Ethanol inhibits dopamine uptake via organic cation transporter 3: Implications for ethanol and cocaine co-abuse.

Concurrent cocaine and alcohol use is among the most frequent drug combination, and among the most dangerous in terms of deleterious outcomes. Cocaine increases extracellular monoamines by blocking dopamine (DA), norepinephrine (NE) and serotonin (5-HT) transporters (DAT, NET and SERT, respectively). Likewise, ethanol also increases extracellular monoamines, however evidence suggests that ethanol does so independently of DAT, NET and SERT. Organic cation transporter 3 (OCT3) is an emergent key player in the regulation of monoamine signaling. Using a battery of in vitro, in vivo electrochemical, and behavioral approaches, as well as wild-type and constitutive OCT3 knockout mice, we show that ethanol's actions to inhibit monoamine uptake are dependent on OCT3. These findings provide a novel mechanistic basis whereby ethanol enhances the neurochemical and behavioral effects of cocaine and encourage further research into OCT3 as a target for therapeutic intervention in the treatment of ethanol and ethanol/cocaine use disorders.

The TGM2 inhibitor cysteamine hydrochloride does not impact corneal epithelial and stromal wound healing in vitro and in vivo.

Corneal wound healing is integral for resolution of corneal disease or for post-operative healing. However, corneal scarring that may occur secondary to this process can significantly impair vision. Tissue transglutaminase 2 (TGM2) inhibition has shown promising antifibrotic effects and thus holds promise to prevent or treat corneal scarring. The commercially available ocular solution for treatment of ocular manifestations of Cystinosis, Cystaran®, contains the TGM2 inhibitor cysteamine hydrochloride (CH). The purpose of this study is to assess the safety of CH on corneal epithelial and stromal wounds, its effects on corneal wound healing, and its efficacy against corneal scarring following wounding. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) were first used to quantify and localize TGM2 expression in the cornea. Subsequently, (i) the in vitro effects of CH at 0.163, 1.63, and 16.3 mM on corneal epithelial cell migration was assessed with an epithelial cell migration assay, and (ii) the in vivo effects of application of 1.63 mM CH on epithelial and stromal wounds was assessed in a rabbit model with ophthalmic examinations, inflammation scoring, color and fluorescein imaging, optical coherence tomography (OCT), and confocal biomicroscopy. Post-mortem assessment of corneal tissue post-stromal wounding included biomechanical characterization (atomic force microscopy (AFM)), histology (H&E staining), and determining incidence of myofibroblasts (immunostaining against α-SMA) in wounded corneal tissue. TGM2 expression was highest in corneal epithelial cells. Application of the TGM2 inhibitor CH did not affect in vitro epithelial cell migration at the two lower concentrations tested. At 16.3 mM, decreased cell migration was observed. In vivo application of CH at 57 mM was well tolerated and did not adversely affect wound healing. No difference in corneal scarring was found between CH treated and vehicle control eyes. This study shows that the TGM2 inhibitor CH, at the FDA-approved dose, is well tolerated in a rabbit model of corneal wound healing and does not adversely affect epithelial or stromal wound healing. This supports the safe use of this medication in Cystinosis patients with open corneal wounds. CH did not have an effect on corneal scarring in this study, suggesting that Cystaran® administration to patients with corneal wounds is unlikely to decrease corneal fibrosis.

Transgenic expression of human S100A12 induces structural airway abnormalities and limited lung inflammation in a mouse model of allergic inflammation.

BACKGROUND: The calcium-binding protein S100A12 is highly up-regulated in the serum and sputum of patients with allergic asthma and is suggested to be a biomarker and pathologic mediator of asthma. OBJECTIVE: To test the role of S100A12 in mediating airway inflammation in a mouse model of allergic lung inflammation. METHODS: Transgenic (TG) mice that express human S100A12 and wild-type (WT) littermates were sensitized and challenged with ovalbumin (OVA) and assessed for inflammation, lung structure, and function. RESULTS: Following OVA sensitization and challenge, S100A12 TG mice showed reduced peribronchial and perivascular inflammation, mucus production, and eosinophilia as well as attenuated airway responsiveness to contractile agonist compared with WT sensitized and challenged animals. This is explained, at least in part, by remodelled airways in S100A12 TG mice with thinning of the airway smooth muscle. S100A12 exposure induced Fas expression and activation of caspase 3 in cultured airway smooth muscle cells, suggesting that airway smooth muscle abnormalities observed in S100A12 TG mice may be mediated through myocyte apoptosis. CONCLUSION AND CLINICAL RELEVANCE: S100A12 is one of the most abundant proteins found in the airways of human asthmatics, and it was postulated that S100A12 could mediate the inflammatory process. Our study shows for the first time that TG expression of S100A12 in the lung of mice does not exacerbate lung inflammation in a model of OVA-induced allergic inflammation. We speculate that the high levels of S100/calgranulins found in bronchoalveolar lavage fluid of asthmatics and of OVA-treated TG S100A12 mice do not significantly mediate pulmonary inflammation.

The European Study of the Epidemiology of Mental Disorders (ESEMeD/MHEDEA 2000) project: rationale and methods.

The European Study of the Epidemiology of Mental Disorders (ESEMeD/MHEDEA 2000) is a new cross-sectional study investigating the prevalence and the associated factors of mental disorders, as well as their effect on health-related quality of life and the use of services in six European countries. This paper describes the rationale, methods and the plan for the analysis of the project. A total of 22,000 individuals representative of the non-institutionalized population aged 18 and over from Belgium, France, Germany, Italy, the Netherlands and Spain are being interviewed in their homes. Trained interviewers use a computer-assisted personal interview (CAPI) including the most recent version of the Composite International Diagnostic Interview (CIDI, 2000), a well-established epidemiological survey for assessing mental disorders. This is the first international study using the standardized up-to-date methodology for epidemiological assessment. Sizeable differences in prevalence, impact and level of need that is met by the health services are expected. The analysis of these differences should facilitate the monitoring of ongoing mental health reform initiatives in Europe and provide new research hypotheses.

A review of the evidence for the use of phytoestrogens as a replacement for traditional estrogen replacement therapy.

Estrogen replacement therapy (ERT) is recommended for postmenopausal women primarily for reduction of menopausal symptoms and prevention of osteoporosis and cardiovascular disease. However, only 35% to 40% of women ever start ERT, and many do not continue it. One of the reasons women are reluctant to receive postmenopausal ERT is that they perceive prescription estrogens as being "unnatural." Because of this, there is increasing interest in the use of plant-derived estrogens, also known as phytoestrogens. This article reviews the evidence for the potential of phytoestrogens, either in dietary or supplemental form, to replace traditional forms of ERT. A comprehensive search of the English-language literature identified more than 1000 articles published in the past 30 years about phytoestrogens. In total, 74 studies were selected for inclusion in this review based on relevance, inclusion of human subjects wherever possible, and study design. The studies examine phytoestrogens' inhibition of the growth of cancer cell lines in vitro and in animals. They also look at the role of phytoestrogens in the reduction of cholesterol levels, and the use of one phytoestrogen derivative, ipriflavone, in the prevention of osteoporosis. Some small studies examine the role of phytoestrogens in the prevention of menopausal symptoms. Evidence for the potential health benefits of phytoestrogens is increasing. However, the clinically proven health benefits of prescribed ERT far outweigh those of phytoestrogens. Therefore, there is insufficient evidence to recommend the use of phytoestrogens in place of traditional ERT, or to make recommendations to women about specific phytoestrogen products.

Journal article content as a predictor of commitment to change among continuing medical education respondents.

BACKGROUND: Journal reading is a time-tested means of continuing medical education (CME) among physicians. Asking physicians to make a written statement of commitment to change has been shown to increase the likelihood of eventual change in practice behavior when used in conjunction with CME lectures. We describe the type and medical content of articles responsible for commitment to change comments among readers of a large circulation primary care journal. METHODS: Response to the question "what change(s) do you plan to make in your practice as a result of reading the articles in this issue?" were analyzed from CME response cards associated with six issues (1 year's publication) of the Archives of Family Medicine. Responses indicating a commitment to change were analyzed to characterize the type and content of articles responsible for their generation. RESULTS: During the 1-year study period, original contributions (reports of research trials) dealing with medicine and preventive medicine content accounted for the greatest number of comments. After adjusting for the frequency of article type and content, special articles and those dealing with complementary medicine accounted for the highest number of comments on a per-article basis. FINDINGS: Family physicians make commitment to change statements on the basis of a broad range of journal articles. Certain articles are more likely to generate statements of commitment to planned changes in practice.

Family practice triumphs by the year 2020: what will we have done right?

For family practice in the United States to be considered a success in the year 2020, several things will need to be done right between now and then. These include (1) an emphasis on quality of care, (2) a dependence on new technologies to enhance quality, (3) availability of and access to primary care for the entire US population, (4) increased political power for the specialty of family practice, (5) enhanced research and research funding, and (6) learning to work with patients so that they are the masters of their own care. If successful in 2020, family physicians will be perceived as quality physicians who use technology that everyone wants and who use their political power to advocate for patients' rights to quality health care and the research important to the discipline and quality health care. Family physicians will have become the "go-to doctors" who put patients in charge.

Changes in functional status related to health maintenance visits to family physicians.

BACKGROUND: Physicians do not provide preventive care at the level recommended by national organizations. This may be because of physicians' lack of training or low level of confidence or because of patients' fears, beliefs, and lack of health knowledge. METHODS: We used an observational prospective cohort study in an academic family practice office to investigate changes in patients' functional status associated with receiving recommendations to change behavior from family physicians. Patients 18 years and older presenting for health maintenance visits to family physicians completed a functional status instrument and a brief intake questionnaire by telephone before their visit. After the visit patients were randomized to a debriefing interview or an observation-only group. The interview included the Patient/Doctor Interaction Scale and an assessment of whether patients received a recommendation to change behavior. RESULTS: One hundred thirty-two patients were randomized to the debriefing group, and of those, 92% completed assessments at 3 months. Patients reporting recommendations to change behavior had lower scores at 1 and 3 months for mental health, social health, and self-esteem and higher anxiety and depression scores than patients not receiving these recommendations. CONCLUSIONS: There are declines in social and emotional functional status in patients presenting to family practice clinicians for health maintenance visits during which recommendations for behavioral change were made. Such declines may inhibit physicians from making recommendations for behavioral change or patients from accepting them.

Osteoporosis in women.

Many preventive and treatment strategies are now available for osteoporosis, offering many women the opportunity to forego its many complications. Exercise with calcium and vitamin D supplements is recommended for most patients. Estrogens are a preferred treatment but not acceptable to many women. Alendronate, a bisphosphonate, recently became available to treat osteoporosis. Calcitonin, subcutaneous or intranasal, also can be useful.

Characteristics of medical students by level of interest in family practice.

BACKGROUND AND OBJECTIVES: This study provides information on student factors associated with a career choice in family practice. METHODS: Information was used from multiple surveys completed by medical students, including the Premedical Questionnaire, the Matriculating Student Questionnaire, and the Graduation Questionnaire, as well as information from residency directors about residents in the Graduate Medical Education Tracking Census. These questionnaires are all a part of the Student and Applicant Information Management System of the Association of American Medical Colleges. Participants were 30,789 students graduating from US medical schools in 1991 and 1992. Comparisons were made between longitudinal student responses on the surveys to four types of outcomes. RESULTS: A total of 1,029 (3.3%) students were in the "Maintained" group (students who originally planned to enter family practice and were in a family practice residency at postgraduate year 1; 1,958 (6.4%) were "Gained" (originally chose a specialty other than family practice but entered a family practice residency); 1,950 (6.3%) were "Lost Interest" (originally identified family practice but entered another residency-two thirds of whom selected non-primary care specialties); 21,573 (70.1%) were "Never Interested" (did not express an early interest nor select a family practice residency); and the remainder (13.9%) had incomplete specialty data. Of those originally interested in family practice, 34.5% entered family practice residencies. Only 8.3% of those not originally interested entered family practice residencies. The four groups of students differed on many demographic, attitudinal, and experiential characteristics. Prestige, income, opportunities for research, and faculty status were more important to future specialists, while emphasis on primary care and prevention and practice in smaller communities were more important to the future family physicians. CONCLUSIONS: Medical schools could potentially increase the number of students selecting family practice residencies through both admissions policies and medical school experiences. These data provide some specifics on how to recruit students and prevent loss of those originally interested in family practice.

Pharmacokinetics of aminoguanidine administration and effects on the diabetes frequency in nonobese diabetic mice.

In vitro studies suggest that intra-islet nitric oxide production may contribute to the pathogenesis of autoimmune insulin-dependent diabetes mellitus. We tested whether aminoguanidine (AG), a competitive inhibitor of inducible nitric oxide synthase, might block beta cell destruction and prevent insulin-dependent diabetes mellitus in vivo. A total of 50 female nonobese diabetic mice, from the time of weaning until 32 wk of age, received injections (i.p.) twice daily with 50 mg AG/kg body weight and received AG in drinking water (350 mg/liter). A total of 50 littermates treated with vehicle alone served as controls. A 24-hr pharmacokinetic analysis showed that AG was readily absorbed after i.p. administration, peaked in plasma (9.0 micrograms/ml) at 0.5 hr and had a half-life of 1.88 hr. Steady-state values for the area under the curve for the therapeutic regimen were 20.51 and 16.35 (micrograms)(hr)/ml for the 0000 to 1600 and 1600 to 2400 hr, respectively. In terms of therapy, life-table analysis indicated the frequency of insulin-dependent diabetes mellitus (6/30 AG-treated vs. 11/31 vehicle-treated, P = .25) and insulitis scores (2.0 +/- 1.1 vs. 2.4 +/- 1.2 in nondiabetic AG- and vehicle-treated mice at 32 wk, respectively, P = .20) were similar in both groups. Flow cytometric analysis revealed no quantitative differences in islet infiltrating macrophages, CD4+ or CD8+ T lymphocytes between groups of animals randomly killed at 8, 16 and 32 wk. Although not eliminating a role for nitric oxide in the pathogenesis of insulin-dependent diabetes mellitus, prophylactic treatment with AG did not significantly impact the onset of insulitis or diabetes in nonobese diabetic mice.