ABSORPTION AND BIOAVAILABILITY OF NEBULIZED MORPHINE

During anaesthesia seven patients received a bolus of morphine 10 mg injected into the nebulization reservoir placed between the tracheal tube and the anaesthetic circle (lH). Five days after operation the same seven patients received morphine 10 mg i.m. On both occasions, venous blood samples were taken before and every 15 min after administration over 4.5 h for measurement of free morphine immunoreactivity by radioimmunoassay. There was marked individual variation in the serum morphine concentrations produced following each route of administration. The maximum serum morphine concentration following inhaled morphine was approx. six times lower than that after morphine i.m. and the time of occurrence differed significantly (P < 0.001). The individual relative bioavailabilities of inhaled morphine varied from 9% to 35%, with a mean of 17

Skeletal muscle properties and fatigue resistance in relation to smoking history

Although smoking-related diseases, such as chronic obstructive pulmonary disease (COPD), are often accompanied by increased peripheral muscle fatigability, the extent to which this is a feature of the disease or a direct effect of smoking per se is not known. Skeletal muscle function was investigated in terms of maximal voluntary isometric torque, activation, contractile properties and fatigability, using electrically evoked contractions of the quadriceps muscle of 40 smokers [19 men and 21 women; mean (SD) cigarette pack years: 9.9 (10.7)] and age- and physical activity level matched non-smokers (22 men and 23 women). Maximal strength and isometric contractile speed did not differ significantly between smokers and non-smokers. Muscle fatigue (measured as torque decline during a series of repetitive contractions) was greater in smokers (P = 0.014), but did not correlate with cigarette pack years (r = 0.094, P = 0.615), cigarettes smoked per day (r = 10.092, P = 0.628), respiratory function (%FEV1pred) (r = −0.187, P = 0.416), or physical activity level (r = −0.029, P = 0.877). While muscle mass and contractile properties are similar in smokers and non-smokers, smokers do suffer from greater peripheral muscle fatigue. The observation that the cigarette smoking history did not correlate with fatigability suggests that the effect is either acute and/or reaches a ceiling, rather than being cumulative. An acute and reversible effect of smoking could be caused by carbon monoxide and/or other substances in smoke hampering oxygen delivery and mitochondrial function

Activity of a Novel bcl-2/bcl-xL-Bispecific Antisense Oligonucleotide Against Tumors of Diverse Histologic Origins

Background: Increased expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL is involved in the development and progression of many tumors. We recently reported that the bcl-2/bcl-xL-bispecific antisense oligonucleotide 4625 induces apoptosis in lung carcinoma cells. To further assess the therapeutic potential of oligonucleotide 4625, we investigated its effect on a series of human tumor cell lines of diverse histologic origins in vitro and in vivo. Methods: Oligonucleotide 4625-mediated inhibition of bcl-2 and bcl-xL expression in vitro was measured in breast carcinoma cells with the use of reverse transcription-polymerase chain reaction (PCR), real-time PCR, and western blotting. Cytotoxicity was assessed in several different cell lines by measurement of tumor cell growth, propidium iodide uptake, and nuclear apoptosis. The in vivo activity of oligonucleotide 4625 was determined by the inhibition of growth of established tumor xenografts in nude mice, immunohistochemical staining of Bcl-2 and Bcl-x proteins in the tumors, and western blotting of tumor lysates. Apoptosis in tumor xenografts was detected with the use of in situ TUNEL (i.e., terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick end labeling) staining. All statistical tests are two-sided. Results: In breast carcinoma cells, oligonucleotide 4625 treatment reduced bcl-2 and bcl-xL messenger RNA levels in a dose-dependent manner. At 600 nM, oligonucleotide 4625 reduced Bcl-2 and Bcl-xL protein levels to 25% (95% confidence interval [CI] = 16% to 34%) and 20% (95% CI = 14% to 26%), respectively, of the levels in untreated cells and it decreased viability in all cell lines mainly by inducing apoptosis. In vivo, oligonucleotide 4625 statistically significantly inhibited the growth of breast and colorectal carcinoma xenografts by 51% (95% CI = 28% to 74%) and 59% (95% CI = 44% to 74%), respectively, relative to those treated with control oligonucleotide 4626; it also reduced Bcl-2 and Bcl-xL protein levels and induced tumor cell apoptosis. Conclusion: The bcl-2/bcl-xL-bispecific antisense oligonucleotide 4625 merits further study as a novel compound for cancer therap

Capillary rarefaction during bed rest is proportionally less than fibre atrophy and loss of oxidative capacity

Background: Muscle disuse from bed rest or spaceflight results in losses in muscle mass, strength and oxidative capacity. Capillary rarefaction may contribute to muscle atrophy and the reduction in oxidative capacity during bed rest. Artificial gravity may attenuate the negative effects of long-term space missions or bed rest. The aim of the present study was to assess (1) the effects of bed rest on muscle fibre size, fibre type composition, capillarization and oxidative capacity in the vastus lateralis and soleus muscles after 6 and 55 days of bed rest and (2) the effectiveness of artificial gravity in mitigating bed-rest-induced detriments to these parameters. Methods: Nineteen participants were assigned to a control group (control, n = 6) or an intervention group undergoing 30 min of centrifugation (n = 13). All underwent 55 days of head-down tilt bed rest. Vastus lateralis and soleus biopsies were taken at baseline and after 6 and 55 days of bed rest. Fibre type composition, fibre cross-sectional area, capillarization indices and oxidative capacity were determined. Results: After just 6 days of bed rest, fibre atrophy (−23.2 ± 12.4%, P < 0.001) and reductions in capillary-to-fibre ratio (C:F; 1.97 ± 0.57 vs. 1.56 ± 0.41, P < 0.001) were proportional in both muscles as reflected by a maintained capillary density. Fibre atrophy proceeded at a much slower rate between 6 and 55 days of bed rest (−11.6 ± 12.1% of 6 days, P = 0.032) and was accompanied by a 19.1% reduction in succinate dehydrogenase stain optical density (P < 0.001), without any further significant decrements in C:F (1.56 ± 0.41 vs. 1.49 ± 0.37, P = 0.459). Consequently, after 55 days of bed rest, the capillary supply–oxidative capacity ratio of a fibre had increased by 41.9% (P < 0.001), indicating a capillarization in relative excess of oxidative capacity. Even though the heterogeneity of capillary spacing (LogRSD) was increased after 55 days by 12.7% (P = 0.004), tissue oxygenation at maximal oxygen consumption of the fibres was improved after 55 days bed rest. Daily centrifugation failed to blunt the bed-rest-induced reductions in fibre size and oxidative capacity and capillary rarefaction. Conclusions: The relationship between fibre size and oxidative capacity with the capillary supply of a fibre is uncoupled during prolonged bed rest as reflected by a rapid loss of muscle mass and capillaries, followed at later stages by a more than proportional loss of mitochondria without further capillary loss. The resulting excessive capillary supply of the muscle after prolonged bed rest is advantageous for the delivery of substrates needed for subsequent muscle recovery

Cumulative Load of Depressive Symptoms Is Associated With Cortisol Awakening Response in Very Old Age.

This study examined links of cumulative and present depressive symptoms with present cortisol diurnal profiles in oldest-old adults. Five waves of data from 50 older adults (M age = 89.05 years; 64% women) who participated in the Australian Longitudinal Study of Ageing were used to combine 15 years of longitudinal data with seven cortisol samples per day over a one-week period. Findings revealed that individuals with more past depressive symptoms showed a lower cortisol awakening response (CAR). Interestingly, present depressive symptoms were not associated with the CAR. These findings inform our understanding of distal health factors in very old age

A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia

Metabolic reprogramming has emerged as a crucial regulator of immune cell activation, but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic, and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2-mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function

Altered mitochondrial metabolism in the insulin-resistant heart.

Obesity-induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA-induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.COST Action MitoEAGL