Mucin is produced by clara cells in the proximal airways of antigen-challenged mice

Airway mucus hypersecretion is a prominent feature of many obstructive lung diseases. We thus determined the ontogeny and exocytic phenotype of mouse airway mucous cells. In naive mice, ciliated (approximately 40%) and nonciliated (approximately 60%) epithelial cells line the airways, and > 95% of the nonciliated cells are Clara cells that contain Clara cell secretory protein (CCSP). Mucous cells comprise < 5% of the nonciliated cells. After sensitization and a single aerosol antigen challenge, alcian blue-periodic acid Schiff's positive mucous cell numbers increase dramatically, appearing 6 h after challenge (21% of nonciliated/nonbasal cells), peaking from Days 1-7 (99%), and persisting at Day 28 (65%). Throughout the induction and resolution of mucous metaplasia, ciliated and Clara cell numbers identified immunohistochemically change only slightly. Intracellular mucin content peaks at Day 7, and mucin expression is limited specifically to a Clara cell subset in airway generations 2-4 that continue to express CCSP. Functionally, Clara cells are secretory cells that express the regulated exocytic marker Rab3D and, in antigen-challenged mice, rapidly secrete mucin in response to inhaled ATP in a dose-dependent manner. Thus, Clara cells show great plasticity in structure and secretory products, yet have molecular and functional continuity in their identity as specialized apical secretory cells.     

Zika Virus and the Eye

Zika virus (ZIKV), a mosquito-borne flavivirus, is the latest global health concern. Transmission is mainly via Aedes mosquitoes and the infection can be diagnosed on molecular or serologic testings. It typically causes a mild self-remitting illness of low-grade fever, maculopapular rash, and myalgia, but when severe, it is associated with neurological deficits and congenital structural defects. Ocular manifestations are usually mild like nonpurulent conjunctivitis in adults, though it may be linked to uveitis, maculopathy, and hypertensive iridocyclitis. Ocular signs seem to be more significant in congenital ZIKV—macular pigment mottling, neuroretinal atrophy with macular involvement, iris coloboma, and changes in retinal vasculature are noted in infants with infected mothers. Risk factors include ZIKV infection in first trimester and smaller cephalic diameter at birth. Hence, ophthalmic examination in newborns is now recommended. Currently, prevention and active surveillance are integral as there is no known vaccine, and treatment is only symptomatic.     

Evaluation and in vivo efficacy study of pyrano[3,2‐c]quinoline analogues as TNF‐α inhibitors

A series of pyrano[3,2 c]quinoline was evaluated for its in vivo efficacy as TNF‐α inhibitor using LPS, phosphodiesterase (PDE)‐4, and CIA assays in different mice/rat models. The synthesis was performed using one‐pot multicomponent condensation between 2,4‐dihydroxy‐1‐methylquinoline, malononitrile, and diverse un(substituted) aromatic aldehydes. In vivo efficacy of the title compounds was evaluated using LPS assay in BALB/c mice, PDE4 inhibition in ketamine–xylazine‐induced anesthetize SD rats, and CIA assay was performed in DBA/1J mice as per the standard literature protocols. The outcome of the study revealed that compound 4v was found to be most promising candidate of the series. It was efficacious with 48.8 ± 13.0% inhibition of TNF‐α release at 100 mg/kg p.o., in the LPS assay in Balb/c mice model. It was effective in PDE4 assay in ketamine–xylazine‐induced anesthetize SD rats with duration of 38.3 ± 4.5 min for reversal of anesthetic effect and also showed significant inhibition of PDE4 in salbutamol treated U937 cell assay. It was also abolished TNF‐α induced phosphorylation and degradation of IκBα. Ultimately, its effect on CIA‐related bone and cartilage damage was found statistically similar to Enbrel.     

Assistive Framework for Automatic Detection of All the Zones in Retinopathy of Prematurity Using Deep Learning

Journal of Digital Imaging - Retinopathy of prematurity (ROP) is a potentially blinding disorder seen in low birth weight preterm infants. In India, the burden of ROP is high, with nearly 200,000...     

Association of pulse pressure,pulse pressure index,and ambulatory arterial stiffness index with kidney function in a cross‐sectional pediatric chronic kidney disease cohort from the CKiD study

The morbidity and mortality of adult and pediatric chronic kidney disease (CKD) and end‐stage renal disease (ESRD) populations are mainly driven by cardiovascular disease (CVD). Improving CVD outcomes focuses on risk assessment of factors including diastolic blood pressure (DBP), systolic blood pressure (SBP), left ventricular mass index (LVMI), pulse pressure (PP), and pulse pressure index (PPi), which is calculated as PP/SBP. These markers are also proven predictors of CKD progression; however, their role in children has not been established. This study aims to evaluate the relationship between PP, PPi, ambulatory arterial stiffness index (AASI), and proteinuria with kidney function in pediatric CKD patients; it is a retrospective analysis of 620 patients (1‐16 years) from the NIDDK Chronic Kidney Disease in Children (CKiD) registry. The authors analyzed data for three separate cohorts: an overall CKD as well as immunological versus non‐immunological cause for CKD groups. An inverse relationship was found between SBP, DBP, and PP with iGFR and LVMI in the overall CKD group. Our immunological CKD subgroup showed significantly higher serum creatinine, SBP, DBP, and PP values with significantly lower serum albumin levels compared to the non‐immunological group. There were no significant differences with iohexol‐based glomerular filtration rate (iGFR), LVMI, PPi, or high‐sensitivity C‐reactive protein (hs‐CRP) between the two groups. A subgroup analysis demonstrated that SBP, DBP, and PP all correlated significantly with LVMI in the immunological CKD patients but not the non‐immunological subgroup. Additionally, AASI data in the overall CKD population were significantly correlated with PP, PPi, and DBP. This study is one of the first to correlate noninvasive measurements of vascular compliance including PP, PPi, and AASI with iGFR and LVMI in a pediatric CKD cohort. Improving our understanding of surrogate markers for early CVD is integral to improving the care of pediatric CKD population as these patients have yet to develop the hard end points of ESRD, heart failure, myocardial infarction, or stroke.     

Increased thrombin generation in splanchnic vein thrombosis is related to the presence of liver cirrhosis and not to the thrombotic event

Introduction

In recent years there have been increasing evidence associating liver disease with hypercoagulability, rather than bleeding. The aim of the study was to evaluate the haemostatic potential in patients with liver disease.

Patients and methods

We measured thrombin generation in the presence and absence of thrombomodulin in patients with portal vein thrombosis (PVT, n = 47), Budd-Chiari syndrome (BCS, n = 15) and cirrhosis (n = 24) and compared the results to those obtained from healthy controls (n = 21). Fifteen patients with PVT and 10 patients with BCS were treated with warfarin and were compared to an equal number of patients with atrial fibrillation matched for prothrombin time-international normalized ratio. We assessed resistance to thrombomodulin by using ratios [marker measured in the presence/absence of thrombomodulin].

Results

There were no differences in thrombin generation between patients on warfarin treatment and their controls. Cirrhotic patients generated more thrombin in the presence of thrombomodulin and exhibited thrombomodulin resistance compared to controls [p = 0.006 for endogenous thrombin potential (ETP) and p < 0.001 for peak thrombin and both ratios ETP and peak] and patients with non-cirrhotic PVT (p = 0.001, p = 0.006, p < 0.001, p < 0.001 for ETP, peak, ratio ETP, ratio peak, respectively). The patients with cirrhotic PVT exhibited higher ETP (p = 0.044) and peak (p = 0.02) in the presence of thrombomodulin than controls, as well as thrombomodulin resistance (ETP and peak ratios: p = 0.001).

Conclusions

Hypercoagulability and thrombomodulin resistance in patients with cirrhosis were independent of the presence of splanchnic vein thrombosis. The hypercoagulability in patients with cirrhotic PVT could have implications for considering longer or more intensive treatment with anticoagulants in this group.