Citations

Background— Coronary artery disease (CAD) is the major cause of death in patients with type 2 diabetes mellitus. Although demographic and clinical factors associated with extent of CAD in patients with diabetes mellitus have been described, genetic factors have not. We hypothesized that genetic variation in peroxisome proliferator-activated receptor (PPAR) pathway genes, important in diabetes mellitus and atherosclerosis, would be associated with extent of CAD in patients with diabetes mellitus. Methods and Results— We genotyped 1043 patients (702 white, 175 blacks) from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) genetic cohort for 3351 variants in 223 PPAR pathway genes using a custom targeted-genotyping array. Angiographic end points were determined by a core laboratory. In whites, a single variant (rs1503298) in TLL1 was significantly ( P =5.5×10 −6 ) associated with extent of CAD, defined as number of lesions with percent diameter stenosis ≥20%, after stringent Bonferroni correction for all 3351 single nucleotide polymorphisms. This association was validated in the diabetic subgroups of 2 independent cohorts, the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) post–myocardial infarction registry and the prospective Family Heart Study (FHS) of individuals at risk for CAD. TLL1 rs1503298 was also significantly associated with extent of severe CAD (≥70% diameter stenosis; P =3.7×10 −2 ) and myocardial jeopardy index ( P =8.7×10 −4 ). In general linear regression modeling, TLL1 rs1503298 explained more variance of extent of CAD than the previously determined clinical factors. Conclusions— We identified a variant in a single PPAR pathway gene, TLL1 , that is associated with the extent of CAD independently of clinical predictors, specifically in patients with type 2 diabetes mellitus and CAD. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00006305.

A newly identified gene fusion defines the vascular cancer epithelioid hemangioendothelioma and encodes a chimeric transcription factor.

Abstract Detection of specific chromosomal abnormalities by FISH and metaphase cytogenetics allows risk stratification in multiple myeloma; however, gene expression profiling (GEP) based signatures may enable more specific risk categorization. We examined the utility of 2 GEP-based risk stratification systems among patients undergoing initial therapy with lenalidomide in the context of a phase 3 trial. Among 45 patients studied at baseline, 7 (16%) and 10 (22%), respectively, were high-risk using the GEP70 and GEP15 signatures. The median overall survival for the GEP70 high-risk group was 19 months versus not reached for the rest (hazard ratio = 14.1). Although the medians were not reached, the GEP15 also predicted a poor outcome among the high-risk patients. The C-statistic for the GEP70, GEP15, and FISH based risk stratification systems was 0.74, 0.7, and 0.7, respectively. Here we demonstrate the prognostic value for GEP risk stratification in a group of patients primarily treated with novel agents. This trial was registered at www.clinicaltrials.gov as #NCT00098475.

Abstract BACKGROUND: Ventral spinal epidural meningeal cysts are rare entities for which the pathogenesis is poorly understood. OBJECTIVE: We present the clinical, radiographic, surgical, and pathologic findings of 4 patients with extensive ventral spinal epidural meningeal cysts and review the relevant literature. In addition, we discuss a suspected mechanism for pathogenesis. METHODS: Four patients with anterior spinal epidural meningeal cysts are retrospectively reviewed. RESULTS: Ventral spinal epidural meningeal cysts are often large, extending on average from C2 to L1 in our series. Patients typically present with a prolonged course of symptoms and signs, including segmental muscle weakness and atrophy, subtle myelopathy, mild to moderate spinal pain, and headache. Histopathologic analysis of the cyst wall demonstrates collagenous tissue consistent with dura but without arachnoid features. Dynamic computed tomographic myelography is the study of choice for localization of the primary dural defect. Patient symptoms and neurological deficits routinely improve after appropriate surgical intervention. CONCLUSION: Diverse signs and symptoms herald the presentation of ventral spinal meningoceles. Intraoperative, radiographic, and pathological findings are all suggestive of an intradural dissection as the etiology. Hence, they may be more appropriately named “ventral spinal intradural dissecting meningoceles.” Definitive treatment involves identification and obliteration of the dural defect.

Background and Purpose —Hypercholesterolemia is associated with abnormal endothelium-dependent vasorelaxation due to decreased nitric oxide bioavailability. Our aim was to examine the effect of adenovirus-mediated gene transfer of endothelial nitric oxide synthase (eNOS) to the hypercholesterolemic rabbit carotid artery in vivo. In addition, we examined whether adenovirus-mediated gene transfer was associated with vascular dysfunction. Methods —Rabbits were fed a 1% cholesterol diet for 4 weeks followed by a 0.5% cholesterol diet for 6 weeks. Vascular reactivity was assessed in nontransduced carotid arteries from chow- and cholesterol-fed animals. In addition, carotid arteries were surgically isolated, and 2 separate doses of adenoviral vectors encoding eNOS or β-galactosidase (AdβGal) on the contralateral side were delivered to the lumen (1×10 10 and 5×10 10 pfu/mL). Results —Abnormal acetylcholine-mediated endothelium-dependent vasorelaxation was detected in the carotid artery from cholesterol-fed animals, whereas responses to calcium ionophore A23187 and diethylamine NONOate were normal. Vascular reactivity was similar in nontransduced and AdβGal-transduced hypercholesterolemic vessels. In vessels transduced with eNOS, transgene expression was demonstrated by immunostaining in both the endothelium and the adventitia and by Western blot analysis. High-dose but not low-dose eNOS gene transfer enhanced endothelium-dependent relaxation in vessels from cholesterol-fed rabbits. Conclusions —Adenovirus-mediated gene transfer of eNOS to carotid arteries of cholesterol-fed animals improves endothelium-dependent relaxation when an optimal viral titer is administered.

Background and Purpose Proto-oncogene activation and induction of heat shock protein (HSP) occur in response to various stimuli to brain, but the role in neuronal survival after cerebral ischemia remains uncertain. We compared the extent of insults and induction of c- fos and c- jun gene products (c-FOS and c-JUN) as well as HSP in ischemic and postischemic gerbil brains immunohistochemically. Methods Common carotid arteries of Mongolian gerbils were occluded for 5 or 15 minutes and recirculated for 0 minutes to 7 days. Antibodies for c-FOS, c-JUN, and HSP 70 were used for immunohistochemistry, and positive reactions were semiquantitatively analyzed. The presence of ischemic and postischemic lesions was ascertained with an antibody for microtubule-associated proteins. Results After ischemia for 15 minutes and reperfusion, c-FOS was induced promptly after 1 to 6 hours in pyramidal cells of the CA3 and CA4 regions, while c-JUN became visible in the same areas after recirculation for 4 to 48 hours. HSP 70 was detected after recirculation for 24 hours in the CA3 region. In layers I and II of the cerebral cortex, c-FOS and c-JUN peaked at 3 hours and HSP 70 at 96 hours. Induction of these proteins was absent or negligible in the areas that developed ischemic or postischemic lesions, including the subiculum-CA1 and CA1 regions of the hippocampus and layers III/IV and Vb/VI of the cerebral cortex. After shorter ischemia for 5 minutes and reperfusion, c-FOS and c-JUN were rapidly induced at 15 minutes to 1 hour except for the subiculum-CA1 and CA1 regions of the hippocampus. Induction of HSP 70 did not occur for 24 hours and was noted only in the hippocampus. Conclusions Induction of c-FOS and c-JUN occurred in the areas surviving after transient cerebral ischemia, but the extent of induction and the latent period varied depending on the duration of the insult and the location. In the areas with ischemic or postischemic damage detected by loss of the reaction for microtubule-associated proteins, the induction of c-FOS and c-JUN was either absent or minimal, suggesting that active induction of those immediate early gene products occurred early in surviving neurons. On the other hand, the induction of HSP 70 did not occur until reperfusion for 24 hours and actively occurred only in the areas with earlier induction of c-FOS and/or c-JUN, suggesting that the induction of HSP 70 occurred in neurons that survived to that point, but it did not participate in early responses for neuronal survival after global cerebral ischemia.