RESUMO
The ongoing US Glatiramer Acetate (GA) Trial is the longest evaluation of continuous immunomodulatory therapy in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to evaluate up to 15 years of GA as a sole disease-modifying therapy. Two hundred and thirty-two patients received at least one GA dose since study initiation in 1991 (mITT cohort), and 100 (43%, Ongoing cohort) continued as of February 2008. Patients were evaluated every 6 months using the Expanded Disability Status Scale (EDSS). Mean GA exposures were 8.6 +/- 5.2, 4.81 +/- 3.69, and 13.6 +/- 1.3 years and mean disease durations were 17, 13, and 22 years for mITT, Withdrawn and Ongoing cohorts, respectively. For Ongoing patients, annual relapse rates (ARRs) maintained a decline from 1.12 +/- 0.82 at baseline to 0.25 +/- 0.34 per year; 57% had stable/improved EDSS scores (change < or = 0.5 points); 65% had not transitioned to secondary progressive multiple sclerosis (SPMS); 38%, 18%, and 3% reached EDSS 4, 6, and 8. For all patients on GA therapy (the mITT cohort), ARRs declined from 1.18 +/- 0.82 to 0.43 +/- 0.58 per year; 54% had stable/improved EDSS scores; 75% had not transitioned to SPMS; 39%, 23%, and 5% reached EDSS 4, 6, and 8. In conclusion, multiple sclerosis patients with mean disease duration of 22 years administering GA for up to 15 years had reduced relapse rates, and decreased disability progression and transition to SPMS. There were no long-term safety issues.
Assuntos
Fatores Imunológicos/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Peptídeos/administração & dosagem , Adulto , Distribuição de Qui-Quadrado , Estudos Cross-Over , Avaliação da Deficiência , Método Duplo-Cego , Esquema de Medicação , Feminino , Acetato de Glatiramer , Humanos , Fatores Imunológicos/efeitos adversos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Pacientes Desistentes do Tratamento , Peptídeos/efeitos adversos , Pontuação de Propensão , Estudos Prospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND AND OBJECTIVES: Brief cognitive tests to monitor cognitive impairment in patients with multiple sclerosis (MS) are needed. METHODS: Performance on monthly administrations of the Symbol Digit Modalities Test (SDMT) and the MS Neuropsychological Questionnaire (MSNQ) was assessed in 660 patients with MS in 21 countries (109 sites) for 48 weeks in an open-label, safety-extension study of natalizumab. RESULTS: At baseline, the cohort's mean age was 40.1 years, 67.6% were female and the median Expanded Disability Status Scale score was 2.5. Test-retest correlations were high for both SDMT (range 0.89 for weeks 0-4 to 0.96 for weeks 44-48) and MSNQ (0.82 for weeks 0-4 to 0.93 for weeks 44-48). There were no statistically significant effects of geographic region. While SDMT scores improved by 15 points over 48 weeks (p < 0.0001), incremental monthly changes were small (effect size d < 0.3). Similar results were obtained on the MSNQ except that scores moved downward, suggesting fewer cognitive complaints over 48 weeks (p < 0.0001), but again the incremental monthly changes were small (d <-0.2). CONCLUSIONS: These results replicate earlier work in a smaller cohort treated with conventional disease-modifying therapy, and support the reliability of the SDMT and MSNQ as potential screening for monitoring tools for cognition over time.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Transtornos Cognitivos/diagnóstico , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/complicações , Testes Neuropsicológicos , Adulto , Anticorpos Monoclonais Humanizados , Transtornos Cognitivos/etiologia , Feminino , Humanos , Masculino , Esclerose Múltipla/tratamento farmacológico , Natalizumab , Inquéritos e QuestionáriosRESUMO
PURPOSE: To estimate the rate of surgical treatment of paediatric proximal humerus fractures over time utilizing a large, publicly available national database. METHODS: The Healthcare Cost and Utilization Project Kids' Inpatient Database was evaluated between the years 2000 and 2012. Proximal humerus fractures were identified using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9 CM) diagnosis codes. ICD-9 CM procedure codes were used to identify patients who received surgical treatment. Univariable and multivariable logistic regression were used to determine variables associated with greater proportions of surgical treatment. All statistical analyses were performed utilizing SAS statistical software v.9.4. Statistical significance was set at p < 0.05. RESULTS: A total of 7520 proximal humerus fracture admissions were identified; 3247 (43.2%) were treated surgically. The percentage of patients receiving surgery increased from 39.3% in 2000 to 46.4% in 2012 (p < 0.001). After adjustment for potential confounders, increased age, increased ICD-9 derived injury severity scores (ICISS) and more recent year were associated with an increased proportion of patients receiving surgical treatment (p < 0.001). Medicaid payer status (p < 0.001) and admission to a children's hospital (p = 0.045) were associated with a lower proportion of surgical treatment. CONCLUSION: The rate of operative treatment of paediatric proximal humerus fractures increased over time between 2000 and 2012. Increased surgical rates were independently associated with older age, increased ICISS, treatment at a non-children's hospital and non-Medicaid insurance status. Further study is needed to provide evidence to support improved outcomes after operative treatment of paediatric proximal humerus fractures.
RESUMO
In studies employing rat renal cortical slices, the addition of adenosine 3',5'-monophosphate (cyclic AMP) to the incubation medium caused an increase in production of glucose from glutamine, glutamate, alpha-ketoglutarate, fumarate, malate, and oxalacetate, but not from glycerol and fructose. These observations suggest that cyclic AMP accelerates a rate-limiting gluconeogenic reaction between oxalacetate and the triose phosphates. The addition to the medium of parathyroid hormone, which is known to increase renal cortical cyclic AMP, also stimulated glucose production from glutamine. When renal cortical slices were incubated in the presence of glutamine, the addition of cyclic AMP caused a fall in tissue glutamate concentration and a rise in ammonia production, as well as an increase in gluconeogenesis. These changes are similar to those observed in renal cortex of rats with induced metabolic acidosis. The present observations are consistent with a previously advanced hypothesis that cortical gluconeogenesis, ammonia production, and glutamate concentration may be interdependent.
Assuntos
Nucleotídeos de Adenina/farmacologia , Amônia/biossíntese , Gluconeogênese/efeitos dos fármacos , Rim/efeitos dos fármacos , Animais , AMP Cíclico/farmacologia , Frutose/metabolismo , Fumaratos/metabolismo , Glutamatos/análise , Glutamina/metabolismo , Glicerol/metabolismo , Técnicas In Vitro , Ácidos Cetoglutáricos/metabolismo , Rim/metabolismo , Malatos/metabolismo , Masculino , Oxaloacetatos/metabolismo , Hormônio Paratireóideo/farmacologiaRESUMO
Glutamate is an inhibitor of phosphate dependent glutaminase (PDG), and renal cortical glutamate is decreased in metabolic acidosis. It has been postulated previously that the rise in renal production of ammonia from glutamine in metabolic acidosis is due primarily to activation of cortical PDG as a consequence of the fall in glutamate. The decrease in cortical glutamate has been attributed to the increase in the capacity of cortex to convert glutamate to glucose in acidosis. In the present study, administration of ammonium chloride to rats in an amount inadequate to decrease cortical glutamate increased the capacity of cortex to produce ammonia from glutamine in vitro and increased cortical PDG. Similarly, cortex from potassium-depleted rats had an increased capacity to produce ammonia and an increase in PDG, but glutamate content was normal. The glutamate content of cortical slices incubated at pH 7.1 was decreased, and that at 7.7 was increased, compared to slices incubated at 7.4, yet ammonia production was the same at all three pH levels. These observations suggest that cortical glutamate concentration is not the major determinant of ammonia production. In potassium-depleted rats there was a 90% increase in the capacity of cortex to convert glutamate to glucose, yet cortical glutamate was not decreased. In vitro, calcium more than doubled conversion of glutamate to glucose by cortical slices without affecting the glutamate content of the slices, and theophylline suppressed conversion of glutamate to glucose yet decreased glutamate content. These observations indicate that the rate of cortical gluconeogenesis is not the sole determinant of cortical glutamate concentration. The increase in cortical gluconeogenesis in acidosis and potassium depletion probably is not the primary cause of the increase in ammonia production in these states, but the rise in gluconeogenesis may contribute importantly to the maintenance of increased ammoniagenesis by accelerating removal of the products of glutamine degradation.
Assuntos
Acidose/metabolismo , Amônia/biossíntese , Gluconeogênese , Glutamatos/metabolismo , Rim/metabolismo , Deficiência de Potássio/metabolismo , Equilíbrio Ácido-Base , Nucleotídeos de Adenina/metabolismo , Alcalose/metabolismo , Animais , Cálcio/farmacologia , Meios de Cultura , AMP Cíclico/metabolismo , Privação de Alimentos , Glutaminase/metabolismo , Glutamina/metabolismo , Rim/análise , Masculino , Métodos , Nucleosídeos/metabolismo , Ratos , Teofilina/farmacologiaRESUMO
Most of the immunoreactive growth hormone (IRGH) in human plasma elutes from Sephadex G-75 as "little" GH (LGH), mol wt 22,000, but 14-39% elutes earlier ("big" GH, BGH). In saline extracts of human pituitary, 11-17% of IRGH eluted as BGH. On gel filtration of pituitary and plasma BGH in 8 M urea, 59-81% ran as LGH, but when the remaining BGH was refiltered in urea, all ran as BGH. Thus there is a "urea-stable" and a "urea-labile" form of BGH. SImilarly, freezing and thawing converted over half of pituitary and plasma BGH to LGH, but when the "freeze-stable" BGH was again frozen, thawed, and refiltered, almost all ran as BGH. Urea-stable BGH was not dissociated by freezing, and most of the freeze-stable BGH was stable in urea, so the two forms are very similar or identical. Since 8 M urea and freezing dissociate peptides linked by noncovalent bonds, probably the BGH that is dissociated by urea and freezing consists of LGH bound noncovalently to another moiety, while in stable BGH the LGH is bound to another molecule by covalent or unusually strong noncovalent linkage. On centrifugation, the sedimentation of urea-stable BGH was consistent with a mol wt about twice that of LGH. Trypsinization of urea-stable BGH converted 36-59% to LGH, suggesting that some BGH may be a "prohormone" of LGH. On retrypsinization of the BGH that was not converted to LGH, only 13-24% converted, suggesting that there may be two forms of urea-stable BGH which vary in their response to trypsin.
Assuntos
Hormônio do Crescimento , Acromegalia/sangue , Reações Antígeno-Anticorpo , Antígenos , Barbitúricos , Centrifugação com Gradiente de Concentração , Fenômenos Químicos , Química , Cromatografia em Gel , Congelamento , Hormônio do Crescimento/análise , Hormônio do Crescimento/sangue , Hormônio do Crescimento/imunologia , Humanos , Radioisótopos do Iodo , Peso Molecular , Hipófise/análise , Radioimunoensaio , Cloreto de Sódio , Sacarose , Extratos de Tecidos/análise , Tripsina/farmacologia , UreiaRESUMO
It has been suggested that elevated levels of insulin or insulin-like growth factors (IGFs) play a role in the development of diabetic vascular complications. Previously, we have shown a differential response to insulin between vascular cells from retinal capillaries and large arteries with the former being much more insulin responsive. In the present study, we have characterized the receptors and the growth-promoting effect of insulinlike growth factor I (IGF-I) and multiplication-stimulating activity (MSA, an IGF-II) on endothelial cells and pericytes from calf retinal capillaries and on endothelial and smooth muscle cells from calf aorta. We found single and separate populations of high affinity receptors for IGF-I and MSA with respective affinity constants of 1 X 10(-9) M-1 and 10(-8) M-1 in all four cell types studied. Specific binding of IGF-I was between 7.2 and 7.9% per milligram of protein in endothelial cells and 9.1 and 10.4% in the vascular supporting cells. For 125I-MSA, retinal endothelial cells bound only 1.7-2.5%, whereas the aortic endothelial cells and the vascular supporting cells bound between 5.6 and 8.5% per milligram of protein. The specificity of the receptors for IGF-I and MSA differed, as insulin and MSA was able to compete with 125I-IGF-I for binding to the IGF-I receptors with 0.01-0.1, the potency of unlabeled IGF-I, whereas even 1 X 10(-6) M, insulin did not significantly compete with 125I-MSA for binding to the receptors for MSA. For growth-promoting effects, as measured by the incorporation of [3H]thymidine into DNA, confluent retinal endothelial cells responded to IGF-I and MSA by up to threefold increase in the rate of DNA synthesis, whereas confluent aortic endothelial cells did not respond at all. A similar differential of response to insulin between micro- and macrovascular endothelial cells was reported by us previously. In the retinal endothelium, insulin was more potent than IGF-I and IGF-I was more potent that MSA. In the retinal and aortic supporting cells, no differential response to insulin or the IGFs was observed. In the retinal pericytes, IGF-I, which stimulated significant DNA synthesis beginning at 1 X 10(-9) M, and had a maximal effect at 5 X 10(-8) M, was 10-fold more potent than MSA and equally potent to insulin. In the aortic smooth muscle cells, IGF-I was 10-100 times more potent than insulin or MSA. In the retinal and aortic supporting cells, no differential response to insulin or the IGFs was observed. In the retinal pericytes, IGF-I, which stimulated significant DNA synthesis beginning at 1 X 10(-9) M, and had a maximal effect at 5 X 10(-8) M, was 10-fold more potent than MSA and equally potent to insulin. In the aortic smooth muscle cells, IGF-I was 10-100 times more potent than insulin or MSA. In addition, insulin and IGF-I at 1 X 10(-6) and 1 X 10(-8) M, respectively, stimulated these cells to grow by doubling the number of cells as well. In all responsive tissues, the combination of insulin and IGFs were added together, no further increase in effect was seen. These data showed that vascular cells have insulin and IGF receptors, but have a differential response to these hormones. These differences in biological response between cells from retinal capillaries and large arteries could provide clues to understanding the pathogenesis of diabetic micro- and macroangiopathy.
Assuntos
Insulina/farmacologia , Peptídeos/farmacologia , Receptores de Superfície Celular/análise , Somatomedinas/farmacologia , Animais , Aorta , Ligação Competitiva , Capilares , Bovinos , DNA/biossíntese , Endotélio/citologia , Endotélio/metabolismo , Hormônio do Crescimento/farmacologia , Insulina/metabolismo , Fator de Crescimento Insulin-Like II , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Peptídeos/metabolismo , Receptores de Superfície Celular/fisiologia , Receptores de Somatomedina , Retina , Somatomedinas/metabolismoRESUMO
In previous studies it was found that renal cortical slices from rats with induced metabolic acidosis have an increased capacity to produce glucose, whereas cortical slices from rats with metabolic alkalosis manifest decreased gluconeogenesis. To evaluate the relative influence of extracellular fluid pH, [HCO(3) (-)], and carbon dioxide tension on renal gluconeogenesis, we observed glucose production by cortex from rats with induced respiratory acidosis, and by cortex taken from normal animals and incubated in acid and alkaline media. We found glucose production to be increased in cortex from rats with respiratory acidosis, as is the case in metabolic acidosis. Glucose production by slices from normal rats was increased in media made acidic by reducing [HCO(3) (-)], and decreased in media made alkaline by raising [HCO(3) (-)]. These effects were evident whether the gluconeogenic substrate employed was glutamine, glutamate, alpha-ketoglutarate, or oxalacetate. Glucose production was also increased in media made acidic by raising CO(2) tension and decreased in media made alkaline by reducing CO(2) tension. These data indicate that both in vivo and in vitro, pH, rather than CO(2) tension or [HCO(3) (-)], is the most important acid-base variable affecting renal gluconeogenesis. The findings suggest that a decrease in extracellular fluid pH enhances renal gluconeogenesis through direct stimulation of one of the rate-limiting reactions involved in the conversion of oxalacetate to glucose. We hypothesize that the resultant increase in the rate of removal of glutamate, a precursor of oxalacetate, may constitute an important step in the mechanism by which acidosis increases renal ammonia production.
Assuntos
Alcalose/metabolismo , Gluconeogênese/efeitos dos fármacos , Rim/metabolismo , Acidose Respiratória/induzido quimicamente , Acidose Respiratória/metabolismo , Animais , Bicarbonatos/farmacologia , Dióxido de Carbono , Glutamatos/metabolismo , Glutamina/metabolismo , Glutaratos/metabolismo , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Masculino , Oxaloacetatos/metabolismo , Pressão Parcial , RatosRESUMO
GTP, in physiologic concentration, enhances the binding of cAMP to a protein in the hepatic cytosol that may be the regulatory subunit of protein kinase II. Ingestion of carbohydrate suppresses hepatic gluconeogenesis and glycogenolysis, two processes that are stimulated by cAMP. In this study, we have examined the possibility that carbohydrate inhibits these processes partly by decreasing the sensitivity of the GTP-responsive cAMP-binding protein to the effect of GTP. We found that 100 muM GTP was much less effective in enhancing cAMP binding in the hepatic cytosol of rats given 15% glucose for 2 days than in the cytosol of fasted rats [21 +/- 3% (mean +/- SE) increase vs. 67 +/- 6%, P less than .01]. Corresponding results were noted in diethylaminoethyl (DEAE)-cellulose extracts of the hepatic cytosol of these rats. GTP stimulation of cAMP binding was also diminished in the hepatic cytosol of diabetic rats treated for 7 days with insulin compared with that of untreated diabetic rats (29 +/- 10 vs. 81 +/- 11% increase, P less than .01), but this could have been due to increased food intake in the treated rats. We conclude that GTP stimulation of hepatic cAMP binding is decreased in the carbohydrate-fed state and that this effect may be mediated by the increase in plasma insulin induced by carbohydrate. Our observations suggest that some of the cellular effects of cAMP may be regulated by modulation of the stimulatory effect of GTP on the GTP-responsive cAMP-binding protein.
Assuntos
AMP Cíclico/metabolismo , Ingestão de Alimentos , Jejum , Guanosina Trifosfato/farmacologia , Insulina/farmacologia , Fígado/metabolismo , Animais , Citosol/metabolismo , Fígado/efeitos dos fármacos , Masculino , Ratos , Ratos EndogâmicosRESUMO
We have measured plasma von Willebrand factor (VWF) as the factor VIII-related antigen, plasma fibronectin, and two of the serum somatomedins, insulin-like growth factor I (IGF I) and IGF II, in 51 diabetic patients and 25 nondiabetic control subjects. VWF was significantly higher in the diabetic group than in the controls (173 +/- 9% SEM versus 101 +/- 9%, P less than 0.001), as has been reported by others. However, within the diabetic group there was no significant difference in VWF between those patients without retinopathy, those with background or proliferative retinopathy, or those with macular edema. There was also no difference in VWF between the diabetic subjects with and those without proteinuria. These results rule against a previously advanced hypothesis that the increase in VWF in patients with diabetes is secondary to microangiopathy. No significant difference was observed in fibronectin, IGF I, or IGF II between the diabetic and control groups, between the diabetic group without retinopathy and the retinopathic subgroups, and between the diabetic subjects with and without proteinuria. In the diabetic patients, there was no correlation between diabetic control as assessed by glycosylated hemoglobin and glycosylated serum protein, and the plasma levels of VWF, fibronectin, IGF I, or IGF II. The results of this study strongly suggest that neither plasma VWF, fibronectin, IGF I, nor IGF II plays an important primary role in the pathogenesis of diabetic microvascular disease, although one or more of these factors might play a permissive role.
Assuntos
Fatores de Coagulação Sanguínea/fisiologia , Nefropatias Diabéticas/sangue , Retinopatia Diabética/sangue , Fibronectinas/sangue , Insulina/sangue , Peptídeos/sangue , Somatomedinas/sangue , Fator de von Willebrand/fisiologia , Adulto , Fatores Etários , Idoso , Peso Corporal , Nefropatias Diabéticas/fisiopatologia , Retinopatia Diabética/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteinúria/sangueRESUMO
The 2 most common forms of X-linked adreno-leukodystrophy (ALD) are the juvenile or childhood cerebral form with inflammatory demyelination and the adult adrenomyeloneuropathy (AMN) involving spinal cord tracts without significant inflammation. Modifier genes or environmental factors may contribute to the phenotypic variability. We performed immunohistochemical, an in situ polymerase chain reaction, and TUNEL analyses to identify several viruses, lymphocyte subpopulations, apoptotic cells, and effector molecules, focusing on morphologically normal white matter, dysmyelinative and acute demyelinative lesions. No distinguishing viral antigens were detected. Most lymphocytes were CD8 cytotoxic T cells (CTLs) with the alpha/beta TCR, and they infiltrated morphologically unaffected white matter. Only a few oligodendrocytes were immunoreactive for caspase-3. MHC class II- and TGF-beta-positive microglia were present. CD44, which can mediate MHC-unrestricted target cell death, was seen on many lymphocytes and white matter elements. CD1 molecules, which play major roles in MHC-unrestricted lipid antigen presentation, were noted. Our data indicate that unconventional CD8 CTLs are operative in the early stages of dysmyelination/demyelination and that cytolysis of oligodendrocytes, rather than apoptosis, appears to be the major mode of oligodendrocytic death. The presentation of lipid antigens may be a key pathogenetic element in ALD and AMN-ALD.
Assuntos
Adrenoleucodistrofia/patologia , Apresentação de Antígeno , Antígenos CD1/fisiologia , Encéfalo/patologia , Citotoxicidade Imunológica , Lipídeos/imunologia , Oligodendroglia/patologia , Linfócitos T Citotóxicos/imunologia , Adrenoleucodistrofia/imunologia , Adrenoleucodistrofia/metabolismo , Encéfalo/imunologia , Morte Celular/imunologia , Antígenos de Histocompatibilidade Classe I/análise , Antígenos de Histocompatibilidade Classe II/análise , Humanos , Imuno-Histoquímica , Metabolismo dos Lipídeos , Oligodendroglia/imunologiaRESUMO
We have found that in female rats a variety of stressful stimuli, including sc inflammation, skin incision, endotoxin injection, and cold exposure, cause a significant decrease (30-86%) in the capacity of the hepatic cell membranes to specifically bind [125I]ovine PRL. Stress-induced decrease in food intake was not a factor in these studies, as nourishment was given only by tube feeding. Neither sc inflammation nor cold exposure affected hepatic binding of [125I]insulin. Further, the induction of inflammation in lactating rats and rats bearing 7,12-dimethylbenz[a]anthracene-induced mammary carcinomas did not affect the binding of PRL by the lactating or malignant mammary tissue. The suppressive effect of inflammation on hepatic binding of PRL was demonstrable in adrenalectomized-ovariectomized rats, in hypophysectomized rats receiving hormone replacement, and in adrenalectomized rats that had undergone partial chemical sympathectomy. We conclude that sc inflammation, as well as other forms of stress, decreases hepatic binding of PRL, but does not affect hepatic binding of insulin or mammary binding of PRL. The decrease in hepatic PRL binding is not mediated by a hormone secreted by the adrenals, ovaries, or pituitary, or by catecholamines, but could be mediated by another plasma factor or by peripheral dopaminergic neurons. Stress-induced decrease in hepatic PRL binding, or a related decrease in the binding of other polypeptide hormones, could play a role in the physiological response to stress.
Assuntos
Inflamação/metabolismo , Fígado/metabolismo , Prolactina/metabolismo , Estresse Fisiológico/metabolismo , Adrenalectomia , Animais , Castração , Temperatura Baixa , Feminino , Hipofisectomia , Inflamação/induzido quimicamente , Lactação , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Gravidez , Ratos , Ratos EndogâmicosRESUMO
Previous experimental observations have suggested to us that PRL and GH may be involved in regulating the metabolism of carnitine, a factor that plays a critically important role in fatty acid oxidation and ketogenesis. In the present study we administered bovine PRL (bPRL) or bovine GH (bGH) at a physiologic rate to hypophysectomized female rats for 2-3 days, and observed that bPRL caused a small (16%) increase (P less than 0.01), and bGH a 36% increase (P less than 0.01), in hepatic carnitine, bPRL decreased serum carnitine by 24% (P less than 0.05), and bPRL and bGH each increased the liver/serum carnitine ratio by 58% (P less than 0.01), suggesting that these hormones enhance the active uptake of carnitine from plasma. bPRL and bGH, alone or in combination, did not affect the carnitine content of cardiac or skeletal muscle, but in combination they increased the heart/serum and muscle/serum carnitine ratios by 45-76% (P less than 0.01), thus allowing maintenance of normal cardiac and skeletal muscle carnitine despite a decreased plasma level. In hypophysectomized male rats, bPRL did not affect liver or epididymal carnitine. We hypothesize that PRL and GH may play a role in the regulation of the carnitine concentration of female liver by enhancing hepatic uptake of carnitine from plasma, and through this mechanism may affect hepatic fatty acid oxidation and ketogenesis. The effect of lactogenic and somatogenic hormones on hepatic carnitine and ketogenesis could be of particular physiological importance in late pregnancy and during lactation.
Assuntos
Carnitina/metabolismo , Epididimo/metabolismo , Hormônio do Crescimento/farmacologia , Fígado/metabolismo , Músculos/metabolismo , Miocárdio/metabolismo , Prolactina/farmacologia , Animais , Carnitina/sangue , Epididimo/efeitos dos fármacos , Feminino , Coração/efeitos dos fármacos , Hipofisectomia , Fígado/efeitos dos fármacos , Masculino , Músculos/efeitos dos fármacos , Especificidade de Órgãos , Ratos , Ratos Endogâmicos , Valores de ReferênciaRESUMO
Immunoreactive growth hormone (GH) from human pituitary and plasma contains "big" (BGH) and "little" (LGH) components. BGH itself consists of a "urea-labile" form and a "urea-stable" form (usBGH). In the present study we determined the amino acid composition of a BGH preparation containing both the urea-labile and urea-stable components and bound it to be indistinguishable from that of LGH. This finding, coupled with observations of others, suggests that urea-labile BGH is a simple LGH dimer and that usBGH is a disulfide dimer. We have prepared LGH, BGH, and usBGH from human pituitary GH, and studied their radioreceptor activity, in relation to their immunoreactivity, in plasma membrane systems from rabbit, rat and human liver and rabbit mammary gland. When 125I-LGH was used as the radioligand, LGH and usBGH caused parallel displacement, usBGH was 60-74% as active as LGH in the animal preparations, while in human liver the two forms were equally active. Three different BGH preparations studied in the animal systems were 26-33% as active as LGH. The receptor activity of these BGH preparations was greater than expected from their usBGH content, suggesting that urea-labile BGH also binds to the LGH receptor. When 125I-usBGH was employed as radioligand, we found that in the presence of 2,000 ng/ml of LGH, which caused maximal displacement of 125I-usBGH, the addition of 2 ng/ml of usBGH produced additional displacement. This suggested the presence of a receptor specific for usBGH. However, the phenomenon proved to be due to a contaminant in the usBGH preparations which decreased binding of 125I-usBGH. BGH containing a substantial fraction of usBGH, and "freeze-stable" BGH which is probably identical with usBGH, both failed to displace 125I-usBGH in the presence of 2,000 ng/ml LGH. These observations rule against the existence of a specific receptor for usBGH.
Assuntos
Hormônio do Crescimento/metabolismo , Aminoácidos/análise , Animais , Membrana Celular/ultraestrutura , Hormônio do Crescimento/análise , Hormônio do Crescimento/imunologia , Humanos , Coelhos , Ensaio Radioligante , Ratos , Receptores de Superfície Celular/metabolismo , UreiaRESUMO
Infusion of alpha-adrenergic catecholamines increases plasma cyclic guanosine monophosphate (pcGMP), raising the possibility that the pressor effect of these agents may be mediated by cyclic GMP. We infused pressor doses of angiotensin II in 10 studies in 8 normal subject and measured pcGMP and plasma cyclic adenosine monophosphate (pcAMP) by radioimmunoassay. After 120 minutes of infusion, mean pcGMP was 128 +/- 31% (SE) higher than baseline values (P less than 0.01) while pcAMP was increased 30 +/- 10% (P less than 0.05).
Assuntos
Angiotensina II/farmacologia , AMP Cíclico/sangue , GMP Cíclico/sangue , Atropina/farmacologia , GMP Cíclico/fisiologia , Humanos , Masculino , Sistema Nervoso Parassimpático/efeitos dos fármacos , RadioimunoensaioRESUMO
OBJECTIVE: To report symptomatic autoimmune hyperthyroidism developing in patients with multiple sclerosis (MS) treated with interferon beta-1b (IFN-beta-1b). REPORT OF CASES: A 44-year-old woman experienced gradually worsening fatigue, depression, and motor function several months after beginning therapy with IFN-beta-1b for MS. Graves disease associated with episodic palpitations, shortness of breath, hair loss, increased appetite, weight loss, and insomnia was confirmed with endocrinologic studies. Increased fatigue and weakness developed in a 52-year-old woman several months after starting IFN-beta-1b therapy. She also noted sweats, heat intolerance, palpitations, increased appetite, and irritability, and endocrinologic evaluation supported a diagnosis of Graves disease. CONCLUSIONS: To our knowledge, this is the first report of autoimmune thyroid disease associated with IFN-beta-1b treatment in patients with MS. Psoriasis has also been reported during interferon therapy for MS, and similar phenomena occur during interferon therapy for hepatitis C. Since some symptoms of thyroid dysfunction may be difficult to distinguish from typical MS-related symptoms, thyroid hormone levels should be checked when unexplained constitutional symptoms occur during IFN-beta-1b therapy.
Assuntos
Adjuvantes Imunológicos/efeitos adversos , Doença de Graves/etiologia , Interferon beta/efeitos adversos , Esclerose Múltipla/terapia , Adjuvantes Imunológicos/uso terapêutico , Adulto , Feminino , Humanos , Interferon beta-1a , Interferon beta-1b , Interferon beta/uso terapêutico , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Bone mineral density is reduced in patients with multiple sclerosis (MS), but the reduction has not been shown to correlate with steroid use retrospectively. OBJECTIVE: To prospectively measure bone density following a single corticosteroid pulse using dual energy x-ray absorptiometry. PATIENTS AND METHODS: Thirty acutely relapsing patients with MS were given 1000 mg of methylprednisolone intravenously daily for 3 days followed by an oral prednisone taper for 2 weeks. The bone density was determined at the lumbar spine and femoral neck prior to treatment. Seventeen patients were reevaluated 2,4, and 6 months following treatment. RESULTS: Prior to treatment, bone density in patients with MS was already reduced at the femoral neck compared with an age-matched reference population, but the degree of this reduction did not correlate with prior steroid exposure. Lumbar density, in contrast, was normal. Following the steroid pulse, lumbar bone density increased, becoming 1.7% greater than baseline 6 months later (P = .02). Femoral bone density did not change on average, but the patients who required a cane or walker for ambulation had a 1.6% decrease in femoral bone density, while those with better ambulation had a 2.9% increase (P = .04). CONCLUSIONS: Bone density is decreased in MS. A single corticosteroid pulse did not reduce bone density in fully ambulatory patients with MS and multiple pulses did not have a cumulative effect on bone density in retrospective analysis. The change in femoral density in poorly ambulatory patients may have been related to inactivity rather than the steroid pulse.
Assuntos
Corticosteroides/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Osteoporose/tratamento farmacológico , Adulto , Densidade Óssea/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Fatores de TempoRESUMO
OBJECTIVE: Magnetic resonance imaging, computed tomography, cerebrospinal fluid analysis, and evoked potential testing are used to assist in the diagnosis of patients suspected to have multiple sclerosis (MS). The impact of these tests on a clinician's diagnosis of patients suspected to have MS has not been studied systematically. DESIGN: Clinicians made a diagnosis of each patient following clinical evaluation, again after reviewing the results of magnetic resonance imaging, and finally after reviewing information from other laboratory testing. These diagnoses were compared with the criterion standard of a masked "gold standard" panel reviewing all information after a mean follow-up of 0.9 year. SETTING: The General Neurology Clinic and Multiple Sclerosis Clinic of the University of Rochester (NY). PATIENTS: A consecutive sample of 62 patients diagnosed as having either possible or probable MS following clinical evaluation. MAIN OUTCOME MEASURE: Changes in diagnostic certainty of clinicians following incremental presentation of new laboratory data and the accuracy of such diagnoses. RESULTS: Clinicians used magnetic resonance imaging findings to diagnose definite MS or to eliminate MS from diagnostic consideration in 44% of cases. In these cases, further laboratory testing did not alter clinicians' decisions. In the remaining 56% of cases, in which magnetic resonance imaging did not lead to a diagnosis of definite MS or eliminate MS from diagnostic consideration, further laboratory testing led to such diagnoses in an additional 13% of cases. Gold standard diagnoses were in agreement with the clinician's assessments. CONCLUSIONS: Magnetic resonance imaging aids in the evaluation of patients suspected to have MS; other subsequent studies (computed tomography, cerebrospinal fluid analysis, and evoked potential testing) have less impact. After all studies are performed, about half of such patients still have a tentative diagnosis.
Assuntos
Esclerose Múltipla/diagnóstico , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Potenciais Evocados , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico por imagem , RadiografiaRESUMO
BACKGROUND: Glatiramer acetate (Copaxone) therapy reduces clinical disease activity in relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To study the effect of glatiramer therapy on neuropsychologic function as part of a randomized, placebo-controlled, multicenter trial. METHODS: Two hundred forty-eight patients with relapsing-remitting MS and mild to moderate disability (Expanded Disability Status Scale score, <5.0) were tested before and 12 and 24 months after randomization to administration of glatiramer acetate, 20 mg/d, or matching placebo. Neuropsychologic tests examined 5 cognitive domains most often disrupted in patients with MS: sustained attention, perceptual processing, verbal and visuospatial memory, and semantic retrieval. RESULTS: Baseline neuropsychologic test performance was similar in both treatment groups and was within normal range, except for impaired semantic retrieval. Mean neuropsychologic test scores were higher at 12 and 24 months than at baseline, and no differences were detected between treatment groups over time. No significant interactions were detected between treatment and either time or baseline impairment. CONCLUSIONS: Our 2-year longitudinal study showed no effect of glatiramer therapy on cognitive function in relapsing-remitting MS. Although it is possible that glatiramer therapy has no effect on cognitive function, the lack of measurable decline in cognitive function in both patient groups for 2 years limits the opportunity for glatiramer to demonstrate a therapeutic effect by minimizing such decline. Emerging treatments for MS should continue to be examined for their effect on cognitive impairment because it can be a critical determinant of disability. A greater understanding of the natural history of cognitive decline in MS is essential for a rational design of these drug trials.
Assuntos
Cognição/efeitos dos fármacos , Imunossupressores/farmacologia , Esclerose Múltipla/tratamento farmacológico , Peptídeos/farmacologia , Adolescente , Adulto , Método Duplo-Cego , Feminino , Acetato de Glatiramer , Humanos , Imunossupressores/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/psicologia , Testes Neuropsicológicos , Peptídeos/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The MSFC is the primary outcome measure in the ongoing multinational phase 3 trial of interferon beta-1a (Avonex) in patients with secondary progressive MS. OBJECTIVE: To assess the practice effects, reliability, and validity of the MSFC clinical outcome measure. DESIGN: Examining technicians underwent formal training using standardized materials. The MSFC was performed according to a standardized protocol. The 436 patients enrolled in the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial underwent 3 prebaseline MSFC testing sessions before randomization. RESULTS: Practice effects were evident initially for the MSFC but stabilized by the fourth administration. The Paced Auditory Serial Addition Test demonstrated the most prominent practice effects. The reliability of the MSFC was excellent, with an intraclass correlation coefficient for session 3 (final prebaseline session) vs session 4 (baseline) of 0.90. The MSFC at baseline correlated moderately strongly with the Kurtzke Expanded Disability Status Scale. Among the MSFC components, the Timed 25-Foot Walk correlated most closely. Correlations among the 3 MSFC components were weak, suggesting they assess distinct aspects of neurologic function in patients with MS. CONCLUSIONS: The MSFC demonstrated excellent intrarater reliability in this multinational phase 3 trial. Three prebaseline testing sessions were sufficient to compensate for practice effects. The pattern of correlations among the MSFC, its components, and the Kurtzke Expanded Disability Status Scale supported the validity of the MSFC.