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Biomedical subjects

D Goldman

Publications and source records attributed to D Goldman.

At least 109 records · Page 6Linked to original sources
PubMed1999

Effects of alcohol use and gender on the dynamics of EKG time-series data.

Hurst analysis of EKG data obtained from a population of alcoholic (n = 13) and nonalcoholic (n = 48) subjects was undertaken. Potential subjects (n = 120) were screened using the Schedule for Affective Disorders and Schizophrenia and Structured Clinical Interview for DSM-III instruments. Data from subjects with a diagnosis of current alcohol dependence were analyzed. Subjects with diagnoses such as major depression, bipolar disorder or schizophrenia (Axis I diagnoses), or personality disorders (Axis II diagnoses) were excluded from analysis. Subjects undergoing testing were free of alcohol and illicit drugs. Alcoholic subjects had no clinical evidence of alcohol withdrawal symptoms at the time of testing. EKG data were obtained with eyes open or with eyes closed. Approximately 3.5 min of data were obtained for each condition. Alcoholic subjects had less complex heart rate dynamics as evidenced by higher values of H = 0.18 +/- 0.05 (mean +/- SEM), compared with healthy comparison subjects with H = 0.09 +/- 0.02, p < 0.014 for the eyes closed condition, and H = 0.17 +/- 0.05 (mean +/- SEM) compared with healthy comparison subjects with H = 0.07 +/- 0.02,p < 0.011 for the eyes open condition. A gender effect was seen, with female subjects showing evidence of more complex heart rate dynamics than male subjects.

Alcohol Drinking↗
PubMed1999

Association of low-voltage alpha EEG with a subtype of alcohol use disorders.

BACKGROUND: Neurophysiological traits may identify more homogeneous subgroups of alcoholics. Such discoveries could yield information regarding pathophysiological development, leading to more specific preventive measures and treatments. In an earlier study of 127 individuals, 59 of whom were unrelated, we found that a heritable resting Electroencephalographic (EEG) phenotype, i.e., the low-voltage alpha (LVA) trait, was associated with alcohol use disorders and anxiety disorders. METHODS: We evaluated these findings using an independent, similarly established, dataset of 120 subjects. We also extended the study to a larger set of 149 unrelated individuals from a total sample of 247 subjects for whom psychiatric diagnoses and resting EEG phenotypes were available. Blind-rated psychiatric diagnoses were formulated according to DSM-III-R criteria. RESULTS: In the replication sample, the LVA trait was again more common among subjects with anxiety disorders than among those without. In the total group of unrelated individuals, alcoholics were significantly (3 times) more likely to show the LVA trait than were nonalcoholics. Again, individuals with anxiety disorders were significantly (3 times) more likely to exhibit the LVA trait than were those without anxiety disorders. Of 11 unrelated alcoholics with anxiety disorders, seven showed the LVA trait. It was specifically the LVA trait and not low-amplitude alpha activity that was associated with alcohol use disorders. CONCLUSIONS: The results of this replication study and the analysis of the total sample of unrelated individuals support an association between LVA EEG and the subtype of alcohol use disorders associated with anxiety disorders. The LVA phenotype may be a vulnerability factor for alcohol use disorders and anxiety disorders.

Adolescent↗
PubMed1999

C4A deficiency due to a 2 bp insertion is increased in patients with systemic lupus erythematosus.

OBJECTIVE: The association of C4A deficiency with systemic lupus erythematosus (SLE) is well documented. In Caucasian populations, the most common cause of C4A deficiency is a large gene deletion in linkage disequilibrium with a conserved MHC haplotype. Because of this linkage disequilibrium, it has been difficult to determine which of the genes constitutes the disease susceptibility allele. Evidence from non-caucasoid populations has supported a role for C4A deficiency in SLE. We investigated whether a specific genetic cause of C4A deficiency, not associated with A1, B8, DR3, is found with increased frequency in SLE compared to controls. METHODS: Polymerase chain reaction was used to identify carriers of a 2 base pair (bp) insertion in exon 29. In total, 188 patients with SLE from the Johns Hopkins lupus cohort and 222 controls were genotyped. RESULTS: The 2 bp insertion was found more frequently in patients with SLE compared to controls and was more common in Caucasian than in African American SLE patients. There were no clinical differences between patients that carried the mutation and those that did not. CONCLUSION: The association of this C4A null allele with SLE supports a role for C4A deficiency independent of other MHC associations in the etiopathogenesis of SLE.

Black People↗
PubMed1999

Correlation of serum measures of nitric oxide production with lupus disease activity.

OBJECTIVE: To determine whether serum measures of nitric oxide production correlate with disease activity in patients with systemic lupus erythematosus (SLE). METHODS: We assayed the levels of serum nitrate/nitrite from 26 patients with SLE followed for 1-3 years and nitrotyrosine levels in sera from 28 additional patients with SLE; sera from 19 controls were tested in both assays. Lupus disease activity was determined via the physician's global assessment, the Lupus Activity Index, and the SLE Disease Activity Index (SLEDAI) at the time of serum collection for the initial set of 26 patients. Statistical correlations were determined using the Wilcoxon rank sum method and one-way ANOVA testing. RESULTS: Serum levels of nitrate/nitrite were significantly higher in 26 patients with SLE compared to 19 controls (SLE, mean 29.5 microM/ml, range 1-438; controls, mean 9.6 microM/ml, range 0-51; p = 0.0004). Overall, there was a significant correlation between serum nitrate/nitrite levels and SLEDAI scores (p = 0.0065). Renal variables within the SLEDAI had the highest correlation with serum nitrate/nitrite (p = 0.0028). Serum nitrotyrosine levels were also significantly higher in patients with SLE versus controls (p = 0.007) and in active SLE versus those with inactive SLE (p = 0.008). CONCLUSION: Serum nitrate/nitrite levels correlated with SLE disease activity, especially nephritis, in the majority of patients studied. Serum nitrotyrosine levels also differentiated controls from patients with lupus and patients with active from those with inactive disease. Due to the ease and low cost of these assays, serum measures of nitric oxide production appear a potentially useful adjunctive laboratory measure of disease activity in SLE and further implicate nitric oxide as an important mediator of disease in SLE.

Adult↗
PubMed1998

Induction of alpha1-tubulin gene expression during development and regeneration of the fish central nervous system.

The alpha1- and alpha2-tubulin encoding genes were cloned from a goldfish genomic DNA library. alpha1- and alpha2-tubulin RNA expression was examined in developing and adult retinas. These studies demonstrated increased alpha1-tubulin RNA in presumptive ganglion cells that grow axons early in retinal development and in adult retinal ganglion cells whose optic axons had been damaged. The alpha2-tubulin RNA was undetectable in developing retina and constitutively expressed in adult retinal ganglion cells regardless of optic nerve crush. To determine if these changes in alpha1-tubulin RNA reflected changes in alpha1-tubulin promoter activity, we introduced into zebrafish embryos and adult goldfish retinal explants expression vectors harboring the alpha1-tubulin gene's promoter. These studies showed that the alpha1-tubulin promoter confers a developmentally regulated, neuron-restricted pattern of reporter gene expression in vivo and its activity is increased in adult retinal neurons induced to regenerate their axons. Promoter deletions defined regions of alpha1-tubulin DNA necessary for this pattern of expression. These results suggest that DNA sequences necessary for alpha1-tubulin gene induction during central nervous system development and regeneration are contained within the alpha1-tubulin gene's 5'-flanking DNA and that this promoter will be useful for identifying these elements and their DNA binding proteins.

Animals↗
PubMed1998

Cloning and characterization of GETS-1, a goldfish Ets family member that functions as a transcriptional repressor in muscle.

An Ets transcription factor family member, GETS-1, was cloned from a goldfish retina cDNA library. GETS-1 contains a conserved Ets DNA-binding domain at its N-terminus and is most similar to ternary complex factor (TCF) serum-response-factor protein-1a (SAP-1a). GETS-1 is expressed in many tissues, but is enriched in retina and brain. As with the TCFs SAP-1a and ets-related protein (ERP), overexpression of the GETS-1 promoter suppresses nicotinic acetylcholine receptor epsilon-subunit gene expression in cultured muscle cells. A consensus Ets binding site sequence in the promoter of the epsilon-subunit gene is required for GETS-1-mediated repression. GETS-1 repressor activity is abrogated by overexpression of an activated Ras/mitogen-activated protein kinase (MAP kinase) or by mutation of Ser-405, a MAP kinase phosphorylation site in GETS-1. Fusion proteins created between GETS-1 and the Gal4 DNA-binding domain show that, like other TCFs, GETS-1 contains a C-terminal activation domain that is activated by a Ras/MAP kinase signalling cascade. Interestingly, mutation of Ser-405 located within this activation domain abrogated transcriptional activation of the fusion protein.

Amino Acid Sequence↗
PubMed1998

Variants in the alpha2A AR adrenergic receptor gene in psychiatric patients.

In various studies of psychiatric patients, alterations in adrenergic receptor (AR) expression or function have been suggested. Herein, the alpha2A AR gene was screened in 206 patients with schizophrenia, attention deficit hyperactivity disorder (ADHD), autism, alcohol dependence, or cocaine dependence. The entire coding region was examined for single base pair changes, using restriction endonuclease fingerprinting (REF), a screening method that can detect virtually 100% of mutations in 2-kb DNA segments. In the approximately 600 kb of screened sequence, six novel nucleotide changes were identified. The changes resulted in four missense changes (A25G, N251K, R368L, and K370N), and a sequence in the 3' untranslated region. In addition, a silent change (G363G) was found at high frequency in Asians and Native Americans. Of the four missense changes, two found in patients with alcohol/drug dependence occur in highly conserved amino acids, suggesting that these are of likely functional significance. As the alpha2A ARs are widely distributed both pre- and postsynaptically, and as many pharmacological agents with multiple effects target these receptors, the novel missense changes described herein may be candidates for involvement in alcohol/drug dependence, in other clinical disorders or traits, or in differential response to pharmacotherapy.

Animals↗
PubMed1998

Identification of a naturally occurring Pro15-Ser15 substitution in the serotonin5A receptor gene in alcoholics and healthy volunteers.

We screened the serotonin5A receptor gene coding region in 186 unrelated alcoholic patients and 187 controls. A relatively abundant amino acid substitution and two synonymous DNA substitutions were detected. Two synonymous variants, A12T and C789T, had rarer-allele frequencies of 23% and 1%, respectively. The Pro15Ser substitution is located in the amino terminal, extracellular domain of the receptor adjacent to a putative phosphorylation site. Pro15Ser had rarer-allele frequencies of 8.1% and 5.9% in Finnish alcoholic patients and controls, respectively (p=n.s.).

Alcoholism↗
PubMed1998

Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population.

To identify specific genes affecting vulnerability or resistance, we performed a whole-autosomal genome scan for genetic linkage to alcohol dependence in a Southwestern American Indian tribe. Genotypes at 517 autosomal microsatellite loci and clinical evaluations were available for 152 subjects belonging to extended pedigrees and forming 172 sib-pairs. Highly suggestive evidence for linkage emerged for two genomic regions using two- and multipoint sib-pair regression methods; both regions harbored neurogenetic candidate genes. The best evidence is seen with D11S1984 (nominal P = 0.00007, lod approximately equal to 3.1) on chromosome 11p, in close proximity to the DRD4 dopamine receptor and tyrosine hydroxylase (TH) genes. Good evidence is seen with D4S3242 (nominal P = 0.0002, lod approximately equal to 2.8) on chromosome 4p, near the beta1 GABA receptor gene. Interestingly, three loci in the alcohol dehydrogenase gene cluster on chromosome 4q showed evidence for linkage with two-point analyses, but not multipoint analysis.

Adult↗
PubMed1998

Scanning of the dopamine D1 and D5 receptor genes by REF in neuropsychiatric patients reveals a novel missense change at a highly conserved amino acid.

In previous analyses of schizophrenic patients, multiple missense changes and one nonsense change were identified in the D5 dopamine receptor (DRD5) gene, but no sequence changes of likely functional significance were identified in the D1 dopamine receptor (DRD1) gene. In the present study, we examined these genes in patients with certain other neuropsychiatric disorders that may be related to dopaminergic dysregulation. The coding regions of the DRD1 and DRD5 genes were examined in 25 and 25 autistic patients, 25 and 28 attention deficit hyperactivity disorder patients, and 51 and 43 alcoholic patients, respectively. In addition, the DRD5 gene was examined in 75 schizophrenic patients to search for additional variants affecting protein structure or expression (VAPSEs). These patients were analyzed with REF (restriction endonuclease fingerprinting), a hybrid between SSCP and restriction endonuclease digestion, which allows the entire coding sequence to be screened in one lane of a gel. Approximately 800 kb of genomic sequence were examined. No sequence changes were identified in the DRD1 gene among the 101 patient samples analyzed. Two sequence changes were identified in the DRD5 gene among the 171 patient samples. These included one previously identified silent polymorphism at base pair 978 (P326P). The change was identified in patients from all disease categories and from different ethnic backgrounds. One novel missense change, L88F, occurred in transmembrane domain II at a highly conserved amino acid in all dopamine receptors as well as in alpha1- and beta-adrenergic receptors. The mutation was identified in a Caucasian male patient with autism. Further analysis is necessary to determine if this missense change is associated with a particular neuropsychiatric phenotype.

Adult↗
PubMed1998

Mutation screening of the 5-hydroxytryptamine7 receptor gene among Finnish alcoholics and controls.

Impaired central serotonin neurotransmission has been associated with increased aggression, impaired impulse control and diurnal activity rhythm disturbances among humans. Neuroanatomic distribution and pharmacological properties of the serotonin 5-HT7 receptor suggest that it may play a role in psychiatric disorders and in circadian rhythm regulation. In this study a point mutation causing proline279 --> leucine amino acid substitution in the 5-hydroxytryptamine7 (5-HT7) receptor gene was discovered. This 5-HT7Leu279 variant was observed in six of 825 individuals, all of whom are heterozygous for the substitution. Three of them are alcoholic offenders (3/255), two are relatives of an offender without the 5-HT7Leu279 allele (2/255) and one is a healthy control without any psychiatric diagnosis (1/248). The allele frequency of the 5-HT7Leu279 variant is 0.004 (6/758) among Finns. Although the 5-HT7Leu279 variant is approximately three times more common among alcoholic offenders than among healthy controls, it is not significantly associated with alcoholism or impulsivity in the present study. The 5-HT7Leu279 allele may, however, be a predisposing allele in a subgroup of alcoholic offenders with multiple behavioral problems.

Adult↗
PubMed1998

Identification of a neuregulin and protein-tyrosine phosphatase response element in the nicotinic acetylcholine receptor epsilon subunit gene: regulatory role of an Rts transcription factor.

At the neuromuscular synapse, innervation induces endplate-specific expression of adult-type nicotinic acetylcholine receptors by selective expression of their subunit-encoding genes (alpha2betaepsilondelta) in endplate-associated myonuclei. These genes are specifically regulated by protein-tyrosine phosphatase (PTPase) activity. In addition, neuregulin/acetylcholine-receptor-inducing activity, a nerve-derived factor that stimulates nicotinic acetylcholine receptor synthesis, induces adult-type specific epsilon subunit gene expression via activation of a Ras/mitogen-activated protein kinase pathway. However, the DNA regulatory elements and the binding proteins that mediate PTPase and neuregulin-dependent gene expression remain unknown. Herein we report that PTPase, neuregulin, and Ras-dependent regulation of the epsilon subunit gene map to a 15-bp promoter sequence. Interestingly, this same 15-bp sequence appears to be necessary for low epsilon subunit gene expression in extrajunctional regions of the muscle fiber. Site-directed mutagenesis of a putative Ets binding site located within this 15-bp sequence, reduced PTPase, neuregulin, and Ras-dependent regulation. Overexpression of the rat muscle Ets-2 transcription factor resulted in a sequence-specific induction of epsilon subunit promoter activity. Further, a dominant negative mutant of Ets-2 abolished neuregulin-dependent induction of epsilon subunit gene expression. Thus, these results indicate a crucial role for the 15-bp element in determining synapse-specific and neuregulin-mediated motor neuron control of epsilon subunit gene expression and suggest the participation of Ets transcription factor(s) in this control.

Animals↗
PubMed1998

Role of the serotonin transporter promoter polymorphism in anxiety-related traits.

BACKGROUND: The heritability of interindividual variation in anxiety and other aspects of personality establishes that variants of genes influence these traits. A functional polymorphism in the promoter of the human serotonin transporter gene (SLC6A4*C) was identified and found to be linked to an anxiety-related personality trait, Neuroticism. The polymorphism affects gene transcription and, ultimately, gene function. We have attempted to confirm the role of SLC6A4*C in anxiety-related personality traits by sibpair analysis and association studies. METHODS: Sibpair linkage analysis and association study were performed in 655 Finns. The index cases were 182 alcoholic criminal offenders, through which 258 relatives were ascertained to obtain 366 sibpairs. In addition, 215 unrelated population controls were collected. Each individual was psychiatrically interviewed, blind-rated for DSM-III-R diagnoses, and assessed with the Tridimensional Personality Questionnaire. RESULTS: The sibpair analysis revealed a positive linkage between SLC6A4*C and the 2 anxiety-related subdimensions of Harm Avoidance: HA1 (Anticipatory Worry) and HA2 (Fear of Uncertainty) (P = .003). However, there was no consistent association between SLC6A4*C and any Tridimensional Personality Questionnaire trait. CONCLUSIONS: In the present study we replicated the relationship of SLC6A4*C to anxiety by sibpair linkage analysis but found no evidence of association, raising the question of whether SLC6A4*C locus is itself affecting anxiety or is linked to another still unknown functional variant.

Alcoholism↗
PubMed1998

Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations.

BACKGROUND: In mice, quantitative trait locus studies and behavioral evaluation of animals deleted for 5-HT1B have implicated this serotonin autoreceptor in alcohol consumption and aggressive behavior. We therefore investigated whether the 5-HT1B gene (HTR1B) is linked to alcoholism with aggressive and impulsive behavior in the human, as represented by 2 psychiatric diagnoses: antisocial personality disorder and intermittent explosive disorder comorbid with alcoholism. METHODS: Linkage was first tested in 640 Finnish subjects, including 166 alcoholic criminal offenders, 261 relatives, and 213 healthy controls. This was followed by a study in a large multigenerational family derived from a Southwestern American Indian tribe (n=418) with a high rate of alcoholism. All subjects were psychiatrically interviewed, blind-rated for psychiatric diagnoses, and typed for a HTR1B G861C polymorphism and for a closely linked short-tandem repeat locus, D6S284. Linkage was evaluated in sib pairs, and by using an association approach in which pedigree randomization corrects for nonindependence of observations on related subjects. RESULTS: In Finnish sib pairs, antisocial alcoholism showed significant evidence of linkage to HTR1B G861C (P=.04) and weak evidence with D6S284 (P=.06). By association analysis, the 183 Finnish antisocial alcoholics had a significantly higher HTR1B-861C allele frequency than the other 457 Finns we studied (P=.005). In the Southwestern American Indian tribe, significant sib pair linkage of antisocial alcoholism to HTR1B G861C (P=.01) was again observed, and there was also significant linkage to D6S284 (P=.01). CONCLUSION: These results suggest that a locus predisposing to antisocial alcoholism may be linked to HTR1B at 6q13-15.

Adolescent↗
PubMed1998

A tryptophan hydroxylase gene marker for suicidality and alcoholism.

BACKGROUND: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. Low turnover rate of this monoamine neurotransmitter is associated with impaired impulse control. We previously reported that, in Finns, TPH genotype was associated with suicidality, a pathophysiological mechanism that may involve impaired impulse control. METHODS: Association and sib-pair linkage analyses of a polymorphism in intron 7 of the TPH gene with suicidality, alcoholism, and the Karolinska Scales of Personality were conducted in 804 Finnish alcoholic offenders, controls, and their relatives, in a sample that included 369 sib pairs. RESULTS: The association of the TPH 17 779C (L) allele to suicidality in impulsive offenders reported previously was replicated in a new group of Finnish offenders (P=.001, n=122). The intron 7 variant in the TPH gene showed significant evidence for linkage to suicidality (P=.006 in unaffected sib pairs), severe suicide attempts (P=.006 in unaffected sib pairs; regression: P=.01), alcoholism (P=.003 in unaffected sib-pairs; regression: P=.02), and Karolinska Scales of Personality socialization score (regression: P=.002). CONCLUSIONS: The status of the TPH A779C allele as a marker for suicidality was replicated and linkage with alcoholism and Karolinska Scales of Personality socialization score was also observed. A functional variant(s) in or close to the TPH gene may predispose individuals to suicidality and other behaviors thought to be influenced by serotonin.

Adult↗