Severe Elevated Bile Acids in Early Pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) typically presents in the second half of pregnancy. Severe ICP is associated with increased risk of stillbirth. Little is known regarding elevated bile acids in the first trimester. We present a case of severely elevated bile acids in the first trimester, resistant to conservative management, in a patient with pre-existing cholestatic liver disease and aortic valve disease requiring anticoagulation. Therapeutic plasma exchange was used. In those with pre-existing cholestatic disease, early bile acid elevation is likely distinct from ICP, and conservative strategies may not be useful. In addition, therapeutic enoxaparin appears safe in therapeutic plasma exchange.

Xanthogranulomatous oophoritis mimicking a dermoid cyst with ovarian torsion: A case report and review of the literature.

Xanthogranulomatous oophoritis (XO) is a rare pseudotumor representing a destructive chronic inflammatory process often mistaken for malignancy or tubo-ovarian abscess. Xanthogranulomatous inflammation is most commonly seen in the kidneys and gallbladder and very rarely affects the genitourinary system. Definitive treatment is with surgical removal of affected tissue. This report presents the case of a 42-year-old woman with an 8 cm complex right adnexal cyst concerning for a dermoid cyst presenting with intermittent torsion. Final pathology after right salpingo-oophorectomy demonstrated xanthogranulomatous oophoritis. This case is of clinical significance for distinguishing the condition from common benign pathology or cancer since the recommended surgical procedure is different than for a dermoid cyst or malignancy. Correct identification of the condition is crucial for appropriate treatment and to avoid unnecessary morbid procedures if the mass is mistaken for malignancy or future repeat surgery if mistaken for a dermoid cyst or other common benign condition. This case documents the presentation of xanthogranulomatous oophoritis masquerading as a dermoid cyst for a condition with very few reported cases worldwide.

Microfluidic device facilitates in vitro modeling of human neonatal necrotizing enterocolitis-on-a-chip.

Necrotizing enterocolitis (NEC) is a deadly gastrointestinal disease of premature infants that is associated with an exaggerated inflammatory response, dysbiosis of the gut microbiome, decreased epithelial cell proliferation, and gut barrier disruption. We describe an in vitro model of the human neonatal small intestinal epithelium (Neonatal-Intestine-on-a-Chip) that mimics key features of intestinal physiology. This model utilizes intestinal enteroids grown from surgically harvested intestinal tissue from premature infants and cocultured with human intestinal microvascular endothelial cells within a microfluidic device. We used our Neonatal-Intestine-on-a-Chip to recapitulate NEC pathophysiology by adding infant-derived microbiota. This model, named NEC-on-a-Chip, simulates the predominant features of NEC, including significant upregulation of proinflammatory cytokines, decreased intestinal epithelial cell markers, reduced epithelial proliferation, and disrupted epithelial barrier integrity. NEC-on-a-Chip provides an improved preclinical model of NEC that facilitates comprehensive analysis of the pathophysiology of NEC using precious clinical samples. This model is an advance toward a personalized medicine approach to test new therapeutics for this devastating disease.

Fetal brain ultrasound measures and maternal nutrition: A feasibility study in Ecuador.

OBJECTIVE: Nutrition during pregnancy is an important modifiable determinant of fetal growth and development. This pilot study aimed to characterize the association between fetal anthropometry, fetal brain development, and maternal diet among women in Ecuador using portable ultrasound in resource-limited clinics, including measurements of brain structures not typically imaged in this setting. METHODS: Pregnant women (n = 47) from four resource-limited health centers were surveyed on demographic, socioeconomic, morbidity, and dietary information. Maternal height, weight, and blood pressure were taken. A sonographer took 15 images per participant, including those standardly assessed during the fetal survey and additional brain structures identified as potentially responsive to maternal nutrition, but not part of the standard fetal survey. RESULTS: Mean percentiles for all standard fetal survey measurements generated from WHO Fetal Growth Curves fell below 50%, and negative mean Z scores were found for biparietal diameter (-0.95 ± 1.11) and femur length (-0.22 ± 1.10). Generalized linear modeling adjusting for gestational age and other covariates showed frequency of seafood consumption was positively associated with fetal biparietal diameter Z score (P = 0.005), beans and legumes positively associated with femur length (P = 0.006), and a negative association was found for soda consumption and fetal head circumference (P = 0.013). CONCLUSIONS: This pilot study demonstrated the feasibility of capturing images of nutrition-relevant fetal brain structures not part of the standard fetal survey in resource-limited settings using portable ultrasound. Our study revealed associations between anthropometry, brain structure size, and maternal diet demonstrating potential for prenatal nutrition research using ultrasound in the field.

Cooperative Changes in Solvent Exposure Identify Cryptic Pockets, Switches, and Allosteric Coupling.

Proteins are dynamic molecules that undergo conformational changes to a broad spectrum of different excited states. Unfortunately, the small populations of these states make it difficult to determine their structures or functional implications. Computer simulations are an increasingly powerful means to identify and characterize functionally relevant excited states. However, this advance has uncovered a further challenge: it can be extremely difficult to identify the most salient features of large simulation data sets. We reasoned that many functionally relevant conformational changes are likely to involve large, cooperative changes to the surfaces that are available to interact with potential binding partners. To examine this hypothesis, we introduce a method that returns a prioritized list of potentially functional conformational changes by segmenting protein structures into clusters of residues that undergo cooperative changes in their solvent exposure, along with the hierarchy of interactions between these groups. We term these groups exposons to distinguish them from other types of clusters that arise in this analysis and others. We demonstrate, using three different model systems, that this method identifies experimentally validated and functionally relevant conformational changes, including conformational switches, allosteric coupling, and cryptic pockets. Our results suggest that key functional sites are hubs in the network of exposons. As a further test of the predictive power of this approach, we apply it to discover cryptic allosteric sites in two different ß-lactamase enzymes that are widespread sources of antibiotic resistance. Experimental tests confirm our predictions for both systems. Importantly, we provide the first evidence, to our knowledge, for a cryptic allosteric site in CTX-M-9 ß-lactamase. Experimentally testing this prediction did not require any mutations and revealed that this site exerts the most potent allosteric control over activity of any pockets found in ß-lactamases to date. Discovery of a similar pocket that was previously overlooked in the well-studied TEM-1 ß-lactamase demonstrates the utility of exposons.

Prediction of New Stabilizing Mutations Based on Mechanistic Insights from Markov State Models.

Protein stabilization is fundamental to enzyme function and evolution, yet understanding the determinants of a protein's stability remains a challenge. This is largely due to a shortage of atomically detailed models for the ensemble of relevant protein conformations and their relative populations. For example, the M182T substitution in TEM ß-lactamase, an enzyme that confers antibiotic resistance to bacteria, is stabilizing but the precise mechanism remains unclear. Here, we employ Markov state models (MSMs) to uncover how M182T shifts the distribution of different structures that TEM adopts. We find that M182T stabilizes a helix that is a key component of a domain interface. We then predict the effects of other mutations, including a novel stabilizing mutation, and experimentally test our predictions using a combination of stability measurements, crystallography, NMR, and in vivo measurements of bacterial fitness. We expect our insights and methodology to provide a valuable foundation for protein design.