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Folic acid supplements can protect against neural tube defects (NTDs). Low folate and low vitamin B12 status may be maternal risk factors for having an NTD affected pregnancy. However, not all NTDs are preventable by having an adequate folate/ B12 status and other potentially modifiable factors may be involved. Folate and vitamin B12 status have important links to iron metabolism. Animal studies support an association between poor iron status and NTDs but human data are scarce. We examined the relevance of low iron status in a nested NTD case-control study of women within a pregnant population-based cohort.
Pregnant women were recruited between 1986 and 1990, when vitamin or iron supplementation in early pregnancy was rare. Blood samples, taken at an average of 14 weeks gestation, were used to measure ferritin and hemoglobin in 64 women during an NTD affected pregnancy and 207 women with unaffected pregnancies.
No significant differences in maternal ferritin or hemoglobin concentrations were observed between NTD affected and non-affected pregnancies (case median ferritin 16.8μg/L and hemoglobin 12.4g/dL versus 15.4μg/L and 12.3g/dL in controls). As reported previously, red cell folate and vitamin B12 concentrations were significantly lower in cases. Furthermore, there was no significant association of iron status with type of NTD lesion (anencephaly or spina bifida)
We conclude that low maternal iron status during early pregnancy is not an independent risk factor for NTDs. Adding iron to folic acid for periconceptional use may improve iron status but is not likely to prevent NTDs.
PMCID: PMC4018583  PMID: 24535840
ferritin; iron; hemoglobin; neural tube defects
2.  High expression of long intervening non-coding RNA OLMALINC in the human cortical white matter is associated with regulation of oligodendrocyte maturation 
Molecular Brain  2015;8:2.
Long intervening non-coding RNAs (lincRNAs) are a recently discovered subclass of non-coding RNAs. LincRNAs are expressed across the mammalian genome and contribute to the pervasive transcription phenomenon. They display a tissue-specific and species-specific mode of expression and are present abundantly in the brain.
Here, we report the expression patterns of oligodendrocyte maturation-associated long intervening non-coding RNA (OLMALINC), which is highly expressed in the white matter (WM) of the human frontal cortex compared to the grey matter (GM) and peripheral tissues. Moreover, we identified a novel isoform of OLMALINC that was also up-regulated in the WM. RNA-interference (RNAi) knockdown of OLMALINC in oligodendrocytes, which are the major cell type in the WM, caused significant changes in the expression of genes regulating cytostructure, cell activation and membrane signaling. Gene ontology enrichment analysis revealed that over 10% of the top 25 up- and down-regulated genes were involved in oligodendrocyte maturation. RNAi experiments in neuronal cells resulted in the perturbation of genes controlling cell proliferation. Furthermore, we identified a novel cis-natural antisense non-coding RNA, which we named OLMALINC-AS, which maps to the first exon of the dominant isoform of OLMALINC.
Our study has demonstrated for the first time that a primate-specific lincRNA regulates the expression of genes critical to human oligodendrocyte maturation, which in turn might be regulated by an antisense counterpart.
Electronic supplementary material
The online version of this article (doi:10.1186/s13041-014-0091-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4302521  PMID: 25575711
Long intervening non-coding RNA; OLMALINC; Human brain; Frontal cortex; White and grey matter; Antisense RNA
3.  Association Between Stool Enteropathogen Quantity and Disease in Tanzanian Children Using TaqMan Array Cards: A Nested Case-Control Study 
Etiologic studies of diarrhea are limited by uneven diagnostic methods and frequent asymptomatic detection of enteropathogens. Polymerase chain reaction-based stool pathogen quantification may help distinguish clinically significant infections. We performed a nested case-control study of diarrhea in infants from a community-based birth cohort in Tanzania. We tested 71 diarrheal samples and pre-diarrheal matched controls with a laboratory-developed TaqMan Array Card for 19 enteropathogens. With qualitative detection, no pathogens were significantly associated with diarrhea. When pathogen quantity was considered, rotavirus (odds ratio [OR] = 2.70 per log10 increase, P < 0.001), astrovirus (OR = 1.49, P = 0.01), and Shigella/enteroinvasive Escherichia coli (OR = 1.47, P = 0.04) were associated with diarrhea. Enterotoxigenic E. coli (0.15 SD decline in length-for-age z score after 3 months per log10 increase, P < 0.001) and Campylobacter jejuni/C. coli (0.11 SD decline, P = 0.003) in pre-diarrheal stools were associated with poor linear growth. Quantitative analysis can help refine the association between enteropathogens and disease in endemic settings.
PMCID: PMC3886409  PMID: 24189366
4.  Etiology of Diarrhea in Bangladeshi Infants in the First Year of Life Analyzed Using Molecular Methods 
The Journal of Infectious Diseases  2013;208(11):1794-1802.
Background. Diarrhea causes enormous morbidity and mortality in developing countries, yet the relative importance of multiple potential enteropathogens has been difficult to ascertain.
Methods. We performed a longitudinal cohort study from birth to 1 year of age in 147 infants in Dhaka, Bangladesh. Using multiplex polymerase chain reaction, we analyzed 420 episodes of diarrhea and 1385 monthly surveillance stool specimens for 32 enteropathogen gene targets. For each infant we examined enteropathogen quantities over time to ascribe each positive target as a probable or less-likely contributor to diarrhea.
Results. Multiple enteropathogens were detected by the first month of life. Diarrhea was associated with a state of overall pathogen excess (mean number of enteropathogen gene targets (±SE), 5.6 ± 0.1 vs 4.3 ± 0.1 in surveillance stool specimens; P < .05). After a longitudinal, quantitative approach was applied to filter out less-likely contributors, each diarrheal episode still had an average of 3.3 probable or dominant targets. Enteroaggregative Escherichia coli, Campylobacter, enteropathogenic E. coli, rotavirus, and Entamoeba histolytica were the most frequent probable contributors to diarrhea. Rotavirus was enriched in moderate to severe diarrheal episodes.
Conclusions. In this community-based study diarrhea seemed to be a multipathogen event and a state of enteropathogen excess above a high carriage baseline.
PMCID: PMC3814844  PMID: 24041797
Diarrhea; PCR; rotavirus; enteroaggregative e.coli; Campylobacter
5.  Maternal overweight and obesity and risk of congenital heart defects in offspring 
Obesity is a risk factor for congenital heart defects (CHD), but whether risk is independent of abnormal glucose metabolism is unknown. Data on whether overweight status increases risk is also conflicting.
Research Design and Methods
We included 121815 deliveries from a cohort study, the Consortium on Safe Labor, after excluding women with pregestational diabetes as recorded in the electronic medical record. CHD were identified via medical record discharge summaries. Adjusted odds ratios (OR) for any CHD were calculated for prepregnancy body mass index (BMI) categories of overweight (25 to <30 kg/m2), obese (30 to <40 kg/m2), and morbidly obese (≥40 kg/m2) compared to normal weight (18.5 to <25 kg/m2) women, and for specific CHD with obese groups combined (≥30 kg/m2). A sub-analysis adjusting for oral glucose tolerance test (OGTT) results where available was performed as a proxy for potential abnormal glucose metabolism present at the time of organogenesis.
There were 1388 (1%) infants with CHD. Overweight (OR=1.15 95% CI: 1.01–1.32), obese (OR=1.26 95% CI: 1.09, 1.44), and morbidly obese (OR=1.34 95% CI: 1.02–1.76) women had greater odds of having a neonate with CHD than normal weight women (P< 0.001 for trend). Obese women (BMI ≥30 kg/m2) had higher odds of having an infant with conotruncal defects (OR=1.34 95%CI: 1.04–1.72), atrial septal defects (OR =1.22 95% CI: 1.04–1.43), and ventricular septal defects (OR=1.38 95% CI: 1.06–1.79). Being obese remained a significant predictor of CHD risk after adjusting for OGTT.
Increasing maternal weight class was associated with increased risk for CHD. In obese women, abnormal glucose metabolism did not completely explain the increased risk for CHD; the possibility that other obesity-related factors are teratogenic requires further investigation.
PMCID: PMC4053485  PMID: 24362506
Prepregnancy BMI; Obesity; Congenital Heart Defects
6.  Physical Activity and Sedentary Behaviors Associated With Risk of Progression From Gestational Diabetes Mellitus to Type 2 Diabetes Mellitus 
JAMA internal medicine  2014;174(7):1047-1055.
Women with a history of gestational diabetes mellitus (GDM) are at substantially increased risk of type 2 diabetes mellitus (T2DM). The identification of important modifiable factors could help prevent T2DM in this high-risk population.
To examine the role of physical activity and television watching and other sedentary behaviors, and changes in these behaviors in the progression from GDM to T2DM.
Prospective cohort study of 4554 women from the Nurses’ Health Study II who had a history of GDM, as part of the ongoing Diabetes & Women’s Health Study. These women were followed up from 1991 to 2007.
Physical activity and television watching and other sedentary behaviors were assessed in 1991, 1997, 2001, and 2005.
Incident T2DM identified through self-report and confirmed by supplemental questionnaires.
We documented 635 incident T2DM cases during 59287 person-years of follow-up. Each 5–metabolic equivalent hours per week (MET-h/wk) increment of total physical activity, which is equivalent to 100 minutes per week of moderate-intensity physical activity, was related to a 9% lower risk of T2DM (adjusted relative risk [RR], 0.91; 95% CI, 0.88–0.94); this inverse association remained significant after additional adjustment for body mass index (BMI). Moreover, an increase in physical activity was associated with a lower risk of developing T2DM. Compared with women who maintained their total physical activity levels, women who increased their total physical activity levels by 7.5 MET-h/wk or more (equivalent to 150 minutes per week of moderate-intensity physical activity) had a 47% lower risk of T2DM (RR, 0.53; 95% CI, 0.38–0.75); the association remained significant after additional adjustment for BMI. The multivariable adjusted RRs (95% CIs) for T2DM associated with television watching of 0 to 5, 6 to 10, 11 to 20, and 20 or more hours per week were 1 (reference), 1.28 (1.04–1.59), 1.41 (1.11–1.79), and 1.77 (1.28–2.45), respectively (P value for trend <.001); additional adjustment for BMI attenuated the association.
Increasing physical activity may lower the risk of progression from GDM to T2DM. These findings suggest a hopeful message to women with a history of GDM, although they are at exceptionally high risk for T2DM, promoting an active lifestyle may lower the risk.
PMCID: PMC4209161  PMID: 24841449
7.  Detection of Campylobacter in Stool and Determination of Significance by Culture, Enzyme Immunoassay, and PCR in Developing Countries 
Journal of Clinical Microbiology  2014;52(4):1074-1080.
Campylobacter is a common bacterial enteropathogen that can be detected in stool by culture, enzyme immunoassay (EIA), or PCR. We compared culture for C. jejuni/C. coli, EIA (ProSpecT), and duplex PCR to distinguish Campylobacter jejuni/C. coli and non-jejuni/coli Campylobacter on 432 diarrheal and matched control stool samples from infants in a multisite longitudinal study of enteric infections in Tanzania, Bangladesh, and Peru. The sensitivity and specificity of culture were 8.5% and 97.6%, respectively, compared with the results of EIA and 8.7% and 98.0%, respectively, compared with the results of PCR for C. jejuni/C. coli. Most (71.6%) EIA-positive samples were positive by PCR for C. jejuni/C. coli, but 27.6% were positive for non-jejuni/coli Campylobacter species. Sequencing of 16S rRNA from 53 of these non-jejuni/coli Campylobacter samples showed that it most closely matched the 16S rRNA of C. hyointestinalis subsp. lawsonii (56%), C. troglodytis (33%), C. upsaliensis (7.7%), and C. jejuni/C. coli (2.6%). Campylobacter-negative stool spiked with each of the above-mentioned Campylobacter species revealed reactivity with EIA. PCR detection of Campylobacter species was strongly associated with diarrhea in Peru (odds ratio [OR] = 3.66, P < 0.001) but not in Tanzania (OR = 1.56, P = 0.24) or Bangladesh (OR = 1.13, P = 0.75). According to PCR, Campylobacter jejuni/C. coli infections represented less than half of all infections with Campylobacter species. In sum, in infants in developing country settings, the ProSpecT EIA and PCR for Campylobacter reveal extremely high rates of positivity. We propose the use of PCR because it retains high sensitivity, can ascertain burden, and can distinguish between Campylobacter infections at the species level.
PMCID: PMC3993515  PMID: 24452175
8.  Characterization of Depression in Prodromal Huntington Disease in the Neurobiological Predictors of HD (PREDICT-HD) Study 
Journal of psychiatric research  2013;47(10):10.1016/j.jpsychires.2013.05.026.
Depression causes significant morbidity and mortality, and this also occurs in Huntington Disease (HD), an inherited neurodegenerative illness with motor, cognitive, and psychiatric symptoms. The presentation of depression in this population remains poorly understood, particularly in the prodromal period before development of significant motor symptoms. In this study, we assessed depressive symptoms in a sample of 803 individuals with the HD mutation in the prodromal stage and 223 mutation-negative participants at the time of entry in the Neurobiological Predictors of HD (PREDICT-HD) study. Clinical and biological HD variables potentially related to severity of depression were analyzed. A factor analysis was conducted to characterize the symptom domains of depression in a subset (n=168) with clinically significant depressive symptoms. Depressive symptoms were found to be more prevalent in HD mutation carriers but did not increase with proximity to HD diagnosis and were not associated with length of the HD mutation. Increased depressive symptoms were significantly associated with female gender, self-report of past history of depression, and a slight decrease in functioning, but not with time since genetic testing. The factor analysis identified symptom domains similar to prior studies in other populations. These results show that individuals with the HD mutation are at increased risk to develop depressive symptoms at any time during the HD prodrome. The clinical presentation appears to be similar to other populations. Severity and progression are not related to the HD mutation.
PMCID: PMC3808084  PMID: 23790259
Huntington Disease; Depression; Suicide; Genetic testing
9.  Unawareness of motor phenoconversion in Huntington disease 
Neurology  2013;81(13):1141-1147.
To determine whether Huntington disease (HD) mutation carriers have motor symptoms (complaints) when definite motor onset (motor phenoconversion) is diagnosed and document differences between the groups with and without unawareness of motor signs.
We analyzed data from 550 HD mutation carriers participating in the multicenter PREDICT-HD Study followed through the HD prodrome. Data analysis included demographics, the Unified Huntington’s Disease Rating Scale (UHDRS) and the Participant HD History of symptoms, self-report of progression, and cognitive, behavioral, and imaging measures. Unawareness was identified when no motor symptoms were self-reported but when definite motor HD was diagnosed.
Of 38 (6.91%) with onset of motor HD, almost half (18/38 = 47.36%) had no motor symptoms despite signs of disease on the UHDRS motor rating and consistent with unawareness. A group with motor symptoms and signs was similar on a range of measures to the unaware group. Those with unawareness of HD signs reported less depression. Patients with symptoms had more striatal atrophy on imaging measures.
Only half of the patients with newly diagnosed motor HD had motor symptoms. Unaware patients were less likely to be depressed. Self-report of symptoms may be inaccurate in HD at the earliest stage.
PMCID: PMC3795599  PMID: 23966256
10.  Functional Linear Models for Association Analysis of Quantitative Traits 
Genetic epidemiology  2013;37(7):726-742.
Functional linear models are developed in this paper for testing associations between quantitative traits and genetic variants, which can be rare variants or common variants or the combination of the two. By treating multiple genetic variants of an individual in a human population as a realization of a stochastic process, the genome of an individual in a chromosome region is a continuum of sequence data rather than discrete observations. The genome of an individual is viewed as a stochastic function that contains both linkage and linkage disequilibrium (LD) information of the genetic markers. By using techniques of functional data analysis, both fixed and mixed effect functional linear models are built to test the association between quantitative traits and genetic variants adjusting for covariates. After extensive simulation analysis, it is shown that the F-distributed tests of the proposed fixed effect functional linear models have higher power than that of sequence kernel association test (SKAT) and its optimal unified test (SKAT-O) for three scenarios in most cases: (1) the causal variants are all rare, (2) the causal variants are both rare and common, and (3) the causal variants are common. The superior performance of the fixed effect functional linear models is most likely due to its optimal utilization of both genetic linkage and LD information of multiple genetic variants in a genome and similarity among different individuals, while SKAT and SKAT-O only model the similarities and pairwise LD but do not model linkage and higher order LD information sufficiently. In addition, the proposed fixed effect models generate accurate type I error rates in simulation studies. We also show that the functional kernel score tests of the proposed mixed effect functional linear models are preferable in candidate gene analysis and small sample problems. The methods are applied to analyze three biochemical traits in data from the Trinity Students Study.
PMCID: PMC4163942  PMID: 24130119
rare variants; common variants; association mapping; quantitative trait loci; complex traits; functional data analysis
11.  Maternal Vitamin B12 Status and Risk of Neural Tube Defects in a Population With High Neural Tube Defect Prevalence and No Folic Acid Fortification 
Pediatrics  2009;123(3):917-923.
Folic acid fortification has reduced neural tube defect prevalence by 50% to 70%. It is unlikely that fortification levels will be increased to reduce neural tube defect prevalence further. Therefore, it is important to identify other modifiable risk factors. Vitamin B12 is metabolically related to folate; moreover, previous studies have found low B12 status in mothers of children affected by neural tube defect. Our objective was to quantify the effect of low B12 status on neural tube defect risk in a high-prevalence, unfortified population.
We assessed pregnancy vitamin B12 status concentrations in blood samples taken at an average of 15 weeks’ gestation from 3 independent nested case-control groups of Irish women within population-based cohorts, at a time when vitamin supplementation or food fortification was rare. Group 1 blood samples were from 95 women during a neural tube defect–affected pregnancy and 265 control subjects. Group 2 included blood samples from 107 women who had a previous neural tube defect birth but whose current pregnancy was not affected and 414 control subjects. Group 3 samples were from 76 women during an affected pregnancy and 222 control subjects.
Mothers of children affected by neural tube defect had significantly lower B12 status. In all 3 groups those in the lowest B12 quartiles, compared with the highest, had between two and threefold higher adjusted odds ratios for being the mother of a child affected by neural tube defect. Pregnancy blood B12 concentrations of <250 ng/L were associated with the highest risks.
Deficient or inadequate maternal vitamin B12 status is associated with a significantly increased risk for neural tube defects. We suggest that women have vitamin B12 levels of >300 ng/L (221 pmol/L) before becoming pregnant. Improving B12 status beyond this level may afford a further reduction in risk, but this is uncertain.
PMCID: PMC4161975  PMID: 19255021
vitamin B12; cobalamin; neural tube defects; folic acid fortification; folate
12.  A Prospective Cohort Study of the Prevalence of Growth, Facial, and Central Nervous System Abnormalities in Children with Heavy Prenatal Alcohol Exposure 
Most children who are exposed to large quantities of alcohol in utero do not develop fetal alcohol syndrome (FAS). Population-based prospective data on the risk of developing components of fetal alcohol spectrum disorders (FASD), however, are limited.
This was a prospective cohort study of 9,628 women screened during their first prenatal appointment in Chile, which identified 101 who consumed at least 4 drinks/d (exposed) matched with 101 women with no reported alcohol consumption during pregnancy (unexposed). Detailed alcohol consumption data were collected during the pregnancy. Children were evaluated up to 8.5 years of age by clinicians masked to exposure status.
One or more functional central nervous system abnormalities were present in 44.0% (22/50) of the exposed children compared to 13.6% (6/44) of the unexposed (p = 0.002). Growth restriction was present in 27.2% (25/92) of the exposed and 12.5% (12/96) of the unexposed (p = 0.02). Abnormal facial features were present in 17.3% (14/81) of the exposed children compared to 1.1% (1/89) of the unexposed children (p = 0.0002) by direct examination. Of the 59 exposed children with data available to detect at least 1 abnormality, 12 (20.3%) had no abnormalities. Binge drinking from conception to recognition of pregnancy (OR = 1.48 per day, 95% CI: 1.15 to 1.91, p = 0.002) and after recognition of pregnancy (OR= 1.41 per day, 95% CI: 1.01 to 1.95, p = 0.04) and total number of drinks consumed per week from conception to recognition of pregnancy (OR = 1.02 per drink, 95% CI: 1.01 to 1.04, p = 0.0009) were significantly associated with abnormal child outcome.
After exposure to heavy alcohol consumption during pregnancy, 80% of children had 1 or more abnormalities associated with alcohol exposure. Patterns of alcohol use that posed the greatest risk of adverse outcomes were binge drinking and high total weekly intake. Functional neurologic impairment occurred most frequently and may be the only sign to alert physicians to prenatal alcohol exposure.
PMCID: PMC4162305  PMID: 22823161
Alcohol; Pregnancy; Fetal Alcohol Spectrum Disorders; Growth Restriction; Neurodevelopment
13.  Acyclovir Exposure and Birth Defects 
PMCID: PMC4158607  PMID: 20736478
14.  Malformations in Infants of Diabetic Mothers 
Maternal insulin-dependent diabetes has long been associated with congenital malformations. As other causes of mortality and morbidity have been eliminated or reduced, malformations have become increasingly prominent. Although there is not universal agreement, the great majority of investigators find a two- to threefold increase in malformations in infants of insulin-dependent diabetic mothers. This increase is not seen in infants of gestational diabetics. It probably is not present in women whose diabetes can be controlled by diet or oral hypoglycemic agents. The risk does not appear to be primarily genetic since diabetic fathers do not have an increased number of malformed offspring. Most studies show a generalized increase in malformations involving multiple organ systems. Multiple malformations seem to be more common in diabetic than non-diabetic infants. Caudal regression has the strongest association with diabetes, occurring roughly 200 times more frequently in infants of diabetic mothers than in other infants. The teratogenic mechanism in diabetes is not known. Hyperglycemia may be important but human studies focusing on the period of organogenesis are lacking. Hypoglycemia has also been suggested based mainly on animal experiments. Insulin appears unlikely. Numerous other factors including vascular disease, hypoxia, ketone and amino acid abnormalities, glycosylation of proteins, or hormone imbalances could be teratogenic. None has been studied in sufficient detail to make a judgment. A large-scale prospective study is required to determine early fetal loss rates, correlate metabolic status during organogenesis with outcome, and assess the effect of diabetic control on malformation rates.
PMCID: PMC4158942  PMID: 20973049
15.  Lack of Association between Folate-Receptor Autoantibodies and Neural-Tube Defects 
The New England journal of medicine  2009;361(2):152-160.
A previous report described the presence of autoantibodies against folate receptors in 75% of serum samples from women with a history of pregnancy complicated by a neural-tube defect, as compared with 10% of controls. We sought to confirm this finding in an Irish population, which traditionally has had a high prevalence of neuraltube defects.
We performed two studies. Study 1 consisted of analysis of stored frozen blood samples collected from 1993 through 1994 from 103 mothers with a history of pregnancy complicated by a neural-tube defect (case mothers), 103 mothers with a history of pregnancy but no complication by a neural-tube defect (matched with regard to number of pregnancies and sampling dates), 58 women who had never been pregnant, and 36 men. Study 2, conducted to confirm that the storage of samples did not influence the folate-receptor autoantibodies, included fresh samples from 37 case mothers, 22 control mothers, 10 women who had never been pregnant, and 9 men. All samples were assayed for blocking and binding autoantibodies against folate receptors.
In Study 1, blocking autoantibodies were found in 17% of case mothers, as compared with 13% of control mothers (odds ratio, 1.54; 95% confidence interval [CI], 0.70 to 3.39), and binding autoantibodies in 29%, as compared with 32%, respectively (odds ratio, 0.82; 95% CI, 0.44 to 1.50). Study 2 showed similar results, indicating that sample degradation was unlikely.
The presence and titer of maternal folate-receptor autoantibodies were not significantly associated with a neural-tube defect–affected pregnancy in this Irish population.
PMCID: PMC4149290  PMID: 19587340
16.  Heavy prenatal alcohol exposure and risk of stillbirth and preterm delivery 
We prospectively identified 96 women consuming at least 4 drinks/day during pregnancy by screening 9628 pregnant women. In these women with heavy prenatal alcohol use, there were three stillbirths and one preterm delivery; 98 matched nondrinking women had no stillbirths and two preterm births. Preterm rates did not differ significantly. The stillbirth rate was higher in the exposed group (p = 0.06). Additional investigation showed the stillbirth rate in the exposed population (3.1%) was significantly higher (p = 0.019) than the reported Chilean population rate (0.45%). Our data suggest that heavy alcohol consumption may increase the risk for stillbirth but not preterm delivery.
PMCID: PMC4148070  PMID: 21728738
alcohol; pregnancy; stillbirth; preterm delivery; binge drinking
17.  Risk Factors for Delirium in Patients Undergoing Hematopoietic Stem Cell Transplantation 
Delirium is common following hematopoietic stem-cell transplantation (HSCT) and is associated with increased morbidity and mortality. Early recognition and treatment have been shown to improve long term outcomes. We sought to investigate the relationship between potential risk-factors and the development of delirium following HSCT.
Fifty-four inpatients admitted for HSCT were assessed prospectively for delirium every 2-3 days through their inpatient stay using standardized delirium and neuropsychological measures. Patient’s self-reports of medical history, medical records, and neurocognitive and psychiatric assessments were used to identify risk factors. Both pre- and post-HSCT risk factors were examined.
Delirium incidence was 35% and occurred with highest frequency in the 2 weeks following transplant. The only pre-transplantation risk factors was lower oxygen saturation (p=0.003). Post-transplantation risk factors for delirium included higher creatinine (p<0.0001), higher blood urea nitrogen levels (p=0.005), lower creatinine clearance (p=0.0006), lower oxygen saturation (p=0.001), lower hemoglobin (p=0.04) and lower albumin (p=0.03). There was no observed association with level of cognitive performance, transplant type, disease severity, medical co-morbidity index, age or conditioning regimen.
Routine laboratory values can assist in the identification of high risk patients before delirium onset to improve early detection and treatment of delirium following HSCT.
PMCID: PMC4120828  PMID: 22860240
delirium; risk factors; cancer; hematopoietic stem-cell transplantation
18.  Transcobalamin II Receptor Polymorphisms Are Associated with Increased Risk for Neural Tube Defects 
Journal of medical genetics  2010;47(10):677-685.
Women who have low cobalamin (vitamin B12) levels are at increased risk for having children with neural tube defects (NTDs). The transcobalamin II receptor (TCblR) mediates uptake of cobalamin into cells. We evaluated inherited variants in the TCblR gene as NTD risk factors.
Case-control and family-based tests of association were used to screen common variation in TCblR as genetic risk factors for NTDs in a large Irish group. A confirmatory group of NTD triads was used to test positive findings.
We found two tightly linked variants associated with NTDs in a recessive model: TCblR rs2336573 (G220R) (pcorr=0.0080, corrected for multiple hypothesis testing) and TCblR rs9426 (pcorr =0. 0279). These variants were also associated with NTDs in a family-based test prior to multiple test correction (log-linear analysis of a recessive model: rs2336573 (G220R) (RR=6.59, p=0.0037) and rs9426 (RR=6.71, p=0.0035)). We describe a copy number variant (CNV) distal to TCblR and two previously unreported exonic insertion-deletion polymorphisms.
TCblR rs2336573 (G220R) and TCblR rs9426 represent a significant risk factor in NTD cases in the Irish population. The homozygous risk genotype was not detected in nearly one thousand controls, indicating this NTD risk factor may be of low frequency and high penetrance. Nine other variants are in perfect LD with the associated SNPs. Additional work is required to identify the disease-causing variant. Our data suggest that variation in TCblR plays a role in NTD risk and that these variants may modulate cobalamin metabolism.
PMCID: PMC4112773  PMID: 20577008
neural tube defects; spina bifida; transcobalamin II receptor (TCblR); cobalamin; vitamin B12; copy number variant (CNV)
19.  Plasma 24S-hydroxycholesterol correlation with markers of Huntington disease progression 
Neurobiology of disease  2013;55:37-43.
24S-hydroxycholesterol (24OHC) is involved in the conversion of excess cholesterol in the brain, and its level in plasma is related to the number of metabolically active neuronal cells. Previous research suggests that plasma 24OHC is substantially reduced in the presence of neurodegenerative disease. Huntington disease (HD) is an inherited autosomal dominant neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) triplet repeat expansion in the coding region of the huntingtin (HTT) gene. The current study focused on the relative importance of 24OHC as a marker of HD progression. Using mass spectrometry methods, plasma 24OHC levels were examined in three groups of gene-expanded individuals (Low, Medium, High) characterized by their progression at entry into the parent PREDICT-HD study, along with a group of non-gene-expanded controls (total N = 150). In addition, the correlation of 24OHC with a number of motor, cognitive, and imagining markers was examined, and effect sizes for group differences among the markers were computed for comparison with 24OHC. Results show a progression gradient as 24OHC levels decreased as the progression group increased (Low to High). The effect size of group differences for 24OHC was larger than all the other variables, except striatal volume. 24OHC was significantly correlated with many of the other key variables. The results are interpreted in terms of cholesterol synthesis and neuronal degeneration. This study provides evidence that 24OHC is a relatively important marker of HD progression.
PMCID: PMC3671851  PMID: 23557875
20.  Plasma Lipids, Genetic Variants near APOA1, and the Risk of Infantile Hypertrophic Pyloric Stenosis 
Infantile Hypertrophic Pyloric Stenosis (IHPS) is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. IHPS shows strong familial aggregation and heritability, but knowledge about specific genetic risk variants is limited.
To search the genome comprehensively for genetic associations with IHPS and validate findings in three independent sample sets.
Design, Setting, and Participants
In stage 1, we used reference data from the 1000 Genomes Project for imputation into a genome-wide dataset of 1001 Danish surgery-confirmed cases (diagnosed between 1987–2008) and 2371 disease-free controls. In stage 2, the five most significantly associated loci were tested in independent case-control sample sets from Denmark (cases diagnosed between 1983–2010), Sweden (cases diagnosed between 1958–2011), and the United States (cases diagnosed between 1998–2005) with a total of 1663 cases and 2315 controls.
Main Outcome Measure
Presence of Infantile Hypertrophic Pyloric Stenosis
We found a new genomewide significant locus for IHPS at chromosome 11q23.3. The most significant SNP at the locus, rs12721025 (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.38–1.83, P = 1.9×10−10), is located 301 bases downstream of the Apolipoprotein A-I (APOA1) gene and is correlated (r2 between 0.46 and 0.80) with SNPs previously found to be associated with levels of circulating cholesterol. For these SNPs, the cholesterol lowering allele consistently conferred increased risk of IHPS.
Conclusions and Relevance
We have identified a new genomewide significant locus for IHPS. Characteristics of this locus suggest the possibility of an inverse relationship between levels of circulating cholesterol in neonates and IHPS risk which warrants further investigation.
PMCID: PMC4031654  PMID: 23989729
21.  A comparison of bats and rodents as reservoirs of zoonotic viruses: are bats special? 
Bats are the natural reservoirs of a number of high-impact viral zoonoses. We present a quantitative analysis to address the hypothesis that bats are unique in their propensity to host zoonotic viruses based on a comparison with rodents, another important host order. We found that bats indeed host more zoonotic viruses per species than rodents, and we identified life-history and ecological factors that promote zoonotic viral richness. More zoonotic viruses are hosted by species whose distributions overlap with a greater number of other species in the same taxonomic order (sympatry). Specifically in bats, there was evidence for increased zoonotic viral richness in species with smaller litters (one young), greater longevity and more litters per year. Furthermore, our results point to a new hypothesis to explain in part why bats host more zoonotic viruses per species: the stronger effect of sympatry in bats and more viruses shared between bat species suggests that interspecific transmission is more prevalent among bats than among rodents. Although bats host more zoonotic viruses per species, the total number of zoonotic viruses identified in bats (61) was lower than in rodents (68), a result of there being approximately twice the number of rodent species as bat species. Therefore, rodents should still be a serious concern as reservoirs of emerging viruses. These findings shed light on disease emergence and perpetuation mechanisms and may help lead to a predictive framework for identifying future emerging infectious virus reservoirs.
PMCID: PMC3574368  PMID: 23378666
trait-based approaches; zoonoses; viral richness; reservoir host; spillover; Chiroptera
22.  Assessing Multivariate Constraints to Evolution across Ten Long-Term Avian Studies 
PLoS ONE  2014;9(3):e90444.
In a rapidly changing world, it is of fundamental importance to understand processes constraining or facilitating adaptation through microevolution. As different traits of an organism covary, genetic correlations are expected to affect evolutionary trajectories. However, only limited empirical data are available.
Methodology/Principal Findings
We investigate the extent to which multivariate constraints affect the rate of adaptation, focusing on four morphological traits often shown to harbour large amounts of genetic variance and considered to be subject to limited evolutionary constraints. Our data set includes unique long-term data for seven bird species and a total of 10 populations. We estimate population-specific matrices of genetic correlations and multivariate selection coefficients to predict evolutionary responses to selection. Using Bayesian methods that facilitate the propagation of errors in estimates, we compare (1) the rate of adaptation based on predicted response to selection when including genetic correlations with predictions from models where these genetic correlations were set to zero and (2) the multivariate evolvability in the direction of current selection to the average evolvability in random directions of the phenotypic space. We show that genetic correlations on average decrease the predicted rate of adaptation by 28%. Multivariate evolvability in the direction of current selection was systematically lower than average evolvability in random directions of space. These significant reductions in the rate of adaptation and reduced evolvability were due to a general nonalignment of selection and genetic variance, notably orthogonality of directional selection with the size axis along which most (60%) of the genetic variance is found.
These results suggest that genetic correlations can impose significant constraints on the evolution of avian morphology in wild populations. This could have important impacts on evolutionary dynamics and hence population persistence in the face of rapid environmental change.
PMCID: PMC3946496  PMID: 24608111
23.  Measuring Executive Dysfunction Longitudinally and in Relation to Genetic Burden, Brain Volumetrics, and Depression in Prodromal Huntington Disease 
Executive dysfunction (ED) is a characteristic of Huntington disease (HD), but its severity and progression is less understood in the prodromal phase, e.g., before gross motor abnormalities. We examined planning and problem-solving abilities using the Towers Task in HD mutation-positive individuals without motor symptoms (n = 781) and controls (n = 212). Participants with greater disease progression (determined using mutation size and current age) performed more slowly and with less accuracy on the Towers Task. Performance accuracy was negatively related to striatal volume while both accuracy and working memory were negatively related to frontal white matter volume. Disease progression at baseline was not associated with longitudinal performance over 4 years. Whereas the baseline findings indicate that ED becomes more prevalent with greater disease progression in prodromal HD and can be quantified using the Towers task, the absence of notable longitudinal findings indicates that the Towers Task exhibits limited sensitivity to cognitive decline in this population.
PMCID: PMC3569950  PMID: 23246934
Huntington's disease; Genetic disorders; Executive functions; Neuroimaging (structural); Norms/normative studies; Practice effects/reliable change; longitudinal change
24.  Continuing analysis of microRNA origins 
Mobile Genetic Elements  2014;3(6):e27755.
MicroRNAs (miRs) are small noncoding RNAs that typically act as regulators of gene expression by base pairing with the 3′ UTR of messenger RNAs (mRNAs) and either repressing their translation or initiating degradation. As of this writing over 24,500 distinct miRs have been identified, but the functions of the vast majority of these remain undescribed. This paper represents a summary of our in depth analysis of the genomic origins of miR loci, detailing the formation of 1,213 of the 7,321 recently identified miRs and thereby bringing the total number of miR loci with defined molecular origin to 3,605. Interestingly, our analyses also identify evidence for a second, novel mechanism of miR locus generation through describing the formation of 273 miR loci from mutations to other forms of noncoding RNAs. Importantly, several independent investigations of the genomic origins of miR loci have now supported the hypothesis that miR hairpins are formed by the adjacent genomic insertion of two complementary transposable elements (TEs) into opposing strands. While our results agree that subsequent transcription over such TE interfaces leads to the formation of the majority of functional miR loci, we now also find evidence suggesting that a subset of miR loci were actually formed by an alternative mechanism—point mutations in other structurally complex, noncoding RNAs (e.g., tRNAs and snoRNAs).
PMCID: PMC3891635  PMID: 24475369
LINE; microRNA; miR; miRNA; noncoding RNA; repetitive; retrotransposon; SINE; transposable; transposon
25.  Anorectal atresia and variants at predicted regulatory sites in candidate genes 
Annals of human genetics  2012;77(1):31-46.
Anorectal atresia is a serious birth defect of largely unknown etiology but candidate genes have been identified in animal studies and human syndromes. Because alterations in the activity of these genes might lead to anorectal atresia, we selected 71 common variants predicted to be in transcription factor binding sites, CpG windows, splice sites, and miRNA target sites of 25 candidate genes, and tested for their association with anorectal atresia. The study population comprised 150 anorectal atresia cases and 623 control infants without major malformations. Variants predicted to affect transcription factor binding, splicing, and DNA methylation in WNT3A, PCSK5, TCF4, MKKS, GLI2, HOXD12, and BMP4 were associated with anorectal atresia based on a nominal P value <0.05. The GLI2 and BMP4 variants are reported to be moderately associated with gene expression changes (Spearman’s rank correlation coefficients between −0.260 and 0.226). We did not find evidence for interaction between maternal pre-pregnancy obesity and variants in MKKS, a gene previously associated with obesity, on the risk of anorectal atresia. Our results for MKKS support previously suggested associations with anorectal malformations. Our findings suggest that more research is needed to determine whether altered GLI2 and BMP4 expression is important in anorectal atresia in humans.
PMCID: PMC3535506  PMID: 23127126
anorectal malformations; imperforate anus; hindgut; congenital abnormalities

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