Close relation between lipoprotein (a) levels and atherothrombotic disease in Japanese subjects >75 years of age

Levels of lipoprotein (a) (Lp[a]) and various hemostatic factors were studied in 132 Japanese aged >75 years (mean 83). The group consisted of 50 healthy persons, 36 hypertensive subjects, 31 patients with chronic cerebral infarction, and 15 with coronary artery disease. Lp(a) levels were slightly lower in the healthy “old old” subjects than in the 184 healthy younger adults (mean ± SD: 10.7 ± 7.9 vs 12.1 ± 10.1 mg/dl). There were no gender-related differences in the Lp(a) levels of healthy adults and healthy old old subjects. Lp(a) levels were higher in the hypertensive old old subjects (14.6 ± 15.4 mg/dl) and the old old patients with cerebral infarction (21.3 ± 16.2 mg/dl) and coronary artery disease (26.5 ± 20.4 mg/dl). The prevalence of subjects with high Lp(a) levels (>30 mg/dl) was the greatest among old old patients with coronary artery disease (27%). Lp(a) levels in the 132 old old subjects showed positive correlations with sialic acid, fibrinogen, factor VII activity, and D-dimer levels. These results indicate a close association between Lp(a) levels and atherothrombotic disease as well as the characteristics of Lp(a) as an acute phase reactant in old old Japanese. Subjects with higher Lp(a) levels may develop cardiovascular disease later in life, whereas the remaining healthy old old subjects have lower Lp(a) levels.     

Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration

Stem cell factor (SCF) has crucial roles in proliferation, survival, and differentiation of hematopoietic stem cells and mast cells through binding to c-Kit receptor (KIT). Chemotaxis is another unique function of SCF. However, little is known about the intracellular signaling pathway of SCF/KIT-mediated cell migration. To investigate the signaling cascade, we made a series of 22 KIT mutants, in which tyrosine (Y) residue was substituted for phenylalanine (F) in the cytoplasmic domain, and introduced into BAF3 cells or 293T cells. On stimulation with SCF, BAF3 expressing KIT(WT)(WT) showed cell migration and Ca(2+) mobilization. Among 22 YF mutants, Y567F, Y569F, and Y719F showed significantly reduced cell migration and Ca(2+) mobilization compared to WT. In Y567F, Lyn activation on SCF stimulation decreased and C-terminal Src kinase (Csk) suppressed KIT-mediated Ca(2+) influx and cell migration, suggesting that Y567-mediated Src family kinase (SFK) activation leads to Ca(2+) influx and migration. Furthermore, we found that p38 mitogen-activated protein kinase (p38 MAPK) and Erk1/2 were also regulated by Y567/SFK and involved in cell migration, and that p38 MAPK induced Ca(2+) influx, thereby leading to Erk1/2 activation. In Y719F, the binding of phosphatidylinositol 3'-kinase (PI3K) to KIT was lost and KIT-mediated cell migration and Ca(2+) mobilization were suppressed by PI3K chemical inhibitors or dominant-negative PI3K, suggesting the involvement of Y719-mediated PI3K pathway in cell migration. Combination of Csk and the PI3K inhibitor synergistically reduced cell migration, suggesting the cooperation of SFK and PI3K. Taken together, these results indicate that 2 major KIT signaling pathways lead to cell migration, one is Y567-SFK-p38 MAPK-Ca(2+) influx-Erk and the other is Y719-PI3K-Ca(2+) influx.     

Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial

OBJECTIVE: Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody, MRA, in patients with RA. METHODS: In a multicenter, double-blind, placebo-controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria. RESULTS: Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients. CONCLUSION: Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.     

Relationship between the weight-bearing ratio on the affected lower extremity and gait ability using a portable electronic foot sensor shoe (Step Aid?) in hemiplegic stroke patients

[Purpose] This study investigated the association between the weight-bearing ratio (WBR) and gait ability of a paretic lower limb while walking using a shoe-type load-measuring apparatus. [Subjects] The Subjects comprised 17 stroke patients who were classified into the following two groups: the independent walking group, and the non-independent walking group. [Methods] The 10-m walking time (inside and outside parallel bars) and the Berg Balance Scale (BBS) were measured. The WBR of the paretic lower limb was measured during static standing and while walking inside and outside parallel bars, and the coefficient of variation (CV) was calculated. WBR was evaluated using the Step Aid. [Results] The BBS and WBR were significantly decreased in the non-independent walking group, while the 10-m walking time and the CV were significantly increased in the non-independent walking group. [Conclusion] The CV and WBR of a paretic lower limb while walking appear to be important indices of achievement of independent gait in hemiplegic stroke patients, and they may be used in gait rehabilitation for diseases requiring weight-bearing training to follow the course of training using a shoe-type load-measuring apparatus.Key words: Stroke, Weight-bearing ratio, Shoe-type load-measuring apparatus     

Effect of statin on restenosis after radius stent implantation in patients with acute coronary syndrome

Despite reports that statin treatment reduces the rate of coronary restenosis with a balloon expandable stent, there is no evidence that statins affect the incidence of restenosis with a self-expanding Radius stent. Ninety-five patients with acute coronary syndrome who had been implanted with a Radius stent were classified into two groups: those with hyperlipidemia and initial statin treatment (statin group, n = 38) and those without statin treatment (comparative group, n = 57). At six months after stent implantation, the rate of coronary restenosis was significantly lower in the statin group (10.5%) than control group (28.1%) (p = 0.033), while there were no differences in morphology, maximal inflation pressure or stent size between the two groups. Interestingly, there was no difference in the serum lipid profile between the two groups at the 6-month follow-up, although the statin group had a significantly lower rate of restenosis. In conclusion, initial statin therapy reduced the rate of coronary restenosis even when a Radius stent was implanted.     

Effect of nicorandil on coronary spasm

In patients in whom dynamic coronary obstruction plays a predominant role in the pathogenesis of angina pectoris, dilatation of large coronary arteries and relief of coronary spasm account for the main mechanism of action of antianginal drugs. In this study, the acute vasodilating effects of nicorandil, a newly developed antianginal drug, were assessed in 10 patients who had spontaneous and ergonovine-evoked coronary spasms. The prompt, complete relief of both spontaneous and evoked coronary spasms was obtained in all of 10 patients with nicorandil. The coronary spasmolytic effect of nicorandil in the present series is thus considered to be beneficial to the treatment of coronary spasm.