Citations

Background and Purpose —The safety and the effectiveness of the surgical treatment of spontaneous intracerebral hemorrhage (ICH) remain controversial. To investigate the feasibility of urgent surgical evacuation of ICH, we conducted a small, randomized feasibility study of early surgical treatment versus current nonoperative management in patients with spontaneous supratentorial ICH. Methods —Patients with spontaneous supratentorial ICH who presented to 1 university and 2 community hospitals were randomized to surgical treatment or best medical treatment. Principal eligibility criteria were ICH volume >10 cm 3 on baseline CT scan with a focal neurological deficit, Glasgow Coma Scale score >4 at the time of enrollment, randomization and therapy within 24 hours of symptom onset, surgery within 3 hours of randomization, and no evidence for ruptured aneurysm or arteriovenous malformation. The primary end point was the 3-month Glasgow Outcome Scale (GOS). A good outcome was defined as a 3-month GOS score >3. Results —Twenty patients were randomized over 24 months, 9 to surgical intervention and 11 to medical treatment. The median time from onset of symptoms to presentation at the treating hospitals was 3 hours and 17 minutes, the time from randomization to surgery was 1 hour and 20 minutes, and the time from onset of symptoms to surgery was 8 hours and 35 minutes. The likelihood of a good outcome (primary outcome measure: GOS score >3) for the surgical treatment group (56%) did not differ significantly from the medical treatment group (36%). There was no significant difference in mortality at 3 months. Analysis of the secondary 3-month outcome measures showed a nonsignificant trend toward a better outcome in the surgical treatment group versus the medical treatment group for the median GOS, Barthel Index, and Rankin Scale and a significant difference in the National Institutes of Health Stroke Scale score (4 versus 14; P =0.04). Conclusions —Very early surgical treatment for acute ICH is difficult to achieve but feasible at academic medical centers and community hospitals. The trend toward less 3-month morbidity with surgical intervention in patients with spontaneous supratentorial ICH warrants further investigation of very early clot removal in larger randomized clinical trials.

In cats in which one middle cerebral artery was occluded, cortical blood flow (CBF) was measured and the superficial cortical microvasculature was observed bilaterally before and after the intravenous injection of a vasoactive drug. Aminophylline produced decreased CBF in the nonischemic cerebral hemispheres of five of seven animals and arterial constriction in three. Ergotamine tartrate produced arterial constriction in the nonischemic hemispheres of four animals and decreased CBF in three. Neither drug consistently produced increased CBF in ischemic cerebral tissue. Acetazolamide caused vasodilatation in the nonischemic hemispheres of seven animals and increased CBF in five. Increased CBF was not due entirely to changes of Pa CO 2 . CBF also increased in ischemic hemispheres of four of the seven animals given acetazolamide.

To assess the effects of Pa CO CO 2 on cerebral ischemia and reactive hyperemia, the right middle cerebral artery was occluded in 18 cats. Four to six hours later, Pa CO 2 was adjusted by mechanical ventilation, with or without CO 2 , to less than 20 torr in four cats, 31 to 38 torr in six, and 46 to 68 torr in eight. Regional cerebral blood flow (CBF) then was measured at multiple sites in each hemisphere by autoradiography. In regions of brain tissue outside the distribution of the occluded middle cerebral artery, log 10 CBF correlated positively with Pa CO CO 2 . In ischemic regions, CBF was higher in normocapnic cats. Reactive hyperemia occurred in two cats of the hypocapnic group, in four cats of the normocapnic group, but in only one hypercapnic cat (Pa CO CO 2 = 46 torr). Hyperemia also was found outside potentially ischemic regions in five cats. Multiple hyperemic foci developed in six cats. Neither hypocapnia nor hypercapnia was associated with a smaller size or higher CBF of regions of cerebral ischemia produced by occlusion of a middle cerebral artery, although hypercapnia inhibited the development of hyperemia.

The right middle cerebral artery (MCA) was occluded in cats; after subsequent craniectomy cortical blood flow (CBF) was measured bilaterally with 85 Kr, and photographs of the superficial microvasculature were made. Ventilation was controlled, and Pa CO CO2 was altered by changing the concentration of CO 2 in the inspired air. In nonischemic cortex CBF varied as an exponential function of Pa CO CO2 , and the caliber of superficial arterial vessels (50 to 200µ in diameter) increased with increasing Pa CO CO2 . In ischemic cortex, changes of Pa CO CO2 produced no change of CBF in six of ten animals studied within one day of occlusion; in four of these six, there was no change in the caliber of arterial vessels. In the four other animals of this group, there was a paradoxical response (an increase of Pa CO CO2 produced a decrease of CBF of ischemic cortex), and in two of these four animals, there also was a paradoxical response of the caliber of arterial vessels. In eight animals allowed to survive 5 to 12 days after MCA occlusion, the arterial vessels of ischemic cortex regained some reactivity: a normal response of CBF to changes of Pa CO CO2 was found in four, and appropriate changes of vessel caliber were found in all eight. The ischemia-induced impairment of the reactivity of cortical vessels to changes of Pa CO CO2 casts doubt on the usefulness of CO 2 inhalation for the treatment of strokes of humans.

Background and Purpose —Thoracic aortic plaque identified by transesophageal echocardiography heightens the risk of stroke associated with atrial fibrillation (AF). We sought to identify the prevalence, predictors, and implications of aortic plaque in patients with nonvalvular AF. Methods —Thoracic aortic plaque was prospectively sought in 770 persons with AF with the use of transesophageal echocardiography and classified as simple or complex on the basis of thickness ≥4 mm, ulceration, or mobility. Clinical and echocardiographic features of thromboembolism were correlated by multivariate analysis. Results —Aortic plaque was detected in 57% of the cohort, and complex plaque was detected in 25%. Both were found more frequently in the descending than in the proximal aorta. Potentially etiologic patient characteristics independently associated with complex plaque included advanced age, history of hypertension, diabetes, and past or present tobacco use. Comorbidities associated with aortic plaque were prior thromboembolism, increased pulse pressure, ischemic heart disease, stenosis or sclerosis of the aortic valve, mitral annular calcification (>10%), elevated serum creatinine concentration, spontaneous echo contrast in the left atrium or appendage, and left atrial appendage thrombus. The prevalence of complex plaque in patients aged <70 years with <10% mitral annular calcification, without ischemic heart disease, or without pulse pressure ≥65 mm Hg was 4% (95% CI, 1% to 6%). Conclusions —Aortic plaque is prevalent in patients with AF and is associated with atherosclerosis risk factors and with left atrial stasis or thrombosis, which are themselves independent stroke risk factors. Since the predominant location of complex plaque was in the descending aorta, the role of aortic plaque as a source of embolism in AF is uncertain.

Background and Purpose— There is uncertainty whether warfarin-treated patients (despite international normalized ratio <1.7) have increased risks of symptomatic intracerebral hemorrhage after intravenous thrombolysis. Methods— Vascular risk factors, stroke subtype, and outcome measures were compared between warfarin- and nonwarfarin-treated patients undergoing acute thrombolysis within 3 hours of symptom onset. Results— From 212 patients (mean age, 74±14 years; 50% men) studied, 14 (6.5%) had prior warfarin use. After adjusting for age, baseline National Institutes of Health Stroke Scale, and stroke subtype, warfarin-treated patients had significantly increased risks of developing symptomatic intracerebral hemorrhage (adjusted OR, 14.7; 95% CI, 1.3 to 54.3). A trend for poorer stroke recovery and increased mortality was observed in warfarin-treated patients on univariate, but not on multivariable, analyses. Conclusions— Warfarin-treated patients with stroke have increased risks of symptomatic intracerebral hemorrhage after thrombolytic treatment. These data raise safety concerns of thrombolytic treatment in warfarin-treated patients with subtherapeutic international normalized ratio.

Background—Women with congenital long-QT syndrome experience an increased risk for cardiac events after the onset of adolescence that is more pronounced among carriers of the LQT2 genotype. We hypothesized that the hormonal changes associated with menopause may affect clinical risk in this population.Methods and Results—We used a repeated-events analysis to evaluate the risk for recurrent syncope during the menopause transition and postmenopausal periods (5 years before and after the age at onset of menopause, respectively) among 282 LQT1 (n=151) and LQT2 (n=131) women enrolled in the Long-QT Syndrome Registry. Multivariate analysis showed that the risk for recurrent syncope (n=150) among LQT2 women was significantly increased during both menopause transition (hazard ratio, 3.38;P=0.005) and the postmenopausal period (hazard ratio, 8.10;P<0.001) compared with the reproductive period. The risk increase was evident among women who did or did not receive estrogen therapy. In contrast, among LQT1 women, the onset of menopause was associated with a reduction in the risk for recurrent syncope (hazard ratio, 0.19;P=0.05;P=0.02 for genotype-by-menopause interaction). Only 22 women (8%) experienced aborted cardiac arrest or sudden cardiac death during follow-up. The frequency of aborted cardiac arrest/sudden cardiac death showed a similar genotype-specific association with the onset of menopause.Conclusions—The onset of menopause is associated with a significant increase in the risk of cardiac events (dominated by recurrent episodes of syncope) in LQT2 women, suggesting that careful follow-up and continued long-term therapy are warranted in this population.

Abstract Background: Ongoing phase III trials are comparing accelerated PBI around the lumpectomy site to standard whole breast irradiation in early stage breast cancer. Recent studies have questioned the late toxicity from PBI delivered with 3DCRT. We evaluated late toxicity on patients (pts) treated on RTOG 0319. Methods:52 pts with stage I-II breast cancer, ≥3 cm, negative margins, and &lt; 3 nodes positive were treated with 3DCRT PBI and received 38.5 Gy in 10 BID fractions over 5 days. Median follow-up was 5.3 years (min-max: 1.7-6.4 years). Five pts were deceased at 5 years. NCI CTCAE v3.0 was used to grade adverse events (AEs). At 3 years, 50 pts were available for AE reporting or late toxicity assessment. Results: The treatment-related AEs were primarily grade 1 36.5%, 50% grade 2, and only 3 (5.8%) pts had grade 3 AEs. The grade 3 AEs in these pts were radiation dermatitis, skin fibrosis, telangectasia, and myositis. No baseline self-assessment of breast appearance is available. Patient self-assessment of breast appearance and satisfaction was available in 45 (87%) pts at 1 year and 36 (72%) at 3 years. At 1 year, 82% self reported excellent/good breast appearance and at 3 years, 64%. Pts who reported &lt; excellent/good breast appearance had significantly more grade ≥2 skin AEs (telangectasia, skin atrophy, hyperpigmentation, erythema, skin fibrosis, radiation dermatitis, and breast or nipple/areolar deformity). At 3 years, 31 of 36 pts were satisfied with their treatment, but all 36 would choose 3DCRT PBI again over standard breast RT. Treatment factors were evaluated to establish correlation with patient reported breast appearance. Preliminary observations suggest surgical bed volume, PTV volume, number of beams used, and possible use of bolus are associated with patient reported outcomes (PRO). Surgical factors impacting PRO were not collected. Conclusions: The majority of pts were satisfied with their treatment results at 3 years and would all choose to have 3DCRT PBI again. With a median of 5.3 years, the rate of grade 3 AEs is low. Technical factors from this phase II trial were modified for the phase III NSABP B-39/RTOG 0413 trial, in which bolus is not allowed and both target volumes and required coverage were modified, increasing expectation of improved PRO. Supported by RTOG U10 CA21661, CCOP U10 CA37422 and ATC U24 CA 81647 NCI grants. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-15-07.

Hydrogen sulfide (H2S) is produced endogenously by l-cysteine metabolism. H2S modulates several ion channels with an unclear mechanism of action. A possible mechanism is through reduction-oxidation reactions attributable to the redox potential of the sulfur moiety. The aims of this study were to determine the effects of the H2S donor NaHS on NaV1.5, a voltage-dependent sodium channel expressed in the gastrointestinal tract in human jejunum smooth muscle cells and interstitial cells of Cajal, and to elucidate whether H2S acts on NaV1.5 by redox reactions. Whole cell Na+ currents were recorded in freshly dissociated human jejunum circular myocytes and NaV1.5-transfected human embryonic kidney-293 cells. RT-PCR amplified mRNA for H2S enzymes cystathionine β-synthase and cystathionine γ-lyase from the human jejunum. NaHS increased native Na+ peak currents and shifted the half-point ( V1/2) of steady-state activation and inactivation by +21 ± 2 mV and +15 ± 3 mV, respectively. Similar effects were seen on the heterologously expressed NaV1.5 α subunit with EC50s in the 10−4 to 10−3 M range. The reducing agent dithiothreitol (DTT) mimicked in part the effects of NaHS by increasing peak current and positively shifting steady-state activation. DTT together with NaHS had an additive effect on steady-state activation but not on peak current, suggesting that the latter may be altered via reduction. Pretreatment with the Hg2+-conjugated oxidizer thimerosal or the alkylating agent N-ethylmaleimide inhibited or decreased NaHS induction of NaV1.5 peak current. These studies show that H2S activates the gastrointestinal Na+ channel, and the mechanism of action of H2S is partially redox independent.