Biomedical subjects

D M Donovan

Publications and source records attributed to D M Donovan.

At least 55 records · Page 3Linked to original sources

PubMed1995

Human and mouse dopamine transporter genes: conservation of 5'-flanking sequence elements and gene structures.

Synaptic reaccumulation of the neurotransmitter dopamine is mediated by the dopamine transporter (DAT), a member of the family of twelve transmembrane domain, sodium- and chloride-dependent neurotransmitter transporters. Several DAT features, including its exclusive expression in dopaminergic neurons, implication in cocaine action, and prominent role in the mechanisms of Parkinsonism-inducing neurotoxins, make understanding of the DAT gene of interest. Isolation and characterization of the human and mouse DAT genes has allowed elucidation of similarities between each and other members of this transporter gene family. Sequences 5' to transcriptional start sites contain G-C rich, TATA-less, CAAT-less regions with striking conservation between human and mouse gene flanking regions. These studies suggest sequence elements that are candidates to contribute to the dopamine transporter's dopaminergic cell-specific expression.

Animals↗

PubMed1995

Alcohol use before and after traumatic head injury.

STUDY OBJECTIVE: To determine (1) the significance of blood alcohol level in the emergency department in history of alcohol abuse and (2) the significance of habitual alcohol use in head-injured patients before and after injury. DESIGN: Inception cohort study with 1-year follow-up. SETTING: Level I trauma center. PARTICIPANTS: One hundred ninety-seven hospitalized adult head-injury survivors with a broad spectrum of head-injury severity. RESULTS: Alcohol use and behavioral problems associated with alcohol use were assayed before injury and in the month and year after injury. The patients' blood alcohol levels in the ED were also examined. Preinjury alcohol abuse was frequent; 42% of the subjects were legally intoxicated while in the ED. The amount of drinking and magnitude of reported preinjury alcohol problems decreased soon after the injury but was followed by an increase by 1 year, although the amount of drinking did not return to the preinjury level (P < .0001). Patients with more severe head injuries decreased their drinking more than did those with less severe head injuries. The patients' blood alcohol levels in the ED were a good indicator of the magnitude of their preinjury alcohol problems (r = .51 to .59; each, P < .001). CONCLUSION: Preinjury habitual alcohol abuse is frequent in head-injured patients. Blood alcohol levels in the ED are indicative of history of problem drinking and might serve as a basis for treatment referral. The first weeks after injury in hospitalized patients may provide an opportunity to begin interventions because head-injured patients drink less at that time.

Adolescent↗

PubMed1995

Differentiating "bad drivers" with and without a DWI.

OBJECTIVE: Risk factors for driving while intoxicated (DWI) are still largely unknown. The aim of this study was to determine the risk factors, other than multiple vehicle-related violations, that identify a group of bad drivers at risk of subsequent DWI violations. METHOD: A retrospective cohort study was conducted of drivers with multiple vehicle-related violations who completed a questionnaire on driving and personal characteristics (N = 253). RESULTS: Thirty-six variables were found associated with a 1.8- to 6.3-fold increased risk of subsequent DWI in the following categories: driving behavior, drinking behavior, history of physical trauma, alcohol-related expectancies and family history. CONCLUSIONS: A screening system could be incorporated in DWI prevention programs to target high-risk groups.

Adolescent↗

PubMed1994

Proenkephalin transgenic mice: a short promoter confers high testis expression and reduced fertility.

The regulation and possible function of the preproenkephalin gene in testis were studied in vivo in transgenic mice containing: (1) bases -193 to +210 of the human proenkephalin gene and an additional one kilobase of 3' proenkephalin flanking sequence driving expression of bacterial chloramphenicol acetyltransferase (CAT), and (2) the same promoter and flanking sequences driving expression of a rat proenkephalin cDNA. Five lines of mice, designated HEC1-5, expressed the first construct and 10, HER1-10, the second. Each HEC male and many HER males showed dramatic expression of the transgene in the testis, although much lower expression was observed in the brain and other enkephalin-producing tissues. High levels of expression in testis can thus be achieved with a very short promoter region and do not require intron A sequences previously considered necessary. Altered enkephalin expression may affect testicular function. One founder, HER8, displayed grossly abnormal testicular morphology and was completely infertile. A second founder, HER6, had low sperm motility. Two offspring from other lines also displayed subnormal fertility. These studies support a role for specific promoter sequences in testis expression and may further support a significant role for proenkephalin in testicular function.

Animals↗

PubMed1994

Issues in the selection and development of therapies in alcoholism treatment matching research.

There are a large number of possible approaches to the treatment of alcohol abuse and dependence. From a practical and methodological standpoint, however, only a limited number of interventions can realistically be included in research studies of treatment matching. A key question in planning studies of matching is what treatments to include. The recent book by Beutler and Clarkin on systematic treatment selection in general psychotherapy provides a framework within which to discuss alcoholism treatment matching and the criteria applied to decisions concerning (1) modes of treatment, (2) treatment format, (3) specific therapeutic strategies and the (4) treatment setting. The methodological and practical issues raised and the decisions reached in Project MATCH are presented in each of these areas. The therapies chosen for Project MATCH, based on these criteria, are described.

Alcoholism↗

PubMed1994

Implementing treatment and protecting the validity of the independent variable in treatment matching studies.

Treatment matching research is predicated on heterogeneity among subjects and their differential response to treatments. The sine qua non of a treatment matching study is the integrity of the treatment variable, since detection of client-treatment interactions requires delivery of treatments that are highly specific, consistent and distinct. Matching research thus presents particular challenges in treatment implementation, as greater heterogeneity in subjects may generate a broader array of problems than study treatments are designed to address, leading to several potential threats to treatment integrity. Moreover, as practiced outside of research settings, treatments for alcoholism are marked by ideological heterogeneity and a lack of purity across approaches. In this article we describe the strategies used in Project MATCH to protect treatment integrity while treating a large and heterogeneous sample of alcoholics in a number of geographically distant sites. These include: strategies for treating a variety of alcoholics within a single treatment approach; development of clinical care guidelines and clinical deterioration criteria; specification of treatments in manuals with minimization of overlapping active ingredients; selection criteria for therapists intended to enhance both generalizability of findings as well as treatment integrity; and extensive therapist training and monitoring.

Alcoholism↗

PubMed1994

Clinical applications: the transition from research to practice.

As validated and improved alcoholism treatment methods emerge from Project MATCH and other studies, a dedicated and systematic effort will be needed to incorporate them into ongoing programs, to monitor their success in real world settings and to make adjustments and refinements as needed. Accomplishing this involves responsibilities for both researchers and practitioners. A complex continuum of activities designed to move interventions from research to practice is common to all therapeutic areas, with a fundamental component being researcher-provider interactions. Challenges include "debunking" myths; realistic evaluations of the feasibility of making changes in the treatment system; effective communication between providers and researchers; and proactive guidance from leaders who set standards of practice. Findings from relevant studies in alcoholism research can be assimilated into the treatment system with as little delay as possible as linkages between researchers and providers are strengthened. These linkages will be further strengthened by research in organizational, management and delivery mechanisms conducted by emerging applied research areas such as health services.

Alcoholism↗

PubMed1994

Issues in the development of subject recruitment strategies and eligibility criteria in multisite trials of matching.

Decision-making in selecting and recruiting subjects for treatment matching research is a complex process involving conceptual, methodological and practical considerations. In selecting clients, concerns arise about whether the criteria will produce a subject population that is (1) relevant to the dimensions associated with the treatment matching, (2) representative of persons typically seen in alcohol treatment settings and, for practical purposes, (3) able or willing to comply with the requirements of the study protocol. Also, in order to fulfill sampling requirements, it may be necessary to employ a variety of creative outreach methods. However, these recruitment mechanisms can pose additional logistical and methodological problems for the research. This article focuses on various issues arising in the selection and recruitment of subjects in matching research. Project MATCH serves to highlight issues related to client eligibility and recruitment and to discuss effective strategies for resolving these matters.

Adult↗

PubMed1994

Alcoholism treatment matching research: methodological and clinical issues.

Client-treatment matching is an area receiving increased attention both in clinical practice and research with alcoholism. While the notion of potentially improving treatment outcomes by matching has been suggested for some time, there are a number of methodological and practical barriers that have impeded progress in the development of theoretically and clinically relevant matching models. This article provides an overview of the potential benefits of matching, the methodological factors that increase the complexity of research in this area, and some of the clinical barriers that make implementation more difficult. This overview also serves to introduce this special issue of the Journal of Studies on Alcohol, which examines in more detail each of the methodological issues involved in clinical research on treatment matching. While these methodological issues present unique challenges to the clinical researcher, the potential benefits of matching appear promising and should serve to motivate clinicians and researchers to pursue continued work in this area.

Alcoholism↗

PubMed1993

How much is too much? Advising patients about safe levels of alcohol consumption.

United States physicians are increasingly encouraged to advise patients about health-related behaviors, such as smoking, but there is minimal discussion in the US medical literature about the need to advise patients about safe levels of alcohol consumption. Several factors likely contribute to this lack of focus on safe drinking practices. These include the complex relationship between drinking and health, limitations in the available epidemiologic data, misinterpretation of the disease model of alcoholism, and physician attitudes. Nevertheless, epidemiologic evidence clearly relates increasing levels of alcohol consumption to increased morbidity and mortality, and research has shown that physician advice can reduce both alcohol consumption and alcohol-related problems. We propose that physicians thoroughly assess patients' alcohol consumption and advise patients who drink about safe levels of consumption.

Alcohol Drinking↗

PubMed1993

Recent developments in alcoholism:behavioral treatment.

Behavioral approaches have made significant contributions to understanding the etiology and treatment of alcohol dependence. The present chapter provides a brief overview of changes that have occurred within this perspective over the past decade. Significant changes at a theoretical level have included a move toward mediational cognitive-behavioral models of etiology and maintenance, integrative multivariate models, and an empirical, developmental model based on the natural history of the drinking and alcohol problems. Significant changes in clinical practice have included an expanded role of assessment within the context of a biopsychosocial model of alcoholism, an increased focus on secondary prevention and brief intervention with less-alcohol-impaired individuals, a focus on "harm reduction" as a goal of such interventions, the development of a stepped-care approach to treatment with a reliance on patient-treatment matching, an increased emphasis on the maintenance of therapeutic gain and relapse prevention, and the incorporation of behavioral and cognitive principles into self-help programs.

Alcohol Drinking↗

PubMed1993

Mechanics of anatomic reduction of thoracolumbar burst fractures. Comparison of distraction versus distraction plus lordosis, in the anatomic reduction of the thoracolumbar burst fracture.

The adequate reduction of vertebral burst fractures is dependent on successful application of distractive forces in combination with the restoration of normal spinal lordosis. However, the optimal sequence of distraction in comparison to distraction plus lordosis in the anatomic restoration of the fractured thoracolumbar spine has not been described. Burst fractures of the L1 vertebra were first created and the reduced in vitro using three differing reduction techniques. In six fresh human cadaver spine specimens, the mean fracture severity based on the degree of canal compromise was 31% (SD +/- 20%) after fracture. Reductions were performed using the AO Fixator Intern, the Reduction Fixation (RF) Device, and the Steffee plate systems following standard clinical techniques. The AO Fixator Intern provided independent but variable control of distraction and lordosis, the RF device provided variable distraction with independent, but preset, correction of lordosis and the Steffee system provided set distraction and stabilization. Both the AO and RF devices restored the lordosis (7.6 degrees +/- 5.2 degrees and 9.7 degrees +/- 4.5 degrees, respectively) better than the Steffee plate system (0 degrees +/- 1.6 degrees). However, the AO device provided poorest restoration of the posterior vertebral body height (92% vs 96% for the RF device and 99% for the Steffee plate). The RF device, which restored both lordosis and posterior vertebral body height to the near anatomic prefracture level, provided significantly better canal clearance (9% +/- 8%) than the other techniques, P < 0.05. The study demonstrates that instrumentation systems that provide independent correction of distraction and lordosis can best restore anatomic alignment, with indirect neurodecompression of the compromised spinal canal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding.

Polar amino acids lying within three hydrophobic regions of the dopamine transporter (DAT) are analogous to those important for ligand recognition by catecholamine receptors. Possible functional significance of these amino acids was examined by expressing DAT cDNAs mutated in these polar residues. Replacement of aspartate at position 79 with alanine, glycine, or glutamate dramatically reduced uptake of [3H]dopamine and the tritium-labeled Parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium (MPP+) and reduced the mutants' affinity for the tritium-labeled cocaine analog (-)-2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT) without affecting Bmax. Replacement of the serine residues at positions 356 and 359 in the seventh hydrophobic region by alanine or glycine caused reductions in [3H]dopamine and [3H]MPP+ uptake, whereas [3H]CFT binding was less affected. Substitution of two serines in the eighth hydrophobic region yielded wild-type values for [3H]dopamine and [3H]MPP+ uptake and [3H]CFT binding. These results demonstrate that aspartate and serine residues lying within the first and seventh hydrophobic putative transmembrane regions are crucial for DAT function and provide identification of residues differentially important for cocaine binding and for dopamine uptake.

1-Methyl-4-phenylpyridinium↗

PubMed1992

Preproenkephalin promoter "cassette" confers brain expression and synaptic regulation in transgenic mice.

The preproenkephalin A gene is a neurotransmitter gene whose expression can be modulated "trans-synaptically" by changes in neuronal activity. DNA sequences lying within 200 base pairs of this gene's transcription start site resemble consensus binding sites for several transcription factor families. In nonneuronal cell cultures, this promoter region is sufficient to mediate gene responses to depolarization, phorbol esters, adenylate cyclase, and calcium fluxes. To assess the role that these cis-acting elements could play in preproenkephalin expression and regulation in vivo, the expression of a construct containing this 200-base-pair region fused to the chloramphenicol acetyltransferase gene was examined in transgenic mice. This promoter confers modest expression in brain, adrenal, and small intestine, with substantially higher levels in testis. These elements confer trans-synaptic regulation in two well-studied models of trans-synaptic preproenkephalin upregulation but not in a third system, underscoring the specificity of the regulatory sequence elements implicated in the synaptic regulation of neuronal genes.

Afferent Pathways↗

PubMed1992

Conservation of mouse alpha A-crystallin promoter activity in chicken lens epithelial cells.

Previous transfection experiments have shown that 162 base pairs (bp) of the 5' flanking sequence of the chicken alpha A-crystallin gene are required for promoter activity in primary chicken lens epithelial cells (PLE), while only 111 bp of the 5' flanking sequence are needed for activity of the mouse alpha A-crystallin promoter in transfected chicken PLE cells or in a SV40 T-antigen-transformed transfected mouse lens epithelial cell line (alpha TN4-1). The effect of site-directed mutations covering positions -111 to -34 of the mouse alpha A-crystallin promoter fused to the bacterial chloramphenicol acetyltransferase (CAT) gene was compared in transfected chicken PLE cells and mouse alpha TN4-1 cells; selected mutations were also examined in a nontransformed rabbit lens epithelial cell line (N/N1003A). In general, the same mutations reduced promoter activity in the transfected lens cells from all three species, although differences were noted. The mutations severely affected regions -111/-106 and -69/-40 regions in all the transfected cells examined; by contrast, mutations at positions -105/-99 and -87/-70 had a somewhat greater effect in the chicken PLE than the mouse alpha TN4-1 cells, while mutations of the -93/-88 sequence reduced expression in the alpha TN4-1 but not the PLE cells. A partial cDNA with sequence similarity to alpha A-CRYPB1 of the mouse has been isolated from a chicken lens library; mouse alpha A-CRYBP1 is a putative transcription factor which binds to the -66/-55 sequence of the mouse alpha A-crystallin promoter.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1992

Primary afferent stimulation acts through a 193 base pair promoter region to upregulate preproenkephalin expression in dorsal horn of transgenic mice.

The expression of the principal opioid peptide gene, preproenkephalin A, is exquisitely regulated by primary afferent inputs to the spinal and medullary dorsal horns. This regulated expression in response to neural synaptic activity has been referred to as trans-synaptic regulation. To define which DNA regions could mediate this trans-synaptic regulation, transgenic 'HEC' mice whose genomes include 193 bp of the human preproenkephalin A promoter fused to a chloramphenicol acetyltransferase (CAT) reporter gene were studied. Mice received unilateral electrical stimulation of the trigeminal ganglion or adjuvant injection into the hindpaw, stimuli known to regulate dorsal horn proenkephalin expression in vivo. CAT activity conferred by this promoter displayed trans-synaptic upregulation with both stimuli. Although the level of the upregulation was 2- to 3-fold higher than the change in the wild type gene, several features of this induction paralleled aspects of the behavior of the wild-type gene: the rapidity of responses to trigeminal ganglion stimulation, the stimulation intensity dependence of responses to trigeminal ganglion stimulation and the time course of upregulation noted following adjuvant injection. Regulatory proteins binding to this restricted promoter region are thus likely to mediate aspects of dorsal horn enkephalin regulation by pain and other somatic stimuli.

Afferent Pathways↗

PubMed1992

Combat-related posttraumatic stress disorder and severity of substance abuse in Vietnam veterans.

This study examined the effects of Vietnam war-zone duty and combat-related posttraumatic stress disorder (PTSD) on severity of drug- and alcohol-abuse disorders among veterans seeking treatment for substance dependence. Combat-exposed Vietnam-theater veterans (N = 108) were compared with Vietnam-era veterans without war-zone duty (N = 151) on psychometric measures of drug and alcohol abuse. There were no differences between theater and era veterans on these measures. However, Vietnam-theater veterans with PTSD experienced more severe drug- and alcohol-abuse problems than did theater veterans without PTSD and were at greater risk for having both forms of substance abuse. Further analyses showed that PTSD was significantly related to some dimensions of drug- and alcohol-abuse problems but not to other dimensions. These findings indicate that PTSD, rather than combat stress per se, is linked to severity of substance abuse. Finally, reexperiencing and avoidance/numbing components of PTSD were more strongly associated with drug abuse than alcohol abuse, but physiological arousal symptoms of PTSD were more highly correlated with alcohol abuse.

Adaptation, Psychological↗

PubMed1991

Cloning of the gamma-aminobutyric acid (GABA) rho 1 cDNA: a GABA receptor subunit highly expressed in the retina.

Type A gamma-aminobutyric acid (GABAA) receptors are a family of ligand-gated chloride channels that are the major inhibitory neurotransmitter receptors in the nervous system. Molecular cloning has revealed diversity in the subunits that compose this heterooligomeric receptor, but each previously elucidated subunit displays amino acid similarity in conserved structural elements. We have used these highly conserved regions to identify additional members of this family by using the polymerase chain reaction (PCR). One PCR product was used to isolate a full-length cDNA from a human retina cDNA library. The mature protein predicted from this cDNA sequence in 458 amino acids long and displays between 30 and 38% amino acid similarity to the previously identified GABAA subunits. This gene is expressed primarily in the retina but transcripts are also detected in the brain, lung, and thymus. Injection of Xenopus oocytes with RNA transcribed in vitro produces a GABA-responsive chloride conductance and expression of the cDNA in COS cells yields GABA-displaceable muscimol binding. These features are consistent with our identification of a GABA subunit, GABA rho 1, with prominent retinal expression that increases the diversity and tissue specificity of this ligand-gated ion-channel receptor family.

Amino Acid Sequence↗