Altered pattern of circulating matrix metalloproteinases -2,- 9 and tissue inhibitor of metalloproteinase-2 in patients with HCV-related chronic hepatitis. Relationship to histological features.

AIM: The aim of this paper was to assess circulating levels of metalloprotease2 (MMP2), metalloprotease9 (MMP9) and tissue inhibitor of metalloprotease2 (TIMP2) in patients with HCV-related chronic hepatitis to verify whether there was a relationship between these molecules and biochemical and histological features. METHODS: Forty-nine neodiagnosed and untreated patients affected by chronic C hepatitis and twenty healthy control subjects were investigated. In overall study series, circulating levels of MMP2, MMP9 and TIMP2 were assessed by ELISA commercial kit (R&D Systems). Patients with chronic hepatitis undergone to liver biopsy and histological features were examined according to Histological Activity Index (HAI). RESULTS: Mean values of MMP2 (1989+/-207 ng/mL. vs 1112+/-120 ng/mL), MMP9 (62.44+/-11.9 ng/mL vs 39.67+/-4.6 ng/mL) and TIMP2 (48.3+/-8.1 ng/mL vs 15.16+/-4.1 ng/mL) were significantly higher (P<0.001) in patients than in controls. Among investigated molecules, only MMP2 was independently related to inflammation and fibrosis according to grading (P=0.036) and staging (P=0.032) score. Moreover, MMP2 but not MMP9 and TIMP2 was related to AST (P=0.015), ALT (P=0.049) and AST/platelet ratio index (P=0.001). No relationship (P>0.05) was found between MMP2 and MMP9 or TIMP2. CONCLUSIONS: Our study confirms an altered pattern of metalloproteases and their tissue inhibitors in subjects with chronic C hepatitis and such alterations can contribute to development of liver fibrosis. In addition MMP2 is related to inflammation and fibrosis as assessed by liver biopsy and laboratory features. The serial detection of MMP2 could help to monitor evolution of disease and to predict onset of cirrhosis.

Defective function of the Fas apoptotic pathway in type 1 diabetes mellitus correlates with age at onset.

The Fas death receptor triggers lymphocyte apoptosis through an extrinsic and an intrinsic pathway involving caspase-8 and -9 respectively. Inherited defects of Fas function are displayed by a proportion of patients with Type 1 diabetes mellitus (T1DM) especially those with a second autoimmunity (T1DM-p). This study assesses activation of both pathways in Fas-resistant (FasR) patients to localize the defect. 21/28 (75 percent) T1DM-p, 14/50 (38 percent) T1DM, and 7/150 (5 percent) controls were FasR. Analysis of the 35 FasR patients and 20 Fas-sensitive (FasS) controls showed that caspase-9 activity was lower in T1DM-p and T1DM than in controls, whereas caspase-8 activity was lower in T1DM-p than in T1DM and the controls. Single patient analysis showed that 16/35 patients displayed defective activity of one (FasR1), whereas 19 displayed normal activity of both caspases (FasR2). Ages at onset of diabetes mellitus in T1DM and the second autoimmune disease in T1DM-p were lower in FasR than in FasS patients. All FasR1 patients developed diabetes mellitus before the age of 9 years, whereas a later onset was displayed by 26% FasR2 and 53% FasS patients. These data show that defective Fas function may involve both the extrinsic and intrinsic pathway in T1DM and severity correlates with the precocity of the autoimmune attack and its tissue polyreactivity.

Cephalosporin-induced Hemolytic Anemia in a Sicilian Child.

A 27-month-old child developed acute hemolysis on two occasions after the administration of cephalosporin. On the first occasion, hemolysis was intravascular and was due to the formation of complexes between antibodies and the drug, which bound to red blood cells and caused severe hemolysis. On the second occasion, hemolysis was extravascular and was probably due to antibody-dependent cell mediated cytotoxicity. Marked increases in levels of CD19(+), and CD57(+) CD8(+) cells were detected among the subpopulations of the patient's lymphocytes but only in the level of CD19(+) cells from the patient's father, after incubation of a sample of whole blood with a solution of cephalosporins. These results might explain the differences between the immune response of the patient and those of other members of his family and of an unrelated control.

Cephalosporin-induced Hemolytic Anemia in a Sicilian Child; Erythropoiesis.

A 27-month-old child developed acute hemolysis on two occasions after the administration of cephalosporin. On the first occasion, hemolysis was intravascular and was due to the formation of complexes between antibodies and the drug, which bound to red blood cells and caused severe hemolysis. On the second occasion, hemolysis was extravascular and was probably due to antibody-dependent cell-mediated cytotoxicity. Marked increases in levels of CD(19) (+) and CD(57) (+) CD(8) (+) cells were detected among the subpopulations of the patient's lymphocytes but only in the level of CD(19) (+) cells from the patient's father, after incubation of a sample of whole blood with a solution of cephalosporins. These results might explain the differences between the immune response of the patient and those of other members of his family and of an unrelated control.

Effect of alpha-interferon on natural killer cell activity and lymphocyte subsets in thalassemia patients with chronic hepatitis C.

The variation of natural killer (NK) cell activity and lymphocyte subsets 20 h after a single test dose of alpha-IFN, was studied in 17 thalassemic patients with chronic hepatitis C. All patients had suspended the alpha-IFN therapy at least 12 months before the study: 10 were considered responders and 7 nonresponders. Also NK cell cytotoxicity after in vitro incubation with alpha-IFN was studied. The administration of a single dose of alpha-IFN increased NK cell cytotoxic activity significantly in the group of responders and in non-responders; moreover the NK cell cytotoxic activity after alpha-IFN in vitro incubation increased both in responders and nonresponders, but to a lesser degree than in healthy controls. Absolute values of CD4+ and CD8+ lymphocytes decreased significantly only in responders. In conclusion, our data suggest that the variation of NK cytotoxic activity and lymphocyte subsets after a test dose of alpha-IFN can be considered a parameter related to IFN biological effects.

[Determination of lactic dehydrogenase isoenzymes in precancerous and cancerous gastric mucosa]. / Determinazio degli isoenzimi della latticodeidrogenasi nella mucosa gastrica in corso di lesioni cancerose e precancerose.

We have studied modifications of LDH isoenzymes pattern in normal human gastric mucosa as well as in adenocarcinoma and precancerous lesions of the stomac (gastritis and ulcer); samples from the injured and the surrounding non-injured area were examined, drawing up the isoenzymes, using Tris-buffer pH 7,4 at 4 degrees C and performing the determination within 1 h - because of the high chronolability of the fractions LDH and LDH by cellogol electrophoresis separation. We have always noticed - especially in samples from adenocarcinoma- a shifting toward the M chains, with a clear increase of the fractions LDH4 and LDH5; this has been noticed even in the surrounding non-injured area.

Human maternal and fetal serum insulin and growth hormone (HGH) response to glucose and leucine.

Maternal and fetal serum insulin and HGH responses to glucose, leucine, and glucose plus leucine were examined by infusions to pregnant women at term immediately before cesarean section. Leucine (15 gm.) with glucose (50 gm.) administered for 30 minutes to the mothers stimulates markedly maternal and fetal insulin secretion while infusion of glucose (50 gm.) causes a lower insulin response. When infusing glucose alone we noted that the duration rather than the degree of hyperglycemia determined the fetal insulin response. In fact, when glucose is given to the mother for 60 minutes the fetal insulin response is higher than when the same dose is infused for 30 minutes. Maternal infusion of leucine (15 gm.) for 30 minutes elicits only a very slight increase of insulin secretion in the mother and no change in the fetus. None of the infusions causes any alteration whatsoever in either maternal or fetal HGH secretion.