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Biomedical subjects

A Naji

Publications and source records attributed to A Naji.

At least 55 records · Page 3Linked to original sources
PubMed1997

B-cells are required for the initiation of insulitis and sialitis in nonobese diabetic mice.

Nonobese diabetic (NOD) mice spontaneously develop an acute onset of hyperglycemia reminiscent of human type I diabetes. The disease is the end result of a mononuclear cell infiltration of pancreatic islets (insulitis), culminating in the selective destruction of islet beta-cells by autoreactive T-cells. NOD mice also exhibit defects in B-cell tolerance as manifested by the presence of autoantibodies against islet cell autoantigens. Based on the potential ability of B-cells to act as antigen presenting cells, we hypothesized that autoreactive B-cells of NOD mice may be necessary for the activation of islet reactive CD4+ T-cells. In the present study, we utilized an anti-mu antibody to induce in vivo depletion of B-cells and found that B-cell depletion completely abrogates the development of insulitis and sialitis in NOD mice. In contrast, control IgG-treated NOD mice developed insulitis and sialitis by 5 weeks of age. Additionally, the discontinuation of anti-mu chain antibody treatment led to the full restoration of the B-cell pool and the reappearance of insulitis and sialitis. Thus, we conclude that B-cells are a requisite cell population for the genesis of the inflammatory lesions of the islets of Langerhans. This finding suggests that autoreactive B-cells may act as the antigen presenting cells necessary for the initial activation of beta-cell-reactive CD4+ T-cells implicated in the pathogenesis of autoimmune diabetes.

Age Factors↗
PubMed1996

Reversal of acute renal allograft rejection by extracorporeal photopheresis: a case presentation and review of the literature.

There is a clear need for well-tolerated immunomodulatory agents that can aid in the prevention of acute solid organ rejection. Extracorporeal photopherosis is an apheresis-based therapy that is currently available at many medical centers worldwide. Preliminary studies utilizing photopheresis with standard immunosuppressives have shown this therapy to successfully reverse acute cellular rejection of cardiac allografts with minimal toxicity. No formal evaluation of the role of extracorporeal photopheresis had been performed in renal transplantation. In this report, photopheresis was successfully utilized to treat acute cellular rejection in a patient with a renal allograft. This lends further support to the existing literature suggesting that photopheresis may be useful for the reversal of acute solid organ rejection. Although our experience with this patient is anecdotal, photopheresis merits further study as treatment for severe renal allograft rejection.

Acute Disease↗
PubMed1996

Induction of tolerance by intrathymic inoculation of alloantigen.

The induction of donor-specific unresponsiveness constitutes the most desirable means of securing long-term graft survival, as it would spare the recipient from the deleterious effects of global immunosuppression. Based on recent insights into the factors controlling both intrathymic and extrathymic clonal deletion or inactivation of T cells, this objective can potentially be accomplished by the direct inoculation of the thymus with alloantigen to modulate T cell development at both the thymic and post-thymic level.

Animals↗
PubMed1996

Identification of calcium-dependent phospholipase A2 isoforms in human and rat pancreatic islets and insulin secreting beta-cell lines.

Phospholipase A2 (PLA2) and its end product, arachidonic acid, are thought to be important signaling components in insulin secretion from pancreatic beta-cells. Because there are multiple Ca2+ -dependent and independent PLA2 biochemical activities in beta-cells, we have used a combination of molecular and immunological techniques to identify the isoforms of Ca2+ -dependent PLA2 present in pancreatic beta-cells. Total RNA extracted from the purified rat and human pancreatic islets and from insulin-secreting beta-TC3 and beta-HC6 cells was used as a template for complementary DNA (cDNA) synthesis. The RT-PCR was performed based on the oligonucleotide primers designed for the 14- kDa type II PLA2 and the 85-kDa cytosolic PLA2. The PCR products for both enzymes yielded single bands (375 bp and 910 bp for type II PLA2 and cytosolic PLA2, respectively). The PCR-generated cDNA fragments were confirmed to be identical to the type II and cytosolic PLA2 isoforms expressed in rat tissues, U937 cells, and A9 cells by DNA sequencing of the PCR products. The presence of these two isoforms of PLA2 was further confirmed by immunoblotting of extracts of pancreatic islets and beta-cells using specific antibodies directed toward each type of PLA2. Demonstration of the presence of type II and cytosolic PLA2 isoforms in islets provides the framework for further investigation of the regulation of PLA2 isoforms and their role in insulin secretion.

Animals↗
PubMed1995

Survival of MHC-deficient mouse heterotopic cardiac allografts.

The immunologic mechanisms involved in the destruction of murine cardiac allografts were evaluated using MHC-deficient mice. Specifically, we examined the survival of immediately vascularized heterotopic adult cardiac grafts deficient in MHC class I, MHC class II, or both MHC class I and II antigens following transplantation to allogeneic hosts. We observed indefinite cardiac graft survival when donors lacked MHC class II or both MHC I and II antigens. In parallel experiments, we studied the survival of cardiac grafts harvested from normal donors in recipients severely depleted of either CD4 (class II-deficient mice) or CD8 (class I-deficient mice) T cells. Graft survival was dramatically prolonged in the absence of CD4 but not CD8 T cells. Collectively, our results demonstrate that the interaction of host CD4 T cells with donor class II antigens is critical to the rejection of murine cardiac grafts.

Animals↗
PubMed1995

Blunting of the immediate-early gene and mitogenic response in hepatectomized type 1 diabetic animals.

Studies suggest that liver regeneration is delayed in insulin-deficient animals, but defining a role of insulin as a growth factor in hepatic regeneration has remained elusive. By examining gene expression of hepatectomized liver in type 1 diabetic BB rats, we have identified dramatic changes in the expression of primary or immediate-early growth response genes compared with normal animals. These include altered expression of insulin-regulated genes such as glucose-6-phosphatase (G-6-Pase), phosphoenolpyruvate carboxykinase (PEPCK), and beta-actin, and genes such as CL-6 and map kinase phosphatase-1 (MKP-1) that were previously unlinked to insulin action in animals. Abnormal elevation of mRNAs encoding G-6-Pase, MKP-1, and PEPCK in the time 0 diabetic liver results in decreased induction after partial hepatectomy. Other genes, such as CL-6 and beta-actin, are induced at a lower level in the hepatectomized diabetic animals. The net effect is a blunting of the immediate-early gene response after partial hepatectomy in diabetic animals. As determined by DNA synthesis assays, the regenerative capacity of insulin-deficient BB diabetic livers is reduced, and this defect is corrected at least in part by insulin therapy. These findings suggest that because of insulin deficiency, common intracellular signaling pathways that are required for both metabolism and mitogenesis are aberrant in the type 1 diabetic liver and, as a result, the regenerative response is deficient.

Animals↗
PubMed1995

High levels of glucose-6-phosphatase gene and protein expression reflect an adaptive response in proliferating liver and diabetes.

The regenerating liver after partial hepatectomy is one of the few physiologic models of cellular proliferation in the adult animal. During hepatic regeneration, the animal is able to maintain metabolic homeostasis despite the acute loss of two thirds of hepatic tissue. In examining the molecular mechanisms regulating hepatic regeneration, we isolated novel immediate-early genes that are rapidly induced as the remnant liver undergoes the transition from its normal quiescent state into the G1 phase of the cell cycle. One of the most rapidly and highly induced genes which we initially termed RL-1, encodes rat glucose-6-phosphatase (rG6Pase). G6Pase mRNA peaks at 30 min and 36-48 h after hepatectomy correlating with the first and second rounds of cell division. This finding is compatible with studies that showed that G6Pase enzyme activity increases during liver regeneration. However, the increase in G6Pase mRNA is much more dramatic, indicating that it is a more sensitive indicator of this regulation. G6Pase gene expression peaks in the perinatal time period in the liver and remains elevated during the first month of life. The expression of the G6Pase gene is also dramatically elevated in BB diabetic rats, again higher than the enzyme elevation, and its relative induction after partial hepatectomy is blunted in these animals. Insulin treatment of partially hepatectomized diabetic animals downregulates the expression of G6Pase mRNA. Using specific antibodies against G6Pase, we detect a 36-kD G6Pase protein, and its level is elevated in regenerating and diabetic livers. The pattern of G6Pase mRNA expression appears to reflect similar changes in insulin and glucagon levels which accompany diabetes and hepatic proliferation. The elevation of G6Pase expression in these conditions is indicative of its importance as a regulator of glucose homeostasis in normal and abnormal physiologic states.

3T3 Cells↗
PubMed1994

Randomised trial of hysterectomy, endometrial laser ablation, and transcervical endometrial resection for dysfunctional uterine bleeding.

OBJECTIVE: To evaluate the effectiveness and safety of endometrial laser ablation and transcervical resection of the endometrium compared with hysterectomy in the surgical treatment of women with dysfunctional uterine bleeding. DESIGN: Prospective randomised controlled trial. SETTING: Gynaecology department of a large teaching hospital. SUBJECTS: 204 women who would otherwise have been undergoing hysterectomy for menorrhagia were recruited between August 1990 and March 1992 and randomly allocated to hysterectomy (n = 99) or conservative (hysteroscopic) surgery (transcervical resection (n = 52) and laser ablation (n = 53)). MAIN OUTCOME MEASURES: Operative complications, postoperative recovery, relief of menstrual and other symptoms, patient satisfaction with treatment after six and 12 months. RESULTS: Women treated by hysteroscopic surgery had less early morbidity and a significantly shorter recovery period than those treated by hysterectomy (median time to full recovery 2-4 weeks v 2-3 months, P < 0.001). Twelve months later 17 women in the hysteroscopy group had had a hysterectomy, 11 for continuing symptoms; 11 women had had a repeat hysteroscopic procedure; 45 were amenorrhoeic or had only a brown discharge; and 35 had light periods. Dysmenorrhoea and premenstrual symptoms improved in most women in both groups. After 12 months 89% (79/89) in the hysterectomy group and 78% (75/96) in the hysteroscopy group were very satisfied with the effect of surgery (P < 0.05); 95% (85/89) and 90% (86/96) thought that there had been an acceptable improvement in symptoms, and 72% (64/89) and 71% (68/96) would recommend the same operation to others. CONCLUSIONS: Hysteroscopic endometrial ablation was superior to hysterectomy in terms of operative complications and postoperative recovery. Satisfaction after hysterectomy was significantly higher, but between 70% and 90% of the women were satisfied with the outcome of hysteroscopic surgery. Hysteroscopic surgery can be recommended as an alternative to hysterectomy for dysfunctional uterine bleeding.

Endometrium↗
PubMed1994

The failure of intrathymic transplantation of nonimmunogenic islet allografts to promote induction of donor-specific unresponsiveness.

Freshly isolated allogenic pancreatic islets transplanted into the thymus of transiently immunosuppressed rats are not rejected but survive indefinitely while also inducing a state of specific unresponsiveness that permits survival of secondary donor-strain islets transplanted extrathymically. Since freshly isolated pancreatic islets contain intraislet antigen-presenting cells as well as endocrine cells it is unclear which cellular component is primarily responsible for mediating unresponsiveness. We therefore examined the impact of pretransplant in vitro culture (a maneuver which selectively depletes intraislet APCs) on the capacity of islet allografts to induce unresponsiveness after intrathymic implantation. APC-depleted pancreatic islets, which are known to have reduced immunogenicity, survived indefinitely in the thymus of allogeneic hosts whether or not brief immunosuppression was employed, but failed to promote survival of subsequent donor-strain islets transplanted to an extrathymic site. These findings emphasize the central role of APCs in the induction of transplantation tolerance in this model, and are consistent with the established role of this population in the development of T cell tolerance in the thymus.

Animals↗