The presence of tandem endothelial nitric oxide synthase gene polymorphisms identifying brain aneurysms more prone to rupture

OBJECT: It is becoming apparent that the presence of certain genetic variations (polymorphisms) may increase the individual's susceptibility to cardiovascular diseases, even in the absence of a family history. We hypothesized that brain aneurysms more prone to rupture may be identified on the basis of an individual's genotype for endothelial nitric oxide synthase (eNOS), a critical vasomodulatory protein found to be increasingly relevant to the pathobiology of aneurysms. METHODS: Patients' clinical data were recorded prospectively. Genomic DNA was isolated from blood samples obtained from individuals presenting consecutively to the Mayo Clinic with ruptured (58 patients) or unruptured (49 patients) intracranial saccular aneurysms. Using polymerase chain reaction and gene microarray technology, the following eNOS genetic polymorphisms were studied: intron-4 27-base pair variable number of tandem repeats (27 VNTR); promoter single nucleotide polymorphism (T-786C SNP); and exon-7 SNP (G894T SNP). Both groups of patients had similar demographic and clinical characteristics. For all three polymorphisms, variant alleles (p < or = 0.003) and their corresponding genotypes (p < or = 0.006) were found two to four times more frequently in patients with ruptured aneurysms than in patients with unruptured aneurysms. Strikingly, the odds ratio for presenting with a ruptured brain aneurysm among individuals demonstrating the copresence of all three variant alleles was 11.4 (95% confidence interval 1.7-75.9, p = 0.004). CONCLUSIONS: The authors have uniquely identified a set of tandem eNOS gene variations whose presence can be used to identify patients with aneurysms likely to rupture. We believe that if this finding is reproducible in a large multicenter study, in addition to known anatomical factors a rapid and cost-effective screening tool will become available to clinicians as a genetic aid to predict the risks of rupture in patients presenting with unruptured intracranial aneurysms.     

Using endothelial nitric oxide synthase gene polymorphisms to identify intracranial aneurysms more prone to rupture in Japanese patients

OBJECT: Recent investigators found that the presence of three tandem polymorphisms of the endothelial nitric oxide synthase (eNOS) gene-promoter single nucleotide polymorphism (SNP) T-786C, intron-4 27-bp variable number of tandem repeats, and the G894T SNP in exon 7-was indicative of intracranial aneurysms more prone to rupture in a Caucasian patient sample. In the present study, the authors sought to determine whether the presence of these eNOS polymorphisms could indicate which Japanese patients with aneurysms were more endangered by a subarachnoid hemorrhage (SAH). METHODS: The three eNOS polymorphisms were genotyped in 297 patients with ruptured aneurysms (RAs), 108 patients with unruptured aneurysms (UAs), and 176 healthy volunteers by using polymerase chain reaction. The distribution of the variant alleles did not differ significantly (p > 0.05) between the RA group and the UA group. The frequency of the corresponding genotypes between the two groups and a haplotype analysis did not show any significant differences. Further comparisons of the RA and UA groups with the control group did not yield any significant allele or genotype frequency differences. Conclusions. These data show that the examined set of eNOS polymorphisms were not indicative of which Japanese patients with intracranial aneurysms would suffer an SAH. The presence of eNOS polymorphisms is not useful in identifying intracranial aneurysms that are more prone to rupture in a Japanese patient sample.     

Influence of endothelial nitric oxide synthase T-786C single nucleotide polymorphism on aneurysm size

OBJECT: Among patients with aneurysms, those with heterozygous (T/C) endothelial nitric oxide synthase (eNOS) T-786C single nucleotide polymorphism (SNP), a mutation reducing endothelial nitric oxide synthesis, are reported to have larger ruptured intracranial aneurysms (IAs) than those with homozygous (C/C or T/T) genotype. The authors tested patients harboring aneurysms for eNOS T-786C SNP in two populations--Japanese and Korean. METHODS: The eNOS T-786C SNP was genotyped through direct sequencing in genomic DNA obtained from 336 Japanese and 191 Korean patients with lAs and 214 Japanese and 191 Korean control volunteers. Differences in genotype frequencies among the various aneurysm sizes were evaluated using the Fisher exact test. There was no significant difference in heterozygous (T/C) eNOS T-786C SNP between aneurysms 5 mm or smaller and those from 6 to 9 mm, and between lesions 5 mm or smaller and those 10 mm or larger in 336 Japanese patients harboring aneurysms--220 with ruptured and 116 with unruptured lesions--and in 191 Korean patients with ruptured aneurysms. CONCLUSION: The eNOS T-786C SNP genotype does not influence the size of aneurysms.     

Analysis of endothelial nitric oxide synthase (eNOS) G894T polymorphism and semen parameters in a Chinese Han population

Previous studies have shown that endothelial nitric oxide synthase (eNOS) gene may be involved in abnormal semen parameters. However, the relationship between eNOS G894T polymorphism and semen parameters remains controversial. The purpose of this study was to investigate the association of eNOS G894T polymorphism and semen parameters. The genotype frequency of eNOS G894T was determined in 270 idiopathic asthenozoospermia patients and 248 ethnically matched healthy volunteers using iPLEX genotyping assays on a MassARRAY^® (Sequenom, San Diego, CA, USA) platform. The statistical analysis performed with Fisher's exact test showed no significant difference in frequencies of genotypes between both groups. The logistic regression showed that genotypes GT, TT and allele T were nonassociated with increased risk of asthenozoospermia in the patient group with ≤5% or >5% sperm with normal forms. The dependence on genotypes of semen parameters was further investigated in both patients and control group. There was no significant difference as compared to control group (P > 0.05). Our study indicated that eNOS gene G894T polymorphism may not have an adverse effect on semen parameters in a Chinese Han population.     

Impact of Nitric Oxide Synthase Glu298Asp Polymorphism on the Development of End-Stage Renal Disease in Type 2 Diabetic Egyptian Patients

Abstract

Background: Nitric oxide is an important regulator of renal hemodynamics. This study aimed to investigate the role of endothelial nitric oxide synthase (eNOS) gene polymorphism in type 2 diabetic patients with end-stage renal disease (ESRD) and to elucidate any alteration of nitric oxide synthase (NOS) activity caused by this polymorphism. Methods: The study included 80 patients with type 2 diabetes of >10 years duration (40 with diabetes-derived ESRD, 40 without nephropathy) and 20 healthy controls. Plasma nitrate/nitrite level, and serum NOS activity were measured and eNOS Glu298Asp genotypes were determined. Results: The frequency of Glu/Glu (GG) genotype in diabetics with ESRD was lower than controls. However, the frequency of Asp/Asp (TT) genotype was increased in diabetics with ESRD as compared to those without nephropathy and controls. Diabetics with ESRD had significantly lower nitrate/nitrite level and NOS activity than those without nephropathy. Diabetic patients with TT genotype are at a significant risk for ESRD. Moreover, subjects carrying TT genotype had lower nitrate/nitrite level and NOS activity than those carrying GG genotype. In diabetics with ESRD, creatinine clearance was positively correlated with both nitrate/nitrite level and NOS activity. Conclusions: These results imply that TT genotype of eNOS may be associated with an increased risk of ESRD in Egyptian type 2 diabetics. It could represent a useful genetic marker to identify diabetics at high risk for the development of ESRD. However, larger future prospective studies are required to confirm the role of eNOS gene polymorphism in the progression of diabetic nephropathy to ESRD.     

Relationship between endothelial nitric oxide synthase (eNOS) and natural history of intracranial aneurysms: meta-analysis

The aneurysmal subarachnoid hemorrhage is a major public health problem described as a sudden drastic event with no warning symptoms and high morbidity and mortality rates. The role of the endothelial isoform of nitric oxide synthase gene polymorphism in intracranial aneurysms (IAs) is still a matter of controversy with divergent findings among European, American, and Asian populations. Our study purposed to test the association between intracranial aneurysms formation and nitric oxide gene polymorphisms through a systematic review and meta-analysis. Systematic search on Medline, Lilacs, and EMBASE was performed. The primary search resulted in 139 papers, out of which 9 met our inclusion criteria after a full text analysis. The dominant T786C model found a significant association with IA (OR 1.22, 95 % CI 1.04–1.44, p?=?0.01), so did studies of the recessive T786C model (OR 0.37, 95 % CI 0.30–0.45, p?<?0.0001) but with opposite effect. Our findings support the presence of the T786C polymorphism as a predictor for the development of intracranial aneurysm in the cerebral vascular system. More studies are necessary in order to elucidate the pathways of the endothelial nitric oxide synthase (eNOS) in cerebrovascular diseases and in defining how different allelic combinations of the eNOS gene single-nucleotide polymorphism (SNP) could favor this pathological process.     

Endothelial nitric oxide synthase gene/gender interactions and the renal hemodynamic response to angiotensin II

Endothelial function is dependent on the generation of nitric oxide (NO) by the enzyme endothelial NO synthase (eNOS). One functional coding polymorphism of the eNOS gene (G894-->T) is associated with reduced enzyme activity, increased coronary heart disease, and the development of end-stage renal failure. Because gender and renin-angiotensin system activation also play key roles in the development of renal and cardiovascular disease and because NO plays a role in the response to angiotensin II (AngII), it was hypothesized that the eNOS gene G894-->T polymorphism would be a determinant of the systemic and renal vascular response to AngII. Fifty young, healthy, normotensive individuals who were on a controlled sodium and protein diet for 1 wk underwent assessment of BP and renal hemodynamic function at baseline and during AngII infusion (4 ng/kg per min for 45 min). Participants were genotyped for the eNOS gene G894-->T polymorphism and then segregated into groups on the basis of gender and genotype (GG versus GT/TT). Baseline values for renal blood flow, effective renal plasma flow, and GFR were lower in men with the T allele compared with men who were homozygous for the G allele (P = 0.03), but the polymorphism was not associated with renal hemodynamic function in women. The BP responses to AngII were similar in men and women regardless of genotype. Both multivariate linear regression and analysis of covariance (ANCOVA) revealed a relationship between gender and genotype. Men with the GT/TT genotype exhibited a significantly greater decrease in GFR (P = 0.04) in response to AngII than did those with the GG genotype. This association was not observed in women. The eNOS gene G894-->T polymorphism is a determinant of both baseline renal hemodynamic function and the hemodynamic response to AngII in men but not in women.     

Association of the T-786C, G894T and 4a/4b polymorphisms of the endothelial nitric oxide synthase gene with vasculogenic erectile dysfunction in Iranian subjects

What's known on the subject? and What does the study add? We know that nitric oxide (NO) plays a significant role in penile tumescence. NO is produced during enzymatic conversion of L‐arginine to L‐citrulline by three distinct isoforms of NO synthase (NOS), namely, inducible (iNOS), endothelial (eNOS) and neural (nNOS). The endothelial isoform of NOS (eNOS), encoded by the NOS3 gene, is the main source of NO. We determined all three eNOS gene polymorphisms in men with vasculogenic erectile dysfunction. There was a significant difference between the group of men with vasculogenic erectile dysfunction and normal healthy men when compared by genotype distribution.

OBJECTIVE

? To investigate the association of the T‐786C, G894T and variable number of tandem repeats (VNTRs) in intron 4 (a/b) polymorphisms of the eNOS gene in Iranian subjects with vasculogenic erectile dysfunction (ED).

PATIENTS AND METHODS

? A total of 322 consecutive patients with vasculogenic ED were recruited. Patients with concomitant risk factors for ED were excluded. ? Patients with ED were identified based on history‐taking, detailed physical examination, serum biochemistry, sex hormone measurements, application of the International Index of Erectile Function (IIEF) questionnaire, and penile duplex Doppler ultrasonography after intracavernosal injection of 20 µg prostaglandin E₁. The control group comprised 318 age‐matched healthy male volunteers. ? Genotyping was performed by polymerase chain reaction–restriction fragment length polymorphism and the T‐786C, G894T and VNTR intron 4 polymorphisms of the eNOS gene were determined.

RESULTS

? After multivariate regression analysis, significant differences were seen in the frequencies of genotypes and alleles of the two T‐786C and G894T polymorphisms when patients with ED and normal controls were compared. ? In a multiple logistic regression analysis, the odds ratio (OR) of increased ED was strongly associated with the ‐786C allele [adjusted OR = 3.12, 95% confidence interval (CI) = 2.28–4.25; P= 0.001] and the 894T allele (adjusted OR = 3.87, 95% CI = 2.53–4.87; P= 0.001). ? The data showed a higher prevalence of the T‐786C CC genotype (adjusted OR = 2.72, 95% CI = 1.88–3.65; P= 0.006), and the G894T GT (adjusted OR = 1.72, 95% CI 1.24–2.83; P= 0.037) and G894T TT genotypes (adjusted OR = 3.42, 95% CI 2.42–4.26; P= 0.001) in patients with ED than in the controls.

CONCLUSIONS

? The findings of the present study suggest that the eNOS T‐786C and G894T polymorphisms are strong predictors of the predisposition to ED in addition to traditional risk factors, signifying a genetic influence for this multifactorial disease. ? Further studies in different ethnic populations are needed to better elucidate the role of eNOS gene polymorphism in the pathogenesis of ED.     

Endothelial Nitric Oxide Synthase (eNOS) Gene Polymorphism in Early Term Chronic Allograft Nephropathy

Chronic allograft nephropathy (CAN) is a complex phenomenon caused by underlying kidney disease with superimposed enviromental and genetic factors. CAN development begins with progressive renal microvascular injury. Endothelial cells play key roles in the regulation of vascular tone, permeability, and remodeling. A reduction in basal nitric oxide (NO) release as a result of genetic variation in endothelial NO synthase (eNOS) function may predispose to hypertension, thrombosis, vasospasm, and atherosclerosis, all contributing to the development of CAN. We analyzed the G894T mutation at exon 7 of the eNOS gene in relationship to CAN among 81 children with renal transplantations. The 20 patients who developed CAN underwent renal biopsies for histological confirmation. Proteinuria and hypertension were observed in CAN. We selected 173 healthy reference subjects. The G894T polymorphism of the eNOS gene was determined by PCR–restriction fragment-length polymorphism analysis. The group included 33 male and 48 female subjects who received 32 living-related grafts and 49 from deceased donors (DD) donors. Donor age (y) was 32.7 ± 13.7 and the HLA A,B,DR mismatch number of the cadaveric cases was 3.5 ± 0.79. The distribution of the genotypes were ENOS GG/GT/TT 48%, 33%, 19%, respectively. G-alleles frequency was 64.8%; T-allele frequency was 35.2%. ENOS G894T gene polymorphism did not seem to influence long-term renal allograft outcome. Recipient ENOS G894T gene polymorphism did not alter the risk of chronic allograft failure. Even if NO synthesis and bioactivity are influenced by this polymorphism, many vasoactive factors may have roles to suppress the advantageous effects of NO.     

Influence of eNOS gene polymorphisms on carotid atherosclerosis.

INTRODUCTION: Nitric oxide (NO) is an endothelium-derived relaxing factor which plays a role in atherogenetic events. Polymorphisms in the endothelial NO synthase gene (eNOS) influences the functional activity of the enzyme and affect the susceptibility to atherogenesis. In this study we determined whether T-786C, G894T and 4a/4b eNOS genetic variants may increase the susceptibility to carotid atherosclerosis. METHODS: The study groups included 304 consecutive patients with severe carotid stenosis (>/=70%) and 544 control subjects. The eNOS polymorphisms were analysed by molecular biology techniques. RESULTS: The genotype distribution and allele frequency of eNOS 4a/4b, but not T-786C and G894T, polymorphism was significantly different between patients and controls. Using logistic regression with adjustment for other risk factors, the 4a allele and the combined genotype 4a4a+4a4b/894TT+GT and -786CC+TC/894TT+GT were associated with carotid stenosis (OR=1.5, p=0.02; OR=1.8, p=0.01; OR=1.5, p=0.04, respectively). In a subset of patients (30 of 304) with no traditional risk factors for atherosclerosis, a relatively high incidence of the 4a allele and 4a4a+4a4b/-786CC+TC combined genotype was noted. DISCUSSION: Our findings suggest that the 4a allele and the eNOS combined genotypes are independent predisposing factors to carotid atherosclerosis.     

Ruptured de novo intracranial aneurysms

Summary Objective. We describe the actual state of ruptured de novo intracranial aneurysms to contribute to a guideline of follow-up for the patients with treated intracranial aneurysm.Methods. The authors retrospectively investigated 12 cases drawn from 483 consecutive cases of aneurysmal subarachnoid hemorrhage at our institute over a period of 22 years, in which a previously undemonstrated (hence de novo) intracranial saccular aneurysm formed and ruptured after successful treatment of a prior aneurysm.Findings. The 12 cases constitute 2.5% of the 483 patients who left our hospital alive. Eleven cases were females and one was a male with a mean age of 55.7 years (range 29–75) at the first subarachnoid haemorrhage (SAH) and an interval between the first and the second rupture of 10.7 years (range: 2.6–23.8, standard deviation: 6.86, 95% confidence interval: 6.39–15.1). Four cases did not have risk factors such as hypertension, family history, smoking, multiple aneurysms, and moyamoya disease. None of these ruptured de novo aneurysms was at the same location as the original lesion. One-third (4 cases) of the de novo lesions in our series were found on the opposite side to each prior lesion.Interpretation. For not only young but also elder patients with a treated aneurysm (from the fifth decade to the sixth), especially for women, late angiography or alternative modalities of less-invasive examination should be considered. To detect de novo intracranial aneurysms before rupture, the search for a de novo aneurysm should be performed within 6.39 years after a previous examination that shows an aneurysm to be nonexistent, in view of the 95% confidence interval of the mean time to de novo aneurysmal rupture (6.39–15.1 years). If applied this survey, 75% (8 cases of 12 cases) of our de novo aneurysms would be detected before rupture.     

Nitric Oxide Synthase Gene Polymorphisms in Children with Primary Nocturnal Enuresis: A Preliminary Study

Aims. Recent studies demonstrated some differences in urinary electrolytes of enuretic children. Intrarenal nitric oxide (NO) serves as a major regulator of renal sodium and water excretion like an endogenous diuretic. This study aimed to investigate endothelial (eNOS), and neuronal (nNOS) NO synthase gene polymorphisms in children with primary nocturnal enuresis (PNE). Materials and Methods. The eNOS gene polymorphism was investigated in 171 Turkish children (57 PNE cases and 114 healthy, non-enuretic controls), and nNOS gene polymorphism was determined in 158 Turkish children (83 PNE cases and 75 healthy, non-enuretic controls). The glu298asp (G/T) polymorphism of the eNOS and C276T (C/T) polymorphism of nNOS genes were genotyped using PCR. Results. The distribution of GG, TG, and TT genotypes for eNOS gene was 48%, 33%, and 19% in PNE, compared with 61%, 26%, and 13% in the controls (p > 0.05). The distribution of CC, TC, TT and genotypes for nNOS gene was 31%, 29%, and 40% in PNE compared with 10%, 43%, and 47% in the controls. CC genotype was found higher in enuretic children (p?=?0.002). The eNOS and nNOS gene polymorphisms were not associated with positive family history, frequency of enuresis, and clinical response to desmopressin. Conclusions. This study is the first to search the NOS gene polymorphisms in children with PNE. It was determined that eNOS gene polymorphism may not be associated with PNE, while nNOS gene polymorphism, a predominantly CC genotype, may be associated with PNE in Turkish children. Further studies with larger samples together with the detection of enuresis gene may help determine the exact role of nNOS gene polymorphism in enuresis.     

冠心病与内皮型一氧化氮合酶基因多态性的关系

目的 探讨内皮型一氧化氮合酶(eNOS)基因-786T/C,4a4b,894G/T等3个多态性位点与冠心病(CAD)发病相关.方法 对146例中国汉族人群CAD患者和113例正常对照进行遗传学分析,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)和PCR技术分析2个SNP位点即-786T/C和894G/T,以及1个VNTR位点4a4b,检测各位点基因型和等位基因频率,采用HaploView 4.0及SPSS 13.0软件经x2检验比较两组间各位点基因型及等位基因频率的差异.结果 CAD组中eNOS基因-786T/C位点CC基因型频率为2.0%,4a4b位点4a/4a基因型频率为5.4%,对照组eNOS基因-786T/C位点CC基因型频率为0.0%,4a4b位点4a/4a基因型频率为0.9%,差异有统计学意义(P＜0.05).CAD组和对照组在eNOS基因的894G/T位点等位基因和基因型频率分布差异均无统计学意义(P＞0.05).结论 eNOS基因-786T/C和4a4b多态性与中国汉族人群CAD存在关联,C等位基因和4a等位基因可能是CAD发病的危险因素.eNOS基因894G/T位点与CAD发病无明显相关.

Abstract：

Objective To investigate the relationship between the 3 polymorphisms ( -786T/C,4a4b,894G/T) in endothelial nitric oxide synthase (eNOS) gene and coronary artery disease (CAD).Methods 146 patients with CAD and 113 healthy unrelated individuals in a Chinese Han nation were involved.The genotype and allele frequency of each polymorphism of the eNOS gene in these patients and normal controls were examined by using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) or PCR methods.Genotypes and allele frequency were analyzed by HaploView 4.0 and SPSS13.0 software.Results The frequency of CC genotype of the -786T/C was 2.0%,and that of 4a/4a genotype of the 4a4b was 5.4% in CAD.The frequency of CC genotype of the - 786T/C was 0.0%,and that of 4a/4a genotype of the 4a4b was 0.9% in controls ( P＜0.05 ).There were significant differences in both allele and genotype frequency of -786T/C and 4a4b between CDA group and control group.Between patients with CAD and controls,there were no significant differences in the frequency of the genotypes and alleles of the 894G/T in eNOS gene.Conclusion The - 786T/C and 4a4b polymorphisms of eNOS gene may be associated with CAD.The individuals with C allele of - 786T/C and 4a allele of 4a4b are susceptible to CAD.There is no significant correlation between 894G/T polymorphism in eNOS gene and CAD.     

Glu298Asp endothelial nitric oxide synthase polymorphism is a risk factor for erectile dysfunction in the Mexican Mestizo population

Penile erection depends on the balanced action between antagonist vasoactive molecules such as nitric oxide (NO) and angiotensin. Endothelial nitric oxide synthase (eNOS) and angiotensin-converting enzyme (ACE) polymorphisms have been associated with endothelial dysfunction, which is described as a cause of erectile dysfunction (ED). Endothelial NOS and ACE are both regulators of vascular and corporal smooth muscle tone, which are connected by interaction between the NO-cyclic guanosine monophosphate pathway and the renin-angiotensin system. We analyzed the frequencies of 894 G/T (Glu298Asp) eNOS and ACE I/D polymorphisms in Mexican patients with ED (n=53) and in an age-matched control group (n=62). The populations analyzed were in Hardy Weinberg equilibrium. We found significant differences in allelic (chi2=4.42; P=.03) and genotypic frequencies (chi2=3.96; P=.04) between patients and controls for the 894 G/T eNOS polymorphism. Presence of the 894T allele in carriers increased the risk of ED (odds ratio [TT + GT versus GG] = 2.37; 95% confidence interval, 1.08 to 5.21; P=.02). Multiple logistic regression analysis showed that the Glu298Asp polymorphism was an independent factor for ED, as was diabetes mellitus, hypertension, cardiac disease, and cigarette smoking. No association was found between ACE I/D polymorphism and ED in the population studied. Therefore, our results suggest that Glu298Asp eNOS polymorphism plays a role as a genetic susceptibility factor for ED.     

Endothelial injury and inflammatory response induced by hemodynamic changes preceding intracranial aneurysm formation: experimental study in rats

OBJECT: Intracranial aneurysms are the leading cause of subarachnoid hemorrhage, which is associated with high morbidity and mortality rates. Despite advances in the microsurgical and endovascular treatment of intracranial aneurysms, little is known about the mechanisms by which they originate, grow, and rupture. To clarify the series of early events leading to formation of intracranial aneurysms, the authors compared aneurysmal morphological changes on vascular corrosion casts with parallel pathological changes in the cerebral arteries of rats. METHODS: The authors induced cerebral aneurysms by renal hypertension and right common carotid artery ligation in 40 male Sprague-Dawley rats; 10 intact rats served as the controls. The anterior cerebral artery-olfactory artery bifurcation was assessed morphologically by using vascular corrosion casts of Batson plastic reagent and immunohistochemically by using antibodies against endothelial nitric oxide synthase, alpha-smooth muscle actin, macrophages, and matrix metalloproteinase-9. RESULTS: Surgically treated rats manifested different degrees of aneurysmal changes. Based on these staged changes, the authors propose that the formation of intracranial aneurysms starts with endothelial injury at the apical intimal pad (Stage I); this leads to the formation of an inflammatory zone (Stage II), followed by a partial tear or defect in the inflammatory zone. Expansion of this defect forms the nidus of the intracranial aneurysm (Stage III). CONCLUSIONS: This is the first study to demonstrate the in vivo mechanisms of intracranial aneurysm formation. The inflammatory response that follows endothelial injury is the basic step in the pathogenesis of these lesions. In this study the investigators have expanded the understanding of the origin of intracranial aneurysms and have contributed to the further development of measures to prevent and treat aneurysms.     

Effects of the T-786C,G894T,and Intron 4 VNTR (4a/b) polymorphisms of the endothelial nitric oxide synthase gene on the risk of prostate cancer

Several studies have shown that nitric oxide (NO) and nitric oxide synthase (NOS) system plays an important role in carcinogenesis. Endothelial nitric oxide synthase (eNOS) gene polymorphisms significantly affects serum NO concentrations. Studies addressing the relationship between eNOS gene polymorphisms and prostate cancer (CaP) are very scarce. We examined the association between the 3 eNOS gene polymorphisms (T-786C, G894T, and 4a/b) with risk and clinical features of CaP. One hundred seventy patients with CaP (mean age 63.6 ± 12.4 years) and 340 age-matched healthy controls (mean age 64.9 ± 12.9 years) were recruited in this case-control study. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. For T-786C polymorphism, we found that CC genotype was associated to CaP risk [odds ratio (OR) = 3.62, 95% confidence interval (CI): 1.89–7.74, P = 0.002), high grade tumor (OR = 2.46, 95% CI:1.78–4.72; P = 0.006), and advanced disease (OR = 4.67, 95% CI: 2.64?8.61; P = 0.002). Neither the CaP risk nor clinical features of CaP were associated with the G894T polymorphism. It was found that, compared with 4a/b bb genotype, the 4a/b “a” variant genotypes were associated with an increased risk of CaP in an allele dose dependent manner (OR = 2.12, 95% CI: 1.68–3.44; P = 0.031 for 4a/b ab genotype, and OR = 4.32, 95% CI: 2.21–6.08; P = 0.001 for 4a/b aa genotype). In addition, genotypes with the “a” allele of the eNOS 4a/b polymorphism predispose the patients to high grade (OR = 4.76, 95% CI: 2.74–8.62; P = 0.001) and advanced CaP (OR = 5.28, 95% CI: 3.64–8.72; P = 0.001). Furthermore, the T-Asp-b and C-Asp-b haplotypes were associated with a significantly decreased risk of CaP (OR = 0.44, 95% CI: 0.33–0.77; P = 0.004, and OR = 0.39, 95% CI: 0.26–0.61; P = 0.001, respectively). We found significant differences in genotype distribution and allelic frequencies between CaP patients and controls for the T-786C, and 4a/b eNOS polymorphisms.     

Size of cerebral aneurysms and related factors in patients with subarachnoid hemorrhage

BACKGROUND: As the indication for surgical treatment of incidentally discovered small aneurysms remains controversial. METHODS: We retrospectively investigated the characteristics of small ruptured aneurysms and examined the relationship between the size and location of ruptured intracranial aneurysms and the sex, age, lifestyle, and medical history of 280 patients with ruptured aneurysm treated at our institute. RESULTS: The mean diameter of ruptured aneurysms in this series was 7.6 mm. In diameter, 135 (48.2%) ranged between 5 and 10 mm; 73 (26.1%) were smaller than 5 mm. The size of the ruptured aneurysms was significantly smaller (mean 6.5 mm) in patients with non- or poorly controlled hypertension than in normotensive patients (mean 8.3 mm) (p < 0.05). Ruptured aneurysms in the anterior communicating artery (AcomA) and anterior cerebral artery (ACA) were significantly smaller (p < 0.01) than those in the internal carotid artery or middle cerebral artery. Among 58 patients with multiple aneurysms, only 7 (12%) suffered rupture of aneurysms smaller than 5 mm (p < 0.01). Patients younger than 40 years and patients with a family history of subarachnoid hemorrhage appeared to predispose to the rupture of small-sized aneurysms, although those did not affect the statistical significance. CONCLUSIONS: This study shows that even aneurysms smaller than 10 mm may rupture. However, treatment decisions for unruptured aneurysm should not be based solely on the size of the unruptured aneurysms. Our data implies that even small aneurysms in the AcomA and ACA had an increased tendency for rupture, and that hypertensive patients were at higher risk for the rupture of small aneurysms.     

False localization of rupture site in patients with multiple cerebral aneurysms and subarachnoid hemorrhage

OBJECTIVE: Patients with subarachnoid hemorrhage and multiple intracranial aneurysms present a unique challenge to the neurosurgeon. Unless all aneurysms can be clipped through a single craniotomy, the surgeon must accurately determine which aneurysm has ruptured. Misjudgment may result in disastrous postoperative rebleeding from the untreated but true ruptured lesion. We assessed the risk of false localization of the rupture site and subsequent rebleeding and documented the problems in predicting the true rupture site when patients have multiple intracranial aneurysms. METHOD: We reviewed the records of a consecutive series of 93 patients treated over a period of 12 years who presented with their first subarachnoid hemorrhage and who had multiple intracranial aneurysms. The rupture site was determined on the basis of computed tomographic and angiographic findings, and the supposed ruptured aneurysm was clipped within 2 days of hemorrhage in each patient. Additional aneurysms that could not be accessed in the same surgical session were operated on at a later stage. All patients' records were reviewed, and all computed tomographic scans and angiograms, including repeat studies performed in some patients, were retrospectively reevaluated by the authors, who had no knowledge of the patients' clinical information. RESULTS: The location of the aneurysm that ruptured was verified at the time of surgery or during the autopsy in 76 patients (82%). The aneurysm that ruptured was the one predicted as ruptured by the surgeon before surgery in 69 patients (91%) and in retrospect in 72 patients (95%). Five of the 6 patients in whom the ruptured aneurysm was not correctly identified were thought to have only a single aneurysm. Four patients rebled after surgery, and 2 patients died as a result of the rebleeding. CONCLUSION: In the reported series, the most common cause of rebleeding soon after aneurysm surgery was failure to obliterate the ruptured aneurysm, usually because it was missed on the initial angiogram. The results support not only meticulous radiological investigation of all intracranial arteries before surgery but also thorough surgical inspection of the target aneurysm in all cases of subarachnoid hemorrhage even after one candidate lesion has been discovered.     

The significance of unruptured intracranial saccular aneurysms

The authors report the results of a long-term follow-up study of 130 patients with 161 unruptured intracranial saccular aneurysms. Their findings suggest that unruptured saccular aneurysms less than 10 mm in diameter have a very low probability of subsequent rupture. The mean diameter of the aneurysms that subsequently ruptured was 21.3 mm, compared with a diameter of 7.5 mm for aneurysms defined after rupture at the same institution. Part of the explanation for this discrepancy may be that the size of the filling compartment of the aneurysm decreases after rupture. There is also evidence from the present study that intracranial saccular aneurysms develop with increasing age of the patient and stabilize over a relatively short period, if they do not initially rupture, and that the likelihood of subsequent rupture decreases considerably if the initial stabilized size is less than 10 mm in diameter. Consequently, the critical size for aneurysm rupture is likely to be smaller if rupture occurs at the time of or soon after aneurysm formation. There seems to be a substantial difference in potential for growth and rupture between previously ruptured and unruptured aneurysms.     

Gene-polymorphisms of angiotensin converting enzyme and endothelial nitric oxide synthase in patients with erectile dysfunction.

AIMS OF THE STUDY: Regulation of the penile smooth muscle tone and contractility is closely related to the activity of vasoactive substances, angiotensin II or nitric oxide. We investigated the relationship between gene polymorphism in the angiotensin converting enzyme (ACE) or endothelial nitric oxide synthase (ecNOS) and development of erectile dysfunction. METHODS: In 84 subjects with organic erectile dysfunction and 63 control subjects, gene polymorphisms in the ACE and ecNOS were determined by the polymerase chain reaction (PCR). RESULTS: The DD genotype of ACE was significantly (P < 0.01) more frequent in subjects with organic erectile dysfunction (54%) than in control subjects (24%). There was no significant difference in the distribution of the genotypes of ecNOS. CONCLUSION: The deletion polymorphism in the ACE gene, the DD genotype, as a marker of general vascular disease, may be seen more frequently in men with a diagnosis of vasculogenic erectile dysfunction.