CAR-NKT Cells in Asthma: Use of NKT as a Promising Cell for CAR Therapy.

NKT cells, unique lymphocytes bridging innate and adaptive immunity, offer significant potential for managing inflammatory disorders like asthma. Activating iNKT induces increasing IFN-γ, TGF-ß, IL-2, and IL-10 potentially suppressing allergic asthma. However, their immunomodulatory effects, including granzyme-perforin-mediated cytotoxicity, and expression of TIM-3 and TRAIL warrant careful consideration and targeted approaches. Although CAR-T cell therapy has achieved remarkable success in treating certain cancers, its limitations necessitate exploring alternative approaches. In this context, CAR-NKT cells emerge as a promising approach for overcoming these challenges, potentially achieving safer and more effective immunotherapies. Strategies involve targeting distinct IgE-receptors and their interactions with CAR-NKT cells, potentially disrupting allergen-mast cell/basophil interactions and preventing inflammatory cytokine release. Additionally, targeting immune checkpoints like PDL-2, inducible ICOS, FASL, CTLA-4, and CD137 or dectin-1 for fungal asthma could further modulate immune responses. Furthermore, artificial intelligence and machine learning hold immense promise for revolutionizing NKT cell-based asthma therapy. AI can optimize CAR-NKT cell functionalities, design personalized treatment strategies, and unlock a future of precise and effective care. This review discusses various approaches to enhancing CAR-NKT cell efficacy and longevity, along with the challenges and opportunities they present in the treatment of allergic asthma.

Behavioral Responses of Imidacloprid-Dosed Farmland Birds to a Simulated Predation Risk.

Sublethal exposure to imidacloprid and other neonicotinoid insecticides may affect the neurological functions of birds. As such, behavior may be compromised. Here, we tested experimentally the effects of 1 and 6 mg/kg bw of imidacloprid on the antipredator behavioral responses of the red-legged partridge (Alectoris rufa) to simulated predator threats. Sixty-six partridges were challenged in groups or individually to intra- and interspecific alarm calls, to a raptor silhouette (aerial predation risk), and to a fox model (terrestrial predation risk). Antipredator behaviors were recorded as active (escape, active vigilance) and passive (passive vigilance, crouching, and freezing) responses. Latency in response to the stimuli, percentage of individuals who responded, response duration, speed of active responses, and vocalizations were measured. In experiments with partridges in the group, crouching against simulated predation risk lasted less time in birds treated with 6 mg a.i./kg bw than in control birds. In the experiments with individual partridges, passive vigilance against the intraspecific alarm lasted longer in birds treated with 6 mg a.i./kg bw than in control birds. The observed hyperreactivity to the predatory threat after a sublethal imidacloprid exposure can have consequences on survival under field conditions, where predation is a main driver of population dynamics.

Blood eosinophilia and a higher ethmoid sinus/maxillary sinus score ratio predict new-onset asthma in patients with chronic rhinosinusitis with nasal polyps.

BACKGROUD: Presently, the impact of Chronic rhinosinusitis with nasal polyps (CRSwNP) on asthma onset is unknown. AIMS: To evaluate the role of CRSwNP in asthma onset. MATERIALS AND METHODS: A total of 3107 CRSwNP patients were retrospectively screened from 1 January 2018, to 31 May 2021; 624 patients were enrolled. Clinical data regarding nasal symptoms, Lund-Mackay scores, blood eosinophil percentage, and onset of asthma were analyzed. Patients were divided into different groups according to past history of nasal polyps, Lund-Mackay score, and the extent of blood eosinophilia. Asthma-free rates between these subgroups were analyzed by Kaplan-Meier curves and Cox regression models. RESULTS: The prevalence of asthma was 10.90% in patients with CRSwNP, and new-onset asthma occurred in 3.14% of these patients. Higher Lund-Mackay scores for ethmoid sinus and maxillary sinus (E/M) and blood eosinophil percentages were two independent risk factors for new-onset asthma, with hazard ratios of 1.267 (95%CI, 1.155-1.390) and 1.224 (95%CI, 1.054-1.422), respectively. CRSwNP patients with an E/M ratio > 2.33 or a blood Eos percentage > 5.5% were at risk for asthma onset. CONCLUSIONS AND SIGNIFICANCE: Blood eosinophilia and a higher E/M score ratio were associated with new-onset asthma in patients with CRSwNP.

LY333531 attenuates contraction of tumor necrosis factor-α-sensitized human airway smooth muscle cells.

OBJECTIVE: Protein kinase C (PKC) has been implicated in the increased contraction of human airway smooth muscle cells (HASMCs) in asthma. Using the three-dimensional collagen gel contraction system, the study aimed to determine the effects of LY333531, a specific inhibitor of the PKC-ß isoform, on the contraction of tumor necrosis factor (TNF)-α-sensitized HASMCs. METHODS: Cultured HASMCs were divided into five groups: the control group received no treatment, and the cells in the TNF-α group were sensitized with 10 ng/mL TNF-α for 48 h, while TNF-α was administered to sensitize HASMCs in the presence of 0.1, 0.2, and 0.5 µM LY333531 for 48 h in the 0.1LY, 0.2LY, and 0.5LY groups, respectively. Following this, HASMCs contraction was stimulated with 1 mM acetylcholine (ACh) for up to 24 h in each group and assessed using a three-dimensional collagen gel contraction assay. Furthermore, western blot and immunofluorescence analysis were performed. RESULTS: The collagen gel contraction assay revealed that TNF-α increased the protein expression of phosphorylated PKC-ß2, CPI-17, and MLC while exacerbating ACh-induced HASMCs contraction. LY333531 significantly attenuated HASMCs contraction and downregulated the protein expression of both p-CPI-17 and p-MLC. CONCLUSIONS: At least in part by regulating CPI-17 and MLC phosphorylation, LY333531 attenuates augmented contraction of TNF-α-sensitized HASMCs in a collagen gel contraction system.

Temporal resolution relates to sensory hyperreactivity independently of stimulus detection sensitivity in individuals with autism spectrum disorder.

Researchers have been focusing on perceptual characteristics of autism spectrum disorder (ASD) in terms of sensory hyperreactivity. Previously, we demonstrated that temporal resolution, which is the accuracy to differentiate the order of two successive vibrotactile stimuli, is associated with the severity of sensory hyperreactivity. We currently examined whether an increase in the perceptual intensity of a tactile stimulus, despite its short duration, is derived from high temporal resolution and high frequency of sensory temporal summation. Twenty ASD and 22 typically developing (TD) participants conducted two psychophysical experimental tasks to evaluate detectable duration of vibrotactile stimulus with same amplitude and to evaluate temporal resolution. The sensory hyperreactivity was estimated using self-reported questionnaire. There was no relationship between the temporal resolution and the duration of detectable stimuli in both groups. However, the ASD group showed severe sensory hyperreactivity in daily life than TD group, and the ASD participants with severe sensory hyperreactivity tended to have high temporal resolution, not high sensitivity of detectable duration. Contrary to the hypothesis, there might be different processing between temporal resolution and sensitivity for stimulus detection. We suggested that the atypical temporal processing would affect to sensory reactivity in ASD.

Biomarkers of Airway Disease, Barrett's and Underdiagnosed Reflux Noninvasively (BAD-BURN): a Case-Control Observational Study Protocol.

BACKGROUND: Particulate matter exposure (PM) is a cause of aerodigestive disease globally. The destruction of the World Trade Center (WTC) exposed fifirst responders and inhabitants of New York City to WTC-PM and caused obstructive airways disease (OAD), gastroesophageal Refux disease (GERD) and Barrett's Esophagus (BE). GERD not only diminishes health-related quality of life but also gives rise to complications that extend beyond the scope of BE. GERD can incite or exacerbate allergies, sinusitis, bronchitis, and asthma. Disease features of the aerodigestive axis can overlap, often necessitating more invasive diagnostic testing and treatment modalities. This presents a need to develop novel non-invasive biomarkers of GERD, BE, airway hyperreactivity (AHR), treatment efficacy, and severity of symptoms. METHODS: Our observational case-cohort study will leverage the longitudinally phenotyped Fire Department of New York (FDNY)-WTC exposed cohort to identify Biomarkers of Airway Disease, Barrett's and Underdiagnosed Refux Noninvasively (BAD-BURN). Our study population consists of n = 4,192 individuals from which we have randomly selected a sub-cohort control group (n = 837). We will then recruit subgroups of i. AHR only ii. GERD only iii. BE iv. GERD/BE and AHR overlap or v. No GERD or AHR, from the sub-cohort control group. We will then phenotype and examine non-invasive biomarkers of these subgroups to identify under-diagnosis and/or treatment efficacy. The findings may further contribute to the development of future biologically plausible therapies, ultimately enhance patient care and quality of life. DISCUSSION: Although many studies have suggested interdependence between airway and digestive diseases, the causative factors and specific mechanisms remain unclear. The detection of the disease is further complicated by the invasiveness of conventional GERD diagnosis procedures and the limited availability of disease-specific biomarkers. The management of Refux is important, as it directly increases risk of cancer and negatively impacts quality of life. Therefore, it is vital to develop novel noninvasive disease markers that can effectively phenotype, facilitate early diagnosis of premalignant disease and identify potential therapeutic targets to improve patient care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05216133; January 18, 2022.

Glycoursodeoxycholic Acid Alleviates Arterial Thrombosis via Suppressing Diacylglycerol Kinases Activity in Platelet.

BACKGROUND: Glycoursodeoxycholic acid (GUDCA) has been acknowledged for its ability to regulate lipid homeostasis and provide benefits for various metabolic disorders. However, the impact of GUDCA on arterial thrombotic events remains unexplored. The objective of this study is to examine the effects of GUDCA on thrombogenesis and elucidate its underlying mechanisms. METHODS: Plasma samples from patients with arterial thrombotic events and diet-induced obese mice were collected to determine the GUDCA concentrations using mass spectrometry. Multiple in vivo murine thrombosis models and in vitro platelet functional assays were conducted to comprehensively evaluate the antithrombotic effects of GUDCA. Moreover, lipidomic analysis was performed to identify the alterations of intraplatelet lipid components following GUDCA treatment. RESULTS: Plasma GUDCA level was significantly decreased in patients with arterial thrombotic events and negatively correlated with thrombotic propensity in diet-induced obese mice. GUDCA exhibited prominent suppressing effects on platelet reactivity as evidenced by the attenuation of platelet activation, secretion, aggregation, spreading, and retraction (P<0.05). In vivo, GUDCA administration robustly alleviated thrombogenesis (P<0.05) without affecting hemostasis. Mechanistically, GUDCA inhibited DGK (diacylglycerol kinase) activity, leading to the downregulation of the phosphatidic acid-mediated signaling pathway. Conversely, phosphatidic acid supplementation was sufficient to abolish the antithrombotic effects of GUDCA. More importantly, long-term oral administration of GUDCA normalized the enhanced DGK activity, thereby remarkably alleviating the platelet hyperreactivity as well as the heightened thrombotic tendency in diet-induced obese mice (P<0.05). CONCLUSIONS: Our study implicated that GUDCA reduces platelet hyperreactivity and improves thrombotic propensity by inhibiting DGKs activity, which is a potentially effective prophylactic approach and promising therapeutic agent for arterial thrombotic events.

Gestational diabetes mellitus is associated with in vivo platelet activation and platelet hyperreactivity.

BACKGROUND: Gestational diabetes mellitus is associated with obstetrical and long-term cardiovascular complications. Although platelet hyperresponsiveness in type-2 diabetes mellitus has been well characterized and has been shown to play a crucial role in cardiovascular complications, this aspect has been little studied in gestational diabetes mellitus. OBJECTIVE: We aimed to evaluate platelet reactivity, in vivo platelet activation, and endothelial function in gestational diabetes mellitus in comparison with normal pregnancy. STUDY DESIGN: This was a prospective, case-control study of 23 women with gestational diabetes mellitus and 23 healthy pregnant women who were studied at 26 to 28 and 34 to 36 weeks of gestation and at 8 weeks postpartum. Platelet reactivity and in vivo platelet activation, including light transmission aggregometry, PFA-100, platelet activation antigen expression, platelet adhesion under flow, platelet nitric oxide and reactive oxygen species production, and endothelial dysfunction markers, were assessed. RESULTS: The study of platelet function showed a condition of platelet hyperreactivity in cases with gestational diabetes mellitus when compared with healthy pregnant women at enrollment, which was further enhanced at the end of pregnancy and tended to decrease 2 months after delivery, although it still remained higher in gestational diabetes mellitus. In vivo platelet activation was also evident in gestational diabetes mellitus, especially at the end of pregnancy, in part persisting up to 8 weeks after delivery. Finally, women with gestational diabetes mellitus showed defective platelet nitric oxide production and endothelial dysfunction when compared with healthy pregnancies. CONCLUSION: Our data showed that gestational diabetes mellitus generates a condition of platelet hyperreactivity that in part persists up to 2 months after delivery. Impaired platelet sensitivity to nitric oxide and reduced platelet and endothelial nitric oxide production may contribute to the platelet hyperreactivity condition. Platelet hyperreactivity may play a role in the long-term cardiovascular complications of gestational diabetes mellitus women.

NGF increases Connexin-43 expression and function in pulmonary arterial smooth muscle cells to induce pulmonary artery hyperreactivity.

AIMS: Pulmonary hypertension (PH) is characterised by an increase in pulmonary arterial pressure, ultimately leading to right ventricular failure and death. We have previously shown that nerve growth factor (NGF) plays a critical role in PH. Our objectives here were to determine whether NGF controls Connexin-43 (Cx43) expression and function in the pulmonary arterial smooth muscle, and whether this mechanism contributes to NGF-induced pulmonary artery hyperreactivity. METHODS AND RESULTS: NGF activates its TrkA receptor to increase Cx43 expression, phosphorylation, and localization at the plasma membrane in human pulmonary arterial smooth muscle cells, thus leading to enhanced activity of Cx43-dependent GAP junctions as shown by Lucifer Yellow dye assay transfer and fluorescence recovery after photobleaching -FRAP- experiments. Using both in vitro pharmacological and in vivo SiRNA approaches, we demonstrate that NGF-dependent increase in Cx43 expression and activity in the rat pulmonary circulation causes pulmonary artery hyperreactivity. We also show that, in a rat model of PH induced by chronic hypoxia, in vivo blockade of NGF or of its TrkA receptor significantly reduces Cx43 increased pulmonary arterial expression induced by chronic hypoxia and displays preventive effects on pulmonary arterial pressure increase and right heart hypertrophy. CONCLUSIONS: Modulation of Cx43 by NGF in pulmonary arterial smooth muscle cells contributes to NGF-induced alterations of pulmonary artery reactivity. Since NGF and its TrkA receptor play a role in vivo in Cx43 increased expression in PH induced by chronic hypoxia, these NGF/Cx43-dependent mechanisms may therefore play a significant role in human PH pathophysiology.

Stress hyper-reactivity increases vulnerability to developing binge-type eating and associated anxiety-like behavior; comparison between Wistar-Kyoto and Sprague-Dawley rats.

Introduction: Binge eating disorder (BED) is a widespread eating disorder that primarily affects women worldwide, and it is characterized by the presence of binge eating episodes and the absence of any compensatory behavior to prevent weight gain. BED presents elevated comorbidity with other psychiatric disorders, such as anxiety, and it has been suggested that stress sensibility could be a vulnerability factor for the development of BED and the associated anxiety comorbidity. In this study, we aim to investigate whether the Wistar-Kyoto rat strain (WKY), which has a stress hyper-reactive phenotype, could develop both binge-type eating and anxiety-like behaviors simultaneously. We also aim to compare its vulnerability to developing both behaviors with the Sprague Dawley rat strain (SD), a rat strain commonly used in binge-eating models. Methods: WKY and SD rats were subjected to the model of intermittent access to palatable food (sucrose solution 30% or shortening) without calorie restriction or stress exposure. We evaluated and compared the development of binge-type eating behavior, anxiety-like behavior, and serum corticosterone variation as an index of the stress response in both rat strains. Results: WKY rats presented a higher percentage of binge-type eaters and required less time to develop binge-type eating behavior than SD rats. The WKY eating pattern emulated a binge-eating episode regardless of the palatable food. Although the development of sucrose binge-type eating was similar between strains, WKY developed more easily the shortening binge-type eating than SD and was more susceptible to developing anxiety-like behavior. Additionally, sucrose binge eating seems to differentially affect both strains' hypothalamic-pituitary-adrenal (HPA) axis response to stress since it facilitated its response in SD and blunted it in WKY. Discussion: Our results show that high-stress sensitive phenotype is a common vulnerability factor for the development of binge-type eating and anxiety-like behavior. Regardless of the macronutrient composition of the palatable food, WKY is susceptible to developing a binge-type eating behavior and is more susceptible than SD to developing anxiety-like behavior simultaneously. In conclusion, results showed that a hyper-reactive stress phenotype predisposes the development of binge-type eating behavior and anxiety-like behavior in the absence of calorie restriction and stress exposure.

A novel quinoline with airway relaxant effects and anti-inflammatory properties.

BACKGROUND: In chronic pulmonary diseases characterized by inflammation and airway obstruction, such as asthma and COPD, there are unmet needs for improved treatment. Quinolines is a group of small heterocyclic compounds that have a broad range of pharmacological properties. Here, we investigated the airway relaxant and anti-inflammatory properties of a novel quinoline (RCD405). METHODS: The airway relaxant effect of RCD405 was examined in isolated airways from humans, dogs, rats and mice. Murine models of ovalbumin (OVA)-induced allergic asthma and LPS-induced airway inflammation were used to study the effects in vivo. RCD405 (10 mg/kg) or, for comparisons in selected studies, budesonide (3 mg/kg), were administered intratracheally 1 h prior to each challenge. Airway responsiveness was determined using methacholine provocation. Immune cell recruitment to bronchi was measured using flow cytometry and histological analyses were applied to investigate cell influx and goblet cell hyperplasia of the airways. Furthermore, production of cytokines and chemokines was measured using a multiplex immunoassay. The expression levels of asthma-related genes in murine lung tissue were determined by PCR. The involvement of NF-κB and metabolic activity was measured in the human monocytic cell line THP-1. RESULTS: RCD405 demonstrated a relaxant effect on carbachol precontracted airways in all four species investigated (potency ranking: human = rat > dog = mouse). The OVA-specific IgE and airway hyperresponsiveness (AHR) were significantly reduced by intratracheal treatment with RCD405, while no significant changes were observed for budesonide. In addition, administration of RCD405 to mice significantly decreased the expression of proinflammatory cytokines and chemokines as well as recruitment of immune cells to the lungs in both OVA- and LPS-induced airway inflammation, with a similar effect as for budesonide (in the OVA-model). However, the effect on gene expression of Il-4, IL-5 and Il-13 was more pronounced for RCD405 as compared to budesonide. Finally, in vitro, RCD405 reduced the LPS-induced NF-κB activation and by itself reduced cellular metabolism. CONCLUSIONS: RCD405 has airway relaxant effects, and it reduces AHR as well as airway inflammation in the models used, suggesting that it could be a clinically relevant compound to treat inflammatory airway diseases. Possible targets of this compound are complexes of mitochondrial oxidative phosphorylation, resulting in decreased metabolic activity of targeted cells as well as through pathways associated to NF-κB. However, further studies are needed to elucidate the mode of action.

Respiratory muscles's thermographic analysis in asthmatic youth with and without bronchospasm induced by eucapnic voluntary hyperpnea.

OBJECTIVE: To compare the thermographic pattern of regions of interest (ROI) of respiratory muscles in young asthmatics with and without bronchospasm induced by eucapnic voluntary hyperpnea (EVH). MATERIALS AND METHODS: Cross-sectional study carried out with 55 young (55% male and 45% females) aged 12.5 ± 3.3 years, divided in nine nonasthmatics, 22 asthmatics without exercise-induced bronchospasm compatible response (EIB-cr) and 24 asthmatics with EIB-cr. The diagnosis of EIB was given to subjects with a fall in forced expiratory volume in the first second (FEV1) ≥ 10% compared to baseline. Thermographic recordings of respiratory muscles were delimited in ROI of the sternocleidomastoid (SCM), pectoral, and rectus abdominis intention area. Thermal captures and FEV1 were taken before and 5, 10, 15 and 30 min after EVH. RESULTS: Twenty-four (52.1%) of asthmatics had EIB-cr. There was a decrease in temperature at 10 min after EVH test in the SCM, pectoral and rectus abdominis ROIs in all groups (both with p < 0.05). There was a decrease in temperature (% basal) in asthmatic with EIB-cr compared to nonasthmatics in the rectus abdominis area (p < 0.05). CONCLUSION: There was a decrease in temperature in the ROIs of different muscle groups, especially in asthmatics. The greater drop in FEV1 observed in individuals with EIB-cr was initially associated with a decrease in skin temperature, with a difference between the nonasthmatics in the abdominal muscle area. It is likely that this decrease in temperature occurred due to a temporary displacement of blood flow to the most used muscle groups, with a decrease in the region of the skin evaluated in the thermography.

Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2ß1.

Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2ß1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2ß1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.

High-fat Western diet alters crystalline silica-induced airway epithelium ion transport but not airway smooth muscle reactivity.

OBJECTIVES: Silicosis is an irreversible occupational lung disease resulting from crystalline silica inhalation. Previously, we discovered that Western diet (HFWD)-consumption increases susceptibility to silica-induced pulmonary inflammation and fibrosis. This study investigated the potential of HFWD to alter silica-induced effects on airway epithelial ion transport and smooth muscle reactivity. METHODS: Six-week-old male F344 rats were fed a HFWD or standard rat chow (STD) and exposed to silica (Min-U-Sil 5®, 15 mg/m3, 6 h/day, 5 days/week, for 39 d) or filtered air. Experimental endpoints were measured at 0, 4, and 8 weeks post-exposure. Transepithelial potential difference (Vt), short-circuit current (ISC) and transepithelial resistance (Rt) were measured in tracheal segments and ion transport inhibitors [amiloride, Na+ channel blocker; NPPB; Cl- channel blocker; ouabain, Na+, K+-pump blocker] identified changes in ion transport pathways. Changes in airway smooth muscle reactivity to methacholine (MCh) were investigated in the isolated perfused trachea preparation. RESULTS: Silica reduced basal ISC at 4 weeks and HFWD reduced the ISC response to amiloride at 0 week compared to air control. HFWD + silica exposure induced changes in ion transport 0 and 4 weeks after treatment compared to silica or HFWD treatments alone. No effects on airway smooth muscle reactivity to MCh were observed.

The roles of sensory hyperreactivity and hyporeactivity in understanding infant fearfulness and emerging autistic traits.

BACKGROUND: Existing evidence indicates that atypical sensory reactivity is a core characteristic of autism, and has been linked to both anxiety (and its putative infant precursor of fearfulness) and repetitive behaviours. However, most work has used cross-sectional designs and not considered the differential roles of hyperreactivity and hyporeactivity to sensory inputs, and is thus limited in specificity. METHODS: 161 infants with and without an elevated likelihood of developing autism and attention-deficit hyperactivity disorder (ADHD) were followed from 10 to 36 months of age. Parents rated an infant precursor of later anxiety (fearfulness) using the Infant Behaviour Questionnaire at 10 and 14 months, and the Early Childhood Behavioural Questionnaire at 24 months, and sensory hyperreactivity and hyporeactivity at 10, 14 and 24 months using the Infant Toddler Sensory Profile. Domains of autistic traits (restrictive and repetitive behaviours; RRB, and social communication interaction, SCI) were assessed using the parent-rated Social Responsiveness Scale at 36 months. Cross-lagged models tested (a) paths between fearfulness and hyperreactivity at 10-24 months, and from fearfulness and hyperreactivity to later autism traits, (b) the specificity of hyperreactivity effects by including hyporeactivity as a correlated predictor. RESULTS: Hyperreactivity at 14 months was positively associated with fearfulness at 24 months, and hyperreactivity at 24 months was positively associated with SCI and RRB at 36 months. When hyporeactivity was included in the model, paths between hyperreactivity and fearfulness remained, but paths between hyperreactivity and autistic traits became nonsignificant. CONCLUSIONS: Our findings indicate that alterations in early sensory reactivity may increase the likelihood of showing fearfulness in infancy, and relate to later social interactions and repetitive behaviours, particularly in individuals with a family history of autism or ADHD.

Blocking CD226 regulates type 2 innate lymphoid cell effector function and alleviates airway hyperreactivity.

BACKGROUND: Type 2 innate lymphoid cells (ILC2s) play a pivotal role in type 2 asthma. CD226 is a costimulatory molecule involved in various inflammatory diseases. OBJECTIVE: We aimed to investigate CD226 expression and function within human and mouse ILC2s, and to assess the impact of targeting CD226 on ILC2-mediated airway hyperreactivity (AHR). METHODS: We administered IL-33 intranasally to wild-type mice, followed by treatment with anti-CD226 antibody or isotype control. Pulmonary ILC2s were sorted for ex vivo analyses through RNA sequencing and flow cytometry. Next, we evaluated the effects of CD226 on AHR and lung inflammation in wild-type and Rag2-/- mice. Additionally, we compared peripheral ILC2s from healthy donors and asthmatic patients to ascertain the role of CD226 in human ILC2s. RESULTS: Our findings demonstrated an inducible expression of CD226 in activated ILC2s, enhancing their cytokine secretion and effector functions. Mechanistically, CD226 alters intracellular metabolism and enhances PI3K/AKT and MAPK signal pathways. Blocking CD226 ameliorates ILC2-dependent AHR in IL-33 and Alternaria alternata-induced models. Interestingly, CD226 is expressed and inducible in human ILC2s, and its blocking reduces cytokine production. Finally, we showed that peripheral ILC2s in asthmatic patients exhibited elevated CD226 expression compared to healthy controls. CONCLUSION: Our findings underscore the potential of CD226 as a novel therapeutic target in ILC2s, presenting a promising avenue for ameliorating AHR and allergic asthma.

Lactic acid sting test and capsaicin test differentially induce facial erythematous reaction in subjects with sensitive skin.

BACKGROUND: Sensitivity skin (SS) is a common skin disorders, which have a various of clinical manifestation. Facial erythema is common objective symptom of SS. However, the reasons for the occurrence of erythema in sensitive skin are not fully understood. AIMS: In this study, we preliminarily explain the possible factors inducing erythema of sensitive skin by evaluating facial erythematous reaction to lactic acid sting test (LAST) and capsaicin test (CAT) in subjects with sensitive skin. METHODS: A total of 197 subjects were divided into five groups, that is, normal controls (NC), LAST-positive (LAST+ ), both LAST and CAT positive (L+ C+ ), both LAST and CAT negative (L- C- ) and CAT-positive (CAT+ ). Erythema index (EI), a* value, and tissue viability imaging (TIVI) were measured before and after LAST and CAT, The ΔEI, Δa*, and ΔTIVI before and after LAST and CAT were calculated, and the correlation between the scores of CAT, EI values, a* values, and TIVI values were analyzed to clarify the causes of facial erythema. RESULTS: Our results showed that EI values and a* values were significantly higher in the L+ C+ and CAT+ group than in NC group, TIVI values were higher in the L+ C+ group than in NC group. ΔEI and Δa* values after LAST did not differ significantly among five groups. However, ΔEI values in L+ C+ group were higher than that in L- C- group, while Δa* values were higher in CAT+ group than in NC. Moreover, ΔTIVI values in L+ C+ group and CAT+ group were also significantly higher than that in NC group after capsaicin stimulation. CAT scores correlated positively with EI, a* and TIVI values. CONCLUSION: Our results suggest that sensitive skin subjects with positive CAT are more likely to experience erythema reactions, and vasodilation is more pronounced after capsaicin stimulation. Reducing vascular and neural hyperreactivity could be therapeutic target in management of facial erythema in subjects with sensitive skin.

Análisis bibliométrico de la producción científica cubana sobre asma en Scopus

Introducción: El asma es una entidad con alta prevalencia a nivel mundial y en Cuba, que ha suscitado nuevas investigaciones. Objetivo: Caracterizar la producción científica cubana sobre asma en la base de datos Scopus. Materiales y métodos: Se realizó un estudio observacional, descriptivo y bibliométrico de los artículos publicados sobre asma en Scopus con autores cubanos, desde 1973 hasta 2021. Para la recuperación de los registros se empleó una fórmula de búsqueda. Para el análisis de los datos se usaron los software Bibexcel y VOSviewer. Resultados: Se publicaron 154 investigaciones sobre asma, con predominio de artículos originales (136) y de revisión (12). Las áreas más productivas fueron Medicina (144) e Inmunología y Microbiología (34). Los artículos fueron publicados en 48 revistas; de ellas, 11 fueron cubanas, con la Revista Cubana de Medicina como la más productiva. México aportó el mayor número de colaboraciones (10). El Hospital Clínico Quirúrgico Docente General Calixto García (15) fue el más productivo. Se identificaron tres clústeres de palabras clave, con "human", "asthma" y "Cuban" como términos centrales y de mayor ocurrencia. Conclusiones: Existió una baja producción científica sobre asma, centrada principalmente en artículos originales, en el área de Medicina y en revistas nacionales. Se evidenció colaboración internacional. Los ejes principales de investigación fueron el diagnóstico, tratamiento, investigación básica en modelos animales, nuevas terapéuticas, factores de riesgo y prevención.

Introduction: Asthma is an entity with high prevalence worldwide and in Cuba, which has prompted new research. Objective: To characterize Cuban scientific production on asthma in the Scopus database. Materials and methods: An observational, descriptive and bibliometric study was carried out on articles on asthma published in Scopus by Cuban authors, from 1973 to 2021. A search formula was used to retrieve the records. Bibexcel and VOSviewer were used for data analysis. Results: 154 research papers on asthma were published; with a predominance of original (136) and review articles (12). The most productive areas were Medicine (144) and Immunology and Microbiology (34). Articles were published in 48 journals, of which 11 were Cuban, with the Revista Cubana de Medicina (Cuban Journal of Medicine) being the most productive. Mexico contributed the highest number of collaborations (10). The Teaching Hospital General Calixto García (15) was the most productive. 3 key word clusters were identified, with "human", "asthma" and "Cuban" as central and most occurring terms. Conclusions: There was a low scientific production on asthma, mainly focused on original articles, in the area of Medicine and in national journals. International collaboration was evident. The main areas of research were diagnosis, treatment, basic research in animal models, new therapeutics, risk factors and prevention.

Insights into exercise-induced rhinitis based on nasal aerodynamics induced by airway morphology.

BACKGROUND: Exercise-induced rhinitis (EIR) is a poorly understood phenomenon that may be related to increased inspiratory airflow. Characterization of the development of EIR is important to understand contributing factors. OBJECTIVE: To characterize how different nasal morphologies respond to airflow-related variables during rapid/deep inspiratory conditions. METHODS: Subject-specific nasal airways were reconstructed from radiographic images. Unilateral airways were classified as Standard, Notched, or Elongated accord to their distinct nasal vestibule morphology. Computational fluid dynamics simulations were performed at various airflow rates. RESULTS: For all simulated flow rates, average resistance at the nasal vestibule, airflow velocity and wall sheer stress were highest in Notched. Average mucosal heat flux was highest in Standard. Notched phenotypes showed lower mean percent increases from 10 L/min to 50 L/min in all computed variables. CONCLUSION: Resistance values and airflow velocities depicted a more constricted nasal vestibule in the Notched phenotypes, while perception of nasal mucosal cooling (heat flux) favored the Standard phenotypes. Different nasal phenotypes may predispose to EIR.

Asma bronquial reagudizada y neumonitis por hipersensibilidad provocada por alergia a perros domésticos / Exacerbated Bronchial Asthma and Hypersensitivity Pneumonitis Triggered by Allergy to Domestic Dogs

Se presenta un caso clínico interpretado al principio como asma alérgica al pelo de perro y, luego, documentado como neumonitis por hipersensibilidad no fibrótica vinculada al antecedente ambiental doméstico.

We present a case initially interpreted as allergic asthma triggered by dog hair and later confirmed as non-fibrotic hypersensitivity pneumonitis (HP) associated with domestic environmental conditions.