pH, K+, and PO2 of the extracellular space during ischaemia of primate cerebral cortex.

pH and K+ from the extracellular space, PO2, and CBF have been measured in the same region during progressive ischaemia of primate cerebral cortex. As blood flow was reduced, the other changes had the following sequence. PO2 fell rapidly to 30% of control levels at regional CBF (rCBF) of 30 ml 100 g-1 min-1. As CBF was further reduced, PO2 continued to fall. pH remained stable until around 20 ml 100 g-1 min-1, below which pH fell rapidly, with an exponential increase in H+ concentration. K+ showed the well-known relationship to CBF, remaining normal until around 10 ml 100 g-1 min-1, below which K+ rose rapidly. pHe and log K+ were lin-early related and confirmed that pH fell by 0.3 U before K+ rose significantly, and fell by 0.6 U before the massive rise in K+. The mechanisms involved in this sequence of events and the role of pH changes in the development of the so-called "ischaemic penumbra" are discussed.

The Charing Cross Hospital experience with temozolomide in patients with gliomas.

Temozolomide, a new oral cytotoxic agent, was given to 75 patients with malignant gliomas. The schedule used was for the first course 150 mg/m2 per day for 5 days (i.e. total dose 750 mg/m2), escalating, if no significant myelosuppression was noted on day 22, to 200 mg/m2 per day for 5 days (i.e. total dose 1000 mg/m2) for subsequent courses at 4-week intervals. There were 27 patients with primary disease treated with two courses of temozolomide prior to their radiotherapy and 8 (30%) fulfilled the criteria for an objective response. There were 48 patients whose disease recurred after their initial surgery and radiotherapy and 12 (25%) fulfilled the criteria for an objective response. This gave an overall objective response rate of 20 (27%) out of 75 patients. Temozolomide was generally well tolerated, with little subjective toxicity and predictable myelosuppression. However, the responses induced with this schedule were of short duration and had relatively little impact on overall survival. In conclusion, temozolomide given in this schedule has activity against high grade glioma. However, studies evaluating chemotherapy in primary brain tumours should include a quality-of-life/performance status evaluation in addition to CT or MRI scanning assessment.

Temozolomide: a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours.

Temozolomide, a new oral cytotoxic agent, has been given to 28 patients with primary brain tumours. Treatment was given at a dose of 150 mg/m2/day for 5 days (i.e. total dose 750 mg/m2) escalating, if no significant myelosuppression was noted on day 22, to 200 mg/m2/day for 5 days (i.e. total dose 1000 mg/m2) for subsequent courses at 4 week intervals. A major improvement in computer tomography (CT) scan was noted in 5/10 patients with astrocytomas recurrent after radiotherapy, with a major clinical improvement but minor improvement on CT scan in one further patient. Reduction in the size of the CT lesion was also observed in 4/7 patients with newly diagnosed high grade astrocytomas given 2-3 courses of temozolomide prior to irradiation. 1 patient with recurrent medulloblastoma had a clinical response in bone metastases. Temozolomide was well tolerated with little subjective toxicity and usually predictable myelosuppression and is a promising new drug in the treatment of primary brain tumours.

A simple system of intracranial pressure monitoring for use by non-neurosurgeons.

A technique is described for intracranial pressure monitoring that can be used in the intensive care unit by doctors with no neurosurgical experience. The system uses the extradural route, thus reducing the risks of intracranial haemorrhage and infection associated with techniques requiring opening of the dura and cannulating the brain.

An unusual complication of tapping a ventriculoperitoneal shunt.

A case is reported describing a complication of an unsuccessful attempt to aspirate the reservoir of a ventriculoperitoneal shunt system with a suspected shunt infection. This arose due to a misunderstanding of the anatomy of the shunt and resulted in an intracerebral haematoma. The complications of cerebrospinal fluid shunting and the difficulty in the diagnosis thereof are outlined. We discuss the role and method of shunt tapping in diagnosing shunt problems before reviewing the literature describing the rationale. The variation in shunt design is emphasized. Guidelines are then proposed not to dissuade physicians from tapping shunts but to ensure that the procedure is performed safely and in collaboration with neurosurgical units.

The potential for toxic effects of chronic, low-dose exposure to organophosphates.

Organophosphorus esters have the potential to produce several forms of toxicity. Most produce acute intoxication as a result of inhibition of acetylcholinesterase and, if severe, this can have longer lasting secondary consequences such as intermediate syndrome, or even permanent disability. Some esters produce a very specific syndrome of delayed peripheral neuropathy. This neuropathy is always preceded by severe acute intoxication, except in the case of a few specific agents such as tri-o-cresyl phosphate. All of these effects are reasonably well understood and show a dose threshold. Chronic low level exposure in non-poisoned subjects has been associated with impaired neurobehavioral performance in some, but not all, epidemiological studies. The mechanisms involved are not well understood, but if organophosphates do play a causal role, this will not necessarily be via acetylcholinesterase inhibition. Doses too low to produce cholinergic signs have been shown to produce a variety of effects in experimental animals ranging from enhanced maze learning to slowed nerve conduction. It is likely that other, more sensitive, brain proteins are the targets for such actions. Effects mediated via such target proteins would be expected to show very different structure-activity relationships to acute toxicity mediated by acetylcholinesterase. Hence epidemiological studies expecting similar (class) effects from low-dose exposure to different organophosphorus esters may produce variable results or false negatives.

Electrochemical modification of lysozyme: anodic reaction of tyrosine residues.

Preparative electrooxidation of lysozyme at copper electrodes held at potentials around 1.2 V vs. a saturated calomel reference electrode induces the formation of a yellow chromophore with a concomitant decrease in the pI of the protein. Ion-exchange high-performance liquid chromatography revealed two new lysozyme species with pI values of 10.8 and 10.7 (lysozyme-11.0) which bear the chromophore. Sequence analysis of these two species showed that protein with lower pI was modified at both Tyr 23 and Tyr 20 and the other exclusively at Tyr 23. ribonuclease A, subtilisin BPN', and BSA were also found to produce the same chromophore using similar electrochemical reaction schemes. Characterization of the chromophore by a variety of techniques revealed that it is apparently 3-nitrotyrosine.

Immature teratoma arising from a benign cortical abnormality.

CASE REPORT: The authors report the case of an immature teratoma of the left parieto-occipital region in a 13-year-old girl. The patient had a computed tomographic (CT) scan of the brain aged 10 months old, following a minor head injury. This demonstrated an abnormality in the same region, which had been reported as 'a cortical malformation'. DIAGNOSIS: We propose that the lesion on the original imaging is a mature teratoma or other silent dystopic germ cell element that subsequently transformed into the immature teratoma. DISCUSSION: The potential triggers for such a transformation and the management of patients with similar incidental radiological findings are discussed.

Stable fractures of the atlas and axis in children.

Three cases of stable fractures of the atlas and axis in children are presented. All patients presented with pain, spasm of neck musculature and head tilt along with a neurological deficit. All fractures were apparently stable; with conservative treatment all symptoms and signs resolved.

Rapid, high-sensitivity imaging of radiolabeled gels with microchannel plate detectors.

A microchannel plate detector has been used to image tritium-labeled protein on one- and two-dimensional electrophoresis gels. The good spatial resolution (70 microns) and high sensitivity (6.0 dpm/mm2) of the imaging system allows detection of low levels (femto moles) of labelled proteins. We are currently using the detector for identification of new targets involved in organophosphate neurotoxicity.

Spinal extradural angiosarcoma occurring after treatment for Hodgkin's disease.

An extradural angiosarcoma was found invading the L3 and L4 nerve roots. An angiosarcoma has not previously been reported in this situation. The tumour was diagnosed eighteen years after the patient presented with Hodgkin's disease and was possibly induced by the treatment given for this disease.

Mean hemispheral cerebral blood flow changes after craniotomy. Significance and prognostic value.

The effects of craniotomy on cerebral haemodynamics remains controversial from a study of the literature. This report represents our experience with respect to CBF changes within 10 days of surgery. Our objective was twofold, first to study the effect of craniotomy on the cerebral circulation and second to determine whether the CBF pattern at different post-operative intervals could provide useful prognostic information. A total of 135 CBF measurements were performed at the bedside of 36 patients; 19 patients with an assortment of intracranial tumours and 17 patients with intracranial aneurysm in different clinical grades. Our results indicate a significant rise in CBF in the immediate post-operative period averaging 18% of the pre-operative value. We believe this reflects a normal reaction of the cerebral vasculature to the inevitable disturbance of surgery. Furthermore, this hyperaemia may be of prognostic value as it was observed in 85% of the patients with tumour discharged without post-operative deficit and in 80% of the patients with aneurysms discharged in clinical grade 1 or 2. This is in sharp contrast with its development in only 16% of the patients with tumour discharged with post-operative deficit and 16% of the patients with aneurysm discharged in grade 3 or 4. The study adds to the direct clinical utility of CBF determination as a prognostic tool.

Identification of acylpeptide hydrolase as a sensitive site for reaction with organophosphorus compounds and a potential target for cognitive enhancing drugs.

We describe here the purification and identification of a previously unrecognized target for organophosphorus compounds. The target, acylpeptide hydrolase, was isolated as a tritiated-diisopropylfluorophosphate-reactive protein from porcine brain and purified to homogeneity using a combination of ion-exchange and gel-filtration chromatography. Biochemical characterization and internal sequence analysis confirmed identity. Acylpeptide hydrolase was found to be potently inhibited by the organophosphorus compounds chlorpyrifosmethyl oxon, dichlorvos, and diisopropylfluorophosphate (20-min IC(50) values of 18.3 +/- 2.0, 118.7 +/- 9.7, and 22.5 +/- 1.2 nM, respectively). The in vitro sensitivity of acylpeptide hydrolase toward these compounds is between six and ten times greater than that of acetylcholinesterase (AChE), making it a target of pharmacological and toxicological significance. We show that, in vivo, acylpeptide hydrolase is significantly more sensitive than AChE to inhibition by dichlorvos and that the inhibition is more prolonged after a single dose of inhibitor. Furthermore, using dichlorvos as a progressive inhibitor, it was possible to show that acylpeptide hydrolase is the only enzyme in the brain capable of hydrolyzing the substrate N-acetyl-alanyl-p-nitroanilide. A concentration of 154 +/- 27 pmol of acylpeptide hydrolase/gram of fresh rat brain was also deduced by specific labeling with tritiated-diisopropylfluorophosphate. We also suggest that, by comparison of structure-activity relationships, acylpeptide hydrolase may be the target for the cognitive-enhancing effects of certain organophosphorus compounds. Acylpeptide hydrolase cleaves N(alpha)-acylated amino acids from small peptides and may be involved in regulation of neuropeptide turnover, which provides a new and plausible mechanism for its proposed cognitive enhancement effect.

Foot dystonia and lumbar canal stenosis.

We describe a patient who developed involuntary, painless, dystonic contraction of the toes of the right foot on standing or walking. The development of this abnormal movement had been preceded by sensory disturbance on the soles of both feet, triggered by dorsiflexion of the feet. Examination showed that weight bearing on the right foot and walking brought on clawing of the toes of the right foot, which was relieved within seconds of taking pressure off the right foot. There was sensory and reflex evidence of bilateral S1 root disturbance confirmed by electrophysiology. Magnetic resonance imaging of the lumbar spine showed marked stenosis of the lumbar canal with compression of the L5 and S1 nerve roots bilaterally. The patient underwent a lumbar laminectomy with nerve root exit foramina decompression, which abolished the foot dystonia and has considerably improved the sensory disturbance. This case demonstrates that lumbar canal stenosis and/or nerve root compression, may be responsible for foot dystonia. Amelioration of the abnormal movement by surgical decompression argues strongly in favour of this hypothesis.

Histological surprise: callosal tuberculoma presenting as malignant glioma.

A tumour which on CT is clearly intrinsic, irregular, exhibits patchy enhancement with contrast, and invades periventricular tissues, especially the corpus callosum, is very likely to be a glioma and may not be biopsied. A case is presented with these radiological features in which the tumour proved to be a tuberculoma, with complete clinical and radiological resolution after antituberculous chemotherapy.

The effects of tyrosine nitration on the structure and function of hen egg-white lysozyme.

We have investigated the effects of tyrosine nitration (to form the weak acid, 3-nitrotyrosine) at positions 23 or 20 plus 23, on the structure and function of hen egg-white lysozyme. Enzyme activity against Micrococcus luteus cell-wall fragments or soluble substrates exhibits two phenomena. (a) A decrease in Km and kcat for the hydrolysis of soluble oligo- and poly-saccharides, resulting in only minor changes in the catalytic efficiency (kcat/Km) upon nitration. (b) The hydrolysis of M. luteus cell-wall fragments appeared to be dominated by electrostatic interactions with the protein, giving a decrease in enzyme activity as the 3-nitrotyrosyl group became ionized. Removal of the cell-wall anionic polymer, teichuronic acid, from M. luteus abolished this effect. The 3-nitrotyrosine group was also found to act as a fluorescence quencher of exposed tryptophan residues in lysozyme.