Cigarette smoke alters calcium flux to induce PP2A membrane trafficking and endothelial cell permeability.

Alveolar capillary barrier disruption induces local edema and inflammation that impairs pulmonary function and promotes alveolar destruction in COPD. This study aimed to determine how cigarette smoke modulated the serine-threonine phosphatase protein phosphatase 2 A (PP2A) to alter the barrier function of human lung microvascular endothelial cells (HLMVECs). Cigarette smoke exposure lowered overall PP2A activity and enhanced endothelial permeability in HLMVECs.

Prediction of Donor Heart Acceptance for Transplant and Its Clinical Implications: Results From The Donor Heart Study.

Background: Despite a shortage of potential donors for heart transplant in the United States, most potential donor hearts are discarded. We evaluated predictors of donor heart acceptance in the United States and applied machine learning methods to improve prediction.

Methods: We included a nationwide (2005-2020) cohort of potential heart donors in the United States (n=73 948) from the Scientific Registry of Transplant Recipients and a more recent (2015-2020) rigorously phenotyped cohort of potential donors from DHS (Donor Heart Study; n=4130).

Vertebral Body Erosions After Glue Embolization of an Aortic Endograft Type II Endoleak: A Case Report.

Case: We present a case of a 66-year-old man with lumbar vertebral body erosions after glue embolization of a Type II endoleak secondary to endovascular repair of an infrarenal aortic aneurysm. Multiple biopsies of the affected vertebrae were culture-negative confirming no evidence of infection. He underwent posterior spinal fusion from L2 to L5 with complete resolution of mechanical low back pain and improved functional outcomes.

Extracellular glucose triggers metabolic reprogramming of cultured human bronchial epithelial cells and indirect fibroblast activation.

Glucose is essential for energy metabolism, and its usage can determine other cellular functions, depending on the cell type. In some pathological conditions, cells are exposed to high concentrations of glucose for extended periods. In this study, we investigated metabolic, oxidative stress, and cellular senescence pathways in human bronchial epithelial cells (HBECs) cultured in media with physiologically low (5 mm) and high (12.

Monocyte NLRP3 inflammasome and interleukin-1β activation modulated by alpha-1 antitrypsin therapy in deficient individuals.

Introduction: Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1β secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers.

Testing Alpha-1 Antitrypsin Deficiency in Black Populations.

Alpha-1 antitrypsin (AAT) deficiency (AATD) is an under-recognized hereditary disorder and a significant cause of chronic obstructive pulmonary disease (COPD), a disease that contributes to global mortality. AAT is encoded by the gene, and severe mutation variants of this gene increase the risk of developing COPD. AATD is more frequently screened for in non-Hispanic White populations.

Donor Electrocardiogram Associations With Cardiac Dysfunction, Heart Transplant Use, and Survival: The Donor Heart Study.

Background: Potential organ donors often exhibit abnormalities on electrocardiograms (ECGs) after brain death, but the physiological and prognostic significance of such abnormalities is unknown.

Objectives: This study sought to characterize the prevalence of ECG abnormalities in a nationwide cohort of potential cardiac donors and their associations with cardiac dysfunction, use for heart transplantation (HT), and recipient outcomes.

Methods: The Donor Heart Study enrolled 4,333 potential cardiac organ donors at 8 organ procurement organizations across the United States from 2015 to 2020.

Small-Molecule Activation of Protein Phosphatase 2A Counters Bleomycin-Induced Fibrosis in Mice.

The activity of protein phosphatase 2A (PP2A), a serine-threonine phosphatase, is reduced in the lung fibroblasts of idiopathic pulmonary fibrosis (IPF) patients. The objective of this study was to determine whether the reactivation of PP2A could reduce fibrosis and preserve the pulmonary function in a bleomycin (BLM) mouse model. Here, we present a new class of direct small-molecule PP2A activators, diarylmethyl-pyran-sulfonamide, exemplified by ATUX-1215.

Activation of mTOR signaling in adult lung microvascular progenitor cells accelerates lung aging.

Reactivation and dysregulation of the mTOR signaling pathway are a hallmark of aging and chronic lung disease; however, the impact on microvascular progenitor cells (MVPCs), capillary angiostasis, and tissue homeostasis is unknown. While the existence of an adult lung vascular progenitor has long been hypothesized, these studies show that Abcg2 enriches for a population of angiogenic tissue-resident MVPCs present in both adult mouse and human lungs using functional, lineage, and transcriptomic analyses. These studies link human and mouse MVPC-specific mTORC1 activation to decreased stemness, angiogenic potential, and disruption of p53 and Wnt pathways, with consequent loss of alveolar-capillary structure and function.

Primary results of the SAVAL randomized trial of a paclitaxel-eluting nitinol stent versus percutaneous transluminal angioplasty in infrapopliteal arteries.

Background: Effective and durable options for infrapopliteal artery revascularization for patients with chronic limb-threatening ischemia (CLTI) are limited.

Methods: The SAVAL trial is a prospective, multicenter, randomized trial of patients with CLTI and infrapopliteal artery lesions with total lesion length ⩽ 140 mm, stenosis ⩾ 70%, and Rutherford category 4-5 assigned 2:1 to treatment with the SAVAL self-expandable paclitaxel drug-eluting stent (DES) or percutaneous transluminal angioplasty (PTA) with an uncoated balloon. The primary effectiveness endpoint was primary vessel patency (i.

Type 1 diabetes contributes to combined pulmonary fibrosis and emphysema in male alpha 1 antitrypsin deficient mice.

Type 1 diabetes (T1D) is a metabolic disease characterized by hyperglycemia and can affect multiple organs, leading to life-threatening complications. Increased prevalence of pulmonary disease is observed in T1D patients, and diabetes is a leading cause of comorbidity in several lung pathologies. A deficiency of alpha-1 antitrypsin (AAT) can lead to the development of emphysema.

Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases.

New disease targets and medicinal chemistry approaches are urgently needed to develop novel therapeutic strategies for treating pulmonary diseases. Emerging evidence suggests that reduced activity of protein phosphatase 2A (PP2A), a complex heterotrimeric enzyme that regulates dephosphorylation of serine and threonine residues from many proteins, is observed in multiple pulmonary diseases, including lung cancer, smoke-induced chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency, asthma, and idiopathic pulmonary fibrosis. Loss of PP2A responses is linked to many mechanisms associated with disease progressions, such as senescence, proliferation, inflammation, corticosteroid resistance, enhanced protease responses, and mRNA stability.

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.

Left Ventricular Dysfunction Associated With Brain Death: Results From the Donor Heart Study.

Background: Left ventricular dysfunction in potential donors meeting brain death criteria often results in nonuse of donor hearts for transplantation, yet little is known about its incidence or pathophysiology. Resolving these unknowns was a primary aim of the DHS (Donor Heart Study), a multisite prospective cohort study.

Methods: The DHS enrolled potential donors by neurologic determination of death (n=4333) at 8 organ procurement organizations across the United States between February 2015 and May 2020.

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.

Virtual Interviews: A Cross-Sectional Quality Improvement Project Aimed to Improve the Interview Process in an Internal Medicine Residency Program.

Background: The residency interview is a crucial step that helps the program identify potential new trainees while the trainees find out more about the program. With the onset of the COVID-19 pandemic, it became essential to hold interviews virtually.

Objective: Here, we conducted a questionnaire-based study to identify areas of improvement in the virtual interview process in our program.

The Relationship of Cholesterol Responses to Mitochondrial Dysfunction and Lung Inflammation in Chronic Obstructive Pulmonary Disease.

Hyperlipidemia is frequently reported in chronic obstructive pulmonary disease (COPD) patients and is linked to the progression of the disease and its comorbidities. Hypercholesterolemia leads to cholesterol accumulation in many cell types, especially immune cells, and some recent studies suggest that cholesterol impacts lung epithelial cells' inflammatory responses and mitochondrial responses. Several studies also indicate that targeting cholesterol responses with either statins or liver X receptor (LXR) agonists may be plausible means of improving pulmonary outcomes.

Respiratory Immune Responses during Infection and Pollution Inhalation.

The COVID-19 pandemic highlighted the importance of lung immune responses to pathogens and environmental factors [...

Hypothermia or Machine Perfusion in Kidney Donors.

Background: Therapeutic hypothermia in brain-dead organ donors has been shown to reduce delayed graft function in kidney recipients after transplantation. Data are needed on the effect of hypothermia as compared with machine perfusion on outcomes after kidney transplantation.

Methods: At six organ-procurement facilities in the United States, we randomly assigned brain-dead kidney donors to undergo therapeutic hypothermia (hypothermia group), ex situ kidney hypothermic machine perfusion (machine-perfusion group), or both (combination-therapy group).

EoE behaves as a unique Th2 disease: a narrative review.

Background And Objective: To highlight and interpret two significant differences between eosinophilic esophagitis (EoE), a type 2 helper cell (Th2) disease, and three other representative Th2 diseases. EoE, asthma, atopic dermatitis (AD), chronic rhinosinusitis (CRS) and other Th2 diseases employ epithelial alarmins to recognize triggers, share a prototypical inflammatory cascade, and respond to glucocorticoids. However, EoE also has several distinguishing characteristics which may be explained by a distinct pathophysiologic mechanism.

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.

Socioecological model-based design and implementation principles of lower limb preservation programs as partners for limb-loss rehabilitation programs- A mini-review.

People with lower limb loss, especially of dysvascular etiology, are at substantial risk for both ipsilateral and contralateral reamputation. Additionally, while not as well documented for reamputation, there is recognition that amputation incidence is influenced by not only sociodemographic factors such as sex, race, socioeconomic status, but also by system factors such as service access. A systems strategy to address this disparity within the field of limb-loss rehabilitation is for Limb-loss Rehabilitation Programs (LRP) to partner with medical specialists, mental health professionals, and Limb Preservation Programs (LPP) to provide comprehensive limb care.

Hyperammonemic Encephalopathy Secondary to Urinary Tract Infection.

Hyperammonemic encephalopathy (HE) refers to a clinical condition characterized by abrupt alteration in mental status (AMS) with markedly elevated plasma ammonia levels and frequently results in intractable coma and death. While hepatic cirrhosis is by far the most common etiology for hyperammonemia together with drugs such as valproic acid as well as urea cycle disorders, non-hepatic causes of hyperammonemia are rare and pose a clinical challenge. In this report, we describe a case of HE caused by obstructive urinary tract infection due to urease-producing bacteria in a 69-year-old man with two episodes of obstructive uropathy associated with AMS resolving with treatment with antibiotics and lactulose with normalization of ammonia level.

Pediatric Eosinophilic Esophagitis: Searching for Serologic Markers.

Objective: Eosinophilic esophagitis (EoE) is a Th2 disease that presently is diagnosed and followed by clinical symptoms in the presence of endoscopic biopsies documenting elevated esophageal eosinophilia. To simplify clinical care, multiple studies have attempted to identify a disease specific serologic marker. None have been successful.