Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome

The polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS) syndrome is a rare multisystem disorder of obscure pathogenesis associated with osteosclerotic myeloma. Circulating levels of proinflammatory cytokines (tumor necrosis factor-alpha (TNF-alpha) interleukin-1 beta [IL-1 beta], IL-2, IL-6, and interferon-gamma [IFN- gamma]), anti-inflammatory cytokines (transforming growth factor beta 1 [TGF beta 1], IL-4, IL-10, and IL-13), the cytokine carrier protein alpha 2 macroglobulin, IL-1 receptor antagonist (IL-1ra), soluble TNF receptors (sTNFr) p55 and p75, and soluble IL-6 receptor (sIL-6r) were determined in 15 patients with POEMS syndrome and 15 with multiple myeloma. Patients with POEMS syndrome had higher serum levels of IL-1 beta, TNF-alpha, and IL-6 and lower serum levels of TGF beta 1 than did patients with multiple myeloma. Serum levels of IL-2, IL-4, IL-10, IL- 13, IFN-gamma, alpha 2 macroglobulin, and sIL-6r were similar in both groups. IL-1ra and sTNFrs were increased in POEMS syndrome, but out of proportion to the increase of IL-1 beta and TNF-alpha. Serial evaluations in 1 patient showed that proinflammatory cytokine serum levels paralleled disease activity assessed by platelet count and neurologic involvement. Our results suggest that the manifestations of POEMS syndrome might be regarded as the result of a marked activation of the proinflammatory cytokine network (IL-1 beta, IL-6, and TNF- alpha) associated with a weak or even decreased (TGF beta 1) antagonistic reaction insufficient to counteract the noxious effects of cytokines.     

Tumor-specific, cytotoxic T-lymphocyte response after idiotype vaccination for B-cell, non-Hodgkin's lymphoma

Patients with non-Hodgkin's B-cell lymphoma who received an antitumor vaccine of idiotypic ig protein showed humoral and proliferative immune responses. Because immunity to some antigens, including tumor antigens and human pathogenic viruses, may be better correlated with the cytolytic cellular immune response, we evaluated 16 non-Hodgkin's lymphoma patients immunized with autologous idiotypic ig molecules for changes in tumor-specific cytotoxic T-lymphocyte precursor (CTLp) frequency using limiting dilution analysis. Eleven patients had a significant increase in tumor-specific CTLp. Eight of these 11 patients remain without evidence of disease or with stable minimal disease. In contrast, all five patients who did not have a significant change in tumor-specific CTLp have developed progressive disease. Patient vaccination with tumor associated protein antigens can increase tumor- specific CTLp frequencies. The correlation of increased tumor specific CTLp with freedom from progression is significant at P = .002. This study indicates that measurement of CTLp frequencies are relevant to the clinical evaluation of human tumor vaccines and suggests that cell- mediated cytolytic immune responses may be an important determinant of vaccine efficacy.     

Target setting in intensive insulin management is associated with metabolic control: the Hvidoere Childhood Diabetes Study Group Centre Differences Study 2005

Swift PGF, Skinner TC, de Beaufort CE, Cameron FJ, Åman J, Aanstoot H‐J, Castaño L, Chiarelli F, Daneman D, Danne T, Dorchy H, Hoey H, Kaprio EA, Kaufman F, Kocova M, Mortensen HB, Njølstad PR, Phillip M, Robertson KJ, Schoenle EJ, Urakami T, Vanelli M, Ackermann RW, Skovlund SE for the Hvidoere Study Group on Childhood Diabetes. Target setting in intensive insulin management is associated with metabolic control: the Hvidoere Childhood Diabetes Study Group Centre Differences Study 2005. Objective: To evaluate glycaemic targets set by diabetes teams, their perception by adolescents and parents, and their influence on metabolic control. Methods: Clinical data and questionnaires were completed by adolescents, parents/carers and diabetes teams in 21 international centres. HbA1c was measured centrally. Results: A total of 2062 adolescents completed questionnaires (age 14.4 ± 2.3 yr; diabetes duration 6.1 ± 3.5 yr). Mean HbA 1c = 8.2 ± 1.4% with significant differences between centres (F = 12.3; p < 0.001) range from 7.4 to 9.1%. There was a significant correlation between parent (r = 0.20) and adolescent (r = 0.21) reports of their perceived ideal HbA1c and their actual HbA1c result (p < 0.001), and a stronger association between parents' (r = 0.39) and adolescents' (r = 0.4) reports of the HbA1c they would be happy with and their actual HbA1c result. There were significant differences between centres on parent and adolescent reports of ideal and happy with HbA1c (8.1 < F > 17.4;p < 0.001). A lower target HbA1c and greater consistency between members of teams within centres were associated with lower centre HbA1c (F = 16.0; df = 15; p < 0.001). Conclusions: Clear and consistent setting of glycaemic targets by diabetes teams is strongly associated with HbA1c outcome in adolescents. Target setting appears to play a significant role in explaining the differences in metabolic outcomes between centres.     

Brain swelling and ischaemia in Kenyans with cerebral malaria

Computed tomography was performed on 14 unconscious Kenyan children recovering from cerebral malaria (seven of whom had another scan 12-120 days later) to elucidate the cause of intracranial hypertension and neurological sequelae. Brain swelling, defined as a loss of cerebrospinal fluid spaces, was documented in six children, while a further two had conspicuously small ventricles only. There was severe intracranial hypertension in the two children with definite brain swelling in whom intracranial pressure was monitored. There was no evidence of acute hydrocephalus or vasogenic oedema. Four children with brain swelling also had widespread low density areas suggestive of ischaemic damage. The patterns of damage were not uniform but were consistent with a critical reduction in cerebral perfusion pressure (which was documented in the two in whom this was monitored), hypoglycaemia, or status epilepticus. All four had serious neurological sequelae. These data suggest that brain injury in cerebral malaria may be due in part to secondary systemic and intracranial factors as well as to the direct effect of intravascular sequestration.     

甘草素与异甘草素的合成

甘草素与异甘草素的合成杨立，沈凤嘉（兰州大学化学系，兰州７３００００）甘草（Ｇｌｙｃｙｒｒｈｉｚａｕｒａｌｅｎｓｉｓｆｉｓｃｈ．）为我国一项宝贵的中药资源，历来受到人们重视。甘草素（ｌｉｑｕｉｒｉｔｉｇｅｎｉｎ）和异甘草素（ｉｓｏｌｉｑｕｉｒｉｔｉｇ...     

MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity

P-glycoprotein (PGP), the product of the multidrug resistance gene (MDR1), acts as an energy-dependent efflux pump that exports its substrates out of the cell. PGP expression is an important factor regulating absorption of a wide variety of medications. It has also been associated with intrinsic and acquired cross resistance to a number of structurally unrelated anticancer drugs. A single nucleotide polymorphism (SNP) in exon 26 of the MDR1 gene, C3435T, was recently correlated with PGP protein levels and substrate uptake. Individuals homozygous for the T allele have more than four-fold lower PGP expression compared with CC individuals. As overexpression of PGP has been associated with altered drug absorption, therapy-resistant malignancies, and lower concentrations of HIV-1 protease inhibitors, this SNP may provide a useful approach to individualize therapy. To facilitate clinical application throughout the world, 1280 subjects from 10 different ethnic groups were evaluated for this SNP using the polymerase chain reaction-restriction fragment length polymorphism assay and the genotype and allele frequency for each group were ascertained. Marked differences in genotype and allele frequency were apparent between the African populations and the Caucasian/Asian populations (P < 0.0001). The Ghanaian, Kenyan, African American and Sudanese populations studied had frequencies of 83%, 83%, 84% and 73%, respectively, for the C allele. The British Caucasian, Portuguese, South-west Asian, Chinese, Filipino and Saudi populations had lower frequencies of the C allele compared to the African group (48%, 43%, 34%, 53%, 59%, and 55%, respectively). The high frequency of the C allele in the African group implies overexpression of PGP and may have important therapeutic and prognostic implications for use of PGP dependent drugs in individuals of African origin.     

转化生长因子β与糖尿病性眼部并发症

目的:转化生长因子β是一类生物学功能复杂的细胞因子,与很多眼科疾病相关。综述其分子结构、受体和信号传导通路及其生物学功能,着重介绍转化生长因子β与眼病及糖尿病性眼部并发症的关系和作用。资料来源:应用计算机检索Medline,Pubmed and Springer databases 1990-01/2006-01相关转化生长因子β与眼部并发症的文献,检索词"transforming growth factor-β(TGF-β),ophthalmological disease,diabetic complication",限定文献语言种类为"English"。同时检索CNKI 1990-01/2006-01相关文献,检索词为"转化生长因子β,眼病,糖尿病并发症",限定语言种类为中文。资料选择:对资料进行初审,选取符合研究要求的有关文章找全文。纳入标准:①有关糖尿病性眼部并发症的研究。②有关转化生长因子β在眼科疾病的研究。排除标准:重复研究。资料提炼:共收集到156篇相关文献,纳入30篇符合标准的文献。资料综合:①转化生长因子β是一类人体大多数细胞都能分泌的细胞因子,其生物学功能复杂,表现的生物学效应与浓度、环境等因素密切相关,能导致多种组织发生异常改变。②眼部组织包括角膜上皮细胞、角膜内皮细胞、睫状体色素上皮细胞、晶状体上皮细胞及视网膜色素上皮细胞都能产生转化生长因子β,且有其受体表达,与多种眼部疾病有明确关系。③糖尿病是一种累及全身多器官的代谢异常疾病,在眼部主要是糖尿病性视网膜病变以及白内障等严重致盲性眼病。其病情发生、发展都具有独特特征,发病也可能存在与一般情况不同的机制。结论:转化生长因子β生物学功能复杂,在糖尿病主要致盲眼病(白内障和视网膜病变)发生、发展过程中可能具有重要的作用和特殊的机制。探寻转化生长因子β以及其他具有相似生物学功能生长因子的作用机制和相互影响,为此类疾病的预防、诊断和治疗提供新的思路具有积极的临床意义。     

乳酸水平监测在治疗早期重症监护患者中的指导作用

背景和目的:乳酸水平增高与患者的致病率和病死率显著相关.该研究探讨了在危重患者的早期治疗中,监测乳酸水平是否可以改善患者的预后及其效果.方法:将入住ICU时血乳酸水平≥3.0 mmol/L(3.0 mEq/L)的患者随机分为2组,乳酸组以乳酸水平指导治疗,使患者在最初8h内乳酸水平每2h 下降20%以上;对照组仅有基线乳酸水平,不进行乳酸水平监测.