Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype

Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.     

The So-Called Borderline Patient: Aetiology,Diagnosis, and Treatment

This short paper examines the relationship between borderline psychopathology and various theories regarding the aetiology of this disorder. In the formation of borderline personality organization, distinct structural alterations in personality development are thought to arise from both genetic/neurobiological and environmental/trauma factors. We concur that these variables are instrumental in the formation of borderline personality organization. However, we believe that genetic/neurobiological variables are more closely related to developmental deficits, whereas environmental/trauma factors are primarily associated with either arrested development or regressive phenomenon. Regardless of aetiology, the resultant borderline personality organization disorders may present with comparable symptoms. Further, we hypothesize that the prognosis for response to treatment is related primarily to whether the borderline disorder arises from developmental deficits, arrested development, or regressive phenomena. Diagnostic indicators and treatment considerations for each of the borderline aetiologies are presented.     

HLA-DR residues accessible under the peptide-binding groove contribute to polymorphic antibody epitopes

Many residues involved in polymorphic antibody-binding epitopes on class II molecules are located on the -helix of DRβ chains. Although they have received less attention, residues in the peptide-binding groove and second domain of the DRβ chain may also be critical for polymorphic anti-DR antibody epitopes. In this study, we used transfectants expressing site-directed mutations at positions in the HLA-DR β₁ and β₂ domains and flow cytometry to define the epitopes of several polymorphic anti-DR antibodies. Both DR(β 1^*0403) residues 14 and 25 were shown to be involved in the epitopes of mAbs DA6. 164, HU-20, Q5/6, and 50D6, and DR(β 1^*0701) residue 14 was shown to be critical for the epitopes of two DR7-specific mAbs, SFR16-DR7M and TAL 13. 1. Unlike most other residues shown to be important in antibody-binding epitopes, residue 14 is located in the floor of the peptide-binding groove and residue 25 is in an outer loop, each with their side chains pointing down, such that antibodies may directly contact these residues from below the binding groove. Two residues in the β₂ domain, β180 and β181, were also shown to be involved in the epitopes of three polymorphic anti-DR mAbs, NFLD.D1, NFLD.M1, and LY9. Although these two residues are close to the transmembrane domain in the linear sequence, their solvent accessibility in the DR1 structures is quite impressive. Our data provide new evidence that residues accessible under the peptidebinding groove contribute to polymorphic antibody-binding epitopes.     

Pathogenesis of infectious bronchitis nephritis. 2. Studies of water and electrolyte balance in colostomised chickens

Water and electrolyte balance was examined throughout the course of an experimental infection with T strain infectious bronchitis virus in colostomised chickens. Significant losses of water and negative sodium and potassium balances were observed. The major change in the electrolyte balance was the increased output of sodium in urine and this was associated with a diuresis. A decrease in food intake was the most important contribution to the negative potassium balance. Death resulted from acute renal failure. The implication of the results for electrolyte replacement therapy is discussed and a method for colostomies in birds weighing less than 0.5 kg is described.