Evidence that background GABAergic tone and possible ligand release may alter the action of the 'neutral' benzodiazepine-receptor antagonist, Ro 15-1788, in hypothalamic self-stimulation

Upward or downward shifts in the level of brain GABAergictransmission have been held to be necessary and sufficient to promote release of endogenous ligands ('endocoids') for the benzodiazepine (BZD) recognition site. To investigate this possibility, variable-interval self-stimulation performance was used to monitor 'intrinsic' benzodiazepine-like and anti- benzodiazepine activity by the 'neutral' benzodiazepine-receptor antagonist, Ro 15-1788 (flumazenil) (10 or 30 mg/kg intraperitoneally). Rats were pretreated with either a GABA synthesis blocking agent (isoniazid, 130 mg/kg subcutaneously), or with a GABA agonist (progabide, 30 or 100 mg/kg intraperitoneally). The lower dose of Ro 15-1788 (10 mg/kg), without pretreatment, did not affect self-stimulation; higher doses (30 mg/kg) caused a brief (<20 min) depression. Isoniazid (130 mg/kg) depressed self-stimulation, but did not modify the activity of Ro 15-1788. In rats pretreated with progabide (100 mg/kg), low doses of Ro 15- 1788 (10 mg/kg) that were previously without effect now caused a sharp fall in responding. These findings can be interpreted as showing that even low doses of Ro 15-1788 may affect self-stimulation under certain conditions, and that they do so by competing with an endogenous ligand for the benzodiazepine site, released by upward shifts in GABAergic activity. Alternative explanations in terms of altered receptor function seem less feasible. The results imply that the action of the endogenous ligand would not resemble that of a typical benzodiazepine, but that of an inverse agonist (that is, proconflict and proconvulsant); this conclusion agrees with recent biochemical evidence.     

Blood platelet uptake of serotonin in episodic aggression

Blood platelet uptake of 3H-serotonin (5HT uptake), a potential marker of serotonergic function, was determined in male outpatients with episodic aggression (n = 15) and in age- and sex-matched nonaggressive controls (n = 15). Correlations with rating scales of "impulsivity" (Barratt Impulsivity Scale, 10th revision) and "anger" (Spielberger Anger Expression Scale) were performed. Mean 5HT uptake was 18% lower in patients with episodic aggression. A significant negative correlation between % difference in platelet 5HT uptake and impulsivity score was observed, but the correlation between 5HT uptake and anger was not significant. These results support the hypothesis of disturbed serotonergic function in aggression and suggest that the primary relationship is in the "control" of aggression. The blood platelet may be useful in identifying impulsive subtypes.     

The Complement-Fixation Test in Hepatic Coccidiosis of Rabbits

Antibodies to Eimeria stiedae were measured in rabbit serum by complement fixation. The titre rose to a maximum at about the 22nd day after infection, remained at this level for about 20 days and then declined. Antibodies were still detectable up to 160 days after infection.

Evidence of past or present slight E. stiedae infection was found in clinically normal rabbits whose sera fixed complement with E. stiedae antigens.

Challenge of rabbits which had recovered from a near-fatal infection had no effect upon the complement fixation titres of their sera.

The serum of a rabbit which had been injected with alum-precipitated antigen fixed complement with E. stiedae antigens. However, the animal was still susceptible to a superimposed oral infection which had the effect of further increasing the serum titre.

     

Pediatric solid-organ transplant recipients carry chronic loads of Epstein-Barr virus exclusively in the immunoglobulin D-negative B-cell compartment

Solid-organ transplant recipients are at risk for development of lymphoproliferative diseases. The purpose of this study was to examine the distribution of Epstein-Barr virus (EBV) load in the peripheral blood of pediatric transplant recipients who had become chronic viral load carriers (>8 copies/10(5) lymphocytes for >2 months). A total of 19 patients with viral loads ranging from 20 to 5,000 viral genome copies/10(5) lymphocytes were studied. Ten patients had no previous diagnosis of posttransplant lymphoproliferative disease (PT-LPD), while nine had recovered from a diagnosed case of PT-LPD. No portion of the peripheral blood viral load was detected in the cell-free plasma fraction. Viral DNA was found in a population of cells characterized as CD19(hi) and immunoglobulin D negative, a phenotype that is consistent with the virus being carried exclusively in the memory B-cell compartment of the peripheral blood. There was no difference in the compartmentalization based upon either the level of the viral load or the past diagnosis of an episode of PT-LPD. These results have implications for the design of tests to detect EBV infection and for the interpretation and use of positive EBV PCR assays in the management of transplant recipients.     

Survival versus neglect: redefining thymocyte subsets based on expression of NKG2D ligand(s) and MHC class I

BALB/c thymocytes can be divided into three distinct subsets according to the expression of a ligand for the NK activation receptor NKG2D (NKG2D-L) and the expression of MHC class I (MHC-I). The first subset (MHC-Imid/NKG2D-Lhigh or "N+") is predominately CD4+CD8+ double positive (DP), comprises approximately 35% of thymocytes in a 6-8-week-old adult and contains uncommitted cells that have neither undergone selection nor are committed to death by neglect. The second subset (MHC-Ilow/NKG2D-Llow or "M-"), also mostly DP cells, comprises approximately 50% of thymocytes and consists of cells committed to death by apoptosis, likely due to neglect. By contrast, the third subset (MHC-Ihigh/NKG2D-Llow or "M+") is largely single positive (SP), represents approximately 15% of thymocytes and mostly contains more mature cells that have undergone successful positive selection. The major advantage of the analysis is that it splits DP cells into two subpopulations, one committed to death by apoptosis and the other subjected to selection. The analysis also suggests that NKG2D-L may play a role in thymocyte development.     

Detection of human papillomavirus types 6 and 11 E4 gene products in condylomata acuminatum.

Polyclonal antiserum to an Escherichia coli-produced beta-galactosidase/E4 fusion protein of human papillomavirus type 6b (antiserum 256), and affinity purified HPV 11 anti-E4 antibodies were tested for reactivity in Western blots with bacterially expressed trpE/E4 fusion proteins of HPV types 6b, 11, 16, and 18. To further characterize the affinity purified anti-E4 antibodies, a dot-immunobinding assay was performed using overlapping synthetic HPV 11 E1E4 peptides as antigens. Protein extracts of condylomata acuminatum from 18 patients containing HPV type 6 or 11 DNA sequences were tested in Western blots using antiserum 256 or affinity purified HPV 11 anti-E4 antibodies. In the Western blots of the trpE proteins, antiserum 256 identified the HPV types 6b and 11 fusion proteins; the affinity purified HPV 11 anti-E4 antibodies identified only the HPV 11 fusion protein. In the dot-immunobinding assay, three HPV 11 peptides were recognized, each containing a shared 8 amino acid sequence that differs significantly from the corresponding sequences of HPV types 6b, 16, or 18. In the Western blots of protein extracts from 18 condylomata acuminatum samples shown to contain HPV types 6 or 11 DNA, putative E4 gene products were identified in six samples by antiserum 256. The affinity purified HPV 11 anti-E4 antibodies identified putative E4 gene products in one of these same six lesions, which was shown to contain HPV 11 sequences by the Southern blot method. All six samples containing E4 gene products were from women. Three of these women were pregnant, one had serum antibodies to the human immunodeficiency virus, and one was a renal transplant recipient receiving glucocorticoids.(ABSTRACT TRUNCATED AT 400 WORDS)