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Biomedical subjects

T Ritchie

Publications and source records attributed to T Ritchie.

At least 19 recordsLinked to original sources
PubMed2001

GABA(A) receptor beta 3 subunit gene and psychiatric morbidity in a post-traumatic stress disorder population.

GABAergic systems have been implicated in the pathogenesis of anxiety, depression and insomnia. These symptoms are part of the core and comorbid psychiatric disturbances in post-traumatic stress disorder (PTSD). In a sample of Caucasian male PTSD patients, dinucleotide repeat polymorphisms of the GABA(A) receptor beta 3 subunit gene were compared to scores on the General Health Questionnaire-28 (GHQ). As the major allele at this gene locus (GABRB3) was G1, the alleles were divided into G1 and non-G1 groups. On the total score of the GHQ, which comprises the somatic symptoms, anxiety/insomnia, social dysfunction and depression subscales, patients with the G1 non-G1 genotype had a significantly higher score when compared to either the G1G1 genotype (alpha=0.01) or the non-G1 non-G1 genotype (alpha=0.05). No significant difference was found between the G1G1 and non-G1 non-G1 genotypes. When the G1 non-G1 heterozygotes were compared to the combined G1G1 and non-G1 non-G1 homozygotes, a significantly higher total GHQ score was found in the heterozygotes (P=0.002). These observations suggest a heterosis effect. Further analysis of GHQ subscale scores showed that heterozygotes compared to the combined homozygotes had higher scores on the somatic symptoms (P=0.006), anxiety/insomnia (P=0.003), social dysfunction (P=0.054) and depression (P=0.004) subscales. In conclusion, the present study indicates that in a population of PTSD patients, heterozygosity of the GABRB3 major (G1) allele confers higher levels of somatic symptoms, anxiety/insomnia, social dysfunction and depression than found in homozygosity.

Alleles↗
PubMed2001

GPx-1 gene delivery modulates NFkappaB activation following diverse environmental injuries through a specific subunit of the IKK complex.

Numerous environmental stimuli alter cell functions by the induction of intracellular reactive oxygen species, such as superoxide and hydrogen peroxide (H2O2). These redox alterations can change the activity of kinases and phosphatases responsible for controlling intracellular signal transduction cascades important in determining how cells react to their environment. One such well known pathway includes nuclear factor-kappaB (NFkappaB); however, the exact redox-sensitive factors important in controlling H2O2-mediated activation of NFkappaB remain unclear. In the present study, we have investigated how intracellular clearance of H2O2, using a recombinant adenovirus expressing glutathione peroxidase-1 (GPx-1), modulates NFkappaB activation following UV irradiation, tumor necrosis factor-alpha, or H2O2 treatment of MCF-7 cells. Findings from these studies demonstrate that GPx-1 overexpression can down-regulate NFkappaB DNA binding, and transcriptional activation of an NFkappaB-dependent luciferase reporter, to varying extents following these environmental stimuli. Studies using dominant negative adenoviral vectors expressing IKKalpha(KM) and IKKbeta(KA) suggest that GPx-1-mediated H2O2 clearance appears to preferentially inhibit the activity of IKKalpha, but not IKKbeta. These studies demonstrate for the first time that redox regulation of NFkappaB activation by intracellular H2O2 may be specific for a unique subunit in the IKK complex. Such findings suggest that IKK kinases or IKK phosphatases may have unique redox-regulated components. These studies have shed mechanistic insight into the potential application of redox-modulating gene therapies aimed at altering NFkappaB activation following environmental injury.

Adenoviridae↗
PubMed2001

A computer-based simulator for diagnostic peritoneal lavage.

Diagnostic peritoneal lavage (DPL) is an emergency diagnostic procedure performed when intra-abdominal bleeding secondary to trauma is suspected. This procedure is part of the surgical skills section of the Advanced Trauma Life Support course. DPL is traditionally taught using anesthetized animals or cadavers. For reasons described below, these alternatives are not ideal. We have developed a computer-based diagnostic peritoneal lavage simulator. Our system addresses the shortcomings of the traditional method. We have used our system to teach ATLS. Preliminary results suggests that our system is effective.

Abdominal Injuries↗
PubMed2000

The D(2) dopamine receptor A(1) allele and opioid dependence: association with heroin use and response to methadone treatment.

A total of 95 Caucasian opioid-dependent patients were followed over a one-year period in an outpatient methadone treatment program. The frequency of the TaqI A(1) allele of the D(2) dopamine receptor (DRD2) gene was 19.0% in these patients compared with 4.6% in controls free of past and current alcohol and other drug abuse and free of family history of alcohol and other drug abuse (p = 0.009). Twenty-two of these patients dropped out of the methadone program (Group A), 54 had a successful treatment (Group B), and 19 had a poor treatment (Group C) outcome. The frequency of the A(1) allele was highest in Group C (42.1%), followed by Group A (22.7%) and was lowest in Group B (9.3%). The more than fourfold higher frequency of the A(1) allele in the poor treatment outcome group compared with the successful treatment outcome group was significant (p = 0.00002). Moreover, the average use of heroin (grams/day) during the year prior to study entry was more than twice as great in patients with the A(1)(+) allele (A(1)/A(1) or A(1)/A(2) genotype) than those with the A(1)(-) allele (A(2)/A(2) genotype) (A(1)(+) allele = 0.55 +/- 0. 10, A(1)(-) allele = 0.25 +/- 0.05; p = 0.003). The results indicate that DRD2 variants are predictors of heroin use and subsequent methadone treatment outcome and suggest a pharmacogenetic approach to the treatment of opioid dependence.

Adult↗
PubMed2000

Association of D2 dopamine receptor and alcohol dehydrogenase 2 genes with Polynesian alcoholics.

Alleles of the D2 dopamine receptor (DRD2) and the alcohol dehydrogenase 2 (ADH2) genes were determined in 69 French Polynesian alcoholic patients and 57 controls matched for racial origin. Three racial groups were studied: pure Polynesians (PP), Polynesians mixed with Caucasian (PCA) ancestry and Polynesians mixed with Chinese (PCH) ancestry. DRD2 A1 allele frequencies in the alcoholics compared to their controls in these groups were: PP,.26 vs.32 (P =. 69); PCA,.44 vs.35 (P =.46); PCH,.40 vs 0.39 (P =.88). ADH2 1 allele frequencies in alcoholics compared to their controls groups were: PP, .56 vs.62 (P =.66); PCA,.75 vs.56 (P =.09); PCH,.78 vs.32 (P =.009). In the PCA group, the combination of the DRD2 A1 genotypes and the ADH2 1 homozygotes was strongly associated with alcoholism (P =. 0027). This preliminary study shows the importance of ascertaining racial ancestry in molecular genetic association studies. Moreover, it suggests that a combination of genes are involved in susceptibility to the development of alcoholism.

Adult↗
PubMed1999

Concatamerization of adeno-associated virus circular genomes occurs through intermolecular recombination.

Long-term recombinant AAV (rAAV) transgene expression in muscle has been associated with the molecular conversion of single-stranded rAAV genomes to high-molecular-weight head-to-tail circular concatamers. However, the mechanisms by which these large multimeric concatamers form remain to be defined. To this end, we tested whether concatamerization of rAAV circular intermediates occurs through intra- or intermolecular mechanisms of amplification. Coinfection of the tibialis muscle of mice with rAAV alkaline phosphatase (Alkphos)- and green fluorescent protein (GFP)-encoding vectors was used to evaluate the frequency of circular concatamer formation by intermolecular recombination of independent viral genomes. The GFP shuttle vector also encoded ampicillin resistance and contained a bacterial origin of replication to allow for bacterial rescue of circular intermediates from Hirt DNA of infected muscle samples. The results demonstrated a time-dependent increase in the abundance of rescued plasmids encoding both GFP and Alkphos, which reached 33% of the total circular intermediates by 120 days postinfection. Furthermore, these large circular concatamers were capable of expressing both GFP- and Alkphos-encoding transgenes following transient transfection in cell lines. These findings demonstrate that concatamerization of AAV genomes in vivo occurs through intermolecular recombination of independent monomer circular viral genomes and suggest new viable strategies for delivering multiple DNA segments at a single locus. Such developments will expand the utility of rAAV for splicing large gene inserts or large promoter-gene combinations carried by two or more independent rAAV vectors.

Alkaline Phosphatase↗
PubMed1998

D2 dopamine receptor and GABA(A) receptor beta3 subunit genes and alcoholism.

As the dopaminergic and GABAergic systems have been implicated in alcohol-related behaviors, variants of the D2 dopamine receptor (DRD2) and GABA(A) receptor beta3 subunit (GABRB3) genes were determined in a population-based association study of Caucasian non-alcoholic and alcoholic subjects. In severe alcoholics, compared to non-alcoholics, a significant increase was found in the prevalence (P = 1.7 x 10(-5)) and frequency (P = 1.6 x 10(-5)) of the DRD2 minor (A1) allele. Moreover, a significant progressive increase was observed in A1 allelic prevalence (P = 3.1 x 10(-6)) and frequency (P = 2.7 x 10(-6)) in the order of non-alcoholics, less severe and severe alcoholics. In severe alcoholics, compared to non-alcoholics, a significant decrease was found in the prevalence (P = 4.5 x 10(-3)) and frequency (P = 2.7 x 10(-2)) of the GABRB3 major (G1) allele. Furthermore, a significant progressive decrease was noted in G1 allelic prevalence (P = 2.4 x 10(-3)) and frequency (P = 1.9 x 10(-2)) in non-alcoholics, less severe and severe alcoholics, respectively. In sum, in the same population of non-alcoholics and alcoholics studied, variants of both the DRD2 and GABRB3 genes independently contribute to the risk for alcoholism, with the DRD2 variants revealing a stronger effect than the GABRB3 variants. However, when the DRD2 and the GABRB3 variants are combined, the risk for alcoholism is more robust than when these variants are considered separately.

Adult↗
PubMed1997

D2 dopamine receptor A1 allele in Alzheimer disease and aging.

BACKGROUND: The apolipoprotein E4 (APOE*4) allele is a major risk factor for the common forms of late-onset Alzheimer disease (AD), but does not account for all the genetic variation in late-onset AD; hence, other genetic markers must be examined. The D2 dopamine receptor (DRD2) A1 allele is associated with abnormal brain function and decreased DRD2s. These receptors are decreased in hippocampus and amygdala in AD, and allele frequencies may vary with age. OBJECTIVE: To study APOE and DRD2 genotypes in patients with AD and cognitively intact controls of varying ages. DESIGN: The DRD2 and APOE genotypes were examined in 832 unrelated white subjects, including 554 patients with AD (486 sporadic; 68 familial) and 278 controls. Logistic regressions tested A1 allele effects on disease status and age, and DRD2 linkage with AD was investigated in 60 families with late-onset AD. SETTING: University medical centers. SUBJECTS: Patients (mean +/- SD age, 74.6 +/- 8.1 years; range, 52-98 years) had probable AD, according to standard consensus diagnostic criteria; controls (mean +/- SD age, 69.2 +/- 8.6 years; range, 50-93 years) were cognitively intact. MAIN OUTCOME MEASURES: Disease status, age, and DRD2 linkage with AD. RESULTS: No association between the DRD2 and APOE alleles was found, and the presence of the A1 allele did not increase the risk for AD. There was also no evidence of linkage between DRD2 and AD. Age analyses, including both patients and controls, indicated a decrease in A1 allele frequency with age. CONCLUSIONS: The A1 allele does not contribute to AD risk, alone or in combination with the APOE*4 allele. The DRD2 A1 allele frequencies decrease with age in both patients and controls. Thus, studies of DRD2 disease association need to control for age.

Aged↗
PubMed1996

Similarities and differences in the structure-activity relationships of capsaicin and resiniferatoxin analogues.

Structure-activity relationships in analogues of the irritant natural product capsaicin have previously been rationalized by subdivision of the molecule into three structural regions (A,B, and C). The hypothesis that resiniferatoxin (RTX), which is a high-potency ligand for the same receptor and which has superficial structural similarities with capsaicin, could be analogously subdivided has been investigated. The effects of making parallel changes in the two structural series have been studied in a cellular functional assay which is predictive of analgesic activity. Parallel structural changes in the two series lead to markedly different consequences on biological activity; the 3- and 4-position aryl substituents (corresponding to the capsaicin 'A-region') which are strictly required for activity in capsaicin analogues are not important in RTX analogues. The homovanillyl C-20 ester group in RTX (corresponding to the capsaicin 'B-region') is more potent than the corresponding amide, in contrast to the capsaicin analogues. Structural variations to the diterpene moiety suggest that the functionalized 5-membered diterpene ring of RTX is an important structural determinant for high potency. Modeling studies indicate that the 3D position of the alpha-hydroxy ketone moiety in the 5-membered ring is markedly different in the phorbol (inactive) analogues and RTX (active) series. This difference appears to be due to the influence of the strained ortho ester group in RTX, which acts as a local conformational constraint. The reduced activity of an analogue substituted in this region and the inactivity of a simplified analogue in which this unit is entirely removed support this conclusion.

Analgesics↗
PubMed1996

[3H]naloxone binding in the human brain: alcoholism and the TaqI A D2 dopamine receptor polymorphism.

[3H]Naloxone binding was measured in frontal gray cortex, caudate nucleus, amygdala, hippocampus and cerebellar cortex obtained post mortem from human alcoholic and nonalcoholic subjects. Binding was found to be higher in alcoholics than in nonalcoholics for all of the brain regions examined, with a significant difference in the frontal cortex. When subjects were grouped by the presence or absence of the A1 (minor) allele of the D2 dopamine receptor gene, [3H]naloxone binding was lower in all brain regions examined of subjects with the A1 allele than in those without this allele, with a significant difference in the caudate nucleus. These findings suggest that one of the consequences of chronic alcohol exposure in humans is an enhancement of the brain opiate receptor system. However, the decreased [3H]naloxone binding observed in subjects with the A1 allele may be a compensatory response to their decreased dopaminergic modulation of opiate receptor activity.

Alcoholism↗
PubMed1995

Bromocriptine in the treatment of alcoholics with the D2 dopamine receptor A1 allele.

Various types of alcoholics have been described and heredity has been shown to be involved in some of these types. An important role of the mesolimbic dopamine system has been suggested in the reinforcing effects of alcohol and recent molecular genetic studies are implicating the gene for the D2 dopamine receptor (DRD2) in alcoholism. In a double-blind study, bromocriptine, a DRD2 agonist, or placebo was administered to alcoholics with either the A1 (A1/A1 and A1/A2 genotypes) or only the A2 (A2/A2 genotype) allele of the DRD2 gene. The greatest improvement in craving and anxiety occurred in the bromocriptine-treated A1 alcoholics and attrition was highest in the placebo-treated A1 alcoholics. The feasibility of a pharmacogenetic approach in treating certain types of alcoholics is suggested.

Adult↗
PubMed1994

D2 dopamine receptor gene and obesity.

The prevalence of Taql A D2 dopamine receptor (DRD2) alleles was determined in 73 obese women and men. In this sample with a mean body mass index of 35.1, the A1 (minor) allele of the DRD2 gene was present in 45.2% of these nonalcohol, nondrug abusing subjects. The DRD2 A1 allele was not associated with a number of cardiovascular risk factors examined, including blood lipids (cholesterol, high-density lipoprotein [HDL]- and low-density lipoprotein [LDL]-cholesterol, and triglycerides). However, phenotypic factors characterized by the presence of parental history and postpuberty onset of obesity as well as carbohydrate preference were associated with obese subjects carrying the A1 allele. The cumulative number of these three factors was positively and significantly (p < .0002) related to A1 allelic prevalence. The data showing an association of the minor allele of the DRD2 gene with phenotypic characteristics suggest that this gene, located on q22-q23 region of chromosome 11, confers susceptibility to a subtype of this disorder.

Adolescent↗
PubMed1994

D2 dopamine receptor gene and cigarette smoking: a reward gene?

There is now growing evidence that the less prevalent allele (A1) of the D2 dopamine receptor (DRD2) gene is strongly associated with severe alcoholism. Similarly, subjects who abuse illegal drugs or who are obese also show a significantly higher prevalence of the A1 DRD2 allele compared to controls. Moreover, cigarette smokers, both past and current, demonstrate significantly higher prevalence of the A1 allele than nonsmokers. In as much as alcohol, cocaine, opiates, nicotine and food are known to increase brain dopamine levels and activate the mesocorticolimbic dopaminergic reward pathways of the brain, it is hypothesized that an inherited deficit of D2 dopamine receptor numbers in brain reward areas of A1 allelic subject predisposes them to substance abuse problems.

Alleles↗
PubMed1994

D2 dopamine receptor TaqI A alleles in medically ill alcoholic and nonalcoholic patients.

The prevalence of TaqI A alleles of the D2 dopamine receptor (DRD2) gene was examined in two subgroups of medically ill nonalcoholics (more prevalent and less prevalent substance users, MPSU and LPSU, respectively) and in two subgroups of medically ill alcoholics (more severe and less severe alcoholics, MSA and LSA, respectively). The prevalence of the A1 allele in the 80 nonalcoholic and 73 alcoholic patients was 30.0% and 52.1%, respectively (P = 0.009). In the four subgroups of these patients, the prevalence of this allele was: LPSU = 18.2%, MPSU = 34.5%, LSA = 44.4% and MSA = 58.3%. Linear trend analysis showed that as the use of substances and severity of alcoholism increase, so does A1 prevalence (P = 0.001). Specific, subgroup comparisons showed A1 prevalence in MSA to be about 3-fold (P = 0.007) and 1.5-fold (P = 0.04) higher than in LPSU and MPSU subgroups, respectively. Similarly, in a combined analysis of independent studies, A1 prevalence in MSA was higher when compared to LSA (P < 5 x 10(-3), MPSU (P < 10(-4) and LPSU (P < 10(-8) subgroups. There was virtually no difference in the prevalence of the A1 allele between LSA and MPSU subgroups. None of the specific medical or neuropsychiatric complications of alcoholism was associated with the A1 allele. In conclusion, the severity of alcohol dependence in alcoholics and of substance use behaviors in controls are important variables in DRD2 allelic association. The present report and converging lines of evidence suggest that the DRD2 locus could represent a prominent gene risk factor for susceptibility to severe alcoholism. However, other genes and environmental factors, when combined, still play the larger role.

Adult↗
PubMed1994

Prolonged P300 latency in children with the D2 dopamine receptor A1 allele.

Previous studies have indicated the presence of a hereditary component in the generation of the P300, or P3, a late positive component of the event-related potential. Moreover, the dopaminergic system has been implicated in the P3. In the present study, 98 healthy Caucasian boys, mean age of 12.5 years and of above-average intelligence, were studied. The sample was composed of 32 sons of active alcoholic (SAA) fathers, 36 sons of recovering alcoholic (SRA) fathers, and 30 sons of social drinker (SSD) fathers, with none of them having yet begun to consume alcohol or other drugs. TaqI A D2 dopamine receptor alleles (A1 and A2) were determined. A significant difference in the frequency of the A1 allele was found among these three groups of boys, with the SAA group having the highest A1 allele frequency (.313), followed by the SRA (.139) and the SSD (.133) groups. The relationship of the A1 and A2 alleles to P3 amplitude and latency was also determined. The results showed no significant difference in P3 amplitude between boys with the A1 and A2 allele. However, P3 latency was significantly longer in the total sample of boys with the A1 allele compared with those carrying the A2 allele. These findings suggest that polymorphism of the D2 dopamine receptor gene is an important determinant of P3 latency.

Adolescent↗
PubMed1993

Allelic association of the D2 dopamine receptor gene with cocaine dependence.

The objective of the present study was to examine allelic prevalence of the D2 dopamine receptor (DRD2) gene in male cocaine-dependent (CD) Caucasian (non-Hispanic) subjects and to determine the relationship of DRD2 alleles to family history and selected behavioral measures. The prevalence of the A1 allele in CD subjects (n = 53) was 50.9%. It was significantly higher than either the 16.0% prevalence (P < 10(-4)) in non-substance abusing controls (n = 100) or the 30.9% prevalence (P < 10(-2)) in population controls (n = 265) wherein substance abusers were not excluded. Similarly, a significantly higher prevalence (P < 10(-2)) of the B1 allele was found in CD subjects (n = 52) compared with non-substance abusing controls (n = 53); 38.5% vs. 13.2%. Logistic regression analysis of CD subjects identified potent routes of cocaine use and the interaction of early deviant behaviors and parental alcoholism as significant risk factors associated with the A1 allele. The cumulative number of these three risk factors in CD subjects was positively and significantly (P < 10(-3)) related to A1 allelic prevalence. The data showing a strong association of the minor alleles (A1 and B1) of the DRD2 with cocaine dependence suggest that a gene, located on the q22-q23 region of chromosome 11, confers susceptibility to this drug disorder.

Adult↗
PubMed1992

Regulation of phosphoinositide hydrolysis in cultured astrocytes by sphingosine and psychosine.

The effects of sphingosine and psychosine on phosphoinositide hydrolysis in primary cultured astrocytes were determined. Exposure to sphingosine produced a dose-dependent stimulation of phosphoinositide hydrolysis requiring the presence of external Ca++ for optimal activity. The addition of 10 microM norepinephrine resulted in a stimulation additional to that with sphingosine. The alpha 1-antagonist prazosin completely inhibited norepinephrine-induced phosphoinositide hydrolysis but had no effect on that produced by sphingosine. Psychosine (108 microM), when co-incubated with sphingosine, produced complete inhibition of sphingosine-induced phosphoinositide hydrolysis at all doses of sphingosine tested (33-668 microM). Likewise, psychosine totally inhibited norepinephrine-induced phosphoinositide hydrolysis. The protein kinase C inhibitor staurosporine (1 microM) had no effect on sphingosine-induced phosphoinositide hydrolysis. These findings suggest that lysosphingolipids such as sphingosine and psychosine may play an important role in the regulation of phosphoinositide turnover in astrocytes by a mechanism dependent on extracellular Ca++ and independent of the alpha 1-adrenergic receptor and protein kinase C.

Alkaloids↗