Pediatric prescribing practices and the FDA Black-box warning on antidepressants

BACKGROUND: Since the FDA Black box warning in 2004, there has been a 58% drop in antidepressant use among children and adolescents with depression. Paralleling this decrease is an associated increase in completed suicides in youth. To date, no study has examined, on a clinician level, the changes in practice that have occurred subsequent to the FDA warning. OBJECTIVE: To examine changes in pediatrician clinical practice resulting from the FDA warning on antidepressants. METHODS: Subjects were recruited through a national program sponsored by the Canadian Pediatric Society that regularly surveys practicing pediatricians. The mail survey inquired about knowledge of the Black-box warning, whether their practice changed and reasons for changes in prescribing practices with antidepressants after the warning. We surveyed a total of 2395 pediatricians in Canada. RESULTS: Of the 1748 eligible pediatricians, 670 (38%) responded.Seventy-two percent (n = 484) of respondents were aware of the FDA warning. Of the 484 respondents who were aware of the warning, 80% (n = 386) changed their prescribing practices including 32% (n = 154) who followed their patients more closely. Seven percent (n = 35) stopped treatment with SSRIs in at least one patient.Physicians who had observed worsening depression/suicidality were more likely to discontinue treatment with SSRI's compared to those who had not observed these side effects previously (25% versus 6%, p < 0.001). CONCLUSION: This is the first national study to examine individual pediatrician practice changes in antidepressant use subsequent to the FDA warning. Further research is needed to better understand the reasons for these changes to aid in the development of strategies that could help clinicians to optimally integrate these warnings into clinical practice.     

LPS对BALB/C小鼠肾小管上皮细胞TLR4和TNFα、IL-6表达的影响

目的 探讨TLR4在BALB/C小鼠肾小管上皮细胞(TEC)的表达和内毒素/脂多糖(LPS)刺激后TLR4的变化,以及对产生肿瘤坏死因子α(TNFα)、白细胞介素-6(IL-6)的影响.方法 通过RT-PCR方法 检测TLR4 mRNA、TNFα mRNA和IL-6 mRNA在TEC的表达;流式细胞术检测TEC的TLR4膜蛋白水平;ELISA检测培养的TEC上清中TNFα、IL-6的含量.结果 正常TEC有TLR4 mRNA表达,但TNF αmRNA、IL-6 mRNA表达甚弱.经LPS刺激后,TEC中的TLR4 mRNA、TNF αmRNA和IL-6 mRNA表达均显著增强,TLR4膜蛋白以及培养上清中的TNFα、IL-6水平亦相应增加.结论 TLR4在LPS激活的TEC中表达显著增强,同时TEC分泌的炎症因子TNFα、IL-6的水平也相应上调.     

Characteristics of the diet patterns tested in the optimal macronutrient intake trial to prevent heart disease (OmniHeart): options for a heart-healthy diet

OBJECTIVE: To describe the nutrient and food composition of the diets tested in the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart). DESIGN: Two center, randomized, three-period crossover, controlled feeding trial that tested the effects of three healthful diet patterns on blood pressure, serum lipid levels, and estimated cardiovascular risk. SUBJECTS/SETTING: One hundred sixty-four participants with prehypertension and hypertension. During the 19 weeks of feeding, participants were required to consume only food prepared as part of the trial. INTERVENTION: The OmniHeart trial studied three diet patterns that differed in macronutrient composition: a carbohydrate-rich diet similar to the Dietary Approaches to Stop Hypertension diet (58% carbohydrate, 15% protein, and 27% fat), a higher protein diet that had 10% more protein and 10% less carbohydrate (48% carbohydrate, 25% protein, and 27% fat), and a higher unsaturated fat diet that had 10% more unsaturated fat and 10% less carbohydrate (48% carbohydrate, 15% protein, and 37% fat). Each diet contained 6% saturated fat and 100 to 200 mg cholesterol. Sodium was 2,300 mg at the 2,100 kcal energy level and was indexed across energy levels. Calcium, magnesium, and potassium were consistent with recommendations for the Dietary Approaches to Stop Hypertension diet and also indexed to energy levels. Each diet pattern met the major nutrient recommendations set by the Dietary Guidelines for Americans 2005. The 10% protein increase in the higher protein diet emphasized plant protein; however, meat and dairy food sources were also increased somewhat. Olive oil, canola oil, and olive oil spread were used liberally to achieve the unsaturated fat content of the higher unsaturated fat diet. The 10% reduction in carbohydrate in the higher protein diet and the higher unsaturated fat diet was achieved by replacing some fruits with vegetables, reducing sweets, and using smaller portions of grain products. All three diets reduced blood pressure, total and low-density lipoprotein cholesterol levels, and estimated coronary heart disease risk. CONCLUSIONS: The OmniHeart diet patterns offer substantial flexibility in macronutrient intake that should make it easier to eat a heart-healthy diet and reduce cardiovascular disease risk.     

Targeting health disparities: a model linking upstream determinants to downstream interventions

Certain social/environmental factors put some groups at extraordinary risk for adverse health outcomes, creating health disparities. We present a downward causal model, originating at the population level and ending at disease, with psychological and behavioral responses linking the two. This approach identifies how specific social environments "get under the skin" to cause disease, illustrated with the disparity in mortality from aggressive premenopausal breast cancer suffered by black women. Broadening our lens to consider the entire chain of causal factors, spanning multiple levels and interacting across the life span, heightens our ability to craft specific interventions to address group differences in health.     

Clinical Outcomes of Pregnancies Complicated by Mild Gestational Diabetes Mellitus Differ by Combinations of Abnormal Oral Glucose Tolerance Test Values

OBJECTIVE

To examine the association between levels of hyperglycemia, determined by each prenatal oral glucose tolerance test (OGTT) value (fasting, 1 and 2 h), and maternal and perinatal outcomes and to determine whether the risk for these outcomes differs for women whose value(s) equaled or exceeded the thresholds for gestational diabetes mellitus (GDM) established by the International Association of Diabetes in Pregnancy Study Groups (IADPSG).

RESEARCH DESIGN AND METHODS

This article discusses a retrospective study of 8,711 women, delivering at ≥20 weeks'' gestation, who had a prenatal 2-h 75-g OGTT without a prior 50-g challenge and were not treated with insulin, glyburide, diet, and/or exercise during pregnancy. Associations between adverse outcomes and elevated OGTT values are reported.

RESULTS

After excluding treated women, 19.4% of the remaining women had IADPSG-defined GDM. Continuous fasting, 1- and 2-h OGTT measures, and GDM (yes/no) were significantly associated with most adverse outcomes. However, the magnitude and significance of risk for these outcomes differed by various combinations of abnormal glucose values. Women with normal fasting and elevated postload values were at higher risk for preterm delivery, gestational hypertension, and having an infant with hyperbilirubinema, whereas women with elevated fasting and normal postload values were at higher risk of having a large-for-gestational-age infant, compared with women without GDM.

CONCLUSIONS

Risks for different adverse outcomes vary depending on which single or combined IADPSG-defined OGTT thresholds are equaled or exceeded. Prospective studies are needed to determine whether changing pre- and postprandial glucose targets during pregnancy will more uniformly reduce adverse outcomes.Gestational diabetes mellitus (GDM) is defined as “any degree of glucose intolerance with onset or first recognition during pregnancy” (1). The diagnosis of GDM is typically based on the results of a 2-h 75-g or 3-h 100-g oral glucose tolerance test (OGTT), which measures maternal fasting plasma glucose (FPG) and postload glucose concentrations, administered between 24 and 28 weeks of gestation. American Diabetes Association (ADA) guidelines confer a GDM diagnosis if at least two 75-g or 100-g OGTT values meet the following thresholds: ≥95 mg/dl FPG, 1-h glucose ≥180 mg/dl, 2-h glucose ≥155 mg/dl, and 3-h glucose ≥140 mg/dl (2). These thresholds were initially established to identify women at high risk for type 2 diabetes following pregnancy (3).GDM is associated with increased risk for adverse maternal and perinatal outcomes, such as macrosomia, shoulder dystocia and birth injury, primary cesarean delivery, preeclampsia, preterm delivery, and fetal and neonatal mortality (4–7). However, risk for these outcomes among women with modest hyperglycemia during pregnancy has only recently been studied. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study investigated quantitative associations between maternal glycemia and adverse outcomes and, after excluding women with FPG ≥105 and/or 2-h ≥200 mg/dl, reported significant associations between increasing glucose and adverse events, including birth weight >90th percentile, preterm delivery, shoulder dystocia/birth injury, primary cesarean delivery, preeclampsia, and hyperbilirubinemia (8,9). These findings formed the basis for the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommendations that GDM be identified by at least one abnormal 75-g 2-h OGTT value: FPG ≥92 mg/dl, 1-h glucose ≥180 mg/dl, or 2-h glu≥153 mg/dl (10).In the present study, we examined the association between each of the 75-g OGTT glucose values (fasting, 1-h and 2-h glucose) and several adverse maternal and perinatal outcomes in untreated women, taking into account differences in maternal demographics, prepregnancy BMI, and gestational weight gain. Additionally, we explored associations between adverse outcomes and categories of hyperglycemia that result in GDM diagnosis under IADPSG criteria to determine whether the level of risk is similar for each abnormal OGTT result and combinations thereof.     

The Effects of Anisotropy on the Stress Analyses of Patient-Specific Abdominal Aortic Aneurysms

The local dilation of the infrarenal abdominal aorta, termed an abdominal aortic aneurysm (AAA), is often times asymptomatic and may eventually result in rupture—an event associated with a significant mortality rate. The estimation of in-vivo stresses within AAAs has been proposed as a useful tool to predict the likelihood of rupture. For the current work, a previously-derived anisotropic relation for the AAA wall was implemented into patient-specific finite element simulations of AAA. There were 35 AAAs simulated in the current work which were broken up into three groups: elective repairs (n = 21), non-ruptured repairs (n = 5), and ruptured repairs (n = 9). Peak stresses and strains were compared using the anisotropic and isotropic constitutive relations. There were significant increases in peak stress when using the anisotropic relationship (p < 0.001), even in the absence of the ILT (p = 0.014). Rutpured AAAs resulted in elevated peak stresses as compared to non-ruptured AAAs when using both the isotropic and anisotropic simulations, however these comparisons did not reach significance (p _ani = 0.55, p _iso = 0.73). While neither the isotropic or anisotropic simulations were able to significantly discriminate ruptured vs. non-ruptured AAAs, the lower p-value when using the anisotropic model suggests including it into patient-specific AAAs may help better identify AAAs at high risk.     

硝酸甘油与克罗卡林合用抗大鼠心肌缺血的药理性预适应

目的:观察克罗卡林和硝酸甘油两药单用及合用抗大鼠心肌缺血的药理性预适应早期心脏保护作用。方法:实验于2005-10/2006-05在辽宁医学院药理学实验室进行。①实验分组和方法:取60只雄性SD大鼠随机分为6组,每组10只:假手术组:完成模型全部操作,只穿线不结扎。缺血再灌注组:采用左冠状动脉下穿线,拉紧丝线引起心肌缺血,放松丝线给予再灌注的方法建立心肌缺血再灌注损伤动物模型,缺血30min,再灌注60min。缺血预适应组:缺血前行缺血5min再灌注5min,共3个循环,余同缺血再灌注组。硝酸甘油组:100μg/kg尾静脉缓慢静脉滴注1h,再行缺血再灌注。克罗卡林组:100μg/kg尾静脉缓慢静注,30min后行缺血再灌注。硝酸甘油 克罗卡林组:缺血前1h静滴硝酸甘油100μg/kg,30min时静注克罗卡林,再行缺血再灌注。②实验评估:各组大鼠在再灌注60min后,经颈动脉取血采用比色法测定肌酸激酶;于实验结束后立即取左室游离心肌组织0.5g,采用羟胺法测定超氧化物歧化酶活性,硫代巴比妥钠比色法测定丙二醛含量,硝酸还原酶法测定一氧化氮含量,用虫荧光素酶法测定ATP含量。结果:60只大鼠进入结果分析。①血清中肌酸激酶活力:缺血预适应组、硝酸甘油组、克罗卡林组和硝酸甘油 克罗卡林组均低于缺血再灌注组(P<0.05),硝酸甘油 克罗卡林组下降更显著(P<0.01)。②心肌组织超氧化物酶活力:缺血预适应组、硝酸甘油组、克罗卡林组和硝酸甘油 克罗卡林组均高于缺血再灌注组(P<0.05或P<0.01),硝酸甘油 克罗卡林组高于硝酸甘油组、克罗卡林组(P<0.05)。③心肌组织内丙二醛含量:缺血预适应组、硝酸甘油组、克罗卡林组和硝酸甘油 克罗卡林组均低于缺血再灌注组(P<0.05或P<0.01)。④心肌组织内一氧化氮含量:缺血预适应组、硝酸甘油组、克罗卡林组和硝酸甘油 克罗卡林组均高于缺血再灌注组(P<0.05或P<0.0l),硝酸甘油 克罗卡林组高于硝酸甘油组、克罗卡林组(P<0.05)。⑤心肌组织ATP含量:缺血预适应组、硝酸甘油组、克罗卡林组和硝酸甘油 克罗卡林组均高于缺血再灌注组(P<0.05或P<0.01),硝酸甘油 克罗卡林组高于硝酸甘油组、克罗卡林组(P<0.05)。结论:硝酸甘油、色满卡林具有明显的抗大鼠心肌缺血的药理性预适应早期心脏保护作用,合用优于单用。