PubMed Health⌕ Search

Biomedical subjects

M Mestre

Publications and source records attributed to M Mestre.

At least 19 recordsLinked to original sources
PubMed2001

Lymphocyte populations in Parkinson's disease and in rat models of parkinsonism.

To assess the involvement of the immune system in Parkinson's disease we studied the phenotype of circulating lymphocytes in 30 untreated and 34 treated patients. We found a numeric decrease in helper T cells (higher in CD4(+)CD45RA(+) than in CD4(+)CD29(+)) and B cells, and a rise in activated, CD4(+)CD25(+) lymphocytes that was correlated with lymphocyte depletion. All these alterations were independent of levodopa treatment. In addition, we performed striatal dopamine depletion in rats with either MPP(+) or 6-OHDA, showing that MPP(+) but not 6-OHDA can increase CD4(+)CD25(+) lymphocytes. Thus, mechanisms other than dopamine deficit may explain the immune activation in Parkinson's disease.

Aged↗
PubMed2001

Heart and liver xenotransplantation under low-dose tacrolimus: graft survival after withdrawal of immunosuppression.

BACKGROUND: The hamster-to-rat xenotransplantation model is a useful model to investigate the features of extended host response to long-surviving xenografts. Early xenoantibody responses are T-cell independent and resistant to tacrolimus. Treatment with the combination of mofetil mycophenolate plus FK506 avoids acute xenograft rejection completely, but after withdrawal of immunosuppression hamster grafts are rejected by a process called late xenograft rejection (LXR). METHODS: Hamster hearts and livers were transplanted into Lewis rats. Grafted rats were treated with mofetil mycophenolate (25 mg/kg/day) for 8 days and FK506 (0.2 mg/kg/day) for 31 days. Serum IgM and IgG levels were determined by flow cytometry and interferon-gamma levels by ELISA. IgM, IgG, and C3 deposits were measured in tissue by immunofluorescence, and leukocyte infiltration was measured by immunoperoxidase staining. Results. Survival of heart and liver xenografts in the rats was 48+/-4 days and 63+/-8 days, respectively. After cessation of all immunosuppression, hearts were rejected in 18+/-4 days and livers in 33+/-8 days. Production sequences of xenoantibodies in the two organs differed substantially, especially 7 days after transplantation and at the moment of rejection. Quantification of interferon-gamma levels indicated that there were no significant changes after transplantation. Histological and immunohistochemical studies showed signs of humoral mechanism of LXR in rats undergoing heart transplantation and cellular mechanism of LXR in those that received a liver transplant. Conclusions. These observations suggest that rejection in the hamster-to-rat heart xenotransplantation model is mediated by a T cell-independent B-cell response to which a T cell-dependent B-cell response is added in LXR. In the liver xenotransplantation model, our hypothesis is that LXR is mediated by a mixed cell mechanism, involving lymphocytes CD4+ CD45RC+, macrophages, and cytotoxic T lymphocytes. In summary, we have demonstrated and compared the peculiar features of LXR in two different organs.

Animals↗
PubMed2000

Predictors of atopy in HIV-infected patients.

BACKGROUND: Some studies have reported an increase of atopy in HIV-infected (HIV+) patients, but the cause still remains unclear. OBJECTIVE: To determine the prevalence of atopy in HIV+ patients and to investigate its predictors. METHODS: Seventy-four HIV+ hospitalized patients (46 of them with AIDS) were studied prospectively for the presence of atopy, based on immediate hypersensitivity to common allergens by prick test. Serum immunoglobulins, specific IgE, lymphocyte subsets, and the expression of low affinity IgE receptor (CD23) on B cells were determined. RESULTS: Thirty-one percent of patients presented IgE values greater than 150 ku/L (39% of patients without AIDS and 26% of AIDS patients; P = .23) and 47% showed an increase (> or = 2%) in the percentage of CD23+ B cells. Non-AIDS patients had higher IgE values than AIDS patients (346 +/- 605 versus 175 +/- 276; P = .16). Atopy prevalence was higher in non-AIDS than in AIDS patients (28% versus 11%; P = .06). Specific IgE agreed with positive prick test in 58% of cases. Multivariate analysis showed that a personal history suggestive of allergic disease and IgE > 150 ku/L were predictors of atopy, while gender, risk group, CD4+ T cells, CD23 expression on B cells, and AIDS were not associated. CONCLUSIONS: HIV+ patients present a higher prevalence of atopy in early stages of HIV infection than general population. Since allergic reactions could accelerate HIV-infection by increasing type 2 cytokines, it is important to evaluate the atopic state in HIV+ patients with IgE > 150 ku/L or with suggestive allergic history in order to prevent it.

Adult↗
PubMed2000

Drugs that prolong QT interval as an unwanted effect: assessing their likelihood of inducing hazardous cardiac dysrhythmias.

Medicinal products that, as an unwanted effect, prolong the QT interval of the electrocardiogram (ECG) can trigger episodes of polymorphic ventricular dysrhythmias, called torsades de pointes, which occasionally culminate in sudden death. The accurate measurement of QT interval requires the adoption of appropriate criteria of recording, measurement and data processing. Traditionally, QT interval is standardised to a reference heart rate of 60 beats/min by using the Bazett algorithm. However, this correction method can bias observed QT intervals in either direction. The ECG reflects cardiac electrical currents generated by ions (Na+, K+ and Ca2+) entering and leaving the cytosol mainly via transmembrane channels. Na+ and Ca2+ carry inward depolarising currents (INa, ICa) whereas K+ carries outward repolarising currents (Ito, IKr, IKS and IK1). Sometimes, a prolonged QT interval is a desired drug effect but, more commonly it is not, and reflects abnormalities in cardiac repolarisation heralding torsades de pointes. Furthermore, the potential torsadogenic activity of drugs is favoured by concurrent cardiac risk factors (old age, female gender, bradycardia, electrolyte imbalances, cardiac diseases etc.) which reduce cardiac repolarisation reserve. The evaluation of the cardiac safety of drug candidates can be started by determining their potency as IKr blockers in cloned Human Ether-a-go-go Related Gene (HERG) channels expressed in mammalian cells. Compounds passing successfully this test (desirable cardiac safety index > 30, calculated as ratio of IC50 against IKr over ED50 determined in an efficacy test) should be further investigated in other relevant human cardiac ion currents, in in vitro animal heart preparations and finally in in vivo pharmacodynamic models. The decision as to whether the potential benefit of a new drug outweighs the cardiac risk inherent in its therapeutic use should be made in the light of the condition that it is expected to treat and with reference to alternative drug therapies. If a drug represents a unique therapeutic advance, non-clinical and clinical signals of unsatisfactory cardiac safety may not constitute sufficient grounds to abandon its development. However, if the drug offers only marginal benefits over existing therapies, decisions concerning its possible development should be taken by corporate policy makers.

Animals↗
PubMed1999

Preclinical in vitro cardiac electrophysiology: a method of predicting arrhythmogenic potential of antihistamines in humans?

The cardiac action potential results from a dynamic balance between inward depolarising Na+ and Ca2+ currents and outward K+ repolarising currents. During a cardiac cycle, the resultant of repolarisation phase from all ventricular cells is represented by the QT interval of the surface ECG. Congenital long QT syndrome (LQTS) is characterised by polymorphic ventricular tachycardia sometimes with twisting QRS morphology (torsade de pointes) which, although usually self-limiting, can result in sudden cardiac death. Acquired LQTS can be induced by a variety of drugs, including some nonsedative histamine H1 receptor antagonists (astemizole, terfenadine). The Committee for Proprietary Medicinal Products of the European Union has recently proposed studying the action potential in in vitro heart preparations as a preclinical test for predicting the propensity of noncardiovascular drugs to induce malignant QT prolongation in humans. The effects of several histamine H1 receptor antagonists on the electrically evoked action potential have been evaluated in rabbit Purkinje fibres. In this preparation, astemizole (0.3 to 10 micromol/L) prolongs the duration of the action potential measured at the level where repolarisation is 90% complete (APD90). This effect is dependent on drug concentration, incubation time, pacing frequency and K+ or Mg2+ concentration. Astemizole also markedly depresses the rate of rise of the action potential (Vmax). Terfenadine showed qualitatively similar, but quantitatively smaller, effects in this model. The histamine H1 receptor antagonists cetirizine, ebastine, carebastine, loratadine and fexofenadine do not significantly affect APD90 at 1 micromol/L, but cetirizine and carebastine prolong it slightly at 10 micromol/L. In conclusion, in rabbit Purkinje fibres, astemizole and terfenadine produce adverse electrophysiological effects at concentrations which may be achieved in the human myocardium in certain clinical situations. APD90 lengthening induced by carebastine and cetirizine is minor and occurs at concentrations that are very unlikely to be encountered clinically, since these drugs, in contrast to astemizole and terfenadine, do not accumulate in the myocardium. Direct extrapolation of preclinical results to humans requires great caution, since malignant QT prolongations by terfenadine and astemizole are extremely rare clinical events. However, since prolongation of the QT interval often precedes the development of torsade de pointes, any significant delay in cardiac repolarisation produced by noncardiovascular drugs in preclinical, and particularly in clinical, studies should, in general, be considered to indicate a potential cardiac risk in humans. Its significance should subsequently be evaluated in appropriate studies in patients with conditions known to predispose to arrhythmias.

Animals↗
PubMed1998

Peripheral blood lymphoid subsets and long-term clinical course of kidney recipients: a longitudinal study.

A longitudinal study of peripheral blood lymphocyte subsets was performed in 23 renal allograft recipients treated with prophylactic antilymphocyte antibodies, CsA, and steroids. At day 0 samples were obtained before transplantation (Tx), and afterwards at months +1, +3, +6, +9, +12, +24, +36, and +48. In all patients, after the depletion of lymphoid subsets during antilymphocyte antibody treatment, CD8+ lymphocytes recovered and reached higher values than those observed prior to Tx. This was mainly due to an increase in CD8+CD45RA+ lymphocytes; in contrast, the levels of "memory" CD4+ T cells and the CD4+CD62L+ subset remained low during all the follow-up period. In patients with preserved graft function (n=14) (with creatinine levels below 200 micromol/mL), the initial, relative decrease in CD4+ T cells was never reversed and the recovery of CD8+ lymphocytes started early. They also presented a peak of HLA-DR antigen expression at 1 month, not observed in those patients displaying a suboptimal graft function. At 1 month, the patients with suboptimal graft function (n=9) (with creatinine levels above 200 micromol/mL) showed higher number of CD4+ T cells, delayed recovery of CD8+ lymphocytes, and higher percentage of activated lymphocytes from month +3 on than well-functioning kidney recipients. Both CD8+ lymphocytes and HLA-DR+ T cells, found at month + 1 post-Tx, were negatively correlated with the concentration of creatinine along the follow-up. Interestingly, the mean percentage of CD4+CD25+ T cells found 36 and 48 months after Tx were positively correlated with creatinine concentration at these times. These findings indicate that variations in the distribution of lymphocyte subsets are related with a long-term graft outcome. Within the first month after Tx, a rapid recovery of CD8+ lymphocytes, but not of CD4+ T cells, and a peak of HLA-DR expression, are associated with a good graft function. In contrast, long-term expression of activation markers is related with renal dysfunction.

Adult↗
PubMed1998

Distinct modulation by interferon-gamma (IFN-gamma) of CD23 expression on B and T lymphocytes of atopic subjects.

The low-affinity IgE receptor (FcepsilonRII/CD23) plays a role in IgE production. Cytokines participating in IgE synthesis also modulate CD23 expression on lymphocytes, but whether this modulation is different in atopic subjects remains unclear. We studied CD23 expression on B and T lymphocytes in 10 asthmatic patients with Dermatophagoides pteronyssinus hypersensitivity and 10 healthy non-atopic subjects. Studies were performed by flow cytometry, in phytohaemagglutinin (PHA) or IL-4-stimulated mononuclear cell cultures, alone or in the presence of IFN-gamma. Soluble CD23 (sCD23) released in the culture supernatants was measured by enzyme-linked immunoassay. Both PHA and IL-4 induced the expression of CD23 on lymphocytes of atopic and non-atopic subjects. Whereas PHA increased both the percentage and mean fluorescence intensity of CD23+ B and T cells, IL-4 alone did not increase the percentage of CD23+ T cells. The effects of IFN-gamma were different in both groups, since it was able to reduce the percentage of PHA-stimulated CD23+ T cells only in non-atopic individuals. In non-atopic subjects more than atopic, levels of sCD23 were increased in the supernatants of PHA and IL-4 cultures. These results show that the modulation of CD23 expression is different on B and T cells, and that IFN-gamma acts differently in atopic and non-atopic individuals.

Allergens↗
PubMed1996

Longitudinal study of the frequency of cytotoxic T cell precursors in kidney allograft recipients.

Clonal deletion or inactivation of donor-specific alloreactive cells are important mechanisms that are believed to account for acquired immune tolerance in allograft recipients. Serial assessment of precursor cytotoxic T lymphocyte frequencies (CTLpf) by limiting dilution analysis (LDA) provides information at the clonal level on changes in the alloimmune response of graft recipients. We performed a longitudinal study of 15 cadaveric kidney recipients before and every 3 months throughout the first year after transplantation (Tx). Pre-Tx values of donor CTLpf showed high interindividual variability without a predictive value for the clinical outcome. All patients with well functioning kidneys had decreased CDLpf at 3 months post-Tx in comparison with pre-Tx values. This decrease was donor-specific in four patients and was permanent in two cases throughout the study. Most patients presented decreased anti-donor CTLpf values from 6 to 9 months, whereas a partial recovery of donor CTLpf was observed in three patients. Reversible acute rejection was diagnosed in three patients, and it was associated with a marked increase in anti-donor CTLpf, returning to pre-Tx values by 9 months post-Tx. In addition, one patient with chronic rejection displayed a transient increase in CDLpf 6 months after Tx. The results of this sequential study indicate the establishment of a state of either hyporesponsiveness or functional clonal inactivation, transient or permanent, which could facilitate allograft acceptance.

Adult↗
PubMed1995

T cell subsets in multiple sclerosis: a serial study.

The relevance of abnormalities in the distribution of peripheral blood T lymphocyte subsets to the clinical manifestations of multiple sclerosis is not firmly established. A clinical and immunological follow-up of relapsing-remitting multiple sclerosis patients was performed in order to study the relationship of immune changes with the clinical course of the disease. Twenty patients were monitored monthly during a mean time of nine months for peripheral blood lymphocyte subsets (CD3, CD4, CD8, CD19), including the immunoregulatory subsets CD4CD29 (helper-inducer), and CD4CD25) by flow cytometry. A total of 14 untreated relapses was included. The most significant observations were a decrease in T suppressor-inducer CD4+ CD45RA+ subset during clinical relapses (P = 0.028) that was also detectable one month before (P = 0.020) and the lack of changes in CD4+ CD29+ and CD8+ T cells. In addition, variations in the percentage of CD4+ CD25+ activated T helper cells were not associated with clinical exacerbations. These results indicate the existence of a temporal association of immune changes in peripheral blood, but not activation, with the clinical manifestations of multiple sclerosis.

Adolescent↗
PubMed1994

[Positive inotropic and lusitropic effect of RP 62719, a new class III antiarrhythmia agent].

Antiarrhythmic drugs, especially the Class I family, exert a negative inotropic effect on the myocardium which is particularly undesirable in patients with depressed left ventricular function. Therefore, research has been directed to the development of new, more specific molecules of the Class III family. The authors studies the mechanical effects of RP 62719 on guinea pig left ventricular papillary muscle. This new molecule is a pure Class III antiarrhythmic, known to lengthen the duration of the cardiac action potential by selectively blocking the potassium current iK1 (inward rectifier K+ current). The mechanical parameters were determined during the phases of contraction and relaxation under isotonic and isometric conditions. At 0.2 and 2 microM concentrations, RP 62719 improved cardiac contraction under both isotonic and isometric conditions with an increase of about 30% of Vmax (p < 0.001), the maximum unloaded shortening velocity delta 1 (p < 0.001), the peak isometric active force normalized per cross-sectional area [AF/S (p < 0.001)]. At these two concentrations, a positive lusitropic effect (improved relaxation) was demonstrated by an increase in negative peak of derivative per mm2-dF/s and maximum lengthening velocity VR max (p < 0.01). At higher concentrations (20 microM), the inotropic and lusitropic effects were less marked with a bell-shaped form of the dose-effect curve. This study indicates that RP 62719 has moderate but significant positive inotropic and lusitropic effects. These actions could provide significant therapeutic advantages especially in patients cardiac failure.

Animals↗
PubMed1993

Is the sigma 2 receptor in rat brain related to the K+ channel of class III antiarrhythmic drugs?

The sigma 2 receptor subtype was studied in rat cerebral cortex and in C6 glioma cells homogenates using various compounds including class III antiarrhythmic drugs. The characteristics of (+)-[3H]-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-[3H]-3-PPP) binding were assessed in competition experiments with different displacers which revealed the presence of sigma 2 receptors. Various class III antiarrhythmic drugs inhibited (+)-[3H]-3-PPP binding with high affinity and their binding affinity was found to correlate with the potency of these compounds to increase the duration of action potentials measured in Purkinje fibers in electrophysiological studies. Since class III antiarrhythmic drugs are known to interact with voltage-dependent K+ channels, the present results provide evidence that the (+)-[3H]-3-PPP binding sites in rat brain possess the characteristics of K+ channels of class III antiarrhythmic drugs.

Action Potentials↗
PubMed1993

CD23 expression on B-lymphocytes and its modulation by cytokines in allergic patients.

The aim of this study was to assess the expression of CD23 on peripheral blood B-cells, and its in vitro modulation by recombinant human interferon-gamma (IFN-gamma) in phytohaemagglutinin-(PHA) or recombinant human interleukin-4 (IL-4)-stimulated cultures in atopic patients with Dermatophagoides pteronyssinus hypersensitivity and in healthy non-atopic subjects. Atopic patients with asthma not receiving allergen-specific immunotherapy (n = 21) were studied and further compared with a group of atopic subjects with asthma under allergen-specific immunotherapy (n = 21). They were age-(+/- 5 yr) and sex-matched. The results were also compared with those obtained in the non-atopic group (n = 11). CD23 expression on B-lymphocytes and its modulation were analyzed by flow cytometry using conjugated monoclonal antibodies with a double immunofluorescence method. Atopic patients had an increase in the percentage of B-cells expressing CD23 in peripheral blood. Phytohaemagglutinin and IL-4 induced a rise in the percentage of CD23-positive B-cells in both atopic groups and non-atopic subjects. Phytohaemagglutinin provoked an increase in the intensity of CD23 expression on B-cells from stimulated cultures in all groups, while IL-4 only produced a significant increase in atopic patients. The presence of IFN-gamma decreased the CD23 expression on B-cells in PHA-stimulated culture of atopic patients, whereas it caused an increase in CD23 expression in the non-atopic group. Furthermore, the presence of IFN-gamma in IL-4-stimulated cultures induced a decrease in CD23 expression on B-cells in all cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

IgE antibodies against bovine serum albumin in a case of eosinophilic gastroenteritis.

Eosinophilic gastroenteritis is a disease characterized histologically by an eosinophilic infiltration of the gut. The cause of this disease remains unclear, although both food allergy and food intolerance have been implicated in its pathogenesis. We report the case of a 22-year-old man in whom gastrointestinal symptoms first appeared in childhood, with involvement of mucosa and muscularis layers of stomach and bowel. He presented high IgE blood levels, and his prick test was positive to bovine, pig, and lamb sera. Immunoblots from calf, pig, and lamb sera, incubated with the patient's serum and revealed by autoradiography, demonstrated the presence of a 65-kDa protein band that was recognized by IgE antibodies but not by IgG. This band corresponded to bovine serum albumin, while IgE did not show reactivity with human albumin. These data suggest a possible role for IgE-mediated hypersensitivity mechanisms in the pathogenesis of eosinophilic gastroenteritis.

Adult↗