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D Goldman

Publications and source records attributed to D Goldman.

At least 127 records · Page 7Linked to original sources
PubMed1998

Role for calcium from the sarcoplasmic reticulum in coupling muscle activity to nicotinic acetylcholine receptor gene expression in rat.

Neurally evoked muscle electrical activity suppresses nicotinic acetylcholine receptor (nAChR) gene expression in extrajunctional domains of adult muscle fibers. It has been proposed that this regulation is mediated by calcium influx through voltage-dependent L-type calcium channels but bypasses the sarcoplasmic reticulum in chick and mouse C2C12 cells. Here we report that in rat muscle calcium influx through L-type calcium channels preferentially reduced nAChR epsilon-subunit RNA via a post-transcriptional mechanism. In contrast, calcium release from the sarcoplasmic reticulum (SR) suppressed nAChR subunit RNA levels as a result of decreasing nAChR subunit promoter activity. Finally, we show that this decreased promoter activity is mediated through the same DNA sequences that control activity-dependent gene expression. Therefore, we propose that in rat muscle, calcium release from the SR participates in coupling muscle depolarization to nAChR gene expression.

Animals↗
PubMed1998

A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus.

A four-site haplotype system at the dopamine D2 receptor locus (DRD2) has been studied in a global sample of 28 distinct populations. The haplotype system spans about 25 kb, encompassing the coding region of the gene. The four individual markers include three TaqI restriction site polymorphisms (RSPs) -- TaqI "A", "B", and "D" sites -- and one dinucleotide short tandem repeat polymorphism (STRP). All four of the marker systems are polymorphic in all regions of the world and in most individual populations. The haplotype system shows the highest average heterozygosity in Africa, a slightly lower average heterozygosity in Europe, and the lowest average heterozygosities in East Asia and the Americas. Across all populations, 20 of the 48 possible haplotypes reached a frequency of at least 5% in at least one population sample. However, no single population had more than six haplotypes reaching that frequency. In general, African populations had more haplotypes present in each population and more haplotypes occurring at a frequency of at least 5% in that population. Permutation tests for significance of overall disequilibrium (all sites considered simultaneously) were highly significant (P<0.001) in all 28 populations. Except for three African samples, the pairwise disequilibrium between the outermost RSP markers, TaqI "B" and "A", was highly significant with D' values greater than 0.8; in two of those exceptions the RSP marker was not polymorphic. Except for those same two African populations, the 16-repeat allele at the STRP also showed highly significant disequilibrium with the TaqI "B" site in all populations, with D' values usually greater than 0.7. Only four haplotypes account for more than 70% of all chromosomes in virtually all non-African populations, and two of those haplotypes account for more than 70% of all chromosomes in most East Asian and Amerindian populations. A new measure of the amount of overall disequilibrium shows least disequilibrium in African populations, somewhat more in European populations, and the greatest amount in East Asian and Amerindian populations. This pattern seems best explained by random genetic drift with low levels of recombination, a low mutation rate at the STRP, and essentially no recurrent mutation at the RSP sites, all in conjunction with an "Out of Africa" model for recent human evolution.

Alleles↗
PubMed1998

Low risk of perinatal transmission of human papillomavirus: results from a prospective cohort study.

OBJECTIVE: Our purpose was to evaluate the risk of perinatal transmission of human papillomavirus. STUDY DESIGN: Pregnant women were evaluated at <20 weeks' and between 34 and 36 weeks' gestation for genital human papillomavirus by clinical and colposcopic examination and by polymerase chain reaction. Their 151 infants were evaluated at birth, 6 weeks, and 6, 12, 18, 24, and 36 months of age for detection of human papillomavirus deoxyribonucleic acid by polymerase chain reaction on samples from the mouth, external genitalia, and anus. Polymerase chain reaction was performed with human papillomavirus L1 consensus primers and hybridization to human papillomavirus types 6, 11, 16, 18, 31, 33, 35, 39, and 45 and to a generic probe. RESULTS: During pregnancy 112 (74%) of 151 women had historic, clinical, or deoxyribonucleic acid evidence of genital human papillomavirus infection. At 479 infant visits, human papillomavirus deoxyribonucleic acid was detected from only five (1.5%) of the 335 genital, four (1.2%) of the 324 anal, and none of the 372 oral or nasopharyngeal specimens. A positively reacting specimen was obtained from three (4%) of 80 infants born to women with human papillomavirus deoxyribonucleic acid detected at 34 weeks' gestation and from five (8%) of 63 born to women without human papillomavirus deoxyribonucleic acid (p = 0.47). All positive results in the infants were positive only with the generic probe and were preceded or followed by negatively reacting specimens. No clinical manifestations of human papillomavirus infection were detected in any infant. CONCLUSIONS: The isolated detection of unclassified human papillomavirus types from infants at only single visits may represent low-level genital or nongenital human papillomavirus or may represent contamination. Although perinatal transmission of human papillomavirus is not ruled out by these data, the upper 95% confidence interval for detection of perinatal transmission from women with any evidence of genital human papillomavirus was only 2.8%.

Adolescent↗
PubMed1998

A functionally deficient DRD2 variant [Ser311Cys] is not linked to alcoholism and substance abuse.

Association studies with the DRD2 Taq1A marker have been variable in implicating DRD2 as a "Reward Deficiency Syndrome Gene" for alcoholism and substance abuse. Given that the Taq1A marker is not functionally significant, second-generation studies on the DRD2 receptor to identify functional variants and evaluate their effect on the phenotype are the logical step towards confirming and extending the DRD2 hypothesis. This article discusses the implications and process of progress made in these directions. The new findings are the description of structural variants in the D2 receptor, the demonstration that one of these, Ser311Cys, largely prevents signal transduction following receptor activation and the use of Ser311Cys in a large association and sib-pair linkage anlysis in an American Indian isolate. In this particular population, the Cys311 variant is far more abundant (0.16) than in Caucasians (0.03). Genotyping of Ser311Cys, the DRD2 intron 2 STR, and the Taq1A marker in 459 subjects, including 373 sib-pairs and 15 Cys311/Cys311 homozygous individuals, revealed no association to alcoholism, substance use disorders, or schizophrenia. The implication is that a DRD2 variant that dramatically impairs receptor function was not sufficient to significantly alter alcoholism vulnerability in a relatively large and also genetically and environmentally homogeneous sample.

Alcoholism↗
PubMed1998

The apolipoprotein E epsilon 4 allele is associated with blunting of ketamine-induced psychosis in schizophrenia. A preliminary report.

Interindividual differences in the psychotomimetic response to the N-methyl-d-aspartate receptor antagonist ketamine are commonly observed. The apolipoprotein E (APOE) epsilon 4 allele has been associated with reduced severity of positive psychotic symptoms in schizophrenia. In this study, we sought to determine if the APOE epsilon 4 allele influences the psychotomimetic response to ketamine in schizophrenics. Eighteen patients genotyped at the APOE locus underwent a double-blind infusion of ketamine and of placebo. Ketamine-induced alterations in the brief psychiatric rating scale factors were compared between schizophrenics with and without the APOE epsilon 4 allele. APOE epsilon 4+ schizophrenics displayed significantly reduced ketamine-induced psychosis, as compared to epsilon 4-patients. These preliminary data indicate that the psychotomimetic response to ketamine may be genetically influenced and may provide additional evidence that APOE may modify expression of the positive symptoms in schizophrenia.

Adult↗
PubMed1998

The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response.

Several lines of evidence suggest that the dopamine D3 receptor is involved in the pathophysiology of schizophrenia. The D3 receptor gene (DRD3) contains a polymorphism resulting in a serine-glycine substitution in the N-terminus of the receptor. Shaikh and colleagues have reported a significant association between the DRD3 Ser9 allele and the Ser9/Ser9 genotype with schizophrenia in 133 Caucasians. In a meta-analysis of previous studies, Ser9 and the Ser9/Ser9 genotype were found to be significantly associated with schizophrenia, although these investigators could not confirm reports of excess homozygosity at this locus in schizophrenia. These authors also report that, in an unblinded study, the Ser9/Ser9 genotype was more frequent in patients who did not respond to clozapine. These data represent the most comprehensive examination of DRD3 Ser9Gly in schizophrenia to date. We have therefore determined DRD3 Ser9Gly genotypes in 58 patients with schizophrenia and in their parents. Moreover, we have genotyped 68 schizophrenics participating in double-blind clozapine trials. We do not find that Ser9 is preferentially transmitted in schizophrenia, cannot confirm excess DRD3 homozygosity in schizophrenia, and do not replicate the association between DRD3 and clozapine response. These data suggest that allelic variation in DRD3 may not play a role in the pathophysiology of schizophrenia or in clozapine response.

Alleles↗
PubMed1998

Role of serotonin transporter promoter repeat length polymorphism (5-HTTLPR) in seasonality and seasonal affective disorder.

Seasonal variations in mood and behavior (seasonality) and seasonal affective disorder (SAD) have been attributed to seasonal fluctuations in brain serotonin (5-HT). the short (s), as opposed to the long (l), allele of the 5-HT transporter linked polymorphism (5-HTTLPR) has been associated with neuroticism and depression. We hypothesized that this short allele would also be associated with SAD and with higher levels of seasonality. Ninety-seven SAD patients and 71 non-seasonal healthy controls with low seasonality levels were genotyped for 5-HTTLPR and compared statistically. Patients with SAD were less likely to have the l/l genotype (27.8% vs 47.9%; P < 0.01) and more likely to have the s allele (44.8% vs 32.4%; P < 0.02) as compared to controls. The three 5-HTTLPR genotypes were also differentially distributed in patients and controls (P < 0.03). The SAD patients with the l/l genotype had a lower mean seasonality score than did patients with the other two genotypes (mean +/- s.d. = 15.3 +/- 2.8 vs 17.1 +/- 3.4 respectively; P < 0.02). The 5-HTTLPR short allele contributes to the trait of seasonality and is a risk factor for SAD, providing further evidence for a relationship between genetic variation in the 5-HT transporter (5-HTT) and behavior.

Affect↗
PubMed1998

A functional serotonin transporter (5-HTT) polymorphism is associated with psychosis in neuroleptic-free schizophrenics.

The neurotransmitter serotonin has been implicated in the pathophysiology of psychosis. The serotonin transporter (5-HTT) plays a critical role in regulation of serotonergic function. A recently identified polymorphism in the promoter region of the 5-HTT gene (5-HTTLPR) produces significant differences in 5-HTT expression and function and was found to be associated with anxiety-related traits in healthy volunteers. We investigated whether 5-HTTLPR is associated with psychosis in neuroleptic-free schizophrenic or schizoaffective patients. Fifty patients with schizophrenia or schizoaffective disorder by DSM-III-R criteria were genotyped at 5-HTTLPR and underwent double-blind Brief Psychiatric Rating Scale (BPRS) ratings while neuroleptic-free for approximately 4 weeks. Patients with the 5-HTTLPR II genotype (n = 19) had significantly higher BPRS ratings for psychosis than patients with the Is (n = 25) or ss (n = 6) genotypes. Examination of individual items revealed a specific significant increase in intensity of hallucinations in patients with the 5-HTTLPR II genotpe. These data provide preliminary evidence for a role of serotonin in the pathophysiology of hallucinations and may represent the identification of an allelic variant that modifies the complex clinical presentation of schizophrenia.

Adult↗
PubMed1998

Dual origins of Finns revealed by Y chromosome haplotype variation.

The Finnish population has often been viewed as an isolate founded 2, 000 years ago via a route across the Gulf of Finland. The founding event has been characterized as involving a limited number of homogeneous founders, isolation, and subsequent rapid population growth. Despite the purported isolation of the population, levels of gene diversity for the Finns at autosomal and mitochondrial DNA loci are indistinguishable from those of other Europeans. Thus, mixed or dual origins for the Finns have been proposed. Here we present genetic evidence for the dual origins of Finns by evaluating the pattern of Y chromosome variation in 280 unrelated males from nine Finnish provinces. Phylogenetic analysis of 77 haplotype configurations revealed two major star-shaped clusters of Y haplotypes, indicative of a population expansion from two common Y haplotypes. Dramatic and quite significant differences in Y haplotype variation were observed between eastern and western regions of Finland, revealing contributions from different paternal types. The geographic distribution and time of expansion for the two common Y haplotypes correlate well with archeological evidence for two culturally and geographically distinct groups of settlers. Also, a northeastern to southwestern gradient of Y haplotype frequencies provides convincing evidence for recent male migration from rural areas into urban Finland.

Evolution, Molecular↗
PubMed1998

Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes.

The CCR5-Delta32 deletion obliterates the CCR5 chemokine and the human immunodeficiency virus (HIV)-1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A genotype survey of 4,166 individuals revealed a cline of CCR5-Delta32 allele frequencies of 0%-14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the CCR5-Delta32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275-1,875 years. The geographic cline of CCR5-Delta32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g. , an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Evolution of RPS4Y.

Sequence variation within RPS4Y, a ribosomal protein gene located in the nonpseudoautosomal region of the Y chromosome, was used to elucidate the origin of this gene in primates. Complete coding and additional flanking sequences (949 bp) of the RPS4Y locus were determined in four nonhuman primate species. Phylogenetic reconstruction of RPS4 sequence evolution supports the monophyly of mammalian RPS4 and RPS4Y. Molecular evolutionary rate estimation reveals significantly elevated rates of DNA and protein evolution in RPS4Y compared with its X-chromosome homologs. These rates enable us to estimate the timing of the transposition of RPS4X to the Y chromosome (95% confidence interval, 32 MYA-74 MYA), and this estimate was verified by Southern hybridization analysis of prosimian and simian genomic DNA. These data support a transposition event of ancestral primate RPS4X to the Y chromosome prior to the divergence of Prosimii.

Animals↗
PubMed1998

Molecular mechanisms mediating synapse-specific gene expression during development of the neuromuscular junction.

Adult skeletal muscle locally expresses nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction by selective induction of their subunit-encoding genes (alpha beta epsilon delta) in endplate-associated myonuclei. Neuregulin/ARIA is a nerve-derived factor that is thought to be largely responsible for this local gene induction. Neuregulin/ARIA activates a Ras/MAP kinase signalling cascade, which ultimately induces nAChR epsilon-subunit gene expression via a 15 bp sequence that harbors a core Ets transcription factor binding site (GGA). Interestingly, this same sequence also appears to participate in extrajunctional repression of the epsilon-subunit gene. Muscle Ets 2 overexpression induces nAChR epsilon-subunit gene promoter activity, whereas a dominant/negative Ets blocks neuregulin-dependent induction. These results suggest that Ets transcription factors play a role in mediating synapse-specific and neuregulin-mediated motor neuron control of nAChR gene expression.

Adult↗
PubMed1998

Compatibility evaluation of metered-dose inhaler valve elastomers with tetrafluoroethane (P134a), a non-CFC propellant.

Compatibility of propellants, excipients, and solvents with the components of the valve greatly influences performance of metered-dose inhalers (MDIs). Ozone-friendly hydrofluoroalkane propellant 134a has potential for use as a chlorofluorocarbon (CFC) replacement. No suitable replacement for propellant 11 and 114 has yet been found and the problems arising from this may be overcome by use of ethanol as a solvent. In this study, compatibility of MDI valve elastomers Dowty Nitrile 0117, White Buna, and Type 674 (B) with P134a placebo formulations having different concentrations of ethanol was investigated. The results indicate that formulations containing no ethanol adversely affected the functioning of the valves. Higher concentrations of ethanol improved valve performance, but showed increased leakage. Physical characteristics of the valve elastomers evaluated by determining swelling caused after exposure to the P134a placebo formulations exhibited increased swelling with increasing concentrations of ethanol in the formulation.

Administration, Inhalation↗
PubMed1998

Formulation and evaluation of albuterol metered dose inhalers containing tetrafluoroethane (P134a), a non-CFC propellant.

This study was undertaken to evaluate tetrafluoroethane (P134a) as a possible chlorofluorocarbon (CFC) replacement for albuterol metered dose inhaler (MDI) formulations. Preformulation studies using three conventional (oleic acid, sorbitan trioleate, lecithin) and a nonconventional (oleyl alcohol) surfactant indicated that P134a is a poor solvent for these surfactants. A slight improvement in the solubility of oleic acid and oleyl alcohol was observed by the addition of low concentrations of a nonconventional cosolvent diethyl ether (< or = 0.5% w/w). Formulation screening of the prepared albuterol formulations indicated that suspensions containing oleyl alcohol and diethyl ether had a slower rate of separation. Product performance of four albuterol formulations containing oleyl alcohol, diethyl ether, and P134a was evaluated and compared to a leading commercial formulation containing CFC propellants (Ventolin). Ventolin showed excellent agreement between the emitted dose and the expected dose but only a reasonable agreement was observed with one of the better P134a-containing formulations. P134a formulations showed higher internal pressure in comparison to the CFC formulation. The concentrations of the surfactant, drug, and cosolvent appeared to have a significant impact on the uniformity of the emitted dose. Determination of particle size using the time-of-flight and the laser diffraction analyzer revealed that P134a formulations had equal or smaller particle size than the formulation containing CFC. However, the CFC formulation showed a higher respirable fraction than the P134a formulation when measured by the two inertial impaction methods. The observed particle size distribution of the formulation appeared to depend on the measuring method used.

Aerosol Propellants↗
PubMed1998

Relationship of binge drinking to alcohol dependence, other psychiatric disorders, and behavioral problems in an American Indian tribe.

The hypothesis that binge drinking is a benign behavior not associated with alcohol dependence, other psychiatric disorders, or problem areas, in American Indians, was tested in a sample of 582 adult Southwestern American Indian males and females in large multigenerational pedigrees. All information was obtained from semistructured psychiatric interviews that were independently blind-rated for DSM-III-R diagnoses. Three main outcome measures were used: the relationship between binge drinking and (1) alcohol dependence and other psychiatric disorders, (2) substance abuse treatment, and (3) four behavioral problem categories-violence/lawlessness, physical, social, and work. Binge drinking and alcohol dependence were strongly associated. Most binge drinkers were diagnosed as alcohol dependent. However, when controlling for alcohol dependence and other covariates, binge drinking was independently associated with an increase in odds for positive diagnoses for multiple psychiatric disorders, and for social, work, physical, and violence/lawlessness behavioral problems. In sum, binge drinking was found to be a common and severe problem with deleterious consequences in multiple domains of functioning. Assessment instruments should be designed to elicit information on binge patterns of drinking and strategies devised to provide appropriate treatment.

Adult↗