F. Rogers

EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice.

Upregulation and activation of developmental axon guidance molecules, such as semaphorins and members of the Eph receptor tyrosine kinase family and their ligands, the ephrins, play a role in the inhibition of axonal regeneration following injury to the central nervous system. Previously we have demonstrated in a knockout model that axonal regeneration following spinal cord injury is promoted in the absence of the axon guidance protein EphA4. Antagonism of EphA4 was therefore proposed as a potential therapy to promote recovery from spinal cord injury. To further assess this potential, two soluble recombinant blockers of EphA4, unclustered ephrin-A5-Fc and EphA4-Fc, were examined for their ability to promote axonal regeneration and to improve functional outcome following spinal cord hemisection in wildtype mice. A 2-week administration of either of these blockers following spinal cord injury was sufficient to promote substantial axonal regeneration and functional recovery by 5 weeks following injury. Both inhibitors produced a moderate reduction in astrocytic gliosis, indicating that much of the effect of the blockers may be due to promotion of axon growth. These studies provide definitive evidence that soluble inhibitors of EphA4 function offer considerable therapeutic potential for the treatment of spinal cord injury and may have broader potential for the treatment of other central nervous system injuries.

Developmental vitamin D (DVD) deficiency in the rat alters adult behaviour independently of HPA function

Developmental vitamin D deficiency (DVD) has been shown to alter the orderly pattern of brain development. Even though the period of vitamin D deficiency is restricted to gestation this is sufficient to induce behavioural abnormalities in the adult offspring consistent with those seen in many animal models of schizophrenia. Given that some of these behavioural alterations could also be an indirect result of either impaired maternal hypothalamic pituitary axis (HPA) function (which in turn could influence maternal care) or the result of a permanent alteration in HPA function in the adult offspring we have examined HPA status in both maternal animals and adult offspring. In this study we have established that HPA function is normal in the maternally vitamin D deficient rat. We replicate the behavioural phenotype of hyperlocomotion whilst establishing that HPA function is also unchanged in the adult male offspring. We conclude that the behavioural alterations induced by DVD deficiency are due to some adverse event in brain development rather than via an alteration in stress response.

Prenatal vitamin D Deficiency causes behavioural changes in adult offspring: Evidence of dopaminergic dysregulation

Background: A single-blind, multicentre RCT compared the class of new (non-clozapine) atypical drugs with clozapine in patients in the NHS whose medication was being changed because of poor clinical response to two or more antipsychoticdrugs.Methods: The primary outcome was the Quality of Life Scale. Secondary clinical outcomes included symptoms (PANSS), side effects and participant satisfaction. Economic outcomes were costs of health and social care and a utility measure. A total of 136 (98% of the planned sample) participants were randomised. Followup at 52 weeks, blind to treatment allocation, was complete in 87%.Results: The intent to treat comparison of new atypicals compared with clozapine in people with more narrowly defined treatment resistance showed an advantage for commencing clozapine in quality of life (QLS) at trend level ( p = 0.08) and insymptoms (PANSS), that was statistically significant ( p = 0.01), at 1 year. Clozapine showed approximately a 4-point advantage (not statistically significant) on QLS score at 52 weeks, against the predicted 10 points, and approximately a 5-point advantage on PANSS total score. Clozapine showed a trend towards having less total extrapyramidal side effects ( p = 0.1). Participants reported at 12 weeks that their mental health was significantly better with clozapine than with new atypicals ( p < 0.05). Net costs of care varied widely, with a mean of �33,588 in the clozapine group and �28,122 in the new atypical group, not a statistically significant difference. Of these costs, 4.0% and 3.3%, respectively, were dueto antipsychotic drug costs.Background/objective: Despite the high comorbidity of substance misuse and schizophrenia, few large scale British studies have looked at symptom profile and outcome in this population. The aim of this study was to use data on substance use among subjects with schizophrenia collected in a randomised controlled trial, validated for the purpose of this study, to see if there are differences between substance users and non users on a variety of outcome measures. Method: 1. A sample of subjects in the CUtLASS study were interviewed using the SCID to determine whether SCID-diagnosed substance misuse disorders corresponded to substance misuse categories generated in the CUtLASS study from casenote review. 2. Substance users were compared with non users on a variety of outcome measures. Results: 1. Two CUtLASS categories, no substance use and major substance use, could be validated against SCID diagnoses; the third category, minor use, could not be validated. 2. Substance misusers were more likely to be young men. There were no significant differences between users and non users for positive and negative symptoms, quality of life, number of previous hospitalisations, extrapyramidal side effects or medication compliance. Drug users were younger at age of first treatment than non users. Alcohol users had more depressive symptoms than non users. Substance users had more negative attitudes towards prescribed medication, although this effect disappeared when age and gender were controlled for. Non compliance was associated with more severe psychopathology, and a worse quality of life. Conclusion: Substance misuse did not seem to confer the adverse outcomes that previous studies suggest.Background/objective: There is accumulating evidence for an important role for vitamin D in brain function, including our recent observations that animals deprived of vitamin D in utero had brains that were altered in shape at birth, with increased cell proliferation and reduced levels of NGF and GDNF. In the current study we examined the hypothesis that vitamin D deficiency during two separate developmental periods alters adult behaviour. Methods: Rats were conceived and born to mothers receiving a vitamin D-deficient diet and housed without UV light. At birth, the litters were reduced to three males and three females and half the mothers were placed under normal vitamin D conditions whilst half remained under vitamin D deplete conditions. At weaning, all animals were fed the normal diet. Mothers, and all animals at weaning, were rendered normocalcaemic with calcium supplemented water (2 mM). Control animals were born to mothers fed a normal diet but subject to similar litter size and calcium supplementation. At 10 weeks, all animals were subject to the holeboard test, elevated plus maze test, social interaction, prepulse inhibition of the acoustic startle response and a forced swim test. Results: Early vitamin D deficiency selectively enhanced locomotion in the holeboard test and increased activity in the elevated plus maze. Thus, early vitamin D deficiency appeared to induce quite specific behavioural deficits in adulthood, without inducing severe learning or motor abnormalities. Conclusion: These observations are consistent with an increase in dopaminergic tone, a finding previously reported in vitamin D depleted animals.Background/objective: There is accumulating evidence for an important role for vitamin D in brain function, including our recent observations that animals deprived of vitamin D in utero had brains that were altered in shape at birth, with increased cell proliferation and reduced levels of NGF and GDNF. In the current study we examined the hypothesis that vitamin D deficiency during two separate developmental periods alters adult behaviour. Methods: Rats were conceived and born to mothers receiving a vitamin D-deficient diet and housed without UV light. At birth, the litters were reduced to three males and three females and half the mothers were placed under normal vitamin D conditions whilst half remained under vitamin D deplete conditions. At weaning, all animals were fed the normal diet. Mothers, and all animals at weaning, were rendered normocalcaemic with calcium supplemented water (2 mM). Control animals were born to mothers fed a normal diet but subject to similar litter size and calcium supplementation. At 10 weeks, all animals were subject to the holeboard test, elevated plus maze test, social interaction, prepulse inhibition of the acoustic startle response and a forced swim test. Results: Early vitamin D deficiency selectively enhanced locomotion in the holeboard test and increased activity in the elevated plus maze. Thus, early vitamin D deficiency appeared to induce quite specific behavioural deficits in adulthood, without inducing severe learning or motor abnormalities. Conclusion: These observations are consistent with an increase in dopaminergic tone, a finding previously reported in vitamin D depleted animals.Background: The subjective experience of patients with schizophrenia, receiving antipsychotic medication has been a neglected research area.Methods: In a randomised controlled trial comparing the impact of new atypical antipsychotic drugs versus clozapine, 67 out of 136 patients with schizophrenia were randomised to receive clozapine. Baseline and 12 week assessments included the PANSS, DAI, and the Kemp Compliance scale.Results: The greater percentage improvement in total PANSS scores in patients randomised to clozapine was statistically significant when compared to the atypical group at 12 weeks (p < 0.05). Patients? subjective rating of their mental health improvement since commencing clozapine treatment correlated significantly with actual percentage improvement in PANSS scores from baseline to week 12 (p < 0.01). Significant correlations were also observed between the patients? subjective rating of their mental health improvement and both DAI score and theg12 PANSS insight item (p < 0.05). In a regression analysis, DAI score at week 12 explained 26% of the variance in patients? subjective rating of mental health improvement with clozapine. Percentage PANSS improvement explained a further 8% of the variance.Conclusion: Patients in an RCT of clozapine versus atypicals were able to subjectively rate their own improved mental health status, validated by objective improvement on the PANSS. This was predicted by drug attitude as measured by the DAI. Subjective reports are a useful and valid outcome measure in drug treatment trials.Background: Conceptually quality of life is a broad term and consists of a sense of well-being, life satisfaction and access to resources and opportunities.Methods: A subjective quality of life measure, the Lancashire quality of life scale(Oliver, 1991) was compared with an objective measure, the Heinrichs quality of life scale (Heinrichs et al,1884) in 75 subjects entering a randomised controlled trial comparing conventional and new atypical antipsychotics and clozapine.Results: A significant correlation was found between the two scales (r = 0.386 p < 0.01). Determinants of subjective and objective quality of life were explored using multiple regression analyses. The main determinants of subjective quality of life were depression measured on the Calgary Scale, insight(Birchwood Scale) and nonneurological side-effects, which together explained 44% of the variance p < 0.01. Depression was responsible for 34% of this variance. In contrast, the main determinant of objective QLS were PANSS negative score and PANSS total score. These two together explained 51% of the variance with PANSS negative accounting for most 46% of this p < 0.01.Conclusion: The choice of subjective or objective quality of life measures is likely to reflect different dimensions of outcome,reflecting the underlying psychopathology of schizophrenia as opposed to measuring a discrete construct. A value judgement must therefore be made as to which of these measures best encapsulates what is meant by quality of life in schizophrenic illnesses.Edited by Glen Van Brummelen The purpose of this department is to give sufficient information about the subject matter of each publication to enable users to decide whether to read it. It is our intention to cover all books, articles, and other materials in the field. Books for abstracting and eventual review should be sent to this department. Materials should be sent to Glen Van Brummelen, Bennington College, Bennington, VT 05201, U.S.A. (E-mail: gvanbrum@bennington.edu) Readers are invited to send reprints, autoabstracts, corrections, additions, and notices of publications that have been overlooked. Be sure to include complete bibliographic information, as well as transliteration and translation for non-European languages. We need volunteers willing to cover one or more journals for this department. In order to facilitate reference and indexing, entries are given abstract numbers which appear at the end following the symbol #. A triple numbering system is used: the first number indicates the volume, the second the issue number, and the third the sequential number within that issue. For example, the abstracts for Volume 20, Number 1, are numbered: 20.1.1, 20.1.2, 20.1.3, etc. For reviews and abstracts published in Volumes 1 through 13 there are an author index in Volume 13, Number 4, and a subject index in Volume 14, Number 1. The initials in parentheses at the end of an entry indicate the abstractor. In this issue there are abstracts by Francine Abeles (Kean, NJ), Peter Bernhard (Erlangen, Germany), Herbert Kasube (Peoria, IL), Gary S. Stoudt (Indiana, PA), Kevin VanderMeulen (Hamilton, Canada), David Wallace (Glasgow, UK), and Glen Van Brummelen. Abgrall, Philippe. La Géométrie de l’Astrolabe au Xe Siècle, Arabic Sciences and Philosophy 10(1) (2000), 7–77. An analysis of treatises of al-Saganı̄, al-Qūhı̄, and Ibn Sahl dealing with the projection of the sphere on a plane applied to the construction of the astrolabe. See the review by Emilia Calvo in Mathematical Reviews 2001d:01005. (GSS) #28.4.1 Abraham, George. See #28.4.58. Abramovich, Y. A.; and Veksler, A. I. G. Ya. Lozanovsky: His Contributions to the Theory of Banach Lattices, in Henryk Hudzik and Leszek Skrzypczak, eds., Function Spaces, New York: Dekker, 2000, pp. 5–21. This description of Lozanovsky’s main results in the theory of Banach lattices also contains reflections on his personality and mathematical legacy, as well as a supplement to the papers listed in his obituary. (GVB) #28.4.2 Almgren, Frederick J., Jr. Selected Works of Frederick J. Almgren, Jr., edited by Jean E. Taylor, Providence, RI: American Mathematical Society, 1999, xlvi+586 pp.,

Local administation of EphA4-Fc fusion protein enhances axonal regeneration and improves motor function recovery in adult mice with spinal cord hemisection

105. This book contains a collection of the most significant “short” papers and expository and survey articles written by Frederick J. Almgren, Jr. See the review by Giandomenico Orlandi in Mathematical Reviews 2001f:01053. (HEK) #28.4.3 Amunategui, Godofredo Iommi. See #28.4.87. Andreozzi, Luciano. Vito Volterra as Scientific Organizer and the Origins of Mathematical Biology in Italy [in Italian], Nuncius 15(1) (2000), 79–109. Discusses Volterra’s organizational role in oceanographic studies from 1910 to 1925. (GVB) #28.4.4 Aouad, Maroun. See #28.4.61. Apostol, Tom M. A Centennial History of the Prime Number Theorem, in R. P. Bambah, V. C. Dumir, and R. J. Hans-Gill, eds., Number Theory, Basel: Birkhäuser, 2000, pp. 1–14. A survey article on the prime number 315 0315-0860/01

Investigating the role of kinase-dependent activation of EphA4 in spinal cord injury

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