetase syndrome varies between specific ASAs. OBJECTIVE: We sought to determine whether the myositis-associated ILD (MA-ILD) phenotype differs based on the presence of ASAs and by ASA subtype. METHODS: A cross-sectional and longitudinal analysis of consecutive patients enrolled at the Johns Hopkins Myositis Center with ILD in the setting of clinically diagnosed autoimmune myositis was conducted. RESULTS: Seventy-seven subjects were included; 36 were ASA negative, 28 were anti-Jo1 positive, and 13 were non-Jo1 ASA positive (5 anti-PL-12, 4 anti-PL-7, 2 anti-EJ, and 2 anti-OJ). Non-Jo1 ASA positive participants were more likely to be African-American than Caucasian as compared to both the anti-Jo1 positive (p = 0.01) and ASA negative groups (p < 0.01). ASA negative participants had better mean forced vital capacity percent predicted (FVC%) and total computed tomography scores over time compared to those with anti-Jo1 after controlling for potential confounders. CONCLUSIONS: ASA status was significantly different by race. Those with anti-Jo1 antibodies had worse lung function and CT scores over time compared to those without detectable antisynthetase antibodies. Further prospective study in a larger cohort is needed to determine whether these apparent antibody-specific differences in demographics and manifestations of disease translate into meaningful disparities in clinical outcomes.
Assuntos
Autoanticorpos/imunologia , Doenças Pulmonares Intersticiais/imunologia , Miosite/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Capacidade VitalRESUMO
Chronic graft-vs-host disease (cGVHD) myositis is a rare complication of hematopoietic SCT, for which the pathogenesis and optimal therapy are unclear. We performed immunohistochemistry on muscle biopsies from pediatric cGVHD myositis and typical cases of autoimmune dermatomyositis and polymyositis. The immunostaining pattern of cGVHD myositis was distinct from that of typical cases of autoimmunity. There was a high proportion of CD20+ and CD68+ cells, and the best therapeutic response was achieved with rituximab (anti-CD20). These results suggest that cGVHD myositis may be mediated by different leukocytes than similar autoimmune diseases and that treatment may be optimized by targeting the specific cellular infiltrates identified in affected tissue.
Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Anticorpos Monoclonais Murinos/uso terapêutico , Antígenos CD/imunologia , Antígenos CD20/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Criança , Dermatomiosite/patologia , Dermatomiosite/terapia , Doença Enxerto-Hospedeiro/imunologia , Humanos , Imuno-Histoquímica , Polimiosite/patologia , Polimiosite/terapia , RituximabAssuntos
Hepatite A/epidemiologia , Falência Hepática/epidemiologia , Adolescente , Distribuição por Idade , Criança , Pré-Escolar , Comorbidade , Países em Desenvolvimento , Feminino , Hepatite A/diagnóstico , Humanos , Incidência , Índia/epidemiologia , Lactente , Falência Hepática/diagnóstico , Masculino , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Taxa de SobrevidaAssuntos
Canais Iônicos/metabolismo , Células Cultivadas , Cromatografia em Camada Fina/métodos , Humanos , Ativação do Canal Iônico , Canais Iônicos/genética , Canais Iônicos/imunologia , Ligantes , Mutagênese Sítio-Dirigida , Mapeamento de Peptídeos , Fosfoaminoácidos/análise , Fosforilação , Testes de Precipitina , Proteínas Recombinantes de Fusão/metabolismoAssuntos
Antiestreptolisina/sangue , Glomerulonefrite/complicações , Pioderma/microbiologia , Dermatopatias Infecciosas/microbiologia , Infecções Estreptocócicas , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Streptococcus/isolamento & purificaçãoAssuntos
Doenças Ósseas/genética , Surdez/genética , Doenças do Pé/genética , Úlcera/genética , Nervo Vestibulococlear , Adolescente , Adulto , Atrofia , Criança , Pré-Escolar , Feminino , Gânglios Espinais/patologia , Humanos , Hipestesia , Masculino , Doenças do Sistema Nervoso Periférico/genética , Retinose Pigmentar , Disrafismo EspinalRESUMO
OBJECTIVE: Infant and child mortality are important indicators of the level of development of a society, but are usually collected by governmental agencies on a region wide scale, with little local stratification. In order to formulate appropriate local policies for intervention, it is important to know the patterns of morbidity and mortality in children in the local setting. METHODS: This retrospective study collected and analyzed data on infant mortality for the period 1995 to 2003 in an urban slum area in Vellore, southern India from government health records maintained at the urban health clinic. RESULTS: The infant mortality rate over this period was 37.9 per 1000 live births. Over half (54.3%) of the deaths occurred in the neonatal period. Neonatal deaths were mainly due to perinatal asphyxia (31.9%), pre-maturity (16.8%) and aspiration pneumonia or acute respiratory distress (16.8%), while infant deaths occurring after the first mth of life were mainly due to diarrheal disease (43%) and respiratory infections (21%). CONCLUSION: These results emphasize the need to improved antenatal and perinatal care to improve survival in the neonatal period. The strikingly high death rate due to diarrheal illness highlights the requirements for better sanitation and water quality.
Assuntos
Mortalidade Infantil , Causas de Morte , Feminino , Humanos , Índia/epidemiologia , Lactente , Masculino , Áreas de Pobreza , Estudos Retrospectivos , População Urbana/estatística & dados numéricosRESUMO
Thirteen patients who had worn a maxillary conventional denture and mandibular osseointegrated implant-supported overdenture for at least 3 years were evaluated for subjective assessment of fit of the maxillary denture, occlusal integrity, and the status of the anterior maxillary residual ridge. The findings of this study support the view that this combination of prostheses can result in perceived loosening of the maxillary denture, loss of posterior occlusion, increased anterior occlusal pressure, and anterior maxillary bone loss, similar to the effects seen in Combination Syndrome. It is therefore important to ensure that where an implant-supported mandibular overdenture is planned for the edentulous patient, some form of stabilisation of the maxillary arch is also considered.
Assuntos
Prótese Dentária Fixada por Implante/efeitos adversos , Retenção de Dentadura , Prótese Total Superior/efeitos adversos , Revestimento de Dentadura/efeitos adversos , Adaptação Psicológica , Idoso , Perda do Osso Alveolar/etiologia , Feminino , Seguimentos , Humanos , Incisivo , Masculino , Mandíbula , Pessoa de Meia-Idade , Dente Molar , Planejamento de Assistência ao Paciente , Satisfação do Paciente , Dimensão VerticalRESUMO
We previously demonstrated that abnormal nipple aspirate fluid (NAF) cytology predicted residual breast cancer (RC) and tumour size after excisional biopsy (EB), although normal NAF cytology did not exclude RC. Tumour size correlates with the risk of lymph node (LN) metastases. LN metastases provide prognostic information allowing medical and radiation oncologists to determine the need for adjuvant therapy. We hypothesized that pathologic factors known after EB, combined with NAF cytology, would predict with a high degree of accuracy the presence of RC and LN spread. NAF cytology and pathologic parameters: tumour distance from biopsy margins, multifocal and multicentric disease, sub-type of ductal carcinoma in situ (DCIS) or invasive cancer (IC), grade of DCIS or IC, tumour and specimen size, tumour and biopsy cavity location, presence or absence of extensive DCIS, and biopsy scar distance from the nipple were evaluated bivariately and then by logistic regression (LR) for their association with RC and involved LN (> or = 1 (+) LN, useful to determine chemotherapy need, and > or = 4 (+) LN, useful to determine radiation need to the chest and axilla). Data were analysed using NAF cytology alone, pathologic parameters alone, and NAF cytology and pathologic parameters combined. The combined LR model was superior in predicting residual cancer (94%) to LR models using NAF cytology (36%) or pathologic parameters (75%) alone. When only subjects with normal NAF cytology were evaluated by LR, the model was 92% sensitive in predicting RC. Tumour size and NAF cytology predicted which patients had > or = 1 (+) LN, whereas tumour and specimen size predicted which patients had > or = 4 (+) LN. We propose an algorithm which, if confirmed in a larger study, may allow clinicians to be more selective in their recommendations of re-excision breast biopsy or mastectomy.
Assuntos
Líquidos Corporais/citologia , Neoplasias da Mama/patologia , Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Metástase Linfática/diagnóstico , Células-Tronco Neoplásicas/ultraestrutura , Mamilos , Adulto , Idoso , Biópsia , Células Epiteliais/química , Células Epiteliais/ultraestrutura , Feminino , Humanos , Hiperplasia , Mastectomia , Pessoa de Meia-Idade , Neoplasia Residual , Células-Tronco Neoplásicas/química , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: The rarity of pancreatic tumours other than nesidioblastosis in children is such that the experience of any one surgeon or institution is small. As a consequence, there is limited information on the appropriate management and outcome of these tumours. For this reason a review was conducted of the experience of a large paediatric surgical institution. METHODS: During a 23-year period, six patients with pancreatic tumours other than nesidioblastosis were treated at the Royal Children's Hospital, Melbourne. RESULTS: Despite the varied modes of presentation and surgery undertaken, all six patients with surgery alone, with follow-up from 1 to 18 years. Two of the tumours were malignant; the remaining four being islet cell adenomata. No form of adjuvant treatment (chemotherapy or radiotherapy) was used. CONCLUSION: These rare paediatric tumours appear to have a good prognosis, even when malignant, and respond well to radical surgical ablation. Adjuvant therapy appears to be unnecessary.