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Apoptosis is important for both tissue development and differentiation; its deregulation may contribute to tumourigenesis. In order to clarify the role of Bcl-2, an apoptosis-inhibiting protein, in pancreatic morphogenesis and tumour progression, its immunohistochemical expression was evaluated in 12 samples of fetal pancreas, in 10 samples of adult pancreas with ductal hyperplastic lesions, in 120 cases of primary pancreatic ductal adenocarcinoma, and in 43 synchronous metastatic lymph nodes. To evaluate the role of apoptosis in pancreatic cancer, p53 expression was also studied in tumour samples. Bcl-2 cytoplasmic acinar and ductal immunostaining was found in all fetal and adult tissue samples; ductal hyperplastic lesions were constantly negative. Thirty out of 120 (25%) tumours and 3 out of 43 (7%) lymph nodes expressed Bcl-2, whereas 67 out of 120 (56%) expressed nuclear p53. Well-differentiated tumours (G1) were more frequently Bcl-2-positive (p=0.002); furthermore, there was an inverse correlation between Bcl-2 and p53 expression in primary tumours (p=0.02). Neither Bcl-2 nor p53 influenced patients' prognosis, which was instead affected by N (p=0.02) and M (p<0.0001) status and stage of the disease (p=0.002). It is concluded that Bcl-2 regulates pancreatic morphogenesis and tissue homeostasis from early fetal to adult life and can be considered a phenotypic marker of normal exocrine pancreas. On the other hand, the lack of expression in preneoplastic lesions and the low positivity found in primary tumours and lymph node metastases suggest that Bcl-2 does not play a centralrole in pancreatic tumourigenesis and cancer progression.

We evaluated the possible role of NO in modulating tissue plasminogen activator (t-PA) release in the forearm microcirculation of normotensive subjects and hypertensive patients. Essential hypertensive patients are characterized by endothelial dysfunction because of a reduced NO availability and also show an impaired t-PA release. In healthy volunteers and essential hypertensive patients, we studied local t-PA release and forearm blood flow changes (strain-gauge plethysmography) induced by intrabrachial administration of acetylcholine (0.45 and 1.5 microg/100 mL/min) and of sodium nitroprusside (0.5 and 1.0 microg/100 mL/min), an endothelium-dependent and -independent agonist, respectively. Acetylcholine was also repeated in the presence of intra-arterial infusion of the NO synthase inhibitor N(G)-monomethyl-l-arginine (100 microg/100 mL/min). In normotensive subjects, vasodilation to acetylcholine was blunted by N(G)-monomethyl-l-arginine. In these subjects, acetylcholine infusion induced a significant, dose-dependent increase in net forearm t-PA release. N(G)-monomethyl-l-arginine significantly reduced basal t-PA release, as well as acetylcholine-induced t-PA release. In essential hypertensive patients, vasodilation to acetylcholine was reduced as compared with controls and resistant to N(G)-monomethyl-l-arginine. In contrast to what was observed in healthy control subjects, in hypertensive patients, acetylcholine had no effect on t-PA release. Similarly, N(G)-monomethyl-l-arginine failed to modify either the tonic or the agonist-induced t-PA release. Both tonic and agonist-induced release of NO are directly involved in t-PA release by endothelial cells. Essential hypertension, characterized by a reduction in tonic and stimulated NO availability, is also associated with impaired capacity of t-PA release, suggesting a major role of impaired NO availability in worsening both vasodilation and t-PA release.

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The patterns of degradation and the influence of factor XIII polymerization on fibrin stability were examined in vitro following incubation with leukocyte elastase. In vivo experiments, various factor XIII-polymerized fibrin clots were implanted subcutaneously in mice to evaluate the stability of clots in the extravascular space. Both in vitro and in vivo lysis proceeded faster with nonpolymerized fibrin and was not influenced by the presence of cross-linked alpha 2-plasmin inhibitor. In vivo lysis of implanted clots was prevented by elastatinal, powerful elastase inhibitor, suggesting that granulocyte elastase is chiefly responsible for clot lysis in the extravascular space. To further extend investigations on the mechanisms of fibrinolysis in tissues, we evaluated fibrin and its degradation products in the synovial space. Expression of factor XIII in synovial cells and activities of coagulation factors, fibrinolytic enzymes, and inhibitors were investigated in the synovial fluid of rheumatoid arthritis patients. Immunohistochemical analysis showed deposits of insoluble fibrin on synovial membranes and pannus to an extent related to the progression of the disease. Factor XIII was expressed by fibroblasts and macrophages in the early stages of the disease, whereas in advanced stages factor XIII staining was associated with fibrin. The reduction of certain coagulation factors and high level of thrombin-antithrombin complexes in synovial fluid show a steady activation of the coagulation cascade. The evaluation of fibrinogen degradation products and the pattern of degradation of synovial fibrin(ogen) suggest the participation of leukocyte elastase in fibrin(ogen) lysis in synovial tissue of rheumatoid arthritis.

Sonographically guided percutaneous ethanol injection (PEI) has been recently used with excellent results in the treatment of toxic and pretoxic thyroid adenoma. The aim of the present study was to assess the efficacy of PEI also in the treatment of "cold" thyroid nodules. Twenty patients, each with a single thyroid nodule, underwent PEI. In all cases the nodules were found to be cold by thyroid scintiscan. A total of 16.1 mL +/- 3.1 mL of ethanol was injected once a week. No adverse effects were observed during therapy. A striking nodular shrinkage was obtained in all cases, ranging from 72.8% to 97.6% (mean 84.5%, p < 0.001 vs pretreatment volume). These preliminary results suggest that PEI is an effective and safe therapy that may be useful in the treatment of thyroid nodules as an alternative to other therapies (surgery, L-thyroxine).

The relationship between thyroid dysfunction and breast cancer (BC) is debated. To clarify this controversial issue, a prospective study on thyroid function in BC was performed. The prevalence of thyroid disease was examined in 102 consecutive BC patients with ductal infiltrating carcinoma after surgery and before starting any chemohormonal or x-ray therapy and in 100 age-matched control healthy women living in the same borderline iodine-sufficient geographic area. All subjects were submitted to clinical ultrasound thyroid evaluation and serum free T4, free T3, TSH, thyroperoxidase antibody, and thyroglobulin antibody determination. Fine needle aspiration was performed in all thyroid nodules. Estrogen and progesterone receptors (ER and PR, respectively) were assayed in 92 and 55 BC specimens, respectively. The overall prevalence of thyroid disease was 47 in 102 (46%) in BC patients and 14 in 100 (14%) in controls (P < 0.0001). The prevalence of nontoxic goiter was 27.4% in BC patients and 11% in controls (P = 0.003). Hashimoto's thyroiditis was found in 13.7% of BC patients and in only 2% of the controls (P < 0.005). Other thyroid disorders found in the BC group included 2 cases of Graves' disease, 2 of thyroid carcinoma, and 1 of subacute thyroiditis, whereas in the control group only 1 case of Graves' disease and none of the other disorders were found. Mean free T3, free T4, and TSH concentrations showed no difference between BC patients and controls. The prevalence of thyroperoxidase antibody was higher in BC patients than in controls (23.5% vs. 8%; P < 0.005), whereas the prevalence of thyroglobulin antibody was not different. In BC patients the presence of thyroid antibodies was more frequently associated with clinically detectable autoimmune thyroiditis (14 of 26, 51.8%; P = 0.03) and was more common in the younger group. The positivity of ER was found in 51 of 92 (55.43%) and that of PR was found in 26 of 55 (47.27%) BC specimens. No relationship was found among ER, PR status, and the presence of serum thyroid antibodies. In conclusion, 1) the present study provides evidence that the overall prevalence of thyroid disorders is increased in patients with breast cancer, and 2) thyroid autoimmune disorders, especially Hashimoto's thyroiditis, account to a large extent for the increased prevalence of thyroid disease in patients with breast cancer. This feature is independent from the ER and PR status of the primary tumor. The present findings call attention to the usefulness of screening for thyroid disease in any patient with breast cancer.