Epidemiological studies of Streptococcus pneumoniae carriage in the post-vaccination era among two risk groups: children and the elderly

Dissertation presented to obtain the Ph.D. degree in Biology/ Molecular Biology

Variant Rett Syndrome in a Girl with a Pericentric X-Chromosome Inversion Leading to Epigenetic Changes and Overexpression of the MECP2 Gene

Rett syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene. We investigated the genetic basis of disease in a female patient with a Rett-like clinical. Karyotype analysis revealed a pericentric inversion in the X chromosome -46,X,inv(X)(p22.1q28), with breakpoints in the cytobands where the MECP2 and CDKL5 genes are located. FISH analysis revealed that the MECP2 gene is not dislocated by the inversion. However, and in spite of a balanced pattern of X inactivation, this patient displayed hypomethylation and an overexpression of the MECP2 gene at the mRNA level in the lymphocytes (mean fold change: 2.55±0.38) in comparison to a group of control individuals; the expression of the CDKL5 gene was similar to that of controls (mean fold change: 0.98±0.10). No gains or losses were detected in the breakpoint regions encompassing known or suspected transcription regulatory elements. We propose that the de-regulation of MECP2 expression in this patient may be due to alterations in long-range genomic interactions caused by the inversion and hypothesize that this type of epigenetic de-regulation of the MECP2 may be present in other RTT-like patients.

Knowledge and practices of general practitioners of district Peshawar about schizophrenia

ABSTRACT: Schizophrenia with its disabling features has been placed in the top ten of global burden of disease and is associated with long-term decline in functional ability. General Practitioners not only have an important role in treating patients with an established diagnosis of schizophrenia but they can also contribute significantly by identifying people in early stages of psychosis as they are the first hand medical help available and the duration of untreated psychosis is a good indicator of patient’s prognosis. This cross sectional survey, conducted at the clinics of General Practitioners, was designed to assess the knowledge and practices of general practitioners in Peshawar on diagnosis and treatment of schizophrenia. A semi structured questionnaire was used to assess their knowledge and practices regarding schizophrenia. The Knowledge/Practice was then categorized as good or poor based on their responses to the questions of the administered questionnaire. Overall, the results showed that the knowledge and practices of general practitioners of district Peshawar were poor regarding schizophrenia and may be responsible for delayed diagnosis, inadequate treatment and poor prognosis.

A Review of National Guidelines for Management of COPD in Europe

The quality of care can be improved by the development and implementation of evidence-based treatment guidelines. Different national guidelines for chronic obstructive pulmonary disease (COPD) exist in Europe and relevant differences may exist among them.This was an evaluation of COPD treatment guidelines published in Europe and Russia in the past 7 years. Each guideline was reviewed in detail and information about the most important aspects of patient diagnosis, risk stratification and pharmacotherapy was extracted following a standardised process. Guidelines were available from the Czech Republic, England and Wales, Finland, France, Germany, Italy, Poland, Portugal, Russia, Spain and Sweden. The treatment goals, criteria for COPD diagnosis, consideration of comorbidities in treatment selection and support for use of long-acting bronchodilators, were similar across treatment guidelines. There were differences in measures used for stratification of disease severity, consideration of patient phenotypes, criteria for the use of inhaled corticosteroids and recommendations for other medications (e.g. theophylline and mucolytics) in addition to bronchodilators.There is generally good agreement on treatment goals, criteria for diagnosis of COPD and use of long-acting bronchodilators as the cornerstone of treatment among guidelines for COPD management in Europe and Russia. However, there are differences in the definitions of patient subgroups and other recommended treatments.

Low Socioeconomic Status is an Independent Risk Factor for Survival After Abdominal Aortic Aneurysm Repair and Open Surgery for Peripheral Artery Disease

OBJECTIVE/BACKGROUND: The association between socioeconomic status (SES), presentation, and outcome after vascular surgery is largely unknown. This study aimed to determine the influence of SES on post-operative survival and severity of disease at presentation among vascular surgery patients in the Dutch setting of equal access to and provision of care. METHODS: Patients undergoing surgical treatment for peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), or carotid artery stenosis between January 2003 and December 2011 were retrospectively included. The association between SES, quantified by household income, disease severity at presentation, and survival was studied using logistic and Cox regression analysis adjusted for demographics, and medical and behavioral risk factors. RESULTS: A total of 1,178 patients were included. Low income was associated with worse post-operative survival in the PAD cohort (n = 324, hazard ratio 1.05, 95% confidence interval [CI] 1.00-1.10, per 5,000 Euro decrease) and the AAA cohort (n = 440, quadratic relation, p = .01). AAA patients in the lowest income quartile were more likely to present with a ruptured aneurysm (odds ratio [OR] 2.12, 95% CI 1.08-4.17). Lowest income quartile PAD patients presented more frequently with symptoms of critical limb ischemia, although no significant association could be established (OR 2.02, 95% CI 0.96-4.26). CONCLUSIONS: The increased health hazards observed in this study are caused by patient related factors rather than differences in medical care, considering the equality of care provided by the study setting. Although the exact mechanism driving the association between SES and worse outcome remains elusive, consideration of SES as a risk factor in pre-operative decision making and focus on treatment of known SES related behavioral and psychosocial risk factors may improve the outcome of patients with vascular disease.

Mutations in the MECP2 Gene Are Not a Major Cause of Rett Syndrome-Like or Related Neurodevelopmental Phenotype in Male Patients

Rett syndrome is a genetic neurodevelopmental disorder that affects mainly girls, but mutations in the causative MECP2 gene have also been identified in boys with classic Rett syndrome and Rett syndrome-like phenotypes. We have studied a group of 28 boys with a neurodevelopmental disorder, 13 of which with a Rett syndrome-like phenotype; the patients had diverse clinical presentations that included perturbations of the autistic spectrum, microcephaly, mental retardation, manual stereotypies, and epilepsy. We analyzed the complete coding region of the MECP2 gene, including the detection of large rearrangements, and we did not detect any pathogenic mutations in the MECP2 gene in these patients, in whom the genetic basis of disease remained unidentified. Thus, additional genes should be screened in this group of patients.

Reduction of morbidity in hepatosplenic Schistosomiasis mansoni after treatment with praziquantel: a long term study

Forty-two with hepatosplenic patients treated with praziquantel and followed up for 5 years. One half of the patients received a single 30 mg/kg dose and the other half, two doses of 25 mg/kg given 4 hrs apart. According to Hoffman and Kato-Katz stool exams, an 83.3% cure rate, was observed after twelve months. Stool egg counts in cases of incomplete cure were greatly reduced. Liver function, as assessed by serum levels of aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase and alkaline phosphatase activities as well as albumin and gamma globulin showed marked improvement after one year. Hepatomegaly was reduced in 81.0% of patients and splenomegaly in 78.8%. Spleen regression was complete in 15.1% of the total, and in 18.5% of those with compensated hepatosplenic disease. As a result of these observations, the authors recomend early treatment with anti-schistosomal medication, either oxamniquine or praziquantel, to halt progression of disease and reduce splenomegaly.

Enhancing physical activity coaching through personalized motivational strategies and self-adaptive goal-setting: development of self-adaptive processes in a monitoring and coaching smartphone application

Dissertação para obtenção do Grau de Mestre em Engenharia Biomédica

Sudden sensorineural hearing loss : evaluation of co-morbidities and potential clinical associations

RESUMO: A surdez súbita (SS) caracteriza-se por uma perda abrupta de audição, mais frequentemente unilateral e associada a sensação de preenchimento aural, acufenos e vertigem. Afecta 5-20/100.000pessoas/ano (sobretudo adultos em fase activa na década de 40), com grande impacto na qualidade de vida. Possíveis causas incluem doenças infecciosas, circulatórias, traumáticas, imunológicas, neoplásicas, neurológicas, tóxicas e cocleares. No entanto, a causa da SS permanece desconhecida na maioria dos casos (80%), o que origina tratamentos controversos e frequentemente ineficientes. Os tratamentos disponíveis variam desde corticosteróides a antivirais, vasodilatadores, anti-agregantes, anticoagulantes, vitaminas e oxigénio hiperbárico (OHB). Atendendo a falta de informação relativa à etiologia e fisiopatologia da SS, pretendemos avaliar a evolução clínica dos doentes com SS tratados com OHB no Centro de Medicina Subaquática e Hiperbárica (CMSH) de Lisboa entre 2000 e 2005, durante um período mínimo de 5 anos, na tentativa de identificar eventuais factores de risco ou noxas clínicas com a SS. O estudo retrospectivo proposto baseia-se na revisão de processos clínicos do CMSH e na aplicação telefónica de questionários médicos de “follow-up” confidenciais – tanto a doentes (grupo de estudo), como aos respectivos esposos/companheiros/membros próximos da família (grupo de controlo) –, com particular ênfase nos antecedentes médicos e história clínica actual. Um estudo preliminar de 20 pessoas (10 doentes e 10 controlos) foi efectuado para antecipar dificuldades e estimar as necessidades logísticas. As dificuldades identificadas foram: 1) selecção dos doentes com números de telefone válidos e processos clínicos completos (com audiograma inicial e final); 2) contacto telefónico com os participantes de ambos os grupos (de estudo e controlo); 3) recursos humanos requeridos. Dado que a SS não é uma doença em si, mas um sintoma de uma doença subjacente, acreditamos que este estudo epidemiológico seja importante e útil, capaz de gerar novas luzes sobre a fisiopatologia e mecanismos desta entidade clínica.-------------ABSTRACT:Sudden sensorineural hearing loss (SSHL) is characterized by abrupt, mostly unilateral loss of hearing, frequently associated to aural fullness, tinnitus and vertigo. It affects 5-20/100.000 people/year (particularly working adults in the 40ths), with huge impact on quality of life. Possible causes include infectious, circulatory, traumatic, immunologic, metabolic, neoplastic, neurologic, toxic and unidentified cochlear diseases. Nevertheless, SSHL’s etiology remains unknown in most cases (80%), giving rise to controversial (and frequently ineffective) treatments. Available therapies range from corticosteroids to antivirals, vasodilators, antiaggregants, anticoagulants, vitamins and hyperbaric oxygen (HBO). Given the lack of data concerning SSHL’s etiology and physiopathology, we intend to evaluate clinical evolution of such patients treated with HBO in the Underwater and Hyperbaric Medical Center (UHMC) at Lisbon from 2000 to 2005 during a minimum period of 5 years, in an attempt to identify eventual risk factors or clinical associations to SSHL. The intended retrospective study is based on the review of patients’ medical charts from UHMC and confidential follow-up questionnaires applied telephonically both to patients (study group) and patients’ spouse/partner/close family member (control group), focusing past and present medical history. A preliminary study of 20 subjects (10 of each group) was performed to anticipate difficulties and to estimate the required logistics. The identified difficulties were: 1) selection of subjects with valid phone numbers and complete medical charts (with initial and final audiograms); 2) telephonic contact with subjects from the study and control group; 3) human logistics required. As it is believed that SSHL is not a disease by itself but rather a symptom of an underlying disease, we believe that this epidemiologic study is important and will hopefully generate sound scientific knowledge concerning physiopathology and mechanism of disease of SSHL.

HTLV-I associated myelopathy in the northern region of Brazil (Belém-Pará): serological and clinical features of three cases

Three patients (males, black, ages 37, 40 and 57) attended a university clinic with a progressive paraparesis of obscure origin. One patient who referred disease duration of more than 16 years, showed diminished deep reflexes, bilateral Babinski's sign, diminished sensation of vibration, abnormal bladder function and back pain. The other two patients (with one and six years of disease duration) complained of weakness in one leg, increased deep reflexes and back pain. Babinski's sign and bladder disturbance were also present in the patient with six years of disease. Blood samples tested by an enzyme immune assay and a discriminatory Western blot were positive for HTLV-I. The familial analysis of one patient showed a possible pattern of sexual and vertical transmission of the virus. To the best of our knowledge, these are the first cases of a proven association between HTLV-I and TSP/HAM in Belem, Para, and emphasize the need to actively look for cases of neurological disease associated to the virus.

Efficacy of azithromycin in the treatment of cutaneous leishmaniasis

The present open pilot study was conducted to assess the efficacy of azithromycin for the treatment of patients with cutaneous leishmaniasis in Araçuaí and Varzelândia, MG. Twenty-four patients with less of six months of disease evolution were treated after clinical examination, Montenegro test and a biopsy. The treatment schemes consisted of oral doses of 500 mg per day for 3, 5 and 10 days and of 1000 mg for two days. A clinical control was performed monthly and treatment cycles were repeated when necessary until full reepithelialization of the lesions. On the occasion of the final evaluation, 20 patients had completed the study and 17 of them (85%) were cured. The time to obtain a cure was 60 days ifor 6 (30%) patients, 90 days for 7 (35%), and 120 for 4 (20%). The three patients with treatment failure received a pentavalent antimonial for 20 days. No adverse reactions to the medication were observed and a 14 month follow-up did not show recurrence in any patient. These results suggest that azithromycin can be a good therapeutic option for the treatment of cutaneous leishmaniasis caused by Leishmania Viannia brasiliensis.

Using epidemiological survey data to infer geographic distributions of leishmaniasis vector species

An important aspect of tropical medicine is analysis of geographic aspects of risk of disease transmission, which for lack of detailed public health data must often be reduced to an understanding of the distributions of critical species such as vectors and reservoirs. We examine the applicability of a new technique, ecological niche modeling, to the challenge of understanding distributions of such species based on municipalities in the state of São Paulo in which a group of 5 Lutzomyia sandfly species have been recorded. The technique, when tested based on independent occurrence data, yielded highly significant predictions of species' distributions; minimum sample sizes for effective predictions were around 40 municipalities.

Retrospective study of 151 patients with cutaneous leishmaniasis treated with meglumine antimoniate

We retrospectively analyzed a series of 151 cases of cutaneous leishmaniasis treated between 1967 and 1982. One-hundred-and-thirty-nine (92%) patients presented with active lesions and were treated with daily doses of meglumine antimoniate: 81 adults received a 5-ml vial IM and 58 children received 1 to 5ml. Forty-five (32.4%) patients underwent continuous treatment with meglumine antimoniate for 25 to 116 days without rest intervals, and 94 (67.6%) intermittent treatment with 2 to 5 series of meglumine antimoniate. Intermittent series could include schedules of daily IM applications for 10 to 25 days each and intervals varying from 10 to 60 days. Antimony dose was calculated for 66 (47.5%) patients and ranged from 3.9 to 28.7 Sb5+/kg/day. Of these, 35 patients received >10mg and 31 patients <10mg Sb5+/kg/day. Median time of healing was longer for lesions on the legs and feet - 67.5 days versus 48.7 days (p < 0.001) for other sites. However, there were no significant differences in the median time of healing between adults and children, intermittent and continuous regimens or high and low antimony doses. Fifty-one patients were reassessed 5 to 14 years after treatment and showed no evidence of disease. These results support further investigation (clinical trials) on treatment using low doses of antimony.

Gender influence on treatment of chronic hepatitis C genotype 1

INTRODUCTION: Although various studies have been published regarding the treatment of chronic hepatitis C (CHC) with peginterferon (Peg-IFN) and ribavirin, little is known regarding the real impact of gender on the characteristics that influence the effectiveness and safety of antiviral treatment for CHC patients. The objective of this study was to evaluate the influence of gender on HCV treatment outcomes. METHODS: A retrospective analytical study was conducted among selected carriers of CHC genotype 1, who were treated with Peg-IFN α-2b at a dose of 1.5 μg/kg or Peg-IFN α-2a at a dose of 180 μg/week plus a ribavirin dose of 1,000-1,250 mg/day, according to weight, between 2001 and 2007. RESULTS: Among 181 patients undergoing treatment, the mean age was 46.4 ± 11.0 years and 46% were women. At baseline, 32% of the patients had advanced fibrosis (F3-F4 Scheuer), and 83% of the subjects had viral load > 400,000 IU/ml, without significant difference between the genders (p = 0.428 and p = 0.452, respectively). When compared with men, women had higher incidence of many adverse events such as anemia (p < 0.001) and higher need for dose reduction, for both Peg-IFN (p = 0.004) and ribavirin (p = 0.006). However, the rate of sustained virological response (SVR) did not differ between the genders: 45% (female) vs 41% (male); p=0.464. CONCLUSIONS: This study suggests that women and men react differently to combined therapy, especially in relation to the incidence of adverse events and the need for dose modification. Nevertheless, these differences do not influence the SVR rate.

The impact of leprosy on health-related quality of life

INTRODUCTION: Leprosy is a potentially disabling infectious disease that evolves into emotional issues due to the prejudice that persists about the illness. The endemic has declined substantially with multidrug therapy (MDT) in the 80's; however, new demands associated with the reduction of stigma and the improvement of the affected people's quality of life have emerged. In Brazil, leprosy is still a public health problem. Piauí is the second state in the Northeast in prevalence and detection, and Teresina is a hyperendemic city. This study aimed to analyze the health-related quality of life (HRQoL) of people in treatment for leprosy in Teresina/PI. METHODS: An observational study was conducted using the SF-36 (a specific questionnaire for assessing quality of life), which sought the determinants of poor quality of life among people with leprosy, outlining the sociodemographic, clinical, and epidemiological characteristics of the 107 patients interviewed. RESULTS: The correlations between the variables showed five determinants of HRQoL: late diagnosis, multibacillary forms, reactions, disability diagnosis grade II, and prejudice. The profile of the participants showed that leprosy still affects the lower social classes in historically endemic areas, causing high percentages of secondary injuries that compromise the work capacity and quality of life of the affected people, perpetuating the stigma associated with the disease. CONCLUSIONS: The study reinforces the need to implement more effective strategies of disease control, due to the development of severe and disabling forms of leprosy is directly related to poor HRQoL in the same cured patient.