Hospital Sao Joao

São João da Madeira, Portugal

Hospital Sao Joao

São João da Madeira, Portugal
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Birder L.A.,University of Pittsburgh | Kanai A.J.,University of Pittsburgh | Cruz F.,Hospital Sao Joao | Moore K.,St George Hospital | Fry C.H.,University of Surrey
Neurourology and Urodynamics | Year: 2010

The urothelium separates the urinary tract lumen from underlying tissues of the tract wall. Previously considered as merely an effective barrier between these two compartments it is now recognized as a more active tissue that senses and transduces information about physical and chemical conditions within the urinary tract, such as luminal pressure, urine composition, etc. To understand this sensory function it is useful to consider the urothelium and suburothelium as a functional unit; containing uroepithelial cells, afferent and efferent nerve fibers and suburothelial interstitial cells. This structure responds to alterations in its external environment through the release of diffusible agents, such as ATP and acetylcholine, and eventually modulates the activity of afferent nerves and underlying smooth muscles. This review considers different stresses the urothelium/suburothelium responds to; the particular chemicals released; the cellular receptors that are consequently affected; and how nerve and muscle function is modulated. Brief consideration is also to regional differences in the urothelium/suburothelium along the urinary tract. The importance of different pathways in relaying sensory information in the normal urinary tract, or whether they are significant only in pathological conditions is also discussed. An operational definition of intelligence is used, whereby a system (urothelium/suburothelium) responds to external changes, to maximize the possibility of the urinary tract achieving its normal function. If so, the urothelium can be regarded as intelligent. The advantage of this approach is that input-output functions can be mathematically formulated, and the importance of different components contributing to abnormal urinary tract function can be calculated. Neurourol. Urodynam. 29:598-602, 2010. © 2010 Wiley-Liss, Inc.

Ruiz-Moreno J.M.,University of Castilla - La Mancha | Ruiz-Moreno J.M.,Alicante Institute of Ophthalmology | Arias L.,University of Barcelona | Montero J.,University of Valladolid | And 3 more authors.
British Journal of Ophthalmology | Year: 2013

Objective: To report the visual outcome after 4-year follow-up in a series of highly myopic eyes with choroidal neovascularisation (CNV) treated with antivascular endothelial growth factor (anti-VEGF) drugs. Methods: A retrospective, non-randomised, multicentre, consecutive, interventional case series study was performed. 92 highly myopic eyes with subfoveal CNV were treated with intravitreal injection (IVI) of anti-VEGF. The initial protocol (1 vs 3 injections) was dictated by surgeons' preferences and followed by an as-needed monthly regime. Best-corrected visual acuity (BCVA) was evaluated at baseline and then monthly. The primary aim was to analyse BCVA changes. The effect of age, spherical equivalent (SE) and treating drug were evaluated as secondary objectives. Results: The mean age of the patients was 57 years (SD 14, range 30-93). The mean number of letters read was 46.1 (SD 16.8, range 5-70) at baseline, 55.5 (SD 18.6, range 10-85) at 12 months, 50.1 (SD 20.1, range 5-82) at 24 months, 54.2 (SD 21.9, range 2-85) at 36 months and 53.1 (SD 22.5, range 1-83) at 48 months ( p=0.000, initial vs 12, 24 and 36 months; p=0.01 initial vs 48 months; Student t test for paired data). The mean total number of IVI was 4.9 (SD 5.4, range 1-29). SE and treating drug had no influence on the final visual outcome and number of injections required. Conclusions: Intravitreal bevacizumab and ranibizumab are effective therapies and show similar clinical effects in highly myopic CNV. Visual acuity gain is maintained at 4-year follow-up.

Panagiotou A.,San Bortolo Hospital | Gaiao S.,San Bortolo Hospital | Gaiao S.,Hospital Sao Joao | Cruz D.N.,San Bortolo Hospital | Cruz D.N.,International Renal Research Institute IRRIV
Journal of Intensive Care Medicine | Year: 2013

The treatment of sepsis is an ongoing challenge for clinicians; despite the wide choice of effective antibiotics to treat infection, sepsis remains the leading cause of morbidity and mortality for patients admitted to an intensive care unit. Dysregulation of the immune response is now recognized to be a key factor in multiple organ dysfunction, yet our therapy for inflammation remains ineffective. It has been advocated for more than a decade that cytokine reduction in blood compartment could lead to a reduction in mortality in sepsis. Over the years, multiple extracorporeal techniques have evolved, with the intent of influencing the circulating levels of inflammatory mediators like cytokines and chemokines, the complement system, as well as factors of the coagulation system. These include high-volume hemofiltration, use of high cutoff membranes, and systems based on adsorption, such as coupled plasma filtration adsorption and the polymyxin-B column. In addition, new experimental systems that utilize human phagocytic cells and immobilized antibodies for targeted immunomodulation have emerged. In the context of limited resources and growing expansion in the availability of technologies, a better understanding of these therapies is required before they can be properly integrated into standard clinical practice in the hope of influencing major clinical outcomes. In this article, we will provide a concise overview of selected extracorporeal modalities currently in clinical use and briefly introduce some new promising techniques for sepsis. © The Author(s) 2011.

Engeler D.S.,Kantonsspital St. Gallen | Baranowski A.P.,University College London | Dinis-Oliveira P.,Hospital Sao Joao | Elneil S.,University College London | And 4 more authors.
European Urology | Year: 2013

Context Progress in the science of pain has led pain specialists to move away from an organ-centred understanding of pain located in the pelvis to an understanding based on the mechanism of pain and integrating, as far as possible, psychological, social, and sexual dimensions of the problem. This change is reflected in all areas, from taxonomy through treatment. However, deciding what is adequate investigation to rule out treatable disease before moving to this way of engaging with the patient experiencing pain is a complex process, informed by pain expertise as much as by organ-based medical knowledge. Objective To summarise the evolving changes in the management of patients with chronic pelvic pain by referring to the 2012 version of the European Association of Urology (EAU) guidelines on chronic pelvic pain. Evidence acquisition The working panel highlights some of the most important aspects of the management of patients with chronic pelvic pain emerging in recent years in the context of the EAU guidelines on chronic pelvic pain. The guidelines were completely updated in 2012 based on a systematic review of the literature from online databases from 1995 to 2011. According to this review, levels of evidence and grades of recommendation were added to the text. A full version of the guidelines is available at the EAU office or Web site ( Evidence synthesis The previously mentioned issues are explored in this paper, which refers throughout to dilemmas for the physician and treatment team as well as to the need to inform and engage the patient in a collaborative empirical approach to pain relief and rehabilitation. These issues are exemplified in two case histories. Conclusions Chronic pelvic pain persisting after appropriate treatment requires a different approach focussing on pain. This approach integrates the medical, psychosocial, and sexual elements of care to engage the patient in a collaborative journey towards self-management. © 2013 European Association of Urology.

Cruz F.,Hospital Sao Joao | Nitti V.,New York University
Neurourology and Urodynamics | Year: 2014

Following use of botulinum toxin in the 1980s for the treatment of detrusor sphincter dyssynergia in patients with spinal cord injury (SCI), the potential therapeutic value of this neurotoxin in urology has been the subject of much interest. The DIGNITY (Double-blind InvestiGation of purified Neurotoxin complex In neurogenic deTrusor overactivitY) clinical research program aimed to compare onabotulinumtoxinA with placebo in terms of efficacy and safety in patients with neurogenic detrusor overactivity (NDO) due to SCI or multiple sclerosis. The EMBARK clinical research program mirrored these aims in patients with overactive bladder with urinary incontinence (UI). Each program comprised two phase III, randomized, placebo-controlled studies. In all four trials, primary efficacy endpoints were met, and significant benefits of onabotulinumtoxinA versus placebo were demonstrated across a range of secondary endpoints, including measures of health-related quality of life. The most common adverse event across both programs was urinary tract infection. Interim analyses of data from ongoing long-term extensions to these phase III trials have provided promising evidence for the efficacy of repeated injections. While further investigation is recommended to enrich the dataset, the available evidence indicates that onabotulinumtoxinA provides an effective treatment option for these two populations, which were previously considered very difficult to treat. © 2014 Wiley Periodicals, Inc.

Populo H.,University of Porto | Soares P.,University of Porto | Lopes J.M.,University of Porto | Lopes J.M.,Hospital Sao Joao
Expert Opinion on Therapeutic Targets | Year: 2012

Introduction: Cutaneous melanoma represents < 5% of all skin cancers, but is responsible for the majority of skin cancer-related deaths. Ocular melanoma is the most common primary eye tumor in adults, and accounts for approximately 5% of all melanomas. Despite new diagnostic and therapeutic tools, the overall survival of patients treated for melanoma has not improved and most patients die of metastatic disease. Therefore, clarification of the molecular mechanisms underlying the etiopathogenesis of cutaneous and ocular melanomas may help determining the prognosis and tailoring therapy of patients harboring melanomas. Areas covered: In this review the authors aim to survey relevant research in the molecular mechanisms underlying melanomagenesis, and therapies under evaluation with emphasis in the mTOR pathway. Expert opinion: Despite an increasingly understanding of the genetics and biochemistry of melanoma, the mechanisms underlying their complex interactions are still poorly understood. Their clarification will lead to more successful therapeutic strategies and evidence-based management of patients with melanoma. More active drug combinations together with appropriate melanoma patient stratification based on molecular biomarkers will be essential for new advances in melanoma therapy. © Informa UK, Ltd.

Coelho A.,University of Porto | Cruz F.,University of Porto | Cruz F.,Hospital Sao Joao | Cruz C.D.,University of Porto | Avelino A.,University of Porto
European Urology | Year: 2012

Background: OnabotulinumtoxinA (Onabot/A) has been used to treat detrusor overactivity disorders. The treatment is based on several injections of toxin throughout the bladder wall. However, injection protocols are not well established among clinicians, varying in dose and dilution. Objective: Study the distribution and neurochemistry of cleaved synaptosome-associated protein of 25 kDa (cSNAP-25) after Onabot/A administration in the guinea pig bladder. In addition, we analyzed which factor, dose or volume, contributes more to the diffusion of the toxin. Design, setting, and participants: Guinea pig bladders were treated with Onabot/A via intramural injection or an instillation. Measurements: Bladder cryostat sections were processed for single or dual immunohistochemistry staining with antibodies against cSNAP-25, vesicular acetylcholine transporter, tyrosine hydroxylase, and calcitonin gene-related peptide. Different administration methods and doses were analyzed. Statistical analysis was performed using the chi-square test for colocalization studies after multiple injections and the t test for the evaluation of affected fibers after a single injection. Results and limitations: cSNAP-25 immunoreactive fibers were abundant throughout the bladder tissue in the mucosa and muscular layer. Double labeling showed that parasympathetic fibers are more affected than sympathetic or sensory. A single Onabot/A injection is more effective if diluted in a higher volume. Onabot/A instillation in the bladder does not cleave SNAP-25 protein. Conclusions: A single Onabot/A injection spreads the neurotoxin activity to the opposite side of the guinea pig bladder. This action is more evident when high saline volumes are used to dissolve Onabot/A. The toxin cleaves the SNAP-25 protein mainly in cholinergic but also in adrenergic and sensory fibers. In contrast with intramural injection, instillation of Onabot/A does not cleave SNAP-25 in nerve fibers. © 2012 European Association of Urology.

Ricardo E.,University of Porto | Miranda I.M.,University of Porto | Faria-Ramos I.,University of Porto | Silva R.M.,University of Porto | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

Candida krusei is an important agent of opportunistic infections that often displays resistance to several antifungals. We describe here the in vivo acquisition of resistance to voriconazole (VRC) by C. krusei isolates recovered from a leukemia patient during a long period of VRC therapy. In order to mimic the in vivo development of VRC resistance, a susceptible C. krusei isolate was exposed daily to 1 βg/ml of VRC in vitro. Interestingly, after 5 days of exposure to VRC, a MIC of 4 βg/ml was achieved; this value remained constant after 25 additional days of treatment with VRC and also after 30 consecutive days of incubation in VRC-free medium. Our objective was to determine the associated molecular resistance mechanisms, such as expression of efflux pump genes and ERG11 gene mutations, among the resistant strains. Synergistic effects between the efflux blocker tacrolimus (FK506) and VRC were found in all of the resistant strains. Moreover, ABC1 gene expression increased over time in both the in vivo- and in vitro-induced resistant strains, in contrast to the ABC2 and ERG11 genes, whose expression was invariably lower and constant. ERG11 gene sequencing showed two different types of mutations, i.e., heterozygosity at T1389T/C, corresponding to synonymous mutations, in C. krusei strains and a missense mutation at position T418C, resulting in a change from Tyr to His, among resistant C. krusei clinical isolates. This study highlights the relevance of ATP-dependent efflux pump (namely, Abc1p) activity in VRC resistance and describes new mutations in the ERG11 gene among resistant C. krusei clinical isolates. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Populo H.,University of Porto | Vinagre J.,University of Porto | Lopes J.M.,University of Porto | Lopes J.M.,Hospital Sao Joao | Soares P.,University of Porto
British Journal of Ophthalmology | Year: 2011

Aim: To study the GNAQ mutational status in a series of uveal melanomas and evaluate possible associations with mitogen-activated protein kinase (MAPK) pathway protein expression and tumour proliferation markers. Methods: Mutational analysis was performed by PCR/ sequencing of exon 5 of the GNAQ gene in a series of 22 uveal melanomas in which total and phosphorylated extracellular signal-regulated kinase (ERK) 1/2 overexpression without coexistent BRAF and NRAS mutations had previously been observed. Expression of the cell cycle markers (Ki-67, cyclin D1 and p27) was evaluated by immunohistochemistry. The association between GNAQ mutational status, ERK1/2, phospho-ERK1/2, Ki-67, cyclin D1 and p27 expression levels and the clinicopathological prognostic parameters of uveal melanomas was also assessed. Results: GNAQ mutations were found in 36% of uveal melanomas. No associations were found between the GNAQ mutational status and prognostic parameters, the expression of ERK1/2, pERK1/2 and cell cycle markers. Conclusion: The results of this study suggest that GNAQ mutated uveal melanomas do not exhibit a higher deregulation of proliferation or higher activation of the MAPK signalling pathway than uveal melanomas without GNAQ overactivation.

Populo H.,University of Porto | Lopes J.M.,University of Porto | Lopes J.M.,Hospital Sao Joao | Soares P.,University of Porto
International Journal of Molecular Sciences | Year: 2012

The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma. © 2012 by the authors; licensee MDPI, Basel, Switzerland.

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