Evaluating Novel Protein Phosphatase 2A Activators as Therapeutics for Emphysema.

The activity of PP2A (protein phosphatase 2A), a serine-threonine phosphatase, is reduced by chronic cigarette smoke (SM) exposure and α-1 antitrypsin (AAT) deficiency, and chemical activation of PP2A reduces the loss of lung function in SM-exposed mice. However, the previously studied PP2A-activator tricyclic sulfonamide compound DBK-1154 has low stability to oxidative metabolism, resulting in fast clearance and low systemic exposure. Here we compare the utility of a new more stable PP2A activator, ATUX-792, versus DBK-1154 for the treatment of SM-induced emphysema. ATUX-792 was also tested in human bronchial epithelial cells and a mouse model of AAT deficiency, Serpina1a-e-knockout mice. Human bronchial epithelial cells were treated with ATUX-792 or DBK-1154, and cell viability, PP2A activity, and MAP (mitogen-activated protein) kinase phosphorylation status were examined. Wild-type mice received vehicle, DBK-1154, or ATUX-792 orally in the last 2 months of 4 months of SM exposure, and 8-month-old Serpina1a-e-knockout mice received ATUX-792 daily for 4 months. Forced oscillation and expiratory measurements and histology analysis were performed. Treatment with ATUX-792 or DBK-1154 resulted in PP2A activation, reduced MAP kinase phosphorylation, immune cell infiltration, reduced airspace enlargements, and preserved lung function. Using protein arrays and multiplex assays, PP2A activation was observed to reduce AAT-deficient and SM-induced release of CXCL5, CCL17, and CXCL16 into the airways, which coincided with reduced neutrophil lung infiltration. Our study indicates that suppression of the PP2A activity in two models of emphysema could be restored by next-generation PP2A activators to impact lung function.

The implications of Vitamin E acetate in E-cigarette, or vaping, product use-associated lung injury.

In the summer of 2019, a cluster of cases were observed with users of battery-operated or superheating devices presenting with multiple symptoms, such as dyspnea, cough, fever, constitutional symptoms, gastrointestinal upset, and hemoptysis, that is now termed e-cigarette, or vaping, product use-associated lung injury (EVALI). The Centers for Disease Control and Prevention reported 2807 cases within the USA leading to at least 68 deaths as of February 18, 2020. The heterogeneous presentations of EVALI make diagnosis and treatment difficult; however, treatment focused on identifying and removal of the noxious substance and providing supportive care. Vitamin E acetate (VEA) is a likely cause of this lung injury, and others have reported other components to play a possible role, such as nicotine and vegetable glycerin/propylene glycol. EVALI is usually observed in adolescents, with a history of vaping product usage within 90 days typically containing tetrahydrocannabinol, and presenting on chest radiograph with pulmonary infiltrates or computed tomography scan with ground-glass opacities. Diagnosis requires a high degree of suspicion to diagnose and exclusion of other possible causes of lung disease. Here, we review the current literature to detail the major factors contributing to EVALI and primarily discuss the potential role of VEA in EVALI. We will also briefly discuss other constituents other than just VEA, as a small number of EVALI cases are reported without the detection of VEA, but with the same clinical diagnosis.

Duplicated Inferior Vena Cava Thrombosis Mimicking Acute Pancreatitis in a COVID-19 Patient.

An 86-year-old woman with a recent hospitalization for severe coronavirus disease 2019 (COVID-19) infection presented to the emergency department with abdominal discomfort and bilateral leg swelling. She was mildly tachycardic on physical exam, with superficial abdominal vessel dilation and bilateral lower extremity edema. Her laboratory results were significant for a mildly elevated lipase of 260 U/L (normal range: 0-160 U/L) and a positive COVID-19 PCR test. CT of the abdomen and pelvis did not show any pancreatic abnormality but revealed a duplicated inferior vena cava (IVC) with a thrombus located in the right IVC. The patient was subsequently placed on full-dose anticoagulation with the eventual achievement of clot lysis. It appears that the incidence of thrombosis, including IVC thrombosis, has been on the rise due to COVID-19-associated coagulopathy; therefore, a high index of clinical suspicion in these cases may prove to be lifesaving.

Thrombotic Thrombocytopenic Purpura due to Varicella-Zoster Virus Meningoencephalitis in an Immunocompetent Patient.

Varicella-zoster virus (VZV) can cause variable disease states in individuals with intact and compromised immune systems. Both meningoencephalitis and thrombotic thrombocytopenic purpura (TTP) are uncommon, life-threatening entities associated with VZV. There are few reported cases of TTP due to VZV and this may be the first case of TTP due to VZV meningoencephalitis confirmed through lumbar puncture. The literature tends to emphasize that this pathology mostly occurs in immunocompromised hosts. Here, we present a unique case of TTP due to VZV meningoencephalitis in a patient that was immunocompetent.

Aftermath of Apixaban: Atypical Anticoagulation Aftereffect.

An elderly man with prostate cancer and a deep vein thrombosis (DVT) of the lower extremity diagnosed 12 days ago on apixaban presented with a new-onset palpable rash on both of his legs. Extensive laboratory workup was largely unremarkable, except for multiple skin punch biopsies revealing deposition of immunoglobulin A (IgA) in the superficial blood vessels with infiltration of leukocytes, concerning for a small vessel vasculitis. Given the temporal association along with the negative workup, the rash was attributed to apixaban, and the anticoagulation regimen was switched to dabigatran. At a 2-week follow-up visit, the patient was asymptomatic and tolerating dabigatran without any adverse events.

Multiple Hepatic Abscesses Secondary to Streptococcus anginosus Infection: A Case Report and Review of the Literature.

Hepatic abscesses are rare and generally present as solitary lesions in immunocompromised patients. The development of multiple hepatic abscesses in an immunocompetent patient is relatively uncommon. We report a rare case of a 73-year-old woman who presented with fever and right upper quadrant abdominal tenderness. Laboratory findings were significant for leukocytosis, transaminitis, and elevated inflammatory markers. Peripheral blood culture grew Streptococcus anginosus. Computed tomography of the abdomen and pelvis (CT A/P) revealed multiple hypoattenuating ill-defined cystic lesions in the liver consistent with abscesses formation; this was confirmed by magnetic resonance cholangiopancreatography (MRCP). The patient underwent appropriate treatment with antibiotics. Upon a three-week follow-up, the patient's symptoms subsided, and her laboratory parameters normalized. Although Streptococcus anginosus is a normal gastrointestinal flora, it has the potential to form abscesses. Our report indicates the importance of considering Streptococcus anginosus in the differential diagnosis. Management includes four to six weeks of antibiotic therapy together with drainage of larger abscesses.

Autoimmune Encephalopathy Associated With Anti-thyroid Antibodies: A Case Report.

Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), also known as Hashimoto encephalopathy (HE), is a rare condition. HE is characterized by abnormal brain function associated with elevated titers of anti-thyroid peroxidase (anti-TPO) and/or anti-thyroglobulin (anti-Tg) antibodies. We present a case of a 19-year-old female with rapidly progressing psychosis with mutism, catalepsy, echopraxia, and catatonia that developed over the course of three months. She was found to have high-level anti-thyroid antibodies raising suspicion of subclinical autoimmune thyroiditis and positive antinuclear antibodies. Imaging of the brain revealed generalized cerebral atrophy abnormal for her age. The patient was aggressively treated with corticosteroids and immunomodulators and her symptoms were greatly improved. This case emphasizes the significance of thyroid antibody measurement in patients presenting with psychiatric symptoms to evaluate patients for autoimmune encephalitis, since treatment with steroids and other immunosuppressive agents may be warranted.

Senescence: Pathogenic Driver in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is recognized as a disease of accelerated lung aging. Over the past two decades, mounting evidence suggests an accumulation of senescent cells within the lungs of patients with COPD that contributes to dysregulated tissue repair and the secretion of multiple inflammatory proteins, termed the senescence-associated secretory phenotype (SASP). Cellular senescence in COPD is linked to telomere dysfunction, DNA damage, and oxidative stress. This review gives an overview of the mechanistic contributions and pathologic consequences of cellular senescence in COPD and discusses potential therapeutic approaches targeting senescence-associated signaling in COPD.

A Rare Presentation of Tuberculosis-Related Septic Shock.

Septic shock with multi-organ dysfunction is an exceedingly rare, but known complication of untreated Mycobacterium tuberculosis (TB) infection. TB-associated cases of septic shock are predominantly reported in immunocompromised patients; however, it can manifest in a healthy individual if the infection is not treated. Through the interaction of lipoarabinomannan (LAM) on the mycobacterium cell wall with antigen-presenting cells, the bacteria may be able to survive in host cells for long periods of time. Without prompt treatment, TB may cause bronchiectasis and multi-organ failure. We report a case of a 24-year-old woman with untreated TB who developed widespread bronchiectasis and septic shock.

The Biology and Function of Tissue Inhibitor of Metalloproteinase 2 in the Lungs.

Tissue inhibitors of matrix metalloproteinases (TIMP) are a family of four endogenous proteins that primarily function to inhibit the activities of proteases such as the matrix metalloproteinases (MMP). Altered MMP/TIMP ratios are frequently observed in several human diseases. During aging and disease progression, the extracellular matrix (ECM) undergoes structural changes in which elastin and collagens serve an essential role. MMPs and TIMPs significantly influence the ECM. Classically, elevated levels of TIMPs are suggested to result in ECM accumulation leading to fibrosis, whereas loss of TIMP responses leads to enhanced matrix proteolysis. Here, we outline the known roles of the most abundant TIMP, TIMP2, in pulmonary diseases but also discuss future perspectives in TIMP2 research that could impact the lungs. TIMP2 directly inhibits MMPs, in particular MMP2, but TIMP2 is also required for the activation of MMP2 through its interaction with MMP14. The protease and antiprotease imbalance of MMPs and TIMPs are extensively studied in diseases but recent discoveries suggest that TIMPs, specifically, TIMP2 could play other roles in aging and inflammation processes.