A Rare Case of Atypical Cogan’s Syndrome Presenting as Encephalitis

Cogan’s syndrome (CS) is a rare autoimmune vasculitis of unknown aetiology characterised by non-syphilitic interstitial keratitis, audio-vestibular symptoms, sometimes systemic symptoms and multi-organ involvement. Atypical CS has other ocular features such as scleritis, episcelritis, retinitis and optic neuritis. Diagnosis of CS is purely clinical without a confirmatory test. Hereby, we report a case of atypical CS presenting with features of encephalitis who was treated successfully with intravenous pulse methylprednisolone with cyclophosphamide. It is important to consider Cogan’s syndrome in the differential diagnosis of encephalitis with ocular and vestibular symptoms in young patients, as high morbidity and mortality rates are effectively lowered by early immunosuppressive treatment.

A Rare Case of Adult-onset Still's Disease Revealed by Acute Myopericarditis

Background: Still's disease in adults is a systemic inflammatory pathology of unknown aetiology, characterized by clinical manifestations associating feverish peaks, arthritis or arthtralgia, transient rashes and hyperferritinemia. Currently, this disease remains a multisystemic disease with generally poor outcome, poorly described in the literature with very few studies unlike other rheumatic diseases, probably underdiagnosed due to its clinical polymorphism. Cardiac forms are quite rare and among the manifestations described, pericarditis remains the most reported entity, myocardial involvement is exceptional. The aim of our observation is to report an exceptional case of discovery of stille disease following a myo-pericarditis mimicking a coronary Sd initially.

Discovery of the Retinol STRA6 Receptor as a Novel Binding Receptor for SARS-CoV-2 in COVID-19: In Silico Research.

BackgroundThe COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people causing over 2.4 million deaths over the world, and it is still expanding. Although, ACE2 has been identified as the principal host cell receptor of 2019-nCoV, and it is thought to play a critical role in the virus's entrance into the cell and subsequent infection, many cells can be infected by COVID-19 while also expressing little or no ACE2. Unlike other viral infections, COVID-19 is characterized by widespread and severe systemic manifestations, immune dysregulation and multi-organ involvement. In addition, the range of serious inflammatory, neuropsychiatric and autoimmune diseases called post-COVID syndromes are now left behind as disease tables. This wide and diverse spectrum of diseases seen in COVID-19 cannot be explained by the mechanism of viral tropism mediated by ACE2 and TMPRSS2 receptors. It is possible that different receptor and signaling mechanisms that cannot be explained by the viral tropism mechanism play a role in the pathogenesis of acute systemic effects and chronic post-COVID syndromes in COVID-19. It was showed that COVID-19 infection leads to a loss of smell (anosmia) but the COVID-19 entry receptors, angiotensin-converting enzyme 2 (ACE2), is not expressed in the receptor of olfactory neurons, or its generation is limited to a minor fraction of these neurons. Moreover It was demonstrated that COVID-19 could infect lymphocyte through its ACE2 receptors, but numerous studies found that lymphocytes don't express ACE2 receptors or express it with a little, insufficient amount. It is clear from the information and findings presented and addressed in our article that COVID-19 not only binds to ACE2, but also to additional receptors, leading to more disease lethality and existence of covid-19 symptoms which remain unexplained. As a result, discovering and identifying these receptors could lead to the development of new treatments that could suppress COVID-19 and reduce its severity and pathogenicity. Herein, we insilico discovered that blocking of STRA6 by the SARS-CoV-2 spike protein could disrupt the retinoid signaling mechanism and leads to pathogenetic consequences through some other inflammatory pathways.MethodsThe STRA6 receptor protein were submitted to the server for functional interaction associated network between partners for the STRING (Research Online of Interacting Genes/Proteins Data Basis version 10.0)13 .Docking study of each Spike -ACE 2 and STRA6 receptor protein were carried out using HDOCK server (http://hdock.phys.hust.edu.cn/). The binding mode of Spike -ACE 2 and STRA6 receptor protein is retrieved form the PDB https://www.rcsb.org/ with accession number (7DMU , 5sy1)ResultsOur results showed that COVID-19 Spike protein exhibited a high binding affinity for human STRA6 and a low binding energy with it. The docking score of COVID-19 spike protein with STRA6( -354.68) kcal/mol was higher than the docking score of spike protein with ACE2 (-341.21 ) kcal/mol. Spike protein Receptor Binding Domain(RDB) of COVID-19 strongly and efficiently binds to STRA6 receptor, definitely to the RDB vital residues of RBP-binding motif located in STRA6 receptor. The docking of STRA6 target protein with spike viral protein revealed the involvement of the spike protein into the extracellular and membrane part of the STRA6 receptor and amino acids residues of STRA6 along with spike protein which make interactions and play an important role in formation of complexes. The corresponding distances about the residue contacts between proteins STRA6- Spike protein complex are documented here where the STRA6- Spike protein complexes binding site are the RDB of the CHOLESTEROL in STRA6 receptor which bind with interface residue( ARG 511A , VAL 512A THR 515A ALA 516A ASN 519A with interface residue degree (2.965 , 3.595 , 3.286 , 4.592 , and 4.235) representatively, also the ability of the spike to bind to RDB of the STRA 6 protein in the ILE 131C , MET 145C , HIS 86A with interface residue( 4.961 , 4.953 and 3.271) representatively. STRA6- Spike protein complex with PDB ID (5SY1 , 6LZG).ConclusionsSTRA6 is a critical regulator of many biological processes thorough initiating cellular retinol uptake, in different organs and tissues as in immune cells for improving the immune system homeostasis in various populations. Our docking study reveals that COVID-19 spike protein binds directly to the integral membrane receptor (STRA6) in addition to its binding sites of the cholesterol. STRA6 mediates cellular uptake of retinol (vitamin A) by recognizing a molecule of RBP-retinol to trigger release and internalization of retinol . Therefore COVID-19 may leads to downregulation of STRA6 receptor leading to inhibition the regulatory function of retinoic acid and cholesterol helping in existing symptoms and complications including lymhopenia, Nuerogical disorders, Ineffective RIG-I pathway, Interferon inhibition, Cytokine storm, Diabetes, Hormonal imbalance, Thrombosis, and Smell loss. Therefore, we believe that this novel discovery that STRA6 receptor acts as a novel binding receptor for COVID-19 could explain COVID-19 severity and its common symptoms with unknown aetiology . Moreover, retinoic acid metabolism was found to be defective in COVID-19 (cytokine storm), sepsis, ARDS and SIRS .As a result reconstitution of the retinoid signaling may prove to be a valid strategy for COVID-19 management. We suggest that Vitamin A metabolites ,especially, retinoic acid will be promising and effective treatments for COVID-19 infection and its unknown aetiology symptoms. It worth mentioning that aerosolized all- trans retinoic acid and 13 cis retinoic acid is currently under clinical investigation (ClinicalTrials.gov Identifier: NCT05002530, NCT04353180)

Eosinophilic fasciitis (Shulman disease) with clinical, imaging and pathological correlation

Eosinophilic fasciitis (EF) is a rare subacute fibrosing disorder of unknown aetiology, characterised by thickening of the muscular fascia and subcutaneous tissue, leading to swelling of limbs and trunk and sparing fingers and toes. Eosinophilic infiltration and degranulation may prompt tissue damage and consequent fibrosis due to the accumulation of collagen and extracellular matrix proteins. MRI is the best imaging modality for diagnosis, depicting fascial thickening and enhancement. MRI may also have a significant role in excluding alternative diagnosis and guiding the skin–muscle biopsy.We report a case of EF with clinical and pathological correlation, highlighting the diagnostic value of MRI for early diagnosis and further treatment.

The position of geochemical variables as causal co-factors of diseases of unknown aetiology

The term diseases of unknown aetiology (DUA) or idiopathic diseases refers to diseases that are of uncertain or unknown cause or origin. Among plausible geoenvironmental (co-)factors in causation of DUA, this article focusses on the entry of trace elements, including metals and metalloids into biological systems, and their involvement in humoral and cellular immune responses, representing potentially toxic agents with implications as co-factors for certain DUA. Several trace elements/metals/metalloids (micronutrients) play vital roles as cofactors for essential enzymes and antioxidant molecules, thus, conferring protection against disease. However, inborn errors of trace element/metal/metalloid metabolisms can occur to produce toxicity, such as when there are basic defects in the element transport mechanism. Ultimately, it is the amount of trace element, metal or metalloid that is taken up, its mode of accumulation in human tissues, and related geomedical attributes such as the chemical form and bioavailability that decisively determine whether the exerted effects are toxic or beneficial. Several case descriptions of DUA that are common worldwide are given to illustrate our knowledge so far of how trace element/metal/metalloid interactions in the immune system may engender its dysregulation and be implicated as causal co-factors of DUA.

Molecular Mechanisms and Cellular Contribution from Lung Fibrosis to Lung Cancer Development

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease (ILD) of unknown aetiology, with a median survival of 2–4 years from the time of diagnosis. Although IPF has unknown aetiology by definition, there have been identified several risks factors increasing the probability of the onset and progression of the disease in IPF patients such as cigarette smoking and environmental risk factors associated with domestic and occupational exposure. Among them, cigarette smoking together with concomitant emphysema might predispose IPF patients to lung cancer (LC), mostly to non-small cell lung cancer (NSCLC), increasing the risk of lung cancer development. To this purpose, IPF and LC share several cellular and molecular processes driving the progression of both pathologies such as fibroblast transition proliferation and activation, endoplasmic reticulum stress, oxidative stress, and many genetic and epigenetic markers that predispose IPF patients to LC development. Nintedanib, a tyrosine–kinase inhibitor, was firstly developed as an anticancer drug and then recognized as an anti-fibrotic agent based on the common target molecular pathway. In this review our aim is to describe the updated studies on common cellular and molecular mechanisms between IPF and lung cancer, knowledge of which might help to find novel therapeutic targets for this disease combination.

Birth weight and diazoxide unresponsiveness strongly predict the likelihood of congenital hyperinsulinism due to a mutation in ABCC8 or KCNJ11

Objective Mutations in the KATP channel genes, ABCC8 and KCNJ11, are the most common cause of congenital hyperinsulinism. The diagnosis of KATP-hyperinsulinism is important for the clinical management of the condition. We aimed to determine the clinical features that help to identify KATP-hyperinsulinism at diagnosis. Design We studied 761 individuals with KATP-hyperinsulinism and 862 probands with hyperinsulinism of unknown aetiology diagnosed before 6 months of age. All were referred as part of routine clinical care. Methods We compared the clinical features of KATP-hyperinsulinism and unknown hyperinsulinism cases. We performed logistic regression and ROC analysis to identify the features that predict KATP-hyperinsulinism. Results Higher birth weight, diazoxide unresponsiveness and diagnosis in the first week of life were independently associated with KATP-hyperinsulinism (adjusted Odds Ratio 4.5 (95% CI, 3.4-5.9), 0.09 (0.06-0.13) and 3.3 (2.0- 5.0) respectively). Birth weight and diazoxide unresponsiveness were additive and highly discriminatory for identifying KATP-hyperinsulinism (ROC area under the curve for birth weight 0.80, diazoxide responsiveness 0.77, and together 0.88, 95% CI 0.85-0.90). 86% born large for gestation and 78% born appropriate for gestation who did not respond to diazoxide treatment had KATP-hyperinsulinism. In contrast, of those individuals born small for gestation, none who were diazoxide responsive and only 4% of those who were diazoxide unresponsive had KATP-hyperinsulinism. Conclusions Individuals with hyperinsulinism born appropriate or large for gestation and unresponsive to diazoxide treatment are most likely to have an ABCC8 or KCNJ11 mutation. These patients should be prioritised for genetic testing for KATP channel genes.