Abstract-Effects of smoking on white matter lesions, such as lacunar infarction and leukoaraiosis, are still controversial.We hypothesized that the endothelial NO synthase (eNOS) genotype was a modulating factor for the effect of smoking on cerebral circulation. We took a cross-sectional population from the participants of a health examination to study the effects of smoking and a single-nucleotide polymorphism in the eNOS gene, T-786C. Smokers and nonsmokers were defined as having a smoking index (cigarettes per day times years) of Ն200 and 0, respectively. One hundred sixty-six male nonsmokers and 344 male smokers were recruited. Cerebral blood flow was measured by the 133 Xe inhalation method. Genotyping of T-786C was performed by using a newly developed allele-specific polymerase chain reaction. Smokers were exposed to greater oxidative stress, as estimated by urinary F 2 -isoprostane excretion. In smokers, CC homozygotes of T-786C showed a significant decrease of cerebral blood flow (56.6Ϯ13.3, 57.6Ϯ11.5, and 44.0Ϯ7.2 mL/min per 100 g tissue for TT, TC, and CC, respectively; Pϭ0.03 by ANOVA) and a significant increase of cerebrovascular resistance, whereas the eNOS genotype did not affect these parameters in nonsmokers. This result indicated that the eNOS genotype could modify cerebrovascular circulation in a general population by potentiating the adverse effect of smoking. Key Words: nitric oxide synthase Ⅲ polymorphism Ⅲ cross-sectional studies Ⅲ cerebral circulation S moking is an established risk factor for cardiovascular diseases. However, the adverse effect of smoking is controversial in some areas of cerebrovascular disease, such as lacunar infarction and white matter changes. 1-7 Such inconsistency may imply the importance of other environmental or genetic factors in modifying the effects of smoking. Because lacunar infarction and white matter changes are based on occlusive changes in small arteries perforating into the white matter and are characterized by decreased cerebral blood flow (CBF) and increased cerebrovascular resistance (CVR), the endothelial NO synthase (eNOS) gene is a good candidate for such a factor; eNOS constitutively produces NO, a potent vasodilator as well as an antitrophic factor for the arterial wall. 8 -11 Several reports have indicated that eNOS plays an essential role in the regulation of basal CBF in humans and in mice. 9,10 Furthermore, because smoking antagonizes the action of NO through the induction of oxidative stress, 12 it is logical to hypothesize that genetic alteration of eNOS activity may be a modifier of the effect of smoking on the cerebral circulation.Recently, the eNOS gene was studied extensively for genetic polymorphisms to elucidate its genetic role in cardiovascular diseases. As a result, a single-nucleotide polymorphism (SNP) in the promoter region, T-786C, was found to modify the promoter activity in vitro. 13 In addition, this SNP and a 27-bp repeat polymorphism in intron 4, called ecNOS4 a/b, were reported to influence eNOS mRNA and protein levels ...

This study aimed to clarify the efficacy, safety, and pharmacokinetics of piperacillin-tazobactam (PIPC-TAZ) in late elderly Japanese patients. This is the first antimicrobial pilot study in late elderly patients with nursing and healthcare associated pneumonia. After PIPC-TAZ administration, PIPC concentrations in plasma were measured chromatographically and the pharmacokinetic parameters were estimated. Efficacy, safety, and bacteriological evaluations were also carried out. The mean age was 85.0 years old and most of the patients were late elderly. Chest X-rays, body temperature, white blood cell count, and C reactive protein all improved significantly, and a high efficacy ratio of 90.9% was observed. Serious nephrotoxicity was observed in 4 cases (18.2%) after administration of PIPC-TAZ. Creatinine clearance (mean S.D.) measured before PIPC-TAZ therapy was significantly lower in the nephrotoxicity group (32.5 4.4 mL/min) than in the non-nephrotoxicity group (46.1 16.7 mL/min), although the ages were not different between the 2 groups. In the pharmacokinetic parameters for PIPC, total clearance was slightly lower in the nephrotoxicity group than in the non-nephrotoxicity group. However, no significant difference was observed in plasma PIPC levels between the 2 groups. In patients with renal impairment, especially with a creatinine clearance of <40 mL/ min, renal impairment was found to be an influencing factor for severe nephrotoxicity following PIPC-TAZ administration. In conclusion, the results suggest that physicians should pay close attention in order to avoid possible toxicity, and that deliberate administration planning and careful follow-up are required in late elderly patients with comprised organ dysfunction.

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Objective-Oxidative stress and NO are thought to play important roles in arteriosclerosis pathogenesis, a major cause of white matter lesions in the brain. Therefore, we examined whether NO metabolites (NOx) and 8-iso-prostaglandin F 2␣ (IsoP) levels in vivo correlated with the severity of periventricular hyperintensity (PVH) to evaluate potential roles of oxidative stress and NO in white matter lesions. Methods and Results-Participants (687 males and 528 females) of a health-screening examination were recruited into the study. The plasma NOx and urinary IsoP levels were measured using the Griess method and ELISA, respectively. PVH was diagnosed on the basis of MRIs. In nonparametric univariate trend analyses, plasma NOx as well as aging, presence of hypertension and of lacunes, mean blood pressure, and high-density lipoprotein cholesterol showed highly significant monotone correlation with PVH severity (PՅ0.01). By the multivariate ordinal regression analysis, the plasma NOx (Pϭ0.002) and urinary IsoP (Pϭ0.01) levels were found to be independent factors influencing the severity of PVH together with aging (PϽ0.001), presence of hypertension (PϽ0.001) and lacunes (PϽ0.001), and mean blood pressure (Pϭ0.001). Conclusions-Oxidative stress and NO have a close correlation with PVH severity. (Arterioscler Thromb Vasc Biol.

Invasive fungal infection (IFI) caused by Lecythophora mutabilis occasionally occurs in patients with impaired host immunity; such patients had eosinophilia at onset, and surviving patients were treated with fungal cell-membrane-targeted drugs. An 18-year-old man with mitochondrial encephalomyopathy accompanied with refractory anaemia and chronic renal failure developed septic shock caused by L. mutabilis, which was detected from a blood culture, and was identified morphologically and genetically. During the course of the infection, he had eosinophilia, although b-D-glucan levels were within the normal range. He was treated with micafungin, but deteriorated and died, despite his treatment being changed to liposomal amphotericin B. On the basis of this we suggest that IFI caused by L. mutabilis should be suspected when a compromised host develops infection and eosinophilia, and that antifungal drugs that target b-D-glucan are not advisable.