The interdependencies of viral load, the innate immune response, and clinical outcome in children presenting to the emergency department with respiratory syncytial virus-associated bronchiolitis.

Respiratory syncytial virus (RSV) causes significant infant morbidity and mortality. For decades severe RSV-induced disease was thought to result from an uncontrolled host response to viral replication, but recent work suggests that a strong innate immune response early in infection is protective. To shed light on host-virus interactions and the viral determinants of disease, copy numbers of five RSV genes (NS1, NS2, N, G, F) were measured by quantitative real-time polymerase chain reaction (qPCR) in nasal wash samples from children with RSV-associated bronchiolitis. Correlations were sought with host cytokines/chemokines and biomarkers. Associations with disposition from the emergency department (hospitalized or sent home) and pulse oximetry O2 saturation levels were also sought. Additionally, RNase P copy number was measured and used to normalize nasal wash data. RSV gene copy numbers were found to significantly correlate with both cytokine/chemokine and biomarker levels; and RNase P-normalized viral gene copy numbers (NS1, NS2, N and G) were significantly higher in infants with less severe disease. Moreover, three of the normalized viral gene copy numbers (NS1, NS2, and N) correlated significantly with arterial O2 saturation levels. The data support a model where a higher viral load early in infection can promote a robust innate immune response that protects against progression into hypoxic RSV-induced lower respiratory tract illness.

Robust Cytokine and Chemokine Response in Nasopharyngeal Secretions: Association With Decreased Severity in Children With Physician Diagnosed Bronchiolitis.

BACKGROUND: Bronchiolitis causes substantial disease in young children. Previous findings had indicated that a robust innate immune response was not associated with a poor clinical outcome in bronchiolitis. This study tested the hypothesis that increased concentrations of cytokines and chemokines in nasal wash specimens were associated with decreased severity in bronchiolitis. METHODS: Children <24 months old who presented to the emergency department with signs and symptoms of bronchiolitis were eligible for enrollment. Nasal wash specimens were analyzed for viral pathogens and cytokine/chemokine concentrations. These results were evaluated with regard to disposition. RESULTS: One hundred eleven children with bronchiolitis were enrolled. A viral pathogen was identified in 91.9% of patients (respiratory syncytial virus in 51.4%, human rhinovirus in 11.7%). Higher levels of cytokines and chemokines (interferon [IFN] γ; interleukin [IL] 4, 15, and 17; CXCL10; and eotaxin) were significantly associated with a decreased risk of hospitalization. IL-17, IL-4, IFN-γ, and IFN-γ-inducible protein 10 (CXCL10 or IP-10) remained statistically significant in the multivariate analyses. CONCLUSIONS: The cytokines and chemokines significantly associated with decreased bronchiolitis severity are classified in a wide range of functional groups (T-helper 1 and 2, regulatory, and chemoattractant). The involvement of these functional groups suggest that a broadly overlapping cytokine/chemokine response is required for control of virus-mediated respiratory disease in young children.

Factors associated with real-time RT-PCR cycle threshold values among medically attended influenza episodes.

We evaluated the cycle threshold (CT) values of 1,160 influenza A positive and 806 influenza B positive specimens from two seasons of the US Flu VE Network to identify factors associated with CT values. Low CT values (high genomic load) were associated with shorter intervals between illness onset and specimen collection, young age (ages 3-8 years old), and self-rated illness severity for both influenza A and B. Low CT values were also associated with reported fever/feverishness and age ≥65 years for influenza A.

Infection with novel respiratory syncytial virus genotype Ontario (ON1) in adult hematopoietic cell transplant recipients, Texas, 2011-2013.

BACKGROUND: Respiratory syncytial virus (RSV) can cause severe respiratory disease in adult hematopoietic cell transplant (HCT) recipients. RSV subgroups A and B have evolved into multiple genotypes. We report on a recently described RSV genotype (ON1) in a cohort of adult HCT recipients in Texas. METHODS: Twenty adult HCT recipients were enrolled as a part of an efficacy trial of ribavirin therapy. RSV identification and genotyping was performed using molecular techniques. RSV-specific neutralizing antibody (NAb) responses were measured. RESULTS: ON1 genotype was detected in 3 of 6 patients in the 2011-2012 season and in 8 of 14 patients in 2012-2013 season. Other genotypes detected were NA1 and BA. NAb levels were low at enrollment. Eight of 9 patients who cleared the RSV infection within 2 weeks mounted a ≥4-fold NAb response, compared with 2 of 8 who shed the virus for >2 weeks. The clinical course of those infected with ON1 was comparable to the course for individuals infected with other genotypes. CONCLUSION: This is the first report of RSV ON1 genotype in the United States, and ON1 genotype was dominant genotype in adult HCT recipients. Interestingly, faster viral clearance was associated with a ≥4-fold NAb response, likely indicating a reconstituted immune system.

Lactate dehydrogenase and caspase activity in nasopharyngeal secretions are predictors of bronchiolitis severity.

BACKGROUND: Bronchiolitis is the leading cause of hospitalization in infants. Biomarkers of disease severity might help in clinical management. OBJECTIVE: To determine the clinical predictiveness of NW-LDH, NW-caspase 3/7, and NW-LDH/NW-caspase 3/7 ratio in bronchiolitis. METHODS: Previously healthy children less than 24 months of age with bronchiolitis were recruited from the Texas Children's emergency room and intensive care unit from October 2010 to April 2011. Demographic, clinical information, and NW samples were obtained at enrollment. NW samples were analyzed for respiratory viruses, caspase 3/7, and LDH. RESULTS: A viral pathogen was detected in 91·6% of 131 children, with the most common being respiratory syncytial virus and human rhinovirus. A single infection was found in 61·8% of subjects and co-infection in 29·8%. Children admitted to ICU had significantly higher NW-LDH than children sent home from the ER or admitted to the general floor (P = 0·02). Children infected with RSV had the highest NW-LDH concentration (P = 0·03) compared with other viral infections. NW-LDH and NW-caspase were significantly correlated (r = 0·77, P < 0·0001). The univariate models showed NW-LDH and NW-LDH/NW- caspase 3/7 ratio were directly associated with hospitalization. Mutivariate regression analyses suggested a complex interaction between the biomarkers, demographics, and disposition. CONCLUSIONS: NW-LDH, NW-caspase 3/7 and NW-LDH/NW-caspase 3/7 ratio and their interactions with demographic factors are predictive of bronchiolitis severity and can help distinguish children requiring ICU-level care from those admitted to the general floor, or discharged home from the emergency center.

Combined NIR/MIR analysis: a novel method for the classification of complex substances such as Illicium verum Hook. F. and its adulterants.

A novel combined near- and mid-infrared (NIR and MIR) spectroscopic method has been researched and developed for the analysis of complex substances such as the Traditional Chinese Medicine (TCM), Illicium verum Hook. F. (IVHF), and its noxious adulterant, Iuicium lanceolatum A.C. Smith (ILACS). Three types of spectral matrix were submitted for classification with the use of the linear discriminant analysis (LDA) method. The data were pretreated with either the successive projections algorithm (SPA) or the discrete wavelet transform (DWT) method. The SPA method performed somewhat better, principally because it required less spectral features for its pretreatment model. Thus, NIR or MIR matrix as well as the combined NIR/MIR one, were pretreated by the SPA method, and then analysed by LDA. This approach enabled the prediction and classification of the IVHF, ILACS and mixed samples. The MIR spectral data produced somewhat better classification rates than the NIR data. However, the best results were obtained from the combined NIR/MIR data matrix with 95-100% correct classifications for calibration, validation and prediction. Principal component analysis (PCA) of the three types of spectral data supported the results obtained with the LDA classification method.

The incidence and prevalence of inflammatory bowel disease among U.S. veterans: a national cohort study.

BACKGROUND: Temporal trends in incidence and prevalence of Crohn's disease (CD) and ulcerative colitis (UC) in the United States have been reported only in regional populations. The Veterans Affairs (VA) health care system encompasses a national network of clinical care facilities. The aim of this study was to identify temporal trends in the incidence and prevalence of CD and UC among VA users using national VA data sets. METHODS: Veterans with CD and UC were identified during fiscal years 1998 to 2009 in the national VA outpatient and inpatient files. Incident and prevalent cases were identified by diagnosis code, and age-standardized and gender-standardized annual prevalence and incidence rates were estimated using the VA 1998 population as the standard population. RESULTS: The total of unique incident cases were 16,842 and 26,272 for CD and UC, respectively; 94% were men. The average annual age-standardized and gender-standardized incidence rate of CD was 33 per 100,000 VA users (range, 27-40), whereas the average for UC was 50 per 100,000 VA users (range, 36-65). In 2009, the age-standardized and gender-standardized point prevalence rate of CD was 287 per 100,000 VA users, whereas the point prevalence of UC was 413 per 100,000 VA users. CONCLUSIONS: Prevalence of CD and UC increased 2-fold to 3-fold among VA users between 1998 and 2009. The incidence of UC decreased among VA users from 1998 to 2004 but has remained stable from 2005 to 2009. The incidence of CD has remained stable during the observed time period.

Risk of colorectal cancer among Caucasian and African American veterans with ulcerative colitis.

BACKGROUND: African Americans are at an increased risk of developing sporadic colorectal cancer (CRC) compared to Caucasians. Ulcerative colitis (UC) is a risk factor for developing CRC; however, risk differences for CRC between African Americans and Caucasians with UC are unknown. METHODS: We performed a cohort study of patients with a diagnosis of UC during fiscal years 1998 to 2009 using the national Veterans Affairs administrative datasets. Cumulative CRC incidence rates and incidence rate ratios were calculated and Cox proportional hazards models were used to examine the association between race and the CRC risk. RESULTS: The cohort comprised of 20,949 patients with UC. A total of 168 incident cases of CRC were identified during 112,243 patient-years (PY) of follow-up; overall CRC incidence rate was 163/100,000 PY (95% confidence interval [CI] 139-187/100,000 PY). The CRC incidence rates were 158/100,000 PY (95% CI 134-181/100,000 PY) and 180/100,000 PY (95% CI 155-205/100,000 PY) in Caucasians and African Americans, respectively, with an incidence rate ratio of 1.17 (95% CI 0.69-1.97). The 3, 5, and 10-year cumulative incidence rates for CRC were 0.36%, 0.76%, 1.79% for African Americans and 0.41%, 0.76%, 1.43% for Caucasians. African Americans were not at an increased risk for CRC (adjusted hazard ratio: 1.10, 95% CI 0.65-1.87) compared to Caucasians. CONCLUSIONS: In a national cohort of UC patients the risk of developing CRC in African Americans was no higher than in Caucasians. The reasons for lack of racial differences compared to sporadic CRC are not clear; access to care, genetic factors, and molecular pathways require further study.

The Safety Attitudes Questionnaire as a tool for benchmarking safety culture in the NICU.

BACKGROUND: Neonatal intensive care unit (NICU) safety culture, as measured by the Safety Attitudes Questionnaire (SAQ), varies widely. Associations with clinical outcomes in the adult intensive care unit setting make the SAQ an attractive tool for comparing clinical performance between hospitals. Little information is available on the use of the SAQ for this purpose in the NICU setting. OBJECTIVES: To determine whether the dimensions of safety culture measured by the SAQ give consistent results when used as a NICU performance measure. METHODS: Cross-sectional survey of caregivers in 12 NICUs, using the six scales of the SAQ: teamwork climate, safety climate, job satisfaction, stress recognition, perceptions of management and working conditions. NICUs were ranked by quantifying their contribution to overall risk-adjusted variation across the scales. Spearman rank correlation coefficients were used to test for consistency in scale performance. The authors then examined whether performance in the top four NICUs in one scale predicted top four performance in others. RESULTS: There were 547 respondents in 12 NICUs. Of 15 NICU-level correlations in performance ranking, two were >0.7, seven were between 0.4 and 0.69, and the six remaining were <0.4. The authors found a trend towards significance in comparing the distribution of performance in the top four NICUs across domains with a binomial distribution p=0.051, indicating generally consistent performance across dimensions of safety culture. CONCLUSION: A culture of safety permeates many aspects of patient care and organisational functioning. The SAQ may be a useful tool for comparative performance assessments among NICUs.

Patient resources available to bladder cancer patients: a pilot study of healthcare providers.

OBJECTIVE: To survey thought leaders attending an annual bladder cancer conference about resources available to survivors at, primarily, large academic centers treating a high volume of patients. Bladder cancer is a disease with high treatment burden. Support groups and survivorship programs are effective at managing physical and psychosocial impairments experienced by patients. The Institute of Medicine recommends increased resources for cancer survivorship, but no description of current resources exists for bladder cancer patients. METHODS: Preceding the 4th annual Bladder Cancer Think Tank meeting in August 2009, we carried out an Internet-based survey of registrants that queried respondents about institutional resources and support systems devoted to bladder cancer survivors. Data were collected using SurveyMonkey.com, and descriptive statistics were computed. RESULTS: A total of 43 eligible respondents included urologists (77%), medical oncologists (16%), and other physicians or health professionals (7%). Physician respondents represented 22 academic centers and 2 private groups. Although 63% of respondent institutions had a National Cancer Institute designation, only 33% had an active bladder cancer support group. Survivorship clinics were available in 29% of institutions, and peer support networks, community resources for education, and patient navigation were available in 58%, 13%, and 25% of respondent institutions, respectively. CONCLUSIONS: Resources for bladder cancer survivors vary widely and are lacking at several academic centers with high-volume bladder cancer populations. Bladder cancer providers are often unaware of available institutional resources for patients. Urologists need to advocate for additional survivor resources and partner with other disciplines to provide appropriate care.

Neonatal intensive care unit safety culture varies widely.

BACKGROUND: Variation in healthcare delivery and outcomes in neonatal intensive care units (NICUs) may be partly explained by differences in safety culture. OBJECTIVE: To describe NICU care giver assessments of safety culture, explore variability within and between NICUs on safety culture domains, and test for association with care giver characteristics. METHODS: NICU care givers in 12 hospitals were surveyed using the Safety Attitudes Questionnaire (SAQ), which has six scales: teamwork climate, safety climate, job satisfaction, stress recognition, perception of management and working conditions. Scale means, SDs and percent positives (percent agreement) were calculated for each NICU. RESULTS: There was substantial variation in safety culture domains among NICUs. Composite mean score across the six domains ranged from 56.3 to 77.8 on a 100-point scale and NICUs in the top four NICUs were significantly different from the bottom four (p<0.001). Across the six domains, respondent assessments varied widely, but were least positive on perceptions of management (3%-80% positive; mean 33.3%) and stress recognition (18%-61% positive; mean 41.3%). Comparisons of SAQ scale scores between NICUs and a previously published adult ICU cohort generally revealed higher scores for NICUs. Composite scores for physicians were 8.2 (p=0.04) and 9.5 (p=0.02) points higher than for nurses and ancillary personnel. CONCLUSION: There is significant variation and scope for improvement in safety culture among these NICUs. The NICU variation was similar to variation in adult ICUs, but NICU scores were generally higher. Future studies should validate whether safety culture measured with the SAQ correlates with clinical and operational outcomes in NICUs.

One- and two-dimensional gas chromatography-mass spectrometry and high performance liquid chromatography-diode-array detector fingerprints of complex substances: a comparison of classification performance of similar, complex Rhizoma Curcumae samples with the aid of chemometrics.

Many complex natural or synthetic products are analysed either by the GC-MS (gas chromatography-mass spectrometry) or HPLC-DAD (high performance liquid chromatography-diode-array detector) technique, each of which produces a one-dimensional fingerprint for a given sample. This may be used for classification of different batches of a product. GC-MS and HPLC-DAD analyses of complex, similar substances represented by the three common types of the TCM (traditional Chinese medicine), Rhizoma Curcumae were analysed in the form of one- and two-dimensional matrices firstly with the use of PCA (Principal component analysis), which showed a reasonable separation of the samples for each technique. However, the separation patterns were rather different for each analytical method, and PCA of the combined data matrix showed improved discrimination of the three types of object; close associations between the GC-MS and HPLC-DAD variables were observed. LDA (linear discriminant analysis), BP-ANN (back propagation-artificial neural networks) and LS-SVM (least squares-support vector machine) chemometrics methods were then applied to classify the training and prediction sets. For one-dimensional matrices, all training models indicated that several samples would be misclassified; the same was observed for each prediction set. However, by comparison, in the analysis of the combined matrix, all models gave 100% classification with the training set, and the LS-SVM calibration also produced a 100% result for prediction, with the BP-ANN calibration closely behind. This has important implications for comparing complex substances such as the TCMs because clearly the one-dimensional data matrices alone produce inferior results for training and prediction as compared to the combined data matrix models. Thus, product samples may be misclassified with the use of the one-dimensional data because of insufficient information.

Gaps in the achievement of effectiveness of HCV treatment in national VA practice.

BACKGROUND & AIMS: Antiviral treatment for hepatitis C virus (HCV) has high efficacy rates for achieving sustained viral response (SVR) in randomized controlled trials (RCTs) (40-80%); however, it can be lower in community-based practice settings. We wanted to determine the effectiveness of HCV treatment in Veterans Administration (VA) hospitals nationwide. METHODS: Using the nationwide VA HCV Clinical Case Registry (CCR), we examined a cohort of veterans who had HCV viremia between 2000 and 2005 and identified patients who received pegylated-interferon (PEG-INF) and ribavirin. The duration of treatment and proportion of patients completing treatment was calculated. The effectiveness of treatment was measured as the proportion of patients who achieved SVR (negative viremia at least 12 weeks after the end of treatment) in the entire cohort, and among patients who initiated and completed treatment. RESULTS: We identified 99,166 patients with HCV viremia. Of those, 11.6% received PEG-INF with ribavirin and 6.4% completed treatment. Contraindications were present in 57.2% of the patients that did not receive treatment. SVR was documented in 39.9% and 58.3% of patients who completed treatment; 23.6% and 50.6% of patients who initiated treatment; and 3.9% and 11.2% of the entire HCV cohort for genotype 1 or 4 and 2 or 3, respectively. Overall, only 3.5% of the entire HCV viremic cohort had a documented SVR. CONCLUSIONS: Treatment effectiveness for HCV is low. In addition to fixed factors, such as race and virus genotype, the drop in effectiveness is due to low rates of antiviral treatment initiation and treatment completion.

High resource hospitalizations among children with vaso-occlusive crises in sickle cell disease.

BACKGROUND: Vaso-occlusive crises (VOCs) contribute to frequent hospitalizations among children with sickle cell disease (SCD). The objective of this study was to identify factors associated with high resource utilization during hospitalizations for VOC. PROCEDURE: We analyzed pediatric discharges 0-18 years of age with a primary diagnosis of SCD with crisis from the 2006 Kids' Inpatient Database, a nationally representative sample of pediatric hospital discharges. High resource hospitalizations were defined as those in the highest decile for total charges. We conducted sample-weighted regression analyses to determine associations between independent variables (patient demographics, hospital characteristics, illness severity) and high resource use. RESULTS: There were 9,893 (0.371%) discharges for children with VOCs. Median total hospitalization charges were $10,691. In multivariate analysis, children 15-18 years of age (odds ratio [OR] 3.39, 95% confidence interval [CI] 2.54-4.53), 10-14 years of age (OR 2.72, 95% CI 2.07-3.59), and 5-9 years of age (OR 1.74, 95% CI 1.30-2.34) had higher odds of high resource hospitalizations compared to children 0-4 years of age. Care in a children's hospital had three times the odds of high resource use compared to care in a general hospital. Discharges with secondary diagnoses including pneumonia (OR 2.46, 95% CI 1.96-3.09) and constipation (OR 1.78, 95% CI 1.31-2.40) were also associated with high resource use. CONCLUSIONS: Older age and secondary diagnoses were associated with high resource use during VOC hospitalizations. These findings suggest the need to improve adherence to comprehensive care among older children to prevent VOCs and standardize protocols to manage VOC complications.

Associations between quality of primary care and health care use among children with special health care needs.

OBJECTIVE: To determine whether parent-reported quality of primary care was associated with subsequent health care use for children with special health care needs. DESIGN: Secondary analysis of prospectively collected data. SETTING: The 2004-2005 and 2005-2006 Medical Expenditure Panel Survey panels. PARTICIPANTS: A total of 1591 children with special health care needs. MAIN EXPOSURES: Composite measures for family centeredness of care, timeliness of care, and realized access derived from the Consumer Assessment of Healthcare Providers and Systems survey. MAIN OUTCOME MEASURES: Rates of parent-reported emergency department visits (nonurgent and urgent) and hospitalizations. Only encounters occurring after completion of the Consumer Assessment of Healthcare Providers and Systems survey were assessed. Weighted multivariate Poisson regression analyses, yielding incident rate ratios, were used for analysis. RESULTS: Of the parents of the 1591 children included, 68.3% rated family centeredness, 51.5% rated timeliness, and 80.4% rated realized access as high quality. Low-quality family centeredness was associated with higher rates (incident rate ratio, 2.24; 95% confidence interval, 1.32-3.80) of nonurgent emergency department visits compared with corresponding rates associated with high-quality family centeredness. There were no associations between quality-of-care domains and rates of urgent emergency department visits. For privately insured children, low-quality family centeredness was associated with higher rates (incident rate ratio, 3.87; 95% confidence interval, 1.23-12.13) of hospitalizations compared with corresponding rates associated with high-quality family-centered care. For publicly insured children, no significant associations were found. CONCLUSIONS: Parent-reported, low-quality family centeredness was associated with higher rates of subsequent nonurgent emergency department visits and hospitalizations among children with special health care needs. These findings highlight family-centered care as a critical area for primary care intervention to reduce potentially preventable health care use.

Meeting vaccination quality measures for hepatitis A and B virus in patients with chronic hepatitis C infection.

UNLABELLED: Coinfection with hepatitis A virus (HAV) or hepatitis B virus (HBV) in patients with chronic hepatitis C virus (HCV) is associated with increased morbidity and mortality. The Center for Medicare and Medicaid Services has identified HAV and HBV vaccination as a priority area for quality measurement in HCV. It is unclear to what extent patients with HCV meet these recommendations. We used national data from the Department of Veterans Affairs HCV Clinical Case Registry to evaluate the prevalence and predictors of meeting the quality measure (QM) of receiving vaccination or documented immunity to HAV and HBV in patients with chronic HCV. We identified 88,456 patients who had overall vaccination rates of 21.9% and 20.7% for HBV and HAV, respectively. The QM rates were 57.0% and 45.5% for HBV and HAV, respectively. Patients who were nonwhite or who had elevated alanine aminotransferase levels, cirrhosis, or human immunodeficiency virus were more likely to meet the HBV QM. Factors related to HCV care were also determinants of meeting the HBV QM. These factors included receiving a specialist consult, genotype testing, or HCV treatment. Patients who were older, had psychosis, and had a higher comorbidity score were less likely to meet the HBV QM. With a few exceptions, similar variables were related to meeting the HAV QM. The incidence of superinfection with acute HBV and HAV was low, but it was significantly lower in patients who received vaccination than in those who did not. CONCLUSION: Quality measure rates for HAV and HBV are suboptimal for patients with chronic HCV. In addition, several patient-related factors and receiving HCV-related care are associated with a higher likelihood of meeting QMs.

Folate and homocysteine phenotypes: Comparative findings using research and clinical laboratory data.

OBJECTIVES: A low folate/high homocysteine phenotype is associated with several pathologies, including spina bifida and cardiovascular disease. Folate and total homocysteine (tHcy) measurements are used clinically to assess risk and the need for folic acid supplementation and in research to investigate the metabolic basis of disease. Red blood cell (RBC) folate, the best indicator of long-term folate status, is usually measured as "total" folate. However, different folate derivatives support distinct biochemical functions, suggesting a need to develop more precise methods. This study was designed to evaluate a method based on stable isotope dilution liquid chromatography-multiple reaction monitoring/mass spectrometry (LC-MRM/MS). DESIGN AND METHODS: We used LC-MRM/MS to quantify the RBC folate derivatives 5-methyltetrahydrofolate (5-CH(3)-THF), tetrahydrofolate (THF), and 5,10-methenyltetrahydrofolate (5,10-methenylTHF) in pre-menopausal women. The concentration of each folate derivative was assessed for utility in predicting tHcy levels, and compared to folate and tHcy measurements derived by routine clinical laboratory methods. RESULTS: LC-MRM/MS was qualitatively and quantitatively superior to routine clinical laboratory methods for determining folate and tHcy concentrations. RBC 5-CH(3)-THF had a reciprocal relationship with tHcy (p=0.0003), whereas RBC THF and RBC 5,10-methenylTHF had direct relationships (p=0.01, 0.04 respectively). In combination, these three variables accounted for 42% of the variation in tHcy. CONCLUSIONS: Robust methods for measuring RBC 5-CH(3)-THF would improve the utility of folate/homocysteine phenotyping in patient management. The use of LC-MRM/MS would allow studies of hyperhomocysteinemia and diseases associated with a low folate/high homocysteine phenotype to be performed with less measurement error and greater statistical power to generate data with the potential to elucidate the etiologic mechanisms of complex diseases and traits.

Evaluation of potential modifiers of the cardiac phenotype in the 22q11.2 deletion syndrome.

BACKGROUND: The phenotype associated with deletion of the 22q11.2 chromosomal region is highly variable, yet little is known about the source of this variability. Cardiovascular anomalies, including tetralogy of Fallot, truncus arteriosus, interrupted aortic arch type B, perimembranous ventricular septal defects, and aortic arch anomalies, occur in approximately 75% of individuals with a 22q11.2 deletion. METHODS: Data from 343 subjects enrolled in a study of the 22q11.2 deletion syndrome were used to evaluate potential modifiers of the cardiac phenotype in this disorder. Subjects with and without cardiac malformations, and subjects with and without aortic arch anomalies were compared with respect to sex and race. In addition, in the subset of subjects from whom a DNA sample was available, genotypes for variants of four genes that are involved in the folate-homocysteine metabolic pathway and that have been implicated as risk factors for other birth defects were compared. Five variants in four genes were genotyped by heteroduplex or restriction digest assays. The chi-square or Fisher's exact test was used to evaluate the association between the cardiac phenotype and each potential modifier. RESULTS: The cardiac phenotype observed in individuals with a 22q11.2 deletion was not significantly associated with either sex or race. The genetic variants that were evaluated also did not appear to be associated with the cardiovascular phenotype. CONCLUSIONS: Variation in the cardiac phenotype observed between individuals with a 22q11.2 deletion does not appear to be related to sex, race, or five sequence variants in four folate-related genes that are located outside of the 22q11.2 region.

Genetic and biochemical determinants of serum concentrations of monocyte chemoattractant protein-1, a potential neural tube defect risk factor.

BACKGROUND: Women with the AA genotype at the (-2518)A>G promoter polymorphism of CCL-2, which encodes the potent pro-inflammatory chemokine monocyte chemoattractant protein 1 (MCP-1), may be at increased risk for having offspring affected by spina bifida. As the A allele at this locus has been associated with decreased transcription of MCP-1 mRNA relative to the G allele, the observed genetic association suggests that the risk of spina bifida may be increased in the offspring of women with low MCP-1 levels. The present study was undertaken to identify potential determinants of MCP-1 levels in women of reproductive age. METHODS: A small cohort of Caucasian and African-American women of reproductive age was recruited to participate in an exploratory investigation of the determinants of several disease-related, biochemical phenotypes, including MCP-1. Subjects completed a brief questionnaire and provided a fasting blood sample for biochemical and genetic studies. Potential biochemical, genetic, and lifestyle factors were assessed for their association with MCP-1 levels using linear regression analyses. RESULTS: In this cohort, MCP-1 levels were significantly higher in Caucasians as compared to African-Americans. Further, among women of both races, there was evidence that MCP-1 levels were associated with smoking status, MTHFR 677C>T genotype, and red blood cell tetrahydrofolate levels. CONCLUSIONS: The results of these analyses indicate that, if maternal CCL-2 genotype is related to the risk of spina bifida, this relationship is likely to be more complex than initially hypothesized, perhaps depending upon folate intake, MTHFR 677C>T genotype, the distribution of folate derivatives, and immune/inflammatory activity.