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Background Infants born preterm due to chorioamnionitis are frequently affected by a fetal inflammatory response syndrome (FIRS) and then by subsequent postnatal infections. FIRS and postnatal systemic inflammatory events independently contribute to poor neurocognitive outcomes of preterm infants. Developmental integrity of the hippocampus is crucial for intact neurocognitive outcomes in preterms and hippocampally dependent behaviors are particularly vulnerable to preterm systemic inflammation. How FIRS modulates the hippocampal immune response to acute postnatal inflammatory events is not well understood. Methods Prenatal LPS exposed (FIRS) and control neonatal rats received i.p. LPS or saline at postnatal day (P) 5. On P7, immune response was evaluated in the hippocampus of four treatment groups by measuring gene expression of inflammatory mediators and cytosolic and nuclear NFκB pathway proteins. Microglial activation was determined by CD11b+ and Iba1+ immunohistochemistry (IHC) and inflammatory gene expression of isolated microglia. Astrocyte reactivity was measured using Gfap+ IHC. Results Postnatal LPS resulted in a robust hippocampal inflammatory response. In contrast, FIRS induced by prenatal LPS attenuated the response to postnatal LPS exposure, evidenced by decreased gene expression of inflammatory mediators, decreased nuclear NFκB p65 protein, and fewer activated CD11b+ and Iba1+ microglia. Isolated microglia demonstrated inflammatory gene upregulation to postnatal LPS without evidence of immune tolerance by prenatal LPS. Conclusion Prenatal LPS exposure induced immune tolerance to subsequent postnatal LPS exposure in the hippocampus. Microglia demonstrate a robust inflammatory response to postnatal LPS, but only a partial immune tolerance response.

Sepsis continues to be a major problem for hospitalized patients. Opioids are widely used medications for pain management despite recent evidence revealing their adverse effects. The present study evaluates survival differences between opioid-treated patients and non-opioid-treated patients hospitalized with a diagnosis of sepsis. Clinical data was extracted from the University of Minnesota's Clinical Data Repository, which includes Electronic Health Records (EHRs) of the patients seen at 8 hospitals. Among 5,994 patients diagnosed with sepsis, 4,540 opioid-treated patients and 1,454 non-opioid patients were included based on whether they are exposed to prescription opioids during their hospitalization. Cox proportional hazards regression showed that after adjustments for demographics, clinical comorbidities, severity of illness, and types of infection, opioid-treated patients had a significantly higher risk of death at 28 days.

Intestinal barrier dysfunction and subsequent microbial translocation play crucial roles in persistent immune activation leading to HIV disease progression. Opioid use is associated with worse outcome in HIV-infected patients. The exacerbated disease progression by opioids is mainly driven by excessive intestinal inflammation and increased gut permeability. The objective of this study is to investigate how opioids potentiate HIV disease progression by compromising intestinal barrier function and impairing intestinal epithelial self-repair mechanism. In the present study, abnormal intestinal morphology and reduced epithelial proliferation were observed in bone marrow-liver-thymus humanized mice and in HIV-infected patients who were exposed to opioids. In bone marrow-liver-thymus mice, HIV, and morphine independently, and additively induced gut dysbiosis, especially depletion of Lachnospiraceae, Ruminococcaceae, and Muribaculaceae. We also observed that the abundance of Lachnospiraceae, Ruminococcaceae, and Muribaculaceae negatively correlated with apoptosis of epithelial cells, and intestinal IL-6 levels. Previous studies have shown that these bacterial families play crucial roles in maintaining intestinal homeostasis because they include most short-chain fatty acid-producing members. Short-chain fatty acids have been shown to maintain stem cell populations and suppress inflammation in the gut by inhibiting histone deacetylases (HDAC). In addition, we demonstrate that morphine exposure inhibited growth of intestinal organoids derived from HIV transgenic mice by suppressing Notch signaling in an HDAC-dependent manner. These studies implicate an important role for HDAC in intestinal homeostasis and supports HDAC modulation as a therapeutic intervention in improving care of HIV patients, especially in opioid-abusing population.

PurposePeritoneal dialysis (PD) is a commonly used method for renal support in pediatric patients and can be associated with the risk of post-surgical complications. We evaluated method of placement of PD catheters with regard to post-surgical complications.MethodsPD catheters placed at two institutions between 2005 and 2017 were reviewed. Complication rates were evaluated based on method of placement, delayed usage, omentectomy, and patient age using Fisher’s exact test, two-sided, with significance set at 0.05. Factors influencing complication were evaluated with multivariate logistic regression and Kaplan–Meier survival analysis.ResultsThere were 130 patients with 157 catheters placed, ranging in age from 1 day to 23 years. There was no significant difference in complication rate by method of placement or delayed usage. Infants were significantly more likely to experience leakage (21% vs 8%, p 0.036) and hernias (15% vs 5%, p 0.030). Patients that underwent an omentectomy were less likely to require a catheter replacement (7% vs 27%, p 0.004), and the catheters had a significantly higher survival rate (p 0.009). We found that laparoscopic intervention resulted in catheter salvage. Lateral exit sites may be a risk factor for catheter migration in some patients.ConclusionsOmentectomy is associated with longer PD catheter survival. Laparoscopic salvage of dysfunctional catheters may be a valuable adjunct in management.

Hyperparathyroidism (HPT) is a rare disease in the pediatric population, and optimal management may be unclear if it is due to an occult parathyroid adenoma. We present a case report of a pediatric patient with an occult, ectopic, supernumerary, parathyroid adenoma. A 13-year-old female who initially presented with anxiety was diagnosed with HPT. Preoperative imaging and bilateral neck exploration with four-gland biopsy were negative for any parathyroid adenoma. Postoperative MRI identified a thymic mass. She subsequently underwent video-assisted thoracoscopic thymectomy with resection of an intrathymic parathyroid adenoma. The diagnosis of pediatric HPT is increasing. Supernumerary or occult parathyroid adenomas are rare and add complexity to presurgical planning and management. Our case represents the rare occurrence of a pediatric ectopic supernumerary occult parathyroid adenoma treated with a two-stage approach utilizing multiple imaging studies. We provide a review of the pathology and propose an algorithmic approach to manage these complex patients.

Acetylcholine release from cholinergic neurons regulates pancreatic exocrine function through pathways that are still under investigation. Pancreatic AR42J acinar cells were studied to determine intracellular calcium ([Ca 2+] i) release, enzyme activation, and gene expression in response to the acetylcholine analog carbachol (CCh). CCh stimulated dose-dependent increases in [Ca 2+] i that were inhibited by atropine and by specific inhibitors to the muscarinic receptor subtypes m1 and m3. Polymerase chain reaction analysis was performed, which sequenced products corresponding to the m1 and m3 receptor subtypes but not the m2 subtype. CCh also stimulated mitogen-activated protein kinase activity. CCh induced time-and dose-dependent increases in the c-fos and c-jun early-response genes, which were blocked by m1 and m3 inhibition but not by m2 inhibition.

Pancreatic exocrine function has been demonstrated to be under neuronal regulation. The pathways responsible forthis effect, and the long-term consequences of such interactions, are incompletely described. The effects of neuronal depolarization on pancreatic acinar cells were studied to determine whether calcium signaling and c-fos expression were activated. In pancreatic lobules, which contain both neurons and acinar cells, agonists that selectively stimulated neurons increased intracellular calcium in acinar cells. Depolarization also led to the expression of c-fos protein in 24% ±4% of the acinar cells. In AR42J pancreatic acinar cells, cholinergic stimulation demonstrated an average increase of 398 ±19 nmol/L in intracellular calcium levels, and induced c-fos expression that was time and dose dependent. The data indicate that intrapancreatic neurons induce Ca^sup 2+^ signaling and early-response gene expression in pancreatic acinar cells.[PUBLICATION ABSTRACT]

The enteric nervous system (ENS) regulates multiple functions in the gastrointestinal tract. Within this intricate network, growing evidence suggests that, enteric glia play a vital role in the gut. However, their precise function and inherent signaling mechanisms are poorly characterized. In this thesis, specific mechanisms are revealed in an effort to further characterize these enigmatic cells. Structural and functional similarities of glia of the central and enteric nervous systems exist, reinforcing the conceivable potential for glial involvement in active signaling within the GI tract. Data characterize various well-described neuroligands and their effects on calcium signaling events within enteric glia—a phenomenon in the brain wherein lies the means to modulate neuronal activity and synaptic transmission. These cells within the intestine have unique signaling characteristics, without which enteric neurons, the gastrointestinal tract, and the organism as a whole would be incapable of survival. An investigation of the actions of novel lipid compounds in the ENS is revealed. This series of studies was conducted with the long-range goal of understanding information transfer within the GI tract. Enteric glia, and NOT enteric neurons, are found to selectively respond to a family of recently described bioactive lipids including sphingosine-1-phosphate (S1P), a sphingomyelin metabolite, and a related lipid lysophosphatidic acid (LPA). Both molecules are shown to induce Ca2+ signaling in these cells, and their signaling mechanisms characterized on the cellular level, including a depiction of specific involvement with a novel family of G-protein coupled receptors—EDG receptors. Emerging data are also revealed, serving as the foundation for future endeavors, depicting two other new bioactive lipid family members (sphingosylphosphorylcholine and lysophatidylcholine) that similarly appear to serve as signaling molecules in the GI tract with robust calcium responses, further adding to the complexity with which these cells function. Lastly, S1P and related lipids affect cellular behavior at the transcriptional level: inducing expression of early response genes in a model glial cell line. The work presented here strongly supports a potential role for glia in information transfer within the walls of the bowel and beyond as we demonstrate the increasing diversity of signaling events displayed by these cells.