Asymmetric dimethylarginine determines the improvement of endothelium-dependent vasodilation by simvastatin: Effect of combination with oral L-arginine.

OBJECTIVES: We hypothesized that the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide (NO) synthase (eNOS), might determine the endothelial effects of statins. BACKGROUND: Endothelial NO synthase is up-regulated by statins. However, statins failed to improve endothelial function in some studies. Asymmetric dimethylarginine inhibits eNOS by a mechanism that is reversible by L-arginine. METHODS: Ninety-eight clinically asymptomatic elderly subjects had their plasma ADMA levels screened. Those in the highest (high ADMA, n = 15) and lowest quartiles of the ADMA distribution (low ADMA, n = 13) were eligible to receive, in a randomized order, simvastatin (40 mg/day), L-arginine (3 g/day), or a combination of both, each for 3 weeks. Endothelium-dependent vasodilation (EDD) was assessed by brachial artery ultrasound. RESULTS: Simvastatin had no effect on EDD in subjects with high ADMA (6.2 +/- 1.2% vs. 6.1 +/- 0.9%), whereas simvastatin plus L-arginine significantly improved EDD (9.8 +/- 1.5% vs. 5.3 +/- 0.8%; p < 0.01). In subjects with low ADMA, simvastatin improved endothelial function when given alone (9.5 +/- 3.2% vs. 6.1 +/- 3.8%; p < 0.001) or in combination with L-arginine (9.0 +/- 3.1% vs. 6.3 +/- 3.3%; p = 0.001). L-arginine alone improved endothelial function in both groups. Endothelium-independent vasodilation was not affected. CONCLUSIONS: Simvastatin does not enhance endothelial function in subjects with elevated ADMA, whereas it does so in patients with low ADMA. Combination of simvastatin with oral L-arginine improves endothelial function in subjects with high ADMA, but has no additional effect in subjects with low ADMA. As NO-mediated effects may play a major role in the therapeutic effects of statins, ADMA concentration is an important factor that influences the "pleiotropic" effects of simvastatin.     

Apolipoprotein AI-CIII-AIV gene cluster polymorphisms in relation to cholesterol gallstone

OBJECTIVE: To investigate the frequency of variants at Xmn I, Msp I sites of apolipoprotein (Apo), A I‐CIII‐AIV gene cluster, and its relation to cholesterol gallstones in Chinese patients. METHODS: Restriction fragment length polymorphisms (RFLP) at Xmn I, Msp I sites of ApoAI‐CIII‐AIV gene cluster were studied using a polymerase chain reaction (PCR) in 161 patients with cholesterol gallstones and 94 healthy subjects from a Chinese population in Sichuan Province. RESULTS: In both the cholesterol gallstone group and the healthy control group, X1 and M1 alleles were the major alleles and homozygous X₁X₁ and M₁M₁ genotypes were the most frequent. However, the frequency of X2 allele mutation in female patients of the cholesterol gallstones group was significantly higher than that in women in the healthy control group (P < 0.05), but no difference was found in the frequency of M2 alleles mutation (P > 0.05). CONCLUSION: The data showed that Xmn I RFLP of ApoAI‐CIII‐AIV gene cluster is associated to some extent with cholesterol gallstones in female Chinese patients.     

ATP损耗是MPP+引起α-synuclein转基因线虫多巴胺能神经元死亡和虫体死亡的主要原因

目的 揭示环境神经毒素MPP 对线虫的毒性影响并探讨其毒性机理.方法 以人源α-synuclein转基因线虫作为动物模型,用MPP 处理该线虫,观察MPP 对线虫多巴胺能神经元和其生存能力的影响.通过供给OP50以提高线虫体内ATP的水平,对比分析ATP水平、蛋白质异常沉积等重要指标,探讨二者在MPP 引起的转基因线虫的病变中所起的作用.结果 MPP 能够引起线虫多巴胺能神经元和线虫虫体的死亡;尽管进食OP50也会引起α-synuclein的沉积,但进食OP50能够提高体内ATP的水平并缓解MPP 的毒性.虽无直接证据证明α-synuclein沉积对神经细胞的影响,但结果提示,在该转基因线虫中,与蛋白质的异常沉积相比,MPP 导致的ATP损耗是其毒性作用的最主要诱因.结论 MPP 可以引起α-synuclein转基因线虫多巴胺能神经元的死亡和虫体的死亡,其毒性的主要原因是ATP损耗而不是α-synuclein的异常聚集(沉积).     

Trophic factor induction of human umbilical cord blood cells in vitro and in vivo

The mononuclear fraction of human umbilical cord blood (HUCBmnf) is a mixed cell population that multiple research groups have shown contains cells that can express neural proteins. In these studies, we have examined the ability of the HUCBmnf to express neural antigens after in vitro exposure to defined media supplemented with a cocktail of growth and neurotrophic factors. It is our hypothesis that by treating the HUCBmnf with these developmentally-relevant factors, we can expand the population, enhance the expression of neural antigens and increase cell survival upon transplantation. Prior to growth factor treatment in culture, expression of stem cell antigens is greater in the non-adherent HUCBmnf cells compared to the adherent cells (p < 0.05). Furthermore, treatment of the non-adherent cells with growth factors, increases BrdU incorporation, especially after 14 days in vitro (DIV). In HUCBmnf-embryonic mouse striata co-culture, a small number of growth factor treated HUCBmnf cells were able to integrate into the growing neural network and express immature (nestin and TuJ1) and mature (GFAP and MAP2) neural markers. Treated HUCBmnf cells implanted in the subventricular zone predominantly expressed GFAP although some grafted HUCBmnf cells were MAP2 positive. While short-term treatment of HUCBmnf cells with growth and neurotrophic factors enhanced proliferative capacity in vitro and survival of the cells in vivo, the treatment regimen employed was not enough to ensure long-term survival of HUCBmnf-derived neurons necessary for cell replacement therapies for neurodegenerative diseases.     

Psychotic symptoms in combat-related post-traumatic stress disorder

The presence of psychotic symptoms in post-traumatic stress disorder (PTSD) has already been recognized. Using the Structured Clinical Interview Diagnostic and Statistical Manual, we searched for and assessed psychotic symptoms in 91 males suffering from combat-related PTSD. Hallucinations and delusions were present in 20% of patients. We divided all patients into three groups: the group with hallucinations and delusions, the group without these symptoms, and the group with "subthreshold" psychotic symptoms. Using the Harvard Trauma Questionnaire, Clinician-Administered PTSD Scale, and Structured Clinical Interview Diagnostic and Statistical Manual, we investigated differences between groups in the intensity of traumatization, severity of PTSD symptoms, and the frequency of depression. There were no significant differences between groups; however, there was one exception: severity of hyperarousal symptoms was positively correlated with occurrence of psychotic symptoms.     

Effect of tadalafil on erectile dysfunction in male patients with diabetes mellitus

BACKGROUND/AIM: [corrected] During the first 10 years over 50% of diabetes patients develop erectile dysfunction (ED). It is more severe and resistant to therapy than in male patients with normal glucoregulation. The purpose of this pilot study was to estimate the tadalafil (Cialis) efficacy and safety in male patients with diabetes mellitus (DM), together with moderate to severe ED. METHODS: The study included 30 male patients with diagnozed type 1 or type 2 DM together with ED. ED was estimated through the International Index of Erectile Function (IIEF-6), Sexual Encounter Profile (SEP) questionnaire and prostaglandin test, at the beginning of the research and three months after the 20 mg tadalafil therapy initiation, once a week (on Fridays). Glycosylated haemoglobin in blood (HbAlc) values were also monitored. According to the ED severity (IIEF values at the beginning of the therapy) the patients were divided into 2 groups. The previous experience with sildenafil citrate (Viagra) and prostaglandin E1 intracavernous therapy was recorded. RESULTS: Tadalafil significantly improved ED (p < 0.001) for 7.40 points of the IIEF score, i.e. for 58% and 60% towards SEP2 and SEP3 questionnaire, respectively. Compared to the previous ED therapy subjectively better tadalafil experience was recorded. Each group experienced a significant improvement in IIEF score (p < 0.001), more significantly in the group 2 (8.26+/-1.49 points) compared with the medium improvement in the group 1 (6.27+/-1.35 points). After three months HbA1c values decreased for 2.26+/-1.62 (p < 0.001). CONCLUSION: Tadalafil is an effective tool for treating ED in diabetes patients. In some situations tadalafil application could replace prostaglandin test. The sexual sphere motivation leads to the improvement of glucoregulation in DM patients.     

Hippocampal shape analysis of Alzheimer disease based on machine learning methods

BACKGROUND AND PURPOSE: Alzheimer disease (AD) is a neurodegenerative disease characterized by progressive dementia. The hippocampus is particularly vulnerable to damage at the very earliest stages of AD. This article seeks to evaluate critical AD-associated regional changes in the hippocampus using machine learning methods. MATERIALS AND METHODS: High-resolution MR images were acquired from 19 patients with AD and 20 age- and sex-matched healthy control subjects. Regional changes of bilateral hippocampi were characterized using computational anatomic mapping methods. A feature selection method for support vector machine and leave-1-out cross-validation was introduced to determine regional shape differences that minimized the error rate in the datasets. RESULTS: Patients with AD showed significant deformations in the CA1 region of bilateral hippocampi, as well as the subiculum of the left hippocampus. There were also some changes in the CA2-4 subregions of the left hippocampus among patients with AD. Moreover, the left hippocampal surface showed greater variations than the right compared with those in healthy control subjects. The accuracies of leave-1-out cross-validation and 3-fold cross-validation experiments for assessing the reliability of these subregions were more than 80% in bilateral hippocampi. CONCLUSION: Subtle and spatially complex deformation patterns of hippocampus between patients with AD and healthy control subjects can be detected by machine learning methods.     

Functional cine MRI of the abdomen for the assessment of implanted synthetic mesh in patients after incisional hernia repair: initial results

The aim of our study was to develop a method that allows the vizualiation and evaluation of implanted mesh in patients after incisional hernia repair with MRI. Furthermore, we assessed problems typically related with mesh implantation like adhesions and muscular atrophy. We enrolled 28 patients after incisional hernia repair. In 10 patients mesh implantation was done by laparoscopy (expanded polytetrafluoroethylene=ePTFE mesh) and in 18 by laparotomy (polypropylene mesh). Functional MRI was performed on a 1.5-T system in supine position. Sagittal and axial TrueFISP images of the entire abdomen were acquired with the patient repeatedly straining. Evaluation included: correct position and intact fixation of the mesh, furthermore visceral adhesions, recurrent hernia and atrophy of the rectus muscle. The ePTFE mesh was visible in all cases; the polypropylene mesh was not detectable. In seven of the ten ePTFE meshes the fixation was not intact; two recurrent hernias were detected. Twenty of 28 patients had intraabdominal adhesions. In 5 cases mobility of the abdominal wall was reduced, and 16 patients showed an atropy of the rectus muscle. Functional cine MRI is a suitable method for follow-up studies in patients after hernia repair. ePTFE meshes can be visualized directly, and typical complications like intestinal adhesions and abdominal wall dysmotility can be assessed reliably.     

Structural changes in the epithelium of the small intestine and immune cell infiltration of enteric ganglia following acute mucosal damage and local inflammation

An acute enteritis is commonly followed by intestinal neuromuscular dysfunction, including prolonged hyperexcitability of enteric neurons. Such motility disorders are associated with maintained increases in immune cells adjacent to enteric ganglia and in the mucosa. However, whether the commonly used animal model, trinitrobenzene sulphonate (TNBS)-induced enteritis, causes histological and immune cell changes similar to human enteric neuropathies is not clear. We have made a detailed study of the mucosal damage and repair and immune cell invasion following intralumenal administration of TNBS. Intestines from untreated, sham-operated and TNBS-treated animals were examined at 3 h to 56 days. At 3 h, the mucosal surface was completely ablated, by 6 h an epithelial covering was substantially restored and by 1 day there was full re-epithelialisation. The lumenal epithelium developed from a squamous cell covering to a fully differentiated columnar epithelium with mature villi at about 7 days. Prominent phagocytic activity of enterocytes occurred at 1–7 days. A surge of eosinophils and T lymphocytes associated with the enteric nerve ganglia occurred at 3 h to 3 days. However, elevated immune cell numbers occurred in the lamina propria of the mucosa until 56 days, when eosinophils were still three times normal. We conclude that the disruption of the mucosal surface that causes TNBS-induced ileitis is brief, a little more than 6 h, and causes a transient immune cell surge adjacent to enteric ganglia. This is much briefer than the enteric neuropathy that ensues. Ongoing mucosal inflammatory reaction may contribute to the persistence of enteric neuropathy.