Sustained reduction of serum cholesterol in low-dose 6-year simvastatin treatment with minimum side effects in 51,321 Japanese hypercholesterolemic patients - Implication of the J-LIT study, a large scale nationwide cohort study

金沢大学大学院医学系研究科　The Japan Lipid Intervention Trial (J-LIT) study, a nationwide cohort study utilizing the clinical practice of general physicians, was designed to clarify the relationship between the incidence of coronary heart disease and serum lipid concentrations during simvastatin therapy, as well as the safety of the therapy, in a large number of Japanese hypercholesterolemic patients. All the enrolled patients were treated with simvastatin. The current study analyzed the lipid lowering effect and safety of the low-dose simvastatin therapy used in the J-LIT study. Open-labeled simvastatin was given to 51,321 patients at an initial dose of mostly 5 mg/day. After 6 months of the treatment, the average serum total cholesterol (TC) and low density lipoprotein-cholesterol concentrations in all the patients followed up were reduced by 18.3% and 26.0%, respectively, and that of high density lipoprotein-cholesterol increased 2.3% on average. These concentrations were well maintained throughout the 6-year treatment period. A minority of patients (1.4%) unexpectedly had a remarkable reduction in TC concentration by more than 40%. Hyper-responders, even to low-dose statin, were found for the first time in this large-scale and long-term investigation. Overall adverse drug reactions occurred in 3.3% of subjects during the 6-year treatment, the major events being hepatic and musculoskeletal disorders, of which the incidence was less than 1%. Low-dose simvastatin therapy of 5 mg/day effectively controlled the serum TC concentration by reducing it by approximately 20% on average in hypercholesterolemic Japanese patients, a reduction that corresponds to the effect of simvastatin 20 mg/day in Western studies. In addition, the low incidence of drug-related adverse events in this study may. be also related to the low dosage of simvastatin

Large-scale cohort study on the relationship between serum lipid concentrations and risk of cerebrovascular disease under low-dose simvastatin in Japanese patients with hypercholesterolemia: Sub-analysis of the Japan Lipid Intervention Trial (J-LIT)

金沢大学大学院医学系研究科　Background: The Japan Lipid Intervention Trial was a nationwide cohort study of 52,421 hypercholesterolemic patients treated with open-labeled simvastatin for 6 years under standard clinical practices. Cerebrovascular disease (CVD) is one of the leading causes of death in Japan, but the effect of hypercholesterolemia on CVD has not been well established in Japanese patients. This study aimed to determine the relationship between the risk of CVD and serum lipid concentrations during treatment in Japan. Methods and Results: Patients were treated with 5-10 mg/day of simvastatin and all, including those who discontinued simvastatin for any reason, had their lipid concentrations and incidence of CVD monitored for 6 years. Data of 41,088 patients were analyzed in this study, excluding those who had a history of coronary heart disease or CVD. The risk of cerebral infarction was higher in patients whose mean total cholesterol concentrations during treatment were ≥240 mg/dl, low-density lipoprotein cholesterol concentrations ≥160 mg/dl, triglycerides ≥150 mg/dl and high-density lipoprotein cholesterol concentrations <40 mg/dl. There was no obvious correlation between cerebral hemorrhage and serum lipid concentrations. Conclusion: Improvement of serum lipid concentrations is important for reducing the incidence of cerebral infarction

Activated Microglia Inhibit Axonal Growth through RGMa

By causing damage to neural networks, spinal cord injuries (SCI) often result in severe motor and sensory dysfunction. Functional recovery requires axonal regrowth and regeneration of neural network, processes that are quite limited in the adult central nervous system (CNS). Previous work has shown that SCI lesions contain an accumulation of activated microglia, which can have multiple pathophysiological influences. Here, we show that activated microglia inhibit axonal growth via repulsive guidance molecule a (RGMa). We found that microglia activated by lipopolysaccharide (LPS) inhibited neurite outgrowth and induced growth cone collapse of cortical neurons in vitro—a pattern that was only observed when there was direct contact between microglia and neurons. After microglia were activated by LPS, they increased expression of RGMa; however, treatment with RGMa-neutralizing antibodies or transfection of RGMa siRNA attenuated the inhibitory effects of microglia on axonal outgrowth. Furthermore, minocycline, an inhibitor of microglial activation, attenuated the effects of microglia and RGMa expression. Finally, we examined whether these in vitro patterns could also be observed in vivo. Indeed, in a mouse SCI model, minocycline treatment reduced the accumulation of microglia and decreased RGMa expression after SCI, leading to reduced dieback in injured corticospinal tracts. These results suggest that activated microglia play a major role in inhibiting axon regeneration via RGMa in the injured CNS

Cilostazol Activates Function of Bone Marrow-Derived Endothelial Progenitor Cell for Re-endothelialization in a Carotid Balloon Injury Model

BACKGROUND: Cilostazol(CLZ) has been used as a vasodilating anti-platelet drug clinically and demonstrated to inhibit proliferation of smooth muscle cells and effect on endothelial cells. However, the effect of CLZ on re-endothelialization including bone marrow (BM)-derived endothelial progenitor cell (EPC) contribution is unclear. We have investigated the hypothesis that CLZ might accelerate re-endothelialization with EPCs. METHODOLOGY/PRINCIPAL FINDINGS: Balloon carotid denudation was performed in male Sprague-Dawley rats. CLZ group was given CLZ mixed feed from 2 weeks before carotid injury. Control group was fed normal diet. CLZ accelerated re-endothelialization at 2 weeks after surgery and resulted in a significant reduction of neointima formation 4 weeks after surgery compared with that in control group. CLZ also increased the number of circulating EPCs throughout the time course. We examined the contribution of BM-derived EPCs to re-endothelialization by BM transplantation from Tie2/lacZ mice to nude rats. The number of Tie2-regulated X-gal positive cells on injured arterial luminal surface was increased at 2 weeks after surgery in CLZ group compared with that in control group. In vitro, CLZ enhanced proliferation, adhesion and migration activity, and differentiation with mRNA upregulation of adhesion molecule integrin αvβ3, chemokine receptor CXCR4 and growth factor VEGF assessed by real-time RT-PCR in rat BM-derived cultured EPCs. In addition, CLZ markedly increased the expression of SDF-1α that is a ligand of CXCR4 receptor in EPCs, in the media following vascular injury. CONCLUSIONS/SIGNIFICANCE: CLZ promotes EPC mobilization from BM and EPC recruitment to sites of arterial injury, and thereby inhibited neointima formation with acceleration of re-endothelialization with EPCs as well as pre-existing endothelial cells in a rat carotid balloon injury model. CLZ could be not only an anti-platelet agent but also a promising tool for endothelial regeneration, which is a key event for preventing atherosclerosis or restenosis after vascular intervention

Aminergic and cholinergic innervations of the spinal cord blood vessels of cats

✓ The distribution patterns of aminergic and cholinergic nerve fibers in the feline spinal cord blood vessels were studied by means of amine histofluorescence and acetylcholinesterase (AChE) staining. These patterns were compared with those of the cerebral blood vessels. The anterior spinal artery had a dense network of aminergic and AChE-positive (probably cholinergic) nerve fibers. The posterior spinal vein, in contrast, exhibited only aminergic nerve fibers. Small intraparenchymal blood vessels in the spinal cord also had strongly fluorescent (probably peripheral) aminergic nerve fibers, as well as pial spinal blood vessels. This was a characteristic feature in the spinal cord. The distribution pattern and the density of these two sorts of nerve fibers in the anterior spinal artery varied widely with the individual segment of the spinal cord. The thoracic spinal cord had the lowest number of these nerve fibers of any part of the spinal cord. This fact may explain why the thoracic spinal cord is most susceptible to ischemic change.</jats:p