Spontaneous fluctuations in liver biochemistries in patients with compensated NASH cirrhosis: Implications for drug hepatotoxicity monitoring

Introduction: Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described. Objective: We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials. Methods: We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120. Results: In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy's law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34-299) and 56 U/L (47-85)] than for those with normal baseline values [median 26.5 U/L (range 18-33) and 29 U/L (25.5-30.5)] in both studies, respectively, with p < 0.001. Conclusion: Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed

Anoxia begets anoxia: a positive feedback to the deoxygenation of temperate lakes

Declining oxygen concentrations in the deep waters of lakes worldwide pose a pressing environmental and societal challenge. Existing theory suggests that low deep-water dissolved oxygen (DO) concentrations could trigger a positive feedback through which anoxia (i.e., very low DO) during a given summer begets increasingly severe occurrences of anoxia in following summers. Specifically, anoxic conditions can promote nutrient release from sediments, thereby stimulating phytoplankton growth, and subsequent phytoplankton decomposition can fuel heterotrophic respiration, resulting in increased spatial extent and duration of anoxia. However, while the individual relationships in this feedback are well established, to our knowledge, there has not been a systematic analysis within or across lakes that simultaneously demonstrates all of the mechanisms necessary to produce a positive feedback that reinforces anoxia. Here, we compiled data from 656 widespread temperate lakes and reservoirs to analyze the proposed anoxia begets anoxia feedback. Lakes in the dataset span a broad range of surface area (1–126,909 ha), maximum depth (6–370 m), and morphometry, with a median time-series duration of 30 years at each lake. Using linear mixed models, we found support for each of the positive feedback relationships between anoxia, phosphorus concentrations, chlorophyll a concentrations, and oxygen demand across the 656-lake dataset. Likewise, we found further support for these relationships by analyzing time-series data from individual lakes. Our results indicate that the strength of these feedback relationships may vary with lake-specific characteristics: For example, we found that surface phosphorus concentrations were more positively associated with chlorophyll a in high-phosphorus lakes, and oxygen demand had a stronger influence on the extent of anoxia in deep lakes. Taken together, these results support the existence of a positive feedback that could magnify the effects of climate change and other anthropogenic pressures driving the development of anoxia in lakes around the world

On Your Invention Journey: Helping Inventors Be More Successful

Inventing the Future 2012 A Seminar for Inventors, Entrepreneurs, Researchers, Students and Professionals.Presented at Inventing the Future 2012, Saturday, April 21, 2012 Clough Commons Auditoriums, Georgia Institute of Technology.Dr. Harold Shlevin currently leads Georgia Institute of Technology’s Advanced Technology Development Center (ATDC) as manager of bioscience commercialization efforts. He serves as a startup catalyst and Executive-In-Residence evaluating new technologies, advising faculty and others on product development, licensing and business development, guiding new and emerging bioscience companies as a consultant and advisor, determining the commercial potential of technologies, and oversees and advises client companies in a bioscience incubator facility. He also serves as a consultant and advisor to established bioscience companies. Dr. Shlevin is a 25-year bioscience-industry executive with broad senior management experience in development and commercialization of medical devices, pharmaceuticals, diagnostics and vaccines; he founded two startup companies. He has unusually diverse healthcare business-related and global management experiences in pharmaceuticals, medical devices, diagnostics and vaccines. He has a particularly strong background in business development including strategic planning, licensing, academic/industrial relationships, and mergers & acquisitions. Dr Shlevin earned a BA degree from Boston University, a MS and PhD degrees in physiology from the University of Rochester Medical School and completed post-doctoral training in pharmacology at Mayo Clinic where he subsequently served as Assistant Professor of Pharmacology & Physiology. He is a member of scientific and business societies including IEEE, Licensing Executives Society, Southeast Medical Device Association, Am. Physiological Society, Am. Society of Pharmacology & Experimental Therapeutics, and an inventor on several issued and pending patents. Dr. Shlevin currently serves on the Board of Directors of Cardiome Pharma Corp. (NASDAQ:CRME) and NeurOp, Inc. and as an advisor to Clearside Biomedical, Inc. Further information is available at http://www.linkedin.com/in/hshlevin

IP ecosystem, entrepreneurs, and sustainable technology companies

Patents and Trademarks 101. Workshop on patents and trademarks Sponsored by the Georgia Tech Library and USPTO.Runtime: 40:18 minutesFeatured speaker of Patents and Trademarks 101, presented on November 3, 2010 in the Georgia Tech Student Center Theater

Effects of Depolarization and Low Intracellular pH on Charge Movement Currents of Frog Skeletal Muscle Fibers

The low intracellular pH and membrane depolarization associated with repeated skeletal muscle stimulation could impair the function of the transverse tubular (t tubule) voltage sensor and result in a decreased sarcoplasmic reticulum Ca2+ release and muscle fatigue. We therefore examined the effects of membrane depolarization and low intracellular pH on the t-tubular charge movement. Fibers were voltage clamped in a double Vaseline gap, at holding potential (HP) of 290 or 260 mV, and studied at an internal pH of 7.0 and 6.2. Decreasing intracellular pH did not significantly alter the maximum amount of charge moved, transition voltage, or steepness factor at either HP. Depolarizing HP significantly decreased steepness factor and maximum charge moved and shifted the transition voltage to more positive potentials. Elevated extracellular Ca2+ decreased the depolarization-induced reduction in the charge movement. These results indicate that, although the decrease in intracellular pH seen in fatigued muscle does not impair the t-tubular charge movement, the membrane depolarization associated with muscle fatigue may be sufficient to inactivate a significant fraction of the t-tubular charge. However, if t-tubular Ca2+ increases, some of the charge may be stabilized in the active state and remain available to initiate sarcoplasmic reticulum Ca2+ release