Biomedical subjects

J Mathieu

Publications and source records attributed to J Mathieu.

At least 19 recordsLinked to original sources

PubMed2003

Effect of heavy ions on neuro-endocrine regulations.

During American and Russian short and long-term space flights neuroimmune dysregulations have been observed in man and rats for up to three months after the return. During Extra-Vehicular Activity, radiation exposure risk is greater to elicit short and/or long-term deleterious effects on the functional capacity of the neuroimmune system. In order to assess the effects of high LET events on neuroimmune networks, our preliminary ground-based study was to investigate brain inflammatory responses in mouse after low dose radiation exposure with high LET particles (12C, 95MeV/u, 42 mGy). Plasma corticosterone levels were rapidly (6 hours) increased by two-fold, then decreased 24 hours post-irradiation. At 3 days plasma corticosterone and ACTH concentrations were also two- to three-fold increased. Plasma ACTH levels were still elevated up to seven days to two months. Furthermore immune functions are under current assessment. The results of this study should allow a greater understanding of the effects of high LET particles on neuroimmune system.

Adrenocorticotropic Hormone↗

PubMed2003

Flow cytometry analysis of gamma-radiation-induced Epstein-Barr virus reactivation in lymphocytes.

Epstein-Barr virus (EBV), a member of the gamma-herpesvirus family, is involved in the development of several diseases, and the infection is believed to persist for life in latent form. Ionizing radiation at clinically relevant doses may increase the amount of virus reactivation in B cells, and the combination of radiation with stress could amplify EBV reactivation. In vitro experiments were performed on several cell lines, including EBV-positive Burkitt lymphoma cells. The presence of the immediate-early protein ZEBRA, which is a hallmark of EBV reactivation, was evaluated using flow cytometry, which enabled us to measure the percentage of ZEBRA-positive cells. The process was studied previously in the EBV-positive Burkitt lymphoma cell line B95-8. Forty-eight hours after irradiation alone, 13.6 and 19.9% ZEBRA-positive cells were observed at 2 and 4 Gy, respectively, compared to the basal level of 1.85%. Thus irradiation induces EBV reactivation. The addition of a glucocorticoid (the final effector of the stress response) had no effect on EBV reactivation in our model. However, the combination of radiation and treatment with a glucocorticoid (dexamethasone) increased the expression of ZEBRA in B95-8 cells (15.8 and 28.75% of the cells was positive at 24 and 48 h after gamma irradiation, respectively). Thus the combination of gamma radiation and a glucocorticoid may play an important role in EBV reactivation.

Cell Cycle↗

PubMed2002

Cooperative action of ADMP- and BMP-mediated pathways in regulating cell fates in the zebrafish gastrula.

It was shown in Xenopus and chick that Spemann's organizer activity is regulated through the negative action of Anti-Dorsalizing Morphogenetic Protein (ADMP). We report the characterization and functional properties of admp in zebrafish. admp expression profile is consistent with a role in the organizer, including the tail organizer. We studied admp function through overexpression experiments, with the use of a dominant-negative form (TR-ADMP) and of an antisense morpholino-modified oligonucleotide. Our results indicate that the ADMP pathway causes the restriction of anterior and axial fates and that ADMP, BMP2b, and BMP7 pathways have distinct actions but cooperate in establishing proper dorso-ventral regionalization. This is shown by partial rescue of the dorsalized mutant snailhouse and of the ventralized mutant chordino, upon admp and tr-admp RNA injection, respectively. Moreover, ADMP and BMP7 probably form heterodimers as shown by the ability of TR-ADMP and BMP7 to antagonize each other. We observed that a MYC-tagged ADMP was secreted and detected in the extracellular space, suggesting that admp could act at a distance. Simultaneous local inhibition of bmp function at the blastoderm margin and impairment of ADMP secretion led to the induction of secondary head structures, confirming that the two pathways cooperatively regulate organizer formation and activity.

Amino Acid Sequence↗

PubMed2002

Sibship stability of genotype and phenotype in myotonic dystrophy.

Myotonic dystrophy (DM1) is caused by an unstable CTG repeat expansion. Despite the evidence of birth order effect in congenital DM1, the expansion's dynamics among sibships is still unknown. The objective of this study was to determine phenotype and CTG repeat size variability in DM1 sibships, and to investigate their predictive values. We compared 86 sib pairs for CTG repeat, 61 for age at onset and 89 for DM1 phenotype. CTG repeats remained stable for 66 of the 86 sib pairs, including 25 of 27 maternal transmissions and 30 of 42 paternal transmissions. Variations of less than 10 years in the age at onset were observed in 44 of 61 sib pairs, including 16 of 18 maternal transmissions and 19 of 28 paternal transmissions. The same phenotypic severity or a variation of only one class was observed among 86 of the 89 sib pairs, including all of the 35 maternal transmissions and 30 of the 33 paternal transmissions. Birth order, intergenesic interval, oldest sib's CTG repeat or parental age and CTG repeat did not exert any significant influence. These results suggest that genotype and phenotype remained stable among sibs, although the paternal origin of the mutation seemed to reduce the predictability of the severity.

Adolescent↗

PubMed2002

Gulf war syndrome: could it be triggered by biological warfare-vaccines using pertussis as an adjuvant?

Several recent epidemiological studies have shown that vaccinations against biological warfare using pertussis as an adjuvant were associated with the Gulf war syndrome. If such epidemiological findings are confirmed, we propose that the use of pertussis as an adjuvant could trigger neurodegeneration through induction of interleukin-1beta secretion in the brain. In turn, neuronal lesions may be sustained by stress or neurotoxic chemical combinations. Particular susceptibility for IL-1beta secretion and potential distant neuronal damage could provide an explanation for the diversity of the symptoms observed on veterans.

Adjuvants, Immunologic↗

PubMed2002

The pleiotropic expression of the myotonic dystrophy protein kinase gene illustrates the complex relationships between genetic, biological and clinical covariates of male aging.

Aging is a complex process modulated by multiple interactions between environmental and genetic factors. Myotonic dystrophy (DM1) is an autosomal dominant disorder caused by an unstable (CTG)n repeat expansion in the DM1 protein kinase (DMPK) gene. The affected male patients' life expectancy at birth (53.2 years) is more than two decades below that observed in most occidental populations. The DMPK gene expression is pleiotropic and includes the premature expression of several age-related signs, symptoms and metabolic disturbances including hormonal dysfunctions, progressive decrease in muscular mass, presenile cataracts, alopecia, reduced alertness, insulin resistance, dyslipidemia, erectile dysfunction and hypogonadism. The aim of this study was to analyze the relationship between aging covariates and the severity of DM1 expression in 136 DM1 male subjects. DM1 clinical expression was assessed on a validated neuromuscular disability rating scale and was correlated with plasma total testosterone (rs = -0.31, p < 0.001), luteinizing hormone (LH) (rs = 0.52, p < 0.001) and follicle stimulating hormone (FSH) (rs = 0.54, p < 0.001) levels. Following LH releasing hormone stimulation, FSH and LH concentrations increased as a function of DM1 severity (p < 0.05). Muscular disability in DM1 was also positively associated with fasting plasma insulin and triglyceride concentrations (p < 0.05). The association of plasma apolipoprotein B and low-density lipoprotein cholesterol levels with DM1 was not linear across their distribution and tended to reflect cell membrane damage progression. These results suggest that DM1, a simple Mendelian trait, can represent a valuable model to illustrate the complex relationships between variables associated with male aging.

Adolescent↗

PubMed2001

The bacterial nucleoside N(6)-methyldeoxyadenosine induces the differentiation of mammalian tumor cells.

Contrary to bacterial DNA, mammalian DNA contains very little if any N(6)-methyldeoxyadenosine (MDA). The possible biological effect of this nucleoside on eukaryotic cells has been studied on different tumor cell lines. Addition of MDA to C6.9 glioma cells triggers a differentiation process and the expression of the oligodendroglial marker 2',3'-cyclic nucleotide 3'phosphorylase (CNP). The biological effects of N(6)-methyldeoxyadenosine were not restricted to C6.9 glioma cells since differentiation was also observed on pheochromocytoma and teratocarcinoma cell lines and on dysembryoplastic neuroepithelial tumor cells. The precise mechanism by which MDA induces cell differentiation remains unclear, but is related to cell cycle modifications. These data point out the potential interest of N(6)-methyldeoxyadenosine as a novel antitumoral and differentiation agent. They also raise the intriguing question of the loss of adenine methylation in mammalian DNA. Furthermore, the finding that a methylated nucleoside found in bacterial DNA induces a biological process might have implications in gene therapy approaches when plasmid DNAs are injected into humans.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗

PubMed2001

Role of cellular zinc in programmed cell death: temporal relationship between zinc depletion, activation of caspases, and cleavage of Sp family transcription factors.

Zinc is a potent inhibitor of apoptosis, whereas zinc depletion induces apoptosis in many cell lines. To investigate the mechanisms of zinc depletion-induced apoptosis, HeLa cells were treated with the membrane permeable metal ion chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). TPEN decreased the intracellular level of zinc and induced apoptosis with a characteristic cellular pattern, i.e. cell shrinkage and formation of apoptotic bodies, with DNA fragmentation and formation of a typical DNA ladder pattern. Following TPEN treatment, caspases-3, -8, and -9 were activated and caspase target proteins, poly(ADP-ribose) polymerase, and Sp transcription factors were cleaved. These effects were inhibited by adding zinc to the medium. To assess the role of zinc in the activation of the caspase cascade, we compared zinc inhibition during tumor necrosis factor alpha/cycloheximide- and etoposide-induced apoptosis with that induced by TPEN. Zinc addition partially inhibited caspase-3 activation, but not caspase-8 and -9 cleavage in HeLa cells treated with tumor necrosis factor alpha or etoposide. These results suggest that caspase-3 is rapidly and directly activated by zinc chelation, without a requirement for an upstream event. Caspase-3 activation is therefore the main event leading to apoptosis after intracellular zinc chelation. Finally, we conclude that cellular zinc inhibits apoptosis by maintaining caspase-3 inactive.

Analysis of Variance↗

PubMed2001

Assessment of a disease-specific muscular impairment rating scale in myotonic dystrophy.

OBJECTIVE: To document the intra/interrater reliability and the construct validity of the Muscular Impairment Rating Scale (MIRS) in assessing patients with myotonic dystrophy type 1 (DM1). The MIRS is a ordinal five-point rating scale, established in accordance with the clinically recognized distal to proximal progression of the muscular involvement in DM1, based partly on a manual muscle testing (MMT) of 11 muscle groups. METHODS: To assess the reliability of the MIRS, 55 patients with DM1 were examined by three different observers, one of them evaluating each patient twice. Intra- and interobserver reliability of the MIRS was measured using Cohen's weighted kappa. To assess the construct validity of the MIRS, correlations were made with the Functional Status Index (FSI) and eight timed functional tasks. RESULTS: The intraobserver reliability of the MIRS was excellent (weighted kappa = 0.84), and the interobserver reliability was interpreted as a substantial agreement (weighted kappa = 0.77 to 0.79). The correlation coefficients between MMT scores and MIRS grades were all highly significant (r(s) = -0.81 to -0.88, p < 0.001). The FSI showed a significant progressive increase of the total median dependence score in activities of daily living from 0 in MIRS grade 1 to 39 in MIRS grade 5 (p < 0.001). The time needed to perform the eight functional tasks was also found to significantly increase in relation with the progression of the MIRS grades. CONCLUSION: The MIRS is a quick, simple, and reliable measurement of muscular impairment in DM1. The FSI questionnaire and the timed motor activities supported its construct validity. The MIRS is useful to monitor major stages of DM1 progression, to study the natural history of the disease, and to identify homogeneous groups of patients for clinical trials.

Adolescent↗

PubMed2001

Chronic restraint stress induces severe disruption of the T-cell specific response to tetanus toxin vaccine.

Chronic stress is known to induce immunological disorders. In the present study we examined the consequences of chronic restraint stress on the immune response to tetanus toxin in mice. We investigated the repartition of subsets of lymphoid cells in blood and spleen, the functional ability of lymphocytes to proliferate and to produce cytokines, and antibody titres against tetanus toxin following stress. We report discordance of the stimulation index of lymphocytes in the restraint group: the proliferating rate severely decreased following stimulation with a relevant antigen, whereas it increased with mitogen. Thus, we report a decrease in cytokine production with relevant antigen (interferon-gamma and interleukin-10), without a T helper type 1 and 2 secretion imbalance. Moreover, we observed an alteration in the humoral response, including a delay in isotype maturation and an immunoglobulin G1/G2a imbalance.

Animals↗

PubMed2001

Rapid detection of the sacsin mutations causing autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS; MIM SACS 270550) is frequent in northeastern Québec. Two causal mutations have been identified in the 11.7-kb single exon sacsin gene by sequence-based analyses. Mutation g.6594delT (DeltaT) was reported in 96% of the patients whereas a g.5254C --> T nonsense mutation has been observed only in 2 families. Here we report a reliable and inexpensive method to detect more than 95% of the ARSACS disease alleles from northeastern Québec using allele-specific oligonucleotide (ASO) hybridization. This procedure is being incorporated into the diagnosis of ARSACS, as well as being used for carrier detection in at-risk families from northeastern Québec.

Alleles↗

PubMed2001

Repeatability of lung density measurements with low-dose computed tomography in subjects with alpha-1-antitrypsin deficiency-associated emphysema.

RATIONALE AND OBJECTIVES: Multislice computed tomography (MSCT) of the lungs provides a new opportunity for longitudinal assessment of lung densities because of shorter scan duration. The aim of the present study was to assess the intraindividual variation of lung densities measured by MSCT of patients with emphysema. METHODS: Ten patients with emphysema participated in a study in which MSCT was obtained on two occasions, approximately 2 weeks apart. Scanning parameters were 140 kV, 20 mAs, 4 x 2.5-mm collimation, and effective slice thickness of 2.5 mm. Lung density was measured as the 15th percentile point and the relative area below -910 Hounsfield units (HU) by using Pulmo-LKEB software. RESULTS: The mean difference of the 15th percentile point was -1.29 +/- 3.2 HU, and that for the relative area below the -910-HU parameter was -1.02% +/- 3.09%. Intraclass coefficients of variation were 0.96 (0.86-0.99) and 0.94 (0.8-0.98), respectively (95% confidence interval). CONCLUSIONS: Lung density parameters of emphysema derived by MSCT provide an opportunity for analysis of the treatment effects of new drugs on the progression of emphysema.

Disease Progression↗

PubMed2001

Behavioural, physiological and metabolic responses to long-term starvation and refeeding in a blind cave-dwelling (Proteus anguinus) and a surface-dwelling (Euproctus asper) salamander.

The effects of long-term starvation and subsequent refeeding on haematological variables, behaviour, rates of oxygen consumption and intermediary and energy metabolism were studied in morphologically similar surface- and cave-dwelling salamanders. To provide a hypothetical general model representing the responses of amphibians to food stress, a sequential energy strategy has been proposed, suggesting that four successive phases (termed stress, transition, adaptation and recovery) can be distinguished. The metabolic response to prolonged food deprivation was monophasic in the epigean Euproctus asper (Salamandridae), showing an immediate, linear and large decrease in all the energy reserves. In contrast, the hypogean Proteus anguinus (Proteidae) displayed successive periods of glucidic, lipidic and finally lipido-proteic-dominant catabolism during the course of food deprivation. The remarkable resistance to long-term fasting and the very quick recovery from nutritional stress of this cave organism may be explained partly by its ability to remain in an extremely prolonged state of protein sparing and temporary torpor. Proteus anguinus had reduced metabolic and activity rates (considerably lower than those of most surface-dwelling amphibians). These results are interpreted as adaptations to a subterranean existence in which poor and discontinuous food supplies and/or intermittent hypoxia may occur for long periods. Therefore, P. anguinus appears to be a good example of a low-energy-system vertebrate.

Adaptation, Physiological↗

PubMed2001

[Induction of apoptosis of splenic lymphocytes in mice by accelerated carbon ions].

To assess the capacity of heavy ions to induce apoptosis in lymphocytes, mice have been irradiated with accelerated carbon ions (95 MeV/nucleon) at doses ranging from 0.1 to 4 Gy. Their spleens were removed 24 h later and gently dissociated to prepare a single cell suspension. Mononuclear cells were then maintained in culture at 37 degrees C, and the occurrence of apoptosis in these cells was analysed 24 h later. Lymphocytes were also irradiated in vitro, in the presence of Ac-DEVD-CHO, a potent caspase-3 and -7 inhibitor. Results from three experiments performed at the Grand Accelerateur National d'Ions Lourds (GANIL, Caen, France) are reported here. They indicate that carbon ions induce a marked, dose-dependent, reduction of the spleen weight and cellularity. However, in sharp contrast with spleen cells prepared from X-ray irradiated mice, only a slight increase of apoptosis is evidenced in cultured lymphocytes from mice irradiated with heavy ions. The significance of such results is discussed. So far, few data exist concerning the biological effects of heavy ions, in particular their capacity to induce apoptosis in lymphocytes; the present study provides useful clues for further investigations.

Animals↗

PubMed2000

The mutation of Pro789 to Leu reduces the activity of the fast-twitch skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA1) and is associated with Brody disease.

Brody disease is a rare inherited disorder of fast-twitch skeletal muscle function and is characterized by a lifelong history of exercise-induced impairment of skeletal muscle relaxation, stiffness, and cramps. The autosomal recessive inheritance of mutations in ATP2A1, the gene encoding SERCA1, which is the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, has been associated with Brody disease in three of six Brody families in which ATP2A1 has been sequenced. In the present analysis of the ATP2A1 gene in four unrelated families with autosomal recessive inheritance of Brody disease, three mutations were found in two families, leading to premature stop codons and truncated SERCA1. In a third family, the homozygous substitution of T for C2366 led to the missense mutation of Pro789 to Leu. The Pro789 to Leu mutant was readily expressed in HEK-293 cells, but it demonstrated an almost complete loss of Ca2+ transport activity because of reduced Ca2+ affinity. In a fourth family, the heterozygous substitution of T for C2455, mutating Arg819 to Cys, was identified. This mutation was also readily expressed in HEK-293 cells and shown to have near normal Ca2+ transport activity, indicating that it is not causal for Brody disease. These results confirm the genetic heterogeneity of Brody disease and emphasize the importance of a functional test for mutant SERCA1; immunostaining of skeletal muscle to detect the loss of SERCA1a protein is not adequate for the diagnosis of ATP2A1-linked Brody disease.

Adolescent↗

PubMed2000

Non-thermal effects of continuous 2.45 GHz microwaves on Fas-induced apoptosis in human Jurkat T-cell line.

Non-thermal effects of microwaves (MWs) are one of the main issues studied for revising standards. The effects of MW exposure on apoptosis at non-thermal level (48 h, 2.45 GHz, 5 mW/cm2) have been studied. Results obtained assess non-thermal MW effects on Fas, but neither on butyrate- nor on ceramide-induced apoptosis in human Jurkat T-cell line. These data show that MW interacts either with Fas pathway between receptor and caspase-3 activation or on membrane proteins (i.e. Fas receptor or neurosphyngomyelinase).

Apoptosis↗

PubMed2000

ARSACS, a spastic ataxia common in northeastern Québec, is caused by mutations in a new gene encoding an 11.5-kb ORF.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS or SACS) is an early onset neurodegenerative disease with high prevalence (carrier frequency 1/22) in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region of Quebec. We previously mapped the gene responsible for ARSACS to chromosome 13q11 and identified two ancestral haplotypes. Here we report the cloning of this gene, SACS, which encodes the protein sacsin. The ORF of SACS is 11,487 bp and is encoded by a single gigantic exon spanning 12,794 bp. This exon is the largest to be identified in any vertebrate organism. The ORF is conserved in human and mouse. The putative protein contains three large segments with sequence similarity to each other and to the predicted protein of an Arabidopsis thaliana ORF. The presence of heat-shock domains suggests a function for sacsin in chaperone-mediated protein folding. SACS is expressed in a variety of tissues, including the central nervous system. We identified two SACSmutations in ARSACS families that lead to protein truncation, consistent with haplotype analysis.

Amino Acid Sequence↗

PubMed2000

Ex vivo expanded mobilized peripheral blood CD34+ cells accelerate haematological recovery in a baboon model of autologous transplantation.

To address the value of ex vivo expanded haematopoietic cells for shortening cytopenia in autologous haematopoietic transplantation, we designed an ex vivo expansion protocol based on a cocktail of early acting cytokines and short-term culture and tested it in a baboon model. Expansion involved enriched CD34+ peripheral blood haematopoietic cells cultured for 6 d with a combination of FLT3-L, stem cell factor (SCF), thrombopoietin (TPO) and interleukin (IL)-3 (50 ng/ml each); CD34+ cells, granulocyte-macrophage colony-forming units (GM-CFU) and megakaryocytic colony-forming units (MK-CFU) were amplified, respectively, 10.5-, 20.5- and 17.9-fold. Baboons were submitted to a myeloablative regimen consisting of cyclophosphamide plus total body irradiation (TBI; 6 Gy) and were then grafted with either 2 x 106/kg unmanipulated CD34+ cells (control group, n = 4) or cells cultured from 2 x 106/kg CD34+ cells (expansion group, n = 4). No cytokines were administered after transplantation. All the animals engrafted. The mean times to white blood cell (WBC), granulocyte and platelet recovery were significantly shorter in the expansion group than in the control group: WBC (> 1 x 109/l) and neutrophil (> 0.5 x 109/l) recovery occurred on days 8 (range 6-9) and 9 (range 6-11), respectively, compared with days 12 (range 10-15) and 14 (range 11-16); platelets recovered (> 20 x 109/l) on day 9 (range 7-12) compared with day 13 (range 11-15) in the control group (P < 0.05). No toxicity was observed after reinfusion. No secondary hypoplasia was observed during more than 12 months of follow-up. Functions of both neutrophils and platelets produced from expanded cells were normal in terms of oxidative metabolism, chemotaxis and the bleeding time. This study shows that in comparison with unmanipulated cells peripheral blood haematopoietic cells expanded from similar doses of CD34+ cells, under the conditions defined here, accelerated both neutrophil and platelet recovery without impairing long-term haematopoiesis.

Animals↗