RESUMO
OBJECTIVE: Genetic counseling and carrier screening are part of the gamete donation process by healthy individuals. We aim to review the findings of genetic counseling and carrier screening of a cohort of candidates at our public gametes bank. METHODS: Thirty-four male and 64 female candidates had genetic counseling with a medical geneticist before donation. Of these, one female candidate voluntarily dropped-out. Thirty-four males and 63 females performed karyotype and screening for the more common pathogenic variants for CFTR-related cystic fibrosis and spinal muscular atrophy (SMN1) in the Portuguese population. In addition, all females also performed Fragile X expansion screening (FMR1). Thirty candidates with known or assumed African ancestry performed hemoglobinopathies screening. RESULTS: Six candidates were definitely or temporarily withheld from the donation process given their family or personal history that required further investigation. Of 97 candidates tested, 16.5% presented anomalous laboratory results (16/97): ten candidates were carriers for an autosomal recessive disorder - cystic fibrosis (5/97), sickle cell anemia (3/30), and spinal muscular atrophy (2/97). One female was an FMR1 pre-mutation carrier (1/63). One female candidate presented with triple X mosaicism: 47,XXX[2]/46,XX[50]. Two candidates presented with chromosomal instability of unknown origin. In one candidate, a mosaic for the Philadelphia chromosome was detected, revealing the diagnosis of chronic myeloid leukemia. CONCLUSIONS: From a cohort of 97 candidates, 21.7% had a family/personal history or an anomalous laboratory result that required additional genetic counseling, stressing the importance of performing pre-donation genetic counseling in this population.
Assuntos
Fibrose Cística , Atrofia Muscular Espinal , Humanos , Masculino , Feminino , Aconselhamento Genético , Triagem de Portadores Genéticos/métodos , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Portugal , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Células Germinativas , Proteína do X Frágil da Deficiência Intelectual/genéticaRESUMO
Protein tyrosine phosphatase 1B (PTP1B) is a typical member of the PTP family, considered a direct negative regulator of several receptor and receptor-associated tyrosine kinases. This widely localized enzyme has been involved in the pathophysiology of several diseases. More recently, PTP1B has attracted attention in the field of neuroscience, since its activation in brain cells can lead to schizophrenia-like behaviour deficits, anxiety-like effects, neurodegeneration, neuroinflammation and depression. Conversely, PTP1B inhibition has been shown to prevent microglial activation, thus exerting a potent anti-inflammatory effect and has also shown potential to increase the cognitive process through the stimulation of hippocampal insulin, leptin and BDNF/TrkB receptors. Notwithstanding, most research on the clinical efficacy of targeting PTP1B has been developed in the field of obesity and type 2 diabetes mellitus (TD2M). However, despite the link existing between these metabolic alterations and neurodegeneration, no clinical trials assessing the neurological advantages of PTP1B inhibition have been performed yet. Preclinical studies, though, have provided strong evidence that targeting PTP1B could allow to reach different pathophysiological mechanisms at once. herefore, specific interventions or trials should be designed to modulate PTP1B activity in brain, since it is a promising strategy to decelerate or prevent neurodegeneration in aged individuals, among other neurological diseases. The present paper fails to include all neurological conditions in which PTP1B could have a role; instead, it focuses on those which have been related to metabolic alterations and neurodegenerative processes. Moreover, only preclinical data is discussed, since clinical studies on the potential of PTP1B inhibition for treating neurological diseases are still required.
Assuntos
Diabetes Mellitus Tipo 2 , Doenças do Sistema Nervoso , Humanos , Idoso , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Leptina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo , Insulina/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Tirosina , Inibidores Enzimáticos/farmacologiaRESUMO
OBJECTIVE: To describe the clinical, biochemical, and genetic features of both new and previously reported patients with congenital disorders of glycosylation (CDGs) diagnosed in Portugal over the last 20 years. STUDY DESIGN: The cohort includes patients with an unexplained multisystem or single organ involvement, with or without psychomotor disability. Serum sialotransferrin isoforms and, whenever necessary, apolipoprotein CIII isoforms and glycan structures were analyzed. Additional studies included measurement of phosphomannomutase (PMM) activity and analysis of lipid-linked oligosaccharides in fibroblasts. Sanger sequencing and massive parallel sequencing were used to identify causal variants or the affected gene, respectively. RESULTS: Sixty-three individuals were diagnosed covering 14 distinct CDGs; 43 patients diagnosed postnatally revealed a type 1, 14 a type 2, and 2 a normal pattern on serum transferrin isoelectrofocusing. The latter patients were identified by whole exome sequencing. Nine of them presented also a hypoglycosylation pattern on apolipoprotein CIII isoelectrofocusing, pointing to an associated O-glycosylation defect. Most of the patients (62%) are PMM2-CDG and the remaining carry pathogenic variants in ALG1, ATP6AP1, ATP6AP2, ATP6V0A2, CCDC115, COG1, COG4, DPAGT1, MAN1B1, SLC35A2, SRD5A3, RFT1, or PGM1. CONCLUSIONS: Portuguese patients with CDGs are presented in this report, some of them showing unique clinical phenotypes. Among the 14 genes mutated in Portuguese individuals, 8 are shared with a previously reported Spanish cohort. However, regarding the mutational spectrum of PMM2-CDG, the most frequent CDG, a striking similarity between the 2 populations was found, as only 1 mutated allele found in the Portuguese group has not been reported in Spain.
Assuntos
Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Portugal , Fatores de Tempo , Adulto JovemRESUMO
Neolignan licarin A (1) was isolated from leaves of Nectandra oppositifolia (Lauraceae) and displayed activity against trypomastigote forms of the etiologic agent of American trypanosomiasis, Trypanosoma cruzi. Aiming for the establishment of SAR, five different compounds (1a - 1e) were prepared and tested against T. cruzi. The 2-allyl derivative of licarin A (1d) exhibited higher activity against trypomastigotes of T. cruzi (IC50 = 5.0 µM and SI = 9.0), while its heterocyclic derivative 1e displayed IC50 of 10.5 µM and reduced toxicity against NCTC cells (SI > 19.0). However, these compounds presented limited oral bioavailability estimation (<85%, Papp <1.0 × 10-6 cm/s) in parallel artificial membrane permeability assays (PAMPA) due to excessive lipophilicity. Based on these results, different simplified structures of licarin A were designed: vanillin (2), vanillyl alcohol (3), isoeugenol (4), and eugenol (5), as well as its corresponding methyl (a), acetyl (b), O-allyl (c), and C-allyl (d) analogues. Vanillin (2) and its acetyl derivative (2b) displayed expressive activity against intracellular amastigotes of T. cruzi with IC50 values of 5.5 and 5.6 µM, respectively, and reduced toxicity against NCTC cells (CC50 > 200 µM). In addition, these simplified analogues showed a better permeability profile (Papp > 1.0 × 10-6 cm/s) on PAMPA models, resulting in improved drug-likeness. Vanillyl alcohol acetyl derivative (3b) and isoeugenol methyl derivative (4a) displayed activity against the extracellular forms of T. cruzi (trypomastigotes) with IC50 values of 5.1 and 8.8 µM respectively. Based on these results, compounds with higher selectivity index against extracellular forms of the parasite (1d, 1e, 3d, and 4a) were selected for a mechanism of action study. After a short incubation period (1 h) all compounds increased the reactive oxygen species (ROS) levels of trypomastigotes, suggesting cellular oxidative stress. The ATP levels were increased after two hours of incubation, possibly involving a high energy expenditure of the parasite to control the homeostasis. Except for compound 4a, all compounds induced hyperpolarization of mitochondrial membrane potential, demonstrating a mitochondrial imbalance. Considering the unique mitochondria apparatus of T. cruzi and the lethal alterations induced by structurally based on licarin A, these compounds are interesting hits for future drug discovery studies in Chagas disease.
Assuntos
Antiparasitários/isolamento & purificação , Antiparasitários/farmacologia , Produtos Biológicos/isolamento & purificação , Doença de Chagas/tratamento farmacológico , Lauraceae/química , Lignanas/isolamento & purificação , Lignanas/farmacologia , Folhas de Planta/química , Tripanossomicidas/isolamento & purificação , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiparasitários/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Descoberta de Drogas , Lignanas/síntese química , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Trypanosoma cruzi/metabolismoRESUMO
OBJETIVO: Avaliar a evolução clínica e as complicações agudas e tardias de pacientes portadores de neoplasia de cabeça e pescoço localmente avançada submetidos a cirurgia com radio e quimioterapiaadjuvantes. MATERIAL E MÉTODO: No período de maio de 2004 a junho de 2007 foram analisados 39 pacientes com neoplasia de cabeça e pescoço localmente avançada submetidos a ressecção cirúrgica, radio e quimioterapia adjuvantes. RESULTADOS: A idade mediana foi de 54 anos. Estádio III foi observado em 30,8% e estádio IVA em 61,5% dos pacientes. Setenta e sete por cento dos pacientes realizaram radioterapia com dose de 66 Gy. Em relação às complicações agudas,a mais prevalente foi dermatite grau III em 46,2%, e 48,7% dos pacientes apresentaram fibrosecomo complicação tardia. O seguimento mediano foi de 30 meses, com estimativa de sobrevidalivre de doença locorregional de 70% e sobrevida global de 76% em cinco anos. CONCLUSÃO: Esteestudo mostra que, em pacientes com neoplasia de cabeça e pescoço localmente avançada, a cirurgia seguida de radio e quimioterapia apresentam resultados de controle locorregional e sobrevida livre de doença satisfatórios. Nossos resultados, bem como porcentagens de complicações agudas e tardias, estão compatíveis com a literatura.
OBJECTIVE: To evaluate the clinical outcome of patients with locallyadvanced head and neck cancer treated with postoperative concurrent radio-chemotherapy. MATERIAL AND METHOD: Thirtynine patients with locally advanced head and neck cancer submittedto resection of all visible and palpable disease, followed byradiotherapy (6066 Gy in 30 to 33 fractions over a period of 6 to6.6 weeks) and concurrent cisplatin between May 2004 and June2007 were retrospectively analyzed. RESULTS: A predominance of male with a median age of 54 years was observed; 30.8% of patients were in stage III and 61.5% in stage IVA; 77% of patients received a radiation dose of 66 Gy; dermatitis grade III occurred in 46.2% and fibrosis in 48.7% of patients. The 5-year loco-regional failure and overall survival were 30% and 76%, respectively. CONCLUSION: Data show that surgery followed by concurrent radio-chemotherapypresents reasonable rate of loco-regional control and disease-free survival in high-risk patients. Our index of loco-regionaland distant failure and the rate of acute and late complicationare compatible with other series in the literature.