Human-relevant mechanisms and risk factors for TAK-875-Induced liver injury identified via a gene pathway-based approach in Collaborative Cross mice.

Development of TAK-875 was discontinued when a small number of serious drug-induced liver injury (DILI) cases were observed in Phase 3 clinical trials. Subsequent studies have identified hepatocellular oxidative stress, mitochondrial dysfunction, altered bile acid homeostasis, and immune response as mechanisms of TAK-875 DILI and the contribution of genetic risk factors in oxidative response and mitochondrial pathways to the toxicity susceptibility observed in patients. We tested the hypothesis that a novel preclinical approach based on gene pathway analysis in the livers of Collaborative Cross mice could be used to identify human-relevant mechanisms of toxicity and genetic risk factors at the level of the hepatocyte as reported in a human genome-wide association study.

Small-incision lenticule extraction in the U.S. military: prospective study of visual and military task performance.

Purpose: To assess early visual outcomes and military task performance after small-incision lenticule extraction (SMILE) among U.S. military service members.

Correction to: Preliminary evaluation of the Vision PERformance (VIPER) simulator.

An amendment to this paper has been published and can be accessed via the original article.

Glutamate dehydrogenase as a biomarker for mitotoxicity; insights from furosemide hepatotoxicity in the mouse.

Glutamate dehydrogenase (GLDH) is a liver-specific biomarker of hepatocellular damage currently undergoing qualification as a drug development tool. Since GLDH is located within the mitochondrial matrix, it has been hypothesized that it might also be useful in assessing mitotoxicity as an initiating event during drug-induced liver injury. According to this hypothesis, hepatocyte death that does not involve primary mitochondrial injury would result in release of intact mitochondria into circulation that could be removed by high speed centrifugation and result in lower GLDH activity measured in spun serum vs un-spun serum.

Visual outcomes after SMILE from the first-year experience at a U.S. military refractive surgery center and comparison with PRK and LASIK outcomes.

Purpose: To assess the visual outcomes of small-incision lenticule extraction (SMILE) after the first year of treatments at a military refractive surgery center and compare with photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) outcomes during the same period.

Setting: Warfighter Refractive Eye Surgery Program and Research Center, Fort Belvoir, VA.

Design: Retrospective study.

Preliminary evaluation of the VIsion PERformance (VIPER) simulator.

Background: This study evaluated the VIsion PERformance (VIPER) simulator's ability to assess the functional visual performance in warfighters conducting civilian and military tasks.

Methods: Thirty service members, aged 25-35 years old with a best corrected distance visual acuity (VA) better than or equal to 20/20 or logarithm of the minimum angle of resolution (logMAR) 0.00, were randomized to locate and identify road signs and mock improvised explosive devices (IEDs) under either daytime conditions or with infrared imagery, with (cc) and without (sc) wearing their habitual correction.

Identification of Candidate Risk Factor Genes for Human Idelalisib Toxicity Using a Collaborative Cross Approach.

Idelalisib is a phosphatidylinositol 3-kinase inhibitor highly selective for the delta isoform that has shown good efficacy in treating chronic lymphocytic leukemia and follicular lymphoma. In clinical trials, however, idelalisib was associated with rare, but potentially serious liver and lung toxicities. In this study, we used the Collaborative Cross (CC) mouse population to identify genetic factors associated with the drug response that may inform risk management strategies for idelalisib in humans.

Vision-Related Quality of Life and Perception of Military Readiness and Capabilities Following Refractive Surgery Among Active Duty U.S. Military Service Members.

Purpose: To assess vision-related quality of life and military readiness and capabilities among active duty U.S. military service members undergoing refractive surgery.

Contrast Sensitivity After Wavefront-Guided and Wavefront-Optimized PRK and LASIK for Myopia and Myopic Astigmatism.

Purpose: To compare contrast sensitivity among participants undergoing wavefront-guided or wavefront-optimized photorefractive keratectomy (PRK) or LASIK for the treatment of myopia or myopic astigmatism 12 months after surgery.

Methods: In a prospective, randomized clinical trial, 215 participants with myopia ranging from -0.50 to -7.

Using the Vape Shop Standardized Tobacco Assessment for Retail Settings (V-STARS) to Assess Product Availability, Price Promotions, and Messaging in New Hampshire Vape Shop Retailers.

Objectives: This is the first statewide census of the product availability, price promotions, and product messaging of vape shops.

Methods: A comprehensive list of New Hampshire vape shops was developed through a previously validated online search method. Store audits were conducted in 55 stores between January and February 2016 using the Vape Shop Standardized Tobacco Assessment for Retail Settings (V-STARS).

miR-122 Release in Exosomes Precedes Overt Tolvaptan-Induced Necrosis in a Primary Human Hepatocyte Micropatterned Coculture Model.

Idiosyncratic drug-induced liver injury (IDILI) is thought to often result from an adaptive immune attack on the liver. However, it has been proposed that the cascade of events culminating in an adaptive immune response begins with drug-induced hepatocyte stress, release of exosomal danger signals, and innate immune activation, all of which may occur in the absence of significant hepatocelluar death. A micropatterned coculture model (HepatoPac) was used to explore the possibility that changes in exosome content precede overt necrosis in response to the IDILI drug tolvaptan.

Editor's Highlight: Candidate Risk Factors and Mechanisms for Tolvaptan-Induced Liver Injury Are Identified Using a Collaborative Cross Approach.

Clinical trials of tolvaptan showed it to be a promising candidate for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) but also revealed potential for idiosyncratic drug-induced liver injury (DILI) in this patient population. To identify risk factors and mechanisms underlying tolvaptan DILI, 8 mice in each of 45 strains of the genetically diverse Collaborative Cross (CC) mouse population were treated with a single oral dose of either tolvaptan or vehicle. Significant elevations in plasma alanine aminotransferase (ALT) were observed in tolvaptan-treated animals in 3 of the 45 strains.

Wavefront-guided versus wavefront-optimized photorefractive keratectomy: Clinical outcomes and patient satisfaction.

Purpose: To compare visual outcomes following Visx Star S4 Customvue wavefront-guided and Allegretto Wave Eye-Q 400 Hz wavefront-optimized photorefractive keratectomy (PRK).

Setting: Warfighter Refractive Eye Surgery Program and Research Center, Fort Belvoir, Virginia, and Walter Reed National Military Medical Center, Bethesda, Maryland, USA.

Design: Prospective randomized clinical trial.

Sensitivity to hepatotoxicity due to epigallocatechin gallate is affected by genetic background in diversity outbred mice.

Consumer use of herbal and dietary supplements has recently grown in the United States and, with increased use, reports of rare adverse reactions have emerged. One such supplement is green tea extract, containing the polyphenol epigallocatechin gallate (EGCG), which has been shown to be hepatotoxic at high doses in animal models. The Drug-Induced Liver Injury Network has identified multiple patients who have experienced liver injury ascribed to green tea extract consumption and the relationship to dose has not been straightforward, indicating that differences in sensitivity may contribute to the adverse response in susceptible people.

A systems biology approach utilizing a mouse diversity panel identifies genetic differences influencing isoniazid-induced microvesicular steatosis.

Isoniazid (INH), the mainstay therapeutic for tuberculosis infection, has been associated with rare but serious hepatotoxicity in the clinic. However, the mechanisms underlying inter-individual variability in the response to this drug have remained elusive. A genetically diverse mouse population model in combination with a systems biology approach was utilized to identify transcriptional changes, INH-responsive metabolites, and gene variants that contribute to the liver response in genetically sensitive individuals.

Liver biomarker and in vitro assessment confirm the hepatic origin of aminotransferase elevations lacking histopathological correlate in beagle dogs treated with GABAA receptor antagonist NP260.

NP260 was designed as a first-in-class selective antagonist of α4-subtype GABAA receptors that had promising efficacy in animal models of pain, epilepsy, psychosis, and anxiety. However, development of NP260 was complicated following a 28-day safety study in dogs in which pronounced elevations of serum aminotransferase levels were observed, although there was no accompanying histopathological indication of hepatocellular injury. To further investigate the liver effects of NP260, we assayed stored serum samples from the 28-day dog study for liver specific miRNA (miR-122) as well as enzymatic biomarkers glutamate dehydrogenase and sorbitol dehydrogenase, which indicate liver necrosis.

Synthesis of HCV replicase inhibitors: base-catalyzed synthesis of protected α-hydrazino esters and selective aerobic oxidation with catalytic Pt/Bi/C for synthesis of imidazole-4,5-dicarbaldehyde.

A robust convergent synthesis of the prodrugs of HCV replicase inhibitors 1-5 is described. The central 5H-imidazo[4,5-d]pyridazine core was formed from acid-catalyzed cyclocondensation of an imidazole-4,5-dicarbaldehyde (20) and a α-hydrazino ester, generated in situ from the bis-BOC-protected precursors 25 and 33. The acidic conditions not only released the otherwise unstable α-hydrazino esters but also were the key to avoid facile decarboxylation to the parent drugs from the carboxylic ester prodrugs 1-5.

A mouse diversity panel approach reveals the potential for clinical kidney injury due to DB289 not predicted by classical rodent models.

DB289 is the first oral drug shown in clinical trials to have efficacy in treating African trypanosomiasis (African sleeping sickness). Mild liver toxicity was noted but was not treatment limiting. However, development of DB289 was terminated when several treated subjects developed severe kidney injury, a liability not predicted from preclinical testing.

The effects of heparins on the liver: application of mechanistic serum biomarkers in a randomized study in healthy volunteers.

Heparins have been reported to cause elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but have not been associated with clinically significant liver injury. The mechanisms underlying these benign laboratory abnormalities are unknown. Forty-eight healthy men were randomized to receive subcutaneous injections of unfractionated heparin (UFH; 150 U/kg), enoxaparin sodium (1 mg/kg), dalteparin sodium (120 IU/kg), or adomiparin sodium (125 IU/kg; a novel heparin) every 12 h for 4.

Visual and IOP outcomes after PRK in pigment dispersion syndrome.

Purpose: To report the results of photorefractive keratectomy (PRK) in patients with pigment dispersion syndrome.

Methods: The pre- and postoperative records of patients with pigment dispersion syndrome who underwent PRK between January 2002 and March 2009 were reviewed. Data for analysis included gender, age, ablation depth, surgical complications, manifest refraction spherical equivalent, uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), intraocular pressure (IOP), central corneal thickness (CCT), cup-to-disc (c/d) ratio, and postoperative complications.

Oral gabapentin for photorefractive keratectomy pain.

Purpose: To compare the efficacy of oral gabapentin versus placebo for the control of severe pain after photorefractive keratectomy (PRK).

Setting: Center for Refractive Surgery, Walter Reed Army Medical Center, Washington, DC, USA.

Design: Randomized masked clinical trial.

Basolateral amygdala involvement in memory reconsolidation processes that facilitate drug context-induced cocaine seeking.

Understanding the neurobiological underpinnings of putative memory stabilization processes that maintain context-response-cocaine associations in long-term memory and underlie contextual control over addictive behavior is of great interest from an addiction treatment perspective. Using an instrumental animal model of contextual drug relapse we show that the protein synthesis inhibitor anisomycin, administered into the basolateral amygdala (BLA) immediately after limited (15- or 60-min) re-exposure to a previously cocaine-paired context, subsequently disrupted the ability of the previously cocaine-paired context to reinstate extinguished cocaine-seeking behavior relative to vehicle. Consistent with a BLA-mediated memory reconsolidation deficit, a similar impairment in cocaine-seeking behavior was not observed in (i) 'no-reactivation' control groups that received anisomycin into the BLA after (re)exposure to either a novel unpaired or an extinction-paired context or in (ii) a neuroanatomical control group that received anisomycin into the posterior caudate-putamen, dorsally adjacent to the BLA, after re-exposure to the cocaine-paired context.