Identification of a 10/10 matched donor for patients with an uncommon haplotype is unlikely.

BACKGROUND: Despite over 6 million subjects contributing to the National Marrow Donor Program human leukocyte antigen (HLA) haplotype frequency reference data (HFD), haplotypes cannot be predicted from the HLA assignments of some patients searching for an unrelated donor (URD) in the Be The Match Registry®. We aimed to determine the incidence of these patient searches and whether haplotypes lacking from the HFD can be found among the low-resolution typed URD pool. MATERIALS AND METHODS: New NMDP searches with uncommon patient haplotypes (UPH), defined as a lack of haplotype pairs in any single ethnic group in the HFD based upon HLA-A˜C˜B˜DRB1˜DQB1, were identified. Each search had up to 20 potential 10/10 or 8/8 URDs typed to determine the likelihood of an allele match. RESULTS: The incidence of patient searches without haplotype pairs in a single ethnic group in the HFD was 1.2% (N=144 out of 12,172) and a majority of these patients (117; 81%) had one uncommon haplotype previously uncharacterized in the HFD. Non-White patients had the highest incidence of UPH. Importantly, no patients with UPH had a 10/10 URD identified. The transplant rate among UPH patients was 15%, and a majority of these patients utilized cord blood units as their transplant stem cell source. CONCLUSION: Therefore, the HLA HFD that informs the HapLogic matching algorithm is thorough as UPH patient searches were infrequent. Since such patients are highly unlikely to have a fully 10/10 matched URD identified, this study supports the identification of alternative stem cell sources including cord blood or a mismatched URD early in the search process.

Effects on cognitive and clinical insight with the use of Guided Self-Determination in outpatients with schizophrenia: A randomized open trial.

Poor insight has a negative impact on the outcome in schizophrenia; consequently, poor insight is a logical target for treatment. However, neither medication nor psychosocial interventions have been demonstrated to improve poor insight. A method originally designed for diabetes patients to improve their illness management, Guided Self-Determination (GSD), has been adapted for use in patients with schizophrenia (GSD-SZ). The purpose of this study was to investigate the effect on insight of GSD-SZ as a supplement to treatment as usual (TAU) as compared to TAU alone in outpatients diagnosed with schizophrenia. The design was an open randomized trial. The primary hypothesis was cognitive insight would improve in those patients who received GSD-SZ+TAU as assessed by the BCIS. We additionally explored whether the intervention led to changes in clinical insight, self-perceived recovery, self-esteem, social functioning and symptom severity. Assessments were conducted at baseline, and at 3-, 6- and 12-month follow-up. Analysis was based on the principles of intention to treat and potential confounders were taken into account through applying a multivariate approach. A total of 101 participants were randomized to GSD-SZ+TAU (n=50) or to TAU alone (n=51). No statistically significant differences were found on the cognitive insight. However, at 12-month follow-up, clinical insight (measured by G12 from the Positive and Negative Syndrome Scale), symptom severity, and social functioning had statistically significantly improved in the intervention group as compared to the control group. "Improving insight in patients diagnosed with schizophrenia", NCT01282307, http://clinicaltrials.gov/.

Mpdz expression in the caudolateral substantia nigra pars reticulata is crucially involved in alcohol withdrawal.

Association studies implicate the multiple PDZ domain protein (MUPP1/MPDZ) gene in risk for alcoholism in humans and alcohol withdrawal in mice. Although manipulation of the Mpdz gene by homologous recombination and bacterial artificial chromosome transgenesis has suggested that its expression affects alcohol withdrawal risk, the potential confounding effects of linked genes and developmental compensation currently limit interpretation. Here, using RNA interference (RNAi), we directly test the impact of Mpdz expression on alcohol withdrawal severity and provide brain regional mechanistic information. Lentiviral-mediated delivery of Mpdz short hairpin RNA (shRNA) to the caudolateral substantia nigra pars reticulata (clSNr) significantly reduces Mpdz expression and exacerbates alcohol withdrawal convulsions compared with control mice that delivered a scrambled shRNA. Neither baseline nor pentylenetetrazol-enhanced convulsions differed between Mpdz shRNA and control animals, indicating Mpdz expression in the clSNr does not generally affect seizure susceptibility. To our knowledge, these represent the first in vivo Mpdz RNAi analyses, and provide the first direct evidence that Mpdz expression impacts behavior. Our results confirm that Mpdz is a quantitative trait gene for alcohol withdrawal and demonstrate that its expression in the clSNr is crucially involved in risk for alcohol withdrawal.

Metacognition, social cognition, and symptoms in patients with first episode and prolonged psychoses.

While it has been documented that persons with prolonged schizophrenia have deficits in metacognition and social cognition, it is less clear whether these difficulties are already present during a first episode. To explore this issue we assessed and compared metacognition using the Metacognition Assessment Scale-Abbreviated (MAS-A) and social cognition using the Eyes, Hinting and Bell-Lysaker Emotional Recognition Tests (BLERT) in participants with first episode psychosis (FEP; n=26), participants with a prolonged psychosis (n=72), and a psychiatric control group consisting of persons with a substance use disorder and no history of psychosis (n=14). Analyses revealed that both psychosis cohorts scored lower than controls on the MAS-A total and all subscales except metacognitive mastery. Compared to the FEP group, the persons with prolonged psychosis demonstrated greater metacognitive capacities only in those MAS-A domains reflective of the ability to understand the mental state of others and to see that others may have motivations and desires separate from their own. Other domains of metacognition did not differ between psychosis groups. The Eyes, Hinting and BLERT scores of the two psychosis groups did not differ but were poorer than those produced by the control group. Exploratory correlations in the FEP group showed a pattern similar to that previously observed in prolonged psychosis. Taken together, these findings suggest that while certain domains of metacognition could improve with prolonged psychosis, difficulties with global metacognition and social cognition may be stable features of the disorder and perhaps unique to psychosis.

Spatial variability of total dissolved copper and copper speciation in the inshore waters of Bermuda.

Total dissolved copper (Cu) and Cu speciation were examined from inshore waters of Bermuda, in October 2009 and July-August 2010, to determine the relationship between total dissolved Cu, Cu-binding ligands and bioavailable, free, hydrated Cu(2+) concentrations. Speciation was performed using competitive ligand exchange-adsorptive cathodic stripping voltammetry (CLE-ACSV). Mean total dissolved Cu concentrations ranged from 1.4 nM to 19.2 nM, with lowest concentrations at sites further from shore, consistent with previous measurements in the Sargasso Sea, and localized Cu enrichment inshore in enclosed harbors. Ligand concentrations exceeded dissolved [Cu] at most sites, and [Cu(2+)] were correspondingly low at those sites, typically <10(-13) M. One site, Hamilton Harbour, was found to have [Cu] in excess of ligands, resulting in [Cu(2+)] of 10(-10.7) M, and indicating that Cu may be toxic to phytoplankton here.

Genetic variability of respiratory complex abundance, organization and activity in mouse brain.

Mitochondrial dysfunction is implicated in the etiology and pathogenesis of numerous human disorders involving tissues with high energy demand. Murine models are widely used to elucidate genetic determinants of phenotypes relevant to human disease, with recent studies of C57BL/6J (B6), DBA/2J (D2) and B6xD2 populations implicating naturally occurring genetic variation in mitochondrial function/dysfunction. Using blue native polyacrylamide gel electrophoresis, immunoblots and in-gel activity analyses of complexes I, II, III, IV and V, our studies are the first to assess abundance, organization and catalytic activity of mitochondrial respiratory complexes and supercomplexes in mouse brain. Remarkable strain differences in supercomplex assembly and associated activity are evident, without differences in individual complexes I, II, III or IV. Supercomplexes I1 III2 IV2-3 exhibit robust complex III immunoreactivity and activities of complexes I and IV in D2, but with little detected in B6 for I1 III2 IV2 , and I1 III2 IV3 is not detected in B6. I1 III2 IV1 and I1 III2 are abundant and catalytically active in both strains, but significantly more so in B6. Furthermore, while supercomplex III2 IV1 is abundant in D2, none is detected in B6. In aggregate, these results indicate a shift toward more highly assembled supercomplexes in D2. Respiratory supercomplexes are thought to increase electron flow efficiency and individual complex stability, and to reduce electron leak and generation of reactive oxygen species. Our results provide a framework to begin assessing the role of respiratory complex suprastructure in genetic vulnerability and treatment for a wide variety of mitochondrial-related disorders.

Social cognition and metacognition in schizophrenia: evidence of their independence and linkage with outcomes.

OBJECTIVE: Research suggests that many with schizophrenia experience deficits in the ability to make discrete judgments about the thoughts and feelings of others as well as to form larger integrated representations of themselves and others. Little is known about whether these difficulties may be distinguished from one another and whether they are linked with different outcomes. METHOD: We administered three assessments of social cognition which tapped the ability to identify emotions and intentions and two metacognitive tasks which called for the formation of more integrated and flexible representations of the self and others. We additionally assessed symptoms, social functioning and neurocognition. Participants were 95 individuals with a schizophrenia spectrum disorder. RESULTS: A principle components analysis followed by a varimax rotation revealed two factors which accounted for 62% of the variance. The first factor was comprised of the three social cognition tests and the second of two tasks that tapped the ability to create representations of oneself and others which integrate more discreet information. The first factor was uniquely correlated with negative symptoms, and the second was uniquely correlated with social function. CONCLUSION: Results suggest that deficits in social cognition and metacognition represent different forms of dysfunction in schizophrenia.

Dietary patterns and survival in German postmenopausal breast cancer survivors.

BACKGROUND: Research on the association between dietary patterns and breast cancer survival is very limited. METHODS: A prospective follow-up study was conducted in Germany, including 2522 postmenopausal breast cancer patients diagnosed in 2001-2005 with available food frequency questionnaire data. Vital status, causes of death, and recurrences were verified through the end of 2009. Principle component factor analysis was used to identify pre-diagnostic dietary patterns. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazards models. RESULTS: Two major dietary patterns were identified: 'healthy' (high intakes of vegetables, fruits, vegetable oil, sauces/condiments, and soups/bouillons) and 'unhealthy' (high intakes of red meat, processed meat, and deep-frying fat). Increasing consumption of an 'unhealthy' dietary pattern was associated with an increased risk of non-breast cancer mortality (highest vs lowest quartile: HR, 3.69; 95% CI, 1.66-8.17; P-trend <0.001). No associations with breast cancer-specific mortality and breast cancer recurrence were found. The 'healthy' dietary pattern was inversely associated with overall mortality (HR, 0.74; 95% CI, 0.47-1.15; P-trend=0.02) and breast cancer recurrence (HR, 0.71; 95% CI, 0.48-1.06; P-trend=0.02) in stage I-IIIa patients only. CONCLUSION: Increasing intake of an 'unhealthy' pre-diagnostic dietary pattern may increase the risk of non-breast cancer mortality, whereas increasing intake of a 'healthy' pattern may reduce the risk of overall mortality and breast cancer recurrence.

Estimated enterolignans, lignan-rich foods, and fibre in relation to survival after postmenopausal breast cancer.

BACKGROUND: Lignans - oestrogenic substances present in various foods - are associated with postmenopausal breast cancer risk, but not much is known regarding their effects on survival. METHODS: In a follow-up study of 2653 postmenopausal breast cancer patients diagnosed between 2001 and 2005, vital status and causes of death were verified through end of 2009. Hazard ratios (HRs) and 95% confidence intervals (CIs) for estimated enterolignans, lignan-rich foods, and dietary fibre in relation to overall survival (OS) and breast cancer-specific survival (BCSS) were assessed using Cox proportional hazards models stratified by age at diagnosis and adjusted for prognostic/confounding factors. RESULTS: Median follow-up time was 6.4 years, and 321 women died, 235 with breast cancer. High estimated enterolactone and enterodiol levels were associated with significantly lower overall mortality (highest quintile, HR=0.60, 95% CI=0.40-0.89, P(Trend)=0.02 and HR=0.63, 95% CI=0.42-0.95, P(Trend)=0.02, respectively). Fibre intake was also associated with a significantly lower overall mortality. Differentiated by median fibre intake, associations with estimated enterolignans were still evident at low but not high fibre intake. There was no effect modification by oestrogen receptor status and menopausal hormone therapy. CONCLUSION: Postmenopausal breast cancer patients with high estimated enterolignans may have a better survival.

Rostroventral caudate putamen involvement in ethanol withdrawal is influenced by a chromosome 4 locus.

Physiological dependence and associated withdrawal episodes are thought to constitute a motivational force that sustains alcohol use and abuse and may contribute to relapse in dependent individuals. Although no animal model duplicates alcoholism, models for specific factors, like withdrawal, are useful for identifying potential genetic and neural determinants of liability in humans. Previously, we identified a quantitative trait locus (QTL) and gene (Mpdz, which encodes the multi-PDZ domain protein) on chromosome 4 with a large effect on alcohol withdrawal in mice. Using congenic mice that confirm this QTL and c-Fos expression as a high-resolution marker of neuronal activation, we report that congenic mice show significantly less neuronal activity associated with alcohol withdrawal in the rostroventral caudate putamen (rvCP), but not other parts of the striatum, compared with background strain mice. Moreover, bilateral rvCP lesions significantly increase alcohol withdrawal severity. Using retrograde (fluorogold) and anterograde (Texas Red conjugated dextran amine) tract tracing, we found that ∼25% of c-Fos immunoreactive rvCP neurons project to caudolateral substantia nigra pars reticulata (clSNr), which we previously found is crucially involved in withdrawal following acute and repeated alcohol exposure. Our results expand upon work suggesting that this QTL impacts alcohol withdrawal via basal ganglia circuitry associated with limbic function, and indicate that an rvCP-clSNr projection plays a critical role. Given the growing body of evidence that the syntenic region of human chromosome 9p and human MPDZ gene are associated with alcohol abuse, our results may facilitate research on alcohol dependence and associated withdrawal in clinical populations.

Metacognition as a mediator of the effects of impairments in neurocognition on social function in schizophrenia spectrum disorders.

OBJECTIVE: This study explored whether Mastery, a domain of metacognition that reflects the ability to use knowledge about mental states to respond to psychological challenges, mediated the effects of neurocognition on the frequency of social contact and persons' capacity for social relatedness. METHOD: Participants were 102 adults with schizophrenia or schizoaffective disorder. Neurocognition was represented by a single factor score produced by a principal components analysis of a neurocognitive test battery. Mastery was assessed using the metacognitive assessment scale and social functioning by the quality of life scale. RESULTS: Using structural equation modeling, specifically measured-variable path analysis, a mediational model consisting of neurocognitive capacity linked to mastery and capacity for social relationships and mastery linked with frequency of social contact and capacity for social relatedness showed acceptable fit to the observed data. This persisted after controlling for negative and cognitive symptoms. CONCLUSION: Results suggest that certain forms of metacognition mediate the influence of neurocognition upon function in schizophrenia.

Site-specific action of L-3,4-dihydroxyphenylalanine in the striatum but not globus pallidus and substantia nigra pars reticulata evokes dyskinetic movements in chronic L-3,4-dihydroxyphenylalanine-treated 6-hydroxydopamine-lesioned rats.

Dyskinesia eventually develops in the majority of Parkinson's disease patients treated with l-3,4-dihydroxyphenylalanine (l-DOPA). We have investigated the effect of an acute and local administration of L-DOPA, GABA and glutamate to provoke dyskinetic movements in three basal ganglia structures (striatum, globus pallidus (GP) and substantia nigra pars reticulata (SNr)) of chronically L-DOPA-treated, unilaterally 6-hydroxydopamine-lesioned rats. We demonstrated that L-DOPA administration into the lesioned striatum using the technique of reverse in vivo microdialysis was an effective trigger to switch on dyskinesia. Notably, local L-DOPA perfusion at the same concentration in the ipsilateral GP and SNr did not provoke significant dyskinetic behaviour. Neither GABA nor glutamate triggered dyskinetic movements in the striatum, GP or SNr. We postulate a site-specific action of L-DOPA for the evocation of already established dyskinesia since L-DOPA in the striatum but not in the GP or SNr switched on dyskinetic behaviour.

Comparison of intrastriatal administration of noradrenaline and l-DOPA on dyskinetic movements: a bilateral reverse in vivo microdialysis study in 6-hydroxydopamine-lesioned rats.

l-DOPA-induced dyskinesia is known as involuntary debilitating movement, which limits quality of life in patients suffering from Parkinson's disease. The present study focuses on the role of the neurotransmitter noradrenaline (NA) on dyskinetic movements in comparison to the effect of l-DOPA. Rats were unilaterally lesioned with 6-hydroxydopamine and treated with l-DOPA/benserazide (6/15 mg/kg, p.o.) to induce stable dyskinetic movements. On the day of the experiment, NA (0.04 nmol/min, 0.4 nmol/min) and l-DOPA (0.04 nmol/min, 0.4 nmol/min) were perfused into the lesioned and non-lesioned striatum of dyskinetic rats using the reverse in vivo microdialysis technique. Neither NA nor l-DOPA treatment of the non-lesioned striatum produced any dyskinetic behavior. In contrast, administration of l-DOPA 0.4 nmol/min into the lesioned striatum led to a significant increase in dyskinesia indicated by abnormal axial, limb and orolingual movements. Notably, perfusion with NA 0.4 nmol/min into the lesioned striatum revealed a highly significant induction of dyskinetic movements, which are similar to the dyskinesia subtype profile of l-DOPA. In conclusion, NA is as potent as l-DOPA to express dyskinetic movements in l-DOPA-primed rats.

Molecular analyses and identification of promising candidate genes for loci on mouse chromosome 1 affecting alcohol physical dependence and associated withdrawal.

We recently mapped quantitative trait loci (QTLs) with large effects on predisposition to physical dependence and associated withdrawal severity following chronic and acute alcohol exposure (Alcdp1/Alcw1) to a 1.1-Mb interval of mouse chromosome 1 syntenic with human chromosome 1q23.2-23.3. Here, we provide a detailed analysis of the genes within this interval and show that it contains 40 coding genes, 17 of which show validated genotype-dependent transcript expression and/or non-synonymous coding sequence variation that may underlie the influence of Alcdp1/Alcw1 on ethanol dependence and associated withdrawal. These high priority candidates are involved in diverse cellular functions including intracellular trafficking, oxidative homeostasis, mitochondrial respiration, and extracellular matrix dynamics, and indicate both established and novel aspects of the neurobiological response to ethanol. This work represents a substantial advancement toward identification of the gene(s) that underlies the phenotypic effects of Alcdp1/Alcw1. Additionally, a multitude of QTLs for a variety of complex traits, including diverse behavioral responses to ethanol, have been mapped in the vicinity of Alcdp1/Alcw1, and as many as four QTLs on human chromosome 1q have been implicated in human mapping studies for alcoholism and associated endophenotypes. Thus, our results will be primary to further efforts to identify genes involved in a wide variety of behavioral responses to alcohol and may directly facilitate progress in human alcoholism genetics.

Mapping a locus for alcohol physical dependence and associated withdrawal to a 1.1 Mb interval of mouse chromosome 1 syntenic with human chromosome 1q23.2-23.3.

Physiological dependence and associated withdrawal episodes are thought to constitute a motivational force perpetuating continued alcohol use/abuse. Although no animal model duplicates alcoholism, models for specific factors, like the withdrawal syndrome, are useful to identify potential determinants of liability in humans. We previously detected quantitative trait loci (QTLs) with large effects on predisposition to physical dependence and associated withdrawal following chronic or acute alcohol exposure to a large region of chromosome 1 in mice (Alcdp1 and Alcw1, respectively). Here, we provide the first confirmation of Alcw1 in a congenic strain, and, using interval-specific congenic strains, narrow its position to a minimal 1.1 Mb (maximal 1.7 Mb) interval syntenic with human chromosome 1q23.2-23.3. We also report the development of a small donor segment congenic that confirms capture of a gene(s) affecting physical dependence after chronic alcohol exposure within this small interval. This congenic will be invaluable for determining whether this interval harbors a gene(s) involved in additional alcohol responses for which QTLs have been detected on distal chromosome 1, including alcohol consumption, alcohol-conditioned aversion and -induced ataxia. The possibility that this QTL plays an important role in such diverse responses to alcohol makes it an important target. Moreover, human studies have identified markers on chromosome 1q associated with alcoholism, although this association is still suggestive and mapped to a large region. Thus, the fine mapping of this QTL and analyses of the genes within the QTL interval can inform developing models for genetic determinants of alcohol dependence in humans.

B-cell O-galactosyltransferase activity, and expression of O-glycosylation genes in bone marrow in IgA nephropathy.

In IgA nephropathy (IgAN), pathogenic IgA1 is likely derived from bone marrow (BM) cells and exhibits reduced O-galactosylation. Defective O-galactosylation may arise from the compromised expression or function of the enzyme beta-galactosyltransferase and/or its molecular chaperone (Cosmc). We measured B-cell O-galactosylation activity and the relative gene expression of beta-galactosyltransferase and Cosmc in peripheral blood and BM taken from patients with IgAN and controls. O-galactosylation activity was measured in peripheral and BM B cells by the incorporation of radiolabeled galactose into an asialo-mucin acceptor. Gene expression of beta-galactosyltransferase and Cosmc was measured by real-time PCR and related to that of the enzyme GalNAc-T2 (UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase-2), which synthesizes the core O-glycan. Neither the B-cell O-galactosylation activity nor the gene expression of the enzyme or chaperone was different between patients and controls. However, the relationships between the O-glycosylation of serum IgA1, galactosylation activity, and beta-galactosyltransferase gene expression showed different patterns in IgAN and controls. In IgAN, O-galactosylation activity correlated with beta-galactosyltransferase gene expression, but not with IgA1 O-glycosylation, suggesting that factors other than the availability of beta-galactosyltransferase or Cosmc are responsible for altered IgA1 O-glycosylation.

Case management community care for people living with HIV/AIDS (PLHAs).

A case management approach to support services was developed in a Toronto-based AIDS service organization (ASO) in Canada to support people living with HIV/AIDS (PLHAs) whose needs could not be addressed through usual self-directed access to services. It was therefore important to determine which PLHAs would benefit most from case management. New clients and those who had been receiving support services from an ASO were randomized to receive either self-directed use of support services or self-directed care plus strengths-based case management for a six-month period. Results indicated that those who benefited most from case management were very depressed at baseline. Strengths-based case management compared to usual self-directed care markedly improved the physical, social and mental health function of very depressed PLHAs, and reduced their risk behaviours. In addition, the case management participants' use of community services was associated with an economically important, though not statistically significant, $3,300 per person per annum lower expenditure for the use of all direct health and social services. Although more research is warranted, this research demonstrates that ASOs and funders ought to seriously consider implementing a case management approach to practical assistance for PLHAs with depression.

Synthesis of genomic and subgenomic RNAs by a membrane-bound RNA-dependent RNA polymerase isolated from oat plants infected with cereal yellow dwarf virus.

A membrane-bound RNA-dependent RNA polymerase (RdRp) complex was isolated by differential sedimentation from oat plants infected with cereal yellow dwarf virus (CYDV). When incubated with 32P-labelled UTP, unlabelled ATP, CTP and GTP, and Mg2+ ions, the RdRp preparation catalysed the synthesis of double-stranded (ds) RNAs corresponding in size to the virus genomic RNA (5.7 kbp) and two putative subgenomic RNAs (2.8 and 0.7 kbp). Hybridisation using strand-specific hybridization targets showed that the 5.7-kbp dsRNA was labelled mainly in the plus strand, whereas the 2.8- and 0.7-kbp dsRNAs were labelled only in the minus strand. Genomic-length single-stranded, plus-strand RNA of 5.7 kb and single-stranded, plus-strand subgenomic RNAs of 2.8 and 0.7 kbp were detected in RNA isolated from oat plants infected with CYDV. Mapping experiments were consistent with the genomic and subgenomic RNAs having common 3' ends, but different 5' ends, whether produced in vitro or in vivo. The RdRp-encoding region of the CYDV genome was cloned and expressed in Escherichia coli, and the purified protein was used to raise antibodies in a rabbit. In immunoblots, the antibodies detected a protein of about 68 kDa in RdRp preparations from CYDV-infected oat plants, but not from equivalent preparations from healthy oats. As far as we are aware, this is the first report of an in vitro RNA synthesis system for a phloem-limited virus.

Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11.

We have established that there is a considerable amount of common genetic influence on physiological dependence and associated withdrawal from sedative-hypnotic drugs including alcohol, benzodiazepines, barbiturates and inhalants. We previously mapped two loci responsible for 12 and 9% of the genetic variance in acute alcohol and pentobarbital withdrawal convulsion liability in mice, respectively, to an approximately 28-cM interval of proximal chromosome 11. Here, we narrow the position of these two loci to a 3-cM interval (8.8 Mb, containing 34 known and predicted genes) using haplotype analysis. These include genes encoding four subunits of the GABA(A) receptor, which is implicated as a pivotal component in sedative-hypnotic dependence and withdrawal. We report that the DBA/2J mouse strain, which exhibits severe withdrawal from sedative-hypnotic drugs, encodes a unique GABA(A) receptor gamma2 subunit variant compared with other standard inbred strains including the genetically similar DBA/1J strain. We also demonstrate that withdrawal from zolpidem, a benzodiazepine receptor agonist selective for alpha1 subunit containing GABA(A) receptors, is influenced by a chromosome 11 locus, suggesting that the same locus (gene) influences risk of alcohol, benzodiazepine and barbiturate withdrawal. Our results, together with recent knockout studies, point to the GABA(A) receptor gamma2 subunit gene (Gabrg2) as a promising candidate gene to underlie phenotypic differences in sedative-hypnotic physiological dependence and associated withdrawal episodes.