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INTRODUCTION Mitral annular calcification (MAC) is a chronic degenerative process involving calcification of the fibrous base of the mitral valve accounting for 12% to 26% of all mitral stenosis (MS) and eventually for significant mitral regurgitation. Calcification often extends to other parts of the mitral valve apparatus but, unlike rheumatic stenosis, does not produce commissural fusion. Surgical treatment carries a high mortality rate due to technical difficulties involving the heavily calcified annulus, advanced age and comorbidities of affected patients. In recent years, transcatheter mitral valve replacement using ballon expandable transcatheter aortic valves in severe MAC (valve-in-MAC) has been used with acceptable success rates. PURPOSE To describe the added value of 3D echo in the diagnostic work-up, decision making and monitoring during the interventional procedure of valve-in-MAC. CASE PRESENTATION Two years ago a 90-year-old female in sinus rhythm with hypertension and known coronary artery disease (CAD) was admitted with symptoms of pulmonary congestion (PC). At that time, a transthoracic 3D echocardiogram showed important MAC with a mitral valve area (MVA) estimated through 3D planimetry of 1.1 cm2, pulmonary artery pressure (PAP) of 53 mmHg, preserved biventricular function and left atrial enlargement. One year later, she was readmitted with unstable CAD and treated with percutaneous transluminal angioplasty. At that time a 3D transesophageal echocardiogram (3DTOE) showed worsening of the MVA now estimated in 0.6 cm2, a mean gradient of 19 mmHg and PAP of 88 mmHg. Albeit optimized medical therapy, her functional status worsened and less than a month later she was again readmitted in NYHA functional class III. Therefore decision making for valve-in-MAC was undertaken. Valve sizing was performed with computed tomography (CT) using the D-shape method with similar findings when compared with 3D TOE measurements. Both methods showed a favourable anatomy of the left ventricular outflow tract. Valve-in-MAC procedure was performed through transvenous transseptal access and an Edwards Sapien3-nr 29 balloon-expandable valve was deployed uneventfully, except for a residual interatrial septal defect measuring 2.2x0.8cm closed two weeks after, as she persisted with PC and pulmonary hypertension. During the procedure, 3DTOE showed a partial thrombosis involving one of the prosthesis leaflets with preserved transvalvular gradients despite anticoagulation. After that, PC resolved and PAP dropped dramatically. The patient was discharged under lifelong anticoagulation and remains asymptomatic until now. CONCLUSION Diagnosing and treating patients with severe MS due to MAC remains a challenge as traditional parameters and interventional procedures don’t apply for this population. Valve-in-MAC is a feasible alternative and 3DTOE may have a pivotal role in the diagnostic work-up and interventional monitoring of these cases. Abstract P247 Figure. 3D echo timeline valve in MAC

INTRODUCTION congenital pulmonary valve stenosis (PVS) accounts for approximately 7% of all congenital heart defects. In less severe and untreated asymptomatic forms, it might have variable outcomes with progressive stenosis or development and worsening of pulmonary regurgitation . Atrial septal defect (ASD) might be associated in up to 20% of the cases rendering an even more unpredictable outcome and efect on right ventricular (RV) volumes and function. Cardiac magnetic ressonance is considered the gold standard method to measure RV function and volumes. Three dimensional echocardiography (3D echo) emerges as a valuable, redproducible and portable alternative not only for RV volume and function analysis but also for structural evaluation. PURPOSE To describe the added value of 3D echo for the diagnostic work-up, decision making and post surgical outcome in a patient with longstanding untreated PVS associated with ASD. CASE PRESENTATION a 56 year old asymptomatic , non syndromic man , was referred by the cardiac surgeon for a comprehensive echocardiographic evaluation (CEE) due to a previous diagnosis of PVS .The patient was aware of this diagnosis since the age of 17 and no intervention was undertaken at that time. More recently a conventional echocardiogram described a moderate PVS with RV enlargement (RVE) and no futher details regarding RV function or surgical feasibility. CEE showed RVE due to volume overload (VO) with indexed end diastolic volume (EDV) of 144ml/m2 (upper limit 76ml/m2), end sistolic volume (ESV) of 57ml/m2 (upper limit 37ml/m2) and an RV ejection fraction (RVEF) of 60% (lower limit 45%) on 3D echo. RV free wall strain (RVFWS) was -25,3% , TAPSE 32mm and fractional area change 46%, all paramenters within the normal range except for RV volumes. Anatomical analysis showed PVS with three leaflets, partial comissural fusion and retraction of the edges yelding a closure gap of at least 8mm and consequent severe regurgitation. Peak transvalvular gradient was 38mmHg and pulmonary artery was dilated measuring 6.4cm. An ostium secundum atrial septal defect (ASD) with left to right shunt measuring 15x9mm by 3D echo contributed for futher RVVO. With these information , surgical intervention was undertaken and consisted of PV replacement, excision and reconstruction of the pulmonary trunk dilation and correction of the ASD. The patient recovered well and returned three months after, for a new evaluation. At that time RV volumes reduced dramatically with EDV and ESV respectively of 44ml/m2 and 19ml/m2 RVEF of 55,7% and RWFWS of -25,6%. CONCLUSION untreated congenital PVS associated with ASD may have a variable outcome . Follow-up is mandatory. In the present case a CEE including more recent technologies like 3D echo and strain imaging helped in defining anatomical findings and RV function analysis thus stating the appropriatness for surgical intervention. Abstract P1467 Figure. 3Decho pre and post surgical analysis

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disease caused by mutations in genes encoding sarcomere proteins. It is the major cause of sudden cardiac death in young high-level athletes. Studies have demonstrated a poorer prognosis when associated with specific mutations. The association between HCM genotype and phenotype has been the subject of several studies since the discovery of the genetic nature of the disease. This study shows the effect of a MYBPC3 compound variant on the phenotypic HCM expression. A family in which a young man had a clinical diagnosis of HCM underwent clinical and genetic investigations. The coding regions of the MYH7, MYBPC3 and TNNT2 genes were sequenced and analyzed. The proband present a malignant manifestation of the disease, and is the only one to express HCM in his family. The genetic analysis through direct sequencing of the three main genes related to this disease identified a compound heterozygous variant (p.E542Q and p.D610H) in MYBPC3. A family analysis indicated that the p.E542Q and p.D610H alleles have paternal and maternal origin, respectively. No family member carrier of one of the variant alleles manifested clinical signs of HCM. We suggest that the MYBPC3-biallelic heterozygous expression of p.E542Q and p.D610H may cause the severe disease phenotype seen in the proband. Resumo A cardiomiopatia hipertrófica (CMH) é uma doença autossômica dominante causada por mutações em genes que codificam as proteínas dos sarcômeros. É a principal causa de morte súbita cardíaca em atletas jovens de alto nível. Estudos têm demonstrado um pior prognóstico associado a mutações específicas. A associação entre genótipo e fenótipo em CMH tem sido objeto de diversos estudos desde a descoberta da origem genética dessa doença. Este trabalho apresenta o efeito de uma mutação composta em MYBPC3 na expressão fenotípica da CMH. Uma família na qual um jovem tem o diagnóstico clínico de CMH foi submetida à investigação clínica e genética. As regiões codificadoras dos genes MYH7, MYBPC3 e TNNT2 foram sequenciadas e analisadas. O probando apresenta uma manifestação maligna da doença e é o único em sua família a desenvolver CMH. A análise genética pelo sequenciamento direto dos três principais genes relacionados à essa doença identificou uma variante em heterozigose composta (p.E542Q e p.D610H) em MYBPC3. A análise da família mostrou que os alelos p.E542Q e p.D610H tem origem paterna e materna, respectivamente. Nenhum familiar portador de um dos alelos variantes manifestou sinais clínicos de CMH. Sugerimos que a expressão heterozigótica bialélica de p.E542Q e p.D610H pode ser responsável pelo fenótipo severo da doença encontrada no probando.

The NH2-terminal domain of pro-opiomelanocortin, designated as the 16-kDa fragment, is highly conserved throughout the vertebrate family and is likely therefore to have an important functional role. Bovine 16-kDa fragment is a 77- residue glycopeptide, which has been found to be glycosylated at threonine 45 and asparagine 65. Available evidence suggests that glycoforms lacking glycans at the O-linked site are processed in the intermediate pituitary at -Arg49-Lys50- to give the residue 1-49 amino-terminal peptide and a carboxyl-terminal glycopeptide referred to as Lys1 gamma 3-melanotropin. Glycoforms carrying O-glycans remain unprocessed in the intermediate pituitary. Thus O-glycosylation is likely to play an important role in controlling the fate of the NH2-terminal portion of pro-opiomelanocortin, thereby affecting the biological events that are influenced by peptides and glycopeptides derived from this domain. In a recent study (Siciliano, R. A., Morris, H. R., McDowell, R. A., Azadi, P., Rogers, M. E., Bennett, H. P. J., and Dell, A. (1993) Glycobiology 3, 225-239), we sequenced the N-glycans attached to Asn-65 of bovine 16-kDa fragment and demonstrated that the acidic components contain, in addition to neutral antennae, a single SO4-4GalNAc beta 1-4GlcNAc beta 1- antenna, which is characteristic of the pituitary glycohormone N-glycans (Baenziger, J. U., and Green, E. D. (1988) Biochim. Biophys. Acta 947, 287-306). We now report the structural characterization of the O-linked oligosaccharides found in bovine 16-kDa fragment. The major component, which constitutes about 80% of the O-glycan population, is a novel sulfated tetrasaccharide, which carries the same sulfated epitope as the N-glycans. This is the first time that the SO4-4GalNAc beta 1-4GlcNAc beta 1- moiety has been observed in O-glycans, and it raises the interesting possibility that the beta-N-acetylgalactosaminyltransferase responsible for the addition of N-acetylgalactosamine to the pituitary glycohormones (Smith, P. L., and Baenziger, J. U. (1988) Science, 242, 930-933) might be capable of glycosylating both N- and O-linked acceptors.

We report the case of a patient who experienced a severe neurologic complication after treatment of diffuse large B-cell lymphoma.A 62-year old patient was diagnosed with a diffuse large B-cell lymphoma and treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone under prophylactic G-CSF substitution. After the second cycle she developed severe neurologic complications with generalized seizures and soporous condition. The MRI showed bilateral areas of signal hyperintensity in the subcortical and cortical regions in both hemispheres, consistent with the diagnosis of a reversible posterior leukoencephalopathy syndrome. The patient was under surveillance in intensive care, and a meticulous control of the blood pressure was performed. She fully recovered within a few days, and MRI changes normalized. Antineoplastic treatment had to be continued, and we chose a combination of rituximab, doxorubicin, etoposide, and prednisone.The reversible posterior leukoencephalopathy syndrome is believed to be the result of altered cerebral autoregulation with impaired blood flow control and resultant endothelial damage caused by different situations and agents. Several chemotherapy agents have been described in association with the syndrome. However, little is known about the prevalence of the syndrome and the follow-up of these patients, especially their further treatment.

It has been suggested that HIV plays a role in the generation of myeloproliferative disorders, including polycythemia vera (PV). Seven cases of polycythemia in HIV patients have been described in the literature, but only 3 of these met criteria for determining a primary origin (vera) of polycythemia. We report a case of PV in a patient infected with HIV. A 45 year old non-smoking homosexual male presented with 15.7 g/dl hemoglobin in 1991, and was diagnosed with HIV. After 7 years, he presented with plethora, splenomegaly, an erythrocyte mass of 71 ml/kg, and an oxygen saturation of 93.9% (the latter three constituting the major criteria for the diagnosis of PV). Erythrocytes 7.35 x 10(6)/ml hemoglobin, 21.4 g/dl, hematocrit 63%, leukocytes 12,400, erythropoietin5 nmoll/ml. These values are all compatible with a diagnosis of PV. The CD4 count was 321 cells/mm(3) and HIV viral load was undetectable. The patient was initially treated with zidovudine. He was then treated with didanosine, lamivudine, and saquinavir, but all of them failed to slow the increase in erythrocyte levels. After a diagnosis of PV, he was treated with hydroxyurea and phlebotomy, which normalized the hemogram. CD4 count rose to 474 cells/mm(3) and HIV viral load remained at undetectable levels. The patient remains in stable condition with combination treatment after 1 year. We suggest that this is a case of HIV infection which may have led to the emergence of polycythemia vera. Treatment of the HIV did not prevent the appearance of the myeloproliferative disorder.

Lamivudine and zidovudine are proving to be an important antiretroviral combination against HIV that is superior to monotherapy. Recently, with the appearance of protease inhibitors, ritonavir has been shown to be a powerful drug when used in combination with reverse transcriptase inhibitors. The objective of this study was to observe the efficacy, adverse events, and changes in the quality of life of AIDS patients receiving treatment for the first time using AZT, 3TC and ritonavir as combination therapy. We selected 36 patients diagnosed with AIDS due to opportunistic infections and evaluated them by assessing their score on quality of life scales (Karnofsky, uniscale - Quality of Life, and Quality of Life Scale), T CD(4) and CD(8) lymphocyte counts, bodyweight and symptoms during a 6 month period. Assessments were made at 2 month intervals. One patient was excluded from the trial, therefore, 35 were assessed during 6 months.Bodyweight increased an average of 7.2%, CD(4) increased 260 cells/mm(3) and CD(8) increased 198 cells/mm(3). The Karnofsky and uniscale QOL scales reached 100% on the fourth visit. The Quality of Life Scale showed an important increase during this study from 5.5+/-2.3 to 9.7+/-0.5. Adverse events were observed in 25.0% of the patients, most being slight. One patient had to stop taking ritonavir due to nausea and vomiting. We conclude that AZT, 3TC, and ritonavir restored the quality of life for the AIDS patients studied in terms of psychosocial aspects and overall health conditions during 6 months of treatment. The adverse events were probably related to ritonavir, but they were slight and disappeared after 2 weeks. There was a significant increase in the average number of CD(4) lymphocytes during 6 months of treatment.

Ambulatory blood pressure monitoring (ABPM) over 24 hours was compared to two blood pressure measurements taken in the morning by the 22 test persons themselves. ABPM was carried out at the beginning and the end of the study using a spacelabs SL 90207 apparatus. A semiautomatic sphygmomanometer was used for self-measurements (Visomat OZ 2). Monitored systolic and diastolic 24 hour values and the mean 24 hour value were on the average slightly higher than the self-measured pressures. Both methods yielded almost constant values over the test period. The mean of self-measured systolic and diastolic values from the second measurement over the entire two week period was significantly lower than the initially registered values (p0.001). Therefore a high correlation (r = 0.88, p0.001) was found between the mean systolic value of the second self-measurement with the mean ABPM 24 hour value; the corresponding correlation for the first measurement with ABPM was lower (r = 0.84, p0.01). The correlation of the diastolic values with ABPM was also lower (r = 0.70, p0.01). These results show that ABPM and self-measurements in the morning differ only slightly. The use and reliability of semiautomatic blood pressure measuring devices provide a practicable and economic alternative to ABPM.

Pontos de Aprendizagem […] Massas Pericardicas: Apresentacao Rara de Pericardite Tuberculosa, Documentada em Ecocardiografia 3D

The chemical assessment of the complete disulphide bridge pattern in the beta-chain of human recombinant follicotropin (betaFSH) was accomplished by integrating classical biochemical methodologies with mass spectrometric procedures. A proteolytic strategy consisting of a double digestion of native betaFSH using the broad-specificity protease subtilisin first, followed by trypsin, was employed. The resulting peptide mixture was directly analysed by FAB-MS, leading to the assignment of the first three disulphide bridges. The remaining S-S bridges were determined by HPLC fractionation of the proteolytic digest followed by ESMS analysis of the individual fractions. The pattern of cysteine couplings in betaFSH was determined as: Cys3-Cys5l, Cys17-Cys66, Cys20-Cys104, Cys28-Cys82, Cys32-Cys84 and Cys87-Cys94, confirming the arrangement inferred from the crystal structure of the homologous betaCG. A subset of the S-S bridge pattern comprising Cys3-Cys51, Cys28-Cys82 and Cys32-Cys84 constitutes a cysteine knot motif similar to that found in the growth factor superfamily.

MEN 11300 is a hybrid glycoprotein of 297 amino acids obtained by fusion of the cDNA encoding GM-CSF with the cDNA encoding EPO followed by transfection of the hybrid gene into CHO cells. The oligonucleotide construct incorporated a spacing sequence between the two individual cDNAs which encodes eight amino acids constituting a linker peptide intended to separate the GM-CSF and EPO moieties. The recombinant MEN 11300 protein was submitted to a detailed structural characterization including the verification of the entire amino acid sequence, the assignment of the disulfide bridges pattern, the identification of the glycosylation sites and the definition of the glycosidic moiety, including site-specificity. Partial processing of the C-terminal Arg residue and the occurrence of N-glycosylation sites at Asn27, Asn155, Asn169, Asn214 were established. Moreover, O-glycosylation at Ser257 and at the N-terminal region was also detected. A large heterogeneity was observed in the N-glycans due to the presence of differently sialylated and fucosylated branched complex type oligosaccharides whereas O-linked glycans were constituted by GalGalNAc chains with a different number of sialic acids. The disulfide bridges pattern was established by direct FABMS analysis of the proteolytic digests or by ESMS analysis of HPLC purified fractions. Pairing of the eight cysteine residues resulted in Cys54-Cys96, Cys88-Cys121, Cys138-Cys292, and Cys160-Cys164. This S-S bridges pattern is identical to that occurring in the individual natural GM-CSF and EPO, thus showing that the two protein moieties in MEN 11300 can independently acquire their native three-dimensional structure.

Although in the last 50 years, a significant reduction of gastric cancer cases has been observed, this disease remains one of the most important causes of deaths around the world. Infection with Helicobacter pylori is the main risk factor of gastric cancers. However, despite numerous epidemiological studies, the association between H. pylori infection and gastric cancer (GC) still remains unexplained thus, prevention is most likely the means for reducing the burden of this disease. Our investigation was aimed to define possible molecular markers implicated in H. pylori-related carcinogenesis. Therefore, a proteomic and genomic approach was undertaken on endoscopic biopsy samples of 45 dyspeptic patients (19 H. pylori-positive) and on 28 gastric cancer cases. Sequencing by MALDI-TOF led to identify several proteins in the gastric mucosa. Among these, with respect to H. pylori-negative, in H. pylori-positive samples three proteins were up-regulated (RhoGDI?, IgJ, HSP27) and three others were down-regulated (RBP, GST, GKN1). The alteration of these proteins is in general related to carcinogenesis. Interestingly, two isoforms of GKN1, differing in the first N-terminal amino acid residue, were also identified. In the H. pylori-negative group, both isoforms were always present whereas, a lower expression of the GKN1 basic isoform in a subgroup of H. pylori-positive patients with severe gastritis, was found. In addition, GKN1 was completely absent in all tumoural areas while, it was expressed in all non-tumoural cases. The present data could suggest that GKN1 may play a role in the early phase of H. pylori-related gastric carcinogenesis.