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Biomedical subjects

D Goldman

Publications and source records attributed to D Goldman.

At least 145 records · Page 8Linked to original sources
PubMed1997

Linkage and association of a functional DRD2 variant [Ser311Cys] and DRD2 markers to alcoholism, substance abuse and schizophrenia in Southwestern American Indians.

Alcoholism is one of a group of common psychiatric diseases which are well-defined clinically and strongly influenced genetically, but which are likely to be highly heterogeneous in causation, genetically and otherwise. Dopamine is a key neurotransmitter in drug-mediated reinforcement. Based on association studies with the Taq1A downstream marker, the D2 dopamine receptor has been proposed to be the "Reward Deficiency Syndrome Gene." Ser311Cys, a naturally occurring variant which largely inactivates transduction after D2 receptor activation, was abundant (0.16) in a Southwestern American Indian population we studied. Therefore, we were able to provide a critical test of the D2 hypothesis of vulnerability to alcoholism by evaluating Ser311Cys and also the intron-2 STR and Taq1A markers at this locus in a total of 459 subjects, including 373 sib pairs, from large families. The result is that neither alcoholism, substance use disorders nor schizophrenia show a relationship to Ser311Cys genotype, even when the 15 Cys311/Cys311 homozygous individuals are compared to others. Furthermore, sib pair analysis incorporating information across all three sib pair categories: concordant affected, discordant and concordant unaffected revealed no effect of DRD2 genotype or haplotype on alcoholism or substance use disorder.

Alcoholism↗
PubMed1997

Somatic evolution in the immune system: the need for germinal centers for efficient affinity maturation.

In the course of a humoral immune response, the average affinity of antibody for the immunizing antigen can increase in time. This process of affinity maturation is due to antigen-driven selection of higher affinity B cell clones and somatic hypermutation of the genes that code for the antibody variable region. Through the use of simulation models we show that the efficiency of affinity maturation is substantially improved if mutation and selection occur in germinal centers, specialized regions of lymphoid tissues, rather than in the body as a whole. We show that confining mutation and selection to germinal centers decouples the problem of affinity maturation from the problem of antigen elimination. In the germinal centers, stored antigen, high rates of B cell proliferation and apoptosis combine to create an environment where effective maturation occurs even after the primary response has eliminated much or all of the free antigen. Kepler and Perelson suggested that if hypermutation were turned on and off in a phasic manner, affinity maturation could be made more efficient under circumstances when affinity-improving mutations have a low probability of occurrence. We confirm this in the context of a stochastic model. However, even in the absence of phasic mutation, we show that affinity maturation is significantly improved when proliferation, mutation, and selection are restricted to germinal centers as opposed to occurring systemically.

Antibody Affinity↗
PubMed1997

Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder.

In the present study, we address the role of the gene for catechol-O-methyltransferase (COMT), a key modulator of dopaminergic and noradrenergic neurotransmission, in the genetic predisposition to obsessive-compulsive disorder (OCD). We show that a common functional allele of this gene, which results in a 3- to 4-fold reduction in enzyme activity, is significantly associated in a recessive manner with susceptibility to OCD, particularly in males. This association is further supported by psychiatric evaluation of patients who carry microdeletions encompassing the comt gene. The mechanism underlying this sex-selective association remains to be defined and may include a sexual dimorphism in COMT activity, although close linkage with a nearby disease susceptibility locus cannot be excluded at this point.

Alleles↗
PubMed1997

A promoter polymorphism of tumor necrosis factor alpha associated with systemic lupus erythematosus in African-Americans.

OBJECTIVE: The polymorphic tumor necrosis factor alpha (TNFalpha) gene encodes a cytokine involved in inflammation, angiogenesis, and apoptosis. One polymorphic variant is associated with increased production of TNFalpha. This study examined the frequency of this polymorphic variant in African-American patients with systemic lupus erythematosus (SLE) compared with controls. METHODS: We determined the gene frequency of the polymorphic variant of TNFalpha in an African-American SLE patient population and in a geographically matched African-American control population. RESULTS: The gene frequency of the TNFalpha -308A polymorphism was higher in the African-American SLE population than in the control population. This relationship was independent of major histocompatibility complex DR alleles. CONCLUSION: The TNFalpha -308A polymorphism is associated with an increased risk of SLE in African-Americans.

Adult↗
PubMed1997

Tryptophan hydroxylase and catechol-O-methyltransferase gene polymorphisms: relationships to monoamine metabolite concentrations in CSF of healthy volunteers.

Concentrations of monoamine metabolites (MM) in lumbar cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. We investigated possible relationships between DNA polymorphisms in the tryptophan hydroxylase (TPH) and catechol-O-methyltransferase (COMT) genes and CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 66). Lower CSF 5-HIAA levels were found in men with the TPH U allele (p = 0.005), but not in women. A similar but less significant pattern was observed for CSF HVA. No relationship was found between the TPH polymorphism and CSF MHPG. COMT genotypes did not relate significantly to MM concentrations. The results suggest that TPH genotypes participate differentially in the regulation of serotonin turnover rate under presumed steady state in the central nervous system of men. Due to the uncertain functional relevance of the DNA polymorphism investigated and the many calculations performed, the results should be interpreted with caution until replicated.

Adult↗
PubMed1997

Prevalence, characteristics, and impact of childhood sexual abuse in a Southwestern American Indian tribe.

OBJECTIVE: There were two objectives; first, to investigate the prevalence and characteristics of child sexual abuse in an American Indian community, and second, to determine whether persons with histories of child sexual abuse are at greater risk to develop psychiatric disorders and behavioral problems than persons who report no such history. METHOD: A sample of 582 Southwestern American Indian tribal members was collected for a genetic and linkage study on alcoholism and psychiatric disorders in three large and interrelated pedigrees. Subjects were recruited from the community without knowledge of their clinical histories or those of their relatives. Child sexual abuse and psychiatric disorders were assessed using a semi-structured psychiatric interview. RESULTS: Females were more likely to be sexually abused as children (49%) than were males (14%). Intrafamilial members accounted for 78% of the reported child sexual abuse. Sexually abused males and females were more likely to report childhood and adult behavioral problems than were nonabused subjects. There was a strong relationship between multiple psychiatric disorders and child sexual abuse, with sexually abused males and females more likely to be diagnosed with > or = 3 psychiatric disorders, both including and excluding alcohol dependence or abuse, than were nonabused subjects. CONCLUSION: Child sexual abuse in this population is both an index of family dysfunction and community disorganization as well as a predictor of later behavioral patterns and psychopathology.

Adolescent↗
PubMed1997

Sequence, splice site and population frequency distribution analyses of the polymorphic human tryptophan hydroxylase intron 7.

A human tryptophan hydroxylase intron seven polymorphism previously associated with low CSF 5-HIAA and suicidal behavior was sequenced and characterized for its potential role in TPH pre-mRNA splicing. Two polymorphic sites were identified: A218C and A779C. The 779A allelic frequency in various populations ranged from 0.43 to 0.61 and was in strong linkage disequilibrium with the A218C site. A218C provides a site for restriction fragment length polymorphism analysis. TPH mRNA was reverse-transcribed and sequenced. No aberrant splice products from the 779A or 779G TPH genes were detected nor were any other polymorphic nucleotides found.

Base Sequence↗
PubMed1997

Axon-target interactions maintain synaptic gene expression in retinae transplanted to intracranial regions of the rat.

In the present study we examined the effects of optic axon-CNS target interactions on gene expression in the rat retina. These studies took advantage of a transplantation paradigm that allowed us to assay gene expression in retinae transplanted to different intracranial locations in the neonatal rat that either promoted (dorsal midbrain) or precluded (cerebral cortex) the formation of retino-collicular connections. Using in situ hybridization experiments, we observed that transplantation to the dorsal midbrain resulted in a relatively normal pattern of nicotinic acetylcholine receptor (nAChR) beta-3 subunit and glutamate receptor 3 (GluR3) gene expression. In contrast, retinae transplanted to the cerebral cortex (which did not result in normal retino-collicular interactions) showed a dramatic reduction in nAChR beta-3 subunit and GluR3 gene expression. These results agree with those obtained in the adult goldfish retina, where it has been demonstrated that an optic nerve-optic tectum interaction is responsible for the re-induction nAChR and NMDA receptor gene expression during optic nerve regeneration. Taken together, these results support the hypothesis that proper axon-target interactions are required for maintenance of nAChR and glutamate receptor gene expression in the mature vertebrate retina.

Animals↗
PubMed1997

Seasonal variation of gonadotropins and gonadal steroids receptors in the human pineal gland.

Recently abnormal melatonin secretion was demonstrated in hypogonadal male patients which was normalized during testosterone administration. These results suggested that both gonadal steroids and gonadotropins may modulate melatonin secretion, probably by activating specific receptors in the pineal gland. We used immunohistochemistry to localize luteinizing hormone, follicle stimulating hormone, estrogen and androgen receptors in human pineal glands. Tissues were obtained at autopsy from 53 adult males (aged 19-94 years) over a period of 1 year. Positive staining for the four types of receptors was evident in all 53 specimens examined. The percent of positively stained cells revealed a significant seasonal variation of gonadotropin receptors with higher values in the winter than in the summer. Day-night difference was evident only for follicle stimulating hormone-receptors during the summer and winter, with higher values at night. Androgen receptors and estrogen receptors were present in all specimens but did not reveal day-night or seasonal variations. These data demonstrate the presence of gonadotropin and gonadal steroid receptors in the human pineal gland. Gonadotropin receptors exhibited seasonal variation with higher values in the winter.

Adult↗
PubMed1997

Agonist-promoted down-regulation and functional desensitization in two naturally occurring variants of the human serotonin1A receptor.

We recently reported two naturally occurring polymorphisms of the human serotonin1A (5-HT1A) receptor: glycine22-->serine (Ser22) and isoleucine28-->valine (Val28) in the putative aminoterminal domain of the receptor. To investigate the regulatory properties of these variants, the wild type (WT) and variant 5-HT1A receptors were stably expressed in CHO-K1 cells. WT, Ser22, and Val28 displayed similar high-affinity binding to [3H]-8-OH-DPAT. Competition experiments with 5-HT1A agonists and antagonists demonstrated similar pharmacological profiles. Receptor agonist-promoted down-regulation was tested by exposure to 100 mumol/L 8-OH-DPAT. After 24-h exposure, WT and Val28 underwent 59.3 +/- 3.9% and 59.5 +/- 1.4% reduction in receptor density respectively, whereas the degree of down-regulation was significantly lower for Ser22 (21.4 +/- 4.2%). Cell treatment for 24 h with 100 mumol/L 8-OH-DPAT reduced the 5-HT-induced inhibition of cAMP accumulation by 24.9 +/- 5.1% for WT and 16.4 +/- 0.8% for Val28, but only by 4.8 +/- 3% for Ser22. We conclude that the Ser22 variant is capable of attenuating agonist-mediated receptor down-regulation and desensitization.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

A naturally occurring amino acid substitution of the human serotonin 5-HT2A receptor influences amplitude and timing of intracellular calcium mobilization.

Recently, two naturally occurring amino acid substitutions were identified in the C-terminal region of the serotonin 5-HT2A receptor. One of these, His452Tyr, has a rarer allele Tyr frequency of 9%. If 452Tyr alters 5-HT2A function, it would thus be a candidate allele for human neurobehavioral variation. The present study was designed to evaluate the potential influence of the 452His and 452Tyr alleles on cellular 5-HT2A functions. Platelet 5-HT2A binding and 5-HT-induced Ca2+ response were compared in eight 452His/452His homozygous and eight 452His/452Tyr heterozygous individuals matched for sex, age, and diagnosis (all were patients with seasonal affective disorder). There was no difference in 5-HT2A binding measured using 125I-lysergic acid diethylamide. Nor were levels of G-protein subunits or PKC alpha, delta, epsilon, or zeta significantly altered. However, when Ca2+ response was stimulated by 2, 5, 10, or 25 microM 5-HT, significant differences were found. In 452His/452Tyr heterozygotes, 452Tyr was associated with both smaller peak amplitude in Ca2+ mobilization and a different time course of response, with slower peak latency and longer half-time in 452His/452Tyr heterozygotes compared with 452His/452His homozygotes. The overall difference in the response of the 5-HT2A receptor in individuals with 452Tyr was a blunting of the shape of the Ca2+ mobilization peak. The data reported here suggest that the primary sequence of this intracellular domain is important in function of the receptor and that the 452His and 452Tyr 5-HT2A alleles should be carefully evaluated for effects on human neurobehavioral variation.

Adult↗
PubMed1997

Possible association of a polymorphism of the tryptophan hydroxylase gene with suicidal behavior in depressed patients.

OBJECTIVE: This study was designed to test the hypothesis that serotonin-system-related genes may be correlated with suicide risk. METHOD: Fifty-one unrelated Caucasian inpatients with major depression, with or without a history of suicidal acts, were genotyped for a biallelic polymorphism at the tryptophan hydroxylase locus. RESULTS: The less common tryptophan hydroxylase U allele occurred with greater frequency in the patients who had attempted suicide. A logistic regression analysis confirmed an association between tryptophan hydroxylase genotype and lifetime history of suicide attempts. CONCLUSIONS: Serotonergic-system-related genes may influence the risk of suicide in persons with major depression.

Adult↗
PubMed1997

Prevalence and characteristics of trauma and posttraumatic stress disorder in a southwestern American Indian community.

OBJECTIVE: High rates of violence and trauma in many American Indian communities have been reported. The authors investigated the relationship between both the frequency and type of traumatic events and the prevalence of posttraumatic stress disorder (PTSD) in a Southwestern American Indian tribe. METHOD: A structured psychiatric interview and the Traumatic Events Booklet were administered to a subset of 247 tribal members from an overall study population of 582. Subjects were recruited from the community on the basis of membership in pedigrees, and not by convenience. DSM-III-R diagnoses were assigned by consensus after the interviews were evaluated blindly by independent raters. RESULTS: The prevalence of lifetime PTSD was 21.9% (N = 54), and 81.4% of the subjects (N = 201) had experienced at least one traumatic event apiece. The most predictive factor for lifetime PTSD among women was the experience of physical assault, and for men the most predictive factors were a history of combat and having experienced more than 10 traumatic events. CONCLUSIONS: In this Southwestern American Indian community, the prevalences of lifetime PTSD and of exposure to a traumatic event were higher than in the general U.S. population. However, the nearly 4:1 ratio of subjects who reported at least one traumatic event to those with PTSD diagnoses is similar to findings from studies of non-Indians. Individuals with a history of multiple traumatic events (66.0%, N = 163) had a significantly higher risk of developing PTSD. Chronic and multiple trauma did not preclude the identification of acute and discrete traumatic events that resulted in PTSD.

Adolescent↗
PubMed1997

Factors influencing utilization of mental health and substance abuse services by American Indian men and women.

OBJECTIVE: This study investigated the effects of gender, number of lifetime psychiatric diagnoses, and childhood victimization on utilization of mental health and substance abuse treatment services in a Southwestern American Indian tribe. METHODS: A total of 582 individuals were recruited based on tribal enrollment and membership in large multigenerational pedigrees. Subjects were interviewed using a modified version of the Schedule for Affective Disorders and Schizophrenia-Lifetime Version, a semistructured psychiatric interview. For this study the definition of childhood victimization was limited to childhood sexual abuse. RESULTS: Fifty-six percent of the subjects had received mental health treatment, substance abuse treatment, or both. Patterns of service utilization differed by gender with the odds of inpatient and substance abuse treatment higher for men than for women. Women were more likely than men to receive mental health treatment. Subjects who had been sexually abused as children were more likely to have three or more psychiatric diagnoses and to have received extensive treatment, compared with subjects who reported no childhood sexual abuse history. Logistic regression demonstrated strong relationships between number of psychiatric diagnoses and the likelihood of treatment among both men and women. CONCLUSIONS: Gender, number of psychiatric diagnoses, and childhood sexual abuse are strong predictors of utilization of mental health and substance abuse treatment services. These factors should be considered in designing treatment interventions.

Adult↗
PubMed1997

Immunohistochemical localization of gonadotropin and gonadal steroid receptors in human pineal glands.

Recently, we demonstrated that melatonin secretion was increased in male patients with GnRH deficiency and decreased to normal levels during testosterone treatment. These data suggested that gonadal steroids modulate melatonin secretion, probably by activating specific receptors in the pineal gland. We used immunohistochemistry to localize gonadotropin (LH and FSH) and gonadal steroid (androgens and estrogens) receptors in human pineal glands. Tissues were obtained at autopsy from 25 males, aged 19-87 yr, and five prepubertal children, aged 0.2-10 yr. Positive staining for all four types of receptors (LH, FSH, androgen, and estrogen) in the pineal parenchymal cells, pinealocytes, was evident in all 30 glands examined. Double staining revealed that nuclear receptors (androgen or estrogen) co-existed with cytoplasmatic receptors (LH or FSH) in the same cells. The results demonstrate the presence of gonadotropin and gonadal steroid receptors in human pinealocytes from infancy to old age.

Adult↗
PubMed1996

Two naturally occurring amino acid substitutions of the 5-HT2A receptor: similar prevalence in patients with seasonal affective disorder and controls.

We screened the 5-HT2A receptor gene coding region in 50 patients with seasonal affective disorder (SAD) using a single strand conformational polymorphism analysis and estimated the frequencies of two synonymous and two non-synonymous substitutions we detected in 70 Centre d'Etude du Polymorphism Humain (CEPH) population controls and 62 normal controls. Both of the amino acid substitutions: Ala447-Val447 and His452-Tyr452, were located within the cytoplasmic. C-terminal tail of the receptor. Rarer allele frequencies in CEPH were 0.7% and 9.3% for Val447 and Tyr452, respectively. Allele frequencies of all four polymorphisms, including the two amino acid substitutions, were not significantly different in SAD patients as compared to CEPH and normal controls. Lack of association of Val447 and Tyr452 to SAD is consistent with observations showing normal 5-HT2A receptor Ca2+ response in platelets with this disorder, however, the two 5-HT2A amino acid substitutions may lead to differences in behavioral phenotypes.

Alleles↗