Local blood flow regulation in transplanted rat pancreatic islets: influence of adenosine, angiotensin II, and nitric oxide inhibition

BACKGROUND: Transplanted islets lack endothelial cells immediately after implantation and therefore depend on an adequate revascularization for their survival and function. However, the functional properties of the newly formed islet graft microvessels are largely unknown. This study aimed to investigate the blood flow regulation of transplanted pancreatic islets. METHODS: Pancreatic islets were syngeneically transplanted beneath the renal capsule of control and streptozotocin-diabetic rats. Blood flow measurements were performed 4 weeks later using laser-Doppler flowmetry. Adenosine (0.6 mg x kg(-1) x min(-1), angiotensin II (AT II; 0.17 microg x kg(-1) x min(-1)) and the nitric oxide synthase inhibitor NG-nitro-L-arginine (25 mg/ kg) were given to each animal. RESULTS: An increased basal blood flow and basal vascular conductance in the islet grafts, but not in the renal cortex, were seen in diabetic rats compared with control rats. Adenosine increased, and AT II decreased, the vascular conductance of the islet grafts in both nondiabetic and diabetic animals. A more pronounced circulatory response to AT II was observed in kidneys of diabetic animals, whereas there was no difference in the islet graft blood flow response between nondiabetic and diabetic animals. NG-Nitro-L-arginine decreased islet graft blood flow and vascular conductance in both nondiabetic and diabetic recipients, but the effect was more pronounced in the non-diabetic animals. CONCLUSIONS: Islet graft blood flow was influenced by adenosine, AT II, and nitric oxide inhibition in all animals. However, diabetic animals were less dependent on nitric oxide to maintain a basal blood flow in the islet graft.     

Treatment of hypogonadal adolescent boys with long acting subcutaneous testosterone pellets

AIMS: Long acting subcutaneous testosterone pellets are of proved efficacy for the treatment of hypogonadal men, but have not been reported as a treatment modality in adolescent boys. Pharmacodynamic studies of subcutaneous testosterone release have shown prolonged normalisation of testosterone levels for at least four months. Administration of a long acting, safe, effective, and convenient form of treatment is desirable when life-long treatment is indicated. PATIENTS AND METHODS: Eighteen boys (aged 13.9-17.5 years at the start of treatment)-seven with primary hypogonadism, nine with secondary hypogonadism, and two boys being treated with testosterone for tall stature--were given testosterone pellets (8-10 mg/kg) every six months for 18 months. Height, weight, pubertal status, and psychosocial parameters were assessed and follicle stimulating hormone, luteinising hormone, testosterone, prolactin, and lipids were measured at 0, 1, 3, 6, 12, and 18 months. Bone age was measured at 0 and 12 months. RESULTS: In all boys growth velocity continued appropriately for bone age. Puberty continued to progress in all boys and in two boys the amount of virilisation exceeded that seen with previous treatment with intramuscular testosterone. After testosterone administration, follicle stimulating hormone and luteinising hormone suppressed incompletely in the boys with primary hypogonadism. Serum testosterone ranged from 4.3 to 26.7 nmol/l at three months to less than 10 nmol/l at six months after implantation. Prolactin and lipid levels were normal throughout the study. By report, there was an improvement in mood and emotional wellbeing. No pellet extrusions occurred in a total of 156 pellet insertions. CONCLUSIONS: All boys preferred this mode of testosterone administration to intramuscular injections. Long acting subcutaneous testosterone pellets are safe, efficacious, well tolerated, and convenient, and result in normal physical growth and improved psychological outlook in adolescent hypogonadal boys.     

Familial breast and ovarian cancer: a Swedish population-based register study

A cohort of offspring of mothers with breast or ovarian cancer diagnosed in 1958-1993 was established using Swedish population-based registers. The children (n = 158,041) were born between 1941 and 1993, and their cancer incidence was followed between 1961 and 1993. A total of 3,257 tumors in 3,102 children were found. Observed numbers of cases were compared with expected numbers based on national calendar year-, age-, and sex-specific incidences. For daughters of women with breast cancer, the standardized morbidity ratios for being diagnosed with breast cancer and ovarian cancer before age 50 years were 1.99 (95% confidence interval (CI): 1.86, 2.14) and 1.28 (95% CI: 1.05, 1.54), respectively. The corresponding figures for daughters of women with ovarian cancer were 1.79 (95% CI: 1.55, 2.07) and 2.38 (95% CI: 1.77, 3.12). The risks were raised if the mother's cancer was diagnosed at a young age, the mother had multiple breast/ovarian diagnoses, or there was a sister with breast/ovarian cancer. Among all offspring, increased risks were found for thyroid cancer, testicular cancer, and malignant melanoma, while lung cancer risk was decreased if the mother had had breast cancer. The authors developed a variance estimator for the standardized morbidity ratio to cope with overdispersion due to dependency within families.     

Engraftment and growth of transplanted pancreatic islets

Transplantation of pancreatic islets may provide a cure for type 1 diabetes. However, this treatment can currently be offered only to very few patients. To improve transplantation success we need to understand better the mechanisms of how the implanted islets survive, grow and/or maintain adequate function. We herein report on our studies to evaluate the factors responsible for the engraftment, i.e. revascularization, reinnervation etc., of transplanted islets and relate these factors to the metabolism and growth of the islets. Graft metabolism can be monitored by microdialysis probes that allow for the measurement of minute amounts of islet metabolites and hormonal products. Growth of the endocrine cells can be stimulated both in vitro before implantation and in vivo post-transplantation. Another problem is rejection of transplanted islets, which may be overcome by the microencapsulation of islets. The knowledge gained by the present studies will enable us to elucidate the optimal treatment of islets to ensure a maximal survival of the transplanted islets, and may be applied also to clinical islet transplantation.     

儿童皮下和网膜脂肪组织瘦素表达水平及其临床意义

【目的】　对不同年龄儿童皮下和网膜脂肪组织中瘦素 (leptin)mRNA表达水平进行调查。 　【方法】　配对的皮下和网膜脂肪组织从腹部择期手术患儿 ( 3 7例 ,3月～ 12岁 )和成人 ( 9名 )获取。应用real timeRT PCR方法测定不同部位脂肪组织中leptinmRNA表达水平 ,并探讨其与体块指数 (BMI)、腰围、臀围及腰臀围比 (WHR )、年龄、性别及肥胖的相互关系。　【结果】　与成人相一致 ,儿童leptin的表达亦有明显的部位性差异 ,皮下脂肪组织中leptinmRNA水平显著高于网膜 (P <0 .0 0 1)。皮下脂肪组织leptinmRNA表达水平与BMI呈显著正相关 (r =0 .69,P <0 .0 0 1) ,而网膜leptin与BMI呈较弱的正相关 (r =0 .3 2 ,P <0 .0 5 ) ;皮下和网膜leptin与WHR的均无显著相关 ,但网膜leptin与腰围呈较弱的正相关 (r =0 .3 3 ,P <0 .0 5 )。不同年龄组中脂肪组织的leptin表达水平差异有显著性(P <0 .0 1) ,6～ 12岁组皮下和网膜脂肪组织leptinmRNA表达均高于 1～ 5岁组 (P <0 .0 5 ) ,与成人水平相比 ,则差异无显著性 (P >0 .0 5 )。过重和肥胖儿童脂肪组织leptinmRNA表达水平显著高于非肥胖儿童。 　【结论】　儿童不同部位脂肪组织leptinmRNA表达水平在一定程度上反映了脂肪组织的生长和分布。肥胖儿童脂肪组织leptin的     

The effect of cystectomy, and perioperative methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy on the risk and pattern of relapse in patients with muscle invasive bladder cancer

PURPOSE: Trials have demonstrated decreased relapse with perioperative methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) chemotherapy in patients with muscle invasive bladder cancer. We evaluated whether the benefit of chemotherapy correlates with its effects on distant or pelvic relapse. MATERIALS AND METHODS: We retrospectively evaluated the records of all 107 patients who underwent cystectomy for muscle invasive bladder cancer at our institution between 1988 and 1994. Factors predicting relapse were identified and used to group patients at high or low risk. The outcome in each group with and without M-VAC chemotherapy was then analyzed in terms of overall, metastatic and pelvic relapse. Univariate analysis was performed using the Kaplan-Meier method and log rank statistic, and multivariate analysis was done using the Cox proportional hazards model. Median survival was 29 months for patients free of disease. RESULTS: Pathological stage T3 or greater according to the American Joint Committee on Cancer, tumor greater than 3 cm. and creatinine greater than 1.5-fold normal were independent poor prognostic factors in patients treated with cystectomy only. Patients with any of these factors or metastatic involvement of the pelvic lymph nodes were considered at high risk. All 35 low risk patients were treated with cystectomy only and had an excellent outcome with a 3-year relapse-free survival plus or minus standard error of 93% +/- 5%. The 3-year rates in 52 and 20 high risk patients treated without and with chemotherapy, respectively, were 42% +/- 8% versus 57% +/- 13% for relapse-free survival (p = 0.17), 38% +/- 9% versus 8% +/- 8% for pelvic failure (p = 0.02) and 39% +/- 9% versus 38% +/- 13% for distant metastases (not significant). Multivariate analysis of patients who underwent pelvic lymphadenectomy revealed that perioperative chemotherapy improved relapse-free survival and pelvic control but not metastatic control (p = 0.03, 0.02 and 0.31, respectively). CONCLUSIONS: Low risk patients have excellent disease control when treated with cystectomy only. Those with high risk features are at substantial risk for pelvic failure (38% at 3 years) after cystectomy only. Perioperative M-VAC chemotherapy has a profound impact on pelvic but not on metastatic failure.     

New Characterization Measures of Pore Shape and Connectivity Applied to Coatings used for Controlled Drug Release

Pore geometry characterization-methods are important tools for understanding how pore structure influences properties such as transport through a porous material. Bottlenecks can have a large influence on transport and related properties. However, existing methods only catch certain types of bottleneck effects caused by variations in pore size. We here introduce a new measure, geodesic channel strength, which captures a different type of bottleneck effect caused by many paths coinciding in the same pore. We further develop new variants of pore size measures and propose a new way of visualizing 3-D characterization results using layered images. The new measures together with existing measures were used to characterize and visualize properties of 3-D FIB-SEM images of three leached ethyl-cellulose/hydroxypropyl-cellulose films. All films were shown to be anisotropic, and the strongest anisotropy was found in the film with lowest porosity. This film had very tortuous paths and strong geodesic channel-bottlenecks, while the paths through the other two films were relatively straight with well-connected pore networks. The geodesic channel strength was shown to give important new visual and quantitative insights about connectivity, and the new pore size measures provided useful information about anisotropies and inhomogeneities in the pore structures. The methods have been implemented in the freely available software MIST.     

The pro-inflammatory role of platelets in cancer

Thrombosis is a frequent issue in cancer patients. Tumor-induced platelet activation and coagulation does not only constitute a significant risk for thrombosis, but also contribute to tumor progression by promoting critical processes such as angiogenesis and metastasis. In addition to their role in hemostasis, platelets are increasingly recognized as regulators of inflammation. By modulating the immune system, platelets regulate several aspects of cancer-associated pathology. Platelets influence the inflammatory response in cancer by affecting the activation status of the endothelium and by recruiting leukocytes to primary and metastatic tumor sites, as well as to distant organs unaffected by tumor growth. Furthermore, platelets participate in the formation of neutrophil extracellular traps, which can promote metastasis, thrombosis, and contribute to organ failure. In this review, we discuss the role of platelets as coordinators of the immune system during malignant disease and the potential of targeting platelets to prevent cancer-associated pathology.