Prevalence of radicular neuropathic pain in idiopathic Parkinson's disease: a systematic review and meta-analysis.

Parkinson's disease (PD) is estimated to impact up to 1% of the global population aged 60 years and older. Among the non-motor manifestations of idiopathic PD, radicular neuropathic pain emerges as a noteworthy concern due to its potential for debility in affected individuals. In, this systematic review and meta-analysis we aimed to evaluate the prevalence of radicular neuropathic pain and thus provide evidence of how this painful symptom affects the lives of patients with idiopathic PD. We registered the research protocol for this study in PROSPERO (CRD42022327220). We searched the Embase, Scopus, and PubMed platforms for studies on PD and neuropathic pain until April 2023. The search yielded 36 articles considered to have a low risk of bias. The prevalence of radicular neuropathic pain in patients with PD was 12.7%, without a difference when we consider the duration of diagnosis (cut-off < 7 years) or levodopa dosage (cut-off <600mg/dL). Moreover, there was no variation in the prevalence of radicular neuropathic pain regarding a Hoehn and Yahr stage cut-off of <2.5 or >2.5. Of note, a limited number of patients received pain treatment (21.5%). We also found that the source of publication bias is the use of the Ford criteria (FC), suggesting that this type of diagnostic criteria may contribute to an underdiagnosis of radicular neuropathic pain in patients with PD. This study underlines the necessity for a more discerning and comprehensive approach to the diagnosis and management of radicular neuropathic pain in patients with idiopathic PD.

Targeting TRPV4 Channels for Cancer Pain Relief.

Despite the unique and complex nature of cancer pain, the activation of different ion channels can be related to the initiation and maintenance of pain. The transient receptor potential vanilloid 4 (TRPV4) is a cation channel broadly expressed in sensory afferent neurons. This channel is activated by multiple stimuli to mediate pain perception associated with inflammatory and neuropathic pain. Here, we focused on summarizing the role of TRPV4 in cancer etiology and cancer-induced pain mechanisms. Many studies revealed that the administration of a TRPV4 antagonist and TRPV4 knockdown diminishes nociception in chemotherapy-induced peripheral neuropathy (CIPN). Although the evidence on TRPV4 channels' involvement in cancer pain is scarce, the expression of these receptors was reportedly enhanced in cancer-induced bone pain (CIBP), perineural, and orofacial cancer models following the inoculation of tumor cells to the bone marrow cavity, sciatic nerve, and tongue, respectively. Effective pain management is a continuous problem for patients diagnosed with cancer, and current guidelines fail to address a mechanism-based treatment. Therefore, examining new molecules with potential antinociceptive properties targeting TRPV4 modulation would be interesting. Identifying such agents could lead to the development of treatment strategies with improved pain-relieving effects and fewer adverse effects than the currently available analgesics.

A miniaturised semi-dynamic in-vitro model of human digestion.

Reliable in-vitro digestion models that are able to successfully replicate the conditions found in the human gastrointestinal tract are key to assess the fate and efficiency of new formulations aimed for oral consumption. However, current in-vitro models either lack the capability to replicate crucial dynamics of digestion or require large volumes of sample/reagents, which can be scarce when working with nanomaterials under development. Here, we propose a miniaturised digestion system, a digestion-chip, based on incubation chambers integrated on a polymethylmethacrylate device. The digestion-chip incorporates key dynamic features of human digestion, such as gradual acidification and gradual addition of enzymes and simulated fluids in the gastric phase, and controlled gastric emptying, while maintaining low complexity and using small volumes of sample and reagents. In addition, the new approach integrates real-time automated closed-loop control of two key parameters, pH and temperature, during the two main phases of digestion (gastric and intestinal) with an accuracy down to ± 0.1 °C and ± 0.2 pH points. The experimental results demonstrate that the digestion-chip successfully replicates the gold standard static digestion INFOGEST protocol and that the semi-dynamic digestion kinetics can be reliably fitted to a first kinetic order model. These devices can be easily adapted to dynamic features in an automated, sensorised, and inexpensive platform and will enable reliable, low-cost and efficient assessment of the bioaccessibility of new and expensive drugs, bioactive ingredients or nanoengineered materials aimed for oral consumption, thereby avoiding unnecessary animal testing.

Açai (Euterpe oleracea Mart.) supplementation promotes histological and ultrastructural changes in rats' alveolar bone.

The açai juice contains high concentrations of phenolic compounds, including cyanidin-3-glucoside and others flavonoids. The aim of this study was to evaluate the impact of açai supplementation on healthy mandibular alveolar bone in male albino rats of the Wistar strain. 24 rats were divided into 3 groups, in which one group received a daily dose of saline solution and the other two groups were treated with daily doses of clarified açai juice for 14 or 28 days. After the experiment, hemimandibles were collected and analyzed using Scanning Electron Microscopy (SEM), histological assessments, and micro-CT. Results showed changes in the integrity of the alveolar bone as seen in SEM, increased osteocyte density and higher collagen matrix area in the açai group compared to the control group as seen in histological analysis, and increased bone volume, trabecular thickness and number, and cortical bone as seen in micro-CT analysis. The space between bone trabeculae showed no difference among the groups. These results suggest that açai supplementation may have a structural change effect on alveolar bone, but further research is needed to confirm these findings in humans and to determine the exact mechanisms behind these effects.

Head-to-head comparison of relevant cell sources of small extracellular vesicles for cardiac repair: Superiority of embryonic stem cells.

Small extracellular vesicles (sEV) derived from various cell sources have been demonstrated to enhance cardiac function in preclinical models of myocardial infarction (MI). The aim of this study was to compare different sources of sEV for cardiac repair and determine the most effective one, which nowadays remains limited. We comprehensively assessed the efficacy of sEV obtained from human primary bone marrow mesenchymal stromal cells (BM-MSC), human immortalized MSC (hTERT-MSC), human embryonic stem cells (ESC), ESC-derived cardiac progenitor cells (CPC), human ESC-derived cardiomyocytes (CM), and human primary ventricular cardiac fibroblasts (VCF), in in vitro models of cardiac repair. ESC-derived sEV (ESC-sEV) exhibited the best pro-angiogenic and anti-fibrotic effects in vitro. Then, we evaluated the functionality of the sEV with the most promising performances in vitro, in a murine model of MI-reperfusion injury (IRI) and analysed their RNA and protein compositions. In vivo, ESC-sEV provided the most favourable outcome after MI by reducing adverse cardiac remodelling through down-regulating fibrosis and increasing angiogenesis. Furthermore, transcriptomic, and proteomic characterizations of sEV derived from hTERT-MSC, ESC, and CPC revealed factors in ESC-sEV that potentially drove the observed functions. In conclusion, ESC-sEV holds great promise as a cell-free treatment for promoting cardiac repair following MI.

Shotgun metagenomics and systemic targeted metabolomics highlight indole-3-propionic acid as a protective gut microbial metabolite against influenza infection.

The gut-to-lung axis is critical during respiratory infections, including influenza A virus (IAV) infection. In the present study, we used high-resolution shotgun metagenomics and targeted metabolomic analysis to characterize influenza-associated changes in the composition and metabolism of the mouse gut microbiota. We observed several taxonomic-level changes on day (D)7 post-infection, including a marked reduction in the abundance of members of the Lactobacillaceae and Bifidobacteriaceae families, and an increase in the abundance of Akkermansia muciniphila. On D14, perturbation persisted in some species. Functional scale analysis of metagenomic data revealed transient changes in several metabolic pathways, particularly those leading to the production of short-chain fatty acids (SCFAs), polyamines, and tryptophan metabolites. Quantitative targeted metabolomics analysis of the serum revealed changes in specific classes of gut microbiota metabolites, including SCFAs, trimethylamine, polyamines, and indole-containing tryptophan metabolites. A marked decrease in indole-3-propionic acid (IPA) blood level was observed on D7. Changes in microbiota-associated metabolites correlated with changes in taxon abundance and disease marker levels. In particular, IPA was positively correlated with some Lactobacillaceae and Bifidobacteriaceae species (Limosilactobacillus reuteri, Lactobacillus animalis) and negatively correlated with Bacteroidales bacterium M7, viral load, and inflammation markers. IPA supplementation in diseased animals reduced viral load and lowered local (lung) and systemic inflammation. Treatment of mice with antibiotics targeting IPA-producing bacteria before infection enhanced viral load and lung inflammation, an effect inhibited by IPA supplementation. The results of this integrated metagenomic-metabolomic analysis highlighted IPA as an important contributor to influenza outcomes and a potential biomarker of disease severity.

Increased levels of advanced oxidation protein products (AOPPs) were associated with nociceptive behavior and clinical scores in an experimental progressive autoimmune encephalomyelitis model (PMS-EAE).

Multiple sclerosis (MS) is a neurodegenerative disease that affects the central nervous system (CNS) generating neuropathic pain and anxiety. Primary progressive MS (PPMS) is the most disabling clinical form, and the patients present an intense neurodegenerative process. In this context, the advanced oxidation protein products (AOPPs) are oxidized compounds and their accumulation in plasma has been related to clinical disability in MS patients. However, the involvement of AOPPs in neuropathic pain- and anxiety-like symptoms was not previously evaluated. To assess this, female mice C57BL/6J were used to induce progressive experimental autoimmune encephalomyelitis (PMS-EAE). Clinical score, weight, strength of plantar pressure, rotarod test, mechanical allodynia, and cold hypersensitivity were evaluated before induction (baseline) and on days 7th, 10th, and 14th post-immunization. We assessed nest building, open field, and elevated plus-maze tests 13 days post-immunization. Animals were killed at 14 days post-immunization; then, AOPPs levels, NADPH oxidase, and myeloperoxidase (MPO) activity were measured in the prefrontal cortex, hippocampus, and spinal cord samples. The clinical score increased 14th post-immunization without changes in weight and mobility. Reduced paw strength, mechanical allodynia, and cold allodynia increased in the PMS-EAE animals. PMS-EAE mice showed spontaneous nociception and anxiety-like behavior. AOPPs concentration, NADPH oxidase, and MPO activity increase in CNS structures. Multivariate analyses indicated that the rise of AOPPs levels, NADPH oxidase, and MPO activity influenced the clinical score and cold allodynia. Thus, we indicated the association between non-stimuli painful perception, anxiety-like, and CNS oxidative damage in the PMS-EAE model.

Nitric oxide involvement in the disability and active disease of multiple sclerosis: Systematic review and meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic and immune-mediated disease of unknown etiology and leading to a physical and cognitive disability. Different studies suggest that nitrosative stress may play a pivotal role in the pathogenesis and disability in MS. Besides, reports evaluated NO and their metabolites, expressed by nitrite and nitrate (NOx) levels of MS patients compared with other pathologies, but did not evaluate disability and relapse/remission phases. OBJECTIVE: Thus, this study aimed to conduct a systematic review and meta-analysis of NOx levels in MS patients in relapse/remission phases and its involvement in patient disability. METHODS: The protocol was registered in PROSPERO (CRD42022327161). We used GRADE to estimate the articles' quality and evaluated the publication bias using Egger's and Begg's tests. RESULTS: Here, through a search in the Pubmed, Scopus, and EMBASE databases, 5.276 studies were found, and after the selection process, 20 studies were included in this systematic review and meta-analysis. The studies included data from 1.474 MS patients and 1.717 healthy controls, 1.010 RRMS and 221 primary progressive MS (PPMS). CONCLUSION: NOx levels are increased in relapsing-remitting MS (RRMS) patients in the relapse phase. Also, NOx levels were increased in MS patients with higher disability. However, further studies are still needed to control lifestyle habits, pain, and MS treatment effects in biased NOx levels.

Low circulatory levels of total cholesterol, HDL-C and LDL-C are associated with death of patients with sepsis and critical illness: systematic review, meta-analysis, and perspective of observational studies.

BACKGROUND: Mechanistic studies have established a biological role of sterol metabolism in infection and immunity with clinical data linking deranged cholesterol metabolism during sepsis with poorer outcomes. In this systematic review we assess the relationship between biomarkers of cholesterol homeostasis and mortality in critical illness. METHODS: We identified articles by searching a total of seven electronic databases from inception to October 2023. Prospective observational cohort studies included those subjects who had systemic cholesterol (Total Cholesterol (TC), HDL-C or LDL-C) levels assessed on the first day of ICU admission and short-term mortality recorded. Meta-analysis and meta-regression were used to evaluate overall mean differences in serum cholesterol levels between survivors and non-survivors. Study quality was assessed using the Newcastle-Ottawa Scale. FINDINGS: From 6469 studies identified by searches, 24 studies with 2542 participants were included in meta-analysis. Non-survivors had distinctly lower HDL-C at ICU admission -7.06 mg/dL (95% CI -9.21 to -4.91, p < 0.0001) in comparison with survivors. Corresponding differences were also seen less robustly for TC -21.86 mg/dL (95% CI -31.23 to -12.49, p < 0.0001) and LDL-C -8.79 mg/dL (95% CI, -13.74 to -3.83, p = 0.0005). INTERPRETATION: Systemic cholesterol levels (TC, HDL-C and LDL-C) on admission to critical care are inversely related to mortality. This finding is consistent with the notion that inflammatory and metabolic setpoints are coupled, such that the maladaptive-setpoint changes of cholesterol in critical illness are related to underlying inflammatory processes. We highlight the potential of HDL-biomarkers as early predictors of severity of illness and emphasise that future research should consider the metabolic and functional heterogeneity of HDLs. FUNDING: EU-ERDF-Welsh Government Ser Cymru programme, BBSRC, and EU-FP7 ClouDx-i project (PG).

Ana1/CEP295 is an essential player in the centrosome maintenance program regulated by Polo kinase and the PCM.

Centrioles are part of centrosomes and cilia, which are microtubule organising centres (MTOC) with diverse functions. Despite their stability, centrioles can disappear during differentiation, such as in oocytes, but little is known about the regulation of their structural integrity. Our previous research revealed that the pericentriolar material (PCM) that surrounds centrioles and its recruiter, Polo kinase, are downregulated in oogenesis and sufficient for maintaining both centrosome structural integrity and MTOC activity. We now show that the expression of specific components of the centriole cartwheel and wall, including ANA1/CEP295, is essential for maintaining centrosome integrity. We find that Polo kinase requires ANA1 to promote centriole stability in cultured cells and eggs. In addition, ANA1 expression prevents the loss of centrioles observed upon PCM-downregulation. However, the centrioles maintained by overexpressing and tethering ANA1 are inactive, unlike the MTOCs observed upon tethering Polo kinase. These findings demonstrate that several centriole components are needed to maintain centrosome structure. Our study also highlights that centrioles are more dynamic than previously believed, with their structural stability relying on the continuous expression of multiple components.

Alpha-lipoic acid reduces nociception by reducing oxidative stress and neuroinflammation in a model of complex regional pain syndrome type I in mice.

Complex regional pain syndrome type I (CRPS-I) is a disabling pain condition without adequate treatment. Chronic post-ischemia pain injury (CPIP) is a model of CRPS-I that causes allodynia, spontaneous pain, inflammation, vascular injury, and oxidative stress formation. Antioxidants, such as alpha lipoic acid (ALA), have shown a therapeutic potential for CRPS-I pain control. Thus, we aim to evaluate if ALA repeated treatment modulates neuroinflammation in a model of CRPS-I in mice. We used male C57BL/6 mice to induce the CPIP model (O-ring torniquet for 2 h in the hindlimb). For the treatment with ALA or vehicle (Veh) mice were randomly separated in four groups and received 100 mg/kg orally once daily for 15 days (CPIP-ALA, CPIP-Veh, Control-ALA, and Control-Veh). We evaluated different behavioral tests including von Frey (mechanical stimulus), acetone (cold thermal stimulus), rotarod, open field, hind paw edema determination, and nest-building (spontaneous pain behavior). Also, hydrogen peroxide (H2O2) levels, NADPH oxidase and superoxide dismutase (SOD) activity in the sciatic nerve and spinal cord, and Iba1, Nrf2, and Gfap in spinal cord were evaluated at 16 days after CPIP or sham induction. Repeated ALA treatment reduced CPIP-induced mechanical and cold allodynia and restored nest-building capacity without causing locomotor or body weight alteration. ALA treatment reduced SOD and NADPH oxidase activity, and H2O2 production in the spinal cord and sciatic nerve. CPIP-induced neuroinflammation in the spinal cord was associated with astrocyte activation and elevated Nfr2, which were reduced by ALA. ALA repeated treatment prevents nociception by reducing oxidative stress and neuroinflammation in a model of CRPS-I in mice.

Byrsonima sericea Ethanol Extract Protected PC12 Cells from the Oxidative Stress and Apoptosis Induced by 6-Hydroxydopamine.

Parkinson's disease is characterized by the progressive loss of dopaminergic neurons in the nigrostriatal pathway and oxidative stress is one of the main mechanisms that lead to neuronal death in this disease. Previous studies have shown antioxidant activity from the leaves of Byrsonima sericea, a plant of the Malpighiaceae family. This study aimed to evaluate the cytoprotective activity of the B. sericea ethanolic extract (BSEE) against the cytotoxicity induced by 6-hydroxydopamine (6-OHDA) in PC12 cells, an in vitro model of parkinsonism. The identification of phenolic compounds in the extract by HPLC-DAD revealed the presence of geraniin, rutin, isoquercetin, kaempferol 3-O-ß-rutinoside, and quercetin. The BSEE (75-300 µg/mL) protected PC12 cells from toxicity induced by 6-OHDA (25 µg/mL), protected cell membrane integrity and showed antioxidant activity. BSEE was able to decrease nitrite levels, glutathione depletion, and protect cells from 6-OHDA-induced apoptosis. Thus, we suggest that the BSEE can be explored as a possible cytoprotective agent for Parkinson's disease due to its high antioxidant capacity and anti-apoptotic action.

Desafios da gestão e cuidado em centros de parto normal: estudo qualitativo com enfermeiros obstetras / Challenges of management and care in normal birth centers: qualitative study with obstetric nurses / Retos del manejo y atención en los centros de parto normal: estudio cualitativo con enfermeros obstétricos

RESUMO Objetivo: compreender os desafios para a gestão do trabalho e do cuidado em centros de parto normal por enfermeiras obstétricas. Método: estudo qualitativo realizado em centros de parto normal no Ceará, Brasil. Participaram 13 enfermeiros e coordenadores da assistência obstétrica, por entrevista, no período de abril a julho de 2020. As categorias temáticas foram organizadas no Software Nvivo 12 Pro® e discutidas com referencial teórico-filosófico da Sociologia das Profissões. Resultados: práticas de cuidado, como massagens de conforto, são realizadas associadas aos elementos da gestão do trabalho, como o dimensionamento da equipe de Enfermagem. Evidenciou-se que há habilidades importantes para atuar como autonomia e liderança da equipe de Enfermagem, mas elementos como a frágil confiança e a interação limitam o pleno desenvolvimento das atividades. Considerações finais: existem desafios para a gestão e o cuidado nos centros de parto normal, como a consolidação de autonomia e construção de confiança com a equipe de saúde.

ABSTRACT Objective: To understand obstetric nurses' challenges in managing work and care in normal birth centers. Method: A qualitative study was carried out in normal birth centers in Ceará, Brazil. Thirteen nurses and obstetric care coordinators were interviewed between April and July 2020. The thematic categories were organized in Nvivo 12 Pro® software and discussed using the theoretical-philosophical framework of the Sociology of Professions. Results: care practices, such as comfort massages, are carried out in conjunction with elements of work management, such as the sizing of the nursing team. It emerged that there are important skills for acting as autonomy and leadership of the nursing team, but elements such as fragile trust and interaction limit the full development of activities. Final considerations: there are challenges for management and care in normal birth centers, such as consolidating autonomy and building trust with the health team.

RESUMEN Objetivo: Comprender los desafíos para la gestión del trabajo y la atención en los centros de parto normal por parte de las enfermeras obstétricas. Método: estudio cualitativo realizado en centros de parto normal de Ceará, Brasil. Un total de 13 enfermeros y coordinadores de atención obstétrica participaron en entrevistas de abril a julio de 2020. Las categorías temáticas se organizaron en el Software Nvivo 12 Pro ® y se discutieron con el marco teórico-filosófico de la Sociología de las Profesiones. Resultados: las prácticas de cuidado, como los masajes de confort, se realizan asociadas a elementos de la gestión del trabajo, como el dimensionamiento del equipo de enfermería. Se evidenció que existen habilidades importantes para actuar como autonomía y liderazgo del equipo de enfermería, pero elementos como la confianza frágil y la interacción limitan el desarrollo pleno de las actividades. Consideraciones finales: existen desafíos para el manejo y la atención en los centros de parto normales, como la consolidación de la autonomía y la construcción de confianza con el equipo de salud.

Perception of professors and nurses about sexism in nursing / Percepção de enfermeiros e enfermeiras sobre o machismo na enfermagem

Know the perception of professors of a higher education institution who work in nursing care about sexism in their work environment. Therefore, the guiding question of this research was: What is the perception of professors and nurses about sexism in their work environment? Methodology: Descriptive and exploratory research, with a qualitative approach, carried out with nursing professionals and professors at a private college in the capital of Alagoas. Data were primarily collected through an electronic form developed by the researchers for qualitative analysis of the information, Bardin's content analysis was adopted. The research was approved by the Ethics Committee with opinion number: 4,719,368 Results: The study included 16 professors from the nursing course, who mostly reported having already suffered or witnessed sexist situations during care. Conclusion: From this research, it was observed that despite the predominance of women in nursing, there is still sexism present in care on the part of professionals and patients. Part of the professors participating in this study claimed to have suffered or witnessed situations of sexism and all agreed on the interference in the effectiveness of care. Awareness actions are needed for these professionals and the general public, including patients (AU).

Conhecer a percepção dos(as) docentes de uma instituição de ensino superior, que atuam na assistência de enfermagem sobre o machismo no seu ambiente de trabalho. Diante disso a questão norteadora desta pesquisa foi: Qual a percepção dos(as) docentes sobre o machismo no seu ambiente de trabalho? Métodos: Pesquisa descritiva e exploratória, de abordagem qualitativa, realizada com profissionais da enfermagem, docentes de uma faculdade particular da capital de Alagoas. Os dados foram primários, coletados através de um formulário eletrônico, elaborado pelas pesquisadoras, para análise qualitativa das informações foi adotada a análise de conteúdo de Bardin. Pesquisa aprovada pelo Comitê de Ética com nº de parecer: 4.719.368 Resultados: Foram participantes do estudo 16 docen-tes do curso de enfermagem, que referiram em sua maioria já ter sofrido ou presenciado situações machistas durante a assistência. Conclusão: A partir dessa pesquisa observou-se que ainda existe machismo na assistência, por parte de profissionais e pacientes. Parte dos docentes participantes deste estudo alegaram já ter sofrido ou presenciados situações de sexismo e todos acordaram em relação a interferência na eficácia da assistência. Sendo necessárias ações de conscientização destes profissionais e do público em geral, abrangendo também os pacientes (AU).

A systematic review and meta-analysis of neuropathic pain in multiple sclerosis: Prevalence, clinical types, sex dimorphism, and increased depression and anxiety symptoms.

Chronic pain is the most disability symptom related to multiple sclerosis (MS) brain lesions and can also generate anxiety and depression. There are no updated reports of the general prevalence of neuropathic pain, MS clinical types, sex dimorphism, and its association with depression and anxiety. The protocol was listed in PROSPERO (CRD42022303571). The article selection resulted in 24 studies with a low risk of bias. The prevalence of neuropathic pain in MS patients was 26.8% with higher levels of depression and anxiety. We also observed that female patients (74.2%) have a higher prevalence of neuropathic pain than males (28.9%). We showed the enhanced prevalence of neuropathic pain using the female and male data (58.9%) compared to the total prevalence (26.8%). In addition, the SPMS (40.3%) presented an increased prevalence of neuropathic pain compared to PPMS (15.6%). Thus, we demonstrated the association between neuropathic pain, depression and anxiety symptoms and the influence of diagnosis, age, disease score, and disease duration in the increased prevalence of neuropathic pain in MS patients.

Characterization of Depression- and Anxiety-Like Behaviours in a Mouse Model of Relapsing-Remitting Multiple Sclerosis.

Relapsing-remitting multiple sclerosis (RRMS) is an autoimmune neurological disease and is the most common subtype of MS. In addition, it is associated with the development of depression and anxiety. To date, depressive- and anxiety-like behaviours were only studied using models of progressive MS, which causes severe motor alterations. Thus, we sought to standardise the depressive and anxiety-like behaviours in an RRMS model induced by experimental autoimmune encephalomyelitis (RR-EAE) in mice. The RR-EAE model was induced in C57BL/6 female mice using myelin oligodendrocyte glycoprotein (MOG35-55) antigen and Quillaja saponin (Quil A) as an adjuvant. The immunisation of RR-EAE did not induce locomotor alteration but caused relapsing-remitting induction of clinical scores in mice until 35 post-immunization (p.i.). Also, increased levels of tumour necrosis factor alpha (TNF-α), astrocyte marker (GFAP), and microglial markers (IBA-1) were detected in the prefrontal cortex at 35 p.i. of RR-EAE. In the open field test, RR-EAE mice showed decreased time spent at the centre and sniffing behaviour (at days 21 and 34 p.i.). Also, on day 35 p.i. the RR-EAE group spent less time in the open arms and had decreased open-arm entries compared to control mice in the elevated plus maze (EPM) test, confirming the anxiety-like behaviour. At day 36° p.i. in the tail suspension test, mice showed depression-like behaviour with decreased latency time and increased immobility time. Thus, the RR-EAE model mimics the neuroinflammatory and behavioural features of the RRMS, including depression- and anxiety-like symptoms.

Impact of disease duration on proteomic bioprofile and prognosis in rheumatoid arthritis patients.

OBJECTIVES: Cardiovascular disease worsens the prognosis of rheumatoid arthritis (RA) and vice-versa. Inflammation may be a common pathway for both conditions. It is expected that a longer RA duration leads to a greater inflammatory cumulative exposure burden; however, studies on the association between RA disease duration and outcomes are scarce. Our aim is to compare the characteristics, biomarker expression and outcomes according to the duration of RA. METHODS: Prospective cohort study including 399 RA patients, with detailed clinical, echocardiographic, and proteomic phenotyping that were compared across tertiles of RA disease duration. Cox proportional models were used to study the association of disease duration with cardiovascular outcomes. RESULTS: RA duration tertiles were: tertile 1 with median of 3.2; tertile 2 with median of 8.8; and tertile 3 with median of 21.8 years. Compared to tertile 1, patients in tertile 3 were older, had more erosive disease, more frequent echocardiographic alterations, lower haemoglobin and walked a shorter distance on the 6MWT. Natriuretic peptides, cathepsin L1, galectin 9, matrix metalloproteinase-12, adrenomedullin and tumour necrosis factor receptor 11A were higher in patients with longer disease duration. Compared to patients in tertile 1, those in tertile 3 had higher risk of a subsequent cardiovascular hospitalisation or cardiovascular death (HR 2.71, 95%CI 1.06-6.92, p=0.04). CONCLUSIONS: RA patients with longer disease duration had more organ damage and worse outcomes than those with shorter disease duration. Biomarker expression suggested that patients with longer RA duration had activation of pathways related to inflammation, extracellular matrix organisation, fibrosis and congestion.

From mouth to gut: microfluidic in vitro simulation of human gastro-intestinal digestion and intestinal permeability.

Reproducible in vitro studies of bioaccessibility, intestinal absorption, and bioavailability are key to the successful development of novel food ingredients or drugs intended for oral administration. There is currently a lack of methods that offer the finesse required to study these parameters for valuable molecules typically found in small volumes - as is the case of nanomaterials, which are often used to carry and protect bioactives. Here, we describe a modular microfluidic-based platform for total simulation of the human gastro-intestinal tract. Digestion-chips and cell-based gut-chips were fabricated from PDMS by soft lithography. On-chip digestion was validated using a fluorescently labelled casein derivative, which followed typical Michaelis-Menten kinetics and showed temporal resolution and good agreement with well-established bench-top protocols. Irreversible inhibition of serine proteases using Pefabloc® SC and a 1 : 6 dilution was sufficient to mitigate the cytotoxicity of simulated digestion fluids. Caco-2/HT29-MTX co-cultures were grown on-chip under a continuous flow for 7 days to obtain a differentiated cell monolayer forming a 3D villi-like epithelium with clear tight junction formation, and with an apparent permeability (Papp) of Lucifer Yellow closely approximating values reported ex vivo (3.7 × 10-6 ± 1.4 × 10-6vs. 4.0 × 10-6 ± 2.2 × 10-6). Digesta from the digestion-chips were flowed through the gut-chip, demonstrating the capacity to study sample digestion and intestinal permeability in a single microfluidic platform holding great promise for use in pharmacokinetic studies.

The early impact of diets enriched with saturated and unsaturated fatty acids on intestinal inflammation and tight junctions.

The gut has been suggested as the first organ to be affected by unbalanced diets contributing to the obesogenic process. This study aimed to test a short time-course exposition model to a known pro- or anti-inflammatory enriched fatty diet to understand the early gut alterations. Male mice were exposed to the chow diet (CT), high-fat (HF) diet, or a high-fat diet partially replaced on flaxseed oil (FS), rich in omega-3 (ω3), for 14 days. HF and FS increased the total body weight mass compared with the CT group, but FS reduced the epididymal fat depot compared to HF. The bioinformatics from mice and human databases showed the Zo1-Ocln-Cldn7 tight junctions as the main protein-triad. In the ileum, the HF diet has increased IL1ß transcript and IL1ß, TNFα, and CD11b proteins, but reduced the tight junctions (Zo1, Ocln, and Cld7) compared to the CT group. Despite the FS diet being partially efficient in protecting the ileum against inflammation, the tight junctions were increased, compared to the HF group. The GPR120 and GPR40 receptors were unaffected by diets, but GPR120 was colocalized on the surface of ileum macrophages. The short period of a high-fat diet was enough to start the obesogenic process, ileum inflammation, and reduce the tight junctions. Flaxseed oil did not protect efficiently against dysmetabolism. Still, it increased the tight junctions, even without alteration on inflammatory parameters, suggesting the protection against gut permeability during early obesity development.