Premorbid weight in pulmonary arterial hypertension.

Relationships between obesity and outcomes in pulmonary arterial hypertension (PAH) are complex. Previous work suggested obesity, occurring alongside PAH, may be associated with better survival. In our work, we suggest obesity prior to PAH development is associated with worse survival. This may add a novel temporal element to the "obesity-paradox."

Regional Variation in Pulmonary Arterial Hypertension in the United States: The Pulmonary Hypertension Association Registry.

Rationale: Pulmonary arterial hypertension (PAH) is a heterogeneous disease within a complex diagnostic and treatment environment. Other complex heart and lung diseases have substantial regional variation in characteristics and outcomes; however, this has not been previously described in PAH. Objectives: To identify baseline differences between U.S. census regions in the characteristics and outcomes for participants in the Pulmonary Hypertension Association Registry (PHAR). Methods: Adults with PAH were divided into regional groups (Northeast, South, Midwest, and West), and baseline differences between census regions were presented. Kaplan-Meier survival analyses and Cox proportional hazards were used to estimate the association between region and mortality in unadjusted and adjusted models. Results: Substantial differences by census regions were seen in age, race, ethnicity, marital status, employment, insurance payor breakdown, active smoking, and current alcohol use. Differences were also seen in PAH etiology and baseline 6-minute walk distance test results. Treatment characteristics varied by census region, and mortality appeared to be lower in PHAR participants in the West (hazard ratio, 0.60; 95% confidence interval, 0.43-0.83, P = 0.005). This difference was not readily explained by differences in demographic characteristics, PAH etiology, baseline severity, baseline medication regimen, or disease prevalence. Conclusions: The present study suggests significant regional variation among participants at accredited pulmonary vascular disease centers in multiple baseline characteristics and mortality. This variation may have implications for clinical research planning and represent an important focus for further study to better understand whether there are remediable care aspects that can be addressed in the pursuit of providing equitable care in the United States.

A 44-Year-Old Man Presenting With Massive Hemoptysis and Dyspnea.

CASE PRESENTATION: A 44-year-old man presented to the ED with acute massive hemoptysis and hypoxia. His history was notable for 1 year of progressively worsening shortness of breath at both rest and with exertion. He denied chest discomfort and endorsed near syncope while driving in recent months. He recently had been treated with antibiotics for two episodes of presumed pneumonia, based on right lower lobe opacification on chest radiography.

Natural Killer Cell Phenotype and Functionality Affected by Exposure to Extracellular Survivin and Lymphoma-Derived Exosomes.

The inherent abilities of natural killer (NK) cells to recognize and kill target cells place them among the first cells with the ability to recognize and destroy infected or transformed cells. Cancer cells, however, have mechanisms by which they can inhibit the surveillance and cytotoxic abilities of NK cells with one believed mechanism for this: their ability to release exosomes. Exosomes are vesicles that are found in abundance in the tumor microenvironment that can modulate intercellular communication and thus enhance tumor malignancy. Recently, our lab has found cancer cell exosomes to contain the inhibitor of apoptosis (IAP) protein survivin to be associated with decreased immune response in lymphocytes and cellular death. The purpose of this study was to explore the effect of survivin and lymphoma-derived survivin-containing exosomes on the immune functions of NK cells. NK cells were obtained from the peripheral blood of healthy donors and treated with pure survivin protein or exosomes from two lymphoma cell lines, DLCL2 and FSCCL. RNA was isolated from NK cell samples for measurement by PCR, and intracellular flow cytometry was used to determine protein expression. Degranulation capacity, cytotoxicity, and natural killer group 2D receptor (NKG2D) levels were also assessed. Lymphoma exosomes were examined for size and protein content. This study established that these lymphoma exosomes contained survivin and FasL but were negative for MHC class I-related chains (MIC)/B (MICA/B) and TGF-ß. Treatment with exosomes did not significantly alter NK cell functionality, but extracellular survivin was seen to decrease natural killer group 2D receptor (NKG2D) levels and the intracellular protein levels of perforin, granzyme B, TNF-α, and IFN-γ.

Airway Sensory Nerve Density Is Increased in Chronic Cough.

Rationale: Chronic cough is characterized by frequent urges to cough and a heightened sensitivity to inhaled irritants. Airway sensory nerves trigger cough. We hypothesized that sensory nerve density is increased in chronic cough, which may contribute to excessive and persistent coughing.Objectives: To measure airway nerve density (axonal length) and complexity (nerve branching, neuropeptide expression) in humans with and without chronic cough.Methods: Bronchoscopic human airway biopsies were immunolabeled for nerves and the sensory neuropeptide substance P. Eosinophil peroxidase was also quantified given previous reports showing associations between eosinophils and nerve density. Three-dimensional image z-stacks of epithelium and subepithelium were generated using confocal microscopy, and from these z-stacks, total nerve length, the number of nerve branch points, substance P expression, and eosinophil peroxidase were quantified within each airway compartment.Measurements and Main Results: Nerve length and the number of branch points were significantly increased in epithelium, but not subepithelium, in chronic cough compared with healthy airways. Substance P expression was scarce and was similar in chronic cough and healthy airways. Nerve length and branching were not associated with eosinophil peroxidase nor with demographics such as age and sex in either group.Conclusions: Airway epithelial sensory nerve density is increased in chronic cough, suggesting sensory neuroplasticity contributes to cough hypersensitivity.

Going Skin Deep: Excavating a Diagnosis of Intravascular Large B Cell Lymphoma.

A fever of unknown origin is often pursued diagnostically under the framework of infectious, rheumatologic, and neoplastic causes. When encephalopathy ensues, the differential diagnosis narrows, but can remain elusive, particularly when dealing with rare diseases. We present the case of a patient with fever of unknown origin and intermittent encephalopathy that spanned multiple hospital admissions and ultimately yielded a diagnosis of intravascular large B cell lymphoma complicated by hemophagocytic lymphohistiocytosis. We review the varying presentations of this disease, when to consider this as a diagnosis, and how to most accurately make the diagnosis.

Uptake of lymphoma-derived exosomes by peripheral blood leukocytes.

Exosomes are nanosized lipid vesicles secreted into blood and other body fluids and serve as vehicles for intercellular communication. Despite being an important component of the tumor microenvironment (TME), exosomal targeting and uptake into recipient cells are still not fully understood. Few studies have looked at lymphoma exosomes and their interactions with circulating blood cells. In this study, we examine the exosomal uptake distribution among peripheral blood leukocytes (PBLs) using vesicles derived from a diffuse large B cell lymphoma cell line, WSU-DLCL2. Lymphoma cells survive, proliferate, and are protected from the cytotoxic effects of chemotherapeutic agents by soluble factors or by direct contact with inflammatory and stromal cells within the TME. In an attempt to close the gap in knowledge concerning lymphoma TME immunosuppression, we have treated normal human PBLs with PKH67-labeled lymphoma exosomes and monitored the uptake by measuring fluorescence at different time points using flow cytometry and fluorescent microscopy. Our results show that of the four populations examined, B cells and monocytes demonstrated uptake of PKH67-labeled exosomes, while T cells and NK cells displayed significantly less uptake.