Browsing by Author "Mendonça, D."
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- Assessing risk factors for migraine: differences in gender transmissionPublication . Lemos, C.; Alonso, I.; Barros, J.; Sequeiros, J.; Pereira-Monteiro, J.; Mendonça, D.; Sousa, A.Abstract AIM: Our aim was to assess which specific factors are contributing to an increased risk of migraine in a group of 131 Portuguese families. METHODS: We studied 319 first-degree relatives, using a multilevel approach to account for the dependency among members from the same family. We included in the model relative's gender, the proband's gender and age-at-onset, to evaluate if any of these variables were associated with relative's affection status. We also included in the model proband's migraine subtype. We further assessed female and male transmissions within the proband nuclear family. RESULTS: Relatives' gender was found to be a risk factor for migraine (Odds Ratio = 2.86; 95% CI = 1.75-4.67), with females at a higher risk. When splitting probands according to their migraine subtype, we found that none of the variables studied contributed to relatives of MA-probands affection-status. Our results also show a significant difference between proband's transmission and the gender of the parents and offspring. CONCLUSIONS: With this study, we showed that gender is truly a risk factor for migraine and that a gender-biased transmission is also observed. This reinforce the importance of identifying genes associated with migraine that are modulated by genes located in the sex chromosomes and the study of mitochondrial DNA or X-chromosome and hormonal-related effects associated with migraine susceptibility
- BDNF and CGRP interaction: implications in migraine susceptibilityPublication . Lemos, C.; Mendonça, D.; Pereira-Monteiro, J.; Barros, J.; Sequeiros, J.; Alonso, I.; Sousa, A.Abstract OBJECTIVES: Migraine pathophysiology involves several pathways. Our aims were to explore a possible role of the brain-derived neurotrophic factor gene (BDNF) in migraine susceptibility; to study, for the first time, the calcitonin gene-related peptide gene (CGRP); and a possible interaction between the two. METHODS: Using a case-control approach, four tagging single nucleotide polymorphisms (SNPs) (rs7124442, rs6265, rs11030107, and rs2049046) of BDNF and one tagging SNP-rs1553005-of CGRP were analyzed in 188 cases and 287 controls. A multivariable logistic regression was performed, adjusting for gender. Allelic and haplotypic frequencies were estimated. Interaction was assessed by a stepwise multivariable-logistic regression and confirmed by a multifactor dimensionality reduction analysis. RESULTS: No significant main effects were found; however, a significant interaction was found between BDNF and CGRP, showing an increased risk for the AT-genotype of rs2049046 and the GC-genotype of rs1553005 (odds ratio=1.88, 95% confidence interval: 1.20-2.93) for migraineurs. CONCLUSION: Our data support the hypothesis of an interaction between BDNF and CGRP in migraine susceptibility that should be further explored.
- Evidence of syntaxin 1A involvement in migraine susceptibility: a Portuguese study.Publication . Lemos, C.; Pereira-Monteiro, J.; Mendonça, D.; Ramos, E.; Barros, J.; Sequeiros, J.; Alonso, I.; Sousa, A.Abstract OBJECTIVE: To confirm syntaxin 1A as a risk factor for migraine, given that syntaxin 1A interacts with several factors in migraine pathophysiology. DESIGN: Case-control approach. SETTING: An outpatient clinic. PARTICIPANTS: In a sample of 188 migraineurs (111 without aura and 77 with aura) and 287 migraine-free controls, 3 tagging SNPs of STX1A (rs3793243, rs941298, and rs6951030) were analyzed. A backward stepwise multiple logistic regression was performed. Allelic and haplotypic frequencies were compared between cases and controls. RESULTS: We found that rs941298 and rs6951030 were risk factors for migraines. In particular, the TT genotype of rs941298 is associated with an increased risk of both migraine in general and migraine without aura; the GG and GT genotypes for rs6951030 are also associated with migraine, while the GT genotype of rs6951030 was found to be significant in the migraine without aura group. The single-nucleotide polymorphism rs3793243 did not show any significant association. In the haplotype-based analysis, we found an underrepresentation of the T-C-T haplotype (rs3793243-rs941298-rs6951030) in the global sample and in migraine without aura group. We found an enrichment of the G allele of rs6951030 for female migraineurs only. CONCLUSIONS: We confirmed the involvement of syntaxin 1A in migraine susceptibility regarding rs941298. In addition, we found rs6951030 to also be associated in Portuguese migraine patients. Sex differences should be further explored to disentangle a possible sex susceptibility in syntaxin 1A
- Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onsetPublication . Santos, D.; Coelho, T.; Alves-Ferreira, M.; Sequeiros, J.; Mendonça, D.; Alonso, I.; Lemos, C.; Sousa, A.OBJECTIVES: Familial amyloid polyneuropathy (FAP ATTRV30M) shows a wide variation in age-at-onset (AO) between clusters, families, and among generations. We will now explore some candidate genes involved in altered disease pathways in order to assess their role as genetic modifiers of AO, using a family-centered approach. METHODS: We analyzed 62 tagging SNPs from nine genes-NGAL,MMP-9,BGN,MEK1,MEK2,ERK1,ERK2,HSP27, and YWHAZ - in a sample of 318 V30M Portuguese patients (106 families), currently under follow-up. A generalized estimating equation analysis was used to take into account nonindependency of AO between relatives. Also, an in silico analysis was performed in order to assess the functional impact of significant variants associated with AO. RESULTS: We found for the first time variants from six genes (NGAL,BGN (in the female group), MEK1,MEK2,HSP27, and YWHAZ) that were significantly associated with early- and/or late-onset. Then, we confirmed a strong synergistic interaction between NGAL and MMP-9 genes. Additionally, by an in silico analysis, we found some variants for MEK1 gene that may alter binding of the transcription factors and that influence the regulation of gene expression regarding microRNA binding sites and splicing regulatory factors. INTERPRETATION: These findings showed that different genetic factors can modulate differently the onset of disease's symptoms and revealed new mechanisms with clinical implications in the genetic counseling and follow-up of mutation carriers and could contribute for development of potential therapeutical targets.
- Familial clustering of migraine: further evidence from a Portuguese studyPublication . Lemos, C.; Castro, M.; Barros, J.; Sequeiros, J.; Pereira-Monteiro, J.; Mendonça, D.; Sousa, A.Abstract OBJECTIVE: Our aim was to evaluate familial aggregation of migraine in a large group of Portuguese families, and to assess if familial aggregation differs between MA and MO. METHODS: Familial aggregation was evaluated by estimating relative risk (RR) of migraine in 143 first-degree relatives of 50 probands with MA, in 196 first-degree relatives of 94 probands with MO and also in proband's spouses. Probands were enrolled in the study from a clinical sample and a population sample was used as reference. RESULTS: A significantly increased risk of migraine was found in both first-degree relatives of MO probands (RR = 3.7; 95% CI: 3.2-4.3) and of MA probands (RR = 3.6; 95% CI: 3.1-4.3), comparatively to the general population. Risk for spouses was not increased. First-degree relatives of MA probands and MO probands had a significantly increased risk of both MA and MO compared to the general population. In the group of MA probands, RR of MA in first-degree relatives reached a significant 4-fold increase when compared with RR of MO (RR(MA|MA) = 12.2, 95%CI: 7.7-19.5; RR(MO|MA) = 3.1, 95%CI: 2.5-3.8), while, in the group of MO probands, RR of MA was not significantly increased when compared with RR of MO (RR(MA|MO) = 5.3, 95%CI: 3.1-9.2; RR(MO|MO) = 4.0, 95%CI: 3.5-4.7). CONCLUSIONS: The present study focus on familial aggregation of migraine in a Portuguese population. Our results demonstrate a substantial familial risk of migraine with evidence of both common and specific etiologic mechanisms for either migraine subtypes.
- Hyperhomocysteinemia in Renal Transplantation: Preliminary ResultsPublication . Fonseca, Isabel; Queirós, J; Santos, M.J.; Mendonça, D.; Henriques, A. C.; Sarmento, A.M.; Santos, A.C.; Guimarães, S.; Pereira, M.Cardiovascular disease (CVD) is a major cause of morbidity and mortality after renal transplantation (RT).[1] and [2] The excess risk of CVD in RT is due in part to a higher prevalence of established atherosclerotic risk factors, including hypertension, dyslipidemia, diabetes, obesity, and physical inactivity.[1] and [2] However, some renal-related risk factors like immunosuppressive medication and residual renal insufficiency also contribute to this excess CVD risk and may complicate the management of dyslipidemia and hypertension in this population.[1] and [2] Accordingly, there is a compelling need to identify and safely manage other putative CVD risk factors among RT patients. Elevated plasma homocysteine is emerging as an important risk factor for cardiovascular disease in general populations.[3] and 4 R Clarke, L Daly and K Robinson et al., N Engl J Med 324 (1991), p. 1149. View Record in Scopus | Cited By in Scopus (1372)[4] Some studies have demonstrated that hyperhomocysteinemia is present in patients with impaired renal function and is associated with CVD.[5], [6] and [7] Only a small number of studies are available on the prevalence and determinants of hyperhomocysteinemia in renal transplant recipients.[8], [9], [10], [11], [12], [13], [14] and [15] We undertook this study to 1. estimate the prevalence of hyperhomocysteinemia in renal transplant recipients; 2. examine the relationships between plasma total homocysteine (tHcy) and its metabolic determinants vitamin B6, vitamin B12, and folic acid; and 3. identify other determinants of tHcy.
- Impact of Homocysteinemia on Long-Term Renal Transplant SurvivalPublication . Fonseca, Isabel; Martins, La Salete; Queirós, J.; Mendonça, D.; Dias, L.; Sarmento, A.M.; Henriques, A.C.; Cabrita, A.Impact of Homocysteinemia on Long-Term Renal Transplant Survival I. Fonseca, L. Martins, J. Queirós, D. Mendonça, L. Dias, A.M. Sarmento, A.C. Henriques, and A. Cabrita ABSTRACT Aim. We prospectively followed cohort of 202 renal transplant recipients for years to examine the impact of fasting homocysteinemia on long-term patient and renal allograft survival. Methods. Cox proportional hazards regression analysis was used to identify independent predictors of all-cause mortality and graft loss. Results. Hyperhomocysteinemia (tHcy 15 mol/L) was present in 48.7% of the 202 patients, predominantly among men (55.8%as opposed to women (37.1%)At the end of the follow-up period, 13 (6.4%patients had died including 10 from cardiovascular disease, and 23 had (11.4%had lost their grafts. Patient death with functioning allograft was the most prevalent cause of graft loss (13 recipients)Levels of tHcy were higher among patients who died than among survivors (median 23.9 vs 14.3 mol/L; .005)Median tHcy concentration was also higher among the patients who had lost their allografts than those who did not (median 19.0 vs 14.1 mol/L; .001)In Cox regression model including gender, serum creatinine concentration, transplant duration, traditional cardio- vascular risk factors, and associated conditions, such as past cardiovascular disease, only tHcy concentration (ln) (HR 5.50; 95% CI, 1.56 to 19.36; .008) and age at transplantation (HR 1.07; 95% CI, 1.02 to 1.13; .01) were independent predictors of patient survival. After censoring data for patient death, tHcy concentration was not risk factor for graft loss. Conclusions. This prospective study shows that tHcy concentration is significant predictor of mortality, but not of graft loss, after censoring data for patient death.
- Modelling competing risks in nephrology research: an example in peritoneal dialysisPublication . Teixeira, L.; Rodrigues, A.; Carvalho, M.; Cabrita, A.; Mendonça, D.BACKGROUND: Modelling competing risks is an essential issue in Nephrology Research. In peritoneal dialysis studies, sometimes inappropriate methods (i.e. Kaplan-Meier method) have been used to estimate probabilities for an event of interest in the presence of competing risks. In this situation a competing risk analysis should be preferable. The objectives of this study are to describe the bias resulting from the application of standard survival analysis to estimate peritonitis-free patient survival and to provide alternative statistical approaches taking competing risks into account. METHODS: The sample comprises patients included in a university hospital peritoneal dialysis program between October 1985 and June 2011 (n = 449). Cumulative incidence function and competing risk regression models based on cause-specific and subdistribution hazards were discussed. RESULTS: The probability of occurrence of the first peritonitis is wrongly overestimated using Kaplan-Meier method. The cause-specific hazard model showed that factors associated with shorter time to first peritonitis were age (>=55 years) and previous treatment (haemodialysis). Taking competing risks into account in the subdistribution hazard model, age remained significant while gender (female) but not previous treatment was identified as a factor associated with a higher probability of first peritonitis event. CONCLUSIONS: In the presence of competing risks outcomes, Kaplan-Meier estimates are biased as they overestimated the probability of the occurrence of an event of interest. Methods which take competing risks into account provide unbiased estimates of cumulative incidence for each specific outcome experienced by patients. Multivariable regression models such as those based on cause-specific hazard and on subdistribution hazard should be used in this competing risk setting.
- Neutrophil gelatinase-associated lipocalin in kidney transplantation is an early marker of graft dysfunction and is associated with one-year renal functionPublication . Fonseca, Isabel; Carlos Oliveira, José; Almeida, M.; Cruz, M.; Malho, A.; Martins, La Salete; Dias, L.; Pedroso, S.; Santos, J.; Lobato, L.; Castro-Henriques, A.; Mendonça, D.Urinary neutrophil gelatinase-associated lipocalin (uNGAL) has been suggested as potential early marker of delayed graft function (DGF) following kidney transplantation (KTx). We conducted a prospective study in 40 consecutive KTx recipients to evaluate serial changes of uNGAL within the first week after KTx and assess its performance in predicting DGF (dialysis requirement during initial posttransplant week) and graft function throughout first year. Urine samples were collected on post-KTx days 0, 1, 2, 4, and 7. Linear mixed and multivariable regression models, receiver-operating characteristic (ROC), and areas under ROC curves were used. At all-time points, mean uNGAL levels were significantly higher in patients developing DGF (n = 18). Shortly after KTx (3-6 h), uNGAL values were higher in DGF recipients (on average +242 ng/mL, considering mean dialysis time of 4.1 years) and rose further in following days, contrasting with prompt function recipients. Day-1 uNGAL levels accurately predicted DGF (AUC-ROC = 0.93), with a performance higher than serum creatinine (AUC-ROC = 0.76), and similar to cystatin C (AUC-ROC = 0.95). Multivariable analyses revealed that uNGAL levels at days 4 and 7 were strongly associated with one-year serum creatinine. Urinary NGAL is an early marker of graft injury and is independently associated with dialysis requirement within one week after KTx and one-year graft function.
- Optimism on quality of life in Portuguese chronic patients: moderator/mediator?Publication . Vilhena, E.; Pais-Ribeiro, J.; Silva, I.; Pedro, L.; Meneses, R.; Cardoso, H.; Martins-Silva, A.; Mendonça, D.OBJECTIVE: optimism is an important variable that has consistently been shown to affect adjustment to quality of life in chronic diseases. This study aims to clarify if dispositional optimism exerts a moderating or a mediating influence on the personality traits-quality of life association, in Portuguese chronic patients. METHODS: multiple regression models were used to test the moderation and mediation effects of dispositional optimism in quality of life. A sample of 729 patients was recruited in Portugal's main hospitals and completed self-reported questionnaires assessing socio-demographic and clinical variables, personality, dispositional optimism, quality of life (QoL) and subjective well-being (SWB). RESULTS: the results of the regression models showed that dispositional optimism did not moderate the relationships between personality traits and quality of life. After controlling for gender, age, education level and severity of disease perception, the effects of personality traits on QoL and in SWB were mediated by dispositional optimism (partially and completely), except for the links between neuroticism/openness to experience and physical health. CONCLUSION: dispositional optimism is more likely to play a mediating, rather than a moderating role in personality traits-quality of life pathway in Portuguese chronic patients, suggesting that "the expectation that good things will happen" contributes to a better quality of life and subjective well-being.