Development of fever in the newborn lamb.

Newborn lambs do not become febrile in response to intravenous (iv) bacterial endotoxin in moderate doses. Newborn lambs were tested to see if they could become febrile to large doses of endotoxin or to endogenous pyrogen. At 5 h of age lambs do not become febrile to relatively large doses of endotoxin or to endogenous pyrogen, but rather become hypothermic. At 32 h and all subsequent times, fevers could be elicited. Onset time of fevers in lambs was short initially and gradually lengthened over 9 days, at which time it was similar to the onset time of the adult fever. With respect to the febrile response, newborn lambs showed varying degrees of tolerance after 10 days of daily injections of endotoxin, as compared to the ewe which becomes tolerant in 2 or 3 days.     

Electrical Analysis of Fresh,Excised Human Skin: A Comparison with Frozen Skin

Samples of human allograft skin prepared without freezing ("fresh skin) were found to have electrical and sodium ion transport properties which differed only slightly from those of skin which had been similarly treated but stored frozen (frozen skin). The fresh skin samples were less permeable to sodium ions during passive diffusion and less conductive than frozen skin at low current levels. They were more permselective for sodium versus chloride during constant-current iontophoresis and showed slightly more asymmetry in their current–voltage properties. Overall, the electrical behavior of the two tissues was similar enough to support the use of frozen tissue in iontophoresis studies. However, caution should be exercised when considering the use of frozen skin for applications, such as those based on electroosmosis, where the observed differences could have a major impact on the results.     

How Predictable Are Human Stratum Corneum Lipid/Water Partition Coefficients? Assessment and Useful Correlations for Dermal Absorption

Partition coefficients between human stratum corneum lipids and water (K^sclip/w) are collected or deduced from a variety of sources in a manner that approximately doubles the available data compared to the current state-of-the-art model (Hansen et al., Adv Drug Deliv Rev. 2013;65(2):251-264). An additional datum for water itself in porcine SC that considerably extends the molecular size and lipophilicity range of the data set is considered. The data are analyzed in terms of an extended linear free energy relationship involving octanol/water partition coefficients, Abraham solvation parameters, and a secondary, power law molecular weight dependence. The optimum fit to log K^sclip/w for the full data set reduces the standard error of prediction from 0.50 for a Hansen-like model to 0.39; corresponding multiplicative errors in K^sclip/w are reduced from a factor of 3.1 to one of 2.5. The difference in performance is driven by the water datum, which requires a more complex dependence on molecular size than that afforded by Abraham parameters. In the absence of the water value, the Hansen-like model, which does not include a dependence on molecular size, is essentially optimum. A comparison is presented to fluid-phase phospholipid–water systems, which have a demonstrably different structure–property relationship.     

Modeling Glucose Transport From Systemic Circulation to Sweat

Sweat sensing may provide a noninvasive means of estimating blood biomarker levels if a number of technological hurdles can be overcome. This report describes progress on a physiologically based transport model relating sweat glucose and key electrolyte concentrations to those in blood. Iontophoretically stimulated sweat glucose and fasted blood glucose were simultaneously measured in 2 healthy human subjects. Sweat glucose was measured with a novel, prototype skin sweat collection/analysis system and blood glucose with a commercial fingerstick glucometer. These data, in combination with data from 3 published studies, were used to calibrate a dynamic mathematical model for glucose transport and uptake in human skin, followed by extraction into sweat. Model simulations revealed that experimental and literature sweat glucose values were well represented under varying physiologic conditions. The glucose model, calibrated under a variety of experimental conditions including electrical enhancement, revealed a 10 min blood-to-sweat lag time and a sweat/blood glucose level ranging from 0.001 to 0.02, depending on the sweat rate. These values are consistent with those reported in the literature. The developed model satisfactorily described the sweat-to-blood relationship for glucose concentrations measured under different conditions in 4 human studies including the present pilot study. The algorithm may be used to facilitate sweat biosensor development.     

Permeability of Fluid-Phase Phospholipid Bilayers: Assessment and Useful Correlations for Permeability Screening and Other Applications

Permeability data (P^lip/w) for liquid crystalline phospholipid bilayers composed of egg lecithin and dimyristoylphosphatidylcholine (DMPC) are analyzed in terms of a mathematical model that accounts for free surface area and chain-ordering effects in the bilayer as well as size and lipophilicity of the permeating species. Free surface area and chain ordering are largely determined by temperature and cholesterol content of the membrane, molecular size is represented by molecular weight, and lipophilicity of the barrier region is represented by the 1,9-decadiene/water partition coefficient, following earlier work by Xiang, Anderson, and coworkers. A correlating variable χ = MWⁿσ /(1–σ) is used to link the results from different membrane systems, where different values of n are tried, and σ denotes a reduced phospholipid density. The group (1–σ)/σ is a measure of free surface area, but can also be interpreted in terms of free volume. A single exponential function of χ is developed that is able to correlate 39 observations of P^lip/w for different compounds in egg lecithin at low density, and 22 observations for acetic acid in DMPC at higher densities, spanning nine orders of magnitude to within an rms error for log₁₀ P^lip/w of 0.20. The best fit found for n = 0.87 ultimately makes χ much closer to the ratio of molecular to free volumes than surface areas. The results serve as a starting point for estimating passive permeability of cell membranes to nonionized solutes as a function of temperature and cholesterol content of the membrane.     

Ultrasonic diagnosis of primary sarcoma of the gallbladder

Real-time B-mode ultrasonography was employed in the identification of a primary sarcoma of the gallbladder. The ultrasonic findings of the tumor were an echogenic mass obliterating the gallbladder lumen with a stone in the center of the mass.     

Distributed diffusion-clearance model for transient drug distribution within the skin

Quantitative predictions of molecular transport rates through the skin are key to the development of topically applied and transdermally delivered drugs, as well as risk assessment associated with dermal exposure. Most research to date has focused on correlations for the permeability of the stratum corneum, and transient diffusion models that oversimplify vascular clearance processes in terms of a perfect-removal boundary condition at an artificially introduced lower boundary. Considerations of the spatially distributed nature and action of blood vessels have usually been limited to the steady-state case. This article describes a more comprehensive transient model of percutaneous absorption formulated in terms of volumetric dispersion and clearance coefficients reflecting the spatial distribution of vascular processes. The model was implemented through an analysis of published experimental results on in vivo permeation of salicylic acid (SA) in de-epidermized rat skin. With regard to the characterization of SA in rat dermis ("de") in vivo, it was found that: (i) SA is likely to have a dermal effective partition coefficient (relative to pH 7.4 aqueous buffer "pH7.4") around unity (K(de/pH7.4) = 0.9 +/- 0.3); (ii) vascular processes seem not to increase drug dispersion significantly beyond molecular diffusion [D(de) approximately (D(de))(mol) = (8 +/- 3) . 10(-7) cm(2) s(-1)]; and (iii) vascular clearance is characterized by a rate coefficient k(de) = (7 +/- 2) . 10(-4) s(-1). Application of a whole-skin variant of the model (including the stratum corneum and viable epidermis) allowed realistic predictions to be made of transient subsurface concentration levels after application from a finite dose.     

Refractory hypoxemia associated with neonatal pulmonary disease: the use and limitations of tolazoline.

Thirty-nine critically ill infants with pulmonary disease received tolazoline because of severe hypoxemia refractory to administration of 100% O2 and mechanical ventilation. Twenty-seven (69%) of the infants responded with an increase in PaO2 greater than or equal to 20 torr in the first umbilical arterial gas after completion of the initial ten-minute infusion (1 to 2 mg/kg) of the drug. A response was not correlated with survival. The overall survival was 46%, essentially unchanged from our previous report (44%). Infants with hyaline membrane disease had the poorest survival rate (33%). Complications associated with the use of tolazoline occurred in 82% of the infants. A hypotensive reaction, defined as a 25% decrease in mean arterial pressure from the pre-tolazoline level, occurred in 67% of the infants, and more commonly in the infants with RDS (87%). In 11 infants who did not respond to the initial dose of tolazoline, the dose was increased up to 10 mg/kg/hour; only one infant responded, and eight (73%) had a hypotensive reaction.     

Vasopressin functions as an endogenous antipyretic in the newborn

These experiments sought to determine the role of arginine vasopressin (AVP) in the inability of newborns to produce a fever. Our data demonstrate that the AVP analog, [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid)-2-(O-methyl) tyrosine]arginine vasopressin (M-AVP), administered centrally to adult rats, prevented the antipyretic action of centrally injected AVP. Behaviorally thermoregulating 3-day-old rat pups failed to respond to endoxin with a fever, similar to neonates of other species, but when central AVP antipyretic receptors were blocked by pretreatment with M-AVP, the pups were able to raise their body temperature to febrile levels. The antipyretic drug, indomethacin, prevented these fevers. We conclude that endogenous AVP is a physiologically important antipyretic substance in the brain of the newborn rat.     

Perivascular paclitaxel wraps block arteriovenous graft stenosis in a pig model.

BACKGROUND: Haemodialysis vascular access dysfunction is currently a huge clinical problem. In an attempt to reduce the morbidity associated with haemodialysis vascular access dysfunction, we have previously developed and validated a local perivascular paclitaxel release system that has been shown to release paclitaxel for at least 3 weeks. The aim of the current study was to evaluate the in vivo use of these perivascular wraps (for both safety and efficacy) at different time points in our pig model of arteriovenous graft stenosis. METHODS: Paclitaxel-loaded ethylene vinyl acetate wraps were placed around the graft-vein anastomosis on one side, with control polymers being placed on the contralateral side in our pig model of arteriovenous graft stenosis. Animals were sacrificed at early (10-11 days), middle (23-24 days) and late (32-38 days) time points. The entire graft-vein anastomosis was removed at the time of sacrifice and assessed for the extent of luminal stenosis using histomorphometric techniques. RESULT: Graft-vein anastomoses treated with the paclitaxel-loaded polymers had an almost complete absence of luminal stenosis at the middle (23-24 days) and late (32-38 days) time points (when one would expect the development of neointimal hyperplasia) as compared with the contralateral control graft-vein anastomoses (37.90% luminal stenosis in the controls vs 0.10% in the paclitaxel group). There were minimal local side effects from this procedure. CONCLUSIONS: Our results demonstrate the safety and efficacy of paclitaxel-loaded perivascular wraps in the setting of a pig model of arteriovenous graft stenosis. We believe that such a local approach which could be easily applied at the time of surgery is ideally suited for use in the clinical setting of haemodialysis vascular access dysfunction. It is likely that this novel approach could result in a significant reduction in the huge economic and health morbidity costs currently associated with this recalcitrant clinical problem.