Continuous central venous saturation monitoring in critically ill patients

Table 1 (abstract P39). Patients\u2019 variables according to ScvO2 range ScvO2 75 Patients 15/37 36/37 36/37 SpO2 (%) 95.8 \ub1 3.0 95.0 \ub1 3.3 96.4 \ub1 2.3 HR (bpm) 90.6 \ub1 16.1 90.5 \ub1 18.1 90.7 \ub1 16.5 MAP (mmHg) 82.5 \ub1 10.6 83.4 \ub1 12.7 82.2 \ub1 11.7 CVP (mmHg) 18.3 \ub1 4.6 20.2 \ub1 8.2 19.2 \ub1 5.

The Early Bird Catches The Term: Combining Twitter and News Data For Event Detection and Situational Awareness

Twitter updates now represent an enormous stream of information originating from a wide variety of formal and informal sources, much of which is relevant to real-world events. In this paper we adapt existing bio-surveillance algorithms to detect localised spikes in Twitter activity corresponding to real events with a high level of confidence. We then develop a methodology to automatically summarise these events, both by providing the tweets which fully describe the event and by linking to highly relevant news articles. We apply our methods to outbreaks of illness and events strongly affecting sentiment. In both case studies we are able to detect events verifiable by third party sources and produce high quality summaries

Contribution of red blood cells to the compensation for hypocapnic alkalosis through plasmatic strong ion difference variations

Introduction Chloride shift is the movement of chloride between red blood cells (RBC) and plasma (and vice versa) caused by variations in pCO2. The aim of our study was to investigate changes in plasmatic strong ion diff erence (SID) during acute variations in pCO2 and their possible role in the compensation for hypocapnic alkalosis.Methods Patients admitted in this year to our ICU requiring extracorporeal CO2 removal were enrolled. Couples of measurements of gases and electrolytes on blood entering (v) and leaving (a) the respiratory membrane were analyzed. SID was calculated as [Na+] + [K+] + 2[Ca2+] \u2013 [Cl\u2013] \u2013 [Lac\u2013]. Percentage variations in SID (SID%) were calculated as (SIDv \u2013 SIDa) x 100 / SIDv. The same calculation was performed for pCO2 (pCO2%). Comparison between v and a values was performed by paired t test or the signed-rank test, as appropriate. Results Analysis was conducted on 205 sample-couples of six enrolled patients. A signifi cant diff erence (P <0.001) between mean values of v\u2013a samples was observed for pH (7.41 \ub1 0.05 vs. 7.51 \ub1 0.06), pCO2 (48 \ub1 6 vs. 35 \ub1 7 mmHg), [Na+] (136.3 \ub1 4.0 vs. 135.2 \ub1 4.0 mEq/l), [Cl\u2013] (101.5 \ub1 5.3 vs. 102.8 \ub1 5.2 mEq/l) and therefore SID (39.5 \ub1 4.0 vs. 36.9 \ub1 4.1 mEq/l). pCO2% and SID% signifi cantly correlated (r2 = 0.28, P <0.001). Graphical representation by quartiles of pCO2% is shown in Figure 1. Conclusions As a reduction in SID decreases pH, the observed movement of anions and cations probably limited the alkalinization caused by hypocapnia. In this model, the only source of electrolytes are blood cells (that is, no interstitium and no infl uence of the kidney is present); it is therefore conceivable to consider the observed phenomenon as the contribution of RBC for the compensation of acute hypocapnic alkalosi

Multiple Roles of Transforming Growth Factor Beta in Amyotrophic Lateral Sclerosis

Transforming growth factor beta (TGFB) is a pleiotropic cytokine, known to be dysregulated in many neurodegenerative disorders and particularly in amyotrophic lateral sclerosis (ALS). This motor neuronal disease is non-cell autonomous, as it affects not only motor neurons, but also their surrounding glial cells, and their target skeletal muscle fibers. Here, we analyze the multiple roles of TGFB in these cell types, and how TGFB signaling is altered in ALS tissues. Data reported support a crucial involvement of TGFB in the etiology and progression of ALS, leading us to hypothesize that an imbalance of TGFB signaling, diminished at the pre-symptomatic stage and then increased with time, could be linked to ALS progression. A reduced stimulation of the TGFB pathway at the beginning of disease blocks its neuroprotective effects and promotes glutamate excitotoxicity. At later disease stages, the persistent activation of the TGFB pathway promotes an excessive microglial activation and strengthens muscular dysfunction. The therapeutic potential of TGFB is discussed here, in order to foster new approaches to treat ALS

The role of extracellular vesicles in the removal of aggregated TDP43 responsible for ALS/FTD diseases

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two related neurodegenerative diseases. ALS is caused by the death of both upper and lower motoneurons, while FTD is characterized predominantly by circumscribed atrophy of the frontal and temporal lobes. ALS and FTD overlap each other. This is demonstrated by the presence of cognitive and behavioral dysfunction in up to 50% of ALS patients and by the presence of frontotemporal atrophy in patients with ALS. Moreover, these diseases are both characterize by the presence of TAR DNA binding protein 43 (TDP43) inclusions in affected cells. These inclusions, observed in 97% of patients with ALS and 50% of patients with FTD, are composed by TDP43 and its C-terminal fragments of 35 kDa (TDP35) and 25 kDa (TDP25). These fragments are highly aggregation-prone and probably neurotoxic. Thus, their removal is protective for cells. The mechanism responsible for the clearance of aggregates and misfolded proteins is the intracellular protein quality control (PQC) system. It consists of molecular chaperones/co- chaperones and the degradative pathways. PQC controls the folding status of proteins and prevents the aggregation of misfolded proteins by refolding them or degrading. Recent data demonstrated that also extracellular secretory pathway, represented especially by exosomes (EXOs) and microvesicles (MVs), might be involved in the removal of misfolded proteins from affected cells. Thus, we evaluated the role of EXOs and MVs in the secretion of TDP43 and its C-terminal fragments, using neuronal cell models. We used ultracentrifugation, that allowed us to separate MVs from EXOs on the basis of their dimension. Then we analyzed them through i) Nanoparticle Tracking Analysis (NanoSight) to establish their number and sizes, and ii) western blot analysis, to characterize their protein content. Our preliminary results show that TDP43, TDP35 and TDP25 are all secreted, mainly by MVs. In particular, we found that MVs are enriched of insoluble forms of TDPs and also of superoxide dismutase 1 (SOD1), another ALS-related protein. Finally, both in EXOs and in MVs, we observed the presence of some important PQC-components, suggesting an interplay between the two pathways. GRANTS: Fondazione Cariplo, Italy (n. 2017_0747); Universit\ue0 degli Studi di Milano e piano di sviluppo UNIMI - linea B

Autophagic and proteasomal mediated removal of mutant androgen receptor in muscle models of spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease (MND) caused by a mutant androgen receptor (AR) containing an elongated polyglutamine (polyQ) tract. ARpolyQ toxicity is triggered by androgenic AR ligands, which induce aberrant conformations (misfolding) of the ARpolyQ protein that aggregates. Misfolded proteins perturb the protein quality control (PQC) system leading to cell dysfunction and death. Spinal cord motoneurons, dorsal root ganglia neurons and skeletal muscle cells are affected by ARpolyQ toxicity. Here, we found that, in stabilized skeletal myoblasts (s-myoblasts), ARpolyQ formed testosterone-inducible aggregates resistant to NP-40 solubilization; these aggregates did not affect s-myoblasts survival or viability. Both wild type AR and ARpolyQ were processed via proteasome, but ARpolyQ triggered (and it was also cleared via) autophagy. ARpolyQ reduced two pro-autophagic proteins expression (BAG3 and VCP), leading to decreased autophagic response in ARpolyQ s-myoblasts. Overexpression of two components of the chaperone assisted selective autophagy (CASA) complex (BAG3 and HSPB8), enhanced ARpolyQ clearance, while the treatment with the mTOR independent autophagy activator trehalose induced complete ARpolyQ degradation. Thus, trehalose has beneficial effects in SBMA skeletal muscle models even when autophagy is impaired, possibly by stimulating CASA to assist the removal of ARpolyQ misfolded species/aggregates

Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives

Background: Accumulation of misfolded proteins is a common hallmark of several neurodegenerative disorders (NDs) which results from a failure or an impairment of the proteinquality control (PQC) system. The PQC system is composed by chaperones and the degradative systems (proteasome and autophagy). Mutant proteins that misfold are potentially neurotoxic, thus strategies aimed at preventing their aggregation or at enhancing their clearance are emerging as interesting therapeutic targets for NDs. Methods: We tested the natural alkaloid berberine (BBR) and some derivatives for their capability to enhance misfolded protein clearance in cell models of NDs, evaluating which degradative pathway mediates their action. Results: We found that both BBR and its semisynthetic derivatives promote degradation of mutant androgen receptor (ARpolyQ) causative of spinal and bulbar muscular atrophy, acting mainly via proteasome and preventing ARpolyQ aggregation. Overlapping effects were observed on other misfolded proteins causative of amyotrophic lateral sclerosis, frontotemporal-lobar degeneration or Huntington disease, but with selective and specific action against each different mutant protein. Conclusions: BBR and its analogues induce the clearance of misfolded proteins responsible for NDs, representing potential therapeutic tools to counteract these fatal disorders

Prolapso de uretra em cão da raça maltês. Relato de caso

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Pathogenic variants of Valosin-containing protein induce lysosomal damage and transcriptional activation of autophagy regulators in neuronal cells

Aim: Mutations in the valosin-containing protein (VCP) gene cause various lethal proteinopathies that mainly include inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS). Different pathological mechanisms have been proposed. Here, we define the impact of VCP mutants on lysosomes and how cellular homeostasis is restored by inducing autophagy in the presence of lysosomal damage. Methods: By electron microscopy, we studied lysosomal morphology in VCP animal and motoneuronal models. With the use of western blotting, real-time quantitative polymerase chain reaction (RT-qPCR), immunofluorescence and filter trap assay, we evaluated the effect of selected VCP mutants in neuronal cells on lysosome size and activity, lysosomal membrane permeabilization and their impact on autophagy. Results: We found that VCP mutants induce the formation of aberrant multilamellar organelles in VCP animal and cell models similar to those found in patients with VCP mutations or with lysosomal storage disorders. In neuronal cells, we found altered lysosomal activity characterised by membrane permeabilization with galectin-3 redistribution and activation of PPP3CB. This selectively activated the autophagy/lysosomal transcriptional regulator TFE3, but not TFEB, and enhanced both SQSTM1/p62 and lipidated MAP1LC3B levels inducing autophagy. Moreover, we found that wild type VCP, but not the mutants, counteracted lysosomal damage induced either by trehalose or by a mutant form of SOD1 (G93A), also blocking the formation of its insoluble intracellular aggregates. Thus, chronic activation of autophagy might fuel the formation of multilamellar bodies. Conclusion: Together, our findings provide insights into the pathogenesis of VCP-related diseases, by proposing a novel mechanism of multilamellar body formation induced by VCP mutants that involves lysosomal damage and induction of lysophagy