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Objective: Nutcracker syndrome is a rare condition that involves mechanical compression of the left renal vein, leading to chronic and debilitating left flank pain. The etiology of the pain is misdiagnosed frequently, and patients usually require long-term opioid use to manage their pain. Multiple therapeutic options for nutcracker syndrome have been described in the literature but the reports are limited by small numbers of patients, and the lack of convincing data demonstrating consistently improved outcomes. Here we report the largest series to date of patients undergoing renal autotransplantation for the treatment of nutcracker syndrome., Methods: We performed a multicenter retrospective cohort review of patients 105 patients with nutcracker syndrome who underwent renal autotransplantation as a primary or salvage therapy., Results: During the overall study period, 93.1% of patients treated with autotransplantation had durable, complete flank pain relief at 12 months with both open and robotic surgical approach. After autotransplantation, a statistically significant decrease in the percentage of patients using opioids from 48.6% to 17.0% was demonstrated at 12 months. In those patients using opioids before autotransplantation, a statistically significant decrease in morphine milligram equivalents was demonstrated from an alarming 68.9 ± 15.0 per day to 25.0 ± 11.02 morphine milligram equivalents per day., Conclusions: Our findings suggest that renal autotransplantation, as a primary treatment or a salvage treatment, in patients with nutcracker syndrome provides durable pain relief and a marked decrease in chronic opioid use regardless of surgical approach., Competing Interests: Disclosures None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Perioperative dysfunction of the fibrinolytic system may play a role in adverse outcomes for liver transplant recipients. There is a paucity of data describing the potential impact of the postoperative fibrinolytic system on these outcomes. Our objective was to determine whether fibrinolysis resistance (FR), on postoperative day one (POD-1), was associated with early allograft dysfunction (EAD). We hypothesized that FR, quantified by tissue plasminogen activator thrombelastography, is associated with EAD. Tissue plasminogen activator thrombelastography was performed on POD-1 for 184 liver transplant recipients at a single institution. A tissue plasminogen activator thrombelastography clot lysis at 30 minutes of 0.0% was identified as the cutoff for FR on POD-1. EAD occurred in 32% of the total population. Fifty-nine percent (n=108) of patients were categorized with FR. The rate of EAD was 42% versus 17%, p <0.001 in patients with FR compared with those without, respectively. The association between FR and EAD risk was assessed using multivariable logistic regression after controlling for known risk factors. The odds of having EAD were 2.43 times (95% CI, 1.07-5.50, p =0.03) higher in recipients with FR [model C statistic: 0.76 (95% CI, 0.64-0.83, p <0.001]. An additive effect of receiving a donation after circulatory determination of death graft and having FR in the rate of EAD was observed. Finally, compared with those without FR, recipients with FR had significantly shorter graft survival time ( p =0.03). In conclusion, FR on POD-1 is associated with EAD and decreased graft survival time. Postoperative viscoelastic testing may provide clinical utility in identifying patients at risk for developing EAD, especially for recipients receiving donation after circulatory determination of death grafts., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Introduction: Therapeutic acetaminophen (APAP) ingestion causes asymptomatic drug-induced liver injury in some patients. In most cases, elevations in alanine aminotransferase (ALT) are transient and return to the normal range, even with continued APAP ingestion, though ALT elevation persists in some patients unpredictably. The etiology of this liver injury or adaption is unclear. Our objective was to identify new pharmacogenomic variants associated with elevated ALT or elevated protein adduct concentrations in patients receiving therapeutic acetaminophen., Methods: We performed genome-wide sequencing analysis on eight patients using leftover blood samples from an observational study that administered four grams of acetaminophen for up to 16 days to all patients. Two patients with ALT elevations > two times the upper limit of normal, two patients with no adduct formation, and four control patients were sequenced. The genomes were aligned with the GRCh38 reference sequence, and variants with predicted low, moderate, or high impact on the subsequent proteins were first manually curated for biologic plausibility, then organized and examined in the REACTOME pathway analysis program., Results: We found 394 variants in 107 genes associated with elevated ALT. Variants associated with ALT elevation predominantly involved genes in the immune system (MHC class II complex genes), endoplasmic reticulum stress response (SEC23B and XBP1), oxidative phosphorylation (NDUFB9), and WNT/beta-catenin signaling (FZD5). Variants associated with elevated adducts were primarily in signal transduction (MUC20) and DNA repair mechanisms (P53)., Conclusions: While underpowered, genetic variants in immune system genes may be associated with drug-induced liver injury at therapeutic doses of acetaminophen.

Introduction: Metoprolol succinate is a long-acting beta-blocker prescribed for the management of hypertension (HTN) and other cardiovascular diseases. Metabolomics, the study of end-stage metabolites of upstream biologic processes, yield insight into mechanisms of drug effectiveness and safety. Our aim was to determine metabolomic profiles associated with metoprolol effectiveness for the treatment of hypertension., Methods: We performed a prospective pragmatic trial (NCT02293096) that enrolled patients between 30 and 80 years with uncontrolled HTN. Patients were started on metoprolol succinate at a dose based upon systolic blood pressure (SBP). Urine and blood pressure measurements were collected weekly. Individuals with a 10% decline in SBP or heart rate (HR) were considered responsive. Genotype for the CYP2D6 enzyme, the primary metabolic pathway for metoprolol, was evaluated for each subject. Unbiased metabolomic analyses were performed on urine samples using UPLC-QTOF mass spectrometry., Results: Urinary metoprolol metabolite ratios are indicative of patient CYP2D6 genotypes. Patients taking metoprolol had significantly higher urinary levels of many gut microbiota-dependent metabolites including hydroxyhippuric acid, hippuric acid, and methyluric acid. Urinary metoprolol metabolite profiles of normal metabolizer (NM) patients more closely correlate to ultra-rapid metabolizer (UM) patients than NM patients. Metabolites did not predict either 10% SBP or HR decline., Conclusion: In summary, urinary metabolites predict CYP2D6 genotype in hypertensive patients taking metoprolol. Metoprolol succinate therapy affects the microbiome-derived metabolites.

Background and Aims: The Psychoactive Surveillance Consortium and Analysis Network (PSCAN) is a national network of academic emergency departments (ED), analytical toxicologists and pharmacologists that collects clinical data paired with biological samples to identify and improve treatments of medical conditions arising from use of new psychoactive substances (NPS). The aim of this study was to gather clinical data with paired drug identification from NPS users who presented to EDs within PSCAN during its first year (2016-17)., Design: Observational study involving patient records and biological samples., Setting: Seven academic emergency medical centers across the United States., Participants: ED patients (n = 127) > 8 years of age with possible NPS use who were identified and enrolled in PSCAN by clinical providers or research personnel., Measurements: Clinical signs, symptoms and treatments were abstracted from the patients' health records. Biological samples were collected from leftover urine, serum and whole blood. Biological and drug samples, when available, were tested for drugs and drug metabolites via liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS)., Findings: Patients in whom synthetic opioids were detected (n = 9) showed higher rates of intubation (four of nine), impaired mental status (four of nine) and respiratory acidosis (five of nine) compared with the rest of the cohort (nine of 118, P-value < 0.05). Patients in whom synthetic cannabinoid (SC) were found (n = 27) had lower median diastolic blood pressures (70.5 versus 77 mmHg, P = 0.046) compared with the rest of the cohort. In 64 cases of single drug ingestion, benzodiazepines were administered in 25 cases and considered effective by the treating physician in 21 (84%) cases., Conclusions: During its first year of operation, the Psychoactive Surveillance Consortium and Analysis Network captured clinical data on new classes of drugs paired with biological samples over a large geographical area in the United States. Synthetic cannabinoids were the most common new psychoactive drug identified. Synthetic opioids were associated with a high rate of intubation and respiratory acidosis., (© 2019 Society for the Study of Addiction.)

Drug-drug interactions have been demonstrated to alter cytochrome 2D6 (CYP2D6) enzyme phenotype due to inhibitor ingestion, although it is unclear how substrate interactions affect phenotype. This was a pragmatic clinical trial examining the kinetics of a CYP2D6 enzyme probe drug with and without CYP2D6-dependent substrates. Patients were enrolled into an inpatient study unit, and orally administered a 2 mg microdose of dextromethorphan (DM) to probe enzyme activity with and without CYP2D6-dependent drug-drug interactions. Thirty-nine subjects were enrolled in this trial. Twelve subjects were on no CYP2D6-dependent drugs and 27 were on one or more CYP2D6-dependent drugs. There were 1 poor metabolizer, 5 intermediate metabolizers, 31 normal metabolizers, and 2 ultra-rapid metabolizers. Those with co-ingestion of another CYP2D6-dependent drug were 9.49 (95% confidence interval (CI): 1.54-186.41; P = 0.01) times more likely to have genotype-phenotype discordance based upon the 3 hours dextrophan/dextromethorphan (DX/DM) ratio. CYP2D6 substrate co-ingestions can cause genotype-phenotype discordance., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Mitochondria are the most prominent organelle in the oocyte. Somatic cells maintain a healthy population of mitochondria by degrading damaged mitochondria via mitophagy, a specialized autophagy pathway. However, evidence from previous work investigating the more general macroautophagy pathway in oocytes suggests that mitophagy may not be active in the oocyte. This would leave the vast numbers of mitochondria - poised to be inherited by the offspring - vulnerable to damage. Here we test the hypothesis that inactive mitophagy in the oocyte underlies maternal transmission of dysfunctional mitochondria. To determine whether oocytes can complete mitophagy, we used either CCCP or AntimycinA to depolarize mitochondria and trigger mitophagy. After depolarization, we did not detect co-localization of mitochondria with autophagosomes and mitochondrial DNA copy number remained unchanged, indicating the non-functional mitochondrial population was not removed. To investigate the impact of an absence of mitophagy in oocytes with damaged mitochondria on offspring mitochondrial function, we utilized in vitro fertilization of high fat high sugar (HF/HS)-exposed oocytes, which have lower mitochondrial membrane potential and damaged mitochondria. Here, we demonstrate that blastocysts generated from HF/HS oocytes have decreased mitochondrial membrane potential, lower metabolites involved in ATP generation, and accumulation of PINK1, a mitophagy marker protein. This mitochondrial phenotype in the blastocyst mirrors the phenotype we show in HF/HS exposed oocytes. Taken together, these data suggest that the mechanisms governing oocyte mitophagy are fundamentally distinct from those governing somatic cell mitophagy and that the absence of mitophagy in the setting of HF/HS exposure contributes to the oocyte-to-blastocyst transmission of dysfunctional mitochondria., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Syncytialization is a process essential to the genesis and vitality of the decisive maternal-fetal interface, the syncytiotrophoblast. While the role of specific genes important in syncytial fusion is appreciated, an integrated global analysis of syncytialization is absent., Methods: We leveraged a variety of approaches (RNA-seq, genome-scale DNA methylation and ChIP-seq) to assemble a genome-wide transcriptomic and epigenomic view of syncytialization in BeWo cells., Results: RNA-seq analysis of expression profiles revealed alterations in ∼3000 genes over the 3 day time-course of forskolin, including identification of several previously unrecognized genes to be involved in syncytialization. These genes were enriched for cell differentiation, morphogenesis, blood vessel and placental labyrinth development and steroid hormone response. Genome-scale DNA methylation via reduced representation bisulfite sequencing (RRBS) showed altered methylation of a number of CpGs associated with cell differentiation and commitment. Finally, genome-wide localization of seven key histone marks encompassing permissive (H3K4me3, H3K9ac, H3K27ac), enhancer (H3K4me1), elongation (H3K36me3) and repressive (H3K27me3, H3K9me3) states was performed via ChiP-seq. These analyses clearly revealed that syncytialization was associated with a gain in transcriptionally permissive/active marks (H3K4me3, K9ac, K27ac and K36me3) among genes that are either constitutive or upregulated in syncytialization., Discussion: Overall, these results provide a novel resource to elucidate the underlying epigenetic mechanisms coordinating transcriptional changes associated with syncytialization in BeWo cells., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The umbilical cord (UC) matrix is a source of multipotent mesenchymal stem cells (MSCs) that have adipogenic potential and thus can be a model to study adipogenesis. However, existing variability in adipocytic differentiation outcomes may be due to discrepancies in methods utilized for adipogenic differentiation. Additionally, functional characterization of UCMSCs as adipocytes has not been described. We tested the potential of three well-established adipogenic cocktails containing IBMX, dexamethasone, and insulin (MDI) plus indomethacin (MDI-I) or rosiglitazone (MDI-R) to stimulate adipocyte differentiation in UCMSCs. MDI, MDI-I, and MDI-R treatment significantly increased peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT-enhancer binding protein alpha (C/EBPα) mRNA and induced lipid droplet formation. However, MDI-I had the greatest impact on mRNA expression of PPARγ, C/EBPα, FABP4, GPD1, PLIN1, PLIN2, and ADIPOQ and lipid accumulation, whereas MDI showed the least. Interestingly, there were no treatment group differences in the amount of PPARγ protein. However, MDI-I treated cells had significantly more C/EBPα protein compared to MDI or MDI-R, suggesting that indomethacin-dependent increased C/EBPα may contribute to the adipogenesis-inducing potency of MDI-I. Additionally, bone morphogenetic protein 4 (BMP4) treatment of UCMSCs did not enhance responsiveness to MDI-induced differentiation. Finally to characterize adipocyte function, differentiated UCMSCs were stimulated with insulin and downstream signaling was assessed. Differentiated UCMSCs were responsive to insulin at two weeks but showed decreased sensitivity by five weeks following differentiation, suggesting that long-term differentiation may induce insulin resistance. Together, these data indicate that UCMSCs undergo adipogenesis when differentiated in MDI, MDI-I, and MDI-R, however the presence of indomethacin greatly enhances their adipogenic potential beyond that of rosiglitazone. Furthermore, our results suggest that insulin signaling pathways of differentiated UCMSCs are functionally similar to adipocytes., (© 2014 by the Society for Experimental Biology and Medicine.)

Background: Maternal obesity is associated with unfavorable outcomes, which may be reflected in the as yet undiscovered gene expression profiles of the umbilical cord (UC)., Methods: UCs from 12 lean (pregravid BMI < 24.9) and 10 overweight/obese (pregravid BMI ≥ 25) women without gestational diabetes were collected for gene expression analysis using Human Primeview microarrays. Metabolic parameters were assayed in mother's plasma and cord blood., Results: Although offspring birth weight and adiposity (at 2 wk) did not differ between groups, expression of 232 transcripts was affected in UC from overweight/obese compared with those of lean mothers. Gene-set enrichment analysis revealed an upregulation of genes related to metabolism, stimulus and defense response, and inhibitory to insulin signaling in the overweight/obese group. We confirmed that EGR1, periostin, and FOSB mRNA expression was induced in UCs from overweight/obese mothers, while endothelin receptor B, KLF10, PEG3, and EGLN3 expression was decreased. Messenger RNA expression of EGR1, FOSB, MEST, and SOCS1 were positively correlated (P < 0.05) with mother's first-trimester body fat mass (%)., Conclusion: Our data suggest a positive association between maternal obesity and changes in UC gene expression profiles favoring inflammation and insulin resistance, potentially predisposing infants to develop metabolic dysfunction later on in life.

Obesity is associated with low-grade chronic inflammation, which contributes to cellular dysfunction promoting metabolic disease. Obesity during pregnancy leads to a proinflammatory milieu in the placenta; however, the underlying causes for obesity-induced placental inflammation remain unclear. Here, we examine the mechanisms by which saturated fatty acids and inflammatory cytokines induce inflammation in placental trophoblasts. We conducted global transcriptomic profiling in BeWo cells following palmitate and/or TNFα treatment and gene/protein expression analyses of MAPK pathways and characterized downstream transcription factors directly regulating inflammatory cytokines. Microarray analysis revealed increased expression of genes regulating inflammation, stress response, and immediate early response in cytotrophoblasts in response to palmitic acid (PA), TNFα, or a combination of both (PA + TNFα). Both gene ontology and gene set enrichment analysis revealed MAPK and EGR-1 signaling to be upregulated in BeWo cells, which was confirmed via immunoblotting. Importantly, activation of JNK signaling was necessary for increased proinflammatory cytokine (IL-6, TNFα, and IL-8) and EGR1 mRNA. Consistent with the requirement of JNK signaling, ChIP analysis confirmed the recruitment of c-Jun and other MAPK-responsive immediate early factors on the EGR1 promoter. Moreover, recruitment of EGR-1 on cytokine promoters (IL-6, TNFα, and IL-8) and an impaired proinflammatory response following knockdown of EGR-1 suggested it as a central component of the mechanism facilitating inflammatory gene expression. Finally, akin to in vitro findings, term placenta from obese women also had both increased JNK and p38 signaling and greater EGR-1 protein relative to lean women. Our results demonstrate that lipotoxic insults induce inflammation in placental cells via activation of JNK/EGR-1 signaling.