Objective. To determine whether delayed infusion of COX1/COX2 inhibitors (ketorolac, indomethacin) will stop migraine in allodynic patients, and suppress ongoing sensitization in central trigeminovascular neurons in t...Objective. To determine whether delayed infusion of COX1/COX2 inhibitors (ketorolac, indomethacin) will stop migraine in allodynic patients, and suppress ongoing sensitization in central trigeminovascular neurons in the rat. Background. The majority of migraineurs seeking secondary or tertiary medical care develop cutaneous allodynia during the course of migraine, a sensory abnormality mediated by sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus. Triptan therapy can render allodynic migraineurs pain free within a narrow window of time (20 to 120 minutes) that opens with the onset of pain and closes with the establishment of central sensitization. Can drugs that tackle ongoing central sensitization render allodynic migraineurs pain free after the window for triptan therapy has expired? Methods. Patients exhibiting migraine with allodynia were divided in two groups (n=14, each): group 1 received delayed sumatriptan injection (6 mg) 4 hours after onset of attack-which failed to render them pain free-and ketorolac infusion (two 15 mg boluses) 2 hours later; group 2 received delayed ketorolac monotherapy 4 hours after onset of attack. Pain intensity (visual analog scale) and skin sensitivity (quantitative sensory testing) were measured when the patients were migraine free (baseline); 4 hours after onset of migraine (just before treatment); 2 hours after sumatriptan; 1 hour after ketorolac. In the rat, we tested whether infusion of ketorolac (0.4 mg/kg) or indomethacin (1 mg/kg) will block ongoing sensitization in peripheral and central trigeminovascular neurons. The induction of sensitization (using topical application of inflammatory soup on the dura)and its suppression by COX1/COX2 inhibitors were assessed by monitoring changes in spontaneous activity and responses to mechanical and thermal stimuli. Results. Patients had normal skin sensitivity in the absence of migraine, and presented cutaneous allodynia 4 hours after onset of migraine. In group 1, all patients continued to exhibit allodynia 2 hours after sumatriptan treatment, and none of them became pain free. However, 71%and 64%of the patients in groups 1 and 2, respectively, were rendered free of pain and allodynia within 60 minutes of ketorolac infusion. Nonresponders from both groups, in contrast to the responders, had had a history of opioid treatment. In the rat, infusion of COX1/COX2 inhibitors blocked sensitization in meningeal nociceptors and suppressed ongoing sensitization in spinal trigeminovascular neurons. This inhibitory action was reflected by normalization of neuronal firing rate and attenuation of neuronal responsiveness to mechanical stimulation of the dura, as well as mechanical and thermal stimulation of the skin. Conclusions. The termination of migraine with ongoing allodynia using COX1/COX2 inhibitors is achieved through the suppression of central sensitization. Although parenteral administration of COX1/COX2 inhibitors is impractical as routine migraine therapy, it should be the rescue therapy of choice for patients seeking emergency care for migraine. These patients should never be treated with opioids, particularly if they had no prior opioid exposure.展开更多
Context: Obesity is associated with atrial enlargement and ventricular diastol ic dysfunction, both known predictors of atrial fibrillation(AF). However, it is unclear whether obesity is a risk factor for AF. Objectiv...Context: Obesity is associated with atrial enlargement and ventricular diastol ic dysfunction, both known predictors of atrial fibrillation(AF). However, it is unclear whether obesity is a risk factor for AF. Objective: To examine the asso ciation between body mass index(BMI) and the risk of developing AF. Design, Sett ing, and Participants: Prospective, communitybased observational cohort in Fra mingham, Mass. We studied 5282 participants(mean age, 57[SD, 13] years; 2898 wom en[55%]) without baseline AF(electrocardiographic AF or arterial flutter). Body mass index(calculated as weight in kilograms divided by square of height in met ers) was evaluated as both a continuous and a categorical variable(normal define d as < 25.0; overweight, 25.0 to < 30.0; and obese, ≥30.0). In addition to adju sting for clinical confounders by multivariable techniques, we also examined mod els including echocardiographic left atrial diameter to examine whether the infl uence of obesity was mediated by changes in left atrial dimensions. Main Outcome Measure: Association between BMI or BMI category and risk of developing newon set AF. Results: During a mean followup of 13.7 years, 526 participants(234 wo men) developed AF. Age adjusted incidence rates for AF increased across the 3 BM I categories in men(9.7, 10.7, and 14.3 per 1000 personyears) and women(5.1, 8 .6, and 9.9 per 1000 personyears). In multivariable models adjusted for cardio vascular risk factors and interim myocardial infarction or heart failure, a 4%i ncrease in AF risk per 1-unit increase in BMI was observed in men(95%confidenc e interval[CI], 1%-7%; P=.02) and in women(95%CI, 1%-7%; P=.009). Adjuste d hazard ratios for AF associated with obesity were 1.52(95%CI, 1.09-2.13; P=. 02) and 1.46(95%CI, 1.03-2.07; P=.03) for men and women, respectively, compare d with individuals with normal BMI. After adjustment for echocardiographic left atrial diameter in addition to clinical risk factors, BMI was no longer associat ed with AF risk(adjusted hazard ratios per 1-unit increase in BMI, 1.00[95%CI, 0.97-1.04], P=.84 in men; 0.99 [95%CI, 0.96-1.02], P=.56 in women). Conclusi ons: Obesity is an important, potentially modifiable risk factor for AF. The exc ess risk of AF associated with obesity appears to be mediated by left atrial dil atation. These prospective data raise the possibility that interventions to prom ote normal weight may reduce the population burden of AF.展开更多
Although moderate alcohol consumption is associated with a lower risk of cardiovascular disease(CVD), little is known of the effects of alcohol dehydrogenase 1C(ADH1C) polymorphism on the association between alcohol a...Although moderate alcohol consumption is associated with a lower risk of cardiovascular disease(CVD), little is known of the effects of alcohol dehydrogenase 1C(ADH1C) polymorphism on the association between alcohol and CVD. We used data on 1,805 unrelated subjects in the Framingham Offspring Study to assess whether rs1693482 and rs698, 2 single nucleotide polymorphisms of the ADH1C gene, modify the relation between alcohol consumption and prevalent CVD. The 2 single nucleotide polymorphisms were in linkage disequilibrium(D′=0.99, R2=0.96). There was evidence for a U-shaped association between alcohol consumption and CVD in this population. Multivariable adjusted odds ratios for prevalent CVD were 0.63(95%confidence interval 0.41 to 0.97) and 0.80(95%confidence interval 0.46 to 1.41) for CT and TT genotypes of rs1693482 relative to CC genotype(model p< 0.0001). Corresponding values for AG and GG genotypes of rs698 were 0.68(95%confidence interval 0.45 to 1.04) and 0.84(95%confidence interval 0.49 to 1.46), respectively, compared with the AA genotype(model p< 0.0001). There were nonstatistically significant associations between rs693482 C→T and rs698 A→G mutations and prevalent CVD among current drinkers(lower CVD prevalence with minor allele) but not among nondrinkers in whom the minor allele was associated with a trend toward higher CVD prevalence(p values for interaction are 0.16 for rs1693482 and 0.52 for rs698). Alcohol consumption was associated with high-density lipoprotein cholesterol across all genotypes of the 2 single nucleotide polymorphisms in a dose-response fashion without evidence for interaction. In conclusion, these data suggest borderline interactions between genes and environment of ADH1C variation and alcohol intake on prevalent CVD. The interaction does not appear to be mediated through effects on high-density lipoprotein cholesterol.展开更多
文摘Objective. To determine whether delayed infusion of COX1/COX2 inhibitors (ketorolac, indomethacin) will stop migraine in allodynic patients, and suppress ongoing sensitization in central trigeminovascular neurons in the rat. Background. The majority of migraineurs seeking secondary or tertiary medical care develop cutaneous allodynia during the course of migraine, a sensory abnormality mediated by sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus. Triptan therapy can render allodynic migraineurs pain free within a narrow window of time (20 to 120 minutes) that opens with the onset of pain and closes with the establishment of central sensitization. Can drugs that tackle ongoing central sensitization render allodynic migraineurs pain free after the window for triptan therapy has expired? Methods. Patients exhibiting migraine with allodynia were divided in two groups (n=14, each): group 1 received delayed sumatriptan injection (6 mg) 4 hours after onset of attack-which failed to render them pain free-and ketorolac infusion (two 15 mg boluses) 2 hours later; group 2 received delayed ketorolac monotherapy 4 hours after onset of attack. Pain intensity (visual analog scale) and skin sensitivity (quantitative sensory testing) were measured when the patients were migraine free (baseline); 4 hours after onset of migraine (just before treatment); 2 hours after sumatriptan; 1 hour after ketorolac. In the rat, we tested whether infusion of ketorolac (0.4 mg/kg) or indomethacin (1 mg/kg) will block ongoing sensitization in peripheral and central trigeminovascular neurons. The induction of sensitization (using topical application of inflammatory soup on the dura)and its suppression by COX1/COX2 inhibitors were assessed by monitoring changes in spontaneous activity and responses to mechanical and thermal stimuli. Results. Patients had normal skin sensitivity in the absence of migraine, and presented cutaneous allodynia 4 hours after onset of migraine. In group 1, all patients continued to exhibit allodynia 2 hours after sumatriptan treatment, and none of them became pain free. However, 71%and 64%of the patients in groups 1 and 2, respectively, were rendered free of pain and allodynia within 60 minutes of ketorolac infusion. Nonresponders from both groups, in contrast to the responders, had had a history of opioid treatment. In the rat, infusion of COX1/COX2 inhibitors blocked sensitization in meningeal nociceptors and suppressed ongoing sensitization in spinal trigeminovascular neurons. This inhibitory action was reflected by normalization of neuronal firing rate and attenuation of neuronal responsiveness to mechanical stimulation of the dura, as well as mechanical and thermal stimulation of the skin. Conclusions. The termination of migraine with ongoing allodynia using COX1/COX2 inhibitors is achieved through the suppression of central sensitization. Although parenteral administration of COX1/COX2 inhibitors is impractical as routine migraine therapy, it should be the rescue therapy of choice for patients seeking emergency care for migraine. These patients should never be treated with opioids, particularly if they had no prior opioid exposure.
文摘Context: Obesity is associated with atrial enlargement and ventricular diastol ic dysfunction, both known predictors of atrial fibrillation(AF). However, it is unclear whether obesity is a risk factor for AF. Objective: To examine the asso ciation between body mass index(BMI) and the risk of developing AF. Design, Sett ing, and Participants: Prospective, communitybased observational cohort in Fra mingham, Mass. We studied 5282 participants(mean age, 57[SD, 13] years; 2898 wom en[55%]) without baseline AF(electrocardiographic AF or arterial flutter). Body mass index(calculated as weight in kilograms divided by square of height in met ers) was evaluated as both a continuous and a categorical variable(normal define d as < 25.0; overweight, 25.0 to < 30.0; and obese, ≥30.0). In addition to adju sting for clinical confounders by multivariable techniques, we also examined mod els including echocardiographic left atrial diameter to examine whether the infl uence of obesity was mediated by changes in left atrial dimensions. Main Outcome Measure: Association between BMI or BMI category and risk of developing newon set AF. Results: During a mean followup of 13.7 years, 526 participants(234 wo men) developed AF. Age adjusted incidence rates for AF increased across the 3 BM I categories in men(9.7, 10.7, and 14.3 per 1000 personyears) and women(5.1, 8 .6, and 9.9 per 1000 personyears). In multivariable models adjusted for cardio vascular risk factors and interim myocardial infarction or heart failure, a 4%i ncrease in AF risk per 1-unit increase in BMI was observed in men(95%confidenc e interval[CI], 1%-7%; P=.02) and in women(95%CI, 1%-7%; P=.009). Adjuste d hazard ratios for AF associated with obesity were 1.52(95%CI, 1.09-2.13; P=. 02) and 1.46(95%CI, 1.03-2.07; P=.03) for men and women, respectively, compare d with individuals with normal BMI. After adjustment for echocardiographic left atrial diameter in addition to clinical risk factors, BMI was no longer associat ed with AF risk(adjusted hazard ratios per 1-unit increase in BMI, 1.00[95%CI, 0.97-1.04], P=.84 in men; 0.99 [95%CI, 0.96-1.02], P=.56 in women). Conclusi ons: Obesity is an important, potentially modifiable risk factor for AF. The exc ess risk of AF associated with obesity appears to be mediated by left atrial dil atation. These prospective data raise the possibility that interventions to prom ote normal weight may reduce the population burden of AF.
文摘Although moderate alcohol consumption is associated with a lower risk of cardiovascular disease(CVD), little is known of the effects of alcohol dehydrogenase 1C(ADH1C) polymorphism on the association between alcohol and CVD. We used data on 1,805 unrelated subjects in the Framingham Offspring Study to assess whether rs1693482 and rs698, 2 single nucleotide polymorphisms of the ADH1C gene, modify the relation between alcohol consumption and prevalent CVD. The 2 single nucleotide polymorphisms were in linkage disequilibrium(D′=0.99, R2=0.96). There was evidence for a U-shaped association between alcohol consumption and CVD in this population. Multivariable adjusted odds ratios for prevalent CVD were 0.63(95%confidence interval 0.41 to 0.97) and 0.80(95%confidence interval 0.46 to 1.41) for CT and TT genotypes of rs1693482 relative to CC genotype(model p< 0.0001). Corresponding values for AG and GG genotypes of rs698 were 0.68(95%confidence interval 0.45 to 1.04) and 0.84(95%confidence interval 0.49 to 1.46), respectively, compared with the AA genotype(model p< 0.0001). There were nonstatistically significant associations between rs693482 C→T and rs698 A→G mutations and prevalent CVD among current drinkers(lower CVD prevalence with minor allele) but not among nondrinkers in whom the minor allele was associated with a trend toward higher CVD prevalence(p values for interaction are 0.16 for rs1693482 and 0.52 for rs698). Alcohol consumption was associated with high-density lipoprotein cholesterol across all genotypes of the 2 single nucleotide polymorphisms in a dose-response fashion without evidence for interaction. In conclusion, these data suggest borderline interactions between genes and environment of ADH1C variation and alcohol intake on prevalent CVD. The interaction does not appear to be mediated through effects on high-density lipoprotein cholesterol.
