CPT1A methylation is associated with plasma adiponectin.

BACKGROUND AND AIMS: Adiponectin, an adipose-secreted protein that has been linked to insulin sensitivity, plasma lipids, and inflammatory patterns, is an established biomarker for metabolic health. Despite clinical relevance and high heritability, the determinants of plasma adiponectin levels remain poorly understood. METHODS AND RESULTS: We conducted the first epigenome-wide cross-sectional study of adiponectin levels using methylation data on 368,051 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 991). We fit linear mixed models, adjusting for age, sex, study site, T-cell purity, and family. We have identified a positive association (regression coefficient ± SE = 0.01 ± 0.001, P = 3.4 × 10-13) between plasma adiponectin levels and methylation of a CpG site in CPT1A, a key player in fatty acid metabolism. The association was replicated (n = 474, P = 0.0009) in whole blood samples from the Amish participants of the Heredity and Phenotype Intervention (HAPI) Heart Study as well as White (n = 592, P = 0.0005) but not Black (n = 243, P = 0.18) participants of the Bogalusa Heart Study (BHS). The association remained significant upon adjusting for BMI and smoking in GOLDN and HAPI but not BHS. We also identified associations between methylation loci in RNF145 and UFM1 and plasma adiponectin in GOLDN and White BHS participants, although the association was not robust to adjustment for BMI or smoking. CONCLUSION: We have identified and replicated associations between several biologically plausible loci and plasma adiponectin. These findings support the importance of epigenetic processes in metabolic traits, laying the groundwork for future translational applications.

Self-reported vs state-recorded motor vehicle collisions among older community dwelling individuals.

INTRODUCTION: Motor vehicle collisions (MVCs) continue to place an increased burden on both individuals and health care systems. Self-reported and state-recorded police reports are the most common methods for MVC evaluation in epidemiologic studies, with varying degrees of agreement of information when compared in previous studies. The objective of the current study is to address the differences in MVC reporting and provide a more robust measure of the agreement between self-reported and state-recorded MVCs in a community dwelling population of older adults. METHODS: A three-year prospective study was conducted in a population-based sample of 2000 licensed drivers aged 70 and older. At annual visits, participants were asked to self-report information on any MVC that occurred over the prior year where police were called to the scene. Information on police-reported MVCs was also ascertained from Alabama official state-recorded databases. The kappa coefficient was calculated to determine overall agreement between any self-reported and state-recorded crashes, as well as the raw number of crashes reported. In addition, agreement was stratified by demographics, health status, medication use, functional status (i.e. vision, cognition), and driving habits. RESULTS: 1747 participants who completed three years of follow up were involved in 225 state-recorded MVCs and 208 self-reported MVCs yielding overall substantial agreement between any self-report and state-recorded MVC (kappa=0.64). Cumulative number of self-reported and state-recorded MVCs was also compared, with agreement slightly reduced (kappa=0.55). The clinical characteristic resulting in the greatest variation in agreement with drivers was impaired contrast sensitivity showing better agreement between self-reported and state-recorded MVCs (kappa=0.9) than those with non-impaired contrast sensitivity (kappa=0.6). CONCLUSION: Study results showed substantial agreement between self-reported and state-recorded MVCs for any MVC involvement among the study population. When examining the reporting of the total number of MVCs over the three year period, agreement was reduced to a moderate level. There was consistency in agreement across MVC risk factors except among individuals with contrast sensitivity. These findings have implications for the design and analytic planning of epidemiologic and clinical research focused on MVCs.

The effects of genes implicated in cardiovascular disease on blood pressure response to treatment among treatment-naive hypertensive African Americans in the GenHAT study.

African Americans have the highest prevalence of hypertension in the United States. Blood pressure (BP) control is important to reduce cardiovascular disease-related morbidity and mortality in this ethnic group. Genetic variants have been found to be associated with BP response to treatment. Previous pharmacogenetic studies of BP response to treatment in African Americans suffer limitations of small sample size as well as a limited number of candidate genes, and often focused on one antihypertensive treatment. Using 1131 African-American treatment-naive participants from the Genetics of Hypertension Associated Treatment Study, we examined whether variants in 35 candidate genes might modulate BP response to four different antihypertensive medications, including an angiotensin-converting enzyme inhibitor (lisinopril), a calcium channel blocker (amlodipine), and an a-adrenergic blocker (doxazosin) as compared with a thiazide diuretic (chlorthalidone) after 6 months of follow-up. Several suggestive gene by treatment interactions were identified. For example, among participants with two minor alleles of renin rs6681776, diastolic BP response was much improved on doxazosin compared with chlorthalidone (on average -9.49 mm Hg vs -1.70 mm Hg) (P=0.007). Although several suggestive loci were identified, none of the findings passed significance criteria after correction for multiple testing. Given the impact of hypertension and its sequelae in this population, this research highlights the potential for genetic factors to contribute to BP response to treatment. Continued concerted research efforts focused on genetics are needed to improve treatment response in this high-risk group.

Identification and validation of seven new loci showing differential DNA methylation related to serum lipid profile: an epigenome-wide approach. The REGICOR study.

Lipid traits (total, low-density and high-density lipoprotein cholesterol, and triglycerides) are risk factors for cardiovascular disease. DNA methylation is not only an inherited but also modifiable epigenetic mark that has been related to cardiovascular risk factors. Our aim was to identify loci showing differential DNA methylation related to serum lipid levels. Blood DNA methylation was assessed using the Illumina Human Methylation 450 BeadChip. A two-stage epigenome-wide association study was performed, with a discovery sample in the REGICOR study (n = 645) and validation in the Framingham Offspring Study (n = 2,542). Fourteen CpG sites located in nine genes (SREBF1, SREBF2, PHOSPHO1, SYNGAP1, ABCG1, CPT1A, MYLIP, TXNIP and SLC7A11) and 2 intergenic regions showed differential methylation in association with lipid traits. Six of these genes and 1 intergenic region were new discoveries showing differential methylation related to total cholesterol (SREBF2), HDL-cholesterol (PHOSPHO1, SYNGAP1 and an intergenic region in chromosome 2) and triglycerides (MYLIP, TXNIP and SLC7A11). These CpGs explained 0.7%, 9.5% and 18.9% of the variability of total cholesterol, HDL cholesterol and triglycerides in the Framingham Offspring Study, respectively. The expression of the genes SREBF2 and SREBF1 was inversely associated with methylation of their corresponding CpGs (P-value = 0.0042 and 0.0045, respectively) in participants of the GOLDN study (n = 98). In turn, SREBF1 expression was directly associated with HDL cholesterol (P-value = 0.0429). Genetic variants in SREBF1, PHOSPHO1, ABCG1 and CPT1A were also associated with lipid profile. Further research is warranted to functionally validate these new loci and assess the causality of new and established associations between these differentially methylated loci and lipid metabolism.

Performance outcomes of a pharmacist-managed anticoagulation clinic in the rural, resource-constrained setting of Eldoret, Kenya.

BACKGROUND: It is recommended that warfarin therapy should be managed through an anticoagulation monitoring service to minimize the risk of bleeding and subsequent thromboembolic events. There are few studies in Sub-Saharan Africa that describe warfarin management in spite of the high incidence of venous thromboembolism (VTE) and rheumatic heart disease. OBJECTIVE: To examine the feasibility of the Moi Teaching and Referral Hospital anticoagulation monitoring service and compare its performance with clinics in resource-rich settings. METHODS: A retrospective chart review compared the percentage time in the therapeutic range (TTR) and rates of bleeding and thromboembolic events to published performance targets using the inference on proportions test. Wilcoxon's rank sum analyses were used to establish predictors of TTR. RESULTS: For the 178 patients enrolled, the mean TTR was 64.6% whereas the rates of major bleeds and thromboembolic events per year were 1.25% and 5%, respectively. In the primary analysis, no statistically significant differences were found between the results of TTR, major bleeds and thromboembolic events for the clinic and published performance rates. In the secondary analysis, having an artificial heart valve and a duration of follow-up of > 120 days were positively associated with a higher TTR (P < 0.05) whereas venous thromboembolism, history of tuberculosis, HIV and a duration of follow-up of < 120 days were associated with having a lower TTR (P < 0.05). CONCLUSIONS: The performance of the MTRH anticoagulation clinic is non-inferior to published metrics on the performance of clinics in resource-rich settings.

Systemic lupus erythematosus in a 3-month old male presenting as thrombocytopenia.

We report a case of a 3-month old male infant, born to a mother with a known history of systemic lupus erythematosus (SLE). The infant initially presented with petechiae, anemia, and thrombocytopenia. His evaluation revealed antinuclear antibody (ANA) titer of 1 : 160, negative anti-SS-A/SS-B antibody, positive anti-Smith antibody, elevated anti-dsDNA titer, and a slightly low C4 level. His subsequent development of hematuria with nephrotic grade proteinuria fulfilled criteria for a diagnosis of SLE. His condition improved with corticosteroids, mycophenolate mofetil and low-dose aspirin. At 18 months of age, he is clinically well, off all immunosuppression with normal growth parameters and no detectable autoantibodies.

Rapid turnover of the mTOR complex 1 (mTORC1) repressor REDD1 and activation of mTORC1 signaling following inhibition of protein synthesis.

mTORC1 is a complex of proteins that includes the mammalian target of rapamycin (mTOR) and several regulatory proteins. It is activated by a variety of hormones (e.g. insulin) and nutrients (e.g. amino acids) that act to stimulate cell growth and proliferation and repressed by hormones (e.g. glucocorticoids) that act to reduce cell growth. Curiously, mTORC1 signaling is reported to be rapidly (e.g. within 1-2 h) activated by inhibitors of protein synthesis that act on either mRNA translation elongation or gene transcription. However, the basis for the mTORC1 activation has not been satisfactorily delineated. In the present study, mTORC1 signaling was found to be activated in response to inhibition of either the initiation or elongation phases of mRNA translation. Changes in mTORC1 signaling were inversely proportional to alterations in the expression of the mTORC1 repressor, REDD1, but not the expression of TRB3 or TSC2. Moreover the cycloheximide-induced increase in mTORC1 signaling was significantly attenuated in cells lacking REDD1, showing that REDD1 plays an integral role in the response. Finally, the half-life of REDD1 was estimated to be 5 min or less. Overall, the results are consistent with a model in which inhibition of protein synthesis leads to a loss of REDD1 protein because of its rapid degradation, and in part reduced REDD1 expression subsequently leads to de-repression of mTORC1 activity.

Correlation of cleavage of SNAP-25 with muscle function in a rat model of Botulinum neurotoxin type A induced paralysis.

Injection of botulinum neurotoxin serotype A (BoNT/A) into muscle results in cleavage of the synaptosomal associated protein of 25 kDa (SNAP-25) and relatively long-term paralysis. However, nerve-terminal sprouting, which appears to require intact SNAP-25, has been reported to occur much earlier. The difference between the long-term paralysis induced by injection of BoNT/A and the short time needed for sprouting led us to investigate the relationship between BoNT/A catalyzed cleavage of SNAP-25 and muscle function. The effect of BoNT/A on SNAP-25 present in nerve endings innervating gastrocnemius muscles of rats was monitored over time. Cleaved SNAP-25 was found in nerve terminals innervating the muscles within 24h of inoculation with BoNT/A and was present more than 2 months later. Comparison of the ratios of cleaved to intact SNAP-25 from the onset of BoNT/A-induced paralysis until function was regained indicated that paralysis was probable when the ratio of cleaved to intact SNAP-25 was greater than 0.35.

Risk factors for and trends in gonorrhea incidence among persons infected with HIV in the United States.

OBJECTIVE: To determine the risk factors for and trends in gonorrhea infections among HIV-infected persons. DESIGN: Longitudinal review of medical records of HIV-infected patients. METHODS: We analyzed data about HIV-infected patients obtained from 1991 to 1998 in over 100 facilities participating in the Adult/Adolescent Spectrum of HIV Disease Project. RESULTS: The overall incidence of gonorrhea was 9.5 cases per 1000 person--years. Factors associated with higher gonorrhea incidence (P < 0.01) included younger age, male--male sex, black race, HIV infection without AIDS (namely AIDS-defining opportunistic illness or CD4 cell count < 200 x 10(6) cells/l), and recent recreational use of injection or non-injection drugs. There was an increase in the trend among men who have sex with men (P < 0.01) and a decrease in the trend among patients with heterosexual contact as their HIV exposure risk (P < 0.01). Among injection drug users there was no significant trend from 1991 to 1996, but there was an increase in gonorrhea incidence from 6.6 cases/1000 person-years in 1997 to 16.3 cases/1000 person--years in 1998. CONCLUSIONS: Following HIV diagnosis, some individuals continue to practice risky sexual behaviors which result in gonorrhea and may transmit HIV. The increase in the trend in gonorrhea incidence among HIV-infected men who have sex with men is of particular concern because it suggests an increase in risky sexual behaviors. These findings indicate a need for effective HIV prevention strategies that involve reducing risky sexual behaviors in HIV-infected persons.

Human immunodeficiency virus (HIV) subtype surveillance of African-born persons at risk for group O and group N HIV infections in the United States.

A population-based surveillance registry was used to identify human immunodeficiency virus (HIV)-infected persons in the United States at increased risk for group O and group N infections (those born in or near African countries where group O infection has been reported). Of 155 eligible subjects, 37 gave samples. By phylogenetic and serologic analysis, 32 were infected with group M (16 with subtype A, 5 with B, 7 with C, and 1 each with subtypes D, F2, G, and recombinant A/J) and 2 with group O but none with group N virus. For 3, samples could not be typed by serology or amplified by polymerase chain reaction using group M-, O-, or N-specific primers. In the United States, group O HIV infection is uncommon; no case of group N infection was found. African-born persons may have HIV strains typical of their birth country. Ongoing subtype surveillance may allow early identification of novel or emerging HIV strains.

Increased risk of Mycobacterium tuberculosis infection related to the occupational exposures of health care workers in Chiang Rai, Thailand.

SETTING: Chiang Rai, the northernmost province of Thailand. OBJECTIVE: To evaluate the occupational risk for tuberculous infection of health care workers (HCWs) and the utility of tuberculin skin test (TST) in a developing country setting. DESIGN: A cross-sectional TST survey, including a risk assessment questionnaire, of Chiang Rai Hospital HCWs. RESULTS: Of 911 HCWs tested, 623 (68%) had indurations of > or = 10 mm and 322 (35%) indurations of > or = 15 mm. Factors most predictive for TST positivity, using either cut-off, were employment > 1 year, frequent direct patient contact, and male sex. Moreover, having a bacillus Calmette-Guérin (BCG) scar was predictive of a > or = 10 mm, but not a > or = 15 mm, reaction. CONCLUSIONS: Chiang Rai Hospital HCWs had an increased risk for Mycobacterium tuberculosis infection, which was significantly associated with occupational exposure. Where BCG coverage is high, a TST cut-off of > or = 15 mm may correlate better with M. tuberculosis infection than does a cut-off of > or = 10 mm. Effective, affordable infection control measures are needed for health care facilities in developing countries such as Thailand, where HCWs may be at increased risk for M. tuberculosis infection from occupational exposures.

Persistently negative HIV-1 antibody enzyme immunoassay screening results for patients with HIV-1 infection and AIDS: serologic, clinical, and virologic results. Seronegative AIDS Clinical Study Group.

OBJECTIVE: To describe persons with HIV infection and AIDS but with persistently negative HIV antibody enzyme immunoassay (EIA) results. DESIGN: Surveillance for persons meeting a case definition for HIV-1-seronegative AIDS. SETTING: United States and Canada. PATIENTS: A total of eight patients with seronegative AIDS identified from July 1995 through September 1997. MAIN OUTCOME MEASURES: Clinical history of HIV disease, history of HIV test results, and CD4 cell counts from medical record review; results of testing with a panel of EIA for antibodies to HIV-1, and HIV-1 p24 antigen; and viral subtype. RESULTS: Negative HIV EIA results occurred at CD4 cell counts of 0-230 x 10(6)/l, and at HIV RNA concentrations of 105,000-7,943,000 copies/ml. Using a panel of HIV EIA on sera from three patients, none of the HIV EIA detected infection with HIV-1, and signal-to-cut-off ratios were < or = 0.8 or all test kits evaluated. Sera from five patients showed weak reactivity in some HIV EIA, but were non-reactive in other HIV EIA. All patients were infected with HIV-1 subtype B. CONCLUSIONS: Rarely, results of EIA tests for antibodies to HIV-1 may be persistently negative in some HIV-1 subtype B-infected persons with AIDS. Physicians treating patients with illnesses or CD4 cell counts suggestive of HIV infection, but for whom results of HIV EIA are negative, should consider p24 antigen, nucleic acid amplification, or viral culture testing to document the presence of HIV.

Bloodstream infection associated with needleless device use and the importance of infection-control practices in the home health care setting.

The influence of infection-control practices on bloodstream infection (BSI) risk was examined in a home health care setting in which three needleless devices were used consecutively. A case-control study and a retrospective cohort study were conducted. Risk factors for BSI included lower education level, younger age, having a central venous catheter (CVC) with multiple ports, or having a tunneled CVC. Among patients with a tunneled CVC, those at greatest risk had been allowed to shower rather than bathe and to get their exit site wet (P<.01). A high proportion (49%) of isolates were hydrophilic gram-negative bacteria, suggesting water sources of infection. In the cohort study, the BSI rate decreased as the frequency of changing the needleless device end cap increased from once weekly up to every 2 days, suggesting that the mechanism for BSI may involve contamination from the end cap. These findings may help to develop infection-control measures specific to home health care.

Risk factors for early recurrent Clostridium difficile-associated diarrhea.

Recurrence is a common sequela of Clostridium difficile-associated diarrhea (CDD) and may increase morbidity, costs, and treatment-related antimicrobial resistance. Because recurrent CDD (RCDD) frequently occurs very soon after an initial episode, our goal was to determine the risk factors for early RCDD (occurring < or = 45 days after the initial episode). We conducted a case-control study, comparing 13 patients with early RCDD (case patients) with 46 patients who had only one CDD episode (control patients) at Centre Hospitalier Angrignon (Québec) during January 1993 through November 1994. Risk factors for early RCDD included a history of chronic renal insufficiency, a white blood cell count of > or = 15 x 10(3)/mm3, and community-acquired diarrhea with the first CDD episode. For seven of eight case patients, C. difficile strains from the first and second CDD episodes were identical, suggesting that relapse is more common than reinfection. These results suggest that treatments should be directed at preventing relapses in patients at high risk for early RCDD.