A combination of human leukocyte antigen DQB1*02 and the tumor necrosis factor alpha promoter G308A polymorphism predisposes to an insulin-deficient phenotype in patients with type 2 diabetes

Our previous results have suggested that genes outside the human leukocyte antigen (HLA) class II locus may affect the phenotype of type 2 diabetic patients from families with both type 1 and type 2 diabetes (mixed type 1/2). To study whether the TNF alpha gene could be such a modifying gene, we studied TNF alpha promoter polymorphisms (G-->A substitution at positions -308 and -238) in relation to HLA-DQB1 genotypes in type 2 patients from mixed type 1/2 families or common type 2 diabetes families as well as in patients with adult-onset type 1 diabetes and control subjects. The TNF alpha(308) AA/AG genotype frequency was increased in adult onset type 1 patients (55%, 69 of 126), but it was similar in type 2 patients from type 1/2 families (35%, 33/93) or common type 2 families (31%, 122 of 395), compared with controls (33%, 95/284; P < 0.0001 vs. type 1). The TNF alpha(308) A and DQB1*02 alleles were in linkage disequilibrium in type 1 patients (Ds = 0.81; P < 0.001 vs. Ds = 0.25 in controls) and type 2 patients from type 1/2 families (Ds = 0.59, P < 0.05 vs. controls) but not in common type 2 patients (Ds = 0.39). The polymorphism was associated with an insulin-deficient phenotype in the type 2 patients from type 1/2 families only together with DQB*02, whereas the common type 2 patients with AA/AG had lower waist to hip ratio [0.92 (0.12) vs. 0.94 (0.11), P = 0.008] and lower fasting C-peptide concentration [0.48 (0.47) vs. 0.62 (0.46) nmol/liter, P = 0.020] than those with GG, independently of the presence of DQB1*02. In conclusion, TNF alpha is unlikely to be the second gene in the HLA area responsible for our previous findings in type 1/2 patients. However, we could show an association between TNF alpha(308) polymorphism and the phenotype of common type 2 diabetes.     

Effects of medroxyprogesterone and estradiol on the recovery of spermatogenesis in irradiated rats

Suppression of intratesticular testosterone (ITT) levels is required for spermatogenic recovery in rats after irradiation, but maintenance of peripheral testosterone (T) levels is important for many male functions. Considering the preservation of peripheral T while suppressing ITT, we tested the effects of a combination of a progestin, medroxyprogesterone acetate (MPA), plus T on spermatogenic recovery after irradiation, and compared its effects to those of T alone or T combined with estradiol (E2). Rats were given testicular irradiation (6 Gy) and treated during wk 3-7 after irradiation with MPA + T, or the individual steroids with or without GnRH antagonist (GnRH-ant), or GnRH-ant alone, or T + E2. Whereas GnRH-ant alone stimulated differentiation in 55% of tubules 13 wk after irradiation compared with 0% in irradiated-only rats, the addition of MPA reduced the percentage of tubules showing differentiation to 18%. However, T or MPA alone or the combination of the two induced germ cell differentiation in only 2-4% of tubules. In contrast, E2 stimulated differentiation in 88% of tubules, and T combined with E2 still resulted in differentiation in 30% of tubules. Although both MPA and E2 suppressed ITT levels to approximately 2% of control (2 ng/g testis), MPA was a less effective stimulator of spermatogenic recovery than E2 or GnRH-ant alone. MPA's function as a weak androgen was likely responsible for inhibiting spermatogenic recovery, as was the case for all other tested androgens. Thus, for clinical protection or restoration of spermatogenesis after radiation or chemotherapy by suppressing T production, MPA, at least in the doses used in the present study, is suboptimal. The combination of an estrogen with T appears to be most effective for stimulating such recovery.     

老年心肌缺血者QTc和QTcd变化及临床意义

测定了６４例老年心肌缺血（ＭＩＳ）患者和２１例心肌梗塞（ＭＩ）患者心电图的ＱＴｃ间期和ＱＴｃ离散度（ＱＴｃｄ），并与心血管神经官能症（ＣＶＮ）及正常老年人进行比较；探讨ＱＴｃ、ＱＴｃｄ与致命性室性心律失常（ＦＶＡ）、心原性猝死（ＣＳＤ）的关系；分析ＭＩ不同部位的ＱＴｃｄ变化以及稳定性心绞痛（ＳＡＰ）和不稳定性心绞痛（ＵＳＡＰ）的ＱＴｃｄ差异。结果：老年女性患者ＱＴｃ较男性长（Ｐ＜０．０５），而ＱＴｃｄ两者无差异；老年ＭＩＳ患者ＱＴｃ和ＱＴｃｄ较正常组明显延长（Ｐ＜０．０１）；ＭＩ前壁、下壁和后壁３组ＱＴｃｄ无明显差异（Ｐ＞０．０５）；ＵＳＡＰ患者ＱＴｃｄ较ＳＡＰ长（Ｐ＜０．０５）。     

Effect of interferon-gamma on hepatic fibrosis in chronic hepatitis B virus infection: a randomized controlled study.

BACKGROUND & AIMS: Hepatic fibrosis due to chronic HBV infection has enormous socioeconomic impact. Besides strategies targeting virus elimination, prevention or reversal of liver fibrosis is amenable. Given the antifibrotic activity of interferon-gamma (IFN-gamma), a randomized open-labeled multicenter trial was initiated to test IFN-gamma in HBV infection. METHODS: HBsAg-positive patients with biopsy proven hepatic fibrosis (n = 99, stages 2-4, Scheuer criterion) were treated with diammone-glycyrrhizinate and potassium-magnesium aspartate. Sixty-six randomly assigned patients were treated with 50 mug IFN-gamma intramuscularly on a daily basis for 3 months and on alternate days the subsequent 6 months. Efficacy was evaluated by liver biopsy and serologic markers. RESULTS: Fifty-four patients in the IFN-gamma group and 29 patients in the control group completed the study. The hepatic fibrosis score was significantly reduced in 63% of IFN-gamma treated patients compared with 24.1% in the control group by using a semiquantitative scoring system evaluating both liver architecture and fibrotic deposits. Mean values for the total fibrosis score decreased from 13.8 +/- 5.8 to 10.1 +/- 5.1 in the IFN-gamma group (P = .0001), whereas they were unchanged in control subjects (13.2 +/- 6.8 vs 12.6 +/- 4.8, P = .937). The Scheuer system showed 12 out of 54 patients improved >or=1 stage(s) in the IFN-gamma group compared with 1 of 29 in the control group. Antifibrotic activity might be attributed to decreased transforming growth factor-beta signaling via phosphorylated Smad2 and reduced number of activated, alpha-smooth muscle actin positive hepatic stellate cells. CONCLUSIONS: IFN-gamma treatment for 9 months improves fibrosis scores in patients with chronic HBV infection most likely by antagonizing profibrogenic transforming growth factor-beta effects.     

老年肺心病患者吸入一氧化氮后血流动力学与血管调节因子的变化

自的为探讨血管内皮细胞在慢性阻塞性肺疾病（ＣＯＰＤ）肺心病发生发展中的作用，对该病患者血浆内皮细胞释放的舒血管因子──一氧化氮（Ｎｏ）的含量与血管紧张素转换酶（ＡＣＥ）活性进行测定，并观察提供外源性ＮＯ对肺心病晚期患者肺血流动力学的影响。方法采用分光光度法测定９例老年ＣＯＰＤ肺心病晚期患者血浆ＮＯ的含量与ＡＣＥ活性，另有１２例健康老年人作为对照，并应用右心导管技术观察了吸入４０×１０－６ＮＯ２０分钟对晚期肺心病患者肺血流动力学的影响。结果老年肺心病患者血浆ＮＯ含量与ＡＣＥ活性显著降低；吸入ＮＯ后，血浆ＮＯ代谢产物显著增加的同时，肺动脉平均压（ＰＡＰｍ）从４．１±０．７ｋＰａ（１ｋＰａ＝７．５ｍｍＨｇ）降为３．３±０．５ｋＰａ（Ｐ值＜０．０１），肺血管阻力及其指数显著降低，输氧量（ＤＯ２）、心输出量（ＣＯ）增加，右室作功降低。全血谷胱甘肽过氧化物酶（ＧＳＨ－ｐｘ）活力显著降低（３７．３％）。结论老年慢性心病患者血管内皮依赖性舒张因子缺乏，其肺血管内皮可能存在一定的损伤，外源性补充ＮＯ可显著改善肺循环，增加输氧量，而副作用很少，对老年肺心病患者有益     

基质金属蛋白酶在阻塞性肺气肿大鼠模型中的表达及部分细胞因子的水平

目的　观察基质金属蛋白酶 2 (MMP 2 )和MMP 9在阻塞性肺气肿大鼠模型中的表达及白细胞介素 (IL) 1 0和肿瘤坏死因子 (TNF)α的水平。方法　 2 4只雄性Wistar大鼠随机分为 2组 ,每组1 2只 ,阻塞性肺气肿模型组 :将大鼠置于自制有机玻璃染毒箱内进行被动吸烟 (金键牌香烟 ) ,每天 2次 ,每次 1 6支 ,持续 30min ,2次之间间隔 4h ,连续 75d。健康对照组大鼠 2级实验动物房内室温常规饲养。 2组大鼠行第 0 3秒钟用力呼气容积 (FEV0 3)、FEV0 3/用力肺活量 (FVC)、功能残气量 (FRC)的测定。大鼠处死后 ,行支气管肺泡灌洗 ,测支气管肺泡灌洗液 (BALF)中白细胞总数和各分类细胞数、MMP 2和MMP 9的活性及IL 1 0和TNFα的含量。免疫组化法检测支气管、肺组织中MMP 2和MMP 9的表达及其蛋白相对含量。Weigert弹力纤维染色观察弹力纤维的变化。结果　阻塞性肺气肿模型组大鼠支气管黏膜上皮大片脱落 ,管壁及周围大量的单核细胞和淋巴细胞浸润 ;肺泡结构紊乱 ,肺泡壁变薄或断裂 ,肺泡弹性减弱 ,呈囊状扩张 ,肺泡腔扩大 ,部分融合成肺大疱。与健康对照组相比 ,阻塞性肺气肿模型组大鼠FEV0 3[(5 1 2± 0 42 )ml]、(FEV0 3/FVC)× 1 0 0 % [(71 1 5± 9 84) ]显著降低 ,FRC[(7 2 2± 2 1 8)ml]显著增加 (P值均 <     

Heart assist systems--current status

BACKGROUND: Heart failure is the leading cause of death in the developed countries. Organ-preserving operative procedures on the failing heart like coronary artery bypass procedures or resection of left ventricular aneurysms are part of the routine care in cardiac surgery today. Terminal heart failure refractory to optimized drug therapy, however, will require a heart transplantation or the implantation of artificial blood pumps. While heart transplantation has proven to provide excellent long-term results with 10-year survival rates at 50%, it will remain a casuistic therapy, limited by the comparatively small number of procedures which can be performed. ARTIFICIAL BLOOD PUMPS: The current status of development of artificial blood pumps is represented by the broad availability of partially-implantable electric motor-driven left ventricular assist devices (LVAD), which still require a percutaneous cable for energy supply and device control from external sources while the blood pump itself resides inside the body. The recently introduced axial-flow devices (DeBakey, Jarvik 2000 and HeartMate II LVADs) deliver a continuous blood flow and obviously provide distinct advantages with regard to a reduction in size, weight and energy demands, simplified implantation technique and device control when compared to the previously available partially-implantable electric motor-driven pulsatile blood pumps (Novacor N100, TCl Heart Mate LVADs). The first systems designed for long-term or permanent use (Lion Heart LVAD, AbioCor replacement heart) are completely implantable devices featuring percutaneous energy transmission and device control. However, the latter are more complex devices and their clinical application is still limited to a small number of cases, which precludes a judgment about their potential at this time. INDICATIONS: The use of paracorporeal pneumatically accentuated blood pump systems is still indicated in cases of most severe biventricular heart failure and multiorgan failure or if only short- to mid-term circulatory support is anticipated. Well established indications for utilization of artificial blood pumps are the bridge-to-transplant procedure, which yields results comparable to primary heart transplantation, and acute cardiac failure following myocardial infarction or cardiac surgical procedures. In newborns and children, encouraging results were obtained when miniaturized blood pumps of the Berlin Heart System were utilized for heart failure in myocarditis or dilative cardiomyopathy. With advanced reliability of artificial blood pumps and in face of the high incidence of heart failure, especially in the older age group, the long-term application of artificial bloods pump appears to be justified.     

Tdentification of a new target region on the long arm of chromosome 7 in gastric carcinoma by loss of heterozygosity

AIM: To define the common deleted region on the long arm of haman chromosome 7q linked to primary gastric carcinomas in Chinese by loss of heterozygosity (LOH)and its clinical significance.METHODS: Nine microsatellite markers distributed over chromosome 7q with an average marker density of 10cM were used to examine 70 primary gastric carcinomas for LOH by PCR amplification. The PCR products were separated by electrophoresis on polyacrylamide gel.Genescan and Genotyper soft-wares were used to analyze LOH.RESULTS: LOH with at least one marker on 7q occurred in 34.3% (12/50) of the tumors. Among them, LOH at D7S486 and D7S798 was higher in 24.0% (24/70) and 19.2% (5/26), respectively. By statistical analysis we also observed an obvious genotype-phenotype correlation on 7q (P＜0.05). The frequency of LOH at D7S486 in patients with lymph node metastasis was significantly higher than that in those without lymph node metastasis (P= 0.015).CONCLUSION: The high incidence of LOH at D7S486and its correlation with poorer prognosis suggest that there might be putative tumor suppressor genes in this region involved in the tumorigenesis and progression of gastric carcinoma.     

Temporäre mechanische Linksherzentlastung

Zusammenfassung Hintergrund  Die Implantation eines mechanischen Herzunterstützungssystem (MCSS) bei Patienten mit idiopathischer dilatativer Kardiomyopathie im Endstadium kann zu einer Verbesserung der Herzfunktion führen und die Explantation des Systems erlauben. Wir berichten über die Effekte der ventrikul?ren Entlastung auf die Herzfunktion, die humoralen Anti-β₁-Adrenozeptor-Autoantik?rper (A-β₁-AAK) sowie die myokardiale Fibrose. Methoden  13 Patienten mit nichtisch?mischer dilatativer Kardiomyopathie im Endstadium (NYHA IV-D) erhielten ein monoventrikul?res (zw?lf Patienten) oder ein biventrikul?res (ein Patient) Herzentlastungssystem. Alle hatten zur Zeit der Implantation einen Cardiac Index <1,61·min⁻¹·m² K?rperoberfl?che, eine linksventrikul?re Auswurffraktion (LVEF) von <16%, einen linksventrikul?ren enddiastolischen Diameter (LVEDd)>68 mm und einen positiven A-β₁-AAK-Nachweis. Echokardiographische Auswertungen, Serumtests auf A-β₁-AAK und histologische Untersuchungen hinsichtlich myokardialer Fibrose wurden vor und nach Implantation eines MCSS durchgeführt. Ergebnisse  Die durchschnittliche Unterstützungsdauer betrug 236±201 Tage (30 bis 794 Tage). Innerhalb dieses Zeitraums verbesserte sich die LVEF von ≤15 auf im Durchschnitt 46% und der LVEDd von 74 auf 56 mm. Die A-β₁-AAK waren nach im Mittel 11,7 Wochen im Serum nicht mehr nachweisbar. Ein Wiederanstieg konnte auch nach Explantation bei keinem Patienten beobachtet werden. Ein hochpathologischer Fibroseanteil im Myokard war etwa ein Jahr nach Explantation ebenfalls nicht mehr zu beobachten. Ein Patient dekompensierte sechs Monate nach Explantation und wurde daraufhin mit einem externen monoventrikul?ren System unterstützt. Die nachfolgende Transplantation verlief erfolgreich. Ein weiterer Patient starb unmittelbar nach Explantation an der Folge einer an?sthesiologischen Komplikation. Die mittlere Nachbeobachtungsdauer bei elf Patienten nach Explantation betr?gt (Stand 31. 5. 1997) 12,6±9,77 Monate (drei bis 26 Monate). Kumulativ konnten 139 Patientenmonate nachbeobachtet werden. Schlu?folgerung  Bei ausgew?hlten Patienten mit terminaler idiopathischer dilatativer Kardiomyopathie kann durch eine tempor?re mechanische Herzunterstützung eine weitgehende Normalisierung der Herzfunktion erreicht werden. Die pr?operative myokardiale Fibrose ist ein Jahr nach Explantation nicht mehr nachweisbar. Die A-β₁-AAK verschwinden in der Phase der mechanischen Entlastung des Herzens und treten nach Explantation des Systems nicht mehr auf. “Weaning” von der mechanischen Herzunterstützung kann eine Alternative zur Herztransplantation darstellen.