Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.

Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2LKO) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese Arg2LKO mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease.

Evaluation of Birth by Cesarean Delivery and Development of Early-Onset Colorectal Cancer.

Importance: The incidence of early-onset colorectal cancer (CRC), diagnosed younger than 50 years of age, has increased worldwide. Gut dysbiosis throughout the life course is hypothesized as a leading mechanism, yet epidemiologic data are limited. Objective: To prospectively examine the association between birth by cesarean delivery and early-onset CRC among offspring. Design, Setting, and Participants: In this population-based, nationwide case-control study in Sweden, adults diagnosed with CRC between 18 and 49 years of age from 1991 to 2017 were identified through the Epidemiology Strengthened by Histopathology Reports in Sweden (ESPRESSO) cohort. Up to 5 general population control individuals without CRC were matched with each case on age, sex, calendar year, and county of residence. Pathology-confirmed end points were linked with the Swedish Medical Birth Register and other national registers. Analyses were conducted from March 2022 through March 2023. Exposure: Birth by cesarean delivery. Main Outcomes and Measures: The primary outcome was development of early-onset CRC in the overall population and by sex. Results: We identified 564 case patients with incident early-onset CRC (mean [SD] age, 32.9 [6.2] years; 284 [50.4%] male) and 2180 matched controls (mean [SD] age, 32.7 [6.3] years; 1104 [50.6%] male). Compared with vaginal delivery, birth by cesarean delivery was not associated with early-onset CRC in the overall population (adjusted odds ratio [aOR], 1.28; 95% CI, 0.91-1.79) after multivariable adjustment for matching and maternal and pregnancy-related factors. A positive association was found for females (aOR, 1.62; 95% CI, 1.01-2.60), but there was no association for males (aOR, 1.05; 95% CI, 0.64-1.72). Conclusions and Relevance: In this nationwide, population-based case-control study, birth by cesarean delivery was not associated with early-onset CRC compared with birth by vaginal delivery in the overall population in Sweden. However, females born by cesarean delivery had greater odds of early-onset CRC compared with individuals born through vaginal delivery. This finding suggests that early-life gut dysbiosis may contribute to early-onset CRC in females.

Adult Primary Sclerosing Cholangitis (PSC) subjects have worse biliary disease at diagnosis compared to pediatric PSC subjects.

INTRODUCTION: Adult Primary Sclerosing Cholangitis (PSC) subjects have worse outcomes compared to pediatric PSC subjects. The reasons for this observation are not completely understood. METHODS: In this single-center, retrospective (2005-17) study we compared clinical information, laboratory data, and previously published MRCP-based scores between 25 pediatric (0-18 years at diagnosis) and 45 adult (19 years and above) subjects with large duct PSC at the time of diagnosis. For each subject, radiologists determined MRCP-based parameters and scores after reviewing the MRCP images. RESULTS: The median age at diagnosis for pediatric subjects was 14 years, while that of adult subjects was 39 years. At the time of diagnosis, adult subjects had a higher incidence of biliary complications like cholangitis and high-grade biliary stricture (27% vs. 6%, p = 0.003) and higher serum bilirubin (0.8 vs. 0.4 mg/dl, p = 0.01). MRCP analysis showed that adult subjects had a higher incidence of hilar lymph node enlargement (24.4% vs. 4%, p = 0.03) at diagnosis. Adult subjects had worse sum-IHD score (p = 0.003) and average-IHD score (p = 0.03). Age at diagnosis correlated with higher average-IHD (p = 0.002) and sum-IHD (p = 0.002) scores. Adult subjects had worse Anali score without contrast (p = 0.01) at diagnosis. MRCP-based extrahepatic duct parameters and scores were similar between groups. DISCUSSION: Adult PSC subjects may have higher severity of disease at diagnosis compared to pediatric subjects. Future prospective cohort studies are required to confirm this hypothesis.

Diagnosis of Primary Sclerosing Cholangitis Beyond Childhood is Associated with Worse Outcomes.

BACKGROUND: The elucidation of differences between adult and pediatric-onset primary sclerosing cholangitis (PSC) may inform clinical decision making, and whether results of adult PSC clinical trials can be extrapolated to pediatric subjects. METHODS: A single-center retrospective analysis of PSC subjects diagnosed during the epoch 2000-13 was conducted. Demographic, clinical, and laboratory data were compared between PSC subjects diagnosed between 0-18 (pediatric) and 19+ (adult) years of age. An adverse outcome was defined as PSC-related death, liver transplant, or malignancy. Survival without any of these was defined as event-free survival. RESULTS: Analyses of 28 pediatric-diagnosed and 59 adult-diagnosed subjects revealed that incidence of early portal hypertension (PHT; P = 0.2), laboratory parameters of liver disease severity, and fibrosis grade at diagnosis were comparable between adult and pediatric PSC subjects. Adult-diagnosed PSC subjects had higher incidences of adverse outcomes compared to pediatric-diagnosed PSC subjects (P = 0.02). The age group 0-18 years (n = 30) had significantly better event-free survival compared to the age group more than 40 years (n = 25; P = 0.03). The prevalence of PHT in adult PSC subjects was 2.6 that of pediatric PSC subjects. PHT adversely affected outcomes in both adult (P < 0.001) and pediatric (P = 0.01) subjects. Adult PSC subjects were more likely to develop biliary complications (BCs; P = 0.001), ascites (P = 0.004), and variceal bleed (P = 0.03). Adult PSC subjects were more likely to have extra-hepatic co-morbidities (P < 0.001). Adult subjects had a longer follow-up duration compared to pediatric subjects (P = 0.06). CONCLUSION: Despite having a comparable clinical, laboratory, and histologic biomarkers of liver disease severity at the time of diagnosis, adult PSC subjects had a worse outcome compared to pediatric PSC subjects. Possible reasons for this finding include higher incidence of PHT, BCs, extra-hepatic co-morbidities, and longer duration of follow-up.

How often are clinicians performing genital exams in children with disorders of sex development?

BACKGROUND: We sought to determine the frequency with which genital exams (GEs) are performed in children with disorders of sex development (DSD) and ambiguous genitalia (AG) during routine visits to the pediatric endocrine clinic. METHODS: Medical records of children with DSD and AG seen at one large academic center since 2007 were reviewed. Data analyzed included diagnosis, sex of rearing, age, initial or follow up visit, number of individuals present and sex of the pediatric endocrinologist. Repeated measures analysis was performed to evaluate associations between GEs and patient/physician factors. RESULTS: Eighty-two children with DSD and AG who had a total of 632 visits were identified. Sex of rearing was female in 78% and the most common diagnosis was congenital adrenal hyperplasia (CAH) (68%). GEs were performed in 35.6% of visits. GEs were more likely in patients with male sex of rearing (odds ratio [OR] 17.81, p=0.006), during initial vs. follow-up visits (OR 5.99, p=0.012), and when the examining endocrinologist was female (OR 3.71, p=0.014). As patients aged, GEs were less likely (OR 0.76, p<0.0001). CONCLUSIONS: GEs were performed in approximately one-third of clinic visits in children with DSD and AG. Male sex of rearing, initial visits and female pediatric endocrinologist were associated with more frequent GEs.

Basal forebrain dynamics during a tactile discrimination task.

The nucleus basalis (NB) is a cholinergic neuromodulatory structure that projects liberally to the entire cortical mantle and regulates information processing in all cortical layers. Here, we recorded activity from populations of single units in the NB as rats performed a whisker-dependent tactile discrimination task. Over 80% of neurons responded with significant modulation in at least one phase of the task. Such activity started before stimulus onset and continued for seconds after reward delivery. Firing rates monotonically increased with reward magnitude during the task, suggesting that NB neurons are not indicating the absolute deviation from expected reward amounts. Individual neurons also encoded significant amounts of information about stimulus identity. Such robust coding was not present when the same stimuli were delivered to lightly anesthetized animals, suggesting that the NB neurons contain a sensorimotor, rather than purely sensory or motor, representation of the environment. Overall, these results support the hypothesis that neurons in the NB provide a value-laden representation of the sensorimotor state of the animal as it engages in significant behavioral tasks.