Research Spotlight

Shenje, J., F. I. Adimora-Nweke, I. L. Ross, M. Ntsekhe, L. Wiesner, A. Deffur, H. M. McIlleron, J. Pasipanodya, T. Gumbo and B. M. Mayosi (2015). “Poor Penetration of Antibiotics Into Pericardium in Pericardial Tuberculosis.” Ebiomedicine 2(11): 1640-1649.

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Pericardial tuberculosis (TB) is associated with high therapy failure and high mortality rates. Antibiotics have to penetrate to site of infection at sufficient non-protein bound concentrations, and then enter bacteria to inhibit intracellular biochemical processes. The antibiotic concentrations achieved in pericardial fluid in TB pericarditis have never been measured before. We recruited two cohorts of patients with TB pericarditis, and left a pigtail catheter in-situ for serial drug concentration measurements over 24 h. Altogether, 704 drug concentrations were comodeled for pharmacokinetic analyses. The drug concentrations achieved in pericardial fluid were compared to the minimum inhibitory concentrations (MICs) of clinical Mycobacterium tuberculosis isolates. The total rifampicin concentration pericardial-to-serum ratios in 16 paired samples were 0.19 +/- 0.33. The protein concentrations of the pericardial fluid in TB pericarditis were observed to be as high as in plasma. The non-protein bound rifampicin concentrations in pericardial fluid were 4-fold lower than rifampicin MICs in the pilot study, and the peak concentration was 0.125 versus 0.208 mg/L in the second (p = 0.001). The rifampicin clearance from pericardial fluid was 9.45 L/h versus 7.82 L/h in plasma (p = 0.002). Ethambutol peak concentrations had a pericardial-to-plasma ratio of 0.55 +/- 0.22; free ethambutol peak concentrations were 2.30-lower than MICs (p < 0.001). The pericardial fluid pH was 7.34. The median pyrazinamide peak concentrations were 42.93mg/L versus a median MIC of 800mg/L at pH 7.34 (p < 0.0001). There was no significant difference between isoniazid pericardial fluid and plasma concentrations, and isoniazid peak concentrations were above MIC. This is the first study to measure anti-TB drug concentrations, pH and protein in the pericardial TB fluid. Pericardial concentrations of the key sterilizing drugs for TB were below MIC, which could contribute to poor outcomes. A new regimen that overcomes these limitations might need to be crafted. (C) 2015 The Authors. Published by Elsevier B.V.

Sharma, P., J. Brill, M. Canto, D. DeMarco, B. Fennerty, N. Gupta, L. Laine, D. Lieberman, C. Lightdale, E. Montgomery, R. Odze, J. Tokar and M. Kochman (2015). “White Paper AGA: Advanced Imaging in Barrett’s Esophagus.” Clinical Gastroenterology and Hepatology 13(13): 2209-2218.

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Enhanced imaging technologies such as narrow band imaging, flexible spectral imaging color enhancement, i-Scan, confocal laser endomicroscopy, and optical coherence tomography are readily available for use by endoscopists in routine clinical practice. In November 2014, the American Gastroenterological Association’s Center for GI Innovation and Technology conducted a 2-day workshop to discuss endoscopic image enhancement technologies, focusing on their role in 2 specific clinical conditions (colon polyps and Barrett’s esophagus) and on issues relating to training and implementation of these technologies (white papers). Although the majority of the studies that use enhanced imaging technologies have been positive, these techniques ideally need to be validated in larger cohorts and in community centers. As it stands today, detailed endoscopic examination with high-definition white-light endoscopy and random 4-quadrant biopsy remains the standard of care. However, the workshop panelists agreed that in the hands of endoscopists who have met the preservation and incorporation of valuable endoscopic innovation thresholds (diagnostic accuracy) with enhanced imaging techniques (specific technologies), use of the technique in Barrett’s esophagus patients is appropriate.

Reynolds, J., S. Carroll and C. Sturdivant (2016). “Fiberoptic Endoscopic Evaluation of Swallowing: A Multidisciplinary Alternative for Assessment of Infants With Dysphagia in the Neonatal Intensive Care Unit.” Advances in Neonatal Care 16(1): 37-43.

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BACKGROUND: The standard procedure to assess an infant in the neonatal intensive care unit (NICU) who is suspected of aspirating on oral feedings is a videofluoroscopic swallowing study (VFSS). The VFSS has been used for more than 30 years to assess dysphagia and is considered the gold standard. However, there are challenges to the VFSS, including radiation exposure, transport to radiology, usage of barium, limited positioning options, and cost. An alternative approach is fiberoptic endoscopic evaluation of swallowing (FEES), which uses a flexible endoscope passed transnasally into the pharynx to assess anatomy, movement/sensation of structures, swallow function, and response to therapeutic interventions. Fiberoptic endoscopic evaluation of swallowing has been established as a valid tool for evaluating dysphagia and utilized as an alternative or supplement to the VFSS in both adults and children. PURPOSE: This article provides an overview of the current challenges in the NICU with assessing aspiration and introduces a multidisciplinary FEES program for bottle and breastfeeding. METHODS/SEARCH STRATEGY: A review of the literature of dysphagia, VFSS, and FEES in the adult, pediatric, infant, and neonatal populations was performed. Clinical competency standards were researched and then implemented through an internal process of validation. Finally, a best practice protocolwas designed as it relates to FEES in the NICU. FINDINGS/RESULTS: Fiberoptic endoscopic evaluation of swallowing is a safe alternative to the VFSS. It can be utilized at the infant’s bedside in a NICU for the diagnosis and treatment of swallowing disorders by allowing the clinician the ability to replicate a more accurate feeding experience, therefore, determining a safe feeding plan. IMPLICATIONS FOR PRACTICE: Competency and training are essential to establishing a multidisciplinary FEES program in the NICU.IMPLICATIONS FOR RESEARCH: Further research is needed to compare the efficacy and validity of FEES versus VFSS for infants in the NICU. Furthermore, evaluating the efficacy of FEES during breastfeeding is warranted.

Han, J., Q. Zhao, C. Basmadjian, L. Desaubry and A. L. Theiss (2016). “Flavaglines Ameliorate Experimental Colitis and Protect Against Intestinal Epithelial Cell Apoptosis and Mitochondrial Dysfunction.” Inflammatory Bowel Diseases 22(1): 55-67.E

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BACKGROUND: Flavaglines are a family of natural compounds shown to have anti-inflammatory and cytoprotective effects in neurons and cardiomyocytes. Flavaglines target prohibitins as ligands, which are scaffold proteins that regulate mitochondrial function, cell survival, and transcription. This study tested the therapeutic potential of flavaglines to promote intestinal epithelial cell homeostasis and to protect against a model of experimental colitis in which inflammation is driven by epithelial ulceration. METHODS: Survival and homeostasis of Caco2-BBE and IEC-6 intestinal epithelial cell lines were measured during treatment with the flavaglines FL3 or FL37 alone and in combination with the proinflammatory cytokines tumor necrosis factor (TNF) alpha and interferon gamma. Wild-type mice were intraperitoneally injected with 0.1 mg/kg FL3 or vehicle once daily for 4 days during dextran sodium sulfate-induced colitis to test the in vivo anti-inflammatory effect of FL3. RESULTS: FL3 and FL37 increased basal Caco2-BBE and IEC-6 cell viability, decreased apoptosis, and decreased epithelial monolayer permeability. FL3 and FL37 inhibited TNFalpha- and interferon gamma-induced nuclear factor kappa B and Cox2 expression, apoptosis, and increased permeability in Caco2-BBE cells. FL3 and FL37 protected against TNFalpha-induced mitochondrial superoxide generation by preserving respiratory chain complex I activity and prohibitin expression. p38-MAPK activation was essential for the protective effect of FL3 and FL37 on barrier permeability and mitochondrial-derived reactive oxygen species production during TNFalpha treatment. Mice administered FL3 during dextran sodium sulfate colitis exhibited increased colonic prohibitin expression and p38-MAPK activation, preserved barrier function, and less inflammation. CONCLUSIONS: These results suggest that flavaglines exhibit therapeutic potential against colitis and preserve intestinal epithelial cell survival, mitochondrial function, and barrier integrity.

Gold, R., J. T. Phillips, E. Havrdova, A. Bar-Or, L. Kappos, N. Kim, T. Thullen, P. Valencia, L. Oliva, M. Novas, J. Li, M. T. Sweetser, N. Kurukulasuriya, V. Viglietta and R. J. Fox (2015). “Delayed-Release Dimethyl Fumarate and Pregnancy: Preclinical Studies and Pregnancy Outcomes from Clinical Trials and Postmarketing Experience.” Neurol Ther 4(2): 93-104.

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INTRODUCTION: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is an oral agent for the treatment of relapsing forms of multiple sclerosis (MS). No formal studies of DMF were conducted in pregnant women, although pregnancies have occurred during clinical trials and in the postmarketing setting. METHODS: Preclinical developmental and reproductive toxicology studies were performed with DMF in rats and rabbits. As of March 26, 2014, the DMF clinical development program included a total of 4132 subjects consisting of 2898 patients with MS, 320 psoriasis patients, 101 rheumatoid arthritis patients, and 813 healthy volunteers. Subjects were required to use reliable contraception and immediately discontinue treatment in the event of pregnancy. RESULTS: Animal studies showed no evidence of impaired fertility or teratogenicity with DMF. Overall as of June 30, 2014, 63 pregnancies were reported in clinical trials. Outcomes are known for 39 of 42 subjects receiving DMF and include 26 live births (67%), three spontaneous abortions (8%), and 10 elective terminations (26%); follow-up is ongoing in 2 cases and one patient was lost to follow-up. The incidence of spontaneous abortion in subjects exposed to DMF was consistent with the expected rate of early pregnancy loss in the general population (12-22%). A total of 135 pregnancies were reported in the postmarketing setting (spontaneous and solicited reports). Outcomes are known for 30 cases and include 10 live births, 13 spontaneous abortions, and 5 elective terminations; follow-up is ongoing in 103 cases and 2 patients have been lost to follow-up. CONCLUSION: Although data are limited and all known exposures have occurred in the first trimester, no increased risk of fetal abnormalities or adverse pregnancy outcomes associated with gestational exposure to DMF has been observed. FUNDING: Biogen, Inc.