Immunological tolerance-related genes in a spontaneous tolerant model of rat liver transplantation explored by suppression subtractive hybridization

Natural immunological tolerance can be induced in certain types of allogeneic liver transplantation in rats. To screen for genes associated with the induction of tolerance, suppression subtractive hybridization was performed in the rat liver transplantation model between a DA donor and PVG recipient combination where spontaneous immunological tolerance is known to occur without any immunosuppressive treatment. As a result, 112 genes were cloned from a DA liver graft that survived for 20 days in the fully allogeneic PVG recipient. After confirmation of the expression intensity using an in-house manufactured DNA array with cDNAs from the DA graft, 36 genes were classified in the highly expressed group and 26 moderately expressed group. In the first group, there were 8 immunoglobulin-related genes and 6 MHC class II-related genes, suggesting the existence of an underlying rejection response. Among those genes, an antiapoptotic gene in the p38 MAP kinase pathway, heme oxygenase gene (HO-1), and a ras cascade gene, IQ motif containing GTPase activating protein 1 (Iqgapl), retained biological significance. The results suggested that the molecular response to a liver graft tends to be antiapoptotic and to terminate the rejection response. Unfortunately, there was no gene identified that qualified as a putative immunosuppressive protein, liver suppressor factor-1 (LSF-1). The panel of genes identified in the present work will be a useful panel of candidate genes to investigate the induction of spontaneous tolerance.     

The spleen's role in transplantation immunology

While graft rejection has been studied for many years, recent investigations have focused on the generation and maintenance of transplantation tolerance. This review examines the role of secondary lymphoid organs, especially the spleen, characterizes the maintenance mechanism that is key to the development of tolerance and explores the implications of new strategies for inducing tolerance in transplantation.     

Primary solitary fibrous tumor (SFT) in the retroperitoneum

BACKGROUND: Solitary fibrous tumor (SFT) is an infrequent but distinct neoplasm, which generally arises from submesothelial connective tissue in the pleura. SFT is rarely recognized in extrathoracic sites, and histologically identical conditions have also been reported in the retroperitoneum, although their pathophysiology has not been extensively investigated. METHODS: We present four cases of primary SFT in the retroperitoneum, and review 37 similar cases in the previous literature. RESULTS: About 40% of patients were asymptomatic, and 19.2% and 15.4% presented with an abdominal mass and urinary symptoms, respectively. The tumor size ranged between 2 and 26 (mean 9.1) cm. Sixty-three percent of tumors showed nonspecific development with haphazard distribution of bland short spindle or polygonal cells with or without collagenous bundles and stromal hyalinization. In 22.0%, hemangiopericytomatous appearance was seen. About 15% of cases showed histologically malignant characteristics. The tumor cells were immunoreactive for vimentin in all cases, CD34 in 91% and Bcl-2 in 86%. All tumors were excised, and in 85.4% of cases, tumors did not recur postoperatively for 6 to 48 months. No significant difference was found between the recurrence rate of histologically benign and malignant cases. Cases positive for both CD34 and Bcl-2 had no recurrence. CONCLUSIONS: The identification of SFT in the retroperitoneum is of importance because histopathological indicators of malignancy are not necessarily associated with clinical malignant potential in many cases of retroperitoneal SFT. Retroperitoneal SFT showing typical pathological features with expression of CD34 and Bcl-2 is associated with a favorable outcome following excision.     

Relationship between serum 1,25-dihydroxyvitamin D and mortality in patients with pre-dialysis chronic kidney disease

Background It is known that vitamin D has many functions besides involvement in calcium metabolism. It has recently been recognized that vitamin D deficiency is associated with mortality, especially in cardiovascular disease (CVD). Vitamin D deficiency is common in end-stage renal disease, but develops from the early stage of chronic kidney disease (CKD). So we investigated whether the serum level of the activated form of vitamin D (1,25-dihydroxyvitamin D) affected mortality in patients with CKD stages 3 and 4. Methods Between January 1, 1995, and June 30, 2006 we measured serum 1,25-dihydroxyvitamin D In 226 patients with CKD stages 3 and 4 and classified the results into two groups depending on whether the level was below (group I) or above (group II) 20 pg/ml. We ended the follow-up period on December 31, 2006. We compared all-cause and cardiovascular mortality between the two groups. We also examined predictors of mortality by using Cox proportional regression analysis. Results Two-hundred and twenty-six patients (67 men and 159 women, mean age 67.0) were registered in this study, and groups 1 and 2 comprised 84 and 142 patients, respectively. During the follow-up period 43 patients died. CVD was the major cause of death, followed by infectious disease. The Kaplan–Meier survival curve revealed that all-cause mortality was significantly higher in group I, but a significant difference between CVD mortality in the two groups was not demonstrated. By Cox proportional regression analysis, group I was related to all-cause mortality, but this was not proved to be an independent predictor. Conclusion The results suggested that serum level of 1,25-dihydroxyvitamin D was associated with all-cause mortality in patients with CKD stages 3 and 4.     

Microglia induce neurotoxicity via intraneuronal Zn(2+) release and a K(+) current surge

Microglial cells are critical components of the injurious cascade in a large number of neurodegenerative diseases. However, the precise molecular mechanisms by which microglia mediate neuronal cell death have not been fully delineated. We report here that reactive species released from activated microglia induce the liberation of Zn(2+) from intracellular stores in cultured cortical neurons, with a subsequent enhancement in neuronal voltage-gated K(+) currents, two events that have been intimately linked to apoptosis. Both the intraneuronal Zn(2+) release and the K(+) current surge could be prevented by the NADPH oxidase inhibitor apocynin, the free radical scavenging mixture of superoxide dismutase and catalase, as well as by 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride. The enhancement of K(+) currents was prevented by neuronal overexpression of metallothionein III or by expression of a dominant negative (DN) vector for the upstream mitogen-activated protein kinase apoptosis signal regulating kinase-1 (ASK-1). Importantly, neurons overexpressing metallothionein-III or transfected with DN vectors for ASK-1 or Kv2.1-encoded K(+) channels were resistant to microglial-induced toxicity. These results establish a direct link between microglial-generated oxygen and nitrogen reactive products and neuronal cell death mediated by intracellular Zn(2+) release and a surge in K(+) currents.     

Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload

Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene-targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload-induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin(-/y) and Apelin(+/y) mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.     

Long-term survivors using intraoperative radiotherapy for recurrent gynecologic malignancies

PURPOSE: To analyze the outcomes of therapy and identify prognostic factors for patients treated with surgery followed by intraoperative radiotherapy (IORT) for gynecologic malignancies at a single institution. METHODS AND MATERIALS: We performed a retrospective review of 36 consecutive patients treated with IORT to 44 sites with mean follow-up of 50 months. The primary site was the cervix in 47%, endometrium in 31%, vulva in 14%, vagina in 6%, and fallopian tubes in 3%. Previous RT had failed in 72% of patients, and 89% had recurrent disease. Of 38 IORT sessions, 84% included maximal cytoreductive surgery, including 18% exenterations. The mean age was 52 years (range, 30-74), mean tumor size was 5 cm (range, 0.5-12), previous disease-free interval was 32 months (range, 0-177), and mean IORT dose was 1,152 cGy (range, 600-1,750). RT and systemic therapy after IORT were given to 53% and 24% of the cohort, respectively. The outcomes measured were locoregional control (LRC), distant metastasis-free survival (DMFS), disease-specific survival (DSS), and treatment-related complications. RESULTS: The Kaplan-Meier 5-year LRC, DMFS, and DSS probability for the whole group was 44%, 51%, and 47%, respectively. For cervical cancer patients, the Kaplan-Meier 5-year LRC, DMFS, and DSS estimate was 45%, 60%, and 46%, respectively. The prognostic factors found on multivariate analysis (p 相似文献   

Vascular endothelial growth factor and interleukin 6 production by Hodgkin lymphoma

A 20-year-old man complained of fever, general lymphadenopathy, severe lumbago, and gynecomastia in January 2003. The diagnosis of Hodgkin lymphoma was confirmed by biopsy specimens of the right supraclavicular lymph node. The clinical stage was IIIB, and the prognostic score was 3. Plasma levels of interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) were elevated to 446 pg/mL, and 1,710 pg/mL,respectively. Six-course combination chemotherapy with the ABVD regimen was initiated,and a complete response (CR) was achieved. Clinical signs disappeared and plasma levels of IL-6 and VEGF decreased to 5.0 pg/mL and 100 pg/mL, respectively. The patient remained in CR as of December 2006.Elevated IL-6 and VEGF may be appropriate tumor markers for patients with Hodgkin lymphoma.