Lymphatic endothelial cells are a replicative niche for Mycobacterium tuberculosis

In extrapulmonary tuberculosis, the most common site of infection is within the lymphatic system, and there is growing recognition that lymphatic endothelial cells (LECs) are involved in immune function. Here, we identified LECs, which line the lymphatic vessels, as a niche for Mycobacterium tuberculosis in the lymph nodes of patients with tuberculosis. In cultured primary human LECs (hLECs), we determined that M. tuberculosis replicates both in the cytosol and within autophagosomes, but the bacteria failed to replicate when the virulence locus RD1 was deleted. Activation by IFN-γ induced a cell-autonomous response in hLECs via autophagy and NO production that restricted M. tuberculosis growth. Thus, depending on the activation status of LECs, autophagy can both promote and restrict replication. Together, these findings reveal a previously unrecognized role for hLECs and autophagy in tuberculosis pathogenesis and suggest that hLECs are a potential niche for M. tuberculosis that allows establishment of persistent infection in lymph nodes

On the relations between historical epistemology and students’ conceptual developments in mathematics

There is an ongoing discussion within the research field of mathematics education regarding the utilization of the history of mathematics within mathematics education. In this paper we consider problems that may emerge when the historical epistemology of mathematics is paralleled to students’ conceptual developments in mathematics. We problematize this attempt to link the two fields on the basis of Grattan-Guinness’ distinction between “history” and “heritage”. We argue that when parallelism claims are made, history and heritage are often mixed up, which is problematic since historical mathematical definitions must be interpreted in its proper historical context and conceptual framework. Furthermore, we argue that cultural and local ideas vary at different time periods, influencing conceptual developments in different directions regardless of whether historical or individual developments are considered, and thus it may be problematic to uncritically assume a platonic perspective. Also, we have to take into consideration that an average student of today and great mathematicians of the past are at different cognitive levels

Integrated strategies to prevent intradialytic hypotension: research protocol of the DialHypot study, a prospective randomised clinical trial in hypotension-prone haemodialysis patients

INTRODUCTION: In patients on maintenance haemodialysis (HD), intradialytic hypotension (IDH) is a clinical problem that nephrologists and dialysis nurses face daily in their clinical routine. Despite the technological advances in the field of HD, the incidence of hypotensive events occurring during a standard dialytic treatment is still very high. Frequently recurring hypotensive episodes during HD sessions expose patients not only to severe immediate complications but also to a higher mortality risk in the medium term. Various strategies aimed at preventing IDH are currently available, but there is lack of conclusive data on more integrated approaches combining different interventions. METHODS AND ANALYSIS: This is a prospective, randomised, open-label, crossover trial (each subject will be used as his/her own control) that will be performed in two distinct phases, each of which is divided into several subphases. In the first phase, 27 HD sessions for each patient will be used, and will be aimed at the validation of a new ultrafiltration (UF) profile, designed with an ascending/descending shape, and a standard dialysate sodium concentration. In the second phase, 33 HD sessions for each patient will be used and will be aimed at evaluating the combination of different UF and sodium profiling strategies through individualised dialysate sodium concentration. ETHICS AND DISSEMINATION: The trial protocol has been reviewed and approved by the local Institutional Ethics Committee (Comitato Etico AVEN, prot. 43391 22.10.19). The results of the trial will be presented at local and international conferences and submitted for publication to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03949088)

A balanced formula of essential amino acids promotes brain mitochondrial biogenesis and protects neurons from ischemic insult

Mitochondrial dysfunction plays a key role in the aging process, and aging is a strong risk factor for neurodegenerative diseases or brain injury characterized by impairment of mitochondrial function. Among these, ischemic stroke is one of the leading causes of death and permanent disability worldwide. Pharmacological approaches for its prevention and therapy are limited. Although non-pharmacological interventions such as physical exercise, which promotes brain mitochondrial biogenesis, have been shown to exert preventive effects against ischemic stroke, regular feasibility is complex in older people, and nutraceutical strategies could be valuable alternatives. We show here that dietary supplementation with a balanced essential amino acid mixture (BCAAem) increased mitochondrial biogenesis and the endogenous antioxidant response in the hippocampus of middle-aged mice to an extent comparable to those elicited by treadmill exercise training, suggesting BCAAem as an effective exercise mimetic on brain mitochondrial health and disease prevention. In vitro BCAAem treatment directly exerted mitochondrial biogenic effects and induced antioxidant enzyme expression in primary mouse cortical neurons. Further, exposure to BCAAem protected cortical neurons from the ischemic damage induced by an in vitro model of cerebral ischemia (oxygen-glucose deprivation, OGD). BCAAem-mediated protection against OGD was abolished in the presence of rapamycin, Torin-1, or L-NAME, indicating the requirement of both mTOR and eNOS signaling pathways in the BCAAem effects. We propose BCAAem supplementation as an alternative to physical exercise to prevent brain mitochondrial derangements leading to neurodegeneration and as a nutraceutical intervention aiding recovery after cerebral ischemia in conjunction with conventional drugs

Protect, promote and support: A warm chain of breastfeeding for oncological women-results from a survey of young Italian cancer mothers

The topic of lactation following cancer diagnosis will become increasingly more current. Although oncological research confirms that breastfeeding after cancer might be possible, there is a lack of guidelines and a good recommendation for oncological women. In the absence of specific recommendations, women with past cancer may be at higher risk for psychological distress related to breastfeeding. The objective of this article was to analyse the experience of breastfeeding in new mothers with a history of cancer compared to women without a cancer diagnosis. First, we explored the impact of the cancer diagnosis on the breastfeeding choice. Second, we evaluated the relationship between different feeding methods and the mother's mood states in women with and without a history of cancer. The sample was composed of 74 mothers divided into two groups: 34 with a cancer history (clinical sample) and 40 without a cancer diagnosis (control group). Participants were requested to complete a questionnaire three months after childbirth which assessed: Socio-demographic and clinical data, feeding modes (breastfeeding, formula and mixed feeding) and the profile of mood states (POMS). Results showed that women in the clinical group breastfeed significantly less and use formula more than those in the control group. Moreover, in the clinical group, women who breastfeed feel reported higher levels of confusion (according to POMS) than mothers who bottle-feed or use a mixed feeding method. On the contrary, in the control sample, women who breastfeed feel significantly more vigorous than puerperae who bottle-feed or use mixed methods according to POMS. Our findings suggest the need for a specific warm chain of support and the development of guidelines with clear and specific information for women with a cancer diagnosis in order to reduce their confusion around breastfeeding

Nanoparticles combining host-directed therapeutics and antibiotics to boost bacterial killing and overall survival of Zebrafish embryos infected with mycobacterium Marinum

Drug Delivery Technolog

Real-time imaging of polymersome nanoparticles in zebrafish embryos engrafted with melanoma cancer cells: Localization, toxicity and treatment analysis

BACKGROUND: The developing zebrafish is an emerging tool in nanomedicine, allowing non-invasive live imaging of the whole animal at higher resolution than is possible in the more commonly used mouse models. In addition, several transgenic fish lines are available endowed with selected cell types expressing fluorescent proteins; this allows nanoparticles to be visualized together with host cells. METHODS: Here, we introduce the zebrafish neural tube as a robust injection site for cancer cells, excellently suited for high resolution imaging. We use light and electron microscopy to evaluate cancer growth and to follow the fate of intravenously injected nanoparticles. FINDINGS: Fluorescently labelled mouse melanoma B16 cells, when injected into this structure proliferated rapidly and stimulated angiogenesis of new vessels. In addition, macrophages, but not neutrophils, selectively accumulated in the tumour region. When injected intravenously, nanoparticles made of Cy5-labelled poly(ethylene glycol)-block-poly(2-(diisopropyl amino) ethyl methacrylate) (PEG-PDPA) selectively accumulated in the neural tube cancer region and were seen in individual cancer cells and tumour associated macrophages. Moreover, when doxorubicin was released from PEG-PDPA, in a pH dependant manner, these nanoparticles could strongly reduce toxicity and improve the treatment outcome compared to the free drug in zebrafish xenotransplanted with mouse melanoma B16 or human derived melanoma cells. INTERPRETATION: The zebrafish has the potential of becoming an important intermediate step, before the mouse model, for testing nanomedicines against patient-derived cancer cells. FUNDING: We received funding from the Norwegian research council and the Norwegian cancer society

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

Real-time imaging of polymersome nanoparticles in zebrafish embryos engrafted with melanoma cancer cells: Localization, toxicity and treatment analysis

Background: The developing zebrafish is an emerging tool in nanomedicine, allowing non-invasive live imaging of the whole animal at higher resolution than is possible in the more commonly used mouse models. In addition, several transgenic fish lines are available endowed with selected cell types expressing fluorescent proteins; this allows nanoparticles to be visualized together with host cells. Methods: Here, we introduce the zebrafish neural tube as a robust injection site for cancer cells, excellently suited for high resolution imaging. We use light and electron microscopy to evaluate cancer growth and to follow the fate of intravenously injected nanoparticles. Findings: Fluorescently labelled mouse melanoma B16 cells, when injected into this structure proliferated rapidly and stimulated angiogenesis of new vessels. In addition, macrophages, but not neutrophils, selectively accumulated in the tumour region. When injected intravenously, nanoparticles made of Cy5-labelled poly(ethylene glycol)-block-poly(2-(diisopropyl amino) ethyl methacrylate) (PEG-PDPA) selectively accumulated in the neural tube cancer region and were seen in individual cancer cells and tumour associated macrophages. Moreover, when doxorubicin was released from PEG-PDPA, in a pH dependant manner, these nanoparticles could strongly reduce toxicity and improve the treatment outcome compared to the free drug in zebrafish xenotransplanted with mouse melanoma B16 or human derived melanoma cells. Interpretation: The zebrafish has the potential of becoming an important intermediate step, before the mouse model, for testing nanomedicines against patient-derived cancer cells

Conservative surgery with and without radiotherapy in elderly patients with early-stage breast cancer: a prospective randomised multicentre trial.

ABSTRACT Breast conserving therapy (BCT) including postoperative irradiation of the remaining breast tissue is generally accepted as the best treatment for the majority of patients with early-stage breast cancer. The question is whether there is a necessity for irradiating all patients. Between 2001 and 2005, 749 women aged 55–75 years with infiltrating breast carcinoma were randomly assigned to breast conservative surgery, with or without radiotherapy (RT), to evaluate the incidence of in-breast recurrence (IBR). After 5 years of median follow-up, the cumulative incidence of IBR was 2.5% in the surgery-only arm and 0.7% in the surgery plus RT arm. There are no differences in terms of overall survival and distant disease-free survival. The preliminary evaluation suggests that breast irradiation after conservative surgery can be avoided without exposing these patients to an increased risk of distant-disease recurrence. Prolonged follow-up will further clarify the possible risks and late sequelae potentially induced by breast RT