Search

Resident tissue macrophages (RTMs) are differentiated immune cells that populate distinct niches and exert important tissue-supportive functions. RTM maintenance is thought to rely either on differentiation from monocytes or on RTM self-renewal. Here, we used a mouse model of inducible lung interstitial macrophage (IM) niche depletion and refilling to investigate the development of IMs in vivo. Using time-course single-cell RNA-sequencing analyses, bone marrow chimeras and gene targeting, we found that engrafted Ly6C+ classical monocytes proliferated locally in a Csf1 receptor-dependent manner before differentiating into IMs. The transition from monocyte proliferation toward IM subset specification was controlled by the transcription factor MafB, while c-Maf specifically regulated the identity of the CD206+ IM subset. Our data provide evidence that, in the mononuclear phagocyte system, the ability to proliferate is not merely restricted to myeloid progenitor cells and mature RTMs but is also a tightly regulated capability of monocytes developing into RTMs in vivo.

With the advent of the data age, the continuous improvement and widespread application of medical information systems have led to an exponential growth of biomedical data, such as medical imaging, electronic medical records, biometric tags, and clinical records that have potential and essential research value. However, medical research based on statistical methods is limited by the class and size of the research community, so it cannot effectively perform data mining for large-scale medical information. At the same time, supervised machine learning techniques can effectively solve this problem. Heart attack is one of the most common diseases and one of the leading causes of death, so finding a system that can accurately and reliably predict early diagnosis is an essential and influential step in treating such diseases. Researchers have used various data mining and machine learning techniques to analyze medical data, helping professionals predict heart disease. This paper presents various features related to heart disease, and the model is based on ensemble learning. The proposed system involves preprocessing data, selecting attributes, and then using logistic regression algorithms as meta-classifiers to build the ensemble learning model. Furthermore, using machine learning algorithms (Support Vector Machines, Decision Tree, Random Forest, Extreme Gradient Boosting) for prediction on the Framingham Heart Study dataset and compared with the proposed methodology. The results show that the feasibility and effectiveness of the proposed prediction method based on group learning provide accuracy for medical recommendations and better accuracy than the single traditional machine learning algorithm., С наступлением эпохи данных постоянное совершенствование и широкое применение медицинских информационных систем привели к экспоненциальному росту биомедицинских данных, таких как медицинская визуализация, электронные медицинские записи, биометрические метки и клинические записи, которые имеют потенциальную и существенную исследовательскую ценность. Однако медицинские исследования, основанные на статистических методах, ограничены классом и размером исследовательского сообщества, поэтому они не могут эффективно выполнять интеллектуальный анализ данных при крупномасштабной медицинской информации. В то же время методы машинного обучения с учителем могут эффективно решить эту проблему. Сердечный приступ является одним из наиболее распространенных заболеваний и одной из основных причин смерти, поэтому нахождение системы, которая может точно и надежно прогнозировать диагноз, является важным шагом в лечении таких заболеваний. Исследователи использовали различные методы интеллектуального анализа данных и машинного обучения для анализа медицинских данных, помогающие специалистам прогнозировать сердечные заболевания. В данной статье представлены различные особенности сердечных заболеваний, модель основана на ансамблевом обучении. Предлагаемая система включает предварительную обработку данных, выбор атрибутов, а затем использование алгоритмов логистической регрессии в качестве мета-классификаторов для построения модели ансамблевого обучения. Кроме того, использование алгоритмов машинного обучения (метод опорных векторов, дерево решений, случайный лес, экстремальный градиентный бустинг) для прогнозирования на основе набора данных Фремингемского исследования сердца и сравнение с предложенной методологией. Результаты показывают, что целесообразность и эффективность предлагаемого метода прогнозирования, основанного на групповом обучении, обеспечивают точность медицинских рекомендаций и более высокую точность по сравнению с единым традиционным алгоритмом машинного обучения., З настанням епохи даних постійне вдосконалення та широке застосування медичних інформаційних систем призвели до експоненціального зростання біомедичних даних, таких як медична візуалізація, електронні медичні записи, біометричні мітки та клінічні записи, які мають потенційну та суттєву дослідницьку цінність. Однак медичні дослідження, засновані на статистичних методах, обмежені класом і розміром дослідницької спільноти, тому вони не можуть ефективно виконувати інтелектуальний аналіз даних за великомасштабної медичної інформації. У той же час методи машинного навчання з учителем можуть ефективно вирішити цю проблему. Серцевий напад є одним з найбільш поширених захворювань і однією з основних причин смерті, тому знаходження системи, яка може точно і надійно прогнозувати діагноз, є важливим кроком в лікуванні таких захворювань. Дослідники використовували різні методи інтелектуального аналізу даних і машинного навчання для аналізу медичних даних, які допомагають фахівцям прогнозувати серцеві захворювання. У даній статті представлені різні особливості серцевих захворювань, модель заснована на ансамблевому навчанні. Запропонована система включає попередню обробку даних, вибір атрибутів і використання алгоритмів логістичної регресії як мета-класифікаторів для побудови моделі ансамблевого навчання. Крім того, використання алгоритмів машинного навчання (метод опорних векторів, дерево рішень, випадковий ліс, екстремальний градієнтний бустинг) для прогнозування на основі набору даних Фремінгемського дослідження серця і порівняння із запропонованою методологією. Результати показують, що доцільність і ефективність запропонованого методу прогнозування, заснованого на груповому навчанні, забезпечують точність медичних рекомендацій і більш високу точність в порівнянні з єдиним традиційним алгоритмом машинного навчання

Myotonia congenita is also known as Becker’s disease. It is a genetic disorder in which skeletal muscles are unable to relax quickly after voluntary movements. Symptoms may vary from person to person and may include muscle stiffness and weakness initiated by movement after rest. Myotonia congenita was first described by Thomsen in 1876 as a disorder of skeletal muscles. Patients suffer from muscle contractility and fatigue which occurs as a consequence of the mutation of the chloride channel gene on the 17th chromosome. These patients have a high risk of developing malignant hyperthermia during anesthesia, and call for full preparation to prevent and deal with this complication. Key words: Becker’s disease; Myotonia congenita; Anesthesia; Malignant hyperthermia Citation: Hasan SS. Anesthetic management of a patient with myotonia congenita. Anaesth. pain intensive care 2021;25(6):816–818 ; DOI: 10.35975/apic.v25i6.1712 Received: August 25, 2021, Reviewed: September 19, 2021, Accepted: October 03, 2021

Citation: Hasan SS. Introduction of briefing and debriefing system in operating theaters in Pakistan. Anaesth. pain intensive care 2021;25(2):129–131. DOI: 10.35975/apic.v25i2.1460

England has seen its worst days; past few months have been full of multiple challenges and hard struggle for the people of United Kingdom. No rules in the beginning of the current pandemic to few restrictions like social distancing and eventually implementation of a complete lockdown. To one’s surprise, the restrictions were not very strictly followed in the beginning. I have the vivid memories of the fear surrounding us all by the daily reports from Italy.

Past few weeks have been a challenging time for all the health care workers, especially those who are front liners and directly involved in the management of Corona patient during this pandemic time. As this is a new experience for all of us, hence one can feel the fear and uncertainty in the management of these patients. As intensive care physicians, what we are offering in our hospital at present is to review these patients on the Covid ward in a view to assess them for a need of ventilatory requirement. If they are in need of invasive ventilation then they are brought to a specific area in theatre for intubation and ventilation with all the necessary precautions and preparations. These patients are not currently offered any of the non invasive interventions which are normally offered to non-covid patients such as Nasal high flow oxygen, CPAP or BIPAP as these can be aerosol generating.

Mammalian lungs are organs exhibiting the cellular and spatial complexity required for gas exchange to support life. The respiratory epithelium internally lining the airways is susceptible to infections due to constant exposure to inhaled microbes. Biomedical research into respiratory bacterial infections in humans has been mostly carried out using small mammalian animal models or two-dimensional, submerged cultures of undifferentiated epithelial cells. These experimental model systems have considerable limitations due to host specificity of bacterial pathogens and lack of cellular and morphological complexity. This review describes the in vitro differentiated and polarized airway epithelial cells of human origin that are used as a model to study respiratory bacterial infections. Overall, these models recapitulate key aspects of the complexity observed in vivo and can help in elucidating the molecular details of disease processes observed during respiratory bacterial infections.

Myeloid phagocytes have evolved to rapidly recognize invading pathogens and clear them through opsonophagocytic killing. The adenylate cyclase toxin (CyaA) of Bordetella pertussis and the edema toxin (ET) of Bacillus anthracis are both calmodulin-activated toxins with adenylyl cyclase activity that invade host cells and massively increase the cellular concentrations of a key second messenger molecule, 3&rsquo, 5&rsquo, cyclic adenosine monophosphate (cAMP). However, the two toxins differ in the kinetics and mode of cell entry and generate different cAMP concentration gradients within the cell. While CyaA rapidly penetrates cells directly across their plasma membrane, the cellular entry of ET depends on receptor-mediated endocytosis and translocation of the enzymatic subunit across the endosomal membrane. We show that CyaA-generated membrane-proximal cAMP gradient strongly inhibits the activation and phosphorylation of Syk, Vav, and Pyk2, thus inhibiting opsonophagocytosis. By contrast, at similar overall cellular cAMP levels, the ET-generated perinuclear cAMP gradient poorly inhibits the activation and phosphorylation of these signaling proteins. Hence, differences in spatiotemporal distribution of cAMP produced by the two adenylyl cyclase toxins differentially affect the opsonophagocytic signaling in myeloid phagocytes.

I am writing in order to stress upon the correct and safe rate of propofol infusion in intensive care unit (ICU) as a high rate of infusion can easily be missed and can lead to serious consequences. Propofol infusion syndrome (PRIS) is a well-known entity, which has been reported in both children and adults and is related to its high rates. First death due to PRIS was reported in 1990. The term was originally coined in 1998 by Bray to describe the adverse effects with its use in pediatric population. Though the first case was reported in a child, it has now been increasingly reported in adult ICU patients too.

Since the current coronavirus pandemic still remains as an unsolved mystery in the field of medicine, and a lot many research studies are currently underway on different aspects of the disease and its management on all over the world, no definite treatment or management regimen has agreed upon yet for these patients. The same applies to the ventilation management in these patients. What we have been relying upon so far has largely emanated from the worst effected countries and their experience.

Difficult intubation can be a real challenge for any anesthesiologist. It is particularly hazardous and much more difficult to manage in an emergency situation. We present a case of a 72 years old male patient who was brought to ER with stridor and increasing shortness of breath. He was unstable hemodynamically on presentation, so was managed with adrenaline/salbutamol nebs, I/V fluids and intermittent boluses of vasopressors in the ER. ENT referral was also sought who tried a quick nasal scope, but couldn’t come to any conclusion. During neck examination they could feel a mass in the upper part of the neck and made a provisional diagnosis of a pharyngeal abscess. Portable chest x-ray was unremarkable and there was no time to do a CT neck to confirm the diagnosis due to the patient’s worsening condition. It was decided to rush the patient to OR for an awake fibre-optic intubation in the presence of ENT team in case if there was a need to do an emergency tracheostomy. The OR was prepared accordingly and the patient’s upper airway was sprayed and nebulized with lignocaine. A very small dose of remifentanil infusion was started for better tolerance of the procedure. Patient remained in an extremely critical condition with a systolic blood pressure 60-70 mmHg, despite of I/V fluids and metaraminol infusion. He also required intermittent boluses of 25 mics of adrenaline. There was no time for central venous access.

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, Bordetella pertussis , 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 B. pertussis 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). B. pertussis 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 Bordetella- infected airway epithelia.

Filamentous hemagglutinin (FHA) is an important adhesin of the whooping cough agent Bordetella pertussis and is contained in most acellular pertussis vaccines. Recently, FHA was proposed to exert an immunomodulatory activity through induction of tolerogenic IL-10 secretion from dendritic cells. We have re-evaluated the cytokine-inducing activity of FHA, placing specific emphasis on the role of the residual endotoxin contamination of FHA preparations. We show that endotoxin depletion did not affect the capacity of FHA to bind primary human monocyte-derived dendritic cells, while it abrogated the capacity of FHA to elicit TNF-α and IL-10 secretion and strongly reduced its capacity to trigger IL-6 production. The levels of cytokines induced by the different FHA preparations correlated with their residual contents of B. pertussis endotoxin. Moreover, FHA failed to trigger cytokine secretion in the presence of antibodies that block TLR2 and/or TLR4 signaling. The TLR2 signaling capacity appeared to be linked to the presence of endotoxin-associated components in FHA preparations and not to the FHA protein itself. These results show that the endotoxin-depleted FHA protein does not induce cytokine release from human dendritic cells.

Integrins are heterodimeric cell surface adhesion and signaling receptors that are essential for metazoan existence. Some integrins contain an I-domain that is a major ligand binding site. The ligands preferentially engage the active forms of the integrins and trigger signaling cascades that alter numerous cell functions. Here we found that the adenylate cyclase toxin (CyaA), a key virulence factor of the whooping cough agent Bordetella pertussis, preferentially binds an inactive form of the integrin complement receptor 3 (CR3), using a site outside of its I-domain. CyaA binding did not trigger downstream signaling of CR3 in human monocytes and CyaA-catalyzed elevation of cAMP effectively blocked CR3 signaling initiated by a natural ligand. This unprecedented type of integrin-ligand interaction distinguishes CyaA from all other known ligands of the I-domain-containing integrins and provides a mechanistic insight into the previously observed central role of CyaA in the pathogenesis of B. pertussis. DOI: http://dx.doi.org/10.7554/eLife.10766.001, eLife digest The outer surfaces of animal cells are coated with proteins, including many that are able to sense signals from the environment. The integrins are one such group of proteins. Particular ions or small molecules – collectively known as ligands – can bind to these proteins and activate cascades of signaling events inside the cell. An integrin called complement receptor 3 (CR3) resides on the surface of many immune cells. CR3 binds to molecules found on the surface of bacteria, and prompts the immune cell to engulf and destroy the bacteria. The ligands bind to a region of CR3 called the I-domain, and it is thought that this domain is only able to accept ligands once the integrin protein has adopted an active form. Bordetella pertussis – the bacterium that causes a disease called whooping cough – subverts the immune defenses of the host. B. pertussis produces a toxin known as adenylate cyclase toxin (CyaA) that binds to CR3 in order to penetrate the immune cell and stop immune responses from being activated. However, it is not clear how CyaA is able to bind to CR3 without activating the signaling cascades. Here, Osicka et al. used biochemical techniques to address this question. The experiments reveal that CyaA mostly binds to an inactive form of CR3 through a unique site outside of the I-domain. It enables the toxin to use the integrin without triggering an immune response. Furthermore, the experiments show how CyaA prevents ligand signaling via CR3 proteins to allow B. pertussis to shut down the host’s first line of defense against infection. Osicka et al.’s findings show how CyaA evades the host’s immune system and highlight the central role played by this toxin in B. pertussis infections. In the future, these findings could inform efforts to produce more effective vaccines against whooping cough. DOI: http://dx.doi.org/10.7554/eLife.10766.002

The interaction of Bordetella pertussis adenylate cyclase toxin (CyaA) with complement receptor 3 (CR3, CD11b/CD18) involves N-linked oligosaccharide chains. To investigate the relative importance of the individual N-glycans of CR3 for toxin activity, the asparagine residues of the consensus N-glycosylation sites of CR3 were substituted with glutamine residues that cannot be glycosylated. Examination of CR3 mutant variants and mass spectrometry analysis of the N-glycosylation pattern of CR3 revealed that N-glycans located in the C-terminal part of the CD11b subunit are involved in binding and cytotoxic activity of CyaA. We suggest that these N-glycans form a defined clustered saccharide patch that enables multivalent contact of CR3 with CyaA, enhancing both affinity and specificity of the integrin–toxin interaction.

The objective of this study was to investigate the ascarid infection in Asiatic lions using scat samples, based on microscopic analysis, PCR amplification of the ITS-2 region of ribosomal DNA and sequence analysis of the amplicons. Microscopic analysis indicated the presence of eggs of Toxascaris leonina in eleven of the sixteen scat samples analysed and in one of these eleven scats eggs of Toxocara cati were also detected. In five of the scats eggs were not detectable. The presence of T. leonina in all the infected samples was also confirmed by PCR amplification of the ITS-2 of ribosomal RNA gene and five of these also showed amplicons corresponding to T. cati, respectively. Toxocara canis infection was not observed in any of the scat samples. Nucleotide sequence analysis of the ITS-2 region indicated 97% to 99% similarity with T. leonina and T. cati, respectively. To our knowledge, this is the first molecular characterization of ascarid infection in captive Asiatic lions from a zoological garden of India. This study also indicates that Asiatic lions are more prone to infection either with T. leonina or T. cati and the parasite is not host specific.