Efficacy and safety of growth hormone (GH) in the treatment of adult Japanese patients with GH deficiency: a randomised, placebo-controlled study.

OBJECTIVE: The aim of this study was to assess the effect of growth hormone (GH) replacement therapy on lean body mass (LBM) and other variables including body fat mass, serum lipids and quality of life measures in GH-deficient Japanese adults. DESIGN: This was a multicentre, double-blind, placebo-controlled, parallel group study. Following initial screening, patients were randomly assigned to GH treatment (n=37) or placebo (n=36). GH treatment was started at an initial dose 0.003 mg/kg/day s.c. each day for the first 4 weeks after which the dose was increased to 0.006 mg/kg/day for 4 weeks and then to 0.012 mg/kg/day for the last 16 weeks (n=37). Body composition, serum lipids, serum IGF-I and IGFBP-3 levels were measured during the 24-week study. Short Form-36 and Quality of Life Assessment of GH Deficiency in Adults scores were also determined. RESULTS: LBM was significantly increased from baseline at 24 weeks in GH-treated patients, with a mean (+/-SD) increase of 4.7% (+/-5.3%) compared with an increase of 1.0% (+/-4.4%) in the placebo group (p<0.0001 versus baseline, p=0.0003 versus placebo). Percentage body fat decreased significantly from baseline in GH-treated patients (9.3%, p<0.0001), compared with a non-significant 0.2% increase in the placebo group (p<0.0004 for difference between treatment groups). In addition, significantly increased serum IGF-I and IGFBP-3 levels and improvements in the patients' serum lipid profiles were observed in patients who received GH therapy. Changes in quality of life measures did not differ between treatments, probably because of the small number of patients studied. GH therapy was well tolerated, with adverse events of any cause reported in 86.5% of the GH treatment group and 83.3% of the placebo group. CONCLUSION: GH treatment significantly improved body composition and serum lipid profiles in adult Japanese patients with GH deficiency compared with placebo and had no clinically relevant adverse effects.     

Detection of anti-HTLV-I Tax antibodies in HTLV-I enzyme-linked immunosorbent assay-negative individuals

The HTLV-I tax gene protein (Tax) is not packaged within the mature viral particle from which the proteins for the commercially available enzyme-linked immunosorbent assay (ELISA) are derived. Screening of 162 individuals within a cohort of white intravenous (IV) drug abusers, previously identified as having an increased incidence of HTLV-I infection, demonstrated that seven of them had antibodies to the HTLV-I Tax protein but tested negative in HTLV-I ELISAs and Western blots prepared from purified virion proteins. Three out of 35 individuals in other behaviorally defined high-risk groups also displayed this limited pattern of reactivity to HTLV-I proteins. The presence of the anti-HTLV- I p40/Tax antibodies was determined by radioimmunoprecipitation assay (RIPA), which also revealed low levels of anti-env reactivity. The specificity of the anti-p40 reactivity was confirmed on specific Tax ELISAs and Western blots prepared from recombinantly produced Tax. In vitro gene amplification by the polymerase chain reaction (PCR) was used to establish the presence of sequences homologous to HTLV-I proviral DNA in four/four of these HTLV-I ELISA negative, Tax ELISA/Tax western blot/RIPA positive individuals. These data suggest that the true incidence of HTLV-I infection within high-risk cohorts is greater than previously reported.     

Microsatellite instability in B-cell lymphoma originating from Bloom syndrome

Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by lupus-like erythematous telangiectasias of the face, sun sensitivity, stunted growth infertility and immunodeficiency. In addition, BS patients are highly predisposed to cancers. Although recently the causative gene of BS (BLM) was identified as a DNA helicase homologue, the function of BLM in DNA replication has not been elucidated. In this study, p53 mutation and microsatellite instability in B-cell lymphomas originating from 2 sibling BS patients were investigated. In the originally developed tumor of both patients, no p53 mutation was detected. In one patient, however, after treatment by ionizing radiation the B-cell lymphoma recurred, showing a 9-bp deletion in exon 7. In lymphoma cells and an EB-virus-transformed cell line from BS lymphocytes of this patient, microsatellite instability was also detected from the reduced length of microsatellite DNA markers, although in the other patient microsatellite instability was not detected. Thus, 2 B-cell lymphomas, despite having the same BLM mutation, showed different phenotypes in terms of p53 mutation and microsatellite instability. © 1996 Wiley-Liss, Inc.     

Effects of α1-adrenergic receptor antagonists on the development and progression of urothelial cancer

We recently demonstrated that silodosin, a selective α₁-blocker often prescribed for the symptomatic treatment of benign prostatic hyperplasia (BPH), could inactivate a c-fos proto-oncogene regulator ELK1 in bladder cancer cells possessing a functional androgen receptor (AR). However, the clinical impact of α₁-blockers on the development and progression of bladder cancer remained poorly understood. In the present study, we investigated if α₁-blockers clinically used, including silodosin, tamsulosin, and naftopidil, could prevent the neoplastic/malignant transformation and cell growth, using non-neoplastic urothelial SVHUC sublines with carcinogen/MCA challenge and bladder cancer lines, respectively. Bladder cancers in men treated with silodosin, tamsulosin, or naftopidil for their BPH were then compared. Silodosin at 1-10 µM significantly inhibited the neoplastic transformation of MCA-SVHUC-AR cells, but not that of AR-negative MCA-SVHUC-control cells. In MCA-SVHUC-AR, silodosin significantly reduced the expression levels of oncogenes (c-fos/NF-κB1) and induced those of tumor suppressors (p27/PTEN). However, tamsulosin (up to 1 µM) or naftopidil (up to 10 µM) failed to significantly inhibit the neoplastic transformation of AR-positive or AR-negative urothelial cells. Similarly, cell proliferation/migration of AR-positive bladder cancer lines was considerably inhibited only by silodosin. Meanwhile, the incidence of bladder cancer in patients with silodosin [49/540 (9.1%)] was marginally lower, compared to those with tamsulosin [64/523 (12.2%); P=0.094] or tamsulosin or naftopidil [64+28/523+236 (12.1%); P=0.082]. There were no significant differences in tumor grade/stage among the 3 cohorts. Outcome analysis revealed lower risks for disease progression of non-muscle-invasive bladder tumors in the silodosin group than in the naftopidil group (P=0.011) or tamsulosin+naftopidil groups (P=0.035). Similarly, silodosin patients with muscle-invasive tumor had lower risks for disease progression, compared with tamsulosin (P=0.006) or tamsulosin+naftopidil (P=0.028) patients. Multivariate analysis further showed that silodosin treatment in those with non-muscle-invasive tumor was associated with improved progression-free survival, compared with naftopidil (hazard ratio=0.086; 95% confidence interval=0.008-0.905; P=0.041) or tamsulosin/naftopidil (hazard ratio=0.128; 95% confidence interval=0.016-1.036; P=0.054) treatment. Our in vitro studies thus indicate that both urothelial tumorigenesis and tumor growth are inhibited by silodosin, but not by tamsulosin or naftopidil. Clinical data further suggest that even pharmacological doses (e.g. 0.1 µM) of silodosin contribute to preventing bladder cancer progression.     

Roles of inositol trisphosphate and protein kinase C in the spontaneous outward current modulated by calcium release in rabbit portal vein

We examined the effects of heparin, guanosine nucleotides, protein kinase C (PKC) modulators, such as phorbol 12,13-dibutylate (PDBu) and H-7 on Ca²⁺-dependent K⁺ currents in smooth muscle cells of the rabbit portal vein using the whole-cell patch-clamp technique, to explore the effects of PKC on the oscillatory outward current (I _oo). Neomycin (30 M), an inhibitor of phospholipase C, and intracellular applications of heparin (10 g/ml) and guanosine 5-O-(2-thiodiphosphate) (GDP[S]; 1 mM) partly but consistently inhibited the generation of I _oo, whereas a higher concentration of heparin (100 g/ml) transiently enhanced then suppressed the generation of I _oo. Inhibition of I _oo generation by heparin was more powerful at the holding potential of + 20 mV than at –20 mV. Inositol 1,4,5-trisphosphate (InsP ₃; 30 M) continuously generated I _oo at holding potentials more positive than –60 mV. Noradrenaline (10 M) and caffeine (3–20 mM) transiently augmented, then reduced the generation of I _oo. Heparin (10 g/ml) completely inhibited responses induced by InsP ₃ and noradrenaline, but not those induced by caffeine. Intracellular application of guanosine 5-triphosphate (GTP; 200 M) or low concentrations of guanosine 5-O-(3-thiotriphosphate) (GTP[S]; 3 M) continuously augmented the generation of I _oo. High concentrations of GTP[S] (10 M) transiently augmented, then inhibited I _oo. Neither GTP[S] nor noradrenaline induced the transient augmentation or the subsequent inhibition of I _oo when applied in the presence of GDP[S] (1 mM), neomycin (30 M) or heparin (10 g/ml). PDBu (0.1 M) reduced the generation of I _oo but failed to produce an outward current following application of caffeine (3–5 mM). This action of PDBu was inhibited by pretreatment with H-7 (20 M). In the presence of H-7, GTP[S] continuously enhanced the generation of I _oo. The suppression of the generation of I _oo during application of noradrenaline (10 M) was reduced by pretreatment with H-7. Thus both InsP₃ and protein kinase C contribute to the generation of I _oo in smooth muscle cells of the rabbit portal vein and heparin is not a specific InsP ₃ antagonist on the InsP ₃-induced Ca²⁺-release channel (PIRC). InsP ₃ opens PIRC and protein kinase C may deplete the stored Ca²⁺ by either inhibiting the reuptake of Ca²⁺ or by enhancement of the releasing actions of InsP ₃.     

EDAS (encephalo-duro-arterio-synangiosis) for occlusive/stenotic cerebrovascular disease

The efficacy of encephalo-duro-arterio-synangiosis (EDAS) using superficial temporal artery was evaluated for the treatment of the occlusive/stenotic cerebrovascular disease. Nine patients with the occlusive/stenotic cerebrovascular disease underwent EDAS in our hospital. The mean follow-up period was 6.6 months. Postoperative angiography showed no collateral formation via EDAS in any of the nine patients. We analyzed the following points: 1) operative procedure, 2) follow up period after surgery, 3) preoperative cerebral blood flow, and 4) age of the patients. Results showed that EDAS as a treatment of occlusive/stenotic cerebrovascular disease was not effective. This study failed to reinforce the suggestion that indirect extracranial/intracranial bypass surgery is effective as the treatment of occlusive/stenotic cerebrovascular disease.     

Multivessel coronary revascularization with bilateral internal thoracic artery grafts

Sixteen patients underwent coronary revascularization with bilateral internal thoracic artery (ITA) grafts between 1988 and 1989 at the Okayama University Hospital. A total 39 coronary grafts were performed, being an average of 2.4 grafts per patient. Each patient received bilateral ITA grafts, and in 5 patients an additional 7 grafts were constructed with 5 autologous veins and 2 gastroepiloic arteries. The right ITA was grafted as a free graft in 4 patients. The ITA graft patency rate was 96.8 per cent (31/32) at the time of hospital discharge. The postoperative morbidity included one reoperation for bleeding and one myocardial infarction. Coronary artery bypass grafting with bilateral ITA grafts can be safely performed and its application facilitates complete revascularization with arterial grafts.