Rheumatologists' judgements about the efficacy of anti-TNF therapy in two neighbouring regions

Objectives: The requirement in Northern Ireland to prescribe biologic agents according to NICE/BSR guidelines and within a fixed budget has created a waiting list for treatment that has no parallel in the Republic of Ireland. The study investigated the bearing this situation may have on had on the consultants’ judgements in the respective areas.

Methods: 78 case vignettes created from the data on real patients with RA treated with biologics in the north and south of Ireland were appraised by 9 southern and 8 northern consultants who judged the clinical benefit and significance of the patients’ condition after a trial of therapy. Quantitative (Clinical Judgement Analysis) and Qualitative (Focus groups) techniques were used.

Results: Northern consultants perceived a slightly greater degree of clinical benefit after a trial of therapy than southern consultants. Judgment models of northern and southern consultants were broadly comparable. The latter tended to be more uniform in their judgments than the southern group. Focus group discussions with consultants largely validated the findings of the quantitative analysis but revealed how clinical judgment analysis might be misled by gaming strategies.

Conclusions: Despite the absence of overt rationing in the south of Ireland, as far as the judgment of therapeutic benefit from biologics was concerned, the clinical judgment policies of practitioners were very similar to those in the north. The adoption of NICE/BSR guidelines in the north may have improved the uniformity of clinical practice in Northern Ireland.

Absence of aquaporin-4 expression in lesions of neuromyelitis optica but increased expression in multiple sclerosis lesions and normal-appearing white matter.

Aquaporin-4 (AQP4) has recently been implicated in the pathogenesis of neuromyelitis optica(NMO) where it has been identifed as the first defined autoantigen pertinent to an infammatory demyelinating disorder of the human CNS. Furthermore, a recent case report has shown a lack of AQP4 expression in the spinal cord lesions of NMO. However, the pattern of AQP4 expression in multiple sclerosis (MS) tissues has not been well-defned. In the present investigation we have confirmed a lack of expression of AQP4 in optic and spinal cord lesions in NMO which contrasted sharply with the increased levels of AQP4 expression seen in MS lesions. Furthermore a detailed immunohistochemical and semi-quantitative analysis is used to describe the expression pattern of AQP4 on well-characterized tissue microarray samples of MS and control white matter. Anatomically AQP4 was more highly expressed in all categories of MS tissue compared to normal control tissues with the most abundant expression in active lesions. Within active lesions AQP4 expression was significantly correlated with expression of the pro-infammatory cytokine osteopontin. At the cellular level dual-labelling immunofluoresence demonstrated that increased expression of AQP4 was most pronounced at the astrocytic endfeet but was also associated with the cell bodies of astrocytes in the tissue parenchyma. The finding of increased AQP4 expression in MS lesions in contrast to the lack of expression in NMO lesions may suggest different mechanisms of initiation and progression between the two disease states.

Characterization of a ligand-attenuated binding site on glycoprotein IIb/IIIa

We describe an epitope on the platelet integrin, GPIIb/IIIa, identified by the monoclonal antibody, 4F8, which is attenuated by small-molecule GPIIb/IIIa ligands. 4F8 did not bind to the ligand binding pocket as it did not compete with a radiolabelled antagonist, H-3-SC-52012. This indicates that the 4F8 epitope behaves as a ligand-attenuated binding site (LABS). Ligand-induced attenuation of 4178 was an active process as it was prevented by pretreating platelets with cytochalasin D and reduced by prostaglandin E-1 or inhibition of protein kinase C. Disappearance of the epitope was required for full platelet activation as 4F8 prevented platelet aggregation without inhibiting fibrinogen binding. These results suggest a model where disappearance of the 4F8 epitope is a secondary event required for full

Spatial attentional bias as a marker of genetic risk, symptom severity, and stimulant response in ADHD

Attention-deficit hyperactivity disorder (ADHD) is a heritable childhood onset disorder that is marked by variability at multiple levels including clinical presentation, cognitive profile, and response to stimulant medications. It has been suggested that this variability may reflect etiological differences, particularly, at the level of underlying genetics. This study examined whether an attentional phenotype-spatial attentional bias could serve as a marker of symptom severity, genetic risk, and stimulant response in ADHD. A total of 96 children and adolescents with ADHD were assessed on the Landmark Task, which is a sensitive measure of spatial attentional bias. All children were genotyped for polymorphisms (30 untranslated (UTR) and intron 8 variable number of tandem repeats (VNTRs)) of the dopamine transporter gene (DAT1). Spatial attentional bias correlated with ADHD symptom levels and varied according to DAT1 genotype. Children who were homozygous for the 10-repeat allele of the DAT1 30-UTR VNTR displayed a rightward attentional bias and had higher symptom levels compared to those with the low-risk genotype. A total of 26 of these children who were medication naive performed the Landmark Task at baseline and then again after 6 weeks of stimulant medication. Left-sided inattention (rightward bias) at baseline was associated with an enhanced response to stimulants at 6 weeks. Moreover, changes in spatial bias with stimulant medications, varied as a function of DAT1 genotype. This study suggests an attentional phenotype that relates to symptom severity and genetic risk for ADHD, and may have utility in predicting stimulant response in ADHD.

Dissociation in performance of children with ADHD and high-functioning autism on a task of sustained attention

Attention deficit hyperactivity disorder (ADHD) and autism are two neurodevelopmental disorders associated with prominent executive dysfunction, which may be underpinned by disruption within fronto-striatal and fronto-parietal circuits. We probed executive function in these disorders using a sustained attention task with a validated brain-behaviour basis. Twenty-three children with ADHD, 21 children with high-functioning autism (HFA) and 18 control children were tested on the Sustained Attention to Response Task (SART). In a fixed sequence version of the task, children were required to withhold their response to a predictably occurring no-go target (3) in a 1-9 digit sequence; in the random version the sequence was unpredictable. The ADHD group showed clear deficits in response inhibition and sustained attention, through higher errors of commission and omission on both SART versions. The HFA group showed no sustained attention deficits, through a normal number of omission errors on both SART versions. The HFA group showed dissociation in response inhibition performance, as indexed by commission errors. On the Fixed SART, a normal number of errors was made, however when the stimuli were randomised, the HFA group made as many commission errors as the ADHD group. Greater slow-frequency variability in response time and a slowing in mean response time by the ADHD group suggested impaired arousal processes. The ADHD group showed greater fast-frequency variability in response time, indicative of impaired top-down control, relative to the HFA and control groups. These data imply involvement of fronto-parietal attentional networks and sub-cortical arousal systems in the pathology of ADHD and prefromal cortex dysfunction in children with HFA. (c) 2007 Elsevier Ltd. All rights reserved.