Increased excretion of a lipid peroxidation biomarker in autism.

It is thought that autism could result from an interaction between genetic and environmental factors with oxidative stress as a potential mechanism linking the two. One genetic factor may be altered oxidative-reductive capacity. This study tested the hypothesis that children with autism have increased oxidative stress. We evaluated children with autism for the presence of two oxidative stress biomarkers. Urinary excretion of 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-isoprostane-F2alpha (8-iso-PGF2alpha) were determined in 33 children with autism and 29 healthy controls. 8-iso-PGF2alpha levels were significantly higher in children with autism. The isoprostane levels in autistic subjects were variable with a bimodal distribution. The majority of autistic subjects showed a moderate increase in isoprostane levels while a smaller group of autistic children showed dramatic increases in their isoprostane levels. There was a trend of an increase in 8-OHdG levels in children with autism but it did not reach statistical significance. There was no significant correlation between the levels of the biomarkers and vitamin intake, dietary supplements, medicine, medical disorders, or history of regression. These results suggest that the lipid peroxidation biomarker is increased in this cohort of autistic children, especially in the subgroup of autistic children.

The effect of five forage species on transport and transformation of atrazine and isoxaflutole (balance) in lysimeter leachate.

A field lysimeter study with bare ground and five different ground covers was established to evaluate the effect of forage grasses on the fate and transport of two herbicides in leachate. The herbicides were atrazine (ATR; 2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine) and isoxaflutole [IXF; 5-cyclopropyl-4-(2-methylsulfonyl-4-trifluormethyl-benzoyl)isoxazole], which has the commercial name Balance (Aventis Crop Science, Strasbourg, France). The ground covers included orchardgrass (Dactylis glomerata L.), smooth bromegrass (Bromus inermis Leyss.), tall fescue (Festuca arundinacea Schreb.), timothy (Phleum pratense L.), and switchgrass (Panicum virgatum L.). The results suggested that the total IXF (parent + metabolites) showed higher mobility than ATR and its metabolites. Differences in the timing of transport reflected the rapid degradation of IXF to the more soluble, stable, and biologically active diketonitrile (DKN) metabolite in the system. Although grass treatments did not promote the hydrolysis of DKN, they significantly reduced its transport in the leachate through enhanced evapotranspiration. Grass treatments significantly enhanced ATR degradation in the leachates and soils, especially through N dealkylation, but they did not reduce total ATR transported in the leachate. Leachate from the orchardgrass lysimeters contained the highest proportion of ATR metabolites (64.2%). Timothy and smooth bromegrass treatments also displayed a significant increase in ATR metabolites in leachate. Grass-treated lysimeters showed higher microbial biomass carbon than bare ground. For ATR treatments, the proportion of metabolites in the leachate strongly correlated with the elevated soil microbial biomass carbon in forage treatments. In contrast, DKN degradation was poorly correlated with soil microbial biomass carbon, suggesting that DKN degradation is an abiotic process.

The tau A0 allele in Parkinson's disease.

Parkinson's disease (PD) is primarily an alpha-synucleinopathy, rather than a tauopathy, but there is evidence for an indirect association of tau with the pathogenetic process in PD. We therefore assessed the frequency in PD of the tau A0 allele, a dinucleotide repeat marker that has been associated with a sporadic tauopathy, progressive supranuclear palsy (PSP). We found the A0 allele to comprise 79.2% of 758 alleles from PD patients and 71.2% of 264 control alleles (P = 0.008). We also performed a meta-analysis of three previous reports, two of which failed to produce statistically significant results. Taken together, they also support a PD/A0 allelic association, even after correction for misdiagnosis of PSP as PD (P< 0.001). The A0/A0 genotype frequency in our patients (62.3%) did not differ significantly from that in controls (53.0%, P = 0.062), but the meta-analysis, even after correction for misdiagnosis, showed a significant result, with P = 0.002. The frequency of A0 allele and the A0/A0 genotype were compatible with Hardy-Weinberg equilibrium. The frequency of the A0 allele and the A0/A0 genotype in our patients with familial PD was not significantly greater than in those with sporadic PD. We conclude that the tau protein may play a small role in the pathogenesis of PD and that biochemical characterization of this role may suggest opportunities for PD prophylaxis.

Adolescent version of the questionnaire of eating and weight patterns: reliability and gender differences.

OBJECTIVE: The present study determined the test-retest reliability of the adolescent version of the Questionnaire of Eating and Weight Patterns (QEWP-A) and examined gender differences in QEWP-A responses. METHOD: The QEWP-A was administered to 106 male and female adolescents between the ages of 12 and 18 in a classroom setting and readministered 3 weeks later under the same conditions. Adolescent responses were classified into no diagnosis (ND), nonclinical binge (NCB), and binge eating disorder (BED) diagnostic categories. RESULTS: BED diagnoses were rare, but nonclinical levels were observed. Significant levels of stability for males and females were observed over a 3-week time period (phi = 0.42). Male and female differences were examined. Female responses changed significantly at the second testing. DISCUSSION: The implications for these results regarding the utility for the QEWP-A are reviewed.

Cost-effectiveness studies of medical and chiropractic care for occupational low back pain. a critical review of the literature.

BACKGROUND CONTEXT: Back pain is the single most costly work-related injury. Chiropractors and physicians are the main primary care providers for occupational low back pain (OLBP), but there is no consensus regarding the relative cost-effectiveness of these two modes of care. PURPOSE: To critically appraise and synthesize recent literature on the cost-effectiveness of medical and chiropractic care for OLBP, and to propose a cost-effectiveness methodology that integrates epidemiologic and economic methods for future studies. STUDY DESIGN: Literature review. MEDLINE was searched from 1990 through 1999. Nine articles that met the inclusion criteria were reviewed. The methodological quality of the articles was critically appraised independently by two epidemiologists using standardized review criteria. Two health economists reviewed the studies on cost-effectiveness. RESULTS: The current literature suggests that chiropractors and physicians provide equally effective care for OLBP but that chiropractic patients are more satisfied with their care. Evidence on the relative costs of medical and chiropractic care is conflicting. Several methodological deficiencies limit the validity of the reviewed studies. No studies combine high-quality cost data with adequate sample sizes and controls for confounding factors. CONCLUSION: Existing studies fail to clarify whether medical or chiropractic care is more cost effective. We suggest that future studies must combine epidemiologic and economic methods to answer the question adequately.

Validity of test meals for determining binge eating.

Assessment of binge eating has been criticized because of serious doubts concerning the accuracy of self-report. This experiment tested the validity of a laboratory test meal as an indicator of binge eating. Eight individuals diagnosed with binge-eating disorder (BED), eight obese non-binge-eaters, and eight normal-weight non-binge-eaters ate a test meal under conditions designed to increase the likelihood of inducing a binge episode. Non-binge-eaters, regardless of weight, felt in control of their eating and ate a relatively small amount of the test meal, while participants with BED ate significantly more food and felt significantly more out of control. Eating behavior during test meals can be a useful indicator of BED diagnostic status and may be a useful method for objectively defining binge eating.

Late-onset neurodegenerative diseases--the role of protein insolubility.

Recently, mutations of the alpha-synuclein gene were found to cause dominantly inherited Lewy-body Parkinson's disease (PD) and alpha-synuclein was identified as a major component of the Lewy body. However, the cause of the common form of PD, with a multifactorial rather than autosomal dominant inheritance pattern, remains unknown. Alpha-synuclein precipitates slowly and apparently spontaneously at high concentration in solution and the mutations that cause PD accelerate precipitation. Other dominantly inherited late-onset or adult-onset dominantly inherited neurodegenerative diseases are associated with precipitation of proteins. In Alzheimer disease, beta-amyloid and tau abnormalities are present and in prion disorders, prion proteins are found. In Huntington disease, a disorder with expanded CAG repeats, huntingtin precipitates occur. In dominantly inherited spinocerebellar ataxias, also expanded CAG repeat disorders, the corresponding ataxin protein precipitates are found. In multiple system atrophy, alpha-synuclein precipitates are encountered and in progressive supranuclear palsy, tau precipitates occur. In familial amyotrophic lateral sclerosis, a group of dominantly inherited disorders, SOD1 precipitates are found. Most of these disorders can involve the basal ganglia in some way. Since similar processes seem to affect neurons of adults or older individuals and since a relatively limited group of proteins seems to be involved, each producing a form of neurodegeneration, it is possible that certain common features are present that affect this group of proteins. Candidates include a conformational shift, as in prions, an abnormality of the ubiquitin-proteosome pathway, as seen in PD, an abnormality of a pathway preventing precipitation (e.g. chaperonins), or potentiation of a pathway promoting precipitation (e.g. gamma-glutamyl-transpeptidase) or apoptosis. Elucidation of the pathways causing this protein insolubilisation is the first step towards approaching prevention and reversal in these late-onset neurodegenerative diseases.

Folic acid: influence on the outcome of pregnancy.

The periconceptional use of folic acid-containing supplements reduces the first occurrence, as well as the recurrence, of neural tube defects. Women of populations in which adverse pregnancy outcomes are prevalent often consume diets that contain a low density of vitamins and minerals, including folate. Folate intake may need to be sustained after complete closure of the neural tube to decrease the risk of other poor pregnancy outcomes. A central feature of embryonic and fetal development is widespread cell division; folate is central because of its role in nucleic acid synthesis. During gestation, marginal folate nutriture can impair cellular growth and replication in the fetus or placenta. Folate deficiency can occur because dietary folate intake is low or because the metabolic requirement for folate is increased by a particular genetic defect or defects. During pregnancy, low concentrations of dietary and circulating folate are associated with increased risks of preterm delivery, infant low birth weight, and fetal growth retardation. A metabolic effect of folate deficiency is an elevation of blood homocysteine. Likewise, the presence of maternal homocysteine concentrations have been associated both with increased habitual spontaneous abortion and pregnancy complications (eg, placental abruption and preeclampsia), which increase the risk of poor pregnancy outcome and of decreased birth weight and gestation duration.

What is a binge? The influence of amount, duration, and loss of control criteria on judgments of binge eating.

OBJECTIVE: We investigated the influence of amount of food eaten, duration of eating episode, and loss of control in judgments of eating episodes as binges. METHOD: Participants rated the degree to which the eating behavior of a female actress qualified as a "binge" after observing eight videotaped vignettes in which the amount of food eaten, apparent duration of eating episode, and loss of control were varied. Binge ratings were stable across a test-retest interval of 3-4 weeks, there was minimal observer drift, and the experimental variables were independently perceived. RESULTS: A repeated measures analysis of variance (ANOVA) on binge ratings revealed significant main effects for quantity and loss of control, and a significant Quantity x Time interaction. DISCUSSION: The results are consistent with the definitional criteria of a binge, underscore the independence of loss of control, and highlight the importance of the violation of dietary standards in judgments of binges. Moreover, they illustrate the reliability and sensitivity of the methodology, and its potential for further investigations of binge eating.

Outcomes in work-related upper extremity and low back injuries: results of a retrospective study.

BACKGROUND: The outcomes of treatment for work-related injuries and illnesses are multidimensional and complex, but have rarely been explored in detail. This study was intended to provide information on a sample of workers representing a range of jobs and employers typical of the workers compensation system. METHODS: A mailed, self-report survey measuring multiple dimensions was conducted. Identified through the New Hampshire Division of Workers' Compensation First Report of Injury database, a sample of workers with injuries to their lower back (60%) or upper extremities (40%) a year prior to the study were surveyed. Response rate was 80% (N=169; upper extremity cases=70; low back cases=99). RESULTS: Most (82.8%) were working one year post-injury. Over half reported residual effects of the injury on work or activities of daily living. Many working subjects reported persistent injury-related anxiety and pain at the end of the work day, worse in those with low back pain compared to those with upper extremity injuries. Almost 40% of those who returned to work suffered a reinjury. Forty-four percent of respondents suffered significant injury-related financial problems, which were worse in those who had been out of work for longer periods. CONCLUSIONS: Occupational musculoskeletal injuries do result in significant, long-term adverse physical, economic, and psychological consequences, as demonstrated in self-reported surveys.

Distribution of alleles of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in familial spina bifida.

Spina bifida cystica (SB) is one of the most common and disabling of birth defects. Folic acid supplementation in mothers during the periconceptional period has been shown to prevent more than 70% of neural tube defects (NTD) including SB. However, the mechanism is unknown. We tested a series of multicase SB families in which 224 individuals were genotyped and a group of 215 unrelated unaffected (external) control individuals for association of SB with the T allele of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism that produces a heat-labile enzyme protein. The data were analyzed using first the transmission/disequilibrium test (TDT) and second a modified case-control study design with Monte Carlo sampling methods. No association of SB with the MTHFR T allele was found by either method. Presently, association between SB and the T allele has been found in four studies, a Dutch study, an Irish study, a North American study, and an Italian study. But no association was found in four other studies, a British study, a French study, a Turkish study, and a German study. A California population-based study found only modestly increased risk of SB with this allele that was not significant at the P < 0.05 level. The present study finds no evidence of the association. Only one other study, the German study, has used TDT analysis. The present study is the first to use a modified case-control study design with Monte Carlo sampling methods to test this association. Thus, it appears that the MTHFR T allele is a risk factor for SB in some populations but not others. Major genetic risk factors for folate-related SB remain to be found.

Measuring binge eating in adolescents: adolescent and parent versions of the questionnaire of eating and weight patterns.

OBJECTIVE: This study investigated the psychometric properties of an adolescent version of the Questionnaire of Eating and Weight Patterns (QEWP-A). METHOD: Male and female adolescents between 10-18 years completed the QEWP-A and measures of depression and eating attitudes. Height and weight were also measured. Parents completed a parental version (QEWP-P) that was referenced to their children. Adolescent and parent responses to the QEWP were independently categorized into no diagnosis (ND), nonclinical binge eating (NCB), and binge eating disorder (BED) groups. RESULTS: Adolescent and parental agreement over the diagnostic categories was as follows: 81.6% for ND, 15.5% for NCB, and 25% for BED with an overall kappa of. 19. Adolescents with BED had significantly higher levels of depression than the other two groups with NCB being higher than ND. For eating attitudes, BED adolescents were more deviant than the other two groups who did not differ from one another. DISCUSSION: The QEWP-A displayed adequate concurrent validity. The low overall agreement between adolescents and their parents was influenced by high and low base rates in the NCB and BED categories, respectively. This lack of agreement is consistent with other behavioral problems such as depression. The data suggest that parental perceptions of eating problems approximate those of their children when no problem is present. However, parents are not as likely to be aware of eating difficulties when they actually exist.

DNA polymorphism-diet-cofactor-development hypothesis and the gene-teratogen model for schizophrenia and other developmental disorders.

Three problems in identifying genes causing schizophrenia and other developmental disorders may be locus heterogeneity, high disease allele frequency, and unknown mode of inheritance. The DNA polymorphism-diet-cofactor-development (DDCD) hypothesis addresses the first two. The gene-teratogen model addresses the third. The DDCD hypothesis is that schizophrenia results in part from brain abnormality in utero from the aggregate effect of multiple mutations of small effect of genes related to important cofactors (e.g., folate, cobalamin, or pyridoxine) potentiated by maternal dietary deficiency of these cofactors and by pregnancy. The effect results from insufficiency of the cofactors and from resulting effects such as impaired DNA synthesis, immune deficiency, effects on niacin and serotonin metabolism, and teratogens, e.g., hyperhomocysteinemia. The hypothesis addresses all of the unusual features of schizophrenia: e.g., decreased brain gray matter, birth-month effect, geographical differences, socioeconomic predilection, association with obstetrical abnormalities, decreased incidence of rheumatoid arthritis, and association with famine and viral epidemics. In the gene-teratogen model, a teratogenic effect in utero produces a developmental disorder through a teratogenic locus and a modifying or specificity locus, as well as through environmental factors. An example is the major intrauterine effect seen in offspring of phenylketonuric mothers. Thus, the mode of inheritance of genes acting prenatally may in some cases be fundamentally different from that of genes acting postnatally. The model is interesting because it is simple and because teratogenic loci will be difficult to locate by conventional linkage mapping techniques due to misspecification of the affection status of both mother and affected children. A new study design is suggested for identifying teratogenic loci.

Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees.

Restless legs syndrome (RLS) can occur with an autosomal-dominant mode of inheritance. To determine if there are distinguishing features of RLS pedigrees which might clarify molecular mechanisms of pathogenesis, five pedigrees with 81 affected members were analyzed for age of onset, sex ratio, and transmission pattern. One-factor analysis of variance of ages of onset between generations was carried out, and segregation ratios were calculated for each generation. These kindreds showed an autosomal-dominant mode of inheritance and a male:female ratio of 1:1.4 (p = 0.15). One of the five analyzed pedigrees shows some evidence of reduced penetrance. In two of the five analyzed pedigrees, there is statistical support for anticipation (p<0.05). These variations in penetrance and anticipation suggest possible genetic heterogeneity.

Estimation of food intake: effects of the unit of estimation.

While many studies have shown that individuals under-estimate caloric intake, few studies have examined how individuals estimate intake when using other units of measurement (e.g. cups, ounces). Forty-one women (21 obese, 20 normal weight) ate a test meal of Häagen-Dazs chocolate ice cream and were asked to estimate the amount they ate in both calories and cups. As expected, participants under-estimated intake when asked to estimate how much they ate in calories, but considerably over-estimated their intake when measured in cups. Thus, individuals can both under- and over-estimate how much of the same food they have eaten, depending on the unit they are asked to use for estimation. Obesity and eating disorders treatment programs should take into account the tendency to over-estimate volumetric portions as well as under-estimate caloric intake.

Hereditary febrile seizures: phenotype and evidence for a chromosome 19p locus.

The occurrence of febrile seizures (FSs) in large autosomal dominant FS kindreds makes possible accurate delineation of the pure clinical phenotype of hereditary FS among secondary FS cases, and the identification of gene loci causing susceptibility to FS. Recently FS gene loci on chromosomes 8 and 19 were identified. We studied the phenotype of FS in four large families in which FS is an autosomal dominant trait. Among 30 affected secondary FS cases, mean age of onset was 16.3 months (range 4 to 36 months), sex ratio was equal, and 43% were complex (13 of 30). Among these 30 secondary FS cases, the mean number of FSs was 2.1, half had only a single FS, and none had afebrile seizures. Penetrance was 0.67, approximately the same as in our previous larger group of 40 multicase FS families (0.64). The occurrence of DPT encephalopathy in a sib of a patient with FS raises the possibility that these two etiologies are related. Linkage studies showed that one of the four families (Family 1) was linked to chromosome 19p markers, none of the families was linked to chromosome 8q markers, and the largest FS family (Kindred 6) was unlinked to either 19p or 8q markers, supporting the hypothesis of genetic heterogeneity for FS.

Genetics of the febrile seizure susceptibility trait.

Febrile seizures are the commonest form of convulsion, occurring in 2-5% of infants in Europe and North America and 6-9% of infants in Japan. In large families, the febrile seizure susceptibility trait is inherited by the autosomal dominant pattern with reduced penetrance. In the other families, inheritance appears to be multifactorial. Recent linkage studies provide evidence that regions of chromosomes 8 and 19 contain febrile convulsions (FC) susceptibility genes. This opens up the way to cloning a febrile seizure gene and determining the contributions of these gene loci to febrile seizures in the sporadic cases and the small families. Cloning a febrile seizure gene will make possible new approaches to prevention and therapy. It will also be possible to determine whether a febrile seizure gene contributes to other types of seizures.

The alpha-synuclein Ala53Thr mutation is not a common cause of familial Parkinson's disease: a study of 230 European cases. European Consortium on Genetic Susceptibility in Parkinson's Disease.

We report the results of a screen of 230 European familial index cases of Parkinson's disease for the recently described Ala53Thr mutation in the alpha-synuclein gene in an autosomal dominant Parkinson's disease kindred. No mutations were found from this broad white population, and we therefore conclude that although of great interest, this mutation is a very rare cause of familial Parkinson's disease.

Exclusion of genetic linkage to 4q21-23 and 17q21 in a family with Lewy body parkinsonism.

Genetic analysis of markers from chromosomes 4q21-23 and 17q21 in a family with apparently autosomal dominant Lewy body parkinsonism is presented. This analysis shows that the locus leading to this disease is not allelic with that previously shown to lead to Lewy body parkinsonism on chromosome 4 or to the locus on chromosome 17 leading to frontotemporal dementia with parkinsonism. A brief clinical comparison of this family with families showing linkage to these loci is presented. The data suggest that at least one other major genetic determinant for Lewy body parkinsonism remains to be identified.