Salt effects on ligand-DNA binding. Minor groove binding antibiotics

Salt dependent electrostatic effects play a central role in intermolecular interactions involving nucleic acids. In this paper, the finite-difference solution to the nonlinear Poisson-Boltzmann (NLPB) equation is used to evaluate the salt dependent contribution to the electrostatic binding free energy of the minor groove binding antibiotics DAPI, Hoechst 33258 and netropsin to DNA using detailed molecular structures of the complexes. For each of these systems, a treatment based on the NLPB equation accurately describes the variation of the experimentally observed binding constant with bulk salt concentration. A solvation formalism is developed in which salt effects are described in terms of three free energy contributions: the electrostatic ion-molecule interaction free energy, delta delta G degrees im; the electrostatic ion-ion interaction free energy, delta delta G degrees ii; and the entropic ion organization free energy, delta delta G degrees org. The electrostatic terms, delta delta G degrees im and delta delta G degrees ii, have both enthalpic and entropic components, while the term delta delta G degrees org is purely a cratic entropy. Each of these terms depends significantly on salt dependent changes in the counterion and coion concentrations around the DNA. In each of the systems studied, univalent ions substantially destabilize charged ligand-DNA complexes at physiological salt concentrations. This effect involves a salt dependent redistribution of counterions near the DNA. The free energy associated with the redistribution of counterions upon binding is dominated by the unfavorable change in the electrostatic ion-molecule interactions, delta delta G degrees im, rather than the change in the cratic entropy of ion organization, delta delta G degrees org. In addition, the observed slope of the salt dependence of the free energy is determined by electrostatic ion-molecule and ion-ion interactions as well as the cratic entropy of ion release. These findings are in contrast to models in which the cratic entropy of counterion release drives binding.     

Gas-body-based contrast agent enhances vascular bioeffects of 1.09 MHz ultrasound on mouse intestine

Anesthetized hairless mice were exposed to continuous or pulsed 1.09-MHz ultrasound with or without prior injection of a gas-body-based ultrasound contrast agent. Albunex at a dose of 10 mL/kg increased the production of intestinal hyperemia, petechia and hemorrhages by continuous ultrasound. For pulsed ultrasound, with 10 micros pulses and 0.01 duty cycle, petechiae were produced for exposures as low as 1 MPa spatial peak pressure amplitude with added gas bodies. The enhancement of petechiae production was robust for pulsed exposure; for example, at 2.8 MPa, an average of 227 petechiae was obtained with added gas bodies, which was 30 times more than without the agent. The production of petechia was roughly proportional to the dosage of Albunex for pulsed exposure. Results did not appear to be strongly dependent on pulsing parameters, but long bursts (0.1 s) were somewhat more effective than pulses (10 micros). The observed vascular bioeffects appeared to involve both thermal and nonthermal mechanisms for continuous exposure, but to result primarily from gas-body activation for pulsed exposure.     

Quality of life after transthoracic endoscopic sympathectomy for upper limb hyperhidrosis

OBJECTIVE: To assess the outcome after transthoracic endoscopic sympathectomy (TES) for upper limb hyperhidrosis. DESIGN: Prospective cohort study. SETTING: District general hospital. SUBJECTS: Consecutive patients undergoing TES for upper limb hyperhidrosis over a fifteen month period. INTERVENTIONS: One-stage bilateral TES. MAIN OUTCOME MEASURES: Change in quality of life as shown by the Short Form-36 health assessment questionnaire. RESULTS: Sixteen patients (11 women and 5 men, median age 26 years) underwent operation without complications. At median follow-up of 6.2 months, symptomatic improvement was found in 26 of 32 limbs treated (82%). Truncal compensatory hyperhidrosis was reported by 13 patients but was severe in only three. There were significant improvements in social function (p = 0.01) and mental health (p = 0.025) as assessed by the SF-36. CONCLUSION: Despite a high incidence of compensatory hyperhidrosis, TES improved both the symptoms and overall quality of life in patients with upper limb hyperhidrosis.     

Effects of hypesthesia on oral behaviors of the orthognathic surgery patient

PURPOSE: The purpose of this study was to compare orthognathic surgery patients with and without significant hypesthesia with respect to perceived problems with specific oral behaviors. PATIENTS AND METHODS: Data from 116 patients 6 months after bilateral sagittal split osteotomy (BSSO) and mandibular advancement were analyzed. Tactile sensation in the right and left mental nerve areas was determined using monofilaments and brush strokes (von Frey hairs). The right infraorbital region was used as a control. A difference of 450 mg of force between the control and test sites was considered significant hypesthesia. Patients rated their level of subjective problems with swallowing liquids or solids, smiling, spitting, kissing, speaking, eating, and drooling on a scale from 1 (none to mild) to 7 (extreme). A value of 5 or greater was considered significant impairment. RESULTS: Hypesthesia was shown in 23 patients (19.8%) with the monofilaments and in 29 patients (25.0%) using brush stroke direction. In each of these two groups, a significant correlation was observed between hypesthesia and difficulty in chewing and kissing. No correlation was observed between any of the remaining seven oral behaviors and hypesthesia. CONCLUSION: These findings suggest that only certain oral behaviors are affected by hypesthesia of the mental nerve.     

The CTFA Evaluation of Alternatives Program: an evaluation of in vitro alternatives to the Draize primary eye irritation test. (Phase III) surfactant-based formulations

The CTFA Evaluation of Alternatives Program is an evaluation of the relationship between data from the Draize primary eye irritation test and comparable data from a selection of promising in vitro eye irritation tests. In Phase III, data from the Draize test and 41 in vitro endpoints on 25 representative surfactant-based personal care formulations were compared. As in Phase I and Phase II, regression modelling of the relationship between maximum average Draize score (MAS) and in vitro endpoint was the primary approach adopted for evaluating in vitro assay performance. The degree of confidence in prediction of MAS for a given in vitro endpoint is quantified in terms of the relative widths of prediction intervals constructed about the fitted regression curve. Prediction intervals reflect not only the error attributed to the model but also the material-specific components of variation in both the Draize and the in vitro assays. Among the in vitro assays selected for regression modeling in Phase III, the relationship between MAS and in vitro score was relatively well defined. The prediction bounds on MAS were most narrow for materials at the lower or upper end of the effective irritation range (MAS = 0-45), where variability in MAS was smallest. This, the confidence with which the MAS of surfactant-based formulations is predicted is greatest when MAS approaches zero or when MAS approaches 45 (no comment is made on prediction of MAS > 45 since extrapolation beyond the range of observed data is not possible). No single in vitro endpoint was found to exhibit relative superiority with regard to prediction of MAS. Variability associated with Draize test outcome (e.g. in MAS values) must be considered in any future comparisons of in vivo and in vitro test results if the purpose is to predict in vivo response using in vitro data.