Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans.

The transcription factor AhR modulates immunity at multiple levels. Here we report that phagocytes exposed to apoptotic cells exhibited rapid activation of AhR, which drove production of the cytokine IL-10. Activation of AhR was dependent on interactions between apoptotic-cell DNA and the pattern-recognition receptor TLR9 that was required for the prevention of immune responses to DNA and histones in vivo. Moreover, disease progression in mouse systemic lupus erythematosus (SLE) correlated with strength of the AhR signal, and the disease course could be altered by modulation of AhR activity. Deletion of AhR in the myeloid lineage caused systemic autoimmunity in mice, and an enhanced AhR transcriptional signature correlated with disease in patients with SLE. Thus, AhR activity induced by apoptotic cell phagocytes maintains peripheral tolerance.

Utility of WhatsApp in emergency urological practice: An interrater reliability study.

INTRODUCTION: The messaging application 'WhatsApp' is used in clinical practice, often for communication between a medical trainee and a consultant. We designed this study to find the interrater reliability of the data transmitted through this application and validating its use in urological practice. MATERIALS AND METHODS: Clinical details and computerized tomographic (CT) images of 30 patients visiting the urology emergency were posted in a closed WhatsApp group involving three consultants (SKD, APS, and KC). The CT images were posted in the WhatsApp group as Whole Image (WI) and Image of Interest (IOI) format and rated on a scale of 1-5. The consultants formulated a provisional diagnosis and initial management strategy. The interrater reliability of these responses was analyzed in the study. RESULTS: Mean WI rating ranged from 3.03 ± 0.61 to 3.73 ± 0.64 (Cronbach alfa [α]-0.494, P = 0.006). Mean IOI rating ranged from 3.4 ± 0.56 to 4.13 ± 0.73 (α-0.824, P < 0.0001). For diagnosis, the proportion of observed agreement (P0) was 83.3% for SKD and APS, 76.6% for SKD and KC, and 73.3% for APS and KC. For management, P0 was 86.6% for APS and KC, 86.6% for SKD and APS, and 80% for SKD and KC. CONCLUSIONS: WhatsApp Messenger serves to transmit good quality pictures of CT scan images. A reasonable diagnosis and management strategy can be formulated using this app with fair inter-rater reliability.

Teleconsultation for paraphimosis reduction in the geriatric population: Lessons from the COVID-19 pandemic.

The health-care sector has been drastically overwhelmed in the wake of prevailing COVID-19 pandemic, hampering elective and emergency medical services alike. The geriatric population is especially affected in this regard as they are the ones who need access to health care services the most, and unfortunately, they are the ones with the highest risk of cross infection and mortality with SARS-COV-2. Lockdown and public restrictions have made the accessibility even harder. Telemedicine has emerged as a useful tool that avoids the risk of cross infection during the face-to-face consultation. Numerous guidelines have been made regarding the implementation of teleconsultations during this pandemic. Through this report, we describe the "beyond guidelines" emergency management of paraphimosis in an aged, bedridden male with comorbidities, through teleconsultation amid the COVID-19 pandemic.

Anesthetic considerations in patients with cystic pulmonary adenomatoid malformations.

Congenital pulmonary adenomatoid malformation (CPAM) is a rare entity. The authors searched the US National Library of Medicine Database, EMBASE, Google Scholar, PubMed Central for anesthetic management in CPAM. The search was performed using the terms: congenital cystic adenomatoid malformation, congenital pulmonary adenomatoid malformation, CCAM, CPAM, anesthetic management. The prognosis of CPAM depends on timely diagnosis, presence of hydrops, degree of hypoplasia of remaining lung, and the size of the lesion. Symptomatic patients must be treated surgically and lobectomy is considered the gold standard. Anesthetic management of such cases is challenging as it involves thoracotomy or thoracoscopic lobectomy or cystectomy and can lead to sudden hemodynamic Collapse. Early extubation should be considered to avoid iatrogenic ventilator-induced bronchial stump dehiscence resulting from positive pressure ventilation.

Renal iron accelerates the progression of diabetic nephropathy in the HFE gene knockout mouse model of iron overload.

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease associated with high mortality worldwide. Increases in iron levels have been reported in diabetic rat kidneys as well as in human urine of patients with diabetes. In addition, a low-iron diet or iron chelators delay the progression of DN in patients with diabetes and in animal models of diabetes. Possible maladaptive mechanisms of organ damage by tissue iron accumulation have not been well studied. We recently reported that iron induced the retinal renin-angiotensin system (RAS) and accelerated the progression of diabetic retinopathy. However, whether iron regulates the systemic RAS is unknown. To explore if iron alters the expression of intrarenal RAS and its role in the progression of DN, we used the high Fe iron (HFE) knockout mouse, a genetic model of systemic iron overload. We found that diabetes upregulated the expression of iron regulatory proteins and augmented tissue iron accumulation in the kidneys of both type 1 and type 2 diabetic mouse models. Iron accumulation in the kidneys of HFE knockout mice was associated with increase in serum and intrarenal renin expression. Induction of diabetes in HFE knockout mice using streptozotocin caused a much higher accumulation of renal iron and accelerated the progression of nephropathy compared with diabetic wild-type mice. Treatment of diabetic mice with the iron chelator deferiprone reversed the renin upregulation and reduced kidney injury. Thus, our results establish a new link between renal iron and RAS activity. Exploring the mechanisms of iron-induced RAS activation further may have a significant therapeutic impact on hypertension and DN.

Attitude and perceived barriers towards the practice of evidence-based urology amongst urological trainees in India.

INTRODUCTION: Evidence-based medicine requires systematic access and appraisal of contemporary research findings, followed by their application in clinical practice. It assumes an even greater significance in the current era of aggressive, industry-driven marketing. METHODS: A questionnaire was designed combining the McColl questionnaire and Barrier scale with relevant modifications and was administered to the urology trainees attending a continuing urological education program. Statistical analysis was performed using SPSS version 25. RESULTS: The meeting was attended by 110 urological trainees from 55 urological training centers all over India. One hundred and three of them agreed to participate in the study. About 92% of the questionnaires were fully completed. Less than half of the participants (47%) had access to reliable urological literature at work. Only 11% of the respondents claimed to have been formally trained in evidence-based urology (EBU). The inability to understand statistical analysis was the most common (67.4%) perceived barrier to EBU. CONCLUSION: The urological trainees in India are positively inclined towards EBU. The lack of formal training in appraising the available literature and lack of protected time, and portals to access the literature at workplaces hinder them from improving their compliance to EBU.

The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity.

Efficient apoptotic cell clearance and induction of immunologic tolerance is a critical mechanism preventing autoimmunity and associated pathology. Our laboratory has reported that apoptotic cells induce tolerance by a mechanism dependent on the tryptophan catabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in splenic macrophages (MΦ). The metabolic-stress sensing protein kinase GCN2 is a primary downstream effector of IDO1; thus, we tested its role in apoptotic cell-driven immune suppression. In vitro, expression of IDO1 in MΦs significantly enhanced apoptotic cell-driven IL-10 and suppressed IL-12 production in a GCN2-dependent mechanism. Suppression of IL-12 protein production was due to attenuation of IL-12 mRNA association with polyribosomes inhibiting translation while IL-10 mRNA association with polyribosomes was not affected. In vivo, apoptotic cell challenge drove a rapid, GCN2-dependent stress response in splenic MΦs with increased IL-10 and TGF-ß production, whereas myeloid-specific deletion of GCN2 abrogated regulatory cytokine production with provocation of inflammatory T-cell responses to apoptotic cell antigens and failure of long-tolerance induction. Consistent with a role in prevention of apoptotic cell driven autoreactivity, myeloid deletion of GCN2 in lupus-prone mice resulted in increased immune cell activation, humoral autoimmunity, renal pathology, and mortality. In contrast, activation of GCN2 with an agonist significantly reduced anti-DNA autoantibodies and protected mice from disease. Thus, this study implicates a key role for GCN2 signals in regulating the tolerogenic response to apoptotic cells and limiting autoimmunity.

B Cell-Intrinsic IDO1 Regulates Humoral Immunity to T Cell-Independent Antigens.

Humoral responses to nonproteinaceous Ags (i.e., T cell independent [TI]) are a key component of the early response to bacterial and viral infection and a critical driver of systemic autoimmunity. However, mechanisms that regulate TI humoral immunity are poorly defined. In this study, we report that B cell-intrinsic induction of the tryptophan-catabolizing enzyme IDO1 is a key mechanism limiting TI Ab responses. When Ido1(-/-) mice were immunized with TI Ags, there was a significant increase in Ab titers and formation of extrafollicular Ab-secreting cells compared with controls. This effect was specific to TI Ags, as Ido1 disruption did not affect Ig production after immunization with protein Ags. The effect of IDO1 abrogation was confined to the B cell compartment, as adoptive transfer of Ido1(-/-) B cells to B cell-deficient mice was sufficient to replicate increased TI responses observed in Ido1(-/-) mice. Moreover, in vitro activation with TLR ligands or BCR crosslinking rapidly induced Ido1 expression and activity in purified B cells, and Ido1(-/-) B cells displayed enhanced proliferation and cell survival associated with increased Ig and cytokine production compared with wild-type B cells. Thus, our results demonstrate a novel, B cell-intrinsic, role for IDO1 as a regulator of humoral immunity that has implications for both vaccine design and prevention of autoimmunity.

Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy.

Inflammatory kidney disease is a major clinical problem that can result in end-stage renal failure. In this article, we show that Ab-mediated inflammatory kidney injury and renal disease in a mouse nephrotoxic serum nephritis model was inhibited by amino acid metabolism and a protective autophagic response. The metabolic signal was driven by IFN-γ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity with subsequent activation of a stress response dependent on the eIF2α kinase general control nonderepressible 2 (GCN2). Activation of GCN2 suppressed proinflammatory cytokine production in glomeruli and reduced macrophage recruitment to the kidney during the incipient stage of Ab-induced glomerular inflammation. Further, inhibition of autophagy or genetic ablation of Ido1 or Gcn2 converted Ab-induced, self-limiting nephritis to fatal end-stage renal disease. Conversely, increasing kidney IDO1 activity or treating mice with a GCN2 agonist induced autophagy and protected mice from nephritic kidney damage. Finally, kidney tissue from patients with Ab-driven nephropathy showed increased IDO1 abundance and stress gene expression. Thus, these findings support the hypothesis that the IDO-GCN2 pathway in glomerular stromal cells is a critical negative feedback mechanism that limits inflammatory renal pathologic changes by inducing autophagy.

Marginal zone CD169+ macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance.

Tolerance to apoptotic cells is essential to prevent inflammatory pathology. Though innate responses are critical for immune suppression, our understanding of early innate immunity driven by apoptosis is lacking. Herein we report apoptotic cells induce expression of the chemokine CCL22 in splenic metallophillic macrophages, which is critical for tolerance. Systemic challenge with apoptotic cells induced rapid production of CCL22 in CD169(+) (metallophillic) macrophages, resulting in accumulation and activation of FoxP3(+) Tregs and CD11c(+) dendritic cells, an effect that could be inhibited by antagonizing CCL22-driven chemotaxis. This mechanism was essential for suppression after apoptotic cell challenge, because neutralizing CCL22 or its receptor, reducing Treg numbers, or blocking effector mechanisms abrogated splenic TGF-ß and IL-10 induction; this promoted a shift to proinflammatory cytokines associated with a failure to suppress T cells. Similarly, CCR4 inhibition blocked long-term, apoptotic cell-induced tolerance to allografts. Finally, CCR4 inhibition resulted in a systemic breakdown of tolerance to self after apoptotic cell injection with rapid increases in anti-dsDNA IgG and immune complex deposition. Thus, the data demonstrate CCL22-dependent chemotaxis is a key early innate response required for apoptotic cell-induced suppression, implicating a previously unknown mechanism of macrophage-dependent coordination of early events leading to stable tolerance.

Anesthesia for intellectually disabled.

Anesthetizing an intellectually disabled patient is a challenge due to lack of cognition and communication which makes perioperative evaluation difficult. The presence of associated medical problems and lack of cooperation further complicates the anesthetic technique. An online literature search was performed using keywords anesthesia, intellectually disabled, and mentally retarded and relevant articles were included for review. There is scarcity of literature dealing with intellectually disabled patients. The present review highlights the anesthetic challenges, their relevant evidence-based management, and the role of caretakers in the perioperative period. Proper understanding of the associated problems along with a considerate and unhurried approach are the essentials of anesthetic management of these patients.

Disseminated intravascular and intracardiac thrombosis after cardiopulmonary bypass.

Massive intracardiac and intravascular thrombosis is a rare complication following cardiopulmonary bypass (CPB). Most of the cases of the disseminated thrombosis have been reported in patients undergoing complex cardiac surgeries and those receiving antifibrinolytic agents during CPB. We report the occurrence of disseminated intravascular and intracardiac thrombosis after CPB in a patient undergoing mitral valve replacement in which no antifibrinolytic agent was used. The possible pathophysiology and management of the patient is discussed.

Beware of "curare cleft" like changes during unilateral capnothorax.

Capnography is a standard monitoring tool during general anaesthesia. Diaphragmatic movement with the weaning of muscle relaxant effect produces the characteristic "curare cleft" on capnography. Various artefacts can mimick this trace intraoperatively. Cautious interpretation and identification of these is essential to avoid any undue overdosing of the patients with muscle relaxants. We report "curare cleft" like artefact during ventilation with a single lumen tube in a patient with unilateral capnothorax undergoing minimally invasive esophagectomy.

Comparative Analysis of Hemispherotomy in Adults versus Children- A Prospective Observational Series.

BACKGROUND: Hemispherotomy (HS) is an effective treatment for unilateral hemispheric onset epilepsy. There are few publications for HS in adults, and there is no series comparing adults and pediatric patients of HS. OBJECTIVE: To compare the hemispherotomies done in adult patients with pediatric ones in terms of efficacy and safety. METHODS: Data was prospectively collected for HS patients (up to 18 years and more) from Aug 2014 to Aug 2018. Comparison between the groups was made for seizure onset, duration of epilepsy, frequency of seizures, number of drugs, intraoperative blood loss, postoperative seizure control, postoperative stay, postoperative motor functions, and preoperative and postoperative intelligence quotient. Follow-up was one year. RESULTS: A total of 61 pediatric and 11 adults underwent HS. The seizure onset was earlier in children, and the duration of epilepsy was longer in adults. The frequency of seizures per day was more in children being 14.62 ± 26.34 in children, and 7.71 ± 5.21 per day in adults (P - 0.49). The mean number of drugs was similar in the preoperative and postoperative periods in both. Class I seizure outcome was similar in both the groups being 85.24% in children and 90.9% in adults (P - 0.56). Blood loss, postoperative stay, was similar in both the groups. No patient had a new permanent motor deficit. Power worsened transiently in 1 pediatric patient and in 4 adult patients. The visual word reading and object naming improved in both the groups (no intergroup difference), and IQ remained the same in both groups. One adult patient had meningitis, and another had hydrocephalus requiring shunt placement. CONCLUSION: Hemispherotomy is a safe and effective procedure in adults as in children in appropriately selected patients.

Prostaglandin E2 promotes cellular recovery from established nephrotoxic serum nephritis in mice, prosurvival, and regenerative effects on glomerular cells.

We postulated that prostaglandin E2 (PGE2), which exhibits regulatory functions to control immune-mediated inflammation, fibrosis, oxidative stress, and tissue/cellular regeneration, has the potential to improve the course of nephritis. Therefore, the therapeutic potential of prostanoid on established nephritis in mice was evaluated focusing on its role on renal cellular recovery, with emphasis on its cytoprotecting and growth-promoting effects. Acute nephritis was induced in mice by single injection of nephrotoxic serum (NTS), followed by PGE2 administration with severity of nephritis evaluated over time. Mice injected with PGE2 recovered promptly with normalization of blood urea nitrogen and urine protein levels and histology. Recovery was observed with dosing of prostanoid at day 1, as well as day 4. With the use of selective EP1-4 receptor agonists, EP3 receptor has been identified as important in mediating beneficial effects of PGE2 in our system. PGE2 normalized glomerular cell losses during nephrotoxic serum-induced nephritis, restored synaptopodin distribution and F-actin filaments arrangement in glomeruli. In cell culture, PGE2 reduced nephrotoxim serum (NTS)-induced apoptosis of glomerular cells and promoted cell reproliferation after NTS-mediated injury. In conclusion, PGE2 treatment promotes resolution of glomerular inflammation. Consistent with this observation, the regenerative and cytoprotective effects of prostanoid on glomerular cells in culture were observed, suggesting that PGE2 may be beneficial in the treatment of glomerulonephritis.

A human monoclonal antibody against the collagen type IV α3NC1 domain is a non-invasive optical biomarker for glomerular diseases.

Progressive kidney disease is a significant clinical problem. However, despite research aimed toward developing improved predictors of disease, the major tool to assess kidney ultrastructure damage is the kidney biopsy. Here we tested the capability of a labeled human monoclonal antibody (F1.1), directed against the NC1 domain of α3(IV) collagen, to detect pathologic kidney alterations in vivo using mouse models of nephrotoxic serum-induced nephritis and puromycin aminoglycoside nephrosis. The F1.1 antibody-fluorophore conjugate signal rapidly localized specifically to injured glomeruli in both the severe and mild kidney disease models while minimally labeling healthy kidney. This differential labeling is likely due to cryptic NC1-domain exposure as enzymatic or chemical treatment of healthy human or mouse kidney sections significantly increased F1.1 binding to the glomeruli. Finally, kidney tissue from patients with renal disease show significant glomerular staining by F1.1 indicating that exposure of the NC1 domain occurs in clinically relevant circumstances. Thus, NC1 domain exposure may represent an in situ biomarker for assessment of kidney injury. Our study suggests that F1.1 and similar antibodies may represent a new class of non-invasive renal imaging reagents.