João Lavinha

National Institute of Health Dr. Ricardo Jorge, Lisboa, Portugal · N/A

In host organisms with normal micronutrient status, nutritional immunity is a strongly regulated response aiming at decreasing the progression and severity of infections. Zinc deficiency may disturb this balance, impairing immune responses to infections, which may indirectly increase infection-related anemia. Since zinc deficiency may associate dir...

We found no published data in Angola regarding the effect of combining nutrition-specific and nutrition-sensitive approaches in the reduction of anemia in preschool children. Thus, we implemented a cluster-randomized controlled trial to determine the effectiveness of two educational-plus-therapeutic interventions, in Nutrition and WASH/Malaria, in...

Background: Angola is one of the southern African countries with the highest prevalence of anaemia. Identifying anaemia determinants is an important step for the design of evidence-based control strategies. In this study, we aim at documenting the factors associated with Iron Deficiency Anaemia (IDA) in 948 children recruited at the Health Researc...

We investigated biomarkers and genetic modulators of the cerebral vasculopathy (CV) subphenotype in pediatric sickle cell anemia (SCA) patients of sub-Saharan African ancestry. We found that one VCAM1 promoter haplotype (haplotype 7) and VCAM1 single nucleotide variant rs1409419_T were associated with stroke events, stroke risk, as measured by time...

Angola is one of the southern African countries with the highest prevalence of anemia, and despite the high geographic heterogeneity of its distribution across the country, it was reported to be indicative of a severe public health problem in some areas, mainly in children. Despite the relevance of this condition in the country there is still an im...

Sickle cell anemia (SCA) is an autosomal recessive monogenic disease with significant clinical variability. Cerebrovascular disease, particularly ischemic stroke, is one of the most severe complications of SCA in children. This study aimed to investigate the influence of genetic variants on the levels of fetal hemoglobin (Hb F) and biochemical para...

Sickle cell anemia (SCA) is a highly heterogeneous and multifactorial-like monogenic disease that arises from homozygosity for the c.20A>T mutation in the HBB gene. Vascular disease is systemic in SCA, with profound effects in organs like the brain, where stroke is the most severe end of the cerebral vasculopathy (CVA) spectrum. Endothelial dysfunc...

Sickle cell anaemia (SCA) arises from homozygosity for the mutation c.20A>T in the HBB gene. However, it shows a multifactorial-like behaviour with high heterogeneity of clinical features. Cerebral vasculopathy (CVA), namely paediatric ischemic stroke, is one of its most devastating consequences. The risk of CVA development, specifically stroke or...

Angola reports one of the highest infant mortality rates in the world, and anemia represents one of its important causes. Recent studies, in under-five children from the Bengo province of Angola, described high prevalence’s, suggesting malaria, undernutrition and urogenital schistosomiasis as important contributors for the occurrence and spatial va...

Influenza epidemics are a serious global public health and economic problem. The IFITM3 allele (rs12252-C) was suggested as a population-based genetic risk factor for severe influenza virus infection by A(H1N1)pdm09. We analyzed the population genetics of IFITM3 variants in the Portuguese general population (n = 200) and Central Africans (largely A...

The widespread application of carbon nanotubes (CNT) on industrial, biomedical, and consumer products can represent an emerging respiratory occupational hazard. Particularly, their similarity with the fiber-like shape of asbestos have raised a strong concern about their carcinogenic potential. Several in vitro and in vivo studies have been supporti...

Keratolenticular dysgenesis (KLD) and ectopia lentis are congenital eye defects. The aim of this study is the identification of molecular genetic alterations responsible for those ocular anomalies with neurologic impairment in an individual with a de novo balanced chromosome translocation t(11;18)(q23.3;q11.2)dn. Disruption of OAF, the human orthol...

Sickle cell anemia (SCA) is characterized by chronic hemolysis, severe vasoocclusive crises (VOCs), and recurrent often severe infections. A cohort of 95 SCA pediatric patients was the background for genotype-to-phenotype association of the patient's infectious disease phenotype and three non-coding polymorphic regions of the TLR2 gene, the -196 to...

Inherited deletions of α-globin genes and/or their upstream regulatory elements (MCSs) give rise to α-thalassemia, an autosomal recessive microcytic hypochromic anemia. In this study, multiplex ligation-dependent probe amplification performed with commercial and synthetic engineered probes, Gap-PCR, and DNA sequencing were used to characterize lesi...

Characterization of the molecular lesions underlying eight unusual cases of α-thalassemia or Hb H disease, and to understand their origin and functional consequences. Deletions were detected by Multiplex Ligation-dependent Probe Amplification (MLPA) using commercial as well as specifically designed synthetic MLPA probes, Gap-PCR and finnaly Sanger...

Sickle cell anemia (SCA) is an autosomal recessive disease caused by the HBB:c.20A>T mutation that leads to hemoglobin S synthesis. The disease presents with high clinical heterogeneity characterized by chronic hemolysis, recurrent episodes of vaso-oclusion and infection. This work aimed to characterize by in silico studies some genetic modulators...

Background: Sickle cell anemia (SCA) is an inherited blood disorder. SCA patients present clinical and hematologic variability that cannot be only explained by the single mutation in the beta-globin gene. Others genetic modifiers and environmental effects are important for the clinical phenotype. SCA patients present arginine deficiency that contr...

Environmental risk assessment of complex ecosystems such as estuaries is a challenge, where innovative and integrated approaches are needed. The present work aimed at developing an innovative integrative methodology to evaluate in an impacted estuary (the Sado, in Portugal, was taken as case study), the adverse effects onto both ecosystem and human...

Major contributions from pathogen genome analysis and host genetics have equated the possibility of Mycobacterium tuberculosis co-evolution with its human host leading to more stable sympatric host-pathogen relationships. However, the attribution to either sympatric or allopatric categories depends on the resolution or grain of genotypic characteri...

Titanium dioxide (TiO2 ) nanomaterials (NMs) are widely used in a diversity of products including cosmetics, pharmaceuticals, food, and inks, despite uncertainties surrounding the potential health risks that they pose to humans and the environment. Previous studies on the genotoxicity of TiO2 have reported discrepant or inconclusive findings in bot...

The present work developed an integrative methodology to evaluate the adverse effects of impacted estuarine sediments to human and ecosystem health, taking the Sado Estuary (Portugal) as a case study. The best professional judgment for a Weight of Evidence (WOE) approach was based on: i) human contamination pathways; ii) human health effects; iii)...

Carbon nanotubes (CNTs) have been employed in energy appliances and electronics and are the most widely used organic materials for tissue engineering applications. One major concern for human health is the similarity, in size and shape, between multi-walled carbon nanotubes (MWCNTs) and asbestos fibers, which are recognized carcinogens to humans fo...

Estuarine sediments may be reservoirs of hydrophilic and hydrophobic pollutants, many of which are acknowledged genotoxicants, pro-mutagens and even potential carcinogens for humans. Still, studies aiming at narrowing the gap between ecological and human health risk of sediment-bound contaminant mixtures are scarce. Taking an impacted estuary as a...

Complex toxicant mixtures present in estuarine sediments often render contaminant screening unfeasible and compromise determining causation. HepG2 cells were subjected to bioassays with sediment extracts obtained with a series of progressively polar solvents plus a crude extract. The sediments were collected from an impacted area of an estuary othe...

Chronic haemolysis stands out as one of the hallmarks of sickle-cell anaemia, a clinically heterogeneous autosomal recessive monogenic anaemia. However, the genetic architecture of this sub-phenotype is still poorly understood. Here we report the results of an association study between haemolysis biomarkers (serum LDH, total bilirubin and reticuloc...

Sickle cell disease (SCD) is a monogenic disorder under polygenic and environmental control. This aetiopathogenic architecture leads to marked clinical heterogeneity with the emergence of multiple and diverse subphenotypes, which makes the severity stratification of patients particularly difficult (1, 2). A number of severity scores have been propo...

We have estimated the incidence and molecular basis of α-thal-assemia in a Portuguese population, mostly from the Greater Lisbon area. In a group of 100 consecutive cord blood samples, the gene frequency of the rightward deletion (-α3.7) was 0.035, and the leftward deletion (-α4.2) was 0.015. In this group, we have also found four heterozygotes for...

Most studies of European genetic diversity have focused on large-scale variation and interpretations based on events in prehistory, but migrations and invasions in historical times could also have had profound effects on the genetic landscape. The Iberian Peninsula provides a suitable region for examination of the demographic impact of such recent...

Elevated erythrocyte destruction in sickle cell disease (SCD) results in chronic hyperbilirubinaemia and, in a subset of patients, cholelithiasis occurs. We investigated whether the (TA)n promoter polymorphism in the UDP-glucuronosyltransferase 1A1 gene (UGT1A1) may modify bilirubin metabolism, influencing bilirubinaemia, predisposition to cholelit...

Disease-causing alterations within the F8 gene were identified in 177 hemophilia A families of Portuguese origin. The spectrum of non-inversion F8 mutations in 101 families included 67 different alterations, namely: 36 missense, 8 nonsense and 4 splice site mutations, as well as 19 insertions/deletions. Thirty-four of these mutations are novel. Mol...

Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that degrades mRNAs containing premature translation termination codons. In mammalian cells, a termination codon is ordinarily recognized as "premature" if it is located greater than 50-54 nucleotides 5' to the final exon-exon junction. We have described a set of naturally occurring hum...

We explored the phylogeography of human Y-chromosomal haplogroup E3b by analyzing 3,401 individuals from five continents. Our data refine the phylogeny of the entire haplogroup, which appears as a collection of lineages with very different evolutionary histories, and reveal signatures of several distinct processes of migrations and/or recurrent gen...

Homozygosity or compound heterozygosity for beta(0)-thalassemia mutations most commonly results in a transfusion-dependent thalassemia major phenotype. In this report, we describe a 55-year-old male, from Guinea-Bissau, that had been asymptomatic and never transfused until being admitted to hospital with anemia, fever, splenomegaly, and asthenia. F...

The geographic origins of African slave settlers and the Portuguese genetic contribution to the population of São Tomé (Gulf of Guinea) were assessed through the analysis of beta-globin haplotypes in 44 chromosomes bearing the betaS allele and through the study of the genetic variation in eight autosomal markers (APOA1, AT3, FY, LPL, OCA2, RB1, Sb1...

Haematological as well as gene mapping data are reported for three members of a Portuguese Caucasian family with high G(gamma)-globin levels. A gamma-globin gene sextuplication of the G(gamma)AG(gamma)AG(gamma)AG(gamma)AG(gamma)A(gamma) type was present in the proband and her father. Comparison of gene mapping data with quantitative results of feta...

The Turner syndrome (TS) has been described in association with different sex chromosome aberrations. Although most TS patients show no evidence of Y chromosome sequences, according to different authors some TS patients may have Y chromosome material present in a few cells that are not detected by standard cytogenetic analysis. The importance of id...

Haematological as well as gene mapping data are reported for three members of a Portuguese Caucasian family with high Gγ-globin levels. A gamma-globin gene sextuplication of the GγAGγAGγAGγAGγAγ type was present in the proband and her father. Comparison of gene mapping data with quantitative results of fetal haemoglobin (HbF) analysis provided an e...

Initial studies of gene correction using chimeric RNA/DNA oligonucleotides (RDOs), also termed chimeraplasts, reported exciting rates of correction of point mutations (up to 40% in one in vivo model). However, the technique has not yet fulfilled its promise in the fields of transgenics and gene therapy, and some groups have reported persistent fail...

Clinal patterns of autosomal genetic diversity within Europe have been interpreted in previous studies in terms of a Neolithic demic diffusion model for the spread of agriculture; in contrast, studies using mtDNA have traced many founding lineages to the Paleolithic and have not shown strongly clinal variation. We have used 11 human Y-chromosomal b...

Coagulation factor XI (FXI) deficiency is an inherited autosomal recessive mild bleeding disorder. In this study, we report the molecular genetic analysis of FXI deficiency in six unrelated families of Portuguese origin. The Jewish type II mutation was found in two families, of seemingly Portuguese origin. Haplotype analysis in these families demon...

A polymorphism in the coagulation factor XIII gene (FXIII Val34Leu) has been recently described to confer protection for arterial and venous thrombosis and to predispose to intracerebral hemorrhage. At present it is known that FXIII Val34Leu is prevalent in Caucasians, but information upon its distribution in different ethnic groups is scarce. We i...

Generally, nonsense codons 50 bp or more upstream of the 3'-most intron of the human beta-globin gene reduce mRNA abundance. In contrast, dominantly inherited beta-thalassemia is frequently associated with nonsense mutations in the last exon. In this work, murine erythroleukemia (MEL) cells were stably transfected with human beta-globin genes mutat...

Generally, nonsense codons 50 bp or more upstream of the 3′-most intron of the human β-globin gene reduce mRNA abundance. In contrast, dominantly inherited β-thalassemia is frequently associated with nonsense mutations in the last exon. In this work, murine erythroleukemia (MEL) cells were stably transfected with human β-globin genes mutated within...

Present state of knowledge, mostly based on heterologous expression studies, indicates that the cystic fibrosis transmembrane conductance regulator (CFTR) protein bearing the F508del mutation is misprocessed and mislocalized in the cytoplasm, unable to reach the cell surface. Recently, however, it was described that protein levels and localization...

In order to establish the molecular basis of beta-thalassaemia in Cubans, a total of 75 unrelated individuals, with beta-thalassaemia major (7), Hb S-beta-thalassaemia (28), Hb C-beta-thalassaemia (1), and beta-thalassaemia trait (39) yielding 82 beta-thalassaemia alleles, were analyzed. Seventeen different point mutations were identified accountin...

In order to establish the molecular basis of β-thalassaemia in Cubans, a total of 75 unrelated individuals, with β-thalassaemia major (7), Hb S-β-thalassaemia (28), Hb C-β-thalassaemia (1), and β-thalassaemia trait (39) yielding 82 β-thalassaemia alleles, were analyzed. Seventeen different point mutations were identified accounting for 93% of the β...

Clinal patterns of autosomal genetic diversity within Europe have been interpreted in previous studies in terms of a Neolithic demic diffusion model for the spread of agriculture; in contrast, studies using mtDNA have traced many founding lineages to the Paleolithic and have not shown strongly clinal variation. We have used 11 human Y-chromosomal b...

In this study, we sought to clarity the molecular basis of a dominant inherited beta-thalassemia, found in heterozygosity in a northern Portuguese family with thalassemia intermedia. We characterized: i) the alpha-globin gene cluster structure; ii) the beta-globin gene cluster haplotype; and iii) the beta-thalassemia mutation. The alpha-globin gene...

Autosomal dominant polycystic kidney disease is one of the most common hereditary diseases in man with an estimated prevalence of 1:1000. At least three genetic loci are responsible for the development of the disease. PKD1 localized to 16p13 is the most common gene, contributing to almost 85% of all cases, is associated with the most severe form. P...

In this paper the role of molecular biology research and development in establishing etiology and pathogenesis of cardiovascular disease is discussed. Several examples of our own practice in the field (namely, Di George sequence, hereditary protein S deficiency, and hyperhomocysteinaemia) are provided as an illustration of the currently applied str...

We characterized the 3272-26A-->G mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, creating an alternative acceptor splice site in intron 17a, that competes with the normal one, although we predict from consensus values, with lower efficiency. We analyzed five Cystic Fibrosis (CF) Portuguese patients with the 3272-26...

We characterized the 3272-26A→G mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, creating an alternative acceptor splice site in intron 17a, that competes with the normal one, although we predict from consensus values, with lower efficiency. We analyzed five Cystic Fibrosis (CF) Portuguese patients with the 3272-26A→...

A novel mutation in the cystathionine beta-synthase (CBS) gene (a 68-bp insertion in the coding region of exon 8: 844ins68) was recently described, but its prevalence in different human populations is unknown. We analyzed the prevalence of the 68-bp insertion in the CBS gene in 405 unrelated individuals (810 chromosomes) of European, African, Asian...

In a study of 908 males from Europe, northern Africa, and western Asia, the variation of four Y-linked dinucleotide microsatellites was analyzed within three "frames" that are defined by mutations that are nonrecurrent, or nearly so. The rapid generation and extinction of new dinucleotide length variants causes the haplotypes within each lineage to...

Spermatogenesis is a complex physiological process characterized by an orderly proliferation and differentiation of germ cell types, from diploid spermatogonial stem cells to haploid spermatids, and after spermiogenesis to spermatozoa. It is known that male reproductive capacity is deficient in about one half of infertile couples. Effective treatme...

β thalassemia and Hb Lepore heterozygotes included in this study exhibit fetal hemoglobin levels varying from trace quantities to 14% (1.74 g/dl) of total hemoglobin in the adult. In this work, we have examined the correlation of DNA sequence polymorphisms with the observed HbF level. The analysis of polymorphic markers within the β globin cluster...

Beta thalassemia and Hb Lepore heterozygotes included in this study exhibit fetal hemoglobin levels varying from trace quantities to 14% (1.74 g/dl) of total hemoglobin in the adult. In this work, we have examined the correlation of DNA sequence polymorphisms with the observed HbF level. The analysis of polymorphic markers within the beta globin cl...

The chemokine receptor CCR5 is encoded by the CMKBR5 gene located on the p21.3 region of human chromosome 3, and constitutes the major co-receptor for the macrophage-tropic strains of HIV-1. A mutant allele of the CCR5 gene, Delta ccr5 , was shown to provide to homozygotes with a strong resistance against infection by HIV. The frequency of the Delt...

We describe a dominantly inherited beta-thalassemia intermedia phenotype observed in a five-generation Portuguese family. Carriers are characterized by moderate anemia, hypochromia, microcytosis, elevated hemoglobin (Hb)A2 and HbF levels, splenomegaly, hepatomegaly, and inclusion bodies in peripheral red blood cells after splenectomy. The molecular...

We describe a dominantly inherited β-thalassemia intermedia phenotype observed in a five-generation Portuguese family. Carriers are characterized by moderate anemia, hypochromia, microcytosis, elevated hemoglobin (Hb)A2 and HbF levels, splenomegaly, hepatomegaly, and inclusion bodies in pheripheral red blood cells after splenectomy. The molecular b...

In a study of 908 males from Europe, northern Africa, and western Asia, the variation of four Y-linked dinu-cleotide microsatellites was analyzed within three "frames" that are defined by mutations that are non-recurrent, or nearly so. The rapid generation and ex-tinction of new dinucleotide length variants causes the haplotypes within each lineage...

In a study of 908 males from Europe, northern Africa, and western Asia, the variation of four Y-linked dinucleotide microsatellites was analyzed within three “frames” that are defined by mutations that are nonrecurrent, or nearly so. The rapid generation and extinction of new dinucleotide length variants causes the haplotypes within each lineage to...

A case of cystic fibrosis presented in the neonatal period with respiratory symptomatology associated with early pancreatic insufficiency is reported. The CFTR gene molecular analysis was found to be a compound heterozygotes for delta F508 and G542X. The rarity of this mode of presentation and the inclusion of this entity in the differential diagno...

We report the clinical features of 21 unrelated cystic fibrosis (CF) patients from Portugal and Spain, who carry the mutation R1066C in the CFTR gene. The current age of the patients was higher in the R1066C/any mutation group (P < 0.01), as compared to the deltaF508/deltaF508 group. Poor values for lung radiological involvement (Chrispin-Norman) a...