Citations

The diaphragm muscle is essential for breathing, and its dysfunctions can be fatal. Many disorders affect the diaphragm, including muscular dystrophies. Despite the clinical relevance of targeting the diaphragm, there have been few studies evaluating diaphragm function following a given experimental treatment, with most of these involving anti-inflammatory drugs or gene therapy. Cell-based therapeutic approaches have shown success promoting muscle regeneration in several mouse models of muscular dystrophy, but these have focused mainly on limb muscles. Here we show that transplantation of as few as 5000 satellite cells directly into the diaphragm results in consistent and robust myofiber engraftment in dystrophin- and fukutin-related protein-mutant dystrophic mice. Transplanted cells also seed the stem cell reservoir, as shown by the presence of donor-derived satellite cells. Force measurements showed enhanced diaphragm strength in engrafted muscles. These findings demonstrate the feasibility of cell transplantation to target the diseased diaphragm and improve its contractility.

Key Points In heme protein–mediated AKI (HP-AKI), a senescence phenotype promptly occurs, and increased expression of p16 Ink4a contributes to HP-AKI. Renal p16 Ink4a expression is induced by hemoglobin, myoglobin, and heme in vivo and in renal epithelial cells exposed to heme in vitro . Impairing the binding or degradation of heme by hemopexin deficiency or heme oxygenase-1 deficiency, respectively, further upregulates p16 Ink4a . Background Understanding the pathogenetic basis for AKI involves the study of ischemic and nephrotoxic models of AKI, the latter including heme protein–mediated AKI (HP-AKI). Recently, interest has grown regarding the role of senescence as a mechanism of kidney injury, including AKI. We examined whether senescence occurs in HP-AKI and potential inducers of and the role of a key driver of senescence, namely, p16 Ink4a , in HP-AKI. Methods The long-established murine glycerol model of HP-AKI was used, and indices of senescence were examined. To evaluate the interaction of heme and p16 Ink4a expression, murine models of genetic deficiency of hemopexin ( HPX ) and heme oxygenase-1 ( HO-1 ) were used. To determine the involvement of p16 Ink4a in HP-AKI, the population of p16 Ink4a -expressing cells was reduced using the INK-ATTAC model. Results Using multiple indices, a senescence phenotype appears in the kidney within hours after the induction of HP-AKI. This phenotype includes significant upregulation of p16 Ink4a . p16 Ink4a is upregulated in the kidney after the individual administration of myoglobin, hemoglobin, and heme, as well as in renal epithelial cells exposed to heme in vitro . Genetic deficiencies of HPX and HO-1 , which, independently, are expected to increase heme content in the kidney, exaggerate induction of p16 Ink4a in the kidney and exacerbate HP-AKI, the latter shown in the present studies involving HPX −/− mice and in previous studies involving HO-1 −/− mice. Finally, reduction in the population of p16 Ink4a -expressing cells in the kidney improves renal function in HP-AKI even within 24 hours. Conclusions The pathogenesis of HP-AKI involves senescence and the induction of p16 Ink4a , the latter driven, in part, by hemoglobin, myoglobin, and heme.

AbstractLinear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disorder impacting children and adults. In this single‐center retrospective chart review of pediatric patients with LABD at a large tertiary referral center, we report the unifying and unique clinical features of 10 pediatric patients. Patients typically presented with the “cluster of jewels” sign (n = 6; 60%), mucous membrane involvement (n = 5; 50%) and had a mean disease duration of 38 months; six patients (60%) required inpatient admission for management of their skin disease, including all five patients who had mucous membrane involvement. Our findings suggest that pediatric LABD may be a disease with high morbidity and may be associated with severe complications when mucous membranes are involved.

Abstract Aims Graft dysfunction (GD) after heart transplantation (HTx) can develop without evidence of cell- or antibody-mediated rejection. Cardiac magnetic resonance imaging (CMR) has an evolving role in detecting rejection; however, its role in biopsy-negative GD has not been described. This study examines CMR findings, evaluates outcomes based on CMR results, and seeks to identify the possibility of rejection missed through endomyocardial biopsy by using CMR in HTx recipients with biopsy-negative GD. Methods and results HTx recipients with GD [defined as a decrease in left ventricular ejection fraction (LVEF) by >5% and LVEF < 50%] in the absence of rejection by biopsy or allograft vasculopathy and who underwent CMR were included in the study. The primary outcome was a composite of all-cause mortality, re-transplantation, or persistent LVEF < 50%. Overall, 34 HTx recipients developed biopsy-negative GD and underwent CMR. Left ventricular late gadolinium enhancement (LGE) on CMR was observed in 16 patients with two distinct patterns: diffuse epicardial (n = 13) and patchy (n = 3) patterns. Patients with LGE developed GD later after HTx [4 (1.4–6.8) vs. 0.8 (0.3–1.2) years, P < 0.001], were more often symptomatic (88% vs. 56%, P = 0.06), and had greater haemodynamic derangement (pulmonary capillary wedge pressure: 19 ± 7 vs. 13 ± 3 mmHg, P = 0.002) as compared with those without LGE. No significant difference was observed in the primary composite outcome between patients with LGE and those without LGE (50% vs. 38% of patients with events, P = 0.515). During a median follow-up of 3.8 years, mean LVEF improved similarly in the LGE-negative (37–55%) and LGE-positive groups (32–55%) (P = 0.16). Conclusions Biopsy-negative GD occurs with and without LGE when assessed by CMR, indicative of possible rejection/inflammation occurring only in a subset of patients. Irrespective of LGE, LVEF improvement occurs in most GD patients, suggesting that other neurohormonal or immunomodulatory mechanisms may also contribute to GD development.

Abstract A 78-year-old man receiving bicalutamide for prostate cancer was referred for a PSMA PET/CT scan to evaluate his gradually rising prostate-specific antigen level. The PSMA PET/CT revealed gynecomastia with radiotracer uptake in bilateral breast parenchyma, a known but rarely reported effect of bicalutamide monotherapy. This scan also demonstrated metastatic progression of his disease in bone and lymph nodes, and he was started on leuprolide injections. Three months after a decrease in his testosterone level, the radiotracer uptake in his breast tissue had resolved, demonstrating that PSMA-avid bicalutamide-induced gynecomastia is reversible.

Innovations in cardiac imaging have fundamentally advanced the understanding and treatment of cardiovascular disease. These advances in noninvasive cardiac imaging have also expanded the role of the cardiac imager and dramatically increased the demand for imagers who are cross-trained in multiple modalities. However, we hypothesize that there is significant variation in the availability of cardiac imaging expertise and a disparity in the adoption of advanced imaging technologies across the United States. To evaluate this, we have brought together the leaders of cardiovascular imaging societies, imaging trainees, as well as collaborated with national imaging accreditation commissions and imaging certification boards to assess the state of cardiac imaging and the diversity of the imaging workforce in the United States. Aggregate data confirm the presence of critical gaps, such as limited access to imaging and imaging expertise in rural communities, as well as disparities in the imaging workforce, notably among women and underrepresented minorities. Based on these results, we have proposed solutions to promote and maintain a robust and diverse community of cardiac imagers and improve equity and accessibility for cardiac imaging technologies.

Objectives To characterise the prevalence of impostor phenomenon (IP; tendency for high‐achieving individuals to perceive themselves as fraudulent in their successes) amongst attending staff in urology, to identify variables that predict more severe impostorism, and to study the association of IP with burnout. Subjects and Methods A survey composed of the Clance Impostor Phenomenon Scale (CIPS), demographic information, practice details, and burnout levels was e‐mailed to urologists via urological subspecialty societies. Survey results were analysed to identify associations between IP severity, survey respondent characteristics, and symptoms of professional burnout. This study was conducted in the United States of America. Results A total of 614 survey responses were received (response rate 11.0%). In all, 40% ( n = 213) of responders reported CIPS scores qualifying as either ‘frequent’ or ‘intense’ impostorism (i.e., scores of 61–100). On multivariable analysis, female gender, fewer years in practice (i.e., 0–2 years), and lower academic rank were all independently associated with higher CIPS scores (adjusted P < 0.05). Regarding burnout, 46% of responders reported burnout symptoms. On multivariable analysis, increase in CIPS score was independently associated with higher odds of burnout (odds ratio 1.06, 95% confidence interval 1.04–1.07; P < 0.001). Conclusion Impostor phenomenon is prevalent in the urological community and is experienced more severely in younger and female urologists. IP is also independently associated with burnout. Increased female representation may improve IP amongst our female colleagues. More work is needed to determine strategies that are effective in mitigating feelings of IP and professional burnout amongst urologists, particularly those earlier in their careers.