Algorithm for the Parkinson’s disease behavioural models characterization using a biosensor

Dissertação para obtenção do Grau de Mestre em Engenharia Biomédica

CHROMOBLASTOMYCOSIS: A NEGLECTED TROPICAL DISEASE

SUMMARYChromoblastomycosis (CMB) is a chronic fungal infection of the skin and the subcutaneous tissue caused by a transcutaneous traumatic inoculation of a specific group of dematiaceous fungi occurring mainly in tropical and subtropical zones worldwide. If not diagnosed at early stages, patients with CBM require long term therapy with systemic antifungals, sometimes associated with physical methods. Unlike other neglected endemic mycoses, comparative clinical trials have not been performed for this disease. Nowadays, therapy is based on a few open trials and on expert opinion. Itraconazole either as monotherapy or associated with other drugs, or with physical methods, is widely used. Recently, photodynamic therapy has been successfully employed in combination with antifungals in patients presenting with CBM. In the present revision the most used therapeutic options against CBM are reviewed as well as the several factors that may have impact on the patient's outcome.

Regulation of autoimmune neuroinflammation by stress-responsive genes

Dissertation presented to obtain the Ph.D degree in Biology

IMPACT OF THE PEGYLATED-INTERFERON AND RIBAVIRIN THERAPY ON THE TREATMENT-RELATED MORTALITY OF PATIENTS WITH CIRRHOSIS DUE TO HEPATITIS C VIRUS

Although the protease inhibitors have revolutionized the therapy of chronic hepatitis C (CHC), the concomitant use of pegylated-interferon (PEG-IFN) and ribavirin (RBV) is associated to a high rate of adverse effects. In this study, we evaluated the consequences of PEG-IFN and RBV and their relationship with mortality in patients with cirrhosis. METHODS: Medical records of CHC who underwent treatment with PEG-IFN and RBV in a public hospital in Brazil were evaluated. All the patients with cirrhosis were selected, and their clinical and laboratory characteristics, response to treatment, side effects and mortality were evaluated. RESULTS: From the 1,059 patients with CHC, 257 cirrhotic patients were evaluated. Of these, 45 (17.5%) achieved sustained viral response (SVR). Early discontinuation of therapy occurred in 105 (40.8%) patients, of which 39 (15.2%) were due to serious adverse effects. The mortality rate among the 257 cirrhotic patients was 4.3%, occurring in 06/242 (2.4%) of the Child-A, and in 05/15 (33.3%) of the Child-B patients. In conclusion, the treatment of patients with cirrhosis due to HCV with PEG-IFN and RBV shows a low SVR rate and a high mortality, especially in patients with liver dysfunction.

EVALUATION OF THE THERAPEUTIC EFFICACY OF LEVAMISOLE HYDROCHLORIDE ON THIRD-STAGE LARVAE OF Lagochilascaris minor IN EXPERIMENTALLY INFECTED MICE

Lagochilascariosis, a disease caused by Lagochilascaris minor, affects the neck, sinuses, tonsils, lungs, the sacral region, dental alveoli, eyeballs and the central nervous system of humans. A cycle of autoinfection may occur in human host tissues characterized by the presence of eggs, larvae and adult worms. This peculiarity of the cycle hinders therapy, since there are no drugs that exhibit ovicidal, larvicidal and vermicidal activity. Given these facts, we studied the action of levamisole hydrochloride on third-stage larvae in the migration phase (G1) and on encysted larvae (G3) of L. minor. To this end, 87 inbred mice of the C57BL/6 strain were divided into test groups comprising 67 animals (G1-37; G3-30) and a control group (G2-10; G4-10) with 20 animals. Each animal was inoculated orally with 2,000 infective eggs of the parasite. The animals of the test groups were treated individually with a single oral dose of levamisole hydrochloride at a concentration of 0.075 mg. The drug was administered either 30 minutes prior to the parasite inoculation (G1 animals) or 120 days after the inoculation (G3 animals). The mice in the control groups were not treated with the drug. After the time required for the migration and the encysting of L. minor larvae, all the animals were euthanized and their tissues examined. The data were analyzed using the Student's unpaired t-test and the Levene test. The groups showed no statistically significant difference. Levamisole hydrochloride was ineffective on third-stage larvae of L. minor. These findings explain the massive expulsion of live adult worms, as well as the use of long treatment schemes, owing to the persistence of larvae and eggs in human parasitic lesions.

Transplante hepático sequencial com preservação da veia cava inferior (técnica de "Duplo Piggyback") : uma técnica original

RESUMO:Desde a declaração de Bethesda em 1983, a transplantação hepática é considerada um processo válido e aceite na prática clínica para muitos doentes com doença hepática terminal, relativamente aos quais não houvesse outra alternativa terapêutica. Em 1991, por proposta de Holmgren, professor de genética, o cirurgião sueco Bo Ericzon realizou em Huntingdon (Estocolmo) o primeiro transplante hepático num doente PAF (Polineuropatia Amilloidótica Familiar), esperando que a substituição do fígado pudesse frenar a evolução da doença. Nesta doença hereditária autossómica dominante, o fígado, apesar de estrutural e funcionalmente normal, produz uma proteína anormal (TTR Met30) responsável pela doença. A partir de então, a transplantação hepática passou a ser a única terapêutica eficaz para estes doentes. Portugal é o país do mundo com mais doentes PAF, tendo sido o médico neurologista português Corino de Andrade quem, em 1951, identificou e descreveu este tipo particular de polineuropatia hereditária, também conhecida por doença de Andrade. Com o início da transplantação hepática programada em Setembro de 1992, o primeiro doente transplantado hepático em Portugal, no Hospital Curry Cabral, foi um doente PAF. Desde logo se percebeu que a competição nas listas de espera em Portugal, entre doentes hepáticos crónicos e doentes PAF viria a ser um problema clínico e ético difícil de compatibilizar. Em 1995, Linhares Furtado, em Coimbra, realizou o primeiro transplante dum fígado dum doente PAF num doente com doença hepática metastática, ficando este tipo de transplante conhecido como transplante sequencial ou “em dominó”. Fê-lo no pressuposto de que o fígado PAF, funcional e estruturalmente normal, apesar de produzir a proteína mutada causadora da doença neurológica, pudesse garantir ao receptor um período razoável de vida livre de sintomas, tal como acontece na história natural desta doença congénita, cujas manifestações clínicas apenas se observam na idade adulta. A técnica cirúrgica mais adequada para transplantar o doente PAF é a técnica de “piggyback”, na qual a hepatectomia é feita mantendo a veia cava do doente, podendo o transplante ser feito sem recorrer a bypass extracorporal. Antes de 2001, para fazerem o transplante sequencial, os diferentes centros alteraram a técnica de hepatectomia no doente PAF, ressecando a cava com o fígado conforme a técnica clássica, recorrendo ao bypass extracorporal. No nosso centro imaginámos e concebemos uma técnica original, com recurso a enxertos venosos, que permitisse ao doente PAF submeter-se à mesma técnica de hepatectomia no transplante, quer ele viesse a ser ou não dador. Essa técnica, por nós utilizada pela primeira vez a nível mundial em 2001, ficou conhecida por Transplante Sequencial em Duplo Piggyback. Este trabalho teve como objectivo procurar saber se a técnica por nós imaginada, concebida e utilizada era reprodutível, se não prejudicava o doente PAF dador e se oferecia ao receptor hepático as mesmas garantias do fígado de cadáver. A nossa série de transplantes realizados em doentes PAF é a maior a nível mundial, assim como o é o número de transplantes sequenciais de fígado. Recorrendo à nossa base de dados desde Setembro de 1992 até Novembro de 2008 procedeu-se à verificação das hipóteses anteriormente enunciadas. Com base na experiência por nós introduzida, a técnica foi reproduzida com êxito em vários centros internacionais de referência, que por si provaram a sua reprodutibilidade. Este sucesso encontra-se publicado por diversos grupos de transplantação hepática a nível mundial. Observámos na nossa série que a sobrevivência dos doentes PAF que foram dadores é ligeiramente superior àqueles que o não foram, embora sem atingir significância estatística. Contudo, quando se analisaram, apenas, estes doentes após a introdução do transplante sequencial no nosso centro, observa-se que existe uma melhor sobrevida nos doentes PAF dadores (sobrevida aos 5 anos de 87% versus 71%, p=0,047).Relativamente aos receptores observámos que existe um benefício a curto prazo em termos de morbi-mortalidade (menor hemorragia peri-operatória) e a longo prazo alguns grupos de doentes apresentaram diferenças de sobrevida, embora sem atingir significância estatística, facto este que pode estar relacionado com a dimensão das amostras parcelares analisadas. Estes grupos são os doentes com cirrose a vírus da hepatite C e os doentes com doença hepática maligna primitiva dentro dos critérios de Milão. Fora do âmbito deste trabalho ficou um aspecto relevante que é a recidiva da doença PAF nos receptores de fígado sequencial e o seu impacto no longo prazo. Em conclusão, o presente trabalho permite afirmar que a técnica por nós introduzida pela primeira vez a nível mundial é exequível e reprodutível e é segura para os doentes dadores de fígado PAF, que não vêem a sua técnica cirúrgica alterada pelo facto de o serem. Os receptores não são, por sua vez, prejudicados por receberem um fígado PAF, havendo mesmo benefícios no pós-operatório imediato e, eventualmente, alguns grupos específicos de doentes podem mesmo ser beneficiados.---------ABSTRACT: Ever since Bethesda statement in 1983, Liver Transplantation has been accepted as a clinical therapeutic procedure for many patients with advanced hepatic failure Holmgren, professor of genetics, suggested that one could expect that transplanting a new liver could lead to improve progressive neurological symptoms of Familial Amyloidotic Polyneuropathy (PAF). Bo Ericzon, the transplant surgeon at Huddinge Hospital in Stockholm, Sweden, did in 1991 the first Liver Transplant on a FAP patient. FAP is an inherited autosomal dominant neurologic disease in which the liver, otherwise structural an functionally normal, produces more than 90% of an abnormal protein (TTR Met30) whose deposits are responsible for symptoms. Liver Transplantation is currently the only efficient therapy available for FAP patients. Portugal is the country in the world where FAP is most prevalent. The Portuguese neurologist Corino de Andrade was the first to recognize in 1951 this particular form of inherited polyneuropathy, which is also known by the name of Andrade disease. Liver Transplantation started as a program in Portugal in September 1992. The first patient transplanted in Lisbon, Hospital Curry Cabral, was a FAP patient. From the beginning we did realize that competition among waiting lists of FAP and Hepatic patients would come to be a complex problem we had to deal with, on clinical and ethical grounds. There was one possible way-out. FAP livers could be of some utility themselves as liver grafts. Anatomically and functionally normal, except for the inherited abnormal trace, those livers could possibly be transplanted in selected hepatic patients. Nevertheless the FAP liver carried with it the ability to produce the mutant TTR protein. One could expect, considering the natural history of the disease that several decades would lapse before the recipient could suffer symptomatic neurologic disease, if at all. In Coimbra, Portugal, Linhares Furtado performed in 1995 the first transplant of a FAP liver to a patient with metastatic malignant disease, as a sequential or “domino” transplant. FAP Liver Transplant patients, because of some dysautonomic labiality and unexpected reactions when they are subjected to surgery, take special advantage when piggyback technique is used for hepatectomy. This technique leaves the vena cava of the patient undisturbed, so that return of blood to the heart is affected minimally, so that veno-venous extracorporeal bypass will not be necessary. The advantages of piggyback technique could not be afforded to FAP patients who became donors for sequential liver transplantation, before we did introduce our liver reconstruction technique in 2001. The hepatectomy took the vena cava together with the liver, which is the classical technique, and the use of extracorporeal veno-venous bypass was of necessity in most cases. The reconstruction technique we developed in our center and used for the first time in the world in 2001 consists in applying venous grafts to the supra-hepatic ostia of piggyback resected FAP livers so that the organ could be grafted to a hepatic patient whose liver was itself resected with preservation of the vena cava. This is the double piggyback sequential transplant of the liver. It is the objective of this thesis to evaluate the results of this technique that we did introduce, first of all that it is reliable and reproducible, secondly that the FAP donor is not subjected to any additional harm during the procedure, and finally that the recipient has the same prospects of a successful transplant as if the liver was collected from a cadaver donor. Our series of liver transplantation on FAP patients and sequential liver transplants represent both the largest experience in the world. To achieve the analysis of the questions mentioned above, we did refer to our data-base from September 1992 to November 2008. The reconstructive technique that we did introduce is feasible: it could be done with success in every case ion our series. It is also reproducible. It has been adopted by many international centers of reference that did mention it in their own publications. We do refer to our data-base in what concerns the safety for the FAP donor.Five years survival of FAP transplanted patients that have been donors (n=190) has been slightly superior to those who were not (n=77), with no statistical significance. However, if we consider five year survival of FAP transplanted patients after the beginning of sequential transplant program in our center, survival is better among those patients whose liver was used as a transplant (87% survival versus 71%, p=0.047). In what concerns recipients of FAP livers: Some short-term benefit of less perioperative morbi-mortality mainly less hemorrhage. In some groups of particular pathologies, there is a strong suggestion of better survival, however the scarcity of numbers make the differences not statistically significant. Patients with cirrhosis HVC (83% versus73%) and patients with primitive hepatic cancer within Milan criteria (survival of 70% versus 58%) are good examples. There is one relevant problem we left beyond discussion in the present work: this is the long-term impact of possible recurrence of FAP symptoms among recipients of sequential transplants. In Conclusion: The reconstruction technique that we did develop and introduce is consistently workable and reproducible. It is safe for FAP donors with the advantage that removal of vena cava can be avoided. Hepatic patients transplanted with those livers suffer no disadvantages and have the benefit of less hemorrhage. There is also a suggestion that survival could be better in cirrhosis HVC and primary liver cancer patients.

Tilt Training Increases Vasoconstrictor Reserve in Patients with Neurocardiogenic Syncope

Neurocardiogenic syncope (NCS) is a common clinical entity resulting from an excessive reflex autonomic response, particularly during orthostatism. Treatment options are controversial and of limited effectiveness. Tilt training (TT) is a promising option to treat these patients. However, its mechanism of action and clinical impact remain unclear. OBJECTIVE: To characterize hemodynamic and autonomic responses during a TT program in patients with NCS refractory to conventional measures. METHODS: We studied 28 patients (50% male, mean age 41±14 years) without structural heart disease, with NCS documented by tilt testing. The TT program included 9 tilt sessions (3 times a week, 30 min) (60° - 6 sessions, 70° - 3 sessions), under ECG and blood pressure monitoring combined with home orthostatic self-training and 10° head-up during sleep. Systolic volume, cardiac output, total peripheral resistance, baroreflex sensitivity and heart-rate variability were computed. Patients were reassessed at 1 month and every 6 months for a maximum of 36 months (24±12 months). RESULTS: Over the course of the TT program there was a significant increase in total peripheral resistance (1485±225 vs. 1591±187 dyn·s·cm(-5), p<0.05), with a decrease in standard deviation (206±60 vs. 150±42, p<0.05). During follow-up, syncope recurred in five patients (19%), with a significant reduction in the number of episodes (4.0±3.2/patient in the 12 months before TT vs. 1.4±0.8/patient post-TT, p<0.05). CONCLUSION: In refractory NCS, TT may be an effective therapeutic option, with long-term benefits. These results appear to be due to an increase in vasoconstrictor reserve combined with a reduction in its variance.

A Prospective Assessment of Renal Transplantation Versus Haemodialysis: Which Therapeutic Modality Is Good Value for Society?

Background: Economic evaluations help health authorities facing budget constraints. This study compares the health-related quality of life (HRQOL) and costs in patient subgroups on haemodialysis (HD) and renal transplantation (KT). Methods: In a prospective study with follow-up of 1-3 years, we performed a costutility analysis of KT vs. HD, adopting a lifetime horizon. A societal perspective was taken. Costs for organ procurement, KT eligibility, transplant surgery and follow-up of living donors were included. Key clinical events were recorded. HRQOL was assessed using the EuroQol instrument. Results: The HRQOL remained stable on HD patients. After KT, mean utility score improved at 3 months while mean EQ-VAS scores showed a sustained improvement. Mean annual cost for HD was 32,567.57€. Mean annual costs for KT in the year-1 and in subsequent years were, 60,210.09€ and 12,956.77€ respectively. Cost for initial hospitalization averaged 18,740.74€. HLA-mismatches increased costs by 75% for initial hospitalization (p < 0.001) and 41% in the year-1 (p < 0.05), and duplicate the risk of readmission in the year-1 (p < 0.05). The incremental costutility ratio was 5,534.46€/QALY, increasing 35% when costs for organ procurement were added. KT costs were 41,541.63€ more but provided additional 7.51 QALY. Conclusions: The KT is cost-effective compared with HD. Public funding should reflect the value created by the intervention and adapt to the organ demand.

Contraceptive Choices Pre and Post Pregnancy in Adolescence

STUDY OBJECTIVE: The main aim of this study is to evaluate the impact of adolescent pregnancy in the future contraceptive choices. A secondary aim is to verify whether these choices differ from those made after an abortion. DESIGN: Retrospective study. SETTING:Adolescent Unit of a tertiary care center. PARTICIPANTS:212 pregnant teenagers. INTERVENTIONS: Medical records review. MAIN OUTCOME MEASURES:Intended pregnancy rate and contraceptive methods used before and after pregnancy. For contraceptive choices after pregnancy we considered: Group 1 - teenagers who continued their pregnancy to delivery (n = 106) and Group 2 - the same number of adolescents who chose to terminate their pregnancy. RESULTS: The intended pregnancy rate was 14.2%. Prior to a pregnancy continued to delivery, the most widely used contraceptive method was the male condom (50.9%), followed by oral combined contraceptives (28.3%); 18.9% of adolescents were not using any contraceptive method. After pregnancy, contraceptive implant was chosen by 70.8% of subjects (P < .001) and the oral combined contraceptives remained the second most frequent option (17.9%, P = .058). Comparing these results with Group 2, we found that the outcome of the pregnancy was the main factor in the choices that were made. Thus, after a pregnancy continued to delivery, adolescents prefer the use of LARC [78.4% vs 40.5%, OR: 5,958 - 95% (2.914-12.181), P < .001)], especially contraceptive implants [70.8% vs 38.7%, OR: 4.371 - 95% (2.224-8.591), P < .001], to oral combined contraceptives [17.9% vs 57.5%, OR: 0.118 - 95% CI (0.054-0.258), P < .001]. CONCLUSION:Adolescent pregnancy and its outcome constitute a factor of change in future contraceptive choice.

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.

The Impact of the Lisbon Football Derby on the Profile of Emergency Department Admissions

BACKGROUND: Variations in emergency department admissions have been reported to happen as a result of major sports events. The work presented assessed changes in volume and urgency level of visits to a major Emergency Department in Lisbon during and after the city's football derby. MATERIAL AND METHODS: Volume of attendances and patient urgency level, according to the Manchester Triage System, were retrospectively analyzed for the 2008-2011 period. Data regarding 24-hour periods starting 45 minutes before kick-off was collected, along with data from similar periods on the corresponding weekdays in the previous years, to be used as controls. Data samples were organized according to time frame (during and after the match), urgency level, and paired accordingly. RESULTS: A total of 14 relevant periods (7 match and 7 non-match) were analyzed, corresponding to a total of 5861 admissions. During the match time frame, a 20.6% reduction (p = 0.06) in the total number of attendances was found when compared to non-match days. MTS urgency level sub-analysis only showed a statistically significant reduction (26.5%; p = 0.05) in less urgent admissions (triage levels green-blue). Compared to controls, post-match time frames showed a global increase in admissions (5.6%; p = 0.45), significant only when considering less urgent ones (18.9%; p = 0.05). DISCUSSION: A decrease in the total number of emergency department attendances occurred during the matches, followed by a subsequent increase in the following hours. These variations only reached significance among visits triaged green-blue. CONCLUSION: During major sports events an overall decrease in emergency department admissions seems to take place, especially due to a drop in visits associated with less severe conditions.

Impact of Syncope on Quality of Life: Validation of a Measure in Patients Undergoing Tilt Testing

INTRODUCTION AND OBJECTIVES: Recurrent syncope has a significant impact on quality of life. The development of measurement scales to assess this impact that are easy to use in clinical settings is crucial. The objective of the present study is a preliminary validation of the Impact of Syncope on Quality of Life questionnaire for the Portuguese population. METHODS: The instrument underwent a process of translation, validation, analysis of cultural appropriateness and cognitive debriefing. A population of 39 patients with a history of recurrent syncope (>1 year) who underwent tilt testing, aged 52.1 ± 16.4 years (21-83), 43.5% male, most in active employment (n=18) or retired (n=13), constituted a convenience sample. The resulting Portuguese version is similar to the original, with 12 items in a single aggregate score, and underwent statistical validation, with assessment of reliability, validity and stability over time. RESULTS: With regard to reliability, the internal consistency of the scale is 0.9. Assessment of convergent and discriminant validity showed statistically significant results (p<0.01). Regarding stability over time, a test-retest of this instrument at six months after tilt testing with 22 patients of the sample who had not undergone any clinical intervention found no statistically significant changes in quality of life. CONCLUSIONS: The results indicate that this instrument is of value for assessing quality of life in patients with recurrent syncope in Portugal.

Electron impact ionization cross sections and analysis of X-ray spectra

A thesis submitted for the degree of Ph. D. in Physics

Health-Related Quality of Life Impact of a Triple Combination of Olmesartan Medoxomil, Amlodipine Besylate and Hydrochlorotiazide in Subjects with Hypertension

BACKGROUND: A post-hoc analysis was performed on the data from a 54 weeks phase III study (ClinicalTrials.gov identifier: NCT00923091) to measure changes in the health-related quality of life (HRQoL) of 2,690 patients aged ≥18 with moderate-to-severe hypertension who received one of six doses of olmesartan/amlodipine/hydrochlorothiazide (OLM/AML/HCTZ), using the MINICHAL and EQ-5D instruments. METHODS: Descriptive statistics were used to assess blood pressure and HRQoL scores over the study period. Analysis of covariance (ANCOVA) was used to identify those factors that could possibly have influenced HRQoL. Linear regression was used to assess the relationship between changes in blood pressure and HRQoL scores. RESULTS: Patients' baseline MINICHAL mood and somatic domains scores were 5.5 and 2.6. Over the study period HRQoL improved as both MINICHAL scores decreased by 31-33%. Patients' baseline EQ-5D index and VAS scores were 0.9 and 73.4 respectively, increasing by 6% and 12% over the study period. Patients' QALY gain over the 54 weeks study period was estimated to be 0.029 QALYs. The ANCOVA showed that changes in patients' HRQoL was likely to have been influenced by patients' achievement of blood pressure control, the amount of concomitant medication and patients' last used dosage strength of antihypertensive. Linear regression showed that blood pressure improvement may have been associated with improved HRQoL. CONCLUSIONS: This study showed that OLM/AML/HCTZ reduced blood pressure and significantly increased blood pressure control whilst improving patients' HRQoL. Achieving blood pressure control, amount of concomitant medication and dosage strength of antihypertensive impacted on patients' HRQoL.

Studying the impact of co-authorship with external researchers:the case of research community in Portugal using social network analysis.

Project work presented as a partial requirement to obtain a Master Degree in Information Management