This investigation tested the hypothesis that daily parenterally administered parathyroid hormone (1-34) improves fracture healing. Twenty, 3-month-old, male Sprague Dawley rats weighing ...approximately 400 g each, underwent the production of closed, unilateral mid-diaphyseal femoral fractures. Animals were divided into two groups of 10; the animals received either a daily subcutaneous injection of delivery vehicle (0.9% saline) or 80 micrograms/kg parathyroid hormone. On Day 21 after fracture the animals were euthanized, the femurs were removed and subjected to biomechanical testing, bone densitometry (dual energy x-ray absorptiometry, peripheral quantitative computed tomography), and histologic examination. Treatment with parathyroid hormone resulted in statistically significant increases in callus area and strength. Histologic examination of the calluses showed an increase in the amount of new bone formed. No differences were observed in the weights of the animals or the sizes of the bones. Values obtained using dual energy x-ray absorptiometry and peripheral quantitative computed tomography indicate an increase in density in the parathyroid hormone treated fractures consistent with the histologic appearance and the findings of increased strength, although these bone density changes did not achieve statistical significance. These results suggest that parenterally administered parathyroid hormone (1-34) may enhance or accelerate normal fracture healing and support the concept that this hormone be tested clinically as a systemic treatment for fractures that are slow to heal.
Noting and tracing former ownership of rare materials has been a common cataloging practice for many years. This paper explores the value of examining special collections materials that may not be ...old and rare for evidence of provenance in order to provide notes and added entries pointing to former owners in bibliographic records. This case study of a small group of mid-twentieth century books, formerly owned by a Swiss family, demonstrates the significance of the cataloging process in revealing information about the original owners. Building on the bibliographic work of catalogers working with a collection of books on mountaineering topics, the author uses the case study to show how cataloging books as objects with a history can enable users to find new topics of research in special collections materials. PUBLICATION ABSTRACT
A new series of bisphosphonic acids bearing nitrogen containing heterocycles and carbocycles has been designed and synthesized. The most potent novel bisphosphonates were shown to have lower mineral ...affinity but have better inhibition of farnesyl diphosphate synthase, than most clinically used bisphosphonates. However, the high polarity and charged nature of bisphosphonates result in very low oral bioavailability, resulting in highly variable absorption, especially when administered with food. To eliminate side effects and absorption issues while maintaining the bisphosphonate pharmacological activity, a series of novel potential prodrugs-cyclic esters of bisphosphonic acids was developed where the bisphosphonic acid functionality is "masked" as a cyclic ester. A new synthesis and the steric and structural isomerism of these novel cyclic bisphosphonates are discussed. The cyclic esters of bisphosphonates demonstrated better absorption, particularly in the presence of food when dosed orally. Also, several protected bisphosphonates were hydrolytically labile in vivo, thereby releasing the tetra-acid functionality of the bisphosphonates systemically after their oral absorption.
The traditional therapeutic treatment of organophosphate cholinesterase inhibitor (nerve agents) poisoning consists of co-treatment with an antimuscarinic (atropine) and a reactivator of inhibited ...acetylcholinesterase (AChE), which contains a nucleophilic oxime function. Two oximes are presently widely available for clinical use, pralidoxime and obidoxime (toxogonin), but both offer little protection against important nerve agent threats. This has highlighted the real need for the development and availability of more effective oximes for human use, a search that has been going on for up to 30 years. However, despite the demonstration of more effective and safe oximes in animal experiments, no additional oximes have been licensed for human use. HI-6, (1-4(aminocarbonyl)-pyridiniomethoxymethyl-2(hydroxyimino)pyridinium dichloride; CAS 34433-31-3) has been studied intensively and has been proved effective in a variety of species including non-human primates and appears from clinical experience to be safe in humans. These studies have led to the fielding of HI-6 for use against nerve agents by the militaries of the Czech republic, Sweden, Canada and under certain circumstances the Organisation for the Prohibition of Chemical Weapons. Nevertheless HI-6 has not been granted a license for clinical use, must be used only under restricted guidelines and is not available for civilian use as far as is known. This article will highlight those factors relating to HI-6 that pertain to the licensing of new compounds of this type, including the mechanism of action, the clinical and pre-clinical demonstration of safety and its efficacy against a variety of nerve agents particularly in non-human primates, since no relevant human population exists. This article also contains important data on the use of HI-6 in baboons, which has not been available previously. The article also discusses the possibility of successful therapy with HI-6 against poisoning in humans relative to doses used in non-human primates and relative to its ability to reactivate inhibited human AChE.
To evaluate the activity of carprofen and other nonsteroidal anti-inflammatory drugs (NSAID) against isozymes of canine cyclooxygenases (COX1 and COX2).
Constitutive COX1 was obtained from washed ...canine platelets, and COX2 was obtained from a canine macrophage-like cell line that was induced with endotoxin. Activity of carprofen and other NSAID against COX1 and COX2 was compared. Dose-response curves were plotted, and calculations were performed to identify concentrations that caused 50% inhibition (IC50 microM) for each isozyme. Ratio of the COX1-to-COX2 IC50 was used as a measure of isozyme selectivity.
Of the compounds evaluated, carprofen had the greatest selectivity for COX2. Potency of carprofen for canine COX2 was more than 100-fold greater than for canine COX1. Inhibition of canine COX2 (IC50, 0.102 microM) for the racemic mixture of carprofen (S and R stereoisomers) was primarily attributable to the S enantiomer (IC50, 0.0371 microM), which was approximately 200-fold more potent than the R enantiomer (IC50, 5.97 microM). Nimesulide had the next highest selectivity for COX2 (38-fold), and tolfenamic acid and meclofenamic acid had 15-fold selectivity for COX2. The other compounds tested did not have substantial selectivity for canine COX2 or were more selective for canine COX1.
Carprofen was found to be a potent inhibitor of canine COX2. Of the compounds tested, carprofen had the highest selectivity for canine COX2.
The selectivity of carprofen for canine COX2 may be an important factor for its use in dogs.
Seabirds are central place foragers during the breeding season and, as marine food resources are often patchily distributed, flexibility in foraging behaviour may be important in maintaining prey ...delivery rates to chicks. We developed a methodological approach using a combination of GPS data loggers and temperature-depth recorders that allowed us to describe the behaviour of surface-feeding seabirds. Specifically, we tested whether differences in foraging behaviour of black-legged kittiwakesRissa tridactylacould be linked with reproductive success by comparing 2 consecutive years at 2 sites. At Rathlin Island (Northern Ireland) during 2010, foraging differed markedly from that during 2009 and from that at Lambay Island (Republic of Ireland) during both years. Birds exhibited foraging trips of greater duration, travelled a greater total distance, spent more time in transit and spent longer recuperating on the surface of the water. This notable shift was associated with a decline in breeding success, with greater loss of eggs to predation and lower prey delivery rates, resulting in the starvation of 15% of chicks. We suggest that food resources were reduced or geographically less accessible during 2010, with suitable foraging areas located further from the colony. Birds did not invest greater amounts of time attempting to catch prey. Thus, our results indicate that kittiwakes at Rathlin modulated their foraging behaviour not by increasing foraging effort through feeding more intensively within prey patches but by extending their range to increase the probability of encountering more profitable prey patches.
Differences in structural brain connectivity that underlie inattention have been previously investigated in adolescents with attention deficit/hyperactivity disorder, but not in the context of ...premature birth, which is often associated with attentional problems. The purpose of this study was to identify the neural correlates of attentional problems in adolescents born prematurely and determine neonatal predictors of those neural correlates and attention problems.
The study included 24 adolescents (12.5 ± 1.8 years of age; 12 girls, 12 boys) who were born prematurely and underwent MR imaging of the brain and cognitive assessment, both shortly after birth and as adolescents. Structural connectivity was assessed at adolescence using diffusion tensor imaging and tractography.
Of the 24 subjects, 12 had attention deficits. A set of axonal pathways connecting the frontal, parietal, temporal, and occipital lobes had significantly lower fractional anisotropy in subjects with attentional problems. The temporoparietal connection between the left precuneus and left middle temporal gyrus was the most significantly underconnected interlobar axonal pathway. Low birth weight and ventriculomegaly, but not white matter injury or intraventricular hemorrhage on neonatal MR imaging, predicted temporoparietal hypoconnectivity in adolescence. However, neither birth weight nor other neonatal characteristics were associated with attention deficits directly.
We identified an aberrant structural brain connectivity pattern, involving temporoparietal hypoconnectivity, in prematurely born adolescents with attentional problems. We also identified birth weight as a potential neonatal predictor of the temporoparietal hypoconnectivity. These findings add to our understanding of the neural basis and etiology of inattention in adolescents after premature birth.
Abstract This document will address the contributions of defence research to both military and civilian applications. Compared to civilian research capabilities, particularly in terms of personnel, ...defence research resources are limited. Additionally, many of the research targets are either classified or involve applications that have (or had) limited civilian use. Recently, however, spurred by counter-terrorism preparedness particularly in North America, many previously ‘orphaned’ research projects have assumed much greater prominence. This has occurred in all areas of militarily significant research, but this paper will focus on medical countermeasures to weapons of mass destruction and to a lesser extent on detection/identification issues. In the area of countermeasures to chemical weapons, most of the defence research has been devoted to “classical” CWAs such as nerve agents, vesicants, choking and blood agents, with considerable success in some applications. Similarly vaccination programs for the biological weapons have also been quite successful. And recent attention has been directed toward the “emerging” threats such as some of the exquisitely lethal toxins. The difference now is that all of these research programs have the objective of moving from research to development of not only military but also civilian use very much sooner than later.
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