Intrinsic Cellular Susceptibility to Barrett’s Esophagus in Adults Born with Esophageal Atresia

The prevalence of Barrett’s esophagus (BE) in adults born with esophageal atresia (EA) is four times higher than in the general population and presents at a younger age (34 vs. 60 years). This is (partly) a consequence of chronic gastroesophageal reflux. Given the overlap between genes and pathways involved in foregut and BE development, we hypothesized that EA patients have an intrinsic predisposition to develop BE. Transcriptomes of Esophageal biopsies of EA patients with BE (n = 19, EA/BE); EA patients without BE (n = 44, EA-only) and BE patients without EA (n = 10, BE-only) were compared by RNA expression profiling. Subsequently, we simulated a reflux episode by exposing fibroblasts of 3 EA patients and 3 controls to acidic conditions. Transcriptome responses were compared to the differential expressed transcripts in the biopsies. Predisposing single nucleotide polymorphisms, associated with BE, were slightly increased in EA/BE versus BE-only patients. RNA expression profiling and pathway enrichment analysis revealed differences in retinoic acid metabolism and downstream signaling pathways and inflammatory, stress response and oncological processes. There was a similar effect on retinoic acid signaling and immune response in EA patients upon acid exposure. These results indicate that epithelial tissue homeostasis in EA patients is more prone to acidic disturbances

Intrinsic Cellular Susceptibility to Barrett’s Esophagus in Adults Born with Esophageal Atresia

The prevalence of Barrett’s esophagus (BE) in adults born with esophageal atresia (EA) is four times higher than in the general population and presents at a younger age (34 vs. 60 years). This is (partly) a consequence of chronic gastroesophageal reflux. Given the overlap between genes and pathways involved in foregut and BE development, we hypothesized that EA patients have an intrinsic predisposition to develop BE. Transcriptomes of Esophageal biopsies of EA patients with BE (n = 19, EA/BE); EA patients without BE (n = 44, EA-only) and BE patients without EA (n = 10, BE-only) were compared by RNA expression profiling. Subsequently, we simulated a reflux episode by exposing fibroblasts of 3 EA patients and 3 controls to acidic conditions. Transcriptome responses were compared to the differential expressed transcripts in the biopsies. Predisposing single nucleotide polymorphisms, associated with BE, were slightly increased in EA/BE versus BE-only patients. RNA expression profiling and pathway enrichment analysis revealed differences in retinoic acid metabolism and downstream signaling pathways and inflammatory, stress response and oncological processes. There was a similar effect on retinoic acid signaling and immune response in EA patients upon acid exposure. These results indicate that epithelial tissue homeostasis in EA patients is more prone to acidic disturbances

The effect of grapefruit juice on the time-dependent decline of artemether plasma levels in healthy subjects

Background: Artemether is a new and effective treatment for malaria, although relapse is a problem in monotherapy. These relapses could be related to a time-dependent decline in artemether plasma levels described in multiple-dose studies and probably caused by autoinduction. The aim of this study was to evaluate the effect of grapefruit juice on the decreasing bioavailability over time of artemether. Methods: In a randomized, two-phase crossover study, eight healthy male subjects took 100 mg oral artemether with 350 mL water or with 350 mL double-strength fresh frozen grapefruit juice once daily for 5 days. On day 1 and day 5, 17 blood samples were collected over a period of 8 hours. Results: The mean peak artemether plasma concentration (C(max)) and the mean area under the concentration-time curve (AUC) after the last dose at day 5 were about one third compared with day 1, without a change in the elimination half-life after intake with water (P = .006 for C(max); P = .005 for AUC) and with grapefruit juice (P < .001 for C(max) and AUC). Grapefruit juice increased C(max) (P = .021) and AUC (P < .001) twofold on day 1 (P = .021) and day 5 (P = .05 for C(max); P = .004 for AUC). Dihydroartemisinin, the active metabolite, showed a twofold increase in C(max) (P = .006) and AUG (P = .001) with grapefruit juice, without time- dependent changes of pharmacokinetic parameters. Conclusions: Grapefruit juice significantly increased the oral bioavailability of artemether but did not prevent the time-dependent reduction in bioavailability. It suggests that CYP3A4 in the gut wall is one of the metabolizing enzymes of artemether but seems to not be involved in the autoinduction process

Differential Cytokine Production and Toll-Like Receptor Signaling Pathways by Candida albicans Blastoconidia and Hyphae

Toll-like receptors (TLR) are crucial for an efficient antifungal defense. We investigated the differential recognition of blastoconidia and hyphae of Candida albicans by TLRs. In contrast to Candida blastoconidia, which stimulated large amounts of gamma interferon (IFN-γ), the tissue-invasive Candida hyphae did not stimulate any IFN-γ by human peripheral blood mononuclear cells (PBMC) or murine splenic lymphocytes. After stimulation with blastoconidia, the production of IFN-γ was TLR4 dependent, as shown by the significantly decreased IFN-γ production in anti-TLR4-treated PBMC and in splenic lymphocytes from TLR4-defective ScCr mice. In addition, peritoneal macrophages from ScCr mice produced less tumor necrosis factor α (TNF-α) than macrophages of control mice did when stimulated with Candida blastoconidia, but not with hyphae, indicating that TLR4-mediated signals are lost during hyphal germination. In contrast, macrophages from TLR2 knockout mice had a decreased production of TNF-α in response to both Candida blastoconidia and hyphae. Candida hyphae stimulated production of interleukin-10 through TLR2-dependent mechanisms. In conclusion, TLR4 mediates proinflammatory cytokine induction after Candida stimulation, whereas Candida recognition by TLR2 leads mainly to anti-inflammatory cytokine release. TLR4-mediated proinflammatory signals are lost during germination of Candida blastoconidia into hyphae. Phenotypic switching during germination may be an important escape mechanism of C. albicans, resulting in counteracting host defense

Nucleotide Oligomerization Domain 2 (Nod2) Is Not Involved in the Pattern Recognition of Candida albicans

Nucleotide-binding oligomerization domain 2 (Nod2) pathways are known to interact with Toll-like receptor 2 (TLR2) and TLR4, which are pattern recognition receptors for Candida albicans. We observed that the prevalence of Nod2 polymorphisms was not increased in patients with Candida infections. Candida-induced cytokine production in individuals with Nod2 polymorphisms was unaffected. We conclude that Nod2 is unlikely to play an important role in the recognition of Candida albicans

Prophylactic antibiotics reduce hospitalisations and cost in locally advanced head and neck cancer patients treated with chemoradiotherapy: A randomised phase 2 study

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