Biomedical subjects
Publications and source records attributed to C Gros.
A predominantly microvascular localization of aminopeptidase M (APM) was established both by immunohistochemistry and biochemical studies of isolated microvessels. In addition a high relative specific activity of APM was evidenced in fractions enriched in synaptic membranes.
The tripeptide Tyr-Gly-Gly (YGG) was established as an endogenous constituent in rat brain. Its origin from enkephalin neurons is suggested by its regional distribution paralleling that of (Met5)-enkephalin (YGGFM), its decrease following kainate-induced ablation of the striato-pallidal neurons and its enhanced formation following depolarization of pallidal slices. Enkephalinase (EC 3.4.24.11) is selectively responsible for endogenous YGG formation in vitro and in vivo.
The tripeptide Tyr-Gly-Gly (YGG), an extraneuronal metabolite of opioid peptides (OP) derived from proenkephalin A is in a highly dynamic state in mouse striatum. Inhibition of its synthesis by Thiorphan reduced its levels with a t 1/2 of 12 min. Inhibition of its degradation by bestatin elicited its rapid accumulation consistent with a t 1/2 of enkephalins in the one-hour range. Pentobarbital anesthesia markedly reduced its steady state level and turnover rates.
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The tripeptide Tyr-Gly-Gly, a hydrolysis product of enkephalins and related opioid peptides obtained with 'enkephalinase', was identified and quantified in various regions of mouse brain by means of HPLC and a sensitive and specific radioimmunoassay. Similar levels i.e. about 8 pmol/brain were found after the animals were killed by various procedures, including microwave irradiation, suggesting its pre-mortem formation. The distribution of Tyr-Gly-Gly immunoreactivity among brain regions was highly heterogeneous and paralleled to a certain extent the [Met5]enkephalin distribution, molar levels of Tyr-Gly-Gly representing 10-30% of those of the enkephalin. Following gentle homogeneisation of striata in 0.32 M sucrose and centrifugation, 73% of Tyr-Gly-Gly immunoreactivity was recovered in the supernatant, a result consistent with its extracellular localisation in vivo. Administration of enkephalinase inhibitors rapidly elicited marked decrease in Tyr-Gly-Gly immunoreactivity whereas bestatin, an aminopeptidase inhibitor, elicited 100% increase and captopril, an ACE inhibitor, was without significant effect. These data indicate that the tripeptide is in a dynamic state in the brain and that its levels might reflect the release of endogenous enkephalins or related opioid peptides and their subsequent metabolism by enkephalinase.
A sensitive and specific radioimmunoassay has been developed for YGG. The tripeptide was previously derivatised with p-benzoquinone to prepare the immunogen and the 125I tracer as well as in samples submitted to the RIA. The sensitivity is about 1 nM as compared with 8000 nM for underivatised YGG. Measurable amounts of endogenous YGG immunoreactivity, co-eluting in HPLC with authentic YGG, were detected in mouse striatal extracts.
Two membrane-bound enkephalin-hydrolyzing aminopeptidase activities were partially purified from rat brain membranes. The first, which represents 90% of the total activity, was highly sensitive to both puromycin (Ki = 1 microM) and bestatin (Ki = 0.5 microM). The second was inhibited much more by bestatin (Ki = 4 microM) than by puromycin (Ki = 100 microM). The latter puromycin-insensitive aminopeptidase was found to resemble aminopeptidase M purified from rat kidney brush border membranes. Both displayed the same purification pattern and the same kinetic constants of substrates and inhibitors, and both were similarly inactivated by metal chelating agents. Moreover, antibodies raised in rabbits against rat kidney aminopeptidase M inhibited the aminopeptidase activities of both kidney and brain puromycin-insensitive enzymes at similar dilutions, while the brain puromycin-sensitive aminopeptidase activity was not affected. Thus, aminopeptidase M (EC 3.4.11.2) was found to occur in brain, and the role of this enzyme in inactivating endogenous enkephalins released from their neuronal stores is suggested.
In a clinical trial, 10 patients with malignant gliomas underwent partial resection of their tumors and were treated by intraarterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) chemotherapy. The drug was given at least 1 month after the completion of postoperative radiotherapy in total doses of 270-280 mg/m2 in two sessions separated by a 48-hour interval (the two sessions with interval were equal to one course). This therapy was repeated every 8-10 weeks. Four patients had three courses and the other six patients had two courses of chemotherapy. This therapy was the only antitumor chemotherapy for this group of patients. Our preliminary results demonstrate the safety of this new procedure and suggest that intraarterial BCNU chemotherapy may be more effective, and has a better tolerance and less toxicity, than intravenous BCNU chemotherapy. Furthermore, it was demonstrated that, in the case of one patient, higher antitumor activity resulted from intraarterial BCNU chemotherapy as compared to intravenous BCNU therapy.
Two different membrane-bound aminopeptidases were isolated from rat brain membranes, one with a puromycin sensitive activity and the other, not affected by 10 microM puromycin. The physicochemical, catalytic and immunological properties of the latter were compared to those of aminopeptidase M purified from rat kidney membranes and allowed us to conclude to large similarities between these two enzymes. Because the two brain aminopeptidases were both sensitive to bestatin, it remains to be established whether both or only aminopeptidase M is involved in endogenous enkephalin inactivation.
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Recurrent symptoms or signs during or after therapeutic brain irradiation may be due to the progression of the irradiated tumour, necrosis of normal brain tissue, necrosis of tumour, or all three of these. We have studied 12 patients with pathologically proven radiation-induced damage of normal brain tissue. All patients were exposed to a therapeutic range of radiation for an intra or extracranial tumour. Seven patients were exposed to 280 to 300 rads per day, three times weekly to a total dose of 4500 to 6000 rads (fractionated). Five patients received 750 to 850 rads per day, on days 1, 3, 21 and 23 (split-course). The diagnosis of radiation-induced brain lesions is difficult. CT scan is the most informative diagnostic procedure. The various patterns of radiation-induced brain lesions on CT are nonspecific. However where there is sufficient clinical data suggesting radiation-induced brain lesions, and a good correlation between CT abnormalities and the maximum delivered dose, on dose distribution maps of the brain exposed to a high cumulative radiation dose, the diagnosis may be accepted. The time interval between the end of radiation therapy and the occurrence of radiation-induced lesions was shorter in the patient group exposed to a split-course therapy (median time: 9.6 months) as opposed to the patient group exposed to a fractionated radiation (median time: 45 months). Pathologically the lesions corresponded to either a demyelinated area within the white matter with minimal vasculopathy or an area of coagulation necrosis with varying degrees of necrosis, delamination or hyalinosis of small blood vessels.(ABSTRACT TRUNCATED AT 250 WORDS)
Since February 1981, eight patients with neoplastic intractable pain have been treated by intracerebroventricular administration of small doses of morphine. Morphine was injected into the cerebrospinal fluid through a ventricular reservoir either by direct puncture or by self-administration. Clinical results were very good, and there were no deleterious effects.
The authors report on an autopsy-proven case of multifocal widespread radionecrosis involving both cerebral hemispheres and masquerading as tumor dissemination on a CT scan done 13 months after complete resection of an oligodendroglioma followed by radiation therapy. This case demonstrates that radiation damage may be present in a CT scan as a multifocal, disseminated lesion. Since the survival of brain-tumor patients who have undergone radiation therapy is prolonged by aggressive therapy, the incidence and variability of radiation-induced complications in such cases is likely to increase. For similar reasons, the radionecrosis in such cases should be taken into consideration. A short review of the CT scan findings and diagnostic and therapeutic considerations in a case of widespread radionecrosis is presented. The need for appropriate diagnosis and subsequent life-saving management is emphasized.
A 42 year-old woman was admitted with a subacute intracranial hypertension which improved under medical treatment. Angiographic data and CT scan showed enlarged ventricles. CSF showed 1.95 g/l of proteins. Five months later, a relapsing acute intracranial hypertension led to a ventricular derivation. CT scans, angiographies and ventriculography showed progressively enlarged ventricles but failed to disclose any intracranial tumor. A thoraco-lumbar tumor of the spinal cord was incidentally discovered and removed. Histopathology concluded to an ependymoma. No sign of recurrence has occurred after an eighteen month follow up. The pathogenesis of intracranial hypertension occurring in spinal cord tumors is discussed.
(Met5) enkephalin released from slices of Rat globus pallidus by 30 mM or 50 mM K+ is hydrolysed to the extent of 85% before reaching the incubation medium. When thiorphan and bestatin, two peptidase inhibitors, are added, this inactivation process is completely prevented but the peptide release from tissues is significantly diminished. The latter effect being reversed in the presence of an opioid antagonist, naloxone, in moderate concentration, the existence of an auto-inhibition process regulating enkephalin release is suggested.
The authors report their own experience of microsurgery for surgical treatment of lumbar disc herniation. Series include 30 cases with a one year of mean follow up. Comparative studies are discussed according to others microsurgical series already published. Good care of peridural fat and gently retraction of the root seem to be main factors for good functional result.
Three cases of complex pelvic fractures associated with lumbo sacral roots lesions are reported. The authors stress this possible association should be suspected through clinical and conventional radiological findings. The contrast sacco-radiculography brings up confirmation. However the so called pseudo-meningocele is by far of less topographical value than the same myelographic findings at cervical level (for brachial plexus avulsion injuries). Direct and concise evaluation is performed by surgical approach of roots during a homolateral hemi-laminectomy. This procedure allows to appreciate the anatomical lesions and to clarify the anatomo-radiological discrepancies. Moreover endodural closure and reduction of volume of meningoceles and removal of arachnoidal adhesions is to pain relief value and may prevent delayed complications of neighboring roots compression related to increase in volume of meningocele. According to the literature and our findings, in future, the aim should be microsurgical repair of such roots lesions as they ar not avulsed from the conus but merely more distally ruptured on the cauda equina. We could not so far achieve this procedure, because of difficulties to identify the distal part of root, often retracted far away from its spinae foramen.
Intractable pain in 4 patients having disseminated cancer was treated by intraventricular morphine. For all these patients, previous efficiency of opiates therapy was assessed by a positive trial of epidural injections of morphine. The latter method had to be stopped and a switch to intraventricular morphine was motivated, in 3 cases, by a local non-tolérance to the subarachnoid catheter. In one case, an intraventricular system was inserted at the first onset. In all cases, the intraventricular system consisted of a "Holter" type device, using a reservoir implanted subcutaneously in the frontal scalp and connected at right-angle with a catheter inserted in the lateral ventricle. Trial times were respectively of 8 days, one month, two months and six months (this latter case still under trial). In comparison with the epidural and lumbar intrathecal administration of morphine, the authors insisted upon the quality of analgesia obtained, the absence of respiratory depression, the comfort and minimal daily quantities of morphine injected (inferior to one mg daily in three cases). Enlightened by these 4 cases, the authors also discussed the relative importance of the spinal and brain mechanisms involved in morphinic analgesia.