Osteosarcoma of the extremity metastatic at presentation: results achieved in 26 patients treated with combined therapy (primary chemotherapy followed by simultaneous resection of the primary and metastatic lesions).

From September 1986 to December 1989, 26 selected patients with high-grade osteosarcoma of the extremities metastatic at presentation were treated with primary chemotherapy (high doses of methotrexate, -cisplatinum and adriamycin) followed by surgery. Twenty-one cases underwent resections of the primary and metastatic tumor at the same time; owing to the disappearance of lung metastases after preoperative chemotherapy in 3 cases, only the primary tumor was operated on. Due to progression of the disease in 2 patients, no surgery was performed. Histologic examination of the resected specimen was performed to evaluate the percentage of necrosis produced by chemotherapy on the primary and metastatic tumor. After surgery, the patients received further chemotherapy with the same drugs used preoperatively plus ifosfamide and VP-16. The histologic response of the primary tumor was good (> 90% tumor necrosis) in 25% of the cases; in the resected metastatic nodules, 23% had good responses. A discrepancy between the histologic response of the primary and secondary tumor was observed in only 15% of the cases. These results seem to confirm the validity of the strategy (widely used today in the neoadjuvant treatment of non-metastatic osteosarcoma) of changing the postoperative treatment when the histologic response of the primary tumor is poor. At an average follow-up of 3.5 years, only 6 patients remained disease-free; 19 patients relapsed and 1 patient died for adriamycin cardiotoxicity. Of the 19 relapsed patients, 16 died and 3 are still alive but with uncontrolled disease. These results are much worse than those obtained in 144 cases of non-metastatic osteosarcoma of the extremities treated in the same period with the same preoperative chemotherapy (77% with good response in the primary tumor and 78% with continuous disease-free survival). The data suggest that a very effective neoadjuvant chemotherapy for nonmetastatic osteosarcoma of the extremities gives disappointing results in osteosarcoma of the extremities which is metastatic at presentation.     

5-HT(1)-like receptor agonists and the pathophysiology of migraine

Recently, AG-25086 and GR-43175 have been reported to be highly effective in aborting acute migraine attacks. These compounds seem selectively to stimulate a sub-population of 5-HT(1)-like receptors to inhibit noradrenaline release from certain sympathetic neurovascular terminals, to contract dog saphenous vein and dog, monkey and human basilar arteries, and to decrease the arteriovenous anastomotic component of carotid blood flow in the cat. GR-43175 neither has any antinociceptive effect nor crosses the blood-brain barrier. Pramod Saxena and Michel Ferrari review the clinical effectiveness of these 5-HT(1)-like receptor agonists and their selective pharmacology, both of which strongly suggest that excessive dilatation in the extracerebral cranial (scalp and/or dural) vasculature is an integral part of the pathophysiology of migraine.     

The non-immunosuppressive immunophilin ligand GPI-1046 potently stimulates regenerating axon growth from adult mouse dorsal root ganglia cultured in Matrigel

We used explant cultures of adult mouse dorsal root ganglia with spinal nerve attached growing in Matrigel to assess the effects of the non-immunosuppressive immunophilin ligand GPI-1046 [Snyder et al. (1998) TIPS 19, 21-26] on the growth rate of regenerating sensory axons and found a potent stimulation of axon growth. In these explant cultures, naked, unfasciculated axons emerge from the cut end of the spinal nerve and continue to grow in the Matrigel for up to eight days [Tonge et al. (1996) Neuroscience 73, 541-551]. Some axons are entirely smooth whilst others show prominent varicosities. Some of the former express the phosphorylated neurofilament epitope recognised by monoclonal antibody RT97, a marker for large calibre, myelinated axons, whilst the latter express calcitonin gene-related peptide, predominantly a marker for unmyelinated, and small diameter myelinated sensory axons. Many of the axons in these cultures also express the low-affinity neurotrophin receptor p75. GPI-1046 has been shown to have striking stimulatory effects on embryonic primary sensory axons growing in vitro and it was therefore of interest to see whether it could also enhance regenerating sensory axon growth from the adult ganglia in our cultures. GPI-1046 potently stimulated axon growth in our cultures in a dose-dependent manner. The stimulatory effect was not dependent on the class of sensory axon. These observations show that GPI-1046 is a potent stimulator of regenerating axons from adult, primary sensory neurones. The cellular site of action of GPI-1046 is unknown. To distinguish between a direct effect of the drug on neurones and an indirect effect we compared the effects of GPI-1046 on explant and dissociated cultures. In confirmation of previous results, we found that GPI-1046 potently stimulated axon outgrowth from explants of embryonic chick dorsal root ganglia. However, the drug was without effect on dissociated embryonic dorsal root ganglion neurones, suggesting that non-neuronal cells are important for axon growth stimulation.     

Meiotic recombination in the beta globin gene cluster causing an error in prenatal diagnosis of beta thalassaemia.

In the course of a prenatal diagnosis for beta thalassaemia by linkage analysis of restriction fragment length polymorphisms, a homozygous beta thalassaemia fetus was misdiagnosed as beta thalassaemia trait. Extensive studies of the polymorphic sites within the beta globin gene cluster in all the members of the family resulted in the conclusion that the paternal chromosome 11 of the newborn was different from that expected. Paternity was confirmed by HLA typing and blood group studies. The analysis of another polymorphic locus on chromosome 11 within the family was in agreement with the possibility of a crossing over between the two paternal chromosomes in a region 5' to the beta gene, previously indicated to contain a 'hot spot' area for recombination. This report underlines the risk of performing prenatal diagnosis using restriction polymorphisms 5' to the beta gene.     

Interactions between taste receptors in the frog tongue

Summary Receptors sensitive to stimulation with dilute CaCl₂ solutions and located in different fungiform papillae of the frog tongue are cross-connected via branches of the glossopharyngeal nerve fibers to form chemical sensory units comprising on average about 3 papillae; often one or more papillae were found to be common to different units.The receptor response observed when single papillae were individually stimulated increased, when the strength of the stimulus was raised, at a much lower rate than that obtained by stimulating the whole tongue surface. This proves that the antidromic impulses travelling in the cross-connections linking different papillae result in an evident depression of the receptor response to CaCl₂.The possible functional significance of mutual interaction between the receptors in the frog tongue is discussed.This study was supported by grants from the Consiglio Nazionale delle Ricerche (Impresa di Elettrofisiologia) of Rome, Italy.     

Defective Aspergillus killing by neutrophil leucocytes in a case of systemic aspergillosis.

A persistent defect of Aspergillus killing was observed in the neutrophils of a 6-year-old patient with a systemic A. fumigatus infection which was highly refractory to anti-mycotic therapy. Aspergillus phagocytosis in vitro was normal, but nearly 80% of the ingested organisms (versus 30% in the controls) survived intracellularly during the 2-hr assay period. The patient's neutrophils showed a subnormal frequency of nitroblue tetrazolium reduction and a subnormal hexose monophosphate shunt activation in response to phagocytosis. The metabolic responsiveness, however, was clearly superior to that of chronic granulomatous disease neutrophils tested for comparison. The immune status of the patient and the following properties of his neutrophils were found to be normal: random and chemotactic motility, killing of S. aureus and C. albicans, and the contents of several granula enzymes. Our findings suggest the existence of neutrophil factors or functions which are required for killing Aspergillus, but not S. aureus and C. albicans.     

Viral determinants and host immune responses in the pathogenesis of HBV infection

Hepatitis B virus (HBV) is a virus that infects about 350,000,000 people worldwide with a clinical spectrum of acute hepatitis, the healthy carrier state, cirrhosis and hepatocellular carcinoma (HCC). The outcome of HBV infection is the result of complicated viral-host interactions. As in other infections with non-cythopatic viruses, the immune response is thought to play a crucial role in disease pathogenesis but there is increasing evidence that a variety of viral mechanisms, some depending on the function of virally encoded proteins, have a profound impact on the infected hepatocytes, the liver microenvironment, and host anti-viral responses. Indeed, the virus has evolved multiple mechanisms to ensure its success in infecting a susceptible host. The essential aspects of the life cycle of HBV and the host immune response are reviewed and recent new developments in the molecular virology of HBV, including experimental animal models, in the role of accessory viral proteins in disease pathogenesis and HCC development and in the characterisation of the T cell response in the control of HBV infection, are highlighted.     

Cervical muscle response to trunk flexion in whiplash-type lateral impacts

The purpose of this study was to determine the response of the cervical muscles to increasing low-velocity, whiplash-type lateral impacts when the occupant is seated out of the recommended driving position (neutral posture). Twenty healthy volunteers were subjected to left lateral impacts of 4.1, 7.7, 10.5, and 13.7 m/s² acceleration, with their trunk flexed by 45° and laterally flexed to the right and left also by 45° at the time of impact. Bilateral electromyograms of the sternocleidomastoids, trapezii, and splenii capitis were recorded. Under these conditions of trunk-flexed postures, in a left lateral impact, muscle responses were of generally low magnitude with the trunk flexed to either the left or right. Even at the highest acceleration of 13.7 m/s², all muscles generated less than 37% of their known maximal voluntary contraction electromyogram. Also, in these left lateral impacts, the right splenius capitis showed a greater EMG response than the left splenius capitis regardless of whether the subject was flexed to the right or left at the time of impact. The right splenius capitis (the one contralateral to the left lateral impact direction) was more active than its counterpart. Compared to what is known for EMG responses with an occupant in the neutral posture, the right sternocleidomastoid (usually the most active muscle in a left lateral collision) was significantly less-active with trunk flexion than with neutral posture conditions (P<0.01). In the absence of bodily impact, the flexed trunk posture does not produce a biomechanical response that would increase the likelihood of cervical muscle injury in low velocity lateral impacts, and may lessen the risk of injury for some muscles.     

Pulmonary endocrine cells in various species in the Himalaya

The numbers, morphology and distribution of pulmonary endocrine cells in goats, sheep and the yak and its interbreeds with cattle, dzos and stols, were studied after their demonstration by means of the peroxidase-antiperoxidase technique with a polyclonal antiserum raised in the rabbit to human neuron-specific enolase, a marker for neuroendocrine cells. The numbers, morphology and distribution were related to species and not to residence at high altitude. Pulmonary endocrine cells were common and mainly distributed as solitary cells in the epithelium of the bronchial tree in sheep. They were much less common and found mainly as clusters in the alveolar capillary walls in goats and in the yak and its interbreeds with cattle.