No evidence of linkage between schizophrenia and D3 dopamine receptor gene locus in Icelandic pedigrees

Mice homozygous for the lpr gene develop autoantibodies and polyclonal B cell activation similar to what is seen in human systemic lupus erythematosus patients. We have previously shown that an lpr-specific intrinsic B cell defect was necessary for autoantibody production in this model. In the current study, we have further defined these autoantibody-producing B cells. Two major subsets of B cells have been described. B-1 cells (CD5+ B cells) can be distinguished from conventional B cells on the basis of phenotype, cytokine secretion, gene expression, anatomical location, and function. In addition, B-1 cells have been implicated in autoimmunity in several murine and human studies. To address the question of which B cell subset produces autoantibodies in lpr mice, we used immunoglobulin heavy chain (Igh) allotype-marked peritoneal (B-1 cell source) and bone marrow (conventional B cell source) cells from lpr mice to establish B cell chimeras. We used two general approaches. In one, we reconstituted sublethally irradiated mice with B-1 cells of one allotype and bone marrow cells of another allotype. In the second method, we suppressed endogenous B cells in neonatal mice with allotype-specific anti-IgM antibody, and injected peritoneal cells of another allotype. After antibody treatment was stopped, the mouse's conventional B cells recovered, but the B-1 subset was only reconstituted by the donor. In both types of chimeras, antichromatin, rheumatoid factor, and anti-single stranded DNA (ssDNA) autoantibodies were produced by the conventional B cell bone marrow source. In addition, an age-related decrease in peritoneal B-1 cells was seen, even in unmanipulated lpr mice. These data show that lpr B-1 cells are not important producers of autoantibodies. Conventional B cells are the source of autoantibodies directed at chromatin, ssDNA, and IgG.     

Association study between schizophrenia and dopamine D3 receptor gene polymorphism

Crocq et al. [1992: J Med Genet 29:858-860] reported the existence of an association between schizophrenia and homozygosity of a BalI polymorphism in the first exon of the dopamine D3 receptor (DRD3) gene. In response to this report, further studies were conducted; however, these studies yielded conflicting results. In the present study, we examined 100 unrelated Japanese schizophrenics and 100 normal controls to determine any association between this polymorphism and schizophrenia. Results suggest that neither allele nor genotype frequencies of the DRD3 gene in the schizophrenics as a whole are significantly different from those of the controls. Further, we found no association between any allele or genotype and any clinical subtype based on family history of schizophrenia and age-at-onset. A significantly high frequency of homozygosity of a dopamine D3 receptor gene allele was not observed in the schizophrenics as a whole, or in clinical subtypes. Our results suggest that an association between the dopamine D3 receptor gene and schizophrenia is unlikely to exist.     

Genetic linkage study of bipolar disorder and the serotonin transporter

Administration of a low sub-immunosuppressive dose of cyclophosphamide (CY) to naive mice induced a marked increase in the number of splenic cells forming natural antibodies against unrelated antigens such as foot-and-mouth disease virus, keyhole limpet hemocyanin, horseradish peroxidase, or bovine serum albumin, as determined by an enzyme-linked immunosorbent assay spot technique. These results suggest that in mice there exists a repertoire of B cells forming natural antibodies which is restrained by an unknown mechanism and that CY is able to interfere with that restriction.     

Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity

Attention-deficit hyperactivity disorder (ADHD) affects approximately 3%-5% of children in the United States. In the current psychiatric nomenclature, ADHD comprises three subtypes: inattentive, hyperactive-impulsive, and combined. In this study, we used four analytic strategies to examine the association and linkage of the dopamine transporter gene (DAT1) and ADHD. Our sample included 122 children referred to psychiatric clinics for behavioral and learning problems that included but were not limited to ADHD, as well as their parents and siblings. Within-family analyses of linkage disequilibrium, using the transmission disequilibrium test (TDT), confirmed the 480-bp allele as the high-risk allele. In between-family association analyses, levels of hyperactive-impulsive symptoms but not inattentive symptoms were related to the number of DAT1 high-risk alleles. Siblings discordant for the number of DAT1 high-risk alleles differed markedly in their levels of both hyperactive-impulsive and inattentive symptoms, such that the sibling with the higher number of high-risk alleles had much higher symptom levels. Within-family analyses of linkage disequilibrium, using the TDT, suggested association and linkage of ADHD with DAT1 and that this relation was especially strong with the combined but not the inattentive subtype. The relation of DAT1 to ADHD increased monotonically, from low to medium to high levels of symptom severity. Our results replicate and extend previous findings of the association between the DAT1 gene and childhood ADHD. This represents one of the first replicated relations of a candidate gene and a psychiatric disorder in children.     

Manic depressive illness and tyrosine hydroxylase gene: linkage heterogeneity and association

Several studies have implicated the tyrosine hydroxylase (TH) locus within the 11p15 region in susceptibility to manic depressive illness (MDI). This possibility was further investigated by both parametric (lod score) and nonparametric (affected-pedigree-member and a case-control study) methods of analysis in 11 French MDI families and in a sample of 200 unrelated subjects. Both types of analyses corroborate the implication of this locus, and positive lod scores were obtained in two families, which most likely reflects genetic heterogeneity. Statistical analyses were also performed including available data from published reports. These analyses, which allowed for genetic heterogeneity, substantiated our findings. The combined maximum lod score for all the families studied was 3.68 at theta = 0.00 (number of families: 36) assuming heterogeneity (alpha = 15%, P = 0.01). Taken together these results converge to suggest that the risk factors for MDI lie in the 11p15 region with TH being the most likely candidate gene.     

COMT基因多态性rs4818与精神分裂症及迟发性运动障碍的关联性分析

目的:检测中国北方汉族人群中精神分裂症患者COMT基因多态性rs4818基因型及等位基因频数分布,探讨其与精神分裂症及迟发性运动障碍(TD)发生的关系.方法:以273例并发TD的精神分裂症患者(TD组)、114例未发生TD的精神分裂症患者(非TD组)和286例正常健康人群(正常对照组)为研究对象,采用Taqman探针方法检测COMT基因多态rs4818基因型和等位基因频数的分布.结果:与正常对照组比较,精神分裂症患者rs4818 G/G基因型频数分布差异有统计学意义(χ2=6.186,df=3,P=0.045);与正常对照组比较,TD组患者rs4818 G/G基因型频数分布差异有统计学意义(χ2=6.081,df=3,P=0.048);非TD组患者与正常对照组比较,G等位基因频数分布差异有统计学意义(χ2=4.049,df=2,P=0.044);TD组与非TD组比较,rs4818基因型及等位基因频数分布差异无统计学意义(χ2=0.634,df=2,P=0.426;χ2=0.848,df=3,P=0.654).结论:COMT基因多态性与精神分裂症的发生有关联,但与精神分裂症TD的发生无关联性.     

Schizophrenia and the dopamine-beta-hydroxylase gene: results of a linkage and association study

PURPOSE: A dose-finding study to investigate the use of epidural infusions of ropivacaine for postoperative analgesia following orthopaedic surgery. METHODS: This was a randomized, double-blind study. Surgery was performed using a combination of a lumbar epidural block utilizing ropivacaine 0.5% and a standardized general anaesthetic. Postoperatively, an epidural infusion of the study solution (saline, ropivacaine 0.1%, 0.2% or 0.3%) was started at the rate of 10 ml.hr-1 and continued for 21 hr after arrival in the PACU. Analgesia was supplemented with PCA morphine (dose = 1.0 mg, lock-out = 5 min). RESULTS: Forty-four patients completed the study. The ropivacaine 0.1%, 0.2%, 0.3% groups required less morphine over the 21 hr than the saline group (P < 0.01). The VAS pain scores were also lower in the three ropivacaine groups (P < 0.001). The ropivacaine groups maintained sensory anaesthesia to pinprick when compared with saline (P < 0.05). The motor block in the 0.3% group was significantly higher than the saline group at all times (P < 0.05), and higher than the 0.1% group at eight hours (P < 0.01), while the 0.2% group had higher Bromage scores than saline at 4 and 21 hr (P < 0.05). CONCLUSIONS: The use of continuous epidural infusions of ropivacaine 0.1%, 0.2% and 0.3% at 10 ml.hr-1 improved postoperative pain relief and decreased PCA morphine requirements in patients undergoing major orthopaedic surgery. The 0.1% and 0.2% concentrations produced similar sensory anaesthesia with less motor blockade than the 0.3% concentration.     

No association between the serotonin transporter-linked promoter region polymorphism and either schizophrenia or density of the serotonin transporter in human hippocampus

BACKGROUND: Allelic association case-control analysis of a deletion/insertion polymorphism in the serotonin transporter-linked polymorphic region (5-HTTLPR) has suggested associations with unipolar disorder, bipolar disorder, depression, and Alzheimer's disease. Moreover, the heterozygous long form of the 5-HTTLPR has been associated with increased levels of mRNA for the serotonin transporter (5-HTT) and increased serotonin uptake in lymphoblastic cell lines. This study attempts to determine whether there is an association between 5-HTTLPR genotype and schizophrenia or the binding of [3H]paroxetine to the human hippocampal 5-HTT. MATERIALS AND METHODS: DNA from the cerebellum from 58 schizophrenic and 62 control subjects was used to genotype the 5-HTTLPR. In addition, the relationship between 5-HTTLPR genotype and the affinity and density of [3H]paroxetine binding to the hippocampal 5-HTT was assessed. RESULTS: There were no associations between 5-HTTLPR allotype or genotype and/or the parameters of [3H]paroxetine binding to the hippocampal 5-HTT. CONCLUSIONS: Our data suggest that 5-HTTLPR genotype neither confers an increased susceptibility for schizophrenia nor dictates the expression of the 5-HTT in the human hippocampus.     

Meta-analysis of DRD3 gene and schizophrenia: ethnic heterogeneity and significant association in Caucasians

BACKGROUND: Children with asthma may be at increased risk for low immunization rates given that they have recurrent illnesses that often result in acute care visits to their pediatrician, visits to the emergency room, admissions to the hospital, and visits to subspecialists, where immunizations are not routinely administered. OBJECTIVES: To assess immunization rates for routine and influenza vaccines in children with asthma and assess factors that may contribute to delay. METHODS: We conducted a cross-sectional survey of 117 children aged 6 to 48 months with onset of asthma within the first 15 months of life. Subjects were recruited from an allergy and immunology clinic at an urban, tertiary care center. Those judged to have immunization delay did not have the required 4 DTP, 3 OPV, and 1 MMR vaccine by age 24 months (4:3:1 series). Receipt of influenza vaccine was determined for eligible children with moderate to severe asthma. RESULTS: Seventy-four (80%) children had up-to-date immunizations at age 24 months. Those with delay had fewer visits to a subspecialist than those who were up-to-date (1 versus 2 visits P = .010). Twenty-two (25%) of 87 eligible subjects received influenza vaccine. Recipients were more likely to have been hospitalized than nonrecipients (77% versus 49%, P = .022). CONCLUSIONS: Though the majority of young children with asthma were up-to-date for routine immunizations, only 25% of children with moderate to severe asthma received influenza vaccine. Greater efforts must be made by pediatricians and asthma subspecialists to ensure that children with moderate to severe asthma are immunized against influenza virus.     

Genetic linkage between the AH locus and a major gene that inhibits susceptibility to audiogenic seizures in mice

Mice of the DBA/2 (D2) strain are highly susceptible to sound-induced seizures at 21 days of age; whereas, mice of the C57BL/6 (B6) strain are resistant to these seizures. Although the difference in susceptibility to audiogenic seizures (ASs) between these two strains is inherited as a multiple-factor trait, an association was observed between susceptibility to ASs and the Ah locus. The Ah locus controls the inducibility of aryl hydrocarbon hydroxylase (AHH) activity by a number of aromatic hydrocarbons. B6 mice carry the Ahb allele and have inducible AHH activity; whereas, D2 mice carry the Ahd allele and have noninducible activity. Inducibility is inherited as a Mendelian dominant trait in crosses between these strains. Mice carrying the Ahb allele are generally less susceptible to ASs sat 21 days of age than are mice carrying the Ahd allele. The combined results from B6 X D2 recombinant inbred strains, congenic strains (where the Ahb allele was placed into the D2 genome and the Ahd allele placed into the B6 genome), the B6D2F1 X D2 backcross generation, and a random survey of various inbred strains, suggest that the association between these two traits is due to genetic linkage, rather than to pleiotrophy or to chance. A major gene that inhibits susceptibility to ASs appears to be closely linked to the Ah locus. This gene has been designated Ias, for inhibition of ASs. A large portion of the genetic variability of AS susceptibility may be due to the segregation of Ias.     

The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping

Diastrophic dysplasia (DTD) is a well-characterized autosomal recessive osteochondrodysplasia with clinical features including dwarfism, spinal deformation, and specific joint abnormalities. The disease occurs in most populations, but is particularly prevalent in Finland owing to an apparent founder effect. DTD maps to distal chromosome 5q and, based on linkage disequilibrium studies in the Finnish population, we had previously predicted that the DTD gene should lie about 64 kb away from the CSF1R locus. Here, we report the positional cloning of the DTD gene by fine-structure linkage disequilibrium mapping. The gene lies in the predicted location, approximately 70 kb proximal to CSF1R, and encodes a novel sulfate transporter. Impaired function of its product is likely to lead to undersulfation of proteoglycans in cartilage matrix and thereby to cause the clinical phenotype of the disease. These results demonstrate the power of linkage disequilibrium mapping in isolated populations for positional cloning.     

An association study between a transcriptional polymorphism in the serotonin transporter gene and panic disorder in a Japanese population

1. To determine the effects of an acute oral dose of glibenclamide on blood pressure (BP), basal forearm vascular resistance (FVR) and FVR responses to the K+ATP channel activating vasodilator diazoxide, a placebo-controlled, double-blind cross-over study was performed in eight male volunteers with non-insulin-dependent diabetes mellitus. 2. Changes in vascular responses to progressively increasing concentrations of diazoxide (3.75-30 mg/kg per min) and noradrenaline (25-100 ng/kg per min) were measured by venous occlusion plethysmography. 3. Glibenclamide significantly lowered plasma glucose levels compared with placebo (P < 0.02) and attenuated the decrease in FVR (P < 0.05) and the decrease in systolic BP (P < 0.05) that followed a meal. However, vasodilator responses to diazoxide were potentiated by the administration of oral glibenclamide (P < 0.01). 4. Acute administration of oral glibenclamide attenuates the normal decrease in FVR and systolic BP that follows a meal and potentiates rather than inhibits forearm vasodilator responses to intra-arterial diazoxide, probably via indirect humoral effects. These results suggest that glibenclamide has direct or indirect vasoconstrictor effects that antagonize the normal increase in forearm blood flow that follows a meal and that the inhibition of vascular K+ATP channels following acute oral glibenclamide administration is clinically insignificant compared with other indirect vascular effects of the drug.     

The association between season of birth and the risk for schizophrenia

Many epidemiologic studies have been conducted to discover factors that might bear on the origins of schizophrenia. In general, the results of these studies have been contradictory. One consistent finding, however, is an association between season of birth and the risk for schizophrenia. This paper reports a test of the hypothesis that season of birth is associated with the risk for subgroups of the schizophrenic population. The results of regression analyses of data from Monroe County, New York, are reported. All white residents who were reported to have been diagnosed schizophrenic for the first time during the period January 1, 1969, to December 31, 1971, and who were hospitalized at least one day in the five-year period following the first schizophrenic diagnosis formed the group of schizophrenic patients. The population data used for the denominators of the incidence rates consisted of all white residents living in Monroe County, New York, as of April 1, 1970. An effect of month of birth on the risk for schizophrenia was related to the sex and the age of subsets of the whole population.     

Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants

Electrophysiological and pharmacological studies of a cloned human dopamine transporter (hDAT) were undertaken to investigate the mechanisms of transporter function and the actions of drugs at this target. Using two-electrode voltage-clamp techniques with hDAT-expressing Xenopus laevis oocytes, we show that hDAT can be considered electrogenic by two criteria. (1) Uptake of hDAT substrates gives rise to a pharmacologically appropriate "transport-associated" current. (2) The velocity of DA uptake measured in oocytes clamped at various membrane potentials was voltage-dependent, increasing with hyperpolarization. Concurrent measurement of transport-associated current and substrate flux in individual oocytes revealed that charge movement during substrate translocation was greater than would be expected for a transport mechanism with fixed stoichiometry of 2 Na+ and 1 Cl- per DA+ molecule. In addition to the transport-associated current, hDAT also mediates a constitutive leak current, the voltage and ionic dependencies of which differ markedly from those of the transport-associated current. Ion substitution experiments suggest that alkali cations and protons are carried by the hDAT leak conductance. In contrast to the transport-associated functions, the leak does not require Na+ or Cl-, and DAT ligands readily interact with the transporter even in the absence of these ions. The currents that hDAT mediates provide a functional assay that readily distinguishes the modes of action of amphetamine-like "DA-releasing" drugs from cocaine-like translocation blockers. In addition, the voltage dependence of DA uptake suggests a mechanism through which presynaptic DA autoreceptor activation may accelerate the termination of dopaminergic neurotransmission in vivo.     

Interactions between early parenting and a polymorphism of the child's dopamine transporter gene in predicting future child conduct disorder symptoms.

Mounting evidence suggests that genetic risks for mental disorders often interact with the social environment, but most studies still ignore environmental moderation of genetic influences. The authors tested interactions between maternal parenting and the variable number tandem repeat (VNTR) polymorphism in the 3′ untranslated region of the dopamine transporter gene in the child to increase understanding of gene–environment interactions involving early parenting. Participants were part of a 9-year longitudinal study of 4- to 6-year-old children who met criteria for attention-deficit/hyperactivity disorder (ADHD) and demographically matched controls. Maternal parenting was observed during standard mother–child interactions in Wave 1. The child's conduct disorder (CD) symptoms 5–8 years later were measured using separate structured diagnostic interviews of the mother and youth. Controlling for ADHD symptoms and child disruptive behavior during the mother–child interaction, there was a significant inverse relation between levels of both positive and negative parenting at 4–6 years and the number of later CD symptoms, but primarily among children with 2 copies of the 9-repeat allele of the VNTR. The significant interaction with negative parenting was replicated in parent and youth reports of CD symptoms separately. (PsycINFO Database Record (c) 2010 APA, all rights reserved)