Early Life Stress Alters Expression of Glucocorticoid Stress Response Genes and Trophic Factor Transcripts in the Rodent Basal Ganglia.

Early life stress shapes the developing brain and increases risk for psychotic disorders. Yet, it is not fully understood how early life stress impacts brain regions in dopaminergic pathways whose dysfunction can contribute to psychosis. Therefore, we investigated gene expression following early life stress in adult brain regions containing dopamine neuron cell bodies (substantia nigra, ventral tegmental area (VTA)) and terminals (dorsal/ventral striatum). Sprague-Dawley rats (14F, 10M) were separated from their mothers from postnatal days (PND) 2-14 for 3 h/day to induce stress, while control rats (12F, 10M) were separated for 15 min/day over the same period. In adulthood (PND98), brain regions were dissected, RNA was isolated and five glucocorticoid signalling-related and six brain-derived neurotrophic factor (Bdnf) mRNAs were assayed by qPCR in four brain regions. In the VTA, levels of glucocorticoid signalling-related transcripts differed in maternally separated rodents compared to controls, with the Fkbp5 transcript significantly lower and Ptges3 transcript significantly higher in stressed offspring. In the VTA and substantia nigra, maternally separated rodents had significantly higher Bdnf IIA and III mRNA levels than controls. By contrast, in the ventral striatum, maternally separated rodents had significantly lower expression of Bdnf I, IIA, IIC, IV and VI transcripts. Sex differences in Nr3c1, Bag1 and Fkbp5 expression in the VTA and substantia nigra were also detected. Our results suggest that early life stress has long-lasting impacts on brain regions involved in dopamine neurotransmission, changing the trophic environment and potentially altering responsiveness to subsequent stressful events in a sex-specific pattern.

Self-glycerophospholipids activate murine phospholipid-reactive T cells and inhibit iNKT cell activation by competing with ligands for CD1d loading.

Glycosphingolipids and glycerophospholipids bind CD1d. Glycosphingolipid-reactive invariant NKT-cells (iNKT) exhibit myriad immune effects, however, little is known about the functions of phospholipid-reactive T cells (PLT). We report that the normal mouse immune repertoire contains αß T cells, which recognize self-glycerophospholipids such as phosphatidic acid (PA) in a CD1d-restricted manner and don't cross-react with iNKT-cell ligands. PA bound to CD1d in the absence of lipid transfer proteins. Upon in vivo priming, PA induced an expansion and activation of T cells in Ag-specific manner. Crystal structure of the CD1d:PA complex revealed that the ligand is centrally located in the CD1d-binding groove opening for TCR recognition. Moreover, the increased flexibility of the two acyl chains in diacylglycerol ligands and a less stringent-binding orientation for glycerophospholipids as compared with the bindings of glycosphingolipids may allow glycerophospholipids to readily occupy CD1d. Indeed, PA competed with α-galactosylceramide to load onto CD1d, leading to reduced expression of CD1d:α-galactosylceramide complexes on the surface of dendritic cells. Consistently, glycerophospholipids reduced iNKT-cell proliferation, expansion, and cytokine production in vitro and in vivo. Such superior ability of self-glycerophospholipids to compete with iNKT-cell ligands to occupy CD1d may help maintain homeostasis between the diverse subsets of lipid-reactive T cells, with important pathogenetic and therapeutic implications.

Successful treatment of distal intestinal obstruction syndrome with N-acetylcysteine and polyethylene glycol via colonoscopy.

We describe a case of a 46-year-old woman with cystic fibrosis who presented with several days of abdominal pain and distension. She was found to have a small bowel obstruction with inspissated stool in the distal ileum on CT imaging. Despite initial management with conservative measures, her symptoms worsened. She was taken for urgent colonoscopy with administration of 4% N-acetylcysteine (NAC) and polyethylene glycol (PEG) at the distal ileum with resultant dissolution of the fecalith. Over the following days, her symptoms improved, and she was discharged with outpatient follow-up.

Recurrent Clostridium difficile infection is associated with treatment failure and prolonged illness in cancer patients.

BACKGROUND: Cancer patients are susceptible to recurrent Clostridium difficile infection (CDI) that is increasing globally, necessitating new approaches to prevent fatal consequences. We examined the clinical characteristics of cancer patients with recurrent CDI (RCDI). PATIENTS AND METHODS: A retrospective review of cancer patients with C. difficile-positive test between January 2015 and May 2017 was carried out. CDI was defined as diarrhea and toxigenic C. difficile detection in the stool by nucleic acid amplification test and enzyme immunoassay. Patients having two CDI episodes were categorized as single recurrent CDI (SRCDI), and those having three or more CDI episodes were categorized as multiple recurrent CDI (MRCDI). Treatment failure was defined as the requirement of antimicrobial alteration or repetition. RESULTS: We included 170 patients having 270 CDI episodes; 85 patients had non-RCDI, and 85 had RCDI; 14 of them had MRCDI. Previous hospitalization and immunosuppressant use were more frequent in MRCDI group than in SRCDI group (P=0.009 and 0.002, respectively). Physicians treated more SRCDI episodes than MRCDI episodes with metronidazole alone (P=0.017), whereas, more MRCDI episodes needed combination antimicrobials (P=0.072). The mean duration of CDI treatment was longer in the MRCDI group than in the SRCDI group (P=0.030). MRCDI was associated with treatment failure more than SRCDI (P=0.021). The risk for a recurrent episode of CDI was increased in patients who had the following features of the first CDI episode: previous use of antibiotic, NSAID, immunosuppressant, chemotherapy, comorbidities, CDI treatment failure, and severe CDI (P<0.05). CONCLUSION: Risk factors for RCDI in cancer patients are similar to those without cancer, with the exception of chemotherapy that is only given to cancer patients. Long CDI treatment and CDI treatment failure are associated with MRCDI.

Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment.

BACKGROUND: Immune checkpoint inhibitors (ICIs) represent a promising novel class of cancer therapy, but immune-mediated adverse events can complicate ICI treatment. Acute cholecystitis in patients receiving ICI therapy has not been characterized. We aimed to describe the clinical features of patients who developed ICI-related cholecystitis. METHODS: We evaluated a case series of patients at a tertiary cancer center who received ICI therapy and developed cholecystitis, diagnosed by clinical presentation and diagnostic imaging, during 2010-2018. Patients with a history of chronic cholecystitis or other etiologies of acute cholecystitis, such as cholelithiasis, were excluded. A chi-square test was used to compare the frequency of cholecystitis between ICI regimens. Kaplan-Meier and log rank analyses were used to compare survival between subgroups. RESULTS: Of the 4253 patients who received ICIs in the study period, 25 (0.6%) patients developed suspected ICI-related cholecystitis. Alternatively, of the 31,426 cancer-matched patients who received non-ICI therapy, 72 (0.2%) developed acalculous cholecystitis (P < 0.001). Among the 25 included patients, the median time from ICI initiation to cholecystitis was 6 months (range, 0.1-31 months). Fifteen (60%) patients received an inhibitor of programmed death protein 1 (anti-PD-1) or of its ligand (anti-PD-L1) as a single agent, and 10 (40%) patients received an inhibitor of cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) therapy alone or combined with anti-PD-1/L1. Anti-CTLA-4 monotherapy was associated with a higher risk of cholecystitis (P = 0.006). ICI therapy was discontinued in 20 patients, in three (12%) as a result of acute cholecystitis. Two (8%) patients developed sepsis, and four (16%) had perforation of the gallbladder wall. Five (20%) patients underwent surgical cholecystectomy, and eight (32%) underwent percutaneous drainage. Five (20%) patients were treated with steroids; two of them required surgery. Ten (40%) patients were able to restart ICI therapy. Patients who received a combination of anti-CTLA-4 and anti-PD-1/L1 had more complications of cholecystitis than did patients who received either agent alone (P = 0.03). CONCLUSIONS: ICI treatment can result in a clinical condition similar to typical acute cholecystitis in a minority of patients. ICI-related cholecystitis should be managed in a similar fashion to typical cholecystitis. The efficacy of steroids for the treatment of ICI-related cholecystitis is unclear.