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Invasive fungal infections are associated with high mortality rates, and the lack of efficient treatment options emphasizes an urgency to identify underlying disease mechanisms. We report that disseminated Candida albicans infection is facilitated by interleukin-1 receptor antagonist (IL-1Ra) secreted from macrophages in two temporally and spatially distinct waves. Splenic CD169+ macrophages release IL-1Ra into the bloodstream, impeding early neutrophil recruitment. IL-1Ra secreted by monocyte-derived tissue macrophages further impairs pathogen containment. Therapeutic IL-1Ra neutralization restored the functional competence of neutrophils, corrected maladapted hyper-inflammation, and eradicated the otherwise lethal infection. Conversely, augmentation of macrophage-secreted IL-1Ra by type I interferon severely aggravated disease mortality. Our study uncovers how a fundamental immunoregulatory mechanism mediates the high disease susceptibility to invasive candidiasis. Furthermore, interferon-stimulated IL-1Ra secretion may exacerbate fungal dissemination in human patients with secondary candidemia. Macrophage-secreted IL-1Ra should be considered as an additional biomarker and potential therapeutic target in severe systemic candidiasis.
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Proteína Antagonista do Receptor de Interleucina 1 , Sepse , Humanos , Candida albicans , Macrófagos , Receptores de Interleucina-1RESUMO
Interspecies blastocyst complementation enables organ-specific enrichment of xenogenic pluripotent stem cell (PSC) derivatives. Here, we establish a versatile blastocyst complementation platform based on CRISPR-Cas9-mediated zygote genome editing and show enrichment of rat PSC-derivatives in several tissues of gene-edited organogenesis-disabled mice. Besides gaining insights into species evolution, embryogenesis, and human disease, interspecies blastocyst complementation might allow human organ generation in animals whose organ size, anatomy, and physiology are closer to humans. To date, however, whether human PSCs (hPSCs) can contribute to chimera formation in non-rodent species remains unknown. We systematically evaluate the chimeric competency of several types of hPSCs using a more diversified clade of mammals, the ungulates. We find that naïve hPSCs robustly engraft in both pig and cattle pre-implantation blastocysts but show limited contribution to post-implantation pig embryos. Instead, an intermediate hPSC type exhibits higher degree of chimerism and is able to generate differentiated progenies in post-implantation pig embryos.
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Quimerismo , Edição de Genes , Mamíferos/embriologia , Animais , Blastocisto , Sistemas CRISPR-Cas , Bovinos , Embrião de Mamíferos/citologia , Feminino , Humanos , Masculino , Mamíferos/classificação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Células-Tronco Pluripotentes , Ratos , Ratos Sprague-Dawley , Sus scrofaRESUMO
Endolysins are bacteriophage (or phage)-encoded enzymes that catalyse the peptidoglycan breakdown in the bacterial cell wall. The exogenous action of recombinant phage endolysins against Gram-positive organisms has been extensively studied. However, the outer membrane acts as a physical barrier when considering the use of recombinant endolysins to combat Gram-negative bacteria. This study aimed to evaluate the antimicrobial activity of the SAR-endolysin LysKpV475 against Gram-negative bacteria as single or combined therapies, using an outer membrane permeabilizer (polymyxin B) and a phage, free or immobilized in a pullulan matrix. In the first step, the endolysin LysKpV475 in solution, alone and combined with polymyxin B, was tested in vitro and in vivo against ten Gram-negative bacteria, including highly virulent strains and multidrug-resistant isolates. In the second step, the lyophilized LysKpV475 endolysin was combined with the phage phSE-5 and investigated, free or immobilized in a pullulan matrix, against Salmonella enterica subsp. enterica serovar Typhimurium ATCC 13311. The bacteriostatic action of purified LysKpV475 varied between 8.125 µgâ¯ml-1 against Pseudomonas aeruginosa ATCC 27853, 16.25 µgâ¯ml-1 against S. enterica Typhimurium ATCC 13311, and 32.50 µgâ¯ml-1 against Klebsiella pneumoniae ATCC BAA-2146 and Enterobacter cloacae P2224. LysKpV475 showed bactericidal activity only for P. aeruginosa ATCC 27853 (32.50 µgâ¯ml-1) and P. aeruginosa P2307 (65.00 µgâ¯ml-1) at the tested concentrations. The effect of the LysKpV475 combined with polymyxin B increased against K. pneumoniae ATCC BAA-2146 [fractional inhibitory concentration index (FICI) 0.34; a value lower than 1.0 indicates an additive/combined effect] and S. enterica Typhimurium ATCC 13311 (FICI 0.93). A synergistic effect against S. enterica Typhimurium was also observed when the lyophilized LysKpV475 at â MIC was combined with the phage phSE-5 (m.o.i. of 100). The lyophilized LysKpV475 immobilized in a pullulan matrix maintained a significant Salmonella reduction of 2 logs after 6 h of treatment. These results demonstrate the potential of SAR-endolysins, alone or in combination with other treatments, in the free form or immobilized in solid matrices, which paves the way for their application in different areas, such as in biocontrol at the food processing stage, biosanitation of food contact surfaces and biopreservation of processed food in active food packing.
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Antibacterianos , Endopeptidases , Glucanos , Polimixina B , Fagos de Salmonella , Endopeptidases/farmacologia , Endopeptidases/química , Endopeptidases/metabolismo , Polimixina B/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Fagos de Salmonella/genética , Fagos de Salmonella/fisiologia , Fagos de Salmonella/química , Glucanos/química , Glucanos/farmacologia , Animais , Testes de Sensibilidade Microbiana , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/virologia , Camundongos , Salmonella typhimurium/virologia , Salmonella typhimurium/efeitos dos fármacos , Bacteriófagos/fisiologia , Bacteriófagos/genética , Proteínas Virais/genética , Proteínas Virais/metabolismo , Proteínas Virais/farmacologia , Proteínas Virais/químicaRESUMO
AIMS: Lymph node metastases (LNM) are one of the most important prognostic indicators in solid tumours and a major component of cancer staging. Neoadjuvant therapy might influence nodal status by induction of regression. Our aim is to determine the prevalence and role of regression of LNM on outcomes in patients with rectal cancer. METHODS AND RESULTS: Four independent study populations of rectal cancer patients treated with similar regimens of chemoradiotherapy were pooled together to obtain a total cohort of 469 patients. Post-treatment nodal status (ypN) and signs of tumour regression (Reg) were incorporated to form three-tiered (ypN- Reg+, ypN- Reg- and ypN+) and four-tiered (ypN- Reg+, ypN- Reg-, ypN+ Reg+ and ypN+ Reg-) classifications. In our cohort, 31% of patients presented with ypN+ rectal cancer. As expected, we found significantly worse overall survival (OS) in ypN+ patients compared to ypN- patients (P = 0.002). The percentage of ypN- patients with lymph nodes with complete regression was 20% in our cohort. While node-negative patients with and without regression had similar OS (P = 0.09), disease-free survival (DFS) was significantly better in node-negative patients with regression (P = 0.009). CONCLUSIONS: Regression in lymph nodes is frequent, and node-negative patients with evidence of lymph node regression have better DFS compared to node-negative patients without such evidence.
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Terapia Neoadjuvante , Neoplasias Retais , Humanos , Terapia Neoadjuvante/métodos , Linfonodos/patologia , Neoplasias Retais/patologia , Prognóstico , Estadiamento de Neoplasias , Quimiorradioterapia/métodos , Intervalo Livre de Doença , Metástase Linfática/patologia , Estudos RetrospectivosRESUMO
Rare-earth-metal complexes (Ln=Y, La, Ce, Sm and Lu) of tripodal N-donor ligands respecting the CHON principle have been synthetized and characterized. The selectivity of the ligands through the lanthanide cations was investigated and related to their donor strength.
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This study aimed to investigate if washing ram sperm from seminal plasma (SP) could be an effective tool to extend sperm lifespan in medium-term preservation in liquid form to optimize ovine artificial insemination protocols. To this end, in Experiment 1 SP was added to a sperm model without previous contact with this substance (ram epididymal sperm) at the beginning or the end of a 48-hour preservation protocol at 5 °C (n = 13). Sperm motility and kinetic parameters and sperm functionality in terms of sperm viability, apoptosis, mitochondrial activity and reacted acrosomes were assessed after 6 h of storage at 15 °C (standard liquid preservation method) and 24 and 48 h at 5 °C. Extended sperm showed better results after 48 h when stored in the absence than in the presence of SP in most sperm quality parameters. Moreover, the final SP supplementation of this experimental group resulted in the highest sperm motility and kinetic parameters, viability and mitochondrial activity. These results suggested that initial SP deprivation could be beneficial in a medium-term ram sperm preservation protocol in liquid form, as well as a final supplementation. Therefore, we conducted Experiment 2 to evaluate the effect of SP removal from freshly ejaculated ram semen under the same storage conditions as in Experiment 1 (n = 12). Surprisingly, SP withdrawal impaired sperm functionality, leading to increased apoptosis and decreased mitochondrial activity after 24 and 48 h at 5 °C. Conversely, SP supplementation at the end of the preservation protocol of the ejaculate processed as usual had a positive effect on sperm quality and fertility. To summarize, SP absence was beneficial for a medium-term preservation protocol (up to 48 h at 5 °C) of ram epididymal sperm, but the same preservation protocol for ram ejaculated sperm revealed a possible failure of the SP removal method in avoiding the sperm-SP interaction effect. Meanwhile, SP supplementation of ram semen at the end of the preservation protocol increased in vitro sperm quality and fertility after artificial insemination.
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Preservação do Sêmen , Sêmen , Motilidade dos Espermatozoides , Espermatozoides , Animais , Masculino , Preservação do Sêmen/veterinária , Preservação do Sêmen/métodos , Sêmen/fisiologia , Ovinos/fisiologia , Espermatozoides/fisiologia , Inseminação Artificial/veterinária , Análise do Sêmen/veterináriaRESUMO
OBJECTIVE: To evaluate the agreement between noninvasive arterial blood pressure (NIBP) measured from the tongue and thoracic limb with invasive blood pressure (IBP), and to compare NIBP measured from the tongue and thoracic limb in anaesthetized horses. STUDY DESIGN: Prospective clinical study. ANIMALS: A group of eight client-owned healthy horses anaesthetized for scheduled procedures, American Society of Anesthesiologists classification I-II, weighing (mean ± standard deviation) 498 ± 91 kg and aged 7.8 ± 6.75 years. METHODS: Animals were premedicated with intravenous (IV) romifidine (0.04-0.08 mg kg-1) and methadone (0.1 mg kg-1). General anaesthesia was induced IV with ketamine (2.5 mg kg-1) and midazolam (0.05 mg kg-1) and maintained with isoflurane. The facial artery was catheterized for IBP measurements. Systolic (SAP), mean (MAP) and diastolic (DAP) arterial pressures were recorded from the NIBPtongue, NIBPlimb and IBP every 20 minutes during the procedure. Agreement between NIBP and IBP was evaluated based on the American College of Veterinary Internal Medicine criteria and American Association for Medical Instrumentation criteria using the Bland-Altman method. RESULTS: The mean bias and precision between IBP and NIBP measured from the tongue met the standards for all pressure ranges (< 10 mmHg and < 15 mmHg, respectively). NIBP measurements from the tongue and thoracic limb tended to underestimate IBP measurements. During hypotension, MAPtongue and DAPtongue overestimated IBP, but both precision and accuracy met the criteria. The overall accuracy and precision of NIBPlimb was poorer than NIBPtongue. The percentage of NIBPtongue that differed from IBP by < 10 mmHg was higher than that recorded with NIBPlimb for SAP (46% versus 25%), MAP (77% versus 28%) and DAP (79% versus 19%). CONCLUSIONS AND CLINICAL RELEVANCE: The tongue is a clinically suitable alternative for assessing arterial blood pressure compared with the thoracic limb and can reliably detect hypotension in healthy anaesthetized horses.
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Doenças dos Cavalos , Hipotensão , Animais , Pressão Sanguínea , Determinação da Pressão Arterial/métodos , Determinação da Pressão Arterial/veterinária , Monitores de Pressão Arterial/veterinária , Cavalos , Hipotensão/veterinária , Estudos Prospectivos , LínguaRESUMO
Objective: To compare the perioperative opioid requirements among dogs receiving an erector spinae plane (ESP) block with bupivacaine, with or without dexmedetomidine, and a control group. Animals and procedure: Thirty client-owned, healthy adult dogs undergoing hemilaminectomy were included in this randomized, prospective, blinded clinical study. Dogs were randomly assigned to 1 of 3 treatment groups: Group B, ESP block with bupivacaine; Group BD, ESP block with bupivacaine and dexmedetomidine; and Group C, control. Rescue intra- and postoperative analgesia consisted of fentanyl and methadone, respectively. Postoperative pain was evaluated using the short form of the Glasgow Composite Measure Pain Scale (CMPS-SF). Results: In Group BD, 0/10 dogs required intraoperative fentanyl, compared to 9/10 in Group C (P < 0.001), whereas 1/10 required postoperative methadone, compared to 9/10 in Group B (P = 0.003) and 10/10 in Group C (P < 0.001). The total amount of intraoperative fentanyl (µg/kg) was 0 (0 to 4) in Group B and 0 (0 to 0) in BD, compared to 6 (0 to 8) in C (P = 0.004 and P < 0.001, respectively). Postoperative methadone (mg/kg) required during the first 12 h was 0.5 (0 to 1.4) in Group B (P = 0.003) and 0 (0 to 0) in BD (P < 0.001), compared to C (P = 0.003 and P < 0.001, respectively). Conclusion: An ESP block with bupivacaine, with or without dexmedetomidine, was associated with a reduction in perioperative opioid consumption and provided effective acute pain control.
Effets analgésiques périopératoires du bloc des érecteurs du rachis avec de la bupivacaïne ou de la bupivacaïne-dexmédétomidine chez les chiens subissant une hémilaminectomie: un essai contrôlé randomisé. Objectif: Comparer les besoins périopératoires en opioïdes chez les chiens recevant un bloc des érecteurs de la colonne vertébrale (ESP) avec de la bupivacaïne, avec ou sans dexmédétomidine, et un groupe témoin. Animaux et procédure: Trente chiens adultes en bonne santé appartenant à des clients subissant une hémilaminectomie ont été inclus dans cette étude clinique randomisée, prospective et en aveugle. Les chiens ont été répartis au hasard dans 1 des 3 groupes de traitement: groupe B, bloc ESP avec bupivacaïne; groupe BD, bloc ESP avec bupivacaïne et dexmédétomidine; et groupe C, témoin. L'analgésie de secours peropératoire et postopératoire consistait respectivement en fentanyl et en méthadone. La douleur postopératoire a été évaluée à l'aide du formulaire abrégé de l'échelle de mesure de la douleur de Glasgow (CMPS-SF). Résultats: Dans le groupe BD, 0/10 chiens ont eu besoin de fentanyl peropératoire, contre 9/10 dans le groupe C (P < 0,001), tandis que 1/10 ont eu besoin de méthadone postopératoire, contre 9/10 dans le groupe B (P = 0,003) et 10/10 dans le groupe C (P < 0,001). La quantité totale de fentanyl peropératoire (µg/kg) était de 0 (0 à 4) dans le groupe B et de 0 (0 à 0) dans le groupe BD, contre 6 (0 à 8) dans le groupe C (P = 0,004 et P < 0,001, respectivement). La méthadone postopératoire (mg/kg) nécessaire au cours des 12 premières heures était de 0,5 (0 à 1,4) dans le groupe B (P = 0,003) et de 0 (0 à 0) dans le groupe BD (P < 0,001), par rapport au groupe C (P = 0,003). et P < 0,001, respectivement). Conclusion: Un bloc ESP avec de la bupivacaïne, avec ou sans dexmédétomidine, a été associé à une réduction de la consommation peropératoire d'opioïdes et a permis un contrôle efficace de la douleur aiguë.(Traduit par Dr Serge Messier).
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Anestésicos Locais , Bupivacaína , Dexmedetomidina , Laminectomia , Bloqueio Nervoso , Dor Pós-Operatória , Animais , Cães , Bupivacaína/administração & dosagem , Bupivacaína/uso terapêutico , Dexmedetomidina/administração & dosagem , Dexmedetomidina/farmacologia , Dor Pós-Operatória/veterinária , Dor Pós-Operatória/prevenção & controle , Dor Pós-Operatória/tratamento farmacológico , Bloqueio Nervoso/veterinária , Masculino , Feminino , Anestésicos Locais/administração & dosagem , Anestésicos Locais/uso terapêutico , Laminectomia/veterinária , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Fentanila/administração & dosagem , Fentanila/farmacologia , Fentanila/uso terapêutico , Doenças do Cão/cirurgia , Doenças do Cão/tratamento farmacológico , Estudos ProspectivosRESUMO
The benefits, opportunities and growing availability of ultra-high field magnetic resonance imaging (MRI) for humans have prompted an expansion in research and development efforts towards increasingly more advanced high-resolution imaging techniques. To maximize their effectiveness, these efforts need to be supported by powerful computational simulation platforms that can adequately reproduce the biophysical characteristics of MRI, with high spatial resolution. In this work, we have sought to address this need by developing a novel digital phantom with realistic anatomical detail up to 100-µm resolution, including multiple MRI properties that affect image generation. This phantom, termed BigBrain-MR, was generated from the publicly available BigBrain histological dataset and lower-resolution in-vivo 7T-MRI data, using a newly-developed image processing framework that allows mapping the general properties of the latter into the fine anatomical scale of the former. Overall, the mapping framework was found to be effective and robust, yielding a diverse range of realistic "in-vivo-like" MRI contrasts and maps at 100-µm resolution. BigBrain-MR was then tested in three imaging applications (motion effects and interpolation, super-resolution imaging, and parallel imaging reconstruction) to investigate its properties, value and validity as a simulation platform. The results consistently showed that BigBrain-MR can closely approximate the behavior of real in-vivo data, more realistically and with more extensive features than a more classic option such as the Shepp-Logan phantom. Its flexibility in simulating different contrast mechanisms and artifacts may also prove valuable for educational applications. BigBrain-MR is therefore deemed a favorable choice to support methodological development and demonstration in brain MRI, and has been made freely available to the community.
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Encéfalo , Imageamento por Ressonância Magnética , Humanos , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Simulação por Computador , Imagens de Fantasmas , Espectroscopia de Ressonância MagnéticaRESUMO
Type 6 secretion systems (T6SSs) are specialized multiprotein complexes that inject protein effectors into prokaryotic and/or eukaryotic cells. We previously described the role of the T6SS of the phytopathogen Xanthomonas citri pv. citri as an anti-eukaryotic nanoweapon that confers resistance to predation by the amoeba Dictyostelium discoideum. Transcription of the X. citri T6SS genes is induced by a signaling cascade involving the Ser/Thr kinase PknS and the extracytoplasmic function sigma factor EcfK. Here, we used a strain overexpressing a phosphomimetic constitutively active version of EcfK (EcfKT51E ) to identify the EcfK regulon, which includes a previously uncharacterized transcription factor of the AraC-family (TagK), in addition to T6SS genes and genes encoding protein homeostasis factors. Functional studies demonstrated that TagK acts downstream of EcfK, binding directly to T6SS gene promoters and inducing T6SS expression in response to contact with amoeba cells. TagK controls a small regulon, consisting of the complete T6SS, its accessory genes and additional genes encoded within the T6SS cluster. We conclude that a singular regulatory circuit consisting of a transmembrane kinase (PknS), an alternative sigma factor (EcfK) and an AraC-type transcriptional regulator (TagK) promotes expression of the X. citri T6SS in response to a protozoan predator.
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Dictyostelium , Sistemas de Secreção Tipo VI , Xanthomonas , Fator sigma/genética , Fator sigma/metabolismo , Fator de Transcrição AraC/genética , Regulação Bacteriana da Expressão Gênica/genética , Dictyostelium/genética , Dictyostelium/metabolismo , Células Eucarióticas , Eucariotos/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Xanthomonas/genética , Xanthomonas/metabolismo , Sistemas de Secreção Tipo VI/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
We explored structural brain connectomes in children with spastic unilateral cerebral palsy (uCP) and its relation to sensory-motor function using graph theory. In 46 children with uCP (mean age = 10 years 7 months ± 2 years 9 months; Manual Ability Classification System I = 15, II = 16, III = 15) we assessed upper limb somatosensory and motor function. We collected multi-shell diffusion-weighted, T1-weighted and T2-FLAIR MRI and identified the corticospinal tract (CST) wiring pattern using transcranial magnetic stimulation. Structural connectomes were constructed using Virtual Brain Grafting-modified FreeSurfer parcellations and multi-shell multi-tissue constrained spherical deconvolution-based anatomically-constrained tractography. Graph metrics (characteristic path length, global/local efficiency and clustering coefficient) of the whole brain, the ipsilesional/contralesional hemisphere, and the full/ipsilesional/contralesional sensory-motor network were compared between lesion types (periventricular white matter (PWM) = 28, cortical and deep gray matter (CDGM) = 18) and CST-wiring patterns (ipsilateral = 14, bilateral = 14, contralateral = 12, unknown = 6) using ANCOVA with age as covariate. Using elastic-net regularized regression we investigated how graph metrics, lesion volume, lesion type, CST-wiring pattern and age predicted sensory-motor function. In both the whole brain and subnetworks, we observed a hyperconnectivity pattern in children with CDGM-lesions compared with PWM-lesions, with higher clustering coefficient (p = [<.001-.047], η p 2 =[0.09-0.27]), characteristic path length (p = .003, η p 2 =0.19) and local efficiency (p = [.001-.02], η p 2 =[0.11-0.21]), and a lower global efficiency with age (p = [.01-.04], η p 2 =[0.09-0.15]). No differences were found between CST-wiring groups. Overall, good predictions of sensory-motor function were obtained with elastic-net regression (R2 = .40-.87). CST-wiring pattern was the strongest predictor for motor function. For somatosensory function, all independent variables contributed equally to the model. In conclusion, we demonstrated the potential of structural connectomics in understanding disease severity and brain development in children with uCP.
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Paralisia Cerebral , Conectoma , Humanos , Criança , Encéfalo , Imageamento por Ressonância Magnética , Extremidade SuperiorRESUMO
AIMS: Partial response to neoadjuvant chemoradiotherapy (CRT) presents with one of two main response patterns: shrinkage or fragmentation. This study investigated the relevance of these response patterns in rectal cancer, correlation with other response indicators, and outcome. METHODS AND RESULTS: The study included a test (n = 197) and a validation cohort (n = 218) of post-CRT patients with rectal adenocarcinoma not otherwise specified and a partial response. Response patterns were scored by two independent observers using a previously developed three-step flowchart. Tumour regression grading (TRG) was established according to both the College of American Pathologists (CAP) and Dworak classifications. In both cohorts, the predominant response pattern was fragmentation (70% and 74%), and the scoring interobserver agreement was excellent (k = 0.85). Patients with a fragmented pattern presented with significantly higher pathological stage (ypTNM II-IV, 78% versus 35%; P < 0.001), less tumour regression with Dworak (P = 0.004), and CAP TRG (P = 0.005) compared to patients with a shrinkage pattern. As a predictor of prognosis, the shrinkage pattern outperformed the TRG classification and stratified patients better in overall (fragmented pattern, hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.19-3.50, P = 0.008) and disease-free survival (DFS; fragmented pattern, HR 2.50, 95% CI 1.23-5.10, P = 0.011) in the combined cohorts. The multivariable regression analyses revealed pathological stage as the only independent predictor of DFS. CONCLUSIONS: The heterogeneous nature of tumour response following CRT is reflected in fragmentation and shrinkage. In rectal cancer there is a predominance of the fragmented pattern, which is associated with advanced stage and less tumour regression. While not independently associated with survival, these reproducible patterns give insights into the biology of tumour response.
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Quimiorradioterapia , Neoplasias Retais , Humanos , Resultado do Tratamento , Quimiorradioterapia/métodos , Prognóstico , Neoplasias Retais/patologia , Intervalo Livre de Doença , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
The rare earth element complexes (Ln=Y, La, Sm, Lu, Ce) of several podant κ6 N-coordinating ligands have been synthetized and thoroughly characterized. The structural properties of the complexes have been investigated by X-ray diffraction in the solid state and by advanced NMR methods in solution. To estimate the donor capabilities of the presented ligands, an experimental comparison study has been conducted by cyclic voltammetry as well as absorption experiments using the cerium complexes and by analyzing 89 Yâ NMR chemical shifts of the different yttrium complexes. In order to obtain a complete and detailed picture, all experiments were corroborated by state-of-the-art quantum chemical calculations. Finally, coordination competition studies have been carried out by means of 1 H and 31 Pâ NMR spectroscopy to investigate the correlation with donor properties and selectivity.
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INTRODUCTION: Volcanic eruptions emit gases and particulate matter into the atmosphere which, if inhaled, can have an impact on health. The eruption of the volcano situated in the Cumbre Vieja Nature Reserve (La Palma, Canary Islands, Spain) affords a unique opportunity to study the effect of such a phenomenon on health. The aim of the proposed study is to assess the short-, medium- and long-term respiratory health effects of exposure to volcanic emissions from the eruption in three different population groups. METHODS: We propose to undertake a multidesign study: an ambispective cohort study to analyze the effect of the eruption on the general population, the highly exposed population, and the childhood population; and a pre-post quasi-experimental study on subjects with previously diagnosed respiratory diseases. The information will be collected using a personal interview, biologic specimens, air pollution data, data from medical records, respiratory tests and imaging tests. The study has an envisaged follow-up of five years, to run from the date of initial recruitment, with annual data-collection. This study has been approved by the Santa Cruz de Tenerife Provincial Research Ethics Committee (Canary Island Health Service) on March 10, 2022. CONCLUSIONS: This study will make it possible to advance our knowledge of the effect a volcano eruption has on population health, both short- and long-term, and to assess the potential respiratory injury attributable to volcanic eruptions. It may serve as a model for future studies of new volcanic eruptions in the coming years.
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Poluição do Ar , Erupções Vulcânicas , Humanos , Criança , Erupções Vulcânicas/efeitos adversos , Espanha/epidemiologia , Estudos de Coortes , Material Particulado/análise , Poluição do Ar/efeitos adversosRESUMO
BACKGROUND: Respirable crystalline silica (RCS) is associated with the development of lung cancer. However, there is uncertainty around the exposure threshold at which exposure to RCS may pose a clear risk for the development of lung cancer. The objective of this study was to review the cut-off points at which the risk of mortality or incidence of lung cancer due to occupational exposure to RCS becomes evident through a systematic review. METHODS: We conducted a search in PubMed, including cohort and case-control studies which assessed various categories of RCS exposure. A search was also conducted on the webpages of institutional organizations. A qualitative data synthesis was performed. RESULTS: Twenty studies were included. Studies that assessed lung cancer mortality and incidence displayed wide variability both in RCS exposure categories and related risks. Although most studies found no significant association for RCS exposure categories, it appears to be a low risk of lung cancer for mean concentrations of less than 0.07mg/m3. Regulatory agencies set annual RCS exposure limits ranging from 0.025mg/m3 through 0.1mg/m3. CONCLUSIONS: There is a wide degree of heterogeneity in RCS exposure categories, with most studies observing no significant risk of lung cancer for the lowest exposure categories. Cut-off points differ between agencies but are nonetheless very similar and do not exceed 0.1mg/m3.
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Poluentes Ocupacionais do Ar , Neoplasias Pulmonares , Exposição Ocupacional , Humanos , Poluentes Ocupacionais do Ar/análise , Exposição por Inalação/análise , Poeira/análise , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Dióxido de Silício/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/epidemiologiaRESUMO
The aim of this study was to evaluate the efficacy of presurgical interventions for promoting smoking cessation in terms of achieving smoking abstinence and reducing surgical complication rates. A systematic review of randomized clinical trials (RCTs) published from March 2009 to April 2021 was performed following the PRISMA guidelines. References were found in MEDLINE (via PubMed), Web of Science (WOS), and Cumulative Index to Nursing and Allied Health Literature (CINAHL). RCTs comparing the efficacy of a smoking cessation program directed at an intervention group (IG) versus the usual intervention or another directed at a control group (CG) were included. No language restrictions were applied in the search. All approaches to smoking cessation were admitted (face-to-face, telephone, group, individual, multicomponent, etc.), as were all methods for assessing abstinence, follow-up times, surgical specialties, definitions of smokers, and all types of surgical complications. Four hundred forty-four references were pulled out, and 79 duplicates were discarded. We excluded 346 records that were after application of the inclusion/exclusion criteria. In addition to the remaining 19 articles, 1 article obtained from citation searches was also assessed. We finally included 11 original articles in this systematic review, corresponding to 9 studies, because 2 of the RCTs had 2 different articles referring to different aspects of the same study. The results showed long-term postoperative (6 to 12 months) abstinence rates between 25.0% and 36.4% in RCTs with intensive multicomponent interventions, versus rates about 13.0% in brief interventions. Two multicomponent interventions obtained significant improvements regarding the reduction of short-term postoperative surgical complications. In conclusion, presurgical multicomponent smoking cessation interventions are more effective than brief interventions in terms of achieving abstinence and reducing surgical complications. The follow-up time and the intensity of the interventions were predictors of dropout.
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Abandono do Hábito de Fumar , Humanos , Abandono do Hábito de Fumar/métodos , Fumar , Complicações Pós-OperatóriasRESUMO
BACKGROUND: Amblyopia is the most common developmental vision disorder in children. The initial treatment consists of refractive correction. When insufficient, occlusion therapy may further improve visual acuity. However, the challenges and compliance issues associated with occlusion therapy may result in treatment failure and residual amblyopia. Virtual reality (VR) games developed to improve visual function have shown positive preliminary results. The aim of this study is to determine the efficacy of these games to improve vision, attention, and motor skills in patients with residual amblyopia and identify brain-related changes. We hypothesize that a VR-based training with the suggested ingredients (3D cues and rich feedback), combined with increasing the difficulty level and the use of various games in a home-based environment is crucial for treatment efficacy of vision recovery, and may be particularly effective in children. METHODS: The AMBER study is a randomized, cross-over, controlled trial designed to assess the effect of binocular stimulation (VR-based stereoptic serious games) in individuals with residual amblyopia (n = 30, 6-35 years of age), compared to refractive correction on vision, selective attention and motor control skills. Additionally, they will be compared to a control group of age-matched healthy individuals (n = 30) to account for the unique benefit of VR-based serious games. All participants will play serious games 30 min per day, 5 days per week, for 8 weeks. The games are delivered with the Vivid Vision Home software. The amblyopic cohort will receive both treatments in a randomized order according to the type of amblyopia, while the control group will only receive the VR-based stereoscopic serious games. The primary outcome is visual acuity in the amblyopic eye. Secondary outcomes include stereoacuity, functional vision, cortical visual responses, selective attention, and motor control. The outcomes will be measured before and after each treatment with 8-week follow-up. DISCUSSION: The VR-based games used in this study have been conceived to deliver binocular visual stimulation tailored to the individual visual needs of the patient, which will potentially result in improved basic and functional vision skills as well as visual attention and motor control skills. TRIAL REGISTRATION: This protocol is registered on ClinicalTrials.gov (identifier: NCT05114252) and in the Swiss National Clinical Trials Portal (identifier: SNCTP000005024).
Assuntos
Ambliopia , Jogos de Vídeo , Criança , Humanos , Ambliopia/terapia , Visão Binocular/fisiologia , Acuidade Visual , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
SIGNIFICANCE: Some patients show poor visual outcomes after Descemet stripping automated endothelial keratoplasty. In such cases, secondary Descemet membrane endothelial keratoplasty can be performed to achieve complete visual recovery. Anterior segment optical coherence tomography (AS-OCT) is a valuable tool for the follow-up of posterior lamellar keratoplasty outcomes and complications. PURPOSE: This study aimed to report the clinical outcome of secondary Descemet membrane endothelial keratoplasty for managing poor visual results in a patient with graft failure after a previous Descemet stripping automated endothelial keratoplasty, highlighting the importance of AS-OCT in the follow-up of endothelial keratoplasty. CASE REPORT: A 38-year-old woman with high myopia underwent Descemet stripping automated endothelial keratoplasty for bullous keratopathy after explantation of an angle-supported phakic intraocular lens. Two years after keratoplasty, the patient experienced poor visual acuity (counting fingers), and significant corneal edema was observed on clinical examination hindering visualization of the anterior chamber structures. Anterior segment optical coherence tomography showed a failed and thickened graft adhering well to the recipient cornea in an anterior chamber without other comorbidities. Therefore, the graft was removed and replaced with a Descemet membrane endothelial keratoplasty graft without any complications. One year later, the clinical outcome was evaluated by comparing the pre-operative and post-operative best-corrected visual acuity, biomicroscopy findings, endothelial cell density, and corneal central thickness. CONCLUSIONS: Anterior segment optical coherence tomography is an important tool when deciding on the surgical technique to be applied and for the post-surgical monitoring of endothelial corneal grafts. This case demonstrates the successful management of Descemet stripping automated endothelial keratoplasty graft failure with Descemet membrane endothelial keratoplasty graft, highlighting the importance of AS-OCT in detecting complications such as graft dislocation and primary graft failure. In addition, corneal thickness measured using AS-OCT serves as a critical predictor of graft failure, as observed in this case.
Assuntos
Doenças da Córnea , Edema da Córnea , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior , Feminino , Humanos , Adulto , Doenças da Córnea/diagnóstico , Doenças da Córnea/etiologia , Doenças da Córnea/cirurgia , Endotélio Corneano , Tomografia de Coerência Óptica , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior/efeitos adversos , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior/métodos , Acuidade Visual , Estudos Retrospectivos , Edema da Córnea/diagnóstico , Edema da Córnea/etiologia , Edema da Córnea/cirurgia , Lâmina Limitante PosteriorRESUMO
BACKGROUND: Brentuximab vedotin (BV) has been approved for CD30-expressing cutaneous T-cell lymphoma (CTCL) after at least one previous systemic treatment. However, real clinical practice is still limited. OBJECTIVES: To evaluate the response and tolerance of BV in a cohort of patients with CTCL. METHODS: We analysed CTCL patients treated with BV from the Spanish Primary Cutaneous Lymphoma Registry (RELCP). RESULTS: Sixty-seven patients were included. There were 26 females and the mean age at diagnosis was 59 years. Forty-eight were mycosis fungoides (MF), 7 Sézary syndrome (SS) and 12 CD30+ lymphoproliferative disorders (CD30 LPD). Mean follow-up was 18 months. Thirty patients (45%) showed at least 10% of CD30+ cells among the total lymphocytic infiltrate. The median number of BV infusions received was 7. The overall response rate (ORR) was 67% (63% in MF, 71% in SS and 84% in CD30 LPD). Ten of 14 patients with folliculotropic MF (FMF) achieved complete or partial response (ORR 71%). The median time to response was 2.8 months. During follow-up, 36 cases (54%) experienced cutaneous relapse or progression. The median progression free survival (PFS) was 10.3 months. The most frequent adverse event was peripheral neuropathy (PN) (57%), in most patients (85%), grades 1 or 2. CONCLUSIONS: These results confirm the efficacy and safety of BV in patients with advanced-stage MF, and CD30 LPD. In addition, patients with FMF and SS also showed a favourable response. Our data suggest that BV retreatment is effective in a proportion of cases.
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Imunoconjugados , Linfoma Cutâneo de Células T , Transtornos Linfoproliferativos , Micose Fungoide , Síndrome de Sézary , Neoplasias Cutâneas , Feminino , Humanos , Pessoa de Meia-Idade , Brentuximab Vedotin/uso terapêutico , Imunoconjugados/efeitos adversos , Neoplasias Cutâneas/patologia , Micose Fungoide/patologia , Síndrome de Sézary/patologia , Sistema de Registros , Antígeno Ki-1RESUMO
Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and database searches, in silico network analyses, and functional readouts using candidate gene-specific genome-edited cell clones. WES datasets of two patients with HSCR and their non-affected parents were analysed, and four novel HSCR candidate genes could be identified: ATP7A, SREBF1, ABCD1 and PIAS2. Further rare variants in these genes were identified in additional HSCR patients, suggesting disease relevance. Transcriptomics revealed that these genes are expressed in embryonic and fetal gastrointestinal tissues. Knockout of these genes in neuronal cells demonstrated impaired cell differentiation, proliferation and/or survival. Our approach identified and validated candidate HSCR genes and provided further insight into the underlying pathomechanisms of HSCR.