Current perspectives of catabolic mediators of cancer cachexia.

The development of cancer cachexia is perhaps the most common manifestation of advanced malignant diseases and has been recognized as a poor prognostic sign. The abnormalities associated with the condition include progressive weight loss, anorexia, asthenia, and anemia. The degree of cachexia is inversely correlated with the survival time of the patient and always implies a poor prognosis. Currently there is no established mechanism for cancer cachexia, but the severe metabolic disturbances and marked alterations in carbohydrate, lipid, and protein metabolism in the host finally lead to an increased energy deficiency. Weight loss, the key feature of cachexia, is due to a reduction of food intake, an increase in energy expenditure, or a combination of the two. A variety of changes in nutrient metabolism have been described in patients with cancer cachexia. Patients frequently exhibit a relative glucose intolerance and insulin resistance with increased activity of the Cori cycle. The cancer-bearing state affects protein synthesis and breakdown in different tissues of the body in a different manner. An acute-phase protein response can be presented in a significant proportion of patients with cancer with disease progression. A variety of proinflammatory cytokines appears to play a role in aspects of cachexia and a complex network of cytokines in combination with other factors might be involved. Aside from potential humoral mediators of cachexia, tumor-derived biologically active molecules have been reported recently.     

Collagen breakdown products and lung collagen metabolism: an in vitro study on fibroblast cultures.

BACKGROUND--In fibrotic diseases such as pulmonary fibrosis there is evidence suggesting enhanced synthesis and degradation of lung connective tissue components, including collagen. It has therefore been hypothesised that products of collagen degradation may have a role in the promotion of collagen deposition. In support of this hypothesis, it has recently been shown that intravenous injection of lung collagen degradation products in experimental animals stimulated collagen synthesis leading to increased collagen deposition and diffuse interstitial lung disease. METHODS--Rabbit and human fibroblast cultures from lung and skin were used as an in vitro model to study the responses of these cells to rabbit collagen degradation products. The effects of an acute exposure to collagen degradation products on synthesis of collagen and noncollagenous protein have been studied in confluent cultures by [3H]-proline incorporation. The effects of collagen degradation products on fibroblast proliferation and production of genetic types of collagen have also been investigated. RESULTS--The acute exposure of rabbit lung fibroblast cultures to collagen degradation products significantly increased collagen synthesis without affecting non-collagenous protein synthesis. This effect was dose related, specific for lung fibroblasts, and species specific. Collagen degradation products altered the rate of synthesis of genetic types of collagen with a consequent decrease of type III/I+III collagen ratio (0.26 (0.04) treated with collagen degradation products; 0.45 (0.02) controls). These effects occurred without the intervention of serum factors. In addition, collagen degradation products neither affected fibroblast proliferation nor selected specific clones emphasising one type of collagen. CONCLUSIONS--These results suggest that collagen degradation products can influence lung collagen metabolism by stimulating collagen synthesis. The regulation of collagen mass by collagen degradation products may be of importance in lung collagen homeostasis in vivo.     

Genetic variants of homocysteine metabolizing enzymes and the risk of coronary artery disease

It is unresolved whether elevated homocysteine in coronary artery disease (CAD) is the cause of arteriosclerosis or its consequence. In contrast, genetic variants of enzymes that metabolize homocysteine cannot be altered by arteriosclerosis. Consequently, their association with CAD would permit to imply causality. We modeled by regression analysis the effect of 11 variants in the methionine cycle upon CAD manifestation in 591 controls and 278 CAD patients. Among the examined variants only the carriership for the c.844ins68 in the cystathionine beta-synthase (CBS) gene was associated with a significantly lowered risk of CAD (OR=0.56; 95% CI=0.35-0.90 in the univariable, and OR=0.41, 95% CI=0.19-0.89 for obese people in the multivariable analysis, respectively). Healthy carriers of the c.844ins68 variant exhibited, compared to the wild type controls, significantly higher postload ratios of blood S-adenosylmethionine to S-adenosylhomocysteine (61.4 vs. 54.9, p=0.001) and of plasma total cysteine to homocysteine (8.6 vs. 7.3, p=0.004). The changes in these metabolites are compatible with an improved methylation status and with enhanced activity of homocysteine transsulfuration. In conclusion, the coincidence of clinical and biochemical effects of a common c.844ins68 CBS variant supports the hypothesis that compounds relating to homocysteine metabolism may play role in the development and/or progression of CAD.     

Non-linear cardiac output dynamics during ramp-incremental cycle ergometry

Published literature asserts that cardiac output (=O₂×1/C_(a-v)O₂) increases as a linear function of oxygen uptake with a slope of approximately 5–6 during constant work rate exercise. However, we have previously demonstrated that C_(a-v)O₂ has a linear relationship as a function of O₂ during progressively increasing work rate incremental exercise. Therefore, we hypothesized that may indeed have a non-linear relationship with respect to O₂ during incremental, non-steady state exercise. To investigate this hypothesis, we performed five maximal progressive work rate exercise studies in healthy human subjects. was determined every minute during exercise using measured breath-by-breath O₂, and arterial and pulmonary artery measurements of PO₂, hemoglobin saturation, and content. was plotted as a function of O₂ and the linear and non-linear (first order exponential and hyperbolic) fits determined for each subject. Tests for linearity were performed by assessing the significance of the quadratic terms added to the linear relation using least squares estimation in linear regression. Linearity was inadequate in all cases (group P<0.0001). We conclude that cardiac output is a non-linear function of O₂ during ramp-incremental exercise; the pattern of non-linearity suggests that while the kinetics of are faster than those of O₂ they progressively slow as work rate (and O₂) increases.     

Effects of isolated and combined exposures to whole-body vibration and noise on auditory-event related brain potentials and psychophysical assessment

Summary Auditory event-related brain potentials (ERP) in response to two different tone stimuli (1.1 kHz or 1 kHz, 80 dB, 50 ms; given by headphones at a regular interstimulus interval of 5 s with a probability distribution of 70:30) were recorded from 12 healthy male subjects (Ss) during four different conditions with two repetitions: A - 60 dBA white noise (wN), no wholebody vibration (WBV); B - 60 dBA wN plus sinusoidal WBV in the a_z-direction with a frequency of 2.01 Hz and acceleration of 2 m ·s^–2 root mean square; C - 80 dBA wN, no WBV; D - 80 dBA wN plus WBV. Each condition consisted of two runs of about 11 min interrupted by a break of 4 min. During the break with continuing exposure, but without auditory stimuli, Ss judged the difficulty of the tone-detection task and intensity of noise by means of cross-modality matching (CMM). Vibration-synchronous activity in the electrocardiogram was eliminated by a subtraction-technique. Noise caused an attenuation of the N1 and P2 amplitudes and prolongation of P3 latencies. The WBV did not cause systematic ERP effects. Condition B was associated with higher N1 and smaller P3 amplitudes. The factor condition had a significant effect on the peak latencies of P3 to target stimuli and the task difficulty judged by CMM. Both effects exhibited significant linear increases in the sequence of conditions A, B, C, D. For the evaluation of exposure conditions at work, it can be suggested that noise has a strong systematic effect which can be enhanced by WBV. The P3 latency is considered as an advantageous measure for the detection of objective effects of physical environmental factors, correlating with relevant subjective responses.