Toll-like receptor-mediated signaling cascade as a regulator of the inflammation network during alcoholic liver disease

Chronic abuse of alcohol leads to various histological abnormalities in the liver. These are conditions collectively known as alcoholic liver disease (ALD). Currently, ALD is considered to be one of the major causes of death worldwide. An impaired intestinal barrier with related endotoxemia is among the various pathogenetic factors. This is mainly characterized by circulating levels of lipopolysaccharide (LPS), considered critical for the onset of intra-hepatic inflammation. This in turn promotes hepatocellular damage and fibrosis in ALD. Elevated levels of LPS exert their effects by binding to Toll-like receptors (TLRs) which are expressed by all liver-resident cells. The activation of TLR signaling triggers an overproduction and release of some cytokines, which promote an autocatalytic cascade of other proinflammatory signals. In this review, we provide an overview of the mechanisms that sustain LPS-mediated activation of TLR signaling, reporting current experimental and clinical evidence of its role during inflammation in ALD

Sulphur-bearing species in the star forming region L1689N

We report observations of the expected main S-bearing species (SO, SO2 and H2S) in the low-mass star forming region L1689N. We obtained large scale (~300''x200'') maps of several transitions from these molecules with the goal to study the sulphur chemistry, i.e. how the relative abundances change in the different physical conditions found in L1689N. We identified eight interesting regions, where we carried out a quantitative comparative study: the molecular cloud (as reference position), five shocked regions caused by the interaction of the molecular outflows with the cloud, and the two protostars IRAS16293-2422 and 16293E. In the cloud we carefully computed the gas temperature and density by means of a non-LTE LVG code, while in other regions we used previous results. We hence derived the column density of SO, SO2 and H2S, together with SiO and H2CO - which were observed previously - and their relevant abundance ratios. We find that SiO is the molecule that shows the largest abundance variations in the shocked regions, whereas S-bearing molecules show more moderate variations. Remarkably, the region of the brightest SiO emission in L1689N is undetected in SO2, H2S and H2CO and only marginally detected in SO. In the other weaker SiO shocks, SO2 is enhanced with respect to SO. We propose a schema in which the different molecular ratios correspond to different ages of the shocks. Finally, we find that SO, SO2 and H2S have significant abundance jumps in the inner hot core of IRAS16293-2422 and discuss the implications of the measured abundances.Comment: Accepted 08/10/0

Infrared Observations of Hot Gas and Cold Ice toward the Low Mass Protostar Elias 29

We have obtained the full 1-200 um spectrum of the low luminosity (36 Lsun) Class I protostar Elias 29 in the Rho Ophiuchi molecular cloud. It provides a unique opportunity to study the origin and evolution of interstellar ice and the interrelationship of interstellar ice and hot core gases around low mass protostars. We see abundant hot CO and H2O gas, as well as the absorption bands of CO, CO2, H2O and ``6.85 um'' ices. We compare the abundances and physical conditions of the gas and ices toward Elias 29 with the conditions around several well studied luminous, high mass protostars. The high gas temperature and gas/solid ratios resemble those of relatively evolved high mass objects (e.g. GL 2591). However, none of the ice band profiles shows evidence for significant thermal processing, and in this respect Elias 29 resembles the least evolved luminous protostars, such as NGC 7538 : IRS9. Thus we conclude that the heating of the envelope of the low mass object Elias 29 is qualitatively different from that of high mass protostars. This is possibly related to a different density gradient of the envelope or shielding of the ices in a circumstellar disk. This result is important for our understanding of the evolution of interstellar ices, and their relation to cometary ices.Comment: 18 pages and 14 figures, accepted for publication in A&

Permeation of β-Lactamase Inhibitors through the General Porins of Gram-Negative Bacteria

Modern medicine relies upon antibiotics, but we have arrived to the point where our inability to come up with new effective molecules against resistant pathogens, together with the declining private investment, is resulting in the number of untreatable infections increasing worldwide at worrying pace. Among other pathogens, widely recognized institutions have indicated Gram-negative bacteria as particularly challenging, due to the presence of the outer membrane. The very first step in the action of every antibiotic or adjuvant is the permeation through this membrane, with small hydrophilic drugs usually crossing through protein channels. Thus, a detailed understanding of their properties at a molecular level is crucial. By making use of Molecular Dynamics simulations, we compared the two main porins of four members of the Enterobacteriaceae family, and, in this paper, we show their shared geometrical and electrostatic characteristics. Then, we used metadynamics simulations to reconstruct the free energy for permeation of selected diazobicyclooctans through OmpF. We demonstrate how porins features are coupled to those of the translocating species, modulating their passive permeation. In particular, we show that the minimal projection area of a molecule is a better descriptor than its molecular mass or the volume. Together with the magnitude and orientation of the electric dipole moment, these are the crucial parameters to gain an efficient compensation between the entropic and enthalpic contributions to the free energy barrier required for permeation. Our results confirm the possibility to predict the permeability of molecules through porins by using a few molecular parameters and bolster the general model according to which the free energy increase is mostly due to the decrease of conformational entropy, and this can be compensated by a favorable alignment of the electric dipole with respect to the channel intrinsic electric field

Stage-related outcome for thymic epithelial tumours

Background: Thymic epithelial tumours (TETs) are characterized by a wide variety of biological behaviors. Radical resection and stage are strong prognostic factors. Aim of this study is to review our Single Center Experience. Methods: One hundred and seventy-seven patients observed in the period from January 2000 to December 2016 were included in the study. Data regarding clinicopathologic features, treatment, and survival were collected. Stage-related clinical standpoints and therapeutic options were also evaluated. Results: Non-surgical treatment was primarily performed in 15 (8.47%), unresectable disease was intraoperatively found in 12 cases (7.4%). The analysis of 150 patients undergoing curative surgery revealed 70 stage I TET (46.66%), 49 stage II (32.66%), 19 stage III (12.66%), 6 stage IVa (4%) and 6 stage IVb (4%) at the first hospital admission. Histology identified 12 A thymoma (8%), 38 AB (25.33%), 24 B1 (16%), 50 B2 (33.33%), 19 B3 (12.66%) and 7 carcinomas (4.66%). The mean follow up time was 84.14 months (sd = 61.68 months). Disease relapse occurred in 13 patients (8.78%) at a mean period of 78.85 months (sd = 60.87 months) after surgery. Exitus due to thymoma happened in 6 cases (4.05%) after a mean survival of 56.02 months (sd = 25.17 months). The 5-year overall survival rate was 0.94 (95%CI 0.88-0.97) and the 5-year disease-free survival rate was 0.90 (95%CI 0.83-0.94). The 5-year overall survival rates were 96.1% (95% CI, 89.9-98.5%) for the early stages and 87.4% (95% CI, 65.6-95.8%) for the advanced stages (p = 0.670). The 5-year disease-free survival rates resulted being 98.8% (95% CI, 92.3-99.8%) for the early stages and 59.8% (95% CI, 37.8-76.2%) for the advanced stages (p < 0.001). Conclusions: Advanced stage TETs are characterized by higher mortality and recurrence rates. Although technically demanding, surgery, as part of multimodality therapy, could prolong survival. Iterative surgical treatment of recurrences is a viable option for selected patients. Trial registration: The study was approved by the Institutional Review Board of Perugia and Terni University Hospitals [Code T1003] and was retrospectively registered

The Environment and Nature of the Class I Protostar Elias 29: Molecular Gas Observations and the Location of Ices

A (sub-)millimeter line and continuum study of the Class I protostar Elias 29 in the ρ Ophiuchi molecular cloud is presented whose goals are to understand the nature of this source and to locate the ices that are abundantly present along this line of sight. Within 15"-60" beams, several different components contribute to the line emission. Two different foreground clouds are detected, an envelope/disk system and a dense ridge of HCO^+-rich material. The latter two components are spatially separated in millimeter interferometer maps. We analyze the envelope/disk system by using inside-out collapse and flared disk models. The disk is in a relatively face-on orientation (<60°), which explains many of the remarkable observational features of Elias 29, such as its flat spectral energy distribution, its brightness in the near-infrared, the extended components found in speckle interferometry observations, and its high-velocity molecular outflow. It cannot account for the ices seen along the line of sight, however. A small fraction of the ices is present in a (remnant) envelope of mass 0.12-0.33 M_☉, but most of the ices (~70%) are present in cool (T < 40 K) quiescent foreground clouds. This explains the observed absence of thermally processed ices (crystallized H_2O) toward Elias 29. Nevertheless, the temperatures could be sufficiently high to account for the low abundance of apolar (CO, N_2, O_2) ices. This work shows that it is crucial to obtain spectrally and spatially resolved information from single-dish and interferometric molecular gas observations in order to determine the nature of protostars and to interpret Infrared Space Observatory and future Space Infrared Telescope Facility observations of ices and silicates along a pencil beam

Depletion of chlorine into HCl ice in a protostellar core

The freezeout of gas-phase species onto cold dust grains can drastically alter the chemistry and the heating-cooling balance of protostellar material. In contrast to well-known species such as carbon monoxide (CO), the freezeout of various carriers of elements with abundances $<10^{-5}$ has not yet been well studied. Our aim here is to study the depletion of chlorine in the protostellar core, OMC-2 FIR 4. We observed transitions of HCl and H2Cl+ towards OMC-2 FIR 4 using the Herschel Space Observatory and Caltech Submillimeter Observatory facilities. Our analysis makes use of state of the art chlorine gas-grain chemical models and newly calculated HCl-H$_{2}$ hyperfine collisional excitation rate coefficients. A narrow emission component in the HCl lines traces the extended envelope, and a broad one traces a more compact central region. The gas-phase HCl abundance in FIR 4 is 9e-11, a factor of only 0.001 that of volatile elemental chlorine. The H2Cl+ lines are detected in absorption and trace a tenuous foreground cloud, where we find no depletion of volatile chlorine. Gas-phase HCl is the tip of the chlorine iceberg in protostellar cores. Using a gas-grain chemical model, we show that the hydrogenation of atomic chlorine on grain surfaces in the dark cloud stage sequesters at least 90% of the volatile chlorine into HCl ice, where it remains in the protostellar stage. About 10% of chlorine is in gaseous atomic form. Gas-phase HCl is a minor, but diagnostically key reservoir, with an abundance of <1e-10 in most of the protostellar core. We find the 35Cl/37Cl ratio in OMC-2 FIR 4 to be 3.2\pm0.1, consistent with the solar system value.Comment: 13 pages, 12 figures, accepted for publication in A&

Once-daily intrapleural urokinase treatment of complicated parapneumonic effusion in pediatric patients

In this paper, we describe our experience in the treatment of childhood empyema using urokinase. Patients' ages ranged from 2 to 12 years. Urokinase (dosage: 3,100 IU/kg/day) was diluted in normal saline to produce 1000 IU/ml (maximum dosage 100,000 IU in 100 ml of normal saline). After 2 hours, the clamped catheters were released and connected to water-seal suction at a negative pressure of 10 cm H2O. Pleural irrigations were continued once a day until thoracostomy tube output decreased to less than 10 ml/day (urokinase treatment mean duration: 11.5 days). The complete resolution of the chest effusion was assessed on chest ultrasound scan and radiographs. None of the patients experienced any side effects due to urokinase. It would now seem reasonable to advocate small chest tube thoracostomy and intrapleural urokinase as first-line treatment of pleural empyema in children, with surgery indicated as a secondaryintervention

Rational timing of combination therapy with tiotropium and formoterol in moderate and severe COPD.

AIM: To determine which timing of therapy with formoterol (FOR) and/or tiotropium (TIO) shows the greater and more continuous functional improvement during 24 h in patients with moderate to severe COPD. METHODS: In this randomised, blind, crossover study 80 patients with stable COPD (40 moderate and 40 severe) received 5 different bronchodilator 30-day treatments in a random order. Treatments (Tr) were: Tr1: TIO 18 microg once-daily (8 am); Tr2: TIO 18 microg (8 am) + FOR 12 microg (8 pm); Tr3: FOR 12 microg twice-daily (8 am and 8 pm); Tr4: TIO 18 microg (8 am) + FOR 12 microg twice-daily (8 am and 8 pm); Tr5: FOR 12 microg twice-daily (8 am and 8 pm) + TIO 18 microg (8 pm). Spirometries were performed during 24 h (13 steps) on Day1 and Day30. End-points were: gain of FEV(1) (DeltaFEV(1)) from baseline of the Day1 and Day30, AUC (Area Under Curve), Dyspnoea Index, and as-needed use of salbutamol. RESULTS: Sixty-eight patients completed all treatments. The greater and continuous daily functional improvement was showed during Tr4 and Tr5 (Day1 +135.8 mL and +119.1 mL; Day30 +160.2 mL, and +160.5 mL, respectively). Daily means of DeltaFEV(1) were significantly different between single-drug treatments and combination therapy. Dyspnoea was greater in single-drug treatments. Less use of rescue salbutamol was reported in Tr4 (0.80 puffs/die) and Tr5 (0.71 puffs/die). CONCLUSIONS: In patients with moderate to severe COPD, combination therapy with tiotropium administered in the morning (Tr4) was the most effective; in patients with prevailing night-symptoms, treatment with tiotropium in the evening (Tr5) reduced symptoms and use of salbutamol. Tr5 showed less variability of FEV(1) during the 24 h (CV=0.256). These results are relevant for opening new ways in clinical practice