Wnt signaling in rheumatoid synoviocyte activation

Rheumatoid arthritis (RA) is a joint-specific disease with complex pathogenesis. It is characterized by synovial inflammation, cartilage loss, and joint destruction. The reasons why joint damage recurs when therapy is discontinued are not clearly understood. Several lines of evidence suggest that cartilage damage is promoted by the transformed and invasive fibroblast-like synoviocytes (FLS) of the rheumatoid joint. It has been demonstrated in several systems that aberrant wnt-mediated signaling causes blockade of cartilage differentiation and malformation of joints. In this review, we have discussed the importance of wnt–frizzled-mediated signaling in the autonomous activation of FLS in patients with RA. Anti-wnt/anti-frizzled antibodies, frizzled receptor antagonists, or small molecule inhibitors of wnt–frizzled signaling might be useful for therapeutic interventions in RA. Received: May 15, 2001/Accepted: September 28, 2001     

Angiotensin receptor blockers: evidence for preserving target organs

Hypertension is a major problem throughout the developed world. Although current antihypertensive treatment regimens reduce morbidity and mortality, patients are often noncompliant, and medications may not completely normalize blood pressure. As a result, current therapy frequently does not prevent or reverse the cardiovascular remodeling that often occurs when blood pressure is chronically elevated. Blockade of the renin-angiotensin system (RAS) is effective in controlling hypertension and treating congestive heart failure. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) inhibit the activity of the RAS, but these two classes of antihypertensive medications have different mechanisms of action and different pharmacologic profiles. Angiotensin-converting enzyme inhibitors block a single pathway in the production of angiotensin II (Ang II). In addition, angiotensin I is not the only substrate for ACE. The ACE inhibitors also block the degradation of bradykinin that may have potential benefits in cardiovascular disease. Bradykinin is, however, the presumed cause of cough associated with ACE inhibitor therapy. Data from clinical trials on ACE inhibitors serve to support the involvement of the RAS in the development of cardiovascular disease. Angiotensin receptor blockers act distally in the RAS to block the Ang II type 1 (AT1) receptor selectively. Thus, ARBs are more specific agents and avoid many side effects. Experimental and clinical trials have documented the efficacy of ARBs in preserving target-organ function and reversing cardiovascular remodeling. In some instances, maximal benefit may be obtained with Ang II blockade using both ARBs and ACE inhibitors. This review describes clinical trials that document the efficacy of ARBs in protecting the myocardium, blood vessels, and renal vasculature.     

Physician Burnout and Patient-Physician Communication During Primary Care Encounters

Background  Although previous studies suggest an association between provider burnout and suboptimal self-reported communication, no studies relate physician burnout to observed patient-physician communication behaviors. Objective  To investigate the relationship between physician burnout and observed patient-physician communication outcomes in patient-physician encounters. Design  Longitudinal study of enrollment data from a trial of interventions to improve patient adherence to hypertension treatment. Setting  Fifteen urban community-based clinics in Baltimore, MD. Participants  Forty physicians and 235 of their adult hypertensive patients, with oversampling of ethnic minorities and poor persons. Fifty-three percent of physicians were women, and the average practice experience was 11.2 years. Among the 235 patients, 66% were women, 60% were African-American, and 90% were insured. Measurements  Audiotape analysis of communication during outpatient encounters (one per patient) using the Roter Interaction Analysis System and patients’ ratings of satisfaction with and trust and confidence in the physician. Results  The median time between the physician burnout assessment and the patient encounter was 15.1 months (range 5.6–30). Multivariate analyses revealed no significant differences in physician communication based on physician burnout. However, compared with patients of low-burnout physicians, patients of high-burnout physicians gave twice as many negative rapport-building statements (incident risk ratio 2.06, 95% CI 1.58 – 2.86, p < 0.001). Physician burnout was not significantly associated with physician or patient affect, patient-centeredness, verbal dominance, or length of the encounter. Physician burnout was also not significantly associated with patients’ ratings of their satisfaction, confidence, or trust. Conclusions  Physician burnout was not associated with physician communication behaviors nor with most measures of patient-centered communication. However, patients engaged in more rapport-building behaviors. These findings suggest a complex relationship between physician burnout and patient-physician communication, which should be investigated and linked to patient outcomes in future research.     

Rapid Response Events in Hospitalized Patients: Patient Symptoms and Clinician Communication

Context

Patients triggering rapid response team (RRT) intervention are at high risk for adverse outcomes. Data on symptom burden of these patients do not currently exist, and current symptom management and communication practices of RRT clinicians are unknown.

Development and steroidogenic activity of preantral follicles in the neonatal rat ovary

The neonatal rat ovary is completely devoid of antral follicles until the twelfth day of age. During this period the ovary becomes steroidogenically active and responsive to gonadotrophins. The aim of this study was to correlate the onset of ovarian androgen and oestrogen production in vitro with the first appearance of distinct granulosa and theca cells. Although ovarian aromatase activity increased significantly on day 7 of age, ovarian oestrogen production was limited by low progesterone and testosterone production until day 12 of age. Increased aromatase activity on day 7 and androgen production on day 12 were coincident with the first appearance of granulosa and theca cells respectively. These functional and morphological changes were not associated with significant alterations in ovarian weight or concentrations of LH or FSH in serum.     

Physician demographics and the risk of medical malpractice.

PURPOSE: This study was undertaken to clarify which, if any, physician demographic characteristics are associated with an increased rate of medical malpractice claims. METHODS: We analyzed the malpractice experience of 9,250 physicians insured for at least 2 years from 1977 to 1987 in the state of New Jersey. After adjusting for years at risk, physician claims per year was categorized into low, medium, and high. RESULTS: Male physicians were three times as likely to be in the high-claims group as female physicians, even after adjusting for other demographic variables (relative risk, 3.1; 99% confidence interval, 2.2 to 4.4). Specialty was strongly associated with claims rate, with neurosurgery, orthopedics, and obstetrics/gynecology having 7 to 12 times the number of claims per year as psychiatry, the specialty with the fewest claims. The rate of claims varied with age (p < 0.001) and peaked at approximately age 40. No association was evident between claims rate and a physician's site of training or type of degree. CONCLUSION: Male physicians are three times as likely to be in a high-claims category as female physicians. We suspect that the most likely explanation for this finding is that women interact more effectively with patients. Understanding the reasons for the variation in claim rates between physicians may lead to the development of methods to reduce the overall rate of malpractice claims.     

Decreased VMAT2 in the pancreas of humans with type 2 diabetes mellitus measured in vivo by PET imaging

Aims/hypothesis

The progressive loss of beta cell function is part of the natural history of type 2 diabetes. Autopsy studies suggest that this is, in part, due to loss of beta cell mass (BCM), but this has not been confirmed in vivo. Non-invasive methods to quantify BCM may contribute to a better understanding of type 2 diabetes pathophysiology and the development of therapeutic strategies. In humans, the localisation of vesicular monoamine transporter type 2 (VMAT2) in beta cells and pancreatic polypeptide cells, with minimal expression in other exocrine or endocrine pancreatic cells, has led to its development as a measure of BCM. We used the VMAT2 tracer [¹⁸F]fluoropropyl-(+)-dihydrotetrabenazine to quantify BCM in humans with impaired glucose tolerance (prediabetes) or type 2 diabetes, and in healthy obese volunteers (HOV).

Methods

Dynamic positron emission tomography (PET) data were obtained for 4 h with metabolite-corrected arterial blood measurement in 16 HOV, five prediabetic and 17 type 2 diabetic participants. Eleven participants (six HOV and five with type 2 diabetes) underwent two abdominal PET/computed tomography (CT) scans for the assessment of test–retest variability. Standardised uptake value ratio (SUVR) was calculated in pancreatic subregions (head, body and tail), with the spleen as a reference region to determine non-specific tracer uptake at 3–4 h. The outcome measure SUVR minus 1 (SUVR-1) accounts for non-specific tracer uptake. Functional beta cell capacity was assessed by C-peptide release following standard (arginine stimulus test [AST]) and acute insulin response to the glucose-enhanced AST (AIRargMAX). Pearson correlation analysis was performed between the binding variables and the C-peptide AUC post-AST and post-AIRargMAX.

Results

Absolute test–retest variability (aTRV) was ≤15% for all regions. Variability and overlap of SUVR-1 was measured in all groups; HOV and participants with prediabetes and with type 2 diabetes. SUVR-1 showed significant positive correlations with AIRargMAX (all groups) in all pancreas subregions (whole pancreas p?=?0.009 and pancreas head p?=?0.009; body p?=?0.019 and tail p?=?0.023). SUVR-1 inversely correlated with HbA_1c (all groups) in the whole pancreas (p?=?0.033) and pancreas head (p?=?0.008). SUVR-1 also inversely correlated with years since diagnosis of type 2 diabetes in the pancreas head (p?=?0.049) and pancreas tail (p?=?0.035).

Conclusions/interpretation

The observed correlations of VMAT2 density in the pancreas and pancreas regions with years since diagnosis of type 2 diabetes, glycaemic control and beta cell function suggest that loss of BCM contributes to deficient insulin secretion in humans with type 2 diabetes.