CLN -encoded proteins do not interact with each other

The lysosomal storage of lipofuscins is the common pathological feature that characterizes the infantile, late-infantile, juvenile (Batten's disease), and Finnish-variant neuronal ceroid lipofuscinosis (INCL, LINCL, JNCL and FNCL), which are due to mutations in the genes CLN1 , CLN2 , CLN3 , and CLN5 , respectively. The CLN1 and CLN2 genes encode lysosomal enzymes, but the CLN3 and CLN5 genes encode membrane-spanning proteins. Why deficiencies of lysosomal enzymes and membrane-spanning proteins produce similar clinical phenotypes and pathological changes is still unanswered. We hypothesize that CLN -encoded proteins may comprise a functional pathogenic pathway, in which protein associations may play important roles. To test this hypothesis, we studied protein-protein interactions among the CLN1 -, CLN2 -, and CLN3 -encoded proteins using a yeast two-hybrid system. Our results provided no evidence that CLN -encoded proteins interact with each other. This suggests there may be unidentified components in NCL pathogenesis. Received: December 1, 1999 / Accepted: February 2, 2000 / Published online: May 9, 2000     

Evidence for allelic association of the dopamine β-hydroxylase gene (<Emphasis Type="Italic">DBH</Emphasis>) with susceptibility to typical migraine

Migraine is a debilitating neurological disorder characterized by recurrent attacks of severe headache. The disorder is highly prevalent, affecting approximately 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the type and number of genes involved is not yet clear. However, the calcium channel gene, CACNA1A , on chromosome 19 contains mutations responsible for familial hemiplegic migraine, a rare and severe subtype of migraine. There is also evidence to suggest that serotonin- and dopamine-related genes may be involved in the pathogenesis of migraine. This study employed a linkage and association approach to investigate neurotransmitter-related migraine candidate genes. Polymorphisms within the dopamine beta-hydroxylase ( DBH ) gene, serotonin transporter gene ( SERT ), and dopamine receptor gene ( DRD2 ) were tested in 177 unrelated Caucasian migraineurs and 182 control individuals. In addition, an independent sample of 82 families affected with migraine was examined. Unrelated case-control association analysis of a DBH intragenic dinucleotide polymorphism indicated altered allelic distribution between migraine and control groups (χ ² =16.53, P =0.019). Furthermore, the transmission/disequilibrium test, which was implemented on the family data, also indicated distortion of allele transmission for the same DBH marker (χ ² =4.44, P =0.035). Together, these results provide evidence for allelic association of the DBH gene with typical migraine susceptibility (Fisher's combined P value=0.006) and indicate that further research into the role of the DBH gene in the etiology of migraine is warranted. Received: February 14, 2000 / Accepted: July 12, 2000 / Published online: September 15, 2000     

A novel mutation in the predicted TM2 domain of the presenilin 2 gene in a Spanish patient with late-onset Alzheimer's disease

Mutations in the presenilin-2 ( PS-2 ) gene are less frequent than mutations in the PS-1 gene. All mutations described in the PS-1 gene were found in early-onset Alzheimer's disease (AD) patients. At present, there are two missense mutations described for the PS-2 gene in some AD pedigrees. We have therefore analyzed transmembrane 2 (TM2) and TM5 domains of the PS-2 gene in AD patients and in a group of age-matched healthy controls. In a patient who was clinically diagnosed as having late-onset AD, we found a novel missense mutation consisting of a G- 1 A substitution on exon 5 of the PS-2 gene, which results in a Val to Ile substitution at codon 148 within the predicted TM2 domain of the PS-2 protein. This is the third mutation described in the PS-2 gene and the first presenilin mutation detected in a Spanish AD patient. Both, the N141I mutation and the V148I mutation described here are located within the predicted TM2 domain and both were found in late-onset AD kindreds, whereas the mutation within the predicted TM5 domain was found in an early-onset AD pedigree. Carriers of mutations within TM2 of PS-1 have a mean age at onset of 40 years, while the other mutations in PS-1 occur in families with a mean age at onset of 47 years. In summary, we report here the first mutation in a presenilin gene in a Spanish AD case, which is the third mutation detected for the PS-2 gene. Received: March 6, 1998 / Accepted: May 13, 1998     

The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene

Most cases of Friedreich ataxia (FRDA) are due to expansions of a GAA trinucleotide repeat sequence in the FRDA gene coding for frataxin, a protein of poorly understood function which may regulate mitochondrial iron transport. However, between 1% and 5% of mutations are single base changes in the sequence of the FRDA gene, causing missense, nonsense, or splicing mutations. We describe three new mutations, IVS4nt2 (T to G), R165C , and L182F , which occur in patients in association with GAA expansions. These cases, and a further five reported cases of point mutations causing FRDA, demonstrate that splicing, nonsense, or initiation codon mutations (which cause a complete absence of functional frataxin) are associated with a severe phenotype. Missense mutations, even in highly evolutionally conserved amino acids, may cause a mild or severe phenotype. Received: March 24, 1998 / Accepted: May 28, 1998     

A comparative optical aggregometry study of antiplatelet activity of taxanes from Taxus cuspidata

Platelets are highly reactive components of the circulatory system. The cytoskeleton of a platelet is an important structure for platelet aggregation as stimulated by several agonists. An anticancer agent, taxol, has been suggested to exert platelet anti-aggregating activity by stabilizing microtubules during the aggregation process. An activity-guided fractionation was performed with a methanol extract of the leaves and twigs of Taxus cuspidata to isolate taxanes with platelet anti-aggregating effects. Compounds 1 to 7 – taxinine (1), taxinine A (2), taxinine B (3), 2-deacetoxytaxinine B (4), taxacin (5), taxchinin B (6), and taxol (7) – were obtained as the antiplatelet components of this plant. These taxane compounds present the possibility of securing new antiplatelet compounds which differ from currently available antiplatelet agents in chemical structure and possibly in mechanisms of action. All compounds showed stronger inhibitory effects than acetylsalicylic acid (ASA) on platelet aggregation induced by arachidonic acid (AA) (IC₅₀: 14.4, 64.5, 35.5, 16.0, 21.9, 28.6 and 48.2 versus 63.0 μM) or U46619 (IC₅₀: 34.8, 24.9, 36.2, 35.0, 46.9, 71.9 and 68.7 versus 340 μM). Compounds 1, 3, 4 and 5, with a cinnamoyl group at the C₅ position, showed strong inhibitory effects against AA-induced aggregation compared to compound 2 (with an -OH group at C₅) or compounds with an oxetane ring at C₄,₅, such as compounds 6 and 7. All of the seven compounds were 5–13-fold more strongly inhibitory than ASA against U46619-induced aggregation.     

Genomic structure of human anion exchanger 3 and its potential role in hereditary neurological disease

Alterations in ion channel permeability or selectivity have been shown to cause neurological defects in humans. Anion exchanger isoform 3 (AE3) is prominently expressed in the brain and performs an electroneutral exchange of chloride and bicarbonate ions. In order to study the potential role of AE3 in human neurological disease, we characterized AE3 genomic structure and performed mutational analysis on patients with an episodic movement disorder that maps to the same genetic locus. AE3 genomic organization, including the nucleotide sequence of the 5′-untranslated region and intron/exon boundaries, is highly conserved between humans and homologs from mouse and rat. Mutational analysis revealed no disease-causing defect in patients with familial paroxysmal dyskinesia, although several benign polymorphisms were identified. AE3 variation may prove useful for further genetic studies, such as finer resolution mapping. Characterization of genomic structure will facilitate mutational analysis of AE3 in studies of neurological diseases mapped to the same locus. Accepted: May 12, 1998     

SMARTER goal setting in aphasia rehabilitation

Background: There have been numerous calls for rehabilitation professionals to involve patients or clients in decisions about the goals of therapy. And yet collaborative goal setting in rehabilitation remains uncommon and is particularly difficult to achieve for people with aphasia.

Aims: This discussion paper describes a new framework for conceptualising and structuring collaborative goal setting in aphasia rehabilitation. The framework has been developed based on the results of a large, multi-centred Australian study, the Goals in Aphasia Project, which explored client, family, and speech pathology experiences of rehabilitation goal setting. This framework, called SMARTER Goal Setting, describes a process of goal setting that is Shared, Monitored, Accessible, Relevant, Transparent, Evolving and Relationship-centred.

Methods & Procedures: The methods and results from the Goals in Aphasia Project have already been published elsewhere but involved in-depth interviews with 50 people with aphasia, 48 family members, and 34 treating speech pathologists. This paper reviews the broader literature and summarises relevant findings from the Goals in Aphasia Project as a basis for discussion of each category of SMARTER.

Outcomes & Results: Our new SMARTER framework both challenges and complements elements of the pervasive SMART goal paradigm (that goals should be Specific, Measurable, Achievable, Realistic and Time-bound), which currently dominates rehabilitation goal setting. SMARTER offers an easy way to summarise much of the collaborative work that already takes place in clinical practice but also emphasises aspects that could be improved. SMARTER does not replace SMART, but we suggest that SMART goals can be negotiated in a SMARTER way.

Conclusions: While this paper discusses SMARTER goal setting within aphasia rehabilitation, a particularly challenging context for the implementation of collaborative practice, it may be applicable to rehabilitation more broadly. Given that person-centred goal setting within stroke rehabilitation remains infrequent, we suggest that there is an urgent need to raise awareness of its importance and challenge current practice. The SMARTER framework provides a useful structure to support collaborative goal setting.     

Identification of a novel missense mutation of the SMN T gene in two siblings with spinal muscular atrophy

Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations in the telomeric copy of the survival motor neuron ( SMN ^T ) gene. Over 90% of SMA patients harbor a deletion of SMN ^T , but relatively few base-pair mutations have been reported. We report here a novel G279C mutation with a G to T transversion on exon 7 (nucleotide position 868) of SMN ^T . Another missense mutation has been reported recently on position 869. The fact that two mutations on the same codon both result in SMA suggest a functional significance of this amino acid within the SMN protein. Accepted: 19 March 1998     

An Evaluation of Operant Behavioural Economics in Functional Communication Training for Severe Problem Behaviour

ABSTRACT

Objective: This single-case experiment examined the use of behavioural economic concepts in a function-based treatment for problem behaviour.

Methods: Behavioural economic analyses were used to evaluate the strength of functions of problem behaviour and this information was used to inform elements of function-based treatment for one child with a neurodevelopmental disorder.

Results: Findings from this experiment indicated that the incorporation of behavioural economic measures resulted in positive treatment effects that were maintained throughout all phases of the evaluation, including those implemented by caregivers.

Conclusions: These results suggest that behavioural economic concepts and procedures can be successful adjuncts to evidence-based assessments and treatments for problem behaviour.     

Risk factors for negative experiences during psychotherapy

Background: It is estimated that between 3% and 15% of patients have a negative experience of psychotherapy, but little is understood about this. Aims: The aim of this study was to investigate the factors associated with patients’ negative therapy experiences. Method: The data comprised 185 patient and 304 therapist questionnaires, 20 patient and 20 therapist interviews. Patients reported on an unhelpful or harmful experience of therapy, and therapists on a therapy where they thought the patient they were working with had a poor or harmful experience. These were transcribed and analysed using thematic analysis. Results: There was a Lack of fit between Patient needs, Therapist skills, and Service structures. This could result in Fault Lines, a tension between Safety and containment and Power and control. This tension led to Strain and Poor Engagement, which led to Consequences following the negative therapy experience. Conclusions: Patients require clear information, choice, involvement in decision-making, explicit contracting and clarity about sessions and progress. Opportunities for patient feedback should be the norm, where the therapist and service are vigilant for signs of deterioration and solutions considered.

Clinical and methodological significance of this article: Estimates of “unwanted effects,” including long-lasting effects, of psychotherapy have ranged from 3% to 15%. Few empirical studies have been conducted in this area. This study aimed to address this gap and provide clinicians with a model of risk factors for negative therapy effects. The findings of this study indicate the importance of providing patients with a supportive service structure that offers clear information, choice and involvement in decision-making. Explicit contracting at the beginning of therapy and clarity about sessions and progress are also important in managing patient expectations throughout. Opportunities for patient feedback should be provided.     

Paroxysmal sympathetic storm

Introduction: Paroxysmal sympathetic storm (PSS) is a rare syndrome characterized by episodic hypertension, hyperhydrosis, hyperthermia, tachycardia, tachypnea, and extensor posturing. Case reports: This article describes two cases of PSS: one following traumatic brain injury and the other following cardiac arrest. Discussion: The first responded to labetalol, morphine, and codeine, whereas the second responded to labetalol. Conclusion: These observations underscore the importance of central opioid receptors and nonselective β-adrenergic antagonists in modulating catecholamine pathways     

The parental origin of new mutations in neurofibromatosis 2

Neurofibromatosis 2 (NF2) is an autosomal dominant disorder characterized by schwannomas and meningiomas that develop after inactivation of both copies of the NF2 gene. Approximately half of all patients with NF2 have unaffected parents and the disease results from new mutations at the NF2 locus. Loss of heterozygosity (LOH) in tumor specimens due to deletions covering the normal NF2 allele can be used to infer the haplotypes surrounding underlying mutations and determine the allelic origin of new mutations. We studied 71 sporadic NF2 patients using both LOH and pedigree analysis and compared the parental origin of the new mutation with the underlying molecular change. In the 45 informative individuals, 31 mutations (69%) were of paternal and 14 (31%) were of maternal origin ( P =0.016). Comparison with corresponding constitutional mutations revealed no correlation between parental origin and the type or location of the mutations. However, in 4 of 6 patients with somatic mosaicism the NF2 mutation was of maternal origin. A slight parent of origin effect on severity of disease was found. Further clinical and molecular studies are needed to determine the basis of these unexpected observations. Received: December 21, 1999 / Accepted: February 28, 2000 / Published online: May 9, 2000     

Angelman syndrome: how many genes to remain silent?

The clinical features of Angelman syndrome (AS) include microcephaly, severe mental retardation, "puppet-like" ataxic gait with jerky arm movements, hyperactivity, bouts of inappropriate laughter, EEG abnormalities, and seizures. The frequency of occurrence of AS is in the range of 1/10,000 to 1/20,000 births. The AS locus maps to the imprinted chromosome 15q11-q13 region and the disease is caused by the absence of a normal maternal contribution to this region. The genetic complexity of AS is revealed by the existence of at least four molecular classes. A candidate AS gene, ubiquitin protein ligase 3A ( UBE3A/E6-AP ), has been identified, and mutations of this gene have been detected in several cases of AS. Moreover, UBE3A is expressed predominantly from the maternal allele in brain, strongly supporting its causative role in AS. However, there is evidence to suggest that, in addition to UBE3A , another gene(s) may be involved either directly in AS and/or indirectly by regulating UBE3A expression. Received: March 13, 1998 / Accepted: April 8, 1998     

Chronic hallucinatory psychosis, <Emphasis Type="Italic">Bouffée Délirante</Emphasis>, and the classification of psychosis in French psychiatry

The conflict between French nosology and international classifications is mainly linked to the French concepts of chronic hallucinatory psychosis and bouffée délirante. However, these discrepancies are now largely reduced by the evolution of the recent versions of international classifications. The term chronic hallucinatory psychosis is used to describe a chronic hallucinatory and delusional disorder that differs from paranoid schizophrenia in the absence of formal thought disorder and intellectual impairment. This concept appears to be quite similar to paranoid schizophrenia as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Disease (ICD). However, the recent statement that deficit and nondeficit schizophrenia are separate diseases rediscovered French distinctions between chronic hallucinatory psychosis and schizophrenia. The term bouffée délirante describes an acute nonaffective and nonschizophrenic psychotic disorder, which is largely similar to DSM-III-R and DSM-IV brief psychotic and schizophreniform disorders, and was taken up in ICD-10 under the name acute polymorphic psychotic disorder.     

Implication of core beliefs about negative-self in neuroticism

Abstract

Objective: Core beliefs about negative-self are beliefs about self-deficiencies in basic aspects of human adaptation. Meanwhile, neuroticism is a personality trait characterised by negative emotionality, i.e., a tendency to react to stress with negative emotions. The present study tested the hypothesis that core beliefs about negative-self are implicated in neuroticism.

Methods: The subjects were 309 Japanese healthy volunteers. Core beliefs about negative-self were evaluated by the Brief Core Schema Scales, and neuroticism was evaluated by the NEO Personality Inventory-Revised.

Results: In both multiple regression analysis and structural equation modelling, higher neuroticism was strongly predicted by higher levels of core beliefs about negative-self.

Limitations: The present study cannot determine the causal relationship between core beliefs about negative-self and neuroticism, because of its cross sectional design.

Conclusions: The present study suggests that core beliefs about negative-self are deeply implicated in neuroticism.

• Key Points

• Implication of core beliefs about negative-self in neuroticism was examined.

• Neuroticism was predicted by higher levels of these core beliefs.

• These core beliefs may be involved in negative emotionality of neuroticism.

     

Opiate Disruption of Maternal Behavior: Morphine Reduces, and Naloxone Restores, c-fos Activity in the Medial Preoptic Area of Lactating Rats

Morphine significantly impairs maternal behavior; naloxone, an opiate antagonist, restores it. Maternal behavior is associated with c-fos expression, an immediate early gene product, in the medial preoptic area (mPOA) of females. In two experiments, the effects of morphine-alone and morphine plus naloxone on the expression of c-fos were examined. On postpartum day 5, females were injected with morphine or saline (experiment 1), and morphine + naloxone or morphine + saline (experiment 2) and placed back in the home-cage, separated from their pups by a wire-mesh partition. A separate group in experiment 1 was injected but not exposed to pups. Processing for c-fos immunohistochemistry commenced, and c-fos positive cells in a proscribed portion of mPOA were counted. Morphine-treated females had fewer c-fos cells in mPOA compared to saline-treated females, and the presence of pups accounted for a significant increase in c-fos-expressing neurons, whereas in females not exposed to pups, morphine treatment did not significantly reduce baseline c-fos expression (experiment 1). Furthermore, naloxone mitigated the effect as morphine + naloxone-treated females expressed more c-fos cells compared to morphine + saline females (experiment 2). Morphine-treated females, therefore, may exhibit reductions in maternal behavior because of relative opiate-induced inactivation of areas of the brain devoted to the regulation of maternal behavior.     

Circadian genes in major depressive disorder

Abstract

Background: Sleep disturbances are a common symptom of major depressive disorder (MDD). Sleep is highly regulated by circadian rhythms, controlled by circadian genes, that act through a series of feedback loops to regulate the sleep-wake cycle.

Objectives: To the best of our knowledge, a systematic review regarding the core circadian genes and their role in MDD has not been published recently. Also, a review of these genes and their role in sleep disturbances in depressed individuals appears to have never been done. We decided to integrate both concepts into one comprehensive review.

Method: The review was done using the appropriate search terms in the following search engines: OVID Medline, Embase, PsycINFO and Pubmed.

Results: Based on the data reviewed, none of the circadian genes appear to be associated with MDD, but some are more promising than others. These genes are: CRY1, CRY2, PER2 and NPAS2. When investigating the role of circadian genes in sleep disturbances among individuals with MDD, the most promising candidate gene is TIMELESS. Although the results in this area are limited.

Conclusion: Given the promising leads from this review, future studies should investigate circadian genes in sleep disturbances among the depressed population.     

Interpretations of ambiguous social situations and cardiovascular responses in adolescents

Background: Previous research has documented effects of ambiguous outcome social situations on individual differences in cardiovascular reactivity in laboratory contexts.Purpose: This study tested whether interpretations of ambiguous social situations are associated with daily life cardiovascular responses using ambulatory approaches.Methods: There were 206 high school adolescents assessed on interpretations of ambiguous social situations in the laboratory who then completed ambulatory monitoring of blood pressure (BP) and heart rate (HR) for 2 days.Results: Adolescents who perceived threat during ambiguous situations exhibited higher systolicBP when talking to others compared to occasions of not talking with anyone, whereas the opposite was true for those with low threat perception. For high-threat adolescents, higher systolicBP was found when interacting with friends, whereas for low threat adolescents, lower systolicBP was found when interacting with parents. Greater threat interpretations were also associated with elevatedHR at night.Conclusions: Understanding how adolescents perceive social interactions may help in gauging their daily cardiovascular responses. This research was supported by the Pittsburgh Mind-Body Center (HL65111 and HL65112), National Institutes of Health grant HL25767, the Michael Smith Foundation for Health Research, and the William T. Grant Foundation.     

Augmenting Sibling Support with Parent-Sibling Training in Families of Children with Autism

ABSTRACT

Background: Typically developing (TD) siblings are an important part of the family system, but may show strained relationships in families of children with ASD.

Objective: We augmented a sibling support group with parent-sibling training in which parents learned (through instructions, modeling, rehearsal, and feedback) how to prompt and reinforce prosocial behaviors in their TD children.

Method: We examined the effects of parent-sibling training on parent and TD sibling behaviors in a multiple baseline across families design.

Results: Parent prompting and reinforcement of TD sibling prosocial behaviors increase. TD sibling prosocial behaviors such as sharing with and talking to their sibling with ASD also increased. Broader measures of the sibling relationship showed some improvements.

Conclusion: Findings suggest ways to support families of children with ASD with future investigations of parent-sibling training examining longer intervention, all family members’ adjustment and relationships, and sibling characteristics that influence response to parent-sibling training.