RESUMO
Inherited retinal diseases (IRDs) represent a spectrum of clinically and genetically heterogeneous disorders. Our study describes an IRD patient carrying ABCA4 and USH2A pathogenic biallelic mutations as a result of paternal uniparental disomy (UPD) in chromosome 1. The proband is a 9-year-old girl born from non-consanguineous parents. Both parents were asymptomatic and denied family history of ocular disease. Clinical history and ophthalmologic examination of the proband were consistent with Stargardt disease. Whispered voice testing disclosed moderate hearing loss. Next-generation sequencing and Sanger sequencing identified pathogenic variants in ABCA4 (c.4926C>G and c.5044_5058del) and USH2A (c.2276G>T). All variants were present homozygously in DNA from the proband and heterozygously in DNA from the father. No variants were found in maternal DNA. Further analysis of single nucleotide polymorphisms confirmed paternal UPD of chromosome 1. This is the first known patient with confirmed UPD for two recessively mutated IRD genes. Our study expands on the genetic heterogeneity of IRDs and highlights the importance of UPD as a mechanism of autosomal recessive disease in non-consanguineous parents. Moreover, a long-term follow-up is essential for the identification of retinal features that may develop as a result of USH2A-related conditions.
RESUMO
Angiotensin II type 1 receptor agonist antibodies (AT1R-AAs) have been associated with hypertension, atherosclerosis and vascular inflammation in human diseases. The aim of the study was to evaluate the prevalence of AT1R-AAs in active lupus nephritis (LN) patients and their association with vascular damage. One hundred and seven active LN patients underwent a complete clinical examination, measurement of AT1R-AAs, ambulatory blood pressure monitoring, carotid intima-media thickness measurement and morphometric analysis of subintimal fibrosis and medial hyperplasia of the vessels in the kidney tissue. Plasma AT1R-AAs were positive in 58 (54.2%) patients. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, complement C3 and C4 levels and titers of anti-dsDNA antibodies were higher in the group with positive AT1R-AAs compared with those with negative AT1R-AAs. The AT1R-AA titers correlated with anti-dsDNA antibody titers and with complement C3 and C4 serum levels. In the kidney biopsy, the percentage of subintimal fibrosis and the area of medial hyperplasia were greater in the AT1R-AA-positive patients. No differences in arterial pressure, carotid intima-media thickness and response to therapy were detected. In conclusion, AT1R-AAs are prevalent in active LN patients and are associated with histologic features of microvascular damage.
Assuntos
Autoanticorpos/sangue , Rim/irrigação sanguínea , Nefrite Lúpica/imunologia , Receptor Tipo 1 de Angiotensina/agonistas , Adulto , Anticorpos Antinucleares/sangue , Monitorização Ambulatorial da Pressão Arterial/métodos , Espessura Intima-Media Carotídea , Estudos de Casos e Controles , Complemento C3/análise , Complemento C4/análise , Feminino , Fibrose/patologia , Humanos , Hiperplasia/patologia , Imunossupressores/uso terapêutico , Rim/patologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Masculino , Microvasos/patologia , PrevalênciaRESUMO
OBJECTIVE: To compare functional endoscopic sinus surgery with a combined approach (functional endoscopic sinus surgery plus Caldwell-Luc procedure) for the treatment of paediatric antrochoanal polyp, in terms of antrochoanal polyp recurrence and safety. METHOD: This retrospective case series comprises 27 paediatric patients with recurrent antrochoanal polyp, treated from January 2010 to January 2018. RESULTS: The average age of the patients at the time of diagnosis was 10.4 ± 2.49 years. The recurrence rate after functional endoscopic sinus surgery alone was 72.9 per cent, compared with 12.5 per cent after functional endoscopic sinus surgery plus the Caldwell-Luc procedure (p < 0.00001). No complications were reported during surgery or follow up. CONCLUSION: The correct identification of the origin of the antrochoanal polyp and an adequate returning of maxillary ventilation by widening the ostium can prevent recurrences. Although functional endoscopic sinus surgery continues to be the 'gold standard' for antrochoanal polyp treatment, in cases of revision surgery, a combined approach could ensure the complete removal of the polyp through the two openings.
Assuntos
Seio Maxilar/cirurgia , Pólipos Nasais/cirurgia , Adolescente , Criança , Terapia Combinada , Endoscopia , Feminino , Humanos , Masculino , Recidiva , Reoperação , Estudos Retrospectivos , Resultado do TratamentoRESUMO
This work evaluated the qualitative and quantitative cellular changes induced by treatment with 5-aminouracil (5-AU) and a combination of 5-AU and caffeine in plant cells in relation to DNA damage, repaired damage, and residual damage. As biological material, Allium cepa L. root tips were used, grown in filtered water, in darkness, with aeration at constant temperature of 25 degrees C +/- 0.5. Cell populations were synchronized using 5 mM caffeine in order to study the effects of 5-AU and caffeine/5-AU combined treatment on the DNA content and their incidence in the entrance to mitosis. The results showed a delay in the G2 period due to induced DNA damage by the 5-AU and caffeine/5-AU combined treatment, shown by aberrant metaphases, anaphases and telophases. The effect of caffeine in the combined treatment was heightened in spite of lengthening the checkpoints route that retains the cells in G2. The existence of G2 checkpoints was shown in the cell population studied, inducing lesions in the DNA, chromosomic aberrations and cellular instability.
Assuntos
Cafeína/farmacologia , DNA/metabolismo , Uracila/análogos & derivados , Núcleo Celular/metabolismo , Aberrações Cromossômicas , DNA/efeitos dos fármacos , Dano ao DNA , Relação Dose-Resposta a Droga , Fase G2 , Alho/efeitos dos fármacos , Metáfase , Mitose , Inibidores de Fosfodiesterase/farmacologia , Plantas/metabolismo , Temperatura , Fatores de Tempo , Uracila/farmacologiaRESUMO
This work evaluated the qualitative and quantitative cellular changes induced by treatment with 5-aminouracil (5-AU) and a combination of 5-AU and caffeine in plant cells in relation to DNA damage, repaired damage, and residual damage. As biological material, Allium cepa L. root tips were used, grown in filtered water, in darkness, with aeration at constant temperature of 25ºC ± 0.5. Cell populations were synchronized using 5 mM caffeine in order to study the effects of 5-AU and caffeine/5-AU combined treatment on the DNA content and their incidence in the entrance to mitosis. The results showed a delay in the G2 period due t
Assuntos
Cafeína , Cafeína/diagnóstico , Estimulantes do Sistema Nervoso Central , Mitose , DNA/diagnóstico , Plantas/citologiaRESUMO
This work evaluated the qualitative and quantitative cellular changes induced by treatment with 5-aminouracil (5-AU) and a combination of 5-AU and caffeine in plant cells in relation to DNA damage, repaired damage, and residual damage. As biological material, Allium cepa L. root tips were used, grown in filtered water, in darkness, with aeration at constant temperature of 25°C ± 0.5. Cell populations were synchronized using 5 mM caffeine in order to study the effects of 5-AU and caffeine/5-AU combined treatment on the DNA content and their incidence in the entrance to mitosis. The results showed a delay in the G2 period due to induced DNA damage by the 5-AU and caffeine/5-AU combined treatment, shown by aberrant metaphases, anaphases and telophases. The effect of caffeine in the combined treatment was heightened in spite of lengthening the checkpoints route that retains the cells in G2. The existence of G2 checkpoints was shown in the cell population studied, inducing lesions in the DNA, chromosomic aberrations and cellular instability
Assuntos
Cafeína , Estimulantes do Sistema Nervoso Central , Cafeína , DNA , Mitose , Plantas/citologiaRESUMO
This work evaluated the qualitative and quantitative cellular changes induced by treatment with 5-aminouracil (5-AU) and a combination of 5-AU and caffeine in plant cells in relation to DNA damage, repaired damage, and residual damage. As biological material, Allium cepa L. root tips were used, grown in filtered water, in darkness, with aeration at constant temperature of 25 degrees C +/- 0.5. Cell populations were synchronized using 5 mM caffeine in order to study the effects of 5-AU and caffeine/5-AU combined treatment on the DNA content and their incidence in the entrance to mitosis. The results showed a delay in the G2 period due to induced DNA damage by the 5-AU and caffeine/5-AU combined treatment, shown by aberrant metaphases, anaphases and telophases. The effect of caffeine in the combined treatment was heightened in spite of lengthening the checkpoints route that retains the cells in G2. The existence of G2 checkpoints was shown in the cell population studied, inducing lesions in the DNA, chromosomic aberrations and cellular instability.
RESUMO
DNA damage was induced by either 2 mM ethylmethanesulfonate or 1 Gy of gamma-irradiation in Allium cepa L. root meristems. The percentage of DNA that migrated towards the anode during microelectrophoresis after alkali denaturation (pH approximately 13.5) of the isolated nuclei (comet assay) reflects the amount of single strand breaks present in them. There was some DNA migration (12.8+/-2.4%) in untreated roots. This percentage doubled at the end of 1.5 h treatment with the mono-functional alkylating agent 2 mM ethylmethanesulfonate, and trebled after a single exposure to 1 Gy of gamma-rays. A proportion of the DNA migration caused by these two treatments was reversed (repaired) by a 2 h long period of in vivo recovery. However, when 5 mM caffeine was applied after removal of the alkylating agent, the amount of DNA migrating to the comet tail over the same 2 h period was almost double that at the onset of recovery. In both control and irradiated nuclei, caffeine also increased the initial level of DNA migration in the comet assay, but to a lesser extent. These results indicate that caffeine increases the DNA damage that accumulates during the processing of alkylated bases and, to a lesser extent, of the DNA bases damaged by gamma-irradiation. Thus, the potentiation effect of caffeine on induced chromosomal damage may not just be due to caffeine-induced cancellation of the G2 checkpoint, but also to a direct effect this methylxantine has on the processing of DNA damage.
Assuntos
Cafeína/farmacologia , DNA/efeitos dos fármacos , DNA/efeitos da radiação , Fenômenos Fisiológicos Vegetais , Raízes de Plantas/fisiologia , Alquilação , Divisão Celular , Núcleo Celular/metabolismo , Ensaio Cometa , DNA/química , Dano ao DNA , Metanossulfonato de Etila , Fase G2 , Raios gama , Concentração de Íons de Hidrogênio , Processamento de Imagem Assistida por Computador , Mutagênicos , Inibidores de Fosfodiesterase/farmacologia , Fatores de TempoRESUMO
There is a checkpoint pathway in eukaryotic cells that depends on ATM (ataxia telangiectasia mutated) kinase which activates the processes leading to the repair of DNA damage and also lengthens the G(2) stage of the cell cycle. In cells from ataxia telangiectasia patients, due to their lack of active ATM kinase, an increase in chromosomal aberrations and a failure to induce G(2) lengthening could be expected. However, the basal G(2) timing in ataxia telangiectasia cells was longer than in controls and was further extended after X-ray irradiation (0.4 Gy), although to a lesser extent than in controls. Moreover, in control cells caffeine shortened G(2) and increased chromosomal damage 7-fold, while in ataxia telangiectasia cells caffeine only trebled aberration yield without shortening G(2). As caffeine is an inhibitor of ATM kinase, these results suggest the existence of some redundant ATM-independent checkpoint in G(2) of ataxia telangiectasia cells. The differential response to caffeine of ataxia telangiectasia and control lymphocytes may be explained by the presence of two different subpathways in the G(2) checkpoint: one regulating the processing and repair of damaged DNA and the other controlling G(2) timing. While in controls both subpathways may be mediated by ATM kinase, in ataxia telangiectasia cells caffeine-sensitive ATR kinase and the caffeine-insensitive DNA-PK kinases might be responsible for DNA repair and the G(2) delay subpathways, respectively. Confirmation of this model in ataxia telangiectasia cells with another cell type in which both subpathways are mediated by DNA-PK should define whether a metylxanthine such as caffeine may also have an additional direct inhibitory effect on DNA repair.