Declining Use of Corticosteroids for Crohn's Disease Has Implications for Study Recruitment: Results of a Pilot Randomized Controlled Trial.

BACKGROUND: Corticosteroids (CS) have been used extensively to induce remission in Crohn's disease (CD); however, they are associated with severe side effects. We hypothesized that the administration of an exclusive enteral nutrition (EEN) formula to CS would lead to increased CD remission rates and to decreased CS-related adverse events. We proposed to undertake a pilot study comparing EEN and CS therapy to CS alone to assess decrease symptoms and inflammatory markers over 6 weeks. AIM: The overall aim was to assess study feasibility based on recruitment rates and acceptability of treatment in arms involving EEN. METHODS: The pilot study intended to recruit 100 adult patients with active CD who had been prescribed CS to induce remission as part of their care. The patients were randomized to one of three arms: (i) standard-dose CS; (ii) standard-dose CS plus EEN (Modulen 1.5 kcal); or (iii) short-course CS plus EEN. RESULTS: A total of 2009 CD patients attending gastroenterology clinics were screened from October 2018 to November 2019. Prednisone was prescribed to only 6.8% (27/399) of patients with active CD attending outpatient clinics. Of the remaining 372 patients with active CD, 34.8% (139/399) started or escalated immunosuppressant or biologics, 49.6% (198/399) underwent further investigation and 8.8% (35/399) were offered an alternative treatment (e.g., antibiotics, surgery or investigational agents in clinical trials). Only three patients were enrolled in the study (recruitment rate 11%; 3/27), and the study was terminated for poor recruitment. CONCLUSION: The apparent decline in use of CS for treatment of CD has implications for CS use as an entry criterion for clinical trials.

Hypothesis: Bacterial induced inflammation disrupts the orderly progression of the stem cell hierarchy and has a role in the pathogenesis of breast cancer.

BACKGROUND: The hierarchical model of stem cell genesis is based on the idea that the number of cell divisions between the zygote and fully differentiated epithelial cells is kept close to the minimum, which is log to the base 2 of the total number of cells produced in a human lifetime. The model assumes the orderly progression of stem cell divisions requires precise control at every stage in development. If the orderly progression is maintained then cancer will be rare. A prediction of the model is that if the orderly progression of the stem cell hierarchy is disturbed by trauma, ulceration or inflammation then cancer will occur. HYPOTHESIS: Bacterial induced inflammation in breast ducts disturbs the stem cell hierarchy and is a cause of breast cancer. EVIDENCE: Mammalian milk is not sterile. It contains a range of bacteria, derived endogenously by the entero-mammary circulation. The dominant flora consists of lactose fermenting bacteria. Pregnancy and breast feeding reduce the risk of subsequent breast cancer. The implication is that a lactose fermenting bacterial flora in breast ducts is protective. Malignant and benign breast tissue contains bacteria derived endogenously, but studies so far have not revealed a specific flora associated with malignancy. Periodontitis is associated with oral, oesophageal, colonic, pancreatic, prostatic and breast cancer. The pathogenic bacteria which cause periodontitis spread endogenously to cause inflammation at other epithelial sites. Meta-analysis of epidemiological studies shows that the consumption of yoghurt is associated with a reduction in the risk of breast cancer. CONCLUSION: The hypothesis, although not proven, is supported by the available evidence. Lactose fermenting bacteria protect but pathogenic bacteria which induce inflammation raise the risk of breast cancer. The consumption of yoghurt also appears to be protective.

Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells.

T-regulatory cells (Tregs) are essential for immune tolerance, and animal studies implicate their dysfunction in type 1 diabetes (T1D) pathogenesis. Tregs require interleukin-2 (IL-2) for their suppressive function, and variants in IL-2/IL-2R pathway genes have been associated with T1D. We previously reported that recent-onset T1D subjects have an increased population of FOXP3lo Tregs that secrete the pro-inflammatory cytokine, interleukin-17 (IL-17). We hypothesize that IL-2 signaling defects may drive T1D development by skewing protective Tregs towards an inflammatory Th17 phenotype. Overall, we found that the proportion of FOXP3+IL-17+ cells in T1D subjects pre-diagnosis was unchanged compared with healthy controls. However, stratification by IL2RA single-nucleotide polymorphisms revealed that T1D subjects with the rs3118470 CC risk variant have Tregs with IL-2 signaling defects and an increased proportion of FOXP3+IL-17+ cells before diagnosis. These data suggest a potential mechanism for genetically controlled loss of Treg function via dysfunctional IL-2 signaling in T1D.

Why do obstetric patients go to the ICU? A 3-year-study.

BACKGROUND: Pregnant women are at risk to develop complications due to illness related to pregnancy or due to aggravation of pre-existing disease. These patients also require critical care and ICU admissions in some cases. To determine the current spectrum of diseases in an obstetric population resulting in admission to the intensive care unit (ICU) at a tertiary care hospital. METHODS: A retrospective case series study and analysis of data from obstetric patients admitted for critical care management. RESULTS: 0.26% of the total obstetric patients admitted to the hospital required ICU admissions. 46% of patients were admitted to ICU for ventilator support. Pre-eclampsia and obstetrical hemorrhage were the common diagnosis for these patients. CONCLUSION: Critically ill obstetric patients require a team approach of the obstetrician, anesthesiologist and intensive care specialist for the optimal care of these patients.

Mitogen-activated protein kinase upregulation reduces renal D1 receptor affinity and G-protein coupling in obese rats.

Reactive oxygen species play a key role in pathophysiology of cardiovascular diseases by modulating G-protein-coupled receptor signaling. We have shown that treatment of animal models of diabetes and aging with tempol decreases oxidative stress and restores renal dopamine D1 receptor (D1R) function. In present study, we determined whether oxidation of D1R and upregulation of mitogen-activated protein kinases (MAPK) were responsible for decreased D1R signaling in obese animals. Male lean and obese Zucker rats were supplemented with antioxidants tempol or lipoic acid for 2 weeks. Compared to lean, obese animals were hyperglycemic and hyperinsulinemic with increased oxidative stress, D1R oxidation and decreased glutathione levels. These animals had decreased renal D1R affinity and basal coupling to G-proteins. SKF-38393, a D1R agonist failed to stimulate G-proteins and adenylyl cyclase. Obese animals showed marked increase in renal MAPK activities. Treatment of obese rats with tempol or lipoic acid decreased blood glucose, reduced oxidative stress, and restored the basal D1R G-protein coupling. Antioxidants also normalized MAPK activities and restored D1R affinity and SKF-38393 induced D1R G-protein coupling and adenylyl cyclase stimulation. These studies show that D1R oxidation and MAPK upregulation contribute to D1R dysfunction in obese animals. Consequently, antioxidants while reducing the oxidative stress normalize the MAPK activities and restore D1R signaling.

Facile, regioselective [4 + 2] cycloaddition involving 1-aryl-4-phenyl-1-azadienes and allenic esters: an efficient route to novel substituted 1-aryl-4-phenyl-1,4-dihydropyridines.

[reaction: see text]1-Aryl-4-phenyl-1-azadienes undergo facile, regioselective [4 + 2] cycloaddition to the C2,C3 pi-bond of allenic esters in refluxing benzene, and the formed adducts undergo a 1,3-H shift to afford novel 2-alkyl-1-aryl-3-ethoxycarbonyl-4-phenyl-1,4-dihydropyridines (78-97%). However, when the reaction is carried at room temperature, besides the [4 + 2] addition, the [2 + 2] mode of addition involving C=N of azadiene and C3,C4 pi-bond of allenic esters also intervenes. The resulting N-aryl-2-ethoxy-carbonyl-methylidene-4-styrylazetidines (17-28%) undergo reorganization on silica gel to afford 2-cyclohexen-1-ones.