Description: Rationale: The dramatic upregulation of αvβ3-integrin that occurs in the vasculature during tumor growth has long suggested that the endothelial expression of this molecule is an ideal target for antiangiogenic therapy to treat cancer. This discovery led to the development of small-molecule inhibitors directed against αvβ3-integrin that are currently in clinical trials. In 2002, we reported that β3-integrin–knockout mice exhibit enhanced tumor growth and angiogenesis. However, as β3-integrin is expressed by a wide variety of cells, endothelial cell–specific contributions to tumor angiogenesis are muddied by the use of a global knockout of β3-integrin function. Objective: Our aim was to examine the endothelial-specific contribution β3-integrin makes to tumor growth and angiogenesis. Methods and Results: We have crossed β3-integrin–floxed (β3-floxed) mice to 2 endothelial-specific Cre models and examined angiogenic responses in vivo, ex vivo, and in vitro. We show that acute depletion of endothelial β3-integrin inhibits tumor growth and angiogenesis preventatively, but not in already established tumors. However, the effects are transient, and long-term depletion of the molecule is ineffective. Furthermore, long-term depletion of the molecule correlates with many molecular changes, such as reduced levels of focal adhesion kinase expression and a misbalance in focal adhesion kinase phosphorylation, which may lead to a release from the inhibitory effects of decreased endothelial β3-integrin expression. Conclusions: Our findings imply that timing and length of inhibition are critical factors that need to be considered when targeting the endothelial expression of β3-integrin to inhibit tumor growth and angiogenesis.

Description: Background and Purpose— Hypertension is the most important risk factor associated with intracerebral hemorrhage. We explored racial differences in blood pressure (BP) control after intracerebral hemorrhage and assessed predictors of BP control at presentation, 30 days, and 1 year in a prospective cohort study. Methods— Subjects with spontaneous intracerebral hemorrhage were identified from the DiffErenCes in the Imaging of Primary Hemorrhage based on Ethnicity or Race (DECIPHER) Project. BP was compared by race at each time point. Multivariable linear regression was used to determine predictors of presenting mean arterial pressure, and longitudinal linear regression was used to assess predictors of mean arterial pressure at follow-up. Results— A total of 162 patients were included (mean age, 59 years; 53% male; 77% black). Mean arterial pressure at presentation was 9.6 mm Hg higher in blacks than whites despite adjustment for confounders ( P =0.065). Fewer than 20% of patients had normal BP (〈120/80 mm Hg) at 30 days or 1 year. Although there was no difference at 30 days ( P =0.331), blacks were more likely than whites to have Stage I/II hypertension at 1 year ( P =0.036). Factors associated with lower mean arterial pressure at follow-up in multivariable analysis were being married at baseline ( P =0.032) and living in a facility (versus personal residence) at the time of BP measurement ( P =0.023). Conclusions— Long-term BP control is inadequate in patients after intracerebral hemorrhage, particularly in blacks. Further studies are needed to understand the role of social support and barriers to control to identify optimal approaches to improve BP in this high-risk population.

Description: Background and Purpose— To investigate the relationship between chronic kidney disease (CKD) and MRI-defined cerebral microbleeds (CMB), a harbinger of future intracerebral hemorrhage (ICH), among patients with a recent history of primary ICH. Methods— Using data from a predominantly black cohort of patients with a recent ICH-enrolled in an observational study between September 2007 and June 2011, we evaluated the association between CKD (defined as estimated low glomerular filtration rate〈60 mL/min per 1.73 m 2 ) and CMB on gradient-echo MRI. Multivariable models were generated to determine the contribution of CKD to the presence, number, and location of CMB. Results— Of 197 subjects with imaging data, mean age was 59 years, 48% were women, 73% were black, 114 (58%) had ≥1 CMBs, and 52 (26%) had CKD. Overall, CKD was associated with presence of CMB (adjusted odds ratio, 2.70; 95% confidence interval [CI], 1.10–6.59) and number of CMB (adjusted relative risk, 2.04; 95% CI, 1.27–3.27). CKD was associated with CMB presence (adjusted odds ratio, 3.44; 95% CI, 1.64–7.24) and number (adjusted relative risk, 2.46; 95% CI, 1.11–5.42) in black patients, but not CMB presence (adjusted odds ratio, 3.00; 95% CI, 0.61–14.86) or number (adjusted relative risk, 1.03; 95% CI: 0.22–4.89) in non-Hispanic white patients (interactions by race were statistically not significant). Conclusions— CKD is associated with a greater presence and number of CMB in ICH patients, particularly in patients of black race. Future studies should assess whether low estimated glomerular filtration rate may be a CMB risk marker or potential therapeutic target for mitigating the development of CMB.

Description: Background— The mechanisms of the electrocardiographic changes and arrhythmias in Brugada syndrome (BrS) remain controversial. Mutations in the sodium channel gene, SCN5A , and regulatory proteins that reduce or eliminate sodium current ( I Na ) have been linked to BrS. We studied the properties of a BrS-associated SCN5A mutation in a protein kinase A (PKA) consensus phosphorylation site, R526H. Methods and Results— In vitro PKA phosphorylation was detected in the I-II linker peptide of wild-type (WT) channels but not R526H or S528A (phosphorylation site) mutants. Cell surface expression of R526H and S528A channels was reduced compared with WT. Whole-cell I Na through all channel variants revealed no significant differences in the steady-state activation, inactivation, and recovery from inactivation. Peak current densities of the mutants were significantly reduced compared with WT. Infection of 2D cultures of neonatal rat ventricular myocytes with WT and mutant channels increased conduction velocity compared with noninfected cells. PKA stimulation significantly increased peak I Na and conduction velocity of WT but not mutant channels. Oxidant stress inhibits cardiac I Na ; WT and mutant I Na decreases with the intracellular application of reduced nicotinamide adenine dinucleotide (NADH), an effect that is reversed by PKA stimulation in WT but not in R526H or S528A channels. Conclusions— We identified a family with BrS and an SCN5A mutation in a PKA consensus phosphorylation site. The BrS mutation R526H is associated with a reduction in the basal level of I Na and a failure of PKA stimulation to augment the current that may contribute to the predisposition to arrhythmias in patients with BrS, independent of the precipitants.

Description: Background and Purpose— Acute stroke education has focused on stroke symptom recognition. Lack of education about stroke preparedness and appropriate actions may prevent people from seeking immediate care. Few interventions have rigorously evaluated preparedness strategies in multiethnic community settings. Methods— The Acute Stroke Program of Interventions Addressing Racial and Ethnic Disparities (ASPIRE) project is a multilevel program using a community-engaged approach to stroke preparedness targeted to underserved black communities in the District of Columbia. This intervention aimed to decrease acute stroke presentation times and increase intravenous tissue-type plasminogen activator utilization for acute ischemic stroke. Results— Phase 1 included (1) enhancement of focus of emergency medical services on acute stroke; (2) hospital collaborations to implement and enrich acute stroke protocols and transition District of Columbia hospitals toward primary stroke center certification; and (3) preintervention acute stroke patient data collection in all 7 acute care District of Columbia hospitals. A community advisory committee, focus groups, and surveys identified perceptions of barriers to emergency stroke care. Phase 2 included a pilot intervention and subsequent citywide intervention rollout. A total of 531 community interventions were conducted, reaching 〉10 256 participants; 3289 intervention evaluations were performed, and 19 000 preparedness bracelets and 14 000 stroke warning magnets were distributed. Phase 3 included an evaluation of emergency medical services and hospital processes for acute stroke care and a year-long postintervention acute stroke data collection period to assess changes in intravenous tissue-type plasminogen utilization. Conclusions— We report the methods, feasibility, and preintervention data collection efforts of the ASPIRE intervention. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00724555.

Description: Background and Purpose— The National Institutes of Health policy calls for the inclusion of under-represented groups, such as women and minorities, in clinical research. Poor minority recruitment and retention in stroke clinical trials remain a significant challenge limiting safety and efficacy in a general population. Previous research examines participant barriers to clinical trial involvement, but little is known about the investigator perspective. This study addresses this gap and examines researcher-reported barriers and best practices of minority involvement in stroke clinical trials. Methods— Quantitative and qualitative methods, including surveys, focus groups, and key informant interviews were used. Results— In a survey of 93 prominent stroke researchers, 43 (51.2%; 70% response rate) respondents reported proactively setting recruitment goals for minority inclusion, 29 respondents (36.3%) reported requiring cultural competency staff training, and 44 respondents (51.2%) reported using community consultation about trial design. Focus groups and key informant interviews highlighted structural and institutional challenges to recruitment of minorities, including mistrust of the research/medical enterprise, poor communication, and lack of understanding of clinical trials. Researcher-identified best practices included using standardized project management procedures and protocols (eg, realistic budgeting to support challenges in recruitment, such as travel/parking reimbursement for participants), research staff cultural competency and communication training, and developing and fostering community partnerships that guide the research process. Conclusions— This study’s formative evaluation contributes a new dimension to the literature as it highlights researcher-reported barriers and best practices for enhancing participation of minority populations into stroke clinical trials.