Amphiphilic Antimony(V) Complexes for Oral Treatment of Visceral Leishmaniasis

The need for daily parenteral administration is an important limitation in the clinical use of pentavalent antimonial drugs against leishmaniasis. In this study, amphiphilic antimony(V) complexes were prepared from alkylmethylglucamides (L8 and L10, with carbon chain lengths of 8 and 10, respectively), and their potential for the oral treatment of visceral leishmaniasis (VL) was evaluated. Complexes of Sb and ligand at 1:3 (SbL8 and SbL10) were obtained from the reaction of antimony(V) with L8 and L10, as evidenced by elemental and electrospray ionization-tandem mass spectrometry (ESI-MS) analyses. Fluorescence probing of hydrophobic environment and negative-staining transmission electron microscopy showed that SbL8 forms kinetically stabilized nanoassemblies in water. Pharmacokinetic studies with mice in which the compound was administered by the oral route at 200 mg of Sb/kg of body weight indicated that the SbL8 complex promoted greater and more sustained Sb levels in serum and liver than the levels obtained for the conventional antimonial drug meglumine antimoniate (Glucantime [Glu]). The efficacy of SbL8 and SbL10 administered by the oral route was evaluated in BALB/c mice infected with Leishmania infantum after a daily dose of 200 mg of Sb/kg for 20 days. Both complexes promoted significant reduction in the liver and spleen parasite burdens in relation to those in the saline-treated control group. The extent of parasite suppression (>99.96%) was similar to that achieved after Glu given intraperitoneally at 80 mg of Sb/kg/day. As expected, there was no significant reduction in the parasitic load in the group treated orally with Glu at 200 mg of Sb/(kg day). In conclusion, amphiphilic antimony(V) complexes emerge as an innovative and promising strategy for the oral treatment of VL.     

Grief responses of pediatric house officers to a patient's death

Abstract

Twenty-five pediatric house officers were surveyed (14 M; 11 F) to assess their behavioral and psychophysiologic responses to patient death. Vignettes about the deaths of two pediatric patients were included as part of a self-administered questionnaire. The vignettes were followed by 14 behavioral and 20 psychophysiologic responses to the deaths depicted, and physicians were asked to indicate the expected occurrence of these reactions for themselves and for an ideal physician. Reported reactions were found to be similar to grief responses experienced with the death of a loved one. Significant differences were found between the responses of female and male house officers to patient death. Additionally, differences were found between the manner in which the physicians personally responded to a patient's death in comparison to the way they considered an ideal physician would respond. Practical suggestions are given, based on these data, for inclusion of information in death education courses for physicians.     

Aflatoxin metabolism in humans: detection of metabolites and nucleic acid adducts in urine by affinity chromatography.

A high-affinity IgM monoclonal antibody specific for aflatoxins was covalently bound to Sepharose 4B and used as a preparative column to isolate aflatoxin derivatives from the urine of people and experimental animals who had been exposed to the carcinogen environmentally or under laboratory conditions. Aflatoxin levels were quantified by radioimmunoassay and high-performance liquid chromatography after elution from the affinity column. In studies on rats injected with [14C]aflatoxin B1, we identified the major aflatoxin-DNA adduct, 2,3-dihydro-2-(N7-guanyl)-3-hydroxy-aflatoxin B1 (AFB1-N7-Gua), and the oxidative metabolites M1 and P1 as the major aflatoxin species present in the urine. When this methodology was applied to human urine samples obtained from people from the Guangxi Province of China exposed to aflatoxin B1 through dietary contamination, the aflatoxin metabolites detected were also AFB1-N7-Gua and aflatoxins M1 and P1. Therefore, affinity chromatography using a monoclonal antibody represents a useful and rapid technique with which to isolate this carcinogen and its metabolites in biochemical epidemiology and for subsequent quantitative measurements, providing exposure information that can be used for risk assessment.     

Strains in the metatarsals during the stance phase of gait: implications for stress fractures.

BACKGROUND: Stress fractures of the metatarsals are common overuse injuries in athletes and military cadets, yet their etiology remains unclear. In vitro, high bone strains have been associated with the accumulation of microdamage and shortened fatigue life. It is therefore postulated that stress fractures in vivo are caused by elevated strains, which lead to the accumulation of excessive damage. We used a cadaver model to test the hypothesis that strains in the metatarsals increase with simulated muscle fatigue and plantar fasciotomy. METHODS: A dynamic gait simulator was used to load fifteen cadaveric feet during the entire stance phase of gait under conditions simulating normal walking, walking with fatigue of the auxiliary plantar flexors, and walking after a plantar fasciotomy. Strains were measured, with use of axial strain-gauges, in the dorsal, medial, and lateral aspects of the diaphysis of the second and fifth metatarsals as well as in the proximal metaphysis of the fifth metatarsal. RESULTS: When the feet were loaded under normal walking conditions, the mean peak strain in the dorsal aspect of the second metatarsal (-1897 microstrain) was more than twice that in the medial aspect of the fifth metatarsal (-908 microstrain). Simulated muscle fatigue significantly increased peak strain in the second metatarsal and decreased peak strain in the fifth metatarsal. Release of the plantar fascia caused significant alterations in strain in both metatarsal bones; these alterations were greater than those caused by muscle fatigue. After the plantar fasciotomy, the mean peak strain in the dorsal aspect of the second metatarsal (-3797 microstrain) was twice that under normal walking conditions. CONCLUSIONS: The peak axial strain in the diaphysis of the second metatarsal is significantly (p < 0.0001) higher than that in the diaphysis of the fifth metatarsal during normal gait. The plantar fascia and the auxiliary plantar flexors are important for maintaining normal strains in the metatarsals during gait.     

Human erythrocyte ghosts: exploring the origins of multiexponential water diffusion in a model biological tissue with magnetic resonance.

A tissue model composed of erythrocyte ghosts was developed to study the effects of compartmentation on the MR signal acquired from biological tissues. This simple and flexible model offers control over the biophysical parameters that contribute to multicomponent signals arising from cellular systems. Cell density, size, intra- and extracellular composition, and membrane permeability can be independently altered. The effects of cell density and cell size on water diffusion properties were assessed. The data demonstrate non-monoexponential water diffusion in ghost cell suspensions of 17-67% cell density. Data were analysed with the widely employed two-compartment (biexponential) model, and with a two-compartment model that accounted for exchange between compartments. Water exchange between the intra- and extracellular compartments appeared to be significant over the range of diffusion times studied (7-35 ms). The biexponential fit to the ghost data appeared to be underparameterised as the ADCs and relative fractions of the fast and slow components were dependent on the experimental acquisition parameters, specifically the diffusion time. However, both analysis methods proved effective at tracking changes in the ghost model when it was perturbed. This was demonstrated with cell density variation, cell swelling and shrinkage experiments, and reduction of membrane water permeability using a water channel blocker (pCMBS). We anticipate that this model system could be used to investigate compartmental diffusion effects to simulate a range of pathologies, especially ischemic stroke.     

Neurostimulation systems for deep brain stimulation: in vitro evaluation of magnetic resonance imaging-related heating at 1.5 tesla

PURPOSE: To assess magnetic resonance imaging (MRI)-related heating for a neurostimulation system (Activa Tremor Control System, Medtronic, Minneapolis, MN) used for chronic deep brain stimulation (DBS). MATERIALS AND METHODS: Different configurations were evaluated for bilateral neurostimulators (Soletra Model 7426), extensions, and leads to assess worst-case and clinically relevant positioning scenarios. In vitro testing was performed using a 1.5-T/64-MHz MR system and a gel-filled phantom designed to approximate the head and upper torso of a human subject. MRI was conducted using the transmit/receive body and transmit/receive head radio frequency (RF) coils. Various levels of RF energy were applied with the transmit/receive body (whole-body averaged specific absorption rate (SAR); range, 0.98-3.90 W/kg) and transmit/receive head (whole-body averaged SAR; range, 0.07-0.24 W/kg) coils. A fluoroptic thermometry system was used to record temperatures at multiple locations before (1 minute) and during (15 minutes) MRI. RESULTS: Using the body RF coil, the highest temperature changes ranged from 2.5 degrees-25.3 degrees C. Using the head RF coil, the highest temperature changes ranged from 2.3 degrees-7.1 degrees C.Thus, these findings indicated that substantial heating occurs under certain conditions, while others produce relatively minor, physiologically inconsequential temperature increases. CONCLUSION: The temperature increases were dependent on the type of RF coil, level of SAR used, and how the lead wires were positioned. Notably, the use of clinically relevant positioning techniques for the neurostimulation system and low SARs commonly used for imaging the brain generated little heating. Based on this information, MR safety guidelines are provided. These observations are restricted to the tested neurostimulation system.