Relaxin down-regulates renal fibroblast function and promotes matrix remodelling in vitro.

BACKGROUND: Renal fibroblasts are important effector cells in tubulointerstitial fibrosis, with experimental antifibrotic strategies focusing on the functional down-regulation of these cells. Several experimental models of fibrosis have provided evidence for the effectiveness of the polypeptide hormone relaxin as a potential antifibrotic agent. This study was conducted to further elucidate the antifibrotic mechanisms of relaxin on renal fibroblasts in vitro. METHODS: Rat cortical fibroblasts were obtained from outgrowth culture of renal tissue isolated from kidneys 3 days post-unilateral ureteric obstruction and constituted 100% of cells studied. A relaxin radio-receptor assay was used to establish binding of relaxin to renal fibroblasts in vitro. Functional studies then examined the effects of H2 relaxin (0, 1, 10 and 100 ng/ml) on fibroblast kinetics, expression of alpha-smooth muscle actin (alpha-SMA), total collagen synthesis, collagenase production and collagen-I lattice contraction. CTGF mRNA expression was also measured by northern analysis. RESULTS: H2 relaxin bound with high affinity to rat renal fibroblasts, but receptor numbers were low. Consistent with its previously reported bimodal effect, transforming growth factor (TGF-beta 1) reduced fibroblast proliferation, an effect abrogated by H2 relaxin. Fibroblasts exposed to H2 relaxin (100 ng/ml) for 24 h demonstrated decreased immunostaining for alpha-SMA and reduced alpha-SMA protein expression compared with controls. There was a trend for a relaxin-mediated reduction in total collagen synthesis and alpha 1(I) mRNA expression with large dose-related increases in collagenase protein expression being observed. TGF-beta 1-stimulated collagen-I lattice contraction was significantly inhibited following co-incubation with 100 ng/ml relaxin. Incremental doses of H2 relaxin had no significant effect on CTGF mRNA expression. CONCLUSIONS: The findings of this study suggest that the antifibrotic effects of relaxin involve down-regulation of fibroblast activity, increase in collagenase synthesis and restructuring of collagen-I lattices, which are consistent with its known physiological role of matrix remodelling. Although there appears to be an interaction between TGF-beta 1 and H2 relaxin, this does not appear to involve a reduction in CTGF mRNA expression.     

US-guided percutaneous biopsy: use of a screw biopsy stylet to aid needle detection

Insertion of a screw biopsy stylet into a thin-walled biopsy needle greatly enhances detection of the needle during ultrasound-guided percutaneous biopsy. This technique is helpful when precise needle-tip localization is needed for biopsies of small lesions.     

Infection and interferon production in systemic juvenile chronic arthritis: a prospective study.

Twenty-four episodes of disease exacerbation in 19 children suffering from systemic juvenile chronic arthritis were studied. Sixteen of these were preceded by an infection (chi 2 = 20.14, p less than 0.001), mostly of the upper respiratory tract. In the 10 cases seen during an infection causative agents were identified in 5 (herpes simplex, rhinovirus, and on 3 occasions streptococcus). The total number of infections was not increased when compared with infection rates predicted by several reported studies. In the absence of clinical infection, specific antibody titres to a panel of microbial antigens were similar to those of a control group but with a trend toward higher titres in patients with hypergammaglobulinaemia. Interferon (IFN) responses were not defective, though sequential in-vitro IFN production from peripheral blood mononuclear cells (PBM) fluctuated considerably in the same patients, occasionally being absent with no obvious clinical correlate. IFN-alpha was induced by stimulation with Newcastle disease virus (NDV), and the mean responses of the patients were significantly greater than those of controls. IFN-gamma production on phytohaemagglutinin (PHA) stimulation was similar in patients and control groups. IFN was not detected in any of the sera from patients or controls.     

The chemotherapy of lymphoblastic lymphoma

Thirty-two patients treated on consecutive Southwest Oncology Group (SWOG) protocols for malignant lymphoma were subsequently diagnosed as having lymphoblastic lymphoma. Combination chemistry, usually adriamycin-based, produced complete responses (CR) in 17 patients (53%). Median survival was 15 mo. Patients achieving a CR survival significantly longer than patients with partial or no response (p < 0.01). Ten of 24 patients not receiving central nervous system (CNS) prophylaxis developed leptomeningeal lymphoma while none of the seven patients who received prophylactic intrathecal cytosine arabinoside or methotrexate developed CNS lymphoma (p = 0.04). Implications of these results for planning future treatment programs of lymphoblastic lymphoma are discussed.     

Sensitivity of six commercial enzyme immunoassay kits that detect both anti-HIV-1 and anti-HIV-2

The sensitivities of six commercial combined anti-HIV-1/anti-HIV-2 enzyme immunoassays (EIAs) were evaluated, one assay (ELAVIA) based on whole virion antigen, two assays (Abbott, Wellcozyme) based on antigens expressed from recombinant DNA, and three assays (Biochrom, IAF Biochem and Pharmacia) based on synthetic peptides as antigens. All the kits investigated performed well on a panel of 47 routine anti-HIV-1-positive specimens, but on series of anti-HIV-1-seroconversion specimens from seven plasmapheresis donors, two of the peptide assays, Biochrom and Pharmacia, performed less well than the other assays. On a panel of anti-HIV-2-positive specimens, all the assays except Biochrom detected all 33 positive sera, though the reactions of some of them in the Abbott assay were relatively weak. In deciding whether to introduce a combined assay in place of an anti-HIV-1 assay, cost, specificity, the availability of confirmatory tests and the prevalence of HIV-2 in the locality, as well as sensitivity, should be considered.     

NIH conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). An update

The neurofibromatoses comprise at least two autosomal dominant disorders affecting an estimated 100,000 Americans with clinical manifestations that may require care from every type of clinician. Neurofibromatosis 1 and neurofibromatosis 2 have in common the occurrence of many neurofibromas but are distinctly different clinical disorders. The disease genes are on different chromosomes. Magnetic resonance imaging, particularly with gadolinium enhancement, has generally supplanted other techniques for visualizing brain, spinal, and other neural tumors in both disorders. The technique has rekindled the controversy over the nature and frequency of optic pathway tumors in patients with neurofibromatosis 1 and has revealed, throughout the brains of young patients, bright lesions that have uncertain clinical consequences and unknown pathologic bases. In patients with neurofibromatosis 2, small acoustic neuromas can be seen, leading to the possibility of excision with preservation of hearing and facial nerve function. Abnormal hearing may occur to excess in patients with neurofibromatosis 1, but acoustic neuroma has never been documented. In patients with neurofibromatosis 2, a battery of audiologic tests has a high positive predictive power. Lisch nodules or iris hamartomas, probably a universal sign in adults with the neurofibromatosis 1 gene, cause no problem with vision. Posterior capsular lens opacity in patients with neurofibromatosis 2 is a helpful diagnostic sign and a potential source of additional handicap in persons at risk for impaired hearing. Progress in the clinical delineation of the disorders has been matched with considerable research into the still obscure pathogenesis of the disorders. Such rapid advances may necessitate reconsideration of the conclusions of the National Institutes of Health Consensus Development Conference on Neurofibromatosis, especially those on the categories of persons in which a neurofibromatosis should be considered and the need for caution in recommending surgery. Watchful waiting may often be the best management for acoustic neuromas in neurofibromatosis 2.     

Regional mapping of the gene encoding dihydroorotate dehydrogenase,an enzyme involved in UMP synthesis,electron transport,and superoxide generation,to human chromosome region 16q22

De novo UMP synthesis is a critical metabolic pathway for nucleic acid synthesis and for a variety of metabolic pathways. The pathway is a target for many widely used cancer chemotherapy agents, several of which are pyrimidine analogs. Humans and cattle have been described with mutations in UMP synthesis that lead to serious inborn errors of metabolism. Dihydroorotate dehydrogenase (EC 1.3.3.1) (DHODH) carries out the fourth committed step in the pathway and may also be important for mitochondrial electron transport and oxygen radical metabolism. We report here that the gene encoding this enzyme in humans is located in the chromosomal region 16q22. With the mapping of DHODH, the mapping of all the steps of UMP synthesis is complete. All three genes involved map to different human chromosomes. This information is important in consideration of regulation of UMP synthesis in mammals, including humans.