Environmental Exposures and Pediatric Cardiology: A Scientific Statement From the American Heart Association.

Environmental toxicants and pollutants are causes of adverse health consequences, including well-established associations between environmental exposures and cardiovascular diseases. Environmental degradation is widely prevalent and has a long latency period between exposure and health outcome, potentially placing a large number of individuals at risk of these health consequences. Emerging evidence suggests that environmental exposures in early life may be key risk factors for cardiovascular conditions across the life span. Children are a particularly sensitive population for the detrimental effects of environmental toxicants and pollutants given the long-term cumulative effects of early-life exposures on health outcomes, including congenital heart disease, acquired cardiac diseases, and accumulation of cardiovascular disease risk factors. This scientific statement highlights representative examples for each of these cardiovascular disease subtypes and their determinants, focusing specifically on the associations between climate change and congenital heart disease, airborne particulate matter and Kawasaki disease, blood lead levels and blood pressure, and endocrine-disrupting chemicals with cardiometabolic risk factors. Because children are particularly dependent on their caregivers to address their health concerns, this scientific statement highlights the need for clinicians, research scientists, and policymakers to focus more on the linkages of environmental exposures with cardiovascular conditions in children and adolescents.

Adherence to lipid-lowering therapy and reaching treatment goals in youth seen in a preventive cardiology clinic.

INTRODUCTION: The efficacy of lipid-lowering therapy in reducing cardiovascular disease in adults is well-established. Unfortunately, it is also well-established that adults have inadequate adherence to lipid-lowering therapy, which is associated with increased costs and mortality. However, the adherence patterns of youth prescribed lipid-lowering therapy is not well-described. METHODS: We analyzed data that was prospectively collected from patients <27 years-old who were referred to a large regional preventive cardiology clinic from 2010 to 2017. Adherence to lipid-lowering therapy was self-reported at the patient's most recent clinic visit and categorized as either adequate adherence (≥80%) or inadequate adherence (<80%). We compared adherence rates by demographic factors, class of lipid-lowering therapy, length of time on lipid-lowering therapy, family history, lipid parameters, and laboratory measures of adverse effects. RESULTS: In our cohort, we had 318 patients prescribed a lipid-lowering medication over a seven-year period. Of those, 235 (75%) had adequate adherence. Those with adequate adherence had an improved LDL-C (123 mg/dL [standard deviation (SD) 32.3] vs. 167 mg/dL [SD 50.4], p < 0.05), total cholesterol (198 mg/dL [49.5] vs. 239 mg/dL [SD 53.2]), and non-HDL-C (148 mg/dL [SD 38.7] vs. 193 mg/dL [SD 43.9]). In addition, patients with adequate adherence were more likely to reach goal LDL-C of <130 mg/dL than those with inadequate adherence (130 vs. 25, p < 0.01). The relationship between LDL-C and adherence remained statistically significant after controlling for age, gender, and the length of time on therapy (ß = -0.66, p < 0.01). Adherence level did not differ by gender, class of lipid-lowering therapy, length of time on lipid-lowering therapy, or presence of a family history of an atherosclerotic event. The findings were similar when we only analyzed those prescribed a statin. CONCLUSIONS: Self-reported adherence to lipid-lowering therapy in youth is excellent and was associated with achieving goal LDL-C goals. Obtaining adherence data from patients may help more patients reach LDL-C goals.

The relationship between payer type and lipid outcomes in response to clinical lifestyle interventions in youth with dyslipidemia.

BACKGROUND: Payer-type (government-sponsored health coverage versus private health insurance) has been shown to influence a variety of cardiovascular disease outcomes in adults. However, it is unclear if the payer-type impacts the response to a lifestyle intervention in children with dyslipidemia. METHODS: We analyzed data prospectively collected from patients under the age of 25 years who were referred to a large regional preventive cardiology clinic from 2010 to 2016 in Massachusetts. We compared baseline high density lipoprotein cholesterol (HDL-C), triglycerides (TG), non-HDL-C, and low density lipoprotein cholesterol (LDL-C) by payer-type. Further, we analyzed the change in lipid values in response to a clinic-based multidisciplinary intervention over a nearly six-year period by payer-type with multi-variable adjusted linear regression models. We also tested for effect modifications by age, sex, race, and body mass index (BMI) category. RESULTS: Of the 1739 eligible patients (mean age 13 years, 52% female, 60% overweight and obese, 59% White), we found that patients with government-sponsored coverage (n = 354, 20%) presented to referral lipid clinic with lower HDL-C (- 3.5 mg/dL [1.0], p < 0.001) and higher natural log-transformed TG (+ 0.14 [0.04], p < 0.001) as compared to those with private insurance; however, the association was attenuated to the null after additionally adjusting for BMI category (- 1.1 [0.9], p = 0.13, and + 0.05 [0.04], p = 0.2 for HDL-C and natural log-transformed TG, respectively). We found no difference in baseline LDL-C between payer-types (+ 3.4 mg/dL [3.0], p = 0.3). However, longitudinally, we found patients with private insurance and a self-reported race of White to have a clinically meaningful additional improvement in LDL-C, decreasing 12.8 (5.5) mg/dL (p = 0.02) between baseline and first follow-up, as compared to White patients with government-sponsored health coverage, after adjusting for age, sex, time between visits, and baseline LDL-C. CONCLUSIONS: Our results suggest that youth with government-sponsored coverage are referred with poorer lipid profiles than those with private insurance, although this is largely explained by higher rates of overweight and obesity in the government-sponsored health coverage group. White patients with private insurance had substantially better improvement in LDL-C longitudinally, suggesting that higher socioeconomic status facilitates improvement in LDL-C, but is less beneficial for HDL-C and triglyceride levels.

Hepatotoxicity of Statins as Determined by Serum Alanine Aminotransferase in a Pediatric Cohort With Dyslipidemia.

OBJECTIVE: The aim of the study was to evaluate the hepatotoxicity of statins, as determined by serum alanine aminotransferase (ALT), in children and adolescents with dyslipidemia in real-world clinical practice. STUDY DESIGN: Clinical and laboratory data were prospectively collected between September 2010 and March 2014. We compared ALT levels between patients prescribed versus not prescribed 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins), and then compared ALT before and after initiation of statins. RESULTS: Over the 3.5-year observation period, there were 2704 ALT measurements among 943 patients. The mean age was 14 years; 54% were boys, 47% obese, and 208 patients were treated with statins. Median follow-up after first ALT was 18 months. The mean (SD) ALT in statin and non-statin users was 23 (20) U/L and 28 (28) U/L, respectively. In models adjusted for age, sex, and race, ALT was 2.1 U/L (95% CI 0.1 to 4.4; P = 0.04) lower among statin users, which was attenuated after adjustment for weight category. Patients started on statins during the observation period did not demonstrate an increase in ALT over time (ALT 0.9 U/L [95% confidence interval -5.2 to 3.4] increase per year; P = 0.7). CONCLUSIONS: In our study population, we did not observe a higher burden of ALT elevations among pediatric patients on statins as compared to those with dyslipidemia who are not on statins, supporting the hepatic safety of statin use in childhood.

Statin-Associated Myopathy in a Pediatric Preventive Cardiology Practice.

OBJECTIVES: To describe muscle-related statin adverse effects in real-world pediatric practice. STUDY DESIGN: Using prospectively collected quality improvement data from a pediatric preventive cardiology practice, we compared serum creatine kinase (CK) levels among patients prescribed and not prescribed statins, and pre-/poststatin initiation. Multivariable mixed-effect models were constructed accounting for repeated measures, examining the effect of statins on log-transformed CK (lnCK) levels adjusted for age, sex, weight, season, insurance type, and race/ethnicity. RESULTS: Among 1501 patients seen over 3.5 years, 474 patients (14?±?4 years, 47% female) had at least 1 serum CK measured. Median (IQR) CK levels of patients prescribed (n?=?188 patients, 768 CK measurements) and not prescribed statins (n?=?351 patients, 682 CK measurements) were 107 (83) IU/L and 113 (81) IU/L, respectively. In multivariable-adjusted models, lnCK levels did not differ based on statin use (??=?0.02 [SE 0.05], P?=?.7). Among patients started on statins (n?=?86, 130 prestatin and 292 poststatin CK measurements), median CK levels did not differ in adjusted models (? for statin use on lnCK?=?.08 [SE .07], P?=?.2). There was a clinically insignificant increase in CK over time (??=?.08 [SE .04], P?=?.04 per year). No muscle symptoms or rhabdomyolysis were reported among patients with high CK levels. CONCLUSIONS: In a real-world practice, pediatric patients using statins did not experience higher CK levels, nor was there a meaningful CK increase with statin initiation. These data suggest the limited utility to checking CK in the absence of symptoms, supporting current guidelines.

Correlates of Achieving Statin Therapy Goals in Children and Adolescents with Dyslipidemia.

OBJECTIVE: To determine the real-world effectiveness of statins and impact of baseline factors on low-density lipoprotein cholesterol (LDL-C) reduction among children and adolescents. STUDY DESIGN: We analyzed data prospectively collected from a quality improvement initiative in the Boston Children's Hospital Preventive Cardiology Program. We included patients ≤21 years of age initiated on statins between September 2010 and March 2014. The primary outcome was first achieving goal LDL-C, defined as <130 mg/dL, or <100 mg/dL with high-level risk factors (eg, diabetes, etc). Cox proportional hazards models were used to assess the impact of baseline clinical and lifestyle factors. RESULTS: Among the 1521 pediatric patients evaluated in 3813 clinical encounters over 3.5 years, 97 patients (6.3%) were started on statin therapy and had follow-up data (median age 14 [IQR 7] years, 54% were female, and 24% obese, 62% with at least one lifestyle risk factor). The median baseline LDL-C was 215 (IQR 78) mg/dL, and median follow-up after starting statin was 1 (IQR 1.3) year. The cumulative probability of achieving LDL-C goal within 1 year was 60% (95% CI 47-69). A lower probability of achieving LDL-C goals was associated with male sex (HR 0.5 [95% CI 0.3-0.8]) and higher baseline LDL-C (HR 0.92 [95% CI 0.87-0.98] per 10 mg/dL), but not age, body mass index percentile, lifestyle factors, or family history. CONCLUSIONS: The majority of pediatric patients started on statins reached LDL-C treatment goals within 1 year. Male patients and those with greater baseline LDL-C were less likely to be successful and may require increased support.

Successful hemostasis and reversal of highly elevated PT/INR after dabigatran etexilate use in a patient with acute kidney injury.

Dabigatran etexilate is a novel oral anticoagulant indicated for anticoagulation in the management of atrial fibrillation and venous thromboembolism. Before its approval by the US Food and Drug Administration, warfarin, a vitamin K antagonist, was one of few oral anticoagulant options. The burden of therapeutic drug monitoring, dietary restrictions, and various drug interactions associated with warfarin have countered its extensive history of efficacy. Although dabigatran etexilate may alleviate some concerns encountered with warfarin therapy, there remains a paucity of evidence surrounding emergent reversal strategies in severe hemorrhage. We report here a 71-year-old man who presented to the emergency department with gastrointestinal hemorrhage precipitated by acute kidney injury while on dabigatran etexilate, with laboratory derangements highly uncharacteristic of dabigatran therapy (international normalized ratio, > 10, and activated partial thromboplastin time, 93 seconds). After admission to the intensive care unit and 7 U of fresh frozen plasma, the patient remained hemodynamically unstable due to blood loss. Other observations were made that are poorly characterized in medical literature related to dabigatran: refractory hemorrhagic shock after 7 U of fresh frozen plasma, rapid correction of coagulation parameters (international normalized ratio, 1.7, and activated partial thromboplastin time, 44 seconds) achieved 4 hours after 26 U/kg of 4-factor prothrombin complex concentrate (Kcentra; CSL Behring, King of Prussia, PA), and with subsequent achievement of hemostasis. The patient was discharged to home 7 days later without sequelae.

Treatment decision making for adolescents with familial hypercholesterolemia: Role of family history and past experiences.

BACKGROUND: Adolescents and young adults (AYAs) with familial hypercholesterolemia (FH) are at high risk for underdiagnosis and inadequate treatment. Yet, little is known about the factors that influence the medical decision making of AYAs with FH and their families. OBJECTIVE: This study explores how family medical history, family narratives of medical experiences, and AYA medical experiences together function as "experiential evidence" and influence screening and treatment decisions. METHODS: Twenty-four parents and AYAs affected by FH from a pediatric preventive cardiology practice responded to a survey and a semistructured qualitative interview. Transcribed interviews were analyzed using a modified grounded theory approach. Study design, instruments, and interpretation of results were informed by a 20-member stakeholder panel. RESULTS: AYAs and parents reported extensive personal and family experiences with cholesterol and cardiovascular conditions and treatments, sometimes distinct from FH, which were used as evidence to inform their own perceptions of FH risk and treatment. This experiential evidence impacted perceptions of: (1) hereditary risk for FH diagnoses, (2) risk for future cardiovascular disease, (3) risks associated with treatments, and (4) capacity to comply with recommended treatments. Although experiences of family members initially informed screening and treatment decisions, the subsequent personal experiences of AYAs led to new experiential evidence that informed future decisions. CONCLUSIONS: Family cardiovascular history related to and distinct from FH influenced screening and treatment decisions of AYAs and parents affected by FH. Additional clinical assessment of personal and family medical experiences may enhance understanding of the decision-making processes among AYAs and ultimately improve adherence to screening and treatment recommendations.

Response to Transdermal Selegiline Smoking Cessation Therapy and Markers in the 15q24 Chromosomal Region.

INTRODUCTION: Current treatments for smoking cessation have limited efficacy. A potential pharmaceutical treatment for smoking cessation is selegiline, a selective and irreversible monoamine oxidase B inhibitor. A few clinical trials have been carried out using selegiline but the results have been mixed. We sought to determine if genetic markers in cholinergic loci in the 15q24 chromosomal region predict response to smoking cessation therapy with selegiline. METHODS: We performed an 8-week double-blind, placebo-controlled clinical trial of the selegiline transdermal system in heavy smokers, with follow-up at weeks 25 and 52. Eight single nucleotide polymorphisms (SNPs) in the 15q24 region, which contains the genes for the nicotinic acetylcholine receptor subunits CHRNA5, CHRNA3, and CHRNB4, were investigated for association with treatment response. RESULTS: The CHRNB4 promoter SNP rs3813567 was associated with both point prevalence abstinence and post-quit craving. Carriers of the minor C allele treated with selegiline showed lower rates of abstinence and higher levels of craving than selegiline-treated non-carriers, indicating that the rs3813567 C allele adversely affects abstinence in selegiline-treated smokers. This effect was not present among placebo-treated smokers. Selegiline-treated smokers with the CHRNA5 rs680244 GG genotype had lower post-quit craving, and unlike placebo-treated GG-carrying smokers, did not experience a post-quit increase in depressive symptoms. CONCLUSIONS: Variants in genes encoding cholinergic receptors affect abstinence, craving and mood in selegiline-treated smokers. Selegiline primarily affects dopamine levels in the brain, but cholinergic input affects nicotine-induced dopaminergic activity. These markers may have value in identifying those likely to respond to selegiline for smoking cessation.

Serum Survival of Vibrio vulnificus: Role of Genotype, Capsule, Complement, Clinical Origin, and in Situ Incubation.

Virulence of the human pathogen, V. vulnificus, is associated with encapsulation, serum complement resistance, and genotype. The C-genotype of this bacterium is correlated (>90%) with virulence and with isolation source (clinical settings). E-genotype strains are highly correlated with environmental isolation (93%) but appear less virulent. In this study, we characterized the importance of genotype, encapsulation, serum complement, and in situ exposure to estuarine water on the survival of the two genotypes in human serum. Results confirmed the superior ability of C-genotype strains to survive exposure to human serum, as well as the significance of complement, and revealed that lack of capsule allowed serum killing of both C- and E-genotypes. Cells incubated in situ responded similarly to cells incubated in vitro with the exception of E-environmental strains. Interestingly, our studies found that those cells of the E-genotype, typically considered non-pathogenic, which were isolated from wound infections demonstrated serum survival similar to that of virulent, C-genotype, strains.

Urinary isoflavone concentrations are inversely associated with cardiometabolic risk markers in pregnant U.S. women.

Some evidence suggests that phytoestrogens, such as soy-derived isoflavones, may have beneficial effects on cardiovascular health and glycemic control. These data are mainly limited to postmenopausal women or individuals at elevated cardiometabolic risk. There is a lack of data for pregnant women who have elevated estrogen levels and physiologically altered glucose and lipid metabolism. We analyzed data from 299 pregnant women who participated in the NHANES 2001-2008 surveys. Multivariable linear regression analyses were used to examine the association between urinary concentrations of isoflavonoids and cardiometabolic risk markers, adjusted for body mass index, pregnancy trimester, total energy intake, dietary intake of protein, fiber, and cholesterol, and demographic and lifestyle factors. Cardiometabolic risk markers were log-transformed, and geometric means were calculated by quartiles of urinary concentrations of isoflavonoids. Comparing women in the highest vs. lowest quartiles of urine total isoflavone concentrations, we observed significant, inverse associations with circulating concentrations of fasting glucose (79 vs. 88 mg/dL, P-trend = 0.0009), insulin (8.2 vs. 12.8 µU/mL, P-trend = 0.03), and triglyceride (156 vs. 185 mg/dL, P-trend = 0.02), and the homeostasis model assessment of insulin resistance (1.6 vs. 2.8, P-trend = 0.01), but not for total, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. The concentrations of individual isoflavonoids, daidzein, equol, and O-desmethylangolensin were inversely associated with some cardiometabolic risk markers, although no clear pattern emerged. These data suggest that there may be a relation between isoflavone intake and cardiometabolic risk markers in pregnant women.

BDNF and CREB1 genetic variants interact to affect antidepressant treatment outcomes in geriatric depression.

AIM: Brain-derived neurotrophic factor (BDNF) is associated with antidepressant response on the cellular level, in animal models, and in clinical studies. A common variant in the BDNF gene results in a substitution of a methionine (Met) for a valine at the amino acid position 66. Previous studies reported that the Met variant results in enhanced response to antidepressant medications. These findings may be at odds with studies indicating that on a cellular level the Met variant impairs the secretion of BDNF. MATERIALS AND METHODS: We examined the effects of BDNF single nucleotide polymorphisms (SNPs) in response to the antidepressants paroxetine and mirtazapine in a sample of 246 geriatric patients with major depression, treated in a double-blind, randomized, 8-week clinical trial. We also examined the effects of genetic variation at the BDNF-related loci neurotrophic tyrosine kinase receptor 2, cyclic AMP responsive element binding protein 1 (CREB1), and CREB binding protein. A total of 53 SNPs were genotyped. RESULTS: BDNF genetic variation had a significant effect on the efficacy of paroxetine, with patients carrying the Met allele showing impaired response. SNPs at the CREB1 locus, which encodes a transcription factor important in BDNF signaling, also predicted response to paroxetine. Furthermore, we found a significant gene-gene interaction between BDNF and CREB1 that affected response to paroxetine. Because BDNF has been associated with cognitive function, we tested the effects of BDNF SNPs on change in a wide variety of cognitive tests over the 8-week trial, but there were no significant effects of genotype on cognition. CONCLUSION: These results provide new evidence for the importance of the BDNF pathway in antidepressant response in geriatric patients. The negative effect of the Met66 allele on antidepressant outcomes is consistent with basic science findings indicating a negative effect of this variant on BDNF activity in the brain. Further, the effect of BDNF genetic variation on antidepressant treatment is modified by variation in the gene encoding the downstream effector CREB1.

Adult current smoking: differences in definitions and prevalence estimates--NHIS and NSDUH, 2008.

OBJECTIVES: To compare prevalence estimates and assess issues related to the measurement of adult cigarette smoking in the National Health Interview Survey (NHIS) and the National Survey on Drug Use and Health (NSDUH). METHODS: 2008 data on current cigarette smoking and current daily cigarette smoking among adults ≥18 years were compared. The standard NHIS current smoking definition, which screens for lifetime smoking ≥100 cigarettes, was used. For NSDUH, both the standard current smoking definition, which does not screen, and a modified definition applying the NHIS current smoking definition (i.e., with screen) were used. RESULTS: NSDUH consistently yielded higher current cigarette smoking estimates than NHIS and lower daily smoking estimates. However, with use of the modified NSDUH current smoking definition, a notable number of subpopulation estimates became comparable between surveys. Younger adults and racial/ethnic minorities were most impacted by the lifetime smoking screen, with Hispanics being the most sensitive to differences in smoking variable definitions among all subgroups. CONCLUSIONS: Differences in current cigarette smoking definitions appear to have a greater impact on smoking estimates in some sub-populations than others. Survey mode differences may also limit intersurvey comparisons and trend analyses. Investigators are cautioned to use data most appropriate for their specific research questions.

Markers in the 15q24 nicotinic receptor subunit gene cluster (CHRNA5-A3-B4) predict severity of nicotine addiction and response to smoking cessation therapy.

Stopping smoking is difficult even with treatment. Many patients prescribed pharmacologic treatments for smoking cessation experience side effects or lack of efficacy. We performed a pharmacogenetic study of the efficacy and tolerability of bupropion and transdermal nicotine (TN), two treatments for smoking cessation. Samples were drawn from two studies. In the first study (Maintenance 1, MT1), 301 smokers received bupropion plus TN for 11 weeks, followed by 14 weeks of placebo or bupropion. In the second study (MT2), 276 smokers received bupropion and TN for 8 weeks. We focused on eight SNPs in the 15q24 region, which contains the genes for the nicotinic cholinergic receptor subunits CHRNA5, CHRNA3, and CHRNB4, and has previously been implicated in nicotine addiction and smoking cessation. Analyses of baseline smoking quantity (SQ) identified an association between SQ and both the functional CHRNA5 SNP rs16969968 (D398N) and the CHRNA3 SNP rs1051730 (Y215Y) in a combined cohort containing MT1 and MT2. An association between SQ and ethnicity was also identified in the combined cohort. Pharmacogenetic analysis showed a significant association between rs8192475 (R37H) in CHRNA3 and both higher craving after quitting and increased withdrawal symptoms over time in MT2. Two markers for point prevalence abstinence, CHRNA5 SNP rs680244 and CHRNB4 SNP rs12914008, were also identified in MT2, with the strongest findings at week 52. These results provide further support for the role of the CHRNA5/A3/B4 subunits in determining number of cigarettes smoked and response to smoking cessation therapy.

ABCB1 (MDR1) polymorphisms and antidepressant response in geriatric depression.

OBJECTIVE: Variation in the ATP-binding cassette, subfamily B, member 1 transporter (ABCB1) (multidrug-resistance gene 1) gene has been investigated as a predictor of response to treatment with a variety of medications such as antiarrhythmics, chemotherapeutic agents, anti-HIV medications, and some psychotropics. The ABCB1 gene product, P-glycoprotein, affects the transport of drugs out of many cell types, including endothelial cells at the blood-brain barrier. We sought to determine if ABCB1 polymorphisms predict response to antidepressant treatment in geriatric patients. METHODS: We compared the effects of ABCB1 genetic variation on the therapeutic response to paroxetine, a P-glycoprotein substrate, and to mirtazapine, which is not thought to be transported by ABCB1, in a sample of 246 elderly patients with major depression treated in a clinical trial setting. A total of 15 single nucleotide polymorphisms in the ABCB1 gene were assessed in each patient. Two of these ABCB1 single nucleotide polymorphisms were earlier reported to predict treatment response in patients prescribed with P-glycoprotein substrate antidepressants. RESULTS: The two earlier identified ABCB1 markers for antidepressant response predicted time to remission in our paroxetine-treated patients, but not in the mirtazapine-treated patients. These results replicate the published findings of others. If a Bonferroni correction for type I error is made, our results do not reach the criteria for statistical significance. However, the Bonferroni correction may be too conservative given the strong linkage disequilibrium among some of the markers and our aim to replicate the earlier published findings. CONCLUSION: Our study provides confirmation that certain ABCB1 polymorphisms predict response to substrate medications in geriatric patients.

FKBP5 polymorphisms and antidepressant response in geriatric depression.

Genetic variation at the FKBP5 locus has been reported to affect clinical outcomes in patients treated with antidepressant medications in several studies. However, other reports have not confirmed this association. FKBP5 may regulate the sensitivity of the hypothalamic-pituitary-adrenal axis. We tested two FKBP5 single nucleotide polymorphisms (rs1360780 and rs3800373) in a sample of 246 geriatric patients treated for 8 weeks in a double-blind randomized comparison trial of paroxetine and mirtazapine. These two polymorphisms had previously been reported to predict efficacy in depressed patients treated with selective serotonin reuptake inhibitors such as paroxetine, and those treated with mirtazapine, an agent with both serotonergic and noradrenergic actions. However, we found no significant associations between these FKBP5 genetic variants and clinical outcomes. Neither mean Hamilton Depression Rating Scale scores nor time to remission or response were predicted by FKBP5 genetic variation. These results suggest that FKBP5 is unlikely to play a major role in determining antidepressant treatment outcomes in geriatric patients.

Gene expression profile of the PDAPP mouse model for Alzheimer's disease with and without Apolipoprotein E.

The APOE epsilon 4 allele is a strong risk factor for Alzheimer's disease (AD). However, the molecular basis for this effect remains unclear. We examined expression of approximately 12,000 genes and expressed sequence tags in the hippocampus and cortex of PDAPP (APP(V717)) mice modeling AD that show extensive amyloid beta (A beta) deposition, and in PDAPP mice lacking murine APOE expression, which show marked attenuation of A beta deposition in the brain. Wild type and APOE knockout animals were also examined. Expression levels were determined at the initial stage of A beta deposition, as well as in older animals showing extensive neuropathological changes. Fifty-four transcripts were identified using our statistical analysis as differentially regulated between the PDAPP and PDAPP/APOE ko mice, whereas 31 transcripts were classified as differentially regulated among PDAPP mice and WT animals, and seven transcripts were identified as regulated between the PDAPP/APOE ko animals and the APOE ko animals. Interestingly, many of the differentially regulated genes we detected can be related to biological processes previously shown to be important in AD pathophysiology, including inflammation, calcium homeostasis, cholesterol transport and uptake, kinases and phosphatases involved in tau phosphorylation and dephosphorylation, mitochondrial energy metabolism, protein degradation, neuronal growth, endoplasmic reticulum (ER) stress related proteins, antioxidant activity, cytoskeletal organization, and presenilin binding proteins. Regulated genes also included some not directly associated with AD in the past but likely to be involved in known AD pathophysiologic mechanisms, and others that may represent completely novel factors in the pathogenesis of AD. These results provide a global molecular profile of hippocampal and cortical gene expression during the initial and intermediate stages Abeta deposition, and the effects of APOE deletion on this process.

Abeta peptide conformation determines uptake and interleukin-1alpha expression by primary microglial cells.

Microglia clear amyloid beta (Abeta) after immunization. The interaction of Abeta with the microglial cell surface also results in cytokine expression. Soluble oligomers and protofibrils of Abeta may be more neurotoxic than Abeta fibrils. We investigated the effects of oligomeric, protofibrillar and fibrillar Abeta40 and Abeta42 peptides on uptake and IL-1alpha expression by primary microglia. Abeta peptide assemblies were extensively characterized. Primary microglial cells were exposed to different Abeta40 and Abeta42 assemblies and IL-1alpha expression was quantified. To study uptake, microglial cells were exposed to different assemblies of Cy3-labeled Abeta. We found that Abeta42 and Abeta40 oligomers and fibrils induced IL-1alpha expression, but protofibrils did not. We also observed that all forms of Abeta42 (oligomer, protofibril and fibril) and Abeta40 fibrils were taken up by the microglial cells. These results demonstrate that microglial cells can take up non-fibrillar Abeta and that oligomeric peptide induces an inflammatory response. The uptake of oligomeric and protofibrillar Abeta by microglia merits further investigation as a potential means for removing these neurotoxic species from the brain.

Utilization of diagnostic medical imaging: comparison of radiologist referral versus same-specialty referral.

PURPOSE: To retrospectively compare the frequency with which patients underwent diagnostic medical imaging procedures during episodes of outpatient medical care according to whether their physicians referred patients for imaging to themselves and/or physicians in their same specialty or to radiologists. MATERIALS AND METHODS: Institutional review board approval was not necessary for this HIPAA-compliant study. An insurance claims database from a large national employer-based health plan was obtained. Claims data from 1999-2003 were grouped into episodes of care for six conditions: cardiopulmonary disease, coronary and/or cardiac disease, extremity fracture, knee pain, intraabdominal malignancy, and stroke. For each condition, each referring physician's behavior was categorized as either "same-specialty referral" or "radiologist referral" on the basis of that physician's entire history of imaging referrals for the condition. The frequency with which patients underwent diagnostic medical imaging procedures during episodes of care was compared according to whether their physicians referred patients for imaging to themselves and/or same-specialty physicians or to radiologists. Rates were compared by using chi(2) tests, and logistic regression was used to compare utilization rates, with patient age and number of comorbidities as covariates. RESULTS: For the conditions evaluated, physicians who referred patients to themselves or to other same-specialty physicians for diagnostic imaging used imaging between 1.12 and 2.29 times as often, per episode of care, as physicians who referred patients to radiologists (P < .005 for all comparisons). Adjusting for patient age and comorbidity, the likelihood of imaging was 1.196-3.228 times greater for patients cared forby same-specialty-referring physicians. CONCLUSION: Same-specialty-referring physicians tend to utilize imaging more frequently than do physicians who refer their patients to radiologists. These results cannot be explained by differences in case mix (because analyses were performed within six specific conditions of interest), patient age, or comorbidity.