There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

CA : A Cancer Journal for Clinicians

Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.

/pdf/cellular-and-molecular-mechanisms-of-fibrosis-48v3c6itoz.pdf

Cellular and molecular mechanisms of fibrosis.

Background Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been widely spread. We aim to investigate the clinical characteristic and allergy status of patients infected with SARS-CoV-2. Methods Electronic medical records including demographics, clinical manifestation, comorbidities, laboratory data, and radiological materials of 140 hospitalized COVID-19 patients, with confirmed result of SARS-CoV-2 viral infection, were extracted and analyzed. Results An approximately 1:1 ratio of male (50.7%) and female COVID-19 patients was found, with an overall median age of 57.0 years. All patients were community-acquired cases. Fever (91.7%), cough (75.0%), fatigue (75.0%), and gastrointestinal symptoms (39.6%) were the most common clinical manifestations, whereas hypertension (30.0%) and diabetes mellitus (12.1%) were the most common comorbidities. Drug hypersensitivity (11.4%) and urticaria (1.4%) were self-reported by several patients. Asthma or other allergic diseases were not reported by any of the patients. Chronic obstructive pulmonary disease (COPD, 1.4%) patients and current smokers (1.4%) were rare. Bilateral ground-glass or patchy opacity (89.6%) was the most common sign of radiological finding. Lymphopenia (75.4%) and eosinopenia (52.9%) were observed in most patients. Blood eosinophil counts correlate positively with lymphocyte counts in severe (r = .486, P Conclusion Detailed clinical investigation of 140 hospitalized COVID-19 cases suggests eosinopenia together with lymphopenia may be a potential indicator for diagnosis. Allergic diseases, asthma, and COPD are not risk factors for SARS-CoV-2 infection. Older age, high number of comorbidities, and more prominent laboratory abnormalities were associated with severe patients.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/all.14238

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China.

Executive Summary Introduction Methodology Used to Prepare the Guideline Epidemiology Incidence Etiology Major Epidemiologic Points Pathogenesis Major Points for Pathogenesis Modifiable Risk Factors Intubation and Mechanical Ventilation Aspiration, Body Position, and Enteral Feeding Modulation of Colonization: Oral Antiseptics and Antibiotics Stress Bleeding Prophylaxis, Transfusion, and Glucose Control Major Points and Recommendations for Modifiable Risk Factors Diagnostic Testing Major Points and Recommendations for Diagnosis Diagnostic Strategies and Approaches Clinical Strategy Bacteriologic Strategy Recommended Diagnostic Strategy Major Points and Recommendations for Comparing Diagnostic Strategies Antibiotic Treatment of Hospital-acquired Pneumonia General Approach Initial Empiric Antibiotic Therapy Appropriate Antibiotic Selection and Adequate Dosing Local Instillation and Aerosolized Antibiotics Combination versus Monotherapy Duration of Therapy Major Points and Recommendations for Optimal Antibiotic Therapy Specific Antibiotic Regimens Antibiotic Heterogeneity and Antibiotic Cycling Response to Therapy Modification of Empiric Antibiotic Regimens Defining the Normal Pattern of Resolution Reasons for Deterioration or Nonresolution Evaluation of the Nonresponding Patient Major Points and Recommendations for Assessing Response to Therapy Suggested Performance Indicators

Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia the official statement of the American Thoracic Society and the Infectious Disease Society of America (特集 救急診療ガイドライン) -- (海外のガイドライン)

Inhibition of mesenchymal stromal cells' chemotactic effect to ameliorate paraquat-induced pulmonary fibrosis.

Objective
Mitogen-activated protein kinases (MAPKs) are correlated with a more malignant phenotype in many cancers. This study was designed to evaluate the predictive value of the expression of MAPK phosphatase-1 (MKP-1) and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), as the key regulatory mechanism of the MAPKs, in lung squamous cell carcinoma (SCC).

/pdf/imbalanced-expression-of-mitogen-activated-protein-kinase-3vjrm6043p.pdf

Imbalanced expression of mitogen-activated protein kinase phosphatase-1 and phosphorylated extracellular signal-regulated kinases in lung squamous cell carcinoma

Background Airborne fine particulate matter (PM) can induce pulmonary inflammation which may adversely affect human health, but very few reports about its effect on the neonate rats are available. This study aimed to observe the potential impact and toxicity of fine PMs on the airway in neonate rats. Methods Pulmonary inflammation, cytotoxicity, histopathology, and antioxidants as well as oxidant products were assessed 24 hours after intratracheal instillation of fine PM consecutively for 3 days. Cytotoxicity of fine PM was measured in HEp-2 cells. Results Rats treated with high dose fine PM developed significant pulmonary inflammation characterized by neutrophil and macrophage infiltration. The inflammatory process was related to elevated level of TNF-α and prooxidant/antioxidant imbalance in the lung. Cytotoxicity studies performed in human epithelial cells indicated that high dose fine PM significantly reduced cell viability. Conclusion The study demonstrated acute exposure to fine PM induced airway inflammation as well as increased oxidative stress in addition to its direct toxic effect on airway epithelium cells.

Airborne fine particulate matter induced pulmonary inflammation as well as oxidative stress in neonate rats.

Continuous positive airway pressure (CPAP) is the standard treatment for obstructive sleep apnea syndrome (OSAS). However, the impact of CPAP on quality of life (QOL) is controversial. The aim of this study was to sys- tematically review and determine whether CPAP improves QOL in patients with OSAS. We performed a comprehensive literature search to identify studies published between 1966 and 2007comparing values of CPAP with control. Weighted mean difference (WMD) was used to analyze the data. The pooled WMD was calculated by using a fixed or random- effect model. The outcomes for 1,256 patients from 16 studies, of whom 656 patients underwent CPAP and 600 were controls, were included. CPAP led to significant improvements in the Nottingham health profile part 2 (WMD = 1.657; 95% CI = 3.005, -0.308; p = 0.016), but there was no difference in other general QOL scores. Patients undergoing CPAP scored better in physical function (WMD = 3.457; 95% CI = 0.144, 6.771; p = 0.041), body pain (WMD = 4.017; 95% CI =- 0.008, 8.042; p = 0.05), energy vitality (WMD = 6.984; 95% CI = 0.557, 13.411; p = 0.033) and physical component summary (PCS) (WMD = 2.040; 95% CI = 0.045, 4.035; p = 0.045) using the SF-36 tool. This meta-analysis shows that CPAP does not improve general QOL scores but does improve physical domains and vitality. Study design and QOL questionnaire tools are important to capture and evaluate information efficiently. However, generic QOL instruments may not be adequate in detecting important changes in quality of life in patients with OSAS.

Effect on Quality of Life of Continuous Positive Airway Pressure in Patients with Obstructive Sleep Apnea Syndrome

The MUS81 protein belongs to a conserved family of DNA structure-specific nucleases that play important roles in DNA replication and repair. Inactivation of the Mus81 gene in mice has no major deleterious consequences for embryonic development, although cancer susceptibility has been reported. We have investigated the role of MUS81 in human cells by acutely depleting the protein using shRNAs. We found that MUS81 depletion from human fibroblasts leads to accumulation of ssDNA and a constitutive DNA damage response that ultimately activates cellular senescence. Moreover, we show that MUS81 is required for efficient replication fork progression during an unperturbed S-phase, and for recovery of productive replication following replication stalling. These results demonstrate essential roles for the MUS81 nuclease in maintenance of replication fork integrity.

/pdf/acute-mus81-depletion-leads-to-replication-fork-slowing-and-prl42su4gu.pdf

Huahao Shen

Papers

Inhibition of mesenchymal stromal cells' chemotactic effect to ameliorate paraquat-induced pulmonary fibrosis.

Imbalanced expression of mitogen-activated protein kinase phosphatase-1 and phosphorylated extracellular signal-regulated kinases in lung squamous cell carcinoma

Airborne fine particulate matter induced pulmonary inflammation as well as oxidative stress in neonate rats.

Effect on Quality of Life of Continuous Positive Airway Pressure in Patients with Obstructive Sleep Apnea Syndrome

Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response.