RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state

RNF43/ZNRF3 negatively regulate WNT signalling. Both genes are mutated in several types of cancers, however, their contribution to liver disease is unknown. Here we describe that hepatocyte-specific loss of Rnf43/Znrf3 results in steatohepatitis and in increase in unsaturated lipids, in the absence of dietary fat supplementation. Upon injury, Rnf43/Znrf3 deletion results in defective hepatocyte regeneration and liver cancer, caused by an imbalance between differentiation/proliferation. Using hepatocyte-, hepatoblast- and ductal cell-derived organoids we demonstrate that the differentiation defects and lipid alterations are, in part, cell-autonomous. Interestingly, ZNRF3 mutant liver cancer patients present poorer prognosis, altered hepatic lipid metabolism and steatohepatitis/NASH signatures. Our results imply that RNF43/ZNRF3 predispose to liver cancer by controlling the proliferative/differentiation and lipid metabolic state of hepatocytes. Both mechanisms combined facilitate the progression towards malignancy. Our findings might aid on the management of those RNF43/ZNRF3 mutated individuals at risk of developing fatty liver and/or liver cancer

Molecular profile and response to energy deficit of leptin-receptor neurons in the lateral hypothalamus

Leptin exerts its effects on energy balance by inhibiting food intake and increasing energy expenditure via leptin receptors in the hypothalamus. While LepR neurons in the arcuate nucleus of the hypothalamus, the primary target of leptin, have been extensively studied, LepR neurons in other hypothalamic nuclei remain understudied. LepR neurons in the lateral hypothalamus contribute to leptin's effects on food intake and reward, but due to the low abundance of this population it has been difficult to study their molecular profile and responses to energy deficit. We here explore the transcriptome of LepR neurons in the LH and their response to energy deficit. Male LepR-Cre mice were injected in the LH with an AAV carrying Cre-dependent L10:GFP. Few weeks later the hypothalami from fed and food-restricted (24-h) mice were dissected and the TRAP protocol was performed, for the isolation of translating mRNAs from LepR cells in the LH, followed by RNA sequencing. After mapping and normalization, differential expression analysis was performed with DESeq2. We confirm that the isolated mRNA is enriched in LepR transcripts and other known neuropeptide markers of LepRLH neurons, of which we investigate the localization patterns in the LH. We identified novel markers of LepRLH neurons with association to energy balance and metabolic disease, such as Acvr1c, Npy1r, Itgb1, and genes that are differentially regulated by food deprivation, such as Fam46a and Rrad. Our dataset provides a reliable and extensive resource of the molecular makeup of LH LepR neurons and their response to food deprivation

Late-onset postsurgical hypoparathyroidism following parathyroidectomy for recurrent primary hyperparathyroidism : a case report and literature review

Purpose: Previously in 1987, a 21-year-old-male was diagnosed with primary hyperparathyroidism (PHPT) when a right inferior parathyroid adenoma was removed. PHPT recurred after three and six years and on both occasions was cured by resection of parathyroid adenomas. At 52-years-of-age, the patient developed a late-onset hypoparathyroidism (HP), even though postsurgical HP typically occurs as a transient or permanent form soon after neck surgery. The purpose of this work was to report the follow-up of the patient and to review prior cases of late-onset postsurgical HP. Methods: Prior cases of late-onset postsurgical HP were searched and reviewed focusing on clinical and biochemical features. Results: The patient’s asymptomatic hypocalcemia with total serum calcium at 8.2 mg/dL was initially documented in September 2018; PTH was inappropriately low at 15 ng/mL. In February 2020, a mild hypocalcemia was confirmed with low-normal PTH at 15 ng/mL. Autoimmune and familial causes of HP were ruled out including the presence of stimulating autoantibodies against calcium-sensing receptor. Instead, a progressive damage or atrophy of the parathyroid gland(s) ensuing years after surgery is believed to have led to the patient’s hypocalcemia. All 19 previously reported cases of late-onset postsurgical HP occurred after thyroid surgery, with no examples of the condition being found following parathyroidectomy. Conclusions: The case highlights the rare occurrence of late-onset postsurgical HP in a patient who had had multiple parathyroidectomies for PHPT. Thus, monitoring serum calcium, phosphate and PTH during follow-up of such patients is recommended

Enantioseparation of chiral (benzylsulfinyl)benzamide sulfoxides by capillary electrophoresis using cyclodextrins as chiral selectors

Sulfur as a stereogenic center can be found in synthetic compounds and natural products. The current study evaluated the enantioseparation of 16 chiral (benzylsulfinyl)benzamide compounds by capillary electrophoresis using charged cyclodextrins (CDs) as chiral selectors in 50 mM sodium acetate buffer, pH 5.5. The sulfoxides varied in the type and position of the substituent of the benzyl moiety as well as the position and methylation of the amide group. Typically, randomly substituted CDs separated the majority of the model analytes in contrast to single isomer CDs. In case of random substitution, γ-CD derivatives displayed higher resolution ability toward the set of model compounds followed by β-CD and α-CD derivatives. Except for a few examples, the (+)-enantiomer of the analytes migrated before the (-)-isomer irrespective of the type of the CD so that the chiral recognition appeared to be also mostly independent on the structure of the sulfoxides. Evaluation of complexation constants and complex mobilities of selected CD-analyte pairs revealed that the separations were based on the stereoselective complexation by the CD expressed as complexation constants but examples for complex mobilities as the determining factor for the enantiomer migration order were also found. In case of 2-(4-bromobenzylsulfinyl)-N-methyl benzamide in the presence of heptakis(2,3-di-O-methyl-6-O-sulfo)-α-CD reversal of the enantiomer migration order as a function of the CD concentration was observed. Using neutral CD derivatives in the presence of sodium dodecyl sulfate-based micelles at pH 9.0 only few sulfoxides could be enantioseparated

Identification of Patients at high risk for postsurgical hypoparathyroidism

Background/Aim: Postsurgical hypoparathyroidism (PostHypo) is a common complication after total thyroidectomy. We studied the risk factors associated with PostHypo. Patients and Methods: The study included 109 women, (mean age: 50.7±10.75 years), who underwent total thyroidectomy for thyroid diseases. Results: Based on the development of biochemical hypocalcemia on the first postoperative day following total thyroidectomy, (cCa<8.4 mg/dl), 37 women developed PostHypo and 72 did not. Younger age, a lower preoperative corrected calcium and the presence of parathyroid glands in the specimens were related to the development of PostHypo. Of all patients, 51.4% had a vitamin D deficiency. A parathyroid hormone (PTH) value ≥9.4 pg/ml was 84.9% sensitive and 71.4% specific to predict PostHypo on the 1st postoperative day. A 50% reduction of the PTH value on the 1st postoperative day from the preoperative level could identify patients who develop PostHypo with 76% sensitivity and 75% specificity. Conclusion: PTH postoperative measurement and its alteration from the preoperative level can be used to identify patients who are at increased risk to develop PostHypo. © 2020 International Institute of Anticancer Research. All rights reserved

RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state.

RNF43/ZNRF3 negatively regulate WNT signalling. Both genes are mutated in several types of cancers, however, their contribution to liver disease is unknown. Here we describe that hepatocyte-specific loss of Rnf43/Znrf3 results in steatohepatitis and in increase in unsaturated lipids, in the absence of dietary fat supplementation. Upon injury, Rnf43/Znrf3 deletion results in defective hepatocyte regeneration and liver cancer, caused by an imbalance between differentiation/proliferation. Using hepatocyte-, hepatoblast- and ductal cell-derived organoids we demonstrate that the differentiation defects and lipid alterations are, in part, cell-autonomous. Interestingly, ZNRF3 mutant liver cancer patients present poorer prognosis, altered hepatic lipid metabolism and steatohepatitis/NASH signatures. Our results imply that RNF43/ZNRF3 predispose to liver cancer by controlling the proliferative/differentiation and lipid metabolic state of hepatocytes. Both mechanisms combined facilitate the progression towards malignancy. Our findings might aid on the management of those RNF43/ZNRF3 mutated individuals at risk of developing fatty liver and/or liver cancer

A single center experience in pediatric cardiomyopathy. Risk factors, outcomes and the effect of levosimendan

Cardiomyopathies are the leading cause of heart failure (HF) in children with anatomically intact hearts. A retrospective data analysis of a tertiary cardiac surgery and cardiology center cohort was performed. Our objectives were to analyze demographic, clinical, echocardiographic and hemodynamic data of children with HF due to cardiomyopathy – myocarditis, identify risk factors predictive of outcome and evaluate the possible effect of levosimendan administration. A total of 75 patients were included in the study. Median follow up was 24.1 months [interquartile range (IQR) 8.3–85.9]. Forty nine patients (71%) presented with significant HF (stage III/IV), with dilated cardiomyopathy (DCM) being the predominant diagnosis (74%). Twenty five patients (36%) experienced adverse outcome (defined as the composite endpoint of deterioration, transplantation listing and death), 18 (26%) died and 19 (27%) fully recovered. Severe HF at presentation (stage III/IV), presence of fibrosis on endomyocardial biopsy, intubation during admission at presentation and NT-proBNP values were identified as risk factors for death. Sixteen patients received repeated 24-hour levosimendan infusions [median 12 infusions/patient (IQR 9-24)]. All received a loading dose but one. No hypotensive episodes were recorded during loading or the first 24-hour infusion. Levosimendan administration was associated with significant improvement of left ventricular fractional shortening (LVFS, p = .003) and significant reduction of NT-proBNP values (p = .033). No difference was detected in survival time (combined endpoint of death or transplantation) between patients who received levosimendan and those who did not (log-rank test p-value = .645). To conclude, the majority of children in our study presented with significant HF (stage III/IV) with DCM being the predominant diagnosis. During follow up 27% fully recovered while 26% died. Several factors were associated with death. Levosimendan infusions were safe to administrate and associated with improvement of LVFS and reduction of NT-proBNP values but no survival benefit. © 2020 Elsevier B.V

A single center experience in pediatric cardiomyopathy. Risk factors, outcomes and the effect of levosimendan

Cardiomyopathies are the leading cause of heart failure (HF) in children with anatomically intact hearts. A retrospective data analysis of a tertiary cardiac surgery and cardiology center cohort was performed. Our objectives were to analyze demographic, clinical, echocardiographic and hemodynamic data of children with HF due to cardiomyopathy – myocarditis, identify risk factors predictive of outcome and evaluate the possible effect of levosimendan administration. A total of 75 patients were included in the study. Median follow up was 24.1 months [interquartile range (IQR) 8.3–85.9]. Forty nine patients (71%) presented with significant HF (stage III/IV), with dilated cardiomyopathy (DCM) being the predominant diagnosis (74%). Twenty five patients (36%) experienced adverse outcome (defined as the composite endpoint of deterioration, transplantation listing and death), 18 (26%) died and 19 (27%) fully recovered. Severe HF at presentation (stage III/IV), presence of fibrosis on endomyocardial biopsy, intubation during admission at presentation and NT-proBNP values were identified as risk factors for death. Sixteen patients received repeated 24-hour levosimendan infusions [median 12 infusions/patient (IQR 9-24)]. All received a loading dose but one. No hypotensive episodes were recorded during loading or the first 24-hour infusion. Levosimendan administration was associated with significant improvement of left ventricular fractional shortening (LVFS, p = .003) and significant reduction of NT-proBNP values (p = .033). No difference was detected in survival time (combined endpoint of death or transplantation) between patients who received levosimendan and those who did not (log-rank test p-value = .645). To conclude, the majority of children in our study presented with significant HF (stage III/IV) with DCM being the predominant diagnosis. During follow up 27% fully recovered while 26% died. Several factors were associated with death. Levosimendan infusions were safe to administrate and associated with improvement of LVFS and reduction of NT-proBNP values but no survival benefit. © 2020 Elsevier B.V