Prep1 (pKnox1)-deficiency leads to spontaneous tumor development in mice and accelerates EmuMyc lymphomagenesis: a tumor suppressor role for Prep1.

The Prep1 homeodomain transcription factor is essential for embryonic development. 25% of hypomorphic Prep1(i/i) embryos, expressing the gene at 2% of the normal levels, survive pregnancy and live a normal-length life. Later in life, however, these mice develop spontaneous pre-tumoral lesions or solid tumors (lymphomas and carcinomas). In addition, transplantation of E14.5 fetal liver (FL) Prep1(i/i) cells into lethally irradiated mice induces lymphomas. In agreement with the above data, haploinsufficiency of a different Prep1-deficient (null) allele accelerates EmuMyc lymphoma growth. Therefore Prep1 has a tumor suppressor function in mice. Immunohistochemistry on tissue micrroarrays (TMA) generated from three distinct human cohorts comprising a total of some 1000 human tumors revealed that 70% of the tumors express no or extremely low levels of Prep1, unlike normal tissues. Our data in mice are thus potentially relevant to human cancer.

Early, but not advanced, glomerulopathy is reversed by pancreatic islet transplants in experimental diabetic rats: correlation with glomerular extracellular matrix mRNA levels.

In this study, we investigated 1) whether long-term restoration of euglycemia by means of pancreatic islet transplants is capable of preventing and/or reversing renal functional and structural alterations in an experimental model of insulin-deficient diabetes, and 2) whether changes in extracellular matrix (ECM) and cell turnover at the glomerular level and biochemical abnormalities associated with hyperglycemia correlate with the renal outcome after transplantation. Male Lewis rats, rendered diabetic by intravenous injection of streptozotocin, underwent homologous islet transplantation via the portal vein at 2 weeks (study A), at 4 months (study B), and at 8 months (study C) after the induction of diabetes and killed 12 months after transplantation in study A and 4 months after transplantation in studies B and C. Age-matched nondiabetic and untreated diabetic rats were used as control animals and were studied at 4, 8, and 12 months. In the untreated diabetic animals, metabolic derangement was associated with increased erythrocyte polyol and fructose levels, tail-tendon content of advanced glycation end products (AGEs), total proteinuria, albuminuria, kidney weight, and mean glomerular volume as well as with marked glomerular and extraglomerular lesions. Glomerular gene expression for the ECM components fibronectin and collagen IV and for TGF-beta was also increased, whereas glomerular cell proliferation was unaffected by diabetes. In study A, changes in renal function and structure observed in diabetic rats at 12 months were completely prevented by successful islet transplants. In study B, all functional and structural abnormalities detected in diabetic rats at 4 months of disease duration were virtually reversed by 4 months of euglycemia in transplanted animals, whereas they progressed further in untreated diabetic rats. In study C, the course of functional and structural changes observed in untreated diabetic rats was not reversed by islet transplantation. Likewise, tissue AGE accumulation and particularly upregulation of glomerular ECM and transforming growth factor (TGF)-beta gene expression, which are believed to play a role in the pathogenesis of altered renal function and structure in diabetes, were normalized in transplanted rats from study A and study B, but not in those from study C. These experiments show that restoration of euglycemia by islet transplants is capable of preventing experimental diabetic glomerulopathy and reversing early changes in renal function and structure induced by diabetes. In a later phase of the disease, when glomerular matrix gene expression becomes independent of hyperglycemia, possibly because of the persistent increase in tissue AGE accumulation, metabolic control is not capable of reversing renal abnormalities.

G-cell density in the antral mucosa: a feasibility study.

In this work a new method for gastrin-secreting cell (G-cell) density measurement was employed in order to test the hypothesis that G-cell density of the antral mucosa can be estimated with an acceptable degree of error. The zone of antral mucosa where most G-cells are located was demarcated, its area was measured and the G-cells within this area were counted. The variation in the e error of the estimate according to normal distribution theory, and the size of the sampling expected to yield G-cell density values with a given error were assessed. Our data indicate that a very large surface of the G-cell zone should be explored in order to estimate G-cell density with an acceptable degree of error. G-cell density measurement appears not to be feasible on biopsy specimens or, for routine diagnosis, on gastrectomy specimens.

Pharmacological control of intimal hyperplasia in small diameter polytetrafluoroethylene grafts. An experimental study.

OBJECTIVE: The efficacy of a postoperative treatment with Low molecular weight heparin (LMWH) vs Ticlopidine in controlling early thrombosis, intimal hyperplasia and growth of true endothelial cells in small prosthetic expanded polytetrafluoroethylene (ePTFE) grafts (4 mm) interposed in the carotid artery of sheep has been evaluated. EXPERIMENTAL DESIGN: Thirty animals were randomized into three different groups: control group (CTRL); ticlopidine hydrochloride (TICL) 250 mg/b.d. by month for 4 weeks from day 1; LMWH 3,085 IU AXa s.c. preoperatively and once a day for the same period. RESULTS: Complete thrombosis of the graft occurred in 7 sheep in the CTRL group and 5 in the TICL group while 2 partial thrombosis were observed in the LMWH group (n.s.). In all the evaluable cases, hyperplasia was observed in both anastomotic areas and did not involve the middle portion of the graft. The mean +/- SD intimal thickness was 603 +/- 20 micron in the CTRL group, 356 +/- 10 in the TICL group and 152 +/- 17 in the LMWH group (p < 0.001) compared to the 60 +/- 12 of the normal intima. True endothlial cells were found mainly in the LMWH group close to the arterial anastomosis. CONCLUSIONS: The postoperative use of LMWH seems to inhibit intimal hyperplasia, with interesting results also on patency and cellular coverage. Further studies are necessary to support this promising trend.

[Prevention of vascular intimal hyperplasia in small caliber prostheses. Preliminary results]. / Controllo dell'iperplasia intimale in protesi di piccolo calibro. Risultati preliminari.

Intimal hyperplasia is one of the main risk factors for the patency of small diameter bypass grafts. The standard unfractioned heparin (UH) is able to control this phenomenon but the clinical use is not fit for long term treatment; on the other hand the antiplatelet drugs have an anti-thrombotic effect but they seem to be unable to control intimal hyperplasia. Low molecular weight heparins (LMWH) have an anti-thrombotic effect superimposable to that of UH with minimal side-effects and might inhibit intimal hyperplasia too. Based on these criteria, we carried out an experimental study on sheep with the aim of evaluating the efficacy of postoperative treatment with LMWH versus an anti-platelet drug in controlling intimal hyperplasia and growth of true endothelial cells in small prosthetic ePTFE grafts (4 mm) interposed in the carotid artery. At the operation, 30 sheep were randomly located in 3 groups: A = control group, no treatment; B = Ticlopidine hydrochloride 250 mg/bid by mouth for 4 weeks; C = LMWH 3.075 IU AXa (0.3 ml) sc preoperatively and then once a day for the same period. Complete thrombosis of the graft occurred in 7 sheep of group A, 5 in B and 2 partial in group C. The intimal hyperplasia was moderate-severe in group A, mild-moderate in group B and no-mild in group C. True endothelial cells were found mainly in the LMWH group; in the other groups and in other portions of the grafts the cellular coverage was accomplished almost completely by fibroblasts. The study is still in progress with 6 further sheep treated with LMWH.

Short report: erythema nodosum leprosum lymphadenitis.

A case of isolated erythema nodosum lymphadenitis involving the paravertebral, intercostal, and cervical lymph nodes without concomitant skin involvement is reported in a 62-year-old male patient under treatment for lepromatous leprosy.