Glucose Ingestion Attenuates Interleukin-6 Release from Contracting Skeletal Muscle in Humans

To examine whether glucose ingestion during exercise affects the release of interleukin-6 (IL-6) from the contracting limb, seven men performed 120 min of semi-recumbent cycling on two occasions while ingesting either 250 ml of a 6.4 % carbohydrate (GLU trial) or sweet placebo (CON trial) beverage at the onset of, and at 15 min intervals throughout, exercise. Muscle biopsies obtained before and immediately after exercise were analysed for glycogen and IL-6 mRNA expression. Blood samples were simultaneously obtained from a brachial artery and a femoral vein prior to and during exercise and leg blood flow was measured by thermodilution in the femoral vein. Net leg IL-6 release, and net leg glucose and free fatty acid (FFA) uptake, were calculated from these measurements. The arterial IL-6 concentration was lower (   P < 0.05  ) after 120 min of exercise in GLU, but neither intramuscular glycogen nor IL-6 mRNA were different when comparing GLU with CON. However, net leg IL-6 release was attenuated (   P < 0.05  ) in GLU compared with CON. This corresponded with an enhanced (   P < 0.05  ) glucose uptake and a reduced (   P < 0.05  ) FFA uptake in GLU. These results demonstrate that glucose ingestion during exercise attenuates leg IL-6 release but does not decrease intramuscular expression of IL-6 mRNA.     

Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice

Background  

Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are expressed by microglia and infiltrating macrophages following ischemic stroke. Whereas IL-1β is primarily neurotoxic in ischemic stroke, TNF-α may have neurotoxic and/or neuroprotective effects. We investigated whether IL-1β and TNF-α are synthesized by overlapping or segregated populations of cells after ischemic stroke in mice.     

Use of robotized DNA isolation and real-time PCR to quantify and identify close correlation between levels of Neisseria meningitidis DNA and lipopolysaccharides in plasma and cerebrospinal fluid from patients with systemic meningococcal disease

The present study, using robotized DNA isolation and quantitative PCR based on the Neisseria meningitidis-specific capsular transport A gene, demonstrates the ease, rapidity, specificity, and sensitivity of quantifying neisserial DNA in plasma (n = 65) and cerebrospinal fluid (CSF) (n = 12) from patients with systemic meningococcal disease. We found a close correlation between the levels of neisserial DNA and lipopolysaccharides in plasma (r = 0.905) and in CSF (r = 0.964). The median concentration of neisserial DNA in plasma in 23 patients with persistent shock was 2 x 10(7) copies/ml, versus <10(3) copies/ml in 42 nonshock patients. Furthermore, quantitative PCR made possible estimates of the total number of meningococci in plasma, as opposed to conventional blood cultures, suggesting about 1,000 dead meningococci for every viable bacterium. Finally, with logistic regression analyses, neisserial DNA may predict a patient's disease severity and outcome at hospital admission. The number of meningococci in plasma and CSF appears to be the main determinant of the lipopolysaccharide levels, clinical presentation, and outcome.     

Rheumatoid synovial cell hormone responses modulated by cell-cell interactions

Cellular interactions within the rheumatoid synovium are likely to be responsible for the destructive properties of this tissue. The responses to hormones which regulate connective tissue metabolism may also be influenced by these cell-cell interactions. To determine the effect of cellular interactions on responses to hormones, human peripheral blood mononuclear cells were cocultured with adherent rheumatoid synovial cells. Coculture resulted in a decrease in response to prostaglandin E₂ as assessed by a reduction in the magnitude of the acute prostaglandin-induced cyclic AMP response. In contrast, coculture resulted in an increase in the magnitude of the acute parathyroid hormone-induced cyclic AMP response. The decrease in response to prostaglandin was reversed by the presence of indomethacin during the preincubation, whereas indomethacin had no effect on the cyclic AMP response to parathyroid hormone. Increases in endogenous synovial cell prostaglandin production (stimulated by soluble factors released by the mononuclear cells) accounted for the subsequent decrease in the response to exogenous prostoglandin. The increase in cyclic AMP response to parathyroid hormone could not be explained by a soluble factor and was independent of ambient prostaglandin levels.This work was supported by USPHS grants AM-03564 and AM-07258. This is publication number 942 of the Robert W. Lovett Memorial Unit for the study of Diseases Causing Deformities.J.-M. D. received partial support by grants from Fonds National Suisse de Recherche Scientifique.     

Ca2+–calmodulin-dependent protein kinase expression and signalling in skeletal muscle during exercise

Ca²⁺ signalling is proposed to play an important role in skeletal muscle function during exercise. Here, we examined the expression of multifunctional Ca²⁺–calmodulin-dependent protein kinases (CaMK) in human skeletal muscle and show that CaMKII and CaMKK, but not CaMKI or CaMKIV, are expressed. Furthermore, the effect of exercise duration and intensity on skeletal muscle CaMKII activity and phosphorylation of downstream targets was examined. Eight healthy men exercised at ∼67% of peak pulmonary O₂ uptake     with muscle samples taken at rest and after 1, 10, 30, 60 and 90 min of exercise. Ten other men exercised for three consecutive 10 min bouts at 35%, 60% and 85%     with muscle samples taken at rest, at the end of each interval and 30 min post-exercise. There was a rapid and transient increase in autonomous CaMKII activity and CaMKII phosphorylation at Thr²⁸⁷ in skeletal muscle during exercise. Furthermore, the phosphorylation of phospholamban (PLN) at Thr¹⁷, which was identified as a CaMKII substrate in skeletal muscle, was rapidly (< 1 min) increased by exercise, and remained phosphorylated 5-fold above basal level during 90 min of exercise. The phosphorylation of serum response factor at Ser¹⁰³, a putative CaMKII substrate, was higher after 30 min of exercise. PLN phosphorylation at Thr¹⁷ was higher with increasing exercise intensities. These data indicate that CaMKII is the major multifunctional CaMK in skeletal muscle and its activation occurs rapidly and is sustained during continuous exercise, with the activation being greater during intense exercise.     

Prevalence of Masturbation and Associated Factors Among Older Adults in Four European Countries

Solitary sexual activity is a free, safe, and accessible way to experience sexual pleasure. Despite these advantages, research on masturbation in later life is highly understudied. Using data from a cross-sectional probability-based survey of 3816 European adults (mean age 67 years; range 60–75 years), we explored several sociodemographic, health, attitudinal, and sexual behavioral factors associated with reported masturbation frequency. Across all countries, between 41% and 65% of men and 27% and 40% of women reported any masturbation in the preceding month. Satisfaction with sexual activity and attitudes related to disapproval of sex without love were significant predictors of reported masturbation in almost all countries and in both genders. Age, education, self-perceived health, and depression were for the most part predictive of men’s reported masturbation, but not women’s. Generally, those believing sex is beneficial to older people were more likely to masturbate, while less permissive attitudes decreased the likelihood of reporting masturbation. To improve healthy sexual aging, misinformation about masturbation and sexual attitudes in older people need to be addressed.

     

The pharmacokinetics of high-dose epirubicin and of the cardioprotector ADR-529 given together with cyclophosphamide, 5-fluorouracil,and tamoxifen in metastatic breast-cancer patients

A high-pressure liquid chromatographic method for determination of the bisdioxopiperazine derivative ADR-529 (ICRF-187), a compound proven effective in protection against anthracycline-induced cardiotoxicity, has been developed. The limit of quantitation was 5 ng/ml using a narrow-bore 5-m silica column and UV detection. The method was used for determination of pharmacokinetic profiles of ADR-529 after a 3-weekly i.v. administration of different doses of ADR-529 (600–1000 mg/m²) together with different doses of epirubicin (E, 60–100 mg/m²), fixed-dose cyclophosphamide (C, 600 mg/m²), fixed-dose 5-fluorouracil (F, 600 mg/m²), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacokinetic parameters for epirubicin were also determined. The aim of the study was to determine (1) whether the pharmacokinetics of ADR-529 as part of a combination with CEF-T changes with increasing doses of ADR-529 and increasing doses of epirubicin and (2) whether the pharmacokinetics of epirubicin in the same combinations is altered with the administration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no significant difference in epirubicin pharmacokinetic parameters when epirubicin was given with or without concomitant administration of ADR-529. Apart from minor changes in the distributional half-lives, the pharmacokinetic parameters of epirubicin were not altered with increasing doses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 itself. Escalating doses of epirubicin did not significantly alter the pharmacokinetic parameters of ADR-529 with the exception of a 30% increase in the terminal half-life and a decrease in total body clearance when the epirubicin dose was raised from 60 to 100 mg/m². We conclude that concomitant administration of ADR-529 does not alter the distribution and elimination of epirubicin in doses suitable for preventing the anthracycline-induced cardiotoxicity.     

Combined regional and light general anesthesia: are the risks increased or minimized?

Regional anesthesia during general anesthesia has become increasingly popular in recent years. Most pediatric anesthesiologists are proponents of this practice, and believe that surgical morbidity is reduced, but controversy remains regarding safety. Neuraxial anesthesia during general anesthesia is especially controversial. Unfortunately, outcome studies are lacking but the literature reflects an absence of reported serious morbidity or mortality.     

Histomorphometric analysis of age-related structural changes in human clitoral cavernosal tissue

PURPOSE: To characterize age-associated histological changes of human clitoral cavernosal tissue and to determine whether age-related histological changes of clitoral cavernosal tissue correlate with vascular disease-related mortality. MATERIALS AND METHODS: Human clitorises were obtained from 15 fresh cadavers (age: 11 to 90 years) and from 3 patients undergoing clitoral surgery (age: 6 months to 15 years). Cross sections of the clitorises were stained with Masson's trichrome and utilized for computer assisted histomorphometric image analysis to determine the clitoral cavernosal content of smooth muscle and connective tissue. RESULTS: These studies revealed a strong link between increase in age and decreased clitoral cavernosal smooth muscle fibers. In histomorphometry, the percentage of clitoral cavernosal smooth muscle (mean +/- standard error) in an age group of 6 months to 15 years (n = 4) was 65+/-1.5, in 44 to 54 years (n = 7) was 50+/-1.2, and in 55 to 90 years (n = 7) was 37+/-1.3 (ANOVA, p = 0.0001). In the 18 tissues studied, decrease in the percentage of clitoral cavernosal smooth muscle significantly correlated with increase in age (simple regression, r = 0.61). In the age group of 44 to 90 years, clitoral cavernosal fibrosis was significantly greater in the presence of cardiovascular disease-related mortality compared with those without cardiovascular disease-related mortality. CONCLUSION: This study shows that aging women undergo histological changes in clitoral cavernosal erectile tissue. Vascular risk factors may adversely affect the structure of clitoral cavernosal tissue. These findings may be of importance in the pathophysiology of age-associated female sexual arousal disorders.