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Background Burn and trauma injuries need emergency care and resuscitation, which required uninterrupted delivery of inpatient care services during the coronavirus disease 2019 (COVID-19) pandemic. Burn patients are physiologically immunocompromised, increasing the risk of COVID-19 infection in them. This study analyzes the impact of COVID-19 pandemic on patient trends in a burn and plastic unit and assesses the effect of COVID-19 infection in burns. Methods This single-center, retrospective observational case–control study was conducted in the Department of Burns, Plastic and Maxillofacial Surgery of a tertiary care hospital in New Delhi, India. Patient data was collected from April 1, 2019 to August 10, 2019 and from April 1, 2020 to August 10, 2020. All data of burns and trauma patients collected was analyzed and compared. Results There were total 350 admissions during COVID time period and 562 admissions during non-COVID time period. The admission rate, type of burn injury, and death rate did not vary significantly during the two time periods. Thermal burn was the most common type of burn injury. There were total 18 cases diagnosed to be COVID-19 positive during the pandemic. There were two deaths among COVID-19 positive burn cases. Conclusion This study finds no difference in patient patterns during COVID and non-COVID time period. Amongst burn patients, no increased risk of COVID-19 infection is seen with larger body surface area of burns. No increase in mortality is seen in burn patients infected with COVID-19.

Inflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are such autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here we use multiple genetically modified mouse models to monitor activated inflammasomes in situ based on ASC oligomerization in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation was dependent on AIM2, but low IL-1β expression and no significant signs of cell death were found in astrocytes during EAE. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.SIGNIFICANCE STATEMENTInflammasome activation in the peripheral immune system is pathogenic in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, inflammasome activity in the central nervous system (CNS) is largely unexplored. Here, we used genetically modified mice to determine inflammasome activation in the CNS during EAE. Our data indicated heightened AIM2 inflammasome activation in astrocytes after the disease peak. Unexpectedly, neither CNS-infiltrated myeloid cells nor microglia were the primary cells with activated inflammasomes in SC during EAE. Despite AIM2 inflammasome activation, astrocytes did not undergo apparent cell death and produced little of the proinflammatory cytokine, IL-1β, during EAE. This study showed that CNS inflammasome activation occurs during EAE without associating with IL-1β-mediated inflammation.

Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) is identified upon immune reconstitution in immunocompromised patients, who have previously contracted an infection of Cryptococcus neoformans (Cn). C-IRIS can be lethal but how the immune system triggers life-threatening outcomes in patients is still poorly understood. Here, we establish a mouse model for C-IRIS with Cn serotype A strain H99, which is highly virulent and the most intensively studied. C-IRIS in mice is induced by the adoptive transfer of CD4+ T cells in immunocompromised Rag1-deficient mice infected with a low inoculum of Cn. The mice with C-IRIS exhibit symptoms which mimic clinical presentations of C-IRIS. This C-IRIS model is Th1-dependent and shows host mortality. This model is characterized with minimal lung injury, but infiltration of Th1 cells in the brain. C-IRIS mice also exhibited brain swelling with resemblance to edema and upregulation of aquaporin-4, a critical protein that regulates water flux in the brain in a Th1-dependent fashion. Our C-IRIS model may be used to advance our understanding of the paradoxical inflammatory phenomenon of C-IRIS in the context of neuroinflammation.

Pathologic roles for innate immunity in neurologic disorders are well-described, but protective aspects of the immune response are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. However, we found that Dectin-1 is protective in experimental autoimmune encephalomyelitis (EAE), while its canonical signaling mediator, Card9, promotes the disease. Notably, Dectin-1 does not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Myeloid cells mediate the protective function of Dectin-1 in EAE and upregulate gene expression of neuroprotective molecules, including Oncostatin M (Osm) through a non-canonical Card9-independent pathway, mediated by NFAT. Furthermore, we found that the Osm receptor (OsmR) functions specifically in astrocytes to reduce EAE severity. Our study revealed a new mechanism of protective myeloid-astrocyte crosstalk regulated by a non-canonical Dectin-1 pathway and identifies novel therapeutic targets for CNS autoimmunity.Graphical AbstractDectin-1 is a protective C-type lectin receptor (CLR) in experimental autoimmune encephalomyelitis (EAE)Dectin-1 promotes expression of Osm, a neuroprotective IL-6 family cytokine, in myeloid cellsOsmR signaling in astrocytes limits EAE progression and promotes remissionNon-canonical Card9-independent signaling drives a distinct Dectin-1-mediated transcriptional program to induce expression of Osm and other factors with protective or anti-inflammatory functions

Human blood monocytes are divided into populations based on the differential expression of CD14 and CD16 receptors: CD14 (+) CD16(classical), CD14 (+) CD16 (+) (intermediate), and CD14(-)CD16(+) (non-classical). Given their functional differences and their role in pathogenesis of chronic obstructive pulmonary disease (COPD), monocyte profiling is of clinical interest. Here we investigated blood monocyte subsets in clinically stable COPD patients with alpha1-antitrypsin (AAT) deficiency (PiZZ, n = 7) and with normal AAT variant (PiMM, n = 7). Peripheral whole blood was collected in sodium heparin tubes and incubated with LPS (from E. coli; 1 mu g/ml) or placebo for 6 h at 37 degrees C, 5% CO2. To profile monocyte subsets we performed flow cytometry analysis based on HLA-DR and CD14/CD16 staining. HLA-DR + subsets of cells did not differ between PiZZ and PiMM COPD, and healthy controls (n = 7), used as a reference. Monocyte profiling, which express the CD14 and CD16, but not the HLA-DR (HLA-DR-) showed that intermediate monocytes subset was lowest in PiZZ group, and almost totally disappeared from blood treated with LPS. The non-classical subset was almost absent in PiZZ patients independently of LPS treatment. Recent studies demonstrate that non-classical monocytes exhibit a unique ability to protect the vascular endothelium under both homeostatic and inflammatory conditions whereas intermediate monocytes are recruited at a later stage of inflammation, and are associated with secretion of cytokines/chemokines and wound healing. Evident alterations in blood monocyte subsets together with a partial reduction of AAT levels, an important anti-inflammatory protein, can be key factors for the early manifestation of emphysema in some PiZZ AATD carriers.

Avulsion injuries of domes of the diaphragm are rare injuries and may occur following lateral thoracoabdominal trauma. We share our experience of two cases of avulsion injuries of the right dome of the diaphragm. Our first case presented within a week following blunt trauma to the abdomen, and on thoracotomy, an effective repair was performed by restoring attachment of the diaphragm to the parietes. Our second case presented with severe respiratory distress, 1½ months after sustaining blunt injury chest and abdomen in a road traffic accident and on thoracotomy was found to have a completely necrosed right hemidiaphragm, and hence, no repair could be performed. However, the patient could not be weaned off ventilator and died after 3 months of primary injury. These cases highlight the importance of early diagnosis and repair of diaphragmatic injuries for a favorable outcome.

Pathologic roles of innate immunity in neurologic disorders are well described, but their beneficial aspects are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. Here, we report that Dectin-1 limited experimental autoimmune encephalomyelitis (EAE), while its downstream signaling molecule, Card9, promoted the disease. Myeloid cells mediated the pro-resolution function of Dectin-1 in EAE with enhanced gene expression of the neuroprotective molecule, Oncostatin M (Osm), through a Card9-independent pathway, mediated by the transcription factor NFAT. Furthermore, we find that the Osm receptor (OsmR) functioned specifically in astrocytes to reduce EAE severity. Notably, Dectin-1 did not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Instead, endogenous Dectin-1 ligands, including galectin-9, in the central nervous system (CNS) were involved to limit EAE. Our study reveals a mechanism of beneficial myeloid cell-astrocyte crosstalk regulated by a Dectin-1 pathway and identifies potential therapeutic targets for autoimmune neuroinflammation.

Fungal necrotizing fasciitis (NF), particularly in the face, is an unusual infection. It is mostly seen in immunocompromised individuals and can be gravely destructive if diagnosis and treatment are delayed. We report this rare case of a 27-year-old, immunocompetent male who presented with gangrenous patch of skin on the cheek following blunt trauma to the right side of the face. Till now no case has been reported in literature with such an extensive soft tissue loss of face and involvement of facial skeleton due to fungal etiology. Clinical suspicion of necrotizing fasciitis led to early surgical intervention. Histopathological examination of the debrided tissue identified the infective organism as Apophysomyces elegans. Intravenous antifungal therapy with liposomal amphotericin B was initiated. Despite the prompt commencement of the treatment, the infection continued to spread, and the patient had to undergo serial debridement which resulted in orbital exenteration, partial maxillectomy and mandibulectomy on the right side. This resulted in a huge soft tissue defect requiring flap cover. A free anterolateral thigh flap was harvested to cover the soft tissue defect, but the blood flow could not be established. For salvage, scalp and pectoralis major muscle flaps were raised and used to cover the large hemifacial defect. The oral lining was created with a folded deltopectoral flap in a second stage. However, there was persistence of the fungal elements in wound bed even after prolonged systemic liposomal amphotericin B therapy and it invaded the flap margins due to which there was partial necrosis of the flap. In this article, we aim to describe the difficulties faced by us in the management of such devastating infection and the reconstructive challenge that it posed.

PURPOSE OF REVIEW: Despite the increasing number of clinical reports on immune reconstitution inflammatory syndrome (IRIS), mechanistic understanding of IRIS is still largely limited. The main focus of this review is to summarize animal studies, which were performed to better understand the cellular and molecular mechanisms underlying the pathology of IRIS. RECENT FINDINGS: Three IRIS animal models have been reported. They are Mycobacterial IRIS (M-IRIS), cryptococcal IRIS (C-IRIS) and Pneumocystis-IRIS. M-IRIS animal model suggested that, rather than lymphopenia itself, the failure to clear the pathogen by T cells results in excessive priming of the innate immune system. If this happens before T cell reconstitution, hosts likely suffer IRIS upon T cell reconstitution. Interestingly, T cells specific to self-antigens, not only pathogen-specific, could drive IRIS as well. SUMMARY: The mechanism to develop IRIS is quite complicated, including multiple layers of host immune responses; the innate immune system that detects pathogens and prime host immunity, and the adaptive immune system that is reconstituted but hyper-activated particularly through CD4(+) T cells. Animal models of IRIS, although there are still small numbers of studies available, have already provided significant insights on the mechanistic understanding of IRIS.

Several reports indicated an association among inherited A1ATD, pulmonary infections and bronchiectasis. Most reported A1ATD cases with bronchiectasis are elderly homozygous PiZZ (Glu342Lys) smokers with emphysema. Whether there is an increased risk for bronchiectasis in heterozygous PiMZ A1ATD carriers is not clear. We describe a non-smoking 18 years old male with bronchiectasis. Pulmonary function testing showed a moderate airflow obstruction and hyperinflation. Capillary blood gas analysis showed moderate respiratory failure and hyperventilation. A high-resolution CT scan of the chest revealed bronchiectasis in both lower lobes with thickening of bronchial walls and additional tree-in-bud sign, indicating bronchiolitis and mucus plugging, but no emphysema. Analysis of the serum A1AT and phenotyping revealed that this patient had reduced A1AT levels of 0.78 g/L (normal is 0.9-2.0g/L) associated with an intermediate PiMZ A1ATD. Although microscopic examination of Giemsa-stained cytospins revealed normal appearance of PiMZ neutrophils, they had significantly lower A1AT (SERPINA1) but higher elastase (ELANE) expression when compared to PiMM neutrophils. Affinity purified MZ A1AT protein contained a mixture of polymeric forms and lower ability to inhibit endotoxin-induced TNFα and IL-1β expression than MM A1AT. Our findings highlight the quantitative and qualitative deficiency of MZ A1AT and increased expression of neutrophil elastase, which may explain the early-age onset of bronchiectasis. Our data suggest that patients with bronchiectasis, even in the absence of emphysema, need to be tested for A1ATD.

Recurrent infections of the upper airways in early life may be a warning sign of inherited α 1 -antitrypsin deficiency http://ow.ly/iJsF300kbyV

To the Editor: PiZZ (Glu342Lys) alpha-1 antitrypsin deficiency (A1ATD) is a typical genetic risk factor associated with the development of early-onset chronic obstructive pulmonary disease (COPD) with emphysema. Because A1AT is a major circulating inhibitor of serine proteases (serpin), a severe deficiency of this protein may lead to lung tissue damage by uncontrolled activity of neutrophil elastase, proteinase 3 (PRTN3), and other serine proteases. In general, a proteinase/antiproteinase imbalance is among potential mechanisms implicated in the pathophysiology of COPD (1). The importance of A1AT in maintaining protease–antiprotease homeostasis is also supported by a positive correlation between a recently described in vivo marker of neutrophil elastase activity (Aα-Val360) and disease severity in emphysema related to A1ATD (2). There is, however, considerable heterogeneity in the clinical expression among people with type ZZ A1ATD. Some develop emphysema in early adulthood (35–45 years of age), whereas others in late adulthood or not at all, and severity of symptoms also varies. Support provided by the German Center for Lung Research and in part by the research grant from Grifols Pharmaceutical Company (R.K. and S.J.). Sí

Glioblastoma multiforme (GBM) is the most aggressive and the commonest primary brain tumor with a tendency for local invasiveness. The pathways of neoplasia, invasion and inflammation are inextricably linked in cancer and aberrations in several regulatory pathways for these processes have been identified. Here we have studied the FAT1 (Homo sapiens FAT tumor-suppressor homolog 1 (Drosophila)) gene to identify its role in the tumorigenecity of the gliomas. The expression of FAT1 was found to be high in grade IV glioma cell lines (U87MG, A172, U373MG and T98G) but low in grade III glioma cell lines (GOS3 and SW1088). Two cell lines (U87MG and A172) with high FAT1 expression were chosen for in vitro FAT1-knockdown studies. FAT1 knockdown by small interfering RNA resulted in decreased migration and invasion of both the cell lines along with increased expression of the tumor-suppressor gene programmed cell death 4 (PDCD4). Increased PDCD4 expression led to the attenuation of activator protein-1 (AP- 1) transcription by inhibiting c-Jun phosphorylation and resulted in concomitant decrease in the expression of AP-1-target genes like MMP3, VEGF-C and PLAU, the pro-inflammatory regulator COX-2 and cytokines IL1b and IL-6. Conversely, simultaneous silencing of PDCD4 and FAT1 in these cells significantly enhanced AP-1 activity and expression of its target genes, resulting in increase in mediators of inflammation and in enhanced migratory and invasive properties of the cells. We also observed a negative correlation between the expression of FAT1 and PDCD4 (P = 0.0145), a positive correlation between the expression of FAT1 and COX-2 (P = 0.048) and a similar positive trend between FAT1 and IL-6 expression in 35 primary human GBM samples studied. Taken together, this study identifies a novel signaling mechanism mediated by FAT1 in regulating the activity of PDCD4 and thereby the key transcription factor AP-1, which then affects known mediators of neoplasia and inflammation.

α1-Antitrypsin (A1AT) purified from human plasma upregulates expression and release of angiopoietin-like protein 4 (Angptl4) in adherent human blood monocytes and in human lung microvascular endothelial cells, providing a mechanism for the broad immune-regulatory properties of A1AT independent of its antiprotease activity. In this study, we demonstrate that A1AT (Prolastin), a potent inducer of Angptl4, contains significant quantities of the fatty acids (FA) linoleic acid (C18:2) and oleic acid (C18:1). However, only trace amounts of FAs were present in preparations that failed to increase Angplt4 expression, for example, A1AT (Zemaira) or M-type A1AT purified by affinity chromatography. FA pull-down assays with Western blot analysis revealed a FA-binding ability of A1AT. In human blood-adherent monocytes, A1AT-FA conjugates upregulated expression of Angptl4 (54.9-fold, p < 0.001), FA-binding protein 4 (FABP4) (11.4-fold, p < 0.001), and, to a lesser degree, FA translocase (CD36) (3.1-fold, p < 0.001) relative to A1AT devoid of FA (A1AT-0). These latter effects of A1AT-FA were blocked by inhibitors of peroxisome proliferator-activated receptor (PPAR) β/δ (ST247) and PPARγ (GW9662). When compared with controls, cell pretreatment with ST247 diminished the effect of A1AT-LA on Angptl4 mRNA (11.6- versus 4.1-fold, p < 0.001) and FABP4 mRNA (5.4- versus 2.8-fold, p < 0.001). Similarly, preincubation of cells with GW9662 inhibited inducing effect of A1AT-LA on Angptl4 mRNA (by 2-fold, p < 0.001) and FABP4 mRNA (by 3-fold, p < 0.001). Thus, A1AT binds to FA, and it is this form of A1AT that induces Angptl4 and FABP4 expression via a PPAR-dependent pathway. These findings provide a mechanism for the unexplored area of A1AT biology independent of its antiprotease properties.

Context: Low back pain (LBP) is the most common orthopedic problem worldwide and is known to affect both younger and older adults. The stressful and time consuming curriculum of medical students predisposes them to this problem. Few statistics are available on prevalence rates of LBP among medical students in India. This study assesses the prevalence and risk factors of LBP in students of a medical college in Delhi. Methods: A cross-sectional study was carried out in a medical college in Delhi. The study subjects (n = 160; 100% participation) were selected via stratified random sampling from all undergraduate medical students (aged 17-25 years). A validated questionnaire was used to collect the data. Results: The overall prevalence of LBP among the students over the past one year was 47.5% (n = 76) with a prevalence of 32.5% at the time of data collection. Prevalence among males and females was 45.3% and 50%, respectively. Significant associations were found between LBP in the past year and coffee drinking (Regular = 57%, Occasional = 38.9%, Never = 65.2%, χ2 = 7.24, P= 0.02), body posture (Normal = 32.6%, Abnormal = 75%, χ2 = 18.97, P < 0.001), place of study (Study table = 33.8%, Bed = 58.6, Both = 61.5% χ2 = 10.51, P = 0.01), family history of LBP (Present = 75%, Absent = 38.3%, χ2 = 16.17, P < 0.001) and carrying backpacks (Regular = 50%, Occasional = 33%, Never = 0%, χ2 = 16.17, P < 0.001). The mean scores of depression (2.7 vs. 1.6), anxiety (3.5 vs 1.9), and monotonous work (3.9 vs. 1.8) were found to be significantly higher in group with LBP than in the non-LBP group. However, no association with LBP was seen for weight lifting, watching television/working on computers, driving, wearing heels, or body mass index. Discussion: The high prevalence of LBP among medical students and its association with poor study habits, lifestyle habits, and psychological factors highlight a need for life skills training, education, counseling, and restructuring of the medical curriculum.

As an acute phase protein, alpha-antitrypsin (AAT) is thought to play an important role in limiting host tissue injury by proteases released from activated myeloid cells, specifically neutrophil elastase (NE). The clinical importance of AAT is highlighted in individuals with inherited deficiency in circulating AAT who have an increased susceptibility to early onset pulmonary emphysema, chronic bronchitis, bronchiectasis, and liver diseases. Administration of exogenous human plasma-derived AAT is used in various animal models to test the value of AAT augmentation therapy. Unrelated to emphysema models, administration of exogenous AAT inhibits HIV 1 expression, prevents murine islet cell allografts from rejection, blocks cell apoptosis and increases survival in an allogeneic marrow transplantation models. The mechanism of the above mentioned anti-inflammatory activities of AAT has been assumed to be due to its anti-proteolytic activity; however this has not been studied. We hypothesized that the anti-elastase activity of AAT was not required for its anti-inflammatory properties. To investigate this prediction, effects of native human plasma derived (nAAT, inhibitory form) and recombinant (rAAT, non-inhibitory form) on lipopolysaccharide (LPS)-induced IL-8 and TNFα release from neutrophils isolated from human blood or the bone marrow from wild type (WT) and elastase deficient mice (NE-/-) were examined. When WT or NE deficient neutrophils were treated with LPS plus rAAT (50 nM), release of TNFα (42%, p=0.002 and 24%, p=0.011, respectively) as well as of IL-8 was decreased (57%, p=0.004 and 40%, p=0.01, respectively) relative to LPS challenged cells. By comparison, to achieve the same reduction in TNFα from either WT or NE deficient neutrophils, a concentration of nAAT of 2000 nM was required. Next, human blood neutrophils were incubated with LPS (10ng/ml) alone or LPS plus increasing concentrations of nAAT or rAAT. After 8 and 18 hours, cytokines were measured in the supernatants. At 20.000 nM, nAAT reduced TNFα release by 46% (p=0.002) and IL-8 by 29%, (p=0.024). However, markedly lower concentrations of rAAT (5nM) reduced TNFα release by 41% (p=0.004) and IL-8 by 40% (p=0.05). We conclude that anti-proteolytic activity of AAT may be required but less important for its anti-inflammatory function. Acknowledgments: This study was supported by Soohyun Kim who provided the rAAT and our collaborator Charles A. Dinarello.

We describe a child with pathologically proven Hallervorden Spatz disease. He presented with extrapyramidal symptoms and characteristic "eye-of-the-tiger" sign on magnetic resonance imaging. He was given the possible benefit if any of deep brain stimulation with no much improvement. Pathological examination of the brain showed iron deposition in bilateral globus pallidi, spongiform change and neuron axonal degeneration (spheroids).