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1.
Cell Mol Life Sci ; 81(1): 444, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39485512

RESUMO

Alzheimer´s disease (AD) is characterized by neuronal function loss and degeneration. The integrity of the axon initial segment (AIS) is essential to maintain neuronal function and output. AIS alterations are detected in human post-mortem AD brains and mice models, as well as, neurodevelopmental and mental disorders. However, the mechanisms leading to AIS deregulation in AD and the extrinsic glial origin are elusive. We studied early postnatal differences in AIS cellular/molecular mechanisms in wild-type or APP/PS1 mice and combined neuron-astrocyte co-cultures. We observed AIS integrity alterations, reduced ankyrinG expression and shortening, in APP/PS1 mice from P21 and loss of AIS integrity at 21 DIV in wild-type and APP/PS1 neurons in the presence of APP/PS1 astrocytes. AnkyrinG decrease is due to mRNAs and protein reduction of retinoic acid synthesis enzymes Rdh1 and Aldh1b1, as well as ADNP (Activity-dependent neuroprotective protein) in APP/PS1 astrocytes. This effect was mimicked by wild-type astrocytes expressing ADNP shRNA. In the presence of APP/PS1 astrocytes, wild-type neurons AIS is recovered by inhibition of retinoic acid degradation, and Adnp-derived NAP peptide (NAPVSIPQ) addition or P2X7 receptor inhibition, both regulated by retinoic acid levels. Moreover, P2X7 inhibitor treatment for 2 months impaired AIS disruption in APP/PS1 mice. Our findings extend current knowledge on AIS regulation, providing data to support the role of astrocytes in early postnatal AIS modulation. In conclusion, AD onset may be related to very early glial cell alterations that induce AIS and neuronal function changes, opening new therapeutic approaches to detect and avoid neuronal function loss.


Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Astrócitos , Camundongos Transgênicos , Transcriptoma , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Segmento Inicial do Axônio/metabolismo , Técnicas de Cocultura , Anquirinas/metabolismo , Anquirinas/genética , Tretinoína/farmacologia , Tretinoína/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Modelos Animais de Doenças , Axônios/metabolismo , Axônios/patologia , Camundongos Endogâmicos C57BL , Presenilina-1/genética , Presenilina-1/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/genética , Células Cultivadas , Família Aldeído Desidrogenase 1/metabolismo , Família Aldeído Desidrogenase 1/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Retinal Desidrogenase/metabolismo , Retinal Desidrogenase/genética
2.
Int J Colorectal Dis ; 39(1): 178, 2024 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-39496801

RESUMO

PURPOSE: The main aim of this study was to determine the short- and long-term outcomes of the non-operative management of acute left-sided complicated diverticulitis (ALCD) in severely immunocompromised patients (IMS group) and compare them with immunocompetent patients (IC group). The secondary aim was to assess the necessity of an elective surgery following a successful prior non-operative management in the IMS group after a non-operative management of the first episode of ALCD. METHODS: Patients presented with their first episode of ALCD between 2012 and 2018 were retrospectively reviewed. Only severely immunosuppressed patients were considered for the analysis, including the following: long-term oral or intravenous steroid intake, current malignancy undergoing chemotherapy, chronic kidney disease on hemodialysis, or solid organ transplant with immunosuppressive medication. For each group, demographic data, severity of the episode, management decisions (conservative or operative), and short- and long-term outcomes were recorded and compared. A sub-analysis of patients with ALCD associating and abscess (modified Hinchey classification Ib/II) was performed. RESULTS: A total of 290 patients were included in the study: 50 among the IMS and 240 among the IC group. The rate of emergent surgery was higher in the IMS group (50.0% vs. 22.5%, p < 0.001) and was associated with increased morbidity (72.4% vs. 50.0%, p = 0.041) and mortality (24.1% vs. 4.3%, p = 0.003). The duration of the hospital stay was significantly longer in the IMS group (15 vs. 8 days, p < 0.001). The final stoma rate was significantly higher in the IMS group (82.1% vs. 22.9, p < 0.001), with a median follow-up of 51.4 months. A total of 141 patients presented ALCD with an abscess; 25 in the IMS and 116 in the IC group. There was a higher rate of surgical intervention among the IMS group as the initial treatment approach (24.0% vs. 5.2%, p = 0.002), even though the conservative treatment had a similar rate of success (81.3% vs. 92.0%, p = 0.178). The recurrence rate following a non-operative approach was similar (IMS: 31.2% vs. 35.4% in the IC group, p = 0.169). Furthermore, 81.2% of non-operatively managed IMS patients (13 out of 16) did not require a surgical intervention at the end of the follow-up, with similar findings in the IC group (78/96, 81.2%, p = 0.148). CONCLUSION: Medical treatment of immunosuppressed patients during their first ALCD episode associated with an abscess is feasible, with a high success rate and results comparable with the IC group. Moreover, taking into account the readmission rates, the need for emergent surgery of the recurrence, and the perioperative mortality and morbidity in the IMS group, conservative management with no differed scheduled surgery seems to be a safe option in this subgroup of patients.


Assuntos
Hospedeiro Imunocomprometido , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Resultado do Tratamento , Doença Aguda , Fatores de Tempo , Idoso , Diverticulite/complicações , Diverticulite/terapia , Diverticulite/cirurgia , Estudos Retrospectivos , Adulto
3.
Molecules ; 29(5)2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38474569

RESUMO

The sol-gel method, adapted to aqueous media, was used for the synthesis of BaMn0.7Cu0.3O3 (BMC) and Ba0.9A0.1Mn0.7Cu0.3O3 (BMC-A, A = Ce, La or Mg) perovskite-type mixed oxides. These samples were fully characterized by ICP-OES, XRD, XPS, H2-TPR, BET, and O2-TPD and, subsequently, they were evaluated as catalysts for CO oxidation under different conditions simulating that found in cars exhaust. The characterization results show that after the partial replacement of Ba by A metal in BMC perovskite: (i) a fraction of the polytype structure was converted to the hexagonal BaMnO3 perovskite structure, (ii) A metal used as dopant was incorporated into the lattice of the perovskite, (iii) oxygen vacancies existed on the surface of samples, and iv) Mn(IV) and Mn(III) coexisted on the surface and in the bulk, with Mn(IV) being the main oxidation state on the surface. In the three reactant atmospheres used, all samples catalysed the CO to CO2 oxidation reaction, showing better performances after the addition of A metal and for reactant mixtures with low CO/O2 ratios. BMC-Ce was the most active catalyst because it combined the highest reducibility and oxygen mobility, the presence of copper and of oxygen vacancies on the surface, the contribution of the Ce(IV)/Ce(III) redox pair, and a high proportion of surface and bulk Mn(IV). At 200 °C and in the 0.1% CO + 10% O2 reactant gas mixture, the CO conversion using BMC-Ce was very similar to the achieved with a 1% Pt/Al2O3 (Pt-Al) reference catalyst.

4.
Molecules ; 29(13)2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38999142

RESUMO

Ba1-xCexMnO3 (BM-Cex) and Ba1-xLaxMn0.7Cu0.3O3 (BMC-Lax) perovskite-type mixed oxides were synthesized using the sol-gel method adapted for aqueous media with different values of x (0, 0.1, 0.3, 0.6) to estimate the effect of the degree of the partial substitution of Ba by Ce or La on the structure and properties that are relevant for their use as catalysts for gasoline direct injection (GDI) soot oxidation. The samples were deeply characterized by ICP-OES, XRD, XPS, N2 adsorption, H2-TPR, and O2-TPD, and their potential as catalysts for soot oxidation has been analyzed in various scenarios that replicate the exhaust conditions of a GDI engine. By comparing the catalytic performance for soot oxidation of the two tested series (BM-Cex and BMC-Lax) and in the two conditions used (100% He and 1% O2 in He), it could be concluded that (i) in the absence of oxygen in the reaction atmosphere (100% He), BMC-La0.1 is the best catalyst, as copper is also able to catalyze the soot oxidation; and (ii) if oxygen is present in the reaction atmosphere (1% O2/He), BM-Ce0.1 is the most-active catalyst as it presents a higher proportion of Mn(IV) than BMC-La0.1. Thus, it seems that the addition of an amount of Ce or La higher than that corresponding to x = 0.1 in Ba1-xCexMnO3 and Ba1-xLaxCu0.3Mn0.7O3 does not allow us to improve the catalytic performance of BM-Ce0.1 and BMC-La0.1 for soot oxidation in the tested conditions.

5.
J Infect Dis ; 227(7): 873-877, 2023 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35759220

RESUMO

In this case-control study, we evaluated the association between serum antibodies against hepatitis E virus (HEV) and central nervous system (CNS) neurodegenerative disorders (NDs) in older people with dementia. The presence of anti-HEV antibodies was related to a higher adjusted odds ratio (aOR) of having CNS NDs by neuropathological diagnosis (aOR, 2.13; P = .007) and clinical/neuropathological diagnosis (1.84; P = .02). Besides, serum anti-HEV antibodies were directly related to neuropathological injury (higher vascular pathology [aOR, 1.97; P = .006]) and higher probability of Alzheimer-type pathology (1.84; P = .02). In conclusion, the presence of anti-HEV antibodies was related to higher odds of CNS NDs and neuropathological injury in older people.


Assuntos
Demência , Vírus da Hepatite E , Hepatite E , Doenças Neurodegenerativas , Humanos , Idoso , Hepatite E/complicações , Hepatite E/epidemiologia , Estudos Soroepidemiológicos , Estudos de Casos e Controles , Anticorpos Anti-Hepatite , Doenças Neurodegenerativas/epidemiologia , Doenças Neurodegenerativas/complicações , Demência/epidemiologia , Demência/complicações , Imunoglobulina M
6.
Int J Med Microbiol ; 313(6): 151588, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37925748

RESUMO

Microbiological diagnosis of osteoarticular infections (OI) is crucial for a successful treatment. A prospective multicenter study including 262 synovial fluids with suspicion of acute OI was performed between July 2021 and October of 2022. BioFire Joint Infection Panel multiplex-PCR test was performed and results were compared with conventional cultures of synovial fluid specimens. In total, 136 microorganisms were detected, and fourteen samples were positive for more than one microorganism. In monomicrobial infections (n = 87) agreement with culture was 69%. In 26 samples, the multiplex PCR yield an additional positive result when culture result was negative. It helped in the detection of fastidious microorganisms as K. kingae and N. gonorrhoeae. This multiplex PCR has proven to be a useful technique that can be used for patients with high suspicion of acute OI in a rapid and automated manner.


Assuntos
Artrite Infecciosa , Humanos , Estudos Prospectivos , Artrite Infecciosa/diagnóstico , Artrite Infecciosa/microbiologia , Reação em Cadeia da Polimerase Multiplex/métodos
7.
Infection ; 2023 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-37898587

RESUMO

PURPOSE: We aimed to assess IgG antibodies against the SARS-CoV-2 spike protein (anti-SARS-CoV-2 S IgG) in vaccinated mothers and their infants at delivery and 2-3 months of age. METHODS: We conducted a prospective study on mothers who received at least one dose of the COVID-19 vaccine (Pfizer-BNT162b2, Moderna mRNA-1273, or Oxford-AstraZeneca ChAdOx1-S) during pregnancy and on their infants. The baseline was at the time of delivery (n = 93), and the end of follow-up was 2 to 3 months post-partum (n = 53). Serum anti-SARS-CoV-2 S IgG titers and ACE2 binding inhibition levels were quantified by immunoassays. RESULTS: Mothers and infants had high anti-SARS-CoV-2 S IgG titers against the B.1 lineage at birth. However, while antibody titers were maintained at 2-3 months post-partum in mothers, they decreased significantly in infants (p < 0.001). Positive and significant correlations were found between anti-SARS-CoV-2 S IgG titers and ACE2-binding inhibition levels in mothers and infants at birth and 2-3 months post-partum (r > 0.8, p < 0.001). Anti-S antibodies were also quantified for the Omicron variant at 2-3 months post-partum. The antibody titers against Omicron were significantly lower in mothers and infants than those against B.1 (p < 0.001). Again, a positive correlation was observed for Omicron between IgG titers and ACE2-binding inhibition both in mothers (r = 0.818, p < 0.001) and infants (r = 0.386, p < 0.005). Previous SARS-CoV-2 infection and COVID-19 vaccination near delivery positively impacted anti-SARS-CoV-2 S IgG levels. CONCLUSIONS: COVID-19 mRNA vaccines induce high anti-SARS-CoV-2 S titers in pregnant women, which can inhibit the binding of ACE2 to protein S and are efficiently transferred to the fetus. However, there was a rapid decrease in antibody levels at 2 to 3 months post-partum, particularly in infants.

8.
Birth ; 50(2): 418-427, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-35802776

RESUMO

INTRODUCTION: Pregnant women are vulnerable to severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. Neutralizing antibodies against the SARS-CoV-2 spike (S) protein protect from severe disease. This study analyzes the antibody titers to SARS-CoV-2 S protein in pregnant women and their newborns at delivery, and six months later. METHODS: We conducted a prospective study on pregnant women with confirmed SARS-CoV-2 infection and newborns. Antibody (IgG, IgM, and IgA) titers were determined using immunoassays in serum and milk samples. An angiotensin-converting enzyme 2 (ACE2) receptor-binding inhibition assay to the S protein was performed on the same serum and milk samples. RESULTS: At birth, antibodies to SARS-CoV-2 spike protein were detected in 81.9% of mothers' sera, 78.9% of cord blood samples, and 63.2% of milk samples. Symptomatic women had higher antibody titers (IgG, IgM, and IgA) than the asymptomatic ones (P < 0.05). At six months postpartum, IgG levels decreased drastically in children's serum (P < 0.001) but remained high in mothers' serum. Antibody titers correlated positively with its capacity to inhibit the ACE2-spike protein interaction at baseline in maternal sera (R2  = 0.203; P < 0.001), cord sera (R2  = 0.378; P < 0.001), and milk (R2  = 0.564; P < 0.001), and at six months in maternal sera (R2  = 0.600; P < 0.001). CONCLUSIONS: High antibody levels against SARS-CoV-2 spike protein were found in most pregnant women. Due to the efficient transfer of IgG to cord blood and high IgA titers in breast milk, neonates may be passively immunized to SARS-CoV-2 infection. Our findings could guide newborn management and maternal vaccination policies.


Assuntos
COVID-19 , Complicações Infecciosas na Gravidez , Recém-Nascido , Gravidez , Feminino , Criança , Humanos , Mães , Glicoproteína da Espícula de Coronavírus , Enzima de Conversão de Angiotensina 2 , Estudos Prospectivos , SARS-CoV-2 , Imunoglobulina A , Imunoglobulina G , Imunoglobulina M
9.
Molecules ; 28(8)2023 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-37110561

RESUMO

Mixed oxides with perovskite-type structure (ABO3) are promising catalysts for atmospheric pollution control due to their interesting and tunable physicochemical properties. In this work, two series of BaxMnO3 and BaxFeO3 (x = 1 and 0.7) catalysts were synthesized using the sol-gel method adapted to aqueous medium. The samples were characterized by µ-XRF, XRD, FT-IR, XPS, H2-TPR, and O2-TPD. The catalytic activity for CO and GDI soot oxidation was determined by temperature-programmed reaction experiments (CO-TPR and soot-TPR, respectively). The results reveal that a decrease in the Ba content improved the catalytic performance of both catalysts, as B0.7M-E is more active than BM-E for CO oxidation, and B0.7F-E presents higher activity than BF for soot conversion in simulated GDI engine exhaust conditions. Manganese-based perovskites (BM-E and B0.7M-E) achieve better catalytic performance than iron-based perovskite (BF) for CO oxidation reaction due to the higher generation of actives sites.

10.
Molecules ; 28(12)2023 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-37375284

RESUMO

This work evaluates the effect on the adsorption and desorption kinetics of propene and toluene (used as probe molecules for vehicle cold-start emissions) of the isomorph framework substitution of Zr, W, and V on commercial ZSM-5 and beta zeolites. TG-DTA and XRD characterization data indicated that: (i) Zr does not modify the crystalline structure of the parent zeolites, (ii) W develops a new crystalline phase, and (iii) V causes the breakdown of the zeolite structure during the aging step. The CO2 and N2 adsorption data revealed that the substituted zeolites present a narrower microporosity than pristine zeolites. As a consequence of all these modifications, the modified zeolites feature different adsorption capacity and kinetics of HCs, so, different hydrocarbon trapping ability than pristine zeolites. However, a clear correlation is not observed between the changes in the porosity/acidity of zeolites and the adsorption capacity and kinetics, which depends on: (i) the zeolite (ZSM-5 or BEA), (ii) the hydrocarbon (toluene or propene), and (iii) the cation to be inserted (Zr, W, or V).

11.
J Infect Dis ; 225(6): 977-982, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34910814

RESUMO

Mucosal immune response in the upper respiratory tract is crucial for initial control of viral replication, clearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and progression of coronavirus disease 2019 (COVID-19). We analyzed SARS-CoV-2 RNA load and expression of selected immune genes in the upper respiratory tract (nasopharynx) of 255 SARS-CoV-2-infected patients and evaluated their association with severe COVID-19. SARS-CoV-2 replication in nasopharyngeal mucosa induces expression of several innate immune genes. High SARS-CoV-2 viral load and low CCL5 expression levels were associated with intensive care unit admission or death, although CCL5 was the best predictor of COVID-19 severity.


Assuntos
COVID-19 , Quimiocina CCL5/genética , Nasofaringe/virologia , SARS-CoV-2 , COVID-19/diagnóstico , COVID-19/mortalidade , Quimiocina CCL5/metabolismo , Humanos , Unidades de Terapia Intensiva , RNA Viral/genética , Índice de Gravidade de Doença , Carga Viral
12.
J Intern Med ; 291(2): 232-240, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34611927

RESUMO

BACKGROUND: Anti-SARS-CoV-2 S antibodies prevent viral replication. Critically ill COVID-19 patients show viral material in plasma, associated with a dysregulated host response. If these antibodies influence survival and viral dissemination in ICU-COVID patients is unknown. PATIENTS/METHODS: We studied the impact of anti-SARS-CoV-2 S antibodies levels on survival, viral RNA-load in plasma, and N-antigenaemia in 92 COVID-19 patients over ICU admission. RESULTS: Frequency of N-antigenaemia was >2.5-fold higher in absence of antibodies. Antibodies correlated inversely with viral RNA-load in plasma, representing a protective factor against mortality (adjusted HR [CI 95%], p): (S IgM [AUC ≥ 60]: 0.44 [0.22; 0.88], 0.020); (S IgG [AUC ≥ 237]: 0.31 [0.16; 0.61], <0.001). Viral RNA-load in plasma and N-antigenaemia predicted increased mortality: (N1-viral load [≥2.156 copies/ml]: 2.25 [1.16; 4.36], 0.016); (N-antigenaemia: 2.45 [1.27; 4.69], 0.007). CONCLUSIONS: Low anti-SARS-CoV-2 S antibody levels predict mortality in critical COVID-19. Our findings support that these antibodies contribute to prevent systemic dissemination of SARS-CoV-2.


Assuntos
Anticorpos Antivirais/sangue , Antígenos Virais/sangue , COVID-19 , COVID-19/imunologia , COVID-19/mortalidade , Estado Terminal , Humanos , RNA Viral/sangue , SARS-CoV-2
13.
Alcohol Clin Exp Res ; 46(10): 1808-1818, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36016474

RESUMO

BACKGROUND: Prenatal alcohol exposure (PAE) is associated with brain alterations and neurocognitive deficits, but relationships between brain alterations and neurocognitive deficits remain unclear. METHODS: Diffusion tensor imaging (DTI) data were obtained from 31 participants with PAE and 31 unexposed controls aged 7-15 years. Mean diffusivity (MD) and fractional anisotropy (FA) were derived from the genu, body, and splenium of the corpus callosum (CC), bilateral cingulum, and inferior and superior longitudinal fasciculus (ILF, SLF). Participants completed language subtests from the NEPSY-II. Executive functioning was measured using the Behavior Rating Inventory of Executive Functioning (BRIEF-PR) and verbal learning was assessed using the California Verbal Learning Test-Children's Version (CVLT-C) only in children with PAE. Group differences in diffusion metrics and cognitive scores were tested. Principal component analysis was used to reduce redundancy in cognitive and behavior variables; associations between components and brain measures were then assessed. RESULTS: Children with PAE had lower MD in the right SLF compared with unexposed controls. FA was positively related to age in 6 of 9 tracts and MD negatively related to age in all tracts; there were no significant age-by-group interactions. Participants with PAE scored lower than unexposed peers on the NEPSY-II Comprehension of Instructions and Phonological Processing and above population norms (indicating worse performance) on the BRIEF-PR. Children with PAE had a negative association between a principal component closely associated with Speeded Naming and FA in the left SLF (PAE: p = 0.002) and left ILF (PAE: p = 0.002); unexposed controls showed no significant associations. CONCLUSION: We found widespread cognitive difficulties in children with PAE, but relatively limited differences in brain metrics and associations with age. Different brain-cognitive relationships were found in children with PAE compared with controls. Overall, the results provide additional evidence that PAE may lead to cognitive difficulties and disrupt typical brain-function relationships.


Assuntos
Efeitos Tardios da Exposição Pré-Natal , Substância Branca , Humanos , Adolescente , Feminino , Gravidez , Substância Branca/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Efeitos Tardios da Exposição Pré-Natal/diagnóstico por imagem , Anisotropia , Imagem de Difusão por Ressonância Magnética , Encéfalo
14.
J Fish Biol ; 100(1): 203-217, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34714550

RESUMO

Mature albacore tuna (Thunnus alalunga) are expected to have high energy requirements at the time of breeding. However, there are no descriptions of the diet of albacore in the Mediterranean Sea that can help us to understand if such requirements can be obtained from feeding during reproduction. In this study, we analysed the stomach contents of reproductively active albacore captured from 2010 to 2015 in the oligotrophic waters of the western Mediterranean Sea, one of their main spawning grounds. Estimates of stomach fullness revealed intense feeding activity, and prey composition indicated important consumption of mesopelagic fish, including barracudinas, myctophids and small pelagic crustaceans. Plastic debris occurred in 25%-53% of the stomachs sampled across all years. Prey composition was not different between males and females. However, females fed at higher rates and had higher hepatosomatic index values than males, suggesting that increased feeding could contribute to meet their higher energy demand associated with offspring production. We observed a diet shift from small crustaceans to fish prey along fish size. During the spawning period, albacore showed a specialist feeding behaviour by preying on aggregations of vertically migrating myctophids and small crustaceans, probably when they were near the surface. This study provides information and biological data to support ecosystem modelling and to increase the understanding of albacore ecology.


Assuntos
Ecossistema , Atum , Animais , Dieta , Comportamento Alimentar , Feminino , Masculino , Mar Mediterrâneo
15.
Int J Mol Sci ; 23(2)2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35055077

RESUMO

Whilst avoidance of chemical modifications of DNA bases is essential to maintain genome stability, during evolution eukaryotic cells have evolved a chemically reversible modification of the cytosine base. These dynamic methylation and demethylation reactions on carbon-5 of cytosine regulate several cellular and developmental processes such as embryonic stem cell pluripotency, cell identity, differentiation or tumourgenesis. Whereas these physiological processes are well characterized, very little is known about the toxicity of these cytosine analogues when they incorporate during replication. Here, we report a role of the base excision repair factor XRCC1 in protecting replication fork upon incorporation of 5-hydroxymethyl-2'-deoxycytosine (5hmC) and its deamination product 5-hydroxymethyl-2'-deoxyuridine (5hmU) during DNA synthesis. In the absence of XRCC1, 5hmC exposure leads to increased genomic instability, replication fork impairment and cell lethality. Moreover, the 5hmC deamination product 5hmU recapitulated the genomic instability phenotypes observed by 5hmC exposure, suggesting that 5hmU accounts for the observed by 5hmC exposure. Remarkably, 5hmC-dependent genomic instability and replication fork impairment seen in Xrcc1-/- cells were exacerbated by the trapping of Parp1 on chromatin, indicating that XRCC1 maintains replication fork stability during processing of 5hmC and 5hmU by the base excision repair pathway. Our findings uncover natural epigenetic DNA bases 5hmC and 5hmU as genotoxic nucleosides that threaten replication dynamics and genome integrity in the absence of XRCC1.


Assuntos
Desmetilação do DNA , Replicação do DNA , Desoxicitidina/análogos & derivados , Timidina/análogos & derivados , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , 5-Metilcitosina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Dano ao DNA , Replicação do DNA/efeitos dos fármacos , Epigênese Genética , Instabilidade Genômica , Humanos , Origem de Replicação , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo
16.
Clin Gastroenterol Hepatol ; 18(1): 249-251.e1, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30880275

RESUMO

Eosinophilic esophagitis (EoE), when left untreated, may progress from an inflammatory to a fibrostenotic phenotype. Inflammation generally recurs after treatment withdrawal. Thus, long-term treatment has been recommended. Here, we describe a cohort of children with EoE who achieved clinical and histologic remission with elimination diets, and maintained sustained untreated remission (SUR) despite re-introduction of all eliminated food allergens.


Assuntos
Alérgenos/efeitos adversos , Esofagite Eosinofílica/dietoterapia , Hipersensibilidade Alimentar/dietoterapia , Alimentos/efeitos adversos , Suspensão de Tratamento , Criança , Esofagite Eosinofílica/etiologia , Hipersensibilidade Alimentar/complicações , Humanos , Indução de Remissão
17.
J Pediatr Gastroenterol Nutr ; 71(4): 476-483, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32541200

RESUMO

OBJECTIVES: The aim of the study was to assess clinical presentation, endoscopic findings, antibiotic susceptibility and treatment success of Helicobacter pylori (H. pylori) infected pediatric patients. METHODS: Between 2013 and 2016, 23 pediatric hospitals from 17 countries prospectively submitted data on consecutive H. pylori-infected (culture positive) patients to the EuroPedHP-Registry. RESULTS: Of 1333 patients recruited (55.1% girls, median age 12.6 years), 1168 (87.6%) were therapy naïve (group A) and 165 (12.4%) had failed treatment (group B). Patients resided in North/Western (29.6%), Southern (34.1%) and Eastern Europe (23.0%), or Israel/Turkey (13.4%). Main indications for endoscopy were abdominal pain or dyspepsia (81.2%, 1078/1328). Antral nodularity was reported in 77.8% (1031/1326) of patients, gastric or duodenal ulcers and erosions in 5.1% and 12.8%, respectively. Primary resistance to clarithromycin (CLA) and metronidazole (MET) occurred in 25% and 21%, respectively, and increased after failed therapy. Bacterial strains were fully susceptible in 60.5% of group A, but in only 27.4% of group B. Primary CLA resistance was higher in Southern and Eastern Europe (adjusted odds ratio [ORadj] = 3.44, 95% confidence interval [CI] 2.22-5.32, P < 0.001 and 2.62, 95% CI: 1.63-4.22, P < 0.001, respectively) compared with Northern/Western Europe. Children born outside Europe showed higher primary MET resistance (ORadj = 3.81, 95% CI: 2.25-6.45, P < 0.001). Treatment success in group A reached only 79.8% (568/712) with 7 to 14 days triple therapy tailored to antibiotic susceptibility. CONCLUSIONS: Peptic ulcers are rare in dyspeptic H. pylori-infected children. Primary resistance to CLA and MET is markedly dependent on geographical regions of birth and residence. The ongoing survey will show whether implementation of the updated ESPGHAN/NASPGHAN guidelines will improve the eradication success.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Criança , Claritromicina/uso terapêutico , Quimioterapia Combinada , Europa (Continente) , Feminino , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/epidemiologia , Humanos , Israel/epidemiologia , Masculino , Metronidazol/uso terapêutico , Sistema de Registros , Turquia
18.
Cultur Divers Ethnic Minor Psychol ; 25(3): 379-387, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30372093

RESUMO

OBJECTIVES: Previous research has documented that Latinos/as value the cultural script Simpatía, a tendency to be kind, polite, and focus on others. No previous study has been able to capture the behavioral markers of Simpatía in a naturalistic environment. METHOD: Behavioral cross-sectional audio data were collected on the daily interactions between Latina and White European mothers with their partners and other adults using a digital audio recorder across 4 days. A mixed-methods approach was used to analyze the data. RESULTS: Latinas exhibited increased behavioral Simpatía when talking to other adults compared to White European counterparts. Additionally, Latina mothers chose as a main character of their conversations other people rather than themselves. Conversely, White European mothers chose themselves as a main character of their conversations instead of other people. CONCLUSIONS: These results show that core features of Simpatía (kindness and focus on others) can be found at the behavioral level in the environment that Latina mothers face on a daily basis. Implications for the cultural self and future research are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Cultura , Ego , Hispânico ou Latino/psicologia , Relações Interpessoais , Mães/psicologia , Comportamento Social , Adulto , Estudos Transversais , Feminino , Hispânico ou Latino/estatística & dados numéricos , Humanos , Mães/estatística & dados numéricos , População Branca/psicologia , População Branca/estatística & dados numéricos , Adulto Jovem
19.
BMC Psychiatry ; 16: 94, 2016 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-27053286

RESUMO

BACKGROUND: Sadness and anhedonia (loss of interest in activities) are central symptoms of major depression. However, not all people with these symptoms meet diagnostic criteria for major depression. We aimed to assess the importance of suicidality in the outcomes for primary care patients who present with sadness and anhedonia. METHOD: Cohort study of 2,599 unselected primary care attenders in six European countries followed up at 6 and 12 months. RESULTS: 1) In patients with sadness and/or anhedonia who were not depressed at entry to the study, suicide plans (OR = 3.05; 95 % CI = 1.50-6.24; p = 0.0022) and suicide attempts (OR = 9.08; 95 % CI = 2.57-32.03; p = 0.0006) were significant predictors of developing new onset depression at 6 or 12 months. 2) In patients with sadness and/or anhedonia who met CIDI criteria for major depression at entry, suicidal ideation (OR = 2.93; 95 % CI = 1.70-5.07; p = 0.0001), suicide plans (OR = 3.70; 95 % CI = 2.08-6.57; p < 0.0001), and suicide attempts (OR = 3.33; 95 % CI = 1.47-7.54; p = 0.0040) were significant predictors of persistent depression at 6 or 12 months. CONCLUSIONS: Three questions on suicidality could help primary care professionals to assess such patients more closely without necessarily establishing whether they meet criteria for major depression.


Assuntos
Anedonia , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/psicologia , Atenção Primária à Saúde , Suicídio/psicologia , Suicídio/estatística & dados numéricos , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
20.
BMC Cancer ; 15: 327, 2015 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-25925749

RESUMO

BACKGROUND: The optimal sequence of chemotherapeutic agents is not firmly established for the treatment of metastatic colorectal cancer (mCRC). This phase II multi-centre study investigated the efficacy and tolerability of a standard capecitabine plus irinotecan (XELIRI) regimen with bevacizumab in previously untreated patients with mCRC. METHODS: Patients received intravenous irinotecan 175 mg/m(2) on day 1 and oral capecitabine 1000 mg/m(2) (800 mg/m(2) for patients >65 years of age) twice daily on days 2-8, followed by a 1-week rest, and bevacizumab 5 mg/kg as an intravenous infusion on day 1 every 2 weeks. RESULTS: Seventy-seven patients were included in the intention-to-treat and safety populations. Progression-free survival at 9 months was 61%. The overall response and disease control rates were 51% and 84%, respectively. Median progression-free and overall survival times were 11.9 and 24.8 months, respectively. 48 patients (62%) had at least one grade 3/4 adverse event, the most common being asthenia, diarrhoea and neutropenia. Quality of life varied little over the study period with mean visual analogue scale general health scores ranging from 71 to 76 over cycles 1-11. CONCLUSION: Our study found irinotecan and capecitabine administered fortnightly with bevacizumab in patients with mCRC to be an effective and tolerable regimen. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT00875771. Trial registration date: 04/02/2009.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Camptotecina/análogos & derivados , Capecitabina/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Camptotecina/administração & dosagem , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Resultado do Tratamento
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