BACKGROUND AND PURPOSEMost GABAA receptor subtypes comprise 2a, 2b and 1g subunit, although for some isoforms, a d replaces a g-subunit. Extrasynaptic d-GABAA receptors are important therapeutic targets, but there are few suitable pharmacological tools. We profiled DS2, the purported positive allosteric modulator (PAM) of d-GABAA receptors to better understand subtype selectivity, mechanism/site of action and activity at native d-GABAA receptors. EXPERIMENTAL APPROACHSubunit specificity of DS2 was determined using electrophysiological recordings of Xenopus laevis oocytes expressing human recombinant GABAA receptor isoforms. Effects of DS2 on GABA concentration-response curves were assessed to define mechanisms of action. Radioligand binding and electrophysiology utilising mutant receptors and pharmacology were used to define site of action. Using brain-slice electrophysiology, we assessed the influence of DS2 on thalamic inhibition in wild-type and d 0/0 mice. KEY RESULTSActions of DS2 were primarily determined by the d-subunit but were additionally influenced by the a, but not the b, subunit (a4/6bxd > a1bxd >> g2-GABAA receptors > a4b3). For d-GABAA receptors, DS2 enhanced maximum responses to GABA, with minimal influence on GABA potency. (iii) DS2 did not act via the orthosteric, or known modulatory sites on GABAA receptors. (iv) DS2 enhanced tonic currents of thalamocortical neurones from wild-type but not d 0/0 mice. CONCLUSIONS AND IMPLICATIONSDS2 is the first PAM selective for a4/6bxd receptors, providing a novel tool to investigate extrasynaptic d-GABAA receptors. The effects of DS2 are mediated by an unknown site leading to GABAA receptor isoform selectivity. AbbreviationsDS1, delta selective compound 1; DS2, delta selective compound 2; ECx, effective concentration giving the activation degree of X;

It is well known that ischemia causes neuronal necrosis in selectively vulnerable sectors of the hippocampus. Since the hippocampus is involved in spatial navigation, learning, and memory, selective deficits in these areas may arise from ischemic brain damage. The objective of this study was to test whether a minimal ischemic insult, producing selective neuronal necrosis restricted to only a portion of the CA1 pyramidal cells of the hippocampus, could produce a detectable spatial navigation deficit. Male Wistar rats received 9 min of forebrain ischemia induced by carotid clamping and hypotension or sham operation with exposure of the carotid arteries. The rats were allowed to recover and were tested on a simple place task, a place learning-set task, and a pattern discrimination task in swimming pools paradigms. Subsequently, the rats were perfusion-fixed and their entire brains subjected to quantitative histopathologic analysis. Although both ischemic and sham-operated groups learned the simple place task, the learning-set task revealed defects in spatial navigation, reflected as increased errors and latency in the performance of the ischemic rats. In the subsequent pattern discrimination task, the ischemic group was superior to the control group, which perseverated by attempting to use a place strategy to solve the discrimination. Quantitative neuropathology revealed neuronal necrosis in the ischemia group limited to 50% of the CA1 zone of the hippocampus. Extrahippocampal damage consisted of rare cortical neuronal necrosis in 2 of 6 animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Sonohysterography was a sensitive tool and was superior to TVS used alone for evaluation of the uterine cavity in patients who underwent operative surgery for abnormal uterine bleeding. All abnormalities except one were found at SCSH, while TVS alone missed polyps and had almost one in four equivocal findings. The use of TVS, without saline contrast, left one in five of the polyps undiagnosed in referred patients with abnormal bleeding.

Extraocular sebaceous gland carcinomas of the skin are uncommon neoplasms that may recur locally, but in contrast to their ocular counterparts infrequently metastasize. A case is reported in which a 62-year-old woman had a 1 cm scalp tumor incompletely excised. Microscopic examination revealed a sebaceous carcinoma. No further surgical treatment was performed and 31 months after diagnosis the patient presented with regional and distant metastases resulting in death. It is emphasized that extraocular sebaceous carcinoma may behave in a biologically aggressive manner, just as their counterparts arising in the ocular adnexae, and the necessity to ensure complete tumor excision is stressed.

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