Membrane bending and sphingomyelinase-associated, sulfatide-dependent hypoxic adhesion of sickle mature erythrocytes.

Abnormal erythrocyte adhesion owing to polymerization of sickle hemoglobin is central to the pathophysiology of sickle cell disease (SCD). Mature erythrocytes constitute >80% of all erythrocytes in SCD; however, the relative contributions of erythrocytes to acute and chronic vasculopathy in SCD are not well understood. Here, we showed that bending stress exerted on the erythrocyte plasma membrane by polymerization of sickle hemoglobin under hypoxia, enhances sulfatide-mediated abnormal mature erythrocyte adhesion. We hypothesized that sphingomyelinase (SMase) activity, which is upregulated by accumulated bending energy, leads to elevated membrane sulfatide availability, and thus, hypoxic mature erythrocyte adhesion. We found that mature erythrocyte adhesion to laminin in controlled microfluidic experiments is significantly greater under hypoxia than under normoxia (1856 ± 481 vs 78 ± 23, mean ± SEM), whereas sickle reticulocyte (early erythrocyte) adhesion, high to begin with, does not change (1281 ± 299 vs 1258 ± 328, mean ± SEM). We showed that greater mean accumulated bending energy of adhered mature erythrocytes was associated with higher acid SMase activity and increased mature erythrocyte adhesion (P = .022, for acid SMase activity and P = .002 for the increase in mature erythrocyte adhesion with hypoxia, N = 5). In addition, hypoxia results in sulfatide exposure of the erythrocyte membrane, and an increase in SMase, whereas anti-sulfatide inhibits enhanced adhesion of erythrocytes. These results suggest that the lipid components of the plasma membrane contribute to SCD complications. Therefore, sulfatide and the components of its upregulation pathway, particularly SMase, should be further explored as potential therapeutic targets for inhibiting sickle erythrocyte adhesion.

Technologist-Based Implementation of Total Metabolic Tumor Volume into Clinical Practice.

Metabolic tumor volume (MTV) is defined as the total metabolically active tumor volume seen on 18F-FDG PET/CT examinations. Calculating MTV is often time-consuming, requiring a high degree of manual input. In this study, the MTV calculations of a board-certified nuclear radiologist were compared with those of 2 nuclear medicine technologists. As part of the technologists' educational program, after their classroom time they were trained by the radiologist for 30 min. The technologists calculated MTV within 7.5% of the radiologist's calculations in a set of patients who had diffuse large B-cell lymphoma and were undergoing initial staging 18F-FDG PET/CT. These findings suggest that nuclear medicine technologists may help accelerate implementation of MTV into clinical practice with favorable accuracy, possibly as an initial step followed by validation by the interpreting physician. The aim of this study was to explore whether efficiency is improved by integrating nuclear medicine technologists into a semiautomated workflow to calculate total MTV.

Successful removal of a Life-threatening PE using the INARI flow triever device.

The authors report a case of a 75-year-old male with pulmonary embolism (PE) successfully treated using the INARI FlowTriever System, a mechanical thrombectomy device. Imaging confirmed deep vein thrombosis and PE presented after two days of left lower extremity (LLE) pain and dyspnea on exertion with history of peripheral vascular disease, coronary artery disease, insulin dependent diabetes mellitus, hyperlipidemia and LLE percutaneous coronary intervention with coronary stent placement. PE treatment with single session clot burden reduction resulted in immediate improvement in oxygenation and echocardiogram confirmed relief of right heart strain. The patient's immediate hemodynamic improvement without thrombolytic therapy, which can take hours for morbidity reduction, supports the expansion of the use of thrombectomy devices for the treatment of submassive symptomatic PE in clinical practice, with further research indicated.

Small cell neuroendocrine carcinoma presenting as inguinal hernia: A case report.

INTRODUCTION: One of the most common surgical procedures performed annually is inguinal hernia repair. Inguinal hernias are traditionally known to be caused by a weakening in the abdominal wall and precipitated by increased intraabdominal pressure. Recently, intra-abdominal cancer producing the increased intraabdominal pressure, along with metastasis directly into the inguinal canal, have been identified in more studies as causes of inguinal hernias. PRESENTATION OF CASE: This case focuses on a unique presentation of small-cell neuroendocrine carcinoma presenting as an inguinal hernia. DISCUSSION: This patient's rapid demise and advanced metastatic disease upon presentation is alarming, but his advanced disease process presenting as a routine inguinal hernia is noteworthy. Upon literature analysis, the number of advanced disease processes - most notably cancer - presenting as hernias is significant. CONCLUSION: This case emphasis the importance of perioperative screening, and presents the question, should hernias indicate further workup in the appropriate, at-risk patient populations.

Successful removal of an acute deep vein thrombosis by the INARI ClotTriever system.

Pulmonary embolism is most feared sequela of a proximal deep vein thrombosis (DVT). Currently, first-line DVT treatment is anticoagulation to prevent post-thrombotic sequelae like pedal edema as well as a life threatening pulmonary embolism . Advanced therapy considerations for limb- or life-threatening DVT include catheter-directed thrombolysis and thrombectomy. Thrombectomy is necessary when thrombolytics are contraindicated secondary to increased bleeding risk. The authors present a DVT case treated with the mechanical thrombectomy device, ClotTriever (Inari Medical, Irvine, CA), resulting in the efficient and effective removal of thrombus with near-complete resolution of venous symptoms and prompt hospital discharge.

Red blood cell adhesion to ICAM-1 is mediated by fibrinogen and is associated with right-to-left shunts in sickle cell disease.

Sickle cell disease (SCD), which afflicts 100 000 Americans, as well as millions worldwide, is associated with anemia, lifelong morbidity, and early mortality. Abnormal adhesion of sickle red blood cells (RBCs) to activated vascular endothelium may contribute acutely to the initiation of painful vaso-occlusive crises and chronically to endothelial damage in SCD. Sickle RBCs adhere to activated endothelium through several adhesion mechanisms. In this study, using whole blood from 17 people with heterozygous SCD (HbS variant) and 55 people with homozygous SCD (HbSS) analyzed in an in vitro microfluidic assay, we present evidence for the adhesion of sickle RBCs to immobilized recombinant intercellular adhesion molecule 1 (ICAM-1). We show that sickle RBC adhesion to ICAM-1 in vitro is associated with evidence of hemolysis in vivo, marked by elevated lactate dehydrogenase levels, reticulocytosis, and lower fetal hemoglobin levels. Further, RBC adhesion to ICAM-1 correlates with a history of intracardiac or intrapulmonary right-to-left shunts. Studies of potential ICAM-1 ligands on RBC membranes revealed that RBC-ICAM-1 interactions were mediated by fibrinogen bound to the RBC membrane. We describe, for the first time, RBC rolling behavior on ICAM-1 under high shear rates. Our results suggest that firm adhesion of sickle RBCs to ICAM-1 most likely occurs in postcapillary venules at low physiological shear rates, which is facilitated by initial rolling in high shear regions (eg, capillaries). Inhibition of RBC and ICAM-1 interactions may constitute a novel therapeutic target in SCD.

A case report: Delayed gallstone abscess formation 10 years post-cholecystectomy.

INTRODUCTION: Retained gallstones post-cholecystectomy act as a nidus for abscess formation. It is unusual for intraabdominal abscesses to remain asymptomatic due to its propensity to cause inflammation and irritation to the peritoneum. PRESENTATION OF CASE: A 73-year-old female presented with acute onset of right-sided abdominal pain and fever. Her past surgical history was significant for a cholecystectomy in 2010, hysterectomy, and partial nephrectomy. She was diagnosed with an intraabdominal abscess secondary to a retained gallstone post-cholecystectomy. She underwent laparoscopic surgery to drain and remove the abscess. The patient's abdominal pain improved, remains afebrile, and is passing stool regularly. DISCUSSION: Gallbladder perforation is common and is dependent on the integrity of the gallbladder and surrounding structures. It is unusual for an intra-abdominal abscess to develop so late following gallstone spillage. This example brings to light the potential long-term sequelae of gallbladder perforation and future complications. CONCLUSION: This case highlights the importance of irrigation of the peritoneal cavity and retrieval any spilled gallstones during surgery in the event of gallbladder perforation.

Priapism, hemoglobin desaturation, and red blood cell adhesion in men with sickle cell anemia.

Priapism is a serious, but episodic, complication of sickle cell disease (SCD). We had previously reported that subjects with SCD had variable red blood cell (RBC) adhesion to the immobilized sub-endothelial protein laminin (LN). We examined adhesion to LN in a microfluidic device, of RBCs from men with homozygous sickle cell anemia. Adhesion under hypoxic, but not ambient, conditions was greater in men with a history of priapism, with median adhesion of 529 RBCs per 32 mm2/unit area (range 5-5248) rising to 3268 RBCs per 32 mm2/unit area (range 49-18,368, P = 0.004), under ambient and hypoxic conditions, respectively (n = 14). This was not seen in RBCs from men without a history of priapism (median 402 (range 14-785) and 122 (range 31-4112) RBCs per 32 mm2/unit area, ambient and hypoxic conditions, respectively (P = N.S., N = 12)). We also observed an association between hypoxia-enhanced RBC adhesion in vitro and a history of hemoglobin desaturation in vivo independent of priapism. Prolonged Hb desaturation may increase sickle polymer formation and RBC damage, resulting in enhanced RBC adhesion, hemolysis, and endothelial dysfunction. The identification of distinct RBC phenotypes could prompt clinical evaluation for suitability for novel or under-used therapies, like oxygen.

Evidence for GALNT12 as a moderate penetrance gene for colorectal cancer.

Characterizing moderate penetrance susceptibility genes is an emerging frontier in colorectal cancer (CRC) research. GALNT12 is a strong candidate CRC-susceptibility gene given previous linkage and association studies, and inactivating somatic and germline alleles in CRC patients. Previously, we found rare segregating germline GALNT12 variants in a clinic-based cohort (N = 118) with predisposition for CRC. Here, we screened a new population-based cohort of incident CRC cases (N = 479) for rare (MAF ≤1%) deleterious germline GALNT12 variants. GALNT12 screening revealed eight rare variants. Two variants were previously described (p.Asp303Asn, p.Arg297Trp), and additionally, we found six other rare variants: five missense (p.His101Gln, p.Ile142Thr, p.Glu239Gln, p.Thr286Met, p.Val290Phe) and one putative splice-altering variant (c.732-8 G>T). Sequencing of population-matched controls (N = 400) revealed higher burden of these variants in CRC cases compared with healthy controls (P = 0.0381). We then functionally characterized the impact of substitutions on GALNT12 enzyme activity using in vitro-derived peptide substrates. Three of the newly identified GALNT12 missense variants (p.His101Gln, p.Ile142Thr, p.Val290Phe) demonstrated a marked loss (>2-fold reduction) of enzymatic activity compared with wild-type (P ≤ 0.05), whereas p.Glu239Gln exhibited a ∼2-fold reduction in activity (P = 0.077). These findings provide strong, independent evidence for the association of GALNT12 defects with CRC-susceptibility; underscoring implications for glycosylation pathway defects in CRC.