Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas

Overexpression of HMGA1 proteins is a constant feature of human carcinomas. Moreover, rearrangements of this gene have been detected in several human benign tumors of mesenchymal origin. To define the role of these proteins in cell transformation in vivo, we have generated transgenic mice overexpressing ubiquitously the HMGA1 gene. These mice developed mixed growth hormone/prolactin cell pituitary adenomas and natural killer (NK)-T/NK cell lymphomas. The HMGA1-induced expression of IL-2 and IL-15 proteins and their receptors may account for the onset of these lymphomas. At odds with mice overexpressing a wild-type or a truncated HMGA2 protein, adrenal medullar hyperplasia and pancreatic islet cell hyperplasia frequently occurred and no increase in body size and weight was observed in HMGA1 mice. Taken together, these data indicate an oncogenic role of the HMGA1 gene also in vivo.     

Avoidable errors in cardiac surgery: anastomosis of the left internal mammary artery to a vein

We report the case of a patient who had undergone a three-vessel coronary artery bypass graft surgery 6 years earlier, during which the left internal mammary artery was erroneously anastomosed to an epicardial vein instead of the intended target, an intramyocardial left anterior descending artery. Visually distinguishing artery from vein can be occasionally challenging and can lead to errors in distal anastomosis. This case report identifies two difficult problems in cardiac surgery and discusses the techniques to differentiate between arterial and venous targets.     

No evidence of ATP1A2 involvement in 12 multiplex Italian families with benign familial infantile seizures

A missense mutation in the gene encoding the alpha(2) subunit of the Na(+),K(+) ATPase pump (ATP1A2) was found in a family with both familial hemiplegic migraine (FHM) and Benign Familial Infantile Seizures (BFIC). As it is still unclear whether ATP1A2 is responsible for pure BFIC syndromes, we checked mutations of the ATP1A2 gene in probands of 12 Italian multiplex families with pure BFIC, who were negative for mutations in the SCN2A gene. We screened the ATP1A2 gene by denaturing high performance liquid chromatography (D-HPLC) and direct sequencing of DNA fragments showing an aberrant elution pattern. We found one exonic variant and five intronic variants, none leading to significant amino acid changes or causing a modification of the physiological mRNA maturation. The ATP1A2 gene does not appear to be involved in the ethiopathogenesis of pure BFIC syndromes, at least in the explored Italian multiplex families. It could be either responsible of a minority of cases, or of complex syndromes where BFIC and FHM co-occur.     

Pure red-cell aplasia in a peritoneal dialysis patient with HCV-related cryoglobulinemia in the absence of neutralizing antierythropoietin antibodies

Pure red-cell aplasia (PRCA) in recombinant human erythropoietin (rHuEpo) treated patients is a matter of growing concern. In most cases, neutralizing anti-EPO antibodies have been detected in patient serum and held responsible for the development of PRCA. We describe a 68-year-old white woman suffering from HCV-related cryoglobulinemia and chronic kidney disease on renal replacement therapy with peritoneal dialysis. Five months after the introduction of epoetin-b therapy she developed a PRCA, as shown by the bone marrow aspirate. Cryocrit rose from 5% to 15% at this time, reticulocyte count fell, while white blood cells and platelets remained within normal values. Epoetin-b therapy was discontinued and steroid treatment was started. The test for anti-erythropoietin antibodies was negative. Hemoglobin and reticulocytes progressively rose and steroid therapy was tapered and eventually stopped, when the cryocrit was 3%. We propose that a relapse in the HCV-related cryoglobulinemia might be held responsible for the erythropoietic marrow failure.     

Outcome of patients with cardiac diseases admitted to coronary care units: a report from Lazio, Italy

BACKGROUND: Coronary care units (CCUs) currently treat a variety of diseases, but little is known about the effectiveness of CCUs on heart conditions other than acute myocardial infarction. OBJECTIVES: The objectives of this study were to evaluate the association between direct admission to CCUs and the risk of inhospital death in patients with heart disease, to investigate factors affecting direct admission to a CCU, and to assess the effect of CCU admission on the use of invasive procedures in patients with arrhythmias. RESEARCH DESIGN: We conducted a retrospective analysis of discharge-abstract data from Lazio, Italy, hospitals. We used logistic regression, propensity score, and instrumental variable analysis to compare inhospital risk of death between patients admitted to CCUs and to ordinary wards in 13 different groups of heart disease. We used linear regression to study the association between the rate of CCU admission and the relative risk of death. RESULTS: The study included 181,049 heart disease admissions, of which 8620 were admitted to CCUs (4.8%). Risk of death was significantly lower in patients admitted directly to CCUs for "acute myocardial infarction" (odds ratio [OR], 0.57), "acute ischemic heart disease" (OR, 0.55), and "other arrhythmias" (OR, 0.56). Mortality ORs were inversely related to the rate of CCU admission. CCU patients with arrhythmias received more invasive procedures (OR, 2.70) than non-CCU patients. CONCLUSION: Direct admission to a CCU is associated with a decrease in mortality for patients with "acute myocardial infarction," "acute heart ischemia," and "other arrhythmias." Patients most likely to benefit from CCU care are preferentially admitted to CCUs. CCUs make larger use of invasive procedures than ordinary wards.     

Therapy of human pancreatic carcinoma based on suppression of HMGA1 protein synthesis in preclinical models

Pancreatic carcinoma is one of the most aggressive tumors, and, being refractory to conventional therapies, is an excellent target for new therapeutic approaches. Based on our previous finding of high HMGA1 expression in pancreatic cancer cells compared to normal pancreatic tissue, we evaluated whether suppression of HMGA1 protein expression could be a treatment option for patients affected by pancreatic cancer. Here we report that HMGA1 proteins are overexpressed in pancreatic carcinoma cell lines, and their downregulation through an adenovirus carrying the HMGA1 gene in an antisense orientation (Ad Yas-GFP) results in the death of three human pancreatic carcinoma cell lines (PANC1, Hs766T and PSN1). Pretreatment of PANC1 and PSN1 cells with Ad Yas-GFP suppressed and reduced, respectively, their ability to form xenograft tumors in nude mice. To further verify the role of HMGA1 in pancreatic tumorigenesis, we used a HMGA1 antisense phosphorothioate oligodeoxynucleotide (ODN); its addition induced a decrease in HMGA1 protein levels and a significant reduction of the proliferation rate of PANC1-, Hs766T- and PSN1-treated cells. Therefore, suppression of HMGA1 protein synthesis by an HMGA1 antisense approach seems to be a feasible treatment strategy in pancreatic carcinomas.     

The tyrosine phosphatase PTPRJ/DEP-1 genotype affects thyroid carcinogenesis

We recently isolated the r-PTPeta gene, which encodes a receptor-type tyrosine phosphatase protein that suppresses the neoplastic phenotype of retrovirally transformed rat thyroid cells. The human homologue gene PTPRJ/DEP-1 is deleted in various tumors. Moreover, the Gln276Pro polymorphism, located in the extracellular region of the gene, seems to play a critical role in susceptibility to some human neoplasias. Here we report the loss of heterozygosity (LOH) of PTPRJ in 11/76 (14.5%) informative thyroid tumors (including adenomas and carcinomas). We also looked for the Gln276Pro, Arg326Gln and Asp872Glu polymorphisms in exons 5, 6 and 13 of PTPRJ in 88 patients with thyroid tumors and in 54 healthy individuals. We found that the PTPRJ genotypes homozygous for the Gln276Pro and Arg326Gln polymorphisms, and the Asp872 allele were more frequent in thyroid carcinoma patients than in healthy individuals (P=0.032). In addition, PTPRJ LOH was more frequent in thyroid carcinomas of heterozygotes for Gln276Pro and Arg326Gln compared with homozygotes (P=0.006). This suggests that the presence of hemizygosity for these polymorphisms in the tumor facilitates tumor progression. These results indicate that the genotypic profile of PTPRJ affects susceptibility to thyroid carcinomas, and that allelic loss of this gene is involved in thyroid carcinogenesis.