Biomedical subjects

J J Robert

Publications and source records attributed to J J Robert.

At least 19 recordsLinked to original sources

PubMed1996

An adenovirus encoding CuZnSOD protects cultured striatal neurones against glutamate toxicity.

Superoxide dismutase (SOD), a key enzyme in the detoxification of free radicals, catalyses the dismutation of superoxide O2.- to oxygen and hydrogen peroxide (H2O2). It is therefore a promising candidate for gene transfer therapy of neurological diseases in which free radicals are thought to be involved. We have constructed a recombinant adenoviral vector containing the human copper-zinc SOD cDNA. Using this vector we were able to drive the production of an active human copper-zinc SOD protein (hCuZnSOD) in various cell lines and primary cultures. Infection of striatal cells with a recombinant adenovirus expressing hCuZnSOD protected these cells from glutamate-induced cell death.

Adenoviridae↗

PubMed1996

Assessment of insulin sensitivity in glucokinase-deficient subjects.

The chronic hyperglycaemia of glucokinase-deficient diabetes results from a glucose-sensing defect in pancreatic beta cells and abnormal hepatic glucose phosphorylation. We have evaluated the contribution of insulin resistance to this form of chronic hyperglycaemia. Insulin sensitivity, assessed by the homeostasis model assessment (HOMA) method in 35 kindreds with glucokinase mutations, was found to be significantly decreased in 125 glucokinase-deficient subjects as compared to 141 unaffected first-degree relatives. Logistic regression analysis showed that in glucokinase-deficient subjects a decrease in insulin sensitivity was associated with deterioration of the glucose tolerance status. A euglycaemic hyperinsulinaemic clamp was performed in 14 glucokinase-deficient subjects and 12 unrelated control subjects. In six patients and six control subjects the clamp was coupled to dideutero-glucose infusion to measure glucose turnover. Average glucose infusion rates (GIR) at 1 and 5 mU.kg body weight.min-1 insulin infusion rates were significantly lower in (the glucokinase-deficient) patients than in control subjects. Although heterogeneous results were observed, in 8 out of the 14 patients GIRs throughout the experiment were lower than 1 SD below the mean of the control subjects. Hepatic glucose production at 1 mU.kg body weight-1.min-1 insulin-infusion rate was significantly higher in patients than in control subjects. In conclusion, insulin resistance correlates with the deterioration of glucose tolerance and contributes to the hyperglycaemia of glucokinase-deficient diabetes. Taken together, our results are most consistent with insulin resistance being considered secondary to the chronic hyperglycaemia and/or hypoinsulinaemia of glucokinase-deficiency. Insulin resistance might also result from interactions between the unbalanced glucose metabolism and susceptibility gene(s) to low insulin sensitivity likely to be present in this population.

Adolescent↗

PubMed1996

Clinical phenotypes, insulin secretion, and insulin sensitivity in kindreds with maternally inherited diabetes and deafness due to mitochondrial tRNALeu(UUR) gene mutation.

An A-to-G transition in the mitochondrial tRNALeu(UUR) gene at base pair 3243 has been shown to be associated with the maternally transmitted clinical phenotype of NIDDM and sensorineural hearing loss in white and Japanese pedigrees. We have detected this mutation in 25 of 50 tested members of five white French pedigrees. Affected (mutation-positive) family members presented variable clinical features, ranging from normal glucose tolerance (NGT) to insulin-requiring diabetes. The present report describes the clinical phenotypes of affected members and detailed evaluations of insulin secretion and insulin sensitivity in seven mutation-positive individuals who have a range of glucose tolerance from normal (n = 3) to impaired (n = 1) to NIDDM (n = 3). Insulin secretion was evaluated during two experimental protocols: the first involved the measurement of insulin secretory responses during intravenous glucose tolerance test, hyperglycemic clamp, and intravenous injection of arginine. The second consisted of the administration of graded and oscillatory infusions of glucose and studies to define C-peptide kinetics. This protocol was aimed at assessing two sensitive measures of beta-cell dysfunction: the priming effect of glucose on the glucose-insulin secretion rate (ISR) dose-response curve and the ability of oscillatory glucose infusion to entrain insulin secretory oscillations. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp. Evaluation of insulin secretion demonstrated a large degree of between- and within-subject variability. However, all subjects, including those with NGT, demonstrated abnormal insulin secretion on at least one of the tests. In the four subjects with normal or impaired glucose tolerance, glucose failed to prime the ISR response, entrainment of ultradian insulin secretory oscillations was abnormal, or both defects were present. The response to arginine was always preserved, including in subjects with NIDDM. Insulin resistance was observed only in the subjects with overt diabetes. In conclusion, the pathophysiological mechanisms responsible for the development of NIDDM and insulin-requiring diabetes in this syndrome are complex and might include defects in insulin production, glucose toxicity, and insulin resistance. However, our data suggest that a defect of glucose-regulated insulin secretion is an early possible primary abnormality in carriers of the mutation. This defect might result from the progressive reduction of oxidative phosphorylation and implicate the glucose-sensing mechanism of beta-cells.

Adenine↗

PubMed1995

Specific and efficient gene transfer strategy offers new potentialities for the treatment of motor neurone diseases.

Several growth factors are candidates for the therapy of motor neurone diseases. However, there is no efficient, safe, and practicable administration route which hampers the clinical use of these potentially therapeutic agents. We show that specific and high yield gene transfer into motor neurones can be obtained by peripheral intramuscular injections of recombinant adenoviruses. These vectors are retrogradely transported from muscular motor units to motor neurone cell bodies. Gene transfer can thus be specifically targeted to particular regions of the spinal cord by appropriate choice of the injected muscle. The efficiency of gene transfer is high, with 58-100% of the motor neurones afferent to the injected muscle expressing the transgene. This new therapeutic protocol allows specific targeting of motor neurones without lesioning the spinal cord, and should avoid undesirable side effects associated with systemic administration of therapeutic factors.

Adenoviridae↗

PubMed1995

Specific and efficient gene transfer strategy offers new potentialities for the treatment of motor neurone diseases.

Animals↗

PubMed1995

The effects of a work hardening program on cardiovascular fitness and muscular strength.

STUDY DESIGN: This study analyzed improvements in cardiovascular fitness and muscular strength after a 6-week work hardening program. OBJECTIVES: The objective of this study was to document fitness gains after a 6-week work hardening program. SUMMARY OF BACKGROUND DATA: Studies expounded on the success of a functional restoration approach in return-to-work rates, but few documented the physical fitness gains of a work hardening program. METHODS: Thirty-one subjects from the Rehability Center in Lubbock, Texas, who were diagnosed with lower back dysfunction, completed the 6-week study. A submaximal cycle ergometer protocol was used to determine patients' cardiovascular fitness levels, and the Arcon Static Strength Testing Device was used to measure static strength. Pre- and post-tests were identical. RESULTS: A paired Student's t test was used to analyze the significance of difference from pre- to post-testing. For cardiovascular fitness there was a 28% improvement, t(29) = 5.56, P < 0.001; there was a 76% improvement for the static arm lift, t(29) = 7.86, P < 0.001; there was a 57% improvement in the static pull, t(29) = 9.53, P < 0.001; and an 89% improvement in the static push, t(29) = 9.08, P < 0.001. CONCLUSIONS: Analyzed data clearly show a marked improvement in cardiovascular and muscular fitness. There was not a difference in fitness levels between those who returned to work and those who did not, which suggests return-to-work rates are not entirely based on level of fitness.

Adult↗

PubMed1995

Eating and emotional disorders in adolescent obese girls with insulin-dependent diabetes mellitus.

OBJECTIVE: To study eating and emotional disorders in adolescent insulin-dependent diabetic (IDDM) girls. METHODS: 98 adolescent girls, aged 13-19 years, were studied: 15 obese and 37 non-obese IDDM girls, 22 obese non-diabetic and 24 non-obese girls, DSM-III-R eating disorders (anorexia nervosa, bulimia nervosa, eating disorders NOS) and eating habits (snacking, sweet compulsions) were evaluated by a semi-structured diagnostic interview (Kiddie-SADS-E and Eating Habits Interview). Emotional disorders were assessed using self-questionnaires (State-Trait Anxiety Inventory for Children, Beck Depression Inventory, Coopersmith Self-Esteem Inventory). Psychological characteristics were correlated with BMI and, for IDDM girls, with HbA1C. RESULTS: IDDM and non-diabetic obese girls showed high rates of eating disorders NOS (sub-clinical bulimia: 60 and 41%, respectively) and they had more extra-snacks than non-obese girls, suggesting that obesity was the main risk factor for additional eating disorders. However, non-obese IDDM girls had more eating disorders NOS (sub-clinical bulimia: 27%) than did the normal girls (4%). Three IDDM girls had typical bulimia nervosa, while none of the non-diabetic did. The risk of depression was increased by both IDDM and obesity (16 and 18% dysthymia, respectively; 8% in normal girls); both factors cumulated in obese IDDM girls (47% dysthymia). Obesity was linked to marked changes in self-esteem scores and mild effects on anxiety. IDDM had little effect on anxiety and none on self-esteem; it even seemed to preserve the self-esteem of obese girls. Patients with bulimia nervosa had poorer metabolic control than other girls with IDDM. There was no correlation between HbA1C and eating or emotional disorders. CONCLUSIONS: Adolescent IDDM girls are at increased risk of eating and emotional disorders. Obesity appears to be an important factor for psychiatric complications; more obese IDDM girls suffered from eating disorders NOS sub-clinical bulimia), dysthymia, anxiety disorders, depression and low self-esteem (Family Satisfaction SEI sub-score) than did non-obese IDDM girls.

Adolescent↗

PubMed1995

Induction of neuronal apoptosis by excitotoxins associated with long-lasting increase of 12-O-tetradecanoylphorbol 13-acetate-responsive element-binding activity.

We show that excitotoxic cell death, which is associated with pathological neurodegenerative processes, can display morphological and biochemical features characteristic of apoptosis, a mode of cell death typical of physiological neuronal elimination during development. Cortical neurons cultured in the absence of serum, stimulated with NMDA, glutamate, or quisqualate after 3-5 days in vitro, showed significant degeneration. This death was blocked by 1 microM MK-801, indicating that it was mediated by the activation of NMDA receptors. Dying cells displayed an apoptotic morphology, characterized by cytoplasm and chromatin condensation. No internucleosomal DNA degradation was observed, confirming that morphological changes of apoptosis can be dissociated from DNA laddering. Inhibitors of protein or RNA synthesis abolished cell death, and the protective effect of cycloheximide was similar when the drug was applied 2 h before or 8 h after glutamate. These experiments suggest the participation of active gene transcription in the mechanism of death. We thus analyzed the modulation of transcription factors in dying cells using electrophoretic mobility shift assays. The level of factors binding to the 12-O-tetradecanoylphorbol 13-acetate-responsive element (TRE) displayed a late and sustained increase preceding neuronal death, which was not found for factors complexing the Sp1 P, Oct, and USF binding sites. These results raise the possibility that apoptosis is one of the mechanisms of death in the pathologies linked to excitotoxicity and that activation of TRE-binding factors could play a role in these processes.

Animals↗

PubMed1995

Cyclosporin A does not delay insulin dependency in asymptomatic IDDM patients.

OBJECTIVE: To measure the effects of cyclosporin A (CyA) with no insulin therapy on glucose tolerance and beta-cell function in the preclinical phase of insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: beta-cell responses to the intravenous glucose tolerance test (IVGTT), hyperglycemic clamp, intravenous arginine, and intravenous glucagon were evaluated before and after a 6-month course of CyA in seven patients (mean age 19.6 years) with asymptomatic IDDM. RESULTS: Initial insulin secretory responses were severely decreased when the patients were compared with eight healthy control subjects: IVGTT (1 + 3 min): 106 +/- 16 vs. 884 +/- 190 pmol/l (P < 0.001); hyperglycemic clamp: 102 +/- 16 vs. 310 +/- 42 pmol/l (P < 0.001); intravenous arginine: 346 +/- 72 vs. 1104 +/- 168 pmol/l (P < 0.01); and intravenous glucagon: 170 +/- 37 vs. 247 +/- 35 pmol/l (NS). The beta-cell responses remained markedly abnormal after 6 months of CyA, although the response to intravenous glucose and oral glucose tolerance tests improved in three subjects. All the patients became insulin-dependent after 5-36 months. CONCLUSIONS: CyA alone is not a suitable treatment for asymptomatic IDDM. Earlier identification of subjects with substantial beta-cell secretory capacity and newer nontoxic intervention strategies are required for the prevention of IDDM.

Adolescent↗

PubMed1995

Are free fatty acids related to plasma plasminogen activator inhibitor 1 in android obesity?

Plasminogen activator inhibitor 1 (PAI-1) levels are elevated in obese insulin-resistant subjects. However the mechanism underlying increased PAI-1 levels is unknown. To determine the impact of diabetes on PAI-1 levels and its possible relationship to insulin resistance, hyperinsulinemic euglycemic clamp studies were performed in nine lean control subjects, nine non-diabetic obese subjects and eight obese patients with NIDDM. Fasting plasma PAI-1 levels were 4.0 to 4.7 fold higher in the two obese groups than in the control group. During the 40 mU/m2 x min insulin infusion, suppression of FFA concentration was correlated with fasting plasma PAI-1 levels in both obese non-diabetic and obese NIDDM subjects. It is concluded that (1) obesity rather than diabetes itself plays a major role for the increased PAI-1 levels in NIDDM; (2) resistance to the antilipolytic effect of insulin, resulting in increased FFA concentrations, may participate in producing elevated PAI-1 levels in android obese subjects.

Adult↗

PubMed1995

A conceptual graphs modeling of UMLS components.

The Unified Medical Language System (UMLS) of the U.S. National Library of Medicine is a complex collection of terms, concepts, and relationships derived from standard classifications. Potential applications would benefit from a high level representation of its components. This paper proposes a conceptual representation of both the Metathesaurus and the Semantic Network of the UMLS based on conceptual graphs. It shows that the addition of a dictionary of concepts to the UMLS knowledge base allows the capability to exploit it pertinently. This dictionary defines more precisely the core concepts and adds constraints on their use. Constraints are dedicated to guide an "intelligent" browsing of the UMLS knowledge sources.

Dictionaries as Topic↗

PubMed1994

Adenoviral vectors as functional retrograde neuronal tracers.

Adenoviruses have been recently recognized as a highly efficient system for gene delivery to various tissues. The ability of replication-defective recombinant adenovirus to transfer the lacZ reporter gene encoding beta-galactosidase to nerve cells in various brain structures has been demonstrated. Here, on the continuation of these studies, we present evidence that the adenovirus can be transported in a retrograde manner to nerve cell bodies from axonal terminals. This method may be of great value for infecting selected subsets of specific neurons for either anatomo-functional studies or even therapeutic purposes.

Animals↗

PubMed1994

The use of adenovirus vectors for intracerebral grafting of transfected nervous cells.

Grafting genetically-modified cells into the brain is a promising approach to address fundamental and clinical issues in neurobiology. Despite recent substantial progress, most of the methods used for introducing DNA sequences into donor cells result in weak efficacy or transient gene expression after transplantation. We tested whether the use of adenovirus as the vector for foreign genes avoided these problems. A replication-defective adenovirus vector carrying a reporter gene encoding for beta-galactosidase was used to transfect primary astrocytes. After grafting into various brain structures, transfected cells exhibited robust survival and expressed the transgene for at least five months. These results demonstrate the advantage of adenovirus-mediated gene transfer for prolonged transgene expression in grafted primary cells.

Adenoviridae↗

PubMed1994

Users conceptual views on medical information databases.

As information databases we consider all the kinds of information repositories that are handled by computer systems. When querying very large information databases, the end-users are often faced with the problem to parse their questions efficiently into the query languages of the computer systems. Conceptual graphs were initially designed for natural language analysis and understanding. Due to their closeness to semantic networks, their expressiveness is powerful enough to be applied to knowledge representation and use by computer systems. This work demonstrates that conceptual graphs are a suitable means to model both the information in patient databases and the queries to these databases, and that operations on graphs can compute the pattern matching process needed to provide the answers. A prototype that exploits this model is presented. Experiments have been made with the material furnished by the Unified Medical Language System project (version 2, 1992) of the National Library of Medicine, USA.

Abstracting and Indexing↗

PubMed1994

Insulin responses to intravenous glucose and the hyperglycemic clamp in cystic fibrosis patients with different degrees of glucose tolerance.

The relationship between altered insulin secretion and impaired glucose tolerance was studied in 32 cystic fibrosis patients, 16 men and 16 women, aged 8-26 y, using oral and i.v. glucose tolerance tests and a hyperglycemic glucose clamp (10 mmol/L). Seven of these subjects were already being treated with insulin; seven had fasting blood glucose levels below 7.2 mmol/L but satisfied diabetic criteria at the oral glucose tolerance test; glucose tolerance was impaired in 13 subjects and normal in five. The insulin responses to the two i.v. glucose stimuli were inversely correlated with the plasma glucose levels (60 and 120 min) and the area under the curve of the oral glucose tolerance test. However, the acute insulin response to i.v. glucose was severely altered in patients with impaired glucose tolerance, whereas plasma insulin levels during the hyperglycemic clamp did not differ from those of healthy subjects. The responses to the two stimuli were dramatically low in the diabetic patients. These results suggest that cystic fibrosis patients with normal or impaired glucose tolerance retain their capacity to secrete insulin. Alterations in the acute phase of glucose-stimulated insulin secretion seem to be principally responsible for the early impairment in glucose tolerance.

Administration, Oral↗

PubMed1994

Six mutations in the glucokinase gene identified in MODY by using a nonradioactive sensitive screening technique.

We have reported that 56% of French families with maturity-onset diabetes of the young (MODY) carry a mutation in the glucokinase gene (GCK). Therefore, we have established a quick and sensitive nonradioactive technique (with the PhastSystem based on single-strand conformation polymorphism [SSCP] analysis) to routinely screen the 12 exons of GCK for mutations. We have studied GCK in 12 young hyperglycemic patients with a strong family history of type II diabetes. SSCP variants were observed in 6 of those 12 patients (50%), which cosegregated with diabetes in five families where DNA from additional members was available. Direct sequencing identified a 10-bp (base pair) deletion in exon 3; a 33-bp deletion at the exon 5/intron 5 junction, including the two consensus bases (GT) of the donor splice site; a nonsense mutation in exon 5 (Arg186-->Stop) in a Black-African family, which has been identified previously in a Caucasian family; and three missense mutations: Thr209-->Met209 in exon 6, Gly261-->Glu261 in exon 7, and Arg36-->Trp36 in exon 2. The missense mutation in exon 2 was found only in the second and third generation of the tested family but not in the first. To our knowledge, this is the first time that a de novo mutation of GCK is reported within a family. All six families carrying a mutation in GCK were typical MODY and most of their affected members had a mild form of diabetes. This nonradioactive SSCP technique may be useful to routinely diagnose glucokinase deficiency, which is an important cause of hyperglycemia among young type II diabetic patients.

Adult↗

PubMed1994

Arginine-induced insulin release in glucokinase-deficient subjects.

OBJECTIVE: In eight glucokinase (GCK)-deficient subjects, we have investigated insulin secretion rates (ISRs) in response to intravenous arginine. Impairment in the enzymatic activity of mutant GCK leads to a reduced glycolytic flux in beta-cells. This defect translates in vivo as a right shift in the glucose/SR dose-response curve. Insulin secretion in response to other secretagogues has not been reported. RESEARCH DESIGN AND METHODS: The arginine test was performed immediately after a 2-h hyperglycemic (10 mM) clamp. ISR was computed by deconvolution of peripheral C-peptide levels. Linear regression analyses were performed to assess correlations between the beta-cell secretory responses to the arginine test, an intravenous glucose tolerance test (IVGTT), and a hyperglycemic clamp (areas under the C-peptide curves), and between these parameters and the glucose tolerance status (area under the glucose curve during an oral glucose tolerance test). RESULTS: Two minutes after the injection of arginine, the increment in ISR was 30.17 +/- 10.01 pmol insulin.kg-1.min-1 in patients and 36.25 +/- 15.46 pmol insulin.kg-1.min-1 in control subjects (P = 0.38). Throughout the experiment, increments in ISR were comparable in both groups. The amount of insulin secreted in response to arginine (0-5 min) was similar in patients and control subjects: 81 +/- 28 vs. 119 +/- 55 pmol/kg (P = 0.16), respectively. The arginine test C-peptide response was not correlated with the IVGTT or hyperglycemic clamp responses. The arginine test and hyperglycemic clamp responses were not correlated to the glucose tolerance status. The best predictor of the glucose tolerance was the C-peptide response to the IVGTT (r2 = 0.78; P = 0.002). CONCLUSIONS: beta-cell secretory increment in response to arginine was found to be in the normal range in GCK-deficient subjects. The arginine test does not seem to reflect either the beta-cell secretory defect or the glucose tolerance status of these subjects. IVGTT seems to be the best predictor of the latter parameter in this population.

Adolescent↗

PubMed1994

[Eating disorders and insulin dependent diabetes: a current issue].

Association between insulin-dependent diabetes mellitus (IDDM) and eating disorders (anorexia nervosa, bulimia nervosa) was recently described. We have reviewed the systematic studies that were conducted on this topic, particularly for prevalence of anorexia nervosa and bulimia nervosa and their relations with metabolic control (HBA1C) and somatic complications of insulin-dependent diabetes mellitus. We have discussed methodological problems of these studies and etiopathogenic aspects of eating disorders in this somatic disease.

Adolescent↗