Defining Biochemical Cure After Low Dose Rate Prostate Brachytherapy: External Validation of 4-year Prostate-specific Antigen Nadir as a Predictor of 10- and 15-year Disease-free Survival.

AIMS: To externally validate a proposed biochemical definition of cure following low dose rate (LDR) brachytherapy for prostate cancer - 4-year post-implant prostate-specific antigen (PSA) ≤0.2 ng/ml - in a UK population, and report the long-term (10- and 15-year) outcomes for patients stratified by National Comprehensive Cancer Network (NCCN) risk groups, through analysis of a large, prospectively collected, single-centre database. MATERIALS AND METHODS: All patients treated with LDR brachytherapy for prostate cancer at a single UK centre between 2001 and November 2020 (n = 1142) were eligible; 632 patients met the inclusion criteria for the analysis. The primary end point was disease-free survival (DFS), defined as freedom from clinical, radiological or PSA progression requiring androgen deprivation therapy. Four-year PSA was categorised as ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml. Kaplan-Meier analysis to 15 years was undertaken for each group, and sensitivity and specificity of 4-year PSA as a surrogate for long-term cure were calculated. Kaplan-Meier analysis to 15 years was repeated, stratifying patients by NCCN risk groups. RESULTS: The median cohort age was 63 years; the median follow-up was 9.1 years (range 3.5-18.7). In total, 248 patients were available for analysis at year 10, 46 at year 15. Sixty-four patients (10.1%) relapsed during the study period. The 10-year DFS for 4-year PSA categories ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml (95% confidence intervals) were 97.5% (95.4-99.6), 89.0% (82.4-96.1), 81.5% (70.5-94.2) and 41.8% (29.7-58.9), respectively. The 10-year DFS results for NCCN low, favourable-intermediate and unfavourable-intermediate risk disease were 93.1% (89.6-96.7), 92.1% (87.6-96.9) and 75.9% (67.8-84.9), respectively. CONCLUSIONS: Patients with 4-year PSA ≤0.2 ng/ml may be considered cured, and could be discharged to general practitioner follow-up. LDR brachytherapy is an excellent treatment option for patients with low and favourable-intermediate risk prostate cancer, but those with unfavourable-intermediate risk disease should be considered for treatment intensification strategies.

The effects of static magnetic field on action potential propagation and excitation recovery in nerve.

Calculations using the Hodgkin-Huxley and one-dimensional cable equations have been performed to determine the expected sensitivity of conduction and refractoriness to changes in the time constant of sodium channel deactivation at negative potentials, as reported experimentally by Rosen (Bioelectromagnetics 24 (2003) 517) when voltage-gated sodium channels are exposed to a 125 mT static magnetic field. The predicted changes in speed of conduction and refractory period are very small.

Selenium supplementation for critically ill adults.

BACKGROUND: Selenium is a trace mineral essential to human health, which has an important role in the immune response, defence against tissue damage and thyroid function. Improving selenium status could help protect against overwhelming tissue damage and infection in critically ill adults. OBJECTIVES: This review assessed the effects of selenium supplementation including the selenium-containing compound, ebselen, on adults recovering from critical illness. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library, Issue 2, 2003), MEDLINE, (1966 to July 2003), EMBASE (1980 to Week 30 2003),CAB NAR (1973 to March 2003), BIOSIS (1985 to July 2003), CINAHL (1982 to July 2003), HEALTHSTAR (1975 to September 2002), Current Controlled Trials, and reference lists. We contacted investigators, and handsearched four journals. Date of the most recent search: December 2003. SELECTION CRITERIA: Randomized trials of selenium or ebselen supplementation by any route, in adults with critical illness (including burns, head injury, brain haemorrhage, cerebrovascular accident and surgery). DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. We sought additional information as required from trialists. We also undertook pooling of data for outcomes and selected exploratory analyses were undertaken. MAIN RESULTS: Seven randomized trials involving813participants were included. The quality of trials, as reported, was poor, particularly for allocation concealment. The availability of outcome data was limited and trials involving selenium supplementation, were small. Thus the results must be interpreted with caution. Because of heterogeneity, results are presented for the random effects models. Four selenium trials showed no statistically significant difference in mortality (relative risk (RR) 0.52, 95% confidence interval (CI) 0.20 to 1.34). Three trials of ebselen also showed no statistically significant difference in mortality (RR 0.83, 95% CI 0.51 to 1.35). One trial of selenium found no statistically significant difference between groups for participants developing infection (RR 1.33, 95% CI 0.55 to 3.24). Three trials of ebselen provided data for participants developing infections (pyrexia, respiratory infections or meningitis), which was not statistically significant (RR 0.60, 95% CI 0.36 to 1.02). No clear evidence emerged for the benefits of selenium or ebselen supplementation for the outcomes of days on a ventilator, length of intensive care unit stay, length of hospital stay or quality of life. REVIEWERS' CONCLUSIONS: There is insufficient evidence to recommend supplementation of critically ill patients with selenium or ebselen. Trials are required which overcome the defects of the reviewed studies, particularly inadequate size and methodology. This review will be updated when four ongoing trials are completed.

Isolation of translactone-containing triterpenes with thrombin inhibitory activities from the leaves of Lantana camara.

Methanolic extracts prepared from the leaves of Lantana camara have been found to inhibit human thrombin. An assay, in which thrombin activity is measured as a function of clot formation from fibrinogen, was used to guide the fractionation and purification of five principal active constituents (1-5), which were all characterized as 5,5-trans-fused cyclic lactone-containing euphane triterpenes.

The effect of divergent selection for total plasma phosphorus in Japanese quail on fearfulness and selected blood and heart parameters.

A selection experiment utilizing Japanese quail was initiated to study the genetic relationship of growth and reproduction traits. In this study, lines were selected for increased (HP line) and decreased (LP line) total plasma phosphorus at the beginning of lay. The HP and LP lines were derived from a randombred control population (R1 line) that was maintained with the selected lines to remove environmental variation over generations. During the course of selection, it was observed that blood from HP line females was more viscous than that of the LP and R1 females. In later generations of selection, mortality of females during a 120-d egg production period was higher in the HP line than in the LP and R1 lines. The purpose of this experiment was to identify possible factors contributing to the increased mortality in the HP line. Fearfulness, as measured by tonic immobility, was greater in the HP and LP lines than in the R1 line. Indirect blood pressure measurements were made near the beginning and near the end of the 120-d egg production period. No significant line differences were observed in either measurement. Weight of the heart at the end of the laying period was higher in the HP and LP lines than in the R1 line. Histological study of the hearts of the HP and R1 lines indicated significant increases in the HP line in collagen content of the coronary arteries and in myocardial fibrosis. The data suggest that the increased mortality of females of the HP line relative to the R1 line during the laying period may be related to increased fearfulness and changes in the coronary structure leading to heart abnormalities.

Divergent selection for body weight and yolk precursor in Coturnix coturnix japonica. 12. Heterosis in reciprocal crosses between divergently selected lines.

A selection experiment was started using Japanese quail to study the genetics of BW and plasma yolk precursor (measured by total plasma phosphorus; TPP). Lines were divergently selected for 4-wk BW (HW and LW) or plasma TPP (HP and LP). Sublines of HW were developed by continuing to select the males for increased 4-wk BW while selecting the females for increased (HW-HP line) or decreased (HW-LP line) TPP. The purpose of the present study was to determine the inheritance of traits associated with growth and reproduction in reciprocal crosses between the divergently selected lines and sublines. Reciprocal crosses were made between the HW and LW, HP and LP, and HW-HP and HW-LP lines. Traits measured included BW at various ages, age at sexual maturity, egg production, ovarian follicular development, egg weight, TPP, wet and dry liver weights, and occurrence of smooth muscle tumors in the ligaments of the oviduct. The HW line differed from the LW line in all traits measured except TPP and weight of smooth muscle tumors. No offspring were obtained from the HW x LW matings (male listed first). In the LW x HW cross, heterosis was negative for BW through sexual maturity and age at sexual maturity. Positive heterosis was observed for egg production, egg weight, and occurrence of smooth muscle tumors. Differences between the HP and LP lines were observed in the selected trait (TPP) and some correlated traits (BW at some ages, age at sexual maturity in females, egg production, and number and total weight of ovarian follicles). Positive heterosis in the HP and LP crosses was observed for BW, egg production, egg weight, and number of ovarian follicles whereas negative heterosis was observed for TPP and age at sexual maturity in females. The HW-HP and HW-LP lines differed in the selected traits and some correlated traits (egg weight and weights of the liver and smooth muscle tumors). Positive heterosis in the crosses was observed for BW, egg production, and liver weights whereas negative heterosis was evident for age at sexual maturity and TPP.

Modeling of internal pH, ion concentration, and bioenergetic changes during myocardial ischemia.

Arrhythmias are caused by the interdependent processes of change in energy metabolism and alterations in sarcolemmal ion gradients that occur during ischemia. Depletion of energy metabolites and increased proton concentrations in ischemic heart may underlie the observed phenomena of reduced contractile force and also of malignant ventricular arrhythmias that can lead to tachycardia and ventricular fibrillation. Recent advances in measuring changes in ion concentrations and metabolites during cardiac ischemia have provided a wealth of detail on the processes involved. Some of the experimental data have been used to construct a computer model that integrates cardiac energetics with electrophysiological changes. This is a novel approach to studying myocardial ischemia, and the resulting model would aid in the prediction of the effects of therapeutic interventions.

Divergent selection for body weight and yolk precursor in Coturnix coturnix japonica. 11. Correlated responses over thirty generations.

Japanese quail lines were divergently selected for 4-wk BW (HW and LW lines) and plasma yolk precursor [total plasma phosphorus (TPP); HP and LP lines] for 30 generations. The base population was a randombred control line (R1) that was maintained along with the selected lines. Sublines were established from the ninth selected generation of HW by continuing to select males for increased 4-wk BW and selecting females for increased (HW-HP line) or decreased (HW-LP line) TPP. Correlated responses over the entire selection period were measured. Egg production of HW, LW, HP, and HW-HP declined over generations. There was positive quadratic component to the change in HW indicating that the change in egg production over generations was decreasing. There was no significant change in egg production of LP. Number of ovarian follicles in rapid development increased in LP and decreased in LW and HP. Total follicular weight increased in HW and LP and decreased in LW. Production of abnormal eggs increased over generations in HW and HW-HP. Body weight at the beginning and end of the laying period increased in HW, HW-HP, HW-LP, and LP and decreased in LW. Egg weight increased in HW HW-HP and decreased in LW and LP. The increase in egg weight of HW was due to a disproportionate increase in shell and yolk. Wet weight of the liver increased in HW and decreased in LW and HP. Dry liver weight decreased in LW, HP, and LP. Mortality to 4 wk of age increased in LW, HP, and LP.

Divergent selection for body weight and yolk precursor in Coturnix coturnix japonica. 10. Response to selection over thirty generations.

Japanese quail lines were divergently selected for 30 generations for 4-wk BW (HW, LW) or plasma yolk precursor (HP, LP) as measured by total plasma phosphorus (TPP) at the beginning of lay. The HW, LW, HP, and LP lines were initiated from a randombred control line (R1). In the ninth generation of selection in the HW line, sublines were developed by continuing to select males for increased 4-wk BW whereas females were selected for increased (HW-HP line) or decreased (HW-LP) TPP. Individual selection was used in the HW, LW, HW-HP, and HW-LP lines. In the HP and LP lines, females were individually selected whereas males were selected on their full-sisters' performance. Realized heritabilities (h2), based on the linear regression of selection responses (corrected for environmental changes) on accumulated selection differentials (weighted for the number of offspring produced) over generations, declined with selection in the HW, LW, HP, and LP lines. The h2 of 4-wk BW in the HW line was 0.42 during the first 10 generations of selection and then declined to 0.30 during the next 2 generations of selection. In the LW line, realized h2 of 4-wk BW was 0.40, 0.16, and -0.12 in Generations 1 through 10, 11 through 20, and 21 through 30, respectively. The respective h2 for TPP in the HP line were 0.29, 0.17, and 0.14. The h2 of TPP in the LP line was 0.35 during the first 10 generations and essentially zero during the next 20 generations. Four-week BW and TPP were negatively associated in the HW, HP, and LP lines. There was no significant relationship between these two traits in the LW line.

The influence of dietary creatine supplementation on performance during repeated bouts of maximal isokinetic cycling in man.

The effect of dietary creatine (Cr) supplementation on performance during 3, 30 s bouts maximal isokinetic cycling and on plasma ammonia and blood lactate accumulation during exercise was investigated. Placebo (P) ingestion had no effect on peak power output (PPO), mean power output (MPO) and total work output during each bout of exercise. Cr ingestion (4 x 5 g.day-1 for 5 days) significantly increased PPO in exercise bout 1 (p < 0.05) and MPO and total work output in exercise bouts 1 (p < 0.05, p < 0.05, respectively) and 2 (p < 0.05, p < 0.05, respectively). Cr ingestion had no effect on any of the measures of performance during exercise bout 3. No difference was observed in peak plasma ammonia accumulation before (146 + 30 mumol.l-1) and after (122 +/- 17 mumol.l-1) P ingestion, however the corresponding concentration was lower following Cr ingestion (129 +/- 22 mumol.l-1) compared with before Cr ingestion (160 +/- 18 mumol.l-1, p < 0.05), despite subjects performing more work. No difference in peak blood lactate accumulation was observed before and after P or Cr ingestion. The results demonstrate that Cr ingestion can increase whole body exercise performance during the initial two, but not a third, successive bout of maximal exercise lasting 30 s. The lower accumulation of plasma ammonia under these conditions suggests this response is achieved by an effect on muscle ATP turnover.

Discrimination of transiently applied mechanical loads: breathing vs. pulling.

Two groups of 24 subjects each attempted to discriminate between large elastic and resistive loads during 50 randomized presentations of each load. Breathers inspired from the loads through a J valve, whereas pullers reciprocally stroked the plunger of a 2-liter syringe connected to the J valve. A range of load durations was obtained in each subject by prematurely unloading approximately one-half of the trials at graded times from their onset. Breathers produced random discrimination scores [50.8 +/- 2.5% (SE) correct] when loaded inspirations were shorter than unloaded inspirations [trials in which both loads induced equal airway pressure (and probably respiratory muscle tension) waveforms] and nonrandom discrimination scores (65.7 +/- 2.8% correct) when loaded inspirations were longer than unloaded inspirations (trials in which both loads induced different waveforms). In contrast, pullers produced nonrandom discrimination scores (62.2 +/- 2.9% correct) when loaded airflow durations were shorter than unloaded inspirations [trials in which both loads induced equal line pressure (and therefore limb muscle tension) waveforms]. Supplemental audio feedback related to instantaneous airflow (an expression of movement) improved load perception in breathers (to 64.2 +/- 3.0% correct; P < 0.01), indicating that airflow feedback introduced load-specific information that was lacking during breathing but redundant during pulling. In support of this hypothesis, airflow feedback by itself enabled a third group of listeners to identify load type with equal accuracy as pullers but with greater accuracy than breathers. These findings suggest that 1) uniformed subjects rely heavily on feedback from airway pressure and/or muscle tension receptors to perceive added loads to breathing and 2) limb mechanoreceptors provide a more sensitive appreciation of movement than do respiratory mechanoreceptors.

The interaction of ouabain and salicylate on sheep cardiac muscle.

1. The action potential duration in sheep ventricular fibres is rapidly diminished on exposure to 10(-6) M-ouabain. However, if 10--20 mM-sodium salicylate is added to the ouabain solution, glycoside-induced shortening is prevented, and a substantial increase in duration then occurs. Sodium salicylate also reverses the shortening effect of ouabain if applied after the glycoside has been allowed to act alone. 2. Sodium salicylate alone produces a much smaller prolongation than in the presence of ouabain. Alone and in the presence of ouabain it eventually increases the threshold and produces inexcitability. 3. Three other surface charge agents have been compared with salicylate: aminonaphthalene sulphonate, sodium dodecylsulphate and salicylamide, were unable to counter the actions of ouabain at the concentrations used. Since they also produced no changes in excitability it is likely that they did not bind significantly to the cell membrane. 4. In Purkinje fibres the reversal potential for the pacemaker current, iK2, is initially shifted in a negative direction in the presence of 10(-6) M-ouabain and 10 mM-salicylate instead of the positive shift expected with ouabain alone at this concentration. 5. In guinea-pig ventricle, salicylate alone reduces the duration of the action potential. This effect is rapidly reversible. Toxic levels of ouabain also reduce the action potential duration but this effect takes several hours to reverse. By contrast, the effects of salicylate and ouabain applied together are readily reversible. 6. It is suggested that the mechanism of these effects may depend on the ability of a surface negative charge agent like salicylate to increase the surface K+ concentration at the membrane and so protect the sodium-potassium pump from inhibition by large doses of ouabain.