Calcificações vasculares nos doentes em diálise : elo de ligação entre doença óssea e doença vascular

RESUMO: A presente dissertação para tese de doutoramento apresenta o desenvolvimento e a validação de um método simples e original para o diagnóstico de calcificações vasculares em doentes em diálise, utilizando um score semiquantitativo criado por nós e obtido em RX simples da bacia e das mãos, denominado score de calcifi cação vascular simples. Demonstramos que este score vascular simples é preditor de risco cardiovascular nos doentes em diálise. O score de calcificação vascular simples associou-se ainda à baixa densidade mineral óssea avaliada por dual energy X -ray absortiometry (DXA) no colo do fémur. Verifi camos igualmente que, em doentes em diálise, as calcifi cações coronárias quantifi cadas pelo score de Agatston e o score de calcifi cação vascular simples se associaram a um menor volume ósseo avaliado em biopsias ósseas. Estes trabalhos corroboram a hipótese da existência de um elo de ligação entre a doença óssea e a doença vascular nos doentes em diálise, e um dos elementos que contribuem para este elo de ligação podem ser as calcificações vasculares. Este score de calcificação vascular simples avalia calcifi cações em artérias de grande, médio e pequeno calibre, e inclui os dois padrões radiológicos de calcificação: calcificação linear, associada à calcifi cação da camada média da parede arterial, e calcificação irregular, associada à calcifi cação da camada íntima arterial1. Nos diferentes trabalhos por nós publicados demonstramos que as calcificações vasculares avaliadas por este método simples e barato permitem a identificação de indivíduos com elevado risco cardiovascular. Este score vascular associa -se a maior risco de mortalidade cardiovascular2, de mortalidade de causa global3, de internamentos cardiovasculares2, de doença ardiovascular2, de doença arterial periférica2,4,de calcifi cações valvulares5 e de rigidez arterial3. As guidelines KDIGO (Kidney disease: improving global outcomes), publicadas em 2009,sugerem que os doentes renais crónicos nos estadios 3 a 5, com calcificações vasculares e valvulares, devem ser considerados como apresentando o mais elevado risco cardiovascular6. A elevada mortalidade dos doentes renais crónicos não é totalmente explicada pelos fatores de risco tradicionais7. A organização KDIGO defende, desde 2006, a hipótese da existência de um elo de ligação entre a doença óssea e a doença vascular8. Esta ligação pode ser explicada pelas alterações do metabolismo mineral e ósseo e pela sua interação com as calcificações vasculares. Verificamos, nos nossos trabalhos, uma associação entre calcifi cações vasculares e doença óssea. O baixo volume ósseo diagnosticado por análise histomorfométrica de biopsias ósseas foi preditor de maior risco de calcificações vasculares avaliadas pelo score de calcifi cação vascular simples (dados apresentados nesta dissertação, no capítulo 6) e pelo score coronário de Agatston num grupo de doentes em diálise9. A contribuição original deste artigo9 foi considerada merecedora de um editorial feito pelo Dr. Gérard London10, investigador líder na área da calcificação vascular dos doentes renais crónicos e actual Presidente da EDTA (European Dialysis and Transplantation Association). Fomos também os primeiros a descrever uma associação independente e inversa entre a densidade mineral avaliada no colo do fémur por DXA (dual energy X -ray absortiometry) com calcificações vasculares avaliadas pelo score de calcificação vascular simples, com rigidez arterial avaliada por velocidade de onda de pulsocarotidofemoral e com doença arterial periférica diagnosticada por critérios clínicos11. Fomos igualmente os primeiros a mostrar uma correlação signifi cativa entre a densidade mineral óssea avaliada por DXA no colo do fémur, mas não na coluna lombar, com a espessura cortical avaliada por análise histomorfométrica em biopsia óssea12. O nosso estudo atribui pela primeira vez à DXA um papel no diagnóstico de porosidade cortical nos doentes em diálise. A utilidade da avaliação diferencial da densidade mineral óssea cortical e trabecular necessita ainda de ser confirmada em estudos prospectivos. Este achado inovador do nosso estudo foi mencionado pela ERBP (European Renal Best Practice) no comentário feito à posição da KDIGO que considera ser reduzida a utilidade da densidade mineral óssea nos doentes em diálise13. Dois dos trabalhos incluídos nesta dissertação foram referenciados nas guidelines KDIGO 2009 para avaliar a prevalência das calcificações vasculares (KDIGO 2009: Tabela suplementar 10, Fig. 3.6) e para validar a associação entre calcificações vasculares e mortalidade cardiovascular (KDIGO 2009: Tabela suplementar 12, Fig. 3.7)6. A inclusão destes nossos dois estudos nas referências destas guidelines, que utilizaram o exigente sistema GRADE (Grades of recommendation, assessment, development, and evaluation) na classificação e selecção dos estudos, valida o interesse científico dos nossos trabalhos. O diagnóstico de calcificações vasculares tem um interesse prático para os doentes renais crónicos. A presença de calcifi cações vasculares é um sinal de alerta para a existência de um elevado risco cardiovascular, e esta informação pode ser utilizada para modificar a terapêutica nestes doentes6. Diferentes métodos podem ser usados para diagnosticar calcificações vasculares nos doentes em diálise14,15. O score de calcificação vascular simples tem a vantagem da simplicidade e de poder ser facilmente interpretado pelo nefrologista, sem necessidade de um radiologista. A reprodutibilidade deste score já foi demonstrada por diferentes grupos em estudos nacionais e internacionais16-24. Nestes estudos foi demonstrado que as calcifi cações vasculares avaliadas pelo método criado por nós são preditoras de maior risco de eventos cardiovasculares16, de amputações dos membros inferiores17, de velocidade de onda de pulso18,19, de calcificações corneanas e conjuntivais20 e de calcifi cações coronárias21. Também foi demonstrada uma associação inversa entre o score de calcificação vascular simples com os níveis séricos de PTH21, com os níveis de 25(OH)vitamina D 22,23 e com os níveis de fetuína A19,24. Todos estes estudos, realizados por diferentes grupos, que utilizaram o score de calcificação vascular simples na sua metodologia, comprovam a facilidade de utilização deste score e a concordância de resultados atestam a sua reprodutibilidade e a utilidade na avaliação dos doentes renais crónicos. ---------------------------ABSTRACT: This thesis presents the development and validation of a simple and original method to identify vascular calcifications in dialysis patients, using a semi -quantitative score that we have created and that is obtained in plain X -ray of pelvis and hands. This score was named in different publications as “simple vascular calcifi cation score”. We have demonstrated that this score is a predictor of higher cardiovascular risk in dialysis patients. The simple vascular calcification score was also associated with lower mineral bone density evaluated by DXA in femoral neck. In hemodialysis patients coronary calcifications evaluated by the coronary Agatston score and by the simple vascular calcification score were associated with lower bone volume analysed in bone biopsies. These studies corroborate the hypothesis of the existence of a link between bone disease and vascular disease in dialysis patients and one of the elements of this link may be vascular calcifications. This simple vascular calcification score identifi es calcifications in large, medium and small calibre arteries and includes the two radiological patterns of arterial calcifi cation: linear calcification which has been associated with the calcifi cation of the media layer of the arterial wall and irregular and patchy calcification which has been associated with the calcifi cation of the intima layer of the arterial wall1. In the several studies that we have published we have demonstrated that vascular calcifications evaluated by this simple and inexpensive method allow the identification of patients with high cardiovascular risk. This simple vascular calcification score is an independent predictor of cardiovascular mortality2, all -cause mortality3, cardiovascular hospitalizations2, cardiovascular disease2, peripheral artery disease2,4, valvular calcifi cations5 and arterial stiffness3.KDIGO (Kidney Disease: Improving Global Outcomes) guidelines published in 2009 suggest that chronic kidney disease patients in stages 3 to 5, with vascular and valvular calcifications should be considered to be at the highest cardiovascular risk6. The high mortality of chronic kidney disease patients is not completely explained by the traditional risk factors7 and KDIGO group supports, since 2006, the hypothesis of the existence of a link between bone disease and vascular disease8.This link may be explained by the alterations of the bone and mineral metabolism and their interaction with development and progression of vascular calcifications. We have also verifi ed in our studies the existence of an association between vascular calcifications and bone disease. Low bone volume diagnosed by histomorphometric analysis of bone biopsies, in a group of dialysis patients, was independently associated with the simple vascular calcification score (data presented in this thesis,chapter 6) and with coronary calcifications evaluated by the Agatston score9. The original contribution of this article published in CJASN9 deserved a commentary in an Editorial written by Prof. Gérard London10 leader investigator in this area and current EDTA (European Dialysis and Transplantation Association) President. We were also the fi rst group to describe an independent and inverse association between bone mineral density evaluated in the femoral neck by DXA (dual energy X -ray absortiometry) with vascular calcifications evaluated by the simple vascular calcification score, with arterial stiffness evaluated by carotid-femoral pulse wave velocity and with peripheral artery disease diagnosed by clinical criteria11. We were also the first group to demonstrate a significant correlation between bone mineral density evaluated by DXA in femoral neck but not in lumbar spine, with cortical thickness evaluated by histomorphometric analysis of bone biopsy12. Our study has attributed to DXA, for the first time, a role in the diagnosis of cortical porosity in dialysis patients. The clinical utility of the differential evaluation of bone mineral density in cortical or trabecular bone needs, however, to be confi rmed in prospective studies. This original fi nding of our study was mentioned by ERBP (European Renal Best Practice) commenting the KDIGO position in relation with the reduced utility of bone mineral density evaluation in dialysis patients13. Two of the studies included in this thesis have been integrated in a group of studies selected as references by the KDIGO guidelines published in 2009 to evaluate the prevalence of vascular calcifications in CKD patients (KDIGO 2009: Supplementary Table 10, Fig. 3.6) and to corroborate the association between vascular calcifications and cardiovascular mortality (KDIGO 2009: Supplementary Table 12, Fig. 3.7)6. The inclusion of both studies as references in the KDIGO guidelines that have used the exigent GRADE system (Grades of Recommendation, Assessment, Development, and Evaluation) in the classifi cation and selection of studies, validates the scientifi c value of our studies. The diagnosis of vascular calcifi cations has a practical interest for chronic kidney disease patients. The presence of vascular calcifications is an alert sign to the existence of a high cardiovascular risk and this information may be used to modify the treatment of these patients6. Different methods may be used to detect the presence of vascular calcifications in dialysis patients14,15. The simple vascular calcifi cation score has the advantage of being simple, inexpensive and easily evaluated by the Nephrologist without the need for a Radiologist interpretation. The reproducibility of this method has already been demonstrated by other groups in national and international studies16 -24. It was demonstrated in those studies that vascular calcifi cations evaluated by the method created by us, predict higher risk of cardiovascular events16, higher risk of lower limbs amputations17, higher pulse wave velocity18,19, corneal and conjuntival calcifi cations 20 and coronary calcifi cations21. A negative association between the simple vascular calcification score and PTH levels21, 25(OH) vitamin D levels22,23 and Fetuin A levels19,24 has also been demonstrated. All these studies performed by different groups that have used the simple vascular calcifi cation score in their methods demonstrate that this score is simple, useful and reproducible in the evaluation of chronic kidney disease patients simple, useful and reproducible in the evaluation of chronic kidney disease patients.

RuSe Electrocatalysts and Single Wall Carbon Nanohorns Supports for the Oxygen Reduction Reaction

Selenium modified ruthenium electrocatalysts supported on carbon black were synthesized using NaBH4 reduction of the metal precursor. Prepared Ru/C electrocatalysts showed high dispersion and very small averaged particle size. These Ru/C electrocatalysts were subsequently modified with Se following two procedures: (a) preformed Ru/carbon catalyst was mixed with SeO2 in xylene and reduced in H2 and (b) Ru metal precursor was mixed with SeO2 followed by reduction with NaBH4. The XRD patterns indicate that a pyrite-type structure was obtained at higher annealing temperatures, regardless of the Ru:Se molar ratio used in the preparation step. A pyrite-type structure also emerged in samples that were not calcined; however, in this case, the pyrite-type structure was only prominent for samples with higher Ru:Se ratios. The characterization of the RuSe/C electrocatalysts suggested that the Se in noncalcined samples was present mainly as an amorphous skin. Preliminary study of activity toward oxygen reduction reaction (ORR) using electrocatalysts with a Ru:Se ratio of 1:0.7 indicated that annealing after modification with Se had a detrimental effect on their activity. This result could be related to the increased particle size of crystalline RuSe2 in heat-treated samples. Higher activity of not annealed RuSe/C catalysts could also be a result of the structure containing amorphous Se skin on the Ru crystal. The electrode obtained using not calcined RuSe showed a very promising performance with a slightly lower activity and higher overpotential in comparison with a commercial Pt/C electrode. Single wall carbon nanohorns (SWNH) were considered for application as ORR electrocatalysts' supports. The characterization of SWNH was carried out regarding their tolerance toward strong catalyzed corrosion conditions. Tests indicated that SWNH have a three times higher electrochemical surface area (ESA) loss than carbon black or Pt commercial electrodes.

Recycling old screen-printed electrodes with newly designed plastic antibodies on the wall of carbon nanotubes as sensory element for in situ detection of bacterial toxins in water

Using low cost portable devices that enable a single analytical step for screening environmental contaminants is today a demanding issue. This concept is here tried out by recycling screen-printed electrodes that were to be disposed of and by choosing as sensory element a low cost material offering specific response for an environmental contaminant. Microcystins (MCs) were used as target analyte, for being dangerous toxins produced by cyanobacteria released into water bodies. The sensory element was a plastic antibody designed by surface imprinting with carefully selected monomers to ensure a specific response. These were designed on the wall of carbon nanotubes, taking advantage of their exceptional electrical properties. The stereochemical ability of the sensory material to detect MCs was checked by preparing blank materials where the imprinting stage was made without the template molecule. The novel sensory material for MCs was introduced in a polymeric matrix and evaluated against potentiometric measurements. Nernstian response was observed from 7.24 × 10−10 to 1.28 × 10−9 M in buffer solution (10 mM HEPES, 150 mM NaCl, pH 6.6), with average slopes of −62 mVdecade−1 and detection capabilities below 1 nM. The blank materials were unable to provide a linear response against log(concentration), showing only a slight potential change towards more positive potentials with increasing concentrations (while that ofthe plastic antibodies moved to more negative values), with a maximum rate of +33 mVdecade−1. The sensors presented good selectivity towards sulphate, iron and ammonium ions, and also chloroform and tetrachloroethylene (TCE) and fast response (<20 s). This concept was successfully tested on the analysis of spiked environmental water samples. The sensors were further applied onto recycled chips, comprehending one site for the reference electrode and two sites for different selective membranes, in a biparametric approach for “in situ” analysis.

The effect of adhesive thickness on the mechanical behavior of a structural polyurethane adhesive

One parameter that influences the adhesively bonded joints performance is the adhesive layer thickness. Hence, its effect has to be investigated experimentally and should be taken into consideration in the design of adhesive joints. Most of the results from literature are for typical structural epoxy adhesives which are generally formulated to perform in thin sections. However, polyurethane adhesives are designed to perform in thicker sections and might have a different behavior as a function of adhesive thickness. In this study, the effect of adhesive thickness on the mechanical behavior of a structural polyurethane adhesive was investigated. The mode I fracture toughness of the adhesive was measured using double-cantilever beam (DCB) tests with various thicknesses of the adhesive layer ranging from 0.2 to 2 mm. In addition, single lap joints (SLJs) were fabricated and tested to assess the influence of adhesive thickness on the lap-shear strength of the adhesive. An increasing fracture toughness with increasing adhesive thickness was found. The lap-shear strength decreases as the adhesive layer gets thicker, but in contrast to joints with brittle adhesives the decrease trend was less pronounced.

Adhesive thickness effects of a ductile adhesive by optical measurement techniques

Adhesive bonding is an excellent alternative to traditional joining techniques such as welding, mechanical fastening or riveting. However, there are many factors that have to be accounted for during joint design to accurately predict the joint strength. One of these is the adhesive layer thickness (tA). Most of the results are for epoxy structural adhesives, tailored to perform best with small values of tA, and these show that the lap joint strength decreases with increase of tA (the optimum joint strength is usually obtained with tA values between 0.1 and 0.2 mm). Recently, polyurethane adhesives were made available in the market, designed to perform with larger tA values, and whose fracture behaviour is still not studied. In this work, the effect of tA on the tensile fracture toughness (View the MathML source) of a bonded joint is studied, considering a novel high strength and ductile polyurethane adhesive for the automotive industry. This work consists on the fracture characterization of the bond by a conventional and the J-integral techniques, which accurately account for root rotation effects. An optical measurement method is used for the evaluation of crack tip opening (δn) and adherends rotation at the crack tip (θo) during the test, supported by a Matlab® sub-routine for the automated extraction of these parameters. As output of this work, fracture data is provided in traction for the selected adhesive, enabling the subsequent strength prediction of bonded joints.

Dermoid Tumor of the Lateral Wall of the Cavernous Sinus

BACKGROUND: Congenital intracranial dermoid tumors are very rare. The location of these dermoid lesions in the cavernous sinus and the complexity of the operative procedure for these lesions have been noted by several authors. Dermoid tumors originating in the cavernous sinus are usually interdural, and thus blurred vision is an uncommon presentation. CASE DESCRIPTION: Herein we report the first incidental case of a cavernous sinus dermoid cyst in a 21-year-old woman. CONCLUSIONS: A literature review was done and the possible treatments and approaches for this lesion are discussed. We consider that surgical treatment is indicated in most incidental cavernous sinus dermoid lesions due to the possible symptoms related to compression or rupture leading to chemical meningitis.

Dot-Elisa for evaluation of hydatid cyst wall, protoscoleces and hydatid cyst fluid antigens in the serodiagnosis of cystic echinococcosis

The aim of the present study is to evaluate cyst wall and protoscolex as an alternate source of antigen in serodiagnosis of cystic echinococcosis (CE). A total of 90 blood samples, 30 each of confirmed CE cases, disease controls and healthy controls were collected. Dot-ELISA using cyst wall, protoscolex and cyst fluid were used to demonstrate anti-hydatid antibodies. The sensitivity of Dot-ELISA using cyst wall, protoscolex and cyst fluid was 96.66%, 86.66% and 93.33% respectively and the specificity of the assay was 70% for Dot-ELISA using cyst fluid, protoscolex and cyst wall antigens. Results of the present study show that cyst wall and protoscolex can also be an useful source of antigen in detection of hydatid antibodies in the serodiagnosis of CE.

Carotid Intima-Media Thickness and Carotid Plaques Improves Prediction of Obstructive Angiographic Coronary Artery Disease in Women

Does carotid intima-media thickness (cIMT), a surrogate marker of cardiovascular events, have predictive incremental value over established risk factors for stable coronary artery disease (CAD)? Prospective study of 300 patients, with suspected stable CAD, admitted for an elective coronary angiography and carotid ultrasound. The CAD patients had a higher cIMT, which showed a modest predictive accuracy for CAD (area under the receiver-operating characteristic curve 0.638, 95% confidence interval 0.576-0.701, P < .001). The cIMT was an independent predictor of CAD, together with age, gender, and diabetes. C-statistic for CAD prediction by traditional risk factors was not significantly different from a model that included cIMT, carotid plaque presence, or both. However, in women, it was significantly increased by the addition of cIMT or carotid plaque presence. Although cIMT cannot be used as a sole indicator of CAD, it should be considered in the panel of investigations that is requested, particularly in women who are candidates for coronary angiography.

Insights into cell wall synthesis and cell division in Staphylococcus aureus

Dissertation presented to obtain the Ph.D degree in Biology

Evaluation of air lime and clayish earth mortars for earthen wall renders

CIAV2013 – International Conference on Vernacular Architecture, 7º ATP, VerSus, 16-20 october 2013

Regulation and function of the cell wall polymer lipoteichoic acid in staphylococcus aureus

A thesis submitted for the Degree of Master in Medical microbiology

Eco-wall modular solutions for buildings

This paper discusses the development of modular solutions for eco low-cost houses based on a pre-fabricated modular wall system environmentally sustainable, socioeconomically competitive and geared towards developing African nations with a housing deficit. The key point to the research of a modular wall solution is a structural layer complemented with local and materials made by non-specialized workforce. This wall also meets also hydrothermal acoustic and mechanical properties. Thus,the solution also offers good safety and interior comfort conditions to its users while maintaining the flexibility to expand the size of the house. Parameters as dimensions, materials and constructive processes of the existing housing stock were studied. Features such as the family size, typology, different uses, common materials, existing regulations, minimal living conditions, safety and comfort have also been considered to achieve the most efficient solution.

Abdominal wall protrusion following herpes zoster

We present the case of a 62-year-old woman with abdominal segmental paresis consequent to radiculopathy caused by zoster, which was confirmed by electroneuromyography. The paresis resolved completely within three months. Recognition of this complication caused by zoster, which is easily misdiagnosed as abdominal herniation, is important for diagnosing this self-limited condition and avoiding unnecessary procedures.

Precast concrete wall-foundation connection. Development of a seismic dissipative connection

Seismic events are a major factor to consider in structural design of buildings in many countries. With the purpose of saving lives, most of the design codes lead to structural solutions that withstand large seismic actions without collapsing, but without taking into account a possible usage of the structures after the earthquake. As a result, it is necessary to consider the time needed to repair/retrofit the damaged structures (i.e. the downtime) since this period of inactivity may result in huge financial implications for the occupants of the buildings. In order to minimise the damages and simplify repair operations, structural solutions with rocking systems and negligible residual displacements have been developed during the last two decades. Systems with precast concrete rocking walls were studied with the aim of investigat- ing suitable and convenient structural alternatives to minimise the damage in case of an earthquake. Experimental, numerical and analytical analyses on post-tensioned solutions, with and without energy dissipation devices, were carried out in this research. The energy dissipation devices were made from steel angles that were further developed during the research. Different solutions for these devices were experimentally tested under cyclic loading and the results are presented. Numerical and analytical work on steel angles was also carried out. Regarding the concrete rocking wall systems, two concrete rocking wall systems were studied: post-tensioned walls and post-tensioned walls with energy dissipation devices. In the latter, the solution was to fix them externally to the wall, allowing their easy replacement after an earthquake. It is shown that the dissipaters are a viable solution for use in precast concrete rocking wall systems. A building case study is presented. The comparison between a traditional monolithic system and a hybrid solution was carried out, allowing the evaluation of the efficiency of the solution that was developed.

Megabladder in experimental Chagas disease: pathological features of the bladder wall

Mega-organs, primarily in the digestive tract, are well known to occur in chronic Chagas disease. Acute experimental infection with Trypanosoma cruzi results in parasitism of a wide range of cells, tissues, and organs, including the urinary bladder. Infection of BALB/c mice with 100,000 bloodstream forms of the Y strain of T. cruzi induced acute infection with intense parasitism of all layers of the urinary bladder. Parasites were found in the mucosa, lamina propria, muscular, adventitial connective, and fat tissue. Desquamate epithelial cells with amastigotes in the bladder lumen were also found. After 60 days of infection, mice inoculated with 50 bloodstream forms developed dilated, thin-walled bladders that had inflammatory infiltrates and foci of fibrosis replacing areas of damaged muscular layer. These lesions result from direct damage to the muscle fibers by the T. cruzi, leading to myosites, muscle damage, and scarring. Direct damage of paraganglia cells secondary to parasitism, leading to dilatation, damage of muscle fibers, and scarring with replacement of muscular tissue with connective tissue, should also be considered as a cause of functional disturbance of the urinary bladder.