Studies of Photoprotection Against Porphyrin Photosensitization Using Dithiothreitol and Glycerol

Although protection against ionizing radiation by compounds containing sulfhydryl (SN) groups, such as cysteine, has been reported, these agents have been unsuccessful to date in protecting mammals against non-ionizing radiation (>200nm). This study describes successful photoprotection by dithiothreitol (DTT) and glycerol against porphyrin photosensitization having an action spectrum of 400nm. Test models used were red blood cells (RBC) obtained from patients with erythropoietic protoporphyria (EPP) and mice photo-sensitized by hematoporphyrin (HP). A mortality rate approaching a lethal dose in 50% of the animals in 1 day (LD50/24 hrs) was established in 100 white mice that had received an intraperitoneal injection of 100mg HP/kg body wt., and were then irradiated with 5 × 106 ergs/cm2 from a fluorescent light source emitting 320-450nm radiation. Another 100 mice were treated in an identical manner except that they received, in addition to HP, 80mg DTT/kg body weight in a 5.5% glycerol solution. This group showed 75% reduction in mortality (p < 0.03). No lethal effects were observed in animals treated with DTT and glycerol or HP in the above concentrations without 400nm irradiation. RBC obtained from patients with EPP and exposed to 107 ergs/mm2 of 400nm radiation showed 100% hemolysis after 180min. These cells, when irradiated under identical conditions except for the addition of DTT, manifested only 19% hemolysis during this period of time. Measurements of SH groups of RBC from patients with EPP showed a progressive decrease during photohemolysis. Comparison of the rate of photohemolysis of normal and glucose-6-phosphate dehydrogenase (G6PD) deficient RBC irradiated in the presence of protoporphyrin IX revealed that G6PD deficient RBC, which have an impaired ability to produce reduced glutathione (GSH), were more susceptible to porphyrin-induced photohemolysis. These studies demonstrate that DTT and glycerol offer photoprotection in an in vivo mammalian system against porphyrin photosensitization. It is suggested that the mechanism of the photoprotective action against 320-450nm radiation has many features similar to that of radioprotection by thiols and glycerol against ionizing radiation

Confronting the opioid crisis: Practical pain management and strategies: AOA 2018 critical issues symposium

The United States is in the midst of an opioid crisis. Clinicians have been part of the problem because of overprescribing of narcotics for perioperative pain management. Clinicians need to understand the pathophysiology and science of addiction to improve perioperative management of pain for their patients. Multiple modalities for pain management exist that decrease the use of narcotics. Physical strategies, cognitive strategies, and multimodal medication can all provide improved pain relief and decrease the use of narcotics. National medical societies are developing clinical practice guidelines for pain management that incorporate multimodal strategies and multimodal medication. Changes to policy that improve provider education, access to naloxone, and treatment for addiction can decrease narcotic misuse and the risk of addiction

Stockpiling Anti-viral Drugs for a Pandemic: The Role of Manufacturer Reserve Programs

To promote stockpiling of anti-viral drugs by non-government organizations such as hospitals, drug manufacturers have introduced Manufacturer Reserve Programs which, for an annual fee, provide the right to buy in the event of a severe outbreak of influenza. We show that these programs enhance drug manufacturer profits but could either increase or decrease the amount of pre-pandemic stockpiling of anti-viral drugs

Effect of Rosuvastatin on Acute Kidney Injury in Sepsis-Associated Acute Respiratory Distress Syndrome.

Background:Acute kidney injury (AKI) commonly occurs in patients with sepsis and acute respiratory distress syndrome (ARDS). Objective:To investigate whether statin treatment is protective against AKI in sepsis-associated ARDS. Design:Secondary analysis of data from Statins for Acutely Injured Lungs in Sepsis (SAILS), a randomized controlled trial that tested the impact of rosuvastatin therapy on mortality in patients with sepsis-associated ARDS. Setting:44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Patients:644 of 745 participants in SAILS who had available baseline serum creatinine data and who were not on chronic dialysis. Measurements:Our primary outcome was AKI defined using the Kidney Disease Improving Global Outcomes creatinine criteria. Randomization to rosuvastatin vs placebo was the primary predictor. Additional covariates include demographics, ARDS etiology, and severity of illness. Methods:We used multivariable logistic regression to analyze AKI outcomes in 511 individuals without AKI at randomization, and 93 with stage 1 AKI at randomization. Results:Among individuals without AKI at randomization, rosuvastatin treatment did not change the risk of AKI (adjusted odds ratio: 0.99, 95% confidence interval [CI]: 0.67-1.44). Among those with preexisting stage 1 AKI, rosuvastatin treatment was associated with an increased risk of worsening AKI (adjusted odds ratio: 3.06, 95% CI: 1.14-8.22). When serum creatinine was adjusted for cumulative fluid balance among those with preexisting stage 1 AKI, rosuvastatin was no longer associated worsening AKI (adjusted odds ratio: 1.85, 95% CI: 0.70-4.84). Limitations:Sample size, lack of urine output data, and prehospitalization baseline creatinine. Conclusion:Treatment with rosuvastatin in patients with sepsis-associated ARDS did not protect against de novo AKI or worsening of preexisting AKI

A Multibody Slosh Analysis for the Lunar Reconnaissance Orbiter

The Lunar Reconnaissance Orbiter (LRO) undergoes a series of thruster maneuvers to attain lunar orbit. The first of the series of lunar orbit insertion (LOI) maneuvers is crucial to the success of the mission. Therefore, it is important to characterize the disturbances acting on the spacecraft during this phase of the mission. This paper focuses on the internal disturbance force caused by fuel slosh and its impact on attitude control. During the first LOI maneuver (LOI-1), approximately 50% of the total fuel mass is used or roughly 25% of the spacecraft s wet mass, during the 38-minute burn. The forces imparted on the spacecraft from the fuel are dependent on the fill level of the two fuel tanks. During LOI-1, the fill level in both tanks varies greatly and thus so does the disturbance level caused by the fuel. It is therefore necessary to account for the time-varying mass properties of the spacecraft and the effects of the varying fuel levels during the entire 38-minute maneuver. Two simulations are developed in Mathworks s Simulink to analyze the fuel slosh effect. The first model, a baseline model, is a rigid body dynamics model where the fuel slosh is not modeled. The second is a multibody model, developed using a multibody dynamics toolbox, where each of the two fuel tanks and the remaining spacecraft body are treated as separate rigid bodies. The simulations are executed in a piece-wise fashion to account for the time-varying mass properties, and to accommodate the multibody toolbox. Disturbances caused by fuel slosh during both lunar and mission orbit insertions will be analyzed through simulation of different dynamics models. Results of the analysis will show the effects of the slosh disturbance on the spacecraft s attitude

Low-Cost, Commercial Scale Production of Sofosbuvir

Recent advances in antiviral therapeutics have produced highly effective small molecule drugs to treat Hepatitis C, a deadly infection of the liver. Sofosbuvir, a hepatitis C drug developed by Gilead Sciences, is a breakthrough treatment due to its low side effects and high cure rate. However, the cost of treatment is extraordinarily high, priced at $84,000 per treatment in the US. In response to backlash regarding the cost barriers in developing countries, Gilead has reached licensing agreements with generic pharmaceutical companies to produce the drug for markets in low-income countries such as India, Kenya, and Cuba among others. The report describes a cost-effective, commercial scale process design for the production of sofosbuvir. The proposed production facility is designed to deliver 350,000 kg/year of the active pharmaceutical ingredient, enough to treat 10 million patients per year. The production will be completed over one hundred batches, requiring operation of 120 days/year. Assuming an 11-year period of operation, detailed economic analysis suggests that this is a profitable venture with an IRR of 67.7$1.2 billion USD

Eddy interaction model for turbulent suspension in Reynolds-averaged Euler-Lagrange simulations of steady sheet flow

Author Posting. © The Author(s), 2017. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Advances in Water Resources 111 (2018): 435-451, doi:10.1016/j.advwatres.2017.11.019.A Reynolds-averaged Euler–Lagrange sediment transport model (CFDEM-EIM) was developed for steady sheet flow, where the inter-granular interactions were resolved and the flow turbulence was modeled with a low Reynolds number corrected turbulence closure modified for two-phase flows. To model the effect of turbulence on the sediment suspension, the interaction between the turbulent eddies and particles was simulated with an eddy interaction model (EIM). The EIM was first calibrated with measurements from dilute suspension experiments. We demonstrated that the eddy-interaction model was able to reproduce the well-known Rouse profile for suspended sediment concentration. The model results were found to be sensitive to the choice of the coefficient, C0, associated with the turbulence-sediment interaction time. A value was suggested to match the measured concentration in the dilute suspension. The calibrated CFDEM-EIM was used to model a steady sheet flow experiment of lightweight coarse particles and yielded reasonable agreements with measured velocity, concentration and turbulence kinetic energy profiles. Further numerical experiments for sheet flow suggested that when C0 was decreased to C0  1.0). Additional simulations for a range of Shields parameters between 0.3 and 1.2 confirmed that CFDEM-EIM was capable of predicting sediment transport rates similar to empirical formulations. Based on the analysis of sediment transport rate and transport layer thickness, the EIM and the resulting suspended load were shown to be important when the fall parameter is less than 1.25.Z. Cheng and T.-J. Hsu were supported by the U.S. Office of Naval Research (N00014- 16-1-2853) and National Science Foundation (OCE- 1537231). J. Chauchat was supported by the Région Rhones-Alpes (COOPERA project and Explora Pro grant) and the French national programme EC2CO-LEFE MODSED. J. Calantoni was supported under base funding to the U.S. Naval Research Laboratory from the U.S. Office of Naval Research. The authors would also like to acknowledge the support from the program on "Fluid- Mediated Particle Transport in Geophysical Flows" at the Kavli Institute for Theoretical Physics, Santa Barbara, USA

Genetic variants in ARID5B and CEBPE are childhood ALL susceptibility loci in Hispanics.

Recent genome-wide studies conducted in European Whites have identified novel susceptibility genes for childhood acute lymphoblastic leukemia (ALL). We sought to examine whether these loci are susceptibility genes among Hispanics, whose reported incidence of childhood ALL is the highest of all ethnic groups in California, and whether their effects differ between Hispanics and non-Hispanic Whites (NHWs). We genotyped 13 variants in these genes among 706 Hispanic (300 cases, 406 controls) and 594 NHW (225 cases, 369 controls) participants in a matched population-based case-control study in California. We found significant associations for the five studied ARID5B variants in both Hispanics (p values of 1.0 × 10(-9) to 0.004) and NHWs (p values of 2.2 × 10(-6) to 0.018). Risk estimates were in the same direction in both groups (ORs of 1.53-1.99 and 1.37-1.84, respectively) and strengthened when restricted to B-cell precursor high-hyperdiploid ALL (&gt;50 chromosomes; ORs of 2.21-3.22 and 1.67-2.71, respectively). Similar results were observed for the single CEBPE variant. Hispanics and NHWs exhibited different susceptibility loci at CDKN2A. Although IKZF1 loci showed significant susceptibility effects among NHWs (p &lt; 1 × 10(-5)), their effects among Hispanics were in the same direction but nonsignificant, despite similar minor allele frequencies. Future studies should examine whether the observed effects vary by environmental, immunological, or lifestyle factors