Developmental expression of 2ar (osteopontin) and SPARC (osteonectin) RNA as revealed by in situ hybridization.

2ar has been identified as a gene inducible by tumor promoters and growth factors in a variety of cultured mouse cell lines (Smith, J. H., and D. T. Denhardt. 1987. J. Cell. Biochem. 34:13-22). Sequence analysis shows that it codes for mouse osteopontin, an RGDS-containing, phosphorylated, sialic acid-rich Ca++-binding protein originally isolated from bone (Oldberg, A., A. Franzen, and D. Heinegard. 1986. Proc. Natl. Acad. Sci. USA. 83:8819-8823; Prince, C. W., T. Oosawa, W. T. Butler, M. Tomana, A. S. Brown, and R. E. Schrohenloer. 1987. J. Biol. Chem. 262:2900-3907.). In this paper we use Northern blot analysis and in situ hybridization to localize expression of 2ar during mouse embryogenesis. 2ar RNA is first detected in developing limb bones and calvaria at 14.5 d p.c., in a population of cells distinct from those expressing SPARC (osteonectin). High levels of 2ar expression are also seen in the bone marrow-derived granulated metrial gland cells of the deciduum and placenta, and in a number of epithelial tissues, including embryonic and postnatal kidney tubules, uterine epithelium and sensory epithelium of the embryonic ear. The temporal and spatial pattern of 2ar expression seen in vivo suggests that the protein plays a wider role than previously realized, in processes which are not confined to bone development.

Processes of overall similarity sorting in free classification.

The processes of overall similarity sorting were investigated in 5 free classification experiments. Experiments 1 and 2 demonstrated that increasing time pressure can reduce the likelihood of overall similarity categorization. Experiment 3 showed that a concurrent load also reduced overall similarity sorting. These findings suggest that overall similarity sorting can be a time-consuming analytic process. Such results appear contrary to the idea that overall similarity is a nonanalytic process (e.g., T. B. Ward, 1983) but are in line with F. N. Milton and A. J. Wills's (2004) dimensional summation hypothesis and with the stochastic sampling assumptions of the extended generalized context model (K. Lamberts, 2000). Experiments 4 and 5 demonstrated that the relationship between stimulus presentation time and overall similarity sorting is nonmonotonic, and the shape of the function is consistent with the idea that the three aforementioned processes operate over different parts of the time course.

Oculopharyngeal muscular dystrophy: a point mutation which mimics the effect of the PABPN1 gene triplet repeat expansion mutation.

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late onset neuromuscular disease characterised by proximal muscle weakness, ptosis, and swallowing difficulty. The only causative mutation described to date is a triplet repeat expansion consisting of two to seven additional base triplets in a repeat sequence in exon 1 of the polyadenine binding protein nuclear 1 (PABPN1) gene. This results in an increase in length of a polyalanine tract in the PABPN1 protein from 10 to 12-17 residues. OBJECTIVE: Description of another mutation in a case of OPMD. METHODS: Sequence analysis of exon 1 of the PABPN1 gene was undertaken on 202 patients referred for a possible diagnosis of OPMD but negative for the triplet repeat expansion mutation. RESULTS: A case was identified with typical symptoms of OPMD, negative for the repeat expansion mutation but with a missense mutation in PABPN1 close to the 3' end of the normal polyalanine codon repeat sequence. CONCLUSIONS: The single base mutation changes a glycine codon to an alanine codon and results in an increase in the number of contiguous polyalanine codons. This mimics the effect of the common triplet repeat expansion mutation and represents a previously undescribed mechanism of mutation.

Does maintenance of colour categories rely on language? Evidence to the contrary from a case of semantic dementia.

Recent neuropsychological evidence, supporting a strong version of Whorfian principles of linguistic relativity, has reinvigorated debate about the role of language in colour categorisation. This paper questions the methodology used in this research and uses a novel approach to examine the unique contribution of language to categorisation behaviour. Results of three investigations are reported. The first required development of objective measures of category coherence and consistency to clarify questions about healthy control performance on the freesorting colour categorisation task used in previous studies. Between-participant consistency was found to be only moderate and the number of colour categories generated was found to vary markedly between individuals. The second study involved longitudinal neuropsychological examination of a patient whose colour categorisation strategy was monitored in the context of a progressive decline in language due to semantic dementia. Performance on measures of category coherence and consistency was found to be relatively stable over time despite a profound decline in the patient's colour language. In a final investigation we demonstrated that, for both the patient and controls, between- and within-participant consistency were higher than expected by (a) random sorting and (b) sorting perceptually similar chips together. These findings indicate that the maintenance of colour categorisation need not depend on language.

Respiratory involvement in inherited primary muscle conditions.

Patients with inherited muscle disorders can develop respiratory muscle weakness leading to ventilatory failure. Predicting the extent of respiratory involvement in the different types of inherited muscle disorders is important, as it allows clinicians to impart prognostic information and offers an opportunity for early interventional management strategies. The approach to respiratory assessment in patients with muscle disorders, the current knowledge of respiratory impairment in different muscle disorders and advice on the management of respiratory complications are summarised.

2-Aminopurine abolishes EGF- and TPA-stimulated pp33 phosphorylation and c-fos induction without affecting the activation of protein kinase C.

Epidermal Growth Factor (EGF) and Tetradecanoyl Phorbol Acetate (TPA) initiate signalling cascades in C3H 10T1/2 fibroblasts by primarily activating distinct protein kinases, the EGF receptor tyrosine kinase and protein kinase C respectively; there is no signal crossover at the initiation of signalling. Nevertheless, we show here that both agents rapidly elicit common intracellular responses, including the phosphorylation of complexed and chromatin-associated forms of a 33 kDa phosphoprotein (pp33), that of a 15 kDa chromatin-associated phosphoprotein (pp15), as well as the transcriptional activation of a common subset of genes including the c-fos proto-oncogene. 2-aminopurine specifically abolishes complexed and chromatin-associated pp33 phosphorylation in response to EGF and TPA, as well as the induction of c-fos by both agents. The activation of protein kinase C and the levels of transcription factors that bind to the serum response element (SRE), TPA response element (TRE) or NFkB sites in stimulated cells are relatively unaffected by 2-aminopurine. This, to our knowledge, is the first demonstration that it is possible, by using 2-aminopurine which selectively blocks TPA-stimulated pp33 phosphorylation, to block c-fos induction in TPA-treated cells although protein kinase C remains fully active. Further, we show here that although EGF- and TPA-stimulated induction of c-fos is abolished by 2-aminopurine, the appearance of TRE-binding activity in nuclear extracts of stimulated cells is unaffected, suggesting that EGF- and TPA-stimulated induction of TRE-binding activity utilises existing proteins and is not dependent on fresh c-FOS synthesis. These results imply that 2-aminopurine-sensitive complexed and chromatin-associated pp33 phosphorylation may be crucial to c-fos induction in response to EGF and TPA.

Characterization of the mouse met proto-oncogene.

The DNA sequence of cDNA clones prepared from transcripts of the mouse met proto-oncogene reveals that the mouse met gene encodes a 1380 amino acid protein with the characteristics of a growth factor receptor. This protein can be divided into several putative domains, including an intracellular protein tyrosine kinase domain, a transmembrane domain and a 929 amino acid extracellular domain, possessing a potential proteolytic cleavage site with the sequence Lys-Arg-Arg-Lys-Arg-Ser. To gain additional insights into the function of the met protein we have examined the level of met transcripts in tissues of the late-gestation mouse conceptus. Transcription of met was observed in most of the tissues analysed, but the highest levels of met mRNA were detected in the yolk sac, amnion and kidney; no transcripts were detectable in the calvaria. Chromosomal localization using a series of mouse-hamster hybrid cell lines has demonstrated that met is located on mouse chromosome 6.

Involvement of AP1 and PEA3 binding sites in the regulation of murine tissue inhibitor of metalloproteinases-1 (TIMP-1) transcription.

Transcription of tissue inhibitor of metalloproteinases-1 (TIMP-1), a secreted protein that regulates the activities of the metalloproteinases, collagenase and stromelysin, is activated by serum growth factors. Transient transfection experiments have revealed several regions of cis-acting regulatory sequences involved in the response of the murine TIMP-1 gene to serum. One area is in the vicinity of the promoter, consisting of a non-consensus binding site (5'-TGAGTAA-3' at -59/-53) for transcription factor AP1 and an adjacent 24 bp region of dyad symmetry that contains a PEA3-binding site. A second is an upstream region (-1020 to -780) that acts as an enhancer when linked to a heterologous promoter, and contains a consensus AP1 binding site (at -803/ -797). Gel retardation assays revealed differences between nuclear factors in mouse C3H10T1/2 cells that bound to the TIMP(-59/ -53)AP1 site and a consensus collagenase TRE (TPA-response element). The TIMP(-59/ -53)AP1 site is a promiscuous motif that binds c-Fos/c-Jun AP1 translated in vitro and is an effective competitor for binding of nuclear AP1 factors to the consensus TRE, but in addition it binds factors that do not associate with the consensus TRE. The TIMP(-59/ -53)AP1 motif and the dyad symmetry region stimulated expression from a thymidine kinase promoter in an additive fashion, and competition experiments showed that excess copies of these factor binding sites reduced expression from a reporter plasmid driven by the TIMP-1 promoter. Our data show that binding sites for AP1 and PEA3 transcription factors are involved in the regulation of TIMP-1 transcription, which suggests that the coordinated induction of TIMP-1, collagenase and stromelysin may be achieved through the actions of a shared set of nuclear transcription factors. However, the properties of the TIMP-1(-59/ -53)AP1 motif likely reflect an additional type of transcriptional regulation restricted to TIMP-1.

Thymectomy in myasthenia gravis: comparison of outcome in Santiago, Cuba and Nottingham, UK.

OBJECTIVES: We compared the outcome of thymectomy for myasthenia gravis (MG) in two healthcare systems. In Nottingham, UK, thymectomy is performed for thymic enlargement and considered in acetylcholine receptor (AchR) antibody positive patients. In Santiago, Cuba, thymectomy is considered in all generalised MG patients irrespective of their radiological findings or AchR antibodies. METHOD: 22 MG patients in Nottingham and 75 in Santiago who had a thymectomy were identified and their notes reviewed. We compared the median age, stage of disease, thymic histology and clinical outcome at two years post-thymectomy. RESULTS: The median ages for the Cuban and Nottingham patients were 25 and 35 years respectively. The median stage of disease was IIa by Osserman's classification in both. In Nottingham, 59% (13/22) showed an improvement compared with 88 % (66/75) in Santiago (p < 0.01). There were significantly more cases of thymoma in Nottingham whereas thymic hyperplasia and atrophy were a more frequent finding in Cuban patients. The majority of cases who improved post-thymectomy had thymic hyperplasia on histology in both Nottingham (46%) and Cuban (61%) patients. CONCLUSION: Selecting MG patients based on thymic enlargement alone or AchR antibody positivity may be inadequate and thymectomy should perhaps be considered in all patients with generalised myasthenia.

The outcome specificity of learned predictiveness effects: parallels between human causal learning and animal conditioning.

Two experiments examined the outcome specificity of a learned predictiveness effect in human causal learning. Experiment 1 indicated that prior experience of a cue-outcome relation modulates learning about that cue with respect to a different outcome from the same affective class but not with respect to an outcome from a different affective class. Experiment 2 ruled out an interpretation of this effect in terms of context specificity. These results indicate that learned predictiveness effects in human causal learning index an associability that is specific to a particular class of outcomes. Moreover, they mirror demonstrations of the reinforcer specificity of analogous effects in animal conditioning, supporting the suggestion that, under some circumstances, human causal learning and animal conditioning reflect the operation of common associative mechanisms.

A positron emission tomography study of cerebral activation associated with essential and writing tremor.

OBJECTIVE: To compare the abnormal patterns of cerebral activation associated with essential and writing tremors. DESIGN: Positron emission tomography using oxygen 15-labeled water was utilized to determine regional cerebral blood flow. Positron emission tomography images that were taken of the brain in individual patients were coregistered with magnetic resonance images of the same brain to ascertain accurate localization of cerebral activation in single patients. Patients with essential tremor underwent scanning at rest, during involuntary postural tremor, and during passive wrist oscillation. Normal control subjects underwent scanning at rest and during voluntary and passive wrist oscillation. Patients with writing tremor underwent scanning while they were holding a pen to paper with consequent involuntary tremor and again while they were holding a pen in the same supinated arm without tremor. SETTING: Research hospital. PATIENTS OR OTHER PARTICIPANTS: Seven patients with essential tremor, six patients with writing tremor, and six matched control subjects. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Regional cerebral blood flow. RESULTS: Essential tremor was associated with abnormal bilateral cerebellar, red nuclear, and thalamic activation. Writing tremor was also associated with abnormal bilateral cerebellar activation. Voluntary wrist oscillation in control subjects caused only ipsilateral cerebellar activation. These findings were evident in single patients, when positron emission tomography images were coregistered with magnetic resonance images and on group analysis of the pooled positron emission tomography data after transformation into stereotaxic space. CONCLUSION: These results indicate that both essential and writing tremors are associated with abnormal bilateral overactivity of cerebellar connections.

A positron emission tomography study of primary orthostatic tremor.

Primary orthostatic tremor (OT), a clinical syndrome in which a rapid (14 to 16 Hz), regular lower limb tremor causes unsteadiness on standing, may be associated with a postural upper limb tremor of similar frequency. We used H2 15O PET to analyze the abnormal pattern of cerebral activation associated with the postural upper limb tremor in four patients with primary OT. Patients had regional cerebral bloodflow (rCBF) measured during involuntary tremor while maintaining a posture with their outstretched right upper limb and again at rest. Tremor was associated with abnormal bilateral cerebellar and contralateral lentiform and thalamic activation. These findings were evident on group analysis of pooled PET data after transformation into standard stereotactic space and in single subjects when PET images were coregistered with structural MRI of the brain. At rest, cerebellar blood flow was significantly increased bilaterally in OT when compared with age- and sex-matched controls. We have previously demonstrated similar abnormal bilateral cerebellar activation in essential and writing tremors and conclude that abnormal bilateral overactivity of cerebellar connections is a common feature of tremulous disorders.

The influence of stimulus properties on category construction.

It has been demonstrated that when people free classify stimuli presented simultaneously in an array, they have a preference to categorize by a single dimension. However, when people are encouraged to categorize items sequentially, they sort by "family resemblance," grouping by overall similarity. The present studies extended this research, producing 3 main findings. First, the sequential procedure introduced by G. Regehr and L. R. Brooks (1995) does not always produce a preference for family resemblance sorts. Second, sort strategy in a sequential procedure is sensitive to subtle variations in stimulus properties. Third, spatially separable stimuli evoked more family resemblance sons than stimuli of greater spatial integration. It is suggested that the family resemblance sorting observed is due to an analytic strategy.

Urgent 2-week referrals for CNS/brain tumours: a retrospective audit.

OBJECTIVE: To assess the effectiveness of the 2-week referral system for CNS/brain tumours and to contrast this with the number of patients with neurological cancers identified independently of this system. METHOD: Retrospective casenote review of patients referred to emergency neurology clinics pre-implementation of the 2-week referral system. Retrospective review of GP referral letters via this system and comparison to Department of Health referral guidelines. Review of corresponding casenotes to determine the actual neurological diagnosis. Identification of patients with CNS/brain tumours diagnosed independently of this system from a local CNS cancer register. RESULTS: Over a 3-month period pre-implementation of the referral system, of 12 patients referred as emergencies, none had CNS/brain cancer. Forty-three patients were referred via this system over a 9-month period to neurology departments of a teaching hospital and a district general hospital. Thirty per cent of the referrals did not follow the Department of Health guidelines. Only 9% actually had CNS tumours (two astrocytomas, two cerebral metastases). The remainder were diagnosed with chronic daily headache (10), epilepsy (5), migraine (3), demyelination (2), essential tremor (2), other (17). During this period at least 69 neurological cancers were identified independently of the 2-week system. CONCLUSION: These guidelines may increase diagnostic precision if adhered to rigidly. Inappropriate referrals have extended already lengthy outpatient waiting times in other specialities. We suggest early re-consideration of these guidelines and further study for earlier identification of CNS cancer.

Effective strategies in the management of Parkinson's disease.

With the emergence of new pharmacological agents and the resurrection of stereotactic neurosurgery, management of Parkinson's disease has become complex. This article reviews the available and emerging treatments. The value of ancillary services, e.g. physiotherapy, occupational and speech therapy, uroneurology and a multidisciplinary approach are self-evident and will not be discussed.

Modeling human sequence learning under incidental conditions.

This research explored the role that associative learning may play in human sequence learning. Two-choice serial reaction time tasks were performed under incidental conditions using 2 different sequences. In both cases, an experimental group was trained on 4 subsequences: LLL, LRL, RLR, and RRR for Group "Same" and LLR, LRR, RLL, and RRL for Group "Different," with left and right counterbalanced across participants. To control for sequential effects, we assayed sequence learning by comparing their performance with that of a control group, which had been trained on a pseudorandom ordering, during a test phase in which both experimental and control groups experienced the same subsequences. Participants in both groups showed sequence learning, but the group trained on "different" learned more and more rapidly. This result is the opposite that predicted by the augmented simple recurrent network used by F. W. Jones and I. P. L. McLaren (2009, Human sequence learning under incidental and intentional conditions, Journal of Experimental Psychology: Animal Behavior Processes, Vol. 35, pp. 538-553), but can be modeled using a reparameterized version of this network that also includes a more realistic representation of the stimulus array, suggesting that the latter may be a better model of human sequence learning under incidental conditions.

Syntactic transfer in artificial grammar learning.

In an artificial grammar learning (AGL) experiment, participants were trained with instances of one grammatical structure before completing a test phase in which they were required to discriminate grammatical from randomly created strings. Importantly, the underlying structure used to generate test strings was different from that used to generate the training strings. Despite the fact that grammatical training strings were more similar to nongrammatical test strings than they were to grammatical test strings, this manipulation resulted in a positive transfer effect, as compared with controls trained with nongrammatical strings. It is suggested that training with grammatical strings leads to an appreciation of set variance that aids the detection of grammatical test strings in AGL tasks. The analysis presented demonstrates that it is useful to conceptualize test performance in AGL as a form of unsupervised category learning.