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Ali H.Turkmani, Arthur L. Day, Dong H. Kim, and Peng Roc Chen

A common surgical complication of clipping aneurysms with a calcified neck is the calcified atheroma compromising the parent arteries after clipping the neck. Clips can slip downward at the calcified neck or cause calcified atheroma encroaching the parent arteries. This video demonstrates a reconstructive clip technique to avoid these issues. A fenes-trated clip is placed first to reconstruct the distal parent artery-aneurysm neck with the fenestrated ring over the thickest calcification. Then, a straight clip reconstructs the proximal artery-aneurysm junction, leaving the thickest point of calcified walls pinching together by themselves to achieve aneurysm occlusion while preserving the parent arteries.

The video can be found here: http://youtu.be/9CM3o5_qlNQ.

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Vibhor Krishna and Dong H. Kim

Object

Studies on risk factors for subarachnoid hemorrhage (SAH) show heterogeneity. For example, hypertension has been found to be a significant risk factor in some studies but not in others. The authors hypothesized that differences in the ethnicity of the populations studied could account for these findings.

Methods

A metaanalysis was performed using 17 case-control and 10 cohort studies that met specified inclusion criteria. The authors used a random-effect model to calculate the pooled effect estimates for current smoking, hypertension, and alcohol consumption. A meta–regression analysis was performed using the ethnic composition of the study populations as a covariate. Studies were classified as multiethnic or monoethnic, and the pooled effect estimates were compared.

Results

Analysis of the cohort studies yielded a pooled effect estimate or risk ratio of 3.18 (95% confidence interval [CI] 2.37–4.26) for current smoking, 3.05 (95% CI 2.09–4.44) for hypertension, and 2.46 (95% CI 1.42–4.24) for alcohol consumption at a rate of 150 g/week or more. The results were similar for the case-control studies. For current smoking, the ethnic composition of the study population was a statistically significant predictor of heterogeneity among case-control studies (p < 0.001, even after application of the Bonferroni correction). The risk for SAH among current smokers was higher in multiethnic populations (odds ratio 3.832) than in monoethnic populations (odds ratio 2.487).

Conclusions

The results of this metaanalysis suggest that differences in susceptibility to the harmful health effects of smoking may be one cause of the observed differences in SAH incidence for different ethnic groups. The role of ethnicity in risk factors for SAH should be considered in future studies.

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Hariyadarshi Pannu, Dong H. Kim, Dongchuan Guo, Terri M. King, Grace Van Ginhoven, Toinette Chin, Katherine Chang, Yuhua Qi, Sanjay Shete, and Dianna M. Milewicz

Object

Matrix metalloproteinases (MMPs) are a family of endopeptidases that mediate vascular remodeling by degrading extracellular matrix components, such as collagen and elastin. On the basis of accumulating evidence that implicates increased MMP-2 (gelatinase A) and MMP-9 (gelatinase B) amounts and activity in the pathogenesis of aneurysms, the authors investigated the genetic association between polymorphisms in MMP-2 and MMP-9 and sporadic intracranial aneurysms.

Methods

Eight polymorphisms located in MMP-2 and MMP-9 were genotyped, and the association of these variations with disease was assessed in a Caucasian population consisting of 125 patients with intracranial aneurysms and 234 ethnically matched healthy volunteers.

Polymorphisms in the MMP-2 gene and the haplotypes generated from these polymorphisms were not associated with the occurrence of intracranial aneurysms. However, a polymorphism located in the 3′ untranslated region of MMP-9 showed a significant association with disease in the study population, with individuals carrying the TT genotype at increased risk for developing intracranial aneurysms (odds ratio 1.91, p = 0.005). Haplotypes containing the T allele of this polymorphism also showed a comparable association with disease. Similar results were obtained in an analysis of these polymorphisms in a subgroup of patients who presented with ruptured aneurysms.

Conclusions

The study findings support a role for MMP-9, but not MMP-2, in the pathogenesis of intracranial aneurysms.

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Hariyadarshi Pannu, Dong H. Kim, C. Robyn Seaman, Grace Van Ginhoven, Sanjay Shete, and Dianna M. Milewicz

Object

The identification of polymorphisms associated with an increase in the risk of developing disease is integral to the development of genetic biomarkers to identify individuals at risk. Based on reports indicating a role for angiotensin-converting enzyme (ACE) in the pathogenesis of intracranial aneurysms (IAs) as well as hypertension, an independent risk factor for IAs, the authors investigated the association between an insertion/deletion (I/D) polymorphism in the ACE gene and IAs in a Caucasian population in the US.

Methods

The patient population consisted of 162 randomly selected Caucasian patients who underwent surgical repair of an IA at Memorial—Hermann Hospital (Houston, TX) and had no family history of the disease. The ACE I/D polymorphism was typed using polymerase chain reaction amplification of genomic DNA, and allele and genotype frequencies were compared between the patients with IAs and 143 healthy Caucasian volunteers (control group) by performing logistic regression and chi-square tests.

The ACE I/D allele frequencies did not differ significantly between the patient and control populations. There were similar allele and genotype frequencies in male and female study participants in both patient and control populations. The authors found no evidence of an association between the allelic or genotypic distribution of the ACE I/D polymorphism and aneurysmal subarachnoid hemorrhage or unruptured IAs.

Conclusions

Contrary to findings in two European Caucasian populations (one British and one Polish), this polymorphism did not contribute to the risk of developing IAs in a Caucasian population in the US.

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Dong H. Kim, Xiurong Zhao, Christina H. Tu, Patrizia Casaccia-Bonnefil, and Moses V. Chao

Object. Neurotrophins prevent the death of neurons during embryonal development and have potential as therapeutic agents. During development, neuronal death occurs only by apoptosis and not by necrosis. Following injury, however, neurons can die by both processes. Data from prior studies have not clearly indicated whether neurotrophins can decrease apoptosis compared with necrosis. The goal of this study was to determine the effect of neurotrophin treatment on each of these processes following injury and to characterize the receptor(s) required.

Methods. The authors used an in vitro model of injury with the aid of primary cortical neurons obtained from rat embryos. After 9 days in culture and the elimination of glia, homogeneous and mature neurons were available for experimentation. Noxious stimuli were applied, including radiation, hypoxia, and ischemia. Subsequent cell death by apoptosis or necrosis was noted based on morphological and enzymatic assessments (such as lactate dehydrogenase [LDH] release) and assays for DNA fragmentation. The effect of treatment with nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 was determined. Finally, Western blot analyses were performed to note the neurotrophin receptor status in the neurons (tyrosine kinase receptors [Trks] and p75).

The authors studied different stimuli-induced cell death by using different processes. With the application of radiation, cells died primarily by apoptosis, as evidenced by cell shrinkage, the presence of apoptotic bodies, and specific DNA fragmentation. This was a delayed process (> 6 hours) that could be reduced by gene transcription or protein synthesis inhibitors. With ischemia, cells died immediately by necrosis, showing cell enlargement and rupture. Ischemic cell death was not affected by the inhibition of macromolecular synthesis. Hypoxia produced a mixture of the two cell death processes.

Both BDNF and neurotrophin-3 demonstrated protection against apoptotic cell death only. Statistically significant decreases of both LDH release and apoptosis-specific DNA fragmentation were noted following radiation and hypoxia, but not for ischemia. Nerve growth factor, unlike the other neurotrophins, did not affect apoptosis because a functional receptor, Trk A, was not expressed by the cortical neurons. There was expression of both Trk B and Trk C, which bind BDNF and neurotrophin-3.

Conclusions. These findings have significant clinical implications. Neurotrophins may only be effective in disorders in which apoptosis, and not necrosis, is the major process. Furthermore, the Trk signaling cascade must be activated for this response to occur. Because the expression of these receptors diminishes in adulthood, neurotrophin application may be most appropriate in the pediatric population.