Cannabinoid receptor down-regulation without alteration of the inhibitory effect of CP 55,940 on adenylyl cyclase in the cerebellum of CP 55,940-tolerant mice

The objective of this study was to determine whether the development of tolerance to CP 55,940, a potent cannabinoid agonist, was due to changes in the receptor or second messenger system. ICR mice treated with CP 55,940 (2 mg/kg) twice a day for 6 and one-half days developed a high degree of tolerance to the pharmacological effects of CP 55,940. The ability of CP 55,940 to produce motor hypoactivity, hypothermia and immobility was reduced 163-, 97- and 19-fold, respectively. Evaluation of 3H-CP 55,940 binding to rat brain membranes indicated no difference in receptor affinity between the vehicle- and CP 55,940-treated animals. However, these binding studies revealed a 50% decrease in receptor number in the cerebellum of the CP 55,940-tolerant mice. Although cAMP is generally considered to be the second messenger for cannabinoid receptors, little difference was observed in the inhibitory effects of CP 55,940 on adenylyl cyclase activity in cerebellum between vehicle and drug-treated mice. However, there was an increase in receptor mRNA which suggests a compensation for receptor loss. There are several possible explanations for these results. There may be sufficient spare receptors such that CP 55,940-tolerant mice are capable of producing a maximal effect on the second messenger system. On the other hand, one could conclude that cannabinoid receptor down-regulation does not account for the development of tolerance to all of the effects of CP 55,940 in mice.     

Relationship of "bleeding on probing" and "gingival index bleeding" as clinical parameters of gingival inflammation

Abstract Bleeding on probing (BOP) and the gingival index have been used to clinically characterize the degree of gingival inflammation. It is, however, unclear to what extent these parameters correlate to each other and to probing pocket depth (PD). The purpose of this clinical study was to evaluate the association between BOP and GI bleeding (scores of 2 and 3), as well as the relationship of these variables to PD, in a group of patients presenting with naturally-occurring gingivitis. Based on screening examinations of 125 subjects with at least 20 teeth, no more than 4 sites with PD over 6 mm, a BOP frequency of 30% or greater, and no systemic condition that would influence the inflammatory response, were selected. 2 weeks after screening they were examined at 6 sites per tooth for plaque index, GI, PD and BOP. A standardized pressure sensitive probe (Florida Probe) with 20 g probing force was used for BOP and PD measurements. In this population, means of 40.9% (S.E.= 1.36) BOP sites and 35.3% (S.E, = 1.81) GI bleeding sites per patient were found. A total of 20,008 sites ranging in PD up to 5.9 mm were evaluated; however, the majority of sites (19,723, 98.6%) presented with <4 mm PD. When sites were evaluated, BOP demonstrated a positive correlation with PD, whereas GI bleeding correlated with PH. For sites characterized by the absence of BOP as well as the absence of GI bleeding (scores 0 and 1), the highest % of agreement between the 2 indices (77.7%) was found in shallow sites (0.1–2 mm). In contrast, when sites presenting with both BOP and GI bleeding were analyzed, the highest % of agreement (85,4%) was found for sites with PD >4.0 mm. In this gingivitis population group, it appears that BOP and GI bleeding evaluate distinct inflammatory1 conditions of the gingival tissues, and the relationship between the 2 clinical parameters may vary according to PD at the individual site examined.     

BUILDING COMMUNITY: Developing Skills for Interprofessional Health Professions Education and Relationship-Centered Care

In 1995, the National League for Nursing commissioned a Panel on Interdisciplinary/Transdisciplinary Education. The focus of the Panel's work was to examine educational issues that transcend the health professions and to make recommendations for future implementation of an interdisciplinary approach to addressing them. This article is being simultaneously published by several professional journals. The goal is to seek as much feedback as possible.     

The Disablement Experienced by Traumatically Brain-Injured Adults Living in the Community

The disablement that occurs following traumatic brain injury (TBI) can be extensive and severe and consequently has been difficult to report on in a comprehensive and thorough manner. We were able to address this difficulty by analysing a sub group of data from the Canadian Health and Activity Limitation Survey (HALS) using the theoretical framework of disablement developed by the World Health Organization, the International Classification of Impairment, Disability and Handicap (ICIDH). There were 454 survey respondents (representing 12290 in the Canadian population) with disability resulting from a TBI and a mean time post-injury of 13 years. Three handicaps identified in the ICIDH were the focus of the study: physical independence, work, social integration. The prevalence of long term handicap was very high with 66% of the sample reporting the need for ongoing assistance with some activities of daily living, 75% not working, and 90% reporting some limitations or dissatisfaction with their social integration. Multivariate regression analysis was used to investigate the determinants of the handicaps. The determinants included: age, gender, level of education, living alone, physical environment, and specific disabilities. The implications of these findings are discussed in relation to rehabilitation issues, the usefulness of the ICIDH as a model to investigate outcomes, and directions for future research.     

Effect of cortisone on cells at the bone-marrow interface

Summary A study of the association between the rate of proliferation of marrow fibroblast-like stromal cells (in vitro) and the rate of endosteal bone mineralization (EsMR) (in vivo) was undertaken in an osteopenic rat model. We report than 200 g male rats treated with cortisone acetate (5 mg/day for 7 days) exhibit decreases in marrow fibroblast colony-forming units (FCFU) and tetracycline-based measurements of EsMR at the level of the femoral midshaft. In cortisone-treated rats recovering for 1–3 weeks, the FCFU census and EsMR normalized during the first posttreatment week, remained at control levels after 2–3 weeks, and exhibited a relapse in the third week which signified only partial recovery. These changes were unrelated to patterns of body weight gain. The data indicate that the FCFU census can serve to index endosteal osteoblast vigor.     

Evaluating New and Traditional Methods for Aminoglycoside Dosing in Patients With Various Degrees of Renal Function

Aminoglycosides are widely used, and clinicians continue to seek newer and better methods for initial dosing of these agents. Recently, three new methods were introduced: Thomson, Reesor Nimmo, and dosing in Tenopathy by easy-to-use multipliers (DREM). In comparing them with older, traditional dosing methods in patients with various degrees of renal function, the pharmacokinetic variables of gentamicin were determined from steady-state peak (C_max) and trough (C_min) serum concentrations using individualized regimens in 88 patients. Dosages were determined in each patient using the method of Hull-Sarubbi, rule of eights, and the three new methods, and the resultant C_max and C_min values were calculated from dosages generated by each method. The daily doses and C_max values derived with the Hull-Sarubbi, Thomson, and Reesor Nimmo methods were not significantly different (p>0.05). The Hull-Sarubbi was the most precise (root mean squared prediction error 1.3) and least biased (mean prediction error −0.05) of the five methods in predicting target gentamicin serum peak concentrations (C_max 6.5 mg/L). The Hull-Sarubbi (69%), Thomson (86%), and Reesor Nimmo (70%) methods yielded therapeutic C_max (5–8 mg/L) in a significantly higher percentage of patients than did the rule of eights (32%) and DREM (35%), (p<0.05). Therefore, if gentamicin serum concentrations are not available, the first three appear to be reasonable methods for initiating gentamicin dosage regimens, but the last two may not be desirable to use in a clinical setting. These conclusions are based on the assumption that patients are adults with stable renal function and relatively stable clinical conditions.     

Needs and needs assessment: their components and definitions with reference to dementia

The concept of need and the practice of needs assessment are both subject to a wide range of interpretations, to the likely detriment of individual assessments and to multidisciplinary working. Clear definition is important for individual assessment, for the development of multidisciplinary tools and in gathering planning information. The concept of need is clarified, firstly by distinguishing between need and the difficulties that engender it, and secondly through a taxonomy of need. These assist clear definitions of both need and needs assessment when linked with a consideration of the current help a person receives and a specification of the type of help required by a person to meet their needs. Such definitions have implications for the role of needs assessment in individual assessment, service evaluation, service management and planning and in the development of multidisciplinary needs assessment tools.     

The Effect of High-Dose Ascorbate Supplementation on Plasma Lipoprotein(a) Levels in Patients With Premature Coronary Heart Disease

Study Objective . To determine the efficacy of high-dose ascorbate supplementation in lowering lipoprotein(a) [Lp(a)] levels in patients with premature coronary heart disease (CHD). Design . Randomized, double-blind, placebo-controlled trial. Setting . Outpatient clinic. Patients . Forty-four patients with documented premature CHD. defined as confirmed myocardial infarction and/or angiographically determined stenosis of 50% or greater in at least one major coronary artery before age 60 years. Interventions . Patients were block randomized on the basis of age, gender, and screening Lp(a) concentrations to receive ascorbate 4.5 g/day or placebo for 12 weeks. Measurements and Main Results . High-dose ascorbate was well tolerated and produced a marked elevation in mean plasma ascorbate levels (+1.2 mg/dl; p<0.001). Multiple linear regression analysis revealed no significant effect of supplementation on postintervention Lp(a) levels (p=0.39) in a model that included treatment group assignment, and baseline Lp(a) levels. Conclusions . Our findings do not support a clinically important lowering effect of high-dose ascorbate on plasma Lp(a) in patients with premature CHD.     

Prospective survey of investigations in outpatients referred with iron deficiency anaemia.

Recent evidence has suggested that colonic neoplasm may be missed in patients presenting with iron deficiency anaemia unless colonic investigations are performed on all patients even when an alternative cause has been found. This study prospectively surveyed 114 consecutive patients referred from family practitioners to an outpatient clinic for the investigation of iron deficiency anaemia to determine the diagnoses contributing to the anaemia, the usefulness of certain clinical features, and the role of colonic and other investigations in obtaining the diagnosis. Upper gastrointestinal lesions contributing to anaemia were identified in 45 patients while colonic lesions were found in 18. Twenty three patients had a non-gastrointestinal cause for anaemia and in 12 patients no cause was found. Only two patients were identified as having colonic neoplasia (a small adenomatous polyp in each case) coexisting with upper gastrointestinal lesions. Symptoms and signs had a sensitivity and specificity of upper gastrointestinal disease of 50% and 83% respectively, and 44% and 80% for colonic disease. Endoscopy had a high yield (42%) and duodenal biopsy identified coeliac disease in three patients (two were aged > 70 years) each of whom had normal folate values. Barium enema had a yield of 13%. All colonic carcinomas occurred in patients > 65 years. The coexistence of colonic cancer or large polyps with an upper gastrointestinal lesion identified at endoscopy was rare in outpatients referred from family practitioners. Clinical symptoms and signs were poor indicators of the investigations that will detect a cause for the anaemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Body pain and treatment response in late-life depression.

OBJECTIVE: The authors investigated the influence of body pain on 1) time to treatment response and 2) suicidal ideation, in late-life depression. They hypothesized that higher levels of body pain would predict a longer time to and lower likelihood of response, and increased levels of suicidal ideation. METHODS: Subjects (N=187) were older adult outpatients (age > or =69 years), with current episodes of major depression, who were openly treated with paroxetine up to 40 mg daily and weekly interpersonal psychotherapy. Response was defined as 3 consecutive weeks of Hamilton Rating Scale for Depression at < or =10. Body pain was measured with the Bodily Pain Index of the SF-36 quality-of-life assessment. Authors used survival-analysis models on the responder sample to test the effect of body pain on response, after controlling for severity of depression. RESULTS: Overall response rate was 75.4%. Nonresponders reported more severe pain at baseline. After covarying for severity of baseline depression, no effect was found for physical pain on time-to-response or degree of suicidality. Bodily pain remained stable during acute treatment for responders, independent of depression response to combination psychotherapy and antidepressant treatment. CONCLUSIONS: Older adult patients with higher levels of physical pain can still respond to antidepressant treatment; however, reported bodily pain may be associated with a more difficult-to-treat depression.