A transgenic mouse model of neuroepithelial cell specific inducible overexpression of dopamine D1-receptor.

Dopamine and its receptors appear in the brain during early embryonic period suggesting a role for dopamine in brain development. In fact, dopamine receptor imbalance resulting from impaired physiological balance between D1- and D2-receptor activities can perturb brain development and lead to persisting changes in brain structure and function. Dopamine receptor imbalance can be produced experimentally using pharmacological or genetic methods. Pharmacological methods tend to activate or antagonize the receptors in all cell types. In the traditional gene knockout models the receptor imbalance occurs during development and also at maturity. Therefore, assaying the effects of dopamine imbalance on specific cell types (e.g. precursor versus postmitotic cells) or at specific periods of brain development (e.g. pre- or postnatal periods) is not feasible in these models. We describe a novel transgenic mouse model based on the tetracycline dependent inducible gene expression system in which dopamine D1-receptor transgene expression is induced selectively in neuroepithelial cells of the embryonic brain at experimenter-chosen intervals of brain development. In this model, doxycycline-induced expression of the transgene causes significant overexpression of the D1-receptor and significant reductions in the incorporation of the S-phase marker bromodeoxyuridine into neuroepithelial cells of the basal and dorsal telencephalon indicating marked effects on telencephalic neurogenesis. The D1-receptor overexpression occurs at higher levels in the medial ganglionic eminence (MGE) than the lateral ganglionic eminence (LGE) or cerebral wall (CW). Moreover, although the transgene is induced selectively in the neuroepithelium, D1-receptor protein overexpression appears to persist in postmitotic cells. The mouse model can be modified for neuroepithelial cell-specific inducible expression of other transgenes or induction of the D1-receptor transgene in other cells in specific brain regions by crossbreeding the mice with transgenic mouse lines available already.

The effect of levofloxacin concentration on the development and maintenance of antibiotic-resistant clones of Escherichia coli in chemostat culture.

A levofloxacin-sensitive strain of Escherichia coli (broth MIC: 0.0625 mg x l(-1)) was grown in carbon-limited chemostat culture for 316 h (D=0.294 h(-1)). Hyperresistant strains isolated after 58 and 91 generations of culture retained a 16- to 47-fold increase in tolerance to levofloxacin during antibiotic-free serial batch and continuous culture (20 generations, glucose-limited, D=0.2 h(-1)). Isolates differed from the original strain in their maximum growth rates in the presence and absence of subinhibitory levels of levofloxacin, protein-banding profiles, and resistance to a range of antibiotics. Competition between resistant isolates and the original sensitive strain was studied in glucose-limited chemostat cultures (D=0.2 h(-1)). At levofloxacin concentrations less than 0.03 mg x l(-1), the sensitive strain outcompeted resistant isolates and displaced them from the culture, whereas the reverse was true at higher concentrations. These results have clinical and environmental implications for those administering levofloxacin.

ALDH2 status, alcohol expectancies, and alcohol response: preliminary evidence for a mediation model.

BACKGROUND: A genetic variant in the alcohol-metabolizing enzyme (aldehyde dehydrogenase; ALDH2*2 allele), common in individuals of Asian heritage, has been associated with both physiologic response to alcohol and alcohol consumption. Prior research has also demonstrated that those with ALDH2*2 alleles have lower positive alcohol expectancies than those without these alleles. This preliminary study was designed to test whether the level of response to alcohol is the mechanism by which ALDH2 status may affect alcohol expectancies. METHODS: Data were collected from 32 Asian American college students (14 women and 18 men). By use of a randomized, double-blind design, participants were administered oral placebo and alcohol at separate laboratory sessions. Data included blood tests to establish ALDH2 status, questionnaire measures of demographic information and alcohol expectancy, and several physiologic measures collected after placebo and alcohol administration. RESULTS: ALDH2 status was related to alcohol response measures for both men and women. ALDH2 status was also related to tension reduction expectancies for women and to expectancies for cognitive behavioral impairment for men. In the male sample, the ALDH2/expectancy relationship was fully explained by the level of response to alcohol. CONCLUSIONS: These results represent a first step in understanding the mechanisms by which genetic factors, such as ALDH2 status, can affect alcohol-related learning.

Helicobacter pylori and NSAIDs--what interaction.

Much controversy surrounds the interaction of Helicobacter pylori infection and the use of Aspirin (ASA) or non-aspirin nonsteroidal anti-inflammatory drugs (NANSAIDs). The issue is comprised of many components, best dealt with singly. In summary, the severity of drug-associated gastritis, but not its incidence or prevalence, is influenced by infection prior to ASA or NANSAID therapy. Furthermore, the severity of dyspeptic symptoms appears worse in infected drug users. Both Chemical and Helicobacter gastritis, by increasing neutrophils in the tissue, lead to ulcers, although the induction of prostaglandin synthesis by inflammation in some circumstances may also be mildly protective. More ulcers are found in Hp+ve than Hp-ve users of NSAIDS, but ulcers in the stomach may heal more easily with acid suppressive therapy in infected patients. Eradication of infection is beneficial in aspirin users and in those beginning NANSAID therapy. Adaptation to aspirin is confined to Hp-ve cases. However, in long-term users of NANSAIDs, H. pylori eradication does not appear to speed ulcer healing, reduce recurrence, or prevent complications. These are best achieved by long-term maintenance therapy with a proton-pump inhibitor drug.

Prevention and treatment of gastrointestinal symptoms and complications due to NSAIDs.

The mechanisms by which aspirin(ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal symptoms are poorly understood. They probably arise from several causes, including direct and indirect mucosal injury, exacerbation of underlying peptic ulcer disease or non-ulcer dyspepsia, exacerbation of Helicobacter pylori gastritis, and possibly motility disorders. No single form of therapy has been generally successful. Because, in most cases, symptoms abate fairly rapidly with continued treatment, there is little evidence that benefit associated with any symptom-directed drug therapy is superior to placebo beyond 4 weeks. Exceptions may be the subsets of patients with pre-existing ulcer disease or heartburn, exacerbated by the NSAID therapy, who usually benefit from acid-suppressive drug treatment. Different NSAIDs vary in the frequency with which their use leads to gastrointestinal(GI) complications such as haemorrhage, perforation, obstruction, or the symptomatic ulcers from which about 40% of the complications arise. Most gastroduodenal ulcers heal over time, albeit more slowly, with conventional doses of any of the available anti-ulcer drugs. Maintenance therapy may be needed in many patients who continue NSAID therapy. Anti-ulcer drugs have not, thus far, been shown to be more effective than placebo in preventing ulcer complications or their recurrence. The use of COX-2-selective inhibitors appears, in outcome studies, to reduce gastrointestinal bleeding, including bleeding from ulcers, but it is not established that the ulcers protected were caused by NSAIDs, as distinct from ulcers exacerbating or recurring from antecedent peptic ulcer disease. To-date, perforation or obstruction have not been shown to be affected by selective COX-2 inhibitor drugs. If the major problem giving rise to severe NSAID complications is pre-existing peptic ulcer disease, it may yet emerge that the most effective approach will be the use of proton pump inhibitor drugs, for the duration of NSAID therapy, in a small subset of high-risk patients. Most other low-risk patients may not need any special care. Co-morbid conditions have a major impact on outcome of NSAID therapy. Morbidity or even death attributable solely to NSAIDs is probably small in normal patients, and requires little in the way of prophylaxis.

The role of family of origin food-related experiences in bulimic symptomatology.

OBJECTIVE: With the goal of developing a model relating family of origin experiences to maladaptive cognitions to bulimic symptom formation, the authors developed a measure of family of origin food-related experiences called the Family History Inventory. METHOD: A number (N = 662) of sixth to eighth-grade adolescents completed the inventory, eating and dieting expectancy measures, and the Bulimia Test-Revised (BULIT-R). RESULTS: Fourteen scales were identified in the inventory. They emphasized family teasing about weight, negative maternal modeling regarding food, and family rules concerning eating. Eleven of the 14 scales correlated with the BULIT-R. Two superordinate factors called Family Teasing and Negative Maternal Modeling summarized 8 of the 14 subscales. Statistical tests were consistent with the hypothesis that eating and dieting expectancies mediate the influence of Family Teasing and Negative Maternal Modeling on bulimic symptomatology. DISCUSSION: There was good evidence for the validity of the Family History Inventory. The theoretical implications of the mediation tests are discussed.

Disinhibition and expectancy in risk for alcohol use: comparing black and white college samples.

OBJECTIVE: This study tested several predictions of the "acquired preparedness" model in both black and white samples of college students. The acquired preparedness model holds that trait disinhibition affects alcohol-related learning and, ultimately, alcohol use. This model maintains that the reward focus typical of disinhibited individuals increases the likelihood of forming overly positive expectancies about the effects of alcohol. Alcohol expectancy, then, acts as a mediator of the relationship of disinhibition and drinking behavior. METHOD: Participants (N = 479, 341 women) were 279 white and 200 black college students. Self-reported alcohol expectancy, disinhibition and drinking behavior were assessed. Covariance structure analysis was used to test hypotheses separately for each sample, controlling for socioeconomic status. RESULTS: Black participants scored significantly lower on disinhibition, expectancy and drinking. However, invariance testing indicated that the relationships between these variables were not different across groups. Results were consistent with the stated hypotheses in both samples--alcohol expectancy functioned as a mediator of the disinhibition-drinking relationship. Results did not differ across expectancy content. CONCLUSIONS: These results provide support for the validity of the acquired preparedness model. Despite mean differences in risk and drinking levels between black and white samples, psychosocial learning appears to mediate the influence of disinhibition on drinking for both groups.

Four-year outcomes from adolescent alcohol and drug treatment.

OBJECTIVE: Knowledge of treatment response for alcohol and drug problems among adults is mounting; less is known about long-term outcome for adolescents who receive treatment for alcohol and drug problems. The current study examined youth substance involvement over 4 years (using five waves of data collection) following treatment for alcohol and drug abuse. METHOD: A cohort of youth (N = 162, 60% male) treated during adolescence (mean age = 16 years) was followed into young adulthood, a period associated with stabilization of alcohol use patterns and elevated risk for life problems secondary to both alcohol and drug use. Participants (14-18 years old) were consecutive admissions to inpatient adolescent alcohol and drug treatment centers in San Diego that were abstinence focused and based on the 12-step approach. RESULTS: Alcohol and other drug use were reduced during the 4 years posttreatment, with the exception of nicotine. The greatest prevalence reduction occurred for stimulants; modest changes were evident in alcohol and marijuana use. Nicotine was the most commonly used substance throughout the 4 years after treatment. Several distinct substance involvement trajectories were evident during the 4 years following treatment. CONCLUSIONS: Alcohol and drug use patterns during the 4 years following treatment highlight both changes and diversity in substance involvement as youth make the transitions from middle to late adolescence and into young adulthood. Findings demonstrate the importance of identifying transitional periods and the need for alternative intervention strategies that may help the progression of this population into young adulthood.

Pancreatic intraepithelial neoplasia and infiltrating adenocarcinoma: analysis of progression and recurrence by DPC4 immunohistochemical labeling.

Pancreatic intraepithelial neoplasia (PanIN) is thought to be a precursor lesion of infiltrating pancreatic ductal adenocarcinoma (IPA). DPC4 is a tumor-suppressor gene on chromosome 18q21.1 and is inactivated in approximately 55% of IPAs. Recently, immunohistochemical labeling using a monoclonal antibody to the Dpc4 protein has been shown to mirror DPC4 genetic status in invasive adenocarcinomas of the pancreas. In the present study, we examined the role of Dpc4 loss in neoplastic progression and recurrence. Two cases in which a PanIN clinically progressed to an invasive adenocarcinoma and a third of a patient with IPA of the head of the pancreas who later developed invasive adenocarcinoma in the tail of the pancreas were studied using Dpc4 immunolabeling. The first patient underwent pancreatic resection, which revealed PanIN-3 that lacked Dpc4 expression, and the patient developed an invasive pancreatic ductal carcinoma 10 years later that shared this loss of expression. The second patient had a pancreaticoduodenectomy for recurrent pancreatitis, and the resected pancreas contained PanIN-3 with intact Dpc4 expression. Seventeen months later, the patient developed an invasive adenocarcinoma of the distal pancreas that also had intact Dpc4 expression. In the third case, the patient underwent pancreaticoduodenectomy for an invasive ductal adenocarcinoma with negative margins. This carcinoma lacked Dpc4 expression. Three years later, resection of the pancreatic tail showed a second invasive adenocarcinoma. The cancer in the tail of the gland showed intact Dpc4 expression, suggesting it represented a second primary tumor, not a recurrence. We conclude that Dpc4 expression in PanIN can be predictive of Dpc4 expression in the subsequent invasive ductal adenocarcinoma. Additionally, Dpc4 expression can be used to differentiate recurrent or persistent adenocarcinoma from a second primary adenocarcinoma.

Lansoprazole treatment of patients with chronic idiopathic laryngitis: a placebo-controlled trial.

OBJECTIVE: Previous uncontrolled studies suggested a therapeutic benefit for treating gastroesophageal reflux disease (GERD) among patients with laryngitis. The present study is the first randomized, placebo-controlled, double-blind study of gastric acid suppression among patients with laryngitis in the United States. METHODS: Patients diagnosed with idiopathic chronic laryngitis were randomized to receive either lansoprazole 30 mg p.o. b.i.d. or a matching placebo for 3 months. Before randomization, all patients underwent upper endoscopy, dual probe ambulatory 24-h esophageal pH-metry, and laryngoscopy, as well as completing a symptom questionnaire for GERD and laryngitis. The primary outcome of treatment was the complete resolution of laryngeal symptoms. RESULTS: A total of 22 patients with symptoms and signs of chronic laryngitis were enrolled, 20 of whom completed the study. At baseline, there were no significant differences between the two groups with regards to GERD symptoms, erosive esophagitis, proximal and distal esophageal pH-metry, or laryngeal signs and symptoms. In an intention-to-treat analysis, six patients in the lansoprazole group (50%) and only one patient (10%) in the placebo group achieved a complete symptomatic response, p = 0.04. Apart from receiving lansoprazole, there were no significant differences between responders and nonresponders in any of baseline esophageal or laryngeal signs and symptoms. CONCLUSIONS: Empirical treatment with lansoprazole is efficacious in relieving symptoms of laryngitis compared to placebo. Such treatment can be considered as a first-line option in managing patients with idiopathic chronic laryngitis.

Integrating disinhibition and learning risk for alcohol use.

In this study the authors tested the acquired preparedness model of problem drinking, which holds that trait disinhibition, defined as neurotic extraversion by C. M. Patterson and J. P. Newman (1993), leads to the biased formation of positive over negative alcohol expectancies. Positive expectancies thus mediate disinhibition's influence on drinking. The authors also hypothesized that disinhibition moderates the expectancy-drinking relationship such that disinhibited individuals are more likely to act on their positive expectancies. In Study 1, positive expectancies both mediated and moderated the disinhibition-drinking relationship. In Study 2, learning task results indicated that disinhibited individuals sought reward, even when passive avoidance of punishment was indicated. Study 2 also replicated Study I hypotheses for men but generally not for women.

Progression into and out of binge drinking among high school students.

The current study examined binge drinking among high school students over an academic year. Adolescent drinkers (N = 621; 58% female) were grouped into 4 trajectories: drinkers (35%), increasers (14%), decreasers (16%), and persistent binge drinkers (35%). Prospective analyses indicated several factors that predicted escalation and de-escalation of binge drinking. Increasers were more likely to regularly use alcohol and cigarettes at a younger age than drinkers. Compared with decreasers, persistent binge drinkers reported regular alcohol and marijuana use at younger ages. Lower levels of perceived student drinking appeared to be a protective factor for onset of binge drinking. The results highlight the need to study precursors to the naturally occurring fluctuations in binge drinking and suggest factors that may accentuate the risk of binge drinking.

Integrating biological and behavioral factors in alcohol use risk: the role of ALDH2 status and alcohol expectancies in a sample of Asian Americans.

Prior studies have shown that the ALDH2*2 genetic variant, most common in individuals of Asian descent, is related to heightened sensitivity to alcohol and can serve as a protective factor against alcohol problems. This study explored the effect of this factor on alcohol expectancies. It was hypothesized that (a) individuals with ALDH2*2 alleles would have lower positive expectancies and higher negative expectancies, (b) expectancies would mediate the ALDH2-drinking relation, and (c) ALDH2 status would moderate the expectancy-drinking relation. Data were collected from 171 Asian American university students. Positive expectancy and ALDH2 status were correlated with alcohol use. Mediation and moderation hypotheses were supported only in the female sample. Results were not significant for negative expectancies. These results indicate that ALDH2 status may protect against drinking by lowering positive expectancies and reducing the expectancy-drinking relationship.

Basal joint arthroplasty using an allograft tendon interposition versus no interposition: a radiographic, vascular, and histologic study.

To assess the role of a tendon spacer that fills the trapezial void, the trapeziums were excised and anterior oblique ligaments were reconstructed in 25 monkeys. In addition to the ligament reconstruction, 20 of the monkeys had the trapezial void filled with a tendon allograft. The trapezial space was investigated at 0, 3, 6, 15, and 40 weeks using routine histologic staining, arterial perfusion (Spalteholz), and standardized radiographs. There was a statistically greater decline in trapezial height in the animals without tendon interposition allografts. The tendon grafts became progressively neovascularized and populated with fibroblasts. By 40 weeks, the allograft was no longer a folded tendon but a homogeneous mass of collagen, fibroblasts, and capillaries. The specimens without an interpositional tendon graft had loose fibroadipose tissue filling the carpal void. Polarized light microscopy showed fibers crossing the subchondral bone and moving into the adjacent fibrous spacer in the specimens implanted with a tendon graft. The results indicate that filling the trapezial void with an interposition tendon spacer may aid in maintaining normal wrist anatomy.

Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression.

Infiltrating adenocarcinomas of the pancreas are believed to arise from histologically identifiable intraductal precursors [pancreatic intraepithelial neoplasias (PanINs)] that undergo a series of architectural, cytological, and genetic changes. The role of DPC4 tumor suppressor gene inactivation in this progression has not been defined. Immunohistochemistry for the Dpc4 protein in formalin-fixed, paraffin-embedded tissue is a sensitive and specific marker for DPC4 gene status, providing a tool to examine DPC4 status in these putative precursor lesions. A total of 188 PanINs were identified in 40 pancreata, 38 (95%) of which also contained an infiltrating adenocarcinoma. Sections containing these 188 duct lesions were labeled with a monoclonal antibody to Dpc4. All 82 flat (PanIN-1A), all 54 papillary (PanIN-1B), and all 23 atypical papillary (PanIN-2) intraductal lesions expressed Dpc4. In contrast, 9 of 29 (31%) severely atypical lesions (PanIN-3 lesions, carcinomas in situ) did not. The difference in Dpc4 expression between histologically low-grade (PanIN-1 and -2) and histologically high-grade (PanIN-3) duct lesions was statistically significant (P < 0.0001). In three cases, the pattern of Dpc4 expression in the PanIN-3 lesions did not match the pattern of expression in the associated infiltrating carcinomas, indicating that these high-grade lesions did not simply represent infiltrating carcinoma growing along benign ducts. Loss of Dpc4 expression occurs biologically late in the neoplastic progression that leads to the development of infiltrating pancreatic cancer, at the stage of histologically recognizable carcinoma.

On the sins of short-form development.

The empirical short-form literature has been characterized by overly optimistic views of the transfer of validity from parent form to short form and by the weak application of psychometric principles in validating short forms. Reviewers have thus opposed constructing short forms altogether, implying researchers are succumbing to an inappropriate temptation by trying to abbreviate measures. The authors disagree. The authors do not oppose the development of short forms, but they do assert that the validity standards for short forms should be quite high. The authors identify 2 general and 9 specific methodological sins characterizing short-form construction and offer methodological suggestions for the sound development of short forms. They recommend a set of 6 a priori steps researchers should consider and 9 methodological procedures researchers can use to develop valid abbreviated forms of clinical-assessment procedures.

Knee cartilage topography, thickness, and contact areas from MRI: in-vitro calibration and in-vivo measurements.

OBJECTIVE: This study assessed the three-dimensional accuracy of magnetic resonance imaging (MRI) for measuring articular surface topographies and cartilage thicknesses of human cadaveric knee joints, by comparison with the calibrated stereophotogrammetric (SPG) method. METHODS: Six fresh frozen cadaveric knees and the knees of four volunteers were imaged with a three-dimensional spoiled gradient-recalled acquisition with fat suppression using a linear extremity coil in a 1.5 T superconducting magnet. The imaging voxel size was 0.47 x 0.47 x 1.0 mm. Both a manual and a semi-automated segmentation method were employed to extract topographic measurements from MRI. Following MRI, each of the six cadaveric knees was dissected and its articular surfaces quantified using stereophotogrammetry. The MRI surface measurements were compared numerically with the SPG measurements. RESULTS: For six cadaveric knees, the average accuracies of cartilage and subchondral bone surface measurements were found to be 0.22 mm and 0.14 mm respectively and the thickness measurements demonstrated an average accuracy of 0.31 mm. It was found that while most of the error may be attributed to random measurement error, the accuracy was somewhat affected by systematic errors. For each bone of the knee, accuracies were most favorable in the patella, followed by the femur and then the tibia. The more efficient semi-automated method provided equally good and sometimes better accuracies than manual segmentation. CONCLUSIONS: This study demonstrates that clinical MRI can provide accurate measurements of cartilage topography, thickness, contact areas and surface curvatures of the knee.