Citations

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

Abstract Chemotherapy has been reported to upregulate sphingomylinases and increase cellular ceramide, often linked to the induction to cell death. In this work, we show that sublethal doses of doxorubicin and vorinostat still increased cellular ceramide, which was located predominantly at the plasma membrane. To interrogate possible functions of this specific pool of ceramide, we used recombinant enzymes to mimic physiological levels of ceramide at the plasma membrane upon chemotherapy treatment. Using mass spectrometry and network analysis, followed by experimental confirmation, the results revealed that this pool of ceramide acutely regulates cell adhesion and cell migration pathways with weak connections to commonly established ceramide functions (eg, cell death). Neutral sphingomyelinase 2 (nSMase2) was identified as responsible for the generation of plasma membrane ceramide upon chemotherapy treatment, and both ceramide at the plasma membrane and nSMase2 were necessary and sufficient to mediate these “side” effects of chemotherapy on cell adhesion and migration. This is the first time a specific pool of ceramide is interrogated for acute signaling functions, and the results define plasma membrane ceramide as an acute signaling effector necessary and sufficient for regulation of cell adhesion and cell migration under chemotherapeutical stress.

Abstract Introduction: Pyogenic granuloma (PG) or granuloma pyogenicum is essentially a capillary hemangioma on the skin or a mucosal surface which shows an exophytic growth pattern and has a lobulated appearance. The most common sites are skin (40%) and mucosal surfaces (predominantly oral cavity, 60%). We intend to report all available cases of PG of gastrointestinal (GI) tract, diagnosed at the Henry Ford hospital, a tertiary referral center. Patients and Methods: A retrospective review of pathological database was performed on all GI biopsies in the last 10 years using diagnostic codes and pathology codes searching for PG of the GI tract. Results: A total of 23 cases of pathologically diagnosed PG was diagnosed over a 10 year period. The median age of patients was 64 with almost equal gender distribution (47.8% were males, and 52.2% were females). The most common location of PG was sigmoid colon (65.2%), esophagus (17.4%) and transverse colon (13%). PG presented as a polyp in 16 patients (69.6%). The most common indication for endoscopy in these cases was screening colonoscopy (30.4% cases). Discussion: PG of GI tract is rare. To date, only about 15–20 cases have been reported in the literature and most cases have been reported from Japan and Korea. This is the largest case series of this rare pathological lesion of the GI tract. Most cases of PG were diagnosed on an endoscopy done for an unrelated reason in our series. Hence, most cases were asymptomatic, unlike previously reported cases which were mostly associated with GI bleeding.

A retrospective study of 45 patients with symptoms of wrist pain and weakness with clinical evidence of instability is presented. These patients had normal intrinsic interosseous ligaments demonstrated arthrographically or surgically. They were followed for a minimum of 18 months and an average of 5.8 years. All patients demonstrated instability of the proximal carpal row which is referred to as carpal instability non-dissociative (CIND). Seven patients were treated non-operatively and 38 were treated operatively. Surgical management consisted of soft tissue reconstruction directed at the area of instability in 34 cases, joint levelling osteotomy in six, three of whom also had soft tissue reconstructions, and mid-carpal fusion in one. The overall good and excellent results were a disappointing 56% and there was no significant difference between the non-surgical and surgical groups. The best results were found in the ulna-minus CIND patients who underwent a joint levelling osteotomy, with 83% good and excellent results. CIND is associatedwith extrinsic ligamentous laxity; however, significant difficulty exists in locating the precise areas of maximum pathology. This accounts for the unpredictable results of treatment. As our understanding of the pathomechanics of CIND improves, the treatment will become more specific and the results should improve.