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Nader Tarabeih,1,2 Alexander Kalinkovich,1 Adel Shalata,3 Stacey S Cherny,1 Gregory Livshits1,4 1Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 2Maale HaCarmel Mental Health Center, Affiliated to Rappaport Faculty of Medicine Technion, Israel Institute of Technology, Haifa, Israel; 3The Simon Winter Institute for Human Genetics, Bnai Zion Medical Center, The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel; 4Adelson School of Medicine, Ariel University, Ariel, IsraelCorrespondence: Gregory LivshitsDepartment of Morphological Studies, Adelson School of Medicine, Ariel University, Ariel, 40700, Israel, Tel +972-3-6409494, Fax +972-3-6408287, Email zviliv@ariel.ac.ilPurpose: Low back pain (LBP) is one of the major disabling health conditions in aging societies presenting significant cost burdens to health and social care systems. Its complications and associated disability are often accompanied by mental disorders, metabolic comorbidities, changed body composition, and inflammation. However, their mutual relationships in LBP-associated disability remain unclear.Methods: In the present case-control study, a self-report validated questionnaire was used to collect LBP disability data in an ethnically homogeneous Israeli Arab sample (489 males and 589 females). Body composition parameters were assessed through bioelectrical impedance analysis and plasma levels of soluble markers by EISA. Comorbidity status was assessed in personal interview and from the individual medical files.Results: Our mixed multiple regression analysis identified that GDF-15 (β = 0.160, p = 2.95× 10-8), vaspin (β = 0.085, p = 0.003), follistatin (β = 0.076, p = 0.001), extracellular water (β = 0.096, p = 0.001), waist hip ratio (β = 0.072, p = 0.009), mental disorders (β = 0.077, p = 0.001), and metabolic comorbidities (β = 0.059, p = 0.02) were significantly associated with LBP disability scores, when controlling for age and sex effects. Additive Bayesian network modelling further suggests that LBP disability appears to be directly influenced by age, sex, GDF-15, and extracellular water, and indirectly by mental and metabolic disorders, waist-hip ratio, and follistatin. LBP, in turn, seems to affect the vaspin levels directly.Conclusion: Our data suggest the existence of a complex, age-associated, and probably hierarchical, relationship between LBP disability and mental and metabolic disorders, inflammation-related soluble markers, and body composition parameters.Keywords: low back pain, disability, GDF-15, follistatin, vaspin, body composition, depression, comorbidities

It is now established that patients with rheumatoid arthritis (RA) have an increased risk of developing cervical cancer (CC) or its precursor, cervical intraepithelial neoplasia (CIN). However, the underlying mechanisms of this association have not been elucidated. RA is characterized by unresolved chronic inflammation. It is suggested that human papillomavirus (HPV) infection in RA patients exacerbates inflammation, increasing the risk of CC. The tumor microenvironment in RA patients with CC is also marked by chronic inflammation, which aggravates the manifestations of both conditions. Gut and vaginal dysbiosis are also considered potential mechanisms that contribute to the chronic inflammation and aggravation of RA and CC manifestations. Numerous clinical and pre-clinical studies have demonstrated the beneficial effects of various nutritional approaches to attenuate chronic inflammation, including polyunsaturated fatty acids and their derivatives, specialized pro-resolving mediators (SPMs), probiotics, prebiotics, and certain diets. We believe that successful resolution of chronic inflammation and correction of dysbiosis, in combination with current anti-RA and anti-CC therapies, is a promising therapeutic approach for RA and CC. This approach could also reduce the risk of CC development in HPV-infected RA patients.

The associations of cardiovascular disease (CVD) with comorbidities and biochemical and body composition measurements are repeatedly described but have not been studied simultaneously. In the present cross-sectional study, information on CVD and comorbidities [type 2 diabetes mellitus (T2DM), hypertension (HTN), and hyperlipidemia (HDL)], body composition, levels of soluble markers, and other measures were collected from 1079 individuals. When we examined the association of each comorbidity and CVD, controlling for other comorbidities, we observed a clear pattern of the comorbidity-related specific associations with tested covariates. For example, T2DM was significantly associated with GDF-15 levels and the leptin/adiponectin (L/A) ratio independently of two other comorbidities; HTN, similarly, was independently associated with extracellular water (ECW) levels, L/A ratio, and age; and HDL was independently related to age only. CVD showed very strong independent associations with each of the comorbidities, being associated most strongly with HTN (OR = 10.89, 6.46–18.38) but also with HDL (2.49, 1.43–4.33) and T2DM (1.93, 1.12–3.33). An additive Bayesian network analysis suggests that all three comorbidities, particularly HTN, GDF-15 levels, and ECW content, likely have a main role in the risk of CVD development. Other factors, L/A ratio, lymphocyte count, and the systemic inflammation response index, are likely indirectly related to CVD, acting through the comorbidities and ECW.

Metabolic syndrome (MetS) is a complex disease involving multiple physiological, biochemical, and metabolic abnormalities. The search for reliable biomarkers may help to better elucidate its pathogenesis and develop new preventive and therapeutic strategies. In the present population-based study, we looked for biomarkers of MetS among obesity- and inflammation-related circulating factors and body composition parameters in 1079 individuals (with age range between 18 and 80) belonging to an ethnically homogeneous population. Plasma levels of soluble markers were measured by using ELISA. Body composition parameters were assessed using bioimpedance analysis (BIA). Statistical analysis, including mixed-effects regression, with MetS as a dependent variable, revealed that the most significant independent variables were mainly adipose tissue-related phenotypes, including fat mass/weight (FM/WT) [OR (95% CI)], 2.77 (2.01–3.81); leptin/adiponectin ratio (L/A ratio), 1.50 (1.23–1.83); growth and differentiation factor 15 (GDF-15) levels, 1.32 (1.08–1.62); inflammatory markers, specifically monocyte to high-density lipoprotein cholesterol ratio (MHR), 2.53 (2.00–3.15), and a few others. Additive Bayesian network modeling suggests that age, sex, MHR, and FM/WT are directly associated with MetS and probably affect its manifestation. Additionally, MetS may be causing the GDF-15 and L/A ratio. Our novel findings suggest the existence of complex, age-related, and possibly hierarchical relationships between MetS and factors associated with obesity.

Copper has intrinsic antimicrobial properties. Wound dressings impregnated with cuprous oxide microparticles (hereafter termed COD) have been cleared for the management of acute and chronic wounds by the FDA and other regulatory bodies. The COD reduced the viable microbial titers of a wide spectrum of microbes by more than 10,000-fold (4-logs) within 3 h of exposure at 37 °C (p < 0.001). Similar microbial titer reductions were achieved by 3-year naturally aged COD dressings, showing the stability of the biocidal efficacy over time. The potent biocidal efficacy of the COD was maintained even after 7 daily consecutive inoculations of the dressings with ~106 CFU. COD with an adhesive contour blocked the passage of bacteria from the exterior environment to the wound bed side of the dressing even after 7 daily consecutive inoculations of different bacteria on the outer surface of the dressings. Taken together, the study demonstrates the wide spectrum potent in vitro biocidal efficacy of the cuprous oxide impregnated dressings against a wide panel of microorganisms.

Objectives: In our previous study, we reported that low back pain (LBP) severity and disability significantly correlate with body composition and several blood biochemical factors. Herein, we tested the hypothesis that these covariates are associated with anatomical deformations of the lumbar spine, in particular, radiographic facet joint osteoarthritis (FJOA) and lumbar disc degeneration (LDD) features important contributors to LBP. Methods: CT and MRI images of the lumbar spine were obtained from 200 individuals suffering from LBP-sciatica. We examined the FJOA and total LDD score - the sum of the scores of the three radiographic features (intervertebral disc herniation, osteophythosis and spondylolisthesis) at the L1 - S1 vertebral levels. By implementing a bioelectrical impedance analysis, we assessed the participants for body composition, specifically, extracellular water (ECW). Plasma levels of growth and differentiation factor 15 (GDF-15) and visceral adipose tissue-derived serine protease inhibitor (vaspin), were detected by ELISA. Results: By conducting a series of multivariable regression analyses, we report that the circulating levels of GDF-15, vaspin, and ECW are significantly and independently associated with FJOA scores [βGDF15 ​= ​0.38 ​± ​0.08, p ​= ​0.0001; βVASPIN ​= ​0.36 ​± ​0.07, p ​= ​0.000004; βECW ​= ​0.24 ​± ​0.07, p ​= ​0.002]. The levels of GDF-15 (β ​= ​0.30 ​± ​0.10, p ​= ​0.007) and ECW (β ​= ​0.20 ​± ​0.09, p ​= ​0.03) were also found significantly associated with the LDD scores. Conclusion: The obtained new data suggest that GDF-15, vaspin and ECW may serve as biomarkers for FJOA and LDD phenotypes.

Knee osteoarthritis (KOA) is one of the most common progressive, age-dependent chronic degenerative joint diseases. KOA often develops as a result of a gradual articular cartilage loss caused by its wear and tear. Numerous studies suggest that the degradation of the knee joint involves inflammatory components. This process is also associated with body composition, particularly being overweight and muscle mass loss. The present study aimed to search for novel circulating KOA inflammatory biomarkers, taking into account body composition characteristics. To this aim, we recruited 98 patients diagnosed and radiologically confirmed with KOA and 519 healthy controls from the Arab community in Israel. A panel of soluble molecules, related to inflammatory, metabolic, and musculoskeletal disorders, was measured by ELISA in plasma samples, while several body composition parameters were assessed with bioimpedance analysis. Statistical analysis, including multivariable logistic regression, revealed a number of the factors significantly associated with KOA, independently of age and sex. The most significant independent associations [OR (95% CI)] were fat body mass/body weight index—1.56 (1.20–2.02), systemic immune-inflammation index—4.03 (2.23–7.27), circulating vaspin levels—1.39 (1.15–1.68), follistatin/FSTL1 ratio—1.32 (1.02–1.70), and activin A/FSTL1 ratio—1.33 (1.01–1.75). Further clinical studies are warranted to confirm the relevance of these KOA-associated biological factors. Hereafter, they could serve as reliable biomarkers for KOA in the general human population.

It is now established that patients with rheumatoid arthritis (RA) have an increased risk of developing cervical cancer (CC) or its precursor, cervical intraepithelial neoplasia (CIN). However, the underlying mechanisms of this association have not been elucidated. RA is characterized by unresolved chronic inflammation. It is suggested that human papillomavirus (HPV) infection in RA patients exacerbates inflammation, increasing the risk of CC. The tumor microenvironment in RA patients with CC is also marked by chronic inflammation, which aggravates the manifestations of both conditions. Gut and vaginal dysbiosis are also considered potential mechanisms that contribute to the chronic inflammation and aggravation of RA and CC manifestations. Numerous clinical and pre-clinical studies have demonstrated the beneficial effects of various nutritional approaches to attenuate chronic inflammation, including polyunsaturated fatty acids and their derivatives, specialized pro-resolving mediators (SPMs), probiotics, prebiotics, and certain diets. We believe that successful resolution of chronic inflammation and correction of dysbiosis, in combination with current anti-RA and anti-CC therapies, is a promising therapeutic approach for RA and CC. This approach could also reduce the risk of CC development in HPV-infected RA patients. [ABSTRACT FROM AUTHOR]

Musculoskeletal pain (MSP), specifically low back pain (LBP), is often associated with several adipose tissue-derived cytokines (adipokines) and body composition, but their correlations with the LBP-related disability/severity phenotypes remain poorly understood. In this cross-sectional study, two self-reported validated questionnaires were used to collect back pain and disability data in an ethnically homogeneous family-based population sample (N = 1078). Plasma levels of relatively new adipokines, vaspin and adipsin, were detected by ELISA. Body composition parameters, including fat, skeletal muscle mass, extracellular water (ECW), and others were assessed through bioelectrical impedance analysis (BIA) technology. Statistical analysis was conducted, accounting for the familial composition of the sample. The multiple regression analyses with four LBP-related phenotypes as dependent variables consistently showed, for the first time, the significant associations with vaspin levels, regardless of other covariates. The odds ratios (OR)/SD ranged between 1.24 (95%CI = 1.03–1.50) and 1.33 (95%CI = 1.07–1.64), depending on the LBP phenotype. Among the tested body composition covariates, only ECW levels displayed consistent and highly significant associations with all tested LBP phenotypes (OR from 1.43, 95%CI = 1.14–1.79 to 1.68, 95%CI = 1.26–2.24). The results clearly suggest that circulating concentrations of vaspin and ECW levels could serve as biomarkers of MSP/LBP severity and complications.

Bone marrow endothelial cells (BMECs) form a network of blood vessels that regulate both leukocyte trafficking and haematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles, and whether these events occur at the same vascular site. We found that mammalian bone marrow stem cell maintenance and leukocyte trafficking are regulated by distinct blood vessel types with different permeability properties. Less permeable arterial blood vessels maintain haematopoietic stem cells in a low reactive oxygen species (ROS) state, whereas the more permeable sinusoids promote HSPC activation and are the exclusive site for immature and mature leukocyte trafficking to and from the bone marrow. A functional consequence of high permeability of blood vessels is that exposure to blood plasma increases bone marrow HSPC ROS levels, augmenting their migration and differentiation, while compromising their long-term repopulation and survival. These findings may have relevance for clinical haematopoietic stem cell transplantation and mobilization protocols., Vascular-forming endothelial cells form a vast network which participates in homeostasis and metabolism regulation, delivering oxygen, nutrients and other building blocks to distinct organs. This diverse network also serves as [...]

Retention of long-term repopulating hematopoietic stem cells (LT-HSCs) in the bone marrow is essential for hematopoiesis and for protection from myelotoxic injury. We report that signaling cascades that are traditionally viewed as coagulation related also control retention of endothelial protein C receptor-positive (EPCR[sup.+]) LT-HSCs in the bone marrow and their recruitment to the blood via two pathways mediated by protease activated receptor 1 (PAR1). Thrombin-PAR1 signaling induces nitric oxide (NO) production, leading to EPCR shedding mediated by tumor necrosis factor-[alpha]-converting enzyme (TACE), enhanced CXCL12-CXCR4-induced motility and rapid stem and progenitor cell mobilization. Conversely, bone marrow blood vessels provide a microenvironment enriched with activated protein C (aPC) that retains EPCR[sup.+] LT-HSCs by limiting NO generation, reducing Cdc42 activity and enhancing integrin VLA4 affinity and adhesion. Inhibition of NO production by aPC-EPCR-PAR1 signaling reduces progenitor cell egress from the bone marrow, increases retention of bone marrow NO[sup.low] EPCR[sup.+] LT-HSCs and protects mice from chemotherapy-induced hematological failure and death. Our study reveals new roles for PAR1 and EPCR in controlling NO production to balance maintenance and recruitment of bone marrow EPCR[sup.+] LT-HSCs, with potential clinical relevance for stem cell transplantation., Author(s): Shiri Gur-Cohen [1]; Tomer Itkin [1]; Sagarika Chakrabarty [2]; Claudine Graf [3]; Orit Kollet [1]; Aya Ludin [1]; Karin Golan [1]; Alexander Kalinkovich [1]; Guy Ledergor [1, 4]; Eitan [...]

Regulation of hematopoietic stem and progenitor cell (HSPC) steady-state egress from the bone marrow (BM) to the circulation is poorly understood. While glycogen synthase kinase-3β (GSK3β) is known to participate [...]

The mechanisms governing hematopoietic progenitor cell mobilization are not fully understood. We report higher membrane type 1-MMP (MT1-MMP) and lower expression of the MT1-MMP inhibitor, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), on isolated circulating human [CD34.sup.+] progenitor cells compared with immature BM cells. The expression of MT1-MMP correlated with clinical mobilization of [CD34.sup.+] cells in healthy donors and patients with lymphoid malignancies. Treatment with G-CSF further increased MT1-MMP and decreased RECK expression in human and murine hematopoietic cells in a PI3K/Akt-dependent manner, resulting in elevated MT1-MMP activity. Blocking MT1-MMP function by Abs or siRNAs impaired chemotaxis and homing of G-CSF--mobilized human [CD34.sup.+] progenitors. The mobilization of immature and maturing human progenitors in chimeric NOD/SCID mice by G-CSF was inhibited by anti--MT1-MMP treatment, while RECK neutralization promoted motility and egress of BM [CD34.sup.+] cells. BM [c-kit.sup.+] cells from MT1-MMP--deficient mice also exhibited inferior chemotaxis, reduced homing and engraftment capacities, and impaired G-CSF--induced mobilization in murine chimeras. Membranal CD44 cleavage by MT1-MMP was enhanced following G-CSF treatment, reducing [CD34.sup.+] cell adhesion. Accordingly, CD44-deficient mice had a higher frequency of circulating progenitors. Our results reveal that the motility, adhesion, homing, and mobilization of human hematopoietic progenitor cells are regulated in a cell-autonomous manner by dynamic and opposite changes in MT1-MMP and RECK expression., Introduction Release of hematopoietic progenitor cells (HPCs) to the circulation is the outcome of signals provided by cytokines, chemokines, adhesion molecules, proteolytic enzymes, and their inhibitors, resulting in prevention of [...]