Ziad Kanaan

Differential microRNA (miRNA) expression could explain microbial tolerance in a novel chronic peritonitis model.

We observed persistent peritoneal bacteria despite a transient early innate immune response to intraperitoneal (IP) Klebsiella pneumoniae. Pretreatment with LPS prior to peritonitis induced a tolerant pattern of pro-inflammatory cytokine protein production over 72 h, but not at the mRNA level. MicroRNAs (miRNAs) regulate inflammatory cytokines and may explain this paradox. After pretreatment with IP LPS or saline, C57BL/6 mice were given 103 CFU of K. pneumoniae IP. Total RNA was isolated from peritoneal exudate cells (4 h, 24 h and 48 h following infection). mRNA and miRNA expression levels were detected and bioinformatics pathway analysis was performed, followed by measuring TNF-α, IL-1β, IL-6 and High-mobility Group Box 1 (HMBG1) protein levels. Of 88 miRNAs studied, 30 were significantly dysregulated at all time points in the LPS-pretreated group, including MiR-155, -146a, -142-3p, -299, and -200c -132 and -21. TNF-α, regulated by miR-155 and miR-146a, was decreased in the LPS-pretreated group at all time points (P < 0.05), as were HMGB1, a key alarmin regulated by miR-146, -142-3p, -299 and -200c (P < 0.05), and IL-1β and IL-6, both regulated by miR-132and miR-21 respectively (P < 0.05). Specific dysregulation of miR-155, -146a, -142-3p, -299, and -200c -132 and -21 with their corresponding effects on the TLR and NF-κB signaling pathways during inflammation, suggests a plausible mechanism for tolerance in this novel chronic model with persistent peritoneal infection.

Poor outcome in bacterial peritonitis is associated with dysregulated microRNAs and an increased inflammatory response

BACKGROUND Peritonitis is a common cause of surgical sepsis. The failure of the host to mount an appropriate immune response contributes to persistence of the infection. We investigated the role microRNAs may play in this failed immune response. METHODS Klebsiella pneumoniae was injected intraperitoneally in mice. Weight loss was used to predict clinical outcome. Peritoneal exudate cells (PECs) and supernatant were collected. RNA from PECs was run on screening microRNA array cards to determine gene expression, and validated by single assay analysis. Cytokine levels in supernatant were assayed by enzyme-linked immunosorbent assay. RESULTS Despite similar bacterial levels, PEC counts were higher in the predicted death group. The predicted deaths had higher levels of proinflammatory tumor necrosis factor-α/IL-6 and significantly lower levels of interleukin-10. MiR-221 was up-regulated in both the predicted death and predicted survivor groups. Five miRNAs were up-regulated in the predicted survivor group compared with normal controls. CONCLUSION Higher PEC counts and proinflammatory cytokines in the predicted death group indicates an exaggerated inflammatory response, with lower IL-10 levels despite similar bacterial counts. There were two dysregulated miRNAs with transcriptional targets that may explain our results. A more balanced immune response with an appropriate counter inflammatory response may be important for improving survival.

Prognostic implications of recipient or donor hepatitis B seropositivity in thoracic transplantation: analysis of 426 hepatitis B surface antigen-positive recipients

Prognostic data on survival of hepatitis B surface antigen‐positive (HBsAg+) recipients and of hepatitis B core antibody‐positive (HBcAb+) donors are limited in the thoracic transplantation (TT) cohort. Improved understanding of risks could potentially expand the recipient and donor pools.

Guillain-Barré Syndrome following Treatment with Sunitinib Malate.

Sunitinib malate (Sutent, SU011248) is an oral multitargeted tyrosine kinase inhibitor (TKI) used for the treatment of metastatic renal cell carcinoma and imatinib (Gleevec)—resistant gastrointestinal stromal tumor (GIST) with few reported side effects including asthenia, myelosuppression, diarrhea, and mucositis. Scarce literature exists regarding the rare but often serious toxicities of sunitinib. Autoimmune and neurological side effects have been linked to sunitinibs inhibition of VEGF receptors with a corresponding increase in VEGF levels, which is associated with development of different neuropathies. We hereby report an interesting case of Guillain-Barré syndrome in a middle-aged patient with metastatic renal cell carcinoma following sunitinib treatment.

Conscious sedation: a dying practice?

Sedation practices vary according to countries with different health system regulations, the procedures done, and local circumstances. Interestingly, differences in the setting in which the practice of gastroenterology and endoscopy takes place (university-based vs academic practice) as well as other systematic practice differences influence the attitude of endoscopists concerning sedation practices. Conscious sedation using midazolam and opioids is the current standard method of sedation in diagnostic and therapeutic endoscopy. Interestingly, propofol is a commonly preferred sedation method by endoscopists due to higher satisfaction rates along with its short half-life and thus lower risk of hepatic encephalopathy. On the other hand, midazolam is the benzodiazepine of choice because of its shorter duration of action and better pharmacokinetic profile compared with diazepam. The administration of sedation under the supervision of a properly trained endoscopist could become the standard practice and the urgent development of an updated international consensus regarding the use of sedative agents like propofol is needed.

CA11-19: a promising marker for the detection of colorectal cancer.

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Transfusion for Acute Upper Gastrointestinal Bleeding

To the Editor: In their study, Villanueva et al. (Jan. 3 issue)1 conclude that a low hemoglobin threshold for initiating transfusion (hemoglobin level, <7 g per deciliter) improves outcomes in patients with acute upper gastrointestinal bleeding. All the patients in the study who had evidence of upper gastrointestinal bleeding underwent emergency gastroscopy within the first 6 hours after admission. Whereas gastroscopy in the first 6 hours after admission is feasible in clinical research trials, time delays of more than 6 hours may routinely occur in general clinical practice, particularly for patients with low Rockall scores. Furthermore, it would be helpful to compare the effects of a restrictive transfusion strategy in certain subgroups: first, among patients with a low (1 or 2) versus high (>2) Rockall score; and second, among patients who have received aspirin or other oral anticoagulant therapy versus those who have not received such therapy. This analysis would help address whether patients at increased risk for recurrent bleeding (i.e., those with a high Rockall score and those receiving oral anticoagulant therapy2,3) warrant a restrictive transfusion strategy.