X-irradiation, phorbol esters, and H2O2 stimulate mitogen-activated protein kinase activity in NIH-3T3 cells through the formation of reactive oxygen intermediates.

Extracellular signal-regulated kinases (ERKs), also known as mitogen-activated protein (MAP) kinases, are rapidly phosphorylated and activated in response to a number of external factors which promote growth and differentiation (T. G. Boulton, S. H. Nye, D. J. Robbins, N. Y. Ip, E. Radziejewska, S. D. Morgenbesser, R. A. DePinho, N. Panayotatos, M. H. Cobb, and G. D. Yancopoulos, Cell, 65: 663-675, 1991; S. L. Pelech and S. S. Jasbinder, Science (Washington DC), 257: 1355-1356, 1992; G. Thomas, Cell, 68: 3-6, 1992). We have identified two novel stimulators of MAP kinase activity, ionizing radiation and H2O2. Both radiation and H2O2, as well as the known agonist 12-O-tetradecanoylphorbol 13-acetate activate MAP kinase through the production of reactive oxygen intermediates. Our results demonstrate a direct link between the MAP kinase signal transduction pathway and reactive oxygen species and provide a unifying mechanism for activation of early- and late-response genes by inducers of oxidative stress.

Inhibitors of "spontaneous" platelet aggregation in whole blood.

In vitro 'spontaneous' platelet aggregation has been studied in whole blood. The spectrum of activity of materials known to influence platelet aggregation in platelet-rich plasma proved different in whole blood. Thus dipyridamole and one of its analogues SH1242 had a striking effect in whole blood whilst aspirin, chlorpromazine and K3920 had little or no effect. The combination of aspirin and dipyridamole as currently employed in clinical practice had no greater inhibitory effect than dipyridamole alone. The possible clinical relevance of these findings is discussed.

Infection of the central nervous system by Listeria monocytogenes: a review of 54 adult and juvenile cases.

The clinical features in 54 juvenile and adult patients with Listeria monocytogenes infection of the central nervous system are described. Thirty-one of the patients had pre-existing chronic disease; the remainder were previously healthy. Twenty of the patients, the 'meningo-encephalitic group' developed focal neurological signs. The remaining 34, the 'meningitic group' exhibited no focal signs other than those caused by increased intracranial pressure. The 'meningitic group' differed from the 'meningo-encephalitic group' in that the cerebrospinal fluid white cell count, protein and glucose levels were markedly more abnormal and the prognosis worse. Evidence of septicaemia was found only in the 'meningitic group'. Meningo-encephalitis may represent a modified response to listerial infection typified by granulomatous rather than a suppurative response. The predominance of this response that was demonstrated in females may indicate partial immunity, the result of previous Listeria monocytogenes colonisation of the female genital tract. Listeria monocytogenes infection is treatable and should be considered in patients with meningitic or encephalitic illness. Repeated blood cultures may be required to establish the diagnosis.

Red cell deformability is not an independent risk factor in stroke.

Reduced erythrocyte deformability has been implicated in the causation of stroke. We have therefore tested this red cell property by filtration through polycarbonate membranes in 42 patients with either transient ischaemic attacks or completed ischaemic stroke together with age and sex paired controls. We have failed to demonstrate any difference between patients and controls suggesting that reduced red cell deformability is unlikely to be an important independent factor in the production of stroke.

Wilson's disease. Clinical correction with cranial computed tomography.

Cranial computed tomograms of 12 patients with proven Wilson's disease were correlated with clinical disturbances. CT abnormalities occurred only in the eight patients with neurological manifestations. The presence of atrophy and low density lesions of the basal ganglia shown on CT correlated well with clinical signs of extrapyramidal dysfunction. Cerebral atrophy and cerebellar cortical atrophy were only moderately related to the degree of intellectual dysfunction and ataxia, respectively; there were no specific clinical signs in cases with brainstem involvement. Abnormalities may be marked in scans taken within a year of neuropsychiatric symptoms, but the most severely abnormal CT scans occurred in patients with a relatively longer duration of untreated disease. Computed tomography provides the opportunity to follow the response of the abnormalities of the brain to cupruresis and can give some assistance in management.

Monitoring aminoglycoside use in patients with severely impaired renal function.

Twenty patients with severely impaired renal function, 17 of wnom had recently transplanted kidneys, were treated with aminoglycosides for severe infections acquired in hospital. Serum aminoglycoside concentrations were closely monitored and dosages adjusted individually to obtain peak and trough concentrations that ensured adequate treatment while avoiding toxicity. Causative organisms were susceptible to treatment in 21 out of 26 episodes of infection (81%), and 12 of the 17 patients (71%) in whom organisms were isolated were cured. Nephrotoxicity attributable to aminoglycosides alone was not observed during the 35 courses of treatment. Ototoxicity occurred in only one patient, who had excessively high serum concentrations of amikacin. Serum aminoglycoside concentrations were directly affected by carbenicillin and flucytosine. The concurrent administration of cephradine and cephalexin with gentamicin may have produced nephrotoxicity. We conclude that aminoglycosides, when carefully monitored, are effective and safe in patients with severely impaired renal function.