Carvedilol and the kidney

Antihypertensive drugs have differing effects on renal hemodynamics, tubular function, plasma electrolytes, and hormonal responses. Nonselective -blockers without intrinsic sympathomimetic activites, such as propranolol, have been reported to reduce renal blood flow and to cause a modest decrease in glomerular filtration rate. Carvedilol is a new multiple action agent displaying nonselective -blockade without intrinsic sympathicomimetic activity, ₁-adrenoceptor blockade (probably responsible for its vasodilator activity), and possibly also calcium antagonist properties. The presence of these different pharmacodynamic properties results in a different effect on the kidney as compared with, e.g., propranolol. In the dog, intrarenal infusion of carvedilol resulted in a renal vasodilator response with preservation of renal blood flow and without inducing sodium retention; in contrast, propranolol induced a renal vasoconstrictor response and sodium retention in this model. A renal vasodilator response to carvedilol was also reported in spontaneously hypertensive rats (SHR) and in DOCA-salt SHR. In contrast to labetalol, i.v. infusion of hypotensive doses of carvedilol in conscious SHR did not cause sodium retention. Carvedilol was effective in controlling hypertension and preserving renal function in a rat model of progressive hypertensive renal disease. In patients with essential hypertension, carvedilol was reported to reduce renal vascular resistance in the presence of reduced perfusion pressure, allowing for normal renal autoregulation of renal blood flow. Although a small reduction in glomerular filtration rate was seen after acute administration, renal function was preserved during chronic treatment. It is concluded from these studies that renal perfusion and renal function are well maintained during acute and chronic treatment with carvedilol. The compound does not appear to cause sodium retention, and preliminary animal test data suggest the possibility of a renoprotective effect.     

HLA-A,B,C and DR antigen frequencies in acquired immunodeficiency syndrome (AIDS) patients with opportunistic infections

During the past three years, an epidemic of acquired immunodeficiency syndromes (AIDS) involving the presence of specific forms of cancer (notably Kaposi's sarcoma) and infection (e.g., pneumocystis carinii) ordinarily seen only in severely immunosuppressed hosts has occurred among active homosexuals, Haitian immigrants, drug users, and hemophiliacs in large cities in the United States and elsewhere. An as yet unidentified viral agent is presumably the cause of the initial immunodeficiency and host genetic factors may influence the subsequent development of different clinical symptoms in different patients. We have previously reported that the HLA antigens DR5 and DR2 are associated with susceptibility to Kaposi's sarcoma (KS) in different Caucasian subpopulations. We now have also noted that AIDS patients with opportunistic infections have a normal frequency of DR2 and DR5 and a significantly increased frequency of DR3 and that the ultimate clinical expression of AIDS in patients with unexplained lymphadenopathy may depend upon genetic factors associated with these particular DR types.     

Leukocyte migration inhibitory factor (LMIF) profile in primary and secondary immunodeficiency disease.

Lymphocytes from patients with primary and secondary immunodeficiency disease were tested for capacity to produce LMIF after mitogen and antigen stimulation as well as for ability to stimulate and respond in unidirectional MLC-LMIF assay. Different patterns of immune abnormality in vitro were detectable when Con A and Candida albicans antigen were used. In addition, significant abnormalities in LMIF responding and stimulatory capacity were demonstrated in patients with Hodgkin's disease. LMIF production after stimulation with different agents allows for a better characterization of cellular defects in immunodeficiency disease.     

Differential effects of pentoxifylline on the production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) by monocytes and T cells.

Pentoxifylline (PTX) is a methylxanthine compound known to inhibit the production of tumour necrosis factor-alpha (TNF-alpha) by monocytic cells. In this study, we found that PTX differentially regulates the production of TNF-alpha and interleukin-6 (IL-6). Indeed, PTX at high concentrations triggers the production of IL-6 but not of TNF-alpha by peripheral blood mononuclear cells (PBMC). Further experiments indicated that monocytes are responsible for this PTX-induced IL-6 production. When PBMC were stimulated with LPS, PTX was found to inhibit the secretion of TNF-alpha as well as the accumulation of TNF-alpha messenger RNA (mRNA). In contrast, no inhibitory effect was observed on the induction of IL-6. Similar results were obtained when PBMC were stimulated with OKT3 monoclonal antibody (mAb). In addition, the in vivo administration of PTX in transplant patients receiving the first dose of OKT3 allowed to decrease the systemic release of TNF-alpha but not of IL-6. Since monocytes represent a major source of TNF-alpha and IL-6 in these settings, additional experiments were performed in vitro on purified T cells stimulated with the CLB-T3/3, an anti-CD3 mAb which does not require the presence of accessory cells to activate T cells. In this system, PTX was found to inhibit the secretion of both TNF-alpha and IL-6 by T cells. We suggest that cAMP could be involved in these differential effects of PTX on production of TNF-alpha and of IL-6.     

Q fever serology: cutoff determination for microimmunofluorescence.

Q fever, a worldwide zoonosis caused by Coxiella burnetii, lacks clinical specificity and may present as acute or chronic disease. Because of this polymorphism, serological confirmation is necessary to assess the diagnosis. Although microimmunofluorescence is our reference technique, the cutoff titers that are currently used to make a diagnosis of active or chronic Q fever were determined years ago with limited series of patients and sera. We determined the titers of immunoglobulin G (IgG), IgM, and IgA against both phases (I and II) of Coxiella burnetii. Rheumatoid factor was removed before testing IgM and IgA. We report here the various cutoff titers and the kinetics of antibody development from 2,218 first serum samples of patients, among whom 208 suffered from acute Q fever and 53 had chronic Q fever. In active Q fever, we have defined a low cutoff (phase II IgG titer < or = 100) below which the diagnosis cannot be made and would need further confirmation and confirmed a high cutoff (phase II IgG titer > or = 200 and phase II IgM titer > or = 50) over which the diagnosis can be made. For chronic Q fever diagnosis, phase I IgA titers are not contributive despite previous works claiming their usefulness; a phase I IgG titer of > or = 800 is highly predictive (98%) and sensitive (100%). We have also studied the possibility of rejecting or evoking the diagnosis of chronic Q fever by phase II IgG and IgA titers. This method is useful when phase I testing is not available, but the sensitivity remains low (57%).     

Neuropharmacological study of aged MAM-treated rats.

After evaluation of activity in an open field, norepinephrine (NE), serotonin (5HT), 5-hydroxyindolacetic acid (5HIAA), homovanillic acid (HVA), and choline acetyltransferase (CAT) were investigated in cortex of 26-month-old rats poisoned with methylazoxymethanol (MAM) as compared to control rats of the same age. NE and 5HT concentrations showed a marked increase, but levels were normal when expressed as total content, just as in MAM-exposed young adults. Concentrations of 5HIAA were also increased but to a lesser extent than 5 HT. Aged MAM rats did not show any modification of spontaneous activity although hyperactivity is characteristic of young adults exposed to MAM. Together with this behavioral observation, a significant decrease in total HVA content was measured. Because HVA levels seem correlated with activity in MAM-exposed rats, we speculate that the behavioral abnormality recovers in old age. Total CAT activity was also reduced. These results indicate that the neurochemical pattern of young adult MAM-poisoned rats is conserved in aged rats except for some changes in the dopaminergic and cholinergic systems.     

The CCS1 gene from Saccharomyces cerevisiae which is involved in mitochondrial functions is identified as IRA2 an attenuator of RAS1 and RAS2 gene products

Summary The ccs1-1 mutation of Saccharomyces cerevisiae, which has been previously described, is associated with an increase in cytochrome content, in respiration, and in ATP synthesis. In addition, this mutation leads to the same phenotype as cells de-regulated in the cAMP pathway. From a yeast genomic library, we have isolated a DNA fragment in a recombinant plasmid pCD1 which complements the ccs1-1 mutation. Homologous integration of this DNA in the genome occurs at the CCS1 locus. An 11 kb of the DNA insert is necessary for complementation. Sequencing part of the fragment identifies CCS1 as the IRA2 gene. The IRA2 gene is known to encode an attenuator of RAS gene product activity which stimulates the GTPase activity of the RAS proteins. This result underlines the involvement of cAMP-dependent phosphorylation in mitochondrial function. We present the sequence of 1 kb DNA upstream of the putative ATG of the IRA2/CCS1 gene product which is devoid of an ORF and could contain several regulatory sites.     

Review of nocardial infections in France 1987 to 1990

On the basis of the numbers ofNocardia strains referred to the National Reference Center for Mycoses and Antifungal Agents (NRC), Institut Pasteur, Paris, in the period from 1987 to 1990, it was estimated that between 150 and 250 cases of nocardiosis are diagnosed in France each year. A total of 63 clinical isolates were referred to the NRC and identified asNocardia asteroides (66.7 %),Nocardia farcinica (23.8 %),Nocardia brasiliensis (3.2 %),Nocardia otitidiscaviarum (4.8 %) andNocardia carnea (1.5 %).Nocardia asteroides accounted for 71.4 % of pulmonary infections, 80.0 % of central nervous system infections and 80.0 % of systemic infections. Patients infected withNocardia farcinica died in 57.1 % of cases, compared with 17.6 % of patients infected withNocardia asteroides. Corticosteroid therapy represented a significant factor in mortality. Isolates ofNocardia asteroides revealed variable resistance, whereas isolates ofNocardia farcinica were resistant to most antimicrobial agents. Only amoxicillin/clavulanic acid, imipenem, cefoxitin, kanamycin, amikacin, minocycline and vancomycin showed activity against both species. Nocardiosis caused byNocardia farcinica may be a growing problem because of the relatively high incidence in AIDS patients and the resistance of this species to most antimicrobial agents.