Uterine leiomyoma with fumarate hydratase deficiency: A case report.

RATIONALE: Hereditary leiomyomatosis and renal cell carcinoma is an uncommon autosomal dominant disease caused by mutations in the fumarate hydratase (FH) gene. They usually demonstrated multiple uterine myomas and preformed surgical procedures for myomectomy and/or hysterectomy 10 years earlier than sporadic myomas due to early development. This case report describes a woman with multiple uterine leiomyomas diagnosed with FH deficiency. PATIENT CONCERNS: A 37-year-old woman visited a gynecological clinic for the discovery of uterine leiomyoma for more than 1 year. The size of the largest grew from 42 × 27 × 46 to 98 × 85 × 113 mm in 1 year. She had a history of surgery for breast cancer and thyroid cancer but denied a history of uterine leiomyoma in her family. DIAGNOSIS AND INTERVENTIONS: The patient underwent successful transabdominal hysterectomy. The pathological results showed multiple uterine leiomyomas (partly cellular leiomyomas) with scattered large bizarre giant cells. Immunohistochemistry results demonstrated FH deficiency. OUTCOMES: On follow-up, the patient did not have any complications. She was finally referred to the oncologists and urologists for follow-up. LESSONS: Gynecologists should be aware that early onset uterine leiomyoma presenting as large, multiple, and symptomatic lesion, may be associated with FH deficiency.

Characterization of ETFDH and PHGDH Mutations in a Patient with Mild Glutaric Aciduria Type II and Serine Deficiency.

Glutaric aciduria type II (GA-II) is a rare autosomal recessive disease caused by defects in electron transfer flavoprotein (ETF), ultimately causing insufficiencies in multiple acyl-CoA dehydrogenase (MAD). 3-phosphoglycerate dehydrogenase (3-PHGDH) deficiency, is another rare autosomal disorder that appears due to a defect in the synthesis of L-serine amino acid. Several mutations of ETFDH and PHGDH genes have been associated with different forms of GA-II and serine deficiency, respectively. In this study, we report a unique case of GA-II with serine deficiency using biochemical, genetic, and in silico approaches. The proband of Syrian descent had positive newborn screening (NBS) for GA-II. At two years of age, the patient presented with developmental regression, ataxia, and intractable seizures. Results of amino acid profiling demonstrated extremely low levels of serine. Confirmatory tests for GA-II and whole exome sequencing (WES) were performed to determine the etiology of intractable seizure. Sequencing results indicated a previously reported homozygous missense mutation, c.679 C>A (p.Pro227Thr) in the ETFDH gene and a novel missense homozygous mutation c.1219 T>C (p.Ser407Pro) in the PHGDH gene. In silico tools predicted these mutations as deleterious. Here, the clinical and biochemical investigations indicate that ETFDH:p.Pro227Thr and PHGDH:p.Ser407Pro variants likely underlie the pathogenesis of GA-II and serine deficiency, respectively. This study indicates that two rare autosomal recessive disorders should be considered in consanguineous families, more specifically in those with atypical presentation.

Intoxication by a synthetic cannabinoid (JWH-018) causes cognitive and psychomotor impairment in recreational cannabis users.

BACKGROUND: Smoking mixtures containing synthetic cannabinoids (SCs) have become very popular over the last years but pose a serious risk for public health. Limited knowledge is, however, available regarding the acute effects of SCs on cognition and psychomotor performance. Earlier we demonstrated signs of impairment in healthy volunteers after administering one of the first SCs, JWH-018, even though subjective intoxication was low. In the current study, we aimed to investigate the acute effects of JWH-018 on several cognitive and psychomotor tasks in participants who are demonstrating representative levels of acute intoxication. METHODS: 24 healthy cannabis-experienced participants took part in this placebo-controlled, cross-over study. Participants inhaled the vapor of 75 µg JWH-018/kg body weight and were given a booster dose if needed to induce a minimum level of subjective high. They were subsequently monitored for 4 h, during which psychomotor and cognitive performance, vital signs, and subjective experience were measured, and serum concentrations were determined. RESULTS: Maximum subjective high (average 64%) was reached 30 min after administration of JWH-018, while the maximum blood concentration was shown after 5 min (8 ng/mL). JWH-018 impaired motor coordination (CTT), attention (DAT and SST), memory (SMT), it lowered speed-accuracy efficiency (MFFT) and slowed down response speed (DAT). CONCLUSION: In accordance with our previous studies, we demonstrated acute psychomotor and cognitive effects of a relatively low dose of JWH-018.

Improvement of psychomotor retardation after electroconvulsive therapy is related to decreased IL-6 levels.

BACKGROUND: Prior studies suggest that IL-6 may be involved in the pathophysiology of psychomotor symptoms in depression. Electroconvulsive therapy (ECT), as yet the most effective biological treatment of severe depression, is known to improve psychomotor functioning, while recent studies have shown a decrease in the elevated IL-6 levels of depressed patients following ECT. OBJECTIVES: This study investigates whether the improvement in psychomotor functions in patients with depression after ECT is related to changes in IL-6 levels. METHODS: Peripheral IL-6 was quantified and the severity of psychomotor agitation and retardation determined using the CORE assessment of psychomotor symptoms in 62 patients with a (unipolar or bipolar) depressive episode within one week before and within one week after their course of ECT. RESULTS: IL-6 levels had decreased significantly following ECT and both psychomotor retardation and agitation had improved. The decrease in IL-6 levels was related to the improvement of psychomotor retardation, with post-hoc analysis revealing that higher baseline IL-6 levels positively correlated with higher psychomotor retardation scores. CONCLUSION: With this study, we provide the first evidence that the improvement of psychomotor retardation after ECT for depression is related to the immunomodulatory properties of the treatment, most specifically the decrease in IL-6 levels.

Cord Leptin is Associated with Neuropsychomotor Development in Childhood.

OBJECTIVE: Leptin is critical for central nervous system development and maturation. This study aimed to evaluate the potential regulatory role of cord leptin in the neuropsychomotor development of children ages 18 months to 6 years. METHODS: This study included 424 children from a prospective mother-child cohort (Rhea Study; Crete, Greece) with available cord leptin levels and data on neurodevelopmental outcomes at 18 months (Bayley Scales of Infant and Toddler Development, Third Edition), 4 years (McCarthy Scales of Children's Abilities), and 6 years (Raven's Coloured Progressive Matrices and Trail Making Test). Multivariable linear regression models were used to explore the associations. RESULTS: Each 10-ng/mL increase in the cord leptin level was associated with increased scores on the gross motor scale at 18 months (ß coefficient: 3.8; 95% CI: 0.0-7.5), with decreased scores in the general cognitive performance (ß coefficient: -3.0; 95% CI: -5.5 to -0.4), perceptual performance (ß coefficient: -3.4; 95% CI: -6.0 to -9.9), working memory (ß coefficient: -3.1; 95% CI: -5.7 to -0.4), executive function (ß coefficient -3.1; 95% CI: -5.7 to -0.5), and functions of the posterior cortex (ß coefficient: -2.7; 95% CI: -5.2 to -0.1) scales at 4 years, and with a 3.7-unit decrease in the Raven's Coloured Progressive Matrices score at 6 years (ß coefficient: -3.7; 95% CI: -6.9 to -0.5). CONCLUSIONS: Increased cord leptin levels are associated with enhanced gross motor development at 18 months but decreased cognitive performance in early and middle childhood.

Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an inborn error of heme biosynthesis due to the deficiency of hydroxymethylbilane synthase (HMBS) activity. Human AIP heterozygotes have episodic acute neurovisceral attacks that typically start after puberty, whereas patients with homozygous dominant AIP (HD-AIP) have early-onset chronic neurological impairment, including ataxia and psychomotor retardation. To investigate the dramatically different manifestations, knock-in mice with human HD-AIP missense mutations c.500G>A (p.Arg167Glu) or c.518_519GC>AG (p.Arg173Glu), designated R167Q or R173Q mice, respectively, were generated and compared with the previously established T1/T2 mice with ~30% residual HMBS activity and the heterozygous AIP phenotype. Homozygous R173Q mice were embryonic lethal, while R167Q homozygous mice (R167Q+/+) had ~5% of normal HMBS activity, constitutively elevated plasma and urinary 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), profound early-onset ataxia, delayed motor development and markedly impaired rotarod performance. Central nervous system (CNS) histology was grossly intact, but CNS myelination was delayed and overall myelin volume was decreased. Heme concentrations in liver and brain were similar to those of T1/T2 mice. Notably, ALA and PBG concentrations in the cerebral spinal fluid and CNS regions were markedly elevated in R167Q+/+ mice compared with T1/T2 mice. When the T1/T2 mice were administered phenobarbital, ALA and PBG markedly accumulated in their liver and plasma, but not in the CNS, indicating that ALA and PBG do not readily cross the blood-brain barrier. Taken together, these studies suggest that the severe HD-AIP neurological phenotype results from decreased myelination and the accumulation of locally produced neurotoxic porphyrin precursors within the CNS.

Neutropenia and Increased Mean Corpuscular Volume (MCV) With Abnormal Neurologic Findings: A Case of Cobalamin D Deficiency.

BACKGROUND: Disorders of intracellular cobalamin (Cbl) metabolism are classified from A to J according to biochemical phenotype, and genetic and complementation analyses. CblD-deficient patients present with developmental, hematologic, neurologic, and metabolic findings. CLINICAL OBSERVATION: An 11-year-old boy presented with neutropenia, increased mean corpuscular volume, psychomotor retardation, and seizures. His plasma total homocysteine and urinary methylmalonic acid levels were elevated, and a homozygous nonsense mutation [p. R250X (c.748C>T] leading to premature termination of translation was identified in the MMADHC gene, which was compatible with CblD defect. CONCLUSION: In the presence of increased mean corpuscular volume and other hematologic manifestations, such as leukopenia, thrombocytopenia, and megaloblastic anemia, with severe nonspecific or mild neurologic symptoms, Cbl synthesis defects should be considered.

The relationship between serum IGF-1, handgrip strength, physical performance and falls in elderly men and women.

OBJECTIVE: Human aging is accompanied by a decrease in growth hormone secretion and serum insulin-like growth factor (IGF)-1 levels. Also, loss of muscle mass and strength and impairment of physical performance, ending in a state of frailty, are seen in elderly. We aimed to investigate whether handgrip strength, physical performance and recurrent falls are related to serum IGF-1 levels in community-dwelling elderly. DESIGN: Observational cohort study (cross-sectional and prospective). METHODS: We studied the association between IGF-1 and handgrip strength, physical performance and falls in participants of the Longitudinal Aging Study Amsterdam. A total of 1292 participants were included (633 men, 659 women). Serum IGF-1 levels were divided into quartiles (IGF-1-Q1 to IGF-1-Q4). Data on falls were collected prospectively for a period of 3 years. All analyses were stratified for age and physical activity and adjusted for relevant confounders. RESULTS: Men with a low physical activity score in IGF-1-Q1 and IGF-1-Q2 of the younger age group had a lower handgrip strength compared to IGF-1-Q4. In younger more active males in IGF-1-Q2 physical performance was worse. Recurrent fallers were less prevalent in older, low active males with low IGF-1 levels. In females, recurrent fallers were more prevalent in older, more active females in IGF-1-Q2. IGF-1 quartile may predict changes in handgrip strength and physical performance in men and women. CONCLUSIONS: Our results indicate that lower IGF-1 levels are associated with lower handgrip strength and worse physical performance, but less recurrent fallers especially in men. Associations were often more robust in IGF-1-Q2. Future studies on this topic are desirable.

Lower levels of brain-derived neurotrophic factor are associated with melancholic psychomotor retardation among depressed inpatients.

OBJECTIVES: Melancholic depression is a type of depression which is closely related to biological variables than are other types of depression. Its clinical features can be assessed using six items on the Hamilton Depression Rating Scale (HAM-D6 ). Previous studies have shown, using item response theory, that the symptom depressed mood is the least severe melancholic feature; work and activities, somatic symptoms and psychic anxiety are of moderate severity; and feelings of guilt and psychomotor retardation are the most severe. We aimed to evaluate whether the more severe melancholic signs or symptoms were associated with decreases in brain-derived neurotrophic factor (BDNF) levels. METHODS: A total of 151 severely depressed inpatients had their BDNF levels analyzed by comparing those who presented with each HAM-D6 melancholic feature to those for whom the HAM-D6 feature was absent, using multiple linear regressions. The levels of BDNF of patients who presented with each melancholic feature were also compared with those of 100 healthy controls. RESULTS: Depressed patients' median BDNF level was 44.06 ng/mL (interquartile range [IQR]: 33.99-62.4 ng/mL), and controls' median BDNF level was 65.22 ng/mL (IQR: 49.87-76.08 ng/mL) (P < .001). The presence of depressed mood, work and activities, somatic symptoms, psychic anxiety, and guilty feelings was not associated with BDNF levels. However, the presence of psychomotor retardation was associated with reduced BDNF (median reduction -10.07 ng/mL; 95% confidence interval [CI]: -19.43 to -0.71; P = .03). CONCLUSIONS: To the best of our knowledge, this study is the first to associate BDNF levels with melancholic features in a sample of severely depressed inpatients. The main finding of this study was that severely depressed inpatients who presented the most severe melancholic feature, psychomotor retardation, had significantly reduced BDNF levels in the blood.

Neonatal Diabetes: Two Cases with Isolated Pancreas Agenesis due to Homozygous PTF1A Enhancer Mutations and One with Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome due to KCNJ11 Mutation

Neonatal diabetes mellitus is a rare form of monogenic diabetes which is diagnosed in the first six months of life. Here we report three patients with neonatal diabetes; two with isolated pancreas agenesis due to mutations in the pancreas-specific transcription factor 1A (PTF1A) enhancer and one with developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, due to a KCNJ11 mutation. The two cases with mutations in the distal enhancer of PTF1A had a homozygous g.23508363A>G and a homozygous g.23508437A>G mutation respectively. Previous functional analyses showed that these mutations can decrease expression of PTF1A which is involved in pancreas development. Both patients were born small for gestational age to consanguineous parents. Both were treated with insulin and pancreatic enzymes. One of these patients' fathers was also homozygous for the PTF1A mutation, whilst his partner and the parents of the other patient were heterozygous carriers. In the case with DEND sydrome, a previosly reported heterozygous KCNJ11 mutation, p.Cys166Tyr (c.497G>A), was identified. This patient was born to nonconsanguineous parents with normal birth weight. The majority of neonatal diabetes patients with KCNJ11 mutations will respond to sulphonylurea treatment. Therefore Glibenclamide, an oral antidiabetic of the sulphonylurea group, was started. This treatment regimen relatively improved blood glucose levels and neurological symptoms in the short term. Because we could not follow the patient in the long term, we are not able to draw conclusions about the efficacy of the treatment. Although neonatal diabetes mellitus can be diagnosed clinically, genetic analysis is important since it is a guide for the treatment and for prognosis.

Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling.

Serine biosynthesis defects are autosomal recessive metabolic disorders resulting from the deficiency of any of the three enzymes involved in de novo serine biosynthesis, specifically phosphoglycerate dehydrogenase (PGDH), phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP). In this study, we performed metabolomic profiling on 4 children with serine biosynthesis defects; 3 with PGDH deficiency and 1 with PSAT deficiency. The evaluations were performed at baseline and with serine and glycine supplementation. Metabolomic profiling performed at baseline showed low phospholipid species, including glycerophosphocholine, glycerophosphoethanolamine, and sphingomyelin. All children had low serine and glycine as expected. Low glycerophosphocholine compounds were found in 4 children, low glycerophosphoethanolamine compounds in 3 children, and low sphingomyelin species in 2 children. Metabolic profiling with serine and glycine supplementation showed normalization of most of the low phospholipid compounds in the 4 children. Phospholipids are the major component of plasma and intracellular membranes, and phosphatidylcholine is the most abundant phospholipid of all mammalian cell types and subcellular organelles. Phosphatidylcholine is of particular importance for the nervous system, where it is essential for neuronal differentiation. The observed low phosphatidylcholine species in children with serine biosynthesis defects that improved after serine supplementation, supports the role of serine as a significant precursor for phosphatidylcholine. The vital role that phosphatidylcholine has during neuronal differentiation and the pronounced neurological manifestations in serine biosynthesis defects suggest that phosphatidylcholine deficiency occurring secondary to serine deficiency may have a significant contribution to the development of the neurological manifestations in individuals with serine biosynthesis defects.

Molecular and clinical features of KATP -channel neonatal diabetes mellitus in Japan.

BACKGROUND: There are few reports pertaining to Asian patients with neonatal diabetes mellitus (NDM) caused by activating mutations in the ATP-sensitive potassium channel genes (KATP-NDM). OBJECTIVES: To elucidate the characteristics of Japanese patients with KATP-NDM. METHODS: By the amplification and direct sequencing of all exons and exon-intron boundaries of the KCNJ11 and ABCC8 genes, 25 patients with KATP-NDM were identified from a total of 70 patients with NDM. Clinical data were collected from the medical charts. RESULTS: Sixteen patients had mutations in KCNJ11 and nine in ABCC8. Eight novel mutations were identified; two in KCNJ11 (V64M, R201G) and six in ABCC8 (R216C, G832C, F1176L, A1263V, I196N, T229N). Interestingly, V64M caused DEND (developmental delay, epilepsy, neonatal diabetes) syndrome in our patient, while mutation of the same residue (V64G) had been reported to cause congenital hyperinsulinism. Mutations in ABCC8 were associated with TNDM (4/9) or isolated PNDM (5/9), whereas those in KCNJ11 were associated with more severe phenotypes, including DEND (3/16), iDEND (intermediate DEND, 4/16), or isolated PNDM (6/16). Switching from insulin to glibenclamide monotherapy was successful in 87.5% of the patients. Neurological improvement was observed in two patients, one with DEND (T293N) and one with iDEND (R50P) syndrome. Three others with iDEND mutations (R201C, G53D, and V59M) remained neurologically normal at 5, 1, and 4 years of age, respectively, with early introduction of sulfonylurea. CONCLUSION: Overall, clinical presentation of KATP-NDM in Japanese patients was similar to those of other populations. Early introduction of sulfonylurea appeared beneficial in ameliorating neurological symptoms.

Clinical and laboratory outcomes after umbilical cord blood transplantation in a patient with mucolipidosis II alpha/beta.

Mucolipidosis (ML) II alpha/beta is an autosomal recessive disease caused by reduced enzyme activity of N-acetylglucosamine-1-phosphotransferase. Clinical symptoms of ML II are severe psychomotor delay and dysostosis multiplex; death usually occurs by 5-8 years of age from cardiopulmonary complications. Allogeneic hematopoietic stem cell transplantation (HSCT) has been attempted for ML; however, few reports have documented the detailed outcomes of HSCT for ML. A 26-month-old girl received a human leukocyte antigen 3/6-allele-matched transplant from cord blood. The preparative regimen consisted of fludarabine, cyclophosphamide, 6-Gy total body irradiation, and rabbit antithymocyte globulin. Although comparing before and after cord blood transplantation results, we observed that lysosomal enzyme activities in the plasma decreased by approximately 20-40%. Low serum levels of immunoglobulin A, G2, and G4 were also observed before HSCT; however, these values normalized after transplantation. Despite undergoing HSCT, she was treated twice for bacterial pneumonia with acute respiratory distress syndrome at ages 37 and 38 months. Although HSCT effects on the clinical manifestations were limited, laboratory data including plasma lysosomal enzyme activities and serum levels of immunoglobulin showed improvement.

Assessing biomarkers and neuropsychological outcomes in rural populations exposed to organophosphate pesticides in Chile--study design and protocol.

BACKGROUND: Health effects of pesticides are easily diagnosed when acute poisonings occurs, nevertheless, consequences from chronic exposure can only be observed when neuropsychiatric, neurodegenerative or oncologic pathologies appear. Therefore, early monitoring of this type of exposure is especially relevant to avoid the consequences of pathologies previously described; especially concerning workers exposed to pesticides on the job. For acute organophosphate pesticides (OPP) exposure, two biomarkers have been validated: plasma cholinesterase (ChE) and acetylcholinesterase (AChE) from erythrocytes. These enzymes become inhibited when people are exposed to high doses of organophosphate pesticides, along with clear signs and symptoms of acute poisoning; therefore, they do not serve to identify risk from chronic exposure. This study aims to assess a novel biomarker that could reflect neuropsychological deterioration associated with long-term exposure to organophosphate pesticides via the enzyme acylpeptide-hydrolase (ACPH), which has been recently identified as a direct target of action for some organophosphate compounds. METHODS/DESIGN: Three population groups were recruited during three years (2011-2013): Group I having no exposure to pesticides, which included people living in Chilean coastal areas far from farms (external control); Group II included those individuals living within the rural and farming area (internal control) but not occupationally exposed to pesticides; and Group III living in rural areas, employed in agricultural labour and having had direct contact with pesticides for more than five years. Blood samples to assess biomarkers were taken and neuropsychological evaluations carried out seasonally; in three time frames for the occupationally exposed group (before, during and after fumigation period); in two time frames for internal control group (before and during fumigation), and only once for the external controls. Neuropsychological evaluations considered cognitive functions, affectivity and psychomotor activity. The biomarkers measured included ChE, AChE and ACPH. Statistical analysis and mathematical modelling used both laboratory results and neuropsychological testing outcomes in order to assess whether ACPH would be acceptable as biomarker for chronic exposure to OPP. DISCUSSION: This study protocol has been implemented successfully during the time frames mentioned above for seasons 2011, 2012 and 2013-2014.

Mild hypohydration increases the frequency of driver errors during a prolonged, monotonous driving task.

UNLABELLED: The aim of the present study was to examine the effect of mild hypohydration on performance during a prolonged, monotonous driving task. METHODS: Eleven healthy males (age 22±4y) were instructed to consume a volume of fluid in line with published guidelines (HYD trial) or 25% of this intake (FR trial) in a crossover manner. Participants came to the laboratory the following morning after an overnight fast. One hour following a standard breakfast, a 120min driving simulation task began. Driver errors, including instances of lane drifting or late breaking, EEG and heart rate were recorded throughout the driving task RESULTS: Pre-trial body mass (P=0.692), urine osmolality (P=0.838) and serum osmolality (P=0.574) were the same on both trials. FR resulted in a 1.1±0.7% reduction in body mass, compared to -0.1±0.6% in the HYD trial (P=0.002). Urine and serum osmolality were both increased following FR (P<0.05). There was a progressive increase in the total number of driver errors observed during both the HYD and FR trials, but significantly more incidents were recorded throughout the FR trial (HYD 47±44, FR 101±84; ES=0.81; P=0.006) CONCLUSIONS: The results of the present study suggest that mild hypohydration, produced a significant increase in minor driving errors during a prolonged, monotonous drive, compared to that observed while performing the same task in a hydrated condition. The magnitude of decrement reported, was similar to that observed following the ingestion of an alcoholic beverage resulting in a blood alcohol content of approximately 0.08% (the current UK legal driving limit), or while sleep deprived.

Regarding the fitness to ride a bicycle under the acute influence of alcohol.

To determine the threshold for the absolute inability to ride a bicycle, practical cycling tests and medical examinations at different blood alcohol concentrations were performed. Special attention was given to additional medical examinations, reaction tests and alcohol consumption under real-life conditions. Seventy-eight test subjects were included in the trials (37 females, 41 males). Five test subjects participated twice; thus, there were a total of 83 evaluable trials. Alcohol-related deficits were already identifiable at very low BACs. A significant increase in gross motoric disturbances compared to the soberness state did not regularly occur until a BAC of at least 0.8 g/kg was reached. At the BAC of 1.4 g/kg and above, no test subjects were able to achieve or surpass their sober driving results. Isolated highly alcoholised test subjects rode the bike in a manner that was not conspicuously different than the other sober test persons. Contrary to the assumptions of current German legal practise, it cannot be stated that all people are 'absolutely impaired' to the point of being incapable of riding bicycle at BACs of at least 1.6 g/kg.

FADS single-nucleotide polymorphisms are associated with behavioral outcomes in children, and the effect varies between sexes and is dependent on PPAR genotype.

BACKGROUND: Docosahexaenoic acid (DHA), supplied by the diet or endogenous biosynthesis from α-linolenic acid, accretes during the perinatal brain growth spurt. Results regarding a potential programming effect on cognitive function and behavior in humans are inconclusive. OBJECTIVE: Here we aimed to investigate whether behavioral outcomes in childhood were associated with FADS tag-single-nucleotide polymorphisms (SNPs) previously found to have opposing effects on infant erythrocyte DHA. DESIGN: At 36 mo, we assessed psychomotor development with the third edition of the Ages & Stages Questionnaire (n = 256) and physical activity by accelerometry (n = 231) in children from the SKOT [Småbørns Kost Og Trivsel (Diet and Thriving in Young Children)] cohort. Blood samples were taken to determine erythrocyte DHA (n = 200), FADS tag-SNPs (n = 255), and PPARG-Pro12Ala (n = 255). All outcomes were analyzed in models, including all 3 SNPs, SNP-sex interactions, erythrocyte DHA at 36 mo, and covariates. RESULTS: As previously shown, the minor allele carriers of the FADS SNP rs1535 had increased erythrocyte DHA at 9 mo, whereas DHA decreased in minor allele carriers of rs174448 and rs174575 (effect size around 0.5 percentage points per allele). No overall effects were observed for any of the FADS SNPs on the outcomes reported here, but FADS SNP-sex interactions were found for a number of DHA-increasing FADS alleles on both communication and problem solving (P = 0.005 and 0.013). DHA-increasing FADS alleles resulted in reduced scores in girls and improved abilities in boys, with an effect size of ∼1 score-point/allele. No associations were found between current erythrocyte DHA and any of the behavioral outcomes. The P value for the triple interaction between DHA-increasing FADS alleles, PPARG, and sex for communication was 0.051, and subsequent analyses showed the FADS-sex interaction only in PPARG minor allele carriers (n = 70). Furthermore, FADS-PPARG interactions were seen for problem solving in boys and for fine motor skills in girls. CONCLUSION: FADS SNPs seem to have a sex-specific, possibly peroxisome proliferator-activated receptor-mediated effect on behavior in children, indicating a programming effect of early DHA exposure.

Accommodating measurements below a limit of detection: a novel application of Cox regression.

In environmental epidemiology, measurements of exposure biomarkers often fall below the assay's limit of detection. Existing methods for handling this problem, including deletion, substitution, parametric regression, and multiple imputation, can perform poorly if the proportion of "nondetects" is high or parametric models are mis-specified. We propose an approach that treats the measured analyte as the modeled outcome, implying a role reversal when the analyte is a putative cause of a health outcome. Following a scale reversal as well, our approach uses Cox regression to model the analyte, with confounder adjustment. The method makes full use of quantifiable analyte measures, while appropriately treating nondetects as censored. Under the proportional hazards assumption, the hazard ratio for a binary health outcome is interpretable as an adjusted odds ratio: the odds for the outcome at any particular analyte concentration divided by the odds given a lower concentration. Our approach is broadly applicable to cohort studies, case-control studies (frequency matched or not), and cross-sectional studies conducted to identify determinants of exposure. We illustrate the method with cross-sectional survey data to assess sex as a determinant of 2,3,7,8-tetrachlorodibenzo-p-dioxin concentration and with prospective cohort data to assess the association between 2,4,4'-trichlorobiphenyl exposure and psychomotor development.