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PubMed2004

Serotonin 1B (5HT-1B) receptor polymorphism (G861C) in suicide victims: association studies in German and Slavic population.

Serotonergic dysfunction is believed to be involved in the susceptibility to suicide due to functional alternations in the serotonin-related genes. Serotonin 1B (5HT-1B) receptor mediates aggressive behavior in mice models and was proposed to be involved in the control of aggression and impulsivity in humans. In this study we have investigated the association of G861C polymorphism of the 5HT-1B receptor gene with suicide commitment. Study was based on two independent samples, one of German (245 suicide victims vs. 248 controls) and the other of Slavic/Croatian (118 suicide victims vs. 192 controls) ethnicity. No significant differences in allele or genotype frequencies between victims and controls were demonstrated either in German or Croatian sample. There were no differences in allele frequencies between German and Croatian population, and the combined sample, having high statistical power, also did not demonstrate significant differences between victims and controls. Results provide evidence that the investigated 5HT-1B receptor gene variants are not implicated in the susceptibility to suicide.

Adult↗
PubMed2006

The association between behavior and genotype in Rett syndrome using the Australian Rett Syndrome Database.

This study compared the behavior profile of cases in the Australian Rett Syndrome Database (ARSD) with those in a British study using the Rett Syndrome Behavior Questionnaire (RSBQ) and then examined behavioral patterns as measured by the RSBQ by genetic status. There were 145 Australian cases meeting the criteria for the first arm of the study and 135 for the second arm. Comparison of the scores obtained from the British and Australian cohorts indicated that the RSBQ was a satisfactory measure for describing behaviors in Rett Syndrome (RS). Overall, there were some differences among the behavior patterns of cases with the well-known common mutations. Fear/anxiety was more commonly reported in those with R133C and R306C. Those with the R294X mutation were more likely to have mood difficulties and body rocking but less likely to have hand behaviors and to display repetitive face movements. In contrast, hand behaviors were more commonly reported in those with R270X or R255X. We found the RSBQ is an appropriate instrument for measuring behavior in girls with RS. Some behaviors differ according to genetic mutation but there is both inter and intra mutation variation in behavior and there is a need for larger studies involving international collaboration to improve statistical power.

Adolescent↗
PubMed2006

Brain derived neurotrophic factor (BDNF) gene variants and Alzheimer's disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence.

Genetic variation at the locus encoding the brain derived neurotrophic factor (BDNF) has been implicated in some neuropsychiatric disorders such as Alzheimer's disease (AD), affective disorders (AFDs), schizophrenia, and substance dependence. We therefore performed a mutation scan of the BDNF gene to identify novel gene variants and examined the association between BDNF variants and several neuropsychiatric phenotypes in European American (EA) subjects and controls. Using denaturing high performance liquid chromatography (dHPLC), we identified a novel variant (G-712A) in the putative promoter region. This variant and two previously reported BDNF SNPs (C270T and Val66Met) were genotyped in 295 patients with AD, 108 with AFDs, 96 with posttraumatic stress disorder (PTSD), 84 with schizophrenia, 327 with alcohol and/or drug dependence, and 250 normal control subjects. No association was found between these three BDNF gene variants and AD, AFDs, PTSD, or schizophrenia. However, there was a nominally higher frequency of the G-712A G-allele and the G/G genotype in subjects with substance dependence than in controls (Allele: chi(2) = 4.080, df = 1, P = 0.043; Genotype: chi(2) = 7.225, df = 2, P = 0.027). Although after correction for multiple testing, the findings are not considered significant (threshold P-value was set at 0.020 by the program SNPSpD), logistic regression analyses confirmed the modest association between SNP G-712A and substance dependence, when the sex and age of subjects were taken into consideration. The negative results for AFDs, PTSD, and schizophrenia could be due to the low statistical power. Further study with larger samples is warranted.

Adult↗
PubMed2007

Schizotypal dimensions: an intermediate phenotype associated with the COMT high activity allele.

BACKGROUND: Although catechol-O-methyltransferase (COMT) has long been suggested to be implicated in the pathogenesis of schizophrenia, association studies have generated discrepant results concerning the involvement of the COMT gene in schizophrenia. As several studies have suggested that schizotypal traits might be genetically related to schizophrenia, increased statistical power to detect gene effects could be obtained by using dimensional personality traits in unaffected relatives. METHODS: We tested the hypothesis that the functional Val158Met COMT polymorphism might contribute to the variance of self-reported schizotypal scores in a sample of 106 unaffected subjects, composed of controls (N = 57), first-degree relatives of schizophrenic (N = 27) and of bipolar (N = 22) probands. We also looked for specific associations between COMT polymorphisms and the three dimensions of schizotypy (positive, negative, disorganized) assessed by the Schizotypal Personality Questionnaire (SPQ). RESULTS: We found that self-reported SPQ scores are related to COMT genotype (P = 0.01), with individuals homozygous for the high activity allele having the highest scores. This association is primarily due to specific associations with the positive (P = 0.001) and negative (P = 0.04) dimensions. CONCLUSIONS: Our data support the hypothesis that the functional COMT polymorphism could be involved in different psychotic dimensions. This confirms that studying specific schizotypal dimensions can help to identify the genes involved in the pathogenesis of psychosis.

Adult↗
PubMed2007

Preliminary evidence for linkage to chromosome 1q31-32, 10q23.3, and 16p13.3 in a South African cohort with bipolar disorder.

Although the genetic variants predisposing to the development of bipolar disorder (BPD) have yet to be conclusively identified, replicated reports of linkage to particular chromosomal regions have been encouraging. Here we carried out a non-parametric linkage analysis of nine of these candidate loci in a unique South African sample of 47 BPD pedigrees (N = 350). Three polymorphic markers per region of interest (3 x 9) were typed in a Caucasian cohort of Afrikaner and British origin. Statistically significant evidence for linkage was obtained at 1q31-32, 10q23.3, and 16p13.3 with maximum NPL scores of 2.52, 2.01, and 1.84, respectively. Our results add to the growing evidence that these chromosomal regions harbor genetic variants that play a role in the development of bipolar spectrum illness. Negative results were obtained for the remaining six candidate loci, possibly due to limited statistical power.

Bipolar Disorder↗
PubMed2004

Epidemiologic approaches to identifying environmental causes of birth defects.

Epidemiology can be used to elucidate environmental causes of birth defects. This paper discusses 1) different types of environmental causes; 2) the difficulties in comparing the prevalence of birth defects between populations, including the need for a population base and the implications of prenatal diagnosis; 3) the main study designs for observational epidemiological studies and the various sources of bias; 4) how statistical power can be increased by meta-analysis or multicentric studies, and improved grouping of birth defects into etiologically more homogeneous subgroups; 5) the distinction between association and causation; 6) the interpretation of clusters in time and space in relation to local environmental causes; and 7) the potential of genetic epidemiology to help elucidate environmental causes. While further research continues into the environmental causes of birth defects, the epidemiologic evidence base for policy making and clinical practice is poor in many areas. The epidemiologic approach is important not only to elucidate environmental causes but also to assess the implementation of existing research into policy and practice for the prevention of birth defects.

Adult↗
PubMed2006

Current perspectives on the genetic analysis of autism.

Although no definitive genetic mutations leading to autism susceptibility have been established, the field has many new resources to tackle this difficult problem. Numbers of families at many research sites are now large, and new collaborations among these groups will allow for collections of subjects with enough statistical power to detect relatively small gene effects. New technological advances in genotyping will allow for more fine-grained genetic analysis, and more sophisticated techniques have been developed to address the vast amounts of data acquired. Researchers have also begun to focus on intermediate phenotypes associated with autism, such as elevated serotonin, increased head circumference, social difficulties, or language impairment or delay. These phenotypes may help to stratify affected cases into more genetically homogeneous subgroups, and may also occur in their clinically unaffected relatives. The study of intermediate phenotypes may allow investigators to find common gene variants that lead to autism susceptibility. Here we discuss the major intermediate phenotypes, and give an overview of current genetic analysis techniques.

Autistic Disorder↗
PubMed1990

Reliability of age at death in the Hamann-Todd collection: validity of subselection procedures used in blind tests of the summary age technique.

The blind test procedures used by Lovejoy et al., (Am. J. Phys. Anthropol. 68:1-14, 1985a) have been criticized because they used the Hamann-Todd collection as their known-age population. It has been suggested that variation within this sample was reduced by selection procedures designed to ensure accuracy of age at death. Powerful statistical tests for differences in dispersion of ages for pubic symphyseal stages were applied to comparisons between their core sample (N = 238) and those of a large autopsy-room collection used to develop the Suchey-Brooks System (N = 530). The variances in ages of the selected Hamann-Todd Sample are not reduced. The careful subselection of specimens has resulted in a valid statistical core sample for use in the development of aging methodologies.

Adult↗
PubMed1995

American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis.

OBJECTIVE: Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials. The goal of this study was to promulgate a single definition for use in RA trials. METHODS: Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3-step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement. RESULTS: The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved. CONCLUSION: We present a definition of improvement which we hope will be used widely in RA trials.

Adult↗
PubMed2003

Prevalence of birth defects among infants of Gulf War veterans in Arkansas, Arizona, California, Georgia, Hawaii, and Iowa, 1989-1993.

BACKGROUND: Epidemiologic studies of birth defects among infants of Gulf War veterans (GWV) have been limited to military hospitals, anomalies diagnosed among newborns, or self-reported data. This study was conducted to measure the prevalence of birth defects among infants of GWVs and nondeployed veterans (NDV) in states that conducted active case ascertainment of birth defects between 1989-93. METHODS: Military records of 684,645 GWVs and 1,587,102 NDVs were electronically linked with 2,314,908 birth certficates from Arizona, Hawaii, Iowa, and selected counties of Arkansas, California, and Georgia; 11,961 GWV infants and 33,052 NDV infants were identified. Of these, 450 infants had mothers who served in the Gulf War, and 3966 had NDV mothers. RESULTS: Infants conceived postwar to male GWVs had significantly higher prevalence of tricuspid valve insufficicieny (relative risk [RR], 2.7; 95% confidence interval [CI], 1.1-6.6; p = 0.039) and aortic valve stenosis (RR, 6.0; 95% CI, 1.2-31.0; p = 0.026) compared to infants conceived postwar to NDV males. Among infants of male GWVs, aortic valve stenosis (RR, 163; 95% CI, 0.09-294; p = 0.011) and renal agenesis or hypoplasia (RR, 16.3; 95% CI, 0.09-294; p = 0.011) were significantly higher among infants conceived postwar than prewar. Hypospadias was significantly higher among infant sons conceived postwar to GWV women compared to NDV women (RR, 6.3; 95% CI, 1.5-26.3; p = 0.015). CONCLUSION: We observed a higher prevalence of tricuspid valve insufficiency, aortic valve stenosis, and renal agenesis or hypoplasia among infants conceived postwar to GWV men, and a higher prevalence of hypospadias among infants conceived postwar to female GWVs. We did not have the ability to determine if the excess was caused by inherited or environmental factors, or was due to chance because of myriad reasons, including multiple comparisons. Although the statistical power was sufficient to compare the combined birth defects prevalence, larger sample sizes were needed for less frequent individual component defects.

Adult↗
PubMed1990

Comparison of indices of ambient exposure to 60-hertz electric and magnetic fields.

Occupational, environmental, or domestic exposure of human beings to extremely low-frequency (50- or 60-Hz) electric and magnetic fields varies continuously over time. In epidemiological studies of possible health effects, exposures over long durations must be aggregated in terms of simple summary indices. However, there are many different, biologically plausible, ways of aggregating the data. While awake, each of 20 electric utility personnel and 16 office workers had provided minute-by-minute measures of incident electric (V/m) and magnetic (muT) fields over a 7-day period via personal dosimeters. Once the measures were aggregated as means, medians, peaks, and other indices, intercorrelations between all index pairs were calculated; correlation matrices are presented for the utility and office workers both by group and when pooled. Product-moment coefficients (r) greater that .80 were found between the time-weighted arithmetic mean (TWA) and indices that explicitly emphasize short but highly intense exposures, such as peak values and time above thresholds. Medians and geometric means were less highly correlated with the TWA. Use of only a few indices, perhaps the TWA alone, may sacrifice but little statistical power in most epidemiological studies of utility workers exposed to ELF fields. However, correlations between electric-field strength and magnetic-field density were generally quite weak, as were correlations of either with high-frequency transients; these findings underscore the need to measure each of these variables in epidemiological studies. Indices of exposure incurred outside the workplace were less strongly correlated, which may indicate the need to use several indices in general-population studies.

Electromagnetic Fields↗
PubMed1995

Do ELF magnetic fields affect human reaction time?

Two double-blind studies were run in an attempt to confirm the finding that a 0.2 Hz magnetic field affects simple reaction time (RT) in humans, whereas a 0.1 Hz field does not. In the first experiment, 12 volunteer subjects were exposed to a continuous 0.2 Hz, 0.1 Hz, or sham field in a fully counterbalanced, within-subjects design. Subjects were run singly for one condition each day over 3 consecutive days with a field strength of 1.1 mT and a daily exposure duration of 5 min. Neither magnetic field had any effect on RT at any time during the exposure. One condition of a second study, using a new group of 24 volunteer subjects, also failed to find any field effects at 0.2 Hz. Additionally, the second study failed to show any effects when the frequency, flux density, and field orientation were set according to parametric resonance theory. It is suggested that, although ELF magnetic field effects on human behaviour may be elusive, future research can improve detection rates by paying greater attention to reducing error variance and increasing statistical power.

Adult↗
PubMed2001

The effect of a selenium supplementation on the outcome of patients with severe systemic inflammation, burn and trauma.

Patients with systemic inflammatory response syndrome (SIRS) and sepsis exhibit decreased plasma selenium and glutathione peroxidase activity. This has been shown in several clinical studies. Moreover, the degree of selenium deficiency correlates with the severity of the disease and the incidence of mortality. Patients with SIRS and sepsis are exposed to severe oxidative stress. Selenoenzymes play a major role in protecting cells against peroxidation, especially lipid peroxidation and are involved in the regulation of inflammatory processes. Therefore, selenium substitution in those patients might be effective in the prevention of multiorgan failure. The results of randomised clinical trials investigating selenium substitution in critical ill patients with inflammation are reviewed. In two independently performed randomised, prospective clinical trials, including patients with systemic inflammatory response syndrome or sepsis, the supplementation of selenium revealed a significant reduction in multiorgan failure and, especially, a lower incidence of acute renal failure and respiratory distress syndrome. One of those trials also could demonstrate a significant reduction of mortality in the most severely ill patients. Two other studies, where selenium together with other trace elements or a mixture of antioxidants were used in the treatment of patients with severe burn injuries or trauma showed a significant reduction in the secondary infection rate, including sepsis. Thus, selenium supplementation seems to improve the outcome of patients with SIRS, sepsis and severe injury, however, pivotal prospective clinical trials with sufficient statistical power are now necessary to finally prove the efficacy of a selenium supplementation in these diseases.

Adult↗
PubMed2003

Increased secretion of insulin during oral glucose tolerance test can be a predictor of stent restenosis in nondiabetic patients.

Insulin is known to stimulate proliferation and migration of vascular smooth muscle cells. As the predominant mechanism of restenosis after stent implantation is neointimal tissue proliferation, one can expect a relationship between hyperinsulinemia and restenosis in these patients. The aim of this study was to determine whether hyperinsulinemia during oral glucose tolerance test is a predictor of the development of restenosis after stent implantation in nondiabetic patients. We prospectively studied 52 nondiabetic patients with effort angina who underwent elective stent implantation for single-vessel coronary artery disease. In order to increase the statistical power of the study, numerous exclusion criteria were applied. All patients were subjected to a 75 g oral glucose tolerance test a day before the stent implantation and underwent follow-up angiography 6 months later. Plasma insulin levels in fasting (6.77 +/- 1.57 vs. 5.36 +/- 1.35 micro U/ml; P = 0.005), at 30 min (102.48 +/- 10.6 vs. 47.74 +/- 12.75 micro U/ml; P = 0.001), 1 hr after (120.23 +/- 14.1 vs. 63.08 +/- 12.62 micro /ml; P = 0.001), 2 hr after (63.58 +/- 8.64 vs. 34.88 +/- 6.82 micro /ml; P = 0.001), and 3 hr after (25.71 +/- 5.65 vs. 23.02 +/- 4.61 micro /ml; P = 0.04) loading were significantly higher in patients with stent restenosis than in patients without stent restenosis. Insulin area and insulin area/glucose area were also significantly higher in patients with stent restenosis than in patients without (219.5 +/- 23.8 vs. 118.9 +/- 21.8, P = 0.001, and 0.62 +/- 0.09 vs. 0.33 +/- 0.06, P = 0.001, respectively). By multiple logistic regression analysis, insulin area during oral glucose tolerance test was found to be an independent predictor of stent restenosis (OR = 1.12; 95% CI = 1.01-1.25; P = 0.031). In conclusion, nondiabetic patients with hyperinsulinemia during oral glucose tolerance test have a high risk for restenosis after stent implantation, and performing this simple test before intervention may be useful for the prediction of stent restenosis.

Adult↗
PubMed2004

Effect of stents in reducing restenosis in small coronary arteries: a meta-analysis.

The ability of stents to reduce restenosis was established in larger coronary arteries. Clinical trials of stenting in smaller vessels have yielded conflicting results due in part to their sample sizes. The aim of this meta-analysis was to increase the statistical power by pooling data from these clinical trials. Trials were identified from Medline search, review of recent cardiology meetings' abstracts, and manual review of bibliographies. Studies were included if they were prospective randomized controlled trials. Endpoints examined included a dichotomized definition of angiographic restenosis, target lesion revascularization (TLR), target vessel revascularization (TVR), or any repeat revascularization. Pooling of data was performed by calculating a Mantel-Haenszel odds ratio (OR). The analysis included 2,598 patients enrolled in eight clinical trials. Stenting significantly reduced restenosis (OR = 0.62; 95% CI = 0.61-0.63). Concordantly, stenting reduced TLR (OR = 0.49), TVR (OR = 0.90), and any revascularization (OR = 0.48). This meta-analysis supports the hypothesis that stenting reduces restenosis in small coronary arteries as well as in larger coronary arteries. The apparent discordant result of individual clinical trials was due in part to underpowering related to small sample sizes.

Angioplasty, Balloon, Coronary↗
PubMed2002

European Organization for Research and Treatment of Cancer and Groupe d'Etude des Lymphomes de l'Adulte very favorable and favorable, lymphocyte-predominant Hodgkin disease.

BACKGROUND: Lymphocyte-predominant Hodgkin disease (LPHD) is rare and has a natural history different from that of classic Hodgkin disease. There is little information in the literature regarding the role of chemotherapy in patients with early-stage LPHD. The objective of this study was to examine recurrence free survival (RFS), overall survival (OS), and patterns of first recurrence in patients with LPHD who were treated with radiotherapy alone or with chemotherapy followed by radiotherapy. METHODS: From 1963 to 1996, 48 consecutive patients ages 16-49 years (median, 28 years) with Ann Arbor Stage I (n = 30 patients) or Stage II (n = 18 patients), very favorable (VF; n = 5 patients) or favorable (F; n = 43 patients) LPHD, according to the European Organization for Research and Treatment of Cancer and Groupe d'Etude des Lymphomes de l'Adulte (EORTC-GELA) criteria, received radiotherapy alone (n = 37 patients) or received chemotherapy followed by radiotherapy (n = 11 patients). The percentages of patients with VF disease (11% vs. 9% in the radiotherapy group vs. the chemotherapy plus radiotherapy group, respectively) or F disease (89% vs. 91%, respectively) within the two treatment groups were similar (P = 1.00). A median of three cycles of chemotherapy with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or with mitoxantrone, vincristine, vinblastine, and prednisone (NOVP) was given initially to six patients and five patients, respectively. A median total radiotherapy dose of 40 grays (Gy) given in daily fractions of 2.0 Gy was delivered to both treatment groups. RESULTS: The median follow-up was 9.3 years, and 98% of patients were observed for > or = 3.0 years. RFS was similar for patients who were treated with radiotherapy alone and patients who were treated with chemotherapy followed by radiotherapy (10-year survival rates: 77% and 68%, respectively; P = 0.89). The OS rate also was similar for the two groups (10-year survival rates: 90% and 100%, respectively; P = 0.43). MOPP or NOVP chemotherapy did not reduce the risk of recurrence outside of the radiotherapy fields. CONCLUSIONS: MOPP or NOVP chemotherapy did not improve RFS or OS significantly in patients with VF or F LPHD, although the statistical power was limited. Ongoing clinical trials will help to clarify the role of a watch-and-wait strategy or systemic therapy, including anthracycline (epirubicin or doxorubicin), bleomycin, and vinblastine-based chemotherapy or antibody-based approaches, in the treatment of these patients.

Adolescent↗
PubMedDate not supplied

A linkage study of 12 IDDM susceptibility loci in the Finnish population.

BACKGROUND: HLA region is the major locus (IDDM1) of type 1 diabetes (T1D) susceptibility. It explains approximately 50% of the genetic background of T1D, indicating additional genetic determinants. Genome scans and candidate gene studies have generated several chromosomal candidate regions that may have a role in T1D development. METHODS: We tested 12 of these loci for linkage in 107 Finnish T1D multiplex families using 23 microsatellite markers and 2 SNPs. Families were stratified according to the HLA status and sharing at the DQB1 gene. RESULTS: We found no significant or suggestive MLS in our unstratified families outside the IDDM1 locus. The highest MLS was seen close to the IDDM9 region marker D3S3576 at 3q21-q25 (MLS=1.05). This marker also had a global p-value of 0.0032 (ETDT) in maternal transmissions. IDDM6 and 12q12-q15 region showed MLS=1.1 and MLS=1.3 respectively in HLA-DQB1*0302/x (x is not equal to HLA-DQB1*02) stratified families. IDDM12 showed MLS=2.0 in HLA-DQB1 identical sib pairs. Linkage at IDDM12 was supported by a global p-value of 0.0006 (uncorrected) in ETDT. For IDDM2, p-values of 0.028 and 0.009 were observed in ETDT with MspI-2221 SNP in unstratified and HLA-DQB1*0302/x-stratified families respectively. CONCLUSIONS: Our results are consistent with previous findings of linkage or association to T1D at IDDM2, IDDM6, IDDM9, IDDM12 and 12q12-q15 regions but do not unambiguously confirm them. A larger sample set is required to gain statistical power needed to confirm our findings in the Finnish population.

Chromosomes, Human↗
PubMed2006

Relations between dietary restraint, depressive symptoms, and binge eating: A longitudinal study.

OBJECTIVE: Temporal relations between dietary restraint, depressive symptoms, and binge eating were tested by means of three competing models positing that (1) dietary restraint and depressive symptoms predict future increases in binge eating, (2) binge eating predicts future increases in dietary restraint and depressive symptoms, and (3) binge eating is reciprocally related to these two factors. METHOD: Longitudinal data from a community sample of Dutch females (N = 143; M age = 19.6) was used to test these relations while controlling for initial levels of these factors. RESULTS: Dietary restraint did not predict future increases in binge eating, nor did binge eating predict future increases in dietary restraint. Depressive symptoms predicted future increases in binge eating, but binge eating did not predict future increases in depressive symptoms. CONCLUSION: Although this study had limited statistical power, the pattern of relations and effect sizes suggest that depressive symptoms, but not dietary restraint, increase risk of binge eating for late adolescent females.

Adolescent↗