Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

Distribution, location, and transcriptional profile of Peyer's patch conventional DC subsets at steady state and under TLR7 ligand stimulation.

The initiation of the mucosal immune response in Peyer's patch (PP) relies on the sampling, processing, and efficient presentation of foreign antigens by dendritic cells (DCs). Among PP DCs, CD11b+ conventional DCs (cDCs) and lysozyme-expressing DCs (LysoDCs) have distinct progenitors and functions but share many cell surface markers. This has previously led to confusion between these two subsets. In addition, another PP DC subset, termed double-negative (DN), remains poorly characterized. Here we show that both DN and CD11b+ cDCs belong to a unique SIRPα+ cDC subset. At steady state, cDCs and TIM-4+ macrophages are mainly located in T-cell zones, i.e., interfollicular regions, whereas a majority of subepithelial phagocytes are monocyte-derived cells, namely, LysoDCs and TIM-4- macrophages. Finally, oral administration of a Toll-like receptor 7 ligand induces at least three TNF-dependent events: (i) migration of dome-associated villus cDCs in interfollicular regions, (ii) increase of CD8α+ interfollicular cDC number, and (iii) activation of both CD11b+ and CD8α+ interfollicular cDCs. The latter is marked by a genetic reprograming leading to the upregulation of type I interferon-stimulated and of both immuno-stimulatory and -inhibitory gene expression.

Tissue-specific differentiation of colonic macrophages requires TGFß receptor-mediated signaling.

Intestinal macrophages (mφ) form one of the largest populations of mφ in the body and are vital for the maintenance of gut homeostasis. They have several unique properties and are derived from local differentiation of classical Ly6Chi monocytes, but the factors driving this tissue-specific process are not understood. Here we have used global transcriptomic analysis to identify a unique homeostatic signature of mature colonic mφ that is acquired as they differentiate in the mucosa. By comparing the analogous monocyte differentiation process found in the dermis, we identify TGFß as an indispensable part of monocyte differentiation in the intestine and show that it enables mφ to adapt precisely to the requirements of their environment. Importantly, TGFßR signaling on mφ has a crucial role in regulating the accumulation of monocytes in the mucosa, via mechanisms that are distinct from those used by IL10.

The study of the pseudo-polyrotaxane architecture as a route for mild surface functionalization by click chemistry of poly(ε-caprolactone)-based electrospun fibers.

Polycaprolactone (PCL) electrospun fibers are widely developed for biomedical applications. However, their hydrophobicity and passivity towards cell growth is an important limitation. An original method to functionalize PCL nanofibers, making them reactive for bioconjugation of proteins or other molecules of interest in water under mild conditions, is reported here. This method involves the preparation of pseudo-polyrotaxanes (pPRs) of cyclodextrin (CD) and PCL. Core:shell PCL:pPR fibers were then prepared by coaxial electrospinning in order to bring available reactive hydroxyl groups from the CD to the fiber surface. Different pPR architectures (star, miktoarm and block-copolymer-like) were synthesized to study the effect of the pPR structure on fiber morphology and surface reactivity by grafting fluorescein isothiocyanate (FITC). Finally, bicyclononyne groups were grafted onto the star-pPR based fibers allowing the conjugation of a fluorescent dye by click chemistry in water without any copper catalyst proving the potential of the method for the biofunctionalization of PCL-based fibers.

Fungal Fermentation of Lignocellulosic Biomass for Itaconic and Fumaric Acid Production.

The production of high-value chemicals from natural resources as an alternative for petroleum-based products is currently expanding in parallel with biorefinery. The use of lignocellulosic biomass as raw material is promising to achieve economic and environmental sustainability. Filamentous fungi, particularly Aspergillus species, are already used industrially to produce organic acid as well as many enzymes. The production of lignocellulose-degrading enzymes opens the possibility for direct fungal fermentation towards organic acids such as itaconic acid (IA) and fumaric acid (FA). These acids have wide-range applications and potentially addressable markets as platform chemicals. However, current technologies for the production of these compounds are mostly based on submerged fermentation. This work showed the capacity of two Aspergillus species (A. terreus and A. oryzae) to yield both acids by solid-state fermentation and simultaneous saccharification and fermentation. FA was optimally produced at by A. oryzae in simultaneous saccharification and fermentation (0.54 mg/g wheat bran). The yield of 0.11 mg IA/g biomass by A. oryzae is the highest reported in the literature for simultaneous solid-state fermentation without sugar supplements.

Sepiolite as a promising nanoclay for nano-biocomposites based on starch and biodegradable polyester.

The effects of sepiolite addition (0, 1, 3 and 5wt%) were evaluated on dynamic-mechanical behaviour, water uptake, thermal and optical properties of thermoplastic starch (TPS)/poly (butylene adipate-co-terephthalate) (PBAT) nano-biocomposites, with different TPS/PBAT (w/w) ratios and nanofiller contents. The results highlighted the improvement of the dynamic-mechanical behaviour with the addition of sepiolite, producing high performance materials. An increase of 25°C in the Tg of TPS was recorded by DMTA analysis at sepiolite content of 5wt%. The sepiolite influenced the crystallisation of nano-biocomposites, without causing interference in the crystal organisation, evidenced by DSC analysis. The addition of sepiolite nanoclay decreased the water adsorption rate and water adsorption capacity of the corresponding nano-biocomposites. For such multiphase systems, the successful use of natural sepiolite brought a clear benefit, without the need of any modifications or additional processes to produce advanced nano-biocomposites.

Elaboration, morphology and properties of starch/polyester nano-biocomposites based on sepiolite clay.

The incorporation of nano-sized sepiolite clays into thermoplastic starch/poly(butylene adipate-co-terephthalate) (TPS/PBAT) blends has been investigated with the goal of improving the matrix properties. TPS/PBAT nano-biocomposites were elaborated with two different proportions of the polymeric phases. The influence of the sepiolite nanoclays on the mechanical, thermal and structural properties of the corresponding blends was evaluated. SEM images confirmed the good dispersion of the sepiolite clay, with a low occurrence of small aggregates in the polymeric matrix. Wide-angle X-ray diffraction showed no significant alteration of the crystalline structures of PBAT and starch induced by the sepiolite clay. The addition of sepiolite slightly affected the thermal degradation of the nano-biocomposites; however, the mechanical tests revealed an increase in some mechanical properties, demonstrating that sepiolite is a promising nanofiller for TPS-based materials.

Mixed culture polyhydroxyalkanoate (PHA) production from volatile fatty acid (VFA)-rich streams: effect of substrate composition and feeding regime on PHA productivity, composition and properties.

In this study, the possibility of manipulating biopolymer composition in mixed culture polyhydroxyalkanoate (PHA) production from fermented molasses was assessed by studying the effects of substrate volatile fatty acid (VFA) composition and feeding regime (pulse wise versus continuous). It was found that the use of a continuous feeding strategy rather than a pulse feeding strategy can not only help mitigate the process constraints of the pulse-feeding strategy (resulting in higher specific and volumetric productivities) but also be used as means to broaden the range of polymer structures. Continuous feeding increased the hydroxyvalerate content by 8% relatively to that obtained from the same feedstock using pulse wise feeding. Therefore, the feeding strategy can be used to manipulate polymer composition. Furthermore, the range of PHA compositions, copolymers of P(HB-co-HV) with HV fraction ranging from 15 to 39%, obtained subsequently resulted in different polymer properties. Increasing HV content resulted in a decrease of the average molecular weight, the glass transition and melting temperatures and also in a reduction in the crystallinity degree from a semi-crystalline material to an amorphous matrix.

Micromechanically-based formulation of the cooperative model for the yield behavior of starch-based nano-biocomposites.

The tensile yield stress of plasticized starch filled with montmorillonite has been studied as a function of the temperature and the strain rate and has been compared to the yield behavior of the original matrix. Aggregated/intercalated and exfoliated nano-biocomposites, obtained from different nanofillers, have been produced and tested under uniaxial tension (tensile test). To model the nanocomposite tensile yield stress behavior, a preexisting micro-mechanically based cooperative model, which describes properly the yield of semi-crystalline polymers has been modified. According to our development, the yield behavior of nano-biocomposites is strongly dependant on the clay concentration and exfoliation ratio. Based on the thermodynamics properties, an effective activation volume and effective activation energy are computed through the Takayanagi homogenization model. The predicted results for the yield stress at low strain rates and at different temperatures are in agreement with our experimental results.

[Fifty-two cases of postoperative endophthalmitis treated with one protocol: anatomical and functional results]. / 52 cas d'endophtalmie post-opératoire traités par un protocole thérapeutique unique: résultats anatomiques et fonctionnels.

PURPOSE: To evaluate our management of postoperative endophthalmitis and compare our protocol to the Endophthalmitis Vitrectomy Study's (EVS) recommended protocol. PATIENTS AND METHODS: This study comprises 52 patients with postoperative endophthalmitis treated with the same protocol in 1996 and 1997. Patients were given an intravitreal injection of antibiotics (vancomycin-amikacin) and steroids (dexamethasone), systemic antibiotics (pefloxacin-piperracillin), and systemic steroids in bolus. Vitrectomy was not systematic. So as not to delay the treatment, cultures were obtained only from an anterior chamber paracentesis. RESULTS: Visual acuity was measurable in 86.5% of the patients, with 20/100 in 63.4% and 20/40 in 44.2%. Our results are similar to those of the EVS even when initial visual acuity was Light Perception. CONCLUSION: Our protocol is simple and easy to perform in all ophthalmology centers. It is based on intravitreal injection, which must be performed as quickly as possible.

Role of tryptophan oxidation in peroxynitrite-dependent protein chemiluminescence.

Bovine serum albumin oxidation by peroxynitrite is accompanied by chemiluminescence (Watts et al., Arch. Biochem. Biophys. 317, 324-330, 1995). Peak chemiluminescence during the reaction between bovine serum albumin (with or without fatty acids) and peroxynitrite was not modified in the presence of D2O, suggesting that light emission arising from lipid or protein oxidation was not the result of singlet oxygen formation. Light emission from fatty acid-free albumin increased in the presence of diphenylanthracene (DPA), suggesting that it is a consequence of the fluorescent decay of excited species. Exposure of individual amino acids to peroxynitrite in 50 mM potassium phosphate at pH 8.0 showed that tryptophan is the one that emits most light during oxidation, followed by phenylalanine. Tryptophan chemiluminescence correlated with oxygen consumption. The spin trap N-t-butyl-alpha-phenylnitrone (PBN) inhibited both oxygen consumption and chemiluminescence during tryptophan oxidation, suggesting that the reactions leading to light emission start with the abstraction of a H atom, forming a C-centered radical which in turn adds oxygen. When the oxidation of tryptophan by peroxynitrite was carried out in Tris-HCl instead of potassium phosphate, there was a second oxidative reaction between the peroxide and Tris. Chemiluminescence and oxygen consumption during the oxidation of tryptophan by peroxynitrite was 50% lower in the presence of Tris and in this case PBN did not inhibit chemiluminescence, suggesting that the new radicals formed during the reaction of Tris with peroxynitrite reacted with the amino acyl radicals inhibiting the formation of excited intermediates. Exposure of Tris but not phosphate to peroxynitrite (in the absence of amino acids) also resulted in light emission. In summary, these results suggest that tryptophan is one of the amino acids responsible for light emission during protein oxidation. In addition, this study confirms that Tris buffer is a target for strong oxidants and shows that its oxidation also is accompanied by light emission.

[Spontaneous pneumopericardium. Review of the literature apropos of 2 cases in the young adult]. / Les pneumopéricardes spontanés--revue de la littérature. A propos de deux observations chez l'adulte jeune.

Pneumopericardium is defined as the presence of air in the pericardial cavity. It is a rare condition in adults, usually due to trauma; it is commoner in the more exposed neonate and usually iatrogenic. The clinical presentation of chest pain and shortness of breath is associated with the pathognomonic auscultatory sign described by Bricheteau: a water-mill bruit. The diagnosis is confirmed by chest X-ray which shows the air-gap sign surrounding the cardiac silhouette. The principal differential diagnosis is a pneumomediastinum. The prognosis of pneumopericardium depends on the cause and complications of which tamponade and infection are the most serious and potentially life-threatening. The treatment of pneumopericardium is bed rest and surveillance when uncomplicated: evacuation of the air becomes necessary when complications set in.

[Iatrogenic arteriovenous fistula between the internal mammary artery and the innominate venous trunk. Contribution of digital arteriography in the positive and anatomic diagnosis]. / Fistule artérioveineuse iatrogène entre artère mammaire interne et tronc veineux innominé. Apport de l'artériographie digitalisée dans le diagnostic positif et anatomique.

The authors report the case of an arterio-venous fistula between the internal mammary artery and the trunk of the innominate vein following puncture of the internal jugular. The clinical signs of this unusual complication led the authors to list the differential diagnoses which should be considered and to draw attention to the importance of digitalized angiography in anatomical diagnosis.

[Differential analysis of mitral and tricuspid regurgitation by continuous Doppler]. / Analyse différentielle des fuites mitrales et tricuspides par le Doppler continu.

The following parameters have been measured by continuous Doppler in 40 patients with both mitral failure (MF) and tricuspid failure (TF): effusion time (ET), peak time (PT), maximum effusion speed (S. max), maximum anterograde speed (S. ant), taking into account the cardiac rate and the ejection fraction. Only the S. max. and the S. ant. are significantly different and enable the determination of the effusion origin with a percentage error of about 4%. When a straight line is drawn to joint 3.7 m/s on the ordinate (S. ant) and 5 m/s on the abcissa (S. max), the TF lie below the line and the MF above it. The selection of the sub-groups with low ejection fraction (less or equal to 30%) or with arterial pulmonary hypertension (S. max MF higher or equal to 3 m/s) does not modify the precision of the discrimination. The graph suggested seems therefore to be a rapid and reliable means of characterizing TF in order to assess the arterial pulmonary hypertension of dilated hypokinetic cardiomyopathies.

[Natural course of type III traumatic chronic dissection in a patient with Marfan's syndrome]. / Evolution naturelle d'une dissection chronique traumatique de type III chez une malade atteinte d'un syndrome de Marfan.

Description of a traumatic dissection of the descending thoracic aorta, occurring in a female patient with Marfan's syndrome, the chronic course of which over more than three years was complicated by retrograde extension to the ascending thoracic aorta, resulting in death by massive aortic insufficiency and pleuro-pericardial effusion. Advantages of clinical and sonocardiographic monitoring of chronic dissections.

[Comparative study of cibenzoline and flecainide administered via an intravenous route in reducing auricular arrhythmia]. / Etude comparative de la cibenzoline et du flécaïnide par voie intraveineuse dans la réduction des troubles du rythme auriculaire.

The efficacy of intravenous flecainide and cibenzoline acetate in the reduction of atrial rhythm disorders was compared in two groups of 30 patients. These arrhythmias are divided in 31 atrial fibrillation, 11 tachy-systoles, 18 atrial flutters. Parenteral administration of the anti-arrhythmic drug over a 24 hour-period is preceded by a bolus injection of 1.5 mg/kg of flecainide acetate for group I, and a bolus of 1 mg/kg of cibenzoline for group II. The overall efficacy of the two molecules is comparable (53%) as well as the reduction of the atrial fibrillations (65% vs 57%). Flecainide acetate seems more effective in treating effectively atrial tachycardias (66.6% vs 40%), and cibenzoline is more effective in the treatment of atrial flutters (54% vs 14%). The functional, electrical and haemodynamic tolerance has always been good in both group, except in 2 patients, because of the indirect pro-arrhythmic effect of cibenzoline. We are concluding that the efficacy of both molecules is satisfactory and we advocate their use, as first intention, in recent and idiopathic atrial fibrillation; it seems that cibenzoline is more effective on ischemic cardiopathies and flecainide acetate is more effective on valvular cardiopathies. Nevertheless, the possible indirect pro-arrhythmic effect, sometimes poorly tolerated in the first minutes following administration of the bolus, only on organized atrial rhythm disorder, leads us to advocate the prescription of these two drugs when attempts of transesophageal or endocardiac atrial stimulation have failed.

[Diagnostic, prognostic and therapeutic value of Doppler echocardiography in pulmonary embolism. Apropos of 41 cases]. / Intérêt diagnostique, pronostique et thérapeutique de l'échocardiographie Doppler dans l'embolie pulmonaire. A propos de 41 cas.

In 41 patients with acute or recent pulmonary embolus (PE), a prospective study was conducted with cardiac Doppler sonography (CDS). The test is performed first in all patients, then immediately following a treatment fibrinolytics in 10 of them. The PE is confirmed by pulmonary angiography in 39 patients and embolectomy for the 2 patients who presented a mobile thrombus in the right atrium. A tricuspid insufficiency (TI) is almost always recorded by continuous Doppler: the systolic pulmonary artery pressure (sPAP) is calculated from the maximum velocity of the regurgitating tricuspid flow, using Bernouilli's equation. The correlation between Doppler sPAP and sPAP obtained by catheterization is: r = 0.95 (n = 34; p less than 0.001). A severe pulmonary hypertension, corresponding to a TI exceeding 3.5 m/s is related to a pulmonary migration occurring on a pathological heart. There is a satisfactory relationship between the elevation of the Doppler sPAP and the degree of pulmonary obstruction in the "Pe on healthy heart" population: r = 0.6 (n = 29; p less than 0.001). The dilated right ventricle observed on the sonogram (RV) is proportional to the severity of the angiographic image: correlation between the RV/LV ratio and the percentage of vascular obstruction is r = 0.73 (n = 27; p less than 0.001). The drop in the sPAP and the regression of the symptoms of pulmonary heart noted on CDS after fibrinolysis, correspond to a significant improvement of the pulmonary perfusion. The CDS seems to be absolutely necessary in PE because of the major and reliable informations it provides.

[Ultrasonic diagnosis of biventricular thrombus during the acute phase of myocardial infarction]. / Diagnostic échographique d'un thrombus biventriculaire au stade aigu d'un infarctus du myocarde.

The occurrence of a left ventricular thrombus is a classic complication of acute myocardial infarction. On the contrary, this is much less frequent in the right ventricle. The authors report the case of a patient presenting a biventricular thrombus resulting as a complication of an anterior myocardial infarction, diagnosed by bidimensional ultrasonography. The course is characterized by the occurrence of a cerebral vascular accident. The sonogram following this neurological accident shows that the left ventricular thrombus has disappeared, confirming its migration. On the contrary, the right ventricular thrombus regressed under appropriate heparin treatment, without any embolic complication.