Renal lesions in patients with type 2 diabetes: A puzzle waiting to be solved

Three hundred sixty-six million people worldwide will be living with diabetes mellitus (DM) by 2030 ([1, 2]; http://www.idf.org/global-diabetes-plan-2011-2021). Prospectively, 75–150 million of these patients will develop a diabetic nephropathy (DN) or a non-diabetic renal disease (NDRD), either isolated or superimposed on DN [3, 4]. To date, the differential diagnosis between ND and NDRD remains a challenge that nephrologists are trying to win [5]

Diabetic kidney disease. new clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on "the natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function"

Recent epidemiological studies have disclosed heterogeneity in diabetic kidney disease (DKD). In addition to the classical albuminuric phenotype, two new phenotypes have emerged, i.e., “nonalbuminuric renal impairment” and “progressive renal decline”, suggesting that DKD progression toward end-stage kidney disease in diabetic patients may occur through two distinct pathways heralded by a progressive increase in albuminuria and decline in renal function independent of albuminuria, respectively. Besides the natural history of DKD, also the management of hyperglycemia in patients with type 2 diabetes and reduced renal function has profoundly changed in the last two decades. New anti-hyperglycemic drugs have become available for treatment of these individuals and the lowest estimated glomerular filtration rate safety thresholds for some of the old agents have been reconsidered. This joint document of the Italian Diabetes Society (SID) and the Italian Society of Nephrology (SIN) reviews the natural history of DKD in the light of the recent epidemiological literature and provides updated recommendations on anti-hyperglycemic treatment with non-insulin agents in DKD patients

Health Care Financing Reforms in Italy: Projects of Jefferson\u27s Center for Research in Medical Education and Health Care

No abstract available

Erratum to: Proteomics and diabetic nephropathy: what have we learned from a decade of clinical proteomics studies?

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Cardiac Cell Senescence and Redox Signaling

Aging is characterized by a progressive loss of the ability of the organism to cope with stressors and to repair tissue damage. As a result, chronic diseases, including cardiovascular disease, increase their prevalence with aging, underlining the existence of common mechanisms that lead to frailty and age-related diseases. In this frame, the progressive decline of the homeostatic and reparative function of primitive cells has been hypothesized to play a major role in the evolution of cardiac pathology to heart failure. Although initially it was believed that reactive oxygen species (ROS) were produced in an unregulated manner as a byproduct of cellular metabolism, causing macromolecular damage and aging, accumulating evidence indicate the major role played by redox signaling in physiology. Aim of this review is to critically revise evidence linking ROS to cell senescence and aging and to provide evidence of the primary role played by redox signaling, with a particular emphasis on the multifunctional protein APE1/Ref in stem cell biology. Finally, we will discuss evidence supporting the role of redox signaling in cardiovascular cells

The Italian experience of the national registry of renal biopsies

The Italian experience of the national registry of renal biopsies.BackgroundAlthough several registries collecting data of patients with kidney diseases exist, there are only a few registries which specifically collect data relating to renal biopsy; one such registry is the Italian Registry of Renal Biopsies (IRRB). The aim of this study was to report on the relative frequency of nephropathies according to gender, age at time of biopsy, clinical presentation and renal function, based on the histologic diagnosis during the years 1996 to 2000.MethodsWe evaluated data relating to 14607 renal biopsies, provided by 128 renal units in Italy. Data entry was performed by using the Internet-based database directly (URL http://www.irrb.net). Clinical presentation was defined as urinary abnormalities (UA), nephrotic syndrome (NS), acute nephritic syndrome (ANS). Renal diseases were divided in four major categories: (1) primary glomerulonephritides (GN); (2) secondary GN; (3) tubulointerstitial nephropathies (TIN); and (4) vascular nephropathies (VN).ResultsPrimary GN, TIN, and VN were more frequent in males compared to females while secondary GN was more frequent in females. Diseases whose frequency was higher in males were IgA nephropathy (IgAN), benign nephroangiosclerosis (BNA), and acute tubular necrosis (ATN). A significantly higher frequency of immune-mediated secondary GN, as well as primary GN, including minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and mesangiocapillary GN (MCGN), was shown in females. Primary and secondary GN, TIN, and VN were more frequent in the range 15 to 65 years of age. At the time of biopsy 77% of primary GN and 61% of secondary GN presented with normal renal function. Acute renal failure (ACR) was more present in TIN (52%), while chronic renal failure (CRF) was more frequent in VN (47%).ConclusionWe believe collection of data relating to renal biopsies in a national registry is a useful tool for nephrologists in that it meets one of the current challenges facing the clinical research enterprise. The availability of these data will allow epidemiologic studies in health care to answer the several open questions in both prevention and treatment of renal diseases

Role of microenvironment in glioma invasion: What we learned from in vitro models

The invasion properties of glioblastoma hamper a radical surgery and are responsible for its recurrence. Understanding the invasion mechanisms is thus critical to devise new therapeutic strategies. Therefore, the creation of in vitro models that enable these mechanisms to be studied represents a crucial step. Since in vitro models represent an over-simplification of the in vivo system, in these years it has been attempted to increase the level of complexity of in vitro assays to create models that could better mimic the behaviour of the cells in vivo. These levels of complexity involved: 1. The dimension of the system, moving from two-dimensional to three-dimensional models; 2. The use of microfluidic systems; 3. The use of mixed cultures of tumour cells and cells of the tumour micro-environment in order to mimic the complex cross-talk between tumour cells and their micro-environment; 4. And the source of cells used in an attempt to move from commercial lines to patient-based models. In this review, we will summarize the evidence obtained exploring these different levels of complexity and highlighting advantages and limitations of each system used

Systemic T cells immunosuppression of glioma stem cell-derived exosomes is mediated by monocytic myeloid-derived suppressor cells

A major contributing factor to glioma development and progression is its ability to evade the immune system. Nano-meter sized vesicles, exosomes, secreted by glioma-stem cells (GSC) can act as mediators of intercellular communication to promote tumor immune escape. Here, we investigated the immunomodulatory properties of GCS-derived exosomes on different peripheral immune cell populations. Healthy donor peripheral blood mononuclear cells (PBMCs) stimulated with anti-CD3, anti-CD28 and IL-2, were treated with GSC-derived exosomes. Phenotypic characterization, cell proliferation, Th1/Th2 cytokine secretion and intracellular cytokine production were analysed by distinguishing among effector T cells, regulatory T cells and monocytes. In unfractionated PBMCs, GSC-derived exosomes inhibited T cell activation (CD25 and CD69 expression), proliferation and Th1 cytokine production, and did not affect cell viability or regulatory T-cell suppression ability. Furthermore, exosomes were able to enhance proliferation of purified CD4+ T cells. In PBMCs culture, glioma-derived exosomes directly promoted IL-10 and arginase-1 production and downregulation of HLA-DR by unstimulated CD14+ monocytic cells, that displayed an immunophenotype resembling that of monocytic myeloid-derived suppressor cells (Mo-MDSCs). Importantly, the removal of CD14+ monocytic cell fraction from PBMCs restored T-cell proliferation. The same results were observed with exosomes purified from plasma of glioblastoma patients. Our results indicate that glioma-derived exosomes suppress T-cell immune response by acting on monocyte maturation rather than on direct interaction with T cells. Selective targeting of Mo-MDSC to treat glioma should be considered with regard to how immune cells allow the acquirement of effector functions and therefore counteracting tumor progression

Semaphorin-7A on Exosomes: A Promigratory Signal in the Glioma Microenvironment

Exosomes are one of the most important mediators of the cross talk occurring between glioma stem cells (GSCs) and the surrounding microenvironment. We have previously shown that exosomes released by patient-derived glioma-associated stem cells (GASC) are able to increase, in vitro, the aggressiveness of both GSC and glioblastoma cell lines. To understand which molecules are responsible for this tumour-supporting function, we performed a descriptive proteomic analysis of GASC-exosomes and identified, among the others, Semaphorin7A (SEMA7A). SEMA7A was described as a promigratory cue in physiological and pathological conditions, and we hypothesised that it could modulate GSC migratory properties. Here, we described that SEMA7A is exposed on GASC-exosomes' surface and signals to GSC through Integrin \u3b21. This interaction activates focal adhesion kinase into GSC and increases their motility, in our patient-based in vitro model. Our findings suggest SEMA7A-\u3b21-integrin as a new target to disrupt the communication between GSCs and the supporting microenvironment

Size-dependent cellular uptake of exosomes

The ability of exosomes to elicit specific cellular responses suggests that they may be increasingly used as therapeutics. Their vesicular nature makes them suitable as potential nanocarriers for drugs or nucleic acids delivery. Here we address the question whether the method of preparation of enriched exosomal fractions can affect their uptake by cells and their ability to trigger a response. We compared ultracentrifugation and polymer-based precipitation methods on supernatants of glioma-associated stem cells isolated from a high-grade glioma patient. We determined particle size distributions after purification and their correlation with uptake, proliferation and migration in glioblastoma cell cultures. Our findings indicate that polymer-based precipitation leads to smaller particle size distributions, faster uptake by target cells and increased cellular motility. The different effect that isolation method-dependent populations of particles have on cell motility suggests their size distribution could also profoundly affect exosome therapeutic potential