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.
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.
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.
Highlights
Successful removal of gallstones are important to prevent the formation of gallstone abscess and infection.
An increase of reports of gallstone abscess formation shows the importance of awareness in the surgical community of the occurrence and proper treatment techniques.
Proper treatment techniques include abscess drainage either surgically or non-invasive and if possible laparoscopic repair of gallstone abscess.
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