Citations

AbstractWe performed a retrospective review of outcomes after heart transplantation during long‐term follow‐up of a surgical cohort of 1138 Fontan patients who were followed at the Mayo Clinic. Follow‐up information was obtained from medical records and a clinical questionnaire that was mailed to patients not known to be deceased at the initiation of the study. Forty‐four of 1138 Fontan patients with initial or subsequent evaluation at Mayo had cardiac transplantation between 1988 and 2014 (mean age at transplantation was 23.2 ± 12 yr, median was 19.8 yr; mean interval between Fontan and transplantation was 13.0 ± 7.7 yr, median was 13.1 yr). Two patients had combined organ transplantation (one heart–lung, one heart–liver). Twelve of the 44 (27%) patients had PLE prior to transplantation. There was no difference in post‐bypass Fontan pressures or incidence of late reoperations for AVV repair/replacement between transplanted and non‐transplanted patients. There were 16 (36%) deaths in the transplantation cohort; seven occurred within 30 days of transplantation. Overall one, five, 10, and 15 yr post‐transplantation survival was 80%, 72%, 69%, and 55%, respectively. Although this is a challenging group of patients, intermediate‐term results suggest that cardiac transplantation remains a reasonable option for patients with a failed Fontan circulation.

Key pointsThe gastrointestinal epithelial enterochromaffin (EC) cell synthesizes the vast majority of the body's serotonin. As a specialized mechanosensor, the EC cell releases this serotonin in response to mechanical forces. However, the molecular mechanism of EC cell mechanotransduction is unknown.In the present study, we show, for the first time, that the mechanosensitive ion channel Piezo2 is specifically expressed by the human and mouse EC cells.Activation of Piezo2 by mechanical forces results in a characteristic ionic current, the release of serotonin and stimulation of gastrointestinal secretion.Piezo2 inhibition by drugs or molecular knockdown decreases mechanosensitive currents, serotonin release and downstream physiological effects.The results of the present study suggest that the mechanosensitive ion channel Piezo2 is specifically expressed by the EC cells of the human and mouse small bowel and that it is important for EC cell mechanotransduction.AbstractThe enterochromaffin (EC) cell in the gastrointestinal (GI) epithelium is the source of nearly all systemic serotonin (5‐hydroxytryptamine; 5‐HT), which is an important neurotransmitter and endocrine, autocrine and paracrine hormone. The EC cell is a specialized mechanosensor, and it is well known that it releases 5‐HT in response to mechanical forces. However, the EC cell mechanotransduction mechanism is unknown. The present study aimed to determine whether Piezo2 is involved in EC cell mechanosensation. Piezo2 mRNA was expressed in human jejunum and mouse mucosa from all segments of the small bowel. Piezo2 immunoreactivity localized specifically within EC cells of human and mouse small bowel epithelium. The EC cell model released 5‐HT in response to stretch, and had Piezo2 mRNA and protein, as well as a mechanically‐sensitive inward non‐selective cation current characteristic of Piezo2. Both inward currents and 5‐HT release were inhibited by Piezo2 small interfering RNA and antagonists (Gd3+and D‐GsMTx4). Jejunum mucosal pressure increased 5‐HT release and short‐circuit current via submucosal 5‐HT3 and 5‐HT4 receptors. Pressure‐induced secretion was inhibited by the mechanosensitive ion channel antagonists gadolinium, ruthenium red and D‐GsMTx4. We conclude that the EC cells in the human and mouse small bowel GI epithelium selectively express the mechanosensitive ion channel Piezo2, and also that activation of Piezo2 by force leads to inward currents, 5‐HT release and an increase in mucosal secretion. Therefore, Piezo2 is critical to EC cell mechanosensitivity and downstream physiological effects.

Objectives: There is no evidence regarding the effect of ondansetron on the QT interval in pediatric patients in the ICU. This study aimed to describe the effect of ondansetron on the corrected QT interval in patients cared for in the PICU. Design: Retrospective cohort, consecutive enrollment study. Setting: Single-center, tertiary-level, medical/surgical PICU. Patients: All patients less than 8 years old who received ondansetron over an 11-month period were included. Exclusion criteria were atrial arrhythmia, bundle-branch block, known congenital long QT syndrome, and concomitant administration of proarrhythmic antiarrhythmic agents. Interventions: None. Measurements and Main Results: Overall, 210 doses of ondansetron were administered to 107 patients, with a mean age 10.5 ± 4.8 years; 49% were men. Corrected QT interval increased to 460–500 ms in 29% and to more than 500 ms in 11% of events of ondansetron administration. The mean baseline corrected QT interval even before ondansetron administration was higher for these groups (460–500 and > 500 ms; 457 ± 33 and 469 ± 45, respectively; p ≤ 0.05). In multivariate analysis, both groups were associated significantly with underlying electrolyte abnormalities (odds ratio, 2.2; 95% CI, 1.1–4.4 and odds ratio, 5.1; 95% CI, 1.8–15.7, respectively); the group with corrected QT interval more than 500 ms was also significantly associated with organ dysfunction (odds ratio, 3.2; 95% CI, 1.1–9.4). As the numbers of risk factors increased from only ondansetron to three additional QT aggravating factors (electrolyte abnormalities, administration of other QT-prolonging drugs, and organ dysfunction), the likelihood of being associated with corrected QT interval more than 500 ms increased. Conclusions: Prolonged QT interval is observed commonly in PICUs following the administration of ondansetron. Underlying risk factors, such as electrolyte abnormalities and organ dysfunction, seem to pose the highest risk of prolongation of QT interval in these patients. The awareness of prevalent risk factors for increased corrected QT interval may help identify patients at high risk for arrhythmias.

Abstract: Primary cutaneous sweat gland carcinomas (SGCs) are rare tumors that commonly involve axillae, have a high local recurrence rate, and rarely show sarcomatoid transformation. A 68-year-old man presented with rapid enlargement of a previously stable, asymptomatic pea-sized nodule in the left axilla. Initial excision (with positive surgical margins) at another institution showed characteristic histologic features of a high-grade osteosarcoma and molecular analysis using a 92-gene real-time quantitative reverse transcription–polymerase chain reaction assay confirmed a diagnosis of osteosarcoma with 96% certainty. Notably, the molecular assay demonstrated consistently high relative expression of pannexin 3 (PANX3), a gene involved in normal osteoblast differentiation which, when highly expressed, strongly predicts osteosarcoma per the assay's algorithm. However, on further histologic review, the tumor also contained focal cystic areas, nests, and ducts composed of malignant epithelial cells reminiscent of SGC; these areas directly transitioned into the osteosarcomatous component and were strongly positive for pancytokeratin, CK7, and p63. Within 2 weeks, the lesion recurred and grew rapidly, prompting complete resection, histologic sections of which showed high-grade osteosarcoma without residual epithelial elements. This is the fifth report, to our knowledge, of osteosarcomatous transformation in a SGC, and the only report to date including molecular data. This case demonstrates that osteosarcoma arising from a SGC has a similar molecular profile to de novo primary osteosarcoma of bone. It also emphasizes the importance of histopathologic findings as the established diagnostic gold standard and the need to interpret molecular results within the clinical context.

Although mammography screening programs do not include ultrasound examinations, some diagnostic units do provide women with both mammography and ultrasonography. This article is concerned with estimating the risk of a breast cancer patient diagnosed in a hospital‐based mammography unit having a tumor that is visible on ultrasound but not on mammography. A total of 1,399 women with invasive breast cancer from a hospital‐based diagnostic mammography unit were included in this retrospective study. For inclusion, mammograms from the time of the primary diagnosis had to be available for computer‐assisted assessment of percentage mammographic density (PMD), as well as Breast Imaging Reporting and Data System (BIRADS) assessment of mammography. In addition, ultrasound findings were available for the complete cohort as part of routine diagnostic procedures, regardless of any patient or imaging characteristics. Logistic regression analyses were conducted to identify predictors of mammography failure, defined as BIRADS assessment 1 or 2. The probability that the visibility of a tumor might be masked at diagnosis was estimated using a regression model with the identified predictors. Tumors were only visible on ultrasound in 107 cases (7.6%). PMD was the strongest predictor for mammography failure, but age, body mass index and previous breast surgery also influenced the risk, independently of the PMD. Risk probabilities ranged from 1% for a defined low‐risk group up to 40% for a high‐risk group. These findings might help identify women who should be offered ultrasound examinations in addition to mammography.