GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies

A major challenge in understanding complex idiopathic generalized epilepsies has been the characterization of their underlying molecular genetic basis. Here, we report that genetic variation within the GABRD gene, which encodes the GABAA receptor delta subunit, affects GABA current amplitude consistent with a model of polygenic susceptibility to epilepsy in humans. We have found a GABRD Glu177Ala variant which is heterozygously associated with generalized epilepsy with febrile seizures plus. We also report an Arg220His allele in GABRD which is present in the general population. Compared with wild-type receptors, alpha1beta2Sdelta GABAA receptors containing delta Glu177Ala or Arg220His have decreased GABAA receptor current amplitudes. As GABAA receptors mediate neuronal inhibition, the reduced receptor current associated with both variants is likely to be associated with increased neuronal excitability. Since delta subunit-containing receptors localize to extra- or peri-synaptic membranes and are thought to be involved in tonic inhibition, our results suggest that alteration of this process may contribute to the common generalized epilepsies.     

Direct and indirect memory performance in patients with senile dementia

The performance of patients with a presumptive clinical diagnosis of Senile Dementia of the Alzheimer's Type was compared to that of a group of normal elderly on several memory and neuropsychological tasks. The patients were impaired on tasks of free and cued recall, but exhibited normal performance on a word-completion procedure similar to that used by Graf et al. (1984). Reasons for the discrepancy between these findings and those from related research which reports impairment of word completion in patients with Alzheimer's Disease are discussed. Of particular interest is the role the orientating task plays in word-completion performance.     

Distinct protein interaction domains and protein spreading in a complex centromere

Fission yeast (Schizosaccharomyces pombe) centromeres are composed of large (40-100 kb) inverted repeats that display heterochromatic features, thus providing a good model for higher eukaryotic centromeres. The association of three proteins that mediate region-specific silencing across centromere 1 has been mapped by quantitative chromatin immunoprecipitation. Swi6 and Chp1 are confined to the flanking outer repeats and Swi6 can spread across at least 3 kb of extraneous chromatin in cen1. In contrast, Mis6 coats the inner repeats and central core. tRNA genes demarcate this transition zone. These analyses clearly define two distinct domains within this complex centromere which interact with different proteins.     

An intercomparison of IMRT delivery techniques: a case study for breast treatment

Intensity-modulated radiotherapy beams can be delivered using a multileaf collimator by one of two methods: either by superposition of a series of multiple-static fields, or by moving the collimators while the beam is on to produce 'dynamically' modulated beams. The leaf trajectories in this dynamic mode are given by a series of linear steps between control points defining each collimator position at known intervals throughout an exposure. The complexity of the resulting modulation is limited in the first case by the number of fields superposed and in the second case by the number of control points defined. Results are presented for an experimental study that investigates the effect of changing both the number of fields for the multiple-static technique, and the number of control points for a dynamic 'close-in' technique. All deliveries studied are clinical intensity-modulated breast fields. The effect of using a universal wedge in conjunction with the multileaf collimator is also studied, together with a comparison of the relative efficiency, time taken and the absolute dosimetric accuracy of the various delivery options. It is shown that all delivery techniques produce equivalent dose distributions when using 15 control points, with 10 control points being sufficient to produce an adequate breast compensator distribution. Except for the case of a four-control-point dynamic delivery, the universal wedge makes no significant difference to the dose distribution. However, it makes the delivery less efficient. The close-in interpreter consistently produces deliveries that are more efficient than the more conventional sliding-window technique and faster than the multiple-static-field technique. Finally the close-in technique is compared to the more 'standard' leaf-sweep technique and shown to be equivalent.     

The anatomy of the anterior inferior tibiofibular ligament and its relationship with the Wagstaffe fracture

BackgroundOur aim in this study was to identify the fibular footprint of the Anterior Inferior Tibiofibular Ligament (AITFL) and its relation to Wagstaffe fracture fragment size.MethodsWe examined 25 cadaveric lower limbs which were carefully dissected to identify the lateral ankle ligaments. The AITFL anatomy was compared to 40 Wagstaffe fractures identified from our ankle fracture database.ResultsThe AITFL origin was from the anterior fibular tubercle with an average length of 21.61 mm (95% CI 20.22, 22.99). The average distance of the distal aspect of the AITFL footprint to the distal fibula margin was 11.60 mm (95% CI 10.49, 12.71). In the ankle fractures analyzed, the average length of the Wagstaffe fragment was 17.88 mm (95% CI 16.21, 19.54). The average distance from the distal tip of the fibula to the Wagstaffe fracture fragment was 21.40 mm (95% CI 19.78, 23.01).In total there were 22 syndesmosis injuries. There was no statistical difference in Wagstaffe fragment size between stable and unstable groups.ConclusionThe AITFL fibular origin was both larger and more distal than the Wagstaffe fracture fragments seen in our institution. Therefore, this suggests that a ligamentous failure will also have to occur to result in syndesmotic instability. The size of fracture fragment also did not confer to syndesmotic instability on testing.Level of Evidence - 3     

The cost of acute asthma--how much is preventable?

Asthma is known to be widely under-treated, and unnecessary morbidity from the disease is common. This paper reports a prospective survey of hospital admissions for acute asthma and assesses the efficacy of pre-admission therapy in terms of preventing hospital admission. District and national costs were estimated for hospital admission of patients with acute asthma and, although the direct cost to the patients was not measured, a calculation was made of the number of working days lost annually. The results of this survey show the need for improved education of both doctors and patients, and in particular for improved clinical management. The findings also suggest that the cost to the patient, including those costs incurred by hospital admission, are potentially preventable.     

Clinical implementation of a computer controlled milling machine for compensating filter production

The procedures required for the clinical implementation of a computer controlled milling machine for producing compensators for breast radiotherapy are described. Moulds are cut in a rigid polymer foam block and filled with stainless-steel granulate. Quality assurance procedures are described for ensuring that the compensators produced are consistent and accurate. Relative and absolute dosimetric measurements are presented showing that the compensators are accurate to better than 1% and demonstrate the technique to be clinically acceptable.