Spatial attentional bias as a marker of genetic risk, symptom severity, and stimulant response in ADHD

Attention-deficit hyperactivity disorder (ADHD) is a heritable childhood onset disorder that is marked by variability at multiple levels including clinical presentation, cognitive profile, and response to stimulant medications. It has been suggested that this variability may reflect etiological differences, particularly, at the level of underlying genetics. This study examined whether an attentional phenotype-spatial attentional bias could serve as a marker of symptom severity, genetic risk, and stimulant response in ADHD. A total of 96 children and adolescents with ADHD were assessed on the Landmark Task, which is a sensitive measure of spatial attentional bias. All children were genotyped for polymorphisms (30 untranslated (UTR) and intron 8 variable number of tandem repeats (VNTRs)) of the dopamine transporter gene (DAT1). Spatial attentional bias correlated with ADHD symptom levels and varied according to DAT1 genotype. Children who were homozygous for the 10-repeat allele of the DAT1 30-UTR VNTR displayed a rightward attentional bias and had higher symptom levels compared to those with the low-risk genotype. A total of 26 of these children who were medication naive performed the Landmark Task at baseline and then again after 6 weeks of stimulant medication. Left-sided inattention (rightward bias) at baseline was associated with an enhanced response to stimulants at 6 weeks. Moreover, changes in spatial bias with stimulant medications, varied as a function of DAT1 genotype. This study suggests an attentional phenotype that relates to symptom severity and genetic risk for ADHD, and may have utility in predicting stimulant response in ADHD.

Stereotactic radiosurgery as a therapeutic strategy for intracranial metastatic prostate carcinoma.

Intracranial metastatic prostate carcinoma is rare. We sought to determine the clinical outcomes after Gamma Knife® stereotactic radiosurgery (GKSRS) for patients with intracranial prostate carcinoma metastases. We studied data from 10 patients who underwent radiosurgery for 15 intracranial metastases (9 dural-based and 6 parenchymal). Six patients had radiosurgery for solitary tumors and four had multiple tumors. The primary pathology was adenocarcinoma (eight patients) and small cell carcinoma (two patients). All patients received multimodality management for their primary tumor (including resection, radiation therapy, androgen deprivation therapy) and eight patients had evidence of systemic disease at time of radiosurgery. The mean tumor volume was 7.7 cm3 (range 1.1-17.2 cm3) and a median margin dose of 16 Gy was administered. Two patients had progressive intracranial disease in spite of fractionated partial brain radiation therapy (PBRT) prior to SRS. A local tumor control rate of 85% was achieved (including patients receiving boost, upfront and salvage SRS). New remote brain metastases developed in three patients (33%) and one patient had repeat SRS for tumor recurrence. The median survival after radiosurgery was 13 months and the 1-year survival rate was 60%. SRS was a well tolerated and effective therapy either alone or as a boost to fractionated radiation therapy in the management of patients with intracranial prostate carcinoma metastases. © 2009 Springer Science+Business Media, LLC.

Understanding online customer repurchasing intention and the mediating role of trust - an empirical investigation in two developed countries

Although e-commerce adoption and customers initial purchasing behavior have been well studied in the literature, repeat purchase intention and its antecedents remain understudied. This study proposes a model to understand the extent to which trust mediates the effects of vendor-specific factors on customers intention to repurchase from an online vendor. The model was tested and validated in two different country settings. We found that trust fully mediates the relationships between perceived reputation, perceived capability of order fulfillment, and repurchasing intention, and partially mediates the relationship between perceived website quality and repurchasing intention in both countries. Moreover, multi-group analysis reveals no significant between-country differences of the model with regards to the antecedents and outcomes of trust, except the effect of reputation on trust. Academic and practical implications and future research are discussed. © 2009 Operational Research Society Ltd.

Behavior analytic perspective on victimology

The field of victimology has become an area of serious scientific enquiry only recently and now attracts a wide range of theories from within multiple disciplines. In this paper the contribution that the science of behavior analysis can make to the conceptualization of the field is explored by investigating what makes people vulnerable to becoming victims or indeed perpetrators of violence and by examining why some people who have experienced violent incidents become victims while others grow to be survivors. A behavior analytic perspective sheds new light on these issues

Ribosomal 18S RNA processing by the IGF-I-responsive WDR3 protein is integrated with p53 function in cancer cell proliferation.

Insulin-like growth factor-I (IGF-I) signaling is strongly associated with cell growth and regulates the rate of synthesis of the rRNA precursor, the first and the key stage of ribosome biogenesis. In a screen for mediators of IGF-I signaling in cancer, we recently identified several ribosome-related proteins, including NEP1 (nucleolar essential protein 1) and WDR3 (WD repeat 3), whose homologues in yeast function in ribosome processing. The WDR3 gene and its locus on chromosome 1p12-13 have previously been linked with malignancy. Here we show that IGF-I induces expression of WDR3 in transformed cells. WDR3 depletion causes defects in ribosome biogenesis by affecting 18 S rRNA processing and also causes a transient down-regulation of precursor rRNA levels with moderate repression of RNA polymerase I activity. Suppression of WDR3 in cells expressing functional p53 reduced proliferation and arrested cells in the G1 phase of the cell cycle. This was associated with activation of p53 and sequestration of MDM2 by ribosomal protein L11. Cells lacking functional p53 did not undergo cell cycle arrest upon suppression of WDR3. Overall, the data indicate that WDR3 has an essential function in 40 S ribosomal subunit synthesis and in ribosomal stress signaling to p53-mediated regulation of cell cycle progression in cancer cells.

Signals of need in a cooperatively breeding mammal with mobile offspring

In many bird species with biparental care for young in the nest, hungry chicks beg repeatedly and parents adjust their feeding rate to the call rate of young. Repetitive calling also occurs in fledglings and in some mammals where offspring follow provisioners. It is not yet clear whether, in mobile systems with dispersed young where adults cannot compare the vocal behaviour of all young simultaneously, the calls represent a signal of need. We investigated repetitive begging by cooperatively reared meerkat, Suricata suricatta, pups that foraged with the group. Pups produced two types of begging calls: repeat calls over long periods and high-pitched calls mainly confined to feeding events. Food-deprived pups stayed closer to feeders, and begged for longer and more intensely by calling at a higher rate. Hungry pups increased both the rate of repeat calls, which were given continually, and the number of high-pitched bouts, but adults increased their food allocation only in relation to the rate of repeat calls. Our study indicates that hunger may lead to several changes in vocal behaviour, only some of which may be used by adults to assess need.

[[omega-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents.

A series of [(ureidoethoxy)benzyl]-2,4-thiazolidinediones and [[(heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones was synthesized from the corresponding aldehydes. Compds. from the urea series, exemplified by I, showed antihyperglycemic potency comparable with known agents of the type such as pioglitazone and troglitazone (CS-045). The benzoxazole II, a cyclic analog of I, was a very potent enhancer of insulin sensitivity, and by modification of the arom. heterocycle, an aminopyridine, III, was identified as a lead compd. from SAR studies. Evaluation of antihyperglycemic activity together with effects on blood Hb content, to det. the therapeutic index, was performed in 8-day repeat administration studies in genetically obese C57 B1/6 ob/ob mice. From these studies, III (BRL 49653) has been selected, on the basis of antihyperglycemic potency combined with enhanced selectivity against redns. in blood Hb content, for further evaluation.

The role of human demographic history in determining the distribution and frequency of transferase-deficient galactosaemia mutations

Classical or transferase-deficient galactosaemia is an inherited metabolic disorder caused by mutation in the human Galactose-1-phosphate uridyl transferase (GALT) gene. Of some 170 causative mutations reported, fewer than 10% are observed in more than one geographic region or ethnic group. To better understand the population history of the common GALT mutations, we have established a haplotyping system for the GALT locus incorporating eight single nucleotide polymorphisms and three short tandem repeat markers. We analysed haplotypes associated with the three most frequent GALT gene mutations, Q188R, K285N and Duarte-2 (D2), and estimated their age. Haplotype diversity, in conjunction with measures of genetic diversity and of linkage disequilibrium, indicated that Q188R and K285N are European mutations. The Q188R mutation arose in central Europe within the last 20 000 years, with its observed east-west cline of increasing relative allele frequency possibly being due to population expansion during the re-colonization of Europe by Homo sapiens in the Mesolithic age. K285N was found to be a younger mutation that originated in Eastern Europe and is probably more geographically restricted as it arose after all major European population expansions. The D2 variant was found to be an ancient mutation that originated before the expansion of Homo sapiens out of Africa. Heredity (2010) 104, 148-154; doi:10.1038/hdy.2009.84; published online 29 July 2009

The DUB/USP17 deubiquitinating enzymes: A gene family within a tandemly repeated sequence, is also embedded within the copy number variable Beta-defensin cluste

Background: The DUB/USP17 subfamily of deubiquitinating enzymes were originally identified as immediate early genes induced in response to cytokine stimulation in mice (DUB-1, DUB-1A, DUB-2, DUB-2A). Subsequently we have identified a number of human family members and shown that one of these (DUB-3) is also cytokine inducible. We originally showed that constitutive expression of DUB-3 can block cell proliferation and more recently we have demonstrated that this is due to its regulation of the ubiquitination and activity of the 'CAAX' box protease RCE1.

Results: Here we demonstrate that the human DUB/USP17 family members are found on both chromosome 4p16.1, within a block of tandem repeats, and on chromosome 8p23.1, embedded within the copy number variable betadefensin cluster. In addition, we show that the multiple genes observed in humans and other distantly related mammals have arisen due to the independent expansion of an ancestral sequence within each species. However, it is also apparent when sequences from humans and the more closely related chimpanzee are compared, that duplication events have taken place prior to these species separating.

Conclusions: The observation that the DUB/USP17 genes, which can influence cell growth and survival, have evolved from an unstable ancestral sequence which has undergone multiple and varied duplications in the species examined marks this as a unique family. In addition, their presence within the beta-defensin repeat raises the question whether they may contribute to the influence of this repeat on immune related conditions.

Stereotactic radiosurgery for intractable cluster headache: an initial report from the North American Gamma Knife Consortium.

Abstract Object The aim of this study was to evaluate the outcomes of Gamma Knife surgery (GKS) when used for patients with intractable cluster headache (CH). Methods Four participating centers of the North American Gamma Knife Consortium identified 17 patients who underwent GKS for intractable CH between 1996 and 2008. The median patient age was 47 years (range 26-83 years). The median duration of pain before GKS was 10 years (range 1.3-40 years). Seven patients underwent unsuccessful prior surgical procedures, including microvascular decompression (2 patients), microvascular decompression with glycerol rhizotomy (2 patients), deep brain stimulation (1 patient), trigeminal ganglion stimulation (1 patient), and prior GKS (1 patient). Fourteen patients had associated autonomic symptoms. The radiosurgical target was the trigeminal nerve (TN) root and the sphenopalatine ganglion (SPG) in 8 patients, only the TN in 8 patients, and only the SPG in 1 patient. The median maximum TN and SPG dose was 80 Gy. Results Favorable pain relief (Barrow Neurological Institute Grades I-IIIb) was achieved and maintained in 10 (59%) of 17 patients at a median follow-up of 34 months. Three patients required additional procedures (repeat GKS in 2 patients, hypothalamic deep brain stimulation in 1 patient). Eight (50%) of 16 patients who had their TN irradiated developed facial sensory dysfunction after GKS. Conclusions Gamma Knife surgery for intractable, medically refractory CH provided lasting pain reduction in approximately 60% of patients, but was associated with a significantly greater chance of facial sensory disturbances than GKS used for trigeminal neuralgia.

Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16

Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. A recent genome scan for genetic modifiers of age at onset of motor symptoms (AO) in HD suggests that one modifier may reside in the region close to the HD gene itself. We used data from 535 HD participants of the New England Huntington cohort and the HD MAPS cohort to assess whether AO was influenced by any of the three markers in the 4p16 region: MSX1 (Drosophila homeo box homologue 1, formerly known as homeo box 7, HOX7), Delta2642 (within the HD coding sequence), and BJ56 (D4S127). Suggestive evidence for an association was seen between MSX1 alleles and AO, after adjustment for normal CAG repeat, expanded repeat, and their product term (model P value 0.079). Of the variance of AO that was not accounted for by HD and normal CAG repeats, 0.8% could be attributed to the MSX1 genotype. Individuals with MSX1 genotype 3/3 tended to have younger AO. No association was found between Delta2642 (P=0.44) and BJ56 (P=0.73) and AO. This study supports previous studies suggesting that there may be a significant genetic modifier for AO in HD in the 4p16 region. Furthermore, the modifier may be present on both HD and normal chromosomes bearing the 3 allele of the MSX1 marker.

Pygmalion in the reintegration process: Desistance from crime through the looking glass

The study of desistance from crime has come of age in recent years, and there are now several, competing theories to account for the ability of long-term offenders to abstain from criminal behavior. Most prominently, recent explanations have borrowed elements from informal social control theory, differential association theory and cognitive psychology. In the following, we argue that labeling theory may be a neglected factor in understanding the desistance process. Drawing on interview data collected as part of a study of an offender reintegration program, we illustrate how the idea of the

Microsatellite standardization and evaluation of genotyping error in a large multi-partner research programme for conservation of Atlantic salmon (Salmo salar L.).

Microsatellite genotyping is a common DNA characterization technique in population, ecological and evolutionary genetics research. Since different alleles are sized relative to internal size-standards, different laboratories must calibrate and standardize allelic designations when exchanging data. This interchange of microsatellite data can often prove problematic. Here, 16 microsatellite loci were calibrated and standardized for the Atlantic salmon, Salmo salar, across 12 laboratories. Although inconsistencies were observed, particularly due to differences between migration of DNA fragments and actual allelic size ('size shifts'), inter-laboratory calibration was successful. Standardization also allowed an assessment of the degree and partitioning of genotyping error. Notably, the global allelic error rate was reduced from 0.05 ± 0.01 prior to calibration to 0.01 ± 0.002 post-calibration. Most errors were found to occur during analysis (i.e. when size-calling alleles; the mean proportion of all errors that were analytical errors across loci was 0.58 after calibration). No evidence was found of an association between the degree of error and allelic size range of a locus, number of alleles, nor repeat type, nor was there evidence that genotyping errors were more prevalent when a laboratory analyzed samples outside of the usual geographic area they encounter. The microsatellite calibration between laboratories presented here will be especially important for genetic assignment of marine-caught Atlantic salmon, enabling analysis of marine mortality, a major factor in the observed declines of this highly valued species.