Detection, epitope-mapping and function of anti-Fas autoantibody in patients with silicosis

Dysregulation of apoptosis through the Fas-Fas ligand pathway is associated with the onset of autoimmune disease. Since autoantibodies directed against unknown antigens are present in the sera of these patients, sera samples were examined for the presence of autoantibodies directed against the Fas molecule. Using Western blotting and a ProteinChip analysis, autoantibodies against Fas were detected in patients with silicosis, systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), and weakly detected in healthy individuals. Using epitope mapping employing 12-amino-acid polypeptides with the SPOTs system, a minimum of four epitopes and a maximum of 10 epitopes were found. Several amino acid residues involved in binding FasL, such as C66, R87, L90, E93 and H126, were presented within the epitopes. Serum containing a large amount of anti-Fas autoantibody from silicosis patients inhibited the growth of a Fas-expressing human cell line, but did not inhibit the growth of a low Fas-expresser nor a Fas-expresser in which the Fas gene had been silenced by small interference RNA. All epitopes in the intracellular region of Fas were located in the death domain. The possible roles of anti-Fas autoantibody detected in healthy volunteers and patients with silicosis or autoimmune diseases are discussed here.     

A case of advanced gastric cancer with obstructive jaundice that responded to TS-1/CPT-11 combination therapy after percutaneous transhepatic cholangio drainage

TS-1/CPT-11 combination therapy was carried out in a case of advanced gastric cancer with liver and lymph node metastases and obstructive jaundice after percutaneous transhepatic cholangio drainage (PTCD). Regression of the primary carcinoma and reduction in size of metastases were observed. Grade 1 fatigue and grade 2 neutropenia were noted as adverse reactions to the treatment. TS-1/CPT-11 combination therapy was useful in this case of advanced gastric cancer with liver and lymph node metastases.     

SHP2 mediates gp130-dependent cardiomyocyte hypertrophy via negative regulation of skeletal alpha-actin gene

Morphological and biochemical phenotypes of cardiomyocyte hypertrophy are determined by neurohumoral factors. Stimulation of G protein-coupled receptor (GPCR) results in uniform cell enlargement in all directions with an increase in skeletal α-actin (α-SKA) gene expression, while stimulation of gp130 receptor by interleukin-6 (IL-6)-related cytokines induces longitudinal elongation with no increase in α-SKA gene expression. Thus, α-SKA is a discriminating marker for hypertrophic phenotypes; however, regulatory mechanisms of α-SKA gene expression remain unknown. Here, we clarified the role of SH2-containing protein tyrosine phosphatase 2 (SHP2) in α-SKA gene expression. In neonatal rat cardiomyocytes, endothelin-1 (ET-1), a GPCR agonist, but not leukemia inhibitory factor (LIF), an IL-6-related cytokine, induced RhoA activation and promotes α-SKA gene expression via RhoA. In contrast, LIF, but not ET-1, induced activation of SHP2 in cardiomyocytes, suggesting that SHP2 might negatively regulate α-SKA gene expression downstream of gp130. Therefore, we examined the effect of adenovirus-mediated overexpression of wild-type SHP2 (SHP2^WT), dominant-negative SHP2 (SHP2^C/S), or β-galactosidase (β-gal), on α-SKA gene expression. LIF did not upregulate α-SKA mRNA in cardiomyocytes overexpressing either β-gal or SHP2^WT. In cardiomyocytes overexpressing SHP2^C/S, LIF induced upregulation of α-SKA mRNA, which was abrogated by concomitant overexpression of either C3-toxin or dominant-negative RhoA. RhoA was activated after LIF stimulation in the cardiomyocytes overexpressing SHP2^C/S, but not in myocytes overexpressing β-gal. Furthermore, SHP2 mediates LIF-induced longitudinal elongation of cardiomyocytes via ERK5 activation. Collectively, these findings indicate that SHP2 negatively regulates α-SKA expression via RhoA inactivation and suggest that SHP2 implicates ERK5 in cardiomyocyte elongation downstream of gp130.     

Comparison of the effects of acetylsalicylic acid, ticlopidine and cilostazol on primary hemostasis using a quantitative bleeding time test apparatus

We examined and compared the effects of aspirin (ASA), ticlopidine (TP) and cilostazol (CS) on bleeding time (BT) in 10 healthy adult male subjects using a newly developed quantitative bleeding time (QBT) test apparatus capable of simultaneously measuring total blood loss (Tv), maximum bleeding rate (Rmax), and bleeding pattern in addition to BT. All 3 drugs inhibited platelet aggregation response to ADP, collagen, epinephrine and arachidonic acid (p < 0.05), but not to ristocetin. Following oral administration of ASA (330 mg/day) or TP (300 mg/day) for 3 days, BT was significantly prolonged (mean BT increased from 359.3 to 646.0 s, p < 0.001, and from 323.3 to 528. 7 s, p < 0.01, respectively) and Tv was significantly increased (from 14.5 to 30.2 microl, p < 0.05, and from 12.5 to 19.2 microl, p < 0.01, respectively). Aspirin also increased Rmax (from 0.118 to 0. 159 microl/s, p < 0.05). The prolonged bleeding patterns after administration of ASA and TP were both type III, which has been reported to be less likely to lead to bleeding accidents. In contrast, none of these QBT parameters were altered by CS administration.     

Can nasal continuous positive airway pressure decrease clinic blood pressure in patients with obstructive sleep apnea?

Obstructive sleep apnea (OSA) is commonly associated with systemic hypertension and now recognized as an independent risk factor for daytime hypertension. We aimed to study the short- and long-term effect of nasal continuous positive airway pressure (CPAP) in hypertensive and normotensive patients with OSA. Forty-six patients with moderated to severe OSA were treated with nasal CPAP and followed after one year of treatment. Clinic blood pressure, heart rate, and body weight were taken before and followed up for one year after beginning nasal CPAP. In this study 25 patients with OSA were found to have hypertension (54.3%). The hypertensive group showed a significant reduction in clinic blood pressure after nasal CPAP, whereas the normotensive group showed no changes. The subgroup of hypertensive patients with OSA who had no anti-hypertensive medication revealed a decrease in clinic blood pressure comparable to those with anti-hypertensive drugs. The heart rate was not significantly changed in any patients. There was no significant correlation between the decrease in body weight and the reduction in blood pressure. These results suggest that nasal CPAP alone might have a substantial blood pressure lowering effect in hypertensive patients with OSA. This effect could decrease the morbidity and mortality related to cardiovascular complications in patients with OSA.     

A 3-month multicomponent home-based rehabilitation program for older people with restricted life-space mobility: a pilot study

[Purpose] The purpose of this study was to verify the effects of a 3-month multicomponent home-based rehabilitation program developed on the basis of the reevaluation of older people with restricted life-space mobility. [Participants and Methods] The participants were residents in Japan aged ≥65 years who had Life-Space Assessment scores ≤52.3. Multicomponent home-based rehabilitation was conducted by physical and occupational therapists. Each visit included 40–60 min of combined exercise, practicing activities of daily living, improving the home environment, and caregiver support. The programs were developed in accordance with a flow diagram. The primary outcome was life-space mobility evaluated using the Life-Space Assessment score. [Results] Overall, 30 participants completed the intervention. The mean age of the participants was 82.4 ± 7.5 years. Three months after the intervention initiation, the Life-Space Assessment scores significantly improved from 12.0 to 30.5. The proportion of participants at maximal life-space level 5 (unlimited mobility) doubled from 16.7% at baseline to 33.3%. The functional independent measure score, fall efficacy scale score, and lower limb strength associated with standing up also significantly improved. We found no significant changes in the geriatric depression scale 5 and self-rated good health scores. [Conclusion] Multicomponent home-based rehabilitation can improve life-space mobility in older people with restricted life-space mobility.Key words: Home-based rehabilitation, Life-Space mobility, Older people     

Inhibitory effect of small amounts of cellulose on colonic carcinogenesis with low-dose carcinogen

This study set out to evaluate the effects of dietary fiber on cancer development in the large bowel under in vivo experimental conditions as similar as possible to those under which this cancer develops in vivo in humans. Forty-eight Sprague-Dawley rats were divided into three groups that were fed either a nonfiber diet or a 3 g or 10 g/100 g cellulose diet in this experiment, and all groups received doses of a mild carcinogen, 1,2-dimethylhydrazine (5 mg/kg body weight) for 50 weeks. Following endoscopic observation of the large bowel, we found that the induction rates of tumor in the cellulose groups were significantly lower than that in the nonfiber diet group, both endoscopically and histologically. No differences were seen between the 3% and 10% cellulose groups in suppressing carcinogenesis. It is likely that the inhibitory effect of 3% cellulose could be confirmed only by a long-term experiment on carcinogenesis following the administration of a low dose of carcinogen.