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1.  Prescription Acquired Acetaminophen Use and the Risk of Asthma in Adults: A Case Control Study 
The Annals of pharmacotherapy  2012;46(12):1598-1608.
Studies have examined the association between acetaminophen (APAP) use and asthma; however, their interpretation is limited by a number of methodological issues.
We sought to investigate the association between recent and chronic prescription acquired acetaminophen use and asthma.
This was a retrospective case control study using a 10% random sample of the IMS LifeLink commercial claims data from 1997 to 2009. Cases had to have at least 1 incident claim of asthma. 3:1 controls matched on age, gender, and region were randomly chosen. APAP exposure, dose and duration were measured in the 7 and 30 days (recent) and in the 1-year (chronic) look-back period. Multivariable conditional logistic regression was used to estimate the risk of asthma associated with acetaminophen use adjusted for comorbidities, other drugs increasing asthma risk, and health system factors.
There were 28,892 cases and 86,676 controls with mean age 42.7 years and 37.7% were males. 22.6% cases and 18.2% controls had APAP exposure in the pre-index year with mean cumulative doses of 78.7 gm and 59.8 gm respectively. There was no significant association between recent prescription APAP exposure and asthma (7 days: OR = 1.02, p = 0.74; 30 days: OR = 0.97, p = 0.38). Cumulative prescription APAP dose in the year prior increased asthma risk compared to APAP nonusers (<=1 kg: OR = 1.09, p <0.001 and >1 kg: OR = 1.60, p=0.02). Duration of prescription APAP use >30 days was associated with elevated asthma risk (OR = 1.39, p <0.001).
Chronic prescription-acquired APAP use was associated with an increased risk of asthma while recent use was not. However, over the counter APAP use was not captured in this study and further epidemiologic research with complete APAP exposure ascertainment and research on pathophysiological mechanisms is needed to confirm these relationships.
PMCID: PMC3793244  PMID: 23170033
Asthma; Acetaminophen; Pharmacoepidemiology; Acetaminophen toxicity
2.  Associations between maternal genotypes and metabolites implicated in congenital heart defects 
Molecular genetics and metabolism  2012;107(3):596-604.
The development of non-syndromic congenital heart defects (CHDs) involves a complex interplay of genetics, metabolism, and lifestyle. Previous studies have implicated maternal single nucleotide polymorphisms (SNPs) and altered metabolism in folate-related pathways as CHD risk factors.
We sought to discover associations between maternal SNPs and metabolites involved in the homocysteine, folate, and transsulfuration pathways, and determine if these associations differ between CHD cases and controls.
Genetic, metabolic, demographic, and lifestyle information was available for 335 mothers with CHD-affected pregnancies and 263 mothers with unaffected pregnancies. Analysis was conducted on 1160 SNPs, 13 plasma metabolites, and 2 metabolite ratios. A two-stage multiple linear regression was fitted to each combination of SNP and metabolite/ratio.
We identified 4 SNPs in the methionine adenosyltransferase II alpha (MAT2A) gene that were associated with methionine levels. Three SNPs in tRNA aspartic acid methyltransferase 1 (TRDMT1) gene were associated with total plasma folate levels. Glutamylcysteine (GluCys) levels were associated with multiple SNPs within the glutathione peroxidase 6 (GPX6) and O-6-methylguanine-DNA methyltransferase (MGMT) genes. The regression model revealed interactions between genotype and case-control status in the association of total plasma folate, total glutathione (GSH), and free GSH, to SNPs within the MGMT, 5,10-methenyltetrahydrofolate synthetase (MTHFS), and catalase (CAT) genes, respectively.
Our study provides further evidence that genetic variation within folate-related pathways accounts for inter-individual variability in key metabolites. We identified specific SNP-metabolite relationships that differed in mothers with CHD-affected pregnancies, compared to controls. Our results underscore the importance of multifactorial studies to define maternal CHD risk.
PMCID: PMC3523122  PMID: 23059056
3.  Sleep Disturbance in Women Prior to Myocardial Infarction 
To describe the prevalence and correlates of sleep disturbances among women who retrospectively reported sleep disturbance prior to their myocardial infarction (MI).
MI is frequently unrecognized in women because they may have only vague symptoms, such as sleep disturbance. Describing correlates of sleep disturbance prior to MI may assist in recognizing women at risk for coronary heart disease.
Secondary analysis of dataset derived from 15 sites.
Of 1270 women experiencing initial MI, 632 reported new onset of or worsening sleep disturbance before MI. Prevalence was similar across racial groups. Women reporting prodromal sleep disturbance were more likely to be older, heavier, and report cognitive changes (aOR= 1.47), new or increasing anxiety (aOR= 2.21), and unusual fatigue (aOR= 2.16).
Subjective report of sleep disturbance preceding MI appear to be prevalent in women of all races and may be an important warning sign for MI in women.
PMCID: PMC3432660  PMID: 22770599
cardiovascular disease; cognitive disorders; sleep disturbance; menopause; women
4.  Which Drug For Which Patient? Is There a Fluoxetine Responding Versus a Bupropion Responding Personality Profile? 
This paper proposes that a certain premorbid personality type – that of hard driving, achievement-oriented, often exercise-oriented individuals – correlates with bupropion response; conversely, patients without these premorbid traits and whose depression is marked by mood swings, irritability and rumination are likely fluoxetine responders.
The authors developed the Fluoxetine Bupropion Assessment Scale (FBAS), a 10-question, self-administered rating scale, to assess these traits and hypothesized that its use would improve outcomes.
A Marriage and Family Therapist (MFT) and a Registered Nurse/Nurse Practitioner (RN/NP) retrospectively reviewed 72 charts from one psychiatrist’s office for two time periods: before and after the psychiatrist utilized the questionnaire to guide antidepressant selection (33 charts before and 39 charts after). Raters were blinded to the theory and to the treatment time period. On the basis of clinical information in the charts, they formulated Clinical Global Impression assessments of treatment response in patients with Beck Depression Inventory scores ≥17 who were not on either drug at the time of intake, and who were prescribed either fluoxetine or bupropion.
The data were in the direction of better results in the FBAS-guided group, particularly after adjusting for age, gender and marital status (efficacy p = 0.087). When global improvement data were combined into three groups describing treatment response (improved, minimal to no improvement, and worse) there were statistically significant better results (p = 0.047) in the FBAS-guided treatment group. Revision and validation of the questionnaire and a larger, randomized study seem indicated.
PMCID: PMC3735924  PMID: 23935697
Bupropion; depression; exercise; fluoxetine; personality; rating scale; selective serotonin reuptake inhibitor; temperament.
5.  Subarachnoid versus General Anesthesia in Penile Prosthetic Implantation: Outcomes Analyses 
Advances in Urology  2012;2012:696752.
The leading patient complaint during the perioperative period for penile prosthesis implantation is postoperative pain, while emesis and urticaria also affect the procedure's perceived success. In analyzing surgical outcomes, assessment of the anesthetic for postoperative pain and side effects should be included. This paper retrospectively reviews 90 consecutive, primary inflatable penile prosthetic operations performed by a single surgeon at one private medical center. Fifty-seven patients were included in final analysis. Patients who had more than one procedure that day or who used chronic pain medication were excluded. The type and amount of each drug used for each respective side effect (within the first 24 hours after procedure) were compared to determine relative benefit. Twenty patients received general anesthesia (denoted herein as “GA”) and 37 received spinal (or also known as subarachnoid) anesthesia (denoted herein as “SA”). Patients receiving GA had significantly greater (P < 0.0001) occurrence and amount of intravenous pain treatment than those receiving SA. Patients with SA required less intravenous pain medication and less treatment for nausea/emesis.
PMCID: PMC3426176  PMID: 22927841
6.  Association between Selected Folate Pathway Polymorphisms and Nonsyndromic Limb Reduction Defects: A Case-Parental Analysis 
Inadequate folate status due to either genetic variation or nutritional deficiencies has been associated with an increased risk of congenital malformations including orofacial clefting, limb, cardiac and neural tube defects. Few epidemiologic studies have examined the association between limb reduction defects (LRDs) and folate-related genetic polymorphisms other than MTHFR 677C→T. We conducted a case–parental analysis of 148 families who participated in the National Birth Defects Prevention Study (NBDPS) to examine the association between nonsyndromic transverse and longitudinal LRDs with five single nucleotide polymorphisms (SNPs) in genes encoding for enzymes in folate and methionine pathways. Log-linear Poisson regression, adapted for analysis of case–parental data, assuming an additive genetic model was used to estimate genetic relative risks and 95% confidence intervals for the association between LRDs and each SNP. Among women who did not take multivitamin supplements, the MTHFR 677T variant acts via the offspring’s genome to increase the risk of LRDs. No association between LRDs and any fetal SNP was found among women who used multivitamin supplements. These results suggest the possibility that initiating folic acid supplementation prior to pregnancy may reduce the risk of having a LRD-affected pregnancy, especially in women whose offspring inherit one or two copies of the MTHFR 677T variant.
PMCID: PMC3050483  PMID: 21281325
Folic acid; homocysteine; MTHFR; polymorphisms; case-parental analysis
7.  Maternal DNA hypomethylation and congenital heart defects 
Congenital heart defects (CHDs) are among the most prevalent and serious of birth defects. Multiple maternal factors are thought to contribute to CHD development including folate intake. Maternal DNA methylation, which is dependent on folate metabolism, may impact the risk of CHDs.
Our study was designed to determine whether maternal long interspersed nucleotide elements-1 (LINE-1) DNA hypomethylation is associated with increased occurrence of non-syndromic CHDs and whether maternal folate-dependent metabolites are correlated with DNA methylation status.
Using a case-control study design, we measured global DNA methylation status among mothers whose pregnancies were affected by non-syndromic CHDs (n=180) and mothers of unaffected pregnancies (n=187). Methylation of LINE-1 was used as a surrogate marker of global DNA methylation status. The association between DNA methylation and CHD risk was determined while adjusting for selected lifestyle factors.
LINE-1 DNA methylation was significantly lower in cases compared with controls (p=0.049). After covariate adjustments, a significant difference between cases and controls remained (p=0.010). Among women with LINE-1 methylation in the lowest decile of DNA methylation, the estimated risk of having a CHD-affected pregnancy was almost twice that of women in all other deciles (OR=1.91; 95% CI: 1.03, 3.58).
Our findings indicate that maternal LINE-1 DNA hypomethylation is associated with an increased risk of CHDs. Future studies investigating the association between maternal DNA methylation patterns and CHDs should be pursued.
PMCID: PMC3168545  PMID: 21254366
Congenital heart defects; DNA methylation; LINE-1; folate; maternal biomarkers
8.  A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism 
The biologic basis of autism is complex and is thought to involve multiple and variable gene-environment interactions. While the logical focus has been on the affected child, the impact of maternal genetics on intrauterine microenvironment during pivotal developmental windows could be substantial. Folate-dependent one carbon metabolism is a highly polymorphic pathway that regulates the distribution of one-carbon derivatives between DNA synthesis (proliferation) and DNA methylation (cell-specific gene expression and differentiation). These pathways are essential to support the programmed shifts between proliferation and differentiation during embryogenesis and organogenesis. Maternal genetic variants that compromise intrauterine availability of folate derivatives could alter fetal cell trajectories and disrupt normal neurodevelopment. In this investigation, the frequency of common functional polymorphisms in the folate pathway was investigated in a large population-based sample of autism case-parent triads. In case-control analysis, a significant increase in the reduced folate carrier (RFC1) G allele frequency was found among case mothers, but not among fathers or affected children. Subsequent log linear analysis of the RFC1 A80G genotype within family trios revealed that the maternal G allele was associated with a significant increase in risk of autism whereas the inherited genotype of the child was not. Further, maternal DNA from the autism mothers was found to be significantly hypomethylated relative to reference control DNA. Metabolic profiling indicated that plasma homocysteine, adenosine, and S-adenosylhomocyteine were significantly elevated among autism mothers consistent with reduced methylation capacity and DNA hypomethylation. Together, these results suggest that the maternal genetics/epigenetics may influence fetal predisposition to autism.
PMCID: PMC2943349  PMID: 20468076
Autism; reduced folate carrier; maternal; polymorphism; DNA methylation; epigenetics
9.  Maternal Folate-Related Gene Environment Interactions and Congenital Heart Defects 
Obstetrics and gynecology  2010;116(2 Pt 1):316-322.
To investigate whether women with congenital heart defect (CHD)-affected pregnancies were more likely to have functional single nucleotide polymorphisms (SNPs) in genes encoding enzymes in folate-dependent pathways.
A population-based case-control study of 572 women with CHD-affected pregnancies and 363 control women was conducted. DNA samples were genotyped for SNPs in three genes encoding for folate pathway enzymes. Maternal lifestyle factor information was obtained using standardized interviews.
Case women were 1.5 times more likely to be obese (BMI of 30 or higher) compared to control women. Obese women carrying the MTHFR TT genotype were 4.6 times more likely to have an affected pregnancy compared to normal weight women carrying a CC genotype. Obese women carrying one or two copies of the A allele in the BHMT polymorphism were 1.8 times more likely to have a CHD-affected pregnancy than normal weight women carrying a BHMT GG genotype. Among women who smoked, those carrying a TCII CG or GG genotype were 1.8 times more likely to have an affected fetus than women who smoked and carried a CC genotype. Among women who drank alcohol, those carrying a TCII CG or GG genotype were 1.7 times more likely to have an affected fetus than women who drank and carried a CC genotype.
Results indicate that functional polymorphisms in folate-related genes increase the risk of having a fetus with CHD when maternal lifestyle factors that alter folate metabolism are present.
PMCID: PMC3027124  PMID: 20664391
10.  Cluster Analysis of Women’s Prodromal and Acute Myocardial Infarction Symptoms by Race and Other Characteristics 
PMCID: PMC2884391  PMID: 20539165
women’s health; myocardial infarction; minority groups; cluster analysis
11.  Maternal Genome-Wide DNA Methylation Patterns and Congenital Heart Defects 
PLoS ONE  2011;6(1):e16506.
The majority of congenital heart defects (CHDs) are thought to result from the interaction between multiple genetic, epigenetic, environmental, and lifestyle factors. Epigenetic mechanisms are attractive targets in the study of complex diseases because they may be altered by environmental factors and dietary interventions. We conducted a population based, case-control study of genome-wide maternal DNA methylation to determine if alterations in gene-specific methylation were associated with CHDs. Using the Illumina Infinium Human Methylation27 BeadChip, we assessed maternal gene-specific methylation in over 27,000 CpG sites from DNA isolated from peripheral blood lymphocytes. Our study sample included 180 mothers with non-syndromic CHD-affected pregnancies (cases) and 187 mothers with unaffected pregnancies (controls). Using a multi-factorial statistical model, we observed differential methylation between cases and controls at multiple CpG sites, although no CpG site reached the most stringent level of genome-wide statistical significance. The majority of differentially methylated CpG sites were hypermethylated in cases and located within CpG islands. Gene Set Enrichment Analysis (GSEA) revealed that the genes of interest were enriched in multiple biological processes involved in fetal development. Associations with canonical pathways previously shown to be involved in fetal organogenesis were also observed. We present preliminary evidence that alterations in maternal DNA methylation may be associated with CHDs. Our results suggest that further studies involving maternal epigenetic patterns and CHDs are warranted. Multiple candidate processes and pathways for future study have been identified.
PMCID: PMC3031146  PMID: 21297937
12.  Racial Differences in Women’s Prodromal and Acute Myocardial Infarction Symptoms 
Minority women, especially Black and Hispanic, have higher rates of coronary heart disease (CHD) and resulting disability and death than Whites. Because most studies have included insufficient numbers of Blacks and Hispanics for meaningful analyses, lack of knowledge of minority women’s CHD symptoms may contribute to these disparities.
To compare Black, Hispanic and White women’s prodromal CHD and acute myocardial infarction (AMI) symptoms.
Retrospective telephone surveys were conducted with 1270 (545 Black; 539 White, 186 Hispanic) cognitively intact women post AMI at 15 sites. Using general linear models, symptom severity and frequency were compared among racial groups, controlling for cardiovascular risk factors. Using logistic regression models, we examined individual prodromal or AMI symptoms by race, adjusting for cardiovascular risk factors.
Ninety-six percent of all women reported prodromal symptoms. Unusual fatigue (73%) and sleep disturbance (50%) were the most frequent prodromal symptoms. Eighteen symptoms differed significantly by race (p<0.01); Blacks reported higher frequencies of 10 symptoms than Hispanics or Whites. Less than 37% reported prodromal chest discomfort; Hispanics reported more pain/discomfort symptoms than Black or White women.
Minority women reported more acute symptoms (p<0.01). The most frequent symptom, regardless of race, was shortness of breath (62.8%); 22 symptoms differed by race (p<0.01). Twenty-eight percent of Hispanics, 38% Blacks, and 42% Whites reported no chest pain/discomfort.
Significant racial differences existed in prodromal and AMI symptoms reported by women in this study. Racial descriptions of women’s CHD and AMI symptoms should assist providers in interpreting women’s symptoms.
PMCID: PMC2860802  PMID: 20045850
Myocardial infarction; women; minority groups; symptoms
13.  Neural Tube Defects and Maternal Biomarkers of Folate, Homocysteine, and Glutathione Metabolism 
Alterations in maternal folate and homocysteine metabolism are associated with neural tube defects (NTDs). The role that specific micronutrients and metabolites play in the causal pathway leading to NTDs is not fully understood.
We conducted a case-control study to investigate the association between NTDs and maternal alterations in plasma micronutrients and metabolites in two metabolic pathways, the methionine remethylation and glutathione transsulfuration. Biomarkers were measured in a population-based sample of women who had NTD-affected pregnancies (n = 43) and a control group of women who had a pregnancy unaffected by a birth defect (n = 160). Plasma concentrations of folate, Vitamin B12, Vitamin B6, methionine, S-adenosylmethionine (SAM), s- adenosylhomocysteine (SAH), adenosine, homocysteine, cysteine, and reduced and oxidized glutathione were compared between cases and controls after adjusting for lifestyle and sociodemographic factors.
Women with NTD-affected pregnancies had significantly higher plasma concentrations of SAH (29.12 vs. 23.13 nmol/L, P = 0.0011), adenosine (0.323 vs. 0.255 μmol/L, P = 0.0269), homocysteine (9.40 vs. 7.56 μmol/L, P < 0.001), and oxidized glutathione (0.379 vs. 0.262μmol/L, P = 0.0001), but lower plasma SAM concentration (78.99 vs. 83.16 nmol/L, P = 0.0172) than controls. This metabolic profile is consistent with reduced methylation capacity and increased oxidative stress in women with affected pregnancies.
Increased maternal oxidative stress and decreased methylation capacity may contribute to the occurrence of NTDs. Further analysis of relevant genetic and environmental factors is required to define the basis for these observed alterations.
PMCID: PMC2964004  PMID: 16575882
Neural tube defects; maternal biomarkers; folate; methionine; homocysteine; glutathione
14.  Neural Tube Defects and Maternal Folate Intake Among Pregnancies Conceived After Folic Acid Fortification in the United States 
Rates of neural tube defects have decreased since folic acid fortification of the food supply in the United States. The authors’ objective was to evaluate the associations between neural tube defects and maternal folic acid intake among pregnancies conceived after fortification. This is a multicenter, case-control study that uses data from the National Birth Defects Prevention Study, 1998–2003. Logistic regression was used to compute crude and adjusted odds ratios between cases and controls assessing maternal periconceptional use of folic acid and intake of dietary folic acid. Among 180 anencephalic cases, 385 spina bifida cases, and 3, 963 controls, 21.1%, 25.2%, and 26.1%, respectively, reported periconceptional use of folic acid supplements. Periconceptional supplement use did not reduce the risk of having a pregnancy affected by a neural tube defect. Maternal intake of dietary folate was not significantly associated with neural tube defects. In this study conducted among pregnancies conceived after mandatory folic acid fortification, the authors found little evidence of an association between neural tube defects and maternal folic acid intake. A possible explanation is that folic acid fortification reduced the occurrence of folic acid-sensitive neural tube defects. Further investigation is warranted to possibly identify women who remain at increased risk of preventable neural tube defects.
PMCID: PMC3139973  PMID: 18953063
folic acid; neural tube defects
15.  Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism 
Autism is a behaviorally-defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G>A), transcobalamin II (TCN2 776G>C), catechol-O-methyltransferase (COMT 472G>A), methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C), and GST M1. We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism.
PMCID: PMC2610366  PMID: 16917939
autism; oxidative stress; genotype; glutathione; methionine

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