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Biomedical subjects

J M Gabriel

Publications and source records attributed to J M Gabriel.

At least 19 recordsLinked to original sources
PubMed2000

[Survival analysis of diabetic patients on dialysis in Guadeloupe].

BACKGROUND: Both diabetes and hypertension, two conditions that can lead to renal failure, have a high prevalence in Guadeloupe. OBJECTIVE: To determine the clinical and epidemiological features of diabetic patients on end stage renal failure and to evaluate their survival. PATIENTS AND METHOD: Data of the Guadeloupe Kidney registry were analysed for patients who began chronic dialysis during 1978-1997. Follow up information on survival status was obtained up to January 26(th) 1999. Cox proportional hazard analysis was used to determine the relative risk (RR) of death between levels of independant variables. RESULTS: There were 784 dialysis patients of whom 174 (22%) were diabetics. Among the latter, there were 97 women (55,7%), mean age at the start of dialysis was 60.6 years (range 26-83) and arterial hypertension was present before the start of dialysis in 67% of them. Median survival MS (95%CI) was significantly lower in diabetics 42 months (31-52) than in non diabetics 83 months (70-96), p<10(-4). In diabetics, the cumulative probability of survival was 83% (1 year) and 39% (5 years) and the RR of death (95% CI) were 1.90 (1.10-3.22) and 3.43 (2.00-5.87) for diabetics admitted in dialysis in age-class 55-64 years and 65-83 years, respectively, when that for age-class 54 years was set at 1. 00. The RR for diabetics was 1.67 (1.33-2.10) relative to non diabetics. CONCLUSION: Prospective studies are warranted to describe the role of comorbid conditions in diabetic patients survival. Prevention of degenerative complications should be a priority in this population.

Adult↗
PubMed1999

Conserved characteristics of heterochromatin-forming DNA at the 15q11-q13 imprinting center.

Nuclear matrix binding assays (NMBAs) define certain DNA sequences as matrix attachment regions (MARs), which often have cis-acting epigenetic regulatory functions. We used NMBAs to analyze the functionally important 15q11-q13 imprinting center (IC). We find that the IC is composed of an unusually high density of MARs, located in close proximity to the germ line elements that are proposed to direct imprint switching in this region. Moreover, we find that the organization of MARs is the same at the homologous mouse locus, despite extensive divergence of DNA sequence. MARs of this size are not usually associated with genes but rather with heterochromatin-forming areas of the genome. In contrast, the 15q11-q13 region contains multiple transcribed genes and is unusual for being subject to genomic imprinting, causing the maternal chromosome to be more transcriptionally silent, methylated, and late replicating than the paternal chromosome. We suggest that the extensive MAR sequences at the IC are organized as heterochromatin during oogenesis, an organization disrupted during spermatogenesis. Consistent with this model, multicolor fluorescence in situ hybridization to halo nuclei demonstrates a strong matrix association of the maternal IC, whereas the paternal IC is more decondensed, extending into the nuclear halo. This model also provides a mechanism for spreading of the imprinting signal, because heterochromatin at the IC on the maternal chromosome may exert a suppressive position effect in cis. We propose that the germ line elements at the 15q11-q13 IC mediate their effects through the candidate heterochromatin-forming DNA identified in this study.

Amino Acid Motifs↗
PubMed1999

A transgene insertion creating a heritable chromosome deletion mouse model of Prader-Willi and angelman syndromes.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) result from the loss of function of imprinted genes in human chromosome 15q11-q13. The central part of mouse chromosome 7 is homologous to human 15q11-q13, with conservation of both gene order and imprinted features. We report here the characterization of a transgene insertion (Epstein-Barr virus Latent Membrane Protein 2A, LMP2A) into mouse chromosome 7C, which has resulted in mouse models for PWS and AS dependent on the sex of the transmitting parent. Epigenotype (allelic expression and DNA methylation) and fluorescence in situ hybridization analyses indicate that the transgene-induced mutation has generated a complete deletion of the PWS/AS-homologous region but has not deleted flanking loci. Because the intact chromosome 7, opposite the deleted homolog, maintains the correct imprint in somatic cells of PWS and AS mice and establishes the correct imprint in male and female germ cells of AS mice, homologous association and replication asynchrony are not part of the imprinting mechanism. This heritable-deletion mouse model will be particularly useful for the identification of the etiological genes and mechanisms, phenotypic basis, and investigation of therapeutic approaches for PWS.

Angelman Syndrome↗
PubMed1999

Imprinting-mutation mechanisms in Prader-Willi syndrome.

Microdeletions of a region termed the "imprinting center" (IC) in chromosome 15q11-q13 have been identified in several families with Prader-Willi syndrome (PWS) or Angelman syndrome who show epigenetic inheritance for this region that is consistent with a mutation in the imprinting process. The IC controls resetting of parental imprints in 15q11-q13 during gametogenesis. We have identified a larger series of cases of familial PWS, including one case with a deletion of only 7.5 kb, that narrows the PWS critical region to <4. 3 kb spanning the SNRPN gene CpG island and exon 1. Identification of a strong DNase I hypersensitive site, specific for the paternal allele, and six evolutionarily conserved (human-mouse) sequences that are potential transcription-factor binding sites is consistent with this region defining the SNRPN gene promoter. These findings suggest that promoter elements at SNRPN play a key role in the initiation of imprint switching during spermatogenesis. We also identified three patients with sporadic PWS who have an imprinting mutation (IM) and no detectable mutation in the IC. An inherited 15q11-q13 mutation or a trans-factor gene mutation are unlikely; thus, the disease in these patients may arise from a developmental or stochastic failure to switch the maternal-to-paternal imprint during parental spermatogenesis. These studies allow a better understanding of a novel mechanism of human disease, since the epigenetic effect of an IM in the parental germ line determines the phenotypic effect in the patient.

Adult↗
PubMed1999

Paraproteinaemic neuropathies.

In this article, we review the main clinical and pathological features of paraproteinaemic neuropathies and discuss recent experimental findings. Further knowledge of the disease process at the molecular level has allowed a better characterization of clinical syndromes and has given new insights into their pathogenesis. The most convincing evidence for a causal relationship can be drawn from IgM monoclonal gammopathies with specificities directed against carbohydrate determinants of the myelin associated glycoprotein (MAG). There remain however, many unresolved questions, such as how monoclonal anti-MAG IgM antibodies cross the blood-nerve barrier and trigger a chronic demyelinating polyneuropathy while the central nervous system is essentially spared. IgM paraproteins with specificity for other molecules, such as neurofilaments, sulphatide, gangliosides, chondroitin sulphate and tubulin, have also been identified, but their pathogenetic importance remains to be elucidated. Other paraproteinaemic neuropathies such as IgG and IgA neuropathies have to be considered separately. The paraneoplastic endocrine and cytokine manifestations of rare osteosclerotic myelomas provide valuable insights into the interaction between the immune and the nervous system. The antigen-specificity of IgG and IgA monoclonal antibodies are only poorly characterized but some have been found to be directed against endoneurial determinants and a few against axonal proteins such as neurofilaments.

Demyelinating Diseases↗
PubMed1998

A model system to study genomic imprinting of human genes.

Somatic-cell hybrids have been shown to maintain the correct epigenetic chromatin states to study developmental globin gene expression as well as gene expression on the active and inactive X chromosomes. This suggests the potential use of somatic-cell hybrids containing either a maternal or a paternal human chromosome as a model system to study known imprinted genes and to identify as-yet-unknown imprinted genes. Testing gene expression by using reverse transcription followed by PCR, we show that functional imprints are maintained at four previously characterized 15q11-q13 loci in hybrids containing a single human chromosome 15 and at two chromosome 11p15 loci in hybrids containing a single chromosome 11. In contrast, three gamma-aminobutyric acid type A receptor subunit genes in 15q12-q13 are nonimprinted. Furthermore, we have found that differential DNA methylation imprints at the SNRPN promoter and at a CpG island in 11p15 are also maintained in somatic-cell hybrids. Somatic-cell hybrids therefore are a valid and powerful system for studying known imprinted genes as well as for rapidly identifying new imprinted genes.

Chromosomes, Human, Pair 11↗
PubMed1998

Structure and function correlations at the imprinted mouse Snrpn locus.

The human SNRPN gene maps within Chromosome (Chr) 15q11-q13, the region responsible for Prader-Willi syndrome (PWS) and Angelman syndrome (AS). As one of several 15q11-q13 transcripts expressed from the paternal allele-only, SNRPN is a candidate gene to explain at least some of the PWS phenotype in human and in genetic mouse models. The promoter and first exon of the SNRPN gene also correspond to an imprinting center element responsible for resetting of the maternal to paternal imprints within 15q11-q13 during spermatogenesis. Through characterization of the imprinted murine Snrpn locus in mouse Chr 7C, we have found that the gene structure is very similar to the human, with ten conserved exons spanning 22 kb, the last seven of which are tightly clustered. The promoter of Snrpn is differentially methylated in ES cells and adult tissues, supporting a role for DNA methylation at this site in somatic establishment and/or maintenance of Snrpn imprinting. The first intron of the mouse and human genes contains structurally conserved G-rich clustered repeats which may play a role in establishing DNA methylation patterns associated with imprinting of this gene. On the basis of the conserved structural and imprinted features of the human SNRPN and mouse Snrpn genes, we suggest that imprinting mechanisms are conserved between human and mouse.

Angelman Syndrome↗
PubMed1998

Confocal microscopic localization of anti-myelin-associated glycoprotein autoantibodies in a patient with peripheral neuropathy initially lacking a detectable IgM gammopathy.

We report here on a patient with anti-myelin-associated glycoprotein (MAG) neuropathy in whom examination of a sural nerve biopsy by multichannel confocal microscopy showed a partly overlapping distribution of MAG and IgM deposits in myelinated fibers. Our data demonstrate that MAG in Schmidt-Lanterman incisures and paranodal loops, as well as some additional HNK-1-positive components of the basal lamina, are the major targets of the anti-MAG monoclonal IgM autoantibodies in this neuropathy in vivo. Perforation of the basal lamina can allow the penetration and binding of anti-MAG IgM inside myelinated fibers. Our results support and extend the notion that the production of monoclonal anti-MAG IgM may be antigenically driven by MAG molecules and that this process may occur in the immunologically privileged environment of the nerve prior to the appearance of a genuine gammopathy in serum.

Autoantibodies↗
PubMed1997

Clinical spectrum and molecular diagnosis of Angelman and Prader-Willi syndrome patients with an imprinting mutation.

Recent studies have identified a new class of Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients who have biparental inheritance, but neither the typical deletion nor uniparental disomy (UPD) or translocation. However, these patients have uniparental DNA methylation throughout 15q11-q13, and thus appear to have a mutation in the imprinting process for this region. Here we describe detailed clinical findings of five AS imprinting mutation patients (three families) and two PWS imprinting mutation patients (one new family). All these patients have essentially the classical clinical phenotype for the respective syndrome, except that the incidence of microcephaly is lower in imprinting mutation AS patients than in deletion AS patients. Furthermore, imprinting mutation AS and PWS patients do not typically have hypopigmentation, which is commonly found in patients with the usual large deletion. Molecular diagnosis of these cases is initially achieved by DNA methylation analyses of the DN34/ZNF127, PW71 (D15S63), and SNRPN loci. The latter two probes have clear advantages in the simple molecular diagnostic analysis of PWS and AS patients with an imprinting mutation, as has been found for typical deletion or UPD PWS and AS cases. With the recent finding of inherited microdeletions in PWS and AS imprinting mutation families, our studies define a new class of these two syndromes. The clinical and molecular identification of these PWS and AS patients has important genetic counseling consequences.

Adult↗
PubMed1997

Gene dosage effects in hereditary peripheral neuropathy. Expression of peripheral myelin protein 22 in Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies nerve biopsies.

A duplication of a 1.5-Megabase genomic region encompassing the gene for the peripheral myelin protein 22 (PMP22) is found on chromosome 17p11.2-12 in Charcot-Marie-Tooth disease type 1A (CMT1A), whereas the reciprocal deletion is associated with hereditary neuropathy with liability to pressure palsies (HNPP). Since most CMT1A patients harbor three copies of the PMP22 gene, and most HNPP patients carry only a single copy, a gene dosage effect has been proposed as a mechanism for both diseases. We have analyzed the steady-state expression of PMP22 protein in sural nerve biopsies from three CMT1A and four HNPP patients. Quantitative immunohistochemical determination showed that PMP22 protein expression relative to that of myelin protein zero and myelin basic protein was increased in all CMT1A patients and reduced in all HNPP patients, as compared with biopsy samples of patients with normal PMP22 gene expression. These data demonstrate that both neuropathies result from an imbalance of PMP22 protein expression.

Adolescent↗
PubMed1996

[Adult-onset acute rheumatic fever: 4 cases in Guadeloupe].

OBJECTIVE: Rheumatic fever has become infrequent in developed countries. Recent regional epidemics, particularly in North America, brought our attention to this disease in our area. In the French Caribbean Islands, rheumatic fever remains an important health problem despite much progress in the last 15 years. METHODS: A retrospective survey over the last 5 years identified 19 cases of rheumatic fever in Guadeloupe in subjects over 19 years of age. RESULTS: Among these subjects 4 cases of rheumatic fever beginning in adulthood were analysed and compared with data in the literature. CONCLUSION: The diagnosis of rheumatic fever beginning in adulthood is difficult to establish. Joint symptoms are variable and cardiac involvement, which occurs in 30 to 40% of the cases, is highly suggestive. The kinetics of antistreptococci antibodies confirms the diagnosis.

Adult↗
PubMed1996

Selective loss of myelin-associated glycoprotein from myelin correlates with anti-MAG antibody titre in demyelinating paraproteinaemic polyneuropathy.

The IgM monoclonal autoantibodies of patients with demyelinating paraproteinaemic polyneuropathy recognize a carbohydrate structure present on both myelin-associated glycoprotein (MAG) and protein zero (P0). These autoantibodies are sufficient to cause the disease but the mechanism of demyelination remains unclear. We have analysed nerve biopsies from eight patients with polyneuropathy and anti-MAG antibodies by quantitative immunohistochemistry and find a concordant pattern of reduced expression of myelin markers with the loss of myelinated fibres. We report here novel features of this disease, in particular a selective lack of detectable MAG in a large proportion of myelinated-fibres containing P0, myelin basic protein (MBP) and periaxin. There is also an inverse correlation of the distribution of MAG in peripheral nerve myelin with the serum anti-MAG antibody titres but no correlation of these titres with the loss of myelinated fibres. Double immunofluorescence staining of paraproteinaemic polyneuropathy (PPN) nerves shows anti-MAG IgM deposited on the periphery of myelinated fibres associated with or lacking MAG staining. These data suggest that the binding of anti-MAG antibodies to MAG and/or other myelin component(s) results in MAG downregulation and may have an essential role in the molecular mechanisms leading to demyelination and partial regeneration in this disease.

Antibody Specificity↗
PubMed1996

SGPG in ALS.

Explore the source record for details and available documents.

Amyotrophic Lateral Sclerosis↗
PubMed1996

Arterial hypertension in the adult population of Guadeloupe, and associated factors in subjects of African origin.

This study was designed to estimate the prevalence of hypertension in Guadeloupe, the French West Indies, and to evaluate the risk factors associated with hypertension in the largest ethnic group, that of African origin. Households were randomly selected using a two-stage systematic sample of districts and then of houses; all adults aged 18 years in the household were included. In total, 1043 men and women were studied. Blood pressure, plasma glucose concentrations and gamma-glutamyl transferase activity were measured, hypertensive treatment and lifestyle factors recorded. The prevalence of hypertension, age-standardized to the Guadeloupe population was 21% and 26% in men and women of African origin, 28% and 22% in those of Indian-origin and 18% and 16% for other origins. The vast majority of subjects were unaware of their hypertension (90% of men, 74% of women). After adjustment for age, factors associated with high blood pressure in the 826 adults of African origin were: obesity, hyperglycemia, low educational level and family history of hypertension and of stroke. Additional factors in women were alcohol consumption, gamma-glutamyl transferase activity, physical inactivity, occupational category and a retired status, even after adjustment for age. Measures must be taken to diagnose hypertension early, particularly in individuals of African and Indian origin. An effective education program is needed, with an emphasis on life-style factors associated with obesity: diet and physical activity.

Adolescent↗
PubMed1995

Glucoprivic treatments that induce anestrus, but do not affect food intake, increase FOS-like immunoreactivity in the area postrema and nucleus of the solitary tract in Syrian hamsters.

Animals make a wide variety of physiological and behavioral adjustments in order to maintain caloric homeostasis. For example, most animals increase food intake when the availability of cellular metabolic fuels is low. The area postrema (AP) and adjacent, reciprocally-innervated nucleus of the solitary tract (NTS) are important brain areas for metabolic control of food intake in rats. However, in Syrian hamsters, food intake is not affected by decreases in metabolic fuel availability such as those that occur with food deprivation or with pharmacological inhibitors of metabolic fuels. Hamsters make other adjustments that conserve energy when the availability of metabolic fuels is low. Estrous cycles are inhibited by treatment with a high dose of 2-deoxy-D-glucose (2DG), a drug that inhibits cellular glucose utilization, but not by treatment with methyl palmoxirate (MP) a drug that inhibits fatty acid utilization. Recent data suggest that the AP/NTS is critical for the effects of glucoprivation on estrous cycles. Lesions of the AP/NTS prevent 2DG-induced anestrus. If the AP/NTS is involved in anestrus induced by glucoprivation, it might be predicted that glucoprivic treatments that induce anestrus would change patterns of neural activation, as measured by FOS-like immunoreactivity (FOS-li), in the AP/NTS. We examined FOS-li in females that were either food deprived or fed ad libitum, and in females treated with 2DG, MP or the appropriate vehicle. FOS-li was increased in the AP/NTS only in hamsters food deprived or treated with 2DG, the two treatments that induce anestrus but have no effect on food intake. These results are consistent with the notion that metabolic control of estrous cycles involves detection of decreases in the availability of metabolic fuels in the AP/NTS.

Anestrus↗
PubMed1995

[Cerebrovascular accidents and AIDS].

A number of pathological and clinical data suggest that AIDS could be an underestimated cause of cerebro-vascular disease, especially in young individuals. Eight retrospective cases of stroke in AIDS patients are reported. Mean age was 39 years, mean CD4 cells count 57/mm3. Pathogenic mechanism, particularly the role of opportunistic infections remains unclear. Prognosis does not seem constantly pejorative: only one patient died from stroke, six are still alive with a 6 months follow-up, without relapse and with minor or no sequellae. Alcohol or cocaine (crack) abuse was present in half the cases. The role of specific risk factors and consequently adapted prophylaxis is questionned.

AIDS-Related Opportunistic Infections↗
PubMed1994

Proposed three-dimensional structure for the cellular prion protein.

Prion diseases are a group of neurodegenerative disorders in humans and animals that seem to result from a conformational change in the prion protein (PrP). Utilizing data obtained by circular dichroism and infrared spectroscopy, computational studies predicted the three-dimensional structure of the cellular form of PrP (PrPc). A heuristic approach consisting of the prediction of secondary structures and of an evaluation of the packing of secondary elements was used to search for plausible tertiary structures. After a series of experimental and theoretical constraints were applied, four structural models of four-helix bundles emerged. A group of amino acids within the four predicted helices were identified as important for tertiary interactions between helices. These amino acids could be essential for maintaining a stable tertiary structure of PrPc. Among four plausible structural models for PrPc, the X-bundle model seemed to correlate best with 5 of 11 known point mutations that segregate with the inherited prion diseases. These 5 mutations cluster around a central hydrophobic core in the X-bundle structure. Furthermore, these mutations occur at or near those amino acids which are predicted to be important for helix-helix interactions. The three-dimensional structure of PrPc proposed here may not only provide a basis for rationalizing mutations of the PrP gene in the inherited prion diseases but also guide design of genetically engineered PrP molecules for further experimental studies.

Amino Acid Sequence↗