Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Denileukin diftitox (Ontak), a recombinant protein composed of human interleukin 2 (IL-2) fused to diphtheria toxin, has selective cytotoxicity against activated lymphocytes expressing the high-affinity IL-2 receptor. We conducted a phase 1 study of denileukin diftitox in 30 patients with steroid refractory acute graft-versus-host disease (GVHD). Seven patients received 9 microg/kg intravenously on days 1 and 15; 18 received 9 microg/kg intravenously on days 1, 3, 5, 15, 17, and 19; and 5 received 9 microg/kg intravenously on days 1 to 5 and 15 to 19. Hepatic transaminase elevation was the dose-limiting toxicity (DLT), and dose level 2 was the maximum tolerated dose (MTD). Overall, 71% of patients responded with complete resolution (12 of 24; 50%) or partial resolution (5 of 24; 21%) of GVHD. Eight of 24 patients (33%) are alive at 6.3 to 24.6 months (median, 7.2 months). Denileukin diftitox is tolerable and has promising activity in steroid-refractory acute GVHD.     

外科手术中产生的烟气:仅仅是大量的热空气吗?

外科医生和手术室人员经常接触手术设备产生的烟气,病人也会暴露于烟气中,特别是腹腔镜手术中产生的烟气滞留于腹腔内这一密闭空间并被吸收.这些烟气是一种与香烟烟气相似的毒性物质,然而对这种毒性物质的影响还未引起足够重视.应该采取必要措施尽可能减少手术中烟气的不良影响.     

The Sigma-trial protocol: a prospective double-blind multi-centre comparison of laparoscopic versus open elective sigmoid resection in patients with symptomatic diverticulitis

Backround  

Diverticulosis is a common disease in the western society with an incidence of 33–66%. 10–25% of these patients will develop diverticulitis. In order to prevent a high-risk acute operation it is advised to perform elective sigmoid resection after two episodes of diverticulitis in the elderly patient or after one episode in the younger (< 50 years) patient. Open sigmoid resection is still the gold standard, but laparoscopic colon resections seem to have certain advantages over open procedures. On the other hand, a double blind investigation has never been performed. The Sigma-trial is designed to evaluate the presumed advantages of laparoscopic over open sigmoid resections in patients with symptomatic diverticulitis.     

Progesterone improves acute recovery after traumatic brain injury in the aged rat

Recent evidence has demonstrated that treatment with progesterone can attenuate many of the pathophysiological events following traumatic brain injury (TBI) in young adult rats, but this effect has not been investigated in aged animals. In this study, 20-month-old male Fischer 344 rats with bilateral contusions of the frontal cortex (n = 4 per group) or sham operations received 8, 16, or 32 mg/kg of progesterone or vehicle. Locomotor activity was measured at 72 h to assess behavioral recovery. Brain tissue was harvested at 24, 48, and 72 h, and Western blotting was performed for inflammatory and apoptotic factors. Edema was assessed at 48 h by measuring brain water content. Injured animals treated with 8 and 16 mg/kg progesterone showed decreased expression of COX-2, IL-6, and NFkappaB at all time points, indicating a reduction in the acute inflammatory process compared to vehicle. The 16 mg/kg group also showed reduced apoptosis at all time points as well as decreased edema and improved locomotor outcomes. Thus, in aged male rats, treatment with 16 mg/kg progesterone improves short-term motor recovery and attenuates edema, secondary inflammation, and cell death after TBI.     

Superior long-term results of renal transplantation in children under 5 years of age

Despite improving overall results of pediatric renal transplantation children under 5 years of age remain a high-risk group with poorer outcomes often because of a higher rate of surgical complications. This retrospective report details a 12-year experience at a single center and examines the outcome in this high-risk group of patients. We reviewed the medical records of 21 children under 5 years of age who received renal transplantation at Loma Linda University Medical Center between July 1988 and August 2000. The patients were evaluated regularly by the same pediatric nephrologist throughout the study period at our outpatient clinic. Mean recipient age was 3 +/- 1.2 (range 2-5) years; weight at transplantation was 13.3 +/- 5.4 kg. Ten (48%) patients received living related donor (LRD) kidneys and 11 (52%) received cadaver (CAD) kidneys. Mean donor ages for CAD and LRD were 14.4 +/- 10 years and 26.6 +/- 4.9 years, respectively. The mean cold ischemia time (CAD only) was 23.3 +/- 10.6 hours. Renal dysplasia (n = 8) and obstructive uropathy (n = 5) were the most common primary diagnoses. Maintenance immunosuppression consisted of Azathioprine or mycophenolate mofetil (MMF), cyclosporine or tacrolimus and prednisone. Mean follow-up was 80.1 +/- 51.4 months. Twelve (57%) grafts have a follow-up >5 years. Patient survival was 100 per cent. Overall graft survival at one, 3, 5, and 10 years were 95, 95, 88, and 88 per cent respectively. Graft survival for LRD recipients was 100 per cent. No graft was lost as a result of a technical problem or vascular thrombosis. One graft each was lost because of delayed graft function complicated by severe cytomegalovirus infection and chronic rejection. At one year the mean serum creatinine was 0.6 +/- 0.2 mg/dL with a mean calculated glomerular filtration rate of 93 +/- 32 mL/min. All 17 children who are now of school age are attending school. We conclude that excellent rehabilitation and superior long-term patient and graft survival can be achieved with renal transplantation in children of this age group with the use of good surgical techniques and close follow-up.     

Inhibition of experimental neointimal hyperplasia by recombinant human thrombomodulin coated ePTFE stent grafts

OBJECTIVES: The goal of this study was to evaluate the ability of recombinant human thrombomodulin (rTM) to inhibit neointimal hyperplasia when bound to expanded polytetrafluoroethylene (ePTFE) stent grafts placed in a porcine balloon injured carotid artery model. METHODS: The left carotid artery of male pigs, weighing 25 to 30 Kg, was injured with an angioplasty balloon. Two weeks later either a non-coated standard ePTFE stent graft (Viabahn, 6 x 25 mm, W. L. Gore & Associates) or a rTM coated stent graft was implanted into the balloon-injured segment using an endovascular technique. Carotid angiography was performed at the time of the balloon injury, two weeks later and then at 4 weeks to assess the degree of luminal stenosis. One month after stent graft deployment, the grafts were explanted following in situ perfusion fixation for histological analysis. The specimens were then cross-sectioned into proximal, middle and distal segments, and the residual arterial lumen and intimal to media (I/M) ratios were calculated with computerized planimetry. RESULTS: rTM binding onto ePTFE-grafts was confirmed by functional activation of protein C and histopathology with immuno-scanning electron microscopy, backscatter electron emission imaging and x-ray microanalysis. All seven of the rTM coated stent grafts and six of the seven uncoated stent grafts were patent at the time of explantation. The mean luminal diameter of the rTM coated stents was 93% +/- 2.0% of the original diameter, compared with 67% +/- 23% (P = .006) in the control group. Histological analysis demonstrated that the area obliterated by intimal hyperplasia at the proximal portion of the rTM stent was -27% compared with the control group: (2.73 +/- 0.69 mm(2), vs 3.47 +/- 0.67 mm(2), P <.05). CONCLUSIONS: Neointimal hyperplasia is significantly inhibited in ePTFE stent grafts coated with rTM compared with uncoated grafts, as documented by improved luminal diameter by angiography and by computerized planimetry measurements of residual lumen area. These findings suggest that binding of recombinant human thrombomodulin onto ePTFE grafts may improve the long-term patency of covered stents grafts. CLINICAL RELEVANCE: Decrease of neointimal hyperplasia of the magnitude observed in this study could significantly improve blood flow and patency of small caliber prosthetic grafts. If the durability of these results can be confirmed by long-term studies, this technique may prove useful in preventing graft stenosis and arterial thrombosis following angioplasty or vascular bypass procedures.     

Vitamin D receptor genotype and risk of osteoporotic hip fracture in elderly women of Utah: an effect modified by parity

Introduction The associations between vitamin D receptor (VDR) Bsm I and Fok I genotypes, parity, and risk of osteoporotic hip fracture were evaluated in a statewide population-based case-control study in Utah.Methods Women age 50–89 years with hip fracture (n=882) were ascertained via surveillance of 18 Utah hospitals from 1997 to 2001. Age-matched controls were randomly selected (n=897). Participants were interviewed in their homes, and blood samples were collected for genotyping.Results In logistic regression analyses that controlled for multiple confounders, Bsm I VDR genotype but not Fok I genotype was associated with risk of osteoporotic hip fracture (OR bb vs. BB genotype: 0.68; 95% CI: 0.50, 0.95). In similar analyses, no overall association was observed between parity status and risk of osteoporotic hip fracture. However, the effect of VDR genotype was modified by parity status. Among nulliparous women (n=140), Bsm I genotype was not associated with risk of hip fracture (OR bb vs. BB: 0.82; 95% CI: 0.28, 2.4); among primiparous women (n=133), bb genotype was associated with increased risk of hip fracture (OR bb vs. BB: 3.30; 95% CI: 0.96, 11.29); among multiparous women (n=1,400), bb genotype was associated with decreased risk of hip fracture (OR bb vs. BB: 0.59; 95% CI: 0.42, 0.84).Conclusion VDR Bsm I genotype was associated with risk of hip fracture in Utah women, and this effect was modified by parity status. Hormonal or lifestyle factors related to parity may underlie this interaction.     

Androgen receptor characteristics in skin fibroblasts from hirsute women

Hormonal measurements in some women with hirsutism often reveal little or no elevation in androgen levels to explain the disorder. Thus, it has been postulated that increased sensitivity of the hair follicle to androgen may contribute to the development of hirsutism in such patients. We, therefore, sought androgen receptor abnormalities in skin fibroblasts cultured from 10 hirsute women (ages 17-43) and normal or mildly elevated plasma testosterone levels (28-82 ng/dl). Androgen receptor content (Ro) and binding affinity (Kd) in cultured pubic skin fibroblasts were measured using a dispersed, whole cell assay. Ten such cell lines from these women were compared with 19 pubic skin cell lines from 9 normal volunteers (6 males and 3 females) and from 10 other subjects (males with gynecomastia or hypospadias). There was no statistically significant difference in the mean androgen receptor content (11,600 +/- 2700 (SE) sites/cell fibroblasts vs 7900 +/- 700 sites/cell or binding affinity (2.0 +/- 0.3 (SE) X 10(-9) M vs 1.5 +/- 0.2 X 10(-9) M, respectively) between the patients' fibroblasts and those of the controls. We conclude that hirsutism cannot be explained by abnormalities in fibroblast androgen receptor number or affinity. These observations do not exclude the possibility that other mechanisms might lead to increased peripheral androgen sensitivity in such patients.