Redox active or thiol reactive? Optimization of rapid screens to identify less evident nuisance compounds

Compounds that exhibit assay interference or undesirable mechanisms of bioactivity are routinely encountered in assays at various stages of drug discovery. We observed that assays for the investigation of thiol-reactive and redox-active compounds have not been collected in a comprehensive review. Here, we review these assays and subject them to experimental optimization to improve their reliability. We demonstrate the usefulness of our assay cascade by assaying a library of bioactive compounds, chemical probes, and a set of approved drugs. These high-throughput assays should complement the array of wet-lab and in silico assays during the initial stages of hit discovery campaigns to pursue only hit compounds with tractable mechanisms of action.     

Steady state of gradient echo sequences with radiofrequency phase cycling: Analytical solution,contrast enhancement with partial spoiling

Spoiled gradient echo sequences can only reach a homogeneous steady state if sufficiently strong crusher gradients are used in combination with RF phase cycling (RF spoiling). However, the signal depends quite sensitively on the chosen phase increment ? and—lacking analytical solutions—numerical simulations must be used to study the transient and steady‐state magnetization. For the steady state an exact analytical solution is derived, which holds for arbitrary sequence and tissue parameters. Besides a considerably improved computation performance, the analytical approach enables a better understanding of the complicated dependence on ?. For short repetition times (TR) the regime of small ? turns out to be particularly interesting: It is shown that the typical ?_c, where RF spoiling starts to become effective, is essentially inversely proportional to T₂. This tissue dependence implies that contrasts can be considerably larger with partial spoiling (? ≈ ?_c) than with conventional RF spoiling (? ? ?_c). As an example, the uptake of contrast agents in tissues is investigated. For typical parameters a considerably improved contrast enhancement can be obtained, both theoretically and experimentally. Magn Reson Med, 2006. © 2005 Wiley‐Liss, Inc.     

Chronic peritoneal dialysis in paediatrics: Experience of a national registry

The results of the first 3 year' collaboration of the Italian Registry of Paediatric Chronic Peritoneal Dialysis (CPD) (1986–1988) are presented. This Registry acquired data on the majority of the paediatric patients treated with CPD in Italy, thus providing a national picture in a field where few nationwide surveys are available. Patients of less than 15 years of age at the start of dialysis were enrolled and clinical data collected until the age of 19 years. The number of nephrological paediatric centres participating in the Registry increased from 7 in 1986 to 11 in 1988. The total number of patients on CPD was 70 and the percentage of dialysed children treated with CPD ranged from 40.2% to 43.6%. Data on 89 peritoneal catheters were collected: during 1417 dialysis-months 70 catheter-related complications were observed (1:20.8 dialysis-months); actuarial catheter survival was 92.7% at 6 months, 84.8% at 1 year and 68.8% at 2 years. The incidence of peritonitis changed from 1 episode every 10.9 patient-months in 1986 to 1 every 19.8 in 1988. Abdominal hernias were the other main clinical complication observed. The survival of patients was 92.5% at 3 years, while the technique survival at the same time was 84%.     

有训练者和无训练者的心功能和无氧阈的关系

本文观察了10名游泳运动员和10名实验室工作人员在递增负荷运动中心功能的变化及其与无氧阈的关系.结果为:(1)游泳队员的无氧阈值明显高于无训练的实验室工作人员;(2)运动中每搏量稳定时的强度与无氧阈强度是密切相关的;(3)运动至无氧阈强度以后,心输出量的增加主要靠心率的增加来维持;(4)无训练者在运动一开始就动用心力储备,增加心率和每搏量,而游泳队员则在运动至40W以后才开始增加心率和每搏量.这些结果表明,无氧阈与心功能具有很密切的关系,可用它来反映心功能的好坏.     

Secondary reconstruction of the short philtrum in the bilateral cleft deformity

Summary This technique for reconstruction of the short philtrum requires an understanding of the viscoelastic properties of the skin and how to use these to increase skin dimensions. This is combined with contouring and splinting with a subcutaneous cartilage graft. Three representative cases are presented to illustrate the method to achieve an aesthetically acceptable lip and its long-term follow-up. No complications have been encountered using this over a 15-year period. The technique can be combined with other secondary reconstructive procedures on the lip and palate. Work completed at: Providence Hospital, 16001 West Nine Mile Road, P.O. Box 2043, Southfield, Michigan 48037, USA     

Developmental aspects of children's behavior and safety while cycling

OBJECTIVE: To examine children's competence while cycling, as demonstrated in mistakes in performance and failure to comply with safety rules. METHODS: Children in three age groups (8, 10, and 12 years) participated in a realistic yet simulated traffic environment. RESULTS: The boys' cycling speed increased steadily with age, while that of the girls increased from 8 to 10 but decreased at age 12. Most children had adequate motor control by age 10, and the youngest compensated for their less developed skills by cycling slowly and braking early at junctions. Serious mistakes, often related to the children's age and gender, consisted of the children failing to stop at signals or stopping too late, especially at short stopping range. CONCLUSIONS: There are considerable individual differences in children's cycling competence that are related to biological factors, such as age and gender, and psychological factors, such as rule compliance and choice of cycling speed.     

Effects of active recovery on power output during repeated maximal sprint cycling

The effects of active recovery on metabolic and cardiorespiratory responses and power output were examined during repeated sprints. Male subjects (n = 13) performed two maximal 30-s cycle ergometer sprints, 4 min apart, on two separate occasions with either an active [cycling at 40 (1)% of maximal oxygen uptake; mean (SEM)] or passive recovery. Active recovery resulted in a significantly higher mean power output ( ) during sprint 2, compared with passive recovery [ ] 603 (17) W and 589 (15) W, P < 0.05]. This improvement was totally attributed to a 3.1 (1.0)% higher power generation during the initial 10 s of sprint 2 following the active recovery (P < 0.05), since power output during the last 20 s sprint 2 was the same after both recoveries. Despite the higher power output during sprint 2 after active recovery, no differences were observed between conditions in venous blood lactate and pH, but peak plasma ammonia was significantly higher in the active recovery condition [205 (23) vs 170 (20) μmol · 1⁻¹;P < 0.05]. No differences were found between active and passive recovery in terms of changes in plasma volume or arterial blood pressure throughout the test. However, heart rate between the two 30-s sprints and oxygen uptake during the second sprint were higher for the active compared with passive recovery [148 (3) vs 130 (4) beats · min⁻¹;P < 0.01) and 3.3 (0.1) vs 2.8 (0.1) 1 · min⁻¹;P < 0.01]. These data suggest that recovery of power output during repeated sprint exercise is enhanced when low-intensity exercise is performed between sprints. The beneficial effects of an active recovery are possibly mediated by an increased blood flow to the previously exercised muscle.     

Energy cost and mechanical efficiency of riding a four-wheeled, human-powered, recumbent vehicle

Oxygen consumption at steady state (V˙O ₂, l · min⁻¹) and mechanical power (W˙, W) were measured in five subjects riding a human-powered vehicle (HPV, the Karbyk, a four-wheeled recumbent cycle) on a flat concrete road at constant sub-maximal speeds. The external mechanical work spent per unit of distance (W, J · m⁻¹), as calculated from the ratio of W˙ to the speed (v, m · s⁻¹), was found to increase with the square of v: W˙=8.12+(0.262 ·v ²) (r=0.986, n=31), where the first term represents the mechanical energy wasted, over a unit of distance, against frictional forces (rolling resistance, R_r), and the second term (k · v ²) is the work performed, per unit distance, to overcome the air drag. The rolling coefficient (C_r, obtained dividing R_r by m · g, where m is the overall mass and g is the acceleration of gravity) amounted to [mean (SD)] 0.0084 (0.0008), that is about 60% higher than that of a racing bicycle. The drag coefficient was calculated from the measured values of k, air density (ρ) and frontal area (A) [C_x=k · (0.5 · A · ρ)⁻¹], and amounted to 1.067 (0.029), that is about 20% higher than that of a racing bicycle. The energy cost of riding the HPV (C_k, J · m⁻¹) was measured from the ratio of metabolic power above rest (net V˙O ₂, expressed in J · s⁻¹) to the speed (v, m · s⁻¹); the value of this parameter increased with the square of v, as described by: C_k=61.45 + (0.675 · v ²) (r=0.711, n=23). The net mechanical efficiency (η) was calculated from the ratio of W to C_k: over the investigated speed range this turned out to be 0.22 (0.021). Best performance times (BPTs) of a “typical”élite athlete riding the Karbyk were calculated over the distances of 1, 5 and 10 km: these were about 8% longer than the BPTs calculated, on the same subjects, when riding a conventional racing bicycle. Accepted: 7 August 2000