The sequential analysis of T lymphocyte subsets and interleukin-6 in polymyalgia rheumatica patients as predictors of disease remission and steroid withdrawal

CD4 and CD8 T lymphocyte subsets, the late T cell activation marker, HLA-DR, and serum interleukin-6 (IL-6) levels of 57 polymyalgia rheumatica (PMR) patients were followed over 2 yr to investigate whether they could be used to predict the safe withdrawal of steroid therapy. Cell phenotypes were studied by flow cytometry and IL-6 levels by ELISA. %CD8 cells were reduced below the normal range in PMR patients prior to steroid therapy. In 56% of patients, the %CD8 T lymphocytes failed to return to normal levels when quiescent disease allowed cessation of steroid therapy. Activated CD8 T cells, as detected by HLA-DR positivity, were above the normal range at the initiation of therapy and showed a negative correlation with %CD8 T cells. The serum concentration of IL-6 fluctuated over 24 months, and the correlation between IL-6 and erythrocyte sedimentation rate (ESR) seen prior to treatment was not seen at later intervals. The %CD8 T cell and serum IL-6 levels are not a good indicator of disease activity in PMR and are, therefore, unable to predict the safe withdrawal of steroids.      

High prevalence of nonsense, frame shift, and splice-site mutations in 16 patients with full-blown Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome (WAS) is a fully penetrant X-linked recessive disorder characterized by immunodeficiency, thrombocytopenia, and severe eczema. WAS is a life-threatening disease, with a poor quality of life and high mortality rate in childhood. The gene responsible for the disease has been localized to the proximal short arm of the X- chromosome and recently isolated through positional cloning and named WAS protein (WASP). We have characterized 17 WAS families. We have developed a rapid, nonradioactive screening protocol for identifying WASP gene alterations in genomic DNA. Our method allows simultaneous evaluation of single strand confirmation polymorphism and heteroduplex formation. We have identified 15 novel mutations that involve single basepair changes, or small insertions or deletions, all of which result in premature stop cordon, frame shift with secondary premature stop codon, or splice site defect. These studies document the considerable heterogeneity of the location of mutations in the WASP gene causing full-blown WAS and show the efficiency and rapidity of a screening approach for mutation identification in WAS that will be useful for carrier detection and prenatal diagnosis.     

成人脑死亡判定的循证医学指南更新——美国神经病学会质量标准分会报告

目的就如下问题对美国神经病学会1995年脑死亡判定实践标准进行更新：①符合脑死亡临床判定标准的患者神经功能能恢复吗？②确定患者神经功能永久性停止的恰当观察时间是多长？③有时可能观察到脑死亡患者的复合肢体运动,这是否错误地提示仍然保留脑功能？④何种技术手段判断呼吸停止是相对安全的？⑤是否存在新的辅助检测能准确判断患者脑死亡？方法系统回顾MEDLINE及EMBASE数据库1996年1月-2009年5月收录的文献,其研究仅限于成年人（≥18岁）。结果及建议对成年人,按照美国神经病学会于1995年确定的脑死亡判定实践标准,目前尚无判定为脑死亡患者出现神经功能恢复的报告。脑死亡患者可以存在复合的自发运动及假阳性触发呼吸机。目前还无足够的证据用以确定神经功能不可逆性停止的最短观察时间。通过氧扩散来确定呼吸停止是安全的,但目前还无足够证据确定呼吸停止检测技术的相对安全性。目前还无足够的证据确定新型辅助检测能否准确判断患者全脑功能已经停止。     

Endothelin-converting enzyme 1 promotes re-sensitization of neurokinin 1 receptor-dependent neurogenic inflammation

Background and purpose:

The metalloendopeptidase endothelin-converting enzyme 1 (ECE-1) is prominently expressed in the endothelium where it converts big endothelin to endothelin-1, a vasoconstrictor peptide. Although ECE-1 is found in endosomes in endothelial cells, the role of endosomal ECE-1 is unclear. ECE-1 degrades the pro-inflammatory neuropeptide substance P (SP) in endosomes to promote recycling and re-sensitization of its neurokinin 1 (NK₁) receptor. We investigated whether ECE-1 regulates NK₁ receptor re-sensitization and the pro-inflammatory effects of SP in the endothelium.

Experimental approach:

We examined ECE-1 expression, SP trafficking and NK₁ receptor re-sensitization in human microvascular endothelial cells (HMEC-1), and investigated re-sensitization of SP-induced plasma extravasation in rats.

Key results:

HMEC-1 expressed all four ECE-1 isoforms (a-d), and fluorescent SP trafficked to early endosomes containing ECE-1b/d. The ECE-1 inhibitor SM-19712 prevented re-sensitization of SP-induced Ca²⁺ signals in HMEC-1 cells. Immunoreactive ECE-1 and NK₁ receptors co-localized in microvascular endothelial cells in the rat. SP-induced extravasation of Evans blue in the urinary bladder, skin and ears of the rat desensitized when the interval between two SP injections was 10 min, and re-sensitized after 480 min. SM-19712 inhibited this re-sensitization.

Conclusions and implications:

By degrading endocytosed SP, ECE-1 promotes the recycling and re-sensitization of NK₁ receptors in endothelial cells, and thereby induces re-sensitization of the pro-inflammatory effects of SP. Thus, ECE-1 inhibitors may ameliorate the pro-inflammatory actions of SP.     

LIVER RESECTION FOR METASTASES FROM COLORECTAL CANCER

Five percent of patients with liver secondaries from colorectal carcinoma are potentially resectable and several studies have demonstrated significantly improved survival following resection. Two hundred and ten patients operated for colorectal carcinoma were followed up. Computed tomography confirmed potentially resectable metastasis to the liver in 38. On exploration 18 patients who had 4 or less hepatic metastases and no extrahepatic disease, underwent resection of their secondaries. Fourteen were males and 4 females with a mean age of 43.5 (SD 13.6, range 18-72) years. Ten patients presented with synchronous liver metastasis and 8 had metachronous disease. There was no post-operative mortality. All 18 have been followed up. for a median period of 23.5 (range 12-38) months. Seven patients are alive and well with no evidence of recurrence at a median period of 28 months (survival 39%). Four are alive with local recurrence in the liver. Median time to recurrence was 22 months. Seven patients have died of disseminated disease. The disease free survival at 28 months is 39% and the overall survival 61%. A close follow-up protocol for all patient undergoing curative surgery for colorectal cancer is essential, if such patients are to be selected early.KEY WORDS: Colorectal cancer, Liver resection, Metastases     

Infection in diabetic osteoarthropathy: use of indium-labeled leukocytes for diagnosis

Indium-111 labeled leukocyte imaging was compared with three-phase skeletal scintigraphy as a means of determining whether osteomyelitis was complicating diabetic osteoarthropathy. Three-phase scintigraphy demonstrated increased activity in both infected and noninfected osteopathic bone, with a sensitivity of 75% and a specificity of 56% for osteomyelitis. Leukocyte imaging had the same sensitivity but was most helpful for excluding infection (specificity, 89%) when three-phase imaging could not. Abnormal leukocyte localization was seen at the primary site of infection in all cases within 4 hours after injection. Disadvantages of leukocyte imaging included long preparation time, low count rates resulting in poor spatial resolution, and absence of bone landmarks, which made it difficult to differentiate soft tissue from bone infection.     

Inhibition of 2-amino-3-methylimidazo[4,5-f]quinoline-DNA adducts by indole-3-carbinol: dose-response studies in the rat colon

Indole-3-carbinol (I3C) inhibits the formation of colonic aberrant crypt foci and DNA adducts in rats given heterocyclic amine colon carcinogens, such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Mechanism studies indicate that I3C induces cytochromes P4501A1 and 1A2 (CYP1A1 and CYP1A2), isozymes that respectively metabolize IQ via ring hydroxylation or activate the carcinogen by N-hydroxylation. The present study examined the dose-response for induction of CYP1A1 versus CYP1A2 by I3C, and compared the profiles of induction with the dose- response for inhibition of IQ-DNA adducts in the colon of the F344 rat. Dietary equivalent doses of I3C in the range 100-1000 p.p.m. increased in a dose-related manner both ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase (MROD) activities in the liver and colonic mucosa, and Western blots showed a corresponding induction of CYP1A1 and CYP1A2 proteins. However, dietary equivalent doses of I3C in the range 10-25 p.p.m. (i) reduced hepatic EROD and MROD activities and CYP1A protein levels compared with controls, (ii) increased the ratio of CYP1A2 versus CYP1A1, and (iii) activated IQ to a more potent mutagen when liver microsomes from rats given I3C were used for metabolic activation in the Salmonella assay. Rats given a single oral dose of I3C shortly before administering IQ (5 mg/kg body wt, p.o.) exhibited dose-related inhibition of colonic IQ-DNA adducts in the range 25-100 p.p.m. I3C, reaching 95% inhibition at doses > or = 100 p.p.m. I3C, but IQ-DNA adducts were elevated slightly at the lowest I3C dose as compared with the controls. The possible significance of the low versus high dose effects of I3C are discussed in the context of human dietary exposures to I3C and the reported chemopreventive mechanisms of I3C in vivo.