Skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) by inhibiting activation of the IGF-I signaling pathways.

We showed that unloading markedly diminished the effects of IGF-I to activate its signaling pathways, and the disintegrin echistatin showed a similar block in osteoprogenitor cells. Furthermore, unloading decreased alphaVbeta3 integrin expression. These results show that skeletal unloading induces resistance to IGF-I by inhibiting activation of the IGF-I signaling pathways at least in part through downregulation of integrin signaling. INTRODUCTION: We have previously reported that skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) with respect to bone formation. However, the underlying mechanism remains unclear. The aim of this study was to clarify how skeletal unloading induces resistance to the effects of IGF-I administration in vivo and in vitro with respect to bone formation. MATERIALS AND METHODS: We first determined the response of bone to IGF-I administration in vivo during skeletal unloading. We then evaluated the response of osteoprogenitor cells isolated from unloaded bones to IGF-I treatment in vitro with respect to activation of the IGF-I signaling pathways. Finally we examined the potential role of integrins in mediating the responsiveness of osteoprogenitor cells to IGF-I. RESULTS: IGF-I administration in vivo significantly increased proliferation of osteoblasts. Unloading markedly decreased proliferation and blocked the ability of IGF-I to increase proliferation. On a cellular level, IGF-I treatment in vitro stimulated the activation of its receptor, Ras, ERK1/2 (p44/42 MAPK), and Akt in cultured osteoprogenitor cells from normally loaded bones, but these effects were markedly diminished in cells from unloaded bones. These results were not caused by altered phosphatase activity or changes in receptor binding to IGF-I. Inhibition of the Ras/MAPK pathway was more impacted by unloading than that of Akt. The disintegrin echistatin (an antagonist of the alphaVbeta3 integrin) blocked the ability of IGF-I to stimulate its receptor phosphorylation and osteoblast proliferation, similar to that seen in cells from unloaded bone. Furthermore, unloading significantly decreased the mRNA levels both of alphaV and beta3 integrin subunits in osteoprogenitor cells. CONCLUSION: These results indicate that skeletal unloading induces resistance to IGF-I by inhibiting the activation of IGF-I signaling pathways, at least in part, through downregulation of integrin signaling, resulting in decreased proliferation of osteoblasts and their precursors.     

Morphine Enhances Pharmacological Preconditioning by Isoflurane: Role of Mitochondrial KATP Channels and Opioid Receptors

Background: Adenosine triphosphate-regulated potassium channels mediate protection against myocardial infarction produced by volatile anesthetics and opioids. We tested the hypothesis that morphine enhances the protective effect of isoflurane by activating mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors.

Methods: Barbiturate-anesthetized rats (n = 131) were instrumented for measurement of hemodynamics and subjected to a 30 min coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size was determined using triphenyltetrazolium staining. Rats were randomly assigned to receive 0.9% saline, isoflurane (0.5 and 1.0 minimum alveolar concentration [MAC]), morphine (0.1 and 0.3 mg/kg), or morphine (0.3 mg/kg) plus isoflurane (1.0 MAC). Isoflurane was administered for 30 min and discontinued 15 min before coronary occlusion. In eight additional groups of experiments, rats received 5-hydroxydecanoic acid (5-HD; 10 mg/kg) or naloxone (6 mg/kg) in the presence or absence of isoflurane, morphine, and morphine plus isoflurane.

Results: Isoflurane (1.0 MAC) and morphine (0.3 mg/kg) reduced infarct size (41 +/- 3%; n = 13 and 38 +/- 2% of the area at risk; n = 10, respectively) as compared to control experiments (59 +/- 2%; n = 10). Morphine plus isoflurane further decreased infarct size to 26 +/- 3% (n = 11). 5-HD and naloxone alone did not affect infarct size, but abolished cardioprotection produced by isoflurane, morphine, and morphine plus isoflurane.     

The AmRo study: pregnancy outcome in HIV-1-infected women under effective highly active antiretroviral therapy and a policy of vaginal delivery

OBJECTIVE: To explore pregnancy outcome in HIV-1-positive and HIV-negative women, and mother-to-child transmission (MTCT) according to mode of delivery under effective highly active antiretroviral therapy (HAART). DESIGN: Cohort of 143 pregnant HIV-1-infected women including a matched case-control study in a 2:1 ratio of controls to cases (n=98). SETTING: Academic Medical Center in Amsterdam and Erasmus Medical Center in Rotterdam, the Netherlands. POPULATION: Consecutive referred HIV-1 infected pregnant women treated with HAART and matched control not infected pregnant women. MAIN OUTCOME MEASURES: MTCT, preterm delivery, low birthweight, pre-eclampsia. RESULTS: MTCT was 0% (95% CI 0-2.1%). Seventy-eight percent of HIV-1-infected women commenced and 62% completed vaginal delivery. The calculated number of caesarean sections needed to prevent a single MTCT was 131 or more. Preterm delivery rates were 18% (95% CI 11-27) in women infected with HIV-1 and 9% (95% CI 5-13) in controls (P=0.03). HAART used at <13 weeks of gestation was associated with a 44% preterm delivery rate compared with 21% when HAART was started at or after 13 weeks and 14% in controls. (Very) low birthweight and incidence of pre-eclampsia were not different between HIV-1 and controls. CONCLUSIONS: We have not demonstrated any MTCT after vaginal delivery in women effectively treated by HAART. The HAART-associated increase in preterm delivery rate is mainly seen after first trimester HAART use.     

A study of 10 cases of velopharyngeal incompetence treated by flap pharyngoplasty

Velopharyngeal incompetence (VPI) is a condition of incomplete closure of V.P. port area, normally formed by velum and posterior pharyngeal watt. The condition primarily results in various types of speech defects, which form- the main complaint of the patient. We have studied 10 cases of VPI due to various causes and the speech improvement obtained by flap pharyngoplasty procedures. The results have been evaluated with a follow-up of six months. Highly encouraging results only indicate a more frequent need to undertake such surgery without any hesitation if the ENT surgeon is familiar with and has an adequate exposure to this simple and effective procedure.     

Effects of Ethanol Exposure during the Third Trimester Equivalent on Neuron Number in Rat Hippocampus and Dentate Gyrus

An artificial rearing procedure was used to expose neonatal rats to a formula containing 3.74% ethanol during postnatal days 4 through 10. This treatment produced a mean blood ethanol concentration of 379.8 +/- 17.3 mg/dl. When the pups were killed on the afternoon of postnatal day 10, brain weight to body weight ratio in the ethanol-exposed rats was reduced 22.4% and 21.5% compared to suckle and pair-fed controls, respectively. Ethanol exposure also resulted in a 16% reduction of neurons in hippocampal field CA4, compared to controls, but did not produce deficits in fields CA1 or CA3. There was also a 10% increase in the number of neurons (a population of cells in the midst of a proliferative phase at the time of the exposure) in the granule cell layer of the dentate gyrus. The ethanol exposure did not affect cell size in any of the four neuron populations measured. These results suggest, that within the dose and timing parameters examined, ethanol exposure during the third trimester equivalent appears to be preferentially harmful to specific populations of developing neurons.     

Zur Fermentbiologie der Syphilis und Syphilisähnlicher Krankheiten

Zusammenfassung Die Verminderung des Diastasegehalts im Liquor cerebrospinalis bei Syphilis wird auf die Wirksamkeit der Spirochaeta pallida zurückgeführt. Zum Beweis für diese Auffassung wird die Bestimmung des diastatischen Ferments im Hirngewebe bei Paralyse herangezogen: im Gegensatz zu nichtsyphilitischen Kontrollfällen findet sich im Gehirn der Paralytiker, besonders in den von den Spirochäten am stärksten angegriffenen Rindenpartien des Frontalhirns, eine Diastaseverminderung, vielfach ein völliger Diastaseschwund. Auch in vitro führt die Spirochaeta pallida, aus nässenden syphilitischen Papeln in eine Kochsalzaufschwemmung gebracht, zur Vernichtung des diastatischen Fermentes in normalen Liquores.Eine ähnliche Beeinflussung der Diastase ist durch weitere Erreger möglich, die der Spirochaeta pallida morphologisch und biologisch verwandt sind. Sie wird für die Trypanosomen (Nagana) und die Spirillen morsus muris, die Erreger der Rattenbißkrankheit (Sodoku), die in Kochsalzaufschwemmungen auf vorgelegte Diastaselösungen zur Einwirkung gebracht wurden, nachgewiesen. Recurrens- und Weil-Spiro-Chäten üben eine solche Funktion im selben Ausmaße nicht aus. Diese Ergebnisse werden als weitere Stütze für die Auffassung vonStühmer angesehen, daß die Trypanosomiasis und die Sodokuerkrankung im Tierexperiment als Modellinfektionen zum Studium der Biologie der Syphilis beim Menschen herangezogen werden können.An Trypanosomenaufschwemmungen wird geprüft, ob die Vernichtung des diastatischen Ferments allein eine Funktion der lebenden, vitalkräftigen und infektionstüchtigen Erreger ist, oder ob auch die abgetöteten Erreger oder schließlich die zwar beweglichen, aber in ihrer Vitalität und Infektiosität geschädigten Erreger diese Fähigkeit noch besitzen. Während unbeeinflußte Trypanosomen eine deutliche Abnahme im Fermentgehalt von Diastaselösungen bewirken, vermögen durch Aqua dest.-Zusatz, durch Aufkochen oder durch Ultraviolettlichtstrahlen getötete Trypanosomen keinerlei nennenswerten Einfluß auf den Diastasegehalt auszuüben. Nach Röntgenbestrahlung beweglich gebliebene, aber in ihrer Vitalität und Infektiosität geschwächte Trypanosomen lassen ebenfalls die vorgelegte Diastaselösung nahezu unbeeinflußt.Aus diesen Modellstudien wird geschlossen, daß möglicherweise auch bei der Syphilis die Verminderung des Diastasegehalts im Liquor cerebrospinalis auf die Anwesenheit vitalkräftiger und infektionstüchtiger Erreger zu beziehen ist. Die weitere Verwendung der Diastasebestimmung im Liquor cerebrospinalis für die Zwecke der Syphilisdiagnostik wird jedoch von einer Verbesserung der Glykogenbereitung abhängig gemacht, da nur durch ein gleichmäßig hergestelltes Glykogen die Konstanz der Untersuchungsergebnisse gesichert erscheint.Ausgeführt mit Unterstützung der Freiburger Wissenschaftlichen Gesellschaft.