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Context: The associations of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB) levels with the risk of cardiovascular events among patients treated with statin therapy have not been reliably documented.Objective: To evaluate the relative strength of the associations of LDL-C, non-HDL-C, and apoB with cardiovascular risk among patients treated with statin therapy.Design: Meta-analysis of individual patient data from randomized controlled statin trials in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up.Data Sources: Relevant trials were identified by a literature search updated through December 31, 2011. Investigators were contacted and individual patient data were requested and obtained for 62,154 patients enrolled in 8 trials published between 1994 and 2008.Data Extraction: Hazard ratios (HRs) and corresponding 95% CIs for risk of major cardiovascular events adjusted for established risk factors by 1-SD increase in LDL-C, non-HDL-C, and apoB.Results: Among 38,153 patients allocated to statin therapy, 158 fatal myocardial infarctions, 1678 nonfatal myocardial infarctions, 615 fatal events from other coronary artery disease, 2806 hospitalizations for unstable angina, and 1029 fatal or nonfatal strokes occurred during follow-up. The adjusted HRs for major cardiovascular events per 1-SD increase were 1.13 (95% CI, 1.10-1.17) for LDL-C, 1.16 (95% CI, 1.12-1.19) for non-HDL-C, and 1.14 (95% CI, 1.11-1.18) for apoB. These HRs were significantly higher for non-HDL-C than LDL-C (P = .002) and apoB (P = .02). There was no significant difference between apoB and LDL-C (P = .21).Conclusion: Among statin-treated patients, on-treatment levels of LDL-C, non-HDL-C, and apoB were each associated with risk of future major cardiovascular events, but the strength of this association was greater for non-HDL-C than for LDL-C and apoB. [ABSTRACT FROM AUTHOR]

Bestiality, or sexual contact between humans and nonhuman animals, is a poorly understood aspect of sexual behavior. There is a dearth of scientific research on the prevalence of bestiality, the motivations for individuals to engage in the behavior, and the risk that such individuals pose for interpersonal sexual and nonsexual violence. This study is a descriptive analysis of bestiality in all individuals found to be sexually violent predators (SVPs) in the state of Virginia between the years 2003 and 2017. Of 1,248 SVPs, 33 (2.6%) had a history of engaging in bestiality. SVPs with a history of bestiality were significantly more likely to be victims of childhood sexual abuse ( P < .005), to engage in nonsexual animal abuse ( P < .0001), and to have committed child sexual abuse ( P < .005). They were most likely to report sexual contact with dogs and demonstrated a breadth of other atypical sexual behavior. The lifetime prevalence of 2.6 percent is low compared with other published findings, suggesting that offenders may have intentionally minimized their history of atypical sexual behavior. The relationship between childhood sexual victimization and bestiality has not previously been reported in the literature and represents an important nidus for future investigation. Further research is necessary to characterize human-animal sexual interactions in SVPs and other populations., (© 2020 American Academy of Psychiatry and the Law.)

Background: In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, atorvastatin was compared with placebo in 4,731 participants with recent stroke or transient ischemic attack and no known coronary heart disease. Atorvastatin reduced the first occurrence of stroke and the first occurrence of a composite of vascular events., Objectives: The aim of this post hoc analysis was to assess the occurrence of all (first and subsequent) vascular events and the effect of atorvastatin to reduce these events by vascular territory (cerebrovascular, coronary, or peripheral) in SPARCL., Methods: Treatment effects on total adjudicated vascular events, overall and by vascular territory, were summarized by marginal proportional hazards models. Vascular event rates were estimated for each treatment group with cumulative incidence functions., Results: The placebo group had an estimated 41.2 first and 62.7 total vascular events per 100 participants over 6 years. There were 164 fewer first and 390 fewer total vascular events in the atorvastatin group (total events hazard ratio: 0.68; 95% confidence interval: 0.60 to 0.77). The total events reduction included 177 fewer cerebrovascular, 170 fewer coronary, and 43 fewer peripheral events. Over 6 years, an estimated 20 vascular events per 100 participants were avoided with atorvastatin treatment., Conclusions: In participants with recent stroke or transient ischemic attack, the total number of vascular events prevented with atorvastatin was more than twice the number of first events prevented. Total event reduction provides a comprehensive metric to capture the totality of atorvastatin clinical efficacy in reducing disease burden after stroke or transient ischemic attack. (Lipitor in the Prevention of Stroke, for Patients Who Have Had a Previous Stroke [SPARCL]; NCT00147602)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Higher low-density lipoprotein cholesterol is associated with more rapid chronic kidney disease progression; reduction in cholesterol with statins, in conjunction with statins' pleiotropic effects, such as decreasing inflammation, may be renoprotective. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial assessed the effect of statin treatment on the risk of nonfatal and fatal stroke in subjects with a noncardioembolic stroke or transient ischemic attack, no known coronary heart disease, and low-density lipoprotein cholesterol between 2.6 and 4.9 mmol/L (100-190 mg/dL)., Methods: We explored the effect of randomization to atorvastatin 80 mg/d or placebo on the change in estimated glomerular filtration rate (eGFR; using the 4-component Modification of Diet in Renal Disease Study equation) in SPARCL subjects (n=4731) with (eGFR, <60 mL/min per 1.73 m2; n=3119) and without (eGFR, ≥60 mL/min per 1.73 m2; n=1600) chronic kidney disease overall and by glycemic status at baseline., Results: Mean baseline eGFR was similar between treatment groups (65.5±0.26 versus 65.6±0.26 mL/min per 1.73 m2 atorvastatin versus placebo; 33% versus 34% had chronic kidney disease, respectively; P=0.55). After 60 months, eGFR increased 3.46±0.33 mL/min per 1.73 m2 in those randomized to atorvastatin versus 1.42±0.34 mL/min per 1.73 m2 in those randomized to placebo (P<0.001) independent of baseline renal function. In the subgroup with diabetes mellitus at randomization, eGFR increased 1.12±0.92 mL/min per 1.73 m2 in the atorvastatin group and decreased 1.69±0.92 mL/min per 1.73 m2 in placebo group during a period of 60 months (P=0.016)., Conclusions: This post hoc analysis suggests that atorvastatin treatment may improve renal function in patients with prior stroke or transient ischemic attack with and without chronic kidney disease, and that atorvastatin treatment may prevent eGFR decline in patients with stroke and diabetes mellitus., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00147602., (© 2014 American Heart Association, Inc.)

Background: Identifying patients with recent stroke or transient ischemic attack (TIA) at high risk of major vascular events (MVEs; stroke, myocardial infarction, or vascular death) may help optimize the intensity of secondary preventive interventions. We evaluated the relationships between the baseline Framingham Coronary Risk Score (FCRS) and a novel risk prediction model and with the occurrence of MVEs after stroke or TIA in subjects enrolled in the Stroke Prevention by Aggressive Reduction in Cholesterol Level (SPARCL) trial., Methods: Data from the 4731 subjects enrolled in the SPARCL study were analyzed. Hazard ratios (HRs) from Cox regression models were used to determine the risk of subsequent MVEs based on the FCRS predicting 20% or more 10-year coronary heart disease risk. The novel risk model was derived based on multivariable modeling with backward selection. Model discrimination (c-statistics) was assessed using the areas under the receiver operating characteristic curves., Results: Of 3969 subjects with complete data, 27% had a baseline FCRS of 20% or more. In multivariable analysis, an FCRS of 20% or more was associated with twice the risk of subsequent MVEs (HR = 1.92, 95% confidence interval [CI]: 1.63-2.27). The novel model based on a multivariable analysis included age (HR = 1.37, 95% CI: 1.25-1.51 per 10 years), diabetes (HR = 1.82, 95% CI: 1.51-2.18), male sex (HR = 1.35, 95% CI: 1.12-1.61), and an apolipoprotein (APO)-B/APO-A1 ratio (HR = 1.56, 95% CI: 1.16-2.11). The c-statistic was .58 (95% CI: .55-.60) for the FCRS of 20% or more and .65 (95% CI: .63-.67) for the novel model., Conclusions: Both a baseline FCRS of 20% or more and a novel predictive model were associated with future MVEs in SPARCL trial subjects. The novel model needs to be validated, and the benefits of using either the FCRS or the novel model in clinical practice needs to be assessed., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk., Methods and Results: We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38,153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.81-0.86 per 1 standard deviation increment), as were apoA-I levels (HR, 0.79; 95% CI, 0.72-0.82). This association was also observed among patients achieving on-statin low-density lipoprotein cholesterol levels <50 mg/dL. An increase of HDL-C was not associated with reduced cardiovascular risk (HR, 0.98; 95% CI, 0.94-1.01 per 1 standard deviation increment), whereas a rise in apoA-I was (HR, 0.93; 95% CI, 0.90-0.97)., Conclusions: Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low low-density lipoprotein cholesterol. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction.

Background: Previous cross-sectional studies reported an increased risk of suicide attempt in persons with migraine headache, which was sustained when psychiatric comorbidity was statistically controlled., Objective: To estimate the risk of suicide attempt in persons with migraine vs controls with no history of severe headache, using prospective data and validated diagnostic assessment. To examine the specificity of the migraine-suicide attempt risk by comparing it to the risk associated with non-migraine headache of comparable severity and disability., Methods: A cohort of persons with migraine (n = 496), non-migraine severe headaches (n = 151), and controls with no history of severe headache (n = 539) was randomly selected from the general community, assessed in 1997 and reassessed 2 years later., Results: Persons with migraine had an increased risk of suicide attempt during the 2-year follow-up period, compared with controls. Odds ratio, adjusted for sex, psychiatric disorder, and previous history of suicide attempt at baseline was 4.43 (95% confidence interval [CI] 1.93, 10.2). Persons with non-migraine headache of comparable intensity and disability also had an increased risk of suicide attempt, compared to controls: odds ratio, adjusted for the same covariates, was 6.20 (95% CI 2.40, 16.0). The difference between the 2 estimates was not significant. In the entire sample, headache severity at baseline predicted suicide attempt: a difference of 1 standard deviation (SD) in pain score increased the risk of suicide attempt by 79%, adjusting for sex and psychiatric disorders., Conclusions: The results suggest the possibility that pain severity might account in part for the increased risk of suicide attempt associated with migraine., (© 2012 American Headache Society.)

Objective: To perform a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, which tested the effect of treatment with atorvastatin in reducing stroke in subjects with a recent stroke or transient ischemic attack, to explore the effects of treatment in subjects with type 2 diabetes mellitus or metabolic syndrome (MetS)., Methods: The 4731 subjects enrolled in the SPARCL trial were classified as having type 2 diabetes mellitus at enrollment (n = 794), MetS retrospectively (n = 642), or neither diabetes nor MetS (n = 3295, the reference group) based on data collected at baseline. Cox regression models were used to determine whether the effect of treatment on the primary end point (combined risk of nonfatal and fatal stroke) and secondary end points (major coronary events, major cardiovascular events, any coronary heart disease event, and any revascularization procedure) varied based on the presence of type 2 diabetes mellitus or MetS., Results: Subjects with type 2 diabetes mellitus had increased risks of stroke (hazard ratio [HR] = 1.62; 95% confidence interval [CI], 1.33-1.98; P < .001), major cardiovascular events (HR = 1.66; 95% CI, 1.39-1.97; P < .001), and revascularization procedures (HR = 2.39; 95% CI, 1.78-3.19; P < .001) compared with the reference group. Subjects with MetS were not at increased risk for stroke (P = .78) or major cardiovascular events (P = .38) but more frequently had revascularization procedures (HR = 1.78; 95% CI, 1.26-2.5; P = .001). There were no treatment × subgroup interactions for the SPARCL primary end point (P = .47)., Conclusions: The SPARCL subjects with type 2 diabetes were at higher risk for recurrent stroke and cardiovascular events. This exploratory analysis found no difference in the effect of statin treatment in reducing these events in subjects with or without type 2 diabetes or MetS. Trial Registration clinicaltrials.gov Identifier: NCT00147602.

A number of pain conditions, acute as well as chronic, are much more prevalent in women, such as temporomandibular disorder (TMD), irritable bowel syndrome, fibromyalgia, and migraine. The association of female sex steroids with these nociceptive conditions is well known, but the mechanisms of their effects on pain signaling are yet to be deciphered. We reviewed the mechanisms through which female sex steroids might influence the trigeminal nociceptive pathways with a focus on migraine. Sex steroid receptors are located in trigeminal circuits, providing the molecular substrate for direct effects. In addition to classical genomic effects, sex steroids exert rapid nongenomic actions to modulate nociceptive signaling. Although there are only a handful of studies that have directly addressed the effect of sex hormones in animal models of migraine, the putative mechanisms can be extrapolated from observations in animal models of other trigeminal pain disorders, like TMD. Sex hormones may regulate sensitization of trigeminal neurons by modulating expression of nociceptive mediator such as calcitonin gene-related peptide. Its expression is mostly positively regulated by estrogen, although a few studies also report an inverse relationship. Serotonin (5-Hydroxytryptamine [5-HT]) is a neurotransmitter implicated in migraine; its synthesis is enhanced in most parts of brain by estrogen, which increases expression of the rate-limiting enzyme tryptophan hydroxylase and decreases expression of the serotonin re-uptake transporter. Downstream signaling, including extracellular signal-regulated kinase activation, calcium-dependent mechanisms, and cAMP response element-binding activation, are thought to be the major signaling events affected by sex hormones. These findings need to be confirmed in migraine-specific animal models that may also provide clues to additional ion channels, neuropeptides, and intracellular signaling cascades that contribute to the increased prevalence of migraine in women., (© 2011 American Headache Society.)

The purpose of this study was to evaluate the clinical response and side effects of tissue plasminogen activator (tPA) for the treatment of feline arterial thromboembolism (ATE). Previous reports of conservative and thrombolytic therapy were used to provide a historical control group of cats with ATE. The study was terminated due to a high frequency of adverse outcomes. tPA was administered to 11 cats with clinical signs of ATE for a median duration of 4.0 h (range 2-12h) prior to treatment. Pulses were restored in 40% of limbs within 4h and 53% within 24h. Motor function was restored to 33% of limbs within 24h. Adverse effects were seen in 11/11 cats following administration of tPA including azotemia (n=5), neurological signs (n=5), cardiac arrhythmias (n=5), hyperkalemia (n=4), acidosis (n=2) and sudden death in one cat. Ultimately, three cats (27%) were discharged alive from the hospital. While signs compatible with thrombolysis were noted in many cats following tPA administration, a high rate of side effects and low rate of hospital discharge were noted in this study., (Copyright 2009 ESFM and AAFP. Published by Elsevier Ltd. All rights reserved.)

Acute treatment of migraine has benefited first from major advances in pharmacological science followed in short order, sometimes preceded, by an improved understanding of pathogenesis, especially of headache. This chapter reviews the mechanisms of migraine that provide an understanding of the pharmacology and therapeutic targets for acute migraine medications. General clinical approaches to acute therapy are reviewed, and indices of acceptable acute therapeutic outcomes are discussed. Currently the serotonin (5-HT) 1B/1D agonist group of drugs, triptans, forms the mainstay of acute therapeutic regimens. Other approaches to acute treatment such as simple analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), ergots, and combination medications are reviewed. Finally, the newest acute treatments that are currently exploratory or under clinical investigation are discussed., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study is a prospective, randomized, placebo-controlled trial that was designed to determine whether 80 mg/d of atorvastatin reduced the risk of fatal or nonfatal stroke in patients who had previously experienced a stroke or transient ischemic attack. It is unique in that it is the only trial to study this cohort of patients with no known coronary heart disease. The review recaps the results of the primary SPARCL data and discusses the findings of subsequent analyses that extend the conclusions from the study. Atorvastatin reduced the risk of stroke to a clinically persuasive degree. This benefit was present despite a small increase in risk of intracerebral hemorrhage. Factors were identified in SPARCL that might reduce this risk if implemented. Further subanalyses addressed other questions relative to stroke profile of benefit and potential mechanisms of statin action. SPARCL has established that statins have an important role in secondary stroke prevention.

Objective: To explore the relative contributions of baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) and lipoproteins on the risk of recurrent stroke or first major cardiovascular event (MCVE) and their potential impact on the benefit of statin treatment., Methods and Results: The SPARCL trial randomized 4731 patients with recent stroke or transient ischemic attack (TIA) and no known coronary heart disease and LDL-C between 100 and 190 mg/dL to either atorvastatin 80 mg/d or placebo. Baseline assessment included SBP, DBP and measurements of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), and triglyceride levels. After 4.9 years of follow-up, there were 575 primary end points (fatal and nonfatal stroke), including 491 ischemic strokes, and 740 MCVEs (stroke plus myocardial infarction and vascular death). Cox regression models analysis showed a trend (P>0.05 and P<0.10) for higher SBP but not DBP to be associated with an outcome stroke with only SBP associated with MCVE. Only baseline low HDL-C was associated with an outcome stroke. Baseline HDL-C, triglycerides, and LDL/HDL ratio were each associated with MCVEs. There were no interactions between any of these baseline variables and the effect of treatment on outcome strokes., Conclusions: In patients with recent stroke or TIA and no coronary heart disease, only lower baseline HDL-C predicted the risk of recurrent stroke with HDL-C, triglycerides, and LDL/HDL ratio associated with MCVE. Atorvastatin treatment was similarly effective regardless of baseline lipoprotein levels.

Background and Purpose: In SPARCL, treatment with atorvastatin 80 mg daily reduced stroke risk in patients with recent stroke or TIA and no known coronary heart disease by 16% versus placebo over 4.9 years of follow-up. The purpose of this secondary analysis was to determine whether men and women similarly benefited from randomization to statin treatment., Methods: The effect of sex on treatment-related reductions in stroke and other cardiovascular outcomes were analyzed with Cox regression modeling testing for sex by treatment interactions., Results: Women (n=1908) constituted 40% of the SPARCL study population. At baseline, men (n=2823) were younger (62.0+/-0.21 versus 63.9+/-0.27 years), had lower systolic BPs (138.1+/-0.35 versus 139.5+/-0.47 mm Hg), higher diastolic BPs (82.2+/-0.20 versus 81.0+/-0.25 mm Hg), more frequently had a history of smoking (73% versus 38%), and had lower total cholesterol (207.0+/-0.54 versus 218.9+/-0.67 mg/dL) and LDL-C levels (132+/-0.45 versus 134+/-0.57 mg/dL) than women. Use of antithrombotics and antihypertensives were similar. After prespecified adjustment for region, entry event, time since event, and age, there were no sex by treatment interactions for the combined risk of nonfatal and fatal stroke (treatment Hazard Ratio, HR=0.84, 95% CI 0.68, 1.02 in men versus HR=0.84, 95% CI 0.63, 1.11 in women; treatment x sex interaction P=0.99), major cardiac events (HR=0.61, 95% CI 0.42, 0.87 in men versus HR=0.76, 95% CI 0.48, 1.21 in women; P=0.45), major cardiovascular events (HR=0.78, 95% CI 0.65, 0.93 in men versus HR=0.84, 95% CI 0.65, 1.07 in women; P=0.63), revascularization procedures (HR=0.50, 95% CI 0.37, 0.67 in men versus HR=0.76, 95% CI 0.46, 1.24 in women; P=0.17), or any CHD event (HR=0.54, 95% CI 0.41, 0.72 in men versus 0.67 95% CI 0.46, 0.98 in women; P=0.40)., Conclusions: Stroke and other cardiovascular events are similarly reduced with atorvastatin 80 mg/d in men and women with recent stroke or TIA.

Background: In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, atorvastatin 80 mg/day reduced the risk of stroke in patients with recent stroke or TIA. Post hoc analysis found this overall benefit included an increase in the numbers of treated patients having hemorrhagic stroke (n = 55 for active treatment vs n = 33 for placebo)., Methods: We explored the relationships between hemorrhage risk and treatment, baseline patient characteristics, most recent blood pressure, and most recent low-density lipoprotein (LDL) cholesterol levels prior to the hemorrhage., Results: Of 4,731 patients, 67% had ischemic strokes, 31% TIAs, and 2% hemorrhagic strokes as entry events. In addition to atorvastatin treatment (HR 1.68, 95% CI 1.09 to 2.59, p = 0.02), Cox multivariable regression including baseline variables significant in univariable analyses showed that hemorrhagic stroke risk was higher in those having a hemorrhagic stroke as the entry event (HR 5.65, 95% CI 2.82 to 11.30, p < 0.001), in men (HR 1.79, 95% CI 1.13 to 2.84, p = 0.01), and with age (10 y increments, HR 1.42, 95% CI 1.16 to 1.74, p = 0.001). There were no statistical interactions between these factors and treatment. Multivariable analyses also found that having Stage 2 (JNC-7) hypertension at the last study visit before a hemorrhagic stroke increased risk (HR 6.19, 95% CI 1.47 to 26.11, p = 0.01), but there was no effect of most recent LDL-cholesterol level in those treated with atorvastatin., Conclusions: Hemorrhagic stroke was more frequent in those treated with atorvastatin, in those with a hemorrhagic stroke as an entry event, in men, and increased with age. Those with Stage 2 hypertension at the last visit prior to the hemorrhagic stroke were also at increased risk. Treatment did not disproportionately affect the hemorrhagic stroke risk associated with these other factors. There were no relationships between hemorrhage risk and baseline low-density lipoprotein (LDL) cholesterol level or recent LDL cholesterol level in treated patients.

Background and Purpose: The intention-to-treat analysis of data from the placebo-controlled Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial found 80 mg atorvastatin per day reduced the risk of stroke and major coronary events in patients with recent stroke or transient ischemic attack. This benefit was present despite only a 78% net difference in adherence to randomized treatment over the course of the trial. In this exploratory analysis, our aim was to evaluate the benefit and risks associated with achieving a >or=50% low-density lipoprotein cholesterol (LDL-C) reduction from baseline., Methods: This post hoc analysis was based on 55,045 LDL-C measurements among the 4731 patients enrolled in SPARCL (average, 11.6 measurements per patient) during a mean follow-up of 4.9 years. At each postrandomization LDL-C assessment, percent change in LDL-C from baseline for each patient was classified as no change or increase from baseline (32.7% of measurements), <50% LDL-C reduction (39.4%), or >or=50% reduction (27.9%)., Results: Compared with no change or an increase in LDL-C, analysis of time-varying LDL-C change showed that patients with >or=50% LDL-C reduction had a 31% reduction in stroke risk (hazard ratio, 0.69, 95% CI, 0.55 to 0.87, P=0.0016), a 33% reduction in ischemic stroke (P=0.0018), no statistically significant increase in hemorrhagic stroke (P=0.8864), and a 37% reduction in major coronary events (P=0.0323). There was no increase in the incidence of myalgia or rhabdomyolysis. Persistent liver enzyme elevations were more frequent in the group with >or=50% LDL-C reduction., Conclusions: As compared with having no change or an increase in LDL-C, achieving a >or=50% lowering was associated with a greater reduction in the risk of stroke and major coronary events with no increase in brain hemorrhages.

Herein, we report the discovery of novel, proline-based factor Xa inhibitors containing a neutral P1 chlorophenyl pharmacophore. Through the additional incorporation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one 22, as a P4 pharmacophore, we discovered compound 7 (PD 0348292). This compound is a selective, orally bioavailable, efficacious FXa inhibitor that is currently in phase II clinical trials for the treatment and prevention of thrombotic disorders.

Background: Statins reduce the incidence of strokes among patients at increased risk for cardiovascular disease; whether they reduce the risk of stroke after a recent stroke or transient ischemic attack (TIA) remains to be established., Methods: We randomly assigned 4731 patients who had had a stroke or TIA within one to six months before study entry, had low-density lipoprotein (LDL) cholesterol levels of 100 to 190 mg per deciliter (2.6 to 4.9 mmol per liter), and had no known coronary heart disease to double-blind treatment with 80 mg of atorvastatin per day or placebo. The primary end point was a first nonfatal or fatal stroke., Results: The mean LDL cholesterol level during the trial was 73 mg per deciliter (1.9 mmol per liter) among patients receiving atorvastatin and 129 mg per deciliter (3.3 mmol per liter) among patients receiving placebo. During a median follow-up of 4.9 years, 265 patients (11.2 percent) receiving atorvastatin and 311 patients (13.1 percent) receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2 percent; adjusted hazard ratio, 0.84; 95 percent confidence interval, 0.71 to 0.99; P=0.03; unadjusted P=0.05). The atorvastatin group had 218 ischemic strokes and 55 hemorrhagic strokes, whereas the placebo group had 274 ischemic strokes and 33 hemorrhagic strokes. The five-year absolute reduction in the risk of major cardiovascular events was 3.5 percent (hazard ratio, 0.80; 95 percent confidence interval, 0.69 to 0.92; P=0.002). The overall mortality rate was similar, with 216 deaths in the atorvastatin group and 211 deaths in the placebo group (P=0.98), as were the rates of serious adverse events. Elevated liver enzyme values were more common in patients taking atorvastatin., Conclusions: In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke. (ClinicalTrials.gov number, NCT00147602 [ClinicalTrials.gov].)., (Copyright 2006 Massachusetts Medical Society.)

This paper is designed to provide concepts and stimulate directions for further investigation of menstrual migraine. On the basis of experimental studies and literature review, we propose that abnormalities in how estrogen modulates neuronal function in migraine are due to a mismatch between its gene-regulation and membrane effects. In the interictal phase when estrogen levels peak, increased neuronal excitability is balanced by homeostatic gene regulation in brain cortex, and nociceptive systems. When levels fall at menses, mismatch in homeostatic gene regulation by estrogen unmasks non-nuclear mitogen-activated hyperexcitability of cell membranes, sensitizing neurons to triggers that activate migraine attacks. At the trough of estrogen levels, the down-regulating effect on inflammatory genes is lost and peptide modulated central sensitization is increased as is pain and disability of the migraine attack.

Background: Many compounds currently in development for treatment of thrombotic disorders demonstrate high specificity for single targets of blood coagulation such as factor Xa (FXa) or thrombin., Aim: The aim of this study is to determine if inhibition of both FXa and thrombin by simultaneous administration of PD0313052 and argatroban, respectively, synergistically increases the effect of either drug alone in vivo and in vitro., Methods and Results: Analyses of thrombin generation from combined inhibition in human plasma using statistical methods of Bliss independence identified a synergistic reduction in thrombin production 30% lower than predicted by simple additivity. The greatest synergy occurred at concentrations of each compound below their individual IC50 values. In a rabbit arterio-venous shunt model (RAV) of thrombosis, co-administration of PD0313052 and argatroban reduced thrombus weight (TW) to a much greater degree than expected by additivity alone producing a synergistic decrease of 45% over the level predicted by additivity. Analyses of thrombin generation in plasma samples from the RAV also demonstrated 38% synergy ex vivo. Furthermore, at plasma concentrations with the greatest synergistic effect, no increase in bleeding or appreciable change in prothrombin time, activated partial thromboplastin time, or activated clotting time was observed, but thrombus weight reduction was greater than twofold higher than that expected from simple additivity., Conclusions: These results demonstrate a significant synergistic antithrombotic effect of combining low doses of PD0313052 and argatroban and support the hypothesis that simultaneous targeting of multiple coagulation enzymes may offer an improved therapeutic index in the prevention and treatment of thrombosis.

Headache is a frequent accompaniment of acute ischaemic stroke. The predisposing factors and underlying mechanisms are currently incompletely defined. We analysed prospectively collected data relevant to headache occurring at ischaemic stroke onset in consecutive patients included in the Henry Ford Hospital Stroke Data Bank. Patients with headache (HA+) and without headache (HA-) were compared for demographic factors, medical history, medications, examination findings, laboratory findings, and stroke localization and subtype. Group comparisons for categorical data were performed with chi(2) test, and for continuous variables with two-sample t-tests. Stepwise logistic regression analysis, including all variables with P<0.25, was used to define the independent predictors of onset headache. Three hundred and seventy-five patients had complete headache and clinical datasets and were included in the analysis (HA+, N=118; HA-, N=257). Multivariate analysis revealed that the independent predictors of HA+ were: infarct in the distribution of the posterior circulation [P=0.0076, odds ratio (OR) 2.15, 95% confidence interval (CI) 1.23, 3.77], absence of history of hypertension (P=0.0106, OR 0.48, 95% CI 0.27, 0.84), and treatment with warfarin at the time of the index stroke (P=0.0135, OR 4.89, 95% CI 1.39, 17.21). The occurrence of headache at onset of ischaemic stroke is determined by posterior circulation distribution of the ischaemic event, absence of history of hypertension and treatment with warfarin at the time of the index stroke. These results suggest that preserved elasticity and maintenance of the intracranial vasculature in a relaxed state, in combination with coagulation system derangements, and activation of dense perivascular afferent nerves, play a role in the pathogenesis of onset headache.

Objectives: Stroke risk is increased in migraine, the basis of which remains to be established. C-reactive protein (CRP) is a marker of cerebrovascular disease, suggesting in part an inflammatory mechanism. Because attacks of migraine may involve repeated sterile vascular inflammation, we measured CRP in migraine patients., Methods: Retrospective review was conducted of 60 randomly sampled charts of patients with the diagnosis of migraine without aura (MwoA, n = 29) and migraine with aura (MwA, n = 31), in which CRP was recorded as part of the differential diagnostic evaluation. CRP was measured by standard commercial laboratory methods; high sensitivity CRP (hs-CRP) values above 3mg/L were considered abnormal., Results: Elevated hs-CRP was found in 43% of all patients (26 of 60). In MwoA, of 29 subjects, abnormal hs-CRP was recorded in 16; in 10 no other conditions were found to explain the abnormality. In MwA, of 31 subjects, abnormal CRP was recorded in 10; in 5 no other condition could explain the abnormality. No associations were found between other demographic or clinical features., Conclusions: CRP may be abnormal in MwoA and MwA patients who present with atypical, severe, or complex clinical features that require extensive differential diagnostic investigation.

Although migraine is more common in women than men and often linked to the menstrual cycle, few studies have investigated the biological basis of hormonal influences on the trigeminovascular system. In the present study we investigated the effect of physiological levels (10(-9) m) oestrogen on female rat trigeminal ganglia in vitro. Immunocytochemical analysis demonstrated the presence of oestrogen receptor-alpha in a predominantly cytoplasmic location and in neurites. Microarray analysis demonstrated that oestrogen treatment regulates several genes with potential relevance to menstrual migraine. The genes that were upregulated included synapsin-2, endothelin receptor type B, activity and neurotransmitter-induced early gene 7 (ania-7), phosphoserine aminotransferase, MHC-1b, and ERK-1. Down-regulated genes included IL-R1, bradykinin B2 receptor, N-tropomodulin, CCL20, GABA transporter protein, fetal intestinal lactase-phlorizin hydrolase, carcinoembryonic antigen-related protein, zinc finger protein 36, epsin 1 and cysteine string protein. Protein activity assays demonstrated that exposure of the cultured neurons to oestrogen leads to activation of ERK, which has been linked to inflammatory pain. Immunocytochemistry demonstrated that activated ERK was present in neurons containing peripherin, a marker of nociceptive neurons. Several of the genes in the present study may provide potential targets for understanding the association of oestrogen with migraine and other hormone-related orofacial pain.

A complex bidirectional relation between migraine, mostly migraine with aura (MA), and ischaemic stroke is known. A cerebral infarction can occur during a MA, and MA is a risk factor for ischaemic stroke, particularly in young women. Conversely, cerebral ischaemia can induce MA. Both ischaemic stroke and MA might be consequences of many underlying vascular disorders. Despite the relation between migraine and stroke, migraine as a primary headache disorder is mostly benign.

Women are more than three times as likely as men to experience migraine headaches and temporomandibular joint pain, and painful episodes are often linked to the menstrual cycle. To understand how hormone levels may influence head and face pain, we assessed expression of pain-associated neuropeptides and estrogen receptor alpha (ERalpha) during the natural estrous cycle in mice. Gene expression was analyzed in the trigeminal ganglia of cycling female mice at proestrus, estrus and diestrus using RT-PCR. Peptide/protein expression in trigeminal neurons was analyzed using immunohistochemistry. ERalpha mRNA was present at all stages and highest at estrus. ERalpha protein was present in the cytoplasm of medium-sized and small trigeminal neurons. ERalpha immunoreactive neurons were most common at diestrus. CGRP and ANP mRNAs did not change across the estrous cycle, while expression of galanin and NPY mRNAs were strongly linked to the estrous cycle. Galanin mRNA levels peaked at proestrus, when expression was 8.7-fold higher than the diestrus levels. Galanin immunoreactivity also peaked at proestrus. At proestrus, 7.5% of trigeminal neurons contained galanin, while at estrus, 6.2% of trigeminal neurons contained galanin, and at diestrus, 4.9% of trigeminal neurons contained galanin. NPY mRNA peaked at estrus, when levels were 4.7-fold higher than at diestrus. Our findings suggest that estrogen receptors in trigeminal neurons modulate nociceptive responses through effects on galanin and NPY. Variations in neuropeptide content in trigeminal neurons across the natural estrous cycle may contribute to increases in painful episodes at particular phases of the menstrual cycle.

Abnormal brain excitability may provide the susceptibility for triggering migraine attacks. Antiepileptic drugs may diminish neuronal excitability and consequently reduce the frequency of migraine. Because migraine aura is predominantly visual, hyperexcitability of the occipital cortex has been the focus of investigations. Functional magnetic resonance imaging of the brain and magnetoencephalography provide the most consistent evidence for the role of brain hyperexcitability in migraine and confirm that triggering an abnormal electric and metabolic event consistent with the cortical spreading depression (CSD) of Leao is anatomically and functionally linked with migraine aura symptoms. Future drug discovery should focus on the interface between the excitable cell and the earliest events of CSD.

Oligemia is blood flow reduction without acute tissue damage that occurs in shock, migraine, and stroke penumbra. We developed a mouse model of oligemia by lowering mean arterial pressure to 30-40 mm Hg, resulting in a 50% reduction in cerebral blood flow as measured by laser Doppler, and reperfusing the blood after 30 min. Control experiments included anesthesia-only and surgery without blood withdrawal. Using immunohistochemistry, we localized the transcription factors Nrf2, which regulates expression of antioxidant and detoxification protein, and c-Fos, a marker of neuronal activation. Nrf2 was found only in oligemia mice and was localized in neurons of the cingulate cortex and cerebellar Purkinje cells. By contrast, c-Fos was found widely expressed in both groups and was localized in neurons in regions associated with response to stress, immunomodulation, and fluid homeostasis, including the periaqueductal gray and periventricular nucleus. These data indicate that c-Fos expression occurs as a result of surgical stress, but Nrf-2 upregulation is specific to oligemia. The CLONTECH Atlas 1.2 Mouse Array was used to assess genes that were up or down-regulated in oligemia versus surgery controls. Of 1176 genes, 29 differed between oligemia and surgery groups. Upregulation of oxidative stress induced (OSI) protein, heat shock protein (HSP) 84 and transthyretin (TTR) precursor in the oligemia group was confirmed with RT-PCR. The expression of HSP 84, transthyretin precursor, and OSI genes adds further evidence that oligemia induces an oxidative stress response in the brain.

Background: Health care providers frequently cite concerns about cardiovascular safety of the triptans as a barrier to their use. In 2002, the American Headache Society convened the Triptan Cardiovascular Safety Expert Panel to evaluate the evidence on triptan-associated cardiovascular risk and to formulate consensus recommendations for making informed decisions for their use in patients with migraine., Objective: To summarize the evidence reviewed by the Triptan Cardiovascular Safety Expert Panel and their recommendations for the use of triptans in clinical practice., Participants: The Triptan Cardiovascular Safety Expert Panel was composed of a multidisciplinary group of experts in neurology, primary care, cardiology, pharmacology, women's health, and epidemiology., Evidence and Consensus Process: An exhaustive search of the relevant published literature was reviewed by each panel member in preparation for an open roundtable meeting. Pertinent issues (eg, cardiovascular pharmacology of triptans, epidemiology of cardiovascular disease, cardiovascular risk assessment, migraine) were presented as a prelude to group discussion and formulation of consensus conclusions and recommendations. Follow-up meetings were held by telephone., Conclusions: (1) Most of the data on triptans are derived from patients without known coronary artery disease. (2) Chest symptoms occurring during use of triptans are generally nonserious and are not explained by ischemia. (3) The incidence of serious cardiovascular events with triptans in both clinical trials and clinical practice appears to be extremely low. (4) The cardiovascular risk-benefit profile of triptans favors their use in the absence of contraindications.

The pathogenesis of migraine is incompletely understood. Recent discoveries have shed light on the neuronal events mediating both the aura and the headache phases of migraine, identifying a cerebral cortical origin of migraine aura, susceptibility to attacks based on cortical hyperexcitability, and headache originating in the trigeminovascular system and its central projections. Abnormal modulation of brain nociceptive systems, at first transient but becoming permanent with continuing illness and, predisposing to central sensitization, may explain the prolonged headache of the migraine attack and the shift of the migraine phenotype from episodic to chronic headache. Migraine attacks might also originate in abnormal nociceptive neuromodulator centers in the brainstem.