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Biomedical subjects

R Corrocher

Publications and source records attributed to R Corrocher.

At least 73 records · Page 4Linked to original sources
PubMed1997

Hereditary hyperferritinemia-cataract syndrome caused by a 29-base pair deletion in the iron responsive element of ferritin L-subunit gene.

Iron availability regulates ferritin synthesis posttranscriptionally by the interaction between iron-regulatory proteins (IRPs) and an iron responsive element (IRE), a stem-loop sequence located on the 5' untranslated region of ferritin mRNA. IRPs recognize IREs as a sequence/structure motif, blocking ferritin translation. Recently, we and others independently described families with a combination of hyperferritinemia (serum L-ferritin > or = 1,000 microg/L, without iron overload) and congenital bilateral cataract, transmitted as an autosomal-dominant trait. The molecular basis were two distinct point mutations in the highly conserved CAGUG(X) hexaloop of L-ferritin IRE on chromosome 19. A new three-generation family with a similar phenotype and a unique genotype is here reported. DNA amplification by polymerase chain reaction and sequence analysis showed a 29-base pair deletion in the L-ferritin IRE, involving the whole 5' sequence essential to the base pairing of the IRE stem. This deletion is predicted to cause the disruption of IRE stem-loop secondary structure and the nearly complete abolition of the negative control of ferritin synthesis by IRE/IRP binding. Hereditary Hyperferritinemia-Cataract Syndrome (HHCS) appears as a new genetic disorder with a unique phenotype associated with at least four different mutations in the L-ferritin IRE. Hematologists should take into account HHCS in the differential diagnosis of unexplained hyperferritinemia.

Adult↗
PubMed1997

Deficiency of Src family kinases Fgr and Hck results in activation of erythrocyte K/Cl cotransport.

Src-family kinases play a central role in regulation of hematopoietic cell functions. We found that mouse erythrocytes express the Src-family kinases Fgr and Hck, as well as Lyn. To directly test whether Fgr and Hck play any role in erythrocyte function, we analyzed red cells isolated from fgr-/-, hck-/-, and fgr-/- hck-/- knock-out mice. Mean corpuscular hemoglobin concentration and median density are increased, while K content is decreased, in fgr-/- hck-/- double-mutant erythrocytes compared with wild-type, fgr-/-, or hck-/- erythrocytes. Na/K pump and Na/K/Cl cotransport were not altered, but K/Cl cotransport activity was significantly and substantially higher (approximately three-fold) in fgr-/- hck-/- double-mutant erythrocytes. This enhanced K/Cl cotransport activity did not depend on cell age. In fact, in response to bleeding, K/Cl cotransport activity increased in parallel with reticulocytosis in wild-type erythrocytes, while abnormal K/Cl cotransport did not change as a consequence of reticulocytosis in fgr-/- hck-/- double-mutant erythrocytes. Okadaic acid, an inhibitor of a phosphatase that has been implicated in activation of the K/Cl cotransporter, inhibited K/Cl cotransport in wild-type and fgr-/- hck-/- double-mutant erythrocytes to a comparable extent. In contrast, staurosporine, an inhibitor of a kinase that has been suggested to negatively regulate this same phosphatase enhanced K/Cl cotransport in wild-type but not in fgr-/- hck-/- double-mutant erythrocytes. On the basis of these findings, we propose that Fgr and Hck are the kinases involved in the negative regulation of the K/Cl cotransporter-activating phosphatase. Abnormality of erythrocyte K/Cl cotransport in fgr-/- hck-/- double-mutant animals represents the first demonstration that Src-family kinases may be involved in regulation of membrane transport.

Animals↗
PubMed1997

Membrane cation and anion transport activities in erythrocytes of hereditary spherocytosis: effects of different membrane protein defects.

Hereditary spherocytosis (HS) is due to different membrane protein defects (i.e., deficiency of spectrin and ankyrin, band 3, or band 4.2). In order to gain new insight into the relationships between band 3 function and proteins associated with the cytoskeleton, we studied erythrocyte anion transport activity in HS characterized by different membrane protein defects. Anion transport activity was increased in HS due to partial band 4.2 deficiency or to band 4.2 absence, while in HS associated with deficiency of spectrin + ankyrin or band 3, the anion transport results were normal or decreased, respectively. Moreover, since HS erythrocytes are characterized by an increased Na and a decreased K, we studied the principal membrane cation transport pathways. Activity of the Na/K pump was increased in all HS studied, while no changes in Na/K/2Cl cotransport and Na/Li exchange were evident between control and HS as well as between forms of HS associated with different membrane protein defects. K/Cl cotransport activity was decreased in all HS studied compared to normal red cells. In all HS, passive membrane permeability to Na and K was increased compared to normal erythrocytes. The increased Na and the low K content can be attributed to the abnormal membrane permeability to cations, which is not related to a specific membrane protein defect.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1997

Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa. European Concerted Action on Viral Hepatitis (EUROHEP).

The aim of this study was to evaluate whether interferon alfa (IFN-alpha) treatment-associated virological and biochemical remission improves survival in a cohort of 90 white patients with compensated cirrhosis caused by hepatitis B (Child A) followed for a mean period of 7 years. Inclusion criteria were biopsy-proven cirrhosis, hepatitis B e antigen (HBeAg) positivity, abnormal serum aminotransferase levels, exclusion of hepatitis delta virus, and absence of complications of cirrhosis. Of the 40 IFN-treated patients, 27 (67%) showed sustained HBeAg loss with alanine aminotransferase (ALT) normalization. Of the 50 untreated patients, 30 (60%) cleared HBeAg, but only 21 (42%) normalized ALT after HBeAg loss. Compared with the untreated patients, IFN-treated patients had similar cumulative rates of HBeAg clearance (P = .48), but higher rates of ALT normalization (P = .016) and of HBsAg loss (P = .028). During follow-up, liver-related death occurred in 8 treated patients, caused by liver failure in 5 and hepatocellular carcinoma (HCC) in 3; all 8 had continued to be HBeAg-positive with elevated ALT. None of the treated patients undergoing remission developed liver-related complications. At univariate analysis, life expectancy was longer in treated patients showing sustained remission than in those who did not (5-year survival: 100% vs. 81%; P = .048). Fourteen untreated patients died (from liver failure in 10 and HCC in 4); all but 3 had continued to be HBeAg-positive with elevated ALT. Cox's model identified age and ALT normalization as the only significant predictors of survival. In conclusion, in patients with HBeAg-positive compensated cirrhosis, virological and biochemical remission following IFN therapy is associated with improved survival.

Alanine Transaminase↗
PubMed1997

Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP).

BACKGROUND/AIMS: The role of interferon alfa treatment in improving morbidity endpoints in patients with chronic hepatitis C infection is currently under debate. The aim of this study was to evaluate the effectiveness of interferon in preventing hepatocellular carcinoma and decompensation in cirrhosis type C. METHODS: A retrospective cohort study was carried out on 329 consecutive Caucasian patients with cirrhosis followed for a mean period of 5 years at seven tertiary care university hospitals. Inclusion criteria were biopsy-proven cirrhosis, anti-HCV positivity, abnormal serum aminotransferase levels and absence of complications of cirrhosis. RESULTS: The yearly incidence of hepatocellular carcinoma was 2.3% for 136 untreated patients and 1.0% for 193 patients treated with interferon alfa. The yearly incidence of hepatic decompensation was 5.7 for untreated and 1.5 for the treated patients. Fourteen (7%) of 193 treated patients showed sustained aminotransferase normalization and none of them developed complications of cirrhosis. At enrollment, untreated patients were older and had more severe liver disease than patients treated with interferon. After adjustment for clinical and serologic differences at entry between treated and untreated patients, the 5-year estimated probability of the occurrence of hepatocellular carcinoma was 2.1% and 2.7% and of decompensation was 7% and 11% for treated and untreated cases, respectively. CONCLUSIONS: This analysis did not detect any significant benefit of interferon alfa on morbidity in patients with compensated cirrhosis type C, although it suggests a reduction in complications of cirrhosis for those with a sustained response to therapy, and it indicates the need for better therapies.

Antiviral Agents↗
PubMed1997

Increased membrane ratios of metabolite to precursor fatty acid in essential hypertension.

Desaturase enzymes are responsible for the conversion of essential fatty acids to the longer-chain eicosanoid precursors. These enzymes require zinc as an essential cofactor, and the following ratios-C20:4/C18:2, C20:5/C18:3, and C22:6/C20:5-are considered indexes of their activity. We analyzed these parameters in plasma and erythrocyte membranes of 105 essential hypertensive patients, 20 white coat hypertensive patients, and 100 age-matched normotensive control subjects. Dietary analysis excluded significant quantitative and qualitative differences in fatty acid dietary intake between essential hypertensive patients and normotensive control subjects. Zinc levels and C20:4/C18:2, C20:5/C18:3, and C22:6/ C20:5 ratios were significantly higher in essential hypertensive patients than control subjects, whereas white coat hypertensive patients showed intermediate values for all these parameters. These data provide evidence for an alteration in fatty acid metabolism of essential hypertensive patients, consistent with increased activity of desaturase enzymes. The consequent greater bioavailability of eicosanoid precursors, and in particular of arachidonic acid, could affect several vascular functions and have a bearing on the pathogenesis or complications of hypertension.

Adult↗
PubMed1997

["Hyperferritinemia-cataract syndrome." Description of a new hereditary disease, from anamnesis to molecular diagnosis].

A new autosomal-dominant genetic disorder, which has been recently identified by our group is described. The disease is clinically characterized by the combination of a substantial increase of serum ferritin and early-onset bilateral cataract. Moreover, it is clearly distinguishable from genetic hemochromatosis because of: 1) normal to low serum iron and transferrin saturation, without evidence of parenchymal iron overload; 2) the dominant transmission; 3) the lack of any relation with HLA; 4) the rapid development of iron-deficient anemia when unnecessary phlebotomies are performed. The molecular basis of the new syndrome is a mutation in the L-subunit ferritin gene on chromosome 19 (19q13.3-->19qter). The mutation involves a five nucleotide sequence [CAGUG] of the iron-responsive-element (IRE), which is critical for the post-transcriptional regulation of ferritin synthesis by means of the binding with an Iron Regulatory Protein. As a consequence, ferritin synthesis is up-regulated, irrespective of cell iron status.

Adult↗
PubMed1996

Serum laminin P1 in chronic viral hepatitis: correlations with liver histological activity and diagnostic value.

Laminin is a major basement membrane-associated, non-collagenous glycoprotein of the extracellular matrix and is deposited in the space of Disse during sinusoidal capillarisation. Laminin P1, a pepsin-resistant fragment originating from the central portion of the cross-shaped laminin molecule, is detectable in serum and has been related to liver fibrosis and portal hypertension. In this study we investigated the behaviour of serum laminin P1, measured by radioimmunoassay, in a homogeneous group of 95 patients suffering from chronic viral hepatitis, types C or B, in order to determine the relationships between serum laminin P1 and each of the main histological aspects of the disease process (i.e. portal-periportal activity, lobular activity and fibrosis), which were assigned numerical scores. Moreover, we computed, at several cut-off levels, the sensitivity, specificity and positive and negative predictive values of laminin P1 in detecting both necroinflammatory activity and fibrosis in the liver. The results show that serum laminin P1 levels parallel the severity of liver disease, the highest laminin concentrations being observed in cirrhotic patients. They suggest also that serum laminin P1 should be considered a marker of the liver disease process as a whole, rather than a marker exclusively linked to fibrosis. Nevertheless, the usefulness of serum laminin P1 measurement, as investigated in this study, seems too limited to be recommended for routine clinical practice.

Adolescent↗
PubMed1996

[Intermittent chyluria in a young man].

Chyluria is the passage of chylus into urine resulting in fistulization through the lymphatic system and the urinary system. This rare condition is usually caused by filaria infestation or malformations, neoplasia or trauma. We report a case of a 18-year-old man. The patient presented milky urine which had appeared after angiography following minor leg trauma. Physical examination revealed asymmetry of the face and cutaneous dyschromia. Blood tests revealed hypogammaglobulinemia and altered CD4/CD8 ratio (0.6). Urine tests showed proteinuria (30 mg/dl), lipiduria (triglycerides 750 mg/dl) and density of 1025. Renal function was normal. Abdomen computed tomography and urography were normal. Cystoscopy revealed the presence of milky urine in the bladder and selective catheterization revealed that the origin was the right ureter alone. Ascendent pyelography did not reveal any malformation of the urinary tract; but after this the chyluria spontaneously disappeared. The patient was rehospitalized 3 months later for recurrence. Lymphography was then performed and revealed a dilated lymphatic network with minute lacunar images projecting into the right kidney. Chyluria again disappeared spontaneously and recurred sporadically over the next two years in a patient who remained in good physical condition. The etiology of chyluria in a patient without filaria infestation is problematic, particularly when the most common causes (tuberculosis, neoplasia, trauma) are excluded as in our case. The asymmetry of the face, together with cutaneous dyschromia and the presence of a subarachnoidea cyst in the right temporal region suggested our patient had multiple congenital malformations.

Abnormalities, Multiple↗
PubMed1996

Changes of fatty acid composition and oxidative metabolism of human neutrophils migrating into an inflammatory exudate.

The peripheral blood neutrophils and the neutrophils accumulated into a skin-window experimental exudate were compared for their ability to release superoxide anion (O2-) and for their fatty acid composition, determined by capillary gaschromatography. The basal O2- release and the phorbol myristate acetate (PMA)-induced O2- release were not significantly different in the two neutrophil populations, while in response to formyl-methionyl-leucyl-phenylalanine (fMLP) the exudate cells showed an activity that was two fold higher than that of blood cells. The most significant changes of fatty acid composition of exudate versus blood cells were the following: i) increase of C16:0 (palmitic acid) from 21.3 +/- 1.2% to 23.5 +/- 1.3% (+ 10.2%) of total fatty acids (p < 0.001),ii) increase of C18:2 (linoleic acid) from 9.3 +/- 1.7% to 11.0 +/- 2.1% (+ 18.3%) (p = 0.005), iii) decrease of C20:4 (arachidonic acid) from 12.8 +/- 1.6% to 10.6 +/- 1.2% (-17.3%) (p < 0.001), whereas C18:1 (oleic acid) did not change. The total content of saturated or unsaturated fatty acids did not change. In exudate cells, a strong negative correlation was found between palmitic acid content and O2- release in response to both fMLP and PMA (r = -0.52, p < 0.02 and r = -0.49, p < 0.05, respectively) whereas arachidonic acid correlated positively, but weakly, with O2- (r = 0.40, p = 0.07 and r = 0.47, p = 0.05, with fMLP and PMA as stimulants respectively). A positive correlation was also found between the arachidonic acid content of blood cells and the number of cells that migrated into the inflammatory exudate. These results indicate that the process of extravasation from blood into the exudate causes specific and consistent modifications of the fatty acid composition of neutrophils and suggest that these modifications have a role in the activation and the regulation of the O2- forming system.

Chemotaxis, Leukocyte↗
PubMed1996

Selenium, zinc, and thyroid hormones in healthy subjects: low T3/T4 ratio in the elderly is related to impaired selenium status.

Iodothyronine 5' deiodinase, which is mainly responsible for peripheral T3 production, has recently been demonstrated to be a selenium (Se)-containing enzyme. The structure of nuclear thyroid hormone receptors contains Zinc (Zn) ions, crucial for the functional properties of the protein. In the elderly, reduced peripheral conversion of T4 to T3 with a lower T3/T4 ratio and overt hypothyroidism are frequently observed. We measured serum Se and RBC GSH-Px (as indices of Se status), circulating and RBC Zinc (as indices of Zn status), thyroid hormones and TSH in 109 healthy euthyroid subjects (52 women, 57 men), carefully selected to avoid abnormally low thyroid hormone levels induced by acute or chronic diseases or calorie restriction. The subjects were subdivided into three age groups. To avoid under- or malnutrition conditions, dietary records were obtained for a sample of 24 subjects, randomly selected and representative of the whole population for age and sex. Low T3/T4 ratios and reduced Se and RBC GSH-Px activity were observed only in the older group. A highly significant linear correlation between the T3/T4 ratio and indices of Se status was observed in the older group of subjects (r = 0.54; p < 0.002, for Se; r = 0.50; p < 0.002, for RBC GSH-Px). Indices of Zn status did not correlate with thyroid hormones, but RBC Zn was decreased in older as compared with younger subjects. We concluded that reduced peripheral T4 conversion is related to impaired Se status in the elderly.

Adult↗
PubMed1996

Resistance to activated protein C, associated with oral contraceptives use; effect of formulations, duration of assumption, and doses of oestro-progestins.

Resistance to activated protein C (APC-R) is at present considered the most frequent laboratory abnormality in patients with deep vein thrombosis. An increased risk for venous thrombosis is associated with the use of oral contraceptives (OCs). We recently described a statistically significant association between APC-R status and oral contraceptives use in a healthy group of women. We re-evaluated 50 healthy women taking low-dose combination OCs in order to consider a possible correlation between the APC sensitivity ratio (APC-SR) and different oral contraceptive formulations. Seven women showed an APC ratio < or = 2 (APC-resistant). Only one of the seven women was found to be heterozygous for Leiden factor V mutation. We observed no significant differences between normally sensitive and APC-resistant women in terms of duration of OC use, amount of estrogenic or progestogenic dose, or type of formulation. We conclude that APC-resistance associated with oral contraceptives use seems to occur only in predisposed subjects (in our results, about 12% of the healthy population).

Adolescent↗
PubMed1996

Influences of lipid and non-lipid nutritional parameters on factor VII coagulant activity in normal subjects: the Nove study.

Community-based studies have suggested that the dietary intake of total fat influences factor VII coagulant activity (FVIIc), a predictor of fatal events from coronary heart disease (CHD). Nevertheless, the question whether the quality of dietary fats, with special reference to fatty acids (FAs), influences FVIIc is unsolved. The authors investigated in 90 healthy volunteers living in Nove, a village near Vicenza (northern Italy), the relationships between FVIIc and the plasma concentration of individual FAs. Several indices of other nutritional factors that have recently received increasing attention as determinants of CHD risk (antioxidant vitamins A and E, oligoelements) were also included in the multivariate analysis. The stepwise multiple linear regression analysis revealed body mass index (BMI), and the concentrations of plasma stearic acid (C18:0) and serum copper as significant independent predictors of a substantial proportion of FVIIc variability (R = 0 center dot 52; R2 = 0 center dot 27; P < 0 center dot 001). This study substantially supports the role of the plasma concentration of stearic acid as an important factor in modulating FVIIc.

Adult↗
PubMed1996

Cryoglobulinemia in hepatitis C virus chronic active hepatitis: effects of interferon-alpha therapy.

We investigated the prevalence of mixed cryoglobulinemia (MC) in 100 cases of chronic hepatitis C virus (HCV) infection and the effect of a 6-month treatment with interferon-alpha (IFN-alpha). Cryoglobulins were detected on admission in 36 of 100 patients and appeared during observation in a further 18 cases. Cryocrit ranged from 0.5% to 20%. Patients with MC were older and had a higher incidence of cirrhosis than those without MC. Immunologic characterization of the cryoprecipitate showed the presence of type II in 84% of cases and type III in 16%. The patients received IFN-alpha (6 MU three times per week) for 6 months. Fifty-seven were responders (i.e., reached normal aminotransferase levels), 26 of these relapsed within 2 months after IFN withdrawal, and 30 did not relapse. After IFN-alpha treatment, cryoglobulinemia disappeared in 11 of the 21 evaluable responders, but in none of the 15 nonresponder patients (p < 0.003). The clearance of MC was associated in all cases with clearance of HCV RNA. The delayed appearance of cryoglobulinemia in responders seems to be associated with a higher probability of relapse.

Adjuvants, Immunologic↗
PubMed1996

Long-term variations of serum laminin and procollagen III peptide in chronic HCV hepatitis after alpha-interferon therapy.

Twenty-three out of 40 patients affected by chronic HCV hepatitis responded (i.e. aminotransferases returned to normal) after 6-month treatment with 6 MU tiw of recombinant alpha-interferon 2a (IFN); in 11 (Group 1), the remission was maintained for a mean observation time of 33.15 months (range 20-50) after withdrawal of therapy; 12 (Group 2) relapsing after IFN withdrawal, were treated again obtaining in 10 a second response. Seventeen did not respond (Group 3). Serum markers of connective tissue metabolism (laminin and aminoterminal peptide of type III procollagen -NPIIIP-) were assayed in all patients before treatment and every 6th month, to evaluate long-term effects of IFN therapy. In non-responders, NPIIIP after treatment was not different from baseline, while laminin significantly increased at 6 and 12 months; in responders, NPIIIP decreased significantly after therapy, maintaining values lower than baseline on long-term observation. Laminin decreased significantly six months after the end of therapy and remained lower than baseline in all sustained responders. In this group, the drop in laminin was progressive, whereas in Group 2, laminin showed only a slight decrease on long-term control. Our data show that these serum markers persistently decrease in sustained responders to IFN, while in relapsed cases, prolonged therapy is needed to obtain minor effects on laminin; on the contrary, in non-responders, NPIIIP remains unchanged and laminin significantly increases, suggesting a persistence of active fibrogenesis.

Antiviral Agents↗
PubMed1996

Effects on fibrogenesis markers of rheumatoid arthritis therapy with methotrexate.

OBJECTIVE: To evaluate the level of 2 serum markers of hepatic fibrogenesis, aminoterminal peptide of type III procollagen (NPIIIP) and laminin P1 fragment (Lam), in patients with rheumatoid arthritis at baseline and after one year of low dose methotrexate (MTX) therapy. METHODS: Serum levels of NPIIIP and Lam were measured in 20 patients, 17 women and 3 men, mean age 48.83 +/- 9.25 yrs. before and after MTX treatment and compared to levels from 20 sex and age matched, healthy controls. RESULTS: The baseline values of NPIIIP was higher in patients than in controls; it normalized after MTX treatment. The Lam level did not differ between patients and controls; moreover, it did not change after treatment. CONCLUSION: Low dose MTX therapy does not increase serum indicator levels of hepatic fibrogenesis.

Adult↗
PubMed1995

Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the "Verona mutation")

Recently, we described a new genetic disorder (the "hereditary hyperferritinemia-cataract syndrome") clinically characterized by the combination of elevated serum ferritin and congenital bilateral nuclear cataract, both cotransmitted as an autosomal dominant trait. In affected subjects, hyperferritinemia (ranging from 950 to 2,259 micrograms/L) is typically not related to iron overload. Differently from subjects with hereditary hemochromatosis, they have normal to low levels of serum iron and percent of transferrin saturation and absence of iron overload in parenchymal organs. When unnecessary phlebotomies are performed, they rapidly develop iron-deficient anemia, with persistently elevated levels of serum ferritin. By RNA-single-strand conformation polymorphism screening of the L-subunit ferritin gene on chromosome 19, we were able to identify in affected subjects a mutation in the 5' untranslated region. This mutation involves the five nucleotides sequence [CAGUG] of the iron-responsive element (IRE), which is critical for the posttranscriptional regulation of ferritin synthesis by means of IRE-binding protein (IRE-BP). Thus, it is very likely to provide the molecular basis for the iron-insensitive upregulation of ferritin synthesis in affected subjects.

Adult↗