Vibrational corrections to transition properties

The vibrational contributions to second-order transition properties are considered in the framework of the Born—Oppenheimer approximation. It is shown that the usual formula for vibrational second-order transition matrix elements is incomplete and needs to be supplemented by a term of purely vibrational origin. This pure vibrational contribution is calculated for vibrational transition polarizabilities in LiH and BeF and found to be quite significant. Its inclusion in theoretically calculated data for the Raman intensities appears to be necessary

Physicochemical Characterization and Dissolution Studies of Solid Dispersions of Clotrimazole with Pluronic F127

Purpose: To evaluate the physicochemical properties of clotrimazole (CLT) solid dispersion with Pluronic F127 (PLU).Methods: Solid dispersions of the antifungal drug, clotrimazole, were prepared with Pluronic F127 using grinding (PM) and fusion (FUS) methods. Physicochemical characterization of the dispersions were performed using differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD) and Fourier transform infrared spectroscopy (FTIR). In vitro drug release was carried out using the rotating disc method.Results: These studies showed that there was no chemical interaction between CLT and PLU. Release studies on the SDs showed a significant (> 90-fold) improvement in dissolution rate compared to pure CLT. The greatest increase in dissolution (< 80 %) was observed for the solid dispersion (CLT/PLU) prepared by FUS in the ratio 60:40 % w/w.Conclusion: The results demonstrate that the developed solid dispersion system is a suitable approach for enhancing the dissolution rate of CLT.Keywords: Clotrimazole, Pluronic F127, Solid dispersion, Dissolution, Differential scanning calorimetry, Phase diagra

Combination immunotherapy with anti-PD-L1 antibody and depletion of regulatory T cells during acute viral infections results in improved virus control but lethal immunopathology

Combination immunotherapy (CIT) is currently applied as a treatment for different cancers and is proposed as a cure strategy for chronic viral infections. Whether such therapies are efficient during an acute infection remains elusive. To address this, inhibitory receptors were blocked and regulatory T cells depleted in acutely Friend retrovirus-infected mice. CIT resulted in a dramatic expansion of cytotoxic CD4+ and CD8+ T cells and a subsequent reduction in viral loads. Despite limited viral replication, mice developed fatal immunopathology after CIT. The pathology was most severe in the gastrointestinal tract and was mediated by granzyme B producing CD4+ and CD8+ T cells. A similar post-CIT pathology during acute Influenza virus infection of mice was observed, which could be prevented by vaccination. Melanoma patients who developed immune-related adverse events under immune checkpoint CIT also presented with expanded granzyme-expressing CD4+ and CD8+ T cell populations. Our data suggest that acute infections may induce immunopathology in patients treated with CIT, and that effective measures for infection prevention should be applied

An analysis of interplanetary solar radio emissions associated with a coronal mass ejection

Coronal mass ejections (CMEs) are large-scale eruptions of magnetized plasma that may cause severe geomagnetic storms if Earth-directed. Here we report a rare instance with comprehensive in situ and remote sensing observa- tions of a CME combining white-light, radio, and plasma measurements from four different vantage points. For the first time, we have successfully applied a radio direction-finding technique to an interplanetary type II burst detected by two identical widely separated radio receivers. The derived locations of the type II and type III bursts are in general agreement with the white light CME recon- struction. We find that the radio emission arises from the flanks of the CME, and are most likely associated with the CME-driven shock. Our work demon- strates the complementarity between radio triangulation and 3D reconstruction techniques for space weather applications

Subchronic Hepatotoxicity Evaluation of 2,3,4,6-Tetrachlorophenol in Sprague Dawley Rats

Male Sprague Dawley rats were exposed to 2,3,4,6-tetrachlorophenol (TCP) for 5 days, 2 weeks, 4 weeks, or 13 weeks. TCP was administered by gavage at doses of 0, 10, 25, 50, 100, or 200 mg/kg/day. Endpoints evaluated included clinical observations, body weights, liver weights, serum chemistry, blood TCP, gross pathology, and liver histopathology. There were no TCP exposure-related clinical signs of toxicity. Mean body weight decreased 12–22% compared to control in the 100 and 200 mg/kg/day groups. Serum ALT concentrations were increased in rats of the 200 mg/k/day. Liver weight increases were both dose- and exposure time-related and statistically significant at ≥25 mg/kg/day. Incidence and severity of centrilobular hepatocytic vacuolation, hepatocyte hypertrophy, and single cell hepatocytic necrosis were related to dose and exposure time. Following 13 weeks of exposure, bile duct hyperplasia and centrilobular and/or periportal fibrosis were observed in rats primarily of the highest TCP dose group. Blood TCP concentrations increased with dose and at 13 weeks ranged from 1.3 to 8.5 μg/mL (10 to 200 mg/kg/day). A NOAEL of 10 mg/kg/day was selected based on the statistically significant incidence of hepatocyte hypertrophy at doses ≥25 mg/kg/day

Safety and Feasibility of Long-term Intravenous Sodium Nitrite Infusion in Healthy Volunteers

BACKGROUND: Infusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion. METHODOLOGY: Healthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate. Twelve subjects (5 males, 7 females; mean age, 38.8±9.2 years (range, 21-56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 µg/kg/hr; maximal dose of 533.8 µg/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed. FINDINGS: The maximal tolerated dose for intravenous infusion of sodium nitrite was 267 µg/kg/hr. Dose limiting toxicity occurred at 446 µg/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood. CONCLUSION: Sodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov; NCT00103025