bluuebunny/crossref_metadata_2025 huggingface dataset:
Synergistic Induction of the Nicotinamide Adenine Dinucleotide-Linked 15-Hydroxyprostaglandin Dehydrogenase by an Androgen and Interleukin-6 or Forskolin in Human Prostate Cancer Cells
Authors: Tong Min , Tai Hsin-Hsiung
Published: February 2004

The nicotinamide adenine dinucleotide-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of 15 (S)-hydroxyl group of prostaglandins and lipoxins and participates along with cyclooxygenases and lipoxygenases in controlling the cellular levels of prostaglandins and lipoxins. 15-PGDH could be induced by IL-6 and forskolin in addition to androgens in a time- and dose-dependent manner but not by other cytokines and growth factors in LNCaP cells. Concurrent addition of IL-6 and forskolin showed additive effect in the induction of 15-PGDH activity. However, combined addition of dihydrotestosterone (DHT) and IL-6 or DHT plus forskolin exhibited synergistic induction of 15-PGDH activity. The increase in enzyme activity was correlated with the expression of the enzyme protein as shown by Western blot analysis. The induction by DHT or IL-6 or forskolin or their combinations was inhibited by antiandrogen, casodex, in a dose-dependent manner, indicating that a functional androgen receptor was required for the action of any of these three agents. The induction by forskolin plus DHT or by either agent or by IL-6 alone was greatly inhibited by H-89, indicating the involvement of protein kinase A in the actions of forskolin, DHT, and IL-6. The induction of 15-PGDH by IL-6 was also blocked by some other protein kinase inhibitors, indicating the participation of MAPK, MAPK/ERK kinase, and STAT3 in the signaling pathway of IL-6. These results indicate that the induction of 15-PGDH by DHT, IL-6, and forskolin in LNCaP cells may involve a functional androgen receptor and phosphorylation-dependent multiple signaling pathways.
Genetic Analysis of Adenohypophysis Formation in Zebrafish
Authors: Herzog Wiebke , Sonntag Carmen , Walderich Brigitte , Odenthal Jörg , Maischein Hans-Martin , Hammerschmidt Matthias
Published: February 2004

The adenohypophysis consists of at least six different cell types, somatotropes, lactotropes, thyrotropes, melanotropes, corticotropes, and gonadotropes. In mouse, cloning of spontaneous mutations and gene targeting has revealed multiple genes required for different steps of adenohypophysis development. Here, we report the results of a systematic search for genes required for adenohypophysis formation and patterning in zebrafish. By screening F3 offspring of N-ethyl-N-nitrosourea-mutagenized founder fish, we isolated eleven mutants with absent or reduced expression of GH, the product of somatotropes, but a normally developing hypothalamus. Of such mutants, eight were further analyzed and mapped. They define four genes essential for different steps of adenohypophysis development. Two of them, lia and pia, affect the entire adenohypophysis, whereas the other two are required for a subset of adenohypophyseal cell types only. The third gene is zebrafish pit1 and is required for lactotropes, thyrotropes, and somatotropes, similar to its mouse ortholog, whereas the fourth, aal, is required for corticotropes, melanotropes, thyrotropes, and somatotropes, but not lactotropes. In conclusion, the isolated zebrafish mutants confirm principles of adenohypophysis development revealed in mouse, thereby demonstrating the high degree of molecular and mechanistic conservation among the different vertebrate species. In addition, they point to thus far unknown features of adenohypophysis development, such as the existence of a new lineage of pituitary cells, which partially overlaps with the Pit1 lineage. Positional cloning of the lia, pia, and aal genes might reveal novel regulators of vertebrate pituitary development.
Compounded Versus Proprietary Sincalide for Evaluation of Gallbladder Ejection Fraction
Authors: Guarasci Daniel T , Trinh Le Huyen N , Baeumler George R , Bednarczyk Edward M
Published: February 2004

OBJECTIVE

To report a comparison of compounded and proprietary sincalide in the evaluation of gallbladder ejection fraction during hepatobiliary scintigraphy.

CASE SUMMARIES

Two patients were referred to nuclear medicine with symptoms consistent with hepatobiliary dysfunction. Both underwent hepatobiliary scintigraphy to evaluate anatomic and physiologic tract patency of the hepatobiliary system. Compounded sincalide, an adjuvant pharmaceutical used to evaluate gallbladder ejection fraction, was infused during hepatobiliary scintigraphy, and gallbladder ejection fractions were 11% and 24%, respectively. Hepatobiliary scintigraphy was repeated on both patients 72 hours later with proprietary sincalide used as the adjuvant pharmaceutical. The gallbladder ejection fractions were 32% and 72%, respectively.

DISCUSSION

The use of sincalide to evaluate gallbladder ejection fraction in hepatobiliary scintigraphy is widely accepted in the surgical and nuclear medicine community. In late 2001, the sole manufacturer of sincalide announced indefinite unavailability of the product. Following the announcement, several compounding pharmacies began selling extemporaneously compounded sincalide as a replacement. Use of the compounded product has assumed therapeutic equivalence.

CONCLUSION

Significant differences in gallbladder ejection fraction between compounded sincalide and sincalide in our patients are likely due to the intrinsic variability in response to sincalide. Clinicians should be aware of this variability, as well as the potential effect of concomitant medications.
Pharmacologic Therapy for HIV-Associated Lipodystrophy
Authors: Benavides Sandra , Nahata Milap C
Published: February 2004

OBJECTIVE

To evaluate the efficacy and safety of pharmacologic therapy in the treatment of HIV-associated lipodystrophy, with a focus on the treatment of fat redistribution. Drug therapies that have been shown to be beneficial in other forms of lipodystrophy and are currently being evaluated in HIV-associated lipodystrophy are also discussed.

DATA SOURCES

A MEDLINE search was conducted from 1996 to February 2003. Bibliographies of all articles were reviewed and pertinent articles were included. Abstracts from major meetings in 2002 and 2003 were also reviewed.

STUDY SELECTION AND DATA EXTRACTION

All published studies were included in the review.

DATA SYNTHESIS

Lipodystrophy has become more prevalent in patients with HIV. Lipodystrophy consists of adipose redistribution and metabolic abnormalities including dyslipidemia and insulin resistance. Treatment of lipodystrophy has been directed at either decreasing the amount of visceral adipose tissue (VAT), dorsocervical adipose tissue (commonly known as buffalo hump) and/or increase subcutaneous adipose tissue (SAT). Recombinant human growth hormone (rhGH) decreases VAT and buffalo hump, although it has been associated with a high frequency of adverse effects. Metformin and the thiazolidinediones have favorable metabolic effects, but were not found to be effective in correcting body compositional changes associated with lipodystrophy. Anabolic steroids and L-carnitine are not effective in the treatment of lipodystrophy.

CONCLUSION

No drug therapy exists to fully ameliorate or correct the cosmetic changes of HIV-associated lipodystrophy. Clinicians must weigh the benefits and risks of each agent and individualize treatment for each patient.
Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion
Authors: Refsum Helga , Smith A David , Ueland Per M , Nexo Ebba , Clarke Robert , McPartlin Joseph , Johnston Carole , Engbaek Frode , Schneede Jørn , McPartlin Catherine , Scott John M
Published: February 2004

Background: Measurement of plasma total homocysteine has become common as new methods have been introduced. A wide range of disorders are associated with increased concentrations of total homocysteine. The purpose of this review is to provide an international expert opinion on the practical aspects of total homocysteine determinations in clinical practice and in the research setting and on the relevance of total homocysteine measurements as diagnostic or screening tests in several target populations.

Methods: Published data available on Medline were used as the basis for the recommendations. Drafts of the recommendations were critically discussed at meetings over a period of 3 years.

Outcome: This review is divided into two sections: (a) determination of homocysteine (methods and their performance, sample collection and handling, biological determinants, reference intervals, within-person variability, and methionine loading test); and (b) risk assessment and disease diagnosis (homocystinuria, folate and cobalamin deficiencies, cardiovascular disease, renal failure, psychiatric disorders and cognitive impairment, pregnancy complications and birth defects, and screening of elderly and newborns). Each of these subsections concludes with a separate series of recommendations to assist the clinician and the research scientist in making informed decisions. The review concludes with a list of unresolved questions.
Pyrosequencing of TPMT Alleles in a General Swedish Population and in Patients with Inflammatory Bowel Disease
Authors: Haglund Sofie , Lindqvist Malin , Almer Sven , Peterson Curt , Taipalensuu Jan
Published: February 2004

Background: Interindividual differences in therapeutic efficacy in patients treated with thiopurines might be explained by the presence of thiopurine S-methyltransferase (TPMT) alleles that encode for reduced TPMT enzymatic activity. It is therefore of value to know an individual’s inherent capacity to express TPMT.

Method: We developed a pyrosequencing method to detect 10 single-nucleotide polymorphisms (SNPs) in TPMT. A Swedish population (n = 800) was examined for TPMT*3A, TPMT*3B, TPMT*3C, and TPMT*2. Patients with inflammatory bowel disease (n = 24) and healthy volunteers (n = 6), selected on the basis of TPMT enzymatic activity, were investigated for all 10 SNPs to determine the relationship between TPMT genotype and phenotype.

Results: In the general population we identified the following genotypes with nonfunctional alleles: TPMT*1/*3A (*3A allelic frequency, 3.75%), TPMT*1/*3C (*3C allelic frequency, 0.44%), TPMT*1/*3B (*3B allelic frequency, 0.13%), and TPMT*1/*2 (*2 allelic frequency, 0.06%). All nine individuals with normal enzymatic activity were wild-type TPMT*1/*1. Thirteen individuals with intermediate activity were either TPMT*1/*3A (n = 12) or TPMT*1/*2 (n = 1). Eight individuals with low enzymatic activity were TPMT*3A/*3A (n = 4), TPMT*3A/*3C (n = 2), or TPMT*1/*3A (n = 2).

Conclusion: Next to wild type, the most frequent alleles in Sweden are TPMT*3A and TPMT*3C. A previously established phenotypic cutoff for distinguishing normal from intermediate metabolizers was confirmed. To identify the majority of cases (90%) with low or intermediate TPMT activity, it was sufficient to analyze individuals for only 3 of the 10 SNPs investigated. Nevertheless, this investigation indicates that other mutations might be of relevance for decreased enzymatic activity.
Factors behind the Increase in Cardiovascular Mortality in Russia: Apolipoprotein AI and B Distribution in the Arkhangelsk Study 2000
Authors: Averina Maria , Nilssen Odd , Brenn Tormod , Brox Jan , Arkhipovsky Vadim L , Kalinin Alexei G
Published: February 2004

Background: Cardiovascular mortality is markedly higher in Russia than in Western Europe and the US. Little is known about indicators of atherosclerotic risk in the Russian population. To our knowledge, this is the first study of apolipoprotein (apo) AI and B in Russia based on the WHO-IFCC standard.

Methods: We measured apo AI and B by immunoturbidimetric assay in 3694 men and women from Arkhangelsk, Russia, in 1999–2000.

Results: The age-related distribution of apo B was similar to that in other countries, whereas the apo AI profile was different. For men ≥20 years, apo AI was considerably higher than in studies from other countries. Women had also relatively high apo AI concentrations, although the difference was not as pronounced as in men. The apo AI concentration was positively associated with age and lifestyle variables such as alcohol consumption and physical activity, and negatively associated with body mass index and self-reported myocardial infarction. γ-Glutamyltransferase was positively associated with apo AI in both sexes.

Conclusions: The apparently favorable apolipoprotein profiles contrast with official death statistics indicating high cardiovascular mortality in Russia. High apo AI might indicate excessive alcohol consumption.
Parallel Detection of Autoantibodies with Microarrays in Rheumatoid Diseases
Authors: Feng Yanfei , Ke Xue , Ma Rongshui , Chen Ying , Hu Gengxi , Liu Feizhou
Published: February 2004

Background: Clinical needs often dictate testing for several autoantibodies in a single patient with evidence of autoimmune disease. We developed a microarray containing 15 autoantigens for the detection of autoantibodies in rheumatoid autoimmune diseases.

Methods: We synthesized recombinant centromere protein B, cytokeratin 19, SSA 52-kDa antigen, SSA 60-kDa antigen, SSB antigen, and Jo-1 antigen and prepared anti-nuclear antibody antigens. Cyclic citrullinated peptide, histone, goat IgG for detection of rheumatoid factor, double-stranded DNA, and single-stranded DNA were purchased, as were recombinant small nuclear ribonucleoprotein U1, topoisomerase I, and Smith antigen (Sm). All 15 antigens were of human origin except calf thymus Sm. Proteins were printed on polystyrene. The arrays were incubated with serum samples and then with horseradish peroxidase-conjugated secondary antibodies and chemiluminescent substrates, and light signals were captured by a charge-coupled device camera-based chip reader. Antibodies were quantified by use of calibration curves. Positive samples were confirmed by commercially available methods.

Results: The detection limit of the microarray system was 20 pg of IgG printed on the polystyrene support. More than 85% of the confirmed positive sera were detected as positive with the microarray system based on cutoff values established with the microarray system. The imprecision (CV) of the microarrays was <15% for all 15 autoantibody assays, with the exception of single-stranded DNA (18% and 23%) within and between batches. Characteristic autoantibody patterns were seen in patients with clinical diagnoses of rheumatoid arthritis (n = 83), systemic lupus erythematosus (n = 71), systemic sclerosis (n = 36), polymyositis (n = 38), and Sjogren syndrome (n = 20).

Conclusions: This microarray system provides results similar to those by conventional methods. Assessment of the diagnostic accuracy of the system remains to be done.
IFCC Reference System for Measurement of Hemoglobin A1c in Human Blood and the National Standardization Schemes in the United States, Japan, and Sweden: A Method-Comparison Study
Authors: Hoelzel Wieland , Weykamp Cas , Jeppsson Jan-Olof , Miedema Kor , Barr John R , Goodall Ian , Hoshino Tadao , John W Garry , Kobold Uwe , Little Randie , Mosca Andrea , Mauri Pierluigi , Paroni Rita , Susanto Fransiscus , Takei Izumu , Thienpont Linda , Umemoto Masao , Wiedmeyer Hsiao-Mei ,   the IFCC Working Group on HbA1c Standardization
Published: February 2004

Background: The national programs for the harmonization of hemoglobin (Hb)A1c measurements in the US [National Glycohemoglobin Standardization Program (NGSP)], Japan [Japanese Diabetes Society (JDS)/Japanese Society of Clinical Chemistry (JSCC)], and Sweden are based on different designated comparison methods (DCMs). The future basis for international standardization will be the reference system developed by the IFCC Working Group on HbA1c Standardization. The aim of the present study was to determine the relationships between the IFCC Reference Method (RM) and the DCMs.

Methods: Four method-comparison studies were performed in 2001–2003. In each study five to eight pooled blood samples were measured by 11 reference laboratories of the IFCC Network of Reference Laboratories, 9 Secondary Reference Laboratories of the NGSP, 3 reference laboratories of the JDS/JSCC program, and a Swedish reference laboratory. Regression equations were determined for the relationship between the IFCC RM and each of the DCMs.

Results: Significant differences were observed between the HbA1c results of the IFCC RM and those of the DCMs. Significant differences were also demonstrated between the three DCMs. However, in all cases the relationship of the DCMs with the RM were linear. There were no statistically significant differences between the regression equations calculated for each of the four studies; therefore, the results could be combined. The relationship is described by the following regression equations: NGSP-HbA1c = 0.915(IFCC-HbA1c) + 2.15% (r2 = 0.998); JDS/JSCC-HbA1c = 0.927(IFCC-HbA1c) + 1.73% (r2 = 0.997); Swedish-HbA1c = 0.989(IFCC-HbA1c) + 0.88% (r2 = 0.996).

Conclusion: There is a firm and reproducible link between the IFCC RM and DCM HbA1c values.
Sensitivity of Whole-Blood T Lymphocytes in Individual Patients to Tacrolimus (FK 506): Impact of Interleukin-2 mRNA Expression as Surrogate Measure of Immunosuppressive Effect
Authors: Härtel Christoph , Schumacher Nina , Fricke Lutz , Ebel Brigitte , Kirchner Holger , Müller-Steinhardt Michael
Published: February 2004

Background: To optimize immunosuppressive treatment in individual transplant patients, functional measurements of the effects of tacrolimus (FK 506) are of clinical importance. Previous investigations have demonstrated the occurrence of tacrolimus-resistant production of interleukin-2 (IL-2) in vitro, which may explain in part why rejection episodes are still a frequent problem despite attainment of therapeutic blood concentrations and HLA matching. However, an adequate surrogate marker to define the tacrolimus response in individual patients has not been established.

Methods: We investigated the immunosuppressive effects of tacrolimus on anti-CD3/anti-CD28 T-cell costimulation in a human whole-blood assay, analyzing T-cell proliferation, activation marker expression (CD25, CD69), IL-2 protein expression, and cytokine mRNA expression in vitro (n = 11 healthy individuals). We also quantified IL-2 mRNA expression in patients undergoing tacrolimus (n = 4) or cyclosporin A (CsA; n = 4) monotherapy before ex vivo living-donor kidney transplantation.

Results: T-cell proliferation; CD25, CD69, and IL-2 concentrations; and IL-4 mRNA were significantly decreased in vitro. In contrast, cytokine mRNA profiles revealed variable tacrolimus sensitivity. Whole-blood samples from 3 of 11 healthy individuals demonstrated marked suppression of IL-2 mRNA expression (>50%) when tacrolimus was administered in vitro. When CsA was added to whole-blood cultures, the influence on IL-2 mRNA expression was comparable to that of tacrolimus in 9 of 11 individuals. Two individuals responded conversely, indicating that differences in the in vitro response to tacrolimus and CsA among individuals may be attributable to potential heterogeneity in the involvement of the CD28 pathway. Kinetic profiles of IL-2 mRNA expression also revealed individually distinct degrees of calcineurin inhibitor sensitivity in patients undergoing tacrolimus or CsA monotherapy before living-donor kidney transplantation.

Conclusions: Our results suggest an individual degree of calcineurin inhibitor sensitivity of activated whole-blood lymphocytes based on IL-2 mRNA expression. Our approach is potentially valuable for identifying transplant patients in whom IL-2 mRNA expression is unaffected or even enhanced after initiation of immunosuppressive therapy. Such individuals may be less sensitive to the immunosuppressive agent and therefore at increased risk of transplant rejection. Prospective studies are necessary to determine the correlation of IL-2 mRNA expression with the clinical risk of transplant rejection.
Effect of a Controlled Feedback Intervention on Laboratory Test Ordering by Community Physicians
Authors: Bunting Peter S , van Walraven Carl
Published: February 2004

Background: Most studies of interventions to reduce laboratory test utilization have occurred in academic hospital settings, used historical controls, or have had short postintervention follow-up. Interventions with the greatest impact use multiple approaches, are repeated regularly, include comparisons with physician peers, and have a personal approach. We determined whether laboratory test utilization by community physicians could be reduced by a multifaceted program of education and feedback.

Methods: We identified 200 physicians who ordered the largest number of common laboratory tests during 1 year in a nonhospital, commercial community (reference) laboratory. They were assigned to intervention and control groups (100 each). Intervention physicians were visited individually up to three times by laboratory representatives over a 2-year period. At each visit, educational material and the physician’s personal laboratory test utilization data were presented and discussed briefly in general terms, with the latter compared with utilization data for the physician’s peers. Overall test utilization rates 1 year before, during, and 2 years after the intervention were measured using population-based databases. Time-series analysis was used to determine the effect of the intervention on laboratory test utilization.

Results: The two groups began with similar test utilization: control group, 4.06 × 106 tests in 1.48 × 106 visits (2.73 tests/visit); intervention group, 3.90 × 106 tests in 1.41 × 106 visits (2.77 tests/visit). During the 2-year intervention, intention-to-treat analysis showed that utilization decreased significantly in the intervention group compared with the controls [relative reduction of 7.9% (P <0.0001); absolute reduction of 0.22 tests/visit (95% confidence interval, 0.20–0.24)]. This difference persisted until the end of study observation, or more than 2 years after the intervention ended.

Conclusion: A multifaceted education and feedback strategy can significantly and persistently decrease laboratory utilization by practicing community physicians.
Technical and Clinical Characterization of the Bio-PTH (1–84) Immunochemiluminometric Assay and Comparison with a Second-Generation Assay for Parathyroid Hormone
Authors: Inaba Masaaki , Nakatsuka Kiyoshi , Imanishi Yasuo , Watanabe Masakazu , Mamiya Yuji , Ishimura Eiji , Nishizawa Yoshiki
Published: February 2004

Background: The Bio-Intact parathyroid hormone (1–84) assay (Bio-PTH), a newly developed two-site immunochemiluminometric assay, measures exclusively PTH (1–84) in contrast to second-generation “intact PTH” (I-PTH) assays. We investigated the technical performance and clinical significance of this new assay.

Methods: PTH was measured simultaneously by the Bio-PTH assay and Allegro intact PTH IRMA in sera from Japanese patients with calcium disorders.

Results: Measured Bio-PTH in serum was unaffected by six freeze-thaw cycles and was stable at 4 °C for 7 days and during storage at −20 or −80 °C over 28 days. The calibration curve was linear to 1800 ng/L. The detection limit was 3.9 ng/L. The intra- and interassay imprecision was <2.8% and 3.5%, respectively, for analyte concentrations spanning the range of the calibration curve. Bio-PTH was unaffected by a 1000-fold excess of PTH (7–84), although I-PTH reacted equally with PTH (7–84) and PTH (1–84). Bio-PTH was correlated with I-PTH in healthy individuals (r = 0.953; P <0.0001; n = 26) and in the full population without renal dysfunction (r = 0.994; P <0.0001; n = 62). In 72 volunteers, mean (SD) Bio-PTH was 22.2 (7.1) ng/L, or 62% of the mean I-PTH [36.1 (22.3) ng/L]. This ratio was 51% in hemodialysis patients (n = 177). Mean Bio-PTH was high in patients with primary hyperparathyroidism [121 (85) ng/L; n = 18] and hemodialysis patients [102 (104) ng/L; n = 177], low in idiopathic hypoparathyroidism [5.5 (2.8) ng/L; n = 4], and within 2 SD of the mean for healthy controls in Paget disease of the bone [34 (15) ng/L; n = 9] and bone metastasis [24 (12) ng/L; n = 8].

Conclusion: The Bio-PTH assay is sensitive and precise and produces expected results for patients with the studied disorders of calcium metabolism.
Agreeableness as a predictor of aggression in adolescence
Authors: Gleason Katie A. , Jensen‐Campbell Lauri A. , South Richardson Deborah
Published: January 2004

This multi‐method research linked the Big Five personality dimensions to aggression in early adolescence. Agreeableness was the personality dimension of focus because this dimension is associated with motives to maintain positive interpersonal relations. In two studies, middle school children were assessed on the Big Five domains of personality. Study 1 showed that agreeableness was associated with both indirect and direct aggression. In addition, the link between agreeableness and aggression was strongest for direct strategies. Study 2 examined the hypotheses that agreeableness predicts social cognitions associated with aggression, peer reports of direct aggression, and teacher reports of adjustment. Agreeableness predicted peer reports of aggression and social cognitions associated with aggression. In addition, aggression mediated the link between agreeableness and adjustment. Results suggest that of the Big Five dimensions, Agreeableness is most closely associated with processes and outcomes related to aggression in adolescents. Aggr. Behav. 30:43–61, 2004. © 2004 Wiley‐Liss, Inc.
Effects of acute, subchronic and intermittent MDMA (‘ECSTASY’) administration on agonistic interactions between male mice
Authors: Navarro José Francisco , Maldonado Enrique
Published: January 2004

Recent studies suggest that acute administration of 3,4‐methylenedioxymethamphetamine (MDMA), an amphetamine derivative popularly known as “ecstasy,” produces an antiaggressive effect in male mice. However, there is no evidence with respect to the development of tolerance or sensitization after its subchronic or intermittent administration. In this study, we examined the action of low to moderate doses of MDMA (1.25, 2.5 and 5 mg/kg, i.p), administered acutely, subchronically (for 7 days) or intermittently, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to anosmic “standard opponents” 30 minutes after the drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. Acute treatment with MDMA provoked a significant reduction of aggressive behaviors, without altering immobility. However, this action was only selective at 1.25 mg/kg. With the intermediate (2.5 mg/kg) and the highest doses (5 mg/kg) of the drug, it was observed a significant decrease of offensive behaviors, accompanied by an increase of exploration from a distance, avoidance/flee and defense/submission behaviors. This ethopharmacological profile could indicate the existence of an anxiogenic‐like effect of MDMA. The overall picture of the effects of MDMA was very similar in the acutely, intermittently and daily treated animals. No tolerance or sensitization to the actions of the drug was developed after its repeated or intermittent administration.
Effects of viewing videos of bullfights on Spanish children
Authors: Graña J.L. , Cruzado J.A. , Andreu J.M. , Muñoz‐Rivas M.J. , Peña M.E. , Brain P.F.
Published: January 2004

Some of the psychological effects of viewing bullfights on children 8–12 years old are described. Two hundred and forty subjects (120 girls and 120 boys) aged between eight and twelve from a variety of socioeconomic backgrounds were selected from three public or private elementary / secondary schools in Madrid, Spain. The first study used a questionnaire to examine the children's attitudes towards bullfighting by looking at their acceptance and cognitive‐emotional appraisal of the event. Videotapes of bullfights with differing commentaries were then used, along with a battery of questionnaires, to assess the emotional impact of these events, as well as the impact of narrative explanations on aggression and anxiety. Most children were not very positive about bullfights in the initial questionnaire. Viewing of tapes with ‘festive’ or aggressive dialogues (but not tapes without a justification) resulted in more expressed aggression in boys than girls. There was also evidence that age had a significant effect, and that some children appeared disturbed by the exposure. Aggr. Behav. 30:16–28, 2004. © 2004 Wiley‐Liss, Inc.
Friendship and loneliness among bullies and victims: Data from seven countries
Authors: Eslea Mike , Menesini Ersilia , Morita Yohji , O'Moore Mona , Mora‐Merchán Joaquin A. , Pereira Beatriz , Smith Peter K.
Published: January 2004

Research suggests that the relationship between school bullying and its various risk factors should be clearer among girls than boys, and should become stronger with age, as roles within the peer group stabilise. This paper tests this theory by comparing sex, school type, and bully/victim status differences in friendships and playground social interactions, using data from nine surveys in seven countries: China, England, Ireland, Italy, Japan, Portugal, and Spain. A total of approximately 48,000 children completed various translations of the Olweus Bullying Questionnaire. Small but generally consistent main effects were found for sex and school type (boys and primary pupils enjoyed playtimes more and had more friends, but were also more likely to spend playtimes alone). Larger effects were consistently found for bully/victim status (victims were significantly worse off on all the measures in all the samples where a difference was found, while bullies and neutrals did not differ consistently), but the interactions between these factors varied widely between samples and there were few consistent patterns. It is concluded that bullying is a universal phenomenon with many negative correlates for victims and few (if any) for bullies, but that there are cultural variations in the way that bullying is related to sex, age, and social support. Aggr. Behav. 30:71–83, 2004. © 2004 Wiley‐Liss, Inc.
Nongenetic pathologic developments of brain‐wave patterns in monozygotic twins discordant and concordant for schizophrenia
Authors: Weisbrod M. , Hill H. , Sauer H. , Niethammer R. , Guggenbühl S. , Hell D. , Stassen H.H.
Published: January 2004

Evidence from previous studies has suggested that the inter‐individual differences in human brain‐wave patterns (EEG) are predominantly determined by genetic factors. In particular, the within‐pair EEG concordance of monozygotic (mz) twins was found to be typically as high as r = 0.81 across channels and frequency bands, thus being comparable to that between repeated assessments on the same individual with typically r = 0.83. Yet our investigations into mz twins discordant and concordant for schizophrenia yielded a significantly reduced within‐pair EEG concordance for both, the pairs discordant for schizophrenia and the pairs concordant for schizophrenia (with concordance for schizophrenia assessed through a syndrome‐oriented approach). A multivariate discriminant function of EEG parameters distinguished in a reproducible way between affected and unaffected subjects at an overall performance of >75% correctly classified subjects, while the severity of illness, as derived from EEG‐differences between affected and unaffected subjects, was closely related to the severity of illness as provided by psychopathology syndrome scores. Consequently, EEG anomalies associated with schizophrenia and manifested differently in the mz co‐twins concordant for schizophrenia are likely the effect of nongenetic, pathologic processes that evolved independently in the co‐twins' genetically identical brains once the illness began to progress. The existence of such nongenetic processes would suggest a modification of the standard phenotype‐to‐genotype search strategies of molecular‐genetic studies that aim to link the schizophrenia phenotype to genetic vulnerability factors. © 2003 Wiley‐Liss, Inc.
Evidence of a founder effect in families with frontotemporal dementia that harbor the tau +16 splice mutation
Authors: Pickering‐Brown Stuart , Baker Matt , Bird Thomas , Trojanowski John , Lee Virginia , Morris Huw , Rossor Martin , Janssen John C. , Neary David , Craufurd David , Richardson Anna , Snowden Julie , Hardy John , Mann David , Hutton Mike
Published: January 2004

The +16 exon 10 splice mutation of the tau gene (microtubule‐associated protein tau, MAPT) has been reported in numerous families with frontotemporal dementia (FTD). To date, the majority of these families are from England and Wales in the UK, although families with this mutation have been reported from Australia and the USA. Our own analysis has identified eight families with the +16 MAPT splice mutation from around the Manchester and North Wales areas of the UK. Given the proximity of the UK families to one another it is likely that they are related and represent a single extended pedigree. In order to investigate this possibility, and the possibility that the families with this mutation from London, the USA, and Australia are related, we genotyped 11 microsatellite markers around the tau locus. In most cases (20/25, 80%), a common haplotype, approximately 3 cM in size, was identified. In the remaining cases, this haplotype appears to have been varyingly reduced in size by recombination. We demonstrate that the +16 mutation is on the H1 tau haplotype and that H1 specific polymorphisms are also shared by these families. These data provide evidence that the MAPT +16 splice mutation cases from around the world analyzed in this study are indeed related and represent a single pedigree that probably originated in the North Wales area of the UK. Furthermore, this single large pedigree may be of use in the identification of disease modifying loci in FTD. © 2003 Wiley‐Liss, Inc.
No evidence of association or linkage disequilibrium between polymorphisms in the 5′ upstream and coding regions of the dopamine D4 receptor gene and schizophrenia in a Portuguese population
Authors: Ambrósio Alda M. , Kennedy James L. , Macciardi Fabio , Barr Cathy , Soares Maria J. , Oliveira Catarina R. , Pato Carlos N.
Published: January 2004

Alterations in dopaminergic system have been implicated in the pathophysiology of this disease for many years, and this study was performed to assess the possible involvement of the dopamine D4 receptor (DRD4) gene polymorphisms either in the 5′ upstream or in the coding regions, in the etiology of schizophrenia. The approach included an association study with 90 Portuguese trios by doing the analysis of the individual alleles and the haplotypes. For the polymorphisms in the 5′ upstream region (−C616G and −C521T) and in the coding region (48 bp repeat) of the DRD4 gene, negative results were obtained with both haplotype relative risk (HRR) and transmission disequilibrium test (TDT), as well as transmit. These data suggest that polymorphisms (−C616G, −C521T, and 48 bp repeat) at the DRD4 gene do not have a minor effect in the susceptibility to schizophrenia in our sample. © 2003 Wiley‐Liss, Inc.
Association study of cannabinoid receptor gene (CNR1) alleles and anorexia nervosa: Differences between restricting and bingeing/purging subtypes
Authors: Siegfried Z. , Kanyas K. , Latzer Y. , Karni O. , Bloch M. , Lerer B. , Berry E.M.
Published: January 2004

Anorexia nervosa (AN) is a severe and disabling psychiatric disorder, characterized by profound weight loss and body image disturbance. Family and twin studies indicate a significant genetic contribution to this disorder although no genetic mutation has yet been identified. The endocannabinoid system has recently been implicated in many physiological functions including appetite regulation. We, therefore, undertook a family based study to test the hypothesis whether a polymorphism of the CNR1 gene, which encodes human CB1 receptor, a subclass of the central cannabinoid receptor, contributes to the susceptibility to AN. Fifty two families (parents with one or two affected siblings) were genotyped for the (AAT) trinucleotide repeat of CNR1 gene. Using the haplotype relative risk (HRR) method, the distribution of alleles transmitted to the patients was not found to be significantly different from the non‐transmitted parental alleles. However, upon dividing the samples to restricting and bingeing/purging subtypes of AN, the extended transmission disequilibrium test (ETDT) revealed that there is preferential transmission of different alleles in each of the subtypes. The 14 repeat allele was preferentially transmitted in the bingeing/purging AN group (P = 0.05) but not in the restricting AN group, whereas the 13 repeat allele was preferentially transmitted in the restricting AN group (almost significant, P = 0.07) but not in the bingeing/purging AN group. Our study suggests that restricting AN and bingeing/purging AN may be associated with different alleles of the CNR1 gene. © 2003 Wiley‐Liss, Inc.
Genetic mapping using haplotype and model‐free linkage analysis supports previous evidence for a locus predisposing to severe bipolar disorder at 5q31‐33
Authors: Hong Kyung Sue , McInnes L. Alison , Service Susan K. , Song Terry , Lucas Jennifer , Silva Sandra , Fournier Eduardo , León Pedro , Molina Julio , Reus Victor I. , Sandkuijl Lodewijk A. , Freimer Nelson B.
Published: January 2004

We report further evidence for our previous suggestion [Garner et al., 2001: Am J Hum Genet 68:1061–1064] of a locus on 5q predisposing to bipolar I disorder (BP‐I) in an extended Costa Rican pedigree. We genotyped additional microsatellite markers in this region and applied a multi‐point non‐parametric linkage analysis (SimWalk2). Significant identity‐by‐descent allele sharing among affected relatives was observed for all of the 20 markers tested in a segment of approximately 15 cM. Most affected individuals shared a single haplotype over this region; breaks within this haplotype may suggest a more restricted candidate location for a BP‐I gene. These results support the suggestion that a locus at 5q31‐33, together with a previously reported locus at 18q22‐23, may provide the major genetic risk for BP‐I in this family. © 2003 Wiley‐Liss, Inc.
CALCYONgene variation, schizophrenia, and cocaine dependence
Authors: Luo Xingguang , Kranzler Henry , Lappalainen Jaakko , Rosenheck Robert , Charney Dennis , Zuo Lingjun , Erdos Joseph , van Kammen Daniel P. , Gelernter Joel
Published: January 2004

Calcyon is a brain‐specific D1 dopamine receptor‐interacting protein, with a potential role in D1‐mediated physiological processes, including motor control, reward mechanisms, and cognitive processes. Our objective was to investigate the relationship between polymorphism of theCALCYONgene and (1) schizophrenia and (2) cocaine dependence in African‐American (AA) and European‐American (EA) subjects. Two single nucleotide polymorphisms (SNPs) at theCALCYONlocus were genotyped in 70 AA and 206 EA individuals with schizophrenia and 90 AA and 118 EA individuals with cocaine dependence. The control group was comprised of 46 AA and 207 EA subjects screened to exclude those with psychiatric or substance use disorders. The specific polymorphisms studied were markers +295214G/A and +297151T/G. Comparisons of allele and haplotype frequencies between cases and controls were performed with the Fisher's Exact Test. Linkage disequilibrium (LD) between these two SNPs was calculated with the 3LOCUS program. No alleles or haplotypes were found to be associated with schizophrenia or cocaine dependence either in AA or EA subjects. The markers +295214G/A and +297151T/G are in the same haplotype block in all subgroups. Allele and haplotype frequencies differed significantly between EA and AA subjects. These results suggest that these two genetic variants in theCALCYONgene do not play a major role in predisposition to either schizophrenia or cocaine dependence in AA or EA subjects. Furthermore, these findings begin to establish a haplotype map for this gene in the AA and EA populations. © 2003 Wiley‐Liss, Inc.
An investigation into sub‐telomeric deletions of chromosome 22 and pervasive developmental disorders
Authors: Nair‐Miranda Kumudini , Murch Ashleigh , Petterson Beverly , Hill Wayne , Nikolova‐Hill Amelia , Bradley Linda , Jackson Sandy , Hallmayer Joachim
Published: January 2004

Deletions of the sub‐telomeric region of chromosome 22 have been associated with mental retardation, developmental delay, and autistic behaviors. This study investigated sub‐telomeric anomalies of chromosome 22 using fluorescent in situ hybridization (FISH) probes in 82 subjects diagnosed with autism and atypical autism. No microdeletions were detected in this group. Similar FISH analyses were undertaken on two children with developmental delay, who were ascertained to be ring 22 during routine cytogenetic investigations. One subject was shown to have a microdeletion in the sub‐telomeric region tested. Both children met the social and communication cut off for autism on the ADI and but did not meet the cut off for restrictive and repetitive behaviors. Only one of the two children met the criteria for PDD on the ADOS. © 2003 Wiley‐Liss, Inc.
Multiple missense mutations in the diazepam binding inhibitor (DBI) gene identified in schizophrenia but lack of disease association
Authors: Niu N. , Rice S.R. , Heston L.L. , Sobell J.L.
Published: January 2004

The diazepam binding inhibitor (DBI), alternatively known as the acyl‐CoA binding protein (ACBP), is involved in multiple biological actions. The polypeptide binds to the peripheral, or mitochondrial, benzodiazepine receptor and facilitates transport of cholesterol to the inner membrane to stimulate steroid synthesis. Through this action, DBI indirectly modulates gamma‐aminobutyric acid (GABA)‐mediated inhibitory neurotransmission. DBI can be postulated as a candidate gene for psychiatric phenotypes including anxiety, mood, and psychotic disorders. In an examination of the DBI gene among 112 individuals with schizophrenia, our laboratory has identified 18 novel single nucleotide polymorphisms (SNPs), including three missense changes in conserved amino acids, a coding region microdeletion, and multiple SNPs in the putative promoter region. Case‐control association analyses were performed for the missense changes, but none was found to be significantly associated with disease. © 2003 Wiley‐Liss, Inc.
Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: A family based association study
Authors: Fanous Ayman H. , Neale M.C. , Straub R.E. , Webb B.T. , O'Neill A.F. , Walsh D. , Kendler K.S.
Published: January 2004

Schizophrenia is clinically heterogeneous and multidimensional, but it is not known whether this is due to etiological heterogeneity. Previous studies have not consistently reported association between any specific polymorphisms and clinical features of schizophrenia, and have primarily used case‐control designs. We tested for the presence of association between clinical features and polymorphisms in the genes for the serotonin 2A receptor (HT2A), dopamine receptor types 2 and 4, dopamine transporter (SLC6A3), and brain‐derived neurotrophic factor (BDNF). Two hundred seventy pedigrees were ascertained on the basis of having two or more members with schizophrenia or poor outcome schizoaffective disorder. Diagnoses were made using a structured interview based on the SCID. All patients were rated on the major symptoms of schizophrenia scale (MSSS), integrating clinical and course features throughout the course of illness. Factor analysis revealed positive, negative, and affective symptom factors. The program QTDT was used to implement a family‐based test of association for quantitative traits, controlling for age and sex. We found suggestive evidence of association between the His452Tyr polymorphism in HT2A and affective symptoms (P = 0.02), the 172‐bp allele of BDNF and negative symptoms (P = 0.04), and the 480‐bp allele in SLC6A3 (= DAT1) and negative symptoms (P = 0.04). As total of 19 alleles were tested, we cannot rule out false positives. However, given prior evidence of involvement of the proteins encoded by these genes in psychopathology, our results suggest that more attention should be focused on the impact of these alleles on clinical features of schizophrenia. © 2003 Wiley‐Liss, Inc.
Haplotypes of the monoamine oxidase genes and the risk for substance use disorders
Authors: Vanyukov Michael M. , Maher Brion S. , Devlin Bernie , Tarter Ralph E. , Kirillova Galina P. , Yu Ling‐Mei , Ferrell Robert E.
Published: January 2004

Monoamine oxidase A (MAOA) locus is an attractive candidate for exploring genetic contribution to the variation in the risk for substance use disorders (SUD) because of its important role in the metabolism of neurotransmitters, including dopamine and serotonin. Prior findings have suggested an association of the MAOA gene with the risk for early onset SUD. To extend this research, we genotyped four MAOA markers (two VNTR polymorphisms and two SNPs) and built a cladogram reflecting the evolutionary history of MAOA haplotypes [Nguyen et al., under review]. The cladogram served as the framework for nested ANOVA and logit analyses of association between MAOA and indices of liability to SUD (diagnosis, age of onset, and a dimensional index of substance use related problems) in a sample of adult males of European ancestry. Whereas no association was found for the categorical diagnosis, a significant relationship was detected between the dimensional liability indices and MAOA haplotypes. Overall, our results, albeit not definitive, are consistent with the hypothesis that variants in MAOA account for a small portion of the variance of SUD risk, possibly mediated by liability to early onset behavioral problems. © 2003 Wiley‐Liss, Inc.
The gender effect in juvenile Huntington disease patients of Italian origin
Authors: Cannella Milena , Gellera Cinzia , Maglione Vittorio , Giallonardo Patrizia , Cislaghi Giuliana , Muglia Maria , Quattrone Aldo , Pierelli Francesco , Di Donato Stefano , Squitieri Ferdinando
Published: January 2004

We analyzed a population of juvenile Huntington disease (HD) subjects of Italian origin (n = 57). The main aim of this study was to analyze the gender effect of the affected parent on age at onset and clinical presentation of offspring with juvenile HD. We also analyzed molecular features of the disease, including CAG mutation length and GluR6 gene polymorphism, according to the affected parent's gender. The mutation length was longer in paternally than in maternally transmitted HD juvenile patients (P = 0.025), nevertheless a similar mean early onset in the two groups (P > 0.05). This data was even enforced by that obtained from the whole cohort of patients included in the databank (n = 600) where, in the presence of increased mean parent–child CAG repeat change in paternal vs. maternal meiotic transmissions (+7.3 vs. +0.7 CAG, P = 0.0002), the mean parent–child year‐of‐onset change was similar in the two groups (−10.4 and −7.0 years, P > 0.05). A lower TAA‐triplet in GluR6 was associated with an earlier age at onset in juvenile patients (P = 0.031, R2 = 0.10). When we added the GluR6 effect on age at onset to the CAG expanded number effect (P = 0.0001, R2 = 0.68) by multiple regression approach, the coefficient of determination R2 increased to 0.81. This effect in addition to the expanded CAG repeat number, found in juvenile and not in adult patients, was slightly enforced by paternal compared to maternal transmissions (R2=0.82). Our findings suggest the occurrence of a weaker effect of the paternal mutation on juvenile age at onset in our population, possibly amplified by other genetic factors, such as the TAA‐triplet length in the GluR6 gene. © 2003 Wiley‐Liss, Inc.