Trypanosoma musculi survival in the kidneys of chronically infected mice: kidney form ultrastructure, surface characteristics, and serological interactions

Sucrose is the major carbon source in molasses, the traditional substrate employed in the industrial acetonebutanol-ethanol (ABE) fermentation by solventogenic clostridia. The utilization of sucrose by Clostridium beijerinckii NCIMB 8052 was investigated. Extracts prepared from cultures grown on sucrose (but not xylose or fructose) as the sole carbon source possessed sucrose phosphoenolpyruvate (PEP)-dependent phosphotransferase system (PTS) activity. Extract fractionation and reconstitution experiments revealed that the entire sucrose Enzyme II complex resides within the membrane in this organism. Sucrose-6-phosphate hydrolase and fructokinase activities were also detected in sucrose grown cultures. The fructokinase activity, which is required specifically during growth on sucrose, was shown to be inducible under these conditions. A pathway for sucrose metabolism in this organism is proposed.     

Some 6-aza-5-substituted-2'-deoxyuridines show potent and selective inhibition of herpes simplex virus type 1 thymidine kinase

The synthesis and X-ray crystal structures of a series of 5-substituted-6-aza-2'-deoxyuridines is reported. These nucleoside analogues inhibit the phosphorylation of thymidine by HSV-1 TK but have no effect on the corresponding human enzyme. Detailed examination of one analogue proves it to be a competitive inhibitor of thymidine with a Ki of 0.34 microM and is a very poor substrate. The analogues are not substrates for the enzyme and also do not inhibit the degradation of thymidine by thymidine phosphorylase. Molecular modelling showed that the inhibitors fit well in the active site of HSV-1 TK, provided the conformation of the sugar moiety is the same for thymidine in the complex.     

Nitrofurantoin-induced hepatotoxicity mediated by CD8+ T cells

Nitrofurantoin is a synthetic nitrofuran commonly used for the treatment and prophylaxis of urinary tract infections. We describe the case of a 75-yr-old woman who was taking nitrofurantoin as prophylaxis against recurrent urinary tract infections, and who subsequently developed pulmonary and hepatic toxicity. We postulate that a breakdown product of the drug or the drug itself complexed to an endogenous peptide is presented by the class I HLA antigen on the hepatocyte cell membrane, inducing cytotoxic T cell activation and subsequently, hepatocyte death.     

Functional status and depression among men and women with congestive heart failure

OBJECTIVE: The study was designed 1) to examine the prevalence of depression in patients with congestive heart failure (CHF); 2) to explore associations between the physician's rating of functional status (NYHA class) and patient's assessment of functional status (physical limitation, dyspnea) with symptoms of depression; and 3) to explore gender related differences in relation to physician's rating and patient's rating of function status, and symptoms of depression. METHOD: A sample of 119 clinically stable heart failure patients (85 males and 34 females) was recruited from an outpatient cardiology hospital practice. The patients underwent a physical examination and completed a set of questionnaires. Prevalence of depressive symptoms and the association of these symptoms with NYHA class and patient's perceived functional status was studied. RESULTS: Findings indicate that depressive symptoms were not predominant among this sample of CHF patients. Path analyses showed non-significant direct associations between NYHA class as well as patient's perception of dyspnea with depression. In contract, the subjective indicator of physical limitations was strongly associated with symptoms of depression among the males, but this relation was not significant among the females. CONCLUSIONS: Results suggest that men and women respond differently to the burden of heart failure. However, interpretation of the results from the present study should be considered as tentative and additional research is required to examine mechanisms that explain gender differences in response to heart failure.     

Natural killer cells from HIV-1+ patients produce C-C chemokines and inhibit HIV-1 infection

Human NK cells have been shown to produce cytokines (e.g., IFN-gamma and TNF-alpha) and the chemokine macrophage inflammatory protein (MIP)-1alpha following stimulation with the combination of two monokines, IL-15 plus IL-12. The C-C chemokines MIP-1alpha, MIP-1beta, and RANTES have been identified as the major soluble macrophage-tropic HIV-1-suppressive factors produced by CD8+ T cells, which exert their action at the level of viral entry. Here, we demonstrate that monokine-activated NK cells, isolated from both normal and HIV-1+ donors, produce similar amounts of MIP-1alpha, MIP-1beta, and RANTES protein, in vitro. Further, supernatants of monokine-activated NK cells obtained from both normal donors and AIDS patients showed potent (routinely > or = 90%) suppressive activity against HIV-1 replication in vitro, compared with unstimulated control supernatants. NK cell supernatants inhibited both macrophage-tropic HIV-1(NFN-SX) and T cell-tropic HIV-1(NL4-3) replication in vitro, but not dual-tropic HIV-1(89.6). Importantly, the C-C chemokines MIP-1alpha, MIP-1beta, and RANTES were responsible only for a fraction of the HIV-1-suppressive activity exhibited by NK cell supernatants against macrophage-tropic HIV-1. Collectively these data indicate that NK cells from normal and HIV-1+ donors produce C-C chemokines and other unidentified factors that can inhibit both macrophage- and T cell-tropic HIV-1 replication in vitro. Since NK cells can be expanded in patients with HIV-1, AIDS, and AIDS malignancy in vivo, this cell type may have an important role in the in vivo regulation of HIV-1 infection.     

Cellular resistance and hypermutability in mismatch repair-deficient human cancer cell lines following treatment with methyl methanesulfonate

Resistance to the cytotoxic effects of S(N)1 alkylating agents such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU) is well established in mismatch repair-defective cells, however, little is known about the cellular response to S(N)2 alkylating agents in these cells. Here we describe the cytotoxic response and the mutagenic response at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus to the S(N)2 alkylating agent methyl methanesultfonate (MMS) in human cancer cell lines defective in mismatch repair (MMR). Our findings suggest that cytotoxicity to MMS is mediated through MMR, as indicated by an increased resistance to MMS in MMR-deficient cells. Cells in which specific MMR-gene defects were complemented by chromosome transfer were generally more sensitive to the cytotoxic effects of MMS. Additionally, the induced mutant frequency at HPRT following exposure to MMS is significantly increased in MMR-deficient lines. These findings suggest that resistance to S(N)2 alkylation damage is mediated by MMR genes, and that resistance to such damage in MMR-defective cells correlates with an increase in genomic mutations. The results are consistent with the hypothesis that abasic sites may be substrates for repair involving MMR-gene products in human cells.     

NH2-terminally truncated HER-2/neu protein: relationship with shedding of the extracellular domain and with prognostic factors in breast cancer

We identified an NH2-terminally truncated HER-2/neu product of M(r) 95,000 with in vitro kinase activity by Western blotting and immunoprecipitations using domain-specific antibodies. p95 levels correlated with the extracellular domain (ECD) shed from different cells under varied conditions. Both ECD and p95 were at approximately 20-fold lower levels in SKOV3 ovarian carcinoma cells, as compared to BT474 breast carcinoma cells. Both were stimulated by treatment of cells with the phorbol ester tumor promoter phorbol 12-myristate 13-acetate and the lysosomotrophic agent chloroquine. The hydroxamate inhibitor of metalloproteases, TAPI, suppressed both p95 and ECD in a dose-dependent fashion, with maximal inhibition at < or = 10 microM in BT474 cells. Cancer tissues were analyzed by Western blotting and scored for p95HER-2/neu and for p185HER-2/neu expression. Breast and ovarian cancer tissues were both found to express p95HER-2/neu in addition to p185HER-2/neu. Of 161 breast cancer tissues, 22.4% expressed p95, 21.7% overexpressed p185, and 14.3% were p95 positive and overexpressed p185. A higher proportion of node-positive patients (23 of 78) than node-negative patients (9 of 63) expressed p95 in all tumors combined (P = 0.032). In the group that overexpressed p185, those that contained p95 were associated with node-positive patients (15 of 21), whereas those that were p95 negative were associated with node-negative patients (8 of 11; P = 0.017). Neither p95- nor p185-rich patients significantly correlated with tumor size or with hormone receptor status in this study. Our findings show that breast cancers, which express the HER-2/neu oncogene, are heterogeneous with respect to HER-2/neu protein products. p95HER-2/neu appears to distinguish tumors that have metastasized to the lymph nodes from those in node-negative patients.     

The M.V. Bekmetov--T.A. Khodzhimetov odontodynamometer]

21 cases of congenital parotid fistula are reported. The patients' age ranged from 7 to 50 years. Dissection of the fistula under local anesthesia was made in 9 patients. A 7-year-old patient was operated under intravenous calipsol anesthesia. Four kinds of the fistula depending on its shape and size are described. Two of them cause no trouble, the other two manifest from early childhood with inflammation, recurrences with abscesses. In such cases the fistula should be radically removed.