B220- bone marrow progenitor cells from New Zealand black autoimmune mice exhibit an age-associated decline in Pre-B and B-cell generation

New Zealand Black (NZB) autoimmune mice exhibit progressive, age- dependent reduction in bone marrow pre-B cells. To ascertain the capacity of NZB bone marrow B220- cells to generate pre-B cells in a supportive environment, B-lineage (B220+) cell-depleted and T-cell- depleted bone marrow cells from NZB mice at 1 to 3, 6, and 10 to 11 months of age were adoptively transferred into irradiated (200R) C.B17 severe combined immunodeficient (SCID) mice. Bone marrow pre-B cells (sIgM- CD43[S7]- B220+) were assessed 3 and 10 weeks posttransfer. Pre- B cells and B cells were reconstituted in SCID recipients of older NZB progenitor cells by 10 weeks posttransplant, in contrast to the very low numbers of pre-B cells present in the donor bone marrow. However, B220- bone marrow progenitor cells from greater than 10-month-old NZB donors were deficient in the reconstitution of both pre-B and B cells in SCID recipients at 3 weeks post-transfer. This reflected a slower kinetics of repopulation, because older NZB-->SCID recipients had numbers of both pre-B and B cells similar to recipients of young NZB progenitor cells by 10 weeks posttransplant. Adoptive transfer of equal mixtures of BALB/c and older NZB bone marrow B220- progenitor cells into irradiated C.B17 SCID recipients failed to demonstrate active suppression. These results suggest that, with age, NZB bone marrow has reduced numbers and/or function of early B220- B-lineage progenitors. Consistent with this hypothesis, B220- bone marrow cells from older NZB mice were deficient in progenitors capable of yielding interleukin-7 (IL-7) responsive pre-B cells in vitro on stimulation with the pre-B- cell potentiating factor, insulin-like growth factor 1 (IGF-1).     

鸟氨酸脱羧酶的生理病理特点及其药物研究概况

鸟氨酸脱羧酶(ornithinedecarboxylase,ODC)是多胺代谢中的关键酶,广泛存在于人体和动物各组织细胞内,其中对肠细胞的增生、移行和分化起重要作用.机体调节因素比较复杂.在黏膜损伤性疾病及某些癌前病变等细胞大量增生的病理情况下ODC的表达发生改变,可以作为这些疾病分期、预后及药物作用靶点或疗效的指标.寻找对ODC有作用的药物对于治疗其相关疾病是非常有意义的.     

血管紧张素原基因5’端启动子区A-20C和A-6G单核苷酸多态性与蒙古族人群原发性高血压的相关性

目的:分析血管紧张素原基因启动子区A-20C和A-6G单核苷酸多态性与蒙古族人群原发性高血压的相关性。方法:实验于2005-08/2006-01在北京华大实验室完成。选取对象均为生活在内蒙古乌拉特后旗的蒙古族牧民,三代血亲内无其他民族。采用基因测序技术对内蒙古蒙古族人群中107例原发性高血压患者和108例正常对照者进行A-20C和A-6G基因分型,观察高血压组和正常对照组不同基因型的分布和等位基因频率的差异。结果:①两组受试者在性别、年龄及吸烟、饮酒、体质量指数和临床化验检查指标有较好的匹配(P均>0.05)。②两组血管紧张素原基因A-20C位点AA,AC,CC基因型频率比较差异无显著性意义(高血压组分别为0.51,0.29,0.20;正常对照组分别为0.49,0.28,0.23,χ2=0.395,P=0.529)。A,C等位基因频率比较差异无显著性意义(高血压组分别为0.65,0.35;正常对照组分别为0.63,0.37,χ2=0.015,P=0.904)。③两组血管紧张素原基因A-6G位点AA,AG,GG基因型频率比较差异无显著性意义(高血压组分别为0.50,0.33,0.17;正常对照组分别为0.55,0.34,0.11,χ2=1.924,P=0.165)。A,G等位基因频率比较差异无显著性意义(高血压组分别为0.66,0.34;正常对照组分别为0.72,0.28,χ2=1.728,P=0.189)。④高血压组协同存在血管紧张素原基因A-20C基因型CC时,血管紧张素原基因A-6G基因型GG频率稍高于正常对照组,但差异无显著性意义(χ2=2.395,P=0.122,OR=7.52,95%CI0.014～1.250),高血压组G等位基因明显高于正常对照组(分别为0.37,0.22,χ2=4.658,P=0.034),携带该等位基因的蒙古族人群发生原发性高血压的相对危险度升高(OR=2.80,95%CI1.087～7.271)。结论:血管紧张素原基因A-20C和A-6G单核苷酸多态性与蒙古族人群原发性高血压相关,并可能具有协同作用。     

A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.     

hsp70, hsp32, and grp78 are increased in thermally injured skin with and without antithrombin(human) concentrate infusion

An acquired deficiency of antithrombin (AT), an anti-inflammatory protein, develops in patients with thermal injuries. Skin thermotolerance is regulated by heat shock protein (hsp) genes. hsp70, hsp32, hsp27, and glucose-regulated protein78 (grp78) were studied in burned and unburned human skin to determine whether correction of the AT deficiency modulated the intensity of expression of these proteins. Fifty-four human skin samples were prepared by Western blot analysis: 11 unburned and 22 burned control skin samples and 7 unburned and 14 burned skin samples from patients treated with AT(Human), or AT(H). The intensity of hsp32 expression in burned AT(H)-treated skin (P < .001) and in burned control skin (P < .01) was significantly increased compared with unburned control skin. The intensity of expression of hsp70 was statistically significant in burned AT(H)-treated skin compared with unburned control skin (P < .02), as was that of grp78 (P < .01). Thermally injured skin with or without AT(H) treatment had an increased expression of hsp70, hsp32, and grp78 compared with unburned control skin.     

Endotoxin potentiates hepatocyte apoptosis in cholestasis

BACKGROUND:

Cholestasis is a component of liver disease of almost any etiology, including septic liver injury. The cellular mechanisms of liver injury in cholestasis and sepsis remain unresolved. We evaluated apoptosis, a well-orchestrated and potentially reversible mechanism of cell death, in bile duct-ligated and endotoxin-injected rats.

STUDY DESIGN:

Male Sprague-Dawley rats were randomly assigned to six groups (n = 6–9): bile duct-ligated+endotoxin (B+E), sham+endotoxin (S+E), bile duct-ligated (B), sham (S), endotoxin (E), and normal (N). On day 1, the bile ducts of B+E and B rats were ligated and severed. S+E and S animals underwent biliary manipulation only. On day 3, B+E, S+E, and E groups received 3 mg/kg endotoxin IV. On day 4, livers from all rats were excised, fixed, and stained (hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick-end labeling [TUNEL]). Portions were frozen for DNA fragmentation analysis. Caspase 3 activity was determined using isolated hepatocytes.

RESULTS:

Livers from all groups (B+E, S+E, E, and B) except normal and sham displayed apoptosis by hematoxylin and eosin staining, TUNEL staining, and DNA fragmentation. Histologic evaluation revealed 10% to 20% necrosis in endotoxin-treated animals (B+E, S+E, and E). Caspase 3 activity was significantly higher in endotoxin-treated animals versus animals without endotoxin (treated 0.450 ± 0.08 versus nontreated 0.135 ± 0.05, p < 0.0001) (mean ± SD).

CONCLUSIONS:

Cholestatic livers had apoptosis without progression to necrosis. When exposed to the second insult of endotoxin, cholestatic livers received an acute on chronic apoptotic trigger, and proceeded to necrosis. Endotoxin was a potent hepatotoxic insult because all treated rat livers displayed both apoptosis and necrosis.     

What are the primary concerns of recently graduated surgeons and how do they differ from those of the residency training years?

HYPOTHESIS: Graduated surgeons have differences in concerns when comparisons are made between fellows and practicing surgeons, practicing surgeons and residents, and male and female surgeons. DESIGN AND SETTING: A survey was distributed to surgeons who graduated from 17 New England residency programs from 1993 to 1996, consisting of 9 demographic questions and 33 items coded on a Likert-type scale (with scores from 1 [least concerning] to 5 [most concerning]). PARTICIPANTS: Surgical fellows and practicing surgeons recently graduated from general surgical residency programs in New England who had participated in a previous study as residents. INTERVENTION: Distribution and completion of the survey. MAIN OUTCOME MEASURE: Personal and career-oriented concerns of recently graduated surgical residents. RESULTS: Personal issues continue to rank high for graduated residents, but the areas of greatest concern became more financially and career oriented. The top concerns of fellows were personal finances (mean score, 3.2), child rearing (mean score, 3.1), salary (mean score, 3.1), postponing family plans (mean score, 3.0), availability of role models (mean score, 2.9), and number of work hours (mean score, 2.8). The top concerns of practicing surgeons were salary (mean score, 3.2), personal finances (mean score, 3.1), number of referrals (mean score, 3.0), support for research (mean score, 2.7), child rearing (mean score, 2.7), and availability of role models (mean score, 2.7). Differences existed between men and women for child rearing, initiating personal relationships, maintaining personal relationships, maternity leave, and promotional advancement. Women were more concerned than men. CONCLUSIONS: Assistance with career planning and job selection during the residency years should be enhanced to diminish the concerns about financial issues and the availability of role models after graduation. Many of the concerns among male and female graduates are still reflective of larger societal expectations, but some, such as promotional advancement, may be attenuated through guidance and mentoring of residents before job selection.