The microbiome in autoimmune diseases De Luca, F.; Shoenfeld, Y.
Clinical and experimental immunology,
January 2019, Letnik:
195, Številka:
1
Journal Article
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Summary
The microbiome is represented by microorganisms which live in a symbiotic way with the mammalian. Microorganisms have the ability to influence different physiological aspects such as the ...immune system, metabolism and behaviour. In recent years, several studies have highlighted the role of the microbiome in the pathogenesis of autoimmune diseases. Notably, in systemic lupus erythematosus an alteration of the intestinal flora (lower Firmicutes/Bacteroidetes ratio) has been described. Conversely, changes to the gut commensal and periodontal disease have been proposed as important factors in the pathogenesis of rheumatoid arthritis. At the same time, other autoimmune diseases (i.e. systemic sclerosis, Sjögren’s syndrome and anti‐phospholipid syndrome) also share modifications of the microbiome in the intestinal tract and oral flora. Herein, we describe the role of the microbiome in the maintenance homeostasis of the immune system and then the alterations of the microorganisms that occur in systemic autoimmune diseases. Finally, we will consider the use of probiotics and faecal transplantation as novel therapeutic targets.
Objective Hashimoto’s thyroiditis (HT), the most common autoimmune thyroid disease at any age, is often associated with other autoimmune diseases. The present study was aimed to describe the type and ...frequency of non-thyroidal autoimmune diseases (NTADs) in HT patients and to delineate the clinical pattern of diseases clustering in pediatric/adolescent and adult age. Design Cross-sectional study. Methods 1053 newly diagnosed HT patients (500 adults (467 F, mean age 40.2 ± 13.7 years) and 553 children/adolescents (449 F, mean age 11.1 ± 3.0 years)) were evaluated for common NTADs by means of careful recording of medical history, physical examination and assessment of selected autoantibody profiles. Results The prevalence of associated NTADs was significantly higher in adults than that in pediatric/adolescent HT patients (P < .0001). In addition, the number of adult patients suffering from two or more associated NTADs was significantly higher than that of children/adolescent (P < 0.0001). A female prevalence was evident in both cohorts, but was significant in the adults (P < 0.0001). The epidemiological distribution of NTADs was strongly different in the two cohorts, the most frequent associated diseases being arthropathies and connective tissue diseases in adults and type 1 diabetes and coeliac disease in children/adolescents. Skin diseases were represented with similar prevalence in both cohorts, vitiligo being the most common. Conclusions Age at HT presentation may influence autoimmune diseases clustering, favoring the association of specific NTADs in different ages of life. Moreover, the association between HT and NTADs increases with age and occurs most frequently in adults.
Chagas disease (CD) is a neglected tropical disease caused by the intracellular protozoan Trypanosoma cruzi that remains a serious public health issue affecting more than 6 million people worldwide. ...The available treatment includes 2 nitro derivatives, benznidazole (BZ) and nifurtimox, that lack in efficacy in the later chronic phase and when administered against the several naturally resistant parasite strains and present several side-effects, demanding new therapeutic options. One strategy is based on repurposing by testing drugs already used for other illness that may share similar targets. In this context, our previous data on imatinib (IMB) and derivatives motivated the screening of 8 new IMB analogues. Our findings showed that all except 1 were active against bloodstream trypomastigotes reaching drug concentration capable of inducing a 50% of parasite lysis (EC50) values < 12 μm after 2 h while BZ was inactive. After 24 h, all derivatives were more potent than BZ, exhibiting EC50 values 1.5–5.5 times lower. Against intracellular forms, 7 out of 8 derivatives presented high activity, with EC50 values ≤ BZ. LS2/89 stood out as one of the most promising, reaching EC90 values of 1.68 and 4.9 μm on intracellular and trypomastigote forms, respectively, with the best selectivity index (>60) towards the proliferative forms. Physicochemical parameters as well as the absorption, distribution, metabolism, excretion and toxicity properties were predicted to be acceptable and with good chance of a favourable oral bioavailability. The promising results motivate further studies such as in vivo and combinatory assays aiming to contribute for a novel safer and effective therapy for CD.
Key points
GABA depolarized sural nerve axons and increased the electrical excitability of C‐fibres via GABAA receptor.
Axonal excitability responses to GABA increased monotonically with the rate of ...action potential firing.
Action potential activity in unmyelinated C‐fibres is coupled to Na‐K‐Cl cotransporter type 1 (NKCC1) loading of axonal chloride.
Activation of axonal GABAA receptor stabilized C‐fibre excitability during prolonged low frequency (2.5 Hz) firing.
NKCC1 maintains intra‐axonal chloride to provide feed‐forward stabilization of C‐fibre excitability and thus support sustained firing.
GABAA receptor (GABAAR)‐mediated depolarization of dorsal root ganglia (DRG) axonal projections in the spinal dorsal horn is implicated in pre‐synaptic inhibition. Inhibition, in this case, is predicated on an elevated intra‐axonal chloride concentration and a depolarizing GABA response. In the present study, we report that the peripheral axons of DRG neurons are also depolarized by GABA and this results in an increase in the electrical excitability of unmyelinated C‐fibre axons. GABAAR agonists increased axonal excitability, whereas GABA excitability responses were blocked by GABAAR antagonists and were absent in mice lacking the GABAAR β3 subunit selectively in DRG neurons (AdvillinCre or snsCre). Under control conditions, excitability responses to GABA became larger at higher rates of electrical stimulation (0.5–2.5 Hz). However, during Na‐K‐Cl cotransporter type 1 (NKCC1) blockade, the electrical stimulation rate did not affect GABA response size, suggesting that NKCC1 regulation of axonal chloride is coupled to action potential firing. To examine this, activity‐dependent conduction velocity slowing (activity‐dependent slowing; ADS) was used to quantify C‐fibre excitability loss during a 2.5 Hz challenge. ADS was reduced by GABAAR agonists and exacerbated by either GABAAR antagonists, β3 deletion or NKCC1 blockade. This illustrates that activation of GABAAR stabilizes C‐fibre excitability during sustained firing. We posit that NKCC1 acts in a feed‐forward manner to maintain an elevated intra‐axonal chloride in C‐fibres during ongoing firing. The resulting chloride gradient can be utilized by GABAAR to stabilize axonal excitability. The data imply that therapeutic strategies targeting axonal chloride regulation at peripheral loci of pain and itch may curtail aberrant firing in C‐fibres.
Key points
GABA depolarized sural nerve axons and increased the electrical excitability of C‐fibres via GABAA receptor.
Axonal excitability responses to GABA increased monotonically with the rate of action potential firing.
Action potential activity in unmyelinated C‐fibres is coupled to Na‐K‐Cl cotransporter type 1 (NKCC1) loading of axonal chloride.
Activation of axonal GABAA receptor stabilized C‐fibre excitability during prolonged low frequency (2.5 Hz) firing.
NKCC1 maintains intra‐axonal chloride to provide feed‐forward stabilization of C‐fibre excitability and thus support sustained firing.
Abstract
Background
Adequate antibiotic dosing may improve outcomes in critically ill patients but is challenging due to altered and variable pharmacokinetics. To address this challenge, AutoKinetics ...was developed, a decision support system for bedside, real-time, data-driven and personalised antibiotic dosing. This study evaluates the feasibility, safety and efficacy of its clinical implementation.
Methods
In this two-centre randomised clinical trial, critically ill patients with sepsis or septic shock were randomised to AutoKinetics dosing or standard dosing for four antibiotics: vancomycin, ciprofloxacin, meropenem, and ceftriaxone. Adult patients with a confirmed or suspected infection and either lactate > 2 mmol/L or vasopressor requirement were eligible for inclusion. The primary outcome was pharmacokinetic target attainment in the first 24 h after randomisation. Clinical endpoints included mortality, ICU length of stay and incidence of acute kidney injury.
Results
After inclusion of 252 patients, the study was stopped early due to the COVID-19 pandemic. In the ciprofloxacin intervention group, the primary outcome was obtained in 69% compared to 3% in the control group (OR 62.5, CI 11.4–1173.78,
p
< 0.001). Furthermore, target attainment was faster (26 h, CI 18–42 h,
p
< 0.001) and better (65% increase, CI 49–84%,
p
< 0.001). For the other antibiotics, AutoKinetics dosing did not improve target attainment. Clinical endpoints were not significantly different. Importantly, higher dosing did not lead to increased mortality or renal failure.
Conclusions
In critically ill patients, personalised dosing was feasible, safe and significantly improved target attainment for ciprofloxacin.
Trial registration
: The trial was prospectively registered at Netherlands Trial Register (NTR), NL6501/NTR6689 on 25 August 2017 and at the European Clinical Trials Database (EudraCT), 2017-002478-37 on 6 November 2017.
The structural flexibility of RNA underlies fundamental biological processes, but there are no methods for exploring the multiple conformations adopted by RNAs in vivo. We developed cross-linking of ...matched RNAs and deep sequencing (COMRADES) for in-depth RNA conformation capture, and a pipeline for the retrieval of RNA structural ensembles. Using COMRADES, we determined the architecture of the Zika virus RNA genome inside cells, and identified multiple site-specific interactions with human noncoding RNAs.
Abstract
We present the first detailed analysis of the ultra-steep spectrum radio halo in the merging galaxy cluster A521, based on upgraded Giant Metrewave Radio telescope observations. The ...combination of radio observations (300–850 MHz) and archival X-ray data provides a new window into the complex physics occurring in this system. When compared to all previous analyses, our sensitive radio images detected the centrally located radio halo emission to a greater extent of ∼1.3 Mpc. A faint extension of the southeastern radio relic has been discovered. We detected another relic, recently discovered by MeerKAT, and coincident with a possible shock front in the X-rays, at the northwest position of the center. We find that the integrated spectrum of the radio halo is well-fitted with a spectral index of −1.86 ± 0.12. A spatially resolved spectral index map revealed the spectral index fluctuations, as well as an outward radial steepening of the average spectral index. The radio and X-ray surface brightness is well correlated for the entire and different subparts of the halo, with sublinear correlation slopes (0.50–0.65). We also found a mild anticorrelation between the spectral index and X-ray surface brightness. Newly detected extensions of the SE relic and the counter relic are consistent with the merger in the plane of the sky.
Landslides are recurrent phenomena in Italy, but little is known regarding the public perception of related risk. In order to investigate landslide risk perception of recent phenomena, we decided to ...perform a qualitative investigation in Frosinone (Lazio, Central Italy) where, during 2013, a relevant landslide (“Viaduct Biondi”) occurred. Survey results highlighted that Frosinone population have been experiencing landslides but do not consider themselves threatened and prepared in occurrence of this type of emergency. This study pointed out that Frosinone municipality and surrounding town populations behave as an inactive actor in land conservation and management, addressing major responsibility to institutions. For this reason, realization of a purposed designed dissemination campaign would be useful in order to improve citizen knowledge and to enhance their participation in landslide risk reduction activities.
The prominent degradation mechanism of cellulose is the acid-catalyzed hydrolysis of glycosidic bonds, which results in the decrease of the degree of polymerization (DP) and, macroscopically, in the ...dramatic decay of the mechanical resistance of cellulose-based materials. Alkaline nanoparticles in organic solvents have been recently proposed for the deacidification of cellulose-based artworks. Their effectiveness has been demonstrated in previous studies, by pH and DP measurements, colorimetric and thermal analyses. Herein, the changes in the cellulosic network following an acidification bath and a consequent deacidification treatment using Ca(OH)
2
nanoparticles, have been investigated by NMR self-diffusion dynamics of water and related to the changes of samples’ DPs. The deacidification treatment modifies intra- and inter-chain interactions, leading to a buffered cellulose network configuration similar to that characterizing the untreated reference sample in terms of diffusive parameters and confining environment. Such results are plausibly due to a rearrangement in connectivity of the cellulosic network, even though with a different physical fingerprint with respect to the reference sample. The analysis of tortuosity of the cellulosic network in acidic and deacidified samples confirms this conclusion, further corroborating the idea that calcium hydroxide nanoparticles are an effective tool to hamper the degradation of cellulose induced by acids and aging in strong environmental conditions, even from the standpoint of cellulose network arrangement.
•The damaged ship behavior, is studied assuming different arrangements of the flooded engine room compartment.•The effects of the flooded water motions on ship dynamics, in presence of obstructions, ...are studied.•Experimental tests on roll decay and on ship motions in beam waves for the damage cases are performed.•Comparison and analysis of the results for the different damage scenarios are conducted.
The dynamics of a damaged ship in waves is a complex phenomenon regarding fluid and structure interactions. Flooded water motions in the damaged compartment could be influenced by decks, obstructions and obstacles in the compartment. This becomes particularly relevant in case of flooding in the engine room that is usually characterized by the presence of large objects such as engines and machineries. In such cases the possibility to better understand the behavior of a damaged ship, influenced by the fluid and structure interactions, could provide novel outcomes and thus enhance the damaged ship safety.
In this paper an experimental campaign is conducted on a passenger ferry hull. The effects of obstacles in the engine room compartment, such as decks and engines, on ship roll responses, are studied. Roll decay in still water and steady roll responses in beam regular waves at zero speed are measured for the empty compartment and for the compartment with obstructions, as defined above.
The main outcomes from the conducted experiments disclose a mitigation of the resonant behavior of the coupled system, ship with damaged compartment, by having engine shapes occupying the flooded engine room. Moreover it is possible to observe how the resonant frequency of the ship modifies having a more realistic arrangement of damaged compartment and how motion RAOs and roll decay characteristics modify accordingly.
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