mTor-inhibition within the first days after pediatric heart transplantation is a potentially safe option to prevent cardiac allograft vasculopathy.

BACKGROUND: Immunosuppression after heart transplantation (HTX) with mammalian target of rapamycin (mTOR) inhibitors serves as a prophylaxis against rejection and to treat coronary vascular injury. However, there is little data on the early, preventive use of everolimus after pediatric HTX. METHODS: Retrospective study of 61 pediatric HTX patients (48 cardiomyopathy and 13 congenital heart disease), 28 females, median age 10.1 (range 0.1-17.9) years transplanted between 2008 and 2020. We analyzed survival, rejection, renal function, occurrence of lymphoproliferative disorder, and allograft vasculopathy together with adverse effects of early everolimus therapy combined with low-dose calcineurin inhibitors. RESULTS: Everolimus therapy was started at a median 3.9 (1-14) days after HTX. Median follow-up was 4.3 (range 0.5-11.8) years, cumulative 184 patient years. The estimated 1- and 5-year survival probability was 89% (CI 82%:98%) and 87% (CI 78%:97%). Four patients developed rejection (6.6%) (maximum 2R ISHLT criteria). No patient suffered from chronic renal failure. Three patients (4.9%) developed post-transplant lymphoproliferative disorder. Five patients suffered relevant wound-healing disorders after transplantation, four of them carrying relevant risk factors before HTX (mechanical circulatory support (n = 3), delayed chest closure after HTX (n = 3)). No recipient developed cardiac allograft vasculopathy. CONCLUSION: Initiating everolimus within the first 14 days after HTX seems to be well tolerated, enabling a low incidence of rejection, post-transplant lymphoproliferative disorders, renal failure, and reveals no evidence of cardiac allograft vasculopathy as well as good overall survival in pediatric heart transplant recipients.

Risk factors for pancreatic ductal adenocarcinoma specifically stimulate pancreatic duct glands in mice.

Diabetes mellitus type 2 and chronic pancreatitis are regarded as risk factors for pancreatic cancer. Pancreatic duct glands (PDGs) were recently described as a new compartment of the major duct in humans and mice. To evaluate the influence of diabetes and chronic pancreatitis on PDGs, cerulein was injected i.p., repetitively over 10 weeks, in mice exhibiting obesity and a type 2 diabetes-like syndrome (B6.V-Lep(ob/ob)) and in lean littermates. By using 5-bromo-2'-deoxyuridine (BrdU), a label-retaining cell population was characterized in PDGs. Cerulein administration led to more BrdU(+) cells in PDGs of obese mice compared with lean mice. The observed increase was specific to PDGs, because BrdU incorporation in cells of the pancreatic duct was not increased. In addition, the expression of distinct tumor markers in PDGs was characterized by Muc5ac, S100P, regenerating islet-derived 3ß, 14-3-3 σ, and prostate stem cell antigen immunochemistry. Type 2 diabetes-like syndrome, accompanied by chronic pancreatitis, enhanced nuclear localization of S100P. Both risk factors for pancreatic cancer also induced the production of Muc5ac and the nuclear localization of S100P [corrected]. These results demonstrate that diabetes and chronic pancreatitis jointly enhance BrdU incorporation and production of pancreatic cancer-specific proteins in PDGs. The observed alterations suggest that pancreatic tumors might originate from the newly discovered histomorphological structures, called PDGs, which could represent a target for future anticancer therapies.

Epidemiology of paediatric chronic heart failure in Germany-A population-based analysis.

AIMS: Paediatric chronic heart failure (CHF) is associated with significant morbidity. The aim of this study was to describe paediatric CHF epidemiology in Germany. METHODS AND RESULTS: This is a retrospective cross-sectional analysis of anonymized healthcare claims data in the InGef database. This database includes longitudinal data from a representative sample of the German population of approximately 4.8 million insured members. We included individuals <18 years from 2016 to 2021. CHF was defined by ≥2 diagnoses in different quarters of the year as inpatient or outpatient, using ICD-10-GM codes I50.- or P29.0. The number of eligible children in the database was 674 462 in 2016 and 660 692 in 2021. Prevalence of CHF per 100 000 children was 20.6 [95% confidence interval (CI), 17.3-24.3] in 2016 and 19.4 (95% CI, 16.2 to 23.0) in 2021. Incidence per 100 000 children was 9.6 (95% CI, 7.4 to 12.3) in 2016 and 7.6 (95% CI, 5.6 to 10.0) in 2021 for newly diagnosed CHF. All-cause hospitalizations occurred in 47.3% to 57.7% of children with CHF per year. Up to 6.3% of children with CHF were hospitalized, coded primarily for heart failure. Mortality of children with CHF was <5 death per year in the studied population. In 128 children with CHF in 2021, the most common ICD-coded comorbidities were congenital malformations of cardiac septa (57.8%), atrial septal defect (44.5%), congenital malformations of the great arteries (43.0%) and ventricular septal defect (32.0%). Coded treatment modalities for paediatric CHF in 2021 included angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers (18.8%), beta-blockers (17.2%), mineralocorticoid receptor antagonists (14.8%) and surgical procedures (13.3%). CONCLUSIONS: This representative cohort study reveals a relatively high incidence proportion. Approximately half of the children with CHF are hospitalized annually while mortality is low.

Diabetes increases pancreatic fibrosis during chronic inflammation.

Diabetes and fibrosis can be concurrent processes in several diseases such as cystic fibrosis or chronic pancreatitis. To evaluate whether diabetes can influence fibrosis and thus aggravate the pathological process, the progression of chronic pancreatitis was assessed in diabetic and non diabetic mice. For this purpose, insulin producing beta-cells in C57Bl/6J mice were selectively impaired by administration of streptozotocin. Chronic pancreatitis was then induced by repetitive administration of cerulein in normoglycaemic and hyperglycaemic mice. Diabetes caused enhanced collagen I deposition within three weeks of the onset of chronic pancreatitis and increased the proliferation of interstitial cells. This was accompanied by an increased number of interlobular fibroblasts, which expressed S100A4 (fibroblast-specific protein-1) and stimulation of α-smooth muscle actin expression of pancreatic stellate cells. In addition, the observed aggravation of chronic pancreatitis by diabetes also led to a significantly enhanced atrophy of the pancreas, increased infiltration of inflammatory chloracetate esterase positive cells and enhanced acinar cell death. We conclude that diabetes has a detrimental influence on the progression of chronic pancreatitis by aggravating fibrosis, inflammation and pancreatic atrophy.