Molecular approaches for the treatment of atherosclerosis

Advances in vascular biology and the study of molecular pathophysiology have enabled the design and initial testing of therapeutic principles for cardiovascular intervention at the level of gene expression. This approach can offer an avenue to greatly impact the onset and progression of vascular disease at its roots. Early translations of basic research into human clinical protocols might provide novel alternatives for patients without traditional therapeutic options and might provide means of improving and prolonging the success of standard therapies. As the understanding of the genetic basis of vascular disease continues to grow and the tools for in vivo genetic manipulation continue to improve, vascular gene therapies might someday become a part of routine patient care.     

Comparison of incidence of ptosis after combined phacotrabeculectomy with mitomycin C and phacoemulsification

Objective:To compare the incidence of upper eyelid blepharoptosis after combined phacotrabeculectomy with mitomycin C and phacoemulsification surgeries and the relationship of bleb morphology to the incidence of ptosis.Design:Retrospective observation study.Participants:We included 46 patients after combined phacotrabeculectomy and 44 patients with phacoemulsification in the former group, and all eyes underwent a standardized two-site surgery with intra-operative mitomycin C.Results:There were 8 eyes (17.4%) and 5 eyes (11.4%) with postoperative ptosis in the phacotrabeculectomy and phacoemulsification groups, respectively (P = 0.342). In multivariate regression analysis, reduced total bleb area was significantly associated with upper eyelid ptosis after adjusting for age, gender, and type of anesthesia. The trend seemed to show that increased bleb height was also associated with ptosis, but this did not reach statistical significance.Conclusions:Incidence of persistent ptosis after phacoemulsification combined with trabeculectomy and mitomycin C is similar compared to stand alone phacoemulsification surgery in a multiethnic Asian population. Bleb morphology may play an important role in postoperative ptosis development and should be considered in the evaluation of upper eyelid blepharoptosis.     

A novel retroviral mutagenesis screen identifies prognostic genes in RUNX1 mediated myeloid leukemogenesis

Using a novel retroviral shuttle vector approach we identified genes that collaborate with a patient derived RUNX1 (AML1) mutant. RUNX1 mutations occurs in 40% of myelodysplastic syndromes (MDS). MDS are a group of hematopoietic stem cell disorders that are characterized by dysplasia that often progress to acute myeloid leukemia (AML). Our goal was to identify genes dysregulated by vector-mediated genotoxicity that may collaborate with the RUNX1 mutant (D171N). D171N expressing cells have a survival and engraftment disadvantage and require additional genetic lesions to survive and persist. By dysregulating genes near the integrated vector provirus, the shuttle vector can promote transformation of D171N cells and tag the nearby genes that collaborate with D171N. In our approach, a gammaretroviral shuttle vector that expresses D171N is used to transduce CD105⁺, Sca-1⁺ mouse bone marrow. Mutagenized cells are expanded in liquid culture and vector integration sites from surviving cells are then identified using a retroviral shuttle vector approach. We repeatedly recovered integrated vector proviruses near genes (Itpkb, Ccdc12, and Nbeal2). To assess the prognostic significance of the genes identified we examined differential expression, overall survival, and relapse free survival of AML patients with alteration in the genes identified using The Cancer Genome Atlas (TCGA) AML data set. We found that ITPKB functions as an independent factor for poor prognoses and RUNX1 mutations in conjunction with ITPKB, CCDC12, and NBEAL2 have prognostic potential in AML.     

Effects of unilateral stereotactic posterior striatotomy on harmaline‐induced tremor in rats

Although long known and the most prevalent movement disorder, pathophysiology of essential tremor (ET) remains controversial. The most accepted hypothesis is that it is caused by a dysfunction of the olivocerebellar system. Vilela Filho et al. [2001; Stereotact Funct Neurosurg 77:149–150], however, reported a patient with unilateral hand ET that was completely relieved after a stroke restricted to the contralateral posterior putamen and suggested that ET could be the clinical manifestation of posterior putamen hyperactivity. The present study was designed to evaluate this hypothesis in the most often used model of ET, harmaline‐induced tremor in rats. Fifty‐four male Wistar rats were randomly distributed into three groups: experimental (EG), surgical control (SCG), and pharmacological control (PCG) groups. EG animals underwent stereotactic unilateral posterior striatotomy. SCG rats underwent sham lesion at the same target. PCG served exclusively as controls for harmaline effects. All animals received, postoperatively, intraperitoneal harmaline, and the induced tremor was video‐recorded for later evaluation by a blind observer. Thirteen animals were excluded from the study. Limb tremor was reduced ipsilaterally to the operation in 20 of 21 rats of EG and in two of nine of SCG, being asymmetric in one of 10 of PCG rats. Comparisons between EG × SCG and EG × PCG were statistically significant, but not between SCG × PCG. Limb tremor reduction was greater in anterior than in posterior paws. Lateral lesions yielded better results than medial lesions. These results suggest that the posterior striatum is involved with harmaline‐induced tremor in rats and support the hypothesis presented. © 2013 Wiley Periodicals, Inc.