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M Agostini

Publications and source records attributed to M Agostini.

At least 37 records · Page 2Linked to original sources
PubMed1999

Three novel mutations at serine 314 in the thyroid hormone beta receptor differentially impair ligand binding in the syndrome of resistance to thyroid hormone.

The syndrome of resistance to thyroid hormone is associated with diverse mutations in the ligand-binding domain of the thyroid hormone beta receptor, localizing to three clusters around the hormone binding cavity. Here, we report three novel resistance to thyroid hormone mutations (S314C, S314F, and S314Y), due to different nucleotide substitutions in the same codon, occurring in six separate families. Functional characterization of these mutant receptors showed marked differences in their properties. S314F and S314Y receptor mutants exhibited significant transcriptional impairment in keeping with negligible ligand binding and were potent dominant negative inhibitors of wild-type receptor action. In contrast, the S314C mutant bound ligand with reduced affinity, such that its functional impairment and dominant negative activity manifest at low concentrations of thyroid hormone, but are more reversible at higher T3 concentrations. The degree of functional impairment of mutant receptors in vitro may correlate with the magnitude of thyroid dysfunction in vivo. Modelling these mutations using the crystal structure of thyroid hormone receptor beta shows why ligand binding is perturbed and why the phenylalanine/tyrosine mutations are more deleterious than cysteine.

Adolescent↗
PubMed1998

A role for helix 3 of the TRbeta ligand-binding domain in coactivator recruitment identified by characterization of a third cluster of mutations in resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) has hitherto been associated with thyroid hormone beta receptor (TRbeta) mutations which cluster in two regions (alphaalpha 310-353 and alphaalpha 429-461) of the hormone-binding domain and closely approximate the ligand-binding cavity. Here, we describe a third cluster of RTH mutations extending from alphaalpha 234-282 which constitute a third boundary of the ligand pocket. One mutant, T277A, exhibits impaired transactivation which is disproportionate to its mildly reduced ligand affinity (Ka). T3-dependent recruitment of coactivators (SRC-1, ACTR) by mutant receptor-RXR heterodimers was reduced in comparison with wild-type. Cotransfection of SRC-1 restored transactivation by T277A. In the TRbeta crystal structure this helix 3 residue is surface-exposed and is in close proximity to residues L454 and E457 in helix 12 which are known to be critical for coactivator interaction, suggesting that they all constitute part of a receptor-coactivator interface. The transcriptional function of other mutants (A234T, R243W/Q, A268D, Delta276I, A279V, R282S) in this cluster correlated with their reduced Ka and they inhibited wild-type TRbeta action in a dominant negative manner. DNA binding, heterodimerization and corepressor recruitment were preserved in all mutants, signifying the importance of these attributes for dominant negative activity and correlating with the absence of natural mutations in regions bordering the third cluster which mediate these functions.

Amino Acid Sequence↗
PubMed1998

Detection of a new de novo mutation at codon 251 of exon 8 of thyroid hormone receptor beta gene in an Italian kindred with resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) is almost invariably associated with mutations of the thyroid hormone (TH) receptor beta (hTR beta) gene and is inherited as an autosomal dominant disease. Mutations of hTR beta identified in patients affected by RTH cluster generally at two spots of the ligand binding domain. We investigated whether an Italian kindred with RTH had a mutation in the thyroid hormone (TH) receptor beta gene. Blood samples were obtained from the available family members for biochemical and genetic analyses. Thyroid function tests in basal conditions, and in the case of the propositus also following incremental doses of T3, were performed. Exon 4 to 10 of hTR beta gene were amplified using the polymerase chain reaction (PCR) and the mutation was identified by direct sequence analysis. The affinity constant of this mutated receptor for T3 was measured by in vitro transcription-translation and was then compared with that of wild type. We identified a heterozygous G to A transition at nucleotide 1037 of exon 8 at codon 251, resulting in a glycine (G) to glutamic acid (E) substitution (G251E) in the patient affected by RTH and in his affected offspring, but not in the normal family members. This novel mutation represents a de novo mutation since both parents of the index case were unaffected and did not have this genomic mutation. When expressed in vitro, the mutant protein (G251E) showed a marked decrease of the affinity for T3, suggesting an impaired ligand-dependent transactivation activity of this mutant receptor. In vivo studies with incremental doses of L-T3 demonstrated a reduced sensitivity to TH in the index case, in particular at the pituitary level where the thyrotrophs' activity was not completely inhibited even by 200 micrograms/day of L-T3. G251E mutation represents the fourth mutation described up to now in exon 8 of hTR beta among the subjects affected by RTH. A third cluster of mutations of the c-erbA beta gene located proximally with respect to the other two so far described begins to emerge in RTH patients.

Adult↗
PubMed1998

Cisternography in combination with single photon emission tomography for the detection of the leakage site in patients with cerebrospinal fluid rhinorrhea: preliminary report.

The site of leakage in a patients with rhinorrhea of various origin may be difficult to identify. The aim of our paper is to evaluate the contribution of cisternography in combination with single photon emission tomography (SPECT) to identify the fistulous track. From 1/1/1992 to 30/11/1997 we studied 20 patients with rhinorrhea posing a challenging diagnostic problem as to identification of the leakage site. Two mls of Indium DTPA (In 111) were injected into the subarachnoid space by the lumbar route. The tracer was followed by planar scintigraphy until it reached the cranial base and subsequently the SPECT acquisition started. A fistula was demonstrated in all of our cases including patients with no active leakage at the time of examination, patients with no bone defects on thin sliced CT scanning or patients with a normal MRI. At surgery the fistulous track was confirmed in all but two cases when a bilateral fistula was operatively identified only on one side. In conclusion whenever a CT scanning fails to demonstrate significant bone defects and MRI does not localize a fistulous track, SPECT cisternography via the lumbar route proved in our experience to be a reliable examination for a precise diagnosis.

Adolescent↗
PubMed1997

Identification and characterization of a novel de novo mutation (L346V) in the thyroid hormone receptor beta gene in a family with generalized thyroid hormone resistance.

We have investigated an Italian family with generalized resistance to thyroid hormone (RTH), consisting of two individuals with elevated serum thyroid hormones (TH) and a non-suppressed TSH, together with unaffected family members, for a mutation in the thyroid hormone receptor beta gene (hTR beta). We have identified a single nucleotide substitution (1321 CTT to GTT) corresponding to a leucine to valine substitution at codon 346 (L346V) in the predicted protein. The index case and her affected child are heterozygous for the receptor defect, with normal sequence in unaffected family members. Furthermore, both parents of the index case were unaffected, suggesting that the mutation had arisen de novo. When expressed in vitro, the L346V mutant receptor showed a marked reduction in its affinity for tri-iodothyronine (T3), impaired ligand-dependent transactivation and potent dominant negative activity. Its functional impairment could not be alleviated, even at supraphysiological concentrations of T3, suggesting that the mutation might interfere with the intrinsic ligand-dependent transactivation function (AF-2) located in the hormone binding domain of hTR beta. Finally, the presence of the L346V mutation in the son of the propositus, who died from complications associated with congenital heart disease, raises the possibility that RTH might have contributed to the pathogenesis or severity of the latter.

Adult↗
PubMed1997

[A case of a urachal fistula].

The authors report a case of urachal fistula diagnosed after repeated omphalitis, this disease was associated with coronal hypospadias. Diagnosis was done thanks to a fistulography; subsequently, during the operation, to evidence the fistula, this was injected with methylene blue, this expedient showed that the fistula was longer than that disclosed from fistulography. To carry out a complete extirpation of the fistula the authors were bound to make a cystotomy. The course after operation was good and the patient discharged after a few days. After 5 years the patient is in perfect health. This case allowed some anatomic, clinical and semeiotic considerations.

Cutaneous Fistula↗
PubMed1996

The association between rhabdomyolysis and acute renal failure in patients undergoing cardiopulmonary bypass.

OBJECTIVE: The authors describe 9 cases of rhabdomyolytic acute renal failure (ARF) as a complication of cardiopulmonary bypass. EXPERIMENTAL DESIGN: Retrospective research between June 1992 and March 1994. SETTING: Department of Cardiac Surgery. PATIENTS: 931 consecutive patients undergoing major cardiac surgery. INTERVENTIONS: Patients affected by rhabdomyolytic ARF were treated with pharmacological therapy and/or plasmapheresis/continuous arteriovenous hemofiltration. In seven patients indirect cannulation of the femoral artery was used. MEASURES: Incidence, risk factors of syndrome results obtained with pharmacological treatment, CAVH and plasmapheresis were evaluated. Statistical analysis was performed with ANOVA, Tukey Kramer test and chi2 test (p<0.05 as significant). RESULTS: The syndrome occurred in 0.96% (9/931 patients) of the total cases; 11.3% (6/53 -p<0.0000) in patients undergoing a direct femoral artery cannulation for cardiopulmonary bypass and 9.5% (2/21, p<0.01) in patients in which the aortic balloon pump was used. Six patients develop acute anuric renal failure and underwent plasma exchange and hemodialysis (1 case) or CAVH (5 cases); 3 patients underwent early medical treatment and developed developed acute renal failure (ARF) with preserved diuresis. Early medical therapy appeared to prevent the evolution towards anuric ARF. The indirect cannulation of the femoral artery does not seem to produce a rhabdomyolytic ARF syndrome. In patients with direct femoral artery cannulation risk factors appear to be: arteriopathy (p<0.001), prolonged extra corporeal circulation (p<0.001), low cardiac output syndrome (p<0.001), continuous i.v. infusion of epinephrine (p<0.0001). CONCLUSIONS: Rhabdomyolytic acute renal failure is a severe complication, early identification of patients ¿at risk¿ is most important. The preventive measures and the therapy adopted proved efficient.

Acute Kidney Injury↗
PubMed1995

[Traumatic rupture of the chordae tendineae in acute tricuspid insufficiency. Early detection with transesophageal echocardiography].

An uncommon case of traumatic rupture of chordae tendineae with tricuspid regurgitation is described. The early diagnosis, in a patient with polydistrectual injuries, was done by transesophageal echocardiography. This technique allowed accurate diagnosis of the type of lesion suggesting the opportunity to perform an echocardiogram, possibly transesophageal, in all patients with blunt thoracic trauma, even in the absence or with subtle clinical manifestations of cardiovascular involvement.

Accidents, Traffic↗
PubMed1994

[Predictive value of the shunt-to-infarct size ratio as a surgical risk factor in patients with decompensated post-ischemic interventricular septal rupture].

Postischemic septal rupture has always been evaluated, in respect of surgical indication, as regards the time lapse between infarct and rupture, interval between rupture and operation, extension of myocardial damage and general risk factors such as age, sex and associated pathologies. But in fact the surgeon is dealing with a two sided problem, the MI and the rupture, and thus surgical results depend upon both the residual ventricular function after MI and the consequences of volume overload on a damaged muscle. Surgical indication could not be based on a single criterion only. Extension of the MI alone is not fully predictive of operative mortality because, aside the reperfusion injury, the repair further jeopardizes viable myocardium and alters ventricular geometry; although the shunt appears unrelated to mortality it certainly interferes with operative outcome at least because of the time elapsed between rupture and repair. So far an index which could correlate the extension of myocardial damage and the entity of the shunt with each other was not available. Patients with septal rupture follow an emergency protocol and are often insufficiently investigated but every patients has a least one echo-Doppler evaluation or even a ventriculography while one or more ECGs are always available. With the presumption that the Qp/Qs is roughly indicative of the right ventricular volume overload and that ecg signs of myocardial infarct are always reliable, we have reviewed among our 24 patients with septal rupture those where a full ecg tracing and a quantitative Echo or angiographic evaluation of the shunt were available.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

The "fully no-touch" technique for the internal thoracic-coronary artery anastomosis.

Extreme technical accuracy is crucial in coronary artery surgery. Although late graft patency depends mostly upon the patient's own biochemical status in chronic ischemic patients who have undergone elective surgery, graft disease is certainly promoted by an inaccurate technique or by careless arterial harvesting, which may cause both intimal lesions and anastomotic strictures. We describe a technique of internal thoracic-coronary artery anastomosis that fully prevents contact between vessels and surgical instruments. In order to enable the suturing of a fully dilated vessel, intracoronary papaverine is injected into the clamped aortic root while the heart is still beating and before systemic cooling begins. The suturing technique applies some microvascular principles, the chief being a high number of stitches incorporating the least amount of tissue, to avoid bulk.

Aorta↗
PubMed1993

Variability of DA/DAPI and C heterochromatic regions: a population study.

DA/DAPI and C chromosomal heteromorphic sites (1q, 9q, 15p, 16q, Yq) in a sample of 136 unrelated individuals from the Garfagnana valley (Tuscany, Italy) have been analyzed quantitatively and qualitatively. The variations in length, between-homolog heteromorphisms, and intensity of fluorescence of the heterochromatic bands have been compared in two subsamples of the population (upper and middle valley) individualized according to geodemographic criteria. DA/DAPI heterochromatin differed significantly from C heterochromatin, showing a lower average amount and a higher variability at each site. This suggests a differential staining of DNA of the two banding systems. Furthermore, DA/DAPI heterochromatin was less uniformly distributed in the population than C heterochromatin and the regions 16q and Yq discriminated better between subsamples. The variations of DA/DAPI fluorescence at the 15p site demonstrated an excess of homomorphic individuals in the upper valley, which could be related to the mating structure of the population living in this area.

Adolescent↗
PubMed1993

Genetic polymorphism in the Garfagnana population (Tuscany).

Blood group systems ABO, KEL, MN, RH, secretor status for ABH blood group substances, red cell enzymes ACP1, ESD, AK1, 6-PGD, PGM1 subtypes, serum markers GC, TF, PI, AHSG, ORM1 and chromosomal heteromorphism Q, C, DA/DAPI were examined in a population sample of the Garfagnana, a semi-isolated mountainous area in the province of Lucca (Tuscany, Italy). The total sample was subdivided and analysed according to the more recent historical events which have occurred in Garfagnana. The observed phenotype and gene frequencies were discussed in the context of other population samples from the same province and of the same region. As a whole, the results concur in pointing out a certain degree of heterogeneity within the area and a high differentiation from the rest of Tuscany. Such peculiar genetic features of the population have to be related to the historical, geographic and cultural isolation of the Garfagnana.

Blood Group Antigens↗
PubMed1992

Arterial shunt with pump infusion line for the treatment of chronic thoracic aortic aneurysms: the "modified shunt of Gott".

Dissection of the aneurysm is the most dangerous step during graft replacement of the descending thoracic aorta. Sudden hemorrhage may follow wall rupture or disruption of major collaterals before the aorta can be clamped. A simple modification of the classic Gott is illustrated, which makes the shunt work also as a partial bypass if needed, with rapid reinfusion of blood losses. Nineteen of 25 patients requiring resection of descending aortic aneurysms from 1982 to 1990 were treated with this method with no mortality.

Aorta, Thoracic↗
PubMed1992

Ten years of surgery of aortic dissections and aneurysms. Clinical experience and original contributions.

From January '82 to April '91, 117 patients with aortic disease were operated upon at our University Hospital in Genoa, Italy. Thirty-seven had arch dissections or aneurysms; 66 had acute aortic dissection type A and 14 had aortic dissections or aneurysms type B, acute and chronic. Patients with arch or type B aortic pathology but without surgical indication and cases of post-traumatic aortic transections are not included. There were 84 male and 33 female patients with a mean age of 52 (6 min and 74 max). In the acute patients, the mean interval between clinical onset and surgery was 34 hours (6 min-72 max). All patients with primary arch disease had surgical repair with the aid of deep hypothermia and circulatory arrest (17-96 min). Type A dissections were treated with standard CPBP at 28 degrees C. Surgical techniques included direct suture of intimal tear alone, direct suturing of the two aortic stumps; interposition of Dacron tubular prosthesis; Bentall repair; separated valve and aortic replacement; an original aortic bulb aortoplasty with valve repair; arch replacement with resuturing of one or more aortic trunks. Human fibrin glue (Tissucol) was employed either as haemostatic agent, widely spread over the suture lines or as tissue adhesion agent between dissected aortic layers. Human fibrin glue is adopted because it gathers high glueing capacity and maintenance of the elastic property of the vessel wall. Hospital mortality (30 days) has been 25% in ascending aortic dissections (16/66 patients) and 50% in patients with arch disease (18/37 patients) who needed circulatory arrest. Late mortality 5/83 (6%). Reoperations for aortic valve insufficiency or re-dissection have been 7 (8.4%). Early diagnosis (increasing reliability of 2D-Echo and CT scans), aggressive surgery, meticulous myocardial and cerebral protection and introduction in clinical use of biological glues seem to be the milestones of present and further improvements in surgical results.

Acute Disease↗
PubMed1992

[Acute surgically-treated complications of myocardial infarct. Clinical experience and discussion of surgical indications].

Post-infarction free-wall, papillary muscle and septal myocardium rupture yields a lowering mortality, not only due to the improved surgical technique but also to a more careful selection of surgical candidates. The value of pericardial decompression in cases of free-wall rupture is discussed. Echocardiographic evidence of blood in the pericardium after a myocardial infarction is not a direct indication for a diagnostic sampling, decompression or surgery. Pericardiocentesis is not a risk-free procedure and should be limited to patients with life-threatening acute tamponade. Clinical results of 34 patients operated upon for myocardial rupture, regardless of adopted technique or timing of surgery, confirm that the decision about a patient's operability should follow a careful evaluation of the following risk factors in this order: infarct size, age, cardiogenic shock, multiorgan failure, rupture site, cardiac failure and associated diseases.

Aged↗