Clozapine has sub-micromolar affinity for 5-HT1A receptors in human brain tissue.

The affinities of a range of antipsychotic drugs at human hippocampal 5-HT1A receptors, defined by specific [3H]8-OH-DPAT binding, were determined. Clozapine demonstrated the highest affinity; all other antipsychotics studied demonstrated pK(i) values below 6.0 5-HT1A receptors are found on cortical glutamatergic neurons, a dysfunction of which may occur in schizophrenia. Binding at this site indicates a possible mechanism contributing to the unique efficacy of clozapine in the treatment of some schizophrenic patients.     

Competitive ELISA employing monoclonal antibodies specific for coronafacoyl amino acid conjugates

Coronatine (COR) is composed of two structural components, coronafacic acid (CFA) and the amino acid coronamic acid (CMA), linked by an amide bond. Monoclonal antibodies (MAbs) were prepared against COR and incorporated into competitive ELISAs. MAbs were secreted by hybridoma cells which had been prepared from mice immunized with COR and conjugated, through the free carboxyl group on CMA, to ovalbumin, the available amino groups of which had been increased by derivatization with propyl diamine via free carboxyl groups. COR and coronafacoyl valine could be quantified at 6.800 ng ml^‐1(0.34–40 ng/assay) using peroxidase‐labelled MAb 8H3G2 in an indirect competitive ELISA. The corresponding limit of detection was 1 ng ml～’. Reduction and subsequent acetylation of the ketone oxygen of the CFA moiety of COR reduced the affinity of MAb 8H3G2 some 250 times, whereas methylation of the free carboxyl group on COR slightly enhanced the affinity four‐fold. These and other results suggest that CFA and the amide bond are important structural features of the epitope recognized by MAb 8H3G2.     

A Transplacental Carcinogenicity Bioassay in CD-1 Mice with Zidovudine

In oral carcinogenicity bioassays, zidovudine (ZDV) inducedvaginal epithelial cell tumors in mice given 30 or 40 mg/kg/dayand rats given 300 mg/kg/day. To determine if lifetime exposureto ZDV, beginning perinatally, would alter this pattern of carcinogenicity,two groups of 60 pregnant CD-I mice were given 20 or 40 mg/kg/dayof ZDV in 0.5% methyl cellulose from Gestation Day 10 throughLactation Day 21. At weaning, 2 pups per sex from each of 35litters in each group were assigned to the study and given 20or 40 mg/kg/day of ZDV in the drinking water until 17–35days of age, followed by daily gavage for 24 months. Two additionalgroups of 60 pregnant CD-I mice each were given 40 mg/kg/dayof ZDV daily from Gestation Day 10 through Lactation Day 21;in one, ZDV treatment was halted at weaning and in the other,treatment was stopped 90 days after weaning. Two other groupsof 60 pregnant CD-I mice were left untreated (environmentalcontrol) or were given 0.5% methyl cellulose beginning on GestationDay 10 (vehicle control). Vehicle control progeny received plaindrinking water for 17–35 days postweaning and then 0.5%methyl cellulose daily by gavage for 24 months. ZDV treatmentdid not affect survival or body weight in either sex. In femalesgiven 20 or 40 mg/kg/day of ZDV for 24 months there was mildmacrocytic anemia. Similar, non-dose-related changes were seenin males in these groups. ZDV-related tumor findings were limitedto the vagina, where there were 2 and 11 vaginal squamous cellcarcinomas in mice given 20 or 40 mg/kg/day of ZDV daily, respectively.This incidence was not remarkably different from that seen inpreviously reported bioassays. It was concluded that lifetimeoral treatment of mice with ZDV, beginning perinatally, didnot alter the previously reported pattern of carcinogenicityand that under the conditions tested ZDV was not a transplacentalcarcinogen.     

Model system for removing neuroblastoma cells from bone marrow using monoclonal antibodies and magnetic immunobeads

Variables effecting removal of neuroblastoma cells from bone marrow using monoclonal antibodies and magnetic immunobeads were studied. Human neuroblastoma cell lines were labeled with the supravital DNA stain Hoechst 33342, seeded into normal bone marrow, incubated with monoclonal antibodies recognizing neuroblastoma cell surface antigens (HSAN 1.2, antibody 459, antibody 390, BA-1, and Leu-7), and then mixed with magnetic microspheres coated with goat anti-mouse immunoglobulin. Tumor cells that attached to the magnetic immunobeads were then removed from the marrow with magnets. The efficacy of tumor cell removal depended on the amount of monoclonal antibody bound to tumor cells and the immunobead/tumor cell ratio. In addition, two cycles of purging with both monoclonal antibodies and immunobeads was superior to one cycle. Using a cocktail of the five antibodies, 3 to 4 logs of tumor cells could be depleted from marrow with good recovery of viable hematopoietic cells.     

Assessing the predictive validity of psychomotor tests as measures of biological age in mice

Two experiments assessed the predictive validity of a psychomotor test battery in male C57BL/6J mice. First, performance was recorded for 66 mice in rotorod, tightrope, grip strength, exploratory activity, and runwheel activity tasks at 24 mo of age. Except in the rotorod task, performance was positively and significantly correlated to lifespan, i.e. better performance indicated longer lifespan. Body weight and body temperature were also significantly correlated with lifespan, while water consumption was negatively related. Using the five behavioral scores in a multiple regression analysis, about 40% of the variance in lifespan was explainable. When measures of body weight, body temperature, and water consumption were added to the regression equation, about 54% of the variance in lifespan could be explained. As revealed by factor analysis, a high degree of interrelationship existed among variables. In a second experiment, 54 mice were tested in the psychomotor battery every 8 weeks from 24 mo. Scores in the tightrope and both locomotor activity tasks revealed age-related declines, whether considering all individuals or only those surviving to 28 mo. Significant correlations between first and subsequent scores indicated stability of individual differences for tightrope and exploratory activity at most ages and for runwheel activity at 26 mo but not later. Rotorod and grip strength scores were not stable and suggested confounding by learning. Significant correlations with lifespan were obtained at some ages for all tests. In contrast to the first experiment, however, there were no significant correlations between lifespan and scores at 24-mo for any test and little correlation among scores.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation.

There is heterogeneity in the propensity of smokers to develop chronic obstructive pulmonary disease (COPD), and improved treatment strategies are hindered by limited understanding of COPD pathogenesis, especially as distinct from the effects of smoking per se. Although apoptosis is essential for tissue homeostasis, increased apoptosis may cause tissue damage and inflammation. This study addressed whether airway T-lymphocytes and airway epithelial cells (AEC) show an increased likelihood of undergoing apoptosis in COPD and if this was related to smoking. Apoptosis (7-amino-actinomycin D, Annexin, single-stranded DNA and caspase), Bcl-2, Bax and p53 were assessed in cells obtained from bronchial bushing and bronchoalveolar lavage from ex- and continuing smokers with COPD, and nonsmoking controls, using flow cytometry. A mean 87% increase in apoptosis of AEC and a 103% increase in T-lymphocyte apoptosis were found in COPD. There were no significant differences in apoptosis of AEC between current and ex-smokers with COPD. Apoptosis may contribute to chronic obstructive pulmonary disease pathogenesis, and continued excess apoptosis after smoking cessation may offer a new target for therapeutic interventions. Whether the persistence of increased apoptosis after smoking cessation results from changes in the pulmonary milleau after years of noxious insult, or whether some individuals have a natural predisposition toward increased apoptosis and possible development of chronic obstructive pulmonary disease remains to be determined.     

How does depression influence diabetes medication adherence in older patients?

OBJECTIVE: Using various measures (electronic monitoring, patient/provider report, pharmacy data), the authors assessed the association between depression and diabetes medication adherence among older patients with Type 2 diabetes. METHODS: Patients completed a baseline survey on depression (Patient Health Questionnaire) and were given electronic monitoring caps (EMCs) to use with their oral hypoglycemic medication. At the time of the patient baseline survey, providers completed a survey on their patients' overall medication adherence. Upon returning the caps after 30 days, patients completed a survey on their overall medication adherence. EMC adherence was defined as percent of days out of 30 with correct number of doses. Using pharmacy refill data from the patient baseline through 1 year later, they defined adherence as the percentage of days with adequate medication, based on days' supply across refill periods. RESULTS: Of 203 patients (mean age: 67 years), 10% (N=19) were depressed. Depressed patients were less likely to self-report good adherence and had a lower median percentage of days with adequate medication coverage (on the basis of pharmacy refill data). After adjustment for alcohol use, cognitive impairment, age, and other medication use, depression was still negatively associated with adequate adherence, according to patient report and pharmacy data. Depression showed no associated with adherence on the basis of provider or EMC data. CONCLUSIONS: Depression was independently associated with inadequate medication adherence on the basis of patient self-report and pharmacy data.     

Body mass index and intake of selected foods in African American men

BACKGROUND: There are minimal data on the relationship between dietary consumption of fats, vegetables, and fruits and body mass index (BMI) in African American men. OBJECTIVE: This study tested the relationships between selected dietary consumption and BMI. DESIGN: The sample was a community-based cohort of 204 African American Southern men who attended a free prostate cancer educational and screening program. The screening was part of an all-day African American celebration that included a health fair. Diet was assessed with a Brief Dietary Scale for Selected Food Intake and Preparation. RESULTS: Most of the men were overweight (34%) or obese (47%). The majority of men ate their chicken (90%) and fish (96%) fried. Few men ate vegetables at supper (29.4%) or lunch (15.8%). Three fatty food items were significantly associated with BMI: leaving the chicken skin on chicken (p=.03); intake of low-fat or skim milk (p=.02); and cooking vegetables with butter (p=.03). CONCLUSION: African American men need culturally appropriate dietary interventions to reduce obesity.     

Low-volume resuscitation cocktail extends survival after severe hemorrhagic shock

After severe hemorrhage, low-volume resuscitation with hypertonic fluids is increasingly preferred to more aggressive resuscitation strategies. Oxygen delivery to the tissues may be improved by augmentation with hemoglobin [Hb]-based oxygen-carrying compounds (HBOCs); however, previous studies have reported negative outcomes presumably related to extravasation of tetrameric Hb. The purpose of this study was to evaluate a novel large molecular weight polymer of cross-linked bovine Hb (OxyVita; OXYVITA Inc, New Windsor, NY) in a cocktail of hypertonic saline and Hextend (HX; HBOC-C) as an alternative to standard small-volume resuscitation using Hextend (HX) only. Outcomes were survival to 3 h and duration of MAP support more than 60 mmHg without additional fluid support. Conscious male Long-Evans rats were hemorrhaged to 60% total blood volume over 40 min. There were 4 groups: HBOC-C administered in a pressure-titrated infusion, HX titration, HBOC-C administered as a bolus, and HX bolus. Cardiovascular parameters, arterial gases, acid-base status, metabolites, electrolytes, Hb level, and oxygen saturation were measured at baseline, during each 20% hemorrhage increment, and 1, 2, and 3 h after the initiation of hemorrhage. Small-volume resuscitation with HBOC-C significantly improved survival to 3 h and improved MAP support times regardless of method of administration. However, physiological status at the end of hemorrhage significantly influenced survival regardless of resuscitation treatment. These results suggest that HBOC-augmented hypertonic cocktails are of promise in improving survival and providing target MAP support during small-volume resuscitation. Experimental evaluation of any resuscitation therapy should account for the degree of preexisting physiological compromise before therapy is initiated.