Williams-Beuren syndrome: cardiovascular abnormalities in 20 patients diagnosed with fluorescence in situ hybridization

OBJECTIVE: To evaluate the cardiovascular findings and clinical follow-up of patients with Williams-Beuren syndrome. METHODS: We studied 20 patients (11 males, mean age at diagnosis: 5.9 years old), assessed for cardiovascular abnormalities with electrocardiography and Doppler echocardiography. Fluorescence in situ hybridization (FISH) was used to confirm the diagnosis of the syndrome. RESULTS: Elastin gene locus microdeletion was detected in 17 patients (85%) (positive FISH), and in 3 patients deletion was not detected (negative FISH). Sixteen patients with a positive FISH (94%) had congenital cardiovascular disease (mean age at diagnosis: 2,3 years old). We observed isolated (2/16) supravalvular aortic stenosis and supravalvular aortic stenosis associated (11/16) with pulmonary artery stenosis (4/11); mitral valve prolapse (3/11); bicuspid aortic valve (3/11); aortic coarctation (2/11), thickened pulmonary valve (2/11); pulmonary valvular stenosis (1/11); supravalvular pulmonary stenosis (1/11); valvular aortic stenosis (1/11); fixed subaortic stenosis (1/11); pulmonary artery stenosis (2/16) associated with pulmonary valvar stenosis (1/2) and with mitral valve prolapse (1/2); and isolated mitral valve prolapse (1/16). Four patients with severe supravalvular aortic stenosis underwent surgery (mean age: 5.7 years old), and 2 patients had normal pressure gradients (mean follow-up: 8.4 years). CONCLUSION: A detailed cardiac evaluation must be performed in all patients with Williams-Beuren syndrome due to the high frequency of cardiovascular abnormalities.

Treatment of congenital aortic valve stenosis: impact of the Ross operation.

GOAL: To evaluate the impact of the Ross operation, recently (1997) introduced in our unit, for the treatment of patients with congenital aortic valve stenosis. METHODS: The period from January 1997 to December 2000 was compared with the previous 5 years (1992-96). Thirty-seven children (< 16 yrs) and 49 young adults (16-50 yrs) with congenital aortic valve stenosis underwent one of these treatments: percutaneous balloon dilatation (PBD), aortic valve commissurotomy, aortic valve replacement and the Ross operation. The Ross operation was performed in 16 patients, mean age 24.5 yrs (range 9-46 yrs) with a bicuspid stenotic aortic valve, 7/10 adults with calcifications, 2/10 adults with previous aortic valve commissurotomy, 4/6 children with aortic regurgitation following PBD, and 1/6 children who had had a previous aortic valve replacement with a prosthetic valve and aortic root enlargement. RESULTS: PBD was followed by death in two neonates (fibroelastosis); all other children survived PBD. Although there were no deaths, PBD in adults was recently abandoned, owing to unfavourable results. Aortic valve commissurotomy showed good results in children (no deaths). Aortic valve replacement, although associated with good results (no deaths), has been recently abandoned in children in favour of the Ross operation. Over a mean follow-up of 16 months (2-40 months) all patients are asymptomatic following Ross operation, with no echocardiographic evidence of aortic valve regurgitation in 10/16 patients and with trivial regurgitation in 6/16 patients. CONCLUSIONS: The approach now for children and young adults with congenital aortic valve stenosis should be as follows: (1) PBD is the first choice in neonates and infants; (2) Aortic valve commissurotomy is the first choice for children, neonates and infants after failed PBD; (3) The Ross operation is increasingly used in children after failed PBD and in young adults, even with a calcified aortic valve.

Identification of reference genes for quantitative RT-PCR in ascending aortic aneurysms.

Hypertension and congenital aortic valve malformations are frequent causes of ascending aortic aneurysms. The molecular mechanisms of aneurysm formation under these circumstances are not well understood. Reference genes for gene activity studies in aortic tissue that are not influenced by aortic valve morphology and its hemodynamic consequences, aortic dilatation, hypertension, or antihypertensive medication are not available so far. This study determines genes in ascending aortic tissue that are independent of these parameters. Tissue specimens from dilated and undilated ascending aortas were obtained from 60 patients (age ≤70 years) with different morphologies of the aortic valve (tricuspid undilated n = 24, dilated n = 11; bicuspid undilated n = 6, dilated n = 15; unicuspid dilated n = 4). Of the studied individuals, 36 had hypertension, and 31 received ACE inhibitors or AT1 receptor antagonists. The specimens were obtained intraoperatively from the wall of the ascending aorta. We analyzed the expression levels of 32 candidate reference genes by quantitative RT-PCR (RT-qPCR). Differential expression levels were assessed by parametric statistics. The expression analysis of these 32 genes by RT-qPCR showed that EIF2B1, ELF1, and PPIA remained constant in their expression levels in the different specimen groups, thus being insensitive to aortic valve morphology, aortic dilatation, hypertension, and medication with ACE inhibitors or AT1 receptor antagonists. Unlike many other commonly used reference genes, the genes EIF2B1, ELF1, and PPIA are neither confounded by aortic comorbidities nor by antihypertensive medication and therefore are most suitable for gene expression analysis of ascending aortic tissue.

Selection of Reference Genes for Quantitative Real Time PCR (qPCR) Assays in Tissue from Human Ascending Aorta.

Dilatation of the ascending aorta (AAD) is a prevalent aortopathy that occurs frequently associated with bicuspid aortic valve (BAV), the most common human congenital cardiac malformation. The molecular mechanisms leading to AAD associated with BAV are still poorly understood. The search for differentially expressed genes in diseased tissue by quantitative real-time PCR (qPCR) is an invaluable tool to fill this gap. However, studies dedicated to identify reference genes necessary for normalization of mRNA expression in aortic tissue are scarce. In this report, we evaluate the qPCR expression of six candidate reference genes in tissue from the ascending aorta of 52 patients with a variety of clinical and demographic characteristics, normal and dilated aortas, and different morphologies of the aortic valve (normal aorta and normal valve n = 30; dilated aorta and normal valve n = 10; normal aorta and BAV n = 4; dilated aorta and BAV n = 8). The expression stability of the candidate reference genes was determined with three statistical algorithms, GeNorm, NormFinder and Bestkeeper. The expression analyses showed that the most stable genes for the three algorithms employed were CDKN1β, POLR2A and CASC3, independently of the structure of the aorta and the valve morphology. In conclusion, we propose the use of these three genes as reference genes for mRNA expression analysis in human ascending aorta. However, we suggest searching for specific reference genes when conducting qPCR experiments with new cohort of samples.

Aortic valve dysfunction and aortic dilation in adults with coarctation of the aorta.

OBJECTIVES: To determine the prevalence of aortic valve dysfunction, aortic dilation, and aortic valve and ascending aortic intervention in adults with coarctation of the aorta (CoA). BACKGROUND: Aortic valve dysfunction and aortic dilation are rare among children and adolescents with CoA. With longer follow-up, adults may be more likely to have progressive disease. METHODS: We retrospectively reviewed all adults with CoA, repaired or unrepaired, seen at our center between 2004 and 2010. RESULTS: Two hundred sixteen adults (56.0% male) with CoA were identified. Median age at last evaluation was 28.3 (range 18.0 to 75.3) years. Bicuspid aortic valve (BAV) was present in 65.7%. At last follow-up, 3.2% had moderate or severe aortic stenosis, and 3.7% had moderate or severe aortic regurgitation. Dilation of the aortic root or ascending aorta was present in 28.0% and 41.6% of patients, respectively. Moderate or severe aortic root or ascending aortic dilation (z-score > 4) was present in 8.2% and 13.7%, respectively. Patients with BAV were more likely to have moderate or severe ascending aortic dilation compared with those without BAV (19.5% vs. 0%; P < 0.001). Age was associated with ascending aortic dilation (P = 0.04). At most recent follow-up, 5.6% had undergone aortic valve intervention, and 3.2% had aortic root or ascending aortic replacement. CONCLUSION: In adults with CoA, significant aortic valve dysfunction and interventions during early adulthood were uncommon. However, aortic dilation was prevalent, especially of the ascending aorta, in patients with BAV.

Living-engineered valves for transcatheter venous valve repair.

Background: Chronic venous insufficiency (CVI) represents a major global health problem with increasing prevalence and morbidity. CVI is due to an incompetence of the venous valves, which causes venous reflux and distal venous hypertension. Several studies have focused on the replacement of diseased venous valves using xeno- and allogenic transplants, so far with moderate success due to immunologic and thromboembolic complications. Autologous cell-derived tissue-engineered venous valves (TEVVs) based on fully biodegradable scaffolds could overcome these limitations by providing non-immunogenic, non-thrombogenic constructs with remodeling and growth potential. Methods: Tri- and bicuspid venous valves (n=27) based on polyglycolic acid-poly-4-hydroxybutyrate composite scaffolds, integrated into self-expandable nitinol stents, were engineered from autologous ovine bone-marrow-derived mesenchymal stem cells (BM-MSCs) and endothelialized. After in vitro conditioning in a (flow) pulse duplicator system, the TEVVs were crimped (n=18) and experimentally delivered (n=7). The effects of crimping on the tissue-engineered constructs were investigated using histology, immunohistochemistry, scanning electron microscopy, grating interferometry (GI), and planar fluorescence reflectance imaging. Results: The generated TEVVs showed layered tissue formation with increasing collagen and glycosaminoglycan levels dependent on the duration of in vitro conditioning. After crimping no effects were found on the MSC level in scanning electron microscopy analysis, GI, histology, and extracellular matrix analysis. However, substantial endothelial cell loss was detected after the crimping procedure, which could be reduced by increasing the static conditioning phase. Conclusions: Autologous living small-diameter TEVVs can be successfully fabricated from ovine BM-MSCs using a (flow) pulse duplicator conditioning approach. These constructs hold the potential to overcome the limitations of currently used non-autologous replacement materials and may open new therapeutic concepts for the treatment of CVI in the future.

Pilot licensing after aortic valve surgery.

Background and aim of the study: Bicuspid aortic valve is the most common congenital heart malformation, and a high percentage of patients with this condition will develop complications over time. It is rare that pilots undergo aortic valve surgery, and the confirmation of flight-licensing requirements after aortic valve replacement (AVR) is a challenge for the patient's cardiac surgeon and, particularly, for the Aeromedical Examiner (AME). Only AMEs are able to determine the flight status of pilots. Furthermore, in military and in civil aviation (e.g., Red Bull Air Race), the high G-load environment experienced by pilots is an exceptional physiological parameter, which must be considered postoperatively. Methods: A review was conducted of the aeronautical, surgical and medical literature, and of European pilot-licensing regulations. Case studies are also reported for two Swiss Air Force pilots. Results: According to European legislation, pilots can return to flight duty from the sixth postoperative month, with the following limitations: that an aortic bioprosthesis presents no restrictions in cardiac function, requires no cardioactive medications, yet requires a flight operation with co-pilot, the avoidance of accelerations over +3 Gz and, in military aviation, restricts the pilot to non-ejection-seat aircraft. The patient follow up must include both echocardiographic and rhythm assessments every six months. Mechanical prostheses cannot be certified because the required anticoagulation therapy is a disqualifying condition for pilot licensing. Conclusion: Pilot licensing after aortic valve surgery is possible, but with restrictions. The +Gz exposition is of concern in both military and civilian aviation (aerobatics). The choice of bioprosthesis type and size is determinant. Pericardial and stentless valves seem to show better flow characteristics under high-output conditions. Repetitive cardiological controls are mandatory for the early assessment of structural valve disease and rhythm disturbances. A pre-emptive timing is recommended when reoperation is indicated, without waiting for clinical manifestations of structural valve disease.

Efficacy and Safety of Canakinumab Vs Triamcinolone Acetonide in Patients with Gouty Arthritis Unable to Use Nonsteroidal Anti-Inflammatory Drugs and Colchicine, and On Stable Urate Lowering Therapy (ULT) or Unable to Use ULT

Background/Purpose: The primary treatment goals for gouty arthritis (GA) are rapid relief of pain and inflammation during acute attacks, and long-term hyperuricemia management. A post-hoc analysis of 2 pivotal trials was performed to assess efficacy and safety of canakinumab (CAN), a fully human monoclonal anti-IL-1_ antibody, vs triamcinolone acetonide (TA) in GA patients unable to use NSAIDs and colchicine, and who were on stable urate lowering therapy (ULT) or unable to use ULT. Methods: In these 12-week, randomized, multicenter, double-blind, double-dummy, active-controlled studies (_-RELIEVED and _-RELIEVED II), patients had to have frequent attacks (_3 attacks in previous year) meeting preliminary GA ACR 1977 criteria, and were unresponsive, intolerant, or contraindicated to NSAIDs and/or colchicine, and if on ULT, ULT was stable. Patients were randomized during an acute attack to single dose CAN 150 mg s.c. or TA 40 mg i.m. and were redosed "on demand" for each new attack. Patients completing the core studies were enrolled into blinded 12-week extension studies to further investigate on-demand use of CAN vs TA for new attacks. The subpopulation selected for this post-hoc analysis was (a) unable to use NSAIDs and colchicine due to contraindication, intolerance or lack of efficacy for these drugs, and (b) currently on ULT, or contraindication or previous failure of ULT, as determined by investigators. Subpopulation comprised 101 patients (51 CAN; 50 TA) out of 454 total. Results: Several co-morbidities, including hypertension (56%), obesity (56%), diabetes (18%), and ischemic heart disease (13%) were reported in 90% of this subpopulation. Pain intensity (VAS 100 mm scale) was comparable between CAN and TA treatment groups at baseline (least-square [LS] mean 74.6 and 74.4 mm, respectively). A significantly lower pain score was reported with CAN vs TA at 72 hours post dose (1st co-primary endpoint on baseline flare; LS mean, 23.5 vs 33.6 mm; difference _10.2 mm; 95% CI, _19.9, _0.4; P_0.0208 [1-sided]). CAN significantly reduced risk for their first new attacks by 61% vs TA (HR 0.39; 95% CI, 0.17-0.91, P_0.0151 [1-sided]) for the first 12 weeks (2nd co-primary endpoint), and by 61% vs TA (HR 0.39; 95% CI, 0.19-0.79, P_0.0047 [1-sided]) over 24 weeks. Serum urate levels increased for CAN vs TA with mean change from baseline reaching a maximum of _0.7 _ 2.0 vs _0.1 _ 1.8 mg/dL at 8 weeks, and _0.3 _ 2.0 vs _0.2 _ 1.4 mg/dL at end of study (all had GA attack at baseline). Adverse Events (AEs) were reported in 33 (66%) CAN and 24 (47.1%) TA patients. Infections and infestations were the most common AEs, reported in 10 (20%) and 5 (10%) patients treated with CAN and TA respectively. Incidence of SAEs was comparable between CAN (gastritis, gastroenteritis, chronic renal failure) and TA (aortic valve incompetence, cardiomyopathy, aortic stenosis, diarrohea, nausea, vomiting, bicuspid aortic valve) groups (2 [4.0%] vs 2 [3.9%]). Conclusion: CAN provided superior pain relief and reduced risk of new attack in highly-comorbid GA patients unable to use NSAIDs and colchicine, and who were currently on stable ULT or unable to use ULT. The safety profile in this post-hoc subpopulation was consistent with the overall _-RELIEVED and _-RELIEVED II population.

Supernumerary premolars. Report of 10 cases

Supernumerary premolars are 'extra' teeth morphologically belonging to the premolar group. Hyperdontia affecting premolars can be single (when only one supernumerary tooth is found), multiple (if several teeth are involved) or related to a syndrome such as cleidocranial dysplasia. Supernumerary premolars are the third most frequent group of supernumerary teeth, following mesiodens and fourth molars; the prevalence among the general population ranges from 0.09-0.64%. The present study describes 10 cases of supernumerary premolars treated in our Service of Oral and Maxillofacial Surgery of the Dental Clinic of the University of Barcelona. A late onset was demonstrated in one case, contrasting the present pantomograph with another obtained 5 years before. In only one case did the presence of a supernumerary premolar alter normal tooth eruption. Two supernumerary premolars were affected by follicular cysts

Aortic Annulus Stabilization Technique for Rapid Deployment Aortic Valve Replacement.

NlmCategory="UNASSIGNED">Rapid deployment aortic valve replacement (RDAVR) with the use of rapid deployment valve systems represents a smart alternative to the use of standard aortic bioprosthesis for aortic valve replacement. Nevertheless, its use is still debatable in patients with pure aortic valve regurgitation or true bicuspid aortic valve because of the risk of postoperative paravalvular leak. To address this issue, an optimal annulus-valve size match seems to be the ideal surgical strategy. This article describes a new technique developed to stabilize the aortic annulus and prevent paravalvular leak after RDAVR. To confirm the feasibility, this technique was performed in six patients with severe symptomatic aortic stenosis who were scheduled to undergo aortic valve replacement at our center. All patients survived surgery and were discharged from the hospital. There were no new intracardiac conduction system disturbances observed, and a permanent pacemaker implantation was not required in any of the patients. The intraoperative and postoperative echocardiogram confirmed successful positioning of the valve, and no paravalvular leak was observed. In this preliminary experience, RDAVR through a full sternotomy or an upper hemisternotomy approach with the use of aortic annulus stabilization technique was safe, and no leak was observed. Future studies on large series of patients are necessary to confirm the safety and effectiveness of this technique in preventing paravalvular leak in patients with true bicuspid aortic valves or pure aortic regurgitation.

Morfología de los conductos radiculares de premolares superiores e inferiores

El propósito de este estudio fue caracterizar la anatomía de los conductos radiculares de dientes premolares superiores e inferiores provenientes de pacientes españoles. Fueron seleccionados 200 dientes premolares permanentes sometidos a diafanización. Para el estudio de los conductos radiculares se empleó la clasificación de Vertucci. La incidencia de conducto tipo I (un conducto) para los primeros premolares superiores fue de 5.88%, mientras que un 88.22% presentó dos conductos (de tipo II a tipo VI). Sólo el 5.88% de los primeros premolares superiores fueron tipo VIII (tres conductos). En los segundos premolares superiores, la incidencia de un conducto (tipo I) fue de 39.65%, y el 60.31% presentaron dos conductos (de tipo II a tipo VII). La incidencia de un conducto (tipo I) fue de 68.18% para los primeros premolares inferiores, y un 31.8% presentó dos conductos (de tipo II a tipo V). En los segundos premolares inferiores, la incidencia de tipo I (un conducto) fue de 73.91%, mientras que el 26.08% presentó dos conductos (de tipo IV a V). Salvo en el caso del segundo premolar inferior, nuestros resultados coincidieron con los de trabajos previos hechos en otras poblaciones.

Morfología de los conductos radiculares de premolares superiores e inferiores

El propósito de este estudio fue caracterizar la anatomía de los conductos radiculares de dientes premolares superiores e inferiores provenientes de pacientes españoles. Fueron seleccionados 200 dientes premolares permanentes sometidos a diafanización. Para el estudio de los conductos radiculares se empleó la clasificación de Vertucci. La incidencia de conducto tipo I (un conducto) para los primeros premolares superiores fue de 5.88%, mientras que un 88.22% presentó dos conductos (de tipo II a tipo VI). Sólo el 5.88% de los primeros premolares superiores fueron tipo VIII (tres conductos). En los segundos premolares superiores, la incidencia de un conducto (tipo I) fue de 39.65%, y el 60.31% presentaron dos conductos (de tipo II a tipo VII). La incidencia de un conducto (tipo I) fue de 68.18% para los primeros premolares inferiores, y un 31.8% presentó dos conductos (de tipo II a tipo V). En los segundos premolares inferiores, la incidencia de tipo I (un conducto) fue de 73.91%, mientras que el 26.08% presentó dos conductos (de tipo IV a V). Salvo en el caso del segundo premolar inferior, nuestros resultados coincidieron con los de trabajos previos hechos en otras poblaciones.

Essential role of GATA5 in the mammalian heart

réalisé en cotutelle avec le Dr. Marie Kmita et Dr. Marco Horb

Caracterización de las alteraciones en la función renal, la presión arterial y las malformaciones anatómicas renales- urinarias y cardiovasculares en pacientes con Sindrome de Turner en la Fundación Cardioinfantil entre 1999 y 2009

Se caracterizan las malformaciones renales y urinarias (MRU), y cardiovasculares (CV), así como la función renal (FR) y la presión arterial (PA) en pacientes con Sindrome de Turner (ST) mediante un estudio retrospectivo entre 1999 y 2009 en Bogotá. Se encontró 10 pacientes con algún grado de insuficiencia renal crónica (IRC). Además 4 pacientes presentaron prehipertensión arterial, y 5 (HTA); en ellos se encontró hidronefrosis y riñón poliquístico. Las MRU más frecuentes fueron únicas; en ellas las mayores alteraciones cromosómicas son la monosomía y el mosaicismo. La mayor malformación CV fué la válvula aórtica bicúspide. El ST amerita seguimiento de FR y PA para prevenir complicaciones a largo plazo por IRC e HTA.

Efetividade do uso tópico de fluoreto e da escovação no controle de cáries produzidas "in vivo"

The objective of this clinical study was to evaluate the effectiveness of the toothbrushing with and without fluoride and the daily fluoride rinse (NaF 0.05%) on produced white spot, in vivo. This was a clinical study, controlled, randomized and triple blind. Thirty patients were selected for orthodontics reasons from Orthodontics Specialization Course at the Brazilian Dental Association - Section of Rio Grande do Norte. In this study it was used 4 bicuspid upper and lower. They had orthodontic reason for extractions, in 35 days, at least. The sample had one hundred and twenty teeth that received orthodontic bands. The bands were fixed with polycarboxylate cement, and there was a space standardized between bands and one surface of teeth. The four bicuspid of each patients were randomized and nominated as A, B, C and D. These nominations determinated the sequence of the extractions and what was done in each tooth. All the patients had been submitted to the toothbrushing with or without fluoride for 35 days. After this period, the A tooth of each patient was extracted to serve as control. The others teeth (B, C and D) were extracted one by each week. The entire sample was analyzed through the clinical examination and by laser fluorescence (DIAGNOdent®) in three different times: before orthodontic bands, 28 days after fixed and then removed the bands and, the last one, 07 days after one of the three treatments (toothbrushing with or without fluoride, tooth paste with fluoride and mouth rinse with fluoride). At the beginning all groups (A, B, C and D) had the same conditions, no significant difference was found. The same situation was found in a clinical examination. The results of the DIAGNOdent® for the groups that used tooth paste without fluoride, with fluoride and mouth rinse with fluoride, after 28 days, there was no significant difference. Clinically, the white spot was formed in all teeth after 28 days. When it was compared the three treated groups, the group without fluoride in tooth paste had worst result than the others groups. But there was no significant association between the number of active and inactive white spots and the type of treatment that the teeth had received. The demineralization of the enamel surface, under the orthodontic bands, it happened in a few weeks. The exposition of the white spots in oral environmental resulted in an improvement, but it was not enough to return to the values from the base line, either for the toothbrushing and/or the use of fluorite mouth rinse. Mouth rinse and toothpaste with fluoride have showed to reduce the incidence of demineralization in the enamel, but none seems to be superior to another one in an in vivo study