Individual differences in sensitivity to nicotine: implications for genetic research on nicotine dependence

Recent evidence suggests that cigarette smoking has a heritability index around 53%. While related research on underlying mechanisms also supports the idea that genetic factors contribute to nicotine dependence--as well as to cofactors such as substance use and mood disorders--the nature of the behavioral traits and biological capacity for reinforcement that constitutes vulnerability to nicotine dependence is not well understood. The present review explores the problem of why some people become highly nicotine dependent, others develop a pattern of occasional use, and still others avoid the drug entirely despite extensive exposure and widespread experimentation with tobacco in the population. Recent research--both infrahuman and human--suggests that vulnerability to nicotine dependence is related to high initial sensitivity to nicotine and that the development of tolerance is more rapid and self-administration more extensive in such individuals. Relevant findings from neuroscience and biobehavioral research are reviewed in order to identify variables and methodologies that might improve the reliability and validity of behavioral and molecular genetic studies on cigarette smoking. The integration of research in these areas may lead to new insights in the understanding of nicotine dependence as well as to improved techniques for prevention and treatment.     

Caucasian versus African-American differences in orosomucoid: potential implications for therapy

We conducted a prospective, nonrandomized study in healthy volunteers to determine if racial differences exist in orosomucoid (ORM) and its variants, and to examine quinidine and lidocaine binding to the protein. Total ORM serum concentrations were measured by Laurell-Rocket immunoelectrophoresis. Allele types were determined by isoelectric focusing and immunoblotting. Total and unbound quinidine and lidocaine concentrations were measured with standard fluorescence polarization immunoassays after ultrafiltration. The frequency of the common ORM alleles was similar between 38 Caucasians and 67 African-Americans. Mean total ORM concentration was significantly lower in Caucasians (57.3 +/- 25.4 vs 73.2 +/- 33.9 mg/dl, p=0.01). However, more Caucasians took oral contraceptives, which may have decreased ORM concentrations. Quinidine unbound fraction (UF) was related to ORM phenotype. The highest UF was found with ORM 1-S (p=0.009). There were no significant relationships between ORM phenotype and lidocaine UF. Overall, African-Americans had higher ORM concentrations than Caucasians. Quinidine binding showed significant relationships to specific ORM variants.     

Anti-infective drug therapy: implications for the lactating mother and nursing infant

Lipoprotein lipase, hepatic lipase, and lecithin: cholesterol acyltransferase have coordinated enzymatic roles in lipoprotein metabolism. New evidence suggests that the lipases are multifunctional proteins that are able to mediate lipoprotein binding and uptake. The importance of all three enzymes in the control of lipoprotein metabolism can be explored in the future by using the newly generated transgenic animals.     

Molecular basis of P450 inhibition and activation: implications for drug development and drug therapy

In previous studies many benzimidazole, imidazole and benzothiazole derivatives had been synthesized and their antimicrobial activities were tested in vitro conditions. Four of these compounds showed minimal inhibitory concentrations (MIC) of 5-25 micrograms/ml against standard strains and clinical isolates. In order to determine whether these four compounds can be used for therapeutic purpose, their serum MIC values and side effects on hepatic and renal functions were determined. Different concentrations of the compounds were tested on Wistar rats. Compound 1 was administered orally, intramuscularly and intravenously; compounds 2, 3 and 4 were given orally and intramuscularly. Blood samples were taken 4 and 24 h after administration of the compounds. Serum MIC values were investigated by bioassay and serum levels of biochemical parameters by autoanalyzer. None of the tested compounds showed antimicrobial activity at their serum concentrations. Although creatinine activity was found at normal levels in all experiments, compounds 1 and 2 caused a significant increase in blood urea nitrogen (BUN) level. The values of aspartate aminotransferase and/or alanine aminotransferase and/or alkaline phosphatase which are characteristic for liver function were generally found at high levels. According to these results, it can be concluded that the tested compounds caused damage in liver and biliary tracts without antimicrobial activity by their serum concentrations.     

Evidence for genetic heterogeneity supports clinical differences in congenital myasthenic syndromes

Our goal was to prospectively study the course of oppositional defiant disorder (ODD) symptomatology in children and adolescents in the first 2 years after traumatic brain injury (TBI). Fifty children aged 6 to 14, hospitalized after TBI, were assessed soon after TBI regarding injury severity; preinjury psychiatric, socioeconomic, family functioning, and family psychiatric history status; and neuroimaging was analyzed. ODD symptomatology in the first year after TBI was related to preinjury family function, social class, and preinjury ODD symptomatology. Increased severity of TBI predicted ODD symptomatology 2 years after injury. Change (from before TBI) in ODD symptomatology at 6, 12, and 24 months after TBI was influenced by socioeconomic status. Only at 2 years after injury was severity of injury a predictor of change in ODD symptomatology. The influence of psychosocial factors appears greater than severity of injury in accounting for ODD symptomatology and change in such symptomatology in the first but not the second year after TBI in children and adolescents. This appears related to persistence of new ODD symptomatology after more serious TBI.     

A review of racial differences in geriatric depression: implications for care and clinical research

How racial differences influence depressed elders' seeking and obtaining treatment for depression is poorly understood. Studies in other medical illnesses show older African Americans use fewer health-care services for heart disease, stroke, and renal dialysis. This article reviews the racial composition of Duke University's Clinical Research Center (CRC) for the Study of Depression in the Elderly. Possible explanations for low participation of African Americans in such programs also are discussed. During most of the first year of the CRC project, minority enrollment varied from 5% to 10%, at least one third the African-American population of the area. Active efforts to improve minority recruitment increased this percentage to 15% by the end of the project's second year. Likely explanations for low minority participation rates include 1) elders may recognize depressive symptoms, but do not seek or cannot obtain medical treatment, and 2) depressive symptoms may be attributed to a crisis of the spirit (so help is sought through prayer and the church), the "slowing down" process of aging, or part of life's burden to be endured. Future attempts at both treatment and clinical research recruitment efforts are needed to address these possibilities.     

Exercise therapy for patients with psychiatric disorders: Research and clinical implications.

There is now considerable evidence that regular exercise is (a) a viable, cost-effective, but underused treatment for mild to moderate depression that compares favorably to individual psychotherapy, group psychotherapy, and cognitive therapy, and (b) a necessary ingredient in effective behavioral treatments that reduce self-reported pain in individuals with chronic pain. Preliminary evidence also suggests that regular exercise deserves further attention as (a) a singular treatment for some anxiety disorders, for individuals suffering from body image disturbance, and for the reduction of problem behavior of developmentally disabled persons, and (b) an adjunct in treatment programs for schizophrenia, conversion disorder, and alcohol dependence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Antibiotic classification: implications for drug selection

This article presents a useful antibiotic classification model for the busy clinician who must select agents for patients in the critical care setting. The model organizes antibiotics based on their mechanism of action, ie, cell-wall inhibitors, nucleic acid inhibitors, and protein-synthesis inhibitors; clinicians are encouraged to further segregate agents within the broader categories by generation. An overview of the antimicrobial spectrum for each class is presented, and important differences within individual classes are highlighted. The most common indications for each antibiotic class are reviewed, and key pharmacokinetic characteristics that help distinguish one drug from another are outlined.     

Understanding drug addiction: implications for treatment

The addicted brain is qualitatively different from the nonaddicted brain, in ways that include glucose use, gene expression, and responsiveness to environmental cues. Such discoveries place researchers in the early but hopeful stages of translating fundamental findings into new treatments that address the neurobiologic basis of drug craving--even for cocaine, against which there are currently no pharmacologic interventions.     

Muscle maturation: implications for gene therapy

Skeletal muscle is a promising target tissue for gene therapy, for both muscle and non-muscle disorders. A variety of methods have been studied to transfer genes into skeletal muscle, including retroviral, adenoviral and herpes simplex viral vectors. However, various factors impede muscle-based viral gene therapy. Here, we discuss why some viral vectors cannot efficiently transduce mature muscle fibers, and describe some new approaches to overcome this barrier.     

Cognitive-behavioral group therapy for panic disorder in the general clinical setting: a naturalistic study with 1-year follow-up

BACKGROUND: Cognitive-behavioral therapy (CBT) is well documented in the treatment of panic disorder. As most investigators have studied selected patients without comorbid disorders, it is less clear how well the treatment will perform in the usual clinical setting for patients with comorbid disorders and with physicians who do not have training in CBT. During the last 6 years, we have offered CBT in outpatient groups for patients with panic disorder and agoraphobia. The purpose of this prospective study was to assess the outcome of group treatment and compare the results with those of studies that used individual treatment. We wanted to identify variables that might predict outcome at follow-up and to assess the number and characteristics of dropouts. METHOD: Eighty-three consecutive patients with DSM-III-R panic disorder (56 women and 27 men; mean age = 34.5 years) were studied. Mean duration of panic disorder was 7.5 years. There was a high degree of comorbid major depression, social phobia, and psychoactive substance abuse/dependence. Treatment consisted of 4-hour group sessions conducted once a week for 11 weeks. More than half of the patients used antidepressant drugs. Degree of phobic avoidance, bodily sensations, anxiety cognitions, and depression were assessed at pretreatment, baseline, and end of treatment and at follow-up after 3 and 12 months. RESULTS: There was a large decrease in scores from start to end on all assessments. Sixty-three (89%) of 73 completers responded (> or = 50% reduction in Phobic Avoidance Rating Scale scores). Gains were maintained and even improved upon at follow-up. The results are comparable with studies that used individual therapy. A high depression score at the end of treatment predicted poor outcome at 1-year follow-up. Twelve (14%) of 83 did not complete the program. The presence of severe personality disorders and ongoing alcohol or substance abuse or dependence was associated with poor outcome and high dropout rate. CONCLUSION: CBT appears to be effective in the usual clinical setting, even in the hands of therapists without formal competence. Group therapy is a feasible arrangement, and the results from group treatment are comparable to those of individual approaches. Precise diagnosis and treatment of comorbid depression are of utmost importance. Patients with additional substance abuse or dependence, as well as severe personality disorders, may find this treatment modality less helpful.     

Weight loss in the clinical setting: applications for cardiac rehabilitation

A 57-year-old man developed oligoarthritis of the right sacroiliac joint, knee and elbow in the wake of Clostridium difficile pseudomembranous colitis. He was HLA B27-positive and had a history of Reiter's syndrome. His joint manifestations resolved after a course of nonsteroidal antiinflammatory drug therapy and injection of the right knee with triamcinolone acetonide. Clostridium difficile should be recognized as a rare cause of reactive arthritis.     

Stuttering therapy in the elementary school setting: guidelines for clinician-teacher collaboration

This article describes guidelines for developing an effective collaborative/consultative approach to the treatment of stuttering in an elementary school setting. Four primary areas of shared clinician/teacher responsibility are discussed, which include: education, observation, facilitation of fluent speech, and generalization of speech fluency. Although the speech-language pathologist should initiate the teacher's involvement in a child's therapy, both the clinician and teacher should work toward developing a mutually influential partnership, through which the specific needs of individual children who stutter can be addressed in a comprehensive manner.     

Reporting of gender-related information in clinical trials of drug therapy for myocardial infarction

The genomic RNA of Hepatitis A virus (HAV), a picornavirus of the hepatovirus group, is a single-stranded molecule, ca. 7.5 kb in length of positive polarity. Translation of this uncapped RNA starts at the 10th (or 11th) AUG triplet (position 734-36), by a mechanism of internal initiation of translation. The long sequences extending between the uncapped 5'-end and the translation initiation site contain two (instead of just one) pyrimidine-rich tracts (PRTs) spanning nucleotides 94-140 and 711-724, respectively. The latter lies only 11 nucleotides upstream from the initiation site of translation, and the question arose as to whether the notoriously poor replication ability of HAV was a consequence of a down regulation of translation due to the too short "spacer" sequence intervening between the 3'-PRT and the initiation of the main open reading frame. To address this issue, a series of full-length HAV cDNA clones were constructed in which the "spacer" sequence (normally 11 nts) was brought to 45 nts. Following transfection of COS-1 cells with these constructs, the amount of HAV (+)-strand RNA was determined by dot hybridization using a strand-specific RNA probe. HAV cDNA clones carrying a 45-nt "spacer" increased two-fold the rate of (+)-strand viral RNA synthesis, suggesting that the poor translation ability of HAV RNA may be one of the mechanisms responsible for the lengthy replication cycle of HAV.     

Dose-response characteristics of cholesterol-lowering drug therapies: implications for treatment

PURPOSE: To develop an optimal treatment strategy that reduces low-density lipoprotein (LDL) cholesterol levels and improves adherence to therapy by reviewing clinical trials that define the dose-response characteristics for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), bile acid sequestrants, and niacin. DATA SOURCES: Data were obtained from a MEDLINE search of the English-language literature published from 1975 through November 1995 and from an extensive bibliography review. STUDY SELECTION: Controlled, clinical trials were reviewed if they evaluated 1) the effectiveness and toxicity of one LDL cholesterol-lowering agent (statins, bile acid sequestrants, or niacin, at two or more doses) or 2) monotherapy with two LDL cholesterol-lowering agents at defined doses used alone and in combination. Studies that had fewer than 10 patients in a treatment group or that selected patients on the basis of previous response to therapy were not included. DATA EXTRACTION: Trials were reviewed for overall methodology, inclusion and exclusion criteria, sources of bias, and outcomes. DATA SYNTHESIS: Dose-response relations for bile acid sequestrants and statins are nonlinear, and most of their LDL cholesterol-lowering effects can be obtained with lower doses. The few dose-response studies of niacin that have been done suggest that most of niacin's high-density lipoprotein cholesterol-increasing effect can also be achieved with relatively low doses, but higher doses are needed to substantially reduce LDL cholesterol levels. If bile acid sequestrants or niacin are added to statin therapy, the effect of combined therapy on LDL cholesterol levels is additive. CONCLUSION: The nonlinear dose-response relation of statins, bile acid sequestrants, and niacin and their additive LDL cholesterol-lowering effect when used together suggest a strategy for treating hypercholesterolemia that may optimize effectiveness while minimizing adverse effects and cost.     

Transfusion therapy: nursing implications

Blood product transfusion therapy and its concomitant risks pose a special challenge for the oncology nurse. Knowledge of the pathophysiology of transfusion reactions, presenting symptoms, and treatment is necessary to safely monitor transfusions. Through meticulous nursing assessment, detection, and intervention, oncology nurses can prevent and/or minimize morbidity and mortality in patients receiving transfusion therapy.