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PubMed2003

Linkage disequilibrium mapping provides further evidence of a gene for reading disability on chromosome 6p21.3-22.

Linkage disequilibrium (LD) mapping was used to follow up reports of linkage between reading disability (RD) and an 18 cM region of chromosome 6p21.3-22. Using a two-stage approach, we tested for association between RD and 22 microsatellite markers in two independent samples of 101 (Stage 1) and 77 (Stage 2) parent/proband trios in which RD was rigorously defined. The most significant replicated associations were observed between combinations of markers D6S109/422/1665 (Stage 1, P=0.002 (adjusted for multiple testing); Stage 2, P=0.0001) and D6S506/1029/1660 (Stage 1, P=0.02 (adjusted), Stage 2, P=0.0001). The only two-marker association observed in both samples was with D6S422/1665 (P=0.01, 0.04). No single marker showed replicated association but D6S506 produced values of P=0.01 and 0.08 which were significant when combined (P=0.02). We observed weaker and less consistent evidence of association in a region of confirmed linkage to RD in previous studies. The most consistently significant haplotypic association D6S109/422/1665, showed association with single-word reading, spelling, phonological awareness, phonological decoding, orthographic accuracy and random automised naming, but not with vocabulary or Attention Deficit Hyperactivity Disorder. Our findings strongly support the presence of a gene contributing to RD in a region of chromosome 6 between markers D6S109 and D6S1260, but do not rule out the presence of a gene between D6S1556 and MOG.

Adolescent↗

PubMed2001

Accuracy of biomarkers to diagnose acute cardiac ischemia in the emergency department: a meta-analysis.

STUDY OBJECTIVE: We sought to evaluate quantitatively the evidence on the diagnostic performance of presentation and serial biochemical markers for emergency department diagnosis of acute cardiac ischemia (ACI), including acute myocardial infarction (AMI) and unstable angina. METHODS: We conducted a systematic review and meta-analysis of the English-language literature published between 1966 and December 1998. We examined the diagnostic performance of creatine kinase, creatine kinase-MB, myoglobin, and troponin I and T testing. Diagnostic performance was assessed by using estimates of test sensitivity and specificity and was summarized by summary receiver-operating characteristic curves. RESULTS: Only 4 studies were found that evaluated all patients with ACI; 73 were found that focused only on a diagnosis of AMI. To diagnose ACI, presentation biomarker tests had sensitivities of 16% to 19% and specificities of 96% to 100%; serial biomarker tests had sensitivities of 31% to 45% and specificities of 95% to 98%. Considering only the diagnosis of AMI, presentation biomarker tests had summary sensitivities of 37% to 49% and summary specificities of 87% to 97%; serial biomarker tests had summary sensitivities of 79% to 93% and summary specificities of 85% to 96%. Variation of test sensitivity was best explained by test timing. Longer symptom duration or time between serial tests yielded higher sensitivity. CONCLUSION: The limited evidence available to evaluate the diagnostic accuracy of biomarkers for ACI suggests that biomarkers have very low sensitivity to diagnose ACI. Thus, biomarkers alone will greatly underdiagnose ACI and will be inadequate to make triage decisions. For AMI diagnosis alone, multiple testing of individual biomarkers over time substantially improves sensitivity, while retaining high specificity, at the expense of additional time. Further high-quality studies are needed on the clinical effect of using biomarkers for patients with ACI in the ED and on optimal timing of serial testing and in combination with other tests.

Acute Disease↗

PubMed2003

Hla-B genotype in Japanese patients with Crohn's disease.

PURPOSE: The HLA-B gene is one of the susceptibility genes for inflammatory bowel disease. Previous association studies of HLA-B showed several associated alleles and haplotypes of HLA-B in patients with ulcerative colitis, and among the associated alleles HLA-B*52 is well known to be strongly associated with ulcerative colitis in Japanese patients. However, there are no convincing reports about HLA-B including the B*52 allele in patients with Crohn's disease. The purpose of this study was to determine if HLA-B, especially the B*52 allele, confers susceptibility to Crohn's disease or determines the disease phenotype of Crohn's disease. METHODS: A total of 195 patients with Crohn's disease (49 ileitis, 106 ileocolitis, 34 colitis, 6 uncertain) and 185 healthy controls were studied in this case-controlled study. All patients and healthy controls were Japanese. Genotyping of the HLA-B gene was performed by a polymerase chain reaction, sequence-specific primer that can classify the gene into 23 allele groups. Allele frequencies were compared between patients with Crohn's disease and healthy controls with chi-squared test using a 2 x 2 contingency table. P value was corrected by the number of allele groups (n = 23) observed in the Japanese population or the number of clinical subgroups. Corrected P values of <0.05 were considered to be statistically significant. RESULTS: Before the correction for multiple testing, B*4001 and B*44 were associated with patients with Crohn's disease, positively and negatively, respectively. However, after the correction there were no significant differences in any HLA-B alleles between patients with Crohn's disease and healthy controls. In the subgroup analysis according to clinical phenotypes (disease location, anal lesion, age at diagnosis, need for surgery), none of the HLA-B alleles except B*52 showed any disease phenotype-genotype associations. The allele frequency of B*52 in the colitis type (16.2 percent; corrected P = 0.011) was significantly higher than that in the combined group of the ileitis (7.1 percent) and ileocolitis (5.2 percent) types. CONCLUSIONS: These results demonstrated that HLA-B did not confer overall susceptibility to Crohn's disease in Japan, but the B*52 allele may affect the location of the disease.

Adult↗

PubMed2006

Correlation of radiologist rank as a measure of skill in screening and diagnostic interpretation of mammograms.

PURPOSE: To determine whether skill in the interpretation of screening mammograms is correlated with skill in the interpretation of diagnostic mammograms. MATERIALS AND METHODS: The institutional review board of the University of South Florida approved this study. This study was determined to be exempt from informed consent requirements because of the retrospective use of images and was conducted before HIPPA requirements were implemented. A total of 59 radiologists interpreted screening and diagnostic performance test sets of mammograms with a 1-year interval. Interpretations were recorded with modifications of the Breast Imaging and Reporting Data System. Radiologist skill was measured as the radiologist's ranking among his or her cohort in each of several measures of performance (ie, performance test receiver operating characteristic curve area, performance test screening sensitivity, performance test diagnostic sensitivity, and associated specificities). Correlations between radiologist rank in screening and rank in the diagnostic performance test measures were analyzed with the Spearman rank correlation statistical test. RESULTS: Radiologist rank in screening interpretations and in diagnostic interpretations was found to be significantly correlated in all measurements (P < .05). However, only two measurments (ie, receiver operating characteristic curve area rank correlation of 0.327 and sensitivity rank correlation of 0.402) remained significant after adjusting for multiple testing. The correlation between ranked screening specificity and ranked diagnostic specificity (0.296) was significant at only the .05 level. CONCLUSION: The interpretive performance of radiologists among their peers is moderately correlated between screening and diagnostic interpretations. Thus, proficiency in one area does not guarantee proficiency in the other area for some radiologists.

Clinical Competence↗

PubMed1997

The fusiform face area: a module in human extrastriate cortex specialized for face perception.

Using functional magnetic resonance imaging (fMRI), we found an area in the fusiform gyrus in 12 of the 15 subjects tested that was significantly more active when the subjects viewed faces than when they viewed assorted common objects. This face activation was used to define a specific region of interest individually for each subject, within which several new tests of face specificity were run. In each of five subjects tested, the predefined candidate "face area" also responded significantly more strongly to passive viewing of (1) intact than scrambled two-tone faces, (2) full front-view face photos than front-view photos of houses, and (in a different set of five subjects) (3) three-quarter-view face photos (with hair concealed) than photos of human hands; it also responded more strongly during (4) a consecutive matching task performed on three-quarter-view faces versus hands. Our technique of running multiple tests applied to the same region defined functionally within individual subjects provides a solution to two common problems in functional imaging: (1) the requirement to correct for multiple statistical comparisons and (2) the inevitable ambiguity in the interpretation of any study in which only two or three conditions are compared. Our data allow us to reject alternative accounts of the function of the fusiform face area (area "FF") that appeal to visual attention, subordinate-level classification, or general processing of any animate or human forms, demonstrating that this region is selectively involved in the perception of faces.

Adult↗

PubMed2004

Consensus folding of aligned sequences as a new measure for the detection of functional RNAs by comparative genomics.

Facing the ever-growing list of newly discovered classes of functional RNAs, it can be expected that further types of functional RNAs are still hidden in recently completed genomes. The computational identification of such RNA genes is, therefore, of major importance. While most known functional RNAs have characteristic secondary structures, their free energies are generally not statistically significant enough to distinguish RNA genes from the genomic background. Additional information is required. Considering the wide availability of new genomic data of closely related species, comparative studies seem to be the most promising approach. Here, we show that prediction of consensus structures of aligned sequences can be a significant measure to detect functional RNAs. We report a new method to test multiple sequence alignments for the existence of an unusually structured and conserved fold. We show for alignments of six types of well-known functional RNA that an energy score consisting of free energy and a covariation term significantly improves sensitivity compared to single sequence predictions. We further test our method on a number of non-coding RNAs from Caenorhabditis elegans/Caenorhabditis briggsae and seven Saccharomyces species. Most RNAs can be detected with high significance. We provide a Perl implementation that can be used readily to score single alignments and discuss how the methods described here can be extended to allow for efficient genome-wide screens.

Algorithms↗

PubMed2003

Inducible nitric oxide synthase promoter polymorphism in human brucellosis.

Nitric oxide (NO), produced by the inducible nitric oxide synthase (NOS2) protein, is a defence mechanism against various pathogens, including bacteria of the genus Brucella. The aim of this study was to investigate the possible association between the NOS2 gene promoter polymorphism, TAAA(n) and CCTTT(n) microsatellites, and the predisposition to human brucellosis. We performed a case-control study in 85 patients with brucellosis and 100 healthy individuals, matched for age and sex, living in the same geographic area, in whom the NOS2 promoter was genotyped by using a polymerase chain reaction (PCR)-based method combined with fluorescent technology. No statistically significant differences were observed in the distribution of TAAA(n) alleles between the groups under study. When the overall NOS2 CCTTT(n) allele distribution of the brucellosis patients was compared with that of the control subjects, a significant skewing was observed (P = 0.04, by chi(2) test from 2 x 9 contingency table). Interestingly, we observed a trend towards Brucella infection protection with the 9 repeat (181 bp) allele (1.8% patients vs. 7.5% controls; P = 0.01, odds ratios = 0.22, 95% confidence interval = 0.05-0.83), which turned out to be non-significant after applying multiple testing. We concluded that the NOS2 microsatellite polymorphism might not have a major effect on brucellosis; nevertheless, the fact that a non-significant trend towards protection was detected in the CCTTT(n) alleles may be an indication for a follow-up study.

Adolescent↗

PubMed1995

Gender-related differences in clinical management after exercise nuclear testing.

OBJECTIVES: This study sought to determine the rate of referral to cardiac catheterization in men and women early after nuclear testing as a function of the magnitude of myocardial ischemia by radionuclide perfusion imaging. BACKGROUND: Although many previous studies have suggested that gender-related differences are present in the clinical management of coronary artery disease, the presence of such a difference with respect to referral to catheterization after noninvasive testing is disputed. METHODS: We examined 3,211 consecutive patients (1,074 women, 2,137 men) who underwent exercise dual-isotope single-photon emission computed tomography and had follow-up evaluation performed at least 1 year after nuclear testing (mean [+/- SD] follow-up 19 +/- 5 months) for "hard" events (cardiac death and myocardial infarction) and referral to cardiac catheterization or revascularization within 60 days of nuclear testing. Multiple logistic regression analysis was performed to determine the best predictors of referral to catheterization as well as to examine whether gender itself added further information to this model. RESULTS: Although men were referred to catheterization more frequently than women (10.6% vs 7.1%, p < 0.001) early after exercise nuclear testing, there were no differences in the rate of referral to catheterization or revascularization after stratification by the amount of abnormally perfused myocardium detected by the nuclear scan. Both men and women with normal scan results were infrequently referred to subsequent catheterization. In the setting of severe ischemia, women were referred to catheterization more frequently than men. This higher rate appears to be clinically appropriate because women with severely abnormal scan results had a significantly higher event rate than men (17.5% vs. 6.3%, p < 0.0001). This greater risk in women than in men appeared to be underappreciated because the increased rate of hard events in women with severely abnormal scan results was out of proportion to the smaller increase in their rate of referral to cardiac catheterization. Although gender added information to the multivariate model most predictive of referral to catheterization models when nuclear variables were not included, when nuclear variables were considered, the addition of gender added no further significant information. This finding suggests that adjusting for differences in perfusion scan abnormalities by the use of nuclear testing eliminated the apparent gender-related referral bias. CONCLUSIONS: After controlling for differences in perfusion scan abnormalities, no gender-related referral bias to catheterization was present. In the setting of severe ischemia, women had a greater rate referral to catheterization than men. As a function of risk, both men and women were appropriately referred to catheterization at a low rate when the scan result was normal. However, because women with severe perfusion abnormalities had a greater rate of cardiac death and myocardial infarction then men, women in this high risk subgroup were underreferred to catheterization relative to men. This finding points to the need to better identify women at high cardiac risk.

Aged↗

PubMed2005

Detection of quantitative trait loci influencing conformation traits and calving ease in Holstein-Friesian cattle.

An extension of our previous genome scan of a North American Holstein-Friesian population was conducted to identify quantitative trait loci (QTL) affecting conformation traits. Resource families consisted of 1404 sons of 10 elite sires. Genome coverage was estimated to be 2713.5 cM (90%) for 406 markers using a granddaughter design. Regression interval mapping was used to detect QTL affecting 22 conformation traits, including body, udder, feet and legs, and dairy conformation as well as calving ease. Analysis of the families jointly identified 41 chromosome-wise significant QTL influencing conformation traits and 3 significant QTL influencing calving ease on 20 chromosomes. The false discovery rate method was used to account for multiple testing and 3/4 of the suggestive and 5/6 of significant QTL should be real effects. Fourteen of the 44 QTL were significant at the genome-wise level. Comparison of these results with other published reports identifies common QTL affecting conformation traits. Regions on 10 chromosomes appear to affect multiple traits, including conformation, milk production, and somatic cell score, within these particular US Holstein families. Additional work is needed to determine the precise locations of the QTL and select positional candidate genes influencing these traits.

Animals↗

PubMed1986

Screening for oxygen intolerance in U.S. Navy divers.

All U.S. Navy diving candidates are screened for their tolerance to hyperbaric oxygen by taking an oxygen tolerance test (OTT). During a recent experimental oxygen dive series at the U.S. Navy Experimental Diving Unit, three divers were noted to be reproducibly oxygen sensitive. These three divers were then given additional OTTs to see if any evidence of central nervous system oxygen toxicity would be detected by these multiple tests. The additional OTTs did not produce any signs or symptoms of oxygen toxicity in these already proven susceptible divers. A subsequent review of the records of the Naval Safety Center yielded a total of 1347 OTTs from 1 January 1972 to 31 December 1981. A review of diving accidents reported during this period revealed that 26 episodes of oxygen toxicity were noted during OTTs for a derived failure rate of 1.9%. Analysis of oxygen toxicity episodes encountered during operational Navy diving for this period found that 9 episodes of nonconvulsive oxygen toxicity were seen in mixed gas diving and 3 episodes of nonconvulsive oxygen toxicity were noted in closed circuit oxygen diving. Conclusions from this paper are: Screening for oxygen intolerance is complicated by intraindividual variation in oxygen tolerance; U.S. Navy diving using 100% oxygen during the period studied has had an acceptable safety record according to the data on record at the Naval Safety Center; the OTT as currently administered by the U.S. Navy does not identify all individuals who are relatively susceptible to oxygen toxicity; those individuals who do fail the OTT are unusually susceptible to oxygen toxicity; and because of the need to continue to identify these unusually susceptible individuals, the OTT should continue to be administered to U.S. Navy diver candidates.

Adult↗

PubMed2004

Human beta-defensins 2 and 3 demonstrate strain-selective activity against oral microorganisms.

Human beta-defensins 2 and 3 (HBD-2 and HBD-3) are inducible peptides present at sites of infection in the oral cavity. A few studies have reported broad-spectrum antimicrobial activity for both peptides. However, no comprehensive study has thoroughly investigated their potential against oral pathogens. The purpose of this study was to test the effectiveness of HBD-2 and HBD-3 against a collection of oral organisms (Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum, Porphyromonas gingivalis, Peptostreptococcus micros, Actinomyces naeslundii, Actinomyces israelii, Streptococcus sanguis, Streptococcus mutans, Candida tropicalis, Candida parapsilosis, Candida krusei, Candida glabrata, and Candida albicans). Radial diffusion assays were used to test HBD-2 and HBD-3 activities against at least three strains of each species. There was significant variability in MICs, which was strain specific rather than species specific. MICs ranged from 3.9 to >250 micro g/ml for HBD-2 and from 1.4 to >250 micro g/ml for HBD-3. HBD-3 demonstrated greater antimicrobial activity and was effective against a broader array of organisms. Overall, aerobes were 100% susceptible to HBD-2 and HBD-3, whereas only 21.4 and 50% of the anaerobes were susceptible to HBD-2 and HBD-3, respectively. HBD-2 and HBD-3 also demonstrated strain-specific activity against the Candida species evaluated. Interestingly, an association between HBD-2 and HBD-3 activities was noted. This suggests that the two peptides may have similar mechanisms yet utilize distinct pathways. The lack of activity against specific anaerobic strains and Candida warrants further investigation of the potential resistance mechanisms of these organisms. Finally, the significant variability between strains underlies the importance of testing multiple strains when evaluating activities of antimicrobial peptides.

Anti-Infective Agents↗

PubMed1988

[The Huber needle as a special cannula for the puncture of implanted ports and pumps--a mistake in multiple variations].

Huber-point needles, which are thought to be noncoring, are usually recommended for puncture of implanted drug-delivery devices, such as ports and pumps. Nevertheless, we found occlusion by silicone chips deriving from the silicone inlet septum to be a major technical complication. Electron microscopic investigations demonstrated substantial loss of material from the port membrane after repeated puncture with this type of needle. During an in vitro test, multiple puncture with Huber-type cannulas led to a pressure-dependent leakage of a port after only 150 to 750 insertions of a needle. In addition, the forces necessary for puncture or for withdrawal of the needle were increased with Huber-point needles, possibly due to a coring effect. Another disadvantage of the available port needles is the formation of a hook at the tip, which may lead to additional lesion of the port or pump membrane. In our opinion, resterilization of Huber needles, recommended by the manufactures, is not advisable, because it is well known that safe sterilization of small lumina, e.g., the lumen of the needle, is impossible.

Catheterization↗

PubMed2001

Interactions among the glucocorticoid receptor, lipoprotein lipase, and adrenergic receptor genes and plasma insulin and lipid levels in the Quebec Family Study.

The aim of the study was to investigate the possible interactions among the glucocorticoid receptor (GRL), lipoprotein lipase (LPL), and adrenergic receptor (ADR) genes on plasma insulin and lipid levels. The study was cross-sectional and based on 742 individuals from phase 2 of the Quebec Family Study (QFS) cohort. Gene markers were identified by Southern blot analysis or polymerase chain reaction (PCR). Plasma glucose and insulin in the fasted state and during an oral glucose tolerance test (OGTT) were determined and insulin and glucose areas were computed. Triglyceride (TG) and cholesterol concentrations in plasma and lipoprotein fractions were determined enzymatically. The results show that GRL and LPL variants had independent effects on plasma high-density lipoprotein cholesterol (HDL-C) and two beta2-ADR variants were related to total cholesterol concentrations. The alpha2-ADR gene Dral polymorphism was the only variant that had an independent effect on the plasma insulin area. Gene-gene interaction effects were found between GRL and alpha2-ADR genes for low-density lipoprotein cholesterol ([LDL-C] P = .013) and between GRL and LPL genes for HDL-C (P = .045). Higher-order interaction effects involving GRL, LPL, and ADR markers were observed for the plasma insulin area (P = .001 to .025) but not the glucose area. After correction for multiple tests, the findings remained essentially unchanged for the insulin area but became nonsignificant for the lipid phenotypes. In conclusion, multiple interactions among GRL, LPL, and ADR gene markers contribute to insulin metabolism and perhaps to lipid levels, while no significant effect is found for each gene separately. The LPL locus appears to determine the pattern of interactions with ADR and GRL loci. These results suggest that gene-gene interaction effects could play a role in the etiology of risk factors for common chronic diseases.

Area Under Curve↗

PubMed1986

Redox activities of antitumor anthracyclines determined by microsomal oxygen consumption and assays for superoxide anion and hydroxyl radical generation.

To explore the structural characteristics of various derivatives of the anticancer drugs, doxorubicin and daunorubicin, for exhibiting redox activities believed to be associated with toxic radical production, we tested over fifty derivatives in a rapid screening procedure for augmenting oxygen consumption by rat liver microsomes. Measurement of parent drug disappearance and of metabolite appearance for fourteen anthracyclines with a broad range of activities for augmenting oxygen consumption indicated that a single reaction, conversion to the 7-deoxyaglycone, occurred. Multiple tests of selected compounds showed that the liver microsome system exhibited saturation kinetics, and calculated values of Vmax/Km gave the same relative order of activities as did the screening test. The liver microsome system was not found to be stereoselective. Measurements of the abilities of a number of the anthracycline derivatives after chemical activation by reduction with sodium borohydride to convert oxygen to superoxide anion, or to the hydroxyl radical, were also made. The reactivities of the anthracyclines in these latter two assays were positively related to the activities obtained in the rat liver microsome screening test, suggesting that all three tests were measuring various steps in the sequence from anthracycline semiquinone radical formation through oxygen activation and radical formation. Superoxide anion generation from chemically reduced anthracyclines was inhibited by the addition of calf thymus DNA, and the extent of inhibition was positively correlated with the measured DNA association constants of the anthracyclines. However, the DNA association constants were unrelated to superoxide anion generation in the absence of DNA or to the augmentation of oxygen consumption in liver microsomes. Half-wave potentials were negatively correlated with both the results of the microsomal oxygen consumption test and the production of superoxide anion in the chemical test system. No relationships were discerned among the DNA association constants, half-wave potentials, or reoxidizabilities of the anthracyclines tested. Comparisons of the relatively low activities of certain of the anthracyclines in the biochemical and chemical tests for oxygen activation with their known high activities against murine tumors in vivo, but low cardiotoxicities in animal model systems, suggest that the separation of the cytotoxic antitumor and cardiotoxic actions of these derivatives may have been achieved.

Animals↗

PubMed2005

Association between the 5HT1B receptor gene (HTR1B) and the inattentive subtype of ADHD.

BACKGROUND: Preclinical and genetic studies have implicated the 5HT1B receptor gene (HTR1B) in attention-deficit/hyperactivity disorder (ADHD). Association with a single nucleotide polymorphism (SNP; G861C) has been observed, but more extensive linkage disequilibrium analyses have not been reported. METHODS: To examine haplotype structure, we genotyped 21 SNPs in and around the gene in 12 multigenerational CEPH pedigrees. We identified a haplotype block encompassing HTR1B and performed haplotype and single-marker association analyses for the eight SNPs within or flanking this block in 229 families of ADHD probands. In light of previous studies suggesting distinct genetic influences on ADHD subtypes, we also examined association with the inattentive and combined subtypes. RESULTS: We observed nonsignificant overtransmission of the G861 allele to ADHD offspring (one-tailed p = .07). Single-marker and haplotype tests of a haplotype block encompassing HTR1B revealed no other associations with ADHD. However, this haplotype block was associated with the inattentive subtype (global p < .01). Additionally, three SNPs in this block were nominally (p < .05) associated with the inattentive subtype, although these did not remain significant after correction for multiple testing. As reported in previous studies, we found paternal overtransmission of the G861 allele to offspring with ADHD; this appeared to be largely attributable to inattentive cases. CONCLUSIONS: These analyses suggest that variation in the HTR1B gene may primarily affect the inattentive subtype of ADHD.

Adolescent↗

PubMed2004

Anxiety-like behaviors following chronic ethanol exposure.

Rodent models of ethanol withdrawal-induced anxiety have been used to explore the neurobiology underlying withdrawal and to evaluate the utility of therapeutic agents aimed at reducing withdrawal severity. Of the many tests of anxiety-like behavior, the elevated plus maze, light/dark box, and open field are the most commonly used. In general, ethanol withdrawal decreases most or all of the individual behaviors recorded in these tasks, indicating the occurrence of an anxiogenic-like effect of withdrawal in rodents, although these effects of withdrawal have not always been found. Potential problems with interpreting the effects of withdrawal as being indicative of an anxiety-like state include the effects of withdrawal on motivation to explore an apparatus, non-specific effects of withdrawal on locomotion, and the use of test parameters that have not been pharmacologically validated. For example, most of the published studies interpreted as having shown increased anxiety-like behavior during ethanol withdrawal have also observed concurrent decreases in locomotion. At a minimum, a given test of anxiety-like behavior during withdrawal should be responsive to the dose and duration of ethanol exposure that was used to produce physical dependence, and should not non-specifically decrease locomotion. In addition, standard anxiolytic drugs should ameliorate the anxiogenic-like effects of withdrawal, preferably in multiple tests of anxiety-like behavior.

Animals↗

PubMed2006

Fine mapping of a linkage region on chromosome 17p13 reveals that GABARAP and DLG4 are associated with vulnerability to nicotine dependence in European-Americans.

A two-stage association study was conducted targeting a genomic region on chromosome 17p13 that we reported likely to harbor susceptibility gene(s) for nicotine dependence (ND). Participants were 2037 subjects from 602 nuclear families of either African-American (AA) or European-American (EA) origin from our Mid-South Tobacco Family (MSTF) cohort. We first examined 10 single nucleotide polymorphisms (SNPs) in six genes within the targeted region of about 90 kb to determine which SNP/gene was associated with ND, assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerström Test for ND (FTND). Individual SNP analysis revealed that SNPs rs17710 and rs222843 in GABA(A) receptor-associated protein (GABARAP) exhibited a significant association with at least one age- and gender-adjusted ND measure in the EA sample and rs222843 remained significant with the FTND after correction for multiple testing (P = 0.009). Although no SNP in DLG4 was significantly associated with ND, we found a G-G haplotype with a frequency of 14.2% formed by SNPs rs2242449 and rs507506 within the gene that showed significant inverse associations with all three ND measures [P = 0.003, 0.015 and 0.024, for SQ (defined as the number of cigarettes smoked per day), HSI and FTND, respectively]. We also found an A-A haplotype with a frequency of 8.8% formed by SNPs rs17710 and rs222843 in GABARAP, which revealed significant associations with all three ND measures (P = 0.006, 0.019 and 0.024, for SQ, HSI and FTND, respectively). To confirm these findings with a better coverage of GABARAP and DLG4, we conducted a second-stage association analysis by genotyping four more SNPs for GABARAP and nine more for DLG4 on the same set of samples. Our results from the second stage of individual SNP- and/or haplotype-based association analysis supported our finding of significant association of the DLG4 gene with ND. No significant association of GABARAP or DLG4 with ND was detected in the AA sample. Further, by comparing the linkage signal before and after adjustment for the SNPs of GABARAP and DLG4, we found that inclusion of the SNPs of the two genes as covariates largely reduced the linkage signal in the EA sample, but kept nearly unchanged in the AA sample. Taken together, our two-stage association analysis and linkage analysis results indicate that the GABARAP and DLG4 genes are involved in the etiology of ND in EA smokers. Further investigation of neurobiological mechanisms of the two genes in the etiology of ND is thus warranted.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Rapid diagnosis of cholera caused by Vibrio cholerae O139.

Hybridomas secreting specific monoclonal antibodies (MAbs) to Vibrio cholerae serogroup O139 were produced. Six monoclones (hybridomas) secreting MAbs specific only to lipopolysaccharide of V. cholerae O139 strains and which did not cross-react to 137 strains of other enteric microorganisms were obtained. These clones were designated 12F5-G11, 12F5-G2, 15F5-H5, 5B9-F8, 14C9-D2, and 6D2-D8. The immunoglobulin (Ig) heavy chain isotypes secreted by these clones were IgG2b, IgG2b, IgG2b, IgM, IgG2b, and IgG3, respectively. Clone 12F5-G11 was selected for mass production of MAb, which was used as a detection reagent in the antigen detection assay for diagnosis of cholera caused by V. cholerae O139, and this assay was compared to the conventional bacterial isolation method. Five batches of rectal swab cultures in alkaline-peptone water were collected from 6,497 patients with watery diarrhea. These were 6,310 patients admitted to Bamrasnaradura Infectious Diseases Hospital, 16 patients from Krung Thon Hospital, 78 patients from Bangkok Children's Hospital, 19 patients from Karen refugee camps, and 74 Indian patients from the National Institute of Cholera and Enteric Diseases, Calcutta, India. The V. cholerae O139 isolations from the rectal swab cultures and the antigen detection assays (i.e., the MAb-based dot-blot ELISA) were performed by different persons of different laboratories, and the results were revealed after all specimens had been tested. Of the 6,497 samples tested, the dot-blot ELISA correctly identified 42 of 42 V. cholerae O139-positive samples and gave a result of positive for three samples which were culture negative for V. cholerae O139. The diagnostic sensitivity, specificity, and efficacy of the dot-blot ELISA were 100, 99.95, and 99.26%, respectively. The ELISA is easy to perform and relatively inexpensive. It can test multiple samples at a single time, does not require special equipment, and does not produce great quantities of contaminated waste. Most of all, it reduces the diagnostic time from at least 2 days for the bacterial isolation to less than 90 min. The assay is recommended as a rapid screening test of cholera cases caused by V. cholerae O139.

Animals↗