A circumscribed refractory access disorder: A verbal semantic impairment sparing visual semantics

We report the case of a patient (AZ) with a semantic refractory access dysphasia. On matching-to-sample tests assessing comprehension of the spoken word, AZ shows all the hallmarks of a refractory access disorder, namely inconsistent performance on repeated testing and sensitivity to both presentation rate and the semantic similarity between competing responses. However, on tasks examining her visual knowledge, such as matching two structurally different exemplars of the same item, AZ's performance is quantitatively and qualitatively different. In a series of experiments testing her knowledge of animate and inanimate items, AZ demonstrated significantly worse performance with verbal-visual matching than with visual-visual matching. Furthermore, response accuracy was observed to decrease with successive probing of an item in the verbal conditions but not the visual conditions. We also demonstrate that this discrepancy cannot be explained on the basis of either task difficulty or presentation rate. We attribute our results to a build-up of refractoriness in the systems mediating verbal comprehension whilst those underlying visual comprehension remain unaffected. We argue that our data speak against a unitary amodal semantic system and in favour of at least partially separate verbal and visual semantic processing.     

The developmental, dimensional and diagnostic interview (3di): a novel computerized assessment for autism spectrum disorders

OBJECTIVE: Autism is a diagnostic spectrum of variable severity, with significant comorbidity. No existing standardized interview measures autistic features dimensionally. The authors aimed to develop a parental autism interview that could be administered to unselected clinical and general population samples that measures both symptom intensity and comorbidity across the full range of the autistic spectrum. METHOD: A computerized procedure was devised for administration by trained interviewers that generates symptom and diagnostic profiles for both autism and non-autistic conditions. Test-retest reliability and interrater reliability were assessed in unselected clinical (n = 50) and nonclinical (n = 30) populations. Concurrent validity (n = 120), discriminant validity (n = 120), and criterion validity (n = 29) were evaluated in autistic spectrum and non-autistic patients. RESULTS: Test-retest and interrater reliabilities were excellent (most intraclass correlation coefficients > 0.9). Concurrent validity (agreement with independent clinician formulation) was very good (mean kappa = 0.74). Criterion validity, a comparison with the Autism Diagnostic Interview, was excellent. Discrimination between autistic spectrum versus non-autistic subjects was almost perfect (sensitivity 1.0; specificity > 0.97). CONCLUSIONS: The Developmental, Dimensional and Diagnostic Interview (3di) provides an efficient and accurate means of assessing, in dimensional terms, the presence of autistic symptoms in both clinical and normal populations. It offers novel opportunities for those engaged in research and clinical practice.     

Neuron-binding human monoclonal antibodies support central nervous system neurite extension

Two human IgMs (sHIgM12 and sHIgM42) were identified that supported in vitro central nervous system (CNS) neurite extension equal to the potent neurite stimulatory molecule laminin. Both IgMs bound to multiple cell types in unfixed CNS tissue and to the surface of neurons in culture. Both monoclonal antibodies (mAbs) overrode the inhibitory effect of CNS mouse myelin on granule cell neurite extension. Neither mAb bound to the surface of mature oligodendrocytes or strictly colocalized with myelin proteins. Sialidase treatment eliminated the neuronal surface binding of both mAbs, whereas blocking sphingolipid synthesis with Fumonisin B1 or removing GPI-linked proteins with PIPLC did not. When used as substrates for mixed neuron/glia aggregates, sHIgM12 and sHIgM42 supported robust neurite extension while astrocytes remained in the aggregates. In contrast, laminin supported astrocyte migration and spreading. Human mAbs that support neurite extension are novel factors that may be of use in encouraging axon repair following injury while minimizing glial cell infiltration. Both human mAbs were isolated from individuals with monoclonal gammopathy. Each individual has carried high mAb titers in circulation for years without detriment. sHIgM12 and sHIgM42 are therefore unlikely to be systemically pathogenic.     

Human monoclonal IgM antibody promotes CNS myelin repair independent of Fc function

The human monoclonal IgM antibody sHIgM22 and mouse IgM monoclonal antibody 94.03 bind to oligodendrocytes, induce calcium signals in cultured glial cells, and promote remyelination in mouse models of multiple sclerosis. In order to address the mechanisms employed by these antibodies to promote CNS repair, bivalent monomers, F(ab')2 fragments, and monovalent forms of these antibodies were investigated to determine whether they exhibit the same remyelinating potential as the intact IgMs. The two antibodies displayed different structural requirements for retention of function. Antibody sHIgM22 remained functional even when reduced to a bivalent F(ab')2 fragment, while disruption of the pentameric structure of antibody 94.03 destroyed its functional properties. Competition studies demonstrated that the two antibodies recognize different entities on the surface of glial cells. These results indicate that the constant region and pentameric structure of IgM is not always necessary for the stimulation of myelin repair, eliminating the requirement for IgM immune effector functions in this process. The ability of the antibodies to cross-link cell surface determinants on oligodendrocytes appears to be an essential aspect of the mechanism of cellular activation. The finding that two antibodies, which induce similar in vivo effects, bind to different structures, and have different cross-linking requirements suggests that activation of glial cells involves the rearrangement of a complex membrane compartment.     

In vitro,pharmacokinetic, and pharmacodynamic interactions of ketoconazole and midazolam in the rat

Interactions of midazolam and ketoconazole were studied in vivo and in vitro in rats. Ketoconazole (total dose of 15 mg/kg intraperitoneally) reduced clearance of intravenous midazolam (5 mg/kg) from 79 to 55 ml/min/kg (p < 0.05) and clearance of intragastric midazolam (15 mg/kg) from 1051 to 237 ml/min/kg (p < 0.05), increasing absolute bioavailability from 0.11 to 0.36 (p < 0.05). Presystemic extraction occurred mainly across the liver as opposed to the gastrointestinal tract mucosa. Midazolam increased electroencephalographic (EEG) amplitude in the beta-frequency range. Ketoconazole shifted the concentration-EEG effect relationship rightward (increase in EC(50)), probably because ketoconazole is a neutral benzodiazepine receptor ligand. Ketoconazole competitively inhibited midazolam hydroxylation by rat liver and intestinal microsomes in vitro, with nanomolar K(i) values. At a total serum ketoconazole of 2 microg/ml (3.76 microM) in vivo, the predicted reduction in clearance of intragastric midazolam by ketoconazole (to 6% of control) was slightly greater than the observed reduction in vivo (to 15% of control). However, unbound serum ketoconazole greatly underpredicted the observed clearance reduction. Although the in vitro and in vivo characteristics of midazolam in rats incompletely parallel those in humans, the experimental model can be used to assess aspects of drug interactions having potential clinical importance.     

A new low-dose formulation of selegiline: clinical efficacy,patient preference and selectivity for MAO-B inhibition

Summary. Three studies were performed using a fast dissolving formulation of selegiline hydrochloride designed for buccal absorption Zydis Selegiline. The aim of the first study was to compare the therapeutic efficacy of Zydis Selegiline (1.25mg or 10mg) with conventional selegiline hydrochloride tablets conventional selegiline tablets (10mg) in patients with Parkinsons disease (PD) who were previously treated with conventional selegiline tablets as an adjunct to levodopa/dopamine agonist therapy. Patients were observed for 4 weeks to ensure that they were stable. Stable patients (n=197) were then randomised to continue with conventional selegiline tablets 10mg (n=68), or to treatment with Zydis Selegiline 1.25mg (n=64) or Zydis Selegiline 10mg (n=62) for 12 weeks in this randomised, parallel group study. A further aim was to establish the acceptability of Zydis Selegiline compared with conventional selegiline tablets. Patient preference for Zydis Selegiline was also evaluated in a second study, a single-dose, randomised, two-way crossover study conducted in patients with PD (n=148). Patients were stratified by the presence or absence of swallowing and salivation problems and were randomised to either Zydis Selegiline 5mg or a placebo fast-dissolving formulation. In a third study, the degree of potentiation of the tyramine pressor effect following Zydis Selegiline was compared with that following conventional selegiline tablets in healthy volunteers. A total of 24 healthy volunteers were randomised to receive Zydis Selegiline 1.25mg or conventional selegiline tablets 10mg for 14–16 days in an open-label, randomised parallel group study.Both Zydis Selegiline (1.25mg and 10mg) treatments were shown to be therapeutically equivalent to conventional selegiline tablets 10mg based on comparison of mean total Unified Parkinsons Disease Rating Scale (UPDRS) scores. Therapeutic equivalence was defined a priori as the 90% confidence interval (CI) for the difference in total UPDRS scores between groups to lie entirely within the range ±5. The difference (90% CI) in mean adjusted total UPDRS between Zydis Selegiline 1.25mg and conventional selegiline tablets 10mg was –2.50 (–4.84, –0.17), and for Zydis Selegiline 10mg and conventional selegiline tablets 10mg, 0.04 (–2.30, 2.38). For the motor subscores of the UPDRS, differences between adjusted means (90% CI) compared with the conventional selegiline tablets group were: Zydis Selegiline 1.25mg, –2.14 (–3.94, –0.33) and Zydis Selegiline 10mg, –0.90 (–2.70, +0.91). Patients who switched from conventional selegiline tablets to Zydis Selegiline 1.25mg showed a slight improvement in UPDRS scores following 12 weeks of treatment (standard error of difference 1.039; p=0.01).In the single-dose crossover study, most (61%) patients liked Zydis Selegiline 5mg; a significantly greater proportion than the null hypothesis of 50% (p<0.002). However, only 62 patients (46%) indicated that they liked the taste of Zydis Selegiline. Nevertheless, the proportion of patients who preferred Zydis Selegiline (65%) to their usual medication was significantly greater than the null hypothesis of 50% (p<0.001).Similar findings were demonstrated in the 12-week study where a higher proportion of patients who received up to 3 months of treatment indicated a preference for either Zydis Selegiline 1.25mg (90%) or Zydis Selegiline 10mg (86%) over conventional selegiline tablets 10mg. More than 90% of patients found Zydis Selegiline easy to take, with 61% rating it as extremely easy. Most (81%) patients taking Zydis Selegiline 1.25mg liked the taste compared with 45% taking Zydis Selegiline 5mg (in the previous study).Zydis Selegiline did not potentiate the tyramine effect: a pressor effect was elicited after 400mg tyramine both before and after 14 days of treatment with Zydis Selegiline 1.25mg. In contrast, after 14 days treatment with conventional selegiline tablets 10mg, the threshold dose required to elicit the tyramine pressor response was significantly (p<0.0001) reduced from 400mg to 200mg.In summary, Zydis Selegiline at doses of 1.25mg and 10mg was therapeutically equivalent to conventional selegiline tablets 10mg. The Zydis Selegiline formulation was well-liked by all patients, with most preferring Zydis Selegiline 1.25mg to their usual selegiline tablet. Furthermore, Zydis Selegiline was well tolerated and, unlike conventional selegiline tablets, appeared to retain specificity for inhibition of monoamine oxidase type B (MAO-B), since it did not potentiate the pressor response to tyramine.Present address: Cephalon UK Ltd., Surrey Research Park, Guildford, United KingdomPresent address: Safetymednet, Ruscombe, United KingdomPresent address: Oxford Glycosciences (UK) Ltd., Abingdon, United KingdomReceived December 3, 2002; accepted July 23, 2003     

Should the food intake of patients admitted to acute hospital services be routinely supplemented? A randomized placebo controlled trial

BACKGROUND: Many patients admitted to acute hospital services are underweight or harbour vitamin deficiencies. OBJECTIVES: To determine the effect on patient throughput of a policy of routine vitamin supplementation, and of early routine sipfeed supplementation in 'thin' patients (5-10% weight loss or body mass index 18-22). DESIGN: Factorial randomized placebo controlled trial of oral multivitamins from the first day of admission, and, after nutritional screening, of a nutritionally complete sipfeed from the second day in 'thin' patients. SETTING: Acute medical, surgical and orthopaedic hospital services of a London teaching hospital. PARTICIPANTS: 1561 patients admitted as emergencies were included in the vitamin study of which 549 were included in the sipfeed study. MAIN OUTCOME MEASURE: Length of hospital stay (LOS). RESULTS: Offering multivitamins to acute admissions resulted in a mean change (reduction) in LOS of -0.4 days 95% CI (-2-1.2days). The results suggest greater reductions for those discharged after 10 days: mean change=-2.3 days 95% CI (-5.7 to 1.2). Sipfeed supplementation was associated with an increased mean length of stay 2.8 days 95% CI (-0.8-6.3). 18% of acute admissions were classified undernourished on the basis of BMI, MUAC or percent weight loss combined. CONCLUSIONS: No benefit was observed for sipfeed intervention although a small benefit of less than one day is not excluded. Vitamin supplementation may have slight but economically important benefit.