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Ensuring balanced distribution of chromosomes in gametes, meiotic recombination is essential for fertility in most sexually reproducing organisms. The repair of the programmed DNA double strand breaks that initiate meiotic recombination requires two DNA strand-exchange proteins, RAD51 and DMC1, to search for and invade an intact DNA molecule on the homologous chromosome. DMC1 is meiosis-specific, while RAD51 is essential for both mitotic and meiotic homologous recombination. DMC1 is the main catalytically active strand-exchange protein during meiosis, while this activity of RAD51 is downregulated. RAD51 is however an essential cofactor in meiosis, supporting the function of DMC1. This work presents a study of the mechanism(s) involved in this and our results point to DMC1 being, at least, a major actor in the meiotic suppression of the RAD51 strand-exchange activity in plants. Ectopic expression of DMC1 in somatic cells renders plants hypersensitive to DNA damage and specifically impairs RAD51-dependent homologous recombination. DNA damage-induced RAD51 focus formation in somatic cells is not however suppressed by ectopic expression of DMC1. Interestingly, DMC1 also forms damage-induced foci in these cells and we further show that the ability of DMC1 to prevent RAD51-mediated recombination is associated with local assembly of DMC1 at DNA breaks. In support of our hypothesis, expression of a dominant negative DMC1 protein in meiosis impairs RAD51-mediated DSB repair. We propose that DMC1 acts to prevent RAD51-mediated recombination in Arabidopsis and that this down-regulation requires local assembly of DMC1 nucleofilaments.
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Arabidopsis , Proteínas de Saccharomyces cerevisiae , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Reparo do DNA , Recombinação Homóloga/genética , Meiose/genética , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Proteínas de Saccharomyces cerevisiae/genéticaRESUMO
An essential component of the homologous recombination machinery in eukaryotes, the RAD54 protein is a member of the SWI2/SNF2 family of helicases with dsDNA-dependent ATPase, DNA translocase, DNA supercoiling and chromatin remodelling activities. It is a motor protein that translocates along dsDNA and performs multiple functions in homologous recombination. In particular, RAD54 is an essential cofactor for regulating RAD51 activity. It stabilizes the RAD51 nucleofilament, remodels nucleosomes, and stimulates the homology search and strand invasion activities of RAD51. Accordingly, deletion of RAD54 has dramatic consequences on DNA damage repair in mitotic cells. In contrast, its role in meiotic recombination is less clear. RAD54 is essential for meiotic recombination in Drosophila and C. elegans, but plays minor roles in yeast and mammals. We present here characterization of the roles of RAD54 in meiotic recombination in the model plant Arabidopsis thaliana. Absence of RAD54 has no detectable effect on meiotic recombination in otherwise wild-type plants but RAD54 becomes essential for meiotic DSB repair in absence of DMC1. In Arabidopsis, dmc1 mutants have an achiasmate meiosis, in which RAD51 repairs meiotic DSBs. Lack of RAD54 leads to meiotic chromosomal fragmentation in absence of DMC1. The action of RAD54 in meiotic RAD51 activity is thus mainly downstream of the role of RAD51 in supporting the activity of DMC1. Equivalent analyses show no effect on meiosis of combining dmc1 with the mutants of the RAD51-mediators RAD51B, RAD51D and XRCC2. RAD54 is thus required for repair of meiotic DSBs by RAD51 and the absence of meiotic phenotype in rad54 plants is a consequence of RAD51 playing a RAD54-independent supporting role to DMC1 in meiotic recombination.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/citologia , Arabidopsis/metabolismo , Quebras de DNA de Cadeia Dupla , DNA Helicases/metabolismo , Meiose , Rad51 Recombinase/metabolismo , Reparo de DNA por Recombinação , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , DNA Helicases/deficiência , DNA Helicases/genética , Proteínas de Ligação a DNA , Genes Essenciais , Meiose/genética , Mutação , Rad51 Recombinase/genética , Recombinases Rec A/genética , Recombinases Rec A/metabolismo , Proteínas RepressorasRESUMO
AIM: To explore the perceptions and experiences of midwives caring for couples who experience a stillbirth. DESIGN: Qualitative study based on Gadamer's hermeneutic phenomenology. METHODS: This study was conducted with midwives (n = 18) at the birth unit of a third-level public hospital in Jaén (Spain) in 2023. Personal semi-structured interviews were recorded in audio for later transcription by two researchers following steps described by Fleming. RESULTS: Two themes were identified as important aspects of the practise of midwives in a situation of the birth of a stillborn child: (1) the importance of each action of the midwife, and (2) the availability of resources determines the care provided. CONCLUSIONS: Having a stillbirth is a very complex experience, in which the psychological support and human and material resources involved are the basic tool for the care of these families. Acknowledging limitations of the available resources, the assistance and care provided by midwives are in line with the clinical practice guidelines, which can have an emotional impact on them. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The care to be provided in stillbirth requires appropriate human and material resources for these families. Midwifery and nursing professionals are in a unique position for acting in cases of families with a stillbirth, updated protocols and, in general, the coordination of the different agents involved within the healthcare system. WHAT PROBLEM DID THE STUDY ADDRESS?: The midwives´ experiences in cases which end with the delivery of a stillborn. WHAT WERE THE MAIN FINDINGS?: Each action of the midwife is as important as the availability of resources to offer the most appropriate care. WHERE AND ON WHOM WILL THE RESEARCH HAVE AN IMPACT?: In each woman who receives the care of a midwife who attends the birth of a stillborn. REPORTING METHOD: COREQ checklist. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution occurred for this study as this research focused on exploring staffs' perspectives from the specific viewpoint of their personal experience.
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INTRODUCTION: The primary objective of this article was to determine if any histological alterations occur in the round window (RW) and adjacent anatomical structures of an animal model with normal hearing when a cochlear implant (CI) electrode array is inserted. Furthermore, this article aims to relate these histological alterations to the auditory changes generated. METHODS: Cochlear implantation was performed, following the principles of minimally traumatic surgery (MTS), in 15 ears of nonhuman primates (Macaca fascicularis) (Mf) with normal hearing. Auditory brainstem-evoked potentials (ABR) using clicks and tones were used prior to surgery and during a 6-month follow-up period. Histological evaluation was carried out, analyzing the position of the electrode array with respect to the round window membrane (RWM), its percentage of occupation and integrity, the presence of intracochlear damage, and the tissue reaction provoked, the latter of which was quantified in the temporal bones. RESULTS: Surgery was performed on all 15 ears without relevant incidences. Regarding histology, the electrode array in the RW of all ears presented a lateral position with respect to the modiolus. No lesions affecting the integrity of the RW were observed. The mean value of the array's occupation in the RW was 25%. Tissue reaction, in the form of fibrosis, was observed in all ears and more intensely in the trans-RWM and post-RWM areas. In all ears, the electrodes remained on the scala tympani. No profound hearing impairment was recorded in any ear, being the mean loss of 25.4 dB when comparing presurgical thresholds with those collected 6 months after implantation in ABR click and 24.4 dB in ABR tone burst. CONCLUSIONS: The animal model and Hybrid L-14 (HL14) electrode array were optimal for implementing a surgical technique similar to that routinely performed on humans. Mild histological alterations were observed in the round window membrane and adjacent anatomical structures from the insertion of a cochlear implant electrode array. Following the minimally invasive technique, levels of hearing preservation were satisfactory, reaching a pre-post difference of 25.4 dB in the ABR click and 24.4 dB for a high-frequency tone burst. Complete hearing impairment was not observed in either ear. Correlation between the severity of histological alterations and hearing changes recorded in the ABR studies was observed.
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BACKGROUND: Previous works have observed an increase of depression and other psychological disorders on nursing home residents as a consequence of coronavirus disease 2019 (COVID-19) lockdown; however, there are few studies that have performed a comprehensive evaluation of all people involved in nursing homes environment. The objective of the work was to analyse the impact of lockdown on psychosocial factors of nursing home residents, relatives and clinical staff and how these variables have influenced residents' survival. METHODS: A prospective study was designed. Evaluations were performed at three different times: a) at the beginning of Spanish confinement, in March 2020; b) just before the second wave of the pandemic, with relaxation of security measures but in lockdown, and c) in January-February 2021, at the end of the second wave, when visits were already allowed. The study was conducted on three different nursing homes. Three hundred and one residents, 119 clinical staff and 51 relatives took part in the study. Anxiety and depression were evaluated in all participants. A scale on the meaning of suffering was also performed. In addition, burnout status was also determined in the clinical staff. RESULTS: All participants showed lower depression during lockdown, while at the beginning and at the end of the confinement, these values were significantly increased. In residents, these changes were dependent of cognitive status (p = 0.012). Anxiety was significantly higher in residents. The evolution of anxiety was similar than with depression, with lower values during confinement, although clinical staff showed higher anxiety levels at the beginning. The feeling of suffering was significantly lower in the clinical staff than in resident and relative groups. Residents' survival was dependent of cognitive status (p = 0.018) and voluntary confinement (p < 0.001). CONCLUSIONS: During the first COVID-19 lockdown, psychological wellbeing of residents cared in nursing homes, their relatives and staff did not seem to be seriously affected. Previous mental health in relatives and staff together with a resilient approach to the adversity might partly be protecting factors. The lack of consequences on residents' anxiety, depression and perception of social support may reflect the special attention and care they received. Finally, as in the current study only data of the first two COVID-19 waves were analysed, its findings might be partly generalized to all the pandemic.
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COVID-19 , Transtornos Mentais , Humanos , COVID-19/epidemiologia , Estudos Prospectivos , Controle de Doenças Transmissíveis , Casas de SaúdeRESUMO
Neuropsychiatric symptoms (NPS) are common in Alzheimer disease (AD) patients, especially in women. Stress and stress-vulnerability factors (eg, poor social support) may trigger NPS. This cross-sectional study (n=196) aimed to examine the moderating effect of sex on the relationships between both perceived social support and salivary cortisol levels and NPS of AD patients. Only in women, greater cortisol levels were associated with higher scores in Neuropsychiatric Inventory mood, agitation, and frontal subscales whereas higher Psychosocial Support Questionnaire scores were related to lower scores in Neuropsychiatric Inventory mood and psychosis subscales. Given the relevance that sex differences might have on the design of preventive strategies, present findings should be confirmed in longitudinal studies.
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Doença de Alzheimer , Estudos Transversais , Feminino , Humanos , Vida Independente , Masculino , Testes Neuropsicológicos , Apoio Social , EspanhaRESUMO
BACKGROUND: The bispectral index (BIS) is an anaesthesia monitoring technique able to assess the level of central nervous system depression in humans and various animal species. In birds, it has been validated in chickens undergoing isoflurane anaesthesia. The aim of this study was to evaluate in an avian species the influence of isoflurane and sevoflurane on BIS, each at different minimum anaesthetic concentrations (MAC) multiples, alone or combined with butorphanol or medetomidine. Ten chickens (5 males and 5 females) underwent general anaesthesia with isoflurane or sevoflurane alone, and combined with either intramuscular administration of butorphanol (1 mg/kg) or medetomidine (0.1 mg/kg), in a prospective and cross-over study (i.e., 6 treatments per animal). BIS measurements were compared to heart rate (HR), non-invasive blood pressure (NIBP) and to a visual analogue scale (VAS) of anaesthesia depth. RESULTS: HR was significantly increased, and both NIBP and VAS were significantly reduced, with higher gas concentrations. NIBP (but not HR or VAS) was additionally affected by the type of gas, being lower at higher concentrations of sevoflurane. Butorphanol had no additional effect, but medetomidine led to differences in HR, NIBP, and in particular a reduction in VAS. With respect to deeper level of hypnosis at higher concentrations and the absence of difference between gases, BIS measurements correlated with all other measures (except with HR, where no significant relationship was found) The difference in BIS before (BISpre) and after stimulation (BISpost) did not remain constant, but increased with increasing MAC multiples, indicating that the BISpost is not suppressed proportionately to the suppression of the BISpre values due to gas concentration. Furthermore, neither butorphanol nor medetomidine affected the BIS. CONCLUSIONS: The difference of degree of central nervous system depression monitored by BIS compared with neuromuscular reflexes monitored by VAS, indicate that BIS records a level of anaesthetic depth different from the one deducted from VAS monitoring alone. BIS provided complementary information such as that medetomidine suppressed spinal reflexes without deepening the hypnotic state. As a consequence, it is concluded that BIS improves the assessment of the level of hypnosis in chickens, improving anaesthesia monitoring and anaesthesia quality in this species.
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Butorfanol/farmacologia , Galinhas , Monitores de Consciência/veterinária , Isoflurano/farmacologia , Medetomidina/farmacologia , Sevoflurano/farmacologia , Anestésicos Combinados/farmacologia , Animais , Estudos Cross-Over , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Estudos ProspectivosRESUMO
Automatic aesthetic quality assessment is a computer vision problem in which we quantify the attractiveness or the appealingness of a photograph. This is especially useful in social networks, where the amount of images generated each day requires automation for processing. This work presents Aesthetic Selector, an application able to identify images of high aesthetic quality, showing also relevant information about the decisions and providing the use of the most appropriate filters to enhance a given image. We then analyzed the main proposals in the aesthetic quality field, describing their strengths and weaknesses in order to determine the filters to be included in the application Aesthetic Selector. This proposed application was tested, giving good results, in three different scenarios: image selection, image finding, and filter selection. Besides, we carried out a study of distinct visualization tools to better understand the models' behavior. These techniques also allow detecting which areas are more relevant within the images when models perform classification. The application also includes this interpretability module. Aesthetic Selector is an innovative and original program, because in the field of aesthetic quality in photography, there are no applications that identify high-quality images and also because it offers the capability of showing information about which parts of the image have affected this decision.
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Homologous recombination is a key process for maintaining genome integrity and diversity. In eukaryotes, the nucleosome structure of chromatin inhibits the progression of homologous recombination. The DNA repair and recombination protein RAD54 alters the chromatin structure via nucleosome sliding to enable homology searches. For homologous recombination to progress, appropriate recruitment and dissociation of RAD54 is required at the site of homologous recombination; however, little is known about the mechanism regulating RAD54 dynamics in chromatin. Here, we reveal that the histone demethylase LYSINE-SPECIFIC DEMETHYLASE1-LIKE 1 (LDL1) regulates the dissociation of RAD54 at damaged sites during homologous recombination repair in the somatic cells of Arabidopsis (Arabidopsis thaliana). Depletion of LDL1 leads to an overaccumulation of RAD54 at damaged sites with DNA double-strand breaks. Moreover, RAD54 accumulates at damaged sites by recognizing histone H3 Lys 4 di-methylation (H3K4me2); the frequency of the interaction between RAD54 and H3K4me2 increased in the ldl1 mutant with DNA double-strand breaks. We propose that LDL1 removes RAD54 at damaged sites by demethylating H3K4me2 during homologous recombination repair and thereby maintains genome stability in Arabidopsis.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , DNA Helicases/metabolismo , Histona Desmetilases/metabolismo , Reparo de DNA por Recombinação , Arabidopsis/genética , Histonas/metabolismoRESUMO
OBJECTIVES: This study aimed to explore the views and experiences of a group of Spanish patients suffering from new daily persistent headache (NDPH). METHODS: A qualitative descriptive study was conducted with patients diagnosed with NDPH. Purposeful sampling was performed among patients attending a specialized Headache Unit at 2 university hospitals between February 2017 and December 2018. In total, 18 patients (11 women, 7 men; mean age 45.3, standard deviation 10.6) with a median duration of illness of 70 months (interquartile range, 24-219) were recruited to this study. Data were collected through in-depth interviews, researchers' field notes and patients' drawings. Thematic analysis was used to identify emerging themes. RESULTS: Three main themes were identified: (1) the origin of the illness and seeking answers; (2) characteristics of the pain; and (3) the impact of pain on patients' lives. The patients precisely recalled the time of onset and the trigger of the pain. Pain was constantly present, although it varied in form. At the onset, pain was perceived as a sign of alarm while, over time, it became an invisible illness. The headache commonly had a major impact on everyday life and could cause lifestyle changes. In addition, pain could be emotionally disruptive and could also lead to family estrangement and a search for solitude. CONCLUSIONS: Our results provide insight into how NDPH is experienced, which may be helpful in managing NDPH patients. In our cohort, patients identified precipitating events but sought answers regarding the origin of their illness and their pain. Pain was a continuous sensation that had a major impact on patients' daily lives and emotions.
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Atitude Frente a Saúde , Transtornos da Cefaleia/fisiopatologia , Transtornos da Cefaleia/psicologia , Qualidade de Vida , Adulto , Feminino , Transtornos da Cefaleia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , EspanhaRESUMO
Chiroptical spectroscopic methods serve as a practical tool for the structural characterization of chiral systems based on the interaction with polarized light. The higher sensitivity of these methods, compared with their achiral counterparts, not only enables the determination of absolute configuration and conformational preferences, but also supramolecular interactions may be monitored. In order to expand the applicability of chiroptical systems, the development of functional materials exhibiting intense chiroptical responses is essential. As a proof of principle, we previously constructed chiroptical interfaces via thioacetate-derivatized allenes. Because of the photoisomerization issues associated with allenes, we have recently proposed their replacement by spirobifluorenes to achieve robust chiroptical systems. Thus, we hereby present the design and synthesis of chiral spirobifluorenes bearing thioacetates suitable for suface functionalization.
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Replicative erosion of telomeres is naturally compensated by telomerase and studies in yeast and vertebrates show that homologous recombination can compensate for the absence of telomerase. We show that RAD51 protein, which catalyzes the key strand-invasion step of homologous recombination, is localized at Arabidopsis telomeres in absence of telomerase. Blocking the strand-transfer activity of the RAD51 in telomerase mutant plants results in a strikingly earlier onset of developmental defects, accompanied by increased numbers of end-to-end chromosome fusions. Imposing replication stress through knockout of RNaseH2 increases numbers of chromosome fusions and reduces the survival of these plants deficient for telomerase and homologous recombination. This finding suggests that RAD51-dependent homologous recombination acts as an essential backup to the telomerase for compensation of replicative telomere loss to ensure genome stability. Furthermore, we show that this positive role of RAD51 in telomere stability is dependent on the RTEL1 helicase. We propose that a RAD51 dependent break-induced replication process is activated in cells lacking telomerase activity, with RTEL1 responsible for D-loop dissolution after telomere replication.
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Proteínas de Arabidopsis/fisiologia , Arabidopsis/genética , DNA Helicases/fisiologia , Rad51 Recombinase/fisiologia , Encurtamento do Telômero , Arabidopsis/enzimologia , Proteínas de Arabidopsis/análise , Replicação do DNA , Instabilidade Genômica , Recombinação Homóloga , Mutação , Rad51 Recombinase/análise , Sequências Repetitivas de Ácido Nucleico , Ribonucleases/genética , Processos Estocásticos , Telomerase/genética , Telômero/químicaRESUMO
Skin is being increasingly exposed to artificial blue light due to the extensive use of electronic devices. This, together with recent observations reporting that blue light-also known as high-energy visible light-can exert cytotoxic effects associated with oxidative stress and promote hyperpigmentation, has sparked interest in blue light and its potential harmful effects on skin. The photoprotective properties of new extracts of different botanicals with antioxidant activity are therefore being studied. Deschampsia antarctica (Edafence®, EDA), a natural aqueous extract, has shown keratinocyte and fibroblast cell protection effects against ultraviolet radiation and dioxin toxicity. In this regard, we studied the protective capacity of EDA against the deleterious effects of artificial blue light irradiation in human dermal fibroblasts (HDF) and melanocytes. We analyzed the impact of EDA on viability, cell morphology, oxidative stress, melanogenic signaling pathway activation and hyperpigmentation in HDF and melanocytes subjected to artificial blue light irradiation. Our results show that EDA protects against cell damage caused by artificial blue light, decreasing oxidative stress, melanogenic signaling pathway activation and hyperpigmentation caused by blue light irradiation. All these findings suggest that EDA might help prevent skin damage produced by artificial blue light exposure from screen of electronic devices.
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Luz/efeitos adversos , Extratos Vegetais/farmacologia , Poaceae/química , Substâncias Protetoras/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Pele/efeitos dos fármacos , Dispositivos Eletrônicos Vestíveis/efeitos adversos , Sobrevivência Celular , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/efeitos da radiação , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Estresse Oxidativo , Espécies Reativas de Oxigênio , Pele/citologia , Pele/efeitos da radiação , Envelhecimento da Pele/patologiaRESUMO
Tourism is shaped by a wide range of factors and forces, including exogenous ones that have no direct link with the tourism sector. Natural disasters and unexpected events are prime examples of such determining factors, as they have profound effects on individuals and society, and as a result have the potential to affect tourism flows considerably. Several theoretical arguments exist why natural disasters and unexpected events could influence tourist destination choices. However, empirical research to confirm the nature and extent of impacts of disasters on tourism is lacking. To address this gap, this paper incorporates a dataset on natural and man-made disaster events into a model of international tourism flows to evaluate the effect of different types of disasters on international arrivals at the national level. Findings provide evidence that the occurrence of different types of event change tourist flows to varying degrees. Although in some cases a positive effect is estimated, in general the impacts are negative, resulting in reduced tourist arrivals following an event. Understanding the relationship between disaster events and tourism is helpful for destination managers who make critical decisions in relation to recovery, reconstruction and marketing.
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CONTEXT: One of the main reasons why athletes with a high physical condition suffer from low back pain disease is because they often participate in sports that involve disc compression movements during flexion, lifting loads, or torsion movement. OBJECTIVES: This study aims to examine the effectiveness of the postural treatment of the Mézières method on elite rhythmic gymnastics athletes with low back pain. DESIGN: Double-blind, randomized, controlled trial. SETTING: The sports hall of "Puente Tocinos," Murcia, Spain. PARTICIPANTS: Ninety gymnastics athletes were randomized into 2 parallel groups (intervention: n = 39; control: n = 51), of whom 98.9% were women (women = 89; man = 1). INTERVENTION: The Mézières method postural therapy was implemented. It lasted about 60 minutes in repeated sessions of 2 to 3 meetings per week by counting in overall 60 sessions during a 24-week period. MAIN OUTCOME MEASURES: Visual analog scale of pain, sit and reach flexibility test, Runtastic (pedometer performance android application), Roland-Morris Questionnaire for the physical disability, and the Health Status Questionnaire were used. RESULTS: The univariate analysis of variance and independent sample t test revealed a significant improvement in the intervention group concerning the visual analog scale pain assessment scale (P < .05, ηp2=.625), and, also, the between-groups effect size was high during the 24 sessions of treatment (d > 0.8) compared with the control one. The same situation persists even for Roland-Morris Questionnaire (P < .05, ηp2=.802), physical score (P < .05, ηp2=.613), mental score (P < .05, ηp2=.736), sit and reach flexibility test (P < .05, ηp2=.666), and Runtastic performance (P < .05, ηp2=.790), where the between-groups effect size was high during the 24 sessions of treatment (d > 0.8). CONCLUSION: The Mézières method treatment performed on athletes with low back pain has caused positive effects on all the outcomes analyzed compared with the ones of control group.
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Traumatismos em Atletas/fisiopatologia , Traumatismos em Atletas/terapia , Terapia por Exercício/métodos , Ginástica/lesões , Dor Lombar/fisiopatologia , Dor Lombar/terapia , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Medição da Dor , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND & AIMS: Most hepatitis C virus (HCV)-infected patients failing NS5A inhibitors develop resistance-associated substitutions (RASs). Here we report the use of resistance-guided retreatment of patients who failed prior NS5A inhibitor-containing regimens in the GEHEP-004 cohort. This is the largest direct-acting antiviral (DAA)-resistance cohort study conducted in Spain. We aim to provide indications on how to use resistance information in settings where sofosbuvir/velpatasvir/voxilaprevir may not be available. METHODS: GEHEP-004 is a prospective multicenter cohort enrolling HCV-infected patients treated with interferon (IFN)-free DAA regimens. Prior to retreatment, population-based sequencing of HCV NS3, NS5A and NS5B genes was performed. After receiving a comprehensive resistance interpretation report, the retreatment regimen was chosen and the sustained virological response (SVR) at 12â¯weeks after treatment completion (SVR12) was recorded. RESULTS: A total of 342 patients experiencing virological failure after treatment with sofosbuvir/ledipasvir±ribavirin (54%), sofosbuvir/daclatasvir±ribavirin (23%), or paritaprevir-ritonavir/ombitasvir±dasabuvir±ribavirin (20%) were studied. After a resistance report, 186 patients were retreated. An SVR12 was achieved for 88.1% of the patients who failed after sofosbuvir/ledipasvir±ribavirin, 83.3% of the patients who failed after sofosbuvir/daclatasvir±ribavirin, 93.7% of the patients who failed after paritaprevir-ritonavir+ombitasvir±dasabuvir±ribavirin. CONCLUSIONS: In our study, we show how resistance-guided retreatment in conjunction with an interpreted report allows patients to achieve SVR rates close to 90%. We hypothesize that SVR rates may even be improved if resistance data are discussed between experienced virologists and treating clinicians. We believe that our data may be relevant for countries where the access to new DAA combination regimens is limited. LAY SUMMARY: Hepatitis C infection can be cured with currently available antiviral agents. Only a small proportion of patients experience treatment failure, however, in absolute numbers, a high number of patients may require retreatment. Highly effective combinations of antivirals are also available for retreatment. However, these antivirals might not be available in resource-limited settings. Herein, we show how, by analyzing the cause of resistance, retreatment efficacy with old drugs can get very close to the efficacy of new drug combinations.
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Anilidas/uso terapêutico , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Ciclopropanos/uso terapêutico , Farmacorresistência Viral/genética , Fluorenos/uso terapêutico , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Imidazóis/uso terapêutico , Lactamas Macrocíclicas/uso terapêutico , Prolina/análogos & derivados , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/farmacologia , Quimioterapia Combinada , Feminino , Genótipo , Hepatite C/epidemiologia , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Prolina/uso terapêutico , Estudos Prospectivos , Pirrolidinas , Retratamento , Espanha/epidemiologia , Resposta Viral Sustentada , Valina/análogos & derivados , Proteínas não Estruturais Virais/genéticaRESUMO
Structure-specific endonucleases act to repair potentially toxic structures produced by recombination and DNA replication, ensuring proper segregation of the genetic material to daughter cells during mitosis and meiosis. Arabidopsis thaliana has two putative homologs of the resolvase (structure-specific endonuclease): GEN1/Yen1. Knockout of resolvase genes GEN1 and SEND1, individually or together, has no detectable effect on growth, fertility, or sensitivity to DNA damage. However, combined absence of the endonucleases MUS81 and SEND1 results in severe developmental defects, spontaneous cell death, and genome instability. A similar effect is not seen in mus81 gen1 plants, which develop normally and are fertile. Absence of RAD51 does not rescue mus81 send1, pointing to roles of these proteins in DNA replication rather than DNA break repair. The enrichment of S-phase histone γ-H2AX foci and a striking loss of telomeric DNA in mus81 send1 further support this interpretation. SEND1 has at most a minor role in resolution of the Holliday junction but acts as an essential backup to MUS81 for resolution of toxic replication structures to ensure genome stability and to maintain telomere integrity.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Endonucleases/metabolismo , Resolvases de Junção Holliday/metabolismo , Telômero/metabolismo , Arabidopsis/citologia , Arabidopsis/crescimento & desenvolvimento , Ciclo Celular , Cromossomos de Plantas/genética , Reparo do DNA , Replicação do DNA , DNA Bacteriano/genética , Instabilidade Genômica , Meiose , Mutagênese Insercional/genética , Mutação/genética , Fenótipo , Rad51 Recombinase/metabolismoRESUMO
OBJECTIVE: Dermal fillers are an important tool in the field of aesthetic dermatology. Fillers are relatively noninvasive and easy to use but are not free of secondary complications. The main complications are vascular and are due to either the compression of an artery or the direct introduction of the product into the arterial lumen. The aim of this study is to provide an overview of the vascular territories of the face to avoid many possible complications when using facial fillings. Anatomical localization of the main arterial supply to the face has been described to assess the risk of vascular injury. METHODS: The authors dissected 17 hemifaces of embalmed adult cadavers that had previously been injected, through the common carotid artery, with latex containing a red dye. RESULTS: A topographic distribution was generated by facial regions following a clinical approach from where the facial fillings were placed and related to the pathways of the arteries. Following these criteria, we established 8 topographic regions (I-VIII) that indicate the main vascular problems of each of these regions. Detailed anatomical localizations of the main arteries in these topographic regions of the face and their relationships are described. CONCLUSIONS: The highest index of vascular lesions and especially visual alterations occurred for fillings of the upper third of the face. To prevent and avoid this type of lesion, it is advisable to avoid, as much as possible, treatments with filling materials in the upper third of the face, mainly including the glabellar and nasal region (III) and supraorbital region (VIII).
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Preenchedores Dérmicos/efeitos adversos , Face/irrigação sanguínea , Pele/irrigação sanguínea , Cadáver , Bochecha/irrigação sanguínea , Dissecação , Olho/irrigação sanguínea , Testa/irrigação sanguínea , Humanos , Lábio/irrigação sanguínea , Nariz/irrigação sanguínea , Ritidoplastia/efeitos adversosRESUMO
BACKGROUND: Studies of spinal anesthesia in children are limited to a reduced group of high-risk patients and it remains relatively underused compared with general anesthesia in this age group in most institutions. In our experience, spinal anesthesia appears to be a good alternative to general anesthesia during pyloromyotomy in neonates and infants. AIMS: The purpose of this study was to retrospectively evaluate respiratory morbidity of spinal anesthesia compared to general anesthesia in infants undergoing pyloromyotomy. METHODS: The University Hospital of Salamanca used spinal or general anesthesia on infants undergoing pyloromyotomy between 2003 and 2017. The primary outcome assessed was the prevalence of apnea. The second one was the prevalence of oxygen saturation below 95%. An analysis was performed using t test or Mann-Whitney U test for continuous variables, and Chi-square for categorical variables. Logistic regression was done to account for differences in demographic and clinical covariates. RESULTS: The study sample consisted of 68 infants and neonates undergoing pyloromyotomy (48 with spinal anesthesia and 20 with general anesthesia). There was a significant difference in apneic episodes after surgery between general (number/percentage = 5/20, 25%) and spinal (number/percentage = 0/48, 0%) groups. Absolute risk reduction is 25% (CI 95%: 6%-44%), P < .001. CONCLUSION: Spinal anesthesia in neonates with hypertrophic pyloric stenosis undergoing pyloromyotomy was a viable alternative to general anesthesia, reducing the respiratory morbidity associated with the latter.
Assuntos
Anestesia Geral , Raquianestesia , Estenose Pilórica Hipertrófica/cirurgia , Pré-Escolar , Feminino , Humanos , Masculino , Piloromiotomia , Estudos RetrospectivosRESUMO
Objectives: Chronic stress has shown to have marked effects on learning and memory. A broader understanding of these effects has special interest in the context of Alzheimer's disease (AD). This study aims to analyze the moderating effect of cognitive impairment in the relationships between stress and verbal memory performance by considering biological and psychological measures of stress. Method: The sample consisted of 80 AD patients and 104 healthy controls. Salivary cortisol and state anxiety was measured as stress markers. Memory Alteration test (M@T) and Hopkins verbal learning test (HVLT-R) were used to measure verbal memory. Results: In controls, cortisol level was negatively associated with HVLT-R total, learning and delayed recall scores as well as M@T free recall scores, while in patients, such associations were not significant. In this group, cortisol negative effects were limited to HVLT-R learning and M@T semantic memory scores. In both groups, anxiety was associated with better M@T encoding and free recall scores. Besides, inverted U-shaped relationships were observed between anxiety and HVLT-R total recall and learning scores as well as M@T orientation scores. Conclusion: Cortisol levels and anxiety are differentially associated with memory performance in older adults. In general, the negative relationship between cortisol levels and memory observed in healthy elderly weakens in AD. However, moderate state anxiety levels seem to be associated with a better memory performance in AD patients and in healthy elderly.