β‐Arrestin1 regulates the morphology and dynamics of microglia in zebrafish in vivo

Microglia are the primary immune cells in the central nervous system. Microglia typically exist in a ‘resting’ state in the healthy brain, with ramified processes dynamically exploring the surrounding microenvironment. They become ‘activated’ under pathological conditions with marked changes in morphology. However, the regulation of their morphology dynamics remains poorly understood. Here, using in vivo time‐lapse imaging and three‐dimensional morphology analysis of microglia in intact zebrafish larvae, we found that β‐arrestin1, a multifunctional protein involved in various signal transductions, cell‐autonomously regulated the microglial morphology. Knockdown of β‐arrestin1 increased the volume size and process number of microglia but reduced the deformation speed in the resting state. Meanwhile, β‐arrestin1 down‐regulation led to a high frequency of phagocytic behaviour of microglia. These defects were partially rescued by over‐expressing human β‐arrestin1 in microglia. Our study indicated that microglial dynamics in the resting state can be regulated cell‐autonomously by β‐arrestin1 signalling.     

Integrating medical and psychological treatment for sexual problems: the psyche and the soma

I approach the integration of medical and psychological treatment for sexual problems from the perspective of a medical graduate for 41 years, and as a specialist obstetrician, gynaecologist and sexologist I learned that medical practitioners do not have all the answers, but neither do psychologists or all the other ‘-ologists’, but that together we can get so many of the answers. The emergence of Psychosomatic Obstetrics & Gynaecology suited my developing thirst for knowledge in this area to try and make me more effective in managing among other things patients' psychosexual difficulties. Combining this with learning about the actual therapeutic process, what doctoring actually does and how in many instances we can be effective just with the counselling process, not prescribing a ‘silver bullet’ or using the scalpel along the way, as in the Balint model of being a medical instrument. Abnormal illness behaviour, its offshoot – pain behaviour and abnormal treatment behaviour, concepts still not covered in medical schools, will be discussed. A case will be made for using the biopsychological model rather than the traditional medical illness model in the management of sexual dysfunctions.     

‘Thank-you for Saying “No”…’

This case study describes an approach to one individual's non-compliant behaviour, which focuses upon reduction of excessive refusal through change of the caregiver interactional style and acknowledgement of the inherent ‘message value’ of escape and avoidance responses. Positive outcomes include not only increased participation, but also greater personal competence, choice and access to ordinary community facilities, with these gains being maintained at three-month follow up. Implications of the approach are discussed.     

Assessment of progression and prognosis in ‘possible’ and ‘probable’ Alzheimer's disease

Objective. The objective of this study was to assess the rate of progression and clinical predictors of decline in subjects with ‘possible’ and ‘probable’ Alzheimer's disease (AD). Design/setting. The annual rate of change (ARC) for cognitive/functional scales was calculated for 95 subjects with AD attending a memory clinic. Two consecutive ARCs were calculated for a subgroup of 39 subjects. Results. The ARCs were relatively normally distributed; however, there was a large degree of variability. Neither age nor duration of symptoms at presentations were predictive of the rate of decline. However, the data suggested an effect of gender, with males having a greater rate of decline in cognition (p=0·02). Finally, the rate of progression over the first year did not predict the subsequent ARC (p=0·25). Conclusions. The high variability in ARCs observed in this study and poor correlation between consecutive ARCs suggest that neither mean ARC values nor the previous rate of decline can be used to aid clinicians in the assessment of response to acetylcholinesterase inhibitors or other specific treatments for AD. © 1998 John Wiley & Sons, Ltd.     

Increasing body weight enhances prevalence and proximal extent of reflux in GERD patients ‘on’ and ‘off’ PPI therapy

Background Increased body weight is associated with higher intragastric pressure. Proximal extent of reflux is a determinant of symptoms in patients with gastro‐esophageal reflux disease (GERD). We aimed to investigate the association between body mass index (BMI) and abdominal circumference on the incidence and proximal extent of reflux. Methods A total of 95 patients [37 men, age 51(16–82) years] with typical and/or atypical GERD symptoms underwent 24 h impedance‐pH monitoring. Forty‐nine patients were studied ‘off’ and 46 ‘on’ proton pump inhibitors (PPI) treatment. Reflux was classified as acid (pH < 4) or weakly acidic (pH 4–7). Proximal extent was defined as the number of reflux events reaching ≥15 cm above the lower esophageal sphincter. Body mass index and abdominal circumference (cm) were assessed. Key Results In patients ‘off’ PPI, there was a correlation between BMI and esophageal acid exposure (ρ = 0.53, P < 0.001), volume exposure (ρ = 0.48, P < 0.001), total number of reflux events (ρ = 0.47, P < 0.001) and number of acid reflux events (ρ = 0.49, P < 0.001). In patients ‘on’ PPI there was a correlation between BMI and esophageal acid exposure (ρ = 0.32, P = 0.03), volume exposure (ρ = 0.46, P < 0.01) and total number of reflux events (ρ = 0.33, P = 0.03). Similar correlations were found between abdominal circumference and reflux. A correlation between BMI and proximal extent of reflux was present in patients ‘off’ PPI (ρ = 0.32, P = 0.03). In patients ‘on’ PPI, we found a correlation between abdominal circumference and proximal extent (ρ = 0.31, P = 0.03). Conclusions & Inferences Body mass index and abdominal circumference may contribute to GER and its proximal extent, in patients ‘on and ‘off’ PPI. Further studies investigating the role of weight reduction in the control of GERD symptoms are warranted.     

Living ‘a life like ours’: support workers' accounts of substitute decision‐making in residential care homes for adults with intellectual disabilities

Background In England and Wales, the Mental Capacity Act 2005 (MCA) provides a new legal framework to regulate substitute decision‐making relating to the welfare of adults who lack the capacity to make one or more autonomous decisions about their care and support. Any substitute decision made on behalf of an adult lacking capacity must be in his/her ‘best interests’. However, the value of adopting established principles and procedures for substitute decision‐making in practice is uncertain, and little is known about the legal or ethical dynamics of social care support, including the day‐to‐day residential support provided to adults with intellectual disabilities (ID). Methods This paper reports a qualitative, grounded theory analysis of 21 interviews with support workers working in residential care homes for adults with ID, and observations of care practices. Results In contrast to the narrow legal responsibilities placed upon them, it is argued that support workers interpret substitute decision‐making within a broad moral account of their care role, orientating their support towards helping residents to live ‘a life like ours’. In so doing, support workers describe how they draw on their own values and life experiences to shape the substitute decisions that they make on behalf of residents. Conclusions Support workers' accounts reveal clear discrepancies between the legal regulation of substitute decision‐making and the ways that these support workers make sense of their work. Such discrepancies have implications both for the implementation of the MCA, and for the role of support workers' values in the conceptualisation and delivery of ‘good’ care.     

Microtubule‐associated protein tau promotes neuronal class II β‐tubulin microtubule formation and axon elongation in embryonic Xenopus laevis

Compared with its roles in neurodegeneration, much less is known about microtubule‐associated protein tau's normal functions in vivo, especially during development. The external development and ease of manipulating gene expression of Xenopus laevis embryos make them especially useful for studying gene function during early development. To study tau's functions in axon outgrowth, we characterized the most prominent tau isoforms of Xenopus embryos and manipulated their expression. None of these four isoforms were strictly analogous to those commonly studied in mammals, as all constitutively contained exon 10, which is preferentially removed from mammalian fetal tau isoforms, as well as exon 8, which in mammals is rare. Nonetheless, like mammalian tau, Xenopus tau exhibited alternative splicing of exon 4a, which in mammals distinguishes ‘big’ tau of peripheral neurons, and exon 6. Strongly suppressing tau expression with antisense morpholino oligonucleotides only modestly compromised peripheral nerve outgrowth of intact tadpoles, but severely disrupted neuronal microtubules containing class II β‐tubulins while leaving other microtubules largely unperturbed. Thus, the relatively mild dependence of axon development on tau likely resulted from having only a single class of microtubules disrupted by its loss. Also, consistent with its greater expression in long peripheral axons, boosting expression of ‘big’ tau increased neurite outgrowth significantly and enhanced tubulin acetylation more so than did the smaller isoform. These data demonstrate the utility of Xenopus as a tool to gain new insights into tau's functions in vivo.     

Review: Spreading the word: precise animal models and validated methods are vital when evaluating prion‐like behaviour of alpha‐synuclein

Synucleinopathies are characterized by abnormal proteinaceous aggregates, mainly composed of fibrillar α‐synuclein (α‐syn). It is now believed that α‐syn can form small aggregates in a restricted number of cells, that propagate to neighbouring cells and seed aggregation of endogenous α‐syn, in a ‘prion‐like manner’. This process could underlie the stereotypical progression of Lewy bodies described by Braak and colleagues across different stages of Parkinson's disease (PD). This prion‐like behaviour of α‐syn has been recently investigated in animal models of PD or multiple system atrophy (MSA). These models investigate the cell‐to‐cell transfer of α‐syn seeds, or the induction and spreading of α‐syn pathology in transgenic or wild‐type rodent brain. In this review, we first outline the involvement of α‐syn in Lewy body diseases and MSA, and discuss how ‘prion‐like’ mechanisms can contribute to disease. Thereon, we debate the relevance of animal models used to study prion‐like propagation. Finally, we review current main histological methods used to assess α‐syn pathology both in animal models and in human samples and their relevance to the disease. Specifically, we discuss using α‐syn phosphorylated at serine 129 as a marker of pathology, and the novel methods available that allow for more sensitive detection of early pathology, which has relevance for modelling synucleinopathies.     

Cotard's syndrome in the elderly: Historical and clinical aspects

This article explores the conceptual construction of Cotard's syndrome and includes an analysis of 100 cases of which 20 were over 65. Jules Cotard took the view that délire des négations was only a subtype of depressive illness characterized by sadness, guilt, marked anxiety, suicidal behaviour, insensitivity to pain, and delusions of negation, damnation and enormity. Soon after his death, however, a debate ensued as to whether what he had described was specific to melancholia or could be found associated with other psychoses. This view predominated for more than 80 years. Currently, and despite the fact that the French term déAlire means more than ‘delusion’, some authors use ‘Cotard's delusion’ to refer to the isolated of ‘being dead’. From clinical and evolutionary perspectives, it is unclear why an isolated delusion should merit (as some have suggested) a special brain location. Analysis of the cases so far reported suggests that it is only in the elderly that Cotard's syndrome tends to acquire its clinical completeness. There is no evidence, however, that its presence is a function of disease ‘severity’.     

The structure of mental disorders re‐examined: Is it developmentally stable and robust against additions?

Previous research suggests that patterns of comorbidity of a limited number of anxiety, depressive, substance use and antisocial personality (ASP) disorders among adults are best reflected by a hierarchical three‐factor structure with two correlated factors (‘anxious‐misery’ and ‘fear’) that are summarized in a second‐order ‘internalizing’ factor and one ‘externalizing’ factor. It has not been examined whether this structure is developmentally stable and robust against additions of more diagnoses. Using data from a prospective‐longitudinal community study of adolescents and young adults we re‐evaluate the three‐factor model originally proposed by Krueger (Archives of General Psychiatry, 1999; 56, 921–926). Using confirmatory factor analysis with identical conventions as in Krueger's original work we found that the three factor model did not fit robustly across age or a wider range of diagnoses. Using explanatory factor analysis we examined alternative structures. We found various clinically meaningful patterns with good fit that go substantially beyond the original three‐factor structure. However, again, there is little consistency in findings when different age groups or different diagnoses are considered. Our findings suggest that psychopathology cannot be reduced to any simple structure. Copyright © 2009 American Psychiatric Association. This article is being copublished by the International Journal of Methods in Psychiatric Research and the American Psychiatric Association 1 .     

A comparison of UK and US guidelines for drug treatment in borderline personality disorder

Abstract

The UK and USA differ considerably in their guidance regarding the use of drug treatment for borderline personality disorder, but generally agree over the use of psychological treatment. The 2009 UK guidelines from the National Institute for Health and Clinical Excellence (NICE) do not recommend any form of drug treatment except in a crisis with the intention of ceasing such treatment shortly afterwards. The US guidelines from the American Psychiatric Association (APA), published in 2001, are much more positive and suggest that there is a place for selective serotonin reuptake inhibitors (SSRIs), mood stabilizers and antipsychotic drugs as adjunctive treatments in borderline personality disorder. The guidelines are summarized and two main reasons for the differences identified. First, the separation of the borderline personality group into those with ‘affective dysregulation’, ‘impulsive behaviour dyscontrol’ and ‘cognitive–perceptual’ symptoms in the US guidelines was felt by the guideline development group for the NICE guideline to be a post hoc classification not supported by any other evidence. Second, the threshold of evidence necessary for making recommendations was much higher for the UK than the US guideline. Both guidelines recognize that we need more substantial trials, preferably independent of the pharmaceutical industry, before we can have any real confidence in our recommendations.     

Criminal behaviour,personality disorder,and mental illness: the origins of confusion

The statutory concept of psychopathic disorder has only limited correspondence with clinical concepts of psychopathic personality, and obscures the heterogeneity of personality disorder among the antisocial. This is partly reflected in problems in assessing the treatability of ‘psychopaths’. Admission of ‘psychopaths’ for treatment may be justified when their socially deviant behaviour is a function of an identifiable personality disorder. This requires specification of treatment targets. It is proposed that personality disorder can be conceptualised as inflexible interpersonal styles supported by expectations of others which are self-fulfilling prophecies, and that these cut across the medicolegal categories of mental illness and psychopathic disorder. Data are presented from a special hospital sample which support the model, and which have implications for clinical intervention.     

Prevalence of dementia and dementing diseases in the old‐old population in Japan: the Kurihara Project. Implications for Long‐Term Care Insurance data

Background: There have been no reports on the prevalence of dementia among the old‐old people in Japan. Methods: We studied the old‐old population in Kurihara, northern Japan. Analysis 1 of Participants 1 (n = 590) was performed to evaluate the prevalence of dementia and dementing diseases by intensive evaluation including MRI. Analysis 2 aimed to determine a good indicator for detecting ‘suspected dementia condition’ based on the Long‐Term Care Insurance index. Analysis 3 of Participants 2 (n = 3915) aimed to estimate the prevalence of ‘suspected dementia condition’. Results: In Analysis 1, 73 people (12.4%) were diagnosed with dementia. The most common cause was Alzheimer's disease with cerebrovascular disease. In Analysis 2, level I of the Impairment Level of Dementia was found to be a good indicator of ‘suspected dementia condition’. In Analysis 3, the overall estimated prevalence of ‘suspected dementia condition’ was 23.6%. In men, the ratio increased gradually from 75 to 87 years old to about 20%, increased to 40% at the age of 88 and became stable thereafter. In contrast, in women, the ratio increased from 75 to 95+ years old, reaching about 70%. Conclusions: The prevalence was higher than that reported previously. There was a difference between the sexes: an ‘age‐related’ increase occurred in men and an ‘ageing‐related’ increase in women. Alzheimer's disease with cerebrovascular disease was the most common cause, which coincided with the previous findings of individuals aged 65 years and older; however, the ratio of mixed dementia was greater.     

Sensitive delusion of reference, ‘sensitiver Beziehungswahn’

Ten patients discharged with the diagnosis of ‘sensitiver Beziehungswahn’ were followed up 22–28 years after their discharge. In one case, the course of the illness indicates that the patient suffered from a manic-depressive psychosis, and in two cases, this diagnosis was likely. In two cases the disorder seemed definitely to be schizophrenia. One case was presumably a transient paranoid reaction. One patient was likely to have suffered from hysteria or epilepsy, three cases remained uncertain. The study did not prove suitable in the evaluation of the validity of ‘sensitiver Beziehungswahn’ as a nosological entity, since at the time of diagnosis the patients only incompletely fulfilled the criteria set up by Kretschmer, but it throws light on the diagnostic practice and the tendency to a change between the classification into many independent disease entities and the subsequent inclusion into larger and fewer forms.     

Multidimensional anatomy of ‘modern type depression’ in Japan: A proposal for a different diagnostic approach to depression beyond the DSM‐5

Japan's prototype of depression was traditionally a melancholic depression based on the premorbid personality known as shūchaku‐kishitsu proposed by Mitsuzo Shimoda in the 1930s. However, since around 2000, a novel form of depression has emerged among Japanese youth. Called ‘modern type depression (MTD)’ by the mass media, the term has quickly gained popularity among the general public, though it has not been regarded as an official medical term. Likewise, lack of consensus guidelines for its diagnosis and treatment, and a dearth of scientific literature on MTD has led to confusion when dealing with it in clinical practice in Japan. In this review article, we summarize and discuss the present situation and issues regarding MTD by focusing on historical, diagnostic, psychosocial, and cultural perspectives. We also draw on international perspectives that begin to suggest that MTD is a phenomenon that may exist not only in Japan but also in many other countries with different sociocultural and historical backgrounds. It is therefore of interest to establish whether MTD is a culture‐specific phenomenon in Japan or a syndrome that can be classified using international diagnostic criteria as contained in the ICD or the DSM. We propose a novel diagnostic approach for depression that addresses MTD in order to combat the current confusion about depression under the present diagnostic systems.     

The Marke-Nyman Temperament (MNT) Scale in suicide attempters

A total of 89 suicide attempters were diagnosed according to the DSM-III-R, and categorized according to suicide method as ‘violent’ and ‘non-violent’ attempters, and also as those who had made previous suicide attempts (‘repeaters’) and those who had not (‘non-repeaters’). All of the subjects completed the MNT questionnaire. Our hypothesis was that the temperament patterns would reflect specific clinical characteristics, such as psychiatric diagnoses and type of suicidal behaviour. The ‘validity’ (ranging from fatiguableness to a high level of psychic energy) showed a bimodal distribution, suggesting the existence of two subgroups. The subjects with adjustment disorders displayed a significantly higher mean validity than the other patients. The lowest validity scores were found in subjects with bipolar depression. Men showed significantly higher 'stability’ (reflecting emotional distance from others) than women. Subjects with major depression and those who were ‘violent’ suicide attempters showed somewhat higher 'solidity’ (unchangeability, non-impulsiveness) compared with the other groups. Female ‘non-repeaters’ displayed significantly lower solidity than males or other females. In general, no clear temperament patterns were detected in patients categorized according to type of suicidal behaviour. In contrast to the findings of studies of normal populations, the intercorrelations between the dimensions were considerable, especially among the men. This prompted us to perform a cluster analysis procedure in which the subjects were allocated to five clusters according to the MNT dimensions. No distinct clinical characteristics appeared in these clusters, except in the cluster with the highest validity and the lowest stability, as 54% (P= 0.014) of the patients in this cluster had an adjustment disorder diagnosis. These temperament results reflect the clinical heterogeneity of patients who attempt suicide.     

The relationship between pre-morbid personality and challenging behaviour in people with dementia: A systematic review

It has been suggested that challenging behaviour in people with dementia reflects a person's pre-morbid personality traits and a number of studies have explored this hypothesis. However, inconsistencies in outcome between studies suggest a need to review the available evidence systematically. As a result, major bibliographic databases were searched for studies examining the relationship between pre-morbid personality and challenging behaviour in order to conduct a systematic review. We included all English language studies published in referenced journals that assessed pre-morbid personality via a valid comprehensive personality measure, and also explored a relationship with challenging behaviour in people with dementia. A total of 18 studies were identified that covered a wide range of challenging behaviours including ‘wandering’, affective states, aggression, anxiety and delusions/hallucinations. Studies were assessed for their methodological quality and statistical findings. Studies lacked representative samples, were affected by confounding variables and suffered from small sample sizes. However, 72% of the studies reported significant relationships between pre-morbid personality and behaviour. In terms of specific relationships, the strongest evidence was found for a positive relationship between pre-morbid neuroticism and mood, and aggression and overall behavioural acts, thus supporting the inclusion of personality as one factor in the formulation of behaviour (Ballard, C., O’Brien, J., James, I., & Swann, A. (2001). Dementia: Management of Behavioural and Psychological Symptoms. Oxford: Oxford University Press; Kitwood, T. (1993 Kitwood, T. 1993. Person and process in dementia: Editorial. International Journal of Geriatric Psychiatry, 1: 541–545. [Crossref] [Google Scholar]). Person and process in dementia: Editorial. International Journal of Geriatric Psychiatry, 1, 541–545).     

Physiology of diffuse esophageal spasm (DES) – when normal swallows are not normal

Background Diffuse esophageal spasm (DES) is characterized on manometry by a combination of simultaneous contractions and normal swallows. The aim of this study was to examine the manometric characteristics of simultaneous and ‘normal’ swallows in patients with DES patients compared with normal controls. Methods Manometric studies from 69 patients with DES and 20 controls were analysed to determine the proportion of normal, hypertensive, ineffective and simultaneous contractions, and the velocity of propagation along the esophagus, the duration and amplitude of contraction and the relaxation characteristics (nadir and duration) of the lower esophageal sphincter. Key Results The propagation velocity was the only significant difference between normal swallows and simultaneous contractions in DES patients (middle third: 49.2 VS 101.2 mm s⁻¹, P ≤ 0.001 lower third: 44.1 VS 88.7 mm s⁻¹, P ≤ 0.001). ‘Normal’ swallows in patients with DES had a greater velocity of propagation than those in age‐matched control subjects (middle third: 49.2 VS 37.0 mm s⁻¹, P = 0.02, lower third: 44.1 VS 23.3 mm s⁻¹, P ≤ 0.001). Conclusions & Inferences As expected, simultaneous contractions of DES patients differ from ‘normal’ swallows in DES patients mainly regarding the velocity of propagation of contraction but are similar in amplitude, however ‘normal’ swallows of DES patients are also more rapidly propagated along the esophagus than normal swallows of a control group suggesting that all swallows in DES are affected to some degree by the same process.