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•Risk factors shaping host-parasite interactions impact the clinical management of canine leishmaniosis.•Renal and ocular findings are major risk factors for LeishVet stages III and ...IV.•Diagnosis of comorbidities is key to managing dogs with leishmaniosis, although independent of their clinical outcome.•A complex polygenic component underlies the development of severe clinical forms of leishmaniosis in certain purebred dogs.•Protective immunity against Leishmania parasites is related to genetic factors involved in the ER stress and UPR pathways.
Canine leishmaniosis (CanL), caused by Leishmania infantum, is a complex disease of growing importance in Europe. Clinical manifestations result from the down-modulation of the host immune response through multiple host-parasite interactions. Although several factors might influence CanL progression, this is the first known study evaluating risk factors for its different clinical stages in a large referral hospital population (n = 35.669) from an endemic area, over a 20 year period. Genome-wide scans for selection signatures were also conducted to explore the genomic component of clinical susceptibility to L. infantum infection. The prevalence of CanL was 3.2% (16.7% stage I; 43.6% stage II; 32.1% stage III; 7.6% stage IV). Dog breed (crossbreed), bodyweight (<10 kg), living conditions (indoors), regular deworming treatment, and being vaccinated against Leishmania significantly decreased the transmission risk and the risk for developing severe clinical forms. Conversely, the detection of comorbidities was associated with advanced clinical forms, particularly chronic kidney disease, neoplasia, cryptorchidism, infectious tracheobronchitis and urate urolithiasis, although those did not impact the clinical outcome. Significant associations between an increased risk of severe clinical stages and findings in the anamnesis (renal or skin-related manifestations) and physical examination (ocular findings) were also detected, highlighting their diagnostic value in referred cases of CanL. Sixteen breeds were found to be significantly more susceptible to developing severe stages of leishmaniosis (e.g. Great Dane, Rottweiler, English Springer Spaniel, Boxer, American Staffordshire Terrier, Golden Retriever), while 20 breeds displayed a clinical resistantance phenotype and, thus, are more likely to mount an efficient immune response against L. infantum (e.g. Pointer, Samoyed, Spanish Mastiff, Spanish Greyhound, English Setter, Siberian Husky). Genomic analyses of these breeds retrieved 12 regions under selection, 63 candidate genes and pinpointed multiple biological pathways such as the IRE1 branch of the unfolded protein response, which could play a critical role in clinical susceptibility to L. infantum infection.
This paper explores the capacity for political agency of the British Romani Civil Rights Movement, assessing its particular connections with the construction and application of laws in the UK and ...Europe during the late 1960s and the early 1970s. A dual perspective will be adopted in order to trace and bring into dialogue the pressure brought to bear by Romani activism on both the Ministry of Housing and Local Government (MHLG) and the Foreign and Commonwealth Office (FCO) in the United Kingdom following the historic Recommendation 563 of the Council of Europe pertaining to the situation of Gypsies and other Travellers. Based on FCO sources, this study highlights the performative power of ‘Gypsy diplomacy’ while negotiating political spaces in the United Kingdom.
, the etiological agent of canine leishmaniosis (CanL) in Europe, was responsible of the largest outbreak of human leishmaniosis in Spain. The parasite infects and survives within myeloid lineage ...cells, causing a potentially fatal disease if left untreated. The only treatment option relies on chemotherapy, although immunotherapy strategies are being considered as novel approaches to prevent progression of the disease. To this aim, a deeper characterization of the molecular mechanisms behind the immunopathogenesis of leishmaniosis is necessary. Thus, we evaluated, for the first time, the host immune response during
infection through transcriptome sequencing of the popliteal lymph nodes aspirates of dogs with CanL. Differential expression and weighted gene co-expression network analyses were performed, resulting in the identification of 5,461 differentially expressed genes (DEGs) and four key modules in sick dogs, compared to controls. As expected, defense response was the highest enriched biological process in the DEGs, with six genes related to immune response against pathogens (
) included among the ten most expressed genes; and two of the key co-expression modules were associated with regulation of immune response, which also positively correlated with clinical stage and blood monocyte concentration. In particular, sick dogs displayed significant changes in the expression of Th1, Th2, Th17 and Tr1 cytokines (e. g. TNF-α, IFN-γ, IL-21, IL-17, IL-15), markers of T cell and NK cell exhaustion (e. g.
), and B cell, monocyte and macrophage disrupted functionality (e. g.
). In addition, we found an overexpression of
and some other genes involved in endoplasmic reticulum stress and the IRE1 branch of the unfolded protein response, as well as one co-expression module associated with these processes, which could be induced by
to prevent host cell apoptosis and modulate inflammation-induced lymphangiogenesis at lymph nodes. Moreover, 21 lncRNAs were differentially expressed in sick dogs, and one key co-expression module was associated with chromatin organization, suggesting that epigenetic mechanisms could also contribute to dampening host immune response during natural
infection in the lymph nodes of dogs suffering from clinical leishmaniosis.
The inner ear, the organ of equilibrium and hearing, has an extraordinarily complex and intricate arrangement. It contains highly specialized structures meticulously tailored to permit auditory ...processing. However, hearing also relies on both peripheral and central pathways responsible for the neuronal transmission of auditory information from the cochlea to the corresponding cortical regions. Understanding the anatomy and physiology of all components forming the auditory system is key to better comprehending the pathophysiology of each disease that causes hearing impairment. In this narrative review, the authors focus on the pathophysiology as well as on cellular and molecular mechanisms that lead to hearing loss in different neonatal infectious diseases. To accomplish this objective, the morphology and function of the main structures responsible for auditory processing and the immune response leading to hearing loss were explored. Altogether, this information permits the proper understanding of each infectious disease discussed.
About 5 to 15% of all colorectal cancers harbor mismatch repair deficient/microsatellite instability-high status (dMMR/MSI-H) that associates with high tumor mutation burden and increased ...immunogenicity. As a result, and in contrast to other colorectal cancer phenotypes, a significant subset of dMMR/MSI-H cancer patients strongly benefit from immunotherapy. Yet, a large proportion of these tumors remain unresponsive to any immuno-modulating treatment. For this reason, current efforts are focused on the characterization of resistance mechanisms and the identification of predictive biomarkers to guide therapeutic decision-making. Here, we provide an overview on the new advances related to the diagnosis and definition of dMMR/MSI-H status and focus on the distinct clinical, functional, and molecular cues that associate with dMMR/MSI-H colorectal cancer. We review the development of novel predictive factors of response or resistance to immunotherapy and their potential application in the clinical setting. Finally, we discuss current and emerging strategies applied to the treatment of localized and metastatic dMMR/MSI-H colorectal tumors in the neoadjuvant and adjuvant setting.
Antioxidants are of great interest in multiple applications, so there is a growing trend in the search for antioxidant compounds of natural origin, such as the red algae
Palmaria palmata
and
Porphyra
...sp. A green ultrasound-assisted extraction method has been optimised to obtain the highest antioxidant activity, and subsequent characterisation of the antioxidant compounds present in the extracts. The antioxidant activity was determined by DPPH-RSA, FRAP and ORAC assays. The highest antioxidant activity was obtained for
Porphyra
sp. (DPPH: 87.64%, FRAP: 14.23 ± 0.76 µmol Fe
2+
g
-1
(DW) and ORAC: 106.81 ± 1.59 µmol TE g
-1
(DW)) extracts with significant differences in all tests compared to
P. palmata
(DPPH: 78.99%; FRAP: 2.65 ± 0.14 µmol Fe
2+
g
-1
(DW), and ORAC: 44.78 ± 0.53 µmol TE g
-1
(DW)). Subsequently, the content of pigments (phycobiliproteins, chlorophyll
a
and carotenoids), total polysaccharides content, total phenolic content and individual polyphenols of the optimised extracts were determined. The results suggest that the differences in antioxidant activity are mainly due to the presence of pigments and polyphenols, n particular, the polyphenols with the highest number of free hydroxyl groups in their chemical structure.
Graphical abstract
Glial cells participate actively in the early cognitive decline in Alzheimer's disease (AD) pathology. In fact, recent studies have found molecular and functional abnormalities in astrocytes and ...microglia in both animal models and brains of patients suffering from this pathology. In this regard, reactive gliosis intimately associated with amyloid plaques has become a pathological hallmark of AD. A recent study from our laboratory reports that astrocyte reactivity is caused by a direct interaction between amyloid beta (Aβ) oligomers and integrin β1. Here, we have generated four recombinant peptides including the extracellular domain of integrin β1, and evaluated their capacity both to bind in vitro to Aβ oligomers and to prevent in vivo Aβ oligomer-induced gliosis and endoplasmic reticulum stress. We have identified the minimal region of integrin β1 that binds to Aβ oligomers. This region is called signal peptide and corresponds to the first 20 amino acids of the integrin β1 N-terminal domain. This recombinant integrin β1 signal peptide prevented Aβ oligomer-induced ROS generation in primary astrocyte cultures. Furthermore, we carried out intrahippocampal injection in adult mice of recombinant integrin β1 signal peptide combined with or without Aβ oligomers and we evaluated by immunohistochemistry both astrogliosis and microgliosis as well as endoplasmic reticulum stress. The results show that recombinant integrin β1 signal peptide precluded both astrogliosis and microgliosis and endoplasmic reticulum stress mediated by Aβ oligomers in vivo. We have developed a molecular tool that blocks the activation of the molecular cascade that mediates gliosis via Aβ oligomer/integrin β1 signaling.
Aim
This study aimed to explore the experience and management of poor sleep quality in Spanish women with fibromyalgia (FM).
Design
This was a qualitative study based on one‐to‐one interviews.
...Methods
Twenty‐one adult women diagnosed with FM were recruited from the community between January and March 2020. Data were collected through in‐depth semistructured one‐to‐one interviews, using an interview guide of open questions about the experience and management of poor sleep quality, and were analyzed with thematic qualitative analysis. The symptom management theory was used as a biopsychosocial conceptual framework.
Results
The results were organized into two themes: (a) experience of poor sleep quality and (b) management strategies for poor sleep quality. Poor sleep quality was found to be a severe symptom of FM that negatively impacts pain, fatigue, stiffness, mental health, and quality of life. The participants perceived pharmacological treatment to be the main approach of health care professionals for improving sleep, and most did not want this form of treatment. Self‐management strategies lack clear beneficial effects on sleep quality.
Conclusion
Women with FM recognize that they need to receive more information from nurses and allied professions about sleep in the context of FM and how to effectively manage poor sleep quality.
Impact
This study contributes to a better understanding of how women with FM experience and manage poor sleep quality. More information about management strategies for poor sleep quality from nurses and other health care professionals is needed in women with FM. The results of this study can be applied by nurses and health care professionals, including sleep educators, in the treatment of this patient group.
•The algae Fucus vesiculosus has a great potential due to its antioxidant activity.•CE and UAE are equally effective for obtaining antioxidant extracts.•A negative correlation among polyphenols and ...its antioxidant activity was obtained.•HPLC-DAD has proved to be a reliable tool to differentiate antioxidant extracts.
Significant quantities of bioactive compounds have been found in the chemical composition of seaweeds. This source of natural antioxidants such as polyphenols appears to attenuate lipid peroxidation caused by oxidative stress, preventing the harmful effects of a number of injuries including ischemia–reperfusion (I/R). Conventional extraction (CE) has been used for years as a traditional method for obtaining bioactive components from seaweeds. However, recent studies highlight ultrasonic-assisted extraction (UAE) as an alternative and more eco-friendly technique. Therefore, the two methods were optimised and compared to obtain a Fucus vesiculosus extract (FVE) with high antioxidant activity and polyphenol content. The highest antioxidant activity was obtained after 1 h at 25 °C for conventional extraction, and after 5 min at 35 °C for ultrasonic-assisted extraction. Higher concentrations of polyphenols were obtained with the optimal conditions in conventional extraction (13.61 mg PGE/g seaweed), but no significant differences were observed between the antioxidant activity obtained with UAE (89.33%) and CE (89.74%). The characterization of the polyphenols present in both optimised extracts was carried out and compared with reverse-phase high-performance liquid chromatography coupled to a diode array detector (HPLC-DAD). The following compounds were identified: phloroglucinol, gallic acid, catechin, vanillic acid, epicatechin, protocatechuic acid, rutin, gentisic acid, chlorogenic acid, caffeic acid, coumaric acid and ferulic acid. RP-HPLC-DAD results also showed higher concentrations of polyphenols in optimised extracts with CE. Consequently, CE was found to be more effective than UAE in providing extracts with higher concentrations of polyphenols, but UAE constitutes an efficient and more eco-friendly methodology for obtaining a FVE with the highest antioxidant activity.
This work sought to formulate photocrosslinkable chlorhexidine (CHX)-laden methacrylated gelatin (CHX/GelMA) hydrogels with broad spectrum of action against endodontic pathogens as a clinically ...viable cell-friendly disinfection therapy prior to regenerative endodontics procedures.
CHX/GelMA hydrogel formulations were successfully synthesized using CHX concentrations between 0.12 % and 5 % w/v. Hydrogel microstructure was evaluated by scanning electron microscopy (SEM). Swelling and enzymatic degradation were assessed to determine microenvironmental effects. Compression test was performed to investigate the influence of CHX incorporation on the hydrogels’ biomechanics. The antimicrobial and anti-biofilm potential of the formulated hydrogels were assessed using agar diffusion assays and a microcosms biofilm model, respectively. The cytocompatibility was evaluated by exposing stem cells from human exfoliated deciduous teeth (SHEDs) to hydrogel extracts (i.e., leachable byproducts obtained from overtime hydrogel incubation in phosphate buffer saline). The data were analyzed using One- and Two-way ANOVA and Tukey’s test (α = 0.05).
CHX/GelMA hydrogels were effectively prepared. NMR spectroscopy confirmed the incorporation of CHX into GelMA. The addition of CHX did not change the micromorphology (pore size) nor the swelling profile (p > 0.05). CHX incorporation reduced the degradation rate of the hydrogels (p < 0.001); whereas, it contributed to increased compressive modulus (p < 0.05). Regarding the antimicrobial properties, the incorporation of CHX showed a statistically significant decrease in the number of bacteria colonies at 0.12 % and 0.5 % concentration (p < 0.001) and completely inhibited the growth of biofilm at concentration levels 1 %, 2 %, and 5 %. Meanwhile, the addition of CHX, regardless of the concentration, did not lead to cell toxicity, as cell viability values were above 70 %.
The addition of CHX into GelMA showed significant antimicrobial action against the pathogens tested, even at low concentrations, with the potential to be used as a cell-friendly injectable drug delivery system for root canal disinfection prior to regenerative endodontics.
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•Chlorhexidine-laden gelatin methacrylate hydrogel (CHX/GelMA) was synthesized.•CHX/GelMA showed significant antimicrobial action against endodontic pathogens.•CHX/GelMA holds potential for infection eradication prior to regenerative procedures.
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