Variations in strength of vertebrae with age and their relation to osteoporosis

Fourth and fifth lumbar vertebrae were obtained at post mortem examinations of human subjects in the range 26 to 86 years and at the same time specimens were taken from the iliac crests for histological assessment of trabecular density (iliac crest score). After removal of pedicles and spinous processes the vertebrae were compressed in a testing machine to mechanical failure. The following values were obtained; breaking stress (load per unit area at failure), strain (percentage deformation) at failure and relative ash content (ash per unit volume). Strain at failure was independent of the size and strength of the vertebrae. The relative ash content and the iliac crest score were closely correlated. The relative ash content and the breaking stress both declined with increasing age, but the relation between them was not linear since the breaking stress fell more quickly than the ash content. Euler's equation for the buckling stress of a loaded column readily explains how in osteoporosis the reduction of the diameter of the vertical trabeculae and the loss of transverse ties cause loss of strength proportionately greater than the loss of osseous tissue. The results give no reason to suppose that in osteoporosis the quality of the osseous tissue is changed.

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Zusammenfassung Die vierten und fünften Lumbalwirbelknochen wurden von Obduktionen menschlicher Leichen innerhalb der Altersgrenzen von 26 und 86 Jahren gewonnen. Gleichzeitig wurden Proben von der Beckenschaufel entnommen, um Maßstäbe für die Bälkchendichte festzulegen (Beckenschaufelzahl). Nach Entfernung der Ansätze und Dornfortsätze wurden die Wirbelknochen in einer Prüfungsmaschine komprimiert, um mechanisches Versagen zu bestimmen. Folgende Werte wurden erhalten: Bruchbelastung (Gewicht pro Einheitsfläche bei Bruch), Beanspruchung (Prozentsatz von Deformation) bei Bruch und relativer Aschegehalt (Asche pro Einheitsvolumen). Die Beanspruchung bei Bruch war unabhängig von Größe und Stärke der Wirbelknochen. Zwischen dem relativen Aschegehalt und der Beckenschaufelzahl bestand eine enge Verbindung. Der relative Aschegehalt und die Bruchbelastung wurden mit fortschreitendem Alter kleiner, jedoch war die Beziehung zwischen diesen beiden Faktoren nicht linear, da die Bruchbelastung rascher als der Aschegehalt abnahm. MitEulers Gleichung für die Verbiegungsbelastung einer geladenen Säule läßt sich leicht erklären, auf welche Weise bei der Osteoporose die Reduktion des Durchmessers der Wirbeltrabekeln und der Verlust der transversen Verbindungen einen verhältnismäßig größeren Stärkeverlust hervorruft, als durch Verlust von Knochengewebe erklärt werden kann. Die Ergebnisse geben keinen Anlaß zu der Vermutung, daß bei der Osteoporose die Qualität des Knochengewebes eine Veränderung erfährt.

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Résumé Les quatrième et cinquième vertèbres lombaires sont prélevées post-mortem chez des sujets humains, âgés de 26 à 86 ans, et des échantillons de crête iliaque sont collectés simultanément pour établir histologiquement la densité des travées osseuses (index de la crête iliaque). Après avoir enlevé les pédicules et les apophyses épineuses, les vertèbres sont compressées dans une machine pour tester la résistance mécanique. Les valeurs suivantes sont déterminées: force de rupture (en poids par unité de surface au moment de la rupture), effort de rupture (en pourcentage de déformation) et contenu relatif en cendres (en cendres par unité de volume). L'effort de rupture est indépendant de la taille et de la force des vertèbres. Le contenu relatif en cendres et l'index de la crête iliaque sont en rapports étroits. Le contenu relatif en cendres et la force de rupture diminuent en fonction de l'âge, mais ce rapport n'est pas linéaire, car la force de rupture chute plus rapidement que le contenu en cendres. L'équation d'Euler pour une force courbe appliquée à une colonne chargée explique facilement comment, dans l'ostéoporose, la réduction de diamètre des travées verticales et la perte des attaches transversales sont responsables de la perte de force proportionellement plus élevée que la perte de tissu osseux. Les résultats ne permettent pas de supposer que, dans l'ostéoporose, la qualité du tissu osseux est altérée.

     

An experimental investigation of the spray issued from a pMDI using laser diagnostic techniques.

This research was concerned with the experimental investigation of the spray issued from a pressurised metered-dose inhaler (pMDI) using laser diagnostic techniques and has been motivated by the urgent need to find suitable replacements to the environmentally destructive CFC propellants currently used in the device. The experimental work was conducted using phase-Doppler particle analysis (PDPA), a single particle light scattering technique that provides the simultaneous measurement of drop size, velocity, and concentration, yielding the most detailed temporal and spatial analysis of the pMDI spray to date. Three formulations were studied to compare the performance of an "ozone-friendly" hydrofluoroalkane propellant against that of a traditional CFC propellant mixture and a commercially available CFC formulation containing drug and surfactant. The PDPA analysis was complemented by a visual investigation of the near-orifice flow field using copper laserstrobe microcinematography to obtain information on the primary atomization process of the pMDI. This work was conducted in parallel with the theoretical investigation of the spray issued from a pMDI.     

MultiCare Health System saves millions of dollars through redesigned care

When executives at MultiCare Health System in Tacoma looked at future business projections, they knew they could not wait for healthcare reform. They needed to start now on a dramatic change process that would prove crucial to controlling their spiking costs.     

Pulmonary injury from proton and conventional radiotherapy as revealed by CT

OBJECTIVE: Although radiation therapy is used in early-stage inoperable lung cancer, it often results in injury to functional lung tissue. A study was undertaken to determine the frequency and severity of pulmonary injury revealed by CT in patients who had undergone conformal proton (to a limited volume) radiation therapy. We compared these findings with those from a group of patients who had undergone a combination of photon and conformal proton (to a larger volume) radiation therapy. CONCLUSION: Proton radiation therapy was associated with a lower frequency of pulmonary injury than the combined regimen. Injury correlated well with the volume of normal lung that was irradiated. Conformal proton radiation therapy appears to be able to reduce the incidence and severity of pulmonary injury revealed by CT.     

Leptin-induced increase in sympathetic nervous and cardiovascular tone is mediated by proopiomelanocortin (POMC) products

The mechanism underlying the leptin-induced increased sympathetic nerve activity and cardiovascular tone was investigated in normal rats. The melanocortin (MC) peptides and other fragments derived from proopiomelancortin (POMC) have a diverse array of biological activities and have been implicated in mediating the feeding behavioral responses to leptin. In this study we evaluated the possible involvement of two major products of POMC, alpha-melanocyte stimulating hormone (alpha-MSH) and beta-endorphin, in mediating the effects of leptin on sympathetic activity and mean arterial pressure (MAP) in normal rats. Intraventricular (i.c.v.) cannulas were implanted in normal rats and allowed to recover. On the day of the study the animals were anesthetized with urethane alpha-chloralose and instrumented for the recording of MAP, lumbar sympathetic nerve activity (LSNA), and heart rate (HR). To determine the correlation between the leptin response and the POMC products, alpha-MSH and beta-endorphins were also injected into the lateral ventricle. alpha-MSH acted to increase MAP and LSNA while beta-endorphin decreased these parameters. Leptin administration by i.c.v. cannula increased the MAP and LSNA in normal rats. The i.c.v. administration of agouti protein, an alpha-MSH receptor antagonist, prior to leptin infusion blocked this response. Likewise, pretreatment with naloxone a beta-endorphin receptor antagonist also blocked the response to leptin. From these studies we conclude that the acute increased LSNA and MAP in response to i.c.v. leptin may be mediated by increased POMC and its subsequent production of breakdown product alpha-MSH and/or beta-endorphin and it is the subsequent action of alpha-MSH that increases MAP and LSNA by activation of the MC4 receptor. The naloxone antagonism of the leptin response is likely due to the blockade of presynaptic opioid inhibition of the MC4 receptor-mediated pressor response.     

The impact-acceleration model of head injury: injury severity predicts motor and cognitive performance after trauma

This study examines neuropsychological dysfunction after varying severities of the Impact Acceleration Model of diffuse traumatic brain injury. Adult rats (340 g-400 g) were divided into five groups, and exposed to varying degrees of Impact Acceleration Injury (1 m, 2 m, 2.1 m/500 g and second insult). After injury, animals were allowed to recover; acute neurological reflexes, beam walk score, beam balance score, inclined plane score, and Morris Water Maze score were then assessed at multiple time points. Injury of all severities caused significant motor and cognitive deficits. With milder injuries these effects were transient; however, with more severe injuries no recovery in function was seen. The addition of hypoxia and hypotension made a moderate injury worse than a severe injury. The acute neurological reflexes, the beam balance test and the inclined plane test distinguished between the more severely injured groups, but were affected less by mild injury. The beam walk test was sensitive to mild injury, but appeared unable to distinguish between the severe groups. The Morris Water Maze was sensitive for all injury groups, but appeared to adopt a different response profile with secondary insult. This study has for the first time characterized the degree of motor and cognitive deficits in rodents exposed to differing severities of Impact Acceleration Injury. These data confirm that the tests considered, and the Injury Model used, provide a useful system for the consideration of potential therapies which might ameliorate neuropsychological deficits in diffuse brain injury.     

Leukaemia in the vicinity of two tritium-releasing nuclear facilities: a comparison of the Kruemmel Site, Germany, and the Savannah River Site, South Carolina, USA.

In 1991, an increased rate of childhood leukaemia was reported from the small northern German community of Elbmarsch, which is located on the banks of the River Elbe opposite the Kruemmel nuclear power plant. Owing to the fact that the increase occurred six years after the start-up of the plant, radioactive discharges were suspected as being implicated in the development of the cases. Previous investigations have failed to identify any exposure which might be associated with the cluster. Nonetheless, concern regarding the increased tritium burden in the environment remains. To further assess the impact of tritium releases to the environment upon population cancer rates, the releases and leukaemia rates at the Savannah River site, USA, were compared with the Kruemmel site. Based on the data from 1991 to 1995, the incidence of childhood leukaemia in the vicinity of the Savannah River site was non-significantly less than expected compared with the significantly higher than expected rates close to the German plant. In contrast, tritium releases from the Savannah River site exceed those from the Kruemmel site by several orders of magnitude. The results of this observational study suggest that factors other than environmental tritium releases are associated with the increased number of leukaemia cases near the Kruemmel site.     

Metabolism-based inactivation of neuronal nitric-oxide synthase by components of cigarette and cigarette smoke.

It has been shown that administration of cigarette smoke to rats leads to loss of neuronal nitric-oxide synthase (nNOS) activity and nNOS protein in penile tissue. The exact mechanism for this loss of activity and protein is not known. In the current study, we investigated whether extracts prepared from cigarette smoke or from the cigarette itself could directly inhibit nNOS activity. We discovered that the cigarette smoke extract and the cigarette extract cause a time-, concentration-, and calmodulin-dependent inactivation of nNOS in an in vitro system containing the purified enzyme. L-Arginine, but not D-arginine, protects nNOS from this time-dependent inactivation, suggesting an active site directed event. The kinetics of inactivation are consistent with the metabolism-based or suicide inactivation of nNOS. Based on studies with other metabolism-based inactivators, this cigarette-mediated inactivation may render nNOS more susceptible to proteasomal degradation and thereby may explain the loss of nNOS protein in vivo. The component(s) responsible for nNOS inactivation is not volatile, is not retained by a 3,000 molecular weight cut-off membrane, binds to activated charcoal, and is highly water-soluble under both acidic and basic conditions. The discovery of a direct inactivation of nNOS by an organic, cationic compound(s) present in tobacco and tobacco smoke provides a basis for further study of not only the mechanisms responsible for the biological effects of tobacco but also a search for a potentially novel inactivator of nNOS.     

KP544, a nerve growth factor amplifier: Pharmacokinetics,safety, and efficacy in the rat

In cultured cells, KP544 [2‐amino‐5‐(4‐chlorophenylethynyl)‐4‐(4‐trans‐hydroxycyclohexyl amino) pyrimidine] amplifies differentiation initiated by nerve growth factor (NGF) or cAMP. This report describes the pharmacokinetics, safety, and neuroprotective efficacy of KP544 in rats. After an oral dose of 10 mg/kg KP544 was 25% bioavailable with a plasma half‐life of 1.3 h and brain levels 6‐fold higher than plasma levels at 4 and 8 h post‐dose. In a safety study, daily oral dosing for 30 days at 10 and 100 mg/kg was well tolerated. The favorable pharmacokinetic and safety profiles, together with its amplification of NGF in vitro, prompted evaluation of KP544 in two models involving NGF deficiencies. In the first model, brains were lesioned with intrastriatal injections of quinolinic acid. KP544 at oral doses of 0.02 to 1.0 mg/kg/day almost completely prevented the resulting learning deficits as evaluated using a radial‐arm‐water maze. At the lowest dose, there was a slower onset of functional improvement. These effects were accompanied by reductions (16–34%) in the striatal lesion size that were greatest at the highest dose and comparable to those seen with NGF therapy. The second model involved a peripheral neuropathy induced by taxol that is associated with decreases in NGF. KP544 at oral doses of 0.1–10 mg/kg/day decreased the severity of the neuropathy as measured by caudal nerve conduction velocities (30–70% return to control values). In both models, KP544 had a large therapeutic index suggesting its potential as a new approach for treating clinical disorders involving deficiencies in NGF. Drug Dev. Res. 62:60–70, 2004. © 2004 Wiley‐Liss, Inc.     

Hypertension secondary to progressive vascular neurofibromatosis

A 4 year old girl with neurofibromatosis type 1 (NF1) was referred for hypertension. An aortogram showed narrowing of the left main renal artery. An angiogram three and a half years later showed coarctation of the abdominal aorta. She underwent aortoplasty but the stenosis recurred. Vascular involvement in NF1 may be progressive and requires long term follow up.