Inhibition of parathyroid hormone stimulated bone resorptionin vitro by the antibiotic mithramycin

Mithramycin, an antibiotic which blocks DNA-dependent RNA metabolism, has been demonstrated to be hypocalcaemicin vivo. It has been suggested that this effect is obtained by an inhibition of bone resorption. We have tested this antibiotic for its effects on bone resorptionin vitro using new-born mouse calvaria and this report presents evidence that mithramycin not only inhibits bone resorptionin vitro but also inhibits the formation of bone and is cytotoxic at all concentrations which appear to be effective at inhibiting resorption. The effectiveness of this antibiotic at inhibiting resorption appears to be related to the degree of bone resorption activity present when it is introduced to the system. Morphological observations also raised the question as to whether or not this agent may cause abnormalities in the normal processes of bone cell modulation resulting in the formation of cartilage.

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Zusammenfassung Mithramycin, ein Antibioticum, welches den DNS-abhängigen RNS-Stoffwechsel blockiert, wirktin vivo hypocalcämisch. Es wurde vermutet, daß diese Wirkung durch eine Hemmung der Knochenresorption erzielt wurde. Wir haben dieses Antibioticum auf seine Wirkungen auf die Knochenresorptionin vitro geprüft und verwendeten zu diesem Zwecke Schädeldächer von neugeborenen Mäusen. Die vorliegende Arbeit enthält den Beweis, daß Mithramycin nicht nur die Knochenresorptionin vitro, sondern auch die Knochenbildung hemmt und daß es in allen Konzentrationen, welche die Resorptionshemmung bewirken, cytotoxisch ist. Die Wirksamkeit dieses Antibioticums als Resorptionshemmer scheint im Zusammenhang zu stehen mit dem Ausmaß der Knochenresorptions-Aktivität zum Zeitpunkt, da das Antibioticum in das System eingeführt wird. Morphologische Beobachtungen ließen auch die Frage aufkommen, ob Mithramycin Abnormalitäten im normalen Ablauf der Knochenzell-Verwandlungen, welche zur Bildung von Knorpel führen, verursachen könne oder nicht.

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Résumé La mithramycine, qui est un antibiotique bloquant le métabolisme de l'ARN, lié à l'ADN, possède des propriétés hypocalcémiquesin vivo. Cette action pourrait être en rapport avec une inhibition de la résorption osseuse. La résorption osseuse de cet antibiotique a été testéein vitro en utilisant des calottes craniennes de souris nouveau-nés. Il semble que la mithramycine, non seulement inhibe la résorption osseusein vitro, mais inhibe aussi la formation osseuse et se révèle cytotoxique à toutes le concentrati ons qui inhibent la résorption osseuse. L'efficacité de l'antibiotique comme inhibiteur de résorption parait liée au degré d'activité de résorption observée lorsqu'on l'introduit dans ce système. Des observations morphologiques posent le problème des anomalies provoquées par cet agent dans le processus normal de différenciation de cellules osseuses au cours de la formation du cartilage.

     

Encephalitogenic properties of purified preparations of bovine oligodendrocytes tested in guinea pigs

The present study has investigated central nervous system disease in guinea pigs inoculated with emulsions containing purified preparations of bovine oligodendroglia and their fractions isolated with or without trypsinization, whole bovine white matter or myelin basic protein (MBP). The MBP content of the oligodendroglial fractions was determined by radioimmunoassay. It was found that oligodendroglia prepared from trypsinized fresh brain contained minute amounts of MBP and did not induce disease. The corresponding cell fraction from non-trypsinized frozen brain was rich in MBP and induced disease. Bovine white matter and MBP induced typical experimental allergic encephalomyelitis (EAE).The structural preservation of the non-encephalitogenic trypsinized MBP-poor cells was very good and that of the encephalitogenic MBP-rich non-trypsinized cells very poor. It has been concluded that the encephalitogenicity observed was due to MBP, rather than to a specific oligodendroglial antigen.     

Effect of hypothermia on lung compliance

The changes in pulmonary compliance have been studied under conditions of total body hypothermia. Five groups of sheep were used; two groups were controls—one for the effects of anaesthesia and the other for normothermic biventricular bypass. The third group was cooled using a femoro-femoral arterio-venous shunt to 20°-23° C. The fourth group was cooled to 15° C. and rewarmed using the Drew technique. The excised lungs of the remaining sheep were studied at 37° and 15° C. (fifth group). The controls showed little change in compliance. The cooled animals showed a decrease in compliance. In the group subjected to hypothermia by the Drew technique, the rewarming phase initially brought a return towards normal compliance. As the temperature rose to 24°-30° C. the improvement in compliance ceased and thereafter compliance decreased for two hours after rewarming. Histologically the lungs were normal. There was no compliance change caused by cooling the excised lungs.     

Giant cell tumors of the maxilla in children

Three types of giant cell lesions occur in the facial skeleton; namely, giant cell reparative granuloma, Brown tumor of hyperparathyroidism, and true giant cell tumor — osteo-clastoma preferably called giant cell neoplasm. An appraisal of the clinical course biochemical laboratory data, radiographic appearance, and histological features are all necessary to distinguish between these varieties. Differentiation is a prerequisite to treatment because the management differs in each lesion. Three case reports illustrate these features. The important considerations of facial growth following surgery to the facial skeleton of a child are discussed. Long-term observation is imperative.     

Frequent failure of adolescent booster responses to tetanus toxoid despite infant immunization: Waning of infancy-induced immune memory?

To define the capacity of a tetanus toxoid booster to reactivate infant-triggered immunity, anti-tetanus antibodies were assessed before and after boosting 162 adolescents and 219 children from Mfou (Cameroon). Among 63 adolescents with 3 recorded dose of infant DTP, 29/63 (46%) responded with a ≥4-fold increase of antibody titers, 35/63 (55%) reaching the 0.10 UI/ml threshold. Response rates were slightly higher (62%) in children aged 10–11 years. Responders and non-responders only differed significantly in their baseline anti-tetanus antibodies. Thus, early life immune immaturity may limit the persistence of infant-induced immunity and subsequent boosters may be required for sustained protection.     

Effects of fatigue on the temporal neuromuscular control of vastus medialis muscle in humans

The effects of muscle fatigue on the temporal neuromuscular control of the vastus medialis (VM) muscle were investigated in 19 young male subjects. The electromyogram (EMG) activities of VM and the force generation capacities of the quadriceps muscle were monitored before and after a fatigue protocol. In response to light signals, which were triggered randomly, the subjects made three maximal isometric knee extensions. This was then followed by the fatigue protocol which consisted of 30 isometric maximal voluntary contractions at a sequence of 5-s on and 5-s off. Immediately after the exercise to fatigue, the subjects performed another three maximal isometric contractions in response to the light signals. The effects of fatigue on the temporal neuromuscular control were then investigated by dividing the total reaction time (TRT) into premotor time (PMT) and electromechanical delay (EMD). The TRT was defined as the time interval between the light signal and the onset of the knee extension force. The PMT was defined as the time from the light signal to the onset of EMG activities of VM, and EMD as the time interval between onset of EMG activities to that of force generation. Following the contractions to fatigue there was a significant decrease in peak force (F _peak, P = 0.016), an increase in the root mean square (rms)-EMG: F _peak quotient (P = 0.001) but an insignificant change in the median frequency (P = 0.062) and rms-EMG (P = 0.119). Significant lengthening of mean EMD was found after the fatigue protocol [0.0396 (SD 0.009) vs 0.0518 (SD 0.016) s P < 0.001]. The lengthening of EMD in VM would affect the stabilizing effect of the patella during knee extension. The faster mean PMT [0.2445 (SD 0.093) vs 0.2075 (SD 0.074) s, P = 0.042] following the fatigue protocol might have compensated for the lengthened EMD and contributed to the insignificant change in the mean TRT [0.284 (SD 0.09) vs 0.259 (SD 0.073) s, P = 0.164]. This was probably related to the low level of fatigue (15% decrease in force) and the stereotyped nature of the action such that the effects of the fatigue on neuromuscular control were likely to have been attributable to peripheral processes. Accepted: 26 April 1999