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Biomedical subjects

M Kessler

Publications and source records attributed to M Kessler.

At least 145 records · Page 8Linked to original sources
PubMed1996

Effect of cyclothiazide on binding properties of AMPA-type glutamate receptors: lack of competition between cyclothiazide and GYKI 52466.

The effects of cyclothiazide on the properties of (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors were studied using equilibrium binding techniques and interactions with other compounds known to modulate the receptors. Cyclothiazide caused a reduction in [3H]AMPA binding in assays carried out in the presence of thiocyanate, a chaotropic ion that markedly increases the affinity of AMPA receptors and accelerates their desensitization. In the absence of thiocyanate, however, cyclothiazide had no reliable effect on the binding of [3H]AMPA or on the affinity for this agonist assessed from the displacement of [3H]CNQX. The interaction of cyclothiazide with the receptor appears not to be changed by the presence of thiocyanate. Analysis of the results with a kinetic model of the AMPA receptor suggests that cyclothiazide does not block receptor desensitization by making the desensitized state inaccessible but rather by stabilizing the active state, i.e., by increasing the affinity of the latter to a point where it becomes energetically more favorable than the desensitized state. GYKI 52466, an atypical benzodiazepine that blocks AMPA receptor-gated currents, did not reverse the changes in binding affinity produced by cyclothiazide in the presence of thiocyanate. Physiological experiments conducted in excised patches collected from hippocampal pyramidal cells indicated that thiocyanate does not block access of GYKI 52466 to AMPA receptors. These results point to the conclusion that cyclothiazide acts at a site on the AMPA receptor different from that for GYKI 52466.

Animals↗
PubMed1996

IgA nephropathy in patients over 50 years of age: a multicentre, prospective study.

BACKGROUND: IgA nephropathy (IgAN) is considered as a disease of young men under 30 years of age. Findings on clinical and histological presentation and outcome in older patients have rarely been published. METHODS: In a prospective cohort of IgAN patients, recruited over 3 years, 33 patients over age 50 were compared to 96 patients under age 50, according to clinical and histological findings. Actuarial renal survival rate was studied after a mean post-biopsy follow-up of 41 months. RESULTS: Both groups of patients were comparable at baseline for frequency of proteinuria, microscopic haematuria and gross haematuria, but older patients had a significantly higher incidence of hypertension (65 vs 24%, P<0.01). Time between onset and diagnosis of IgAN was similar in both groups. Proteinuria/day, systolic blood pressure, and serum IgA levels were significantly higher, and Ccr was significantly lower in older patients at the time renal biopsy was performed, but serum creatinine and albumin were not. No difference was observed between the two groups for the presence of glomerular or tubulointerstitial lesions. Only endarteritis was significantly more common in older patients (75 vs 34%, P<0.01). End-stage renal failure (ESRF) was confirmed in five patients over 50 and 17 under 50. Renal actuarial survival curves did not show any significant difference between the two groups, even though the six patients who died were classified as ESRF. CONCLUSIONS: When the histological diagnosis of IgAN was established, factors that carry a poor prognosis, i.e. proteinuria, high blood pressure, and decreased Ccr were more commonly present in patients over 50 than under 50. However, after the completion of a relatively short follow-up period, renal survival was identical in the two study groups. Prolonged follow-up is necessary to confirm this trend.

Adolescent↗
PubMed1996

Measurement of hydrostatic intraperitoneal pressure: a necessary routine test in peritoneal dialysis.

This paper summarizes our clinical studies on hydrostatic intraperitoneal pressure (IPP), showing the interest of this measurement in routine clinical practice. IPP can easily be measured routinely be a simple and safe method: the measure of the column of dialysate in the peritoneal dialysis (PD) line before drainage, with point 0 located on the midaxillary line. The normal value is 12 +/- 2 cm of water (cm H2O) with an intraperitoneal volume (IPV) of 2 L, with linear increases of 2.2 cm H2O for each additional liter. IPP must be measured to estimate the tolerance of IPV: the maximal permissible IPV is reached for an IPP of 18 cm H2O, squaring with a decrease of 20% in vital capacity and sometimes arising before clinical symptomatology. However, IPP measured at rest could not predict PD mechanical complications (hernias, dialysis leakages, hemorrhoids, etc.), which are more dependent on parietal previous history or predisposition. IPP is significantly higher during the first three days after peritoneal catheter implantation (17 +/- 3 cm H2O) than during the 12 following days (10 +/- 4 cm H2O). It is recommended to postpone the start of PD until after catheter implantation, and patients should remain supine for the first three days. On the other hand, IPP strongly reduces the overall ultrafiltration (UF) volume: an increase of 1 cm H2O in IPP caused a decrease of 70 mL in global UF after two hours. Therefore, IPP should be measured in diagnosis of losses of UF. However, UF loss during peritonitis is not due to an increase of IPP.

Ascitic Fluid↗
PubMed1996

Slow cluster formation of purified human or rhesus T cells requires protein kinase C and LFA-1.

Homotropic T cell adhesion, as generally studied, consists of a rapid, transient binding process that is measured over a 15-120 min. period. Here we report a slow type of adhesion process occurring with human or rhesus T cells, purified from peripheral blood, that manifests itself by the formation of rounded, multi-layer clusters which may contain hundreds of cells. The maximal number and size of the clusters peak 1-2 days after the addition of phorbol ester, an absolute requirement. The number of clusters formed is proportional to phorbol ester concentration up to 1.25 ng/mL. Phorbol esters such as phorbol myristate acetate (PMA), phorbol dibutyrate (PDB), and 7-octylindolactam (OIL) induced optimal cluster formation at 1-13 ng/mL, levels slightly higher than that required to induce mitogenesis of purified T cells. Phorbol itself and the alpha-form of the ester were inactive. Both cluster formation and mitogenesis (stimulated by Con A or anti-CD3) are completely inhibited by staurosporin at 12.5 ng/mL. Even at 2.5 ng/mL, 74% of cluster formation was inhibited, which strongly implies a crucial role for protein kinase C. In the presence of accessory cells, T cell clusters were suppressed. Monoclonal Ab such as anti-CD3, mouse anti-CD3 followed by anti-mouse IgG, anti-CD4, anti-CD4A, anti-CD2, anti-CD8, and anti-CD45 did not induce cluster formation. None were inhibitory or stimulatory in the presence of PMA, except for anti-CD3 which enhanced cluster formation by 26%. However, anti-LFA-1 beta-chain (mouse monoclonal) completely blocked cluster formation over the range studied (63-1000 ng/mL) for both human and rhesus cells; rat anti-LFA-1 only blocked human cell adhesion. Anti LFA-1 only partially inhibited T cell mitogenesis. These results show that slow cluster formation shares the LFA-1 and phorbol ester requirements of the rapid adhesion of T cells requiring LFA-1 and ICAM-1. However, cluster occurs at a very low phorbol ester concentration, appears more sensitive to staurosporin inhibition, and is not stimulated via the TCR receptor like the rapid adhesion process. We hypothesize that certain neuronal processes, induced by phorbol ester, and which also show a similar protein kinase C activation time course, may share mechanisms in common with cluster formation.

Animals↗
PubMed1996

Effects of a memory-enhancing drug on DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor currents and synaptic transmission in hippocampus.

The benzoylpiperidine drug BDP-12 (1-(quinoxalin-6-ylcarbonyl)piperidine) enhances the encoding of transient and stable forms of memory by rats. Results reported here show that the drug increases fast, excitatory (glutamatergic) synaptic responses in hippocampal slices by about 50% with an EC50 of 170 microM. Analyses with polysynaptic responses indicated that the drug has a facilitatory action at concentrations as low as 12.5 microM. BDP-12 at 1 mM did not change the resting membrane potential, input resistance or spiking threshold and it did not alter monosynaptic potentials mediated by gamma-aminobutyric acid (GABA) receptors; it did, however, enhance disynaptic inhibitory responses. In membrane patches excised from hippocampal neurons, BDP-12 at moderate concentrations (50 microM) increased the steady-state currents mediated by DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and slowed the rate at which the receptors desensitize, with a much larger effect on the former; the drug delayed the closing of the AMPA receptor channel after 1-msec agonist pulses. BDP-12 had no detectable effect on [3H]AMPA binding affinity. A related and more potent analog produced a different pattern of results in that it had about equal effects on steady-state currents and desensitization rates and significantly increased binding to AMPA receptors. These results indicate that the benzoylpiperidine family of modulators has functionally distinct subclasses. The findings also establish that BDP-12: 1) enhances synaptic responses in the same concentration range at which it alters AMPA receptor kinetics, 2) has a lower apparent threshold for effects on complex network operations than on monosynaptic transmission, 3) does not directly influence inhibitory responses and 4) is likely to modulate AMPA receptors on interneurons as well as on pyramidal neurons.

Animals↗
PubMed1996

Factors predisposing to post-renal transplant erythrocytosis. A prospective matched-pair control study.

We conducted a prospective study on 81 consecutive patients who had a kidney transplant with graft function for over 3 months to evaluate the prevalence of erythrocytosis following renal transplantation (PTE) and its potential risk factors. True PTE was defined as a RBC mass > 120% of the theoretical value allowing for sex, weight and height. 18 patients (22.2%) developed PTE (RBC mass = 157 +/- 21%) with no evidence of polycythemia vera (PV), or secondary polycythemia due to reduced arterial oxygen, kidney or hepatic tumors. PTE was more common in males (p = 0.041) and less common in patients treated with recombinant erythropoietin (rHEPO) prior to transplantation. 18 non-polycythemic patients (Hb 12.6 +/- 1.3 g/dl) matched for sex, age and renal function were used as case controls. Fewer PTE patients were transfused post-transplantation (p = 0.026). At the time of diagnosis, mean serum EPO was normal and similar to that of controls. PTE patients had lower serum ferritin (p = 0.005) and more commonly received iron supplementation when PTE occurred (p = 0.003). Other clinical factors did not differ significantly between the two groups. Two patients had a thrombotic event, 6 recovered spontaneously and 11 were successfully treated with angiotensin-converting enzyme inhibitors (ACEI). The normalization of Hb, hematocrit and RBC mass in ACEI treated patients was accompanied by a decline in serum EPO (p = 0.008). We conclude that true erythrocytosis is prevalent in cyclosporine-treated renal transplant patients. PTE seems to be an idiopathic erythrocytosis. Pretransplant rHEPO treatment may limit PTE by blunting the increased sensitivity of erythroid precursors to EPO and iron supplementation, which stimulates the development of PTE. ACEI treatment is effective and safe.

Adult↗
PubMed1996

Prevalence and epidemiology of hepatitis C infection in patients on peritoneal dialysis in France. French PD centers.

We performed a cross-sectional study to establish the hepatitis C virus (HCV) serologic status for all French patients undergoing peritoneal dialysis (PD) on January 1, 1995. We listed a total of 1508 patients, and the exhaustiveness rate was about of 75% of the whole French PD population treated at this date. Only 47 of the 1508 patients were anti-HCV positive (HCV+): the global HCV prevalence was 3.12%. HCV+ patients were treated by PD for a longer time than HCV-patients (4 +/- 4 vs 2 +/- 2 years; p < 0.001); 89% of the HCV+ patients received blood transfusions; 60% had been previously treated by hemodialysis, and 26% previously received a kidney transplantation. In 49% of the HCV+ patients, HCV antibodies were discovered before the start of the peritoneal dialysis program, and a seroconversion was observed in only 4 (0.27%) of them during the PD treatment. All these patients received blood transfusion. In patients without past history of hemodialysis or transplantation (exclusively treated by PD), HCV prevalence was 1.5%, not far off that of the general population. Peritoneal dialysis seems not to be an additional risk factor for hepatitis C infection in France.

Blood Transfusion↗
PubMed1996

[Effects of human interferons and 60cobalt radiation on canine and feline tumour cells-preclinical studies].

This study examined the effects of recombinant human interferons (rHuIFN) alpha 2a, alpha 2b and gamma on canine and feline tumour-cell proliferation and radiosensitivity. Sensitivity of the cell lines to radiation and rHuIFN varied according to the histologic origin of the cells. In radiation experiments, one fraction of 400 cGy produced survival rates of between 76 and 25%. Sensitivity to IFN was higher in cell lines derived from round cell tumours compared to those derived from solid tumors. At doses of 100 and 1000 U/ml IFN alpha and IFN gamma, survival rates of between 70 and 80% were observed. In combined treatment experiments, increase in IFN or radiation dose produced higher cell kills. Increasing the number of fractions had the most pronounced effect. Even small doses of human interferons can have significant effects on animal tumour cells in vitro.

Adenocarcinoma↗
PubMed1996

Phase I trial of inhaled natural interleukin 2 for treatment of pulmonary malignancy: toxicity, pharmacokinetics, and biological effects.

Safety, local and systemic immunomodulation, and tumor response to treatment with aerosolized natural interleukin 2 (nIL-2) applied five times a day were studied in a Phase I trial in 16 patients with pulmonary malignancies refractory to conventional therapy. The toxicity of inhaled nIL-2 was different from that observed after systemic administration. Reversible airway irritation causing a nonproductive cough represented the dose-limiting toxicity. Mild to moderate reduction of the vital capacity and forced expiratory volume (FEV1) with minor effects on relative FEV1, peak expiratory flow, airway resistance, and PaO2 was experienced by individual patients. In 14 patients suffering from pulmonary metastases due to renal cell cancer, one durable complete response, one partial response, and one mixed response were observed. Inhalation of nIL-2 aerosol resulted in a dose-dependent expansion of pulmonary immunocompetent cells in bronchoalveolar lavage fluid. Posttreatment bronchoalveolar lavage showed an activated lymphocyte phenotype with increased HLA-DR expression. The only systemic biological effect detectable in peripheral blood was a marked increase of soluble interleukin 2 receptor serum levels. We conclude that treatment with aerosolized nIL-2 is an effective means for site-specific immunomodulation and deserves further investigation for the treatment of malignant and inflammatory lung disease.

Administration, Inhalation↗