Cardiomyopathy associated with diabetes. the central role of the cardiomyocyte

The term diabetic cardiomyopathy (DCM) labels an abnormal cardiac structure and performance due to intrinsic heart muscle malfunction, independently of other vascular co-morbidity. DCM, accounting for 50%-80% of deaths in diabetic patients, represents a worldwide problem for human health and related economics. Optimal glycemic control is not sufficient to prevent DCM, which derives from heart remodeling and geometrical changes, with both consequences of critical events initially occurring at the cardiomyocyte level. Cardiac cells, under hyperglycemia, very early undergo metabolic abnormalities and contribute to T helper (Th)-driven inflammatory perturbation, behaving as immunoactive units capable of releasing critical biomediators, such as cytokines and chemokines. This paper aims to focus onto the role of cardiomyocytes, no longer considered as "passive" targets but as "active" units participating in the inflammatory dialogue between local and systemic counterparts underlying DCM development and maintenance. Some of the main biomolecular/metabolic/inflammatory processes triggered within cardiac cells by high glucose are overviewed; particular attention is addressed to early inflammatory cytokines and chemokines, representing potential therapeutic targets for a prompt early intervention when no signs or symptoms of DCM are manifesting yet. DCM clinical management still represents a challenge and further translational investigations, including studies at female/male cell level, are warranted

Chitlac-coated Thermosets Enhance Osteogenesis and Angiogenesis in a Co-culture of Dental Pulp Stem Cells and Endothelial Cells

Dental pulp stem cells (DPSCs) represent a population of stem cells which could be useful in oral and maxillofacial reconstruction. They are part of the periendothelial niche, where their crosstalk with endothelial cells is crucial in the cellular response to biomaterials used for dental restorations. DPSCs and the endothelial cell line EA.hy926 were co-cultured in the presence of Chitlac-coated thermosets in culture conditions inducing, in turn, osteogenic or angiogenic differentiation. Cell proliferation was evaluated by 3\u2013[4,5\u2013dimethyl\u2013thiazol\u20132\u2013yl\u2013]\u20132,5\u2013diphenyl tetrazolium bromide (MTT) assay. DPSC differentiation was assessed by measuring Alkaline Phosphtase (ALP) activity and Alizarin Red S staining, while the formation of new vessels was monitored by optical microscopy. The IL-6 and PGE2 production was evaluated as well. When cultured together, the proliferation is increased, as is the DPSC osteogenic differentiation and EA.hy926 vessel formation. The presence of thermosets appears either not to disturb the system balance or even to improve the osteogenic and angiogenic differentiation. Chitlac-coated thermosets confirm their biocompatibility in the present co-culture model, being capable of improving the differentiation of both cell types. Furthermore, the assessed co-culture appears to be a useful tool to investigate cell response toward newly synthesized or commercially available biomaterials, as well as to evaluate their engraftment potential in restorative dentistry

Inhibition of TGF-β1 signaling restores both microenvironmental and stem cells abnormalities in the Gata-1low Mouse Model of Myelofibrosis

Primary myelofibrosis (PMF) is characterized by abnormal megakaryocyte (Mk) development, fibrosis and ineffective hematopoiesis in the marrow and hematopoiesis in extramedullary sites [1]. Studies in animal models have suggested that fibrosis is established by fibroblasts activated by TGF-β1 released by the abnormal Mk. Increased levels of TGF-β1 expression in Mk have been implicated in the development of PMF. To clarify whether TGF-β1 alterations are involved in the development of PMF in Gata1low mice, the TGF-β1 content of Mk from the marrow and spleen from PMF patients and Gata1low mice was compared, the TGF-β1 pathway of the marrow and spleen of the Gata1low mouse PMF model was profiled and the consequences of pharmacological inhibition of TGF-β1 signaling, obtained through treatment with SB431542, was determined. Bone marrow (BM) sections from PMF patients contain 4-times more Mk than those from normal donors and great numbers of Mk are also detectable in their spleen. In addition, Mk from both BM and spleen of PMF patients reacted 34-times more intensely than normal Mk with the TGF-β1 antibody. Similarly the number of Mk in BM and spleen of Gata-1low mice was 2-3- fold greater than normal and these cells reacted 3-8-times more intensely with the TGF-β1 antibody than wild-type(wt)Mk. These results were confirmed by immunoelectron- microscopy. On average, one Mk from wild-type and Gata1low mice contained 10.3±2.2 and 54.3±6.5 immunogold-particles per area (p<0.01). SB431542-treatment reduced the intensity of TGF-β1 staining of Gata1low Mk both in BM (5.3±1.1) and spleen (9.2±0.7) compared to Mk both in BM (18.9±0.8) and spleen (24.3±0.9) of Gata- 1low vehicle-treated mice, while had modest effects on the expression of VEGF and CXCL12. Inhibition of TGF-β1 signaling activates hematopoiesis in BM while reducing extramedullary hematopoiesis in spleen of Gata-1low mice. In addition, it reduced fibrosis, vessel microdensity, increases Ptl counts and decreases WBC and poikilocytes in the blood of Gata1low mice suggesting a potential benefit for treatments targeting microenvironment abnormalities in PMF

Exercise training improves vascular function in patients with Alzheimer’s disease

Purpose: Vascular dysfunction has been demonstrated in patients with Alzheimer’s disease (AD). Exercise is known to positively affect vascular function. Thus, the aim of our study was to investigate exercise-induced effects on vascular function in AD. Methods: Thirty-nine patients with AD (79 ± 8 years) were recruited and randomly assigned to exercise training (EX, n = 20) or control group (CTRL, n = 19). All subjects performed 72 treatment sessions (90 min, 3 t/w). EX included moderate–high-intensity aerobic and strength training. CTRL included cognitive stimuli (visual, verbal, auditive). Before and after the 6-month treatment, the vascular function was measured by passive-leg movement test (PLM, calculating the variation in blood flow: ∆peak; and area under the curve: AUC) tests, and flow-mediated dilation (FMD, %). A blood sample was analyzed for vascular endothelial growth factor (VEGF). Arterial blood flow (BF) and shear rate (SR) were measured during EX and CTRL during a typical treatment session. Results: EX group has increased FMD% (+ 3.725%, p ' 0.001), PLM ∆peak (+ 99.056 ml/min, p = 0.004), AUC (+ 37.359AU, p = 0.037) and VEGF (+ 8.825 pg/ml, p = 0.004). In the CTRL group, no difference between pre- and post-treatment was found for any variable. Increase in BF and SR was demonstrated during EX (BF + 123%, p ' 0.05; SR + 134%, p ' 0.05), but not during CTRL treatment. Conclusion: Exercise training improves peripheral vascular function in AD. These ameliorations may be due to the repetitive increase in SR during exercise which triggers NO and VEGF upregulation. This approach might be included in standard AD clinical practice as an effective strategy to treat vascular dysfunction in this population

Amniotic Fluid Stem Cells cardiomyogenic potential: a preliminary study

The characterization of Amniotic Fluid-derived multipotent Stem Cells (AFSCs) open new paths in stem cell research. hAFSCs have characteristics intermediate between pluripotent embryonic- (ESCs) and lineage-restricted adult stem cells, and are non-tumorigenic and low immunogenic. Moreover, they are obtained without destroying human embryos, so that most of the ethical and social controversy could be prevented. We previously observed that human AFSCs express some genes specific of ESCs and primordial germ cells. We also shown hAFSCs ability to form in vitro three-dimensional aggregates of cells known as embryoid bodies (EBs), that express three germ layer markers. Recent studies reported the ability of hAFSCs to differentiate in vitro into adipocytes and osteocytes. Aim of our study was to analyse the cardiomyogenic potential of hAFSCs. EBs were obtained by modified hanging drops protocol from hAFSCs coltured in presence of ascorbic acid and 5-aza-2’-deoxycytidine (differentiation medium: DM). RT-PCR and Western Blotting analysis conducted on AFSCs and EBs cells evidenced the gene and protein expression of the transcriptor factor Nkx2.5, the earliest marker of heart precursor cells. Immunofluorescence (IF) analysis performed on EBs after 10 days in DM evidenced the cytoplasmic presence of α-myosin heavy chain (α-MHC) organized in parallel, oriented filamets. Microscopical analysis evidenced beating cells mainly at the periphery of the EB. In conclusion, our results evidenced that hAFSCs cultured in permissive conditions give rise to EB able to terminally differentiate in cardiomyocytes

GRB010222: afterglow emission from a rapidly decelerating shock

The GRB010222 optical and near-infrared (NIR) afterglow was monitored at the TNG and other Italian telescopes starting ~1 day after the high-energy prompt event. The optical BVR light curves, which are the best sampled, are continuously steepening, and can be described by two power laws, f(t) = t^(-alpha), of indices alpha_1 ~ 0.7 and alpha_2 ~ 1.3 before and after a break occurring at about 0.5 days after the GRB start time, respectively. This model accounts well also for the flux in the U, I and J bands, which are less well monitored. The temporal break appears to be achromatic. The two K-band points are not consistent with the above behaviour, and rather suggest a constant trend. A low-resolution optical spectrum has also been taken with TNG. In the optical spectrum we found three absorption systems at different redshifts (0.927, 1.155 and 1.475), the highest of which represents a lower limit to, and probably coincides with, the redshift of this GRB. The broad-band optical spectral energy distributions do not appear to vary with time, consistently with the achromatic behaviour of the light curves. We compare our measurements with different afterglow evolution scenarios and we find that they favor a transition from relativistic to non-relativistic conditions in the shock propagation.Comment: Accepted by Astronomy and Astrophysics; modified according to referee's comments. Two figures added, U-band photometry corrected, hydrodynamic description of the afterglow revised, host galaxy absorption considered, references adde

Ghrelin and Growth Hormone Secretagogue Receptor localization in human iris and ciliar body

Ghrelin (Ghr) is a 28-amino acid peptide identified as endogenous, acylated ligand for the growth hormone (GH) secretagogue G-protein-coupled receptor (GHSR). Mainly synthesized from X/A like neuroendocrin cells of gastric fundus, Ghr acts directly on the pituitary gland inducing GH release; moreover Ghr regulates food intake resulting tightly associated with obesity. Several studies reported that Ghr is widely expressed in different tissues and, besides its orexigenic activity, effects on cardiovascular, pulmonary, reproductive and central nervous systems have been described. Recently, functional studies on rats and rabbits indicated Ghr as modulator of iris smooth muscles activity since induces relaxation of both sphincter and dilator muscles. Moreover Ghr mRNA has been found in the ciliary epithelium of ciliar body (CB). On the basis of these observations, we purposed to investigate Ghr and GHSR expression in human eye. The immunohistochemical analysis performed on iris and ciliar body specimens from post-traumatic explanted human eyeballs evidenced that Ghr and its receptor were co-expressed from the pigmented epithelium (PE) of both iris and CB, whereas we did not detect immunoreactivity in smooth muscle cells. Since human ciliar epithelium is a major site of production of neuroendocrine peptides found in aqueous humor (AqH), we analyzed AqH for the Ghr presence but the Enzymatic Immunoassay performed on 80 samples gave always negative results. In conclusion, our data suggest that Ghr may activate autocrine/paracrine signalling in human PE of CB and iris; the absence of GHSR- immunoreactivity on iris smooth muscle cells seem to rule out the possibility that Ghr can exert its myo-active effects directly

Multi-band high resolution spectroscopy rules out the hot Jupiter BD+20 1790b - First data from the GIARPS Commissioning

Context. Stellar activity is currently challenging the detection of young planets via the radial velocity (RV) technique. Aims. We attempt to definitively discriminate the nature of the RV variations for the young active K5 star BD+20 1790, for which visible (VIS) RV measurements show divergent results on the existence of a substellar companion. Methods. We compare VIS data with high precision RVs in the near infrared (NIR) range by using the GIANO - B and IGRINS spectrographs. In addition, we present for the first time simultaneous VIS-NIR observations obtained with GIARPS (GIANO - B and HARPS - N) at Telescopio Nazionale Galileo (TNG). Orbital RVs are achromatic, so the RV amplitude does not change at different wavelengths, while stellar activity induces wavelength-dependent RV variations, which are significantly reduced in the NIR range with respect to the VIS. Results. The NIR radial velocity measurements from GIANO - B and IGRINS show an average amplitude of about one quarter with respect to previously published VIS data, as expected when the RV jitter is due to stellar activity. Coeval multi-band photometry surprisingly shows larger amplitudes in the NIR range, explainable with a mixture of cool and hot spots in the same active region. Conclusions. In this work, the claimed massive planet around BD+20 1790 is ruled out by our data. We exploited the crucial role of multi- wavelength spectroscopy when observing young active stars: thanks to facilities like GIARPS that provide simultaneous observations, this method can reach its maximum potential.Comment: 12 pages, 7 figure

The very red afterglow of GRB 000418 - further evidence for dust extinction in a GRB host galaxy

We report near-infrared and optical follow-up observations of the afterglow of the Gamma-Ray Burst 000418 starting 2.5 days after the occurrence of the burst and extending over nearly seven weeks. GRB 000418 represents the second case for which the afterglow was initially identified by observations in the near-infrared. During the first 10 days its R-band afterglow was well characterized by a single power-law decay with a slope of 0.86. However, at later times the temporal evolution of the afterglow flattens with respect to a simple power-law decay. Attributing this to an underlying host galaxy we find its magnitude to be R=23.9 and an intrinsic afterglow decay slope of 1.22. The afterglow was very red with R-K=4 mag. The observations can be explained by an adiabatic, spherical fireball solution and a heavy reddening due to dust extinction in the host galaxy. This supports the picture that (long) bursts are associated with events in star-forming regions.Comment: Accepted for publication in The Astrophysical Journal. 12 pages; citations & references updated; minor textual change

The extraordinarily bright optical afterglow of GRB 991208 and its host galaxy

Observations of the extraordinarily bright optical afterglow (OA) of GRB 991208 started 2.1 d after the event. The flux decay constant of the OA in the R-band is -2.30 +/- 0.07 up to 5 d, which is very likely due to the jet effect, and after that it is followed by a much steeper decay with constant -3.2 +/- 0.2, the fastest one ever seen in a GRB OA. A negative detection in several all-sky films taken simultaneously to the event implies either a previous additional break prior to 2 d after the occurrence of the GRB (as expected from the jet effect). The existence of a second break might indicate a steepening in the electron spectrum or the superposition of two events. Once the afterglow emission vanished, contribution of a bright underlying SN is found, but the light curve is not sufficiently well sampled to rule out a dust echo explanation. Our determination of z = 0.706 indicates that GRB 991208 is at 3.7 Gpc, implying an isotropic energy release of 1.15 x 10E53 erg which may be relaxed by beaming by a factor > 100. Precise astrometry indicates that the GRB coincides within 0.2" with the host galaxy, thus given support to a massive star origin. The absolute magnitude is M_B = -18.2, well below the knee of the galaxy luminosity function and we derive a star-forming rate of 11.5 +/- 7.1 Mo/yr. The quasi-simultaneous broad-band photometric spectral energy distribution of the afterglow is determined 3.5 day after the burst (Dec 12.0) implying a cooling frequency below the optical band, i.e. supporting a jet model with p = -2.30 as the index of the power-law electron distribution.Comment: Accepted for publication in Astronomy and Astrophysics, 9 pages, 6 figures (Fig. 3 and Fig. 4 have been updated