Early death during chemotherapy in patients with small-cell lung cancer: derivation of a prognostic index for toxic death and progression.
Based on an increased frequency of early death (death within the first treatment cycle) in our two latest randomized trials of combination chemotherapy in small-cell lung cancer (SCLC), we wanted to identify patients at risk of early non-toxic death (ENTD) and early toxic death (ETD). Data were stored in a database and logistic regression analyses were performed to identify predictive factors for early death. During the first cycle, 118 out of 937 patients (12.6%) died. In 38 patients (4%), the cause of death was sepsis. Significant risk factors were age, performance status (PS), lactate dehydrogenase (LDH) and treatment with epipodophyllotoxins and platinum in the first cycle (EP). Risk factors for ENTD were age, PS and LDH. Extensive stage had a hazard ratio of 1.9 (P = 0.07). Risk factors for ETD were EP, PS and LDH, whereas age and stage were not. For EP, the hazard ratio was as high as 6.7 (P = 0.0001). We introduced a simple prognostic algorithm including performance status, LDH and age. Using a prognostic algorithm to exclude poor-risk patients from trials, we could minimize early death, improve long-term survival and increase the survival differences between different regimens. We suggest that other groups evaluate our algorithm and exclude poor prognosis patients from trials of dose intensification. (+info)
Inhibition of doxorubicin toxicity in cultured neonatal mouse cardiomyocytes with elevated metallothionein levels.
Controversial results have been reported regarding whether metallothionein (MT) functions in doxorubicin (DOX) detoxification in the heart. To determine unequivocally the role of MT in cardiac protection against the toxicity of DOX, ventricular cardiomyocytes isolated from 1- to 3-day neonatal transgenic mice with high levels of cardiac MT and from nontransgenic control animals were applied. On the 6th day of culturing, MT concentrations in the transgenic cardiomyocytes were about 2-fold higher than those in the nontransgenic cells. DOX was added directly into the cultures. Compared with nontransgenic controls, transgenic cardiomyocytes displayed a significant (p <.05) resistance to DOX cytotoxicity, as measured by morphological alterations, cell viability, and lactate dehydrogenase leakage from the cells. This cytoprotective effect of MT correlated with its inhibition of DOX-induced lipid peroxidation. These observations demonstrate unequivocally that elevation of MT concentrations in the cardiomyocytes of 2-fold higher than normal provides efficient protection against DOX toxicity. (+info)
Evolutionary analysis of TATA-less proximal promoter function.
Many molecular studies describe how components of the proximal promoter affect transcriptional processes. However, these studies do not account for the likely effects of distant enhancers or chromatin structure, and thus it is difficult to conclude that the sequence variation in proximal promoters acts to modulate transcription in the natural context of the whole genome. This problem, the biological importance of proximal promoter sequence variation, can be addressed using a combination of molecular and evolutionary analyses. Provided here are molecular and evolutionary analyses of the variation in promoter function and sequence within and between populations of Fundulus heteroclitus for the lactate dehydrogenase-B (Ldh-B) proximal promoter. Approximately one third of the Ldh-B proximal promoter contains interspersed regions that are functionally important: (1) they bind transcription factors in vivo, (2) they effect a change in transcription as assayed by transient transfection into two different fish cell lines, and (3) they bind purified transcription factors in vitro. Evolutionary analyses that compare sequence variation in these functional regions versus the nonfunctional regions indicate that the changes in the Ldh-B proximal promoter sequences are due to directional selection. Thus, the Ldh-B proximal promoter sequence variations that affect transcriptional processes constitute a phenotypic change that is subject to natural selection, suggesting that proximal promoter sequence variation affects transcription in the natural context of the whole genome. (+info)
The use of variable lactate/malic dehydrogenase ratios to distinguish between progenitor cells of cartilage and bone in the embryonic chick.
The activities of LDH and MDH have been studied, both in differentiated cartilage and bone from the embryonic chick, and in the pool of mixed osteogenic and chondrogenic stem cells found on the quadratojugal, a membrane bone. In confirmation of the model proposed by Reddi & Huggins (1971) we found that the LDH/MDH ratio was greater than 1 in cartilage and less than 1 in bone. Furthermore we established, for the first time, that ratios occurred in the chondrogenic and osteogenic stem cells, similar to the ratios in their differentiated counterparts. Alteration in LDH/MDH resulted from variations in the level of LDH/mug protein. MDH/mug protein remained constant, even when LDH/MDH was changing. We interpret these results in terms of adaptation of chondrogenic progenitor cells for anaerobic metabolism and anticipate that our model will be applicable to other skeletal systems where stem cells are being studied. (+info)
Enrichment of canalicular membrane with cholesterol and sphingomyelin prevents bile salt-induced hepatic damage.
These studies were undertaken to characterize the role of plasma membrane cholesterol in canalicular secretory functions and hepatocyte integrity against intravenous taurocholate administration. Cholesterol and sphingomyelin concentrations and cholesterol/phospholipid ratios were significantly increased in canalicular membranes of diosgenin-fed rats, suggesting a more resistant structure against solubilization by taurocholate. During taurocholate infusion, control rats had significantly decreased bile flow, whereas diosgenin-fed animals maintained bile flow. Maximal cholesterol output increased by 176% in diosgenin-fed rats, suggesting an increased precursor pool of biliary cholesterol in these animals. Maximal phospholipid output only increased by 43% in diosgenin-fed rats, whereas bile salt output remained at control levels. The kinetics of glutamic oxalacetic transaminase, lactic dehydrogenase, and alkaline phosphatase activities in bile showed a significantly faster release in control than in diosgenin-fed rats. After 30 min of intravenous taurocholate infusion, necrotic hepatocytes were significantly increased in control animals. Preservation of bile secretory functions and hepatocellular cytoprotection by diosgenin against the intravenous infusion of toxic doses of taurocholate was associated with an increased concentration of cholesterol and sphingomyelin in the canalicular membrane. The increase of biliary cholesterol output induced by diosgenin was correlated to the enhanced concentration of cholesterol in the canalicular membrane. (+info)
Development of diving capacity in emperor penguins.
To compare the diving capacities of juvenile and adult emperor penguins Aptenodytes forsteri, and to determine the physiological variables underlying the diving ability of juveniles, we monitored diving activity in juvenile penguins fitted with satellite-linked time/depth recorders and examined developmental changes in body mass (Mb), hemoglobin concentration, myoglobin (Mb) content and muscle citrate synthase and lactate dehydrogenase activities. Diving depth, diving duration and time-at-depth histograms were obtained from two fledged juveniles during the first 2.5 months after their depature from the Cape Washingon colony in the Ross Sea, Antarctica. During this period, values of all three diving variables increased progressively. After 8-10 weeks at sea, 24-41 % of transmitted maximum diving depths were between 80 and 200 m. Although most dives lasted less than 2 min during the 2 month period, 8-25 % of transmitted dives in the last 2 weeks lasted 2-4 min. These values are lower than those previously recorded in adults during foraging trips. Of the physiological variables examined during chick and juvenile development, only Mb and Mb content did not approach adult values. In both near-fledge chicks and juveniles, Mb was 50-60 % of adult values and Mb content was 24-31 % of adult values. This suggests that the increase in diving capacity of juveniles at sea will be most dependent on changes in these factors. (+info)
Protective effects of transient HO-1 overexpression on susceptibility to oxygen toxicity in lung cells.
Rat fetal lung cells (RFL-6) were transiently transfected with a full-length rat heme oxygenase (HO)-1 cDNA construct and then exposed to hyperoxia (95% O2-5% CO2) for 48 h. Total HO activity and HO-1 protein were measured as well as cell viability, lactate dehydrogenase (LDH) release, protein oxidation, lipid peroxidation, and total glutathione to measure oxidative injury. HO-1 overexpression resulted in increased total HO activity (2-fold), increased HO-1 protein (1.5-fold), and increased cell proliferation. Immunohistochemistry revealed perinuclear HO-1 localization, followed by migration to the nucleus by day 3. Decreased cell death, protein oxidation, and lipid peroxidation but increased LDH release and glutathione depletion were seen with HO-1 overexpression. Reactive iron content could not explain the apparent loss of cell membrane integrity. With the addition of tin mesoporphyrin, total HO activity was decreased and all changes in injury parameters were normalized to control values. We conclude that moderate overexpression of HO-1 is protective against oxidative injury, but we speculate that there is a beneficial threshold of HO-1 expression. (+info)
Comparison of a parasite lactate dehydrogenase-based immunochromatographic antigen detection assay (OptiMAL) with microscopy for the detection of malaria parasites in human blood samples.
Microscopic examination of blood smears remains the gold standard for malaria diagnosis, but is labor-intensive and requires skilled operators. Rapid dipstick technology provides a potential alternative. A study was conducted in The Gambia to compare the performance of OptiMAL, an immunochromatographic antigen detection assay for the diagnosis of malaria using parasite lactate dehydrogenase, against standard microscopy in patients with suspected malaria. For initial diagnosis of Plasmodium falciparum, irrespective of stage, this assay had a sensitivity of 91.3%, a specificity of 92%, a positive predictive value of 87.2%, and a negative predictive value of 94.7%. The sensitivity of the test decreased markedly at parasitemias < 0.01%. This assay can be used for the diagnosis of malaria in areas where microscopy is not available and for urgent malaria diagnosis at night and at weekends, when routine laboratories are closed and when relatively inexperienced microscopists may be on duty. (+info)