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Some cognition enhancers were previously shown to potently prevent antagonism of the N-methyl-D-aspartate (NMDA)-evoked release of norepinephrine (NE) brought about in slices of rat hippocampus by kynurenic acid, an endogenous NMDA receptor blocker. We have examined the impact of putative nootropic agents in the kynurenate test performed with slices of human cerebral cortex from patients undergoing neurosurgery. In slices of human neocortex, local application of NMDA evoked release of [3H]NE; the effect of NMDA was antagonized by several NMDA receptor antagonists, including kynurenic acid. The antagonism of the NMDA-evoked [3H]NE release produced by 300 microM kynurenate was potently (EC50 <10 microM) prevented by most of the nootropics tested, including aniracetam, oxiracetam, D-cycloserine, and the glutamate analog CR 2249 (but not its enantiomer CR 2361). Nicotine or tacrine (up to 10 microM) did not show any effect in the kynurenate test. Nicotine (30-100 microM) itself increased the release of [3H]NE; interestingly, the nicotine-evoked overflow was blocked not only by the nicotin receptor antagonist mecamylamine but also by NMDA receptor antagonists, suggesting an indirect mechanism mediated by glutamate/aspartate release. To conclude, the similarities between the data obtained here with human neocortex slices and those previously obtained in the rat indicate that the kynurenate test performed with rat brain slices may represent a useful biochemical assay to study cognition-enhancing drugs.

1. The release of glutamic acid and its modulation by 5-hydroxytryptamine (5-HT) in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply sited tumours. 2. The Ca2+-dependent K+ (15 mM)-evoked overflow of glutamate was inhibited by 5-HT in a concentration-dependent manner (EC50 = 2.9 nM; maximal effect approximately 50%). The inhibition caused by 5-HT was antagonized by the 5-HT1/5-HT2 receptor antagonist methiothepin. The 5-HT1B/5-HT1D receptor agonist sumatriptan mimicked 5-HT (EC50 = 6.4 nM; maximal effect approximately 50%); the effect of sumatriptan was also methiothepin-sensitive. Selective 5-HT1A receptor antagonists could not prevent the inhibition of glutamate release by 5-HT. 3. The 5-HT1B/5-HT1D receptor ligand GR 127935 and the 5-HT2C/5-HT1B/5-HT1D receptor ligand metergoline were unable to prevent the 5-HT effect; instead they inhibited glutamate release, their effects being abolished by methiothepin. Some 5-HT1A receptor antagonists also displayed intrinsic agonist activity. 4. The effect of sumatriptan was prevented by ketanserin, a drug known to display much higher affinity for recombinant h 5-HT1D than for h 5-HT1B receptors. 5. We propose that neocortical glutamatergic nerve terminals in human brain cortex possess release-inhibiting presynaptic heteroreceptors that appear to belong to the h 5-HT1D subtype.

Slices from fresh specimens of human neocortex which had to be removed during neurosurgery to reach subcortical tumours were labelled with [3H]-dopamine and stimulated electrically. Quinpirole, a selective dopamine D2 receptor agonist, inhibited the stimulated tritium overflow (EC50 = 25 nM; maximal inhibition: about 80% at 10 microM). The selective D1 receptor agonist, SKF 38393, was inactive up to 10 microM. Quinpirole was antagonized by the D2 receptor antagonist (-)-sulpiride (apparent pA2 = 8.26). Thus dopaminergic axon terminals in the human mesocortical pathway possess autoreceptors of the D2 type.

Synaptosomes prepared from fresh specimens of human cerebral cortex were labeled with [3H]glycine ([3H]Gly) and distributed in parallel superfusion chambers. Exposure to 15 mM KCl evoked a tritium overflow which was largely prevented by 10 mM Mg++, suggesting a consistent component of Ca(++)-dependent [3H]Gly release. Acetylcholine (ACh; 1-100 microM), added during K(+)-depolarization, increased the release of tritium in a concentration-dependent manner (maximal effect, 60%; EC50 = 7 microM). Oxotremorine (1-100 microM) mimicked ACh. The effect of 10 microM ACh was insensitive to the nicotinic antagonist mecamylamine (100 microM), but it was blocked by the muscarinic antagonist atropine (0.1 microM). Three muscarinic receptor antagonists, pirenzepine, AF-DX 116 (11-[12-[diethylamino-methyl]-1-piperidinyl]acetyl-5-11-dihydro -6H-pyrido-[2-3-b][1,4]benzodiazepine-6-one) and himbacine, endowed with relative selectivity for various muscarinic receptor subtypes, prevented with differential affinities the effect of 10 microM ACh. Himbacine was the most potent antagonist of ACh, its pA2 (8.34) being 20- or 50-fold higher than that of pirenzepine (7.27) or AF-DX 116 (6.65). It is concluded that: 1) ACh can increase the release of Gly in human cerebral cortex; 2) the interaction occurs through muscarinic receptors which resemble most the M4 subtype; and 3) considering that Gly is required to activate the N-methyl-D-aspartate glutamate receptor, the ACh-evoked Gly release may represent a linkage between cholinergic and glutamatergic transmission, two systems strongly implicated in cognitive processes.

Release-regulating 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain belong to the 5-HT1B subtype. On the other hand, the human brain seems to lack 5-HT1B receptors. In the present work 5-HT autoreceptors present in human brain were characterized pharmacologically. Synaptosomes prepared from biopsy samples of human neocortex were labeled with [3H]5-HT and exposed in superfusion to selective 5-HT receptor agonists and antagonists during K+ depolarization. The rank order of potency of agonists as inhibitors of the [3H]5-HT overflow was 5-HT > sumatriptan (5-HT1D/1B) > 8-hydroxy-2-(di-n-propylamino)tetralin (5-HT1A/1D) >> 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (5-HT2/1C). The effect of 5-HT was insensitive to ketanserin (5-HT2) but antagonized by methiothepin (5-HT1/2) or by metergoline (5-HT1C/1D). The data are compatible with a classification of the human 5-HT autoreceptor as being of the 5-HT1D subtype.

1. Release-regulating alpha 2-autoreceptors in human brain were characterized pharmacologically in cortical slices from patients undergoing neurosurgery to remove subcortical tumours; the slices were prelabelled with [3H]-noradrenaline ([3H]-NA) and stimulated electrically (3 Hz, 2 ms, 24 mA) under superfusion conditions. 2. The stimulus-evoked tritium overflow was almost totally Ca(2+)-dependent and tetrodotoxin-sensitive. 3. Clonidine and oxymetazoline 0.01 to 1 microM inhibited in a concentration-dependent manner the evoked overflow of tritium. The two drugs were equipotent (EC50 = 0.03 microM) and their maximal effect was approx. 45%. Phenylephrine and methoxamine, up to 1 microM, did not affect tritium overflow. 4. Yohimbine (0.01-0.1 microM) shifted the concentration-response curve of clonidine to the right. The calculated pA2 value was 8.29. 5. Prazosin and 2-[2-[4-(o-methoxyphenyl)piperazine-1-yl]ethyl]-4,4- dimethyl-1,3(2H,4H)-isoquinolinedione (AR-C 239), tested at 0.3 microM, did not modify the concentration-response curve of clonidine. 6. The effect of clonidine was antagonized by (+)-mianserin (pA2 = 7.74), but not by up to 0.3 microM of the (-)-enantiomer. The concentration-response curve of clonidine was shifted to the right by the novel alpha 2-adrenoceptor antagonist, 5-chloro-4-(1-butyl-1,2,5,6-tetrahydropyridin-3-yl)-thiazole-2-ami ne (Z)-2-butenedioate (1:1) salt (ORG 20350) (pA2 = 7.55). 7. Yohimbine, (+)-mianserin and ORG 20350, but not prazosin and (-)-mianserin, increased the electrically-evoked tritium overflow, suggesting that autoreceptors may be tonically activated by endogenous NA. 8. Desipramine (1 microM) increased evoked tritium overflow from human cortex slices. The effect of clonidine (0.01- 1 g1M) on the evoked overflow of tritium was reduced in presence of 1 muM desipramine.9. It is proposed that autoregulation of NA release can occur in human cerebral cortex. The process involves activation of alpha 2-adrenoceptors which may be either the alpha2X or the alpha2D subtype.

Synaptosomes prepared from freshly obtained human cerebral cortex and labeled with [3H]choline have been used to investigate the modulation of [3H]acetylcholine ([3H]ACh) release by 5-hydroxytryptamine (5-HT). The Ca(2+)-dependent release of [3H]-ACh occurring when synaptosomes were exposed in superfusion to 15 mM KCl was inhibited by 5-HT (0.01-1 microM) in a concentration-dependent manner. The effect of 5-HT was mimicked by 1-phenylbiguanide, a 5-HT3 receptor agonist, but not by 8-hydroxy-2-(di-n-propylamino)tetralin, a 5-HT1A receptor agonist. The 5-HT3 receptor antagonists tropisetron and ondansetron blocked the effect of 5-HT, whereas spiperone and ketanserin were ineffective. It is suggested that cholinergic axon terminals in the human cerebral cortex possess 5-HT receptors that mediate inhibition of ACh release and appear to belong to the 5-HT3 type.

Metastatic tumors of the pituitary gland and parasellar region are unusual and are generally observed both in an advanced phase of the disease and at autopsy. The occurrence of symptomatic lesions is however quite rare. Though some clinical features may suggest the presence of a metastasis, the diagnosis is unlikely both clinically and radiologically and more common pituitary lesions are generally suspected. The Authors present two very unusual cases in which the pituitary lesions represented the onset symptoms of an otherwise unknown malignancy. Moreover the increased survival of cancer patients and the routine utilization of CT scan and MRI will probably induce, in the next years, a more frequent discovery of pituitary metastases. The Authors suggest that the diagnosis of pituitary metastases should be more closely considered even in the absence of a known primary tumor.

The effect of gamma-aminobutyric acid (GABA) on the release of [3H]acetylcholine [( 3H]ACh) from human cerebral cortex nerve terminals was investigated using synaptosomes prepared from neurosurgical specimens (which had to be removed to reach deeply located tumors) prelabeled with [3H]choline and exposed in superfusion to varying concentrations of GABA. The amino acid (3-100 microM) increased in a concentration-dependent manner (maximal effect: 40%; EC50 = 14.7 microM) the release of [3H]ACh but not that of [3H]choline. The GABAA receptor agonist muscimol (up to 100 microM) did not increase significantly the release of [3H]ACh. Accordingly, the effect of GABA was insensitive to the GABAA receptor antagonist bicuculline. The release of [3H]ACh was not affected by the GABAB receptor agonist (-)-baclofen (100-300 microM). The GABA-induced [3H]ACh release was counteracted by two inhibitors of GABA uptake, N-(4,4-diphenyl-3-butenyl)nipecotic acid (SKF 89976A) and nipecotic acid. Moreover, the enhancing effect of GABA on [3H]ACh release was clearly Na+-dependent and was reduced by almost 90% in presence of 23 mM NaCl. The data indicate that, similarly to what had been observed in the rat, cholinergic nerve terminals in the human cerebral cortex possess a GABA transporter. Activation of this carrier brings about release of newly synthesized ACh. GABA and ACh might co-exist in some cerebrocortical nerve endings in the vertebrate brain, including man.

Slices and synaptosomes from human cerebral cortex (which had to be removed to reach deeply located tumours) and, for comparison, synaptosomes from guinea-pig and rat cerebral cortex were preincubated with [3H]5-hydroxytryptamine and superfused with physiological salt solution containing an inhibitor of 5-hydroxytryptamine uptake. The effects of alpha-adrenoceptor agonists and antagonists on the electrically (slices) or potassium-evoked (synaptosomes) tritium overflow were studied. In human cerebral cortical slices, the electrically-evoked [3H] overflow was inhibited by noradrenaline (pIC25 value: 6.35); the non-selective alpha-adrenoceptor antagonist phentolamine, at a concentration of 0.32 mumol/l, strongly antagonized the inhibitory effect of noradrenaline (apparent pA2 value: 8.19) but did not affect the evoked overflow by itself. In synaptosomes from humans, guinea-pigs and rats, noradrenaline also inhibited the K(+)-evoked [3H] overflow in a concentration dependent manner; the alpha 2-adrenoceptor clonidine (1 mumol/l), but not the alpha 1-adrenoceptor agonist methoxamine (1 mumol/l), mimicked the effects of noradrenaline; the effect of noradrenaline (0.3 mumol/l) was abolished by the alpha 2-adrenoceptor antagonist idazoxan (0.5 mumol/l), but not by the alpha 1-adrenoceptor antagonist prazosin (1 mumol/l). It is concluded that release-inhibiting adrenoceptors of the alpha 2-subtype exist on 5-hydroxytryptamine terminals innervating the cerebral cortex in human and guinea-pig brain.

The release of [3H]acetylcholine ([3H]ACh) and its modulation mediated by autoreceptors were investigated in synaptosomes prepared from fresh human cerebral cortex prelabelled with [3H]choline ([3H]Ch) and depolarized in superfusion with 15 mM KCl. The K(+)-evoked release of tritium was almost totally accounted for by unmetabolized [3H]ACh and was largely calcium-dependent. Exogenous ACh decreased the depolarization-evoked release of [3H]ACh in a concentration-dependent manner (EC50 = 1.5 microM). The inhibitory effect of ACh on [3H]ACh release was counteracted by the non-selective muscarinic antagonist atropine. In contrast, the selective M1 receptor antagonist pirenzepine was ineffective. It is concluded that muscarinic autoreceptors regulating the release of ACh are present on cholinergic nerve terminals of human cerebral cortex and appear to belong to a pirenzepine-insensitive subtype.

A rare case of intracranial hypertension associated with subarachnoid bleeding from a spinal tumour is reported. Clinical features, review of the literature and pathogenetic factors are discussed.

We report ten cases of post-traumatic posterior fossa haemorrhage occurring in children. All patients were studied by CT scan. Five had an intracerebellar haemorrhage, three a brain stem haemorrhage, and two an extradural haematoma. In four cases we have found the coexistence of supratentorial and infratentorial haemorrhagic lesions. The incidence of posterior fossa haemorrhage in children, the importance of linear occipital fracture, the clinical course, the conservative or surgical treatment, and the prognosis are discussed.

One hundred and forty consecutive subarachnoid haemorrhages (SAH) which presented either an intracranial vascular malformation (102 cases: aneurysm 80 cases, AVH 22 cases) or remained of "unknown aetiology" (38 cases) were studied. SAH caused by other factors (neoplasms, thrombo-embolisms, systemic diseases etc.) were excluded. The 38 cases with bleeding of "unknown aetiology" have been studied by complete cerebral angiography, pneumoencephalogram or CT scan, and have been followed for two years. The most important clinical factors in the three groups have been compared by a statistical method to verify the hypothesis that SAH of "unknown aetiology" is caused by vascular micromalformations which are angiographically not evident either because of their small size or because of their "spontaneous" recovery after bleeding due to thrombosis and disappearance of the malformation. From the data collected it may be concluded that SAH of "unknown aetiology" is a benign lesion, typically occurring in middle age, but with no clear characteristics that enable identification of the anatomical substratum from it originates.

Motor action potentials evoked by percutaneous electrical stimulation of the scalp and of the cervical (or lumbar) vertebral region were recorded from the biceps, thenar and tibialis anterior muscles in 30 patients with cervical spondylosis. Twelve normal controls were matched for age and height. Abnormalities of central motor conduction (absence or increased central delay of cortical responses) for at least one muscle were observed in all (but one) the patients with myelopathy alone or combined with radiculopathy. An increase in latency of the responses evoked by cervical stimulation occurred in 40% of patients with radiculopathy or myelo-radiculopathy. Changes of motor conduction occurred even in the absence of abnormalities of somatosensory evoked potentials, while the opposite was never observed. Direct stimulation of the motor tracts may be of value in the functional assessment of the motor pathways in cervical spondylosis.

A 49-year-old man was submitted to neurosurgery for a cranio-pharyngioma. The lesion, which appeared to involve the antero-inferior wall of the third ventricle, caused lack of appropriate antidiuretic hormone (ADH) release in response to hypernatraemia and plasma hyperosmolality. The probable mechanism of this hypothalamic syndrome is suggested.

The occurrence of intracranial tumours of diverse histogenesis can be considered occasional. In a careful survey of the literature we have encountered 63 cases of concurrent intracranial tumours: we report five personal observations, too. This review raises the question as to whether the conjoint occurrence of two intracranial tumours is purely coincidental. The statistical analysis of the cases of concurrent intracranial tumours, and the comparison between the frequency found for each different tumour when it is solitary and when it is coincident in a same patient, suggests that a casual connection can be found between tumours of diverse histogenesis.

We report 36 cases of post-traumatic "primary brain stem haemorrhage" visualized by the CT scan and confirmed at autopsy. Clinical experience shows that many technical factors influence the inability to visualize brain stem haemorrhages. Experimental injection of fresh blood into the pons and midbrain of cadavers shows that lesions as small as 0.25 ml in volume may be visualized. The volume and the anatomical configuration of traumatic lesions of the brain stem extended over a rostro-caudal direction, and their proximity to bony structures at the base of the skull are obstacles to the visualization of brain stem haemorrhages.

Plexus-chorioideus carcinomata or malignant plexus papillomas are very rare; only few cases have been described in the literature. A further observation is added now. In a 13-year-old girl, signs of brain pressure occured two weeks before admission to a hospital. Scintigraphy and vertebral angiography showed a process in the atrium of the right lateral ventricle which was removed by temporo-parietal trephination. The tumour had the size of an apricot and a reddish colouration, it proceeded from the plexus. After-irradiation with 5 000 rad. Six years after the operation, signs of brain pressure appeared again. Neuroradiologically the process was located in the right cerebellar hemisphere. After trephination of the cerebellum, the largely vascularised tumour, which appeared to originate from the tela choroidea of the 4th ventricle, could be removed. The further course was without pathological findings. Histologically, the typical criteria were found: Invasion of surrounding brain structures, loss of the regular papillary structure, malignisation of the cells and originating from the plexus choroideus.

The authors test the effectiveness of extradural cooling for the reduction of local edema and metabolic demand in spinal cord injuries. They measure the intramedullar temperature before and during local perfrigeration with a different method as compared to those previously reported in the literature.

An unusual association of thrombosis of the superior sagittal sinus and idiopathic thrombocytosis is reported. Etiology, clinical and radiological findings and therapeutic approach are discussed.

1. The depolarization-evoked release of gamma-aminobutyric acid (GABA) and its modulation mediated by autoreceptors were investigated in superfused synaptosomes prepared from fresh human cerebral cortex. 2. The release of [3H]-GABA provoked by 15 mM K+ from human cortex nerve endings was almost totally (85%) calcium-dependent. 3. In the presence of the GABA uptake inhibitor SK&F 89976A (N-(4,4-diphenyl-3-butenyl)-nipecotic acid), added to prevent carrier-mediated homoexchange, GABA (1-10 microM) decreased in a concentration-dependent manner the K+-evoked release of [3H]-GABA. The effect of GABA was mimicked by the GABAB receptor agonist (-)-baclofen (1-100 microM) but not by the GABAA receptor agonist muscimol (1-100 microM). Moreover, the GABA-induced inhibition of [3H]-GABA release was not affected by two GABAA receptor antagonists, bicuculline or SR 95531 (2-(3'-carbethoxy-2'-propenyl)-3-amino-6-paramethoxy-phenyl-pyr idazinium bromide). 4. (-)-Baclofen also inhibited the depolarization-evoked release of endogenous GABA from human cortical synaptosomes. 5. It is concluded that GABA autoreceptors regulating the release of both newly taken up and endogenous GABA are present in human brain and appear to belong to the GABAB subtype.

A report is given on eight cases of epidural haematoma in children aged 0 to 2 (11 per cent of a total of 70 epidural haematomas found in children). The individual clinical phenomena and courses of the disease are shown on the basis of our own patients. The prognosis of epidural haemorrhages is more favourable for such children than for older children and adults.

The outcome is reported in 62 children with severe head injuries following a road traffic accident. All patients were comatose for at least 6 h; all patients were graded using the Glasgow Coma Score (GCS) or the Children Coma Score (CCS). Fifty-four patients were comatose immediately after injury, 8 after a lucid interval. Thirty patients had isolated head injuries and 32 had associated injuries, either long bone fractures or rupture of an abdominal organ. Additional information concerning main brainstem reflexes, posture and respiration was included in the study. The overall mortality was 32%. The goal of the study was to identify those clinical features available soon after injury which are important indicators of treatment and outcome.

Case histories are reported of 18 patients in whom the diagnosis of primary brain stem haematoma and brain stem haemorrhage was made by computed tomography (CT). The possibility of an early diagnosis of brain stem haematoma, and the differential diagnosis of brain stem haemorrhage by a combination of clinical and tomodensitometric criteria is emphasized. It is concluded that CT is a highly reliable method for the diagnosis, location, and management of brain stem haematoma.

Four cases of CCF treated by embolization of the carotid by Fogarty catheter are reported. The results were excellent in three patient and good in one.