Under homeostatic conditions the release of self-RNA from dying cells does not promote inflammation. However, following injury or inflammatory skin diseases such as psoriasis and rosacea, expression ...of the cathelicidin antimicrobial peptide LL37 breaks tolerance to self-nucleic acids and triggers inflammation. Here we report that LL37 enables keratinocytes and macrophages to recognize self-non-coding U1 RNA by facilitating binding to cell surface scavenger receptors that enable recognition by nucleic acid pattern recognition receptors within the cell. The interaction of LL37 with scavenger receptors was confirmed in human psoriatic skin, and the ability of LL37 to stimulate expression of interleukin-6 and interferon-β1 was dependent on a 3-way binding interaction with scavenger receptors and subsequent clathrin-mediated endocytosis. These results demonstrate that the inflammatory activity of LL37 is mediated by a cell-surface-dependent interaction and provides important new insight into mechanisms that drive auto-inflammatory responses in the skin.
The airway epithelium restricts the penetration of inhaled pathogens into the underlying tissue and plays a crucial role in the innate immune defense against respiratory infections. The whooping ...cough agent,
, adheres to ciliated cells of the human airway epithelium and subverts its defense functions through the action of secreted toxins and other virulence factors. We examined the impact of
infection and of adenylate cyclase toxin-hemolysin (CyaA) action on the functional integrity of human bronchial epithelial cells cultured at the air-liquid interface (ALI).
adhesion to the apical surface of polarized pseudostratified VA10 cell layers provoked a disruption of tight junctions and caused a drop in transepithelial electrical resistance (TEER). The reduction of TEER depended on the capacity of the secreted CyaA toxin to elicit cAMP signaling in epithelial cells through its adenylyl cyclase enzyme activity. Both purified CyaA and cAMP-signaling drugs triggered a decrease in the TEER of VA10 cell layers. Toxin-produced cAMP signaling caused actin cytoskeleton rearrangement and induced mucin 5AC production and interleukin-6 (IL-6) secretion, while it inhibited the IL-17A-induced secretion of the IL-8 chemokine and of the antimicrobial peptide beta-defensin 2. These results indicate that CyaA toxin activity compromises the barrier and innate immune functions of
infected airway epithelia.
The skin typically tolerates exposure to various microbes and chemicals in the environment. Here, we investigated how the epidermis maintains this innate immune tolerance to stimuli that are ...recognized by Toll-like receptors (TLRs). Loss of tolerance to TLR ligands occurred after silencing of the histone deacetylases (HDACs) HDAC8 and HDAC9 in keratinocytes. Transcriptional analysis identified MAP2K3 as suppressed by HDAC8/9 activity and a potential key intermediary for establishing this tolerance. HDAC8/9 influenced acetylation at H3K9 and H3K27 marks in the MAP2K3 promoter. Proteomic analysis further identified SSRP1 and SUPT16H as associated with HDAC8/9 and responsible for transcriptional elongation of MAP2K3. Silencing of MAP2K3 blocked the capacity of HDAC8/9 to influence cytokine responses. Relevance in vivo was supported by observations of increased MAP2K3 in human inflammatory skin conditions and the capacity of keratinocyte HDAC8/9 to influence dendritic cell maturation and T cell proliferation. Keratinocyte-specific deletion of HDAC8/9 also increased inflammation in mice after exposure to ultraviolet radiation, imiquimod, or
These findings define a mechanism for the epidermis to regulate inflammation in the presence of ubiquitous TLR ligands.
Mechanical ventilation (MV) of patients can cause damage to bronchoalveolar epithelium, leading to a sterile inflammatory response, infection and in severe cases sepsis. Limited knowledge is ...available on the effects of MV on the innate immune defense system in the human lung. In this study, we demonstrate that cyclic stretch of the human bronchial epithelial cell lines VA10 and BCi NS 1.1 leads to down-regulation of cathelicidin antimicrobial peptide (CAMP) gene expression. We show that treatment of VA10 cells with vitamin D3 and/or 4-phenyl butyric acid counteracted cyclic stretch mediated down-regulation of CAMP mRNA and protein expression (LL-37). Further, we observed an increase in pro-inflammatory responses in the VA10 cell line subjected to cyclic stretch. The mRNA expression of the genes encoding pro-inflammatory cytokines IL-8 and IL-1β was increased after cyclic stretching, where as a decrease in gene expression of chemokines IP-10 and RANTES was observed. Cyclic stretch enhanced oxidative stress in the VA10 cells. The mRNA expression of toll-like receptor (TLR) 3, TLR5 and TLR8 was reduced, while the gene expression of TLR2 was increased in VA10 cells after cyclic stretch. In conclusion, our in vitro results indicate that cyclic stretch may differentially modulate innate immunity by down-regulation of antimicrobial peptide expression and increase in pro-inflammatory responses.
Abstract
Mitral valve prolapse is a commonly described entity with a highly variable and benign course. However, it is associated with ventricular arrhythmias and sudden cardiac death in a small ...subset of patients. Recent studies have yielded insight into myocardial mechanics and the causation of ventricular arrhythmias in these groups of patients.
Mitral annular disjunction (MAD) characterized by detachment of mitral annulus from left ventricular myocardium is associated with morphological and functional remodeling of the left ventricular myocardium. Resultant fibrosis acts as a substrate of ventricular arrhythmia and sudden cardiac death.
We present two such cases of arrhythmic mitral valve prolapse associated with MAD. Cardiac magnetic resonance imaging provides excellent morphological information and also helps in the assessment of fibrosis.
Background & objectives: India has been reporting the cases of coronavirus disease 2019 (COVID-19) since January 30, 2020. The Indian Council of Medical Research (ICMR) formulated and established ...laboratory surveillance for COVID-19. In this study, an analysis of the surveillance data was done to describe the testing performance and descriptive epidemiology of COVID-19 cases by time, place and person.
Methods: The data were extracted from January 22 to April 30, 2020. The frequencies of testing performance were described over time and by place. We described cases by time (epidemic curve by date of specimen collection; seven-day moving average), place (area map) and person (attack rate by age, sex and contact status), and trends were represented along with public health measures and events.
Results: Between January 22 and April 30, 2020, a total of 1,021,518 individuals were tested for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Testing increased from about 250 individuals per day in the beginning of March to 50,000 specimens per day by the end of April 2020. Overall, 40,184 (3.9%) tests were reported positive. The proportion of positive cases was highest among symptomatic and asymptomatic contacts, 2-3-fold higher than among those with severe acute respiratory infection, or those with an international travel history or healthcare workers. The attack rate (per million) by age was highest among those aged 50-69 yr (63.3) and was lowest among those under 10 yr (6.1). The attack rate was higher among males (41.6) than females (24.3). The secondary attack rate was 6.0 per cent. Overall, 99.0 per cent of 736 districts reported testing and 71.1 per cent reported COVID-19 cases.
Interpretation & conclusions: The coverage and frequency of ICMR's laboratory surveillance for SARS-CoV-2 improved over time. COVID-19 was reported from most parts of India, and the attack rate was more among men and the elderly and common among close contacts. Analysis of the data indicates that for further insight, additional surveillance tools and strategies at the national and sub-national levels are needed.
In India, the incidence of mucormycosis reached high levels during 2021-2022, coinciding with the COVID-19 pandemic. In response to this, we established a multicentric ambispective cohort of patients ...hospitalised with mucormycosis across India. In this paper, we report their baseline profile, clinical characteristics and outcomes at discharge. Patients hospitalized for mucormycosis during March-July 2021 were included. Mucormycosis was diagnosed based on mycological confirmation on direct microscopy (KOH/Calcofluor white stain), culture, histopathology, or supportive evidence from endoscopy or imaging. After consent, trained data collectors used medical records and telephonic interviews to capture data in a pre-tested structured questionnaire. At baseline, we recruited 686 patients from 26 study hospitals, of whom 72.3% were males, 78% had a prior history of diabetes, 53.2% had a history of corticosteroid treatment, and 80% were associated with COVID-19. Pain, numbness or swelling of the face were the commonest symptoms (73.3%). Liposomal Amphotericin B was the commonest drug formulation used (67.1%), and endoscopic sinus surgery was the most common surgical procedure (73.6%). At discharge, the disease was stable in 43.3%, in regression for 29.9% but 9.6% died during hospitalization. Among survivors, commonly reported disabilities included facial disfigurement (18.4%) and difficulties in chewing/swallowing (17.8%). Though the risk of mortality was only 1 in 10, the disability due to the disease was very high. This cohort study could enhance our understanding of the disease's clinical progression and help frame standard treatment guidelines.
We present results of patients diagnosed with unresectable hilar cholangiocarcinomas treated with high dose radiotherapy and concurrent chemotherapy.
From Aug 2005 to Dec 2012, 68 consecutive ...patients were treated. Fifty patients (group 1) presenting to us with obstructive jaundice were planned for endobiliary brachytherapy (EBBT 14 Gy) followed external beam radiotherapy (EBRT 45 Gy). Twenty-two patients (group 2) who had previously undergone biliary drainage underwent EBRT (57 Gy). All patients received injection Gemcitabine 300 mg/m
/weekly along with EBRT.
Twenty-nine patients in group 1 and 22 patients in group 2 completed the treatment. Twenty-six (55%) patients achieved complete radiological response, 16 (64%) belonging to group 1 and 8 (44%) of group 2 (P=0.05). The median overall survival (MOS) was 17.5 and 16 months for group 1 and 2 respectively (P=0.07). The 1- and 2-year survival was 63%, and 18% for group I and 61% and 22% for group II respectively. The MOS was 5 months and 1 year survival was 14% for patients receiving EBBT only. MOS was significantly better after complete response (P=0.001).
Intensity modulated radiotherapy (IMRT) modulated high dose radiotherapy used either alone or with brachytherapy demonstrates potential to prolonged overall survival in unresectable hilar cholangiocarcinomas.
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