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1.
Ann Oncol ; 35(2): 229-239, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37992872

RESUMO

BACKGROUND: Increasingly, circulating tumor DNA (ctDNA) is proposed as a tool for minimal residual disease (MRD) assessment. Digital PCR (dPCR) offers low analysis costs and turnaround times of less than a day, making it ripe for clinical implementation. Here, we used tumor-informed dPCR for ctDNA detection in a large colorectal cancer (CRC) cohort to evaluate the potential for post-operative risk assessment and serial monitoring, and how the metastatic site may impact ctDNA detection. Additionally, we assessed how altering the ctDNA-calling algorithm could customize performance for different clinical settings. PATIENTS AND METHODS: Stage II-III CRC patients (N = 851) treated with a curative intent were recruited. Based on whole-exome sequencing on matched tumor and germline DNA, a mutational target was selected for dPCR analysis. Plasma samples (8 ml) were collected within 60 days after operation and-for a patient subset (n = 246)-every 3-4 months for up to 36 months. Single-target dPCR was used for ctDNA detection. RESULTS: Both post-operative and serial ctDNA detection were prognostic of recurrence [hazard ratio (HR) = 11.3, 95% confidence interval (CI) 7.8-16.4, P < 0.001; HR = 30.7, 95% CI 20.2-46.7, P < 0.001], with a cumulative ctDNA detection rate of 87% at the end of sample collection in recurrence patients. The ctDNA growth rate was prognostic of survival (HR = 2.6, 95% CI 1.5-4.4, P = 0.001). In recurrence patients, post-operative ctDNA detection was challenging for lung metastases (4/21 detected) and peritoneal metastases (2/10 detected). By modifying the cut-off for calling a sample ctDNA positive, we were able to adjust the sensitivity and specificity of our test for different clinical contexts. CONCLUSIONS: The presented results from 851 stage II-III CRC patients demonstrate that our personalized dPCR approach effectively detects MRD after operation and shows promise for serial ctDNA detection for recurrence surveillance. The ability to adjust sensitivity and specificity shows exciting potential to customize the ctDNA caller for specific clinical settings.


Assuntos
DNA Tumoral Circulante , Neoplasias Colorretais , Humanos , DNA Tumoral Circulante/genética , DNA de Neoplasias/genética , Algoritmos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Dinamarca , Biomarcadores Tumorais/genética , Recidiva Local de Neoplasia
2.
J Anat ; 232(2): 263-269, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29148044

RESUMO

Laterally bent dorsal fins are rarely observed in free-ranging populations of cetaceans, contrary to captivity, where most killer whale Orcinus orca adult males have laterally collapsed fins. This topic has been poorly explored, and data/information on its occurrence and possible causes are limited. The present study: (i) undertakes a review of the available information on bent dorsal fins in free-ranging cetaceans, and updates it with new records, (ii) reports on the proportion of bent fins in different study populations, and (iii) discusses possible causes. An empirical approach based on bibliographic research and compilation of 52 new records collected worldwide resulted in a total of 17 species of cetaceans displaying bent dorsal fins. The species with the highest number of records (64%) and from most locations was O. orca. On average, individuals with bent dorsal fins represent < 1% of their populations, with the exception of false killer whales Pseudorca crassidens and O. orca. While line injuries associated with fisheries interactions may be the main cause for P. crassidens, and the vulnerability to health issues caused by the evolutionary enlargement of the fin may be the cause for O. orca adult males, factors contributing to this abnormality for other species are still unclear. The occurrence of bent dorsals could be influenced by a set of variables rather than by a single factor but, irrespective of the cause, it is suggested that it does not directly affect the animals' survivorship. While still rare in nature, this incident is more common (at least 101 known cases) and widespread (geographically and in species diversity) than hypothesized, and is not confined only to animals in captive environments. Investigation into the occurrence of bent fins may be an interesting avenue of research.


Assuntos
Nadadeiras de Animais/anormalidades , Cetáceos/anormalidades , Animais , Incidência
3.
Dement Geriatr Cogn Disord ; 34(5-6): 292-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23208125

RESUMO

BACKGROUND: Little is known about the quality of the diagnostic evaluation and the validity of dementia diagnoses in young patients established in routine clinical practice. The aim of this study was to investigate the validity of the diagnosis of dementia registered in the Danish nationwide hospital registers in young patients. METHODS: Two hundred patients were randomly selected from 891 patients <65 years registered with a dementia diagnosis for the first time in 2008. The patients' medical records were reviewed to evaluate if they fulfilled ICD-10 and/or DSM-IV criteria for dementia and current clinical criteria for specific dementia subtypes. RESULTS: A registered diagnosis was found to be correct in only 59%. A misdiagnosis of dementia occurred primarily in patients with depression or alcohol abuse. CONCLUSION: Our results suggest that dementia is overregistered and overdiagnosed in young patients. This may be due to a different symptom profile of dementia in young patients, lack of knowledge among clinical physicians and the wide range of conditions which may be misinterpreted as dementia.


Assuntos
Demência/diagnóstico , Demência/epidemiologia , Erros de Diagnóstico/estatística & dados numéricos , Adulto , Idoso , Alcoolismo/complicações , Alcoolismo/psicologia , Antidepressivos/uso terapêutico , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Interpretação Estatística de Dados , Dinamarca/epidemiologia , Depressão/complicações , Depressão/psicologia , Erros de Diagnóstico/tendências , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Classificação Internacional de Doenças , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Testes Neuropsicológicos , População , Reprodutibilidade dos Testes
4.
Mol Immunol ; 31(13): 967-75, 1994 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8084337

RESUMO

The alloreactive CD8+ cytotoxic T lymphocyte (CTL) clone 2C was previously shown to recognize complexes made up of the class I MHC (MHC-I) molecule Ld and an octapeptide (LSPFPFDL, termed p2Ca) isolated from tissues of H-2d mice. Because peptide p2Ca has also been found in BALB.B (H-2b) mice, the strain from which clone 2C originated, the question arises as to whether these T cells can recognize peptide p2Ca in association with a self MHC protein of the H-2b haplotype. Here we show that 2C CTL do indeed recognize peptide p2Ca in association with Kb on the surface of H-2b cells or on transfected cells expressing Kb, but that an approximately 1000-fold higher concentration of this peptide is required to sensitize Kb+ than Ld+ target cells for lysis by 2C cells. However, the peptide's binding to Kb was not much weaker than to Ld, with only an approximately 10-fold difference in the respective equilibrium constants. These results predict that the T cell receptor (TcR) of clone 2C has a much lower intrinsic affinity for p2Ca-Kb complexes than for p2Ca-Ld complexes, and they provide some quantitative limits on the requirements for triggering T cell-mediated autoimmune reactivity.


Assuntos
Autoimunidade/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Oligopeptídeos/imunologia , Linfócitos T Citotóxicos/imunologia , Sequência de Aminoácidos , Animais , Ligação Competitiva , Linhagem Celular , Células Clonais , Testes Imunológicos de Citotoxicidade , Citometria de Fluxo , Humanos , Camundongos , Dados de Sequência Molecular
5.
J Clin Endocrinol Metab ; 80(12): 3442-6, 1995 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8530581

RESUMO

A mother and her daughter with a novel type of familial partial lipodystrophy were studied. Both had atrophy of fat in the face, chest, and upper and lower limbs and abdominal obesity caused by intraabdominal fat accumulation. The mother had severe insulin resistance and impaired glucose tolerance, whereas the daughter had normal glucose tolerance and normal insulin sensitivity. Both had metabolic rates about 30% above normal levels, but normal thyroid function and plasma lipids.


Assuntos
Lipodistrofia/genética , Abdome , Tecido Adiposo/patologia , Adulto , Atrofia , Composição Corporal , Metabolismo Energético , Extremidades , Face , Feminino , Intolerância à Glucose , Humanos , Resistência à Insulina , Fator de Crescimento Insulin-Like I/análise , Lipodistrofia/patologia , Lipodistrofia/fisiopatologia , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/patologia , Tórax
6.
J Clin Endocrinol Metab ; 81(4): 1519-24, 1996 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8636361

RESUMO

GH-binding protein (GHBP) is increased in obesity. It is not known whether the increase in GHBP is reversible with weight loss or modulated by acute changes in nutritional intake. To address these questions, we measured GHBP in 18 obese subjects [body mass index (BMI), 40.9 +/- 1.1 kg/m2 (mean +/-SEM)] before and after an average weight loss of 30.3 +/- 4.6 kg and in 18 age- and sex matched normal subjects (BMI, 23.0 +/- 0.4 kg/m2) and studied the effects of a very low calorie diet over 4 days in 5 normal subjects and a subgroup of obese subjects before (n = 6) and after (n = 5) weight loss. GHBP was elevated in the obese subjects compared to levels in age- and sex-matched normal controls (1.48 +/- 0.1 vs. 0.53 +/- 0.1 nmol/L; P < 0.0001). GHBP was positively correlated to BMI and waist circumference (r = 0.71; P < 0.00001 and r = 0.73; P < 0.00001, respectively). In addition, GHBP was positively correlated to insulin as well as proinsulin levels (r = 0.60; P < 0.001 and r = 0.55; P < 0.001, respectively). After diet-induced massive weight loss, GHBP levels were restored to normal in obese subjects (BMI, 27.8 +/- 1.4 kg/m2). Multiple stepwise regression analysis revealed that changes in waist circumference and abdominal sagittal diameter during weight loss were the major determinants of and accounted for 54% of the fall in GHBP levels. Neither insulin nor proinsulin was an independent predictor. No changes were observed in GHBP in normal, obese, or reduced weight obese subjects after 4 days of a very low calorie diet, although mean insulin levels fell significantly in the normal subgroup as well as in the obese subgroup studied after weight loss. In summary, GHBP levels are elevated in obesity, are restored to normal by massive weight loss, and are unaffected by short term hypocaloric feeding. We conclude that GHBP may be regulated by the same or closely related factors that regulate fat mass and abdominal fat mass in particular, but not by insulin or acute changes in nutrition.


Assuntos
Proteínas de Transporte/sangue , Dieta Redutora , Obesidade/fisiopatologia , Redução de Peso , Adulto , Antropometria , Índice de Massa Corporal , Feminino , Hormônio do Crescimento/sangue , Humanos , Insulina/sangue , Masculino , Obesidade/sangue , Proinsulina/sangue , Valores de Referência , Análise de Regressão
7.
J Clin Endocrinol Metab ; 80(3): 796-801, 1995 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-7533771

RESUMO

Obesity is associated with a marked reduction in the spontaneous secretion of GH. To investigate the effect of acute alterations in calorie intake on GH release, 24-hr spontaneous GH release was measured during habitual calorie intake as well as during a short term, very low calorie diet (VLCD) in 6 obese subjects, 5 obese subjects after weight loss, and 5 normal, age- and sex-matched control subjects. Integrated 20-min samples were obtained over 24-h on two occasions in each subject using a constant blood withdrawal technique. In addition, basal levels of serum insulin-like growth factor-I (IGF-I), IGF-binding protein-1 (IGFBP-1), IGF-binding protein-3 (IGFBP-3), insulin, pro-insulin, and blood glucose were measured during habitual energy intake as well as during the hypocaloric diet. Twenty-four-hour GH release profiles and IGFBP-1 were decreased, and insulin as well as proinsulin levels were elevated in obese subjects compared to those in normal age- and sex-matched controls. No differences between obese subjects and normal controls were present regarding IGF-I, IGFBP-3, or IGF-I/IGFBP-3 molar ratio. In the last 24 h during the 96-h VLCD, an increase in 24-h GH release and basal IGFBP-1 levels and a decrease in basal insulin levels occurred in the normal controls, whereas no such changes were observed in the obese subjects. After caloric restriction 24-hr GH release, IGFBP-1 levels and insulin levels were similar in control subjects and obese subjects after weight loss. This suggests a reversible defect in GH release, rather than a persistent preexisting disorder. It is hypothesized that enhanced bioavailability of IGF-I, acting in concert with elevated proinsulin and insulin levels, may account for the lack of stimulation of 24-hr GH release by the hypocaloric diet in obese subjects. We conclude that the increase in 24-h spontaneous GH release and IGFBP-1 levels observed in normal subjects during the last 24 h of a 96-h VLCD is abolished in obese subjects. The lack of short term hypocaloric stimulation of spontaneous GH release may promote the retention of body fat and perpetuate the obese state.


Assuntos
Dieta Redutora , Hormônio do Crescimento/metabolismo , Obesidade/metabolismo , Adulto , Glicemia/análise , Proteínas de Transporte/análise , Feminino , Humanos , Insulina/sangue , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Fator de Crescimento Insulin-Like I/análise , Masculino , Proinsulina/sangue , Fatores de Tempo
8.
J Clin Endocrinol Metab ; 80(4): 1407-15, 1995 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7536210

RESUMO

In the present study, we 1) determined whether the impaired spontaneous 24-h GH secretion as well as the blunted GH response to provocative testing in obese subjects are persistent disorders or transient defects reversed with weight loss and 2) investigated 24-h urinary GH excretion and basal levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), as well as insulin in obese subjects before and after a massive weight loss. We studied 18 obese subjects (age, 26 +/- 1 yr; body mass index, 40.9 +/- 1.1 kg/m2); 18 normal age-, and sex-matched control subjects; and 9 reduced weight obese subjects after a diet-induced average weight loss of 30.3 +/- 4.6 kg. Twenty-four-hour spontaneous GH secretion was estimated by obtaining 3240 integrated 20-min blood samples using a constant blood withdrawal technique and computerized algorithms. Body composition was determined using anthropometric measurements and dual energy x-ray absorptiometry scanning (DXA). In the obese subjects, 24-h spontaneous GH release profiles and the GH responses to insulin-induced hypoglycemia and L-arginine as well as basal IGF-I levels and the IGF-I/IGFBP-3 molar ratio were decreased, whereas insulin levels were elevated compared to those in normal subjects. In obese subjects, 24-h spontaneous GH secretion and serum IGF-I levels were inversely related to abdominal fat (r = -0.67; P < 0.01) and percent body fat (r = -0.69; P < 0.01), respectively. The decreased 24-h spontaneous GH release profiles, the decreased GH responses to insulin-induced hypoglycemia and L-arginine, the decreased basal IGF-I levels and IGF-I/IGFBP-3 molar ratio, as well as the elevated insulin levels were returned to normal after a massive weight loss in the obese subjects. In conclusion, the present study has shown reversible defects in 24-h spontaneous GH release profiles, basal IGF-I levels, and the IGF-I/IGFBP-3 molar ratio in obese subjects. The recovery of the 24-h GH release points to an acquired transient defect rather than a persistent preexisting disorder.


Assuntos
Ritmo Circadiano , Hormônio do Crescimento/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Obesidade/sangue , Redução de Peso , Adulto , Antropometria , Arginina , Proteínas de Transporte/sangue , Feminino , Hormônio do Crescimento/metabolismo , Hormônio do Crescimento/urina , Humanos , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Insulina/sangue , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Masculino , Obesidade/urina , Somatomedinas/metabolismo
9.
J Clin Endocrinol Metab ; 83(12): 4408-15, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9851786

RESUMO

Circulating insulin-like growth factor-I (IGF-I) is predominantly bound in the trimeric complex comprised of IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS). Circulating concentrations of IGF-I, IGFBP-3 and ALS are believed to reflect the GH secretory status, but the clinical use of ALS determination is not known. We therefore, determined the: 1) hepatosplanchnic release of ALS by liver vein catheterization (n=30); 2) 24-h diurnal variation of ALS (n=8); 3) normal age-related ranges of circulating ALS (n=1158); 4) diagnostic value of ALS in 108 patients with childhood-onset GH deficiency (GHD). We found: 1) no significant arteriovenous gradient over the liver ofALS, IGF-I, and IGFBP-3; 2) the diurnal variation of ALS was 12% (mean coefficient of variation percent); 3) ALS levels increased throughout childhood with maximal levels in puberty, with a subsequent decrease with age in adults; and 4) ALS levels were below -2 SD in 57 of 79 GHD patients (sensitivity 72%) and above 2 SD in 22 of 29 patients with normal GH response (specificity 76%), which was similar, compared with the diagnostic utility of IGF-I and IGFBP-3. Finally, our findings indicate that hepatic ALS production is not measurable by this approach or, alternatively, that the liver is not the primary source of circulating ALS, IGF-I, or IGFBP-3 in humans. In conclusion, we have provided extensive normal data for a novel ALS assay and found that circulating ALS levels exhibit minor diurnal variation. We suggest that ALS determination may be used in future classification of adults suspected of GHD.


Assuntos
Proteínas de Transporte/sangue , Ritmo Circadiano/fisiologia , Glicoproteínas/sangue , Hormônio do Crescimento Humano/deficiência , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fígado/metabolismo , Vísceras/metabolismo , Adolescente , Adulto , Idoso , Proteínas de Transporte/metabolismo , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Glicoproteínas/metabolismo , Humanos , Lactente , Recém-Nascido , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Valores de Referência
10.
Eur J Endocrinol ; 140(4): 315-21, 1999 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10097250

RESUMO

OBJECTIVE: The aim of the present study was to investigate whether patients with cystic fibrosis (CF) are GH resistant with increased GH release and decreased concentrations of IGF-I as a result of malabsorption, increased catabolism and impaired glucose tolerance. DESIGN: Twenty CF patients were included, ten with normal glucose tolerance (five male, five female, median age 25.5 years (range 20-31)) and ten with diabetes mellitus (five male, five female, median age 25.3 years (range 17-45). Twenty healthy individuals served as controls (ten male, ten female, median age 28.4 years (range 18-36)). METHODS: GH status was evaluated by 12h spontaneous GH release during the night time, arginine-stimulated GH release and the basal concentrations of IGF-I and insulin-like growth factor-binding protein-3 (IGFBP-3). Twelve hour spontaneous GH profiles were estimated using a constant blood withdrawal technique with sampling every 30min and the Pulsar method was used for the analysis of profiles. RESULTS: No significant differences were found in spontaneous and stimulated GH release in CF patients compared with healthy controls, whereas IGF-I and IGFBP-3 were significantly decreased in CF patients compared with healthy controls. The combination of reduced IGF-I and IGFBP-3 with normal GH release points to a relative GH resistance or a disturbance in the pituitary axis in patients with CF. The spontaneous GH release, the stimulated GH release and the basal concentrations of IGF-I and IGFBP-3 were not significantly different in diabetic CF patients compared with CF patients with normal glucose tolerance and the presence of diabetes mellitus was not consistent with increased GH resistance in CF patients. CONCLUSION: CF patients with normal glucose tolerance and diabetic CF patients had normal GH release and decreased concentrations of IGF-I indicating a relative GH resistance.


Assuntos
Fibrose Cística/sangue , Hormônio do Crescimento Humano/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Adolescente , Adulto , Arginina/farmacologia , Índice de Massa Corporal , Diabetes Mellitus/sangue , Feminino , Teste de Tolerância a Glucose , Hormônio do Crescimento Humano/farmacologia , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Masculino , Pessoa de Meia-Idade
11.
Bone Marrow Transplant ; 18(1): 163-70, 1996 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-8832010

RESUMO

The aim of the present study was to assess growth, final height, growth hormone (GH) secretion and growth factors after BMT including TBI in childhood. The median age of the 25 participants was 11.3 years at BMT, and a median of 7.5 years had elapsed since BMT. The median height standard deviation score (SDS) declined significantly from diagnosis until 4 years after BMT (n = 25, P = 0.015), and decreased 1.08 SDS from diagnosis until final height (n = 14, P = 0.030). Sitting height to standing height ratio was impaired, -0.64 SDS, P < 0.05. GH insufficiency was found in 32% at follow-up. Repeated assessments of GH production over the years indicated improvement in GH secretion in nine individuals. Evaluation of spontaneous 24-h GH secretion indicated a secretory pattern similar to controls, although the total amount of GH secreted was lower. Neither insulin-like growth factor-1 (IGF-1) nor IGF binding protein-3 (IGFBP-3) alone could be used as a marker of GH insufficiency. IGF-1 was low: -1.18 SDS; (P < 0.001). In conclusion, our study demonstrated the impact on growth, final height, body proportions, GH secretion and growth factors after BMT including TBI. We hypothesize that children who receive BMT at a younger age are more at risk of loss of final height and abnormal body proportions. Our data indicate that some improvement in GH production may occur over the years.


Assuntos
Transplante de Medula Óssea , Transtornos do Crescimento/etiologia , Hormônio do Crescimento Humano/deficiência , Adeno-Hipófise/efeitos da radiação , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Lesões por Radiação/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Irradiação Corporal Total/efeitos adversos , Adolescente , Fatores Etários , Antropometria , Estatura/efeitos dos fármacos , Estatura/efeitos da radiação , Criança , Pré-Escolar , Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/etiologia , Nanismo Hipofisário/fisiopatologia , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/complicações , Transtornos do Crescimento/fisiopatologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Lactente , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Adeno-Hipófise/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Lesões por Radiação/fisiopatologia
12.
Metabolism ; 43(6): 776-81, 1994 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8201970

RESUMO

The principal mediators of glucose counterregulation (glucagon and epinephrine) use intracellular cyclic adenosine monophosphate (cAMP) to mediate glucose release. Since theophylline increases cAMP (by inhibiting its decomposition), we investigated the effect of theophylline on glucose recovery after insulin-induced hypoglycemia. Eleven healthy subjects and nine type I (insulin-dependent) diabetic patients each participated in two experiments in randomized order, receiving on both days an insulin bolus of 0.15 IU/kg soluble insulin. On one day, theophylline (intravenous [IV] bolus of 220 mg followed by IV infusion of 1 mg/kg/h) was administered from 1 hour before induction of hypoglycemia until the end of the study period. On the other day, NaCl was administered. Plasma glucose before induction of hypoglycemia was equal on the 2 study days. The plasma glucose area under the curve (AUC) was larger with theophylline than with NaCl (P = .04 for diabetic patients and P = .003 for healthy subjects). During the most active phase of glucose counterregulation, the rate of increase of plasma glucose was larger with theophylline (P = .003 for diabetic patients and P = .03 for healthy subjects). The incremental AUC for cAMP was larger with theophylline for diabetic patients (P = .01). For healthy subjects, cAMP was greater with theophylline 30 minutes after insulin (P = .03). In conclusion, glucose recovery after hypoglycemia is significantly increased when theophylline is administered in an asthma dosage before hypoglycemia is induced. This may be due to a significant enhancement of the cAMP response.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Teofilina/farmacologia , Adulto , Glicemia/efeitos dos fármacos , AMP Cíclico/análise , AMP Cíclico/sangue , Método Duplo-Cego , Sinergismo Farmacológico , Glucagon/sangue , Humanos , Hidrocortisona/sangue , Hipoglicemia/induzido quimicamente , Insulina/efeitos adversos , Insulina/sangue , Fígado/química , Fígado/efeitos dos fármacos , Masculino , Método Simples-Cego , Fatores de Tempo
13.
Metabolism ; 43(3): 315-9, 1994 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-7511202

RESUMO

The aim of this study was to characterize the association between serum insulin-like growth factor-1 (IGF-1) and obesity, as well as fat distribution, before and during moderate energy restriction (1,200 kcal/d). In 51 females and nine males having a body mass index (BMI) between 27 and 39 kg/m2, relationships between serum IGF-1, IGF-binding protein-3 (IGFBP-3), insulin, growth hormone (GH), blood glucose, and anthropometric measurements of body fat were examined. The patients were studied before treatment and again after 8 and 16 weeks of dieting. Visceral adipose tissue (AT) was estimated by anthropometric computed tomography (CT)-calibrated equations. In females, IGF-1 was inversely associated with the abdominal sagittal diameter (SagD) and with the visceral AT (r = -.41, P = .006). No significant correlations were found between IGF-1 and BMI or other indices of adiposity. Weight loss caused a temporary increase in IGF-1 concentrations (P = .03) and continued decrements in blood glucose levels (P = .0004 at 16 weeks). A statistically significant inverse correlation between IGF-1 and blood glucose levels was present before (r = -.30, P = .02) and after 8 (r = -.37, P = .007) and 16 (r = .02, P = .02) weeks of dietary treatment. Both serum IGF-1 and insulin levels were positively correlated with serum IGFBP-3 levels (r = .34, P = .009 and r = .34, P = .008, respectively). We conclude that IGF-1 levels in obese females reflect the intraabdominal fat mass rather than obesity per se. IGF-1 and blood glucose levels are inversely correlated in obesity before and during energy restriction.


Assuntos
Tecido Adiposo/fisiologia , Proteínas de Transporte/sangue , Metabolismo Energético/fisiologia , Hormônio do Crescimento/sangue , Fator de Crescimento Insulin-Like I/análise , Insulina/sangue , Obesidade/fisiopatologia , Tecido Adiposo/patologia , Adulto , Envelhecimento/sangue , Envelhecimento/fisiologia , Antropometria , Glicemia/análise , Índice de Massa Corporal , Feminino , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/dietoterapia , Radioimunoensaio
14.
Growth Horm IGF Res ; 10(2): 93-8, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10931747

RESUMO

The bioequivalence of recombinant human growth hormone (rhGH) for reconstitution, at either 24 IU or 8 mg, and three strengths of liquid formulation of rhGH (5, 10 or 15 mg per 1.5 ml, hGH) was tested in two randomized, single-blind, four-period, crossover studies in healthy subjects. The study drugs were administered by subcutaneous injection at a dose of 2.5 mg rhGH/m(2)body surface area or as a fixed dose of 5 mg rhGH. Endogenous hGH release was suppressed by a continuous somatostatin infusion. The 90% confidence intervals for the estimated mean ratios of AUC(0-24 h)and C(max)(analysis of variance) between all products were within 80-125% in both studies. Also, no significant differences (P> 0.05; Wilcoxon signed rank test) were found between t(max)for the liquid formulations of rhGH. These data demonstrate that there is bioequivalence between rhGH for reconstitution and the liquid formulations of rhGH.


Assuntos
Química Farmacêutica/métodos , Hormônio do Crescimento Humano/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Adulto , Análise de Variância , Peso Corporal , Estudos Cross-Over , Feminino , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/farmacocinética , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/sangue , Proteínas Recombinantes/farmacocinética , Método Simples-Cego , Somatostatina/farmacologia , Equivalência Terapêutica , Fatores de Tempo
15.
BMJ ; 306(6885): 1093-6, 1993 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-8388286

RESUMO

OBJECTIVE: To study the effect of cimetidine suspension compared with placebo suspension on weight loss in moderately obese patients taking a 5 MJ/day diet supplemented with dietary fibre. To determine the relation between the effectiveness of the blinding and weight loss. DESIGN: Randomised double blind study with an eight week parallel group phase and a subsequent eight week crossover or continuation phase. SETTING: Outpatient clinic. SUBJECTS: 60 patients (51 women) aged 18-60. MAIN OUTCOME MEASURE: Weight loss. RESULTS: After eight weeks of treatment the mean weight loss in the cimetidine group (5.7 kg) was similar to that of the placebo group (5.9 kg; p = 0.78, 95% confidence interval -2.0 to 1.5 kg). Body mass index, waist and hip measurements, waist-hip ratio, and systolic and diastolic blood pressures decreased similarly in the two groups. No association was found between weight loss and the patients' ability to guess if they were being given drug or placebo. Correct guesses of current drug were more prevalent than expected by chance (25/37 correct, p = 0.05 for the parallel group phase; 26/30, p = 0.0001 for the crossover phase). CONCLUSIONS: Cimetidine had no effect on weight loss in moderately obese patients. The study underlines the potential problem that blinding of patients to treatment can be compromised.


Assuntos
Cimetidina/uso terapêutico , Obesidade/dietoterapia , Obesidade/tratamento farmacológico , Adolescente , Adulto , Pressão Sanguínea/efeitos dos fármacos , Constituição Corporal , Índice de Massa Corporal , Terapia Combinada , Dinamarca , Fibras na Dieta/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Redução de Peso/efeitos dos fármacos
16.
Ugeskr Laeger ; 158(24): 3451-5, 1996 Jun 10.
Artigo em Dinamarquês | MEDLINE | ID: mdl-8650814

RESUMO

Metabolic control, hypoglycaemia frequency and nasal mucosal physiology were evaluated in 31 insulin-dependent diabetics treated with intranasal insulin at mealtimes for one month and with subcutaneous fast-acting insulin for another month in a randomized crossover trial. During both periods the patients were treated with intermediate-acting insulin at bedtime. Six of the patients were withdrawn from the study during intranasal insulin therapy due to metabolic dysregulation. Insulin concentrations increased more rapidly and decreased more quickly during intranasal as compared with subcutaneous insulin administration. Metabolic control, assessed by haemoglobin A1c concentrations, deteriorated after intranasal as compared with subcutaneous insulin therapy. The bioavailability of intranasally applied insulin was low, since intranasal insulin doses were approximately 20 times higher than subcutaneous doses. The frequency of hypoglycemia was similar during intranasal and subcutaneous insulin therapy, and nasal mucosal physiology was unaffected after intranasal insulin. We conclude that due to low bioavailability and to a high rate of therapeutic failure, intranasal insulin treatment is not a realistic alternative to subcutaneous insulin injections at the present time.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Administração Intranasal , Adolescente , Adulto , Disponibilidade Biológica , Diabetes Mellitus Tipo 1/sangue , Feminino , Humanos , Hipoglicemia , Hipoglicemiantes/farmacocinética , Injeções Subcutâneas , Insulina/farmacocinética , Masculino , Pessoa de Meia-Idade
18.
J Exp Biol ; 211(Pt 4): 642-7, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18245641

RESUMO

This is the first report of an underwater audiogram from a dolphin in a capture-and-release scenario. Two bow-riding white-beaked dolphins Lagenorhynchus albirostris (a female and a male) were captured using the hoop-net technique in Faxaflói Bay, Iceland. The dolphins were transferred to a stretcher and hoisted into a plastic research tank on board a small fishing vessel. Two underwater transducers were used to cover the frequency range from 16 to 215 kHz. Two human EEG electrodes mounted in suction cups, one placed near the blow hole and the other on the dorsal fin, picked up bioelectrical responses to acoustic stimuli. Responses to about 1000 sinusoidal amplitude modulated stimuli for each amplitude/frequency combination were averaged and analyzed using a fast Fourier transform to obtain an evoked auditory response. Threshold was defined as the zero crossing of the response using linear regression. Two threshold frequencies at 50 kHz and 64 kHz were obtained from the female. An audiogram ranging from 16 to 181 kHz was obtained from an adult male and showed the typical ;U' shaped curve for odontocetes. The thresholds for both white-beaks were comparable and demonstrated the most sensitive high frequency hearing of any known dolphin and were as sensitive as the harbor porpoise.


Assuntos
Golfinhos/fisiologia , Audição/fisiologia , Animais , Feminino , Masculino , Som
19.
J Acoust Soc Am ; 120(1): 510-7, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16875247

RESUMO

Recordings of white-beaked dolphin whistles were made in Faxafl6i Bay (Iceland) using a three-hydrophone towed linear array. Signals from the hydrophones were routed through an amplifier to a lunch box computer on board the boat and digitized using a sample rate of 125 kHz per channel. Using this method more than 5000 whistles were recorded. All recordings were made in sea states 0-1 (Beaufort scale). Dolphins were located in a 2D horizontal plane by using the difference of arrival time to the three hydrophones, and source levels were estimated from these positions using two different methods (I and II). Forty-three whistles gave a reliable location for the vocalizing dolphin when using method II and of these 12 when using method I. Source level estimates on the center hydrophone were higher using method I [average source level 148 (rms) +/- 12 dB, n = 36] than for method II [average source level 139 (rms) +/- 12 dB, n = 36]. Using these rms values the maximum possible communication range for whistling dolphins given the local ambient noise conditions was then estimated. The maximum range was 10.5 km for a dolphin whistle with the highest source level (167 dB) and about 140 m for a whistle with the lowest source level (118 dB). Only two of the 43 whistles contained an unequal number of harmonics recorded at the three hydrophones judging from the spectrograms. Such signals could be used to calculate the directionality of whistles, but more recordings are necessary to describe the directionality of white-beaked dolphin whistles.


Assuntos
Acústica , Golfinhos/fisiologia , Vocalização Animal/fisiologia , Análise de Variância , Animais , Espectrografia do Som , Gravação em Fita
20.
Virology ; 337(2): 353-64, 2005 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-15913695

RESUMO

Retroviral activation of the AP-1/ATF super family member Jdp2 was recently reported to be a common event in M-MLV-induced T cell lymphoma in p27-null C57x129 mice as compared to wild type-inoculated mice but has not been found important in other models. On the basis of retroviral tag retrieval from 1190 individual Akv- and SL3-3-induced lymphomas, we here report that insertional mutagenesis into the 250-kb Fos/Jdp2/Batf locus is associated with SL3-3 MLV-induced T but not Akv-induced B cell lymphomas of NMRI and SWR mice. Integration pattern and clonality analyses suggest that Jdp2 participates in SL3-3-induced tumorigenesis distinctly as compared to the M-MLV setting. Northern blot analysis showed Jdp2 to be alternatively spliced in various normal tissues as well as MLV-induced lymphomas. Interestingly, in some tumors, proviral insertion seems to activate different mRNA sub-species. Whereas elevated mRNA levels of the Fos gene could not be correlated with provirus presence, in one case, Northern blot analysis as well as quantitative real-time PCR indicated proviral activation of the AP-1 super family member Batf, a gene not previously reported to be a target of insertional mutagenesis. A novel integration cluster between Jdp2 and Batf apparently did not influence the expression level of either gene, underscoring the importance of addressing expression effects to identify target genes of insertion. Altogether, such distinct insertion patterns point to different mechanism of activation of specific proto-oncogenes and are consequently of importance for the understanding of proviral activation mechanisms as well as the specific role of individual oncogenes in tumor development.


Assuntos
Genes fos , Vírus da Leucemia Murina/genética , Linfoma de Células B/genética , Mutagênese Insercional , Provírus/genética , Proteínas Repressoras/genética , Retroviridae/genética , Fatores de Transcrição/genética , Células 3T3 , Animais , Fatores de Transcrição de Zíper de Leucina Básica , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Viral/genética , Timo/virologia , Células Tumorais Cultivadas , Latência Viral
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