Centro Hospitalar do Porto CHP

Porto Moniz, Portugal

Centro Hospitalar do Porto CHP

Porto Moniz, Portugal

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PubMed | Copenhagen University, University of Groningen, The Childrens Hospital, Centro Hospitalar do Porto CHP and 4 more.
Type: Journal Article | Journal: European journal of clinical nutrition | Year: 2016

Protein substitutes (PS) are an essential component in the dietary management of phenylketonuria (PKU). PS are available as phenylalanine-free amino-acid mixtures (AAM), glycomacropeptide-based PS (GMP) and large neutral amino acids (LNAA). There is a lack of information regarding their availability in different countries and comparison of their nutritional composition is limited. The objectives of this study were to identify the number of PS available in different European countries and Turkey and to compare their nutritional composition.Members of the European Nutritionist Expert Panel on PKU (ENEP) (Portugal, Spain, Belgium, Italy, Germany, Netherlands, United Kingdom, Denmark and Turkey) provided data on PS available in each country. The nutritional composition of PS available in Portugal was analyzed.The number of PS available in each country varied from 30 (Turkey) to 105 (Germany), with a median of 64. GMP was available only in Portugal, whereas LNAA was an option in Portugal, Italy, Turkey and Denmark. Some PS were designed for weaning. Many PS did not contain added fat and fiber. GMP contained the highest carbohydrate (CHO) and energy content as well as higher LNAA content compared with AAM. Only one AAM contained added fructo-oligosaccharides and galacto-oligosaccharides. AAM designed for the first year of life had the highest CHO, fat and LNAA contribution. Liquid AAM had lower CHO and fat contents compared with powdered AAM, but contained higher LNAA.There was widely dissimilar numbers of PS available in different countries. Nutritional composition of different PS was variable and should be considered before prescription.


Silva I.,Centro Hospitalar do Porto | Silva I.,Clinical Immunology Unit | Teixeira A.,Center for Research in Health Technologies and Information Systems Porto | Oliveira J.,Centro Hospitalar do Porto CHP | And 7 more authors.
Clinical Reviews in Allergy and Immunology | Year: 2015

Raynaud’s phenomenon and digital ulcers (DUs) are frequent among systemic sclerosis (SSc) patients. Our aim was to investigate the diagnostic and predictive value for DU of endothelial dysfunction biomarkers (flow-mediated dilatation (FMD), serum levels of endothelin-1 (ET-1), and ADMA), angiogenic/angiostatic biomarkers (vascular endothelial growth factor (VEGF), endoglin, and endostatin), and nailfold videocapillaroscopy (NVC). We compared our results with a literature review. In a cohort study of 77 SSc patients, we followed two groups of patients: (i) naïve DU patients (39) and (ii) active DU at baseline (38 patients) for 3 years. Telangiectasia (p < 0.001) and diffuse disease subset (p = 0.001) were significantly more frequent in patients with active DU at enrolment. Additionally, NVC late scleroderma pattern (AUC 0.846, 95%CI 0.760–0.932), lower values of FMD (AUC 0.754, 95%CI 0.643–0.864), increased serum levels of ET-1 (AUC 0.758, 95%CI 0.649–0.866), ADMA (AUC 0.634, 95%CI 0.511–0.757), and endoglin as well as low VEGF serum levels (AUC 0.705, 95%CI 0.579–0.830) were significantly associated to new DU events in the 3-year follow-up. Cox regression analysis showed that FMD > 9.41 % (HR 0.37, 95%CI 0.14–0.99); ET-1 >11.85 pmol/L (HR 3.81, 95%CI 1.41–10.26) and late NVC pattern (HR 2.29, 95%CI 0.97–5.38) were independent predictors of DU recurrence. When estimating the probability of occurrence of first DU in naïve DU patients, only late NVC pattern (HR 12.66, 95%CI 2.06–77.89) was an independent predictor factor. In conclusion, late scleroderma patterns in NVC are the best independent predictors of SSc patients who are at risk of developing DU. Endothelial dysfunction assessed by FMD and ET-1 was also found to be an independent predictor of DU recurrence in a 3-year follow-up. © 2015, Springer Science+Business Media New York.


Silva-Ramos M.,Abel Salazar Biomedical Sciences Institute | Silva-Ramos M.,Centro Hospitalar do Porto CHP | Silva I.,Abel Salazar Biomedical Sciences Institute | Faria M.,Abel Salazar Biomedical Sciences Institute | And 4 more authors.
Purinergic Signalling | Year: 2015

This study was designed to investigate whether reduced adenosine formation linked to deficits in extracellular ATP hydrolysis by NTPDases contributes to detrusor neuromodulatory changes associated with bladder outlet obstruction in men with benign prostatic hyperplasia (BPH). The kinetics of ATP catabolism and adenosine formation as well as the role of P1 receptor agonists on muscle tension and nerve-evoked [3H]ACh release were evaluated in mucosal-denuded detrusor strips from BPH patients (n = 31) and control organ donors (n = 23). The neurogenic release of ATP and [3H]ACh was higher (P < 0.05) in detrusor strips from BPH patients. The extracellular hydrolysis of ATP and, subsequent, adenosine formation was slower (t1/2 73 vs. 36 min, P < 0.05) in BPH detrusor strips. The A1 receptor-mediated inhibition of evoked [3H]ACh release by adenosine (100 μM), NECA (1 μM), and R-PIA (0.3 μM) was enhanced in BPH bladders. Relaxation of detrusor contractions induced by acetylcholine required 30-fold higher concentrations of adenosine. Despite VAChT-positive cholinergic nerves exhibiting higher A1 immunoreactivity in BPH bladders, the endogenous adenosine tonus revealed by adenosine deaminase is missing. Restoration of A1 inhibition was achieved by favoring (1) ATP hydrolysis with apyrase (2 U mL−1) or (2) extracellular adenosine accumulation with dipyridamole or EHNA, as these drugs inhibit adenosine uptake and deamination, respectively. In conclusion, reduced ATP hydrolysis leads to deficient adenosine formation and A1 receptor-mediated inhibition of cholinergic nerve activity in the obstructed human bladder. Thus, we propose that pharmacological manipulation of endogenous adenosine levels and/or A1 receptor activation might be useful to control bladder overactivity in BPH patients. © 2015, Springer Science+Business Media Dordrecht.


Timoteo M.A.,Abel Salazar Biomedical Sciences Institute | Carneiro I.,Abel Salazar Biomedical Sciences Institute | Silva I.,Abel Salazar Biomedical Sciences Institute | Noronha-Matos J.B.,Abel Salazar Biomedical Sciences Institute | And 4 more authors.
Biochemical Pharmacology | Year: 2014

In contrast to the well-known signaling role of urothelial ATP to control bladder function, the hypothesis that uracil nucleotides (UTP and/or UDP) also exert autocrine/paracrine actions only recently gained experimental support. Urothelial cells express UDP-sensitive P2Y6 receptors, yet their role in the control of bladder activity has been mostly neglected. This study was designed to investigate the ability of PSB0474, a stable UDP analogue which exhibits selectivity for P2Y6 receptors, to modulate urodynamic responses in the anaesthetized rat in vivo. Instillation of PSB0474 into the bladder increased the voiding frequency (VF) without affecting the amplitude (A) and the duration (Δt) of bladder contractions. PSB0474-induced bladder overactivity was prevented by the selective P2Y6 antagonist, MRS2578. The increase in the VF produced by PSB0474 was also blocked by inhibitors of pannexin-1 hemichannels, 10Panx or carbenoxolone, when these drugs were applied inside the bladder lumen but not when they were administered intravenously. Reduction of hemichannels pore permeability with H1152 also prevented PSB0474-induced bladder overactivity, but the exocytosis inhibitor, Exo-1, was inactive. PSB0474 increased by 3-fold the urinary ATP content. Implication of hemichannels permeability on PSB0474-induced ATP release was demonstrated by real-time fluorescence video-microscopy measuring the uptake of propidium iodide by intact urothelial cells in the absence and in the presence of MRS2578 or carbenoxolone. Confocal microscopy studies confirmed the co-localization of pannexin-1 and P2Y6 receptors in the rat urothelium. Data indicate that activation of P2Y6 receptors causes bladder overactivity in the anaesthetized rat indirectly by releasing ATP from the urothelium via pannexin-1 hemichannels. © 2013 Elsevier Inc.


Silva-Ramos M.,Abel Salazar Biomedical Sciences Institute | Silva-Ramos M.,Centro Hospitalar do Porto CHP | Silva I.,Abel Salazar Biomedical Sciences Institute | Oliveira O.,Abel Salazar Biomedical Sciences Institute | And 6 more authors.
PLoS ONE | Year: 2013

Background:Nowadays, there is a considerable bulk of evidence showing that ATP has a prominent role in the regulation of human urinary bladder function and in the pathophysiology of detrusor overactivity. ATP mediates nonadrenergic-noncholinergic detrusor contractions in overactive bladders. In vitro studies have demonstrated that uroepithelial cells and cholinergic nerves from overactive human bladder samples (OAB) release more ATP than controls. Here, we compared the urinary ATP concentration in samples collected non-invasively from OAB women with detrusor overactivity and age-matched controls.Methods:Patients with neurologic diseases, history of malignancy, urinary tract infections or renal impairment (creatinine clearance <70 ml/min) were excluded. All patients completed a 3-day voiding diary, a 24 h urine collection and blood sampling to evaluate creatinine clearance. Urine samples collected during voluntary voids were immediately freeze-preserved for ATP determination by the luciferin-luciferase bioluminescence assay; for comparison purposes, samples were also tested for urinary nerve growth factor (NGF) by ELISA.Results:The urinary content of ATP, but not of NGF, normalized to patients' urine creatinine levels (ATP/Cr) or urinary volume (ATP.Vol) were significantly (P<0.05) higher in OAB women with detrusor overactivity (n = 34) than in healthy controls (n = 30). Significant differences between the two groups were still observed by boosting urinary ATP/Cr content after water intake, but these were not detected for NGF/Cr. In OAB patients, urinary ATP/Cr levels correlated inversely with mean voided volumes determined in a 3-day voiding diary.Conclusion:A high area under the receiver operator characteristics (ROC) curve (0.741; 95% CI 0.62-0.86; P<0.001) is consistent with urinary ATP/Cr being a highly sensitive dynamic biomarker for assessing detrusor overactivity in women with OAB syndrome. © 2013 Silva-Ramos et al.


Carneiro I.,Abel Salazar Biomedical Sciences Institute | Timoteo M.A.,Abel Salazar Biomedical Sciences Institute | Silva I.,Abel Salazar Biomedical Sciences Institute | Vieira C.,Abel Salazar Biomedical Sciences Institute | And 5 more authors.
British Journal of Pharmacology | Year: 2014

Background and purpose Despite the abundant expression of the UDP-sensitive P2Y6 receptor in urothelial cells and sub-urothelial myofibroblasts its role in the control of bladder function is not well understood. Experimental approach We compared the effects of UDP and of the selective P2Y6 receptor agonist, PSB0474, on bladder urodynamics in anaesthetized rats; the voided fluid was tested for ATP bioluminescence. The isolated urinary bladder was used for in vitro myographic recordings and [3H]-ACh overflow experiments. Key results Instillation of UDP or PSB0474 into the bladder increased the voiding frequency (VF) without affecting the amplitude (A) and the duration (Δt) of bladder contractions; an effect blocked by the P2Y 6 receptor antagonist, MRS2578. Effects mediated by urothelial P2Y6 receptors required extrinsic neuronal circuitry as they were not detected in the isolated bladder. UDP-induced bladder hyperactvity was also prevented by blocking P2X3 and P2Y1 receptors, respectively, with A317491 and MRS2179 applied i.v. UDP decreased [3H]-ACh release from stimulated bladder strips with urothelium, but not in its absence. Inhibitory effects of UDP were converted into facilitation by the P2Y1 receptor antagonist, MRS2179. The P2Y6 receptor agonist increased threefold ATP levels in the voided fluid. Conclusions and Implications Activation of P2Y6 receptors increased the voiding frequency indirectly by releasing ATP from the urothelium and activation of P2X3 receptors on sub-urothelial nerve afferents. Bladder hyperactivity may be partly reversed following ATP hydrolysis to ADP by E-NTPDases, thereby decreasing ACh release from cholinergic nerves expressing P2Y1 receptors. © 2014 The British Pharmacological Society.


Silva-Ramos M.,Abel Salazar Biomedical Sciences Institute | Silva-Ramos M.,Centro Hospitalar do Porto CHP | Silva I.,Abel Salazar Biomedical Sciences Institute | Oliveira J.C.,Centro Hospitalar do Porto CHP | Correia-de-Sa P.,Abel Salazar Biomedical Sciences Institute
Prostate | Year: 2016

BACKGROUND: Diagnosis of bladder outflow obstruction (BOO) in patients with lower urinary tract (LUT) symptoms is challenging without using invasive urodynamic tests. Recently, we showed in vitro that urothelial strips from patients with benign prostatic hyperplasia (BPH) release more ATP than controls. Here, we tested whether urinary ATP can be used as a wall tension transducer non-invasive biomarker to detect BOO in patients with BPH. METHODS: 79 male patients with BOO and 22 asymptomatic controls were recruited prospectively. Patients were asked to complete the International Prostate Symptom Score (IPSS) questionnaire and to void at normal desire into a urinary flowmeter; the postvoid residual volume was determined by suprapubic ultrasonography. Urine samples from all individuals were examined for ATP, creatinine, and lactate dehydrogenase. RESULTS: BOO patients had significantly higher (P < 0.001) urinary ATP normalized by the voided volume (456 ± 36 nmol) than age-matched controls (209 ± 35 nmol). Urinary ATP amounts increased with the voided volume, but the slope of this rise was higher in BOO patients than in controls. A negative correlation was detected between urinary ATP and flow rate parameters, namely maximal flow rate (r = −0.310, P = 0.005), Siroky flow-volume normalization (r = −0.324, P = 0.004), and volume-normalized flow rate index (r = −0.320, P = 0.012). We found no correlation with LUT symptoms IPSS score. Areas under the receiver operator characteristics (ROC) curves were 0.91 (95%CI 0.86–0.96, P < 0.001) for ATP alone and 0.88 (95%CI 0.81–0.94, P < 0,001) when adjusted to urinary creatinine. CONCLUSIONS: Patients with BOO release higher amounts of ATP into the urine than the control group. The high area under the ROC curve suggests that urinary ATP can be a high-sensitive non-invasive biomarker of BOO, which may have a discriminative value of detrusor competence when comparing BPH patients with low urinary flow rates. Prostate 76:1353–1363, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.


PubMed | Abel Salazar Biomedical Sciences Institute and Centro Hospitalar do Porto CHP
Type: Journal Article | Journal: The Prostate | Year: 2016

Diagnosis of bladder outflow obstruction (BOO) in patients with lower urinary tract (LUT) symptoms is challenging without using invasive urodynamic tests. Recently, we showed in vitro that urothelial strips from patients with benign prostatic hyperplasia (BPH) release more ATP than controls. Here, we tested whether urinary ATP can be used as a wall tension transducer non-invasive biomarker to detect BOO in patients with BPH.79 male patients with BOO and 22 asymptomatic controls were recruited prospectively. Patients were asked to complete the International Prostate Symptom Score (IPSS) questionnaire and to void at normal desire into a urinary flowmeter; the postvoid residual volume was determined by suprapubic ultrasonography. Urine samples from all individuals were examined for ATP, creatinine, and lactate dehydrogenase.BOO patients had significantly higher (P<0.001) urinary ATP normalized by the voided volume (45636nmol) than age-matched controls (20935nmol). Urinary ATP amounts increased with the voided volume, but the slope of this rise was higher in BOO patients than in controls. A negative correlation was detected between urinary ATP and flow rate parameters, namely maximal flow rate (r=-0.310, P=0.005), Siroky flow-volume normalization (r=-0.324, P=0.004), and volume-normalized flow rate index (r=-0.320, P=0.012). We found no correlation with LUT symptoms IPSS score. Areas under the receiver operator characteristics (ROC) curves were 0.91 (95%CI 0.86-0.96, P<0.001) for ATP alone and 0.88 (95%CI 0.81-0.94, P<0,001) when adjusted to urinary creatinine.Patients with BOO release higher amounts of ATP into the urine than the control group. The high area under the ROC curve suggests that urinary ATP can be a high-sensitive non-invasive biomarker of BOO, which may have a discriminative value of detrusor competence when comparing BPH patients with low urinary flow rates. Prostate 76:1353-1363, 2016. 2016 Wiley Periodicals, Inc.


Lemos C.,University of Porto | Coelho T.,Centro Hospitalar Do Porto CHP | Alves-Ferreira M.,University of Porto | Martins-Da-Silva A.,Centro Hospitalar Do Porto CHP | And 3 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2014

Background Early-onset (≤40 years) and later-onset (≥50 years) cases of familial amyloid polyneuropathy (FAP) ATTRV30M are not different entities, often coexisting in the same family, and showing anticipation (earlier age-at-onset (AO) in younger generations, usually associated with more severe phenotype). Historically, anticipation has been ascribed to ascertainment biases. Our aim was to study anticipation in a very large number of FAP kindreds, removing possible biases, and gain further insight into parent-of-origin effects. Methods We analysed 926 parent-offspring pairs (from the Unidade Clínica de Paramiloidose roster, collected in 70 years), both clinically observed and had well-established AO, correcting for intrafamilial correlations. Results Women had a significantly higher AO, either for daughters (mean: 33.70, SD: 6.84) vs sons (29.43, 6.08); or mothers (39.57, 11.75) vs fathers (35.62, 11.62). Also, 291 pairs showed marked anticipation (≥10 years); the transmitting parent was the mother in 203 pairs. Motherson pairs showed larger anticipation (10.43, 9.34), while father-daughter pairs showed only a residual anticipation (1.23, 9.77). Gender of offspring and parents was highly significant (with no interaction). To remove possible biases, we repeated analyses: (1) excluding the proband; (2) removing pairs with simultaneous onset; and (3) excluding offspring born after 1960. Anticipation was found in all subsamples, with the same trend for a parent-of-origin effect. Noteworthy, parents with AO ≤40 years never had offspring with AO ≥50. Conclusions These findings confirm anticipation as a true biological phenomenon, also in FAP ATTRV30M. Acknowledgment of anticipation may have important clinical implications in genetic counselling of offspring and in follow-up of mutation carriers.


PubMed | University of Porto and Centro Hospitalar do Porto CHP
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2016

Familial amyloid polyneuropathy (FAP) ATTRV30M is a neurodegenerative disorder due to point mutations in the transthyretin gene, with V30M being the commonest. FAP ATTRV30M shows a wide variation in age at onset (AO) between clusters, families and generations. Portuguese patients also show remarkable AO differences between genders. Genes found to be associated with FAP ATTRV30M pathways may act as AO modifiers. Our aim was to further explore the role of APCS and RBP4 genes and to study for the first time the involvement of sex-linked genetic modifiers - AR and HSD17B1 genes - in AO variation in Portuguese families. We collected DNA from a sample of 318 patients, currently under follow-up. A total of 18 tagging SNPs from APCS, RBP4, AR and HSD17B1 and 5 additional SNPs from APCS and RBP4 previously studied were genotyped. To account for nonindependency of AO between members of the same family, we used generalized estimating equations (GEEs). We found that APCS and RBP4 were associated with late AO. In addition, rs11187545 of the RBP4 was associated with an early AO. For the AR, in the male group three SNPs were associated with an early AO, whereas in the female group four were associated with both an early and later AO. These results strengthened the role of APCS and RBP4 genes and revealed for the first time the contribution of AR genes as an AO modifier in both males and females. These findings may have important implications in genetic counseling and for new therapeutic strategies.

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