Baseline Hemodynamic Impairment and Future Stroke Risk in Adult Idiopathic Moyamoya Phenomenon: Results of a Prospective Natural History Study.

BACKGROUND AND PURPOSE: The purpose was to test the hypothesis that increased oxygen extraction fraction (OEF), a marker of severe hemodynamic impairment measured by positron emission tomography, is an independent risk factor for subsequent ischemic stroke in this population. METHODS: Adults with idiopathic moyamoya phenomena were recruited between 2005 and 2012 for a prospective, multicenter, blindly adjudicated, longitudinal cohort study. Measurements of OEF were obtained on enrollment. Subjects were followed up for the occurrence of ipsilateral ischemic stroke at 6-month intervals. Patients were censored at the time of surgical revascularization or at last follow-up. The primary analysis was time to ischemic stroke in the territory of the occlusive vasculopathy. RESULTS: Forty-nine subjects were followed up during a median of 3.7 years. One of 16 patients with increased OEF on enrollment had an ischemic stroke and another had an intraparenchymal hemorrhage. Three of 33 patients with normal OEF had an ischemic stroke. On a per-hemisphere basis, 21 of 79 hemispheres with moyamoya vasculopathy had increased OEF at baseline. No ischemic strokes and one hemorrhage occurred in a hemisphere with increased OEF (n=21). Sixteen patients (20 hemispheres), including 5 with increased OEF at enrollment, were censored at a mean of 5.3 months after enrollment for revascularization surgery. CONCLUSIONS: The risk of new or recurrent stroke was lower than expected. The low event rate, low prevalence of increased OEF, and potential selection bias introduced by revascularization surgery limit strong conclusions about the association of increased OEF and future stroke risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00629915.

Perifosine treatment in chronic lymphocytic leukemia: results of a phase II clinical trial and in vitro studies.

Abstract Because of the importance of the phosphoinositide 3-kinase (PI3K)/AKT pathway in chronic lymphocytic leukemia (CLL), we evaluated in vitro cytotoxicity induced by perifosine, an AKT inhibitor, in CLL lymphocytes and found that the mean 50% effective dose (ED50) was 313 nM. We then performed a phase II trial of perifosine in patients with relapsed/refractory CLL to assess response, outcomes, toxicity and ex vivo correlative measures. After 3 months of treatment, six of eight patients showed stable disease, one achieved a partial response and one had progressive disease. Median event-free survival and overall survival in all patients treated were 3.9 and 9.7 months. Adverse events included hematologic, infectious/fever, pain, gastrointestinal and constitutional toxicities. Unexpectedly, AKT phosphorylation in CLL lymphocytes from treated patients was not correlated with response. Additionally, perifosine did not inhibit AKT phosphorylation in cultured CLL lymphocytes. Perifosine is cytotoxic to CLL cells in vitro, and largely induces stabilized disease in vivo, with an AKT-independent mechanism.

The NIHSS supplementary motor scale: a valid tool for multidisciplinary recovery trials.

BACKGROUND: There is a growing interest in therapies that may augment motor recovery that could be initiated in the acute stroke unit and maintained through the rehabilitation period. Homogenization of the currently fragmented stroke clinicometrics is necessary before such multidisciplinary trials can be conducted. The supplementary motor scale of the NIH Stroke Scale (SMS-NIHSS) is a simple and reliable scale for assessing proximal and distal motor function in the upper and lower extremities. We hypothesized that the currently underutilized SMS-NIHSS is a valid tool for assessing motor recovery with prognosticative value. METHODS: We performed an analysis of SMS-NIHSS scores recorded in 1,281 patients enrolled in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST). We plotted the probability of a favorable outcome (FO) and very favorable outcome (VFO) at 3 months based on the baseline SMS-NIHSS scores. In order to better study the relationship between SMS-NIHSS and 3-month functional outcome, we performed multivariate logistic regression analyses using both FO and VFO as outcome measures. Analyses were adjusted for potential confounders such as age, sex, side of the lesion, time from symptom onset to emergency room arrival, temperature, systolic blood pressure, blood glucose level and treatment group assignment (ORG 10172 vs. placebo). We also calculated the Spearman correlation coefficient between the SMS-NIHSS, Barthel Index (BI) and Glasgow Outcome Score (GOS) obtained at the 3-month visit. RESULTS: The mean SMS-NIHSS scores were 8.18 at baseline and 4.68 at 3 months. The SMS-NIHSS scores showed a gradual improvement during the first 3 months after stroke. There was a linear relationship between the baseline SMS-NIHSS scores and the probability of an FO or VFO at 3 months. The SMS-NIHSS baseline score was an independent predictor of FO (OR = 0.86; 95% CI 0.84-0.87; p < 0.0001) and VFO (OR = 0.85; 95% CI 0.84-0.87; p < 0.0001) at 3 months after adjusting for confounders. The degree of improvement in the SMS-NIHSS scores from baseline to 3 months was also independently associated with FO and VFO (p < 0.0001). At 3 months, SMS-NIHSS scores showed a strong correlation with the BI (r = -0.70; p < 0.0001) and GOS (r = 0.73; p < 0.0001). CONCLUSIONS: The SMS-NIHSS is a valid scale for assessing motor recovery with prognosticative value, and may be sensitive to changes during recovery. Given that the SMS-NIHSS is an extension of the widely accepted NIHSS, it could be easily implemented in trials conducted in a variety of clinical research settings, including acute stroke hospitals and rehabilitation units.

Combined effects of child and adult elevated blood pressure on subclinical atherosclerosis: the International Childhood Cardiovascular Cohort Consortium.

BACKGROUND: Elevated blood pressure (BP) levels in childhood have been associated with subsequent atherosclerosis. However, it is uncertain whether this risk is attenuated in individuals who acquire normal BP by adulthood. The present study examined the effect of child and adult BP levels on carotid artery intima-media thickness (IMT) in adulthood. METHODS AND RESULTS: The cohort consisted of 4210 participants from 4 prospective studies (mean follow-up, 23 years). Childhood elevated BP was defined according to the tables from the National High Blood Pressure Education Program. In adulthood, BP was classified as elevated for individuals with systolic BP ≥120 mm Hg, diastolic BP ≥80 mm Hg or with self-reported use of antihypertensive medications. Carotid artery IMT was measured in the left common carotid artery. High IMT was defined as an IMT ≥90th percentile according to age-, sex-, race-, and cohort-specific levels. Individuals with persistently elevated BP and individuals with normal childhood BP, but elevated adult BP had increased risk of high carotid artery IMT (relative risk [95% confidence interval]) 1.82[1.47-2.38] and 1.57[1.22-2.02], respectively) in comparison with individuals with normal child and adult BP. In contrast, individuals with elevated BP as children but not as adults did not have significantly increased risk (1.24[0.92-1.67]). In addition, these individuals had a lower risk of increased carotid artery IMT (0.66[0.50-0.88]) in compared with those with persistently elevated BP. The results were consistent when controlling for age, sex, and adiposity and when different BP definitions were applied. CONCLUSIONS: Individuals with persistently elevated BP from childhood to adulthood had increased risk of carotid atherosclerosis. This risk was reduced if elevated BP during childhood resolved by adulthood.

Cohort Profile: the international childhood cardiovascular cohort (i3C) consortium.

This is a consortium of large children's cohorts that contain measurements of major cardiovascular disease (CVD) risk factors in childhood and had the ability to follow those cohorts into adulthood. The purpose of this consortium is to enable the pooling of data to increase power, most importantly for the follow-up of CVD events in adulthood. Within the consortium, we hope to be able to obtain data on the independent effects of childhood and early adult levels of CVD risk factors on subsequent CVD occurrence.

Phase II study of cenersen, an antisense inhibitor of p53, in combination with fludarabine, cyclophosphamide and rituximab for high-risk chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) with deletion or mutation of TP53 have exceedingly poor clinical outcomes. Cenersen, an oligonucleotide targeting TP53, has been shown to abrogate the activity of TP53 gain-of-function mutants and to increase sensitivity of lymphoma cells to cytotoxic chemotherapy in vitro. We combined cenersen with fludarabine, cyclophosphamide and rituximab (FCR) as treatment for patients with high-risk CLL. The purpose of this phase II study was to determine the overall response rate, response duration and toxicity of cenersen administered in combination with FCR. Twenty patients with relapsed or high-risk CLL were evaluated. Nineteen patients were previously treated. The complete response rate was 18%; the overall response rate was 53%. Median progression-free and overall survival was 5.3 and 10.6 months, respectively. The most common serious adverse events were neutropenia and thrombocytopenia. In this single arm phase II study, cenersen combined with FCR yielded clinical responses with acceptable toxicity in patients with high-risk CLL.

Childhood adiposity, adult adiposity, and cardiovascular risk factors.

BACKGROUND: Obesity in childhood is associated with increased cardiovascular risk. It is uncertain whether this risk is attenuated in persons who are overweight or obese as children but not obese as adults. METHODS: We analyzed data from four prospective cohort studies that measured childhood and adult body-mass index (BMI, the weight in kilograms divided by the square of the height in meters). The mean length of follow-up was 23 years. To define high adiposity status, international age-specific and sex-specific BMI cutoff points for overweight and obesity were used for children, and a BMI cutoff point of 30 was used for adults. RESULTS: Data were available for 6328 subjects. Subjects with consistently high adiposity status from childhood to adulthood, as compared with persons who had a normal BMI as children and were nonobese as adults, had an increased risk of type 2 diabetes (relative risk, 5.4; 95% confidence interval [CI], 3.4 to 8.5), hypertension (relative risk, 2.7; 95% CI, 2.2 to 3.3), elevated low-density lipoprotein cholesterol levels (relative risk, 1.8; 95% CI, 1.4 to 2.3), reduced high-density lipoprotein cholesterol levels (relative risk, 2.1; 95% CI, 1.8 to 2.5), elevated triglyceride levels (relative risk, 3.0; 95% CI, 2.4 to 3.8), and carotid-artery atherosclerosis (increased intima-media thickness of the carotid artery) (relative risk, 1.7; 95% CI, 1.4 to 2.2) (P ≤ 0.002 for all comparisons). Persons who were overweight or obese during childhood but were nonobese as adults had risks of the outcomes that were similar to those of persons who had a normal BMI consistently from childhood to adulthood (P>0.20 for all comparisons). CONCLUSIONS: Overweight or obese children who were obese as adults had increased risks of type 2 diabetes, hypertension, dyslipidemia, and carotid-artery atherosclerosis. The risks of these outcomes among overweight or obese children who became nonobese by adulthood were similar to those among persons who were never obese. (Funded by the Academy of Finland and others.).

Effect of antidepressants on the course of disability following stroke.

OBJECTIVE: Stroke often produces marked physical and cognitive impairments leading to functional dependence, caregiver burden, and poor quality of life. We examined the course of disability during a 1-year follow-up period after stroke among patients who were administered antidepressants for 3 months compared to patients given placebo for 3 months. METHODS: A total of 83 patients entered a double-blind randomized study of the efficacy of antidepressants to treat depressive disorders and reduce disability after stroke. Patients were assigned to either fluoxetine (N = 32), nortriptyline (N = 22) or placebo (N = 29). Psychiatric assessment included administration of the Present State Examination modified to identify DSM-IV symptoms of depression. The severity of depression was measured using the 17-item Hamilton Depression Rating Scale. The modified Rankin Scale was used to evaluate the disability of patients at initial evaluation and at quarterly follow-up visits for 1 year. Impairment in activities of daily living was assessed by Functional Independence Measure at the same time. RESULTS: During the 1-year follow-up period, and after adjusting for critical confounders including age, intensity of rehabilitation therapy, baseline stroke severity, and baseline Hamilton Depression Rating Scale, patients who received fluoxetine or nortriptyline had significantly greater improvement in modified Rankin Scale scores compared to patients who received placebo (t [156] = -3.17, p = 0.002). CONCLUSIONS: Patients treated with antidepressants had better recovery from disability by 1-year post stroke (i.e., 9 months after antidepressants were stopped) than patients who did not receive antidepressant therapy. This effect was independent of depression suggesting that antidepressants may facilitate the neural mechanisms of recovery in patients with stroke.

Previous statin use is not associated with an increased prevalence or degree of gradient-echo lesions in patients with acute ischemic stroke or transient ischemic attack.

BACKGROUND AND PURPOSE: Microhemorrhages on gradient-echo T2*-weighted MRI sequences are often found in patients with cerebrovascular disease and are related to intracerebral hemorrhage. Because statin therapy is associated with increased risk of intracerebral hemorrhage, we investigated whether statin use was also associated with microhemorrhages in patients with acute ischemic stroke or transient ischemic attack. METHODS: We performed a retrospective analysis on prospectively collected data from a stroke registry containing patients with acute ischemic stroke or transient ischemic attack. The primary and secondary outcome variables were the prevalence and degree of microhemorrhages as detected on gradient-echo MRI sequences and categorized as mild (1-2), moderate (3-10), or severe (>10). The location of the microhemorrhages was noted and rated by 2 neuroradiologists. Previous use of statins and other covariates were assessed as potential predictors. RESULTS: Three hundred forty-nine patients were admitted from June 2008 to July 2009, and 300 of which were analyzed. Microhemorrhages were detected in 70 subjects (23%); 35 had only lobar lesions, 16 had only deep lesions, and 19 had both lobar and deep lesions. On univariate and multivariate analysis, statin therapy was not associated with the prevalence (OR, 0.73; 95% CI, 0.36-1.51; P=0.40) or degree of microhemorrhages modeled for lesser severity (OR, 2.31; 95% CI, 0.61-8.75; P=0.22). CONCLUSIONS: Previous statin therapy was not associated with the prevalence or degree of microhemorrhages in patients with acute ischemic stroke or transient ischemic attack. The association between statins and intracerebral hemorrhage does not appear to be mediated through microhemorrhages.

Influence of age on associations between childhood risk factors and carotid intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Bogalusa Heart Study, and the Muscatine Study for the International Childhood Cardiovascular Cohort (i3C) Consortium.

BACKGROUND: Atherosclerosis has its roots in childhood. Therefore, defining the age when childhood risk exposure begins to relate to adult atherosclerosis may have implications for pediatric cardiovascular disease prevention and provide insights about the early determinants of atherosclerosis development. The aim of this study was to investigate the influence of age on the associations between childhood risk factors and carotid artery intima-media thickness, a marker of subclinical atherosclerosis. METHODS AND RESULTS: We used data for 4380 members of 4 prospective cohorts-Cardiovascular Risk in Young Finns Study (Finland), Childhood Determinants of Adult Health study (Australia), Bogalusa Heart Study (United States), and Muscatine Study (United States)-that have collected cardiovascular risk factor data from childhood (age 3 to 18 years) and performed intima-media thickness measurements in adulthood (age 20 to 45 years). The number of childhood risk factors (high [highest quintile] total cholesterol, triglycerides, blood pressure, and body mass index) was predictive of elevated intima-media thickness (highest decile) on the basis of risk factors measured at age 9 years (odds ratio [95% confidence interval] 1.37 [1.16 to 1.61], P=0.0003), 12 years (1.48 [1.28 to 1.72], P<0.0001), 15 years (1.56 [1.36 to 1.78], P<0.0001), and 18 years (1.57 [1.31 to 1.87], P<0.0001). The associations with risk factors measured at age 3 years (1.17 [0.80 to 1.71], P=0.42) and 6 years (1.20 [0.96 to 1.51], P=0.13) were weaker and nonsignificant. CONCLUSIONS: Our analyses from 4 longitudinal cohorts showed that the strength of the associations between childhood risk factors and carotid intima-media thickness is dependent on childhood age. On the basis of these data, risk factor measurements obtained at or after 9 years of age are predictive of subclinical atherosclerosis in adulthood.

Measurement of aortic intimal-medial thickness in adolescents and young adults.

Atherosclerosis begins in childhood in the distal abdominal aorta and later involves the carotid arteries. Noninvasive screening to detect these lesions may allow early intervention. Ultrasound images of the distal 10 mm of the aorta were obtained after an 8-h fast and were analyzed by an automated program to determine the mean far wall intimal-medial thickness (IMT). The results were compared with the mean carotid IMT obtained concurrently. The mean age of the 313 males and 322 females imaged was 20.4 years (SD 5.6) and 61 participants had a second study to assess reproducibility. The mean aortic IMT was 0.63 mm (SD 0.14) for males and 0.61 mm (SD 0.13) for females while the mean carotid IMT was 0.50 (SD 0.04) mm and 0.49 (SD 0.04) mm, respectively. Images were analyzed in 95% of participants. Intra-subject reproducibility for the mean aortic IMT had a coefficient of variation of 18% with a mean absolute difference of 0.12 mm (SD 0.10). For carotid IMT, the results were 3% and 0.02 mm (SD 0.01), respectively. Aortic IMT can be measured in normal adolescents and young adults with low rates of missing data and reasonable reproducibility. Aortic IMT increased with age at a greater rate than carotid IMT.

"Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma.

The purpose of this study was to evaluate the efficacy and safety of short-course bortezomib, melphalan, prednisone (VMP) in previously untreated multiple myeloma as frontline therapy for transplant-ineligible patients and induction prior to autologous stem cell transplantation (ASCT). Patients received up to 6 28-day cycles of bortezomib 1.3 mg/m(2), days 1, 4, 8, and 11, plus melphalan 6 mg/m(2) and prednisone 60 mg/m(2), days 1-7. After 2-6 cycles, eligible and consenting patients could proceed to ASCT. Responses were assessed by International Uniform Response Criteria. The primary endpoint was complete response (CR) rate with VMP. Forty-five patients were enrolled. Among 44 evaluable patients, response rate was 95%, including 18% >or=CR (9% stringent CR), 27% very good partial responses (VGPR), and 50% partial responses (PR). Twenty patients proceeded to ASCT. Stem cell collection was successful in all; median yield was 5.6 x 10(6) CD34(+) cells/kg. Posttransplant response rates were 30% >or=CR (10% stringent CR), 65% VGPR, and 5% PR. After median follow-up of 14.0/14.6 months, median time to progression and progression-free survival were both 19.8/27.9 months in non-ASCT/ASCT patients. Seven patients have died; 1-year survival rates were 82%/95% in non-ASCT/ASCT patients. The most common grade 3/4 toxicities were thrombocytopenia (20%), neutropenia (28%), and infection (9%). Peripheral neuropathy grade 2-4 was the most common nonhematopoietic side effect occurring 17 patients (38%), although it was typically reversible, and only 5 patients (11%) discontinued therapy as a result of it. Short-course VMP is highly effective and generally well tolerated, both as initial treatment in non-ASCT patients and induction prior to ASCT. VMP did not negatively affect stem cell collection. Longer follow-up and prospective phase III trials are required to validate these initial observations.

Risk factors associated with aortic and carotid intima-media thickness in adolescents and young adults: the Muscatine Offspring Study.

OBJECTIVES: This study sought to determine whether cardiovascular risk factors are associated with aortic intima-media thickness (aIMT) and carotid intima-media thickness (cIMT) in adolescents and young adults. BACKGROUND: Atherosclerotic lesions begin developing in youth, first in the distal abdominal aorta and later in the carotid arteries. Knowledge of how risk factors relate to aIMT and cIMT may help in the design of early interventions to prevent cardiovascular disease. METHODS: Participants were 635 members of the Muscatine Offspring cohort. The mean aIMT and cIMT were measured using an automated reading program. RESULTS: The mean (SD) values of aIMT and cIMT were 0.63 (0.14) and 0.49 (0.04) mm, respectively. In adolescents (age 11 to 17 years), aIMT was associated with triglycerides, systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), and waist/hip ratio, after adjusting for age, sex, and height. In young adults (age 18 to 34 years), aIMT was associated with those same 5 risk factors, plus high-density lipoprotein cholesterol and pulse pressure. In adolescents, cIMT was associated with SBP, pulse pressure, heart rate, BMI, and waist/hip ratio. In young adults, cIMT was associated with total cholesterol, low-density lipoprotein cholesterol, triglycerides, SBP, DBP, BMI, waist/hip ratio, and glycosylated hemoglobin. In both age groups, aIMT and cIMT were significantly correlated with the Pathobiological Determinants of Atherosclerosis in Youth coronary artery risk score. CONCLUSIONS: Both aIMT and cIMT are associated with cardiovascular risk factors. Using aIMT in adolescents gives information beyond that obtained from cIMT alone. Measurement of aIMT and cIMT may help identify those at risk for premature cardiovascular disease.

Cerebral arteriolar thromboembolism in idiopathic hypereosinophilic syndrome.

OBJECTIVE: To describe imaging findings as well as postmortem brain and cardiac pathology in a patient with fulminant idiopathic hypereosinophilic syndrome. DESIGN: Case report. SETTING: University hospital. PATIENT: A 48-year-old right-handed man with hypereosinophilia, rapidly progressive encephalopathy, and focal neurological deficits who died 22 days after presentation. MAIN OUTCOME MEASURES: Physical examination, radiologic, and neuropathologic examination results. RESULTS: Imaging of the brain revealed bihemispheric ischemic changes in and beyond the watershed distributions. Pathology review demonstrated mural cardiac thrombus that likely caused cardioembolism as well as diffuse microangiopathy despite resolution of the hypereosinophilia. CONCLUSIONS: Timely recognition of idiopathic hypereosinophilic syndrome may enable aggressive treatment prior to widespread cardioembolism and degranulation that result in devastating cerebrovascular complications.

Use of oral contraceptives and postmenopausal hormone replacement: evidence on risk of stroke.

Estrogen and progesterone affect endothelial function, coagulation factors, platelet function, lipids, and inflammation and have neuroprotective effects in experimental animals. Oral contraceptives containing low-dose estrogen increase the risk of ischemic stroke, but the absolute risk is low. Risk factors further increasing the risk of stroke in users of oral contraceptives include smoking, hypertension, diabetes, hyperlipidemia, migraine with aura, and thrombophilia. Progestin-only contraceptives do not increase the risk of stroke and are preferable in women with cerebrovascular disease or risk factors. Hormone replacement therapy (HRT) with estrogen alone or combined with progesterone increases the risk of ischemic stroke by 40% with no effect on hemorrhagic stroke. Stroke risk increases with the dose of estrogen. The time between menopause and the initiation of HRT does not influence ischemic stroke risk. The only indication for HRT is the treatment of vasomotor symptoms; if needed for this purpose, the lowest dose of estrogen should be used for the shortest possible duration.

Improving prediction of outcome in "good grade" subarachnoid hemorrhage.

OBJECTIVE: We hypothesize that subtle neurological signs at baseline could be present in some "good grade" subarachnoid hemorrhage (SAH) patients and that they would have negative prognostic implications. METHODS: We analyzed data from 1000 patients randomized to the Intraoperative Hypothermia for Aneurysm Surgery Trial (World Federation of Neurological Societies Grades I, II, and III). Nine hundred and forty-four patients had a complete National Institutes of Health Stroke Scale (NIHSS) examination performed at baseline. We analyzed the relationship between baseline NIHSS scores and Glasgow Outcome Scale scores at 3 months. Using stepwise logistic regression, we identified the individual NIHSS items that independently predicted outcome to construct a useful shorter version of the scale for SAH. RESULTS: The NIHSS was abnormal at baseline in 23% of the Grade I patients and 82% of the Grade II patients. Baseline NIHSS scores strongly predicted 3-month outcomes (P < 0.001). The NIHSS items that were relevant to predict outcome were level of consciousness, dysarthria, visual fields, and worst motor score for the arms. Baseline NIHSS-SAH scores also independently predicted 3-month outcomes (P < 0.001). CONCLUSION: Subtle neurological signs at baseline are common in World Federation of Neurological Societies Grades I and II patients and are associated with a worse outcome at 3 months. These signs are not detected by the World Federation of Neurological Societies classification. A better stratification of "good grade" SAH patients to predict long-term outcomes may be desirable for clinical trials and practice. Either using the full NIHSS or a shortened version testing level of consciousness, visual fields, dysarthria and worst arm motor score will help to better stratify "good-grade" SAH patients.

Slow progressive acceptance of intravenous thrombolysis for patients with stroke by rural primary care physicians.

BACKGROUND: In the rural United States, patients with stroke are usually first evaluated locally by a nonneurologist physician (NNP) before treatment is determined. OBJECTIVE: To determine the evolution of NNPs' familiarity and attitudes about using recombinant tissue plasminogen activator (rtPA) since this therapy has been approved. DESIGN: Cross-sectional design using 2 similar surveys mailed in 1997 and 2003 to all primary care, family, internal, and emergency medicine physicians in the state of Iowa (1582 and 1679 physicians, respectively). PARTICIPANTS: All NNPs (primary care, internal, and emergency medicine) practicing in the state of Iowa. MAIN OUTCOME MEASURES: Comparison of 1997 and 2003 aggregate responses to questions about familiarity and willingness to use rtPA to treat patients who have had an acute ischemic stroke. RESULTS: The willingness of NNPs to use rtPA to treat acute ischemic stroke increased from 18% to 32% between 1997 and 2003. The number of NNPs who were very familiar with the National Institutes of Health Stroke Scale increased from 1% to 13%. Compared with physicians in 1997, more physicians in 2003 knew that prolonged international normalized ratios (42% vs 61%) or excessively high blood pressures (61% vs 78%) were contraindications for the use of rtPA. Still, half of the respondents perceived that they were inadequately exposed to educational material about rtPA during these years. Most expressed preference for personal methods of delivery for future educational efforts. CONCLUSIONS: The familiarity and comfort among NNPs with the administration of rtPA is still relatively low in rural settings. The improvement observed between the years 1997 and 2003 is encouraging. The responses suggest that NNPs' acceptance of rtPA can be further improved with educational campaigns involving personal methods of delivery.

Association between a leukotriene C4 synthase gene promoter polymorphism and coronary artery calcium in young women: the Muscatine Study.

OBJECTIVE: A majority of the recognized risk factors for atherosclerosis and the development of cardiovascular disease have been derived from the study of older populations who have already manifested clinical symptoms. If risk factors can be identified earlier in life, such as genetic variation, preventive measures may be taken before overt symptoms of pathology have manifested, and when treatments may be most effective. METHODS AND RESULTS: In an effort to identify individuals at increased risk for cardiovascular disease, we genotyped 732 members of the Muscatine Study Longitudinal Adult Cohort for candidate genetic markers associated with several pathogenetic processes. We identified age-adjusted increased risks for coronary artery calcium (OR 4.29; 95% CI 1.78, 10.31) and increased mean carotid artery intimal-medial thickness associated with the (-444)A>C promoter polymorphism of Leukotriene C4 Synthase (LTC4S) in women. There were no similar associations in men. CONCLUSIONS: LTC4S plays a key role in the process of inflammation as the rate limiting enzyme in the conversion of arachidonic acid to cysteinyl-leukotrienes, important mediators of inflammatory responses. The (-444)C variant upregulates LTC4S mRNA expression, increasing the synthesis of proinflammatory leukotrienes. Our results support genetic variation modifying inflammatory pathways as an important mechanism in the development of atherosclerosis.

Blood pressure as an independent prognostic factor in acute ischemic stroke.

BACKGROUND AND PURPOSE: Blood pressure is elevated in most patients during acute ischemic stroke, but the prognostic significance of this is unclear as the current data yield conflicting results. METHODS: Admission blood pressure from the 1281 patients in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) was analyzed for prognostic significance as well as the risk of hemorrhagic transformation. We also examined weighted-average blood pressure over seven days, and the impact of a 30% change in blood pressure in 24 hours. Patients with severe hypertension were excluded from the TOAST trial. RESULTS: Increasing systolic blood pressure (SBP) on admission, but not diastolic (DBP) or mean arterial pressure (MAP) was predictive of poor outcome, but this effect was not significant after adjustment for other know prognostic factors. Increasing weighted-average SBP and MAP over seven days were predictive for poor outcome, but a 30% change in blood pressure over 24 hours was not. CONCLUSIONS: Admission blood pressure is not an independent prognostic factor in acute ischemic stroke, but the weighted-average of SBP and MAP over seven days probably does have predictive value with higher values having a worse prognosis. A prospective trial of blood pressure control during acute stroke is needed.

Deep white matter pathologic features in watershed regions: a novel pattern of central nervous system involvement in MELAS.

BACKGROUND: Myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome typically manifests in adults younger than 40 years with encephalopathy, stroke-like episodes, and lactic acidosis. Magnetic resonance imaging (MRI) abnormalities typically involve the cortical gray and the adjacent subcortical white matter. OBJECTIVE: To describe a 58-year-old woman diagnosed with MELAS who was initially seen with acute myopathy, cardiac ischemia, psychosis, and MRI changes in a watershed distribution. RESULTS: Initial MRI of the brain showed the characteristic parieto-occipital gray matter lesions involving the adjacent white matter. Follow-up MRI revealed striking deep white matter involvement in a watershed distribution. A cerebral angiogram and thorough hypercoagulable workup results were normal. Electromyography showed acute denervation and myopathy. A muscle biopsy specimen revealed ragged red and cytochrome-c oxidase-negative fibers. Mitochondrial DNA analysis revealed an A3243G mutation. CONCLUSIONS: Myopathy, encephalopathy, lactic acidosis, and stroke-like episodes should be considered in older patients with myopathy, cardiomyopathy, encephalopathy, and unaccountable MRI findings. Watershed pathologic features are a rare pattern of cerebral involvement in MELAS.