Steroid-Mediated Decrease in Blood Mesenchymal Stem Cells in Liver Transplant could Impact Long-Term Recovery

Orthotopic liver transplant (OLT) remains the standard of care for end stage liver disease. To circumvent allo-rejection, OLT subjects receive gluococorticoids (GC). We investigated the effects of GC on endogenous mesenchymal stem (stromal) cells (MSCs) in OLT. This question is relevant because MSCs have regenerative potential and immune suppressor function. Phenotypic analyses of blood samples from 12 OLT recipients, at pre-anhepatic, anhepatic and post-transplant (2 h, Days 1 and 5) indicated a significant decrease in MSCs after GC injection. The MSCs showed better recovery in the blood from subjects who started with relatively low MSCs as compared to those with high levels at the prehepatic phase. This drop in MSCs appeared to be linked to GC since similar change was not observed in liver resection subjects. In order to understand the effects of GC on decrease MSC migration, in vitro studies were performed in transwell cultures. Untreated MSCs could not migrate towards the GC-exposed liver tissue, despite CXCR4 expression and the production of inflammatory cytokines from the liver cells. GC-treated MSCs were inefficient with respect to migration towards CXCL12, and this correlated with retracted cytoskeleton and motility. These dysfunctions were partly explained by decreases in the CXCL12/receptor axis. GC-associated decrease in MSCs in OLT recipients recovered post-transplant, despite poor migratory ability towards GC-exposed liver. In total, the study indicated that GC usage in transplant needs to be examined to determine if this could be reduced or avoided with adjuvant cell therapy.     

Lymphatic cyst of the mesentery]

Lymphatic cyst of the mesentery is a rare lesion; one case per 100,000 hospital admissions is reported. A case of lymphatic cyst in a sixty-one-year-old woman is presented. The symptoms are extremely variable, not characteristic and correlated to the location and size of the cyst. Abdominal ultrasonography and computed tomography may lead to a correct diagnosis, which is regularly made at the time of abdominal exploration. In this case the cyst was enucleated from the mesentery with open surgery.     

骨形态发生蛋白对去势大鼠股骨颈骨形态、骨密度和骨生物力学的影响

目的:观察在去势大鼠股骨颈植入牛骨形成蛋白后其骨形态、骨密度及骨强度的变化。方法:实验于2006-06/12在解放军兰州军区兰州总医院骨科研究所完成。①实验材料:普通级3个月龄wistar雌性大鼠60只。骨形态发生蛋白冻干粉剂(从幼龄牦牛新鲜长骨皮质中提取)。②实验分组:以同一只大鼠左右肢体为对照,右侧为实验侧,左侧为对照侧。③大鼠摘除卵巢制作绝经后骨质疏松模型经双能X射线骨密度仪检测筛选出造模成功的44只大鼠,实验侧距大转子0.5cm处股骨颈植入牛骨形成蛋白冻干粉剂,对照侧植入牛血清白蛋白。④实验评估:术后4周、8周时麻醉下处死大鼠取材,应用苏木精-伊红染色,组织切片后光镜下观察、CT扫描、双能X射线骨密度仪及万能生物力学机观察大鼠股骨颈骨形态学、骨皮质厚度、骨密度及骨强度的变化。结果:纳入造模成功后的44只大鼠均进入结果分析。①股骨颈骨组织形态学观察:4周时实验侧股骨颈局部骨小梁完整、连续性尚好;对照侧股骨颈局部骨小梁稀少、连续性中断,不完整。8周时实验侧股骨颈骨小梁致密,数量增多、完整,连接成网状结构、分布均匀;对照侧股骨颈骨小梁稀疏、变细、间距变大,呈髓腔扩大。②骨皮质厚度、骨密度及生物力学测定:4周时实验侧和对照侧股骨颈皮质厚度无明显差异,骨密度及最大载荷有明显差异(P<0.05);8周实验侧较对照侧骨皮质厚度明显增加、骨密度、最大载荷均增高[皮质厚度:(2.632±0.042),(1.728±0.034)mm,骨密度:(0.210±0.026),(0.182±0.029)g/mm2,最大载荷:(97.2±8.1),(85.6±7.9)N,P均<0.05]。结论:植入牛骨形成蛋白可以提高去势大鼠股骨颈局部骨皮质厚度、骨密度及生物力学强度,这将可能为绝经后骨质疏松性股骨颈骨折的防治提供一种新的途径。     

Myeloma cell growth arrest, apoptosis, and interleukin-6 receptor modulation induced by EB1089, a vitamin D3 derivative, alone or in association with dexamethasone

We have previously shown that malignant plasma cells expressed the specific receptor for 1,25-dihydroxyvitamin D3 and that this derivative could significantly inhibit the proliferation of such malignant cells. More recently, new vitamin D3 derivatives have been generated with extraordinarily potent inhibitory effects on leukemic cell growth in vitro. These new data prompted us to (re)investigate the capacity of such new vitamin D3 derivatives to inhibit myeloma cell growth in comparison with that of dexamethasone, a potent antitumoral agent in multiple myeloma. In the current study, we show that EB1089, a new vitamin D3 derivative, (1) induces G1 growth arrest of human myeloma cells, which is only partially reversed by interleukin-6 (IL-6); (2) induces apoptosis in synergy with dexamethasone, IL-6, leukemia- inhibitory factor, and Oncostatin M, with an agonistic anti-gp130 monoclonal antibody being unable to prevent this apoptosis; (3) downregulates both the gp80 (ie, the alpha chain of the IL-6 receptor [IL-6Ralpha]) expression on malignant plasma cells and the production of soluble IL-6Ralpha, and finally (4) inhibits the deleterious upregulation of gp80 expression induced by dexamethasone while limiting the dexamethasone-induced upregulation of gp130 expression. Considering that these in vitro effects of EB1089 have been observed at doses obtainable in vivo (without hypercalcemic effects), our present data strongly suggest that EB1089 could have a true interest in the treatment of multiple myeloma, especially in association with dexamethasone.     

Noninvasive monitoring of ovarian endocrine activity in the chinchilla (Chinchilla lanigera)

Reproductive endocrinology information is limited for Chinchilla lanigera, a South American species characterized by extremely long gestation and estrus cycle compared with others rodents. This study was designed to validate a non-invasive technique for monitoring ovarian endocrine activity. Animals were exposed indoors to natural photoperiod (31 degrees S-64 degrees W, Argentina); temperature range: 17-26 degrees C, with food and water ad libitum. Radiolabelled infusion (n=4): (3)H-estradiol ((3)H-E(2)) and (14)C-progesterone ((14)C-P(4)) were injected (i.p). Biochemical validation: HPLC-UV detector was employed to determine natural steroids in urine and fecal extracts and to determine immunoreactive metabolites. Physiological validation: (1) pregnancy (n=5): body weight and urinary and fecal steroidal metabolites were measured until birth; (2) Seasonality (n=9): urine and feces were collected in May, August, November, and February. Total (3)H-E(2) and (14)C-P(4) radioactivity recovered was 60.5+/-15.5 and 74.5+/-19.4%, respectively. After (3)H-E(2) injection, urinary radioactivity peaked at 7.0+/-0.6 hr; in contrast, urinary (14)C-P(4) excretion peaked at 44.0+/-4.0 hr (p=0.000). Peak radioactivity in feces occurred between 24-48 hr for both hormones. Several correlations were detected during pregnancy between body weight vs. urinary progestagens/day (r=0.44, p<0.03); vs. urinary progestagens/creatinine (r=0.73, p=2.9 x 10(-5)); vs. urinary estrogens/day (r=0.74; p<0.2); and vs. urinary estrogens/creatinine (r=0.74; p<2.0 x 10(-5)). On the other hand, urinary and fecal progestagen excretion exhibited significant seasonal fluctuations and urinary estrogen concentrations showed a similar pattern (p=0.062 for winter-spring vs. summer-autumn). This methodology proved to be useful for monitoring ovary endocrine activity in urine of chinchilla female.     

Effect of di-(2-ethylhexyl) phthalate on N-cadherin and catenin protein expression in rat testis

This study investigated the effect of DEHP exposure on N-cadherin and alpha-, beta- and p120-catenin immunoreactivities in the rat testis. DEHP was administered by daily gavage to 25-day-old male Sprague-Dawley rats at a dose of 2 g DEHP/5 ml corn oil/kg body weight for 2 days or 7 days. Control rats were treated with corn oil vehicle under the same conditions. Animals were killed at 24h after the last treatment. Another group of rats treated with DEHP or corn oil vehicle (control group) for 2 days were held for 30 days without treatment to observe recovery. Testes were analyzed for histopathology, TUNEL staining, immunofluorescence (IF) and Western blot analyses. Animals exposed to DEHP for 2 days or 7 days showed severe alterations of seminiferous tubules characterized by germ cell sloughing. Animals from the longer term recovery group treated with DEHP showed foci of delayed spermatogenesis. A linear and continuous pattern of N-cadherin was observed in the basal compartment of the seminiferous tubules. A similar pattern but with higher IF intensity was observed for N-cadherin in rats treated with DEHP for 2 days or 7 days, compared to control animals. The alpha-, beta- and p120-catenins were detected in the basal compartment of seminiferous tubules in similar localization and IF pattern for DEHP and control groups. A significant increase in testicular N-cadherin and alpha-catenin levels was detected by Western blot analysis in DEHP-exposed versus control rats. No variations in N-cadherin or catenin expression were detected in the recovery groups. These findings demonstrate that DEHP induces an up-regulation of N-cadherin and alpha-catenin expression and may perturb cell-cell adhesion phenomena in the seminiferous tubule.     

Anamnestic response to administration of purified non-adsorbed hepatitis B surface antigen in healthy responders to hepatitis B vaccine with long-term non-protective antibody titres

A clinical trial with four groups receiving either 0.6, 3.5, 10 or 20 micro g of purified non-adsorbed hepatitis B surface antigen (HBsAg) was performed to study the kinetics as well as the capacity of the immune memory to respond following exposure to HBsAg in responders to a complete course of hepatitis B vaccine, in whom anti-HBs titres had declined below the seroprotective level. The study population included 64 healthy individuals. All response parameters seropositivity, seroprotection rates, booster response rates and geometric mean titres (GMTs), consistently showed that the immune response was highly satisfactory and dose-dependent. A remarkable immune response was obtained even with a trace amount of HBsAg. This study further supports recent indication that booster hepatitis B vaccine doses may be unnecessary in healthy adult responders to a full course of hepatitis B vaccination.     

Heart-lung transplantation for patients under 10 with cystic fibrosis

The outcome of patients with cystic fibrosis aged under 10 years referred for heart-lung transplantation assessment (n = 58) was determined and compared with older children (n = 109). Similar proportions were placed on to the active waiting list (64% v 71%) and received transplants (35% v 31%). Three year post-transplantation survival figures were also similar (41% v 46%), as were the figures for overall survival for those placed on to the active list (27% v 29%). Paediatricians should not be deterred from referring younger patients for transplantation.