Alterations in the self-renewal and differentiation ability of bone marrow mesenchymal stem cells in a mouse model of rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease primarily involving the synovium. Evidence in recent years has suggested that the bone marrow (BM) may be involved, and may even be the initiating site of the disease. Abnormalities in haemopoietic stem cells' (HSC) survival, proliferation and aging have been described in patients affected by RA and ascribed to abnormal support by the BM microenvironment. Mesenchymal stem cells (MSC) and their progeny constitute important components of the BM niche. In this study we test the hypothesis that the onset of inflammatory arthritis is associated with altered self-renewal and differentiation of bone marrow MSC, which alters the composition of the BM microenvironment. Methods: We have used Balb/C Interleukin-1 receptor antagonist knock-out mice, which spontaneously develop RA-like disease in 100% of mice by 20 weeks of age to determine the number of mesenchymal progenitors and their differentiated progeny before, at the start and with progression of the disease. Results: We showed a decrease in the number of mesenchymal progenitors with adipogenic potential and decreased bone marrow adipogenesis before disease onset. This is associated with a decrease in osteoclastogenesis. Moreover, at the onset of disease a significant increase in all mesenchymal progenitors is observed together with a block in their differentiation to osteoblasts. This is associated with accelerated bone loss. Conclusions: Significant changes occur in the BM niche with the establishment and progression of RA-like disease. Those changes may be responsible for aspects of the disease, including the advance of osteoporosis. An understanding of the molecular mechanisms leading to those changes may lead to new strategies for therapeutic intervention

Psi clustering for the assessment of underground infrastructure deterioration

Remote sensing images find application in several different domains, such as land cover or land usage observation, environmental monitoring, and urbanization. This latter field has recently witnessed an interesting development with the use of remote sensing for infrastructural monitoring. In this work, we present an analysis of Sentinel-1 images, which were used to monitor the Italian provinces of Bologna and Modena located at the Emilia Region Apennines foothill. The goal of this study was the development of a machine learning-based detection system to monitor the deterioration of public aqueduct infrastructures based on Persistent Scatterer Interferometry (PSI). We evaluated the land deformation over a temporal range of five years; these series feed a k-means clustering algorithm to separate the pixels of the region according to different deformation patterns. Furthermore, we defined the critical areas as those areas where different patterns collided or overlapped. The proposed approach provides an informative tool for the structural health monitoring of underground infrastructures

miR‐24 and its target gene Prdx6 regulate viability and senescence of myogenic progenitors during aging

Satellite cell-dependent skeletal muscle regeneration declines during aging. Disruptions within the satellite cells and their niche, together with alterations in the myofibrillar environment, contribute to age-related dysfunction and defective muscle regeneration. In this study, we demonstrated an age-related decline in satellite cell viability and myogenic potential and an increase in ROS and cellular senescence. We detected a transient upregulation of miR-24 in regenerating muscle from adult mice and downregulation of miR-24 during muscle regeneration in old mice. FACS-sorted satellite cells were characterized by decreased levels of miR-24 and a concomitant increase in expression of its target: Prdx6. Using GFP reporter constructs, we demonstrated that miR-24 directly binds to its predicted site within Prdx6 mRNA. Subtle changes in Prdx6 levels following changes in miR-24 expression indicate miR-24 plays a role in fine-tuning Prdx6 expression. Changes in miR-24 and Prdx6 levels were associated with altered mitochondrial ROS generation, increase in the DNA damage marker: phosphorylated-H2Ax and changes in viability, senescence, and myogenic potential of myogenic progenitors from mice and humans. The effects of miR-24 were more pronounced in myogenic progenitors from old mice, suggesting a context-dependent role of miR-24 in these cells, with miR-24 downregulation likely a part of a compensatory response to declining satellite cell function during aging. We propose that downregulation of miR-24 and subsequent upregulation of Prdx6 in muscle of old mice following injury are an adaptive response to aging, to maintain satellite cell viability and myogenic potential through regulation of mitochondrial ROS and DNA damage pathways

Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies

Metodologias utilizadas para detectar distúrbios emocionais em clínicas de assistência primária à saúde: revisão de literatura

A series of studies in the field of Epidemiological Psychiatry have been performed over the last two decades, and these have focused on the ability of primary care physicians to detect emotional disorders in the patients that attend their practices. The scientific methodology utilized in these studies is the subject of this review, which contains a discussion concerning: a) interviewer awareness bias; b) accuracy of the instruments and c) medical and psychological concepts involved in defining minor emotional disorders. Suggestions for change in the methodology are made in each of the sections of the review.Na área de epidemiologia psiquiátrica vêm sendo realizados, nos últimos vinte anos, estudos que têm como finalidade medir a habilidade que clínicos gerais possuem em detectar distúrbios emocionais nos pacientes que procuram atendimento na rede básica de saúde. A metodologia utilizada nesses estudos é o tema central da atual revisão, que contém a) viés do entrevistador; b) acuidade dos instrumentos; e c) conceitos médicos e psicológicos envolvidos na definição de distúrbio psiquiátrico menor. São também apresentadas sugestões para mudanças de metodologia

A toolbox for the longitudinal assessment of healthspan in ageing mice

The number of people aged over 65 is expected to double in the next 30 years. For many, living longer will mean spending more years with the burdens of chronic diseases such as Alzheimer’s, cardiovascular disease, and diabetes. Although researchers have made rapid progress in developing geroprotective interventions that target mechanisms of ageing and delay or prevent the onset of multiple concurrent age-related diseases, a lack of standardized techniques to assess healthspan in preclinical murine studies has resulted in reduced reproducibility and slowed progress. To overcome this, major centres in Europe and the USA skilled in healthspan analysis came together to agree upon a toolbox of techniques which can be used to consistently assess the healthspan of mice. Here, we describe the agreed toolbox which contains protocols for echocardiography, novel object recognition, grip strength, rotarod, glucose and insulin tolerance tests, body composition, and energy expenditure. They can be performed longitudinally in the same mouse over a period of 4-6 weeks to test how candidate geroprotectors affect cardiac, cognitive, neuromuscular and metabolic health

Human Embryonic and Fetal Mesenchymal Stem Cells Differentiate toward Three Different Cardiac Lineages in Contrast to Their Adult Counterparts

Mesenchymal stem cells (MSCs) show unexplained differences in differentiation potential. In this study, differentiation of human (h) MSCs derived from embryonic, fetal and adult sources toward cardiomyocytes, endothelial and smooth muscle cells was investigated. Labeled hMSCs derived from embryonic stem cells (hESC-MSCs), fetal umbilical cord, bone marrow, amniotic membrane and adult bone marrow and adipose tissue were co-cultured with neonatal rat cardiomyocytes (nrCMCs) or cardiac fibroblasts (nrCFBs) for 10 days, and also cultured under angiogenic conditions. Cardiomyogenesis was assessed by human-specific immunocytological analysis, whole-cell current-clamp recordings, human-specific qRT-PCR and optical mapping. After co-culture with nrCMCs, significantly more hESC-MSCs than fetal hMSCs stained positive for α-actinin, whereas adult hMSCs stained negative. Furthermore, functional cardiomyogenic differentiation, based on action potential recordings, was shown to occur, but not in adult hMSCs. Of all sources, hESC-MSCs expressed most cardiac-specific genes. hESC-MSCs and fetal hMSCs contained significantly higher basal levels of connexin43 than adult hMSCs and co-culture with nrCMCs increased expression. After co-culture with nrCFBs, hESC-MSCs and fetal hMSCs did not express α-actinin and connexin43 expression was decreased. Conduction velocity (CV) in co-cultures of nrCMCs and hESC-MSCs was significantly higher than in co-cultures with fetal or adult hMSCs. In angiogenesis bioassays, only hESC-MSCs and fetal hMSCs were able to form capillary-like structures, which stained for smooth muscle and endothelial cell markers.Human embryonic and fetal MSCs differentiate toward three different cardiac lineages, in contrast to adult MSCs. Cardiomyogenesis is determined by stimuli from the cellular microenvironment, where connexin43 may play an important role

Educating and Informing Patients Receiving Psychopharmacological Medications: Are Family Physicians in Pakistan up to the Task?

Introduction: Studies have shown a high prevalence of psychiatric illnesses among Patients in primary health care settings. Family physicians have a fundamental role in managing psychiatric illness with psychopharmacological medications. Providing information about the disease, its management and the potential adverse effects of the medications is an important part of the management of mental illnesses. Our objective was to determine if Patients who were prescribed psychopharmacological drugs by family physicians at a community health center in Karachi, Pakistan were provided adequate education about their disease and its management. Methods: A cross-sectional study was conducted at the Community Health Centre (CHC), Aga Khan University Hospital Karachi, Pakistan. Details about the prescriptions and Patient education were acquired from the Patients after their consultations. Results: A total of 354 adult Patients were interviewed during 3 days. Among them, 73 (20.6%) were prescribed psychopharmacological medications. Among Patients receiving psychopharmacological medicines, 37 (50.7%) did not know their diagnosis, 50 (68.5%) were unaware of the disease process, 52 (71.2%) were unaware of alternative treatments, 63 (86.3%) were not cautioned about the potential adverse effects of the drugs, 24 (32.9%) were unaware of the duration of treatment and in 60 (82.2%) of the participants an appropriate referral had not been discussed. For all aspects of education, Patients prescribed psychopharmacological medications knew less as compared to those Patients that were prescribed other medications. Discussion: The practice of imparting information to Patients who receive psychopharmacological medications seems to be inadequate in Pakistan. We have hypothesized about the possible reasons for our findings, and identified a need for further research to determine the cause for such findings and to address them accordingly. At the same time there is a need to educate family physicians in Pakistan about the special importance of providing adequate information to such Patients

Integrins α2β1 and α11β1 regulate the survival of mesenchymal stem cells on collagen I

Although mesenchymal stem cells (MSCs) are the natural source for bone regeneration, the exact mechanisms governing MSC crosstalk with collagen I have not yet been uncovered. Cell adhesion to collagen I is mostly mediated by three integrin receptors – α1β1, α2β1 and α11β1. Using human MSC (hMSC), we show that α11 subunit exhibited the highest basal expression levels but on osteogenic stimulation, both α2 and α11 integrins were significantly upregulated. To elucidate the possible roles of collagen-binding integrins, we applied short hairpin RNA (shRNA)-mediated knockdown in hMSC and found that α2 or α11 deficiency, but not α1, results in a tremendous reduction of hMSC numbers owing to mitochondrial leakage accompanied by Bcl-2-associated X protein upregulation. In order to clarify the signaling conveyed by the collagen-binding integrins in hMSC, we analyzed the activation of focal adhesion kinase, extracellular signal-regulated protein kinase and serine/threonine protein kinase B (PKB/Akt) kinases and detected significantly reduced Akt phosphorylation only in α2- and α11-shRNA hMSC. Finally, experiments with hMSC from osteoporotic patients revealed a significant downregulation of α2 integrin concomitant with an augmented mitochondrial permeability. In conclusion, our study describes for the first time that disturbance of α2β1- or α11β1-mediated interactions to collagen I results in the cell death of MSCs and urges for further investigations examining the impact of MSCs in bone conditions with abnormal collagen I