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Kupffer cells (KCs) are highly abundant, intravascular, liver-resident macrophages known for their scavenger and phagocytic functions. KCs can also present antigens to CD8+ T cells and promote either tolerance or effector differentiation, but the mechanisms underlying these discrepant outcomes are poorly understood. Here, we used a mouse model of hepatitis B virus (HBV) infection, in which HBV-specific naive CD8+ T cells recognizing hepatocellular antigens are driven into a state of immune dysfunction, to identify a subset of KCs (referred to as KC2) that cross-presents hepatocellular antigens upon interleukin-2 (IL-2) administration, thus improving the antiviral function of T cells. Removing MHC-I from all KCs, including KC2, or selectively depleting KC2 impaired the capacity of IL-2 to revert the T cell dysfunction induced by intrahepatic priming. In summary, by sensing IL-2 and cross-presenting hepatocellular antigens, KC2 overcome the tolerogenic potential of the hepatic microenvironment, suggesting new strategies for boosting hepatic T cell immunity.

The responses of CD8+ T cells to hepatotropic viruses such as hepatitis B range from dysfunction to differentiation into effector cells, but the mechanisms that underlie these distinct outcomes remain poorly understood. Here we show that priming by Kupffer cells, which are not natural targets of hepatitis B, leads to differentiation of CD8+ T cells into effector cells that form dense, extravascular clusters of immotile cells scattered throughout the liver. By contrast, priming by hepatocytes, which are natural targets of hepatitis B, leads to local activation and proliferation of CD8+ T cells but not to differentiation into effector cells; these cells form loose, intravascular clusters of motile cells that coalesce around portal tracts. Transcriptomic and chromatin accessibility analyses reveal unique features of these dysfunctional CD8+ T cells, with limited overlap with those of exhausted or tolerant T cells; accordingly, CD8+ T cells primed by hepatocytes cannot be rescued by treatment with anti-PD-L1, but instead respond to IL-2. These findings suggest immunotherapeutic strategies against chronic hepatitis B infection.

Il contributo propone un'analisi dei cambiamenti delle forme di povertà e marginalità sociale indotti dall'emergenza Covid-19 nel contesto della città di Brescia

Il contributo propone un'analisi dei cambiamenti delle forme di povertà e marginalità sociale indotti dall'emergenza Covid-19 nel contesto della città di Brescia

This paper estimates a discrete choice model of time allocation decisions made by university students. We consider investments in academic and non-academic activities, such as job placements or volunteering. Identification is achieved using data collected through a recent survey of UK university students on subjective expectations about the returns to these activities, and the enjoyment students derive from them. Unobserved heterogeneity in the choice set is addressed using a sufficient set logit method. The analysis reveals significant ethnic differences in the level of investments, expected academic and labour market returns, and enjoyment of academic and non-academic activities. Simulations suggest that existing constraints play an important role in explaining ethnic gaps in investments.

This paper estimates a discrete choice model of time allocation decisions made by university students. We consider investments in academic and non-academic activities, such as job placements or volunteering. Identification is achieved using data collected through a recent survey of UK university students on subjective expectations about the returns to these activities, and the enjoyment students derive from them. Unobserved heterogeneity in the choice set is addressed using a sufficient set logit method. The analysis reveals significant ethnic differences in the level of investments, expected academic and labour market returns, and enjoyment of academic and non-academic activities. Simulations suggest that existing constraints play an important role in explaining ethnic gaps in investments.

Background Generic formulations of imatinib mesylate have been introduced in Western Europe since 2017 to treat patients with chronic myeloid leukemia (CML). However, results on the safety and efficacy of generic formulations are contrasting. The aim of this study was to investigate the safety and efficacy of generic imatinib in CML patients treated in 12 Italian institutes. Methods This is an observational, retro-prospective analysis of patients with CML for whom the treatment was switched from brand to generic imatinib. We analyzed and compared the variation in quantitative PCR values before and after the switch, and the proportion of patients who maintained molecular response after changing from brand to generic imatinib. Adverse events (AEs) were also evaluated. Results Two hundred patients were enrolled. The median PCR value after the switch was reduced by 0.25 compared to the values before the switch. A significant difference was found between median PCR values before and after the switch in favor of generic imatinib (P = 0.003). Molecular responses remained stable in 69.0%, improved in 25.5%, and worsened in 5.5% of patients. AEs were similar in the pre- and post-switch periods; however, a significant difference was found in favor of generic imatinib for muscular cramps (P < 0.0001), periorbital edema (P=0.0028), edema of the limbs (P <0.0001), fatigue (P =0.0482), and diarrhea (P=0.0027). Conclusion Our data indicate that generic imatinib does not have deleterious effects on CML control and present an acceptable safety profile, similar or better than brand imatinib.

Contains fulltext : 118639.pdf (publisher's version ) (Open Access), Somatic mutations of the RNA splicing machinery have been recently identified in myelodysplastic syndromes. In particular, a strong association has been found between SF3B1 mutation and refractory anemia with ring sider-oblasts, a condition characterized by ineffective erythropoiesis and parenchymal iron overload. We studied the relationship between SF3B1 mutation, erythroid activity and hepcidin levels in myelodysplastic syndrome patients. Erythroid activity was evaluated through the proportion of marrow erythroblasts, soluble transferrin receptor and serum growth differentiation factor 15. Significant relationships were found between SF3B1 mutation and marrow erythroblasts (P=0.001), soluble transferrin receptor (P=0.003) and serum growth differentiation factor 15 (P=0.033). Serum hepcidin varied considerably, and multivariable analysis showed that the hepcidin to ferritin ratio, a measure of adequacy of hepcidin levels relative to body iron stores, was inversely related to the SF3B1 mutation (P=0.013). These observations suggest that patients with SF3B1 mutation have inappropriately low hepcidin levels, which may explain their propensity to parenchymal iron loading.

Contains fulltext : 118639.pdf (publisher's version ) (Open Access), Somatic mutations of the RNA splicing machinery have been recently identified in myelodysplastic syndromes. In particular, a strong association has been found between SF3B1 mutation and refractory anemia with ring sider-oblasts, a condition characterized by ineffective erythropoiesis and parenchymal iron overload. We studied the relationship between SF3B1 mutation, erythroid activity and hepcidin levels in myelodysplastic syndrome patients. Erythroid activity was evaluated through the proportion of marrow erythroblasts, soluble transferrin receptor and serum growth differentiation factor 15. Significant relationships were found between SF3B1 mutation and marrow erythroblasts (P=0.001), soluble transferrin receptor (P=0.003) and serum growth differentiation factor 15 (P=0.033). Serum hepcidin varied considerably, and multivariable analysis showed that the hepcidin to ferritin ratio, a measure of adequacy of hepcidin levels relative to body iron stores, was inversely related to the SF3B1 mutation (P=0.013). These observations suggest that patients with SF3B1 mutation have inappropriately low hepcidin levels, which may explain their propensity to parenchymal iron loading.

The aim of this paper is to disentangle the role of gender and partnership status in the caring commitments of older people (age 65 and over). Logistic and interval regression models are applied to individual records from the 2001 UK Census to estimate: (1) the impact of gender on the likelihood of being a carer; (2) the impact of gender on the hours of care provided; and (3) the impact of gender on the likelihood of being a carer for different groups defined by marital status. In the general population the share of women who provide care is higher than the corresponding share of men, but men have a higher probability of being carers among people aged 65 or above. This phenomenon is largely explained by gender differences in marital status. As older men are more likely to be married, and married people are more likely to be carers, we observe higher levels of caring among older men. Once differences in marital status are accounted for, the relationship between gender and care provision among older people is overturned. In particular, we find that, without controlling for household size, limiting long-term illness or marital status, the odds of being an informal carer are lower for older women than men [odds ratio (OR): 0.85; 95% confidence interval (CI): 0.83–0.87]. Once these factors are accounted for, older women have higher odds of caring than older men (OR: 1.12; 95% CI: 1.09–1.15). Restricting the sample to care providers, and controlling for the same factors, it is shown that older women supply on average 3.77 (95% CI: 3.14–4.40) more hours of care per week than older men. Gender differences in the provision of care among older people disappear only when considering married individuals and adjusting for the presence of other household residents affected by a limiting long-term illness.

Nowadays, intervertebral disc (IVD) degeneration is one of the principal causes of low back pain involving high expense within the health care system. The long-term goal is the development of a medical treatment modality focused on a more biological regeneration of the inner nucleus pulposus (NP). Hence, interest in the endoscopic implantation of an injectable material took center stage in the recent past. We report on the development of a novel polyurethane (PU) scaffold as a mechanically stable carrier system for the reimplantation of expanded autologous IVD-derived cells (disc cells) to stimulate regenerative processes and restore the chondrocyte-like tissue within the NP. Primary human disc cells were seeded into newly developed PU spheroids which were subsequently encapsulated in fibrin hydrogel. The study aims to analyze adhesion properties, proliferation capacity and phenotypic characterization of these cells. Polymerase chain reaction was carried out to detect the expression of genes specifically expressed by native IVD cells. Biochemical analyses showed an increased DNA content, and a progressive enhancement of total collagen and glycosaminoglycans (GAG) was observed during cell culture. The results suggest the synthesis of an appropriate extracellular matrix as well as a stable mRNA expression of chondrogenic and/or NP specific markers. In conclusion, the data presented indicate an alternative medical approach to current treatment options of degenerated IVD tissue.

The methodology, significance and clinical importance of the bronchial challenge based on the inhalation of an ultrasonic mist of distilled water is discussed in detail

The UN Security Council's response to Ebola in 2014 legitimised militarised responses. It also influenced responses to COVID-19 in some African countries. Yet, little is known about the day-to-day impacts for ordinary citizens of mobilising armies for epidemic control. Drawing on 18 months ethnographic research, this article analyses militarised responses to COVID-19 during, and following, two lockdowns at contrasting sites in Uganda: a small town in Pakwach district and a village in Kasese district. Both field sites lie close to the border of the Democratic Republic of Congo. Although the practice of health security varied between sites, the militarised response had more impact than the disease in these two places. The armed forces scaled back movement from urban conurbations to rural and peri-urban areas; while simultaneously enabling locally based official public authorities to use the proclaimed priorities of President Museveni's government to enhance their position and power. This led to a situation whereby inhabitants created new modes of mutuality to resist or subvert the regulations being enforced, including the establishment of new forms of cross-border movement. These findings problematise the widely held view that Uganda's response to COVID-19 was successful. Overall, it is argued that the on-going securitisation of global health has helped to create the political space to militarise the response. While this has had unknown effects on the prevalence of COVID-19, it has entrenched unaccountable modes of public authority and created a heightened sense of insecurity on the ground. The tendency to condone the violent practice of militarised public health programmes by international and national actors reflects a broader shift in the acceptance of more authoritarian forms of governance.