Use of a water-soluble busulfan formulation--pharmacokinetic studies in a canine model

In a canine model we investigated the toxicity and pharmacokinetics of a water soluble busulfan preparation. Busulfan was dissolved in dimethylsulfoxide (DMSO) and administered either orally or intravenously in a single dose of 1 mg/kg. The application in either preparation was well tolerated. In seven dogs, peak levels in the range of 730 ng/mL to 1,000 ng/mL were measured after intravenous injection with an area under curve (AUC) of 75 ng.h/kg.mL to 146 ng.h/kg.mL. It was of note that even the oral administration of the same busulfan preparation resulted in AUC values in the same range as observed after parenteral application. The absorption rate of busulfan tablets in our model was as unpredictable as documented in clinical trials. On the basis of the present study, clinical trials using busulfan dissolved in DMSO given either intravenously or orally appear warranted. This approach should lead to predictable blood levels, reduced toxicity, and increased efficacy of busulfan-containing regimens.     

Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin's disease

CD40 was originally described as a B-cell-restricted antigen and was subsequently found to be a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 is also expressed on dendritic cells, thymic epithelium, monocytes, and some carcinoma cell lines, and plays a critical role in cell contact-dependent activation. Primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells, the presumed malignant cells of Hodgkin's disease (HD); were found to express high levels of cell surface CD40. We found that recombinant CD40 ligand (CD40L) induced interleukin-8 (IL-8) secretion and enhanced IL-6, TNF, and lymphotoxin-alpha (LT-alpha/TNF-beta) release from cultured H-RS cells. These cytokines play a significant role in the clinical presentation and pathology of HD, a tumor of cytokine-producing cells. CD40L had no mitogenic activity for HD-derived cell lines. In contrast, CD40L enhanced expression of costimulatory molecules intracellular adhesion molecule-T and B7-1 on cultured H-RS cells, both of which are overexpressed on primary H-RS cells. In addition, CD40L induced a 40% to 60% reduction of the expression of the HD-associated CD30 antigen, another member of the TNF receptor superfamily. Primary and cultured H- RS cells express not only CD30, but also CD40. CD40L has pleiotropic biologic activities on H-RS cells, and the CD40-CD40L interaction might be a critical element in the deregulated cytokine network and cell contact-dependent activation cascade typical for HD.     

Physical inactivity in patients with rheumatoid arthritis: data from twenty-one countries in a cross-sectional, international study

OBJECTIVE: Regular physical activity is associated with decreased morbidity and mortality. Traditionally, patients with rheumatoid arthritis (RA) have been advised to limit physical exercise. We studied the prevalence of physical activity and associations with demographic and disease-related variables in patients with RA from 21 countries. METHODS: The Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis (QUEST-RA) is a cross-sectional study that includes a self-report questionnaire and clinical assessment of nonselected consecutive outpatients with RA who are receiving usual clinical care. Frequency of physical exercise (>or=30 minutes with at least some shortness of breath, sweating) is queried with 4 response options: >or=3 times weekly, 1-2 times weekly, 1-2 times monthly, and no exercise. RESULTS: Between January 2005 and April 2007, a total of 5,235 patients from 58 sites in 21 countries were enrolled in QUEST-RA: 79% were women, >90% were white, mean age was 57 years, and mean disease duration was 11.6 years. Only 13.8% of all patients reported physical exercise>or=3 times weekly. The majority of the patients were physically inactive with no regular weekly exercise: >80% in 7 countries, 60-80% in 12 countries, and 45% and 29% in 2 countries, respectively. Physical inactivity was associated with female sex, older age, lower education, obesity, comorbidity, low functional capacity, and higher levels of disease activity, pain, and fatigue. CONCLUSION: In many countries, a low proportion of patients with RA exercise. These data may alert rheumatologists to motivate their patients to increase physical activity levels.     

Functional impairment in spondyloarthropathy and fibromyalgia

OBJECTIVE: To compare the functional ability of patients with spondyloarthropathy (SpA) and fibromyalgia (FM) using the Bath Ankylosing Spondylitis Functional Index (BASFI), the Dougados Functional Index (DFI), and and the Health Assessment Questionnaire for Spondyloarthropathy (HAQ-S), to establish whether these indicators can differentiate between these patient groups, and to ascertain how well the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) functions in patients with FM. METHODS: Twenty-four patients with SpA and 70 with FM, all female, filled in 4 self-administered questionnaires: BASFI, DFI, HAQ-S, and the BASDAI; results were compared between the 2 groups. RESULTS: The decline in functional ability was similar in patients with SpA and FM when assessed by BASFI, but slightly greater in the SpA group when assessed by DFI and HAQ-S. BASDAI was significantly (p = 0.018) greater in the FM group. CONCLUSION: An almost similar functional decline was observed in both SpA and FM patients when measured by the indices developed for patients with AS and SpA. The specificity of BASDAI in measuring disease activity in SpA was poor, as disease activity in FM was rated higher than in SpA.     

Screening for cardiovascular risk factors and self-rated health in a community setting: a cross-sectional study in Finland

Background

Self-rated health is an independent predictor of mortality. However, general health checks in populations unselected for disease or risk factors have not been shown to reduce mortality or morbidity.

Aim

To describe new comorbidities and cardiovascular risk factors in apparently healthy people and to relate this to their self-rated health.

Design and setting

A targeted screening programme identified 462 middle-aged people with cardiovascular risk factors without previously diagnosed chronic disease in a Finnish community in 2005–2006.

Method

Home blood pressure monitoring, oral glucose tolerance test, estimated glomerular filtration rate, and ankle brachial index were used to detect previously undiagnosed conditions. The Short-Form Health Survey and Beck’s Depression Inventory were completed by participants before the diagnostic tests were performed.

Results

The prevalence of previously undiagnosed disease was: hypertension 113/462 (24% [95% confidence interval {CI} = 21% to 29%]), diabetes 19/462 (4% [95% CI = 2% to 6%]), renal insufficiency 23/462 (5% [95% CI = 3% to 7%]), and peripheral arterial disease 17/462 (4% [95% CI = 2% to 5%]). Of the 139 participants who regarded their health as ‘fair–poor’, 60 (43%) had a previously undetected condition affecting their vasculature.

Conclusion

Out of the screen-detected apparently healthy cardiovascular risk subjects, one in three had undiagnosed hypertension, diabetes, peripheral arterial disease, or renal insufficiency. Those individuals experiencing ill health tended to be at high risk of cardiovascular problems.     

Time to change the glomerular filtration rate estimating formula in primary care?

BackgroundThe most commonly used equation for estimated glomerular filtration rate (eGFR) is nowadays the four-variable Modification of Diet in Renal Disease (MDRD) equation. This formula was derived from patients with non-diabetic chronic kidney disease (CKD) with mean GFR 40 ml/min.MethodsWe compared the MDRD study equation and the recently developed Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation by applying the two formulas in 1747 middle-aged cardiovascular risk persons in primary care.ResultsThe prevalence of renal insufficiency defined as eGFR < 60 ml/min was 6.7% (95% CI 5.6–8.0) according to the MDRD formula, and 3.6% (95% CI 2.8–4.6) according to the CKD-EPI formula. The subjects who were classified as having CKD according to the MDRD equation, but no-CKD according to the CKD-EPI formula, were mostly women (86%) and slightly younger than the subjects having CKD according to both formulas.ConclusionThe characteristics of the subjects commonly treated in primary care resemble more closely the population from which the CKD-EPI than the MDRD study equation was derived from. Thus, we suppose that in general practice, the CKD-EPI equation is more suitable for estimating renal function than the MDRD equation.     

Change in physical activity and health‐related quality of life in old age—A 10‐year follow‐up study

The aim of the study was to examine the association between change in leisure‐time physical activity (LTPA) and change in health‐related quality of life (HRQoL) and symptoms of depression during a 10‐year follow‐up. This prospective study included 1036 men and women (mean age at baseline = 61.2 years) from the Helsinki Birth Cohort Study. Leisure‐time physical activity was measured with a questionnaire, HRQoL with SF36 and depression symptoms with Beck's depression inventory (BDI). The association between the change in LTPA and change in HRQoL and BDI were investigated with sex‐stratified general linear models adjusted for age, smoking, educational attainment, comorbidity score, and baseline value of outcomes. One standard deviation (SD) increase in LTPA was associated with increase in physical summary component of HRQoL in women (B = 0.7 unit, 95% CI = 0.1‐1.3, P = 0.032) and in men (B = 0.8 unit, 95% CI = 0.2‐1.5, P = 0.014). In women, the 1SD increase in LTPA was also associated with an increase in mental summary component score (B = 1.0, 95% CI = 0.3‐1.7, P = 0.005) and a reduction in depressive symptoms (B = ?0.7, 95% CI = ?1.1 to ?0.2, P = 0.003). In conclusion, increase in the volume of LTPA over a 10‐year period in late adulthood was associated with improved HRQoL in both men and women, and also diminished depressive symptoms in women. The findings support the promotion of physical activity in later years to enhance HRQoL and mental well‐being.     

Glucose regulation and pain in older people—The Helsinki Birth Cohort Study

AimsTo assess if individuals with diabetes or prediabetes report more pain or have increased use of pain medication compared to normoglycaemic individuals.MethodsUsing cross-sectional data, we studied 928 men and 1075 women from the Helsinki Birth Cohort Study in 2001–2004 at a mean age of 61.5 years. Glucose regulation was assessed with a 2-h 75 g oral glucose tolerance test, and applying World Health Organization criteria, participants were defined as having normoglycaemia, prediabetes (impaired fasting glucose or impaired glucose tolerance), newly diagnosed diabetes or previously diagnosed diabetes. Self-reported pain intensity and interference during the previous 4 weeks was estimated using the RAND 36-Item Health Survey 1.0. Information on use of pain medication during the past 12 months was obtained from the Social Insurance Institution of Finland.ResultsThere was no difference in pain intensity or interference between glucose regulation groups for neither men nor women after adjusting for covariates (age, body mass index, education years, Beck Depression Inventory and physical activity). In addition, use of pain medication was similar between glucose regulation groups.ConclusionsAlthough pain is a common symptom in the general population, impairments in glucose regulation alone does not seem to increase pain among older individuals.