Impaired LAIR-1-mediated immune control due to collagen degradation in fibrosis.

Tissue repair is disturbed in fibrotic diseases like systemic sclerosis (SSc), where the deposition of large amounts of extracellular matrix components such as collagen interferes with organ function. LAIR-1 is an inhibitory collagen receptor highly expressed on tissue immune cells. We questioned whether in SSc, impaired LAIR-1-collagen interaction is contributing to the ongoing inflammation and fibrosis. We found that SSc patients do not have an intrinsic defect in LAIR-1 expression or function. Instead, fibroblasts from healthy controls and SSc patients stimulated by soluble factors that drive inflammation and fibrosis in SSc deposit disorganized collagen products in vitro, which are dysfunctional LAIR-1 ligands. This is dependent of matrix metalloproteinases and platelet-derived growth factor receptor signaling. In support of a non-redundant role of LAIR-1 in the control of fibrosis, we found that LAIR-1-deficient mice have increased skin fibrosis in response to repeated injury and in the bleomycin mouse model for SSc. Thus, LAIR-1 represents an essential control mechanism for tissue repair. In fibrotic disease, excessive collagen degradation may lead to a disturbed feedback loop. The presence of functional LAIR-1 in patients provides a therapeutic opportunity to reactivate this intrinsic negative feedback mechanism in fibrotic diseases.

Cumulative epinephrine dose during cardiac arrest and neurologic outcome after extracorporeal cardiopulmonary resuscitation.

BACKGROUND: Epinephrine is recommended without an apparent ceiling dosage during cardiac arrest. However, excessive alpha- and beta-adrenergic stimulation may contribute to unnecessarily high aortic afterload, promote post-arrest myocardial dysfunction, and result in cerebral microvascular insufficiency in patients receiving extracorporeal cardiopulmonary resuscitation (ECPR). METHODS: This was a retrospective cohort study of adults (≥ 18 years) who received ECPR at large academic ECMO center from 2018 to 2022. Patients were grouped based on the amount of epinephrine given during cardiac arrest into low (≤ 3 mg) and high (> 3 mg) groups. The primary endpoint was neurologic outcome at hospital discharge, defined by cerebral performance category (CPC). Multivariable logistic regression was used to assess the relationship between cumulative epinephrine dosage during arrest and neurologic outcome. RESULTS: Among 51 included ECPR cases, the median age of patients was 60 years, and 55% were male. The mean cumulative epinephrine dose administered during arrest was 6.2 mg but ranged from 0 to 24 mg. There were 18 patients in the low-dose (≤ 3 mg) and 25 patients in the high-dose (> 3 mg) epinephrine groups. Favorable neurologic outcome at discharge was significantly greater in the low-dose (55%) compared to the high-dose (24%) group (p = 0.025). After adjusting for age, those who received higher doses of epinephrine during the arrest were more likely to have unfavorable neurologic outcomes at hospital discharge (odds ratio 4.6, 95% CI 1.3, 18.0, p = 0.017). CONCLUSION: After adjusting for age, cumulative epinephrine doses above 3 mg during cardiac arrest may be associated with unfavorable neurologic outcomes after ECPR and require further investigation.

Respiratory rhythm modulates membrane potential and spiking of nonolfactory neurons.

In recent years, several studies have shown a respiratory drive of the local field potential (LFP) in numerous brain areas so that the respiratory rhythm could be considered as a master clock promoting communication between distant brain locations. However, outside of the olfactory system, it remains unknown whether the respiratory rhythm could shape membrane potential (MP) oscillations. To fill this gap, we co-recorded MP and LFP activities in different nonolfactory brain areas, medial prefrontal cortex (mPFC), primary somatosensory cortex (S1), primary visual cortex (V1), and hippocampus (HPC), in urethane-anesthetized rats. Using respiratory cycle-by-cycle analysis, we observed that respiration could modulate both MP and spiking discharges in all recorded areas during episodes that we called respiration-related oscillations (RRo). Further quantifications revealed that RRo episodes were transient in most neurons (5 consecutive respiratory cycles in average). RRo development in MP was largely correlated with the presence of respiratory modulation in the LFP. By showing that the respiratory rhythm influenced brain activities deep to the MP of nonolfactory neurons, our data support the idea that respiratory rhythm could mediate long-range communication between brain areas.NEW & NOTEWORTHY In this study, we evidenced strong respiratory-driven oscillations of neuronal membrane potential and spiking discharge in various nonolfactory areas of the mammal brain. These oscillations were found in the medial prefrontal cortex, primary somatosensory cortex, primary visual cortex, and hippocampus. These findings support the idea that respiratory rhythm could be used as a common clock to set the dynamics of large-scale neuronal networks on the same slow rhythm.

Targeting epidermal growth factor receptor to recruit newly generated neuroblasts in cortical brain injuries.

BACKGROUND: Neurogenesis is stimulated in the subventricular zone (SVZ) of mice with cortical brain injuries. In most of these injuries, newly generated neuroblasts attempt to migrate toward the injury, accumulating within the corpus callosum not reaching the perilesional area. METHODS: We use a murine model of mechanical cortical brain injury, in which we perform unilateral cortical injuries in the primary motor cortex of adult male mice. We study neurogenesis in the SVZ and perilesional area at 7 and 14 dpi as well as the expression and concentration of the signaling molecule transforming growth factor alpha (TGF-α) and its receptor the epidermal growth factor (EGFR). We use the EGFR inhibitor Afatinib to promote neurogenesis in brain injuries. RESULTS: We show that microglial cells that emerge within the injured area and the SVZ in response to the injury express high levels of TGF-α leading to elevated concentrations of TGF-α in the cerebrospinal fluid. Thus, the number of neuroblasts in the SVZ increases in response to the injury, a large number of these neuroblasts remain immature and proliferate expressing the epidermal growth factor receptor (EGFR) and the proliferation marker Ki67. Restraining TGF-α release with a classical protein kinase C inhibitor reduces the number of these proliferative EGFR+ immature neuroblasts in the SVZ. In accordance, the inhibition of the TGF-α receptor, EGFR promotes migration of neuroblasts toward the injury leading to an elevated number of neuroblasts within the perilesional area. CONCLUSIONS: Our results indicate that in response to an injury, microglial cells activated within the injury and the SVZ release TGF-α, activating the EGFR present in the neuroblasts membrane inducing their proliferation, delaying maturation and negatively regulating migration. The inactivation of this signaling pathway stimulates neuroblast migration toward the injury and enhances the quantity of neuroblasts within the injured area. These results suggest that these proteins may be used as target molecules to regenerate brain injuries.

HOXA5 is a key regulator of class 3 semaphorins expression in the synovium of rheumatoid arthritis patients.

OBJECTIVE: Class 3 semaphorins are reduced in the synovial tissue of RA patients and these proteins are involved in the pathogenesis of the disease. The aim of this study was to identify the transcription factors involved in the expression of class 3 semaphorins in the synovium of RA patients. METHODS: Protein and mRNA expression in synovial tissue from RA and individuals at risk (IAR) patients, human umbilical vein endothelial cells (HUVEC) and RA fibroblast-like synoviocytes (FLS) was determined by ELISA, immunoblotting and quantitative PCR. TCF-3, EBF-1 and HOXA5 expression was knocked down using siRNA. Cell viability, migration and invasion were determined using MTT, calcein, wound closure and invasion assays, respectively. RESULTS: mRNA expression of all class 3 semaphorins was significantly lower in the synovium of RA compared with IAR patients. In silico analysis suggested TCF-3, EBF-1 and HOXA5 as transcription factors involved in the expression of these semaphorins. TCF-3, EBF-1 and HOXA5 silencing significantly reduced the expression of several class 3 semaphorin members in FLS and HUVEC. Importantly, HOXA5 expression was significantly reduced in the synovium of RA compared with IAR patients and was negatively correlated with clinical disease parameters. Additionally, TNF-α down-regulated the HOXA5 expression in FLS and HUVEC. Finally, HOXA5 silencing enhanced the migratory and invasive capacities of FLS and the viability of HUVEC. CONCLUSION: HOXA5 expression is reduced during the progression of RA and could be a novel therapeutic strategy for modulating the hyperplasia of the synovium, through the regulation of class 3 semaphorins expression.

Cereal bran proteins: recent advances in extraction, properties, and applications.

The projected global population is expected to reach around 9.7 billion by 2050, indicating a greater demand for proteins in the human diet. Cereal bran proteins (CBPs) have been identified as high-quality proteins, with potential applications in both the food and pharmaceutical industries. In 2020, global cereal grain production was 2.1 billion metric tonnes, including wheat, rice, corn, millet, barley, and oats. Cereal bran, obtained through milling, made up 10-20% of total cereal grain production, varying by grain type and milling degree. In this article, the molecular composition and nutritional value of CBPs are summarized, and recent advances in their extraction and purification are discussed. The functional properties of CBPs are then reviewed, including their solubility, binding, emulsifying, foaming, gelling, and thermal properties. Finally, current challenges to the application of CBPs in foods are highlighted, such as the presence of antinutritional factors, low digestibility, and allergenicity, as well as potential strategies to improve the nutritional and functional properties by overcoming these challenges. CBPs exhibit nutritional and functional attributes that are similar to those of other widely used plant-based protein sources. Thus, CBPs have considerable potential for use as ingredients in food, pharmaceutical, and other products.

First-Attempt Intubation Success Among Emergency Medicine Trainees by Laryngoscopic Device and Training Year: A National Emergency Airway Registry Study.

STUDY OBJECTIVE: We compare intubation first-attempt success with the direct laryngoscope, hyperangulated video laryngoscope, and standard geometry video laryngoscope among emergency medicine residents at various postgraduate years (PGY) of training. METHODS: We analyzed prospective data from emergency department (ED) patients enrolled in the National Emergency Airway Registry from January 1, 2016 to December 31, 2018 using mixed-effects logistic regression to assess the association between PGY of training and first-attempt success by the device. RESULTS: Among 15,204 intubations performed by emergency medicine trainees, first-attempt success for PGY-1, PGY-2, and PGY3+ residents, respectively were: 78.8% (95% CI, 75.0 to 82.2%), 81.3% (79.4 to 83.0), and 83.6% (95% CI, 82.1 to 85.1) for direct laryngoscope; 87.2% (95% CI, 84.2 to 89.7), 90.4% (95% CI, 88.8 to 91.9%), and 91.2% (95% CI, 89.8 to 92.5%) for hyperangulated video laryngoscope; and 88.7% (95% CI, 86.1 to 90.9), 90.2% (95% CI, 88.7 to 91.5%), and 94.6% (95% CI 93.9 to 95.3%) for standard geometry video laryngoscope. Direct laryngoscope first-attempt success improved for PGY-2 (adjusted odds ratio [aOR],1.41; 95% CI, 1.09 to 1.82) and PGY-3+ (aOR, 1.76; 1.36 to 2.27) trainees compared to PGY-1. Hyperangulated video laryngoscope success also improved for PGY-2 (aOR, 1.51; 1.1 to 2.05) and PGY-3+ (aOR, 1.56; 1.15 to 2.13) trainees compared to PGY-1. For the standard geometry video laryngoscope, only PGY-3+ (aOR, 1.72; 1.25 to 2.36) was associated with improved first-attempt success compared to PGY-1. CONCLUSION: Each laryngoscopy device class was associated with improvement in first-attempt success as training progressed. The video laryngoscope outperformed the direct laryngoscope for all operator groups, and PGY-1 trainees achieved higher first-attempt success using a standard geometry video laryngoscope than PGY-3+ trainees using a direct laryngoscope. These findings support the conjecture that in adult patients, a direct laryngoscope should not be routinely used for the first intubation attempt unless clinical circumstances, such as the presence of a soiled airway, would favor its success. These findings need to be validated with prospective randomized clinical trials.

The utility of selective partial neurectomy of the musculocutaneous nerve in children with bilateral spastic elbow.

PURPOSE: This study aims to determine the utility of selective partial neurectomy of the musculocutaneous nerve (MCN) in pediatric patients with bilateral spastic elbow. METHODS: A prospective, cross-sectional, case series study was performed in nine pediatric patients (four females and five males) with bilateral spastic elbow, all with a 11.4-year-old average age, where 18 selective partial neurectomies of the MCN were carried out. They were evaluated with goniometry of both spastic elbows at resting position and active amplitude, and staging spasticity employing the Modified Ashworth Scale (MAS) in the preoperative and postoperative period. The results are reported 1 year after surgery. RESULTS: The etiology of the spasticity was secondary to cerebral palsy in eight patients (88.8%) and in one patient (11.11%) secondary to traumatic brain injury. A clinical improvement was observed in goniometry comparing the preoperative and postoperative resting position, a mean preoperative of 44.38 degrees (SD ± 7.61) versus 98.05 degrees (SD ± 24.44), respectively, and preoperative active amplitude a mean of 86.55 degrees (SD ± 15.97) versus the mean postoperative of 47.33 (SD ± 17.86). A relevant decrease on the MAS after surgical intervention was observed, resulting from an average preoperative state according to MAS of 3.78 (SD ± 0.42) to a postoperative state according to MAS of 1.44 (SD ± 0.51), these changes being statistically significant (p ≤ 0.001). No postoperative complications were observed. CONCLUSIONS: Selective partial neurectomy of the MCN has shown good results in patients with bilateral spastic elbow in whom antispastic drugs and physical therapy have failed, and has prove permanent effects.

Episodic memory and recognition are influenced by cues' sensory modality: comparing odours, music and faces using virtual reality.

Most everyday experiences are multisensory, and all senses can trigger the conscious re-experience of unique personal events embedded in their specific spatio-temporal context. Yet, little is known about how a cue's sensory modality influences episodic memory, and which step of this process is impacted. This study investigated recognition and episodic memory across olfactory, auditory and visual sensory modalities in a laboratory-ecological task using a non-immersive virtual reality device. At encoding, participants freely and actively explored unique and rich episodes in a three-room house where boxes delivered odours, musical pieces and pictures of face. At retrieval, participants were presented with modality-specific memory cues and were told to 1) recognise encoded cues among distractors and, 2) go to the room and select the box in which they encountered them at encoding. Memory performance and response times revealed that music and faces outperformed odours in recognition memory, but that odours and faces outperformed music in evoking encoding context. Interestingly, correct recognition of music and faces was accompanied by more profound inspirations than correct rejection. By directly comparing memory performance across sensory modalities, our study demonstrated that despite limited recognition, odours are powerful cues to evoke specific episodic memory retrieval.

Migratory Response of Cells in Neurogenic Niches to Neuronal Death: The Onset of Harmonic Repair?

Harmonic mechanisms orchestrate neurogenesis in the healthy brain within specific neurogenic niches, which generate neurons from neural stem cells as a homeostatic mechanism. These newly generated neurons integrate into existing neuronal circuits to participate in different brain tasks. Despite the mechanisms that protect the mammalian brain, this organ is susceptible to many different types of damage that result in the loss of neuronal tissue and therefore in alterations in the functionality of the affected regions. Nevertheless, the mammalian brain has developed mechanisms to respond to these injuries, potentiating its capacity to generate new neurons from neural stem cells and altering the homeostatic processes that occur in neurogenic niches. These alterations may lead to the generation of new neurons within the damaged brain regions. Notwithstanding, the activation of these repair mechanisms, regeneration of neuronal tissue within brain injuries does not naturally occur. In this review, we discuss how the different neurogenic niches respond to different types of brain injuries, focusing on the capacity of the progenitors generated in these niches to migrate to the injured regions and activate repair mechanisms. We conclude that the search for pharmacological drugs that stimulate the migration of newly generated neurons to brain injuries may result in the development of therapies to repair the damaged brain tissue.

Ambient Particulate Air Pollution and Daily Mortality in 652 Cities.

BACKGROUND: The systematic evaluation of the results of time-series studies of air pollution is challenged by differences in model specification and publication bias. METHODS: We evaluated the associations of inhalable particulate matter (PM) with an aerodynamic diameter of 10 µm or less (PM10) and fine PM with an aerodynamic diameter of 2.5 µm or less (PM2.5) with daily all-cause, cardiovascular, and respiratory mortality across multiple countries or regions. Daily data on mortality and air pollution were collected from 652 cities in 24 countries or regions. We used overdispersed generalized additive models with random-effects meta-analysis to investigate the associations. Two-pollutant models were fitted to test the robustness of the associations. Concentration-response curves from each city were pooled to allow global estimates to be derived. RESULTS: On average, an increase of 10 µg per cubic meter in the 2-day moving average of PM10 concentration, which represents the average over the current and previous day, was associated with increases of 0.44% (95% confidence interval [CI], 0.39 to 0.50) in daily all-cause mortality, 0.36% (95% CI, 0.30 to 0.43) in daily cardiovascular mortality, and 0.47% (95% CI, 0.35 to 0.58) in daily respiratory mortality. The corresponding increases in daily mortality for the same change in PM2.5 concentration were 0.68% (95% CI, 0.59 to 0.77), 0.55% (95% CI, 0.45 to 0.66), and 0.74% (95% CI, 0.53 to 0.95). These associations remained significant after adjustment for gaseous pollutants. Associations were stronger in locations with lower annual mean PM concentrations and higher annual mean temperatures. The pooled concentration-response curves showed a consistent increase in daily mortality with increasing PM concentration, with steeper slopes at lower PM concentrations. CONCLUSIONS: Our data show independent associations between short-term exposure to PM10 and PM2.5 and daily all-cause, cardiovascular, and respiratory mortality in more than 600 cities across the globe. These data reinforce the evidence of a link between mortality and PM concentration established in regional and local studies. (Funded by the National Natural Science Foundation of China and others.).

Impact of a Nurse-Driven Patient Empowerment Intervention on the Reduction in Patients' Anxiety and Depression During ICU Discharge: A Randomized Clinical Trial.

OBJECTIVES: To assess the impact of a nurse-driven patient empowerment intervention on anxiety and depression of patients during ICU discharge. DESIGN: A prospective, multicenter, randomized clinical trial. SETTING: Three ICUs (1 medical, 1 medical and surgical, and 1 coronary) of three tertiary hospitals. PATIENTS: Adults admitted to the ICU greater than 18 years old for greater than or equal to 48 hours with preserved consciousness, the ability to communicate and without delirium, who were randomized to receive the nurse-driven patient empowerment intervention (NEI) (intervention group [IG] or standard of care [control group (CG)]) before ICU discharge. INTERVENTION: The NEI consisted of an individualized intervention with written information booklets, combined with verbal information, mainly about the ICU process and transition to the ward, aimed at empowering patients in the transition process from the ICU to the general ward. MEASUREMENTS AND RESULTS: Patients completed the Hospital Anxiety and Depression Scale before and after (up to 1 wk) ICU discharge. IG ( n = 91) and CG ( n = 87) patients had similar baseline characteristics. The NEI was associated with a significant reduction in anxiety and depression ( p < 0.001) and the presence of depression ( p = 0.006). Patients with comorbidities and those without family or friends had greater reductions in anxiety and depression after the NEI. After the intervention, women and persons with higher education levels had lower negative outcomes. CONCLUSIONS: We found that a NEI before ICU discharge can decrease anxiety and depression in critically ill survivors. The long-term effect of this intervention should be assessed in future trials. TRIAL REGISTRATION: NCT04527627 ( https://clinicaltrials.gov/ct2/show/NCT04527627 ).

Enhanced Communications on Satellite-Based IoT Systems to Support Maritime Transportation Services.

Maritime transport has become important due to its ability to internationally unite all continents. In turn, during the last two years, we have observed that the increase of consumer goods has resulted in global shipping deadlocks. In addition, the future goes through the role of ports and efficiency in maritime transport to decarbonize its impact on the environment. In order to improve the economy and people's lives, in this work, we propose to enhance services offered in maritime logistics. To do this, a communications system is designed on the deck of ships to transmit data through a constellation of satellites using interconnected smart devices based on IoT. Among the services, we highlight the monitoring and tracking of refrigerated containers, the transmission of geolocation data from Global Positioning System (GPS), and security through the Automatic Identification System (AIS). This information will be used for a fleet of ships to make better decisions and help guarantee the status of the cargo and maritime safety on the routes. The system design, network dimensioning, and a communications protocol for decision-making will be presented.

The Transcriptomic Landscape of Pediatric Astrocytoma.

Central nervous system tumors are the most common solid neoplasia during childhood and represent one of the leading causes of cancer-related mortality. Tumors arising from astrocytic cells (astrocytomas) are the most frequently diagnosed, and according to their histological and pathological characteristics, they are classified into four categories. However, an additional layer of molecular classification considering the DNA sequence of the tumorigenesis-associated genes IDH1/2 and H3F3A has recently been incorporated into the classification guidelines. Although mutations in H3F3A are found exclusively in a subtype of grade IV pediatric astrocytoma, mutations in IDH1/2 genes are very rare in children under 14 years of age. The transcriptomic profiles of astrocytoma in adults and children have been extensively studied. However, there is scarce information on these profiles in pediatric populations considering the status of tumorigenesis-associated genes. Therefore, here we report the transcriptomic landscape of the four grades of pediatric astrocytoma by RNA sequencing. We found several well-documented biological functions associated with the misregulated genes in the four grades of astrocytoma, as well as additional biological pathways. Among the four grades of astrocytoma, we found shared misregulated genes that could have implications in tumorigenesis. Finally, we identified a transcriptional signature for almost all grades of astrocytoma that could be used as a transcription-based identification method.

Biomarker profiles of endothelial activation and dysfunction in rare systemic autoimmune diseases: implications for cardiovascular risk.

OBJECTIVES: Vasculopathy is an important hallmark of systemic chronic inflammatory connective tissue diseases (CICTD) and is associated with increased cardiovascular risk. We investigated disease-specific biomarker profiles associated with endothelial dysfunction, angiogenic homeostasis and (tissue) inflammation, and their relation to disease activity in rare CICTD. METHODS: A total of 38 serum proteins associated with endothelial (dys)function and inflammation were measured by multiplex-immunoassay in treatment-naive patients with localized scleroderma (LoS, 30), eosinophilic fasciitis (EF, 8) or (juvenile) dermatomyositis (34), 119 (follow-up) samples during treatment, and 65 controls. Data were analysed by unsupervised clustering, Spearman correlations, non-parametric t test and ANOVA. RESULTS: The systemic CICTD, EF and dermatomyositis, had distinct biomarker profiles, with 'signature' markers galectin-9 (dermatomyositis) and CCL4, CCL18, CXCL9, fetuin, fibronectin, galectin-1 and TSP-1 (EF). In LoS, CCL18, CXCL9 and CXCL10 were subtly increased. Furthermore, dermatomyositis and EF shared upregulation of markers related to interferon (CCL2, CXCL10), endothelial activation (VCAM-1), inhibition of angiogenesis (angiopoietin-2, sVEGFR-1) and inflammation/leucocyte chemo-attraction (CCL19, CXCL13, IL-18, YKL-40), as well as disturbance of the Angiopoietin-Tie receptor system and VEGF-VEGFR system. These profiles were related to disease activity, and largely normalized during treatment. However, a subgroup of CICTD patients showed continued elevation of CXCL10, CXCL13, galectin-9, IL-18, TNFR2, VCAM-1, and/or YKL-40 during clinically inactive disease, possibly indicating subclinical interferon-driven inflammation and/or endothelial dysfunction. CONCLUSION: CICTD-specific biomarker profiles revealed an anti-angiogenic, interferon-driven environment during active disease, with incomplete normalization under treatment. This warrants further investigation into monitoring of vascular biomarkers during clinical follow-up, or targeted interventions to minimize cardiovascular risk in the long term.

Effect of hydroxychloroquine, azithromycin and lopinavir/ritonavir on the QT corrected interval in patients with COVID-19.

BACKGROUND: Administration of Hydroxychloroquine and Azithromycin in patients with coronavirus disease 2019 (COVID-19) prolongs QTc corrected interval (QTc). The effect and safety of Lopinavir/Ritonavir in combination with these therapies have seldom been studied. OBJECTIVES: Our aim was to evaluate changes in QTc in patients receiving double (Hydroxychloroquine + Azithromycin) and triple therapy (Hydroxychloroquine + Azithromycin + Lopinavir/Ritonavir) to treat COVID-19. Secondary outcome was the incidence of in-hospital all-cause mortality. METHODS: Patients under treatment with double (DT) and triple therapy (TT) for COVID-19 were consecutively included in this prospective observational study. Serial in-hospital electrocardiograms were performed to measure QTc at baseline and during therapy. RESULTS: 168 patients (±66.2 years old) were included: 32.1% received DT and 67.9% received TT. The mean baseline QTc was 410.33 ms. Patients under DT and TT prolonged QTc interval respect baseline values (p < 0.001), without significant differences between both therapy groups (p = 0.748). Overall, 33 patients (19.6%) had a peak QTc and/or an increase QTc 60 ms from baseline, with a higher prevalence among those with hypokalemia (p = 0.003). All-cause mortality was similar between both strategy groups (p = 0.093) and high risk QTc prolongation was no related to clinical events in this series. CONCLUSIONS: DT and TT prolong the QTc in patients with COVID-19. Addition of Lopinavir/Ritonavir on top of Hydroxychloroquine and Azithromycin did not increase QTc compared to DT.

Calcineurin and Systemic Lupus Erythematosus: The Rationale for Using Calcineurin Inhibitors in the Treatment of Lupus Nephritis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a broad spectrum of clinical presentations that can affect almost all organ systems. Lupus nephritis (LN) is a severe complication that affects approximately half of the systemic erythematosus lupus (SLE) patients, which significantly increases the morbidity and the mortality risk. LN is characterized by the accumulation of immune complexes, ultimately leading to renal failure. Aberrant activation of T cells plays a critical role in the pathogenesis of both SLE and LN and is involved in the production of inflammatory cytokines, the recruitment of inflammatory cells to the affected tissues and the co-stimulation of B cells. Calcineurin is a serine-threonine phosphatase that, as a consequence of the T cell hyperactivation, induces the production of inflammatory mediators. Moreover, calcineurin is also involved in the alterations of the podocyte phenotype, which contribute to proteinuria and kidney damage observed in LN patients. Therefore, calcineurin inhibitors have been postulated as a potential treatment strategy in LN, since they reduce T cell activation and promote podocyte cytoskeleton stabilization, both being key aspects in the development of LN. Here, we review the role of calcineurin in SLE and the latest findings about calcineurin inhibitors and their mechanisms of action in the treatment of LN.

Extracellular SPARC cooperates with TGF-ß signalling to induce pro-fibrotic activation of systemic sclerosis patient dermal fibroblasts.

OBJECTIVES: SSc is an autoimmune disease characterized by inflammation, vascular injury and excessive fibrosis in multiple organs. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that regulates processes involved in SSc pathology, such as inflammation and fibrosis. In vivo and in vitro studies have implicated SPARC in SSc, but it is unclear if the pro-fibrotic effects of SPARC on fibroblasts are a result of intracellular signalling or fibroblast interactions with extracellular SPARC hampering further development of SPARC as a potential therapeutic target. This study aimed to analyse the potential role of exogenous SPARC as a regulator of fibrosis in SSc. METHODS: Dermal fibroblasts from both healthy controls and SSc patients were stimulated with SPARC alone or in combination with TGF-ß1, in the absence or presence of a TGF receptor 1 inhibitor. mRNA and protein expression of extracellular matrix components and other fibrosis-related mediators were measured by quantitative PCR and western blot. RESULTS: Exogenous SPARC induced mRNA and protein expression of collagen I, collagen IV, fibronectin 1, TGF-ß and SPARC by dermal fibroblasts from SSc patients, but not from healthy controls. Importantly, exogenous SPARC induced the activation of the tyrosine kinase SMAD2 and pro-fibrotic gene expression induced by SPARC in SSc fibroblasts was abrogated by inhibition of TGF-ß signalling. CONCLUSION: These results indicate that exogenous SPARC is an important pro-fibrotic mediator contributing to the pathology driving SSc but in a TGF-ß dependent manner. Therefore, SPARC could be a promising therapeutic target for reducing fibrosis in SSc patients, even in late states of the disease.

Promotion of macrophage activation by Tie2 in the context of the inflamed synovia of rheumatoid arthritis and psoriatic arthritis patients.

OBJECTIVE: To examine the role of Tie2 signalling in macrophage activation within the context of the inflammatory synovial microenvironment present in patients with RA and PsA. METHODS: Clinical responses and macrophage function were examined in wild-type and Tie2-overexpressing (Tie2-TG) mice in the K/BxN serum transfer model of arthritis. Macrophages derived from peripheral blood monocytes from healthy donors, RA and PsA patients, and RA and PsA synovial tissue explants were stimulated with TNF (10 ng/ml), angiopoietin (Ang)-1 or Ang-2 (200 ng/ml), or incubated with an anti-Ang2 neutralizing antibody. mRNA and protein expression of inflammatory mediators was analysed by quantitative PCR, ELISA and Luminex. RESULTS: Tie2-TG mice displayed more clinically severe arthritis than wild-type mice, accompanied by enhanced joint expression of IL6, IL12B, NOS2, CCL2 and CXCL10, and activation of bone marrow-derived macrophages in response to Ang-2 stimulation. Ang-1 and Ang-2 significantly enhanced TNF-induced expression of pro-inflammatory cytokines and chemokines in macrophages from healthy donors differentiated with RA and PsA SF and peripheral blood-derived macrophages from RA and PsA patients. Both Ang-1 and Ang-2 induced the production of IL-6, IL-12p40, IL-8 and CCL-3 in synovial tissue explants of RA and PsA patients, and Ang-2 neutralization suppressed the production of IL-6 and IL-8 in the synovial tissue of RA patients. CONCLUSION: Tie2 signalling enhances TNF-dependent activation of macrophages within the context of ongoing synovial inflammation in RA and PsA, and neutralization of Tie2 ligands might be a promising therapeutic target in the treatment of these diseases.

Kinetic Isotope Effect as a Tool To Investigate the Oxygen Reduction Reaction on Pt-based Electrocatalysts - Part II: Effect of Platinum Dispersion.

We investigated the oxygen reduction reaction (ORR) mechanism on Pt nanoparticles (NPs) dispersed on several carbon blacks with various physicochemical properties (i. e. specific surface ranging from 80 to 900 m2 g-1 , different graphitization degree, etc.). Using the kinetic isotope effect (KIE) along with various electrochemical characterizations, we determined that the rate determining step (RDS) of the ORR is a proton-independent step when the density of Pt NPs on the surface of the carbon support is high. Upon decrease of the density of Pt NPs on the surface, the RDS of the ORR starts involving a proton, as denoted by an increase of the KIE >1. This underlined the critical role played by the carbon support in the oxygen reduction reaction electrocatalysis by Pt supported on high surface area carbon.