Biomedical subjects

D Goldman

Publications and source records attributed to D Goldman.

At least 37 records · Page 2Linked to original sources

PubMed2003

Analysis of polymorphisms affecting immune complex handling in systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a polygenic disorder of dysregulated inflammation. Numerous specific candidate genes have been identified and most relate to the handling of immune complexes or antigen presentation. This is consistent with the classic finding of immune complex deposition in affected end organs. We wished to examine combinatorial effects of polymorphic variants of genes involved in immune complex clearance in susceptibility to lupus. METHODS: This study examined the occurrence of polymorphisms in genes which encode proteins known to be involved in immune complex handling and clearance. Each polymorphic variant of a complement protein (C2, mannose binding protein and C4), complement receptor (CR1) or Fc receptor (FcgammaRIIA and FcgammaRIIIA) gene is known to affect function adversely. One hundred and sixty SLE patients and 212 control subjects were genotyped using polymerase chain reaction methods. RESULTS: We found an increasing association of SLE with increasing numbers of gene defects. Combinations of severe defects in FcgammaRIIA and FcgammaRIIIA were particularly deleterious for both African American and Caucasian patients, even though only one defective variant was individually statistically significantly associated with SLE. CONCLUSIONS: The results of the study suggest that genes may interact in ways that either synergize or modify the effect of a single genetic effect and imply that association studies must be interpreted within the genetic background of the populations.

Antigen-Antibody Complex↗

PubMed2003

Neurocognitive impairment due to chronic alcohol consumption in an American Indian community.

OBJECTIVE: Studies have shown that clinically ascertained alcoholics tend to have lower scores than nonalcoholics on cognitive performance tests, particularly the Block Design (BD) and Digit Symbol (DS) tests of the Weschler Adult Intelligence Scale-Revised (WAIS-R). The aim of this study was to determine whether similar differences are found in a community sample of Plains Indian men and women with an episodic pattern of drinking and a high lifetime prevalence of alcoholism (71% for men, 44% for women). METHOD: We administered a truncated form of the WAIS-R to 334 members of a Plains Indian tribe (197 women and 137 men). Blind-rated psychiatric diagnoses were assigned according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III-R) criteria and based on the Schedule for Affective Disorders, Lifetime Version (SADS-L) interview. We compared 68 currently drinking alcoholics (38 men and 30 women), 116 abstaining alcoholics (59 men and 57 women) and 150 nonalcoholics (40 men and 110 women). RESULTS: Current and past heavy drinking had no impact on WAIS-R scores in women. Male alcoholics who were abstinent > or = 2years had similar scores to nonalcoholic men. Male current drinkers showed a trend for lower overall verbal and performance (PIQ) scores and BD performance subtest. Further analysis showed that drinking for > or = 15 years was significantly associated with reduced DS in male current drinkers. CONCLUSIONS: These findings suggest that for the men in this community sample, the impact on PIQ is due to the direct effect of chronic alcohol consumption on cognitive performance and is at least partially reversible after 2 years of abstinence.

Adult↗

PubMed2003

Candidate gene analysis of the Price Foundation anorexia nervosa affected relative pair dataset.

The eating disorders are severe psychiatric illnesses with significant morbidity and mortality that exhibit statistically significant familial risk and heritability, providing support for a molecular genetic approach toward defining etiological factors. An emerging candidate gene literature has concentrated on serotinergic and dopaminergic candidates. With the financial support of the Price Foundation, a group of investigators initiated an international multi-center collaboration (Price Foundation Collaborative Group) in 1995 to study the genetics of anorexia and bulimia nervosa by collecting and analyzing phenotypes and genotypes of individuals and their relatives affected with eating disorders. The first sample of families collected by this collaborative group, known as the Price Foundation Anorexia Nervosa Affected Relative Pair (AN-ARP) dataset, was ascertained on an proband affected with Anorexia Nervosa (AN), with relative pairs affected with the eating disorders AN, Bulimia Nervosa or Eating Disorders Not Otherwise Specified [1]. Biognosis U.S., Inc. was founded to identify and characterize candidate susceptibility genes for anorexia and bulimia nervosa phenotypes in the Price Foundation eating disorder datasets. During 2000-2001, Biognosis U.S., Inc. developed and implemented a research program with a focus on the analysis of candidate genes nominated by neurochemical characteristics of eating disorder patients [2], serotonergic and dopaminergic candidate gene polymorphisms [3], neuroendocrine regulation of appetite [4], and by a positional hypothesis from a linkage analysis of the AN-ARP dataset [5]. This report reviews the anorexia nervosa candidate gene literature through 2001, the candidate gene research program implemented at Biognosis U.S., Inc. and selected candidate gene findings in the AN-ARP dataset derived from that research program.

Animals↗

PubMed2002

Evidence for a susceptibility gene for anorexia nervosa on chromosome 1.

Eating disorders, such as anorexia nervosa (AN), have a significant genetic component. In the current study, a genomewide linkage analysis of 192 families with at least one affected relative pair with AN and related eating disorders, including bulimia nervosa, was performed, resulting in only modest evidence for linkage, with the highest nonparametric linkage (NPL) score, 1.80, at marker D4S2367 on chromosome 4. Since the reduction of sample heterogeneity would increase power to detect linkage, we performed linkage analysis in a subset (n=37) of families in which at least two affected relatives had diagnoses of restricting AN, a clinically defined subtype of AN characterized by severe limitation of food intake without the presence of binge-eating or purging behavior. When we limited the linkage analysis to this clinically more homogeneous subgroup, the highest multipoint NPL score observed was 3.03, at marker D1S3721 on chromosome 1p. The genotyping of additional markers in this region led to a peak multipoint NPL score of 3.45, thereby providing suggestive evidence for the presence of an AN-susceptibility locus on chromosome 1p.

Adult↗

PubMed2002

An osteopontin (SPP1) polymorphism is associated with systemic lupus erythematosus.

Osteopontin (SPP1) is a soluble ligand with pleomorphic immunologic activities including activation of macrophage chemotaxis, promotion of Th1 responses, and activation of B1 B cells. It has been implicated in the development of murine lupus and is overexpressed in humans with systemic lupus erythematosus (SLE). We examined a polymorphism of osteopontin for an association with lupus in humans in an effort to determine whether there is any evidence that a genetic predisposition to altered osteopontin expression might explain the overexpression seen in human SLE patients. A silent polymorphism (707C>T, rs1126616) of osteopontin was significantly associated with SLE. Additional associations with renal disease and opportunisitic infections were suggested. This is the first phenotypic association with a polymorphic variant of osteopontin.

Chi-Square Distribution↗

PubMed2001

Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.

Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11-16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.

Adult↗

PubMed2001

CaM kinase II-dependent suppression of nicotinic acetylcholine receptor delta-subunit promoter activity.

Nerve-induced muscle activity suppresses nicotinic acetylcholine receptor (nAChR) gene expression by increasing intracellular calcium levels. This suppression is mediated by nAChR promoter sequences harboring at least 1 E-box (CANNTG) that bind myogenic helix-loop-helix transcription factors. How muscle depolarization or increased calcium mediates changes in nAChR promoter activity is not well understood. In chick muscle, protein kinase C (PKC) activation is necessary for activity-dependent nAChR gene suppression. Similar effects of PKC activation have not been found in mammalian skeletal muscle. Therefore, we used rat primary muscle cultures to screen for other calcium-regulated enzymatic activities that may mediate the effects of muscle activity and calcium on nAChR promoter activity. We report here that calcium/calmodulin-dependent protein kinase II (CaM kinase II) can specifically suppress nAChR promoter activity in mammalian muscle. This regulation was mediated by a single E-box sequence residing in the previously characterized nAChR delta-subunit genes 47-base pair activity-dependent enhancer. In vitro protein/DNA interaction studies suggest that CaM kinase II inhibits binding of the myogenic factor, myogenin, to the delta-promoter 47-base pair activity-dependent enhancer. CaM kinase activity is increased in active muscle and inhibition of this enzymatic activity results in increased nAChR delta-promoter activity. Therefore, CaM kinase II may represent a previously unappreciated activity that participates in coupling muscle depolarization to nAChR gene expression.

Animals↗

PubMed2001

No association of CCK and CCK(B) receptor polymorphisms with alcohol dependence.

Cholecystokinin (CCK) is the most widely distributed neuropeptide in the central nervous system. One of its several functions is to modulate the release of dopamine in brain areas involved in reinforcement and reward behavior. The aim of this study was to investigate the association of CCK system genes (CCK, CCK(A) and CCK(B) receptor genes) with alcohol dependence using single nucleotide polymorphisms (SNPs) as genetic markers. A total of 257 psychiatrically interviewed Finns were genotyped for CCK (-45C>T), CCK(A) (Val365Ile) and CCK(B) (Val125Ile) receptor polymorphisms. Allele frequencies were compared between 150 unrelated healthy Finnish controls and 107 unrelated alcohol-dependent subjects (DSM-III-R criteria), who were also criminal offenders. The frequency of the CCK -45T allele was not significantly different between controls [0.07] and alcoholics [0.09]. The CCK(B) receptor polymorphism Val125Ile was also not associated with alcoholism and the Ile125 allele frequencies were 0.05 in controls vs. 0.06 in alcohol-dependent subjects. A CCK(A) receptor marker, Val365Ile, was uninformative in this Finnish dataset; all subjects were Val365/Val365 homozygous. The results suggest that CCK -45C>T and CCKBR Val125Ile polymorphisms do not have a major role in alcohol dependence in the population studied. The role of the CCK(A) the receptor in alcohol dependence remains open until additional DNA sequence variants for this gene become available.

Alcoholism↗

PubMed2001

Serotonin transporter promoter polymorphism is associated with attenuated prolactin response to fenfluramine.

Disturbances in central serotonin (5-HT) function may have a role in impulsive aggression in patients with a wide range of psychiatric diagnoses. The underlying mechanism, however, remains unknown. There are several naturally occurring mutations in the 5-HT signaling pathway that may underlie differences in 5-HT function and responsivity to drugs that affect 5-HT functioning. In the present study, we examined the relationship between polymorphisms in the promoter region of the gene coding for the neuronal 5-HT transporter, fenfluramine-induced prolactin release, and aggressive impulsivity (as measured by Barratt Impulsivity Scale, Buss-Durkee Hostility Inventory, and Brown-Goodwin Aggression Scale scores), in a group of abstinent alcoholic patients and healthy volunteers. We report here that possession of the short variant of the 5-HT transporter promoter polymorphism was associated with a blunting of overall central 5-HT function, as measured by fenfluramine-induced prolactin release. We found no relationship between aggressive, hostile, or impulsive traits and fenfluramine-induced prolactin release or between these traits and polymorphisms in the 5-HT transporter promoter. Thus, we have shown that a 5-HT transporter promoter genotype, which has previously been associated with anxiety-based behaviors, alters an in vivo measure of central 5-HT function (fenfluramine-induced prolactin release), providing an important mechanism for linkage between a gene, physiological function, and behavior. Published 2001 Wiley-Liss, Inc.

Adult↗

PubMed2001

Scanning of estrogen receptor alpha (ERalpha) and thyroid hormone receptor alpha (TRalpha) genes in patients with psychiatric diseases: four missense mutations identified in ERalpha gene.

Estrogen and thyroid hormones exert effects on growth, development, and differentiation of the nervous system. Hormone administration can lead to changes in behavior, suggesting that genetic variants of the estrogen receptor alpha (ERalpha) and the thyroid hormone receptor alpha (TRalpha) genes may predispose to psychiatric diseases. To investigate this possibility, regions of likely functional significance (all coding exons and flanking splice junctions) of the ERalpha and TRalpha genes were scanned in patients with schizophrenia (113), along with pilot studies in patients with bipolar illness (BPI), puerperal psychosis, autism, attention-deficit hyperactivity disorder (ADHD), and alcoholism. A total of 1.18 megabases of the ERalpha gene and 1.16 megabases of the TRalpha gene were scanned with Detection of Virtually All Mutations-SSCP (DOVAM-S), a method that detects virtually all mutations. Four missense mutations, seven silent mutations and one deletion were identified in the ERalpha gene, while only four silent mutations were present in the TRalpha gene. Two of the missense mutations in ERalpha are conserved in the six available mammalian and bird species (H6Y, K299R) and a third sequence variant (P146Q) is conserved in mammals, birds, and Xenopus laevis, hinting that these sequence changes will be of functional significance. These changes were found in one patient each with BPI, puerperal psychosis, and alcoholism, respectively. Analysis of the ERalpha and TRalpha genes in 240 subjects reveals that missense changes and splice site variants are uncommon (1.7% and 0%, respectively). Further analyses are necessary to determine if the missense mutations identified in this study are associated with predisposition or outcome for either psychiatric or nonpsychiatric diseases.

Alleles↗

PubMed2001

A computational study of the effect of vasomotion on oxygen transport from capillary networks.

The objective of this study was to investigate the effect of arteriolar vasomotion on oxygen transport from capillary networks. A computational model was used to calculate blood flow and oxygen transport from a simulated network of striated muscle capillaries. For varying tissue oxygen consumption rates, the importance of the frequency and amplitude of vasomotion-induced blood flow oscillations was studied. The effect of myoglobin on oxygen delivery during vasomotion was also examined. In the absence of myoglobin, it was found that when consumption is high enough to produce regions of hypoxia under steady flow conditions, vasomotion-induced flow oscillations can significantly increase tissue oxygenation and decrease oxygen transport heterogeneity. The largest effect was seen for low-frequency, high-amplitude oscillations (1.5-3 cycles min(-1), 90% of steady-state velocity). By contrast, at physiological tissue myoglobin concentrations, vasomotion did not improve tissue oxygenation. This unexpected finding is due to the buffering effect of myoglobin, suggesting that in highly aerobic muscles short-term storage of oxygen is more important than the possibility of increasing transport through vasomotion.

Animals↗

PubMed2001

Sexually dimorphic relationship of a 5-HT2A promoter polymorphism with obsessive-compulsive disorder.

BACKGROUND: In an earlier analysis of 73 subjects from this study, the reduced activity catechol O-methyltransferase variant was shown to be associated with obsessive-compulsive disorder in men only. We hypothesized that the 5-HT2A promoter polymorphism, -1438G>A, previously associated with anorexia nervosa, would be more abundant in women with obsessive-compulsive disorder. METHODS: One hundred and one Caucasian obsessive-compulsive disorder patients (48 women, 53 men) and 138 control subjects (77 women, 61 men), were genotyped. DSM-III-R psychiatric diagnoses were assigned based on the SCID-I. RESULTS: As hypothesized, the -1438A allele frequency was higher in obsessive-compulsive disorder women (.57) than female control subjects (.42) (p =.015). The genotype frequencies were also significantly different (p =.020). Allele frequencies did not differ between male obsessive-compulsive disorder patients (.44) and male control subjects (.41). CCONSLUSIONS: We have found that a 5-HT2A promoter polymorphism is associated with obsessive-compulsive disorder in women but not in men, strengthening the argument that there may be fundamental gender differences in the genetic susceptibility to obsessive-compulsive disorder.

Adult↗

PubMed2001

The genetics of alcoholism and alcohol abuse.

Twin studies have established that there are substantial genetic influences on alcoholism (0.5-0.6) in both men and women. Our knowledge of behaviors predisposing to alcoholism, including anxiety and impulsivity, is advancing rapidly through animal and human studies. Although alcoholism is often comorbid with other substance abuse and psychiatric disorders, recent studies have shown that, with the exception of nicotine, the heritability of alcoholism is largely substance-specific. Increasing understanding of the neurobiology of addiction has identified neural pathways in which genetic variation at candidate genes could influence vulnerability. Some functional variants of these genes have been identified. Recent linkage analyses in humans and rodents have pointed to genomic regions harboring genes that influence alcoholism. Refinement of clinical phenotypes and use of intermediate phenotypes will improve chances of gene identification. All these advances in the understanding of the genetics of alcoholism should facilitate the development of more accurately targeted therapies using molecular diagnostic approaches.

Alcoholism↗

PubMed2001

Transgenic zebrafish for studying nervous system development and regeneration.

Alpha1 tubulin gene expression is induced in the developing and regenerating CNS of vertebrates. Therefore, alpha1 tubulin gene expression may serve as a good probe for mechanisms underlying CNS development and regeneration. One approach to identify these mechanisms is to work backwards from the genome. This requires identification of alpha1 tubulin DNA sequences that mediate its developmental and regeneration-dependent expression pattern. Therefore, we generated transgenic zebrafish harboring a fragment of the alpha1 tubulin gene driving green fluorescent protein expression (GFP). In these fish, and similar to the endogenous gene, transgene expression was dramatically induced in the developing and regenerating nervous system. Although transgene expression generally declined during maturation of the nervous system, robust GFP expression was maintained in progenitor cells in the retinal periphery, lining brain ventricles and surrounding the central canal of the spinal cord. When these cells were cultured in vitro they divided and gave rise to new neurons. We also show that optic nerve crush in adult fish re-induced transgene expression in retinal ganglion cells. These studies identified a relatively small region of the alpha1 tubulin promoter that mediates its regulated expression pattern in developing and adult fish. This promoter will be extremely useful to investigators interested in targeting gene expression to the developing or regenerating nervous system. As adult transgenic fish maintain transgene expression in neural progenitors, these fish also provide a valuable resource of labeled adult neural progenitor cells that can be studied in vivo or in vitro. Finally, these fish should provide a unique in vivo system for investigating mechanisms mediating CNS development and regeneration.

Animals↗

PubMed2001

Interferon-gamma polymorphisms in systemic lupus erythematosus.

Interferon-gamma is a cytokine which is believed to play a role in both the susceptibility and pathogenesis of lupus. To determine whether genetic variants might influence the development of this polygenic autoimmune disease, we analyzed the gene frequency of eight different alleles in controls and patients with SLE. Ninety-nine controls and 136 patients with systemic lupus erythematosus were genotyped for a CA repeat in the first intron of the interferon-gamma gene. There were no statistically significant differences in the allele frequencies between patients and controls suggesting that these polymorphic variants do not influence susceptibility. We then examined whether any of these alleles were associated with specific clinical manifestations. Allele 1 was associated with gastrointestinal lupus while allele 6 was associated with more severe lupus. Allele 2 appeared to be protective for arthritis. This suggests that genetic variation in interferon-gamma expression might influence the disease course.

Alleles↗

PubMed2001

An in-frame deletion in the alpha(2C) adrenergic receptor is common in African--Americans.

alpha(2) adrenergic receptors are activated by adrenaline and noradrenaline, and three subtypes (ie, A, B, C) have differential affinities for antagonists and medications. The alpha(2c) adrenergic receptor (ADRA2C), located on chromosome 4p16.3, is a candidate gene for schizophrenia because it binds clozapine, an atypical neuroleptic useful for treatment-resistant schizophrenia. In addition, ADRA2C binds clonidine which is prescribed for three psychiatric diseases. This report communicates the findings of the genetic scanning of this gene of very tough GC content. The complete coding sequences and splice junctions were scanned with [DOVAM]-S in 104 schizophrenics, and pilot probes of patients with alcoholism (41 patients), cocaine abuse (25 patients), puerperal psychosis (30 patients), attention deficient/hyperactivity disorder (25 patients) and autism (25 patients). Six sequence variants were found, including five silent polymorphisms (allele frequencies 0.6--25%) and an in-frame deletion of a homologous repeat at nucleotides 967--978 (ie, TIDRU(1)). Genotyping of the normal two repeat unit of the Third Intracytoplasmic Domain Repeat Unit (TIDRU(2)) and the deleted variant (TIDRU(1)) revealed that TIDRU(1) had allelic frequencies of 39% (11/28) and 3.5% (6/172) in African-American and Caucasian schizophrenics, respectively, and it occurred with equal frequency in controls (44%, 31/70 and 3.0%, 6/198). TIDRU(1) occurs at a location similar to the third intracytoplasmic 48-nucleotide repeat unit in the DRD4 that is associated with ADHD. Although these data do not suggest an association of TIDRU(1) with schizophrenia, additional studies are needed to see whether TIDRU(1) confers a clinical phenotype.

Black People↗

PubMed2001

Association of a 5-HT(5A) receptor polymorphism, Pro15Ser, to schizophrenia.

Several different lines of evidence suggest that genes involved in serotonergic neurotransmission are factors in the pathogenesis of schizophrenia. For example, 5-HT(5A) knockout mice revealed decreased locomotor response to lysergic diethylamide (LSD), which produces a psychotic-like state in healthy people. Recently, we reported a naturally occurring conservative Pro15Ser substitution in the 5-HT(5A) receptor. Here, we evaluate whether this substitution is associated with schizophrenia in a sample including 249 unrelated Japanese schizophrenia patients and 253 unrelated controls. Patients and controls were genotyped for the Pro15Ser polymorphism by a PCR-RFLP assay. Ser15 allele frequencies were 0.07 in patients with schizophrenia and 0.02 in controls (chi(2) = 17.42, df =1, P < 0.0001). thus, we detected a highly significant association of pro15ser to schizophrenia in a large population of japanese schizophrenia patients and controls. since case-control studies have an inherent potential for false-positive results due to population stratification, this finding is preliminary pending further studies, including studies using the transmission/disequilibrium test to eliminate stratification bias or control loci to assess ethnic matching of cases and controls.

Adult↗

PubMed2001

Tacrolimus ointment for the treatment of steroid-induced rosacea: a preliminary report.

BACKGROUND: Excessive topical corticosteroid application to facial areas commonly leads to steroid-induced rosacea. This may be a recalcitrant problem that requires months of antibiotic and anti-inflammatory therapy before it resolves. OBJECTIVE: The purpose of this article is to review the use of tacrolimus ointment, a macrolide anti-inflammatory ointment for the treatment of 3 patients with steroid-induced rosacea. METHODS: Three patients with steroid-induced rosacea applied tacrolimus ointment, 0.075% twice daily for 7 to 10 days. Patients were also instructed to avoid topical corticosteroid use and other rosacea-aggravating substances including caffeine, spicy foods, alcohol, hot fluids, and fluoride. Patients were observed for tenderness, erythema, and relief of pruritus. RESULTS: Pruritus, tenderness, and erythema were resolved in all 3 patients after 7 to 10 consecutive days' use of tacrolimus 0.075% ointment in conjunction with avoidance of topical steroids, caffeine, spicy food, alcohol, hot fluids, and fluoride. CONCLUSION: This preliminary study demonstrates that tacrolimus 0.075% ointment may be effective for patients with steroid-induced rosacea, when combined with avoidance of topical steroid use, as well as avoidance of other agents known to aggravate rosacea (caffeine, spicy foods, alcohol, hot fluids, and fluoride).

Administration, Topical↗