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.

Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes.

Insulin-dependent diabetes (IDD) results from the autoimmune destruction of the insulin-producing pancreatic beta cells. Autoreactive T-lymphocytes are thought to play a pivotal role in the pathogenesis of IDD; however, the target antigens of these cells, as well as the inductive events in the disease, are unclear. PBMC in persons with or at increased risk for IDD show elevated reactivity to the beta cell enzyme glutamate decarboxylase (GAD). To identify the T-lymphocyte-reactive determinants of GAD, an overlapping set of synthetic peptides was used to stimulate the PBMC from these individuals, PBMC responsiveness to GAD peptides was not restricted to those with IDD, and a number of peptides elicited responses in PBMC. However, the major determinant of GAD recognized by persons at increased risk for IDD was amino acids 247-279, a region which has significant sequence similarity to the P2-C protein of Coxsackie B virus (47% of 15 increased risk [islet cell autoantibody-positive relatives]; 25% of 16 newly diagnosed IDD patients; and 0% of 13 healthy control subjects). Responses to tetanus and insulin antigens were not different between the study groups. In addition, PBMC from individuals responding to GAD peptides within 247-279 also responded to a Coxsackie viral peptide (i.e., P2-C amino acids 32-47), an observation supporting potential molecular mimicry in this immune response. Although the role of environmental agents in the pathogenesis of the disease remains unclear, these cellular immunological findings support the epidemiological evidence suggesting an inductive role for enteroviruses like Coxsackie B in the autoimmunity underlying IDD.

Immunological and metabolic effects of prophylactic insulin therapy in the NOD-scid/scid adoptive transfer model of IDDM.

Prophylactic insulin therapy prevents IDDM in spontaneous animal models of the disease and has shown promise in preventing the disease in humans. Although large clinical trials have been formed to use this therapy, a comparative analysis of the efficiency of different pharmaceutical forms and doses of insulin in preventing IDDM has not been performed, and the mechanism underlying the observed prevention of disease is unknown. In the NOD-scid/scid adoptive transfer model of IDDM (10(7) new-onset NOD splenocytes injected intravenously into 6- to 8-week NOD/scid-scid recipients; insulitis develops at 6-9 days post-transfer and 100% IDDM by 32 days post-transfer), life-table (log-rank) analyses revealed that IDDM can be delayed (compared with insulin-free diluent, once daily, n = 8) with equivalent efficiency by prophylactic administration (-9-50 days post-transfer) of high (metabolism-altering) doses of short-acting (0.5 U, once daily, regular, n = 13) or long-acting (0.5 U, once daily, ultralente, n = 9) insulin as well as non-metabolism-altering low-dose insulin (0.02 U, once daily, regular, n = 8). Furthermore, IDDM was delayed with somatostatin (0.2 microgram, twice daily, n = 11), an agent that suppresses endogenous insulin production. No significant difference was seen between the preventative effects of these agents. In an assessment of when therapies can be initiated and still maintain clinical efficiency, only prophylactic somatostatin therapy delayed IDDM (n = 10, P = 0.02) when initiated at 14 days post-transfer, whereas the short-acting insulin regimen did not retard the onset of IDDM (n = 8, P = 0.25) compared with diluent-treated controls. The 24-h urinary C-peptide levels were significantly reduced with short-acting (-56%, P = 0.01) and long-acting (-67%, P = 0.02) insulin products and somatostatin (-59%, P = 0.02) compared with diluent-treated controls. These results indicate that both immunological and metabolic (i.e., beta-cell rest) factors may contribute to the beneficial effects of prophylactic insulin therapy.

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.

The effect of educational preparation on physician performance with a sexually transmitted disease-simulated patient.

BACKGROUND: Simulated patients are used with increased frequency for medical students and residents, but have not been used very often with practicing physicians. We hypothesized that educational materials could improve primary care physicians sexual practices history taking and counseling as assessed by a simulated patient in the physician's office. METHODS: Simulated patient (SP) visits were made to 232 (75% of eligible) primary care physicians. The patient simulated was a sexually active young woman with vaginitis and sexually transmitted disease/human immunodeficiency virus risk behaviors. In advance of the visit, physicians were provided educational materials (monograph, pamphlet, and audiotape) developed for the study, including a risk assessment questionnaire that could be used with patients. RESULTS: Most physicians randomly allocated to the intervention participated. Twenty-one percent of physicians refused to schedule an SP visit. Physicians who received an SP rated the experience highly. Physicians who prepared for the visit with the educational materials performed significantly better than those who did not. About two thirds of physicians reviewed the materials, many for the second time, after the SP visit. Physicians who used the study risk assessment questionnaire performed better. Many physicians (24.9% to 39.8%) did not meet each of the four goals for the visit, as assessed subjectively by the SP. Physician performance was better for measures of general patient interaction than for measures of sexual practices history taking and counseling techniques. CONCLUSION: The SP visit was acceptable to most physicians practicing in a community and was evaluated by them as an appealing and an effective educational experience. The SP, however, has limited feasibility because of cost. The SP led to review of materials by nearly all physicians either before or after the visit. Physicians who prepared before the visit performed better on every dimension, eliciting more information, displaying better patient interaction skills, and meeting more of the educational goals. Even with educational preparation, however, many physicians were not perceived as being effective counselors.

Estimating physician requirements for neurology: a needs-based approach.

Applying the adjusted needs-based model developed by the Graduate Medical Education National Advisory Committee (GMENAC), physician requirements in neurology were estimated for the year 1990. A Delphi panel of physician experts estimated appropriate patterns of treatment for 56 neurologic conditions. Their median estimates implied a need for 14,500 neurologists in 1990, suggesting a shortage relative to the projected supply. An advisory panel of former GMENAC members reviewed those estimates and recommended certain adjustments to ensure internal consistency and compatibility with those for other specialties. Adoption of these adjustments significantly reduces requirements, implying a total need for 8,400 neurologists--a figure in near balance with the projected supply of 8,650. The difference between the Delphi and Advisory Panel estimates reflects divergent views, apparent as well among the Delphi panelists, of the appropriate role of neurologists--consultants versus principal care providers.

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.

Fatal hydrothorax and empyema complicating a malpositioned nasogastric tube.

Blind nasogastric intubation was attempted in a chronically debilitated patient. The nasogastric tube entered the trachea and was advanced through the left lower lobe bronchus into the left pleural cavity. During the subsequent two days of dietary supplement (Isocal) infusion, the patient developed fever, chills, decreased responsiveness, and left shoulder pain. This complication ultimately led to the patient's death. We have reviewed the known complications of nasogastric intubation and recommend that difficult intubations in weak or debilitated patients be followed by chest roentgenogram in order to confirm the correct placement of the tube.

Changes in drug prescribing patterns related to commercial company funding of continuing medical education.

In order to determine the impact of commercial company funding of continuing medical education (CME) courses, a survey was undertaken. Drug prescribing rates for drugs related to course content were determined by self-report survey of physician attendees (374 in number) for three different CME courses. The survey was performed immediately before and six months after the courses. A single, though different, drug company provided the majority of the funding for each course. Courses I and III were related to calcium channel blockers and Course II to beta blockers. The return rate before Course I was 73.0 percent; after, 54.0 percent (unmatched). The return rate for Course II was 49.4 percent before and 42.9 percent after (unmatched). There were 121 (61.4%) matched returns for Course III. While the rates for prescribing some of the related drugs increased after the courses, overall the sponsoring drug company's products were favored. Although physicians attending CME and accredited sponsors of CME need to be aware of this potential influence, the final burden of adequate evaluation of drugs remains with the physician prescriber. Further studies should be done to substantiate the findings and elucidate the mechanism(s) of the increase in sponsoring company's drug prescriptions.

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.

Assessment of the patient-doctor interaction scale for measuring patient satisfaction.

This study assessed the validity, reliability and usability of the Patient-Doctor Interaction Scale (PDIS) in a university-based family practice center. Health maintenance visits and problem visits were included, and data were collected at the time of the visit and again 1 month later. Three different methods of administration (in-person, telephone, and mail) were used to assess usability. Of 91 patients approached, 1 refused to participate. A total of 64 (70%) patients completed the instrument adequately to permit analysis. PDIS scores correlated with overall assessment of patient satisfaction (P < 0.01), suggesting criterion-based validity. Internal consistency (reliability) of the PDIS was indicated by Cronbach's alpha which were consistently greater than 0.80. Scores and return rates varied by method of administration, with the telephone method performing best. The PDIS appears to fulfill the requirements for a valid, reliable and useful instrument to assess patient satisfaction in family practice settings.

Family physicians: supply and demand.

The nation's supply of family physicians as estimated by the Graduate Medical Education National Advisory Committee appears fairly accurate. At the same time, the demands for family physicians appear to be strong, partially because case-management systems recognize the cost-effectiveness and appropriate training of family physicians for their needs. The largest factor inhibiting the supply of such physicians appears to be the relatively lower income of family practice compared to other specialty fields. This creates more difficulties in funding training positions and may limit the attractiveness of the field to medical school graduates.

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.

Family practice resident attrition: reasons and rates by sex.

A survey of all family practice residency programs in the country was done to determine resident attrition reasons and rate by sex. Of 383 programs mailed surveys, four returns were from programs too new to have data, and 238 returns were usable, for an effective response rate of 62.7%. The overall attrition rate was 12.4% (699/5,656), and varied by the type of residency program. The most frequent reason for attrition as identified by the survey respondent was switching specialties (41.0%), followed by private practice 16.4% and involuntarily released 11.9%. The remainder left for a variety of other reasons. There was a slightly higher attrition rate for women (14.2%) than men (11.9%). The odds ratio for this was 1.22 (95% confidence interval 1.03 to 1.41). Women were more likely to leave for childbearing or rearing, or spouse relocation, although overall these numbers were small, and men also left for these same reasons.

Methods for determining patient improvement following visits to family physicians.

Two instruments were used to assess patient improvement following visits to providers in a university based family practice center--the Modified Williamson Functional Assessment (MWFA) and the Mini-Duke-UNC Health Profile (Mini-DUHP). Of the 90 patients over the age of 18 seen for problem or health maintenance visits who were included in the study, 64 adequately completed the instruments at the time of the visit and one month later. Functional assessments by in-person, mail, and telephone methods of administration were similar. Patients' MWFA scores did not significantly improve by the time of the one-month follow-up. Mini-DUHP subscales for symptom and physical function also did not significantly improve. Mini-DUHP emotional, social, and composite scores indicated a decrease in function following the visits, particularly visits for health maintenance. MWFA and Mini-DUHP scores correlated only modestly, with the highest correlation occurring between Mini-DUHP Physical Score and the MWFA (0.414 or 0.509, P less than .001). Additional study is needed to identify or develop an instrument that can adequately assess broad changes in functioning for multiple diagnoses following specific physician interventions, and the reason for the decline in emotional and social function following visits needs further elucidation and evaluation.

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.

Developmental alterations in the regulation of glucagon and insulin secretion in Holstein calves.

Twenty-one Holstein bull calves were randomly assigned at birth to 3 groups. Two groups (each of 7 calves) were raised as follows: fed a milk diet alone or fed milk with grain supplementation after 2 weeks of age; studies were done when calves reached 4 weeks of age. The 3rd group was fed on milk with grain supplementation until weaning after which the calves were maintained on grain and pasture. These calves (older calves) were studied at 12 weeks of age. Either propionate (0.28 mmol/kg) or glucose (0.56 mmol/kg) was injected IV in a random order. Samples of blood were obtained from the calves before and immediately after injections were done and at 2, 5, 10, 15, 30, 45, and 60 minutes after secretagogue injection. Plasma was examined for glucose by a glucose oxidase procedure and for immunoreactive insulin (IRI) and glucagon (IRG) by radioimmunoassay. The IRI response to the injection of glucose was greater in older calves (P less than 0.02). Patterns of IRI secretion, as determined by heterogeneity of regression, showed age differences for both secretagogues (P less than 0.05). Base-line IRG was greater in milk/grain-fed calves than in milk-fed calves (P less than 0.05). Mean IRG response to propionate injection was higher (P less than 0.05) in milk/grain-fed calves than in milk-fed calves. Plasma glucose concentration increased in older calves, but decreased in milk-fed calves after propionate injection. The data indicate that maturation in the ruminant is accompanied by altered regulation of insulin and glucagon secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

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.