Mitral Valve Myxomas: an Unusual Entity

Primary tumours of the heart are uncommon entities, cardiac myxomas being the most frequent. However, mitral valve myxomas are exceptionally rare. In the last 12 years, there have been 25 myxomas diagnosed at our institution, with only two of them originating from the mitral valve. Both patients were female, the first, 25, and the second, 72 years old. The younger patient was very symptomatic with a large mass, 4 cm long, which involved both leaflets causing significant obstruction to the left ventricular inflow. The second one had a smaller mass located at the atrial side of the posterior leaflet that only produced some flow divergence. Neither of them had constitutional nor embolic symptoms. Both patients were submitted to emergent surgical resection that in the first case involved the mitral valve and replacement with mechanical prosthesis. The macroscopic appearance of these tumours suggested a malignant aetiology which may represent somewhat different features of the myxomas when originating from the cardiac valves. Both patients are well reflecting the good prognosis of this illness after resection, although the younger patient was re-operated because of prosthetic valve obstruction and suspicion of recurrence that was not confirmed. Because of the illustrative images and different presentations, we found it interesting to report and discuss them together.

Laparoscopic Assisted Vaginal Hysterectomy Versus Vaginal Hysterectomy

Introduction: Hysterectomy is the commonest gynecologic operation, performed for malignant and benign conditions. There are many approaches to hysterectomy for benign disease. Studies comparing the techniques have showed that vaginal hysterectomy has benefits in terms of reduced hospital stay, faster recovery and less operating time. Objective: The purpose of this study is to compare the surgical and immediate postoperative outcomes of Laparoscopic Assisted Vaginal Hysterectomy (LAVH) with those of Vaginal Hysterectomy (VH). Methods: Retrospective descriptive study, comparing two groups of women who underwent LAVH or VH in our department during a 24 months period, from January 2009 to December 2010. The two groups were compared regarding age, vaginal deliveries, previous abdominal surgery, uterine and adnexal pathology, intra-operative and post-operative complications, uterus weight, blood loss and number of days until discharge. Results: In our study 42 LAVH and 99 VH were included, with a patient mean age of 47 and 59, respectively. The most frequent indication for hysterectomy was fibroids (80%) for LAVH and POP(58.6%) for HV. In LAVH group 47.6% of patients had previous abdominal surgery, vs 28.2% in VH group. The medium operative time was 167 minutes for LAVH vs 99 minutes for HV. The intra-operative complications were one case (2%) of accidental incision of rectum in LAVH, and one bladder incision in the VH (1%). There were 3 conversions to laparotomy for difficult technique (7%) in LAVH group. There were no significant post-operative complications for LAVH. In VH group there were 2 cases of haemoperitoneum (2%) and 1 case requiring blood transfusion (1%). The mean time for discharge was 4.23 days for LAVH and 4.46 days for VH. Conclusions: In our study, the main advantage for VH was the reduced operative time. In terms of time to discharge there was no difference between the 2 groups. The main intra-operative complication of LAVH was the risk of conversion to laparotomy, but post-operatively this procedure had fewer complications than VH. In conclusion, LAVH is a safe option for women requiring hysterectomy in cases where VH is anticipated to be technically difficult.

Morphological changes in the digestive system of 93 human immunodeficiency virus positive patients: an autopsy study

Involvement of the digestive system in patients with acquired immunodeficiency syndrome (AIDS) is frequent and many changes in these patients are diagnosed only at autopsy. There are few studies of autopsy with detailed analysis of this system and only one was conducted in Brazil. We evaluated each segment of the digestive system in 93 consecutive autopsies of patients infected with human immunodeficiency virus (HIV) and the importance of these lesions to death. Of these, 90 (96.8%) patients had AIDS. We reviewed medical records, autopsy reports and histological sections from tongue to rectum stained with hematoxylin-eosin. When necessary, we analyzed special stains and immunohistochemistry to investigate infections. There was damage to the digestive system in 73 (78.5%) cases. The most common infections were candidiasis (42%), cytomegalovirus (29%), histoplasmosis (11.8%), toxoplasmosis (9.7%) and mycobacterial infection (9.7%). Malignancies were rare, present in four (4.3%) cases (two Kaposi's sarcoma, one adenocarcinoma and one metastatic embryonal carcinoma). All segments showed lesions: tongue (48.6%), esophagus (44.8%), stomach (44.7%), colon (43.2%) and small intestine (28.9%). The lesions found were immediate cause of death in five (5.4%) cases. In another 36 (38.7%) cases the basic disease was systemic and also compromised the digestive system.

A go-to-market strategy for green extration and impregnation

Dissertação para obtenção do Grau de Mestre em Biotecnologia

Position Statement on Bioresorbable Vascular Scaffolds in Portugal

BACKGROUND: Bioresorbable vascular scaffolds (BVS) were recently approved for percutaneous coronary intervention in Europe. The aim of this position statement is to review the information and studies on available BVS, to stimulate discussion on their use and to propose guidelines for this treatment option in Portugal. METHODS AND RESULTS: A working group was set up to reach a consensus based on current evidence, discussion of clinical case models and individual experience. The evidence suggests that currently available BVS can produce physiological and clinical improvements in selected patients. There are encouraging data on their durability and long-term safety. Initial indications were grouped into three categories: (a) consensual and appropriate - young patients, diabetic patients, left anterior descending artery, long lesions, diffuse disease, and hybrid strategy; (b) less consensual but possible - small collateral branches, stabilized acute coronary syndromes; and (c) inappropriate - left main disease, tortuosity, severe calcification. CONCLUSION: BVS are a viable treatment option based on the encouraging evidence of their applicability and physiological and clinical results. They should be used in appropriate indications and will require technical adaptations. Outcome monitoring and evaluation is essential to avoid inappropriate use. It is recommended that medical societies produce clinical guidelines based on high-quality registries as soon as possible.

FACTORS RELATED TO ORAL CANDIDIASIS IN ELDERLY USERS AND NON-USERS OF REMOVABLE DENTAL PROSTHESES

This study examined the association between oral candidiasis in elderly users and nonusers of prosthesis and its predisposing factors. To this end, we performed a cross-sectional study where saliva samples from 48 patients were collected they used prosthesis and 43 patients (control group) who did not use. Among the 91 patients, Candida spp were isolated in 40 (83.3%) who used prosthesis and in 23 (53.5%) in the control group. A statistically significant association was determined between the two groups, the isolation of yeasts and dental prosthesis (p < 0.05, OR = 4.3). The most common etiological agent was Candida albicans (37 isolates), with 23 (62.2%) in the denture group and 14 (37.8%) (control group). Among patients who presented clinical manifestations of oral candidiasis (n = 24), 83.3% (n = 20) belonged to the group that wore dentures, while only 16.7% (n = 4) belonged to the control group. Elderly patients with diabetes had 4.4 times higher estimated risk of developing oral candidiasis when compared with individuals without this condition. There was no statistically significant association between being user prostheses and have diabetes with the onset of candidiasis. No statistically significant association was determined between xerostomia, use of prosthesis and oral candidiasis. The use of prosthetics and poor oral hygiene in elderly patients predisposes to the development of oral candidiasis.

Familial Abdominal Aortic Aneurysm Is Associated With More Complications After Endovascular Aneurysm Repair

OBJECTIVE: A familial predisposition to abdominal aortic aneurysms (AAAs) is present in approximately one-fifth of patients. Nevertheless, the clinical implications of a positive family history are not known. We investigated the risk of aneurysm-related complications after endovascular aneurysm repair (EVAR) for patients with and without a positive family history of AAA. METHODS: Patients treated with EVAR for intact AAAs in the Erasmus University Medical Center between 2000 and 2012 were included in the study. Family history was obtained by written questionnaire. Familial AAA (fAAA) was defined as patients having at least one first-degree relative affected with aortic aneurysm. The remaining patients were considered sporadic AAA. Cardiovascular risk factors, aneurysm morphology (aneurysm neck, aneurysm sac, and iliac measurements), and follow-up were obtained prospectively. The primary end point was complications after EVAR, a composite of endoleaks, need for secondary interventions, aneurysm sac growth, acute limb ischemia, and postimplantation rupture. Secondary end points were specific components of the primary end point (presence of endoleak, need for secondary intervention, and aneurysm sac growth), aneurysm neck growth, and overall survival. Kaplan-Meier estimates for the primary end point were calculated and compared using log-rank (Mantel-Cox) test of equality. A Cox-regression model was used to calculate the independent risk of complications associated with fAAA. RESULTS: A total of 255 patients were included in the study (88.6% men; age 72 ± 7 years, median follow-up 3.3 years; interquartile range, 2.2-6.1). A total of 51 patients (20.0%) were classified as fAAA. Patients with fAAA were younger (69 vs 72 years; P = .015) and were less likely to have ever smoked (58.8% vs 73.5%; P = .039). Preoperative aneurysm morphology was similar in both groups. Patients with fAAA had significantly more complications after EVAR (35.3% vs 19.1%; P = .013), with a twofold increased risk (adjusted hazard ratio, 2.1; 95% confidence interval, 1.2-3.7). Secondary interventions (39.2% vs 20.1%; P = .004) and aneurysm sac growth (20.8% vs 9.5%; P = .030) were the most important elements accounting for the difference. Furthermore, a trend toward more type I endoleaks during follow-up was observed (15.6% vs 7.4%; P = .063) and no difference in overall survival. CONCLUSIONS: The current study shows that patients with a familial form of AAA develop more aneurysm-related complications after EVAR, despite similar AAA morphology at baseline. These findings suggest that patients with fAAA form a specific subpopulation and create awareness for a possible increase in the risk of complications after EVAR.

The Impact of Multifocal Intraocular Lens in Retinal Imaging with Optical Coherence Tomography

Multifocal intraocular lenses (MF IOLs) have concentric optical zones with different dioptric power, enabling patients to have good visual acuity at multiple focal points. However, several optical limitations have been attributed to this particular design. The purpose of this study is to access the effect of MF IOLs design on the accuracy of retinal optical coherence tomography (OCT). Cross-sectional study conducted at the Refractive Surgery Department of Central Lisbon Hospital Center. Twenty-three eyes of 15 patients with a diffractive MF IOL and 27 eyes of 15 patients with an aspheric monofocal IOL were included in this study. All patients underwent OCT macular scans using Heidelberg Spectralis®. Macular thickness and volume values and image quality (Q factor) were compared between the two groups. There were no statistically significant differences between both groups regarding macular thickness or volume measurements. Retinal OCT image quality was significantly lower in the MF IOL group (p < 0.01). MF IOLs are associated with a significant decrease in OCT image quality. However, this fact does not seem to compromise the accuracy of spectral domain OCT retinal measurements.

Mid-Term Results of EVAR in Severe Proximal Aneurysm Neck Angulation.

OBJECTIVE: To determine if mid-term outcome following endovascular aneurysm repair (EVAR) with the Endurant Stent Graft (Medtronic, Santa Rosa, CA, USA) is influenced by severe proximal neck angulation. METHODS: A retrospective case-control study was performed using data from a prospective multicenter database. All measurements were obtained using dedicated reconstruction software and center-lumen line reconstruction. Patients with neck length >15 mm, infrarenal angle (β) >75°, and/or suprarenal angle (α) >60°, or neck length >10 mm with β >60°, and/or α >45° were compared with a matched control group. Primary endpoint was primary clinical success. Secondary endpoints were freedom from rupture, type 1A endoleak, stent fractures, freedom from neck-related reinterventions, and aneurysm-related adverse events. Morphological neck variation over time was also assessed. RESULTS: Forty-five patients were included in the study group and were compared with a matched control group with 65 patients. Median follow-up time was 49.5 months (range 30.5-58.4). The 4-year primary clinical success estimates were 83% and 80% for the angulated and nonangulated groups (p = .42). Proximal neck angulation did not affect primary clinical success in a multivariate model (hazard ratio 1.56, 95% confidence interval 0.55-4.41). Groups did not differ significantly in regard to freedom from rupture (p = .79), freedom from type 1A endoleak (p = .79), freedom from neck-related adverse events (p = .68), and neck-related reinterventions (p = .68). Neck angle reduction was more pronounced in patients with severe proximal neck angulation (mean Δα -15.6°, mean Δβ -30.6°) than in the control group (mean Δα -0.39°, mean Δβ -5.9°) (p < .001). CONCLUSION: Mid-term outcomes following EVAR with the Endurant Stent Graft were not influenced by severe proximal neck angulation in our population. Despite the conformability of the device, moderate aortic neck remodeling was identified in the group of patients with angulated neck anatomy on the first computed tomography scan after implantation with no important further remodeling afterwards. No device integrity failures were encountered.

Femoral Approach: an Exceptional Alternative for Permanent Pacemaker Implantation

The classic transvenous implantation of a permanent pacemaker in a pectoral location may be precluded by obstruction of venous access through the superior vena cava or recent infection at the implant site. When these barriers to the procedure are bilateral and there are also contraindications or technical difficulties to performing a thoracotomy for an epicardial approach, the femoral vein, although rarely used, can be a viable alternative. We describe the case of a patient with occlusion of both subclavian veins and a high risk for mini-thoracotomy or videothoracoscopy, who underwent implantation of a permanent single-chamber pacemaker via the right femoral vein.

Clinical Outcome and Morphologic Determinants of Mural Thrombus in Abdominal Aortic Endografts

OBJECTIVE:Endograft mural thrombus has been associated with stent graft or limb thrombosis after endovascular aneurysm repair (EVAR). This study aimed to identify clinical and morphologic determinants of endograft mural thrombus accumulation and its influence on thromboembolic events after EVAR. METHODS: A prospectively maintained database of patients treated by EVAR at a tertiary institution from 2000 to 2012 was analyzed. Patients treated for degenerative infrarenal abdominal aortic aneurysms and with available imaging for thrombus analysis were considered. All measurements were performed on three-dimensional center-lumen line computed tomography angiography (CTA) reconstructions. Patients with thrombus accumulation within the endograft's main body with a thickness >2 mm and an extension >25% of the main body's circumference were included in the study group and compared with a control group that included all remaining patients. Clinical and morphologic variables were assessed for association with significant thrombus accumulation within the endograft's main body by multivariate regression analysis. Estimates for freedom from thromboembolic events were obtained by Kaplan-Meier plots. RESULTS: Sixty-eight patients (16.4%) presented with endograft mural thrombus. Median follow-up time was 3.54 years (interquartile range, 1.99-5.47 years). In-graft mural thrombus was identified on 30-day CTA in 22 patients (32.4% of the study group), on 6-month CTA in 8 patients (11.8%), and on 1-year CTA in 17 patients (25%). Intraprosthetic thrombus progressively accumulated during the study period in 40 patients of the study group (55.8%). Overall, 17 patients (4.1%) presented with endograft or limb occlusions, 3 (4.4%) in the thrombus group and 14 (4.1%) in the control group (P = .89). Thirty-one patients (7.5%) received an aortouni-iliac (AUI) endograft. Two endograft occlusions were identified among AUI devices (6.5%; overall, 0.5%). None of these patients showed thrombotic deposits in the main body, nor were any outflow abnormalities identified on the immediately preceding CTA. Estimated freedom from thromboembolic events at 5 years was 95% in both groups (P = .97). Endograft thrombus accumulation was associated with >25% proximal aneurysm neck thrombus coverage at baseline (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.3), neck length ≤ 15 mm (OR, 2.4; 95% CI, 1.3-4.2), proximal neck diameter ≥ 30 mm (OR, 2.4; 95% CI, 1.3-4.6), AUI (OR, 2.2; 95% CI, 1.8-5.5), or polyester-covered stent grafts (OR, 4.0; 95% CI, 2.2-7.3) and with main component "barrel-like" configuration (OR, 6.9; 95% CI, 1.7-28.3). CONCLUSIONS: Mural thrombus formation within the main body of the endograft is related to different endograft configurations, main body geometry, and device fabric but appears to have no association with the occurrence of thromboembolic events over time.

Percutaneous Treatment of Mitral Valve Regurgitation: Initial Experience with the MitraClip Device

INTRODUCTION: Mitral regurgitation (MR) is the most common valvular disease and has recently become the target of a number of percutaneous approaches. The MitraClip is virtually the only device for which there is considerable experience, with more than 20,000 procedures performed worldwide. OBJECTIVE: To describe our initial experience of the percutaneous treatment of MR with the MitraClip device. METHODS: We describe the first six MitraClip cases performed in this institution (mean age 58.5 ± 13.1 years), with functional MR grade 4+ and New York Heart Association (NYHA) heart failure class III or IV (n=3), with a mean follow-up of 290 ± 145 days. RESULTS: Procedural success (MR ≤ 2+) was 100%. Total procedure time was 115.8 ± 23.7 min, with no in-hospital adverse events and discharge between the fourth and eighth day, and consistent improvement in the six-minute walk test (329.8 ± 98.42 vs. 385.33 ± 106.95 m) and in NYHA class (three patients improved by two NYHA classes). During follow-up there were two deaths, in two of the four patients who had been initially considered for heart transplantation. CONCLUSION: In patients with functional MR the MitraClip procedure is safe, with both a high implantation and immediate in-hospital success rate. A longer follow-up suggests that the clinical benefit decreases or disappears completely in patients with more advanced heart disease, namely those denied transplantation or on the heart transplant waiting list.

Minimally Invasive Repair of Morgagni Hernia - A Multicenter Case Series

Children may benefit from minimally invasive surgery (MIS) in the correction of Morgagni hernia (MH). The present study aims to evaluate the outcome of MIS through a multicenter study. National institutions that use MIS in the treatment of MH were included. Demographic, clinical and operative data were analyzed. Thirteen patients with MH (6 males) were operated using similar MIS technique (percutaneous stitches) at a mean age of 22.2±18.3 months. Six patients had chromosomopathies (46%), five with Down syndrome (39%). Respiratory complaints were the most common presentation (54%). Surgery lasted 95±23min. In none of the patients was the hernia sac removed; prosthesis was never used. In the immediate post-operative period, 4 patients (36%) were admitted to intensive care unit (all with Down syndrome); all patients started enteral feeds within the first 24h. With a mean follow-up of 56±16.6 months, there were two recurrences (18%) at the same institution, one of which was repaired with an absorbable suture; both with Down syndrome. The application of MIS in the MH repair is effective even in the presence of comorbidities such as Down syndrome; the latter influences the immediate postoperative recovery and possibly the recurrence rate. Removal of hernia sac does not seem necessary. Non-absorbable sutures may be more appropriate.

Atherogenesis and atherosclerosis in primary antiphospholipid syndrome

ABSTRACT: In the late seventies the term “Haematological Stress Syndrome” defined some haematological abnormalities appearing in the course of acute and chronic disorders, such as raised plasma levels of fibrinogen (FNG) and factor VIII, reduced fibrinolytic activity and hyperviscosity. In the early nineties the “Membrane stress syndrome hypothesis” proposed the unification of the concepts of haematological stress syndrome with those of oxidation, inflammation and immune activation to explain the pathogenesis of the antiphospholipid syndrome (APS) Antiphospholipid antibodies, coagulation, fibrinolysis and thrombosis. This chapter investigated the occurrence of the “Haematological Stress Syndrome” and thrombosis in 144 participants positive for aPL detected by clotting and immune tests. Among the clotting assays for the detection of lupus anticoagulant, dilute Russell's viper venom time better correlated with a history of venous thrombosis than activated partial thromboplastin time (p<0.0002 vs p<0.009) and was the only test correlated with a history of arterial thrombosis (p<0.01). By regression analysis, serum levels of IgG anticardiolipin antibodies (aCL) associated with the number of venous occlusions (p<0.001). With regards to FNG and von Willebrand factor (vWF), the former rose by 36% (95% CI; 21%, 53%) and the latter by 50% (95% CI; 29%, 75%) at the first venous occlusion and remained unchanged after subsequent occlusions. At variance FNG rose by 45% (95% CI; 31%, 60%) per arterial occlusion and vWF by 27% (95% CI; 10%, 47%) per arterial occlusion throughout. The coagulation/fibrinolytic balance was cross-sectionally evaluated on 18 thrombotic PAPS patients, 18 subjects with persistence of idiopathic aPL and in healthy controls. Markers of thrombin generation prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and of fibrin turnover D-Dimer (D-D) were higher in thrombotic (p=0.006)and non-thrombotic subjects (p=0.0001) than in controls as were those of D-D (p<0.0001 and p=0.003 respectively). TAT levels did not differ. Gender analysed data revealed blunted tPA release (hence a negative venous occlusion test) in thrombotic females but neither in thrombotic males (p=0.01) nor in asymptomatic subjects of either sex. Also, in both patient groups females had higher mean PAI than males (p<0.0002) and control females (p<0.02). The activity of factor XIII (FXIIIa) was evaluated was evaluated in 29 patients with PAPS, 14 persistent carriers of aPL without thrombosis, 24 thrombotic patients with inherited thrombophilia, 28 healthy controls and 32 patients with mitral and aortic valve prosthesis as controls for FXIII only. FXIIIa was highest in PAPS (p=0.001), particularly in patients with multiple (n=12) than single occlusion (p=0.02) and in correlation with PAI (p=0.003) and FNG (p=0.005). Moreover FXIIIa was strongly associated with IgG aCL and IgG anti-2GPI (p=0.005 for both) in the PAPS group and to a lesser degree in the aPL group (FXIIIa with IgG aCL, p=0.02, with IgG anti-2GPI, p=0.04). Altogether these results indicate: 1) a differential relationship of aPL, vWF and FNG with venous and arterial thrombosis; 2) heightened thrombin generation, accelerated fibrin turnover and fibrinolysis abnormalities also in asymptomatic carriers of aPLs; 3) enhanced FXIIIa that may contribute to atherothrombosis via increased fibrin/fibrinogen cross-linking. Lipid profile, lipid peroxidation and anti-lipoprotein antibodies in thrombotic primary antiphospholipid syndrome. Given the atherogenic lipid profile of SLE, the same possibility was explored in PAPS by comparing high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (CHO), apolipoprotein AI (ApoAI), apolipoprotein B (ApoB), triglycerides (TG), anti-lipoprotein antibodies, beta-2-glycoprotein I complexed to oxidized low-density lipoprotein (oxLDL-2GPI) and C-reactive protein (CRP) in 34 thrombotic PAPS patients compared to 36 thrombotic patients with inherited thrombophilia (IT), to 18 subjects persistently positive for antiphospholipid antibodies (aPL) with no underlying autoimmune or non-autoimmune disorders and to 28 healthy controls. Average concentrations of HDL (p<0.0001), LDL (p<0.0001), CHO (p=0.0002), ApoAI (p=0.002) were lower in PAPS whereas average TRY was higher (p=0.01) than other groups. Moreover PAPS showed higher IgG anti-HDL (p=0.01) and IgG anti-ApoAI (p<0.0001) as well as greater average oxLDL-2GPI (p=0.001) and CRP (p=0.003). Within PAPS, IgG anti-HDL correlated negatively to HDL (p=0.004) and was an independent predictor of oxLDL-2GPI (p=0.009). HDL and ApoAI correlated negatively with CRP (p=0.001 and p=0.007, respectively). IgG anti-HDL may hamper the antioxidant and anti-inflammatory effect of HDL favouring low-grade inflammation and enhanced oxidation in thrombotic PAPS. Indeed plasma 8-epi-prostaglandin F2α (a very specific marker of lipid peroxidation) was significantly higher in 10 patients with PAPS than 10 age and sex matched healthy subjects (p=0.0002) and strongly related to the titre of plasma IgG aCL (r=0.89, p=0.0004). Hence oxidative stress, a major player in atherogenesis, also characterises PAPS. Nitric oxide and nitrative stress in thrombotic primary antiphosholipid syndrome. Oxidative stress goes hand in hand with nitrative stress and to address the latter plasma nitrotyrosine (NT, marker of nitrative stress), nitrite (NO2-) and nitrate (NO3-) were measured in 46 thrombotic PAPS patients, 21 asymptomatic but persistent carriers of antiphospholipid antibodies (PCaPL), 38 patients with inherited thrombophilia (IT), 33 patients with systemic lupus erythematosus (SLE) and 29 healthy controls (CTR). Average crude NT was higher in PAPS and SLE (p=0.01) whereas average plasma NO2- was lower in PAPS and average NO3- highest in SLE (p<0.0001). In PAPS, IgG aCL titer and number of vascular occlusions negatively predicted NO2-, (p=0.03 and p=0.001, respectively) whereas arterial occlusions and smoking positively predicted NO3- (p=0.05 and p=0.005). Moreover CRP (an inflammatory marker) positively predicted NT (p=0.004). Nitric oxide metabolites relates to type and number of vascular occlusions and to aPL titers, whereas nitrative stress relates to low grade marker) positively predicted NT (p=0.004). Nitric oxide metabolites relates to type and number of vascular occlusions and to aPL titers, whereas nitrative stress relates to low grade inflammation and both phenomena may have implications for thrombosis and atherosclerosis in PAPS Inflammation and immune activation in thrombotic primary antiphospholipid syndrome. To investigate inflammation and immune activation in thrombotic PAPS high-sensitivity CRP (hs-CRP), serum amyloid A (SAA), oxLDL-2GPI, CRP bound to oxLDL-2GPI (CRP-oxLDL-2GPI) (as inflammatory markers) neopterin (NPT) and soluble CD14 (sCD14) (as immune activation markers) were measured by ELISA in 41 PAPS patients, in 44 patients with inherited thrombophilia (IT) and 39 controls (CTR). Compared to other groups, PAPS presented with higher plasma concentrations of inflammatory, hs-CRP (p=0.0004), SAA (p<0.01), CRP-oxLDL-2GPI (p=0.0004) and immune activation markers, NPT (p<0.0001) and sCD14 (p=0.007). By regression analysis SAA independently predicted thrombosis number (p=0.003) and NPT independently predicted thrombosis type (arterial, p=0.03) and number (p=0.04). These data confirm that low-grade inflammation and immune activation occur and relate to vascular features of PAPS. Antiphosholipid antibodies, haemostatic variables and atherosclerosis in thrombotic primary antiphospholipid syndrome To evaluate whether IgG aCL titre, haemostatic variables and the lipid profile bore any relationship to the intima media thickness (IMT) of carotid arteries high-resolution sonography was applied to the common carotid (CC), carotid bifurcation (CB) and internal carotid (IC) of 42 aPL subjects, 29 with primary thrombotic antiphospholipid syndrome and 13 with persistence of aPL in the absence of any underlying disorder. The following were measured: plasma FNG, vWF, PAI, homocysteine (HC), CHO, TG, HDL, LDL, platelet numbers and aCL of IgG and IgM isotype. By multiple regression analysis, IgG aCL titre independently predicted IMT at all carotid segments examined (p always <0.005). Plasma FNG and HC independently predicted IMT at the CB (p=0.001 and p<0.0001, respectively) and IC (p=0.03 and p<0.0001, respectively). These data strongly support an atherogenic role for IgG aCL in patients with aPL in addition to traditional risk factors. The atherosclerosis hypothesis was investigated in an age and sex-matched case-double-control study including 49 thrombotic PAPS patients (18 M, 31 F, mean age 37 ± 11), 49 thrombotic patients for IT and 49 healthy subjects. Average IMT was always greater in PAPS than control patients (CC: p=0.004, CB: p=0.013, IC: p=0.001). By dividing participants into age tertiles the IMT was greater in the second (CC: p=0.003, CB: p=0.023, IC: p=0.003) and third tertiles (CC: p=0.03, CB: p=0.004, IC: p=0.007). Conclusion: Coagulation activation, fibrinolysis depression, hightened fibrin turnover, oxidative and nitrative stress in parallel with low grade inflammation and immune activation characterise thrombotic PAPS: all these are early atherogenic processes and contribute to the demonstrated premature atherosclerosis that should be considered a clinical feature of PAPS.

Métodos estatísticos aplicados à modelação de dados oncológicos

RESUMO: A estrutura demográfica portuguesa é marcada por baixas taxas de natalidade e mortalidade, onde a população idosa representa uma fatia cada vez mais representativa, fruto de uma maior longevidade. A incidência do cancro, na sua generalidade, é maior precisamente nessa classe etária. A par de outras doenças igualmente lesivas (e.g. cardiovasculares, degenerativas) cuja incidência aumenta com a idade, o cancro merece relevo. Estudos epidemiológicos apresentam o cancro como líder mundial na mortalidade. Em países desenvolvidos, o seu peso representa 25% do número total de óbitos, percentagem essa que mais que duplica noutros países. A obesidade, a baixa ingestão de frutas e vegetais, o sedentarismo, o consumo de tabaco e a ingestão de álcool, configuram-se como cinco dos fatores de risco presentes em 30% das mortes diagnosticadas por cancro. A nível mundial e, em particular no Sul de Portugal, os cancros do estômago, recto e cólon apresentam elevadas taxas de incidência e de mortalidade. Do ponto de vista estritamente económico, o cancro é a doença que mais recursos consome enquanto que do ponto de vista físico e psicológico é uma doença que não limita o seu raio de ação ao doente. O cancro é, portanto, uma doença sempre atual e cada vez mais presente, pois reflete os hábitos e o ambiente de uma sociedade, não obstante as características intrínsecas a cada indivíduo. A adoção de metodologia estatística aplicada à modelação de dados oncológicos é, sobretudo, valiosa e pertinente quando a informação é oriunda de Registos de Cancro de Base Populacional (RCBP). A pertinência é justificada pelo fato destes registos permitirem aferir numa população específica, o risco desta sofrer e/ou vir a sofrer de uma dada neoplasia. O peso que as neoplasias do estômago, cólon e recto assumem foi um dos elementos que motivou o presente estudo que tem por objetivo analisar tendências, projeções, sobrevivências relativas e a distribuição espacial destas neoplasias. Foram considerados neste estudo todos os casos diagnosticados no período 1998-2006, pelo RCBP da região sul de Portugal (ROR-Sul). O estudo descritivo inicial das taxas de incidência e da tendência em cada uma das referidas neoplasias teve como base uma única variável temporal - o ano de diagnóstico - também designada por período. Todavia, uma metodologia que contemple apenas uma única variável temporal é limitativa. No cancro, para além do período, a idade à data do diagnóstico e a coorte de nascimento, são variáveis temporais que poderão prestar um contributo adicional na caracterização das taxas de incidência. A relevância assumida por estas variáveis temporais justificou a sua inclusão numaclasse de modelos designada por modelos Idade-Período-Coorte (Age-Period-Cohort models - APC), utilizada na modelação das taxas de incidência para as neoplasias em estudo. Os referidos modelos permitem ultrapassar o problema de relações não lineares e/ou de mudanças súbitas na tendência linear das taxas. Nos modelos APC foram consideradas a abordagem clássica e a abordagem com recurso a funções suavizadoras. A modelação das taxas foi estratificada por sexo. Foram ainda estudados os respectivos submodelos (apenas com uma ou duas variáveis temporais). Conhecido o comportamento das taxas de incidência, uma questão subsequente prende-se com a sua projeção em períodos futuros. Porém, o efeito de mudanças estruturais na população, ao qual Portugal não é alheio, altera substancialmente o número esperado de casos futuros com cancro. Estimativas da incidência de cancro a nível mundial obtidas a partir de projeções demográficas apontam para um aumento de 25% dos casos de cancro nas próximas duas décadas. Embora a projeção da incidência esteja associada a alguma incerteza, as projeções auxiliam no planeamento de políticas de saúde para a afetação de recursos e permitem a avaliação de cenários e de intervenções que tenham como objetivo a redução do impacto do cancro. O desconhecimento de projeções da taxa de incidência destas neoplasias na área abrangida pelo ROR-Sul, levou à utilização de modelos de projeção que diferem entre si quanto à sua estrutura, linearidade (ou não) dos seus coeficientes e comportamento das taxas na série histórica de dados (e.g. crescente, decrescente ou estável). Os referidos modelos pautaram-se por duas abordagens: (i)modelos lineares no que concerne ao tempo e (ii) extrapolação de efeitos temporais identificados pelos modelos APC para períodos futuros. Foi feita a projeção das taxas de incidência para os anos de 2007 a 2010 tendo em conta o género, idade e neoplasia. É ainda apresentada uma estimativa do impacto económico destas neoplasias no período de projeção. Uma questão pertinente e habitual no contexto clínico e a que o presente estudo pretende dar resposta, reside em saber qual a contribuição da neoplasia em si para a sobrevivência do doente. Nesse sentido, a mortalidade por causa específica é habitualmente utilizada para estimar a mortalidade atribuível apenas ao cancro em estudo. Porém, existem muitas situações em que a causa de morte é desconhecida e, mesmo que esta informação esteja disponível através dos certificados de óbito, não é fácil distinguir os casos em que a principal causa de morte é devida ao cancro. A sobrevivência relativa surge como uma medida objetiva que não necessita do conhecimento da causa específica da morte para o seu cálculo e dar-nos-á uma estimativa da probabilidade de sobrevivência caso o cancro em análise, num cenário hipotético, seja a única causa de morte. Desconhecida a principal causa de morte nos casos diagnosticados com cancro no registo ROR-Sul, foi determinada a sobrevivência relativa para cada uma das neoplasias em estudo, para um período de follow-up de 5 anos, tendo em conta o sexo, a idade e cada uma das regiões que constituem o registo. Foi adotada uma análise por período e as abordagens convencional e por modelos. No epílogo deste estudo, é analisada a influência da variabilidade espaço-temporal nas taxas de incidência. O longo período de latência das doenças oncológicas, a dificuldade em identificar mudanças súbitas no comportamento das taxas, populações com dimensão e riscos reduzidos, são alguns dos elementos que dificultam a análise da variação temporal das taxas. Nalguns casos, estas variações podem ser reflexo de flutuações aleatórias. O efeito da componente temporal aferida pelos modelos APC dá-nos um retrato incompleto da incidência do cancro. A etiologia desta doença, quando conhecida, está associada com alguma frequência a fatores de risco tais como condições socioeconómicas, hábitos alimentares e estilo de vida, atividade profissional, localização geográfica e componente genética. O “contributo”, dos fatores de risco é, por vezes, determinante e não deve ser ignorado. Surge, assim, a necessidade em complementar o estudo temporal das taxas com uma abordagem de cariz espacial. Assim, procurar-se-á aferir se as variações nas taxas de incidência observadas entre os concelhos inseridos na área do registo ROR-Sul poderiam ser explicadas quer pela variabilidade temporal e geográfica quer por fatores socioeconómicos ou, ainda, pelos desiguais estilos de vida. Foram utilizados os Modelos Bayesianos Hierárquicos Espaço-Temporais com o objetivo de identificar tendências espaço-temporais nas taxas de incidência bem como quantificar alguns fatores de risco ajustados à influência simultânea da região e do tempo. Os resultados obtidos pela implementação de todas estas metodologias considera-se ser uma mais valia para o conhecimento destas neoplasias em Portugal.------------ABSTRACT: mortality rates, with the elderly being an increasingly representative sector of the population, mainly due to greater longevity. The incidence of cancer, in general, is greater precisely in that age group. Alongside with other equally damaging diseases (e.g. cardiovascular,degenerative), whose incidence rates increases with age, cancer is of special note. In epidemiological studies, cancer is the global leader in mortality. In developed countries its weight represents 25% of the total number of deaths, with this percentage being doubled in other countries. Obesity, a reduce consumption of fruit and vegetables, physical inactivity, smoking and alcohol consumption, are the five risk factors present in 30% of deaths due to cancer. Globally, and in particular in the South of Portugal, the stomach, rectum and colon cancer have high incidence and mortality rates. From a strictly economic perspective, cancer is the disease that consumes more resources, while from a physical and psychological point of view, it is a disease that is not limited to the patient. Cancer is therefore na up to date disease and one of increased importance, since it reflects the habits and the environment of a society, regardless the intrinsic characteristics of each individual. The adoption of statistical methodology applied to cancer data modelling is especially valuable and relevant when the information comes from population-based cancer registries (PBCR). In such cases, these registries allow for the assessment of the risk and the suffering associated to a given neoplasm in a specific population. The weight that stomach, colon and rectum cancers assume in Portugal was one of the motivations of the present study, that focus on analyzing trends, projections, relative survival and spatial distribution of these neoplasms. The data considered in this study, are all cases diagnosed between 1998 and 2006, by the PBCR of Portugal, ROR-Sul.Only year of diagnosis, also called period, was the only time variable considered in the initial descriptive analysis of the incidence rates and trends for each of the three neoplasms considered. However, a methodology that only considers one single time variable will probably fall short on the conclusions that could be drawn from the data under study. In cancer, apart from the variable period, the age at diagnosis and the birth cohort are also temporal variables and may provide an additional contribution to the characterization of the incidence. The relevance assumed by these temporal variables justified its inclusion in a class of models called Age-Period-Cohort models (APC). This class of models was used for the analysis of the incidence rates of the three cancers under study. APC models allow to model nonlinearity and/or sudden changes in linear relationships of rate trends. Two approaches of APC models were considered: the classical and the one using smoothing functions. The models were stratified by gender and, when justified, further studies explored other sub-models where only one or two temporal variables were considered. After the analysis of the incidence rates, a subsequent goal is related to their projections in future periods. Although the effect of structural changes in the population, of which Portugal is not oblivious, may substantially change the expected number of future cancer cases, the results of these projections could help planning health policies with the proper allocation of resources, allowing for the evaluation of scenarios and interventions that aim to reduce the impact of cancer in a population. Worth noting that cancer incidence worldwide obtained from demographic projections point out to an increase of 25% of cancer cases in the next two decades. The lack of projections of incidence rates of the three cancers under study in the area covered by ROR-Sul, led us to use a variety of forecasting models that differ in the nature and structure. For example, linearity or nonlinearity in their coefficients and the trend of the incidence rates in historical data series (e.g. increasing, decreasing or stable).The models followed two approaches: (i) linear models regarding time and (ii) extrapolation of temporal effects identified by the APC models for future periods. The study provide incidence rates projections and the numbers of newly diagnosed cases for the year, 2007 to 2010, taking into account gender, age and the type of cancer. In addition, an estimate of the economic impact of these neoplasms is presented for the projection period considered. This research also try to address a relevant and common clinical question in these type of studies, regarding the contribution of the type of cancer to the patient survival. In such studies, the primary cause of death is commonly used to estimate the mortality specifically due to the cancer. However, there are many situations in which the cause of death is unknown, or, even if this information is available through the death certificates, it is not easy to distinguish the cases where the primary cause of death is the cancer. With this in mind, the relative survival is an alternative measure that does not need the knowledge of the specific cause of death to be calculated. This estimate will represent the survival probability in the hypothetical scenario of a certain cancer be the only cause of death. For the patients with unknown cause of death that were diagnosed with cancer in the ROR-Sul, the relative survival was calculated for each of the cancers under study, for a follow-up period of 5 years, considering gender, age and each one of the regions that are part the registry. A period analysis was undertaken, considering both the conventional and the model approaches. In final part of this study, we analyzed the influence of space-time variability in the incidence rates. The long latency period of oncologic diseases, the difficulty in identifying subtle changes in the rates behavior, populations of reduced size and low risk are some of the elements that can be a challenge in the analysis of temporal variations in rates, that, in some cases, can reflect simple random fluctuations. The effect of the temporal component measured by the APC models gives an incomplete picture of the cancer incidence. The etiology of this disease, when known, is frequently associated to risk factors such as socioeconomic conditions, eating habits and lifestyle, occupation, geographic location and genetic component. The "contribution"of such risk factors is sometimes decisive in the evolution of the disease and should not be ignored. Therefore, there was the need to consider an additional approach in this study, one of spatial nature, addressing the fact that changes in incidence rates observed in the ROR-Sul area, could be explained either by temporal and geographical variability or by unequal socio-economic or lifestyle factors. Thus, Bayesian hierarchical space-time models were used with the purpose of identifying space-time trends in incidence rates together with the the analysis of the effect of the risk factors considered in the study. The results obtained and the implementation of all these methodologies are considered to be an added value to the knowledge of these neoplasms in Portugal.