Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis.

Hepatic steatosis is a highly prevalent liver disease, yet research is hampered by the lack of tractable cellular and animal models. Steatosis also occurs in cats, where it can cause severe hepatic failure. Previous studies demonstrate the potential of liver organoids for modeling genetic diseases. To examine the possibility of using organoids to model steatosis, we established a long-term feline liver organoid culture with adult liver stem cell characteristics and differentiation potential toward hepatocyte-like cells. Next, organoids from mouse, human, dog, and cat liver were provided with fatty acids. Lipid accumulation was observed in all organoids and interestingly, feline liver organoids accumulated more lipid droplets than human organoids. Finally, we demonstrate effects of interference with β-oxidation on lipid accumulation in feline liver organoids. In conclusion, feline liver organoids can be successfully cultured and display a predisposition for lipid accumulation, making them an interesting model in hepatic steatosis research

Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis

Hepatic steatosis is a highly prevalent liver disease, yet research is hampered by the lack of tractable cellular and animal models. Steatosis also occurs in cats, where it can cause severe hepatic failure. Previous studies demonstrate the potential of liver organoids for modeling genetic diseases. To examine the possibility of using organoids to model steatosis, we established a long-term feline liver organoid culture with adult liver stem cell characteristics and differentiation potential toward hepatocyte-like cells. Next, organoids from mouse, human, dog

A Study of the Literature on Intrauterine Treatment Options for Chronic Placental Insufficiency with Intrauterine Growth Restriction Using Intrauterine Intravascular Amino Acid Supplementation

Background: Intrauterine growth retardation (IUGR) is a very serious prenatal condition with 3–5% incidence of all pregnancies. It results from numerous factors, including chronic placental insufficiency. IUGR is associated with an increased risk of mortality and morbidity and is considered a major cause of fetal mortality. Currently, treatment options are significantly limited and often result in preterm delivery. Postpartum, IUGR infants also have higher risks of disease and neurological abnormalities. Methods: The PubMed database was searched using the keywords “IUGR”, “fetal growth restriction”, “treatment”, “management” and “placental insufficiency” for the period between 1975 and 2023. These terms were also combined together. Results: There were 4160 papers, reviews and articles dealing with the topic of IUGR. In total, only 15 papers directly dealt with a prepartum therapy of IUGR; 10 of these were based on an animal model. Overall, the main focus was on maternal intravenous therapy with amino acids or intraamniotic infusion. Treatment methods have been tested since the 1970s to supplement the fetuses with nutrients lacking due to chronic placental insufficiency in various ways. In some studies, pregnant women were implanted with a subcutaneous intravascular perinatal port system, thus infusing the fetuses with a continuous amino acid solution. Prolongation of pregnancy was achieved, as well as improvement in fetal growth. However, insufficient benefit was observed in infusion with commercial amino acid solution in fetuses below 28 weeks’ gestation. The authors attribute this primarily to the enormous variation in amino acid concentrations of the commercially available solutions compared with those observed in the plasma of preterm infants. These different concentrations are particularly important because differences in the fetal brain caused by metabolic changes have been demonstrated in the rabbit model. Several brain metabolites and amino acids were significantly decreased in IUGR brain tissue samples, resulting in abnormal neurodevelopment with decreased brain volume. Discussion: There are currently only a few studies and case reports with correspondingly low case numbers. Most of the studies refer to prenatal treatment by supplementation of amino acids and nutrients to prolong pregnancy and support fetal growth. However, there is no infusion solution that matches the amino acid concentrations found in fetal plasma. The commercially available solutions have mismatched amino acid concentrations and have not shown sufficient benefit in fetuses below 28 weeks’ gestation. More treatment avenues need to be explored and existing ones improved to better treat multifactorial IUGR fetuses

BOB.1 controls memory B-cell fate in the germinal center reaction

International audienceDuring T cell-dependent (TD) germinal center (GC) responses, naïve B cells are instructed to differentiate towards GC B cells (GCBC), high-affinity long-lived plasma cells (LLPC) or memory B cells (Bmem). Alterations in the B cell-fate choice could contribute to immune dysregulation leading to the loss of self-tolerance and the initiation of autoimmune disease. Here we show that mRNA levels of the transcription regulator BOB.1 are increased in the lymph node compartment of patients with rheumatoid arthritis (RA), a prototypical auto-immune disease caused by the loss of immunological tolerance. Investigating to what extent levels of BOB.1 impact B cells during TD immune responses we found that BOB.1 has a crucial role in determining the B cell-fate decision. High BOB.1 levels promote the generation of cells with phenotypic and functional characteristics of Bmem. Mechanistically, overexpression of BOB.1 drives ABF1 and suppresses BCL6, favouring Bmem over LLPC or recycling GCBC. Low levels of BOB.1 are sufficient for LLPC but not for Bmem differentiation. Our findings demonstrate a novel role for BOB.1 in B cells during TD GC responses and suggest that its dysregulation may contribute to the pathogenesis of RA by disturbing the B cell-fate determination

Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis

Hepatic steatosis is a highly prevalent liver disease, yet research is hampered by the lack of tractable cellular and animal models. Steatosis also occurs in cats, where it can cause severe hepatic failure. Previous studies demonstrate the potential of liver organoids for modeling genetic diseases. To examine the possibility of using organoids to model steatosis, we established a long-term feline liver organoid culture with adult liver stem cell characteristics and differentiation potential toward hepatocyte-like cells. Next, organoids from mouse, human, dog, and cat liver were provided with fatty acids. Lipid accumulation was observed in all organoids and interestingly, feline liver organoids accumulated more lipid droplets than human organoids. Finally, we demonstrate effects of interference with β-oxidation on lipid accumulation in feline liver organoids. In conclusion, feline liver organoids can be successfully cultured and display a predisposition for lipid accumulation, making them an interesting model in hepatic steatosis research

Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis

Hepatic steatosis is a highly prevalent liver disease, yet research is hampered by the lack of tractable cellular and animal models. Steatosis also occurs in cats, where it can cause severe hepatic failure. Previous studies demonstrate the potential of liver organoids for modeling genetic diseases. To examine the possibility of using organoids to model steatosis, we established a long-term feline liver organoid culture with adult liver stem cell characteristics and differentiation potential toward hepatocyte-like cells. Next, organoids from mouse, human, dog, and cat liver were provided with fatty acids. Lipid accumulation was observed in all organoids and interestingly, feline liver organoids accumulated more lipid droplets than human organoids. Finally, we demonstrate effects of interference with β-oxidation on lipid accumulation in feline liver organoids. In conclusion, feline liver organoids can be successfully cultured and display a predisposition for lipid accumulation, making them an interesting model in hepatic steatosis research

Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry

Background: Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. Methods: We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Findings: Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (