Biomedical subjects
Publications and source records attributed to F Santini.
Two cases are presented of accelerated aortic allograft fibrocalcification after right ventricular outflow tract (RVOT) reconstruction occurring within 2 months after surgery in a 5-year-old and 22-month-old. Potential determinants of early calcification, clinical management after implantation and surgical alternatives are discussed.
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The fundamental mechanisms by which receptors once targeted for endocytosis are found in coated pits is an important yet unresolved question. Specifically, are activated receptors simply trapped on encountering preexisting coated pits, subsequently being rapidly internalized? Or do the receptors themselves, by active recruitment, gather soluble coat and cytosolic components and initiate the rapid assembly of new coated pits that then mediate their internalization? To explore this question, we studied the relationship between activation of IgE-bound high affinity Fc receptors (FCepsilonRI) and coated pit formation. Because these receptors are rapidly internalized via clathrin-coated pits only when cross-linked by the binding of multivalent antigens, we were able to separate activation from internalization by using an immobilized antigen. The FCepsilonRIs, initially uniformly distributed over the cell surface. relocalized and aggregated on the antigen-exposed membrane. The process was specific for the antigen, and temperature- and time-dependent. This stimulation initiated a cascade of cellular responses typical of FCepsilonRI signaling including membrane ruffling, cytoskeletal rearrangements, and, in the presence of Ca2+, exocytosis. Despite these responses, no change in coated pit disposition or in the distribution of clathrin and assembly protein AP2 was detected, as monitored by immunoblotting and by quantitative (vertical sectioning) confocal microscopy analysis of immunofluorescently stained cells. Specifically, there was no decrease in the density of clathrin-coated pits in regions of the cell membrane not in contact with the antigen, and there was no apparent increase in clathrin-coated pits in proximity to stimulated FCepsilonRI receptors as would have been expected if the receptors were inducing formation of new pits by active recruitment. These results indicate that de novo formation of clathrin-coated pits is not a prerequisite for rapid internalization or a direct response to stimulation of FCepsilonRI receptors. Therefore, increases in coated pits reported to occur in response to activation of some signaling receptors must be consequences of the signal transduction processes, rather than strictly serving the purpose of the internalization of the receptors.
Percutaneous intranodular ethanol injection (PEI) has been proposed for the therapy of autonomously functioning thyroid nodules. In 1992, an Italian multicenter study was undertaken to confirm the usefulness and the feasibility of this procedure. The study included 429 patients: 242 (56.4%) were affected by a toxic adenoma (TA) and 187 (43.5%) by pretoxic adenoma (PTA). Free thyroid hormone levels (FT4, FT3) and thyroid stimulating hormone (TSH) were measured before and 3, 6, 12 months after the end of treatment; thyroid ultrasound and thyroid scintiscan were performed in the majority of patients before and after treatment. Patients underwent 2-12 sessions of ethanol injection under sonographic guidance (median 4). The total amount of ethanol administered per patient (1.5 mL/mL nodular volume) was 2-50 mL (mean +/- SD, 17 +/- 9 mL), and the amount per each injection was 1-8 mL (3.2 +/- 1.3 mL). The treatment was judged successful when both TSH and free thyroid hormone serum levels returned within the normal range and recovery of tracer uptake in extranodular tissue was observed at scintiscan, at any time during the follow-up period. The treatment was considered unsuccessful when no change was observed at scintiscan and/or serum TSH levels remained less than 0.4 mU/L. A successful treatment was achieved in 66.5% of patients with TA and in 83.4% of patients with PTA, when assessed after a 12-month follow-up. In all cases a reduction of the nodular size was observed. Almost all positive results were obtained in nodules whose initial volume was less than 15 mL; large nodules responded less favorably. The treatment was generally well tolerated, only transient side-effects, mainly local pain at the time of injection, were observed. Once normalization of scintigraphic image and of FT4, FT3 and TSH serum concentrations was achieved, no recurrence of hyperthyroidism nor development of hypothyroidism were observed for the length of the study. In conclusion, percutaneous ethanol injection for treatment of autonomously functioning thyroid nodules is effective and safe. Better results are obtained in patients with PTA than in patients with TA, particularly when the initial volume of the nodule is less than or equal to 15 mL. PEI may be considered as an alternative to surgery and to radioiodine for treatment of autonomously functioning thyroid nodules.
Sulfation is an important pathway of triiodothyronine (T3) metabolism. Increased serum T3 sulfate (T3S) values have been observed during fetal life and in pathological conditions such as hyperthyroidism and selenium deficiency. Similar variations have also been reported in a small number of patients with systemic non-thyroidal illness, but the underlying mechanisms have not been elucidated. In this study, serum T3S concentrations have been measured by a specific radioimmunoassay in 28 patients with end-stage neoplastic disease (ESND) and in 44 patients with chronic renal failure (CRF); 41 normal subjects served as controls. Both ESND and CRF patients had lower serum total T4 (TT4) and total T3 (TT3) than normal controls, while serum reverse T3 (rT3) was increased significantly in ESND (0.7 +/- 0.5 nmol/l; p < 0.001 vs. controls) but not in CRF (0.3 +/- 0.1 nmol/l). The TT3/rT3 ratio, an index of type I iodothyronine monodeiodinase (type I MD) activity, was reduced significantly in both groups of patients. Serum T4-binding globulin (TBG) was decreased in CRF but not in ESND patients. Serum T3S was significantly higher both in ESND (71 +/- 32 pmol/l) and CRF (100 +/- 24 pmol/l) than in controls (50 +/- 16 pmol/l, p < 0.001). Serum T3S values showed a positive correlation with rT3 values and a negative correlation with both TT3 and FT3 values in ESND, but not in CRF. In the latter group a positive correlation was observed between T3S and TBG values. The T3S/FT3 ratio was higher both in CRF (18 +/- 5) and in ESND (23 +/- 18) as compared to controls (10 +/- 4). Serum inorganic sulfate was increased and correlated positively with T3S values in CRF patients. In conclusion, the results of this study in a large series of patients confirm that patients with systemic non-thyroidal illness have increased serum T3S levels. The mechanisms responsible for these changes appear to be different in ESND and CRF patients. In ESND the increase in serum T3S levels is mainly related to reduced degradation of the hormone by type I MD, whereas in CRF it might be driven by the enhanced sulfate ion concentration, and could be partially dependent on the impaired renal excretion of T3S. Because T3S can be reconverted to T3, it is possible that increased T3S concentrations contribute to maintenance of the euthyroid state in systemic non-thyroidal disease.
The authors describe the clinical profile and epidemiology of contagious bovine pleuropneumonia in Europe. This disease, once considered to have been eradicated several years ago, has now become endemic in southern countries of Europe. The status of contagious bovine pleuropneumonia in Portugal and Italy, and the evolution of the disease during the last ten years, are analysed in detail, in addition to the measures undertaken for control and eradication. The authors also refer to hosts and possible reservoirs of the infection.
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The Mg(2+)-dependent serine/threonine protein phosphatases, also known as type 2C phosphatases (PP2C), belong to a gene family distinct from the other serine/threonine phosphatases and tyrosine phosphatases. Here we report the purification to apparent homogeneity of a novel Mg(2+)-dependent, Ca(2+)-inhibitable serine/threonine protein phosphatase from bovine brain. It is a type 2C enzyme in view of its Mg2+ requirement, resistance to okadaic acid and calyculin A, inability to use phosphorylase alpha as substrate, and a segment of amino acid sequence typical of all PP2C type phosphatases known to date. However, it differs from the other PP2C enzymes, particularly the mammalian PP2C alpha and -beta isoforms, in that its molecular weight, 76,000, is considerably larger and that it is inhibited by Ca2+, NaF, and polycations, but not by orthovanadate. The Ca2+ inhibition may not be related to its cellular regulation because of Ki values in the 20-90 microM range, but this property permits distinction of this enzyme from the other phosphatases. Although the precise physiological role of this phosphatase is not yet known, its ability to dephosphorylate a wide variety of phosphoproteins and its broad distribution, as shown by a survey of mouse tissues for its activity, suggest that it may serve an important cellular function.
The role of mitogen-activated protein (MAP) kinase in the release of arachidonic acid was examined in a mutated mast cell (RBL-2H3(m1)) line that expressed both native Fc epsilon R1 and the G protein-coupled muscarinic m1 receptor. Stimulation of these cells with Ag, carbachol, Ca(2+)-ionophore, or thapsigargin resulted in the phosphorylation of Raf1, MEK1, p42mapk MAP kinase, and the recently cloned cytosolic phospholipase A2 (PLA2) and increased activities of both MAP kinase and PLA2, as well as release of arachidonic acid. Because this cascade of reactions was inhibited by guanosine 5'-(2-thiodiphosphate), it appeared to be dependent on a GTP-binding protein(s). These reactions, however, were not dependent on protein kinase C; the cascade was totally resistant to the actions of a selective protein kinase C inhibitor, Ro31-7549, whereas release of the secretory granule marker, hexosaminidase, was blocked by this agent. Differences between the stimulatory pathways for release of arachidonic acid and hexosaminidase were evident also from the effects of the kinase inhibitor, quercetin. The above cascade of reactions, including release of arachidonic acid, was inhibited by 50% with approximately 5 microM quercetin, whereas secretion was inhibited only at higher concentrations of inhibitor. Moreover, inhibition of the activation of MAP kinase and release of arachidonic acid were closely correlated. This and previous findings suggested that release of arachidonic acid was attributable to the regulation of cytosolic PLA2 by MAP kinase (for activation of PLA2) and Ca2+ (for association of PLA2 with the membrane), whereas release of hexosaminidase was regulated primarily by Ca2+ and protein kinase C.
Type I-iodothyronine monodeiodinase (type I-MD) is abundant in thyroid tissue and contributes to the generation of T3 secreted by the gland. The availability of a specific antibody against rat type I-MD (type I-MD Ab) allowed us to directly identify this enzyme in rat thyroid glands, and in a differentiated strain of rat thyroid cells maintained in continuous culture (FRTL-5 cells). FRTL-5 cells maintain many differentiated functions of thyroid cells, including the expression of TSH receptor and thyroid peroxidase. Using an immunohistochemical technique on rat thyroid sections, a clear staining for type I-MD was demonstrated in follicular cells. The degree of immunoreactivity was greater in small follicles containing little amounts of colloid compared to large follicles lined by functionally inactive cells. Using immunofluorescence (IFL), a strong staining for type I-MD was observed in FRTL-5 cells grown in medium containing TSH. Both in vivo and in culture the staining for type I-MD was localised in the cytoplasm of thyroid cells, while nuclei were negative. Interestingly, no surface staining was shown when viable FRTL-5 cells were submitted to the same IFL procedure. TSH deprivation for 7 days was followed by the disappearance of type I-MD. Immunoreactivity for type I-MD was recovered by addition of TSH, forskolin or thyroid stimulating antibody (TSAb) to TSH-deprived FRTL-5 cells. The effect of TSH was prevented by cycloheximide. There was no induction of type I-MD when IGF-I was added to FRTL-5 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Tetralogy of Fallot [S,D,I] is a recently discovered form of tetralogy with solitus atria (S) and D-loop ventricles (D), but with inverted normally related great arteries (I). Because of infundibuloarterial inversion, the right coronary artery must traverse the stenotic pulmonary outflow tract, increasing the risk of surgical trauma to the right coronary artery. Here we report a case of successful surgical repair of tetralogy of Fallot [S,D,I] without the use of an extracardiac conduit.
BACKGROUND: The use of homograft tissue in cardiac surgery has progressively increased so that supply is limited, especially in the sizes required for neonatal and infant cardiac operations. METHODS: We developed in recent years a technique for surgically reducing the size of more readily available large-diameter homografts, making them suitable for right ventricular outflow tract reconstruction in small infants. This is achieved by means of a longitudinal incision of the oversized conduit, excision of one homograft cusp, and oversewing of the "bicuspid" homograft wrapped around a dilator of appropriate size. Five patients (2 male, 3 female) ranging in age from 20 days to 11 months (mean age, 8.3 months) and ranging in weight from 3.2 to 7.4 kg (mean 6.2 kg) underwent reconstruction of the right ventricular outflow tract using this surgical technique (tetralogy of Fallot/pulmonary atresia, 3 cases; truncus arteriosus, 1 case; double-outlet right ventricle, 1 case). RESULTS: There were no operative deaths and no instances of valve-related complications at a mean follow-up of 19 months. Serial echocardiography shows mild homograft stenosis in 1 patient (15 mm Hg) and mild homograft insufficiency in 1 patient. CONCLUSIONS: Although a longer follow-up is certainly required to determine whether the surgically modified bicuspid homografts will be as durable as the intact ones when positioned in the right ventricular outflow tract, we believe that this technique may represent a valuable therapeutic alternative, at least in the short term, to the use of synthetic grafts when an appropriately sized homograft is not available.
Spontaneous rupture of an aortic aneurysm into the pulmonary artery is unusual and is rarely reported in the literature. The case of a patient with a syphilitic aneurysm of the ascending aorta perforated into the pulmonary artery is presented. In an attempt to define the best surgical treatment for this complication the literature has been comprehensively reviewed.
Between January 1992 and June 1994, 23 patients underwent surgery for aortic valve endocarditis at the Department of Cardiovascular Surgery of the University of Verona; a subgroup of 10 patients underwent aortic valve replacement with a porcine stentless valve (Biocor LTDA n = 8; Toronto SPV n = 2). There were 7 males and 3 females with a mean age of 56.3 years (range, 36 to 73 years). Eight patients had active endocarditis and two had healed endocarditis. Nine patients had native valve in endocarditis, the presence of a bicuspid aortic valve in 2, and 1 patient had recurrent prosthetic valve endocarditis (PVE), 7 of whom were in New York Heart Association (NYHA) Functional Class IV. The main indications for operation were congestive cardiac failure, active sepsis, and presence of large and mobile vegetations by echo and arrhythmias. There were no operative or late mortalities in this subgroup of patients. Short-term survival is 100% at a mean follow-up time of 11.2 months (range, 4 to 18 months), with no recurrent endocarditis or valve-related complications.
A 73-year old man developed an acute prosthetic aortic valve dehiscence for which emergent operation was undertaken. The intraoperative evidence of an aortic annular disruption and of a subannular abscess led to the hypothesis that an endocarditis process was involved. The aortic valve was replaced with a stentless porcine bioprosthesis. Cultures taken intraoperatively from the aortic area had a pure growth of aerobic, spore-forming, gram-positive bacilli identified as Bacillus licheniformis. The patient responded to specific antibiotic therapy with no relapse at a 20-month follow-up. The potentiality of B. licheniformis as a pathogen should be reconsidered.
Male Sprague-Dawley rats were fed a selenium-deficient yeast-based laboratory diet or a control diet for 6 wk. The tissue type I 5'-monodeiodinase (5'-MDI) activity and the immunoassayable 5'-MDI were significantly (P < 0.05) reduced in the liver and the kidney but not in the thyroid of selenium-deficient rats. The mean serum concentrations of thyroxine sulfate (T4S), 3,3',5'-triiodothyronine sulfate (T3S), and reverse T3 sulfate (rT3S) (ng/dl) were significantly increased in selenium-deficient rats (15.7, 59.4, and 22.8, respectively, n = 12) compared with control rats (< 1.0, 18.5, and 9.1, respectively, n = 12, P < 0.01). Kinetic studies were carried out during a constant infusion of unlabeled sulfated iodothyronines (T4S, T3S, or rT3S, n = 5-6/group) at a rate of 1 microgram/h by Alzet minipump for 48 h. The data showed that elevated serum concentrations of T4S or T3S in the selenium-deficient rat are due both to reduced metabolic clearance rate (MCR, mean, l.kg-1.day-1, 7.4 for T4S and 4.5 for T3S in selenium deficiency vs. 12 and 9.2, respectively in controls, P < 0.05) and increased production rate (mean, microgram.kg-1.day-1, 1.2 for T4S, and 2.7 for T3S in selenium deficiency vs. 0.12 and 1.7, respectively, in the controls, P < 0.05). However, the increased serum rT3S concentration in selenium-deficient rats is due mainly to reduced MCR (mean, l.kg-1.day-1, 34 vs. 67 in controls, P < 0.05) and its daily production rate remained unchanged in selenium deficiency (mean, microgram.kg-1.day-1, 7.6 vs. 6.1 in the control group, P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
A role of thyroid autoimmunity in the pathogenesis of myxedematous endemic cretinism was suggested by reports indicating the presence of thyroid growth-blocking antibodies in the sera of these patients. To check this hypothesis, we searched for TSH receptor antibodies with thyroid growth-blocking or adenylate cyclase (AC)-inhibiting (TSH-blocking) activity in immunoglobulin G (IgG) from 18 euthyroid and 21 hypothyroid endemic cretins living in Italy and Peru. Among hypothyroid cretins, 12 had no palpable goiter. Stages I-III goiters were present in 12 of 18 euthyroid cretins. Controls included 25 euthyroid nongoitrous subjects living in the same endemic regions as cretins, and 10 normal subjects from an iodine-sufficient area. IgG from 4 selected patients with autoimmune atrophic thyroiditis and from 2 neonates with sporadic transient congenital hypothyroidism due to maternal TSH-blocking antibodies were included in the study. The blocking effect of the IgG was assessed in FRTL-5 cells by measuring TSH-stimulated [3H]thymidine incorporation, DNA accumulation, and AC activation. A radioreceptor assay was used to detect TSH-binding inhibiting antibodies (TBIAb). No IgG from hypothyroid endemic cretins without goiter contained TBIAb or inhibited TSH-stimulated cell growth or AC activation. The effect of IgG from hypothyroid nongoitrous cretins did not differ from that produced by IgG from hypothyroid cretins with goiter, euthyroid cretins with or without goiter, or normal controls. In contrast to these results, IgG from patients with autoimmune atrophic thyroiditis and from neonates with sporadic transient congenital hypothyroidism contained TBIAb that inhibited both TSH-stimulated cell growth and AC activation. In conclusion, our results indicate that, similar to other types of endemic cretinism, hypothyroid endemic cretins without goiter do not have TSH receptor antibodies able to inhibit TSH-stimulated thyroid cell growth or function. These observations argue against a role of humoral thyroid autoimmunity in the development of myxedematous endemic cretinism.
Between July 1994 and March 1995, seven patients (six male) with a mean age of 27 years (range 18 to 34 years) were selected for aortic valve replacement with a pulmonary autograft (Ross operation). The aortic valve disease was isolated insufficiency in four cases, stenosis in one and mixed lesion in two. Three patients had a bicuspid aortic valve. Previous cardiac surgical procedures had been performed in two cases (coarctation repair and valvuloplasty in one; isolated aortic valvuloplasty in one). Two patients were in NYHA class II and five in class III. In two cases the autograft was inserted as a scalloped subcoronary implant. Four patients had total aortic root replacement with re-implantation of the coronary ostia. The RVOT was reconstructed with a cryopreserved homograft (five pulmonary two aortic). The aortic cross-clamp time was 150 +/- 10 minutes with a total bypass time of 212 +/- 14 minutes. There was neither operative nor late mortality. Postoperative echocardiography revealed trivial autograft insufficiency in one case with a mean transvalvular gradient of 15.8 mmHg. All patients improved symptomatically (100% in NYHA class I). Freedom from reoperation, valve related complications and endocarditis is 100% at a mean follow up of 5.6 months (range 1-9 months). This preliminary experience supports the concept of pulmonary autograft implantation in selected patients.