Late clinical outcomes after implantation of drug-eluting stents coated with biodegradable polymers: 3-year follow-up of the PAINT randomised trial

Aims: The long-term clinical performance of drug-eluting stents (DES) coated with biodegradable polymers is poorly known. Methods and results: A total of 274 coronary patients were randomly allocated to paclitaxel-eluting stents, sirolimus-eluting stents, or bare metal stems (2:2:1 ratio). The two DES used the same biodegradable polymers and were identical except for the drug. At three years, the pooled DES population had similar rates of cardiac death or myocardial infarction (9.0% vs. 7.1; p=0.6), but lower risk of repeat interventions (10.0% vs. 29.9%; p<0.01) than controls with bare stents. The cumulative 3-year incidence of definite or probable stent thrombosis in the pooled DES group was 2.3% (first year: 1.8%; second year: 0.4%; third year: zero). There were no significant differences in outcomes between paclitaxel- and sirolimus-eluting stents. Conclusions: The biodegradable-polymer coated DES releasing either paclitaxel or sirolimus were effective in reducing the 3-year rate of re-interventions.

Design of laminated piezocomposite shell transducers with arbitrary fiber orientation using topology optimization approach

Sensor and actuator based on laminated piezocomposite shells have shown increasing demand in the field of smart structures. The distribution of piezoelectric material within material layers affects the performance of these structures; therefore, its amount, shape, size, placement, and polarization should be simultaneously considered in an optimization problem. In addition, previous works suggest the concept of laminated piezocomposite structure that includes fiber-reinforced composite layer can increase the performance of these piezoelectric transducers; however, the design optimization of these devices has not been fully explored yet. Thus, this work aims the development of a methodology using topology optimization techniques for static design of laminated piezocomposite shell structures by considering the optimization of piezoelectric material and polarization distributions together with the optimization of the fiber angle of the composite orthotropic layers, which is free to assume different values along the same composite layer. The finite element model is based on the laminated piezoelectric shell theory, using the degenerate three-dimensional solid approach and first-order shell theory kinematics that accounts for the transverse shear deformation and rotary inertia effects. The topology optimization formulation is implemented by combining the piezoelectric material with penalization and polarization model and the discrete material optimization, where the design variables describe the amount of piezoelectric material and polarization sign at each finite element, with the fiber angles, respectively. Three different objective functions are formulated for the design of actuators, sensors, and energy harvesters. Results of laminated piezocomposite shell transducers are presented to illustrate the method. Copyright (C) 2012 John Wiley & Sons, Ltd.

Role of Neutralizing Antibodies in Adults With Community-Acquired Pneumonia by Respiratory Syncytial Virus

Background. Respiratory syncytial virus (RSV) has been implicated in the etiology of adult community-acquired pneumonia (CAP). We investigated RSV infection in Chilean adults with CAP using direct viral detection, real-time reverse-transcription polymerase chain reaction (rtRT-PCR), and serology (microneutralization assay). Methods. RSV, other respiratory viruses, and bacteria were studied by conventional and molecular techniques in adults aged >= 18 years presenting with CAP to the healthcare facilities in Santiago, Chile from February 2005 through December 2007. Results. All 356 adults with CAP enrolled had an acute blood sample collected at enrollment, and 184 had a convalescent blood sample. RSV was detected in 48 cases (13.4%). Immunofluorescence assay and viral isolation each detected only 1 infection (0.2%), whereas rtRT-PCR was positive in 32 (8.9%) cases and serology was positive in 20 (10.8%) cases. CAP clinical characteristics were similar in RSV-infected and non-RSV-infected cases. RSV-specific geometric mean serum-neutralizing antibody titer (GMST) was significantly lower at admission in the 48 RSV-infected cases compared with 308 non-RSV-infected adults (GMST in log(2): RSV/A 8.1 vs 8.9, and RSV/B 9.3 vs 10.4; P < .02). Conclusions. RSV infection is frequent in Chilean adults with CAP. Microneutralization assay was as sensitive as rtRT-PCR in detecting RSV infection and is a good adjunct assay for diagnostic research. High RSV-specific serum-neutralizing antibody levels were associated with protection against common and severe infection. The development of a vaccine could prevent RSV-related CAP in adults.

Clinical Usefulness of Coronary Angiography in Patients with Left Ventricular Dysfunction

Background: Performing a coronary angiography in patients with heart failure of unknown etiology is often justified by the diagnostic assessment of ischemic heart disease. However, the clinical benefit of this strategy is not known. Objective: To evaluate the prevalence of ischemic heart disease by angiographic criteria in patients with heart failure and reduced ejection fraction of unknown etiology, as well as its impact on therapy decisions. Methods: Consecutive outpatients with heart failure and systolic dysfunction, who had an indication for coronary angiography to clarify the etiology of heart disease were assessed from 1 January 2009 to December 31, 2010. Patients diagnosed with coronary artery disease, positive serology for Chagas disease, congenital heart disease, valve disease or patients undergoing cardiac transplantation were excluded from the analysis. The sample was divided into two groups according to the indication for catheterization. Group-1: Symptomatic due to angina or heart failure. Group-2: Presence of >= 2 risk factors for coronary artery disease Results: One hundred and seven patients were included in the analysis, with 51 (47.7%) patients in Group 1 and 56 (52.3%) in Group 2. The prevalence of ischemic heart disease was 9.3% (10 patients), and all belonged to Group 1 (p = 0.0001). During follow-up, only 4 (3.7%) were referred for CABG; 3 (2.8%) patients had procedure-related complications. Conclusion: In our study, coronary angiography in patients with heart failure and systolic dysfunction of unknown etiology, although supported by current guidelines, did not show benefits when performed only due to the presence of risk factors for coronary artery disease. (Arq Bras Cardiol 2012;98(5):437-441)

The contrast-enhanced Doppler ultrasound with perfluorocarbon exposed sonicated albumin does not improve the diagnosis of renal artery stenosis compared with angiography

There are no studies investigating the effect of the contrast infusion on the sensitivity and specificity of the main Doppler criteria of renal artery stenosis (RAS). Our aim was to evaluate the accuracy of these Doppler criteria prior to and following the intravenous administration of perfluorocarbon exposed sonicated albumin (PESDA) in patients suspected of having RAS. Thirty consecutive hypertensive patients (13 males, mean age of 57 ± 10 years) suspected of having RAS by clinical clues, were submitted to ultrasonography (US) of renal arteries before and after enhancement using continuous infusion of PESDA. All patients underwent angiography, and haemodynamically significant RAS was considered when ≥50%. At angiography, it was detected RAS ≥50% in 18 patients, 5 with bilateral stenosis. After contrast, the examination time was slightly reduced by approximately 20%. In non-enhanced US the sensitivity was better when based on resistance index (82.9%) while the specificity was better when based on renal aortic ratio (89.2%). The predictive positive value was stable for all indexes (74.0%–88.0%) while negative predictive value was low (44%–51%). The specificity and positive predictive value based on renal aortic ratio increased after PESDA injection respectively, from 89 to 97.3% and from 88 to 95%. In hypertensives suspected to have RAS the sensitivity and specificity of Duplex US is dependent of the criterion evaluated. Enhancement with continuous infusion of PESDA improves only the specificity based on renal aortic ratio but do not modify the sensitivity of any index.

Assessment of MMP-9, TIMP-1, and COX-2 in normal tissue and in advanced symptomatic and asymptomatic carotid plaques

Abstract Background Mature carotid plaques are complex structures, and their histological classification is challenging. The carotid plaques of asymptomatic and symptomatic patients could exhibit identical histological components. Objectives To investigate whether matrix metalloproteinase 9 (MMP-9), tissue inhibitor of MMP (TIMP), and cyclooxygenase-2 (COX-2) have different expression levels in advanced symptomatic carotid plaques, asymptomatic carotid plaques, and normal tissue. Methods Thirty patients admitted for carotid endarterectomy were selected. Each patient was assigned preoperatively to one of two groups: group I consisted of symptomatic patients (n = 16, 12 males, mean age 66.7 ± 6.8 years), and group II consisted of asymptomatic patients (n = 14, 8 males, mean age 67.6 ± 6.81 years). Nine normal carotid arteries were used as control. Tissue specimens were analyzed for fibromuscular, lipid and calcium contents. The expressions of MMP-9, TIMP-1 and COX-2 in each plaque were quantified. Results Fifty-eight percent of all carotid plaques were classified as Type VI according to the American Heart Association Committee on Vascular Lesions. The control carotid arteries all were classified as Type III. The median percentage of fibromuscular tissue was significantly greater in group II compared to group I (p < 0.05). The median percentage of lipid tissue had a tendency to be greater in group I than in group II (p = 0.057). The percentages of calcification were similar among the two groups. MMP-9 protein expression levels were significantly higher in group II and in the control group when compared with group I (p < 0.001). TIMP-1 expression levels were significantly higher in the control group and in group II when compared to group I, with statistical difference between control group and group I (p = 0.010). COX-2 expression levels did not differ among groups. There was no statistical correlation between MMP-9, COX-2, and TIMP-1 levels and fibrous tissue. Conclusions MMP-9 and TIMP-1 are present in all stages of atherosclerotic plaque progression, from normal tissue to advanced lesions. When sections of a plaque are analyzed without preselection, MMP-9 concentration is higher in normal tissues and asymptomatic surgical specimens than in symptomatic specimens, and TIMP-1 concentration is higher in normal tissue than in symptomatic specimens.

Accuracy of five electronic foramen locators with different operating systems: na ex vivo study

Objective: The aim of this study was to evaluate, ex vivo, the precision of five electronic root canal length measurement devices (ERCLMDs) with different operating systems: the Root ZX, Mini Apex Locator, Propex II, iPex, and RomiApex A-15, and the possible influence of the positioning of the instrument tips short of the apical foramen. Material and Methods: Forty-two mandibular bicuspids had their real canal lengths (RL) previously determined. Electronic measurements were performed 1.0 mm short of the apical foramen (-1.0), followed by measurements at the apical foramen (0.0). The data resulting from the comparison of the ERCLMD measurements and the RL were evaluated by the Wilcoxon and Friedman tests at a significance level of 5%. Results: Considering the measurements performed at 0.0 and -1.0, the precision rates for the ERCLMDs were: 73.5% and 47.1% (Root ZX), 73.5% and 55.9% (Mini Apex Locator), 67.6% and 41.1% (Propex II), 61.7% and 44.1% (iPex), and 79.4% and 44.1% (RomiApex A-15), respectively, considering ±0.5 mm of tolerance. Regarding the mean discrepancies, no differences were observed at 0.0; however, in the measurements at -1.0, the iPex, a multi-frequency ERCLMD, had significantly more discrepant readings short of the apical foramen than the other devices, except for the Propex II, which had intermediate results. When the ERCLMDs measurements at -1.0 were compared with those at 0.0, the Propex II, iPex and RomiApex A-15 presented significantly higher discrepancies in their readings. Conclusions: Under the conditions of the present study, all the ERCLMDs provided acceptable measurements at the 0.0 position. However, at the -1.0 position, the ERCLMDs had a lower precision, with statistically significant differences for the Propex II, iPex, and RomiApex A-15.

Effect of Nd:YAG laser combined with fluoride on the prevention of primary tooth enamel demineralization

Most studies dealing with the caries preventive action of Nd:YAG laser have been done in permanent teeth and studies on primary teeth are still lacking. The aim of this study was to evaluate in vitro the effect of Nd:YAG laser combined or not with fluoride sources on the acid resistance of primary tooth enamel after artificial caries induction by assessing longitudinal microhardness and demineralization depth. Sixty enamel blocks obtained from the buccal/lingual surface of exfoliated human primary molars were coated with nail polish/wax, leaving only a 9 mm² area exposed on the outer enamel surface, and randomly assigned to 6 groups (n=10) according to the type of treatment: C-control (no treatment); APF: 1.23% acidulated phosphate fluoride gel; FV: 5% fluoride varnish; L: Nd:YAG laser 0.5 W/10 Hz in contact mode; APFL: fluoride gel + laser; FVL: fluoride varnish + laser. After treatment, the specimens were subjected to a des-remineralization cycle for induction of artificial caries lesions. Longitudinal microhardness data (%LMC) were analyzed by the Kruskal-Wallis test and demineralization depth data were analyzed by oneway ANOVA and Fisher’s LSD test (á=0.05). APFL and APF groups presented the lowest percentage of microhardness change (p<0.05). Demineralization depth was smaller in all treated groups compared with the untreated control. In conclusion, Nd:YAG laser combined or not with fluoride gel/varnish was not more effective than fluoride alone to prevent enamel demineralization within the experimental period.

A retrospective study of oral manifestations in patients with paracoccidioidomycosis

South American blastomycosis, paracoccidioidomycosis (Pb mycosis) or Lutz disease is an endemically fungal infection in Latin America. It is caused by the dimorphic fungus Paracoccidioides brasiliensis and may cause oral mucosal lesions. The incidence of Pb mycosis oral lesions was evaluated in patients assisted at a Brazilian Dental School's Specialized Oral Diagnosis Service with special focus on the different clinical forms of these lesions, its location, patients' occupation, deleterious habits, and diagnosis methodology. Students' and professionals' initial diagnoses were compared with the definitive diagnosis. Lesions were detected 31 cases (18 patients). The results show that 88.8% of the patients were male with a mean age of 50 years and 39% work(ed) with activities related to agriculture. As much as 88.9% were smokers and 72.2% were alcohol users. Exfoliative cytology was performed in 66.6% of the patients. Oral mucosa (30%), gingiva (16.6%) and lips 16.6% were the most common sites of Pb mycosis oral lesions. Comparing the initial with the definitive diagnosis made by the professionals their accuracy was 33% (6 out of 18 patients). Students' diagnosis was more accurate demonstrating 72.5% of initial correct diagnosis (13 out of 18). Statistical analysis by ANOVA (α=0.05, SPSS WIN) demonstrated a significant difference between the diagnosis of Pb mycosis made by students and professionals when considering initial diagnosis and final diagnosis (after histopathological analysis) (p=0.25). Incisional biopsy and exfoliate cytology are efficient for an early diagnosis of this disease in mouth. Students' training in diagnosis of oral pathologies to recognize lesions is urgent to improve public health.

A mathematical model for optimizing the indications of liver transplantation in patients with hepatocellular carcinoma

Abstract Background The criteria for organ sharing has developed a system that prioritizes liver transplantation (LT) for patients with hepatocellular carcinoma (HCC) who have the highest risk of wait-list mortality. In some countries this model allows patients only within the Milan Criteria (MC, defined by the presence of a single nodule up to 5 cm, up to three nodules none larger than 3 cm, with no evidence of extrahepatic spread or macrovascular invasion) to be evaluated for liver transplantation. This police implies that some patients with HCC slightly more advanced than those allowed by the current strict selection criteria will be excluded, even though LT for these patients might be associated with acceptable long-term outcomes. Methods We propose a mathematical approach to study the consequences of relaxing the MC for patients with HCC that do not comply with the current rules for inclusion in the transplantation candidate list. We consider overall 5-years survival rates compatible with the ones reported in the literature. We calculate the best strategy that would minimize the total mortality of the affected population, that is, the total number of people in both groups of HCC patients that die after 5 years of the implementation of the strategy, either by post-transplantation death or by death due to the basic HCC. We illustrate the above analysis with a simulation of a theoretical population of 1,500 HCC patients with tumor size exponentially. The parameter λ obtained from the literature was equal to 0.3. As the total number of patients in these real samples was 327 patients, this implied in an average size of 3.3 cm and a 95% confidence interval of [2.9; 3.7]. The total number of available livers to be grafted was assumed to be 500. Results With 1500 patients in the waiting list and 500 grafts available we simulated the total number of deaths in both transplanted and non-transplanted HCC patients after 5 years as a function of the tumor size of transplanted patients. The total number of deaths drops down monotonically with tumor size, reaching a minimum at size equals to 7 cm, increasing from thereafter. With tumor size equals to 10 cm the total mortality is equal to the 5 cm threshold of the Milan criteria. Conclusion We concluded that it is possible to include patients with tumor size up to 10 cm without increasing the total mortality of this population.

Organocatalytic tandem reactions of polyfunctional compounds for the synthesis of enantioenriched heterocycles. Reazioni tandem organocatalitiche di composti polifunzionali per la sintesi di eterocicli enantioarricchiti.

In questo lavoro di tesi sono state sviluppate reazioni domino, tandem e procedure one-pot per ottenere eterocicli enatioarricchiti. Lo sviluppo di queste metodologie sintetiche è molto importante perché permettono di ottenere molecole complesse partendo da prodotti semplici, senza effettuare ripetuti passaggi di purificazione (stop-and-go or step-by-step synthesis). Lo scopo di questo lavoro è di ottenere derivati tetraidrofuranici modificati e derivati ossoazzolinici enantioarrichiti tramite reazioni SN2-Michael o tramite reazioni aldolica-ciclizzazione-Michael usando la catalisi asimmetrica a trasferimento di fase (PTC). Come catalizzatori PTC per imprimere enantioselezione sono stati utilizzati sali di ammonio quaternario derivati dagli alcaloidi della Cinchona. Sono state ottimizzate le condizioni di reazione (base inorganica, temperatura, solvente, tempo di reazione) per i diversi substrati presi in considerazione. I prodotti target sono stati ottenuti con buone rese, ottime diastereoselezioni ma con bassa enantioselezione. I risultati ottenuti richiedono un’ulteriore ottimizzazione e dovranno essere valutate variazioni strutturali dei nucleofili utilizzati. In this thesis were developed domino, tandem reactions and one-pot procedures to obtained enantioenriched heterocycles. The development of these methodologies is very fundamental because they allow to obtain complex molecules starting from raw materials, without carrying out repeated purification steps (stop-and-go or step-by-step synthesis). The purpose of this work is to obtain enantioenriched tetrahydrofuran and oxazoline derivatives through a SN2-Michael reaction or a aldol- cyclization-Michael reaction using the phase-transfer asymmetric catalysis (PTC). For imprint enantioselection we used Cinchona alkaloids quaternary ammonium salts derivatives. The reaction conditions (inorganic base, temperature, solvent, reaction time) were optimised for the different substrates taken into account. The target products were obtained with good yields, excellent diastereoselections but with low enantioselections. The obtained results require further optimization and structural changes in the nucleophiles used must be evaluated.

Role of (R)-9-hydroxystearic acid in zebrafish development

9-hydroxystearic acid (9-HSA) belongs to a class of lipid peroxidation products identified in several human and murine cell lines. These products are greatly diminished in tumors compared to normal tissues and their amount is inversely correlated with the malignancy of the tumor. 9-HSA activity has been tested in cancer cell lines, where it showed to act as a histone deacetylase 1 (HDAC1) inhibitor. In particular, in a colon cancer cell line (HT29), its administration resulted in an inhibition of proliferation together with an induction of differentiation. In this thesis the effect of (R)-9-hydroxystearic acid has been tested in vivo on cell proliferation and differentiation processes, in the early stages of zebrafish development. The final aim of this work was to elucidate the role of (R)-9-HSA in the control of cell differentiation and proliferation during normal development, in order to better understand its molecular control of cancerogenesis. The molecule has been administered via injection in the yolk of zebrafish embryos. The analysis of the histone acetylation pattern showed a hyperacetilation of histone H4 after treatment with the molecule, as detectable in HDAC1 mutants. (R)-9-HSA was also demonstrated to interfere with the signaling pathways that regulate proliferation and differentiation in zebrafish retina and hindbrain. This resulted in a reduction of proliferation in the hindbrain at 24 hours post injection (hpi), and in a hyperproliferation at 48 and 72 hpi in the retina, with a concomitant inhibition of differentiation. Finally, (R)-9-HSA effects were evident on proliferation of stem cell located in the ciliary marginal zone (CMZ) of the retina. The presence of ROS and 4-hydroxynoneal in the CMZ of wild-type embryos supports the hypothesis that oxidative stress could regulate stem cells fate in zebrafish retina.

The updated European Consensus 2009 on the use of Botulinum toxin for children with cerebral palsy

An interdisciplinary European group of clinical experts in the field of movement disorders and experienced Botulinum toxin users has updated the consensus for the use of Botulinum toxin in the treatment of children with cerebral palsy (CP). A problem-orientated approach was used focussing on both published and practice-based evidence. In part I of the consensus the authors have tabulated the supporting evidence to produce a concise but comprehensive information base, pooling data and experience from 36 institutions in 9 European countries which involves more than 10,000 patients and over 45,000 treatment sessions during a period of more than 280 treatment years. In part II of the consensus the Gross Motor Function Measure (GMFM) and Gross Motor Function Classification System (GMFCS) based Motor Development Curves have been expanded to provide a graphical framework on how to treat the motor disorders in children with CP. This graph is named "CP(Graph) Treatment Modalities - Gross Motor Function" and is intended to facilitate communication between parents, therapists and medical doctors concerning (1) achievable motor function, (2) realistic goal-setting and (3) treatment perspectives for children with CP. The updated European consensus 2009 summarises the current understanding regarding an integrated, multidisciplinary treatment approach using Botulinum toxin for the treatment of children with CP.

Prognosis of Atrial Fibrillation in Patients with Symptomatic Peripheral Arterial Disease: Data from the REduction of Atherothrombosis for Continued Health (REACH) Registry

BACKGROUND: Atrial fibrillation (AF) is a significant risk factor for cardiovascular (CV) mortality. This study aims to evaluate the prognostic implication of AF in patients with peripheral arterial disease (PAD). METHODS: The International Reduction of Atherothrombosis for Continued Health (REACH) Registry included 23,542 outpatients in Europe with established coronary artery disease, cerebrovascular disease (CVD), PAD and/or >/=3 risk factors. Of these, 3753 patients had symptomatic PAD. CV risk factors were determined at baseline. Study end point was a combination of cardiac death, non-fatal myocardial infarction (MI) and stroke (CV events) during 2 years of follow-up. Cox regression analysis adjusted for age, gender and other risk factors (i.e., congestive heart failure, coronary artery re-vascularisation, coronary artery bypass grafting (CABG), MI, hypertension, stroke, current smoking and diabetes) was used. RESULTS: Of 3753 PAD patients, 392 (10%) were known to have AF. Patients with AF were older and had a higher prevalence of CVD, diabetes and hypertension. Long-term CV mortality occurred in 5.6% of patients with AF and in 1.6% of those without AF (p<0.001). Multivariable analyses showed that AF was an independent predictor of late CV events (hazard ratio (HR): 1.5; 95% confidence interval (CI): 1.09-2.0). CONCLUSION: AF is common in European patients with symptomatic PAD and is independently associated with a worse 2-year CV outcome.

Comparison of two scoring systems for evaluation of treatment outcome in patients with complete bilateral cleft lip and palate

Objective : To compare two scoring systems: the Huddart/Bodenham system (HB system) and the Bauru-BCLP yardstick (BCLP yardstick), which classify treatment outcome in terms of dental arch relationships in patients with complete bilateral cleft lip and palate (CBCLP). The predictive value of these scoring systems for treatment outcome was also evaluated. Design : Retrospective longitudinal study. Patients : Dental arch relationships of 43 CBCLP patients were evaluated at 6, 9, and 12 years. Setting : Treatment outcome in BCLP patients using two scoring systems. Main Outcome Measures : For each age group, the HB scores were correlated with the BCLP yardstick scores using Spearman's correlation coefficient. The predictive value of the two scoring systems was evaluated by backward regression analysis. Results : Intraobserver Kappa values for the BCLP yardstick scoring for the two observers were .506 and .627, respectively, and the interobserver reliability ranged from .427 and .581. The intraobserver reliability for the HB system ranged from .92 to .97 and the interobserver reliability from .88 to .96. The BCLP yardstick scores of 6 and 9 years together were predictors for the outcome at 12 years (explained variance 41.3%). Adding the incisor and lateral HB scores in the regression model increased the explained variance to 67%. Conclusions : The BCLP yardstick and the HB system are reliable scoring systems for evaluation of dental arch relationships of CBCLP patients. The HB system categorizes treatment outcome into similar categories as the BCLP yardstick. In case a more sensitive measure of treatment outcome is needed, selectively both scoring systems should be used.