Alternative Fuels for Platelet Storage: A Metabolic Study

We have studied the metabolism of platelets in vitro using washed platelets. Oxygen uptake and fuel utilization were measured. It was found that glucose is never oxidized to any significant extent and is always converted to lactate, regardless of oxygen availability. Oxidative metabolism fuels 70-100% of the ATP turnover, and oxygen uptake is the same whether the platelet is consuming glucose, acetate or only an unidentified endogenous fuel. When acetate is the added fuel, no endogenous fuel is oxidized, whereas the addition of glucose results in sparing of only 8% of endogenous fuel. Preliminary storage experiments using plasma-free media show that an acetate-containing buffered salt solution provided excellent storage conditions and that a medium without any exogenous fuel is better than one containing glucose. Thus we conclude that a successful storage medium should contain minimal amounts of glucose, and an oxidizable fuel such as acetate, in order to supplement the endogenous one.     

Direct analyses of in vivo colony survival after single and fractionated doses of radiation.

Several methods are described for analysing the results of in vivo colony assays using the statistical procedure called maximum-likelihood analysis. The methods differ in the way in which they take into account possible sources of variability in the data. The methods described here for analysing microcolony data are direct methods, in that they use the observed colony counts rather than transformed (e.g. Poisson-corrected) data. Each method can be used to estimate the average number of surviving cells per tissue structure (e.g. per jejunal crypt) in a single dose group, together with 95% confidence intervals, or to fit cell-survival models to data from a range of dose groups (e.g. to obtain estimates of D0 or of the linear-quadratic parameters alpha and beta). Experimental microcolony data from murine jejunum, colon, and hair follicles irradiated in anagen (proliferative) or telogen (resting) phase have been analysed. Estimates of D0 have been derived from single-dose data and estimates of alpha, beta, and the initial number of clonogenic cells per structure have been derived from fractionation data. For hair follicles, the half-time of repair of sublethal radiation injury has also been derived from fractionation data.     

Exercise training and blood lipids in hyperlipidemic and normolipidemic adults: a meta-analysis of randomized, controlled trials.

OBJECTIVE: To determine the effectiveness of exercise training (aerobic and resistance) in modifying blood lipids, and to determine the most effective training programme with regard to duration, intensity and frequency for optimizing the blood lipid profile. DESIGN: Trials were identified by a systematic search of Medline, Embase, Science Citation Index (SCI), published reviews and the references of relevant trials. The inclusion criteria were limited to randomized, controlled trials of aerobic and resistance exercise training which were conducted over a minimum of four weeks and involved measurement of one or more of the following: total cholesterol (TC), high density lipoprotein (HIDL-C), low density lipoprotein (LDL-C) and triglycerides (TG). SUBJECTS: A total of 31 trials ( 1833 hyperlipidemic and normolipidemic participants) were included. RESULTS: Aerobic exercise training resulted in small but statistically significant decreases of 0.10 mmol/L (95% CI: 0.02, 0.18). 0.10 (95% CI: 0.02, 0.19), 0.08 mmol/L (95% CI: 0.02, 0.14), for TC, LDL-C, and TG, respectively, with an increase in HDL-C of 0.05 mmol/L (95% CI: 0.02, 0.08). Comparisons between the intensities of the aerobic exercise programmes produced inconsistent results; but more frequent exercise did not appear to result in greater improvements to the lipid profile than exercise three times per week. The evidence for the effect of resistance exercise training was inconclusive. CONCLUSIONS: Caution is required when drawing firm conclusions from this study given the significant heterogeneity with comparisons. However, the results appear to indicate that aerobic exercise training produced small but favourable modifications to blood lipids in previously sedentary adults.     

Dose fractionation and regeneration in radiotherapy for cancer of the oral cavity and oropharynx. Part 2. Normal tissue responses: acute and late effects

The early responses of normal tissues of the oral cavity and oropharynx in 498 patients, and the slowly-developing responses in 268 patients who survived a minimum of 18 months after radiotherapy for squamous cell carcinoma were analyzed. The severity of acute responses correlated with dose intensity. The incidence of severe late responses increased with increase in dose per fraction and was characterized by a low alpha/beta ratio. Severe late responses were significantly associated with severe acute responses independently of dose per fraction and total dose, and were also ameliorated slightly by protraction of treatment time suggesting that some late effects were, at least partly, a consequence of acute injury. Probability of local tumor control correlated with severity of acute response, suggesting that excessive protraction of overall treatment time to minimize acute toxicity may compromise local control of the tumor. There was no demonstrable correlation between the volume of tissue irradiated and the severity of acute or late response.     

Cloning of the t(11;14)(q13;q32) translocation breakpoints from two human leukemia cell lines

The t(11;14)(q13;q32) translocation has been associated with several subtypes of human leukemia and lymphoma. It has been proposed that this translocation activates a proto-oncogene designated BCL1. In an effort to better understand the mechanism by which this translocation leads to malignancy, we have studied this translocation in two human cell lines. MO1094 and MO2058 were derived from patients with prolymphocytic variants of chronic lymphocytic leukemia. Southern blotting of the MO2058 cell line documented that the translocation linked the Jh region in the immunoglobulin heavy chain gene to the previously described BCL1 major translocation cluster (MTC). Using the polymerase chain reaction, we cloned this translocation and showed that the chromosome 11 breakpoint was within 7 bp of two other samples reported previously. Southern blotting of the MO1094 cell line suggested that the translocation in this cell line might link Jh sequences to a new region in the BCL1 locus on chromosome 11. Therefore, the MO1094 breakpoint was cloned from a genomic library. Comparison with normal cloned DNA from the BCL1 locus showed that the chromosome 11 breakpoint occurred 24 kb telomeric of the MTC. This work reinforces the concept that translocation breakpoints in the BCL1 locus are scattered over at least 63 kb.     

Inexpensive probes for the determination of body temperature.

Two-terminal integrated circuit temperature transducers (Analog Devices' AD 590) were used to fabricate skin and rectal probes for the monitoring of mean body temperature. They are inexpensive, robust, easily constructed and of low mass. The skin sensor system described is capable of being solidly attached regardless of the body contour such that it remains integral throughout profuse sweating and vigorous movement. Both types of probe are stable, accurate to within +/- 0.05 degree C over the physiological range of measurement and exhibit 100% response times of approximately 60 s to a square wave stimulus of 10 degrees C.     

Lymphoceles: imaging characteristics and percutaneous management

Twenty-five patients who had lymphoceles underwent sectional imaging and interventional radiologic procedures. Viewed using sonography, lymphoceles were hypoechoic to anechoic, occasionally with internal septa and debris. Low numbers (occasionally negative values) were observed using computed tomography (CT); these numbers strongly suggest the diagnosis of lymphocele. Calcification was observed on CT images of one patient. Diagnostic aspiration revealed tan to yellow fluid containing many lymphocytes; pathognomonic fat globules were observed in four cases. Malignant cells were found in two collections, an unusual occurrence. Therapeutic needle aspiration and short-term catheter drainage were usually unsuccessful (only one of five patients [20%] was cured). Long-term (1-5-week) catheter drainage cured 11 of 14 patients (78.6%). Sclerosing agents may have been beneficial for lymphocele obliteration in three of four patients. For most patients, lymphoceles may be diagnosed and treated successfully using radiologic means.     

N-alkyl urea hydroxamic acids as a new class of peptide deformylase inhibitors with antibacterial activity

Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P(1)' site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors with N-alkyl urea at the P(1)' site. Compounds with MICs of 200 micro M for matrilysin and other mammalian metalloproteases. Structure-activity relationship analysis identified preferred substitutions resulting in improved potency and decreased cytotoxity. One of the compounds (VRC4307) was cocrystallized with PDF, and the enzyme-inhibitor structure was determined at a resolution of 1.7 A. This structural information indicated that the urea compounds adopt a binding position similar to that previously determined for succinate hydroxamates. Two compounds, VRC4232 and VRC4307, displayed in vivo efficacy in a mouse protection assay, with 50% protective doses of 30.8 and 17.9 mg/kg of body weight, respectively. These N-alkyl urea hydroxamic acids provide a starting point for identifying new PDF inhibitors that can serve as antimicrobial agents.