What evidence is there for the existence of individual genes with antagonistic pleiotropic effects?

Classical evolutionary theory predicts the existence of genes with antagonistic effects on longevity and various components of early-life fitness. Quantitative genetic studies have provided convincing evidence that such genes exist. However, antagonistic pleiotropic effects have rarely been attributed to individual loci. We examine several classes of longevity-assurance genes: those involved in regulation of the gonad; the insulin-like growth factor pathway; free-radical scavenging; heat shock proteins and apoptosis. We find initial evidence that antagonistic pleiotropic effects are pervasive in each of these classes of genes and in various model systems--although most studies lack explicit studies of fitness components. This is particularly true of human studies. Very little is known about the early-life fitness effects of longevity loci. Given the possible medical importance of such effects we urge their future study.     

Vinyl monomer complexes in copolymerization processes. Studies on the complexes of acrylonitrile and methyl methacrylate with lewis acids

Complexes of acrylonitrile and of methyl methacrylate with various Lewis acids, 1 and 2 , were studied by means of IR, NMR, and UV spectroscopy. The influence of the Lewis acid strength on the induction effect and on the delocalization of π-electrons in the complexed monomer molecule was established. As the relative acidity of the complexing agent is increased, the inductive effect of the nitrile or of the carbonyl group in the complex molecule rises, whereby the electron density on the carbon atom in β-position in the vinyl group diminishes. Complexation of the monomer also results in increased delocalization of π-electrons in the molecule. In the complexes with moderately strong Lewis acids like CH₃AlCl₂ and C₂H₅AlCl₂, delocalization of π-electrons seems to reach its maximum. The methyl methacrylate-C₂H₅AlCl₂ complex was found to give a charge-transfer complex with 1,5-cyclooctadiene. On the basis of the present spectroscopic studies and of earlier studies on copolymerization of acryl monomers with butadiene, the delocalization of π-electrons in the complexed monomer molecule is believed to be one of the major factors controlling the rate of copolymerization.     

T cell subpopulations in myocardial inflammatory infiltrates detected by confocal microscopy: dose dependence in mice treated with cyclophosphamide during acute Trypanosoma cruzi infection

In this article, we have characterized cell subpopulations found in the hearts of mice presenting acute Chagas' disease by immunocytochemistry and subjected to different schedules of an immunosuppressive therapy with cyclophosphamide (CY). In this comparative study, CY treatment with different doses was carried out before or after infection with Trypanosoma cruzi Y strain trypomastigotes, enabling us to discriminate the parasitemic kinetics and inflammatory processes in the heart, 12 d after infection. Animals treated with 200 mg/kg of CY 2 d before infection presented high parasitaemia as well as heavy inflammation and low parasite loads in the heart. Mice treated 5 d after infection with the same dose, developed the same parasitaemic peak but were not able to control it. Their heart did not present inflammation, but a high number of parasites could be seen. Animals treated with five 3 mg/kg doses of CY every other day presented heavy inflammatory reaction and low parasitaemia. In this group, as well as the one treated before infection, immunocytochemistry studies have shown predominance of CD8(+) T cells in the myocardium. On the other hand, mice treated with 200 mg/kg of CY 5 d after infection, presented small amounts of CD4(+) T cells while no CD8(+) could be found. These results have confirmed the dose dependence influence of this drug on the T cell populations in the inflammatory infiltrates as well as the importance of the schedule employed.     

The results of the interference of nitrates and vitamin E in the metabolism in the connective tissue of rat''s liver

We examined 72 female Wistar rats which were divided into 6 groups. The animals were administered sodium nitrate (V), vitamin E or both compounds at the same time. In order to estimate the interference of nitrates in the presence of vitamin E with the metabolism of rat's liver, we determined the composition and the amount of glycosoaminoglycans (GAGs). It was stated that the total amount of GAGs increased in livers of all rats. Basing on all fractions of the examined GAGs it was determined that the most significant differences between individual groups appeared in the amount of heparane sulphate (HS). The results obtained confirmed the fact of the changes taking place in the picture of liver GAGs in the process of ageing of the examined animals. The results obtained, however, allowed to state the normalising influence of vitamin E on the quantitative composition of GAGs of rats which drank nitrates.     

B-1 cells are pivotal for in vivo inflammatory giant cell formation

The mechanisms that govern giant cell (GC) formation in inflammatory, neoplastic and physiologic conditions are far from being understood. Here, we demonstrate that B-1 cells are essential for foreign-body GC formation in the mouse. GCs were analysed on the surface of glass cover slips implanted into the subcutaneous tissue of the animals. It was demonstrated that GCs are almost absent on cover slips implanted into the subcutaneous tissue of BALB/c or CBA/N X-linked immunodeficient mice. As these animals do not have B-1 cells in the peritoneal cavity, they were reconstituted with B-1 cells obtained from cultures of adherent mouse peritoneal cells. Results showed that in B-1-reconstituted animals, the number of GCs on the implant surface surpassed the values obtained with preparations from wild animals. In animals selectively irradiated (pleural and peritoneal cavities) to deplete these cavities of B-1 cells, GCs were also not formed. Enriched suspensions of B-1 cells grown in culture were labelled with [(3)H]-tymidine and injected into the peritoneal cavity of naive mice before implantation of glass cover slips. After 4 days, about 17% of mononuclear cells had their nuclei labelled, and almost 70% of GCs had one or more of their nuclei labelled when analysed by histoautoradiographic technique. A few GCs expressed an immunoglobulin M when analysed by immunostaining and confocal microscopy. Overall, these data demonstrate that B-1 cells are pivotal in the mechanisms of foreign-body GC formation in the mouse.     

Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility

BACKGROUND: Male fertility largely depends on the quality of sperm production, which may be affected by environmental and genetic factors. In this study, we explored a possible role of the polymerase gamma (POLG) gene polymorphism, recently reported to be associated with male infertility in some populations. METHODS: The polymorphic CAG repeat (usually 10 codons long) in the POLG gene was studied in 1298 male subjects: 429 patients with infertility/subfertility, and 869 controls (495 men from the general population with unknown fertility and 374 recent fathers). In all subjects, the POLG polymorphism was assessed in relation to their semen quality, and--in the fertile controls--with biological fecundity measured as waiting time-to-pregnancy (TTP) for the couples. In the patients lacking the common POLG allele, the outcome of the assisted reproductive techniques (ART) for the couples was evaluated. RESULTS: The absence of one (10/ not equal to 10) or both common POLG alleles (not equal to 10/not equal to 10) was more frequent among the subfertile patients than among fertile controls (P=0.021 and P=0.04 respectively). The estimated predictive value for infertility in a man homozygous for the POLG polymorphism was 15.5% (95% CI: 4.8-51%). There was a positive association with sperm concentration: 14.3% of the normospermic subfertile patients were homozygous for the absence of the common POLG allele (not equal to 10/not equal to 10), in comparison with 2.3% of unselected controls (P=0.001) and 0.9% of the fertile men (P=0.0001). No association with sperm motility, morphology and TTP was found. Spermatozoa of the three not equal to 10/not equal to 10 patients treated with IVF retained the ability to penetrate the egg, but the fertilization rate was low. Nine homozygous not equal to 10/ not equal to 10 patients were treated with ICSI, resulting in pregnancy in seven couples. CONCLUSIONS: The POLG gene polymorphism should be considered as a possible contributing factor in patients with unexplained subfertility and normal spermiograms. The oocyte penetration ability of sperm may be partially impaired in the not equal to 10/not equal to 10 patients but most of them can be successfully treated with ICSI.     

Type of isoniazid (INH) acetylation determined in tuberculosis patients treated at the Institute of Tuberculosis and Lung Diseases in Warsaw during the years 1990-1997

The researched has dealt with the type of acetylation in 237 TB patients treated with standard course of chemotherapy with a dose of 300 mg of INH in period 1990-1997 in National Research Institute of Tuberculosis and Lung Disease in Warsaw Blood samples were taken before (time 0) and 1, 3, 6 and 24 h after drug administration. Plasma concentrations of isoniazid were determined with biological methods. Two indies of acetylation rate--I3 and C6 have been used to determine an acetylation type. Majority of the treated patients (68.8%) have shown fast type of INH acetylation. After similar dose of isoniazid different profile of absorption and excretion of the drug and significant differences (p < 0.01) in INH concentrations, acetylation rate and bioavailability between 163 fast and 74 slow acetylators have been observed. In plasma of 38.6% fast acetylators drug concentration 3 h after ingestion of a dose did not achieve the concentration of 1 mcg/ml. In plasma of 29.7% slow acetylators, concentrations of INH 6 h after ingestion were higher than 2 mcg/ml.