Characteristics of a Diverse Cohort of Stroke Patients with SARS-CoV-2 and Outcome by Sex.

BACKGROUND AND PURPOSE: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is associated with stroke. The role of sex on stroke outcome has not been investigated. To objective of this paper is to describe the characteristics of a diverse cohort of acute stroke patients with COVID-19 disease and determine the role of sex on outcome. METHODS: This is a retrospective study of patients with acute stroke and SARS-CoV-2 infection admitted between March 15 to May 15, 2020 to one of the six participating comprehensive stroke centers. Baseline characteristics, stroke subtype, workup, treatment and outcome are presented as total number and percentage or median and interquartile range. Outcome at discharge was determined by the modified Rankin Scale Score (mRS). Variables and outcomes were compared for males and females using univariate and multivariate analysis. RESULTS: The study included 83 patients, 47% of which were Black, 28% Hispanics/Latinos, and 16% whites. Median age was 64 years. Approximately 89% had at least one preexisting vascular risk factor (VRF). The most common complications were respiratory failure (59%) and septic shock (34%). Compared with females, a higher proportion of males experienced severe SARS-CoV-2 symptoms requiring ICU hospitalization (73% vs. 49%; p = 0.04). When divided by stroke subtype, there were 77% ischemic, 19% intracerebral hemorrhage and 3% subarachnoid hemorrhage. The most common ischemic stroke etiologies were cryptogenic (39%) and cardioembolic (27%). Compared with females, males had higher mortality (38% vs. 13%; p = 0.02) and were less likely to be discharged home (12% vs. 33%; p = 0.04). After adjustment for age, race/ethnicity, and number of VRFs, mRS was higher in males than in females (OR = 1.47, 95% CI = 1.03-2.09). CONCLUSION: In this cohort of SARS-CoV-2 stroke patients, most had clinical evidence of coronavirus infection on admission and preexisting VRFs. Severe in-hospital complications and worse outcomes after ischemic strokes were higher in males, than females.

Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma.

Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.

In vivo evaluation of quantitative MR angiography in a canine carotid artery stenosis model.

BACKGROUND AND PURPOSE: Large-vessel cerebral blood flow quantification has emerged as a potential predictor of stroke risk. QMRA uses phase-contrast techniques to noninvasively measure vessel flows. To evaluate the in vivo accuracy of QMRA for measuring the effects of progressive arterial stenosis, we compared this technique with invasive flow measurements from a sonographic transit-time flow probe in a canine model. MATERIALS AND METHODS: A sonographic flow probe was implanted around the CCA of hound dogs (n = 4) under general anesthesia. Pulsatile blood flow and arterial pressure were continuously recorded during CCA flow measurements with QMRA. A vascular tourniquet was applied around the CCA to produce progressive stenosis and varying flow rates. Statistical comparisons were made by using the Pearson product moment correlation coefficient. RESULTS: A total of 60 paired CCA flow measurements were compared. Mean blood flows ranged between 21 and 691 mL/min during QMRA acquisition as measured by the flow probe. The correlation coefficients between flow probe and QMRA measurements for mean, maximum, and minimum volume flow rates were 0.99 (P < .0001), 0.98 (P < .0001), and 0.96 (P < .0001), respectively. The overall proportional difference between the 2 techniques was 7.8 ± 1%. Measurements at higher flow rates and in the absence of arterial stenosis had the lowest PD. CONCLUSIONS: Noninvasive CCA flow measurements by using QMRA are accurate compared with invasive flow-probe measurements in a canine arterial flow model with stenosis and may be useful for the evaluation of the hemodynamic effects of stenosis caused by cerebrovascular atherosclerosis.

Retrospective study of dasatinib for recurrent glioblastoma after bevacizumab failure.

There is no effective treatment for recurrent glioblastoma (GBM) after bevacizumab failure. Putative mechanisms of resistance to bevacizumab include increased pericyte coverage, mediated partly by platelet-derived growth factor receptor (PDGFR) signaling, and an infiltrative tumor growth pattern potentially dependent on SRC. We explored the efficacy of dasatinib, a SRC, BCR-ABL, c-KIT, EPHA2, and PDGFRß inhibitor, in patients with recurrent GBM after bevacizumab failure. Adult patients with histologically confirmed GBM who failed bevacizumab therapy were treated with dasatinib 70-100 mg twice daily in combination with bevacizumab (n = 14), until tumor progression or unacceptable toxicity. Fourteen patients were treated. Median age was 55 years (range 32-66) and median KPS was 80 (range 50-90). All patients (100%) had glioblastomas. The median number of prior regimens was 4 (range from 2 to 6). Of the thirteen evaluable patients, none had a complete or partial response. Only one patient had stable disease after an 8 week interval. Median progression-free survival (PFS) was 28 days (95% confidence interval [CI] 26-35 days). Six month progression-free survival (PFS6) was 0%. Median overall survival (OS) was 78 days (95% CI 41-137 days). Treatment was moderately well-tolerated, although one patient sustained a grade 4 intracerebral hemorrhage. Dasatinib in conjunction with bevacizumab does not appear to have activity in patients with recurrent, heavily pretreated GBM.

Regional cerebral blood flow using quantitative MR angiography.

BACKGROUND AND PURPOSE: We sought to derive regional cerebral blood flow using vessel flows from quantitative MR angiography (qMRA). MATERIALS AND METHODS: Flow rates in the 15 major cerebral arteries were measured on retrospectively gated fast 2D phase-contrast MR angiography obtained in 83 healthy adult volunteers (age range, 24-74 years; mean, 42 years). The arterial network of the brain was partitioned into 12 different regions, in which flows were calculated from the measured flows of the 15 cerebral arteries. RESULTS: The mean flows of the 15 arteries and the 12 regions were calculated. The mean total cranial flow and the mean total cerebral blood flow were 949 +/- 158 mL/min and 695 +/- 113 mL/min, respectively. The mean regional flows for the anterior and posterior circulation were 483 +/- 87 mL/min and 212 +/- 34 mL/min, respectively. The relative contributions of the flows in the 11 regions to their parent regions were obtained. The mean flows in the individual arteries and the regions with age were also calculated. The mean flows for the female group were significantly lower than those for the male group (P < .001) for the 2 common carotids and the cranial circulation and left/right extracranial circulation. However, the intracranial circulation was not different between sexes. CONCLUSIONS: The 12 regions in the cerebral circulation were identified and formed into a partition tree, and the mean regional flow for each region was determined using vessel flows from qMRA.

Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib.

BACKGROUND: Evidence suggests that both selective cyclooxygenase (COX)-2 inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of cardiovascular events. However, evidence from prospective studies of currently available COX-2 inhibitors and non-selective NSAIDs is lacking in patients at high cardiovascular risk who are taking aspirin. OBJECTIVE: To determine the cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. METHODS: The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of 18 325 patients with osteoarthritis comprised two parallel substudies, comparing lumiracoxib (COX-2 inhibitor) with either ibuprofen or naproxen. A post hoc analysis by baseline cardiovascular risk, treatment assignment, and low-dose aspirin use was performed. The primary composite end point was cardiovascular mortality, non-fatal myocardial infarction, and stroke at 1 year; a secondary end point was the development of congestive heart failure (CHF). RESULTS: In high risk patients among aspirin users, patients in the ibuprofen substudy had more primary events with ibuprofen than lumiracoxib (2.14% vs 0.25%, p = 0.038), whereas in the naproxen substudy rates were similar for naproxen and lumiracoxib (1.58% vs 1.48%, p = 0.899). High risk patients not taking aspirin had fewer primary events with naproxen than with lumiracoxib (0% vs 1.57%, p = 0.027), but not for ibuprofen versus lumiracoxib (0.92% vs 0.80%, p = 0.920). Overall, CHF developed more often with ibuprofen than lumiracoxib (1.28% vs 0.14%; p = 0.031), whereas no difference existed between naproxen and lumiracoxib. CONCLUSIONS: These data suggest that ibuprofen may confer an increased risk of thrombotic and CHF events relative to lumiracoxib among aspirin users at high cardiovascular risk. The study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non-aspirin users. This study is subject to inherent limitations, and therefore should be interpreted as a hypothesis-generating study.

Predictors of recurrent stroke in African Americans.

BACKGROUND: Stroke incidence and mortality are disproportionately higher among African Americans than among whites. OBJECTIVE: To describe the recurrent stroke characteristics and determine the predictability of known vascular risk factors for stroke recurrence in African Americans. METHODS: The authors followed 1,809 African Americans in the African-American Antiplatelet Stroke Prevention Study with recent noncardioembolic ischemic stroke for recurrent stroke, recurrent stroke subtype, and disability. RESULTS: Of the subjects, 10.6% experienced a recurrent stroke during follow-up. The mean interval between eligibility and recurrent stroke was 325 days (median 287 days, SD = 224 days). Stroke recurrence resulted in an average 1.5-point increase in the National Institute of Health Stroke Scale (p < 0.001) and a 3.5-point decrease in modified Barthel Index (p < 0.001). Of previously nondisabled subjects, 48% became disabled or died after stroke recurrence (p < 0.0001). Longitudinal analysis resulted in a hazard for recurrent stroke for each 10-mm Hg increase in systolic blood pressure of 1.103 (95% CI: 1.031 to 1.179, p = 0.004), pulse pressure 1.123 (95% CI: 1.041 to 1.213, p = 0.003), and mean arterial pressure 1.123 (95% CI: 1.001 to 1.260, p = 0.048). Multivariate analysis revealed increases in the recurrent stroke hazard for increases in baseline Glasgow Outcome Score (1.449, 95% CI: 1.071 to 1.961, p = 0.016) and increases in longitudinal pulse pressure (1.009, 95% CI: 1.001 to 1.017, p = 0.029). CONCLUSION: Recurrent stroke leads to disability and disability predicts recurrent stroke. Hypertension is the most predictive modifiable stroke risk factor.

Awareness, treatment, and control of vascular risk factors in African Americans with stroke.

OBJECTIVE: To investigate control of risk factors in African American patients with previous stroke. METHODS: The baseline history, physical examination, and laboratory data for 1,086 subjects enrolled in the African American Antiplatelet Stroke Prevention Study from 1995 to 1999 were studied. The level of awareness, pharmacologic treatment, and control of diabetes mellitus (casual plasma glucose level > or =200 mg/dL), hypertension (blood pressure > or =140/90 mm Hg), and hypercholesterolemia (serum total cholesterol level > or =240 mg/dL) were determined. RESULTS: Forty percent of subjects reported a history of diabetes mellitus or use of diabetic medication, and 2% of the remaining subjects had a serum glucose level of > or =200 mg/dL. Of those subjects known to be diabetic, 33% had a serum glucose level of > or =200 mg/dL. A history of hypertension or use of antihypertensive medication was reported in 87% of subjects, and 48% of the remaining subjects were found to have a blood pressure of > or =140/90 mm Hg on exam. Of those subjects known to be hypertensive by history, 73% were on antihypertensive medication, but only 30% of the treated subjects had a blood pressure under 140/90 mm Hg. A history of hypercholesterolemia or use of a lipid-lowering agent was reported in 40% of subjects, and 24% of the remaining subjects had a cholesterol level of > or =240 mg/dL. Use of a lipid-lowering agent was reported in 43% of subjects known to be hypercholesterolemic, and 38% of the hypercholesterolemic subjects had a cholesterol level of > or =240 mg/dL. CONCLUSION: Inadequate rates of awareness and control of cardiovascular disease and stroke risk factors are seen in a clinical trial of African American stroke patients and are comparable with those of previously published reports.

Lack of effects of lesions of the dorsal noradrenergic bundle on behavioral vigilance.

The effects of 6-hydroxydopamine (6-OHDA)-induced lesions of the dorsal noradrenergic bundle (DNB) were assessed in animals trained in a task designed to measure sustained attention, or vigilance. Infusions of 6-OHDA reduced frontal cortical noradrenaline contents but did not significantly affect striatal and hypothalamic noradrenaline contents. The performance of lesioned animals did not differ significantly from sham-lesioned controls. The performance of both the lesioned and sham-lesioned animals was impaired by the presentation of a visual distractor and by a decrease in the probability for a signal. The results from this study largely coincide with the results from previous studies on the effects of noradrenergic lesions on various aspects of attention. In contrast to the attentional functions assessed in this experiment, the ability to detect and select stimuli that are associated with activation of sympathetic functions is hypothesized to be sensitive to the effects of DNB lesions.

Phenotypic analysis of mice expressing exclusively apolipoprotein B48 or apolipoprotein B100.

Apolipoprotein (apo)-B is found in two forms in mammals: apo-B100, which is made in the liver and the yolk sac, and apo-B48, a truncated protein made in the intestine. To provide models for understanding the physiologic purpose for the two forms of apo-B, we used targeted mutagenesis of the apo-B gene to generate mice that synthesize exclusively apo-B48 (apo-B48-only mice) and mice that synthesize exclusively apo-B100 (apo-B100-only mice). Both the apo-B48-only mice and apo-B100-only mice developed normally, were healthy, and were fertile. Thus, apo-B48 synthesis was sufficient for normal embryonic development, and the synthesis of apo-B100 in the intestines of adult mice caused no readily apparent adverse effects on intestinal function or nutrition. Compared with wild-type mice fed a chow diet, the levels of low density lipoprotein (LDL)-cholesterol and very low density lipoprotein- and LDL-triacylglycerols were lower in apo-B48-only mice and higher in the apo-B100-only mice. In the setting of apo-E-deficiency, the apo-B100-only mutation lowered cholesterol levels, consistent with the fact that apo-B100-lipoproteins can be cleared from the plasma via the LDL receptor, whereas apo-B48-lipoproteins lacking apo-E cannot. The apo-B48-only and apo-B100-only mice should prove to be valuable models for experiments designed to understand the purpose for the two forms of apo-B in mammalian metabolism.

A novel function for apolipoprotein B: lipoprotein synthesis in the yolk sac is critical for maternal-fetal lipid transport in mice.

Apolipoprotein (apo) B, the principal structural component necessary for the synthesis and secretion of triglyceride-rich lipoproteins by the intestine and liver, is highly expressed in the yolk sac visceral endoderm of mammals, although its function in this tissue has been hitherto unclear. Disruption of the apoB gene in mice results in embryonic lethality (approximately 9.5 - 10.5 d). Here we demonstrate that apoB is normally expressed at early time points in embryonic development in yolk sac visceral endodermal cells, and that this expression is associated with the synthesis and secretion of apoB-containing lipoproteins. The lack of apoB in the visceral endoderm resulted in an accumulation of intracellular lipid droplets, an absence of lipoproteins from the secretory pathway, and reduced concentrations of cholesterol and alpha-tocopherol in tissues of apoB-/- embryos. Visceral endoderm of apoB+/- embryos exhibited an intermediate phenotype. Our results suggest that apoB plays an essential role in the transport of lipid nutrients to the developing mouse embryo via the yolk sac-mediated synthesis and secretion of apoB-containing lipoproteins.

A central cholinergic link in the cardiovascular effects of the benzodiazepine receptor partial inverse agonist FG 7142.

Previous work demonstrated that systemic administration of the benzodiazepine receptor (BZR) partial inverse agonist beta-carboline FG 7142 (FG) augments the cardiovascular response to non-signal stimuli, similar to the effects of an aversive context. Analysis of the parasympathetic and sympathetic contributions to the effects of FG prompted the hypothesis that increases in central cholinergic activity mediates the potentiation of the cardioacceleratory response by FG. Consistent with this hypothesis, the present experiments demonstrate: (a) intracerebroventricular (ICV) infusion of the cholinergic receptor agonist carbachol mimics the response-potentiating effects of FG; (b) this effect of carbachol was blocked by ICV co-administration of the muscarinic antagonist atropine; (c) ICV infusions of atropine blocked the potentiation of the cardioacceleratory response by systemically administered FG, but did not alter the basal response to the stimulus; and (d) 192 IgG-saporin-induced lesions of basal forebrain cholinergic neurons prevented the FG-induced potentiation of the cardioacceleratory response, again without altering the basal cardiac response. These data strongly support the hypothesis that the effects of FG on cardiac reactivity are mediated via an activation of central muscarinic cholinergic mechanisms.

Benzodiazepine receptor agonists and inverse agonists yield concordant rather than opposing effects on startle responses.

Benzodiazepine receptor agonists and inverse agonists exert generally opposite actions at both the cellular and behavioural levels. The present study, however, reveals that both the benzodiazepine receptor agonist, chlordiazepoxide and the partial inverse agonist, FG7142, yield a dose-dependent (2-16 mg/kg, i.p) reduction in the amplitude of the acoustic startle response in the rat. The similarity in drug effects on startle was not attributable to congruent effects on basal somatic activity, as chlordiazepoxide resulted in a dose-dependent decrease in activity whereas FG7142 was associated with a small but non-significant increase in activity. As these results contrast with the bidirectional actions of benzodiazepine receptor agonists and inverse agonists in behavioural tests of fear or anxiety, the neuronal mechanisms mediating the effects of benzodiazepine receptor ligands on the acoustic startle response may be distinct from those that underlie the specific fear- attenuating and potentiating actions, respectively, of benzodiazepine receptor agonists and inverse agonists.

Knockout of the mouse apolipoprotein B gene results in embryonic lethality in homozygotes and protection against diet-induced hypercholesterolemia in heterozygotes.

Apolipoprotein B is synthesized by the intestine and the liver in mammals, where it serves as the main structural component in the formation of chylomicrons and very low density lipoproteins, respectively. Apolipoprotein B is also expressed in mammalian fetal membranes. To examine the consequences of apolipoprotein B deficiency in mice, we used gene targeting in mouse embryonic stem cells to generate mice containing an insertional disruption of the 5' region of the apolipoprotein B gene. Mice that were heterozygous for the disrupted apolipoprotein B allele had an approximately 20% reduction in plasma cholesterol levels, markedly reduced plasma concentrations of the pre-beta and beta-migrating lipoproteins, and an approximately 70% reduction in plasma apolipoprotein B levels. When fed a diet rich in fat and cholesterol, heterozygous mice were protected from diet-induced hypercholesterolemia; these mice, which constitute an animal model for hypobetalipoproteinemia, should be useful for studying the effects of decreased apolipoprotein B expression on atherogenesis. The breeding of heterozygous mice yielded no viable homozygous apolipoprotein B knockout mice. Most homozygous embryos were resorbed by midgestation (before gestational day 11.5); several embryos that survived until later in gestation exhibited exencephalus. The embryonic lethal phenotype was rescued by complementation with a human apolipoprotein B transgene--i.e., human apolipoprotein B transgenic mice that were homozygous for the murine apolipoprotein B knockout mutation were viable. Our findings indicate that apolipoprotein B plays an essential role in mouse embryonic development.