Frontal and temporo-parietal lobe contributions to theory of mind: neuropsychological evidence from a false-belief task with reduced language and executive demands

A model of the functional and anatomical basis of belief reasoning is essential for understanding the relationship between belief reasoning and other cognitive processes in both normal development and pathology. Studies of brain-damaged patients can give valuable insights into the nature of belief processing but pose unique methodological problems. The current study addresses these problems by using a nonlinguistic belief-reasoning task with substantially reduced executive demands. A case series of 12 brain-damaged patients is presented. The belief-reasoning errors of four patients with damage to the prefrontal cortex appeared to arise from these patients' executive function problems. The belief-reasoning errors of three patients with damage to the temporo-parietal junction could not easily be accounted for in this way, raising the possibility that this brain region has a necessary role in representing beliefs, rather than handling the executive demands of belief-reasoning tasks. We discuss the importance of gaining empirical evidence about the scope of 'theory of mind' impairments, and the important role for neuropsychological studies in this project.     

BRAF mutations are detectable in conjunctival but not uveal melanomas

Activating mutations in exon 15 of BRAF have been detected in a high proportion of cutaneous melanomas. To determine whether such mutations are a feature of conjunctival or uveal melanomas, we screened DNA from these tumours. Twenty-one conjunctival and 88 uveal tumours were included in the study. Mutation analysis of BRAF exons 11 and 15 was undertaken using a combination of conformationally sensitive gel electrophoresis and direct sequencing. Mutations in exon 15 were detected in three of the conjunctival tumours (two V599E and one E585 K). None of the uveal tumours possessed a BRAF mutation in either exon 15 or 11. We conclude that uveal melanomas arise independently of oncogenic BRAF mutations, but the development of a proportion of conjunctival tumours involves mutation of this gene.     

Role of periplasmic peptidylprolyl isomerases in Salmonella enterica serovar Typhimurium virulence

FkpA is a peptidylprolyl isomerase whose expression is regulated by the alternative sigma factor, sigma factor E (sigma(E)). In contrast to the results of a previous report, inactivation of fkpA was found to have only a minor effect on the ability of Salmonella enterica serovar Typhimurium to invade and survive within epithelial and macrophage cell lines and cause infection in mice. However, an effect of the fkpA mutation on serovar Typhimurium virulence was seen if the mutation was combined with mutations in surA or htrA, two other sigma(E)-regulated genes, which encode proteins involved in protein folding and/or degradation in the periplasm.     

Implicit location encoding via stored representations of familiar objects: neuropsychological evidence

We report data on the visual localisation ability of a patient with Balint's syndrome, GK. We show that, with relatively long exposures of displays, GK is better able to judge the spatial relations between separate objects (a "between-object judgement") than the spatial relations between a part and a whole object (a "within-object judgement") (Experiments 1-3). This dissociation occurred even when the same stimulus was used for both judgements, and the task instructions biased GK to parse the stimulus as either a single or as two separate objects (Experiments 2 and 6). However, when he could use a stored representation to make a within-object judgement, then performance was better than on a comparable spatial judgement of the relations between two separate objects (Experiments 4-7). The data demonstrate that stored representations of objects can support the spatial coding of parts to perceptual wholes. In the absence of stored representations, part-whole relations must be explicitly coded by attention, a process that is impaired in this patient.     

Neuroimaging in low back pain

Patients commonly present to family physicians with low back pain. Because the majority of patients fully or partially recover within six weeks, imaging studies are generally not recommended in the first month of acute low back pain. Exceptions include patients with suspected cauda equina syndrome, infection, tumor, fracture, or progressive neurologic deficit. Patients who do not improve within one month should obtain magnetic resonance imaging if a herniated disc is suspected. Computed tomographic scanning is useful in demonstrating osseous structures and their relations to the neural canal, and for assessment of fractures. Bone scans can be used to determine the extent of metastatic disease throughout the skeletal system. All imaging results should be correlated with the patient's signs and symptoms because of the high rate of positive imaging findings in asymptomatic persons.     

Application of structure-metabolism relationships in the identification of a selective endothelin A antagonist, BMS-193884, with favourable pharmacokinetic properties

1. Based on binding affinity, 2'-amino-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1,1'-biphenyl]-2-sulfonamide (2) was identified as an initial lead in a programme to identify selective endothelin (ET) receptor antagonists. However, the compound was extensively metabolized in preclinical animal species and human in vitro systems due to oxidative biotransformation. 2. To optimize this structural class, the site of metabolism of 2 was determined. This allowed for focussed structure-activity and structure-metabolism studies aimed at finding more metabolically stable analogues that maintained potency. New analogues were screened for their ET binding characteristics and their stability in rat and human liver microsomes. 3. The use of the microsomal stability screen was tested by the determination of the pharmacokinetic parameters of select analogues. A good correlation was found between reduced rates of rat microsomal metabolism and reduced clearance in the rat. 4. N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (3) was identified as an analogue with improved in vitro properties and further studies revealed that the compound had improved pharmacokinetic properties. 5. N-[[2'-[[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]acetamide (4) was subsequently identified as a compound with superior in vitro properties compared with compound 3, but when tested in vivo it had a substantially increased rate of clearance. Further studies demonstrated that the clearance of this closely related structural analogue was not dictated by metabolic processes, but was mediated by transport-mediated direct biliary excretion. 6. The utility of screening for in vitro liver microsomal stability as part of the lead optimization process for compounds with metabolic liabilities was shown. It was also shown that relatively small molecular changes can dramatically change the disposition of closely related analogues and care must be used when screening for a single property.     

Psychiatric treatment in prison: a missed opportunity?

National Health Service Executive guidelines require psychiatric services to maintain links with prisoners previously subject to the Care Programme Approach (CPA) and to participate in discharge planning. We are unaware of previous studies assessing the involvement of general psychiatric services with patients in prison or prisoners' perceptions of their needs. Consecutive referrals to a prison psychiatric liaison service over a three-month period were screened for previous psychiatric contact. Half of those interviewed reported previous psychiatric contact. Two-thirds were in contact with services at the time of detention. One-third believed services knew of their imprisonment. Ninety-three per cent believed they would require psychiatric support after release. Few patients received input from general psychiatric services during imprisonment despite a high level of perceived need. Improved liaison would help facilitate both care in prison and discharge planning in the spirit of CPA and the government directive.