Childhood cardiomyopathies are progressive and often lethal disorders, forming the most common cause of heart failure in children. Despite severe outcomes, their genetic background is still poorly ...characterized.
The purpose of this study was to characterize the genetics of severe childhood cardiomyopathies in a countrywide cohort.
The authors collected a countrywide cohort, KidCMP, of 66 severe childhood cardiomyopathies from the sole center in Finland performing cardiac transplantation. For genetic diagnosis, next-generation sequencing and subsequent validation using genetic, cell biology, and computational approaches were used.
The KidCMP cohort presents remarkable early-onset and severe disorders: the median age of diagnosis was 0.33 years, and 17 patients underwent cardiac transplantation. The authors identified the pathogenic variants in 39% of patients: 46% de novo, 34% recessive, and 20% dominantly-inherited. The authors report NRAP underlying childhood dilated cardiomyopathy, as well as novel phenotypes for known heart disease genes. Some genetic diagnoses have immediate implications for treatment: CALM1 with life-threatening arrhythmias, and TAZ with good cardiac prognosis. The disease genes converge on metabolic causes (PRKAG2, MRPL44, AARS2, HADHB, DNAJC19, PPA2, TAZ, BAG3), MAPK pathways (HRAS, PTPN11, RAF1, TAB2), development (NEK8 and TBX20), calcium signaling (JPH2, CALM1, CACNA1C), and the sarcomeric contraction cycle (TNNC1, TNNI3, ACTC1, MYH7, NRAP).
Childhood cardiomyopathies are typically caused by rare, family-specific mutations, most commonly de novo, indicating that next-generation sequencing of trios is the approach of choice in their diagnosis. Genetic diagnoses may suggest intervention strategies and predict prognosis, offering valuable tools for prioritization of patients for transplantation versus conservative treatment.
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Background
In Henoch–Schönlein nephritis (HSN), a risk factor for unfavorable outcome is prolonged proteinuria, but the value of renal biopsies in prognosis assessment is debatable.
Methods
We ...evaluated serial renal biopsies from 26 HSN patients. Follow-up biopsy occurred at median 2.1 years after diagnostic biopsy. Patients formed two groups at the follow-up biopsy: patients without proteinuria (group I;
n
= 11) and with proteinuria (group II;
n
= 15). Biopsies underwent evaluation according to three classifications: International Study of Kidney Disease in Children (ISKDC), Oxford (MEST-C), and semiquantitative classification (SQC) including an activity and chronicity score. Analysis also included expression of pro-fibrotic (alpha-smooth muscle actin and vimentin) and inflammatory (P-selectin glycoprotein ligand-1) molecules in the diagnostic biopsy specimens. Definition of unfavorable outcome was active renal disease or reduced renal function at last follow-up.
Results
Between the biopsies, SQC chronicity score increased in 22 (85%) patients, whereas activity score and ISKDC grade decreased in 21 (81%) and 17 (65%), respectively. Of the MEST-C parameters, endocapillary proliferation (from 83 to 13%;
p
< 0.001) and crescents (from 63 to 25%;
p
= 0.022) showed significant reduction, and segmental glomerulosclerosis (from 38 to 79%;
p
= 0.006) significant increment. These changes occurred similarly in groups I and II. Expression of the pro-fibrotic and inflammatory molecules showed no clinically significant differences between groups I and II. None in group I and five (33%) patients in group II had unfavorable outcome (
p
= 0.053).
Conclusions
Our results suggest that follow-up biopsies provide limited additional information to clinical symptoms in HSN outcome prediction.
Biliary atresia (BA) is a chronic neonatal cholangiopathy characterized by fibroinflammatory bile duct damage. Reliable biomarkers for predicting native liver survival (NLS) following ...portoenterostomy (PE) surgery are lacking. Herein we explore the utility of 22 preidentified profibrotic molecules closely connected to ductular reaction (DR) and prevailing after successful PE (SPE), in predicting PE outcomes and liver injury. We used qPCR and immunohistochemistry in a BA cohort including liver samples obtained at PE (n = 53) and during postoperative follow-up after SPE (n = 25). Of the 13 genes over-expressed in relation to cholestatic age-matched controls at PE, only secretin receptor (SCTR) expression predicted cumulative 5-year NLS and clearance of jaundice. Patients in the highest SCTR expression tertile showed 34-55% lower NLS than other groups at 1-5 years after PE (P = 0.006-0.04 for each year). SCTR expression was also significantly lower 42 (24-63) vs 75 (39-107) fold, P = 0.015 among those who normalized their serum bilirubin after PE. Liver SCTR expression localized in cholangiocytes and correlated positively with liver fibrosis, DR, and transcriptional markers of fibrosis (ACTA2) and cholangiocytes (KRT7, KRT19) both at PE and after SPE. SCTR is a promising prognostic marker for PE outcomes and associates with liver injury in BA.
The aim of this study was to evaluate the long‐term effects of pediatric intestinal failure (IF) on liver histology. Altogether, 38 IF patients (median age: 7.2 years; range, 0.2‐27) underwent liver ...biopsy, gastroscopy, abdominal ultrasound, and laboratory tests. Sixteen patients were on parenteral nutrition (PN) after 74 PN months (range, 2.5‐204). Twenty‐two had weaned off PN 8.8 years (range, 0.3‐27) earlier, after 35 PN months (range, 0.7‐250). Fifteen transplant donor livers served as controls. Abnormal liver histology was found in 94% of patients on PN and 77% of patients weaned off PN (P = 0.370). During PN, liver histology weighted with cholestasis (38% of patients on PN versus 0% of patients weaned off PN; P = 0.003) and portal inflammation (38% versus 9%; P = 0.050) were found. Fibrosis (88% versus 64%; P = 0.143; Metavir stage: 1.6 range, 0‐4 versus 1.1 range, 0‐2; P = 0.089) and steatosis (50% versus 45%; P = 1.000) were equally common during and after weaning off PN. Plasma alanine aminotransferase (78 U/L range, 19‐204 versus 34 range, 9‐129; P = 0.009) and conjugated bilirubin (43 μmol/L range, 1‐215 versus 4 range, 1‐23; P = 0.037) were significantly higher during than after weaning off PN. Esophageal varices were encountered in 1 patient after weaning off PN. Metavir stage was associated with small bowel length (r = −0.486; P = 0.002) and number of septic episodes (r = 0.480; P = 0.002). In a multivariate analysis, age‐adjusted small bowel length (ß = −0.533; P = 0.001), portal inflammation (ß = 0.291; P = 0.030), and absence of an ileocecal valve (ß = 0.267; P = 0.048) were predictive for fibrosis stage. Conclusion: Despite resolution of cholestasis and portal inflammation, significant liver fibrosis and steatosis persist after weaning off PN. Extensive small intestinal resection was the major predictor for liver fibrosis stage. (Hepatology 2013;58:729–738)
Background & Aims The pathogenesis of intestinal failure (IF) associated liver disease (IFALD) is uncertain, we therefore investigated the role of FGF19 and pro-inflammatory cytokines has on this ...disease state. Methods Serum FGF19, IL-6 and, TNF-α were measured in 52 IF patients at median age 6.0 years (IQR 2.2–13) after 10 months (4.1–39) on parenteral nutrition (PN). Thirty-nine patients underwent liver biopsies. Results In IF patients, FGF19 concentrations were lower and those of IL-6 and TNF-α higher compared to healthy matched controls ( p ⩽0.001 for all). FGF19 concentrations were further decreased in patients without a remaining ileum 37 pg/ml (IQR 30–68) vs. 74 (35–135) p = 0.028, and correlated with remaining ileum length (r = 0.333, p = 0.018) and markers of cholesterol synthesis (r = −0.552 to −0.643, p <0.001). Patients with histological portal inflammation 30 pg/ml (28–45) vs. 48 (33–100), p = 0.019 or fibrosis 35 pg/ml (30–66) vs. 99 (38–163), p = 0.013 had lower serum FGF19 concentrations than others. FGF19 negatively correlated with portal inflammation grade (r = −0.442, p = 0.005), serum TNF-α (r = −0.318, p = 0.025), METAVIR fibrosis stage (r = −0.441, p = 0.005) and APRI (r = −0.328, p = 0.028). IL-6 was higher during PN 6 pg/ml (2–31) than after weaning off PN 2 pg/ml (1–5), p = 0.009, correlated weakly with cholestasis grade (r = 0.328, p = 0.044), and tended to associate with histological cholestasis n = 5, 5 pg/ml (5–267) vs. n = 34, 2 pg/ml (1–7), p = 0.058. Conclusions In pediatric onset of IF, total or partial loss of ileum decreases serum FGF19 concentration corresponding to hepatic inflammation and fibrosis, along with increased cholesterol synthesis. In contrast, serum IL-6 increases during PN and may associate with concurrent cholestasis. These data suggests that FGF19 may contribute to the pathogenesis of IFALD.
Abstract
Background
Primary tumors of the heart are a rare phenomenon. Lymphatic malformations are congenital anomalies of the lymphatic system that tend to grow progressively. Lymphatic ...malformations are typically found in the cervical and axillary regions and found on pediatric patients. We report a 40-year-old woman with giant epimyocardial lymphatic malformation.
Case presentation
A 40-year-old woman was assessed due to suspected traumatic cardiac tamponade. Computed tomography of the heart and cardiac magnetic resonance imaging were compatible with either a large pericardial hemangioma or angiosarcoma. The tumor infiltrated deeply into the myocardium and could only be partially resected. Histopathological diagnosis was a cardiac lymphatic malformation with micro- and macrocystic components. The patient has remained asymptomatic for fourteen years after the surgery. In the latest follow-up, her left ventricular function had remained normal and the maximum thickness of the residual tumor had regressed.
Conclusions
Even when a complete removal of a cardiac lymphatic malformation is not possible, a debulking procedure can yield a good long-term result.
Sporadic venous malformation (VM) and angiomatosis of soft tissue (AST) are benign, congenital vascular anomalies affecting venous vasculature. Depending on the size and location of the lesion, ...symptoms vary from motility disturbances to pain and disfigurement. Due to the high recurrence of the lesions, more effective therapies are needed.
As targeting stromal cells has been an emerging concept in anti-angiogenic therapies, here, by using VM/AST patient samples, RNA-sequencing, cell culture techniques, and a xenograft mouse model, we investigated the crosstalk of endothelial cells (EC) and fibroblasts and its effect on vascular lesion growth.
We report, for the first time, the expression and secretion of transforming growth factor A (TGFA) in ECs or intervascular stromal cells in AST and VM lesions. TGFA induced secretion of vascular endothelial growth factor (VEGF-A) in paracrine fashion, and regulated EC proliferation. Oncogenic
variant in p.H1047R, a common somatic mutation found in these lesions, increased TGFA expression, enrichment of hallmark hypoxia, and in a mouse xenograft model, lesion size, and vascularization. Treatment with afatinib, a pan-ErbB tyrosine-kinase inhibitor, decreased vascularization and lesion size in a mouse xenograft model with ECs expressing oncogenic
p.H1047R variant and fibroblasts.
Based on the data, we suggest that targeting of both intervascular stromal cells and ECs is a potential treatment strategy for vascular lesions having a fibrous component.
Academy of Finland, Ella and Georg Ehnrooth foundation, the ERC grants, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Jane and Aatos Erkko Foundation, GeneCellNano Flagship program, and Department of Musculoskeletal and Plastic Surgery, Helsinki University Hospital.
Background
Histological findings from primary kidney biopsies were correlated with patient outcomes in a national cohort of paediatric Henoch–Schönlein nephritis (HSN) patients.
Methods
Primary ...kidney biopsies from 53 HSN patients were re-evaluated using the ISKDC (International Study of Kidney Disease in Children) classification and a modified semiquantitative classification (SQC) that scores renal findings and also takes into account activity, chronicity and tubulointerstitial indices. The ISKDC and SQC classifications were evaluated comparatively in four outcome groups: no signs of renal disease (outcome A,
n
= 27), minor urinary abnormalities (outcome B,
n
= 18), active renal disease (outcome C,
n
= 3) and renal insufficiency, end-stage renal disease or succumbed due to HSN (outcome D,
n
= 5). For the receiver operating characteristic and logistic regression analyses, outcomes A and B were considered to be favourable and outcomes C and D to be unfavourable. The median follow-up time was 7.3 years.
Results
The patients with an unfavourable outcome (C and D), considered together due to low patient numbers, had significantly higher total biopsy SQC scores and activity indices than those who had a favourable one (groups A and B). The chronicity and tubulointerstitial indices differed significantly only between group C + D and group A. The difference in areas under the curve between the total biopsy SQC scores and ISKDC findings was 0.15
p
= 0.04, normal-based 95% confidence interval (CI) 0.007–0.29, bias-controlled 95% CI −0.004 to 0.28.
Conclusions
Our results suggest that the modified SQC is more sensitive than ISKDC classification for predicting the outcome in HSN cases.
Lymphatic invasion and accumulation of continuous collagen bundles around tumor cells are associated with poor melanoma prognosis, but the underlying mechanisms and molecular determinants have ...remained unclear. We show here that a copy-number gain or overexpression of the membrane-type matrix metalloproteinase MMP16 (MT3-MMP) is associated with poor clinical outcome, collagen bundle assembly around tumor cell nests, and lymphatic invasion. In cultured WM852 melanoma cells derived from human melanoma metastasis, silencing of MMP16 resulted in cell-surface accumulation of the MMP16 substrate MMP14 (MT1-MMP) as well as L1CAM cell adhesion molecule, identified here as a novel MMP16 substrate. When limiting the activities of these trans-membrane protein substrates toward pericellular collagen degradation, cell junction disassembly, and blood endothelial transmigration, MMP16 supported nodular-type growth of adhesive collagen-surrounded melanoma cell nests, coincidentally steering cell collectives into lymphatic vessels. These results uncover a novel mechanism in melanoma pathogenesis, whereby restricted collagen infiltration and limited mesenchymal invasion are unexpectedly associated with the properties of the most aggressive tumors, revealing MMP16 as a putative indicator of adverse melanoma prognosis.
Background Stillbirth often remains unexplained, mostly due to a lack of any postmortem examination or one that is incomplete and misinterpreted. Methods This retrospective cohort study was conducted ...at the Department of Obstetrics and Gynecology, Helsinki University Hospital, Finland, and comprised 214 antepartum singleton stillbirths from 2003 to 2015. Maternal and fetal characteristics and the results of the systematic postmortem examination protocol were collected from medical records. Causes of death were divided into 10 specific categories. Re-evaluation of the postmortem examination results followed. Results Based on our systematic protocol, the cause of death was originally defined and reported as such to parents in 133 (62.1%) cases. Re-evaluation of the postmortem examination results revealed the cause of death in an additional 43 (20.1%) cases, with only 23 (10.7%) cases remaining truly unexplained. The most common cause of stillbirth was placental insufficiency in 56 (26.2%) cases. A higher proportion of stillbirths that occurred at ≥39 gestational weeks remained unexplained compared to those that occurred earlier (24.1% vs. 8.6%) (P = 0.02). Conclusion A standardized postmortem examination and a re-evaluation of the results reduced the rate of unexplained stillbirth. Better knowledge of causes of death may have a major impact on the follow-up and outcome of subsequent pregnancies. Also, closer examination and better interpretation of postmortem findings is time-consuming but well worth the effort in order to provide better counseling for the grieving parents.
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