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M Tremblay

Publications and source records attributed to M Tremblay.

At least 73 records · Page 4Linked to original sources
PubMed1996

HIV-induced apoptosis requires the CD4 receptor cytoplasmic tail and is accelerated by interaction of CD4 with p56lck.

The roles of the CD4 receptor and the src kinase p56lck were examined in the process of HIV-induced apoptosis of CD4+ T lymphocytes. The presence of the CD4 cytoplasmic tail was found to be essential in delivering an apoptotic signal, and interaction of CD4 with p56lck potentiated HIV-induced apoptosis. Apoptosis, but not HIV replication, was abrogated by deleting the NH2-terminal intracytoplasmic tail of CD4, or by mutating the two critical cysteines in this tail that are responsible for CD4-p56lck interaction. Introduction of p56lck in C8166-45 or MT-2 cells, CD4+ T cell lines deficient for this protein, greatly increased HIV-induced apoptosis and syncytium formation. The ability of p56lck to deliver an apoptotic signal did not depend on its kinase function, since a kinase-deficient mutant was as effective as its normal counterpart in inducing apoptosis, suggesting that p56lck may act as an adapter to anchor other proteins to transduce the death signal.

Apoptosis↗
PubMed1996

In vivo toxicity of foscarnet and zidovudine given alone or in combination.

The toxicities of foscarnet (PFA) and zidovudine (AZT) given alone or in combination have been investigated in mice. PFA administered at a dose of 500 mg/kg/day and AZT at a dose of 400 mg/kg/day for 17 days caused clear hematotoxicity and nephrotoxicity. Each drug alone showed little hematotoxicity, but using a combination of both drugs significantly and dramatically decreased RBC (approximately 50%), Hb (approximately 43%), and hematocrit (approximately 43%) and increased platelets (approximately 45%) on Day 11 of treatment. It seems that there is a synergistic or at least an additive effect between PFA and AZT in terms of red blood cell toxicity. Surprisingly, AZT significantly increased serum creatinine levels on Days 5 and 11 of treatment (up to 40% increase), whereas PFA was less toxic (only approximately 17% increase on Day 5 of treatment). Using a combination of the two drugs, PFA seems to reduce the nephrotoxic effect of AZT on Day 11 of treatment. None of the treatments had any effect on BUN. At a lower dose level of 340 mg PFA/kg/day and 270 mg AZT/kg/day for 15 days there was hematotoxicity (much less evident than that at the higher dose level), but no nephrotoxicity. Electron microscopic examination of the renal cortex of animals from the experiments testing the higher dose levels revealed a clear vacuolization in proximal tubules and necrosis of mitochondria in distal tubules. These effects were more striking with the combination and less evident with PFA or AZT alone. In conclusion, even though we have used a high dose of AZT, there was synergistic/additive hematotoxicity. The combination was less nephrotoxic, only on Day 11 of treatment, than either of these agents used alone although histopathology, at the time of euthanization, showed more severe damage.

Animals↗
PubMed1996

Leishmania and the pathogenesis of HIV infection.

Acquired immunodeficiency syndrome (AIDS) and leishmaniasis overlap in several parts of the world, and microorganisms responsible for these human diseases infect and replicate within the macrophage. Therefore, the opportunity that the pathogenesis of the human immunodeficiency virus (HIV) and Leishmania infections could be modulated within dually infected individual is optimized. The most prominent clinical feature of AIDS is the development of debilitating secondary infections induced by several opportunistic microorganisms, including protozoa. Michel Tremblay, Martin Olivier and Richard Bernier here focus on the recently reported information on the putative cofactor role that the intracellular pathogen of the genus Leishmania may play in the pathogenesis of HIV infection.

Journal Article↗
PubMed1996

Comparative pharmacokinetics, distributions in tissue, and interactions with blood proteins of conventional and sterically stabilized liposomes containing 2',3'-dideoxyinosine.

The pharmacokinetics and distribution in tissue of 2',3'-dideoxyinosine (ddI) encapsulated in sterically stabilized liposomes have been evaluated in rats. Most of the sterically stabilized liposomes concentrated in the spleen with a peak level at 24 h after their intravenous injection. An extended half-life in plasma was observed for sterically stabilized liposomes (14.5 h) compared with that of conventional liposomes (3.9 h). The systemic clearance of ddI incorporated in sterically stabilized liposomes was 180 times lower than that of the free drug. The levels of in vitro and in vivo protein binding on both conventional and sterically stabilized liposomes were also evaluated. Results suggest that the amount of proteins associated with liposomes might not be the only factor involved in the in vivo clearance of liposomes, as this process may also be influenced by the nature of the bound blood proteins.

Animals↗
PubMed1996

Repression of human immunodeficiency virus type 1 long terminal repeat-driven gene expression by binding of the virus to its primary cellular receptor, the CD4 molecule.

We have previously postulated that the binding of the human immunodeficiency virus type 1 (HIV-1) to cell surface CD4 induces signal transduction pathways that down-modulate production of progeny virions in acutely infected T cells (M. Tremblay, S. Meloche, S. Gratton, M. A. Wainberg, and R.-P. Sékaly, EMBO J. 13:774-783, 1994). To evaluate the possibility that CD4 cross-linking might indeed affect viral gene expression, we have introduced a molecular construct made of the luciferase reporter gene placed under the control of the regulatory elements of HIV-1 in several CD4-positive T-cell lines. We found that cross-linking of CD4 with defective HIV-1 particles and heat-inactivated viruses inhibits long terminal repeat-dependent luciferase expression. Experiments revealed that the gp120-CD4 interaction was necessary to repress HIV-1 long terminal repeat-dependent luciferase activity. The cytoplasmic domain of CD4 was also found to be required for this effect to occur. The virus-mediated signal transduction was shown to be mediated via p56lck-dependent and -independent pathways. These results indicate that the earliest event in the HIV-1 replicative cycle, namely, the binding of the virus to its cellular receptor, can lead to signal transduction culminating in down-modulation of viral gene expression. Thus we propose that defective viruses could regulate the pathogenesis of HIV disease as they constitute the vast majority of circulating HIV-1 particles.

CD4 Antigens↗
PubMed1996

Plasma concentration of apolipoprotein E in intermediate-sized remnant-like lipoproteins in normolipidemic and hyperlipidemic subjects.

Triglyceride-rich lipoprotein (TRL) remnants have been strongly implicated in the pathogenesis of atherosclerosis. To further investigate plasma remnant lipoprotein metabolism, we have determined the plasma concentration of apolipoprotein (apo) E (by polyclonal enzyme-linked immunoassay) in remnant-like lipoproteins, isolated by automated gel filtration chromatography as a fraction intermediate in size between VLDL and HDL. In normolipidemic subjects (n = 12), 1.2 +/- 0.11 mg/dL (33 +/- 2%, mean +/- SE) of total plasma apoE was associated with this fraction (termed ISL apoE). In hypercholesterolemic (type IIa, n = 12), hypertriglyceridemic (type IV, n = 12), and mixed hyperlipidemic (type IIb, n = 12) subjects, mean ISL apoE concentrations were 2.1 +/- 0.2, 2.5 +/- 0.2, and 3.8 +/- 0.4 mg/dL, respectively (P < .001 versus normal values) (45 +/- 2%, 32 +/- 2%, and 44 +/- 2% of total). ISL apoE was 8.7 +/- 1.4 mg/dL (42 +/- 3%) in type III dyslipidemic subjects (apoE2/2, n = 8). ISL apoE was positively correlated with plasma triglyceride (r = .41, P < .01), and at any given level of plasma triglyceride, subjects with an apoE2/2 or apoE3/2 phenotype tended to have a higher concentration of ISL apoE (P < .01) than apoE3/3 or E4/3 individuals. ISL apoE was also correlated (P < .001) with total plasma cholesterol (r = .66), TRL cholesterol (r = .49), TRL apoE (r = .47), LDL apoB (r = .42), and LDL+HDL triglyceride (r = .74). These results suggest that (1) a significant proportion of plasma apoE resides within an intermediate-sized remnant-like lipoprotein fraction in both normolipidemic and hyperlipidemic subjects; (2) plasma remnant lipoprotein accumulation is associated with an elevation in ISL apoE concentration; and (3) ISL apoE concentration is significantly correlated with various proatherogenic lipid parameters and may itself be a potentially important atherogenic index.

Adult↗
PubMed1996

Ribavirin potentiates the efficacy and toxicity of 2',3'- dideoxyinosine in the murine acquired immunodeficiency syndrome model.

The efficacy and toxicity of ribavirin (25 or 125 mg/kg/day), 2',3'-dideoxyinosine (ddI) (200 mg/kg/day) and a combination of both drugs at these doses given for 6 weeks were investigated in the murine acquired immunodeficiency syndrome model. Our results showed a significant protection against splenomegaly, lymphadenopathy and hypergammaglobulinemia in mice treated with ribavirin at 25 mg/kg/day alone or in combination with ddI at 200 mg/kg/day. A good synergistic effect was observed with the drug combination, whereas ddI alone (200 mg/kg/day) did not give any protection. Ribavirin/ddI combination protected against the loss of CD8 T cells in spleen and restored the capacity of splenocytes to proliferate after activation with a mitogenic agent. Moreover, the drug combination resulted in a protection of the spleen and cervical lymph node architectures and a regression of germinal centers. Hematotoxicity appeared at a dose of 125 mg/kg of ribavirin alone and increased when used concomitantly with ddI. In conclusion, ribavirin and ddI at low doses are synergistic and effective in the murine acquired immunodeficiency disease model, but at high doses they are toxic.

Animals↗
PubMed1996

Genetic analysis of genealogies in mentally retarded autistic probands from Saguenay Lac-Saint-Jean (Quebec, Canada).

Autism is a heterogeneous disorder for which we have evidence of both genetic and environmental determination. The genealogies of 16 autistic probands born in Saguenay Lac-Saint Jean were reconstructed and compared to those of 48 matched control individuals distributed in three different groups. The mean inbreeding and kinship coefficients were calculated. Both coefficients were not found to be increased in the autistic group compared to the control groups. These findings support the conclusions reached by Jorde et al. (1990) which indicated that a single gene was unlikely to account for most cases of autism.

Adolescent↗
PubMed1995

Increased granzyme B mRNA after alloincompatible myoblast transplantation.

Normal C57BL/10SnJ myoblasts were transplanted into the tibialis anterior of C57BL/10SnJ, C57BL/ScSn mdx, or BALB/c mice. These transplantations allowed us to investigate the immune response not only against MHC but also against dystrophin introduced in the dystrophic muscles by such transplantations. Recently, our group reported following myoblast transplantations cellular infiltration of the host muscle by class II MHC cells, macrophages, and lymphocytes expressing CD4 or CD8 and IL-2 receptors. In the present study, activation of these infiltrating lymphocytes was investigated by measuring the expression of granzyme B mRNA. We used reverse-transcriptase polymerase chain reaction to detect granzyme B mRNA at various intervals after myoblast transplantations. To standardize the results, the mRNA were reverse transcribed using an oligo (dt) so that beta-actin mRNA could also be amplified from the same cDNA preparation. Granzyme B mRNA was increased for at least 3 weeks after MHC alloincompatible grafts. The absence of increased granzyme B expression after allocompatible transplantation in mdx mice suggests that dystrophin is not sufficiently immunogenic to induce short term acute rejection. These results indicate that lymphocytes infiltrated in muscles injected with histoincompatible myoblasts are activated and sustain the requirement for an adequate immunosuppression after such transplantations.

Animals↗
PubMed1995

Effect of 6-OHDA lesions on striatal mRNA levels encoding for glutamate receptor subunits.

Levels of mRNAs encoding for subunits of glutamate receptors were measured by in situ hybridization in the rat striatum after unilateral injections of 6-hydroxydopamine in the substantia nigra. When compared with the contralateral striatum, levels of NMDAR1, GluR1 and GluR2 mRNAs were significantly higher in the dopamine-deafferented striatum. Comparison with saline-injected rats showed that the NMDAR1 and the GluR1 mRNA labelling was increased in the striatum ipsilateral to the lesion. In contrast, GluR2 mRNA labelling in 6-OHDA-injected rats was not different from that in saline-injected rats. These results support the hypothesis that experimental dopamine deafferentation induces functional changes at the level of glutamatergic synapses in the striatum.

Afferent Pathways↗
PubMed1995

Differential regulation of Hox C6 in the appendages of adult urodeles and anurans.

Morphogenesis and pattern formation are biological processes that rely on the expression of positional determinants to divide the embryo into compartments. Hox genes are among the selector genes that direct the mechanism of positional information. Here we report the molecular structure and pattern of expression of a new Hox C6 transcript in the adult newt. Molecular analysis showed that the gene transcribes a long primary transcript in both limb and tail regeneration territories and subsequently uses maturation events to produce two RNAs that share the same DNA binding domain and differ in their 5' extremity. Both RNAs were found in the limb and showed a proximal-distal gradient of expression. The tail sample showed accumulation of only one Hox C6 transcript. These results suggest that both transcriptional and post-transcriptional regulations are involved in the appendage-specific expression of Hox C6 in the adult newt. Finally, the adult frog, which has lost its regeneration capacity, also post-transcriptionally regulates the expression of Hox C6 in its appendages.

Amino Acid Sequence↗
PubMed1995

Uptake and binding of liposomal 2',3'-dideoxycytidine by RAW 264.7 cells: a three-step process.

It was recently reported that the sequestration of virus by macrophages in reticuloendothelial system organs, such as lymph nodes, is possibly responsible for the clinical latency of disease in asymptomatic HIV-infected patients. Since macrophages may sequester HIV after phagocytosis, and because phagocytosis is a specialized function of any mammalian macrophage, a mouse-macrophage cell line (RAW 264.7) was used as a macrophage model to evaluate the uptake and binding of 2',3'-dideoxycytidine (ddC) encapsulated in liposomes of an average size of 300 nm containing 350 mumols of ddC per mmol of lipids. Liposomal ddC (L-ddC) was rapidly taken up by macrophages. In contrast, its free form (ddC) accumulated slowly in these cells. The accumulation of ddC from L-ddC into cells seemed to consist of two components: a saturable one, which fitted with the Michaelis-Menten model, and a nonsaturable one, which proceeded linearly in the presence of an excess amount of unlabeled liposomes. Under these conditions, we found an apparent Michaelis-Menten constant (Km) of 40 microM and an initial velocity of 0.12 nmol ddC/mg protein/min for the saturable component and a constant rate of accumulation (KN) of 0.017/min for the nonsaturable component. The inhibition of uptake of ddC from L-ddC in the presence of phagocytosis inhibitors (deoxyglucose plus sodium azide) and nucleoside transport inhibitors (dipyridamole or nitrobenzylthioinosine) also confirmed the existence of several mechanisms in the liposome-mediated accumulation process of ddC into macrophages. Furthermore, studies of efflux of ddC in drug-free medium from cells preloaded with L-ddC or ddC established longer retention of ddC in cells preloaded with L-ddC than with ddC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Quantification of normal dystrophin mRNA following myoblast transplantation in mdx mice.

A mutagenesis RT-PCR method was used to detect normal dystrophin mRNA following the injection of normal myoblasts in mdx mice using two immunosuppressors. A specific sequence of the dystrophin mRNA (257 bp) was amplified by RT-PCR from the muscle total RNA. MaeIII digestion of the amplified products allowed us to distinguish the normal messenger of dystrophin from the dystrophic one and to establish the percentage of normal and of dystrophic (mdx) dystrophin mRNA. Normal dystrophin mRNA was detected using this technique in mdx muscles transplanted with histocompatible normal myoblasts. For this type of transplantation, no significant difference in the percentage of normal dystrophin mRNA was observed between immunosuppressed mice and those not immunosuppressed. No normal dystrophin mRNA was, however, observed in mdx mice following histoincompatible normal myoblast transplantation without immunosuppression. When such transplantations were done in mice immunosuppressed with cyclosporine or FK-506, normal dystrophin mRNA accounted for 31% and 36% of the total dystrophin mRNA, respectively. In fact, one animal immunosuppressed with FK-506 expressed as much as 57% of normal dystrophin mRNA. These results thus show that FK-506 makes it possible to restore dystrophin expression to a level comparable to that observed in DMD carriers that are usually asymptomatic.

Animals↗
PubMed1995

The radiosensitivity of uveal melanoma cells and the cell survival curve.

BACKGROUND: No study of the radiosensitivity of uveal melanoma cells and their survival curve has been published. The purpose of this study was to investigate the sensitivity to different single radiation doses of SP6.5, a human uveal melanoma cell line. METHODS: Cells were irradiated with cobalt-60 at doses from 0 to 1200 cGy. Radiosensitivity was measured by three methods: soft-agar bilayer assay, tritiated thymidine incorporation, and bromodeoxyuridine (BrdU) incorporation. RESULTS: The soft-agar bilayer assay, by assessing the colony-forming units, showed that the D1 value was 470 cGy, the Dq value was 400 cGy, and the n value exceeded 10, thus indicating a broad, shoulder and relative radioresistance. The doubling time as estimated by [3H]thymidine incorporation was unaffected at doses below 600 cGy, another indication of radioresistance. BrdU incorporation revealed no significant increase between 0 and 1000 cGy, indicating that the cell cycle was not interrupted. CONCLUSION: Cell survival, doubling time, and cell phases are parameters of growth kinetics, and the results suggest that SP6.5 is radioresistant and virtually unaffected by single radiation doses lower than 600 cGy. Our data parallel published data for cutaneous melanomas.

Aged↗
PubMed1995

Behavioral diagnosis of 30 to 60 year-old men in the Fabreville Heart Health Program.

To develop effective interventions in the Fabreville Heart Health Program, a behavioral diagnosis was conducted on a sample of 1,600 men 30 to 60 years of age residing in the Fabreville district of Laval, Quebec's second most populous city. The response rate of the self-administered postal questionnaire was 73.5%. The results indicate that dietary fat consumption, smoking and a sedentary lifestyle were more prevalent among the younger respondents, particularly those less-educated. The results underline the importance of segmenting the target population so that heart health interventions can respond to the specific needs of each sub-population. Furthermore, the data seem to suggest the need to adapt educational messages to the target lifestyle habits. The results showed that in terms of diet, consumption of meat and dairy products contributed the most to fat intake. Of the 30% who were smokers, a large proportion would be reluctant to stop the habit; 20% smoked 26 cigarettes or more a day, and more than half had already tried once or more to stop. Although 60% of respondents indicated they engaged in physical activity, only 37.0% did it regularly. These results demonstrate the need to clearly target specific behaviours and subgroups in our promotion messages for a healthy heart.

Adult↗
PubMed1995

Lymphoid tissues targeting of liposome-encapsulated 2',3'-dideoxyinosine.

OBJECTIVE: To improve the pharmacokinetics and lymphoid tissues targeting of 2',3'-dideoxyinosine (ddI) by encapsulation in liposomes. METHODS: The pharmacokinetics and tissue distribution of free and liposome-encapsulated ddI were determined in C57BL/6 mice following intravenous and subcutaneous administration of a single bolus dose (3 mg ddI/kg). RESULTS: Intravenous administration of liposome-encapsulated ddI greatly reduced the systemic clearance of the anti-HIV agent. The elimination plasma half-life of ddI incorporated in 112 and 83 nm liposomes was 46 and 14 times higher than that of the free drug, respectively. The tissue distribution profile of liposomal lipids clearly showed that the use of liposomes allows efficient targeting of lymph nodes and macrophage-rich tissues (spleen and liver) for at least 24 h following intravenous injection. In contrast, the accumulation of liposomes in these tissues was much lower following subcutaneous administration. CONCLUSION: Incorporation of ddI in liposomes greatly improved the pharmacokinetics of the anti-HIV agent after intravenous injection. The use of liposomes could represent a convenient approach to targeting lymphoid tissues. Strategies aimed at improving drug retention within liposomes should further enhance and prolong drug delivery to lymphoid organs.

Animals↗