Linear regression models and k-means clustering for statistical analysis of fNIRS data

We propose a new algorithm, based on a linear regression model, to statistically estimate the hemodynamic activations in fNIRS data sets. The main concern guiding the algorithm development was the minimization of assumptions and approximations made on the data set for the application of statistical tests. Further, we propose a K-means method to cluster fNIRS data (i.e. channels) as activated or not activated. The methods were validated both on simulated and in vivo fNIRS data. A time domain (TD) fNIRS technique was preferred because of its high performances in discriminating cortical activation and superficial physiological changes. However, the proposed method is also applicable to continuous wave or frequency domain fNIRS data sets

The osmo-metabolic approach: a novel and tantalizing glucose-sparing strategy in peritoneal dialysis.

Peritoneal dialysis (PD) is a viable but under-prescribed treatment for uremic patients. Concerns about its use include the bio-incompatibility of PD fluids, due to their potential for altering the functional and anatomical integrity of the peritoneal membrane. Many of these effects are thought to be due to the high glucose content of these solutions, with attendant issues of products generated during heat treatment of glucose-containing solutions. Moreover, excessive intraperitoneal absorption of glucose from the dialysate has many potential systemic metabolic effects. This article reviews the efforts to develop alternative PD solutions that obviate some of these side effects, through the replacement of part of their glucose content with other osmolytes which are at least as efficient in removing fluids as glucose, but less impactful on patient metabolism. In particular, we will summarize clinical studies on the use of alternative osmotic ingredients that are commercially available (icodextrin and amino acids) and preclinical studies on alternative solutions under development (taurine, polyglycerol, carnitine and xylitol). In addition to the expected benefit of a glucose-sparing approach, we describe an 'osmo-metabolic' approach in formulating novel PD solutions, in which there is the possibility of exploiting the pharmaco-metabolic properties of some of the osmolytes to attenuate the systemic side effects due to glucose. This approach has the potential to ameliorate pre-existing co-morbidities, including insulin resistance and type-2 diabetes, which have a high prevalence in the dialysis population, including in PD patients

Impact of the rs1024611 polymorphism of ccl2 on the pathophysiology and outcome of primary myelofibrosis

Single nucleotide polymorphisms (SNPs) can modify the individual pro-inflammatory background and may therefore have relevant implications in the MPN setting, typified by aberrant cytokine production. In a cohort of 773 primary myelofibrosis (PMF), we determined the contribution of the rs1024611 SNP of CCL2—one of the most potent immunomodulatory chemokines—to the clinical and biological characteristics of the disease, demonstrating that male subjects carrying the homozygous genotype G/G had an increased risk of PMF and that, among PMF patients, the G/G genotype is an independent prognostic factor for reduced overall survival. Functional characterization of the SNP and the CCL2-CCR2 axis in PMF showed that i) homozygous PMF cells are the highest chemokine producers as compared to the other genotypes; ii) PMF CD34+ cells are a selective target of CCL2, since they uniquely express CCR2 (CCL2 receptor); iii) activation of the CCL2-CCR2 axis boosts pro-survival signals induced by driver mutations via Akt phosphorylation; iv) ruxolitinib effectively counteracts CCL2 production and down-regulates CCR2 expression in PMF cells. In conclusion, the identification of the role of the CCL2/CCR2 chemokine system in PMF adds a novel element to the pathophysiological picture of the disease, with clinical and therapeutic implications

Efficacy and safety of tacrolimus compared with ciclosporin A in renal transplantation: three-year observational results

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HOXB7 expression by myeloma cells regulates their pro-angiogenic properties in multiple myeloma patients

The deregulation of the homeobox genes as homeoboxB (HOXB)-7 has been previously associated to tumor progression and angiogenesis; here we investigated the potential role of HOXB7 in the pro-angiogenic properties of multiple myeloma (MM) cells. We found that HOXB7 was expressed in 10 out of 22 MM patients analyzed at the diagnosis related to high bone marrow angiogenesis and overexpressed in about 40% of myeloma cell lines compared with normal plasma cells. Enforced HOXB7 expression in MM cells by a lentiviral vector significantly modified their transcriptional and angiogenic profile, checked by combined microarray and angiogenesis PCR analyses, upregulating VEGFA, FGF2, MMP2, WNT5a and PDGFA and downregulating thrombospoindin-2. The pro- and anti-angiogenic HOXB7-related gene signature was also validated in a large independent dataset of MM patients. Accordingly, MM-induced vessel formation was significantly increased by HOXB7 overexpression both in vitro angiogenic and chorioallantoic membrane assays, as well as the HOXB7 silencing by small interfering RNA inhibited the production of angiogenic factors, and the pro-angiogenic properties of MM cells. Finally, in SCID-NOD mice we confirmed that HOXB7 overexpression by MM cells stimulated tumor growth, increased MM-associated angiogenesis and the expression of pro-angiogenic genes by microarray analysis supporting the critical role of HOXB7 in the angiogenic switch in M

Why is soluble intercellular adhesion molecule-1 related to cardiovascular mortality?

Background: Increased plasma levels of soluble adhesion molecules are associated with an increased risk of atherothrombosis. The pathophysiological mechanisms responsible for these associations are not known. The aim of the present study was to investigate the association of soluble intercellular adhesion molecule-1 (sICAM-1) concentration and risk of cardiovascular and all-cause mortality among individuals with and without type 2 diabetes. In addition, we assessed potential pathophysiological mechanisms by which sICAM-1 may promote mortality. Materials and methods: Six hundred and thirty-one subjects taken from a general population of the middle-aged and elderly participated in this prospective cohort study. Baseline data collection was performed from 1989 to 1992; subjects were followed until 1 January 2000. Results: Subjects who died had higher levels of sICAM-1 than those who survived (506(164) vs. 477(162) ng m

IL21R expressing CD14+CD16+ monocytes expand in multiple myeloma patients leading to increased osteoclasts

Bone marrow monocytes are primarily committed to osteoclast formation. It is, however, unknown whether potential primary alterations are specifically present in bone marrow monocytes of multiple myeloma patients, smoldering myeloma or monoclonal gammopathy of uncertain significance. Herein, we analyzed the immunophenotypic and transcriptional profiles of bone marrow CD14+ monocytes in a cohort of patients with different types of monoclonal gammopathies to identify alterations involved in myeloma-enhanced osteoclastogenesis. A higher number of bone marrow CD14+CD16+ cells was found in patients with active myeloma as compared to those with smoldering myeloma and monoclonal gammopathy of uncertain significance. Interestingly, sorted bone marrow CD14+CD16+ cells from myeloma patients were more pro-osteoclastogenic than CD14+CD16- cells in cultures ex vivo. Moreover, transcriptional analysis demonstrated that bone marrow multiple myeloma (but neither monoclonal gammopathy of uncertain significance nor smoldering myeloma) CD14+ cells significantly upregulated genes involved in osteoclast formation, including IL21R. IL21R mRNA over-expression by bone marrow CD14+ cells was independent from the presence of IL-21. Consistently, IL-21 production by T cells as well as IL-21 bone marrow levels were not significantly different among monoclonal gammopathies. Thereafter, we showed that IL21R over-expression in CD14+ cells increased osteoclast formation. Consistently, IL-21R signaling inhibition by Janex 1 suppressed osteoclast differentiation from bone marrow CD14+ cells of myeloma patients. Our results indicated that multiple myeloma patients showed distinct bone marrow monocyte features compared to those with indolent monoclonal gammopathies, supporting the role of IL21R over-expression by bone marrow CD14+ cells in enhanced osteoclast formation

Mechanisms of Endothelial Dysfunction in Resistance Arteries from Patients with End-Stage Renal Disease

The study focuses on the mechanisms of endothelial dysfunction in the uremic milieu. Subcutaneous resistance arteries from 35 end-stage renal disease (ESRD) patients and 28 matched controls were studied ex-vivo. Basal and receptor-dependent effects of endothelium-derived factors, expression of endothelial NO synthase (eNOS), prerequisites for myoendothelial gap junctions (MEGJ), and associations between endothelium-dependent responses and plasma levels of endothelial dysfunction markers were assessed. The contribution of endothelium-derived hyperpolarizing factor (EDHF) to endothelium-dependent relaxation was impaired in uremic arteries after stimulation with bradykinin, but not acetylcholine, reflecting the agonist-specific differences. Diminished vasodilator influences of the endothelium on basal tone and enhanced plasma levels of asymmetrical dimethyl L-arginine (ADMA) suggest impairment in NO-mediated regulation of uremic arteries. eNOS expression and contribution of MEGJs to EDHF type responses were unaltered. Plasma levels of ADMA were negatively associated with endothelium-dependent responses in uremic arteries. Preserved responses of smooth muscle to pinacidil and NO-donor indicate alterations within the endothelium and tolerance of vasodilator mechanisms to the uremic retention products at the level of smooth muscle. We conclude that both EDHF and NO pathways that control resistance artery tone are impaired in the uremic milieu. For the first time, we validate the alterations in EDHF type responses linked to kinin receptors in ESRD patients. The association between plasma ADMA concentrations and endothelial function in uremic resistance vasculature may have diagnostic and future therapeutic implications

Computational approaches to explainable artificial intelligence: Advances in theory, applications and trends

Deep Learning (DL), a groundbreaking branch of Machine Learning (ML), has emerged as a driving force in both theoretical and applied Artificial Intelligence (AI). DL algorithms, rooted in complex and non-linear artificial neural systems, excel at extracting high-level features from data. DL has demonstrated human-level performance in real-world tasks, including clinical diagnostics, and has unlocked solutions to previously intractable problems in virtual agent design, robotics, genomics, neuroimaging, computer vision, and industrial automation. In this paper, the most relevant advances from the last few years in Artificial Intelligence (AI) and several applications to neuroscience, neuroimaging, computer vision, and robotics are presented, reviewed and discussed. In this way, we summarize the state-of-the-art in AI methods, models and applications within a collection of works presented at the 9th International Conference on the Interplay between Natural and Artificial Computation (IWINAC). The works presented in this paper are excellent examples of new scientific discoveries made in laboratories that have successfully transitioned to real-life applications.MCIU - Nvidia(UMA18-FEDERJA-084