Peroxisomes during postnatal development of mouse endocrine and exocrine pancreas display cell-type- and stage-specific protein composition.

Peroxisomal dysfunction unhinges cellular metabolism by causing the accumulation of toxic metabolic intermediates (e.g. reactive oxygen species, very -chain fatty acids, phytanic acid or eicosanoids) and the depletion of important lipid products (e.g. plasmalogens, polyunsaturated fatty acids), leading to various proinflammatory and devastating pathophysiological conditions like metabolic syndrome and age-related diseases including diabetes. Because the peroxisomal antioxidative marker enzyme catalase is low abundant in Langerhans islet cells, peroxisomes were considered scarcely present in the endocrine pancreas. Recently, studies demonstrated that the peroxisomal metabolism is relevant for pancreatic cell functionality. During the postnatal period, significant changes occur in the cell structure and the metabolism to trigger the final maturation of the pancreas, including cell proliferation, regulation of energy metabolism, and activation of signalling pathways. Our aim in this study was to (i) morphometrically analyse the density of peroxisomes in mouse endocrine versus exocrine pancreas and (ii) investigate how the distribution and the abundance of peroxisomal proteins involved in biogenesis, antioxidative defence and fatty acid metabolism change during pancreatic maturation in the postnatal period. Our results prove that endocrine and exocrine pancreatic cells contain high amounts of peroxisomes with heterogeneous protein content indicating that distinct endocrine and exocrine cell types require a specific set of peroxisomal proteins depending on their individual physiological functions. We further show that significant postnatal changes occur in the peroxisomal compartment of different pancreatic cells that are most probably relevant for the metabolic maturation and differentiation of the pancreas during the development from birth to adulthood.

Multidimensional assessment of infant, parent and staff outcomes during a family centered care enhancement project in a tertiary neonatal intensive care unit: study protocol of a longitudinal cohort study.

BACKGROUND: The therapeutic advances and progress in the care for preterm infants have enabled the regular survival of very immature infants. However, the high burden of lifelong sequelae following premature delivery constitutes an ongoing challenge. Regardless of premature delivery, parental mental health and a healthy parent-child relationship were identified as essential prerogatives for normal infant development. Family centered care (FCC) supports preterm infants and their families by respecting the particular developmental, social and emotional needs in the Neonatal Intensive Care Unit. Due to the large variations in concepts and goals of different FCC initiatives, scientific data on the benefits of FCC for the infant and family outcome are sparse and its effects on the clinical team need to be elaborated. METHODS: This prospective single centre longitudinal cohort study enrols preterm infants ≤ 32 + 0 weeks of gestation and/or birthweight ≤ 1500 g and their parents at the neonatal department of the Giessen University Hospital, Giessen, Germany. Following a baseline period, the rollout of additional FCC elements is executed following a stepwise 6-months approach that covers the NICU environment, staff training, parental education and psychosocial support for parents. Recruitment is scheduled over a 5.5. year period from October 2020 to March 2026. The primary outcome is corrected gestational age at discharge. Secondary infant outcomes include neonatal morbidities, growth, and psychomotor development up to 24 months. Parental outcome measures are directed towards parental skills and satisfaction, parent-infant-interaction and mental health. Staff issues are elaborated with particular focus on the item workplace satisfaction. Quality improvement steps are monitored using the Plan- Do- Study- Act cycle method and outcome measures cover the infant, the parents and the medical team. The parallel data collection enables to study the interrelation between these three important areas of research. Sample size calculation was based on the primary outcome. DISCUSSION: It is scientifically impossible to allocate improvements in outcome measures to individual enhancement steps of FCC that constitutes a continuous change in NICU culture and attitudes covering diverse areas of change. Therefore, our trial is designed to allocate childhood, parental and staff outcome measures during the stepwise changes introduced by a FCC intervention program. TRIAL REGISTRATION: Clinicaltrials.gov, trial registration number NCT05286983, date of registration 03/18/2022, retrospectively registered, http://clinicaltrials.gov .

Schistosoma mansoni Egg-Secreted Antigens Activate Hepatocellular Carcinoma-Associated Transcription Factors c-Jun and STAT3 in Hamster and Human Hepatocytes.

Clinical data have provided evidence that schistosomiasis can promote hepatocellular carcinogenesis. c-Jun and STAT3 are critical regulators of liver cancer development and progression. The aim of the present study was to investigate the hepatocellular activation of c-Jun and STAT3 by Schistosoma mansoni infection. Expression and function of c-Jun and STAT3 as well as proliferation and DNA repair were analyzed by western blotting, electrophoretic mobility-shift assay, and immunohistochemistry in liver of S. mansoni-infected hamsters, Huh7 cells, primary hepatocytes, and human liver biopsies. Hepatocellular activation of c-Jun was demonstrated by nuclear translocation of c-Jun, enhanced phosphorylation (Ser73), and AP-1/DNA-binding in response to S. mansoni infection. Nuclear c-Jun staining pattern around lodged eggs without ambient immune reaction, and directionally from granuloma to the central veins, suggested that substances released from schistosome eggs were responsible for the observed effects. In addition, hepatocytes with c-Jun activation show cell activation and DNA double-strand breaks. These findings from the hamster model were confirmed by analyses of human biopsies from patients with schistosomiasis. Cell culture experiments finally demonstrated that activation of c-Jun and STAT3 as well as DNA repair were induced by an extract from schistosome eggs (soluble egg antigens) and culture supernatants of live schistosome egg (egg-conditioned medium), and in particular by IPSE/alpha-1, the major component secreted by live schistosome eggs. The permanent activation of hepatocellular carcinoma-associated proto-oncogenes such as c-Jun and associated transcription factors including STAT3 by substances released from tissue-trapped schistosome eggs may be important factors contributing to the development of liver cancer in S. mansoni-infected patients. Therefore, identification and therapeutic targeting of the underlying pathways is a useful strategy to prevent schistosomiasis-associated carcinogenesis.

Preeclampsia was a risk factor for pulmonary interstitial emphysema in preterm infants born ≤32 weeks of gestational age.

AIM: This study determined the prenatal and postnatal risk factors for pulmonary interstitial emphysema (PIE) in preterm infants born at up to 32 weeks of gestational age (GA) and their contribution to severe complications. METHODS: We studied 179 preterm infants, who had undergone chest X-rays during the first five days of life at Justus Liebig University Giessen, Germany, between 2016 and 2017. Of these, 33 were retrospectively classified as PIE and 146 as non-PIE. The PIE cases were also matched with 33 non-PIE cases by GA and gender. Risk factors were identified by univariate analyses and multivariable logistic regression. RESULTS: Previously known risk factors for pulmonary interstitial emphysema were confirmed, including GA and birthweight and the associations with adverse outcomes like intraventricular haemorrhage and mortality. We identified preeclampsia and haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome as additional risk factors for PIE (P = .027), and lung impairment was associated with respiratory distress syndrome (P = .001), higher maximum inspired oxygen (P = .014) and needing surfactant (P = .006). CONCLUSION: Preeclampsia and HELLP syndrome were identified as possible additional risk factors for PIE in preterm infants. These conditions should be included in future studies, to identify preterm infants at risk of PIE straight after birth.

Clinical characteristics of patients with familial idiopathic pulmonary fibrosis (f-IPF).

BACKGROUND: The aim of this study was to analyze the relative frequency, clinical characteristics, disease onset and progression in f-IPF vs. sporadic IPF (s-IPF). METHODS: Familial IPF index patients and their family members were recruited into the European IPF registry/biobank (eurIPFreg) at the Universities of Giessen and Marburg (UGMLC). Initially, we employed wide range criteria of f-IPF (e.g. relatives who presumably died of some kind of parenchymal lung disease). After narrowing down the search to occurrence of idiopathic interstitial pneumonia (IIP) in at least one first grade relative, 28 index patients were finally identified, prospectively interviewed and examined. Their family members were phenotyped with establishment of pedigree charts. RESULTS: Within the 28 IPF families, overall 79 patients with f-IPF were identified. In the same observation period, 286 f-IIP and s-IIP patients were recruited into the eurIPFreg at our UGMLC sites, corresponding to a familial versus s-IPF of 9.8%. The both groups showed no difference in demographics (61 vs. 79% males), smoking history, and exposure to any environmental triggers known to cause lung fibrosis. The f-IPF group differed by an earlier age at the onset of the disease (55.4 vs. 63.2 years; p < 0.001). On average, the f-IPF patients presented a significantly milder extent of functional impairment at the time point of inclusion vs. the s-IPF group (FVC 75% pred. vs. FVC 62% pred., p = 0.011). In contrast, the decline in FVC was found to be faster in the f-IPF vs. the s-IPF group (4.94% decline in 6 months in f-IPF vs. 2.48% in s-IPF, p = 0.12). The average age of death in f-IPF group was 67 years vs. 71.8 years in s-IPF group (p = 0.059). The f-IIP group displayed diverse inheritance patterns, mostly autosomal-dominant with variable penetrance. In the f-IPF, the younger generations showed a tendency for earlier manifestation of IPF vs. the older generation (58 vs. 66 years, p = 0.013). CONCLUSIONS: The 28 f-IPF index patients presented an earlier onset and more aggressive natural course of the disease. The disease seems to affect consecutive generations at a younger age. TRIAL REGISTRATION: Nr. NCT02951416 http://www.www.clinicaltrials.gov.

Characteristics and Rates of Preterm Births During the COVID-19 Pandemic in Germany.

Importance: Population-based analyses provided divergent data on the changes in preterm birth rates during the COVID-19 pandemic, and there is a gap of knowledge on the variations in birth characteristics. Objective: To study changes in perinatal care, causes of preterm delivery, and very preterm (VPT; defined as <32 weeks' gestation) birth rates before and during the COVID-19 pandemic. Design, Setting, and Participants: This population-level cohort study used data from the quality assurance registry, which covers all births in Hesse, Germany. Deliveries during the COVID-19 pandemic (2020) were compared with the corresponding grouped prepandemic time intervals (2017 to 2019). Analyses were executed between August 2023 and July 2024. Exposures: Analyses were directed to study differences in preterm births before and during 3 pandemic phases: first (March 14 to May 15, 2020) and second (October 19 to December 31, 2020) lockdowns and a period of less-vigorous restrictions between them (May 16 to October 18, 2020). Main Outcomes and Measures: Outcomes of interest were variations in preterm birth rates in the context of baseline characteristics and causes of preterm births during vs before the first year of the COVID-19 pandemic. Results: From the total cohort of 184 827 births from 2017 to 2020, 719 stillbirths occurred and 184 108 infants were liveborn. Compared with the prepandemic period, medical care characteristics did not differ during the COVID-19 period. The odds of VPT births were lower during the pandemic period (odds ratio [OR], 0.87; 95% CI, 0.79-0.95) compared with the prepandemic period, with the greatest reduction observed during the second lockdown period (OR, 0.69; 95% CI, 0.55-0.84). Reduction in VPT births was attributed to fewer births in pregnancies among individuals with a history of serious disease (OR, 0.64; 95% CI, 0.50-0.83), pathologic cardiotocography (OR, 0.66; 95% CI, 0.53-0.82), and intrauterine infection (OR, 0.82; 95% CI, 0.72-0.92) while incidences of history of preterm birth, multiple pregnancies, serious or severe psychological distress, and preeclampsia, eclampsia, or hemolysis, elevated liver enzymes, and low platelet count syndrome as cause for preterm delivery remained unchanged. Conclusions and Relevance: In this population-based cohort study on the COVID-19 pandemic and preterm birth rates, the duration of exposure to mitigation measures during pregnancy was associated with accelerated reductions in preterm births. The findings of lower rates of baseline risks and causes of preterm deliveries support efforts to intensify health care prevention programs during pregnancy to reduce the preterm birth burden. These findings of this study put particular focus on hygiene measures to reduce the rate of deliveries for intrauterine infection and highlight the potential of expanding strategies to the different risks and causes of preterm delivery.

Skin Transillumination Improves Peripheral Vein Cannulation by Residents in Neonates: A Randomized Controlled Trial.

INTRODUCTION: Establishing peripheral vein access is challenging for pediatric residents and a painful procedure for neonates. We assessed the efficacy of a red light-emitting diode transilluminator during peripheral vein catheter insertion performed by pediatric residents. METHODS: Patients were stratified by current weight (≤1,500 g, >1,500 g) and randomized to the transillumination or the control group. The first three attempts were performed by pediatric residents, followed by three attempts by a neonatologist. The primary outcome was success at first attempt. Secondary comparisons included time to successful insertion and overall success rates of residents and neonatologists. RESULTS: A total of 559 procedures were analyzed. The success rate at resident's first attempt was 44/93 (47%) with transillumination versus 44/90 (49%) without transillumination (p = 0.88) in the strata ≤1,500 g and 103/188 (55%) with transillumination versus 64/188 (34%) without transillumination in the strata >1,500 g (p < 0.001). The overall success rate for residents was 86% in the transillumination versus 73% in the control group in the strata >1,500 g (p = 0.003) but not different in the strata ≤1,500 g (78/93 [84%] vs. 72/90 [80%], p = 0.57). There was no effect when the experience level of residents exceeded 6 months. Neonatologists' overall success rate and time to successful cannulation did not differ significantly in both weight strata. CONCLUSION: Transillumination improves the first-attempt success rate of peripheral vein cannulation performed by pediatric residents in neonates >1,500 g, while no benefit was found in infants ≤1,500 g.

Noninvasive Ventilation and Rapid Enteral Feeding Advances in Preterm Infants-2-Year Follow-Up of the STENA-Cohort.

The importance of nutritional supply for somatic growth and neurodevelopmental outcome in very-low-birthweight infants is an established medical strategy for reducing long-term morbidities. Our cohort study on rapid enteral feeding advances using a standardized protocol (STENA) previously demonstrated a 4-day reduction of parenteral nutrition. STENA did not impede the success of noninvasive ventilations strategies but significantly less infants required mechanical ventilation. Most importantly, STENA resulted in improved somatic growth at 36 weeks of gestation. Here, we evaluated our cohort for psychomotor outcomes and somatic growth at 2 years of age. n = 218 infants of the original cohort were followed-up (74.4%). Z-scores for weight and length did not differ but the benefits of STENA for head circumference persisted until the age of 2 years (p = 0.034). Concerning the psychomotor outcome, we neither found any statistically significant differences in the mental developmental index (MDI) (p = 0.738), norin the psychomotor developmental index (PDI) (p = 0.122). In conclusion, our data adds important insights on the topic of rapid enteral feeding advances and confirms the safety of STENA with respect to somatic growth and psychomotor outcome measures.

Fluctuations in Oxygen Saturation during Synchronized Nasal Intermittent Positive Pressure Ventilation and Nasal High-Frequency Oscillatory Ventilation in Very Low Birth Weight Infants: A Randomized Crossover Trial.

BACKGROUND: Very low birth weight (VLBW) infants on noninvasive ventilation (NIV) experience frequent fluctuations in oxygen saturation (SpO2) that are associated with an increased risk for mortality and severe morbidities. METHODS: In this randomized crossover trial, VLBW infants (n = 22) born 22+3 to 28+0 weeks on NIV with supplemental oxygen were allocated on two consecutive days in random order to synchronized nasal intermittent positive pressure ventilation (sNIPPV) and nasal high-frequency oscillatory ventilation (nHFOV) for 8 h. nHFOV and sNIPPV were set to equivalent mean airway pressure and transcutaneous pCO2. Primary outcome was the time spent within the SpO2 target (88-95%). RESULTS: During sNIPPV, VLBW infants spent significantly more time within the SpO2 target (59.9%) than during nHFOV (54.6%). The proportion of time spent in hypoxemia (22.3% vs. 27.1%) and the mean fraction of supplemental oxygen (FiO2) (29.4% vs. 32.8%) were significantly reduced during sNIPPV, while the respiratory rate (50.1 vs. 42.6) was significantly higher. Mean SpO2, SpO2 above the target, number of prolonged (>1 min) and severe (SpO2 <80%) hypoxemic episodes, parameters of cerebral tissue oxygenation using NIRS, number of FiO2 adjustments, heart rate, number of bradycardias, abdominal distension and transcutaneous pCO2 did not differ between both interventions. CONCLUSIONS: In VLBW infants with frequent fluctuations in SpO2, sNIPPV is more efficient than nHFOV to retain the SpO2 target and to reduce FiO2 exposure. These results demand more detailed investigations into cumulative oxygen toxicities during different modes of NIV over the weaning period, particularly with regard to consequences for long-term outcomes.

Hepatocyte integrity depends on c-Jun-controlled proliferation in Schistosoma mansoni infected mice.

Schistosomiasis is a parasitic disease affecting more than 250 million people worldwide. The transcription factor c-Jun, which is induced in S. mansoni infection-associated liver disease, can promote hepatocyte survival but can also trigger hepatocellular carcinogenesis. We aimed to analyze the hepatic role of c-Jun following S. mansoni infection. We adopted a hepatocyte-specific c-Jun knockout mouse model (Alb-Cre/c-Jun loxP) and analyzed liver tissue and serum samples by quantitative real-time PCR array, western blotting, immunohistochemistry, hydroxyproline quantification, and functional analyses. Hepatocyte-specific c-Jun knockout (c-JunΔli) was confirmed by immunohistochemistry and western blotting. Infection with S. mansoni induced elevated aminotransferase-serum levels in c-JunΔli mice. Of note, hepatic Cyclin D1 expression was induced in infected c-Junf/f control mice but to a lower extent in c-JunΔli mice. S. mansoni soluble egg antigen-induced proliferation in a human hepatoma cell line was diminished by inhibition of c-Jun signaling. Markers for apoptosis, oxidative stress, ER stress, inflammation, autophagy, DNA-damage, and fibrosis were not altered in S. mansoni infected c-JunΔli mice compared to infected c-Junf/f controls. Enhanced liver damage in c-JunΔli mice suggested a protective role of c-Jun. A reduced Cyclin D1 expression and reduced hepatic regeneration could be the reason. In addition, it seems likely that the trends in pathological changes in c-JunΔli mice cumulatively led to a loss of the protective potential being responsible for the increased hepatocyte damage and loss of regenerative ability.

Monocyte signature as a predictor of chronic lung disease in the preterm infant.

Introduction: Inflammation is a key driver of morbidity in the vulnerable preterm infant exposed to pre- and postnatal hazards and significantly contributes to chronic lung disease, i.e. bronchopulmonary dysplasia (BPD). However, the early changes in innate immunity associated with BPD development are incompletely understood. Methods: In very immature preterm infants below 32 weeks gestational age (GA; n=30 infants), monocyte subtypes were identified by Flow Cytometry at birth and throughout the postnatal course including intracellular TNF expression upon LPS stimulation. Complementing these measurements, cytokine end growth factor expression profiles (Luminex® xMAP®; n=110 infants) as well as gene expression profiles (CodeLinkTM Human I Bioarray; n=22) were characterized at birth. Results: The abundance of monocyte subtypes differed between preterm and term neonates at birth. Specifically, CD14++CD16+ (intermediate) monocytes demonstrated a dependency on PMA and elevated levels of nonclassical (CD14+CD16++) monocytes characterized preterm infants with developing BPD. Postnatally, lung injury was associated with an increase in intermediate monocytes, while high levels of nonclassical monocytes persisted. Both subtypes were revealed as the main source of intracellular TNF-α expression in the preterm infant. We identified a cytokine and growth factor expression profile in cord blood specimen of preterm infants with developing BPD that corresponded to the disease-dependent regulation of monocyte abundances. Multivariate modeling of protein profiles revealed FGF2, sIL-2 Rα, MCP-1, MIP1a, and TNF-α as predictors of BPD when considering GA. Transcriptome analysis demonstrated genes predicting BPD to be overrepresented in inflammatory pathways with increased disease severity characterized by the regulation of immune and defense response pathways and upstream regulator analysis confirmed TNF-α, interleukin (IL) -6, and interferon α as the highest activated cytokines in more severe disease. Whereas all BPD cases showed downstream activation of chemotaxis and activation of inflammatory response pathways, more severe cases were characterized by an additional activation of reactive oxygen species (ROS) synthesis. Discussion: In the present study, we identified the early postnatal presence of nonclassical (CD14+CD16++) and intermediate (CD14++CD16+) monocytes as a critical characteristic of BPD development including a specific response pattern of monocyte subtypes to lung injury. Pathophysiological insight was provided by the protein and transcriptome signature identified at birth, centered around monocyte and corresponding granulocyte activation and highlighting TNFα as a critical regulator in infants with developing BPD. The disease severity-dependent expression patterns could inform future diagnostic and treatment strategies targeting the monocytic cell and its progeny.

Corrigendum: Monocyte signature as a predictor of chronic lung disease in the preterm infant.

[This corrects the article DOI: 10.3389/fimmu.2023.1112608.].

A systematic review on urolithiasis in small ruminants according to nutrition-dependent prevalence and outcome after surgery.

Background and Aim: Obstructive urolithiasis is a common disease in small ruminants with fatal outcomes if left untreated. Many methods have been established; however, long-term success rates remain unsatisfactory. Four bibliographic databases (PubMed, HeBis, Medline (OvidSP), and Web of Science) were searched to evaluate the prevalence of urolithiasis in small ruminants and long-term outcomes after surgery using a systematic review. The study aimed to give evidence-based data concerning prevalence and success rates after surgery. Materials and Methods: The analysis included 24 (total 239) peer-reviewed journal articles dealing with the prevalence of urolithiasis and 16 (total 39) concerning long-term outcomes after surgery. Literature was included if it referred to species, language, availability, and relevant statements to the specific questions, including the presence of control groups. Heterogeneity tests included Χ 2, I2, and τ2, respectively. A 95% confidence interval was determined, and effects were estimated using the fixed effect model. Due to a feeding-associated bias, prevalence analysis was conducted for a sorghum-based and a corn-based feeding resulting in a weighted prevalence of 62% and 17%, respectively. Analysis of long-term outcomes after surgical interventions revealed long-term success rates of 15-77% after ultrasonographic tube cystotomy and marsupialization of the urinary bladder, respectively. Results: The prevalence of urolithiasis is strongly associated with feeding and may be calculated as 17% in corn-based rations and 62% in sorghum-based rations. Surgical interventions result in guarded to moderate long-term success rates of 15-66%. Urethral stoma and marsupialization of the bladder provide acceptable long-term success rates with 71-77% but are rather salvage techniques than accepted surgical methods, especially when used in companion animals. Conclusion: The development of urolithiasis is mainly influenced by nutrition. Effective prophylaxis of this disease should, therefore, always include advisory service for the owners. Existing surgical techniques should be critically re-evaluated concerning their long-term success rates.

Compatibility of rapid enteral feeding advances and noninvasive ventilation in preterm infants-An observational study.

AIM: To evaluate safety and clinical outcome of rapid enteral feeding advances in preterm infants <1500 g birthweight (BW). METHODS: In this single-center retrospective cohort study, 293 preterm infants born during 2015-2018 were comparatively analyzed before (n = 145) and after (n = 148) the implementation of a rapid enteral feeding protocol with daily milk increments of 20-30 ml/kg of body weight. Major outcome parameters were focused toward pulmonary morbidities and nutritional variables. RESULTS: Preterm infants in the rapid feeding advancement group were more successfully stabilized on noninvasive ventilation (p < 0.001) never requiring mechanical ventilation. Duration of respiratory support (0.465) and frequency of bronchopulmonary dysplasia (BPD) (p = 0.341) and severe BPD (0.273) did not differ between both groups. Furthermore, patients in the rapid feeding group achieved full volume feedings faster (p < 0.001), regained BW earlier (p = 0.009), and displayed significantly improved somatic growth at 36 weeks gestational age (p < 0.001). There was no increased risk for further morbidities of prematurity including feeding intolerance, necrotizing enterocolitis (NEC), and focal intestinal perforation. CONCLUSION: Rapid enteral feeding advancements in preterm infants <1500 g BW are safe and do not impede stabilization on noninvasive ventilation.

Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4-/- Mice.

BACKGROUND & AIMS: The endocannabinoid system is involved in the modulation of inflammatory, fibrotic, metabolic, and carcinogenesis-associated signaling pathways via cannabinoid receptor (CB)1 and CB2. We hypothesized that the pharmacologic antagonization of CB1 receptor improves cholestasis in Abcb4-/- mice. METHODS: After weaning, male Abcb4-/- mice were treated orally with rimonabant (a specific antagonist of CB1) or ACEA (an agonist of CB1) until up to 16 weeks of age. Liver tissue and serum were isolated and examined by means of serum analysis, quantitative real time polymerase chain reaction, Western blot, immunohistochemistry, and enzyme function. Untreated Abcb4-/- and Bagg Albino Mouse/c wild-type mice served as controls. RESULTS: Cholestasis-induced symptoms such as liver damage, bile duct proliferation, and enhanced circulating bile acids were improved by CB1 antagonization. Rimonabant treatment also improved Phosphoenolpyruvat-Carboxykinase expression and reduced inflammation and the acute-phase response. The carcinogenesis-associated cellular-Jun N-terminal kinase/cellular-JUN and signal transducer and activator of transcription 3 signaling pathways activated in Abcb4-/- mice were reduced to wild-type level by CB1 antagonization. CONCLUSIONS: We showed a protective effect of oral CB1 antagonization in chronic cholestasis using the established Abcb4-/- model. Our results suggest that pharmacologic antagonization of the CB1 receptor could have a therapeutic benefit in cholestasis-associated metabolic changes, liver damage, inflammation, and carcinogenesis.

IL-13 as Target to Reduce Cholestasis and Dysbiosis in Abcb4 Knockout Mice.

The Th2 cytokine IL-13 is involved in biliary epithelial injury and liver fibrosis in patients as well as in animal models. The aim of this study was to investigate IL-13 as a therapeutic target during short term and chronic intrahepatic cholestasis in an Abcb4-knockout mouse model (Abcb4-/-). Lack of IL-13 protected Abcb4-/- mice transiently from cholestasis. This decrease in serum bile acids was accompanied by an enhanced excretion of bile acids and a normalization of fecal bile acid composition. In Abcb4-/-/IL-13-/- double knockout mice, bacterial translocation to the liver was significantly reduced and the intestinal microbiome resembled the commensal composition in wild type animals. In addition, 52-week-old Abcb4-/-IL-13-/- mice showed significantly reduced hepatic fibrosis. Abcb4-/- mice devoid of IL-13 transiently improved cholestasis and converted the composition of the gut microbiota towards healthy conditions. This highlights IL-13 as a potential therapeutic target in biliary diseases.

Encephalopathy Associated With Neurochondrin Autoantibodies.

We determined the prevalence of autoantibodies against an extended number of established and novel neural antigens in children and adolescents with suspected autoimmune encephalitis, epilepsy, single seizures, or marked epileptiform activity in electroencephalography (EEG). Prospectively, 103 patients were recruited aged between 0 and 18 years and 104 controls. A panel of 35 autoantibodies against neural cell-surface and intracellular antigens was screened. Sixteen of 103 patients (15.5%) showed a positive result for 1 or more autoantibodies, compared to 6 of 104 controls (5.8%, P = .02). Neurochondrin was identified as a possible new target of autoantibodies in 3 patients within this cohort, but none in controls. The patients showed severe behavioral disturbances, memory and cognitive impairment, episodes of reduced responsiveness, but no seizures, and normal MRI. Clinical findings, course, and treatment response of these 3 patients are presented.

Epigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1.

Genetic, epigenetic, and environmental factors contribute to the multifactorial disorder progressive supranuclear palsy (PSP). Here, we study epigenetic changes by genome-wide analysis of DNA from postmortem tissue of forebrains of patients and controls and detect significant (P < 0.05) methylation differences at 717 CpG sites in PSP vs. controls. Four-hundred fifty-one of these sites are associated with protein-coding genes. While differential methylation only affects a few sites in most genes, DLX1 is hypermethylated at multiple sites. Expression of an antisense transcript of DLX1, DLX1AS, is reduced in PSP brains. The amount of DLX1 protein is increased in gray matter of PSP forebrains. Pathway analysis suggests that DLX1 influences MAPT-encoded Tau protein. In a cell system, overexpression of DLX1 results in downregulation of MAPT while overexpression of DLX1AS causes upregulation of MAPT. Our observations suggest that altered DLX1 methylation and expression contribute to pathogenesis of PSP by influencing MAPT.

Gene expression profiling at birth characterizing the preterm infant with early onset infection.

Early onset infection (EOI) in preterm infants <32 weeks gestational age (GA) is associated with a high mortality rate and the development of severe acute and long-term complications. The pathophysiology of EOI is not fully understood and clinical and laboratory signs of early onset infections in this patient cohort are often not conclusive. Thus, the aim of this study was to identify signatures characterizing preterm infants with EOI by using genome-wide gene expression (GWGE) analyses from umbilical arterial blood of preterm infants. This prospective cohort study was conducted in preterm infants <32 weeks GA. GWGE analyses using CodeLink human microarrays were performed from umbilical arterial blood of preterm infants with and without EOI. GWGE analyses revealed differential expression of 292 genes in preterm infants with EOI as compared to infants without EOI. Infants with EOI could be further differentiated into two subclasses and were distinguished by the magnitude of the expression of genes involved in both neutrophil and T cell activation. A hallmark activity for both subclasses of EOI was a common suppression of genes involved in natural killer (NK) cell function, which was independent from NK cell numbers. Significant results were recapitulated in an independent validation cohort. Gene expression profiling may enable early and more precise diagnosis of EOI in preterm infants. KEY MESSAGE: Gene expression (GE) profiling at birth characterizes preterm infants with EOI. GE analysis indicates dysregulation of NK cell activity. NK cell activity at birth may be a useful marker to improve early diagnosis of EOI.