A Synthetic Peptide Corresponding to the Extracellular Loop 2 Region of Claudin-4 Protects against Clostridium perfringens Enterotoxin In Vitro and In Vivo

Clostridium perfringens enterotoxin (CPE) action starts when the toxin binds to claudin receptors. Claudins contain two extracellular loop domains, with the second loop (ECL-2) being slightly smaller than the first. CPE has been shown to bind to ECL-2 in receptor claudins. We recently demonstrated that Caco-2 cells (a naturally CPE-sensitive enterocyte-like cell line) can be protected from CPE-induced cytotoxicity by preincubating the enterotoxin with soluble full-length recombinant claudin-4 (_rclaudin-4), which is a CPE receptor, but not with recombinant nonreceptor claudins, such as _rclaudin-1. The current study evaluated whether a synthetic peptide corresponding to the claudin-4 ECL-2 sequence can similarly inhibit CPE action in vitro and in vivo. Significant protection of Caco-2 cells was also observed using either _rclaudin-4 or the claudin-4 ECL-2 peptide in both a preincubation assay and a coincubation assay. This inhibitory effect was specific, since _rclaudin-1 and a synthetic peptide based on the claudin-1 ECL-2 offered no protection to Caco-2 cells. However, the claudin-4 ECL-2 peptide was unable to neutralize cytotoxicity if CPE had already bound to Caco-2 cells. When the study was repeated in vivo using a rabbit small intestinal loop assay, preincubation or coincubation of CPE with the claudin-4 ECL-2 peptide significantly and specifically inhibited the development of CPE-induced luminal fluid accumulation and histologic lesions in rabbit small intestinal loops. No similar in vivo protection from CPE was afforded by the claudin-1 ECL-2 peptide. These results suggest that claudin-4 ECL-2 peptides should be further investigated for their potential therapeutic application against CPE-associated disease.     

Systematic screen for tyrosine kinase rearrangements identifies a novel C6orf204-PDGFRB fusion in a patient with recurrent T-ALL and an associated myeloproliferative neoplasm

Gene fusions involving the catalytic domain of tyrosine kinases (TKs) are found in a variety of hematological and solid tumor malignancies. Clinically, TK fusions have emerged as prime targets for therapy with small molecule kinase inhibitors. Unfortunately, identification of TK fusions has been hampered by experimental limitations. Here, we developed version 2.0 of a genomically based systematic kinase fusion screen and used it to detect a novel imatinib-sensitive C6orf204-PDGFRB fusion in a patient with precursor T lymphoblastic lymphoma (T-ALL) and an associated myeloproliferative neoplasm with eosinophilia. These data validate the ability of this targeted capture-sequencing approach to detect TK fusion events in small amounts of DNA extracted directly from patient samples.     

Measuring quality: one hospice's process

This article describes the recent modifications to the Medicare Conditions of Participation as they relate to hospice programs' quality requirements. The process used by one hospice program in the Washington Metropolitan Area to implement the National Hospice and Palliative Care Organizations Quality Partners Self-Assessment Surveys is explained. Baseline survey results were used to identify and prioritize areas for improvement related to the standards of hospice care.     

Gain in growth after surgical repair of congenital heart disease among children with Down syndrome

Down syndrome (DS) is a common genetic disorder among Saudi children, for which limited data is available on growth for those who undergo surgery for congenital heart disease (CHD). We assessed the magnitude of growth over time following surgery and the factors associated with growth change. Eighty-eight children with DS and CHD who underwent surgery between 2009 and 2017 at the tertiary children's hospital in Al-Qassim, Saudi Arabia, were eligible. Information on gender, height, and weight (at surgery, 6 and 12 months), age at surgery, and type of CHD were abstracted from the medical records. Repeated measure analysis of variance (ANOVA) was used for data analysis. The sample's mean age (SD) was 16.2 months (20.1); 47% were male. Height, weight, and body mass index (BMI) increased significantly at both follow-up points. There was a significant interaction between age at surgery, type of heart disease, and time for all three physical indices (p-values <0.001). The increase in height, weight, and BMI was significantly greater for children ≤8 months old with acyanotic CHD compared to children >8 months with cyanotic CHD. Overall, the gain in growth was greater for the children with DS who had had surgery at a younger age.