Disposition and activity in experimental allergic encephalomyelitis of flumizole, a nonacidic, nonsteroidal, anti-inflammatory agent

The nonacidic, nonsteroidal, anti-inflammatory agent, flumizole, penetrates the central nervous system of rats following oral drug administration, reaching concentrations in brain and spinal cord which are several-fold higher than plasma concentrations. Maximum drug concentrations in brain and plasma are achieved simultaneously and decay with similar half-lives (8 h). The drug is well absorbed orally and is excreted primarily with feces after biliary secretion. The distribution and elimination of flumizole is comparable in normal rats and in rats afflicted with experimental allergic encephalomyelitis; the drug is not selectively concentrated at either peripheral or central nervous system sites of inflammation. Flumizole is inactive in the rat model of the disorder under conditions that demonstrate therapeutic success with myelin basic protein.     

Acute dieldrin exposure in relation to brain monoamine oxidase activity and concentration of brain serotonin and 5-hydroxyindoleacetic acid

Rainbow trout, White Leghorn chickens and golden hamsters were administered dieldrin or the vehicle in various dosages and routes of injection. Whole brain serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were measured. In separate experiments, monoamine oxidase (MAO) activity was determined in brain homogenates incubated with pargyline or dieldrin. Serotonin content increased maximally at 10 mg/kg dieldrin. Brain MAO activity was significantly decreased by dieldrin in chicken and hamster, but trout enzyme activity was unaffected. The 5-HIAA content reflected MAO inhibition and interference with 5-HIAA transport from brain.     

The neurotoxicity of aflatoxin B1 in the rat

The effects of repeated intraperitoneal administration of aflatoxin B₁ on the peripheral and central nervous systems of rats were investigated. Biochemical markers of neurotoxicity were monitored in nervous tissues following aflatoxin B₁ dosage and after the cessation of aflatoxin B₁ administration. Aflatoxin B₁ increased the activities of β-glucoronidase and β-galactosidase in the central and peripheral nervous systems. Repeated exposure of rats to aflatoxin B₁ also activated Na⁺ K⁺-ATPase and inhibited Mg²⁺-ATPase. Nervous tissue levels of DNA and total protein increased while the concentrations of RNA and phospholipid were depressed by aflatoxin B₁. The alterations in these parameters were specific for each of the tissues examined during the recovery of the rats. The findings indicate that the repeated administration of aflatoxin B₁ to rats results in degeneration in the central and peripheral nervous systems that may be related to the overt toxicity observed following aflatoxin administration.     

Pathway choice by regenerating optic fibers following tectal lobectomy in the goldfish: Inferences from the study of gliosis in tectal efferent bundles

Cell counts in various fiber bundles of the goldfish brain have demonstrated a profound, but transient gliosis of tectal (and pretectal) efferent pathways following removal of a tectal lobe. In the majority of cases, the pathways which underwent gliosis were also those which were penetrated by regenerating optic fibers which had been sectioned by the tectal surgery. However, the dorsal trunk of the horizontal commissure on the intact side of the brain showed only a minimal gliotic response but was consistently innervated by the optic fibers. Conversely, the ansate commissure and the crossed tectobulbar tract invariably demonstrated a marked gliotic response but only rarely received more than minimal innervation by the regenerating fibers.These observations are discussed with regard to the modifications which they demand of the hypothesis that degenerating axon bundles in the goldfish brain are in some way attractive to regenerating axons.     

Biochemical research into psychosis.

A strategy is presented for biological psychosis research with neuroleptics acting as a point of crystallisation like antidepressants do in biological depression research. The neuroleptics chlorpromazine, haloperidol and oxypertine were studied, and it was found that they influence central catecholamine (CA) metabolism in man. An increased central dopamine (DA) turnover was found to occur in psychotic disorders, mostly in the form of motor agitation. As the first of a planned series of studies, chlorpromazine with presumed ability to reduce both DA-ergic and noradrenaline (NA)-ergic transmission and oxypertine as a more selective blocker of NA-ergic transmission were selected for comparison. The overall therapeutic effect of oxypertine was inferior to that of chlorpromazine, whereas oxypertine proved more effective in cases where loss of initiative was predominant. On the other hand, chlorpromazine exerted a more marked influence on extrapyramidal motor functions than oxypertine. In chronic psychotic disorders with inertia, oxypertine thus seems to be a neuroleptic which is strong enough to prevent exacerbation of delusions and hallucinations while at the same time increasing the level of motivation. These findings were in accordance with our predictions. The comparative study is illustrative of the practical significance of the research approach in this study: The biochemical action profile of a neuroleptic seems to be a more reliable indicator of its clinical action than does its chemical structure.     

Tentative identification of a second central nervous system myelin membrane autoantigen (M2) by a biochemical comparison with the basic protein (BP)

Two central nervous system myelin autoantigens, M2 and basic protein (BP), were examined, using complement-fixing antibodies against each autoantigen as markers on myelin. M2 activity was very labile and very insoluble, PB activity was very resistant. Trypsin reduced both activities an this reduction was greater after phospholipase treatment. Both activities were slightly solubilized in 8 M urea. It is known that BP is not present on the surface of myelin and is considered a peripheral membrane protein. M2 appears to be a surface and integral membrane protein, and as such resembles Folch Pi proteolipid protein. The relationship between M2 and BP requires further study.     

Acute lymphoblastic leukaemia associated antigen. III Alterations in expression during treatment and in relapse

315 adult patients with untreated leukaemia or lymphoma attending St. Bartholomew's Hospital, London, between June 1973 and December 1978 were studied. Forty-five had blast cells which were specifically reactive with antibody to common (non-T, non-B) ALL ( = cALL⁺). The morphological diagnosis was of ALL (33 cases), AUL (5 cases) or Ph¹ positive CML in blast crisis (4 cases). Four of the ALL cases were Ph¹ positive and had had no clinically evident CML phase. Bone marrow suspensions from 19 of these patients have been examined serially for up to 4 years in order to assess the stability of the immunological phenotype and the possible prognostic value of monitoring levels of ALL⁺ cells throughout treatment.In some instances the re-appearance of cALL⁺ cells preceded relapse. Isolated relapses of the CNS, skin or testis were also associated with transient increases in cALL⁺ cells in the bone marrow. The potential monitoring value of anti-ALL was compromised by three observations: the rapid appearance of leukaemic blasts in relapse with no prior detectable increase in cALL⁺ cells, the re-appearance of weakly stained cALL⁺ cells without subsequent relapse particularly during post maintenance chemotherapy associated lymphocytosis and finally the emergence of cALL antigen negative leukaemic cells in relapse. Of 119 other ALL cases studied (mostly children) 20 showed a phenotypic shift of membrane marker expression in relapse. The clinical and biological implications of these observations are discussed.     

Multiple unit activity recorded from amygdala central nucleus during Pavlovian heart rate conditioning in rabbit

Using a Pavlovian heart rate conditioning paradigm, a rapid development of short latency increases in the multiple unit activity of the amygdala central nucleus were observed in response to a tone conditioned stimulus. In some cases the increases in multiple unit response showed a parallel development with the conditioned develerative heart rate response and were significantly correlated with it. These results suggest a direct role for the central nucleus in the expression of conditioned heart rate responding in rabbit.     

Cerebral zygomycosis

Fifty-six patients with cerebral zygomycosis (mucormycosis) were seen during the period 1971-2001 in two tertiary care hospitals located in south India with tropical climate and catering to neurological diseases. Forty-four patients had rhinocerebral and twelve patients had isolated central nervous system (CNS) zygomycosis. Of these, ten were culture proven (Rhizopus oryzae in eight and Mucor in two); 30 were diagnosed as probable and 16 were diagnosed possible; mixed infections were seen in three patients. Diabetes mellitus was the predisposing condition in a majority (31/44) of patients with the rhinocerebral form of zygomycosis. The tissue obtained at biopsy/autopsy in either form showed necrotic/infarcted tissue with neutrophilic infiltration with broad non-septate hyphae showing irregular branching. The outcome was poor despite surgical excision and antifungal therapy. The high concentration of spores in a mouldy environment, the bird population and improper disposal of hospital waste may facilitate healthy hosts presenting with primary CNS disease.     

Type distribution, viral load and integration status of high-risk human papillomaviruses in pre-stages of cervical cancer (CIN)

A series of 176 archival cervical intraepithelial neoplasia (CIN) was analysed for the presence, viral load and integration status of 'high-risk' types of human papillomavirus (HR-HPV). The samples were assayed using newly developed methods based on real-time PCR. Two methods for the extraction of DNA from the paraffin-embedded biopsies were compared: a protocol based on the MagNA pure system (Roche) and a Qiagen spin column kit (Qiagen). It was possible to amplify 94% (166) of the samples. Of these, 36, 63 and 80% of the CIN I, II and III cases contained HR-HPV. HPV 16 was the most prevalent, and was found in 20, 28 and 46% of the CIN I, II and III cases, respectively. The second most frequent HR-HPV was type 33 group, and in CIN II it was as prevalent as HPV 16. The median number of copies of HR-HPV per cell was not significantly different in the CIN I, II and III cases, but there was a wide range of viral load values over several magnitudes, regardless of the grade of CIN. All samples were found to contain integrated forms of HPV 16, frequently mixed with an episomal form.