Differential regulation of Na+ and Cl- conductances by PTX-sensitive G proteins in fetal lung apical membrane vesicles

In late 1990 the National Institute on Drug Abuse (NIDA) initiated the Cooperative Agreement (CA) for AIDS Community-Based Outreach/Intervention Research Program. The goal of this program was to prevent the further spread of HIV among out-of-treatment drug users, in particular injection drug users (IDUs) and crack cocaine users, their sexual partners, and those at risk for initiating injection behavior. To accomplish this goal, the CA set out to monitor drug use and HIV risk behaviors, assess the efficacy of various HIV risk reduction interventions, and develop and refine outreach and intervention strategies. Twenty-three research sites, 21 rural and urban sites in the United States and one each in Puerto Rico and Brazil, were included in the CA program. This article presents an overview of the CA as well as a synopsis of the studies covered in this special issue examining the total CA database.     

Coccidioides immitis presenting as a hyphal form in cerebrospinal fluid

This article reports a case of Coccidioides immitis that presented as a hyphal form in a 38-year-old patient. The organism was observed growing exclusively as hyphae in the cerebrospinal fluid by microscopic examination. Coccidioides immitis was the only organism cultured. The identification of C immitis was confirmed by both standard culture methods and DNA probe studies.     

Hepatocyte growth factor and c-MET in benign and malignant peripheral nerve sheath tumors

Hepatocyte growth factor (HGF), secreted by mesenchymal cells, has pleiotropic biological activities on several cell types. HGF and its receptor, the c-met proto-oncogene product (c-MET) have been implicated in the genesis and progression of several carcinomas and sarcomas. It has been suggested that MET/HGF autocrine signaling may contribute to tumorigenesis in sarcomas. HGF has been recently found to be a mitogen for rat Schwann cells and to be present in neurofibromas in NF1 patients. In this investigation, we assessed the immunoreactive patterns of HGF and MET in benign and malignant peripheral nerve sheath tumors (PNST) using archival formalin-fixed tissue. The standard avidin-biotin-peroxidase method was used. All benign tumors were negative with HGF. Eight cases of MPNST were positive with both HGF and MET. In some malignant PNST, positivity with both ligand and the receptor may be indicative of an autocrine mediated signal transduction and may implicate HGF/MET in tumor progression. Immunoreactivity with MET was strikingly greater in MPNST in contrast to benign PNST; this finding may prove to be helpful in distinguishing some histologically low-grade MPNST from cellular and atypical benign PNST.     

The pathogenesis of bladder cancer

Carcinoma of the urinary bladder appears to arise, in at least some cases, from carcinoma in situ developing in a field of atypical epithelial proliferation. There is both a spatial and temporal relationship between invasive and in situ bladder cancer, although the exact relationship between the noninvasive flat and papillary types of tumors is not known. Prenoeplastic bladder lesions are defined as irreversible, although not necessarily progressive, and an experimental animal model of the disease has been developed. The appearance of pleomorphic microvilli on the luminal surface of epithelial cells of the urinary bladders of Fischer rats is correlated with the irreversibility of hyperplastic epithelial lesions induced by feeding N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) to the test animals. This alteration can be visualized by scanning electron microscopy of cytologic and histologic preparations.     

2-Iminothiazolidine-4-carboxylic acid produces hippocampal CA1 lesions independent of seizure excitation and glutamate receptor activation

Impaired wound healing is a common complication of diabetes mellitus. The underlying pathophysiology of diabetes-impaired healing is poorly understood. In the present study we have compared cell proliferation rates, apoptosis (programmed cell death), the myofibroblast marker alpha-smooth muscle actin and procollagen I mRNA expression, between diabetic and control mice. Full-thickness skin wounds were made in non-obese diabetic (NOD) mice and C57B6 controls. NOD mice showed a marked retardation of wound healing at both 7 and 14 days after wounding. Comparison of cell proliferation rates 7 days after wounding, using 5-bromo-2'-deoxy-Uridine incorporation, showed higher rates of cell proliferation in controls (88.1 +/- 12.8) than in NOD wounds (52.1 +/- 9.9, p < 0.02, n = 4). Immunohistochemical detection of alpha-smooth muscle actin, showed a later onset in diabetic wounds, suggesting that wound contraction may be delayed in the diabetic animals. In situ hybridisation for alpha 1 (I) procollagen mRNA expression, showed reduced procollagen I expression in the diabetic wounds when compared with controls. Lastly, there appeared to be higher levels of apoptosis in diabetic wounds, shown by the terminal transferase mediated UTP nick end-labelling technique. Apoptotic cells were rare in control wounds confirming previous studies, which showed that apoptosis occurs late in normal wound healing as the wound matures into scar tissue. In conclusion, we hypothesize that reduced cell proliferation, retarded onset of the myofibroblast phenotype, reduced procollagen I mRNA expression and aberrant control of apoptotic cell death may contribute to impaired wound healing seen in this diabetic model.     

Multiple-system atrophy is genetically distinct from identified inherited causes of spinocerebellar degeneration

Multiple system atrophy (MSA) is a neurodegenerative disorder of unknown cause. The only case-control study conducted in MSA patients to date suggested a possible contributory genetic component in the pathogenesis of this disorder. The aim of this study was to evaluate a possible overlap between clinically or pathologically well-defined MSA and other conditions with an identified genetic defect causing spinocerebellar degeneration in humans or mutant mice strains. The spinocerebellar ataxia type 1 and 3 genes (SCA1 and SCA3) were analyzed for a pathologic expansion in 80 patients with MSA to evaluate a possible overlap between MSA and SCA1 or SCA3. Weaver mice and lurcher mice are animal models for spinocerebellar degeneration; both share pathologic features with MSA. We sequenced the H5 pore region of the human homologue of the weaver mouse gene, hiGIRK2, in all our patients. In lurcher mice, previous biochemical studies have shown a decreased intracellular response to insulin-like growth factor 1 (IGF-1) in the cerebellar cortex, and we thus investigated the possibility of an allelic association between MSA and the receptor for IGF-1. In addition, we evaluated a possible involvement of the ciliary neurotrophic factor gene (CNTF) and examined the role of HLA-A32 to clarify the conflicting data from previous studies. No changes were detected in any of the analyzed genes. Our studies strongly suggest that MSA is an autonomous syndrome distinct from identified genetic causes for spinocerebellar degeneration.     

Prevalence of nephrotoxicosis associated with a four-hour saline solution diuresis protocol for the administration of cisplatin to dogs with naturally developing neoplasms

We evaluated the development of nephrotoxicosis in 64 dogs with malignant neoplasia given cisplatin during 4-hour saline solution diuresis. Cisplatin (70 mg/m2 of body surface area, IV, q 21 d) was given to 8 dogs once, 22 dogs twice, 9 dogs 3 times, and 25 dogs 4 times. For each treatment, cisplatin was given over a 20-minute period after saline (0.9% NaCl) solution was administered IV for 3 hours at a rate of 25 ml/kg/h. After cisplatin infusion, saline solution diuresis was continued at the same rate for 1 hour. Before each treatment with cisplatin, the dogs were evaluated by conducting a physical examination, CBC; and analysis of serum urea nitrogen and creatinine concentrations, and in most cases, serum phosphorus concentration and urine specific gravity were determined. Exogenous creatinine clearance also was evaluated in 8 dogs prior to 1 (n = 8), 2 (n = 8), 3 (n = 6), and 4 (n = 4) treatments. Five (7.8%) of 64 dogs developed clinically evident renal disease after two (n = 3) and three (n = 2) doses of cisplatin. Two of the 5 dogs had preexisting diseases of the urinary tract prior to the start of treatment. Survival time in dogs that developed renal disease (median, 114 days; range, 26 to 273 days) was similar to that of all dogs in this study (median, 145 days; range, 5 to 586 days), with 30 dogs still alive at the conclusion of the study. Three of the 5 dogs that developed renal disease were alive at the conclusion of the study, 1 died of tumor-related causes, and another died as a direct result of nephrotoxicosis. There was a significant (P < 0.05) decrease in median neutrophil counts and a significant (P < 0.05) increase in median creatinine concentrations prior to the third and fourth treatments, compared with pretreatment values.(ABSTRACT TRUNCATED AT 250 WORDS)