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As a feature of many chronic health problems, stigma contributes to a hidden burden of illness. Health-related stigma is typically characterized by social disqualification of individuals and populations who are identified with particular health problems. Another aspect is characterized by social disqualification targeting other features of a person's identity--such as ethnicity, sexual preferences or socio-economic status--which through limited access to services and other social disadvantages result in adverse effects on health. Health professionals therefore have substantial interests in recognizing and mitigating the impact of stigma as both a feature and a cause of many health problems. Rendering historical concepts of stigma as a discrediting physical attribute obsolete, two generations of Goffman-inspired sociological studies have redefined stigma as a socially discrediting situation of individuals. Based on that formulation and to specify health research interests, a working definition of health-related stigma is proposed. It emphasizes the particular features of target health problems and the role of particular social, cultural and economic settings in developing countries. As a practical matter, it relates to various strategies for intervention, which may focus on controlling or treating target health problems with informed health and social policies, countering the disposition of perpetrators to stigmatize, and supporting those who are stigmatized to limit their vulnerability and strengthen their resilience. Our suggestions for health studies of stigma highlight needs for disease- and culture-specific research that serves the interests of international health. [ABSTRACT FROM AUTHOR]

Background: Pediatric-onset Multiple Sclerosis (POMS) patients show more inflammatory disease compared with adult-onset MS. However, highly effective treatments are limited with only fingolimod being approved in Italy and natalizumab prescribed as off-label treatment., Objectives: to compare the efficacy of natalizumab versus fingolimod in POMS., Methods: This is an observational longitudinal multicentre study including natalizumab- and fingolimod-treated POMS patients (N-POMS and F-POMS, respectively). We collected Annual Relapse Rate (ARR), Expanded Disability Status Scale (EDSS), Symbol Digit Modality Test (SDMT), and MRI activity at baseline (T0), 12-18 months (T1), and last available observation (T2)., Results: We enrolled 57 N-POMS and 27 F-POMS patients from six Italian MS Centres. At T0, N-POMS patients showed higher ARR (p = 0.03), higher EDSS (p = 0.003) and lower SDMT (p = 0.04) at baseline compared with F-POMS. Between T 0 and T 1 ARR improved for both N-POMS and F-POMS (p < 0.001), while EDSS (p < 0.001) and SDMT (p = 0.03) improved only for N-POMS. At T 2 (66.1 ± 55.4 months) we collected data from 42 out of 57 N-POMS patients showing no further ARR decrease., Conclusion: Both natalizumab and fingolimod showed high and sustained efficacy in controlling relapses and natalizumab also associated to a disability decrease in POMS. This latter effect might be partly mediated by the high inflammatory activity at baseline in N-POMS., (© 2024. The Author(s).)

MicroRNAs (miRs) are known to regulate pro-inflammatory effector functions of myeloid cells, and miR dysregulation is implicated in rheumatoid arthritis (RA), a condition characterized by inflammation and destruction of the joints. We showed previously that miR-155 is increased in myeloid cells in RA and induces pro-inflammatory activation of monocytes and macrophages; however, its role at the interface between innate and adaptive immunity was not defined. Here, RNA-sequencing revealed that overexpression of miR-155 in healthy donor monocytes conferred a specific gene profile which bears similarities to that of RA synovial fluid-derived CD14+ cells and HLAhighISG15+ synovial tissue macrophages, both of which are characterized by antigen-presenting pathways. In line with this, monocytes in which miR-155 was overexpressed, displayed increased expression of HLA-DR and both co-stimulatory and co-inhibitory molecules, and induced activation of polyfunctional T cells. Together, these data underpin the notion that miR-155-driven myeloid cell activation in the synovium contributes not only to inflammation but may also influence the adaptive immune response., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Immunology.)

Since its discovery over 30 years ago the NF-ĸB family of transcription factors has gained the status of master regulator of the immune response. Much of what we understand of the role of NF-ĸB in immune development, homeostasis and inflammation comes from studies of mice null for specific NF-ĸB subunit encoding genes. The role of inflammation in diseases that affect a majority of individuals with health problems globally further establishes NF-ĸB as an important pathogenic factor. More recently, genomic sequencing has revealed loss of function mutations in the NFKB1 gene as the most common monogenic cause of common variable immunodeficiencies in Europeans. NFKB1 encodes the p105 subunit of NF-ĸB which is processed to generate the NF-ĸB p50 subunit. NFKB1 is the most highly expressed transcription factor in macrophages, key cellular drivers of inflammation and immunity. Although a key role for NFKB1 in the control of the immune system is apparent from Nfkb1 -/- mouse studies, we know relatively little of the role of NFKB1 in regulating human macrophage responses. In this study we use the THP1 monocyte cell line and CRISPR/Cas9 gene editing to generate a model of NFKB1 -/- human macrophages. Transcriptomic analysis reveals that activated NFKB1 -/- macrophages are more pro-inflammatory than wild type controls and express elevated levels of TNF , IL6 , and IL1B , but also have reduced expression of co-stimulatory factors important for the activation of T cells and adaptive immune responses such as CD70 , CD83 and CD209 . NFKB1 -/- THP1 macrophages recapitulate key observations in individuals with NFKB1 haploinsufficiency including decreased IL10 expression. These data supporting their utility as an in vitro model for understanding the role of NFKB1 in human monocytes and macrophages and indicate that of loss of function NFKB1 mutations in these cells is an important component in the associated pathology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Somma, Kok, Kerrigan, Wells and Carmody.)

We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1+ and FCN1+SPP1+ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48hiS100A12+ and CD48+SPP1+ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4+ predominant in healthy lung was transcriptionally related to STM cluster TREM2+ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post-COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1+ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14+ monocytes and development of PD-L1+ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post-COVID-19 pathology.

The transcription factor NF-ĸB is a master regulator of the innate immune response and plays a central role in inflammatory diseases by mediating the expression of pro-inflammatory cytokines. Ubiquitination-triggered proteasomal degradation of DNA-bound NF-ĸB strongly limits the expression of its target genes. Conversely, USP7 (deubiquitinase ubiquitin-specific peptidase 7) opposes the activities of E3 ligases, stabilizes DNA-bound NF-ĸB, and thereby promotes NF-ĸB-mediated transcription. Using gene expression and synthetic peptide arrays on membrane support and overlay analyses, we found here that inhibiting USP7 increases NF-ĸB ubiquitination and degradation, prevents Toll-like receptor-induced pro-inflammatory cytokine expression, and represents an effective strategy for controlling inflammation. However, the broad regulatory roles of USP7 in cell death pathways, chromatin, and DNA damage responses limit the use of catalytic inhibitors of USP7 as anti-inflammatory agents. To this end, we identified an NF-ĸB-binding site in USP7, ubiquitin-like domain 2, that selectively mediates interactions of USP7 with NF-ĸB subunits but is dispensable for interactions with other proteins. Moreover, we found that the amino acids 757 LDEL 760 in USP7 critically contribute to the interaction with the p65 subunit of NF-ĸB. Our findings support the notion that USP7 activity could be potentially targeted in a substrate-selective manner through the development of noncatalytic inhibitors of this deubiquitinase to abrogate NF-ĸB activity., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Mitxitorena et al.)

Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTK pos TREM2 high and MerTK pos LYVE1 pos ) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTK pos STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTK pos STM subpopulations could therefore be a potential treatment strategy for RA.

Proinflammatory responses induced by Toll-like receptors (TLRs) are dependent on the activation of the NF-ĸB and mitogen-activated protein kinase (MAPK) pathways, which coordinate the transcription and synthesis of proinflammatory cytokines. We demonstrate that BCL-3, a nuclear IĸB protein that regulates NF-ĸB, also controls TLR-induced MAPK activity by regulating the stability of the TPL-2 kinase. TPL-2 is essential for MAPK activation by TLR ligands, and the rapid proteasomal degradation of active TPL-2 is a critical mechanism limiting TLR-induced MAPK activity. We reveal that TPL-2 is a nucleocytoplasmic shuttling protein and identify the nucleus as the primary site for TPL-2 degradation. BCL-3 interacts with TPL-2 and promotes its degradation by promoting its nuclear localization. As a consequence, Bcl3 -/- macrophages have increased TPL-2 stability following TLR stimulation, leading to increased MAPK activity and MAPK-dependent responses. Moreover, BCL-3-mediated regulation of TPL-2 stability sets the MAPK activation threshold and determines the amount of TLR ligand required to initiate the production of inflammatory cytokines. Thus, the nucleus is a key site in the regulation of TLR-induced MAPK activity. BCL-3 links control of the MAPK and NF-ĸB pathways in the nucleus, and BCL-3-mediated TPL-2 regulation impacts on the cellular decision to initiate proinflammatory cytokine production in response to TLR activation., Competing Interests: The authors declare no competing interest., (Copyright © 2019 the Author(s). Published by PNAS.)

In Italy, the Banco Alimentare Onlus manages a network of 8,000 charitable organizations that distribute 67,000 tons of foodstuffs to 1.6 million needy persons. To provide their volunteers with the required food safety knowledge, the Banco Alimentare del Piemonte Onlus commissioned the Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta to hold training courses in food safety. Before and after each session, the participants completed a questionnaire to evaluate their knowledge on the topic of food safety. The responses were entered in a dedicated database and analyzed using STATA ver. 15.1. Comparison of the scores for each participant before and after training revealed a considerable discordance [ICC 0.06, 95% confidence interval (CI) 0.00-0.18]. Analysis of the post-training questionnaires showed that the number of questions left unanswered decreased and the number of correct answers increased. The difference between the percentage of correct and incorrect responses before and after the training course was statistically significant (P<0.001). Comparison of responses to the pre- and post-training questionnaires provided the data for statistical evaluation of the efficacy of the training course., Competing Interests: Conflict of interest: The authors declare no potential conflict of interest., (©Copyright: the Author(s), 2019.)

Phosphorylation of the NF-κB transcription factor is an important regulatory mechanism for the control of transcription. Here we identify serine 80 (S80) as a phosphorylation site on the p50 subunit of NF-κB, and IKKβ as a p50 kinase. Transcriptomic analysis of cells expressing a p50 S80A mutant reveals a critical role for S80 in selectively regulating the TNFα inducible expression of a subset of NF-κB target genes including pro-inflammatory cytokines and chemokines. S80 phosphorylation regulates the binding of p50 to NF-κB binding (κB) sites in a sequence specific manner. Specifically, phosphorylation of S80 reduces the binding of p50 at κB sites with an adenine at the -1 position. Our analyses demonstrate that p50 S80 phosphorylation predominantly regulates transcription through the p50:p65 heterodimer, where S80 phosphorylation acts in trans to limit the NF-κB mediated transcription of pro-inflammatory genes. The regulation of a functional class of pro-inflammatory genes by the interaction of S80 phosphorylated p50 with a specific κB sequence describes a novel mechanism for the control of cytokine-induced transcriptional responses., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Sphingosine 1-phosphate (S1P) has a role in many cellular processes. S1P is involved in cell growth and apoptosis, regulation of cell trafficking, production of cytokines and chemokines. The kinases SphK1 and SphK2 (SphKs) phosphorilate Sphingosine (Sph) to S1P and several phosphatases revert S1P to sphingosine, thus assuring a balanced pool that can be depleted by a Sphingosine lyase in hexadecenal compounds and aldehydes. There are evidences that SphK1 and 2 may per se control cellular processes. Here, we report that Sph kinases regulate IL-17 expression in human T cells. SphKs inhibition impairs the production of IL-17, while their overexpression up-regulates expression of the cytokine through acetylation of IL-17 promoter. SphKs were up-regulated also in PBMCs of patients affected by IL-17 related diseases. Thus, S1P/S1P kinases axis is a mechanism likely to promote IL-17 expression in human T cells, representing a possible therapeutic target in human inflammatory diseases.

Water monitoring requires expensive instrumentations and skilled technicians. In developing Countries as Africa, the severe economic restrictions and lack of technology make water safety monitoring approaches applied in developed Countries, still not sustainable. The need to develop new methods that are suitable, affordable, and sustainable in the African context is urgent. The simple, economic and rapid Micro Biological Survey (MBS) method does not require an equipped laboratory nor special instruments and skilled technicians, but it can be very useful for routine water analysis. The aim of this work was the application of the MBS method to evaluate the microbiological safety of different water sources and the effectiveness of different drinking water treatments in the Horn of Africa. The obtained results have proved that this method could be very helpful to monitor water safety before and after various purification treatments, with the aim to control waterborne diseases especially in developing Countries, whose population is the most exposed to these diseases. In addition, it has been proved that Moringa oleifera water treatment is ineffective in decreasing bacterial load of Eritrea water samples.

The aim of our study is to investigate the behaviour of healthy and tendinopathic human tenocytes after a heat shock. After we harvested tendinopathic and healthy human tendon samples, we split tenocytes into 4 groups: 3 groups were submitted to heat shock, followed by different periods of post-heating (2, 4 and 20 h). The other group represents our negative control. The target genes were analysed using Real Time PCR. IL-1β and IL-6 expression were significantly increased in tendinopathic samples after heat shock. COL1 and COL3 expression were increased in non-stimulated tendinopathic tenocytes, but their levels significantly decreased after heat shock (p less than 0.01). COL3 levels increase in healthy samples after 20 h post-heating (p less than 0.01). COL1 and COL3 decreased after heat shock as a sign of the failure of repair mechanisms in tendinopathic tendons. Heat shock in in vitro models was insufficient to trigger pro-inflammatory cytokines in healthy human tenocytes.

Diatoms are an important class of unicellular algae that produce bioactive secondary metabolites with cytotoxic activity collectively termed oxylipins, including polyunsaturated aldehydes (PUAs), hydroxyacids (HEPEs), oxo-acids and epoxyalcohols. Previous results showed that at higher concentrations, the PUA decadienal induced apoptosis on copepods and sea urchin embryos via caspase-3 activation; at lower concentrations decadienal affected the expression levels of the caspase-8 gene in embryos of the sea urchin Paracentrotus lividus. In the present work, we studied the effects of other common oxylipins produced by diatoms: two PUAs (heptadienal and octadienal) and four hydroxyacids (5-, 9- 11- and 15-HEPE) on P. lividus cell death and caspase activities. Our results showed that (i) at higher concentrations PUAs and HEPEs induced apoptosis in sea urchin embryos, detected by microscopic observation and through the activation of caspase-3/7 and caspase-8 measured by luminescent assays; (ii) at low concentrations, PUAs and HEPEs affected the expression levels of caspase-8 and caspase-3/7 (isolated for the first time here in P. lividus) genes, detected by Real Time qPCR. These findings have interesting implications from the ecological point of view, given the importance of diatom blooms in nutrient-rich aquatic environments., (Copyright © 2016 Elsevier B.V. All rights reserved.)

IL-17 is a proinflammatory cytokine that promotes the expression of different cytokines and chemokines via the induction of gene transcription and the posttranscriptional stabilization of mRNAs. In this study, we show that IL-17 increases the half-life of the Zc3h12a mRNA via interaction of the adaptor protein CIKS with the DEAD box protein DDX3X. IL-17 stimulation promotes the formation of a complex between CIKS and DDX3X, and this interaction requires the helicase domain of DDX3X but not its ATPase activity. DDX3X knockdown decreases the IL-17-induced stability of Zc3h12a without affecting the stability of other mRNAs. IKKε, TNFR-associated factor 2, and TNFR-associated factor 5 were also required to mediate the IL-17-induced Zc3h12a stabilization. DDX3X directly binds the Zc3h12a mRNA after IL-17 stimulation. Collectively, our findings define a novel, IL-17-dependent mechanism regulating the stabilization of a selected mRNA., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Context: We have previously identified neutrophil gelatinase-associated lipocalin (NGAL) as one of the genes mediating the oncogenic activity of nuclear factor-κB in human anaplastic thyroid carcinomas (ATCs)., Objectives: To further investigate the role of NGAL in thyroid cancer, we established NGAL knocked-down and NGAL overexpressing ATC cell lines., Results: We found that the ability of NGAL knocked-down cells to degrade Matrigel in a transwell invasion assay and to form lung metastasis in nude mice was decreased. Because NGAL binds matrix metalloproteinase-9 (MMP-9), to form a macromolecular complex involved in the regulation of metastatic spread of cancer cells and given the strong expression of both genes in tissue specimens from human ATCs, we analyzed the MMP-9 enzymatic activity in NGAL-null ATC cells. Enzymatic immunoassays show that MMP-9 activity is reduced in NGAL-null ATC cells, even if its expression is not affected by NGAL inhibition. Ectopic expression of NGAL in an ATC cell line not expressing NGAL determines an increase of its metastatic property. The use of a mutated form of NGAL, unable to bind MMP-9, has no positive effect on the invasive potential of ATC cells and does not improve the MMP-9 enzymatic activity., Conclusions: Our results indicate NGAL as a novel target of nuclear factor-κB prometastatic activity in thyroid cancer through enhancement of MMP-9 enzymatic activity.

Meningiomas of the spine are the most common benign intradural extramedullary lesions and account for 25%-46% of all spinal cord tumors in adults. The goal of treatment is complete surgical resection while preserving spinal stability. Usually, these lesions occur in the thoracic region and in middle-aged women. Clinical presentation is usually nonspecific and the symptoms could precede the diagnosis by several months to years, especially in older people, in whom associated age-related diseases can mask the tumor for a long time. We report a series of 30 patients, aged 70 years or more, harboring intradural extramedullary spinal meningiomas. No subjects had major contraindications to surgery. A minimally invasive approach ( hemilaminectomy and preservation of the outer dural layer) was used to remove the tumor, while preserving spinal stability and improving the watertight dural closure. We retrospectively compared the outcomes in these patients with those in a control group subjected to laminectomy or laminotomy with different dural management. In our experience, the minimally invasive approach allows the same chances of complete tumor removal, while providing a better postoperative course than in a control group.

Setting: TB control programmes in Bangladesh, India and Malawi., Objective: To identify and compare socio-cultural features of tuberculosis (TB) and the distribution of TB-related experiences, meanings and behaviours with reference to gender across cultures in three high-endemic low-income countries., Design: Approximately 100 patients at three sites were interviewed with in-depth semi-structured Explanatory Model Interview Catalogue (EMIC) interviews inquiring about patterns of distress, perceived causes and help-seeking behaviours in the context of illness narratives., Results: Female patients reported more diverse symptoms and men more frequently focused on financial concerns. Most patients reported psychological and emotional distress. Men emphasised smoking and drinking alcohol as causes of TB, and women in Malawi reported sexual causes associated with HIV/AIDS. In Bangladesh, exaggerated concerns about the risk of spread despite treatment contributed to social isolation of women. Public health services were preferred in Malawi, and private doctors in India and Bangladesh., Conclusion: Cross-site analysis of these studies has identified features of TB that influence the burden of disease and are likely to affect timely help seeking and adherence to treatment. Health systems benefit from sex-disaggregated epidemiological data complemented by cultural epidemiological study, which together clarify the role of gender and contribute to the knowledge base for TB control at various levels.

Setting: Tuberculosis (TB) control programmes in Bangladesh, India, Malawi and Colombia., Objective: Assess indicators of TB-related stigma and socio-cultural and gender-related features of illness associated with stigma., Design: Semi-structured Explanatory Model Interview Catalogue (EMIC) interviews were administered to 100 or more patients at each site, assessing categories of distress, perceived causes and help seeking. Indicators of self-perceived stigma were analysed individually and in a validated index, which was compared across sites and between men and women at each site. Cultural epidemiological explanatory variables for stigma and interactions with female sex were analysed at each site. Qualitative illness narratives were examined to explain the role and context of explanatory variables., Results: The overall stigma index was highest in India, lowest in Malawi and greater for women in Bangladesh. In India and Malawi, women were more likely to be concerned about impact on marital prospects. Associations with HIV/AIDS were linked to TB stigma in Malawi, where sexual contact as a perceived cause was more associated with stigma for men and less for women., Conclusion: Stigma both influences and indicates the effectiveness of TB control. Cultural epidemiological methods clarify cross-cutting and local features of stigma and gender for TB control.