ABSTRACT␣5IA is a compound that binds with equivalent subnanomolar affinity to the benzodiazepine (BZ) site of GABA A receptors containing an ␣1, ␣2, ␣3, or ␣5 subunit but has inverse agonist efficacy selective for the ␣5 subtype. As a consequence, the in vitro and in vivo effects of this compound are mediated primarily via GABA A receptors containing an ␣5 subunit. In a mouse hippocampal slice model, ␣5IA significantly enhanced the burst-induced long-term potentiation of the excitatory postsynaptic potential in the CA1 region but did not cause an increase in the paroxysmal burst discharges that are characteristic of convulsant and proconvulsant drugs. These in vitro data suggesting that ␣5IA may enhance cognition without being proconvulsant were confirmed in in vivo rodent models. Hence, ␣5IA significantly enhanced performance in a rat hippocampaldependent test of learning and memory, the delayed-matchingto-position version of the Morris water maze, with a minimum effective oral dose of 0.3 mg/kg, which corresponded to a BZ site occupancy of 25%. However, in mice ␣5IA was not convulsant in its own right nor did it potentiate the effects of pentylenetetrazole acutely or produce kindling upon chronic dosing even at doses producing greater than 90% occupancy. Finally, ␣5IA was not anxiogenic-like in the rat elevated plus maze nor did it impair performance in the mouse rotarod assay. Together, these data suggest that the GABA A ␣5-subtype provides a novel target for the development of selective inverse agonists with utility in the treatment of disorders associated with a cognitive deficit.Agonists at the benzodiazepine (BZ) binding site of the GABA A receptor, such as diazepam, enhance the inhibitory effects of GABA and have been used as anxiolytics and hypnotics for more than 40 years (Argyropoulos and Nutt, 1999). In addition, they have therapeutic utility in inducing not only sedation and muscle relaxation but also amnesia before surgical procedures (Williams and Bowie, 1999). Although the amnesic effects of BZ agonists in animals and humans have been known for some time (Ghoneim and Mewaldt, 1990), the precise nature of the processes underlying these effects are still uncertain. Since the anterograde rather than retrograde amnesia (McNaughton and Morris, 1987) produced by BZ agonists is similar to deficits induced by hippocampal lesions in animals and humans, it has been suggested that these drugs may exert their amnesic effects by modulating hippocampal function.At present, 19 GABA A receptor subunits have been identified (␣1-␣6, 1-3, ␥1-␥3, ␦, ⑀, , 1-3, and ; Simon et al.,
Thiamine-responsive megaloblastic anaemia (TRMA), also known as Rogers syndrome, is an early onset, autosomal recessive disorder defined by the occurrence of megaloblastic anaemia, diabetes mellitus and sensorineural deafness, responding in varying degrees to thiamine treatment (MIM 249270). We have previously narrowed the TRMA locus from a 16-cM to a 4-cM interval on chromosomal region 1q23.3 (refs 3,4) and this region has been further refined to a 1.4-cM interval. Previous studies have suggested that deficiency in a high-affinity thiamine transporter may cause this disorder. Here we identify the TRMA gene by positional cloning. We assembled a P1-derived artificial chromosome (PAC) contig spanning the TRMA candidate region. This clarified the order of genetic markers across the TRMA locus, provided 9 new polymorphic markers and narrowed the locus to an approximately 400-kb region. Mutations in a new gene, SLC19A2, encoding a putative transmembrane protein homologous to the reduced folate carrier proteins, were found in all affected individuals in six TRMA families, suggesting that a defective thiamine transporter protein (THTR-1) may underlie the TRMA syndrome.
The use of telemedicine is becoming increasingly popular in assisting with the home management of People with Dementia (PwD) by offering services to the carers that may enhance their ability to care for their relative for longer. A computerized platform, ALADDIN, was evaluated in its usefulness to reduce carer burden and distress and to improve their quality of life, in an attempt to delay institutionalization of PwD. ALADDIN offers educational material about dementia to carers and provides the opportunity to contact other carers and clinicians. ALADDIN also facilitates remote monitoring of the PwD and their carers by the clinicians to enable speedy delivery of appropriate intervention. The ALADDIN platform was piloted at three European sites, and used by thirty carers of PwD living in the community (platform group). The platform group and a control group of thirty PwD and their carers were assessed at baseline, 3 months, and 6 months. The results showed a significant improvement in the quality of life of the carers in the platform group, with some reduction in carer burden and distress. The platform was useful in monitoring the patients and facilitating contact with other professionals. Access to and use of the ALADDIN platform was rated positively by carers and clinicians. The ALADDIN platform's usefulness and applicability for prolonging the home management of PwD are discussed.
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