The importance of drug safety and tolerability in the development of new immunosuppressive therapy for transplant recipients: The Transplant Therapeutics Consortium's position statement

The Transplant Therapeutics Consortium (TTC) is a public‐private partnership between the US Food and Drug Administration and the transplantation community including the transplantation societies and members of the biopharmaceutical industry. The TTC was formed to accelerate the process of developing new medical products for transplant patients. The initial goals of this collaboration are the following: (a) To define which aspects of the kidney transplant drug‐development process have clear needs for improvement from an industry and regulatory perspective; (b) to define which of the unmet needs in the process could be positively impacted through the development of specific drug‐development tools based on available data; and (c) to determine the most appropriate pathway to achieve regulatory acceptance of the proposed process‐accelerating tools. The TTC has identified 2 major areas of emphasis: new biomarkers or endpoints for determining the efficacy of new therapies and new tools to assess the safety or tolerability of new therapies. This article presents the rationale and planned approach to develop new tools to assess safety and tolerability of therapies for transplant patients. We also discuss how similar efforts might support the continued development of patient‐reported outcome measures in the future.     

Hereditary coproporphyria and epilepsy

A 9-year-old boy with mental deterioration and epilepsy suffered an acute attack of hereditary coproporphyria associated with worsening of seizure control. Leucocyte coproporphyrinogen oxidase activity was undetectable in the patient during this attack, and was reduced in his mother, a latent case. The complex relationship between porphyria, epilepsy, and anticonvulsant drugs is discussed.     

Gamma-interferon in aplastic anemia: inability to detect significant levels in sera or demonstrate hematopoietic suppressing activity

A radioimmunoassay (RIA) was used to quantitate biologically active gamma interferon (INF-gamma) in sera and in supernatants of cultured mononuclear cells obtained from 50 patients with aplastic anemia. Only five of the 50 serum samples had INF-gamma levels above background (greater than 0 less than 0.5 units per mL). Detectable levels of spontaneous INF-gamma (0.3 to 868 U/mL) were found in 18 of the 50 mononuclear cell supernatants tested. The addition of patient sera or INF-gamma positive supernatants to cultures of normal hematopoietic colonies did not result in reduced colony growth. Flow cytofluorimetric analysis of mononuclear cells failed to establish a correlation between the presence of INF-gamma in supernatants and the number of activated T cells or natural killer (NK) cells in the mononuclear cell population. However, a significant correlation did exist between the presence of monocytes and the production of INF-gamma. Contrary to previous reports, our data suggest that patients with aplastic anemia do not have high circulating levels of INF-gamma. Unstimulated mononuclear cells from some patients will produce significant levels of INF-gamma, but this does not result in decreased in vitro hematopoiesis.     

Acquired malposition of the colon and gallbladder in patients with cirrhosis: CT findings and clinical implications

Topographic relationships among the gallbladder, liver, hepatic flexure of the colon, right hemidiaphragm, and anterolateral peritoneal reflection were evaluated with computed tomography in 75 patients with biopsy-proved cirrhosis and in 200 control subjects to determine the effect of cirrhotic liver morphology on the anatomy of the right upper quadrant of the abdomen. Interposition of the colon between the liver and anterolateral abdominal wall and/or diaphragm was seen in 18 of the 75 (24%) cirrhotic patients and in six of the 200 (3%) control subjects. There was a strong correlation among gallbladder malposition, colonic interposition, and a ratio of transverse caudate lobe width to right lobe width (C/RL) exceeding 0.60. Patients with cirrhosis, colonic interposition, and gallbladder malposition had a mean C/RL of 0.62, compared with a mean of 0.50 for cirrhotic patients without interposition (P less than .0001). The mean C/RL for control subjects without interposition was 0.43, as compared with 0.69 for control subjects with interposition (P less than .01). These acquired malpositions of the colon and gallbladder may pose a diagnostic dilemma and increase the risk of inadvertent injury during percutaneous liver biopsy, interventional biliary tract procedures, and laparotomy.     

Normal instability of the hip in the neonate: US standards

In recent years, the use of real-time ultrasonography (US) has enabled dynamic evaluation of the infant hip through a range of motion and stress. Preliminary experience has suggested that a certain amount of instability in the hips of newborns is normal, but no standards have been established. In this study, a group of term neonates whose physical examinations were normal were examined with US on the 1st and 2d days of life. Each hip was imaged in the transverse plane in nonstressed and stressed positions, and movement of the femoral head under stress was quantitated. This displacement under stress was used to establish a normal range of hip instability in neonates. Patterns of hip laxity in boys and girls are identical, and in most infants hip instability diminishes between the 1st and 2d days of life. Our method of quantitating hip instability produces consistent results, with intraobserver 95% confidence intervals of +/- 1.2 mm for each measurement.     

兔膝关节软骨表面形态在短时非周期大强度运动训练后的变化

目的:观察正常软骨表面的形态结构以及短时非周期大强度运动训练对关节软骨的影响。方法:实验于2001-01/09在四川省骨科医院完成。①实验动物:10～12个月龄日本大耳白兔8只,雌雄各半,体质量(3.5±0.2)kg。②实验分组:将动物分为对照组2只,训练组6只,其中训练1,2,3周各2只。③实验干预:训练组兔在电刺激笼中进行训练,训练量为20s刺激1次,刺激时间为0.2～0.5s,动物受刺激后沿刺激笼跑跳数步并转弯。训练120min/d,每组训练60min后休息20min,训练6d/周,星期日休息,分别训练1,2,3周。对照组不放在电刺激笼中,也不进行训练。④实验评估:扫描电子显微镜下观察训练前后兔股骨和胫骨髁软骨表面形态结构的变化;MIAS99图形处理软件计算浅坑(pits)的直径和面积。结果:8只兔均进入结果分析。①正常兔膝关节软骨的表面形态结构:正常软骨表面低倍镜下显示为均匀排列的浅坑,在高倍镜下呈现一种均匀多孔状结构。②运动训练后软骨表面结构的变化:训练后浅坑形态不规则,边缘粗糙,胶原纤维增粗,孔隙不均匀增大。结论:软骨表面正常的形态结构是浅坑,短时非周期大强度训练,未引起纤维断裂和碎屑,说明不会损伤软骨表面形态结构。     

正常兔膝关节表面结构的扫描电镜观察

目的:扫描电镜观察正常兔膝关节表面的结构,为研究关节软骨表面结构提供正常参照。方法:实验于2001-01/09在四川省骨科医院完成。日本大耳白兔8只,10～12个月龄,雌雄各半,体质量(3.5±0.2)kg。通过扫描电镜对8只实验兔股骨髁、胫骨髁的软骨表面进行观察,其中4个髁用锐器划伤。结果:纳入日本大耳白兔8只,均进入结果分析。每个正常髁的表面都显示有大量的浅坑,有锐器划伤的髁则出现了垄沟及隆突。软骨表面在高倍镜下呈现一种均匀多孔状结构。结论:软骨表面唯一呈现的结构是浅坑,垄沟和隆突可能是标本的采集、制作过程中形成的赝象。     

Defective Translocation of PKCε in EtOH‐Induced Inhibition of Mg2+ Accumulation in Rat Hepatocytes

Background: Rats chronically fed ethanol for 3 weeks presented a marked decreased in total hepatic Mg²⁺ content and required approximately 12 days to restore Mg²⁺ homeostasis upon ethanol withdrawal. This study was aimed at investigating the mechanisms responsible for the EtOH‐induced delay. Methods: Hepatocytes from rats fed ethanol for 3 weeks (Lieber‐De Carli diet—chronic model), rats re‐fed a control diet for varying periods of time following ethanol withdrawal, and age‐matched control rats fed a liquid or a pellet diet were used. As acute models, hepatocytes from control animals or HepG2 cells were exposed to varying doses of ethanol in vitro for 8 minutes. Results: Hepatocytes from ethanol‐fed rats presented a marked inhibition of Mg²⁺ accumulation and a defective translocation of PKCε to the cell membrane. Upon ethanol withdrawal, 12 days were necessary for PKCε translocation and Mg²⁺ accumulation to return to normal levels. Exposure of control hepatocytes or HepG2 cells to a dose of ethanol as low as 0.01% for 8 minutes was already sufficient to inhibit Mg²⁺ accumulation and PKCε translocation for more than 60 minutes. Also in this model, recovery of Mg²⁺ accumulation was associated with restoration of PKCε translocation. The use of specific antisense in HepG2 cells confirmed the involvement of PKCε in modulating Mg²⁺ accumulation. Conclusions: Translocation of PKCε isoform to the hepatocyte membrane is essential for Mg²⁺ accumulation to occur. Both acute and chronic ethanol administrations inhibit Mg²⁺ accumulation by specifically altering PKCε translocation to the cell membrane.