The relationship between physical ill-health and mental ill-health in adults with intellectual disabilities.

BACKGROUND: People with intellectual disabilities face a much greater burden and earlier onset of physical and mental ill-health than the general adult population. Physical-mental comorbidity has been shown to result in poorer outcomes in the general population, but little is known about this relationship in adults with intellectual disabilities. AIMS: To identify whether physical ill-health is associated with mental ill-health in adults with intellectual disabilities and whether the extent of physical multi-morbidity can predict the likelihood of mental ill-health. To identify any associations between types of physical ill-health and mental ill-health. METHOD: A total of 1023 adults with intellectual disabilities underwent comprehensive health assessments. Binary logistic regressions were undertaken to establish any association between the independent variables: total number of physical health conditions, physical conditions by International Classification of Disease-10 chapter and specific physical health conditions; and the dependent variables: problem behaviours, mental disorders of any type. All regressions were adjusted for age, gender, level of intellectual disabilities, living arrangements, neighbourhood deprivation and Down syndrome. RESULTS: The extent of physical multi-morbidity was not associated with mental ill-health in adults with intellectual disabilities as only 0.8% of the sample had no physical conditions. Endocrine disease increased the risk of problem behaviours [odds ratio (OR): 1.22, 95% confidence interval (CI): 1.02-1.47], respiratory disease reduced the risk of problem behaviours (OR: 0.73, 95% CI: 0.54-0.99) and mental ill-health of any type (OR: 0.73, 95% CI: 0.58-0.92), and musculoskeletal disease reduced the risk of mental ill-health of any type (OR: 0.84, 95% CI: 0.73-0.98). Ischaemic heart disease increased the risk of problem behaviours approximately threefold (OR: 3.29, 95% CI: 1.02-10.60). CONCLUSIONS: The extent of physical multi-morbidity in the population with intellectual disabilities is overwhelming, such that associations are not found with mental ill-health. Mental health interventions and preventative measures are essential for the entire population with intellectual disabilities and should not be focussed on subgroups based on overall health burden.

Statistical modelling studies examining the dimensional structure of psychopathology experienced by adults with intellectual disabilities: Systematic review.

Diagnosing mental ill-health using categorical classification systems has limited validity for clinical practice and research. Dimensions of psychopathology have greater validity than categorical diagnoses in the general population, but dimensional models have not had a significant impact on our understanding of mental ill-health and problem behaviours experienced by adults with intellectual disabilities. This paper systematically reviews the methods and findings from intellectual disabilities studies that use statistical methods to identify dimensions of psychopathology from data collected using structured assessments of psychopathology. The PRISMA framework for systematic review was used to identify studies for inclusion. Study methods were compared to best-practice guidelines on the use of exploratory factor analysis. Data from the 20 studies included suggest that it is possible to use statistical methods to model dimensions of psychopathology experienced by adults with intellectual disabilities. However, none of the studies used methods recommended for the analysis of non-continuous psychopathology data and all 20 studies used statistical methods that produce unstable results that lack reliability. Statistical modelling is a promising methodology to improve our understanding of mental ill-health experienced by adults with intellectual disabilities but future studies should use robust statistical methods to build on the existing evidence base.

Prevalence and associations of anxiety disorders in adults with intellectual disabilities.

BACKGROUND: Anxiety disorders are known to be common in the general population. Previous studies with adults with intellectual disabilities (IDs) report a prevalence of general anxiety disorder ranging from <2% to 17.4%. Little is known about associated factors in this population. This study investigates point prevalence of anxiety disorders and determines the factors independently associated with them. METHODS: Information was collected with 1023 adults with IDs who participated in a large-scale, population-based study. All had a comprehensive physical and mental health assessment. The point prevalence of anxiety disorders according to different diagnostic criteria was determined, as were independently associated factors by using logistic regression analysis. RESULTS: Three point eight per cent (95% CI=2.7-5.2%) of the cohort had an anxiety disorder at the time of assessment. Generalised anxiety disorder was the most common (1.7%), then agoraphobia (0.7%). Factors independently associated with having an anxiety disorder were not having any daytime employment, and having a recent history of life events. Having previously been a long-term hospital resident was independently associated with not having an anxiety disorder. CONCLUSIONS: Anxiety disorders are common in the ID population. At times of significant life events, it might be sensible for carers to consider proactively providing additional support and being vigilant to seek early health-care interventions should there be any suggestion of emerging mental ill-health. The study further highlights the range of mental ill-health that is experienced by the population with IDs, and therefore the need for appropriate care, supports and development of effective interventions.

Neighbourhood deprivation, health inequalities and service access by adults with intellectual disabilities: a cross-sectional study.

BACKGROUND: Adults with intellectual disabilities (IDs) experience health inequalities and are more likely to live in deprived areas. The aim of this study was to determine whether the extent of deprivation of the area a person lives in affects their access to services, hence contributing to health inequalities. METHOD: A cross-sectional study design was used. Interviews were conducted with all adults with IDs within a defined location (n = 1023), and their medical records were reviewed. The extent of area deprivation was defined by postcode, using Carstairs scores. RESULTS: Area deprivation did not influence access to social supports, daytime primary health-care services or hospital admissions, but people in more deprived areas made less use of secondary outpatient health care [first contacts (P = 0.0007); follow-ups (P = 0.0002)], and more use of accident and emergency care (P = 0.02). Women in more deprived areas were more likely to have had a cervical smear; there was little association with other health promotion uptake. Area deprivation was not associated with access to paid employment, daytime occupation, nor respite care. These results were essentially unchanged after adjusting for type of accommodation and level of ability. CONCLUSIONS: Deprivation may not contribute to health inequality in the population with IDs in the same way as in the general population. Focusing health promotion initiatives within areas of greatest deprivation would be predicted to introduce a further access inequality.

Adults with intellectual disabilities: prevalence, incidence and remission of aggressive behaviour and related factors.

INTRODUCTION: Aggressive behaviours can be disabling for adults with intellectual disabilities (ID), with negative consequences for the adult, their family and paid carers. It is surprising how little research has been conducted into the epidemiology of these needs, given the impact they can have. This study investigates point prevalence, 2-year incidence and 2-year remission rates for aggressive behaviour (physically aggressive, destructive and verbally aggressive), and it investigates which factors are independently associated with aggressive behaviour. METHODS: All adults with ID - within a geographically defined area of Scotland, UK - were recruited to a longitudinal cohort. At baseline, assessments were undertaken of demography, lifestyle, supports, development, problem behaviours, disabilities and physical and mental health. These were repeated for a 2-year period. RESULTS: At baseline, the participation rate was 1023 (65.5%). After 2 years, the cohort retention was 651 adults. The point prevalence of Diagnostic Criteria for Psychiatric Disorders for Use with Adults with Learning Disabilities/Mental Retardation (DC-LD) aggressive behaviour was 9.8% (95% confidence interval = 8.0-11.8%), 2-year incidence was 1.8%, and 2-year remission rate from all types of aggressive behaviour meeting DC-LD criteria was 27.7%. The factors independently associated with aggressive behaviours were lower ability, female gender, not living with a family carer, not having Down syndrome, having attention-deficit hyperactivity disorder and having urinary incontinence. Incidence of aggressive behaviour meeting DC-LD criteria in adult life is similar to that for each of psychotic, anxiety and organic disorders. CONCLUSIONS: Aggressive behaviour is common among adults with ID, but contrary to previous suggestions, more than a quarter remit within the short to medium term. This is important knowledge for professionals as well as the person and her/his family and paid carers. There is much yet to learn about the mechanisms underpinning aetiology and maintenance of aggressive behaviour in this population, and exploratory epidemiological investigations such as this have a role to play in progressing research towards further hypothesis testing and trials to influence clinical practice, service development and policy.

Adults with intellectual disabilities: prevalence, incidence and remission of self-injurious behaviour, and related factors.

BACKGROUND: Self-injurious behaviour (SIB) is a serious condition, with implications for the person, their family and financial costs to the state providing care. The previously reported prevalence of SIB has ranged from 1.7% to 41%, or 1.7%-23.7% in community studies. There has been little study of remission rate, and incidence has not previously been reported. SIB has been reported to be individually associated with lower ability, autism and communication impairments, but given the inter-relationships between these three factors, it is not known whether they are independently associated with SIB. This study investigates the point prevalence, incidence and remission rates of SIB among the adult population with intellectual disabilities (ID), and explores which factors are independently associated with SIB. METHOD: A prospective cohort study design was used in a general community setting. The participants were all adults (16 years and over) with ID in a defined geographical area. Individual assessments were conducted with all participants. RESULTS: The point prevalence of SIB (as defined by DC-LD) was 4.9%, the two-year incidence was 0.6%, and two-year remission rate was 38.2%. Independently related to SIB were: lower ability level, not living with a family carer, having attention deficit hyperactivity disorder, visual impairment, and not having Down syndrome. Other factors, including communication impairment, autism, and level of deprivation of the area resided within, were not related. CONCLUSIONS: SIB is not as enduring and persistent as previously thought; a significant proportion gains remission in this time period. This should provide hope for families, paid carers and professionals, and reduce therapeutic nihilism. Our study is a first tentative step towards identifying risk-markers for SIB, and developing aetiological hypotheses for subsequent testing. The extent to which SIB may be a relapsing-remitting (episodic) condition requires further investigation, so does further hypothesis-based investigation of factors that might be predictive of incidence of, and remission from, SIB.

The prevalence and incidence of mental ill-health in adults with Down syndrome.

BACKGROUND: While there is considerable literature on adults with Down syndrome who have dementia, there is little published on the epidemiology of other types of mental ill-health in this population. METHOD: Longitudinal cohort study of adults with Down syndrome who received detailed psychiatric assessment (n = 186 at the first time point; n = 134 at the second time point, 2 years later). RESULTS: The prevalence of Down syndrome for the 16 years and over population was 5.9 per 10 000 general population. Point prevalence of mental ill-health of any type, excluding specific phobias, was 23.7% by clinical, 19.9% by Diagnostic Criteria for Psychiatric Disorders for use with Adults with Learning Disabilities/Mental Retardation (DC-LD), 11.3% by ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research (DCR-ICD-10) and 10.8% by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Revised (DSM-IV-TR) criteria. Two-year incidence of mental ill-health of any type was 14.9% by clinical and DC-LD, 9.0% by DCR-ICD-10 and 3.7% by DSM-IV-TR criteria. The highest incidence was for depressive episode (5.2%) and dementia/delirium (5.2%). Compared with persons with intellectual disabilities (ID) of all causes, the standardized rate for prevalence of mental ill-health was 0.6 (0.4-0.8), or 0.4 (0.3-0.6) if organic disorders are excluded, and the standardized incidence ratio for mental ill-health was 0.9 (0.6-1.4), or 0.7 (0.4-1.2) if organic disorders are excluded. Urinary incontinence was independently associated with mental ill-health, whereas other personal factors, lifestyle and supports, and other types of health needs and disabilities were not. CONCLUSIONS: Mental ill-health is less prevalent in adults with Down syndrome than for other adults with ID. The pattern of associated factors differs from that is found for other adults with ID, with few associations found. This suggests that the protection against mental ill-health is biologically determined in this population, or that there are other factors protective for mental ill-health yet to be identified for the population with Down syndrome.

Specialist health services for people with intellectual disability in Scotland.

BACKGROUND: People with intellectual disability (ID) are known to have a high prevalence of health needs, and to require access to specialist health services in addition to primary care and generic secondary care health services. However, there is no national database of each locality's specialist health service provision. Such a record would highlight variation in provision and enable benchmarking. METHOD: A 15-item questionnaire was developed which included questions on ID health services and staffing levels. This was sent to the chief executive of each of the 15 identified National Health Service primary care trusts/health boards which provide ID services in Scotland. The same questionnaire was also sent to the lead clinician/clinical director of each service. The results were converted to per 100 000 population per trust and presented in cumulative frequency tables to allow benchmarking. RESULTS: A response rate of 100% was achieved. The results show a wide range in the type of services provided by each locality in Scotland. Only three services (21%) have completed the process of resettlement. There was a wide-ranging variability in the number of beds/day places and professionals employed per 100 000 population per trust. CONCLUSIONS: There is widespread diversity in the service provision between different parts of Scotland. Geographical distances and responsibilities for service provision to remote and rural communities did not appear to account for these differences.

Low molecular weight disulfide cross-linking peptides as nonviral gene delivery carriers.

Cross-linking peptides have been developed by inserting multiple Cys residues into a 20 amino acid condensing peptide that polymerizes through disulfide bond formation when bound to DNA resulting in small, highly stable DNA condensates that mediate efficient in vitro gene transfer [McKenzie et al. (2000) J. Biol. Chem. 275, 9970-9977]. In the present study, a minimal peptide of four Lys and two terminal Cys residues was found to substitute for Cys-Trp-(Lys)(17)-Cys, resulting in DNA condensates with similar particle size and gene expression in HepG2 cells. Substitution of His for Lys residues resulted in an optimal peptide of Cys-His-(Lys)(6)-His-Cys that, in addition to the attributes described above, also provided buffering capacity to enhance in vitro gene expression in the absence of chloroquine. The reported structure-activity relationships systematically explore peptides with combinations of Lys, Cys, and His residues resulting in low molecular weight peptides with improved gene transfer properties.

Engineered smooth muscle tissues: regulating cell phenotype with the scaffold.

Culturing cells on three-dimensional, biodegradable scaffolds may create tissues suitable either for reconstructive surgery applications or as novel in vitro model systems. In this study, we have tested the hypothesis that the phenotype of smooth muscle cells (SMCs) in three-dimensional, engineered tissues is regulated by the chemistry of the scaffold material. Specifically, we have directly compared cell growth and patterns of extracellular matrix (ECM) (e.g. , elastin and collagen) gene expression on two types of synthetic polymer scaffolds and type I collagen scaffolds. The growth rates of SMCs on the synthetic polymer scaffolds were significantly higher than on type I collagen sponges. The rate of elastin production by SMCs on polyglycolic acid (PGA) scaffolds was 3.5 +/- 1.1-fold higher than that on type I collagen sponges on Day 11 of culture. In contrast, the collagen production rate on type I collagen sponges was 3.3 +/- 1.1-fold higher than that on PGA scaffolds. This scaffold-dependent switching between elastin and collagen gene expression was confirmed by Northern blot analysis. The finding that the scaffold chemistry regulates the phenotype of SMCs independent of the scaffold physical form was confirmed by culturing SMCs on two-dimensional films of the scaffold materials. It is likely that cells adhere to these scaffolds via different ligands, as the major protein adsorbed from the serum onto synthetic polymers was vitronectin, whereas fibronectin and vitronectin were present at high density on type I collagen sponges. In summary, this study demonstrates that three-dimensional smooth muscle-like tissues can be created by culturing SMCs on three-dimensional scaffolds, and that the phenotype of the SMCs is strongly regulated by the scaffold chemistry. These engineered tissues provide novel, three-dimensional models to study cellular interaction with ECM in vitro.

Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration.

The inability to deliver growth factors locally in a transient but sustained manner is a substantial barrier to tissue regeneration. Systems capable of localized plasmid gene delivery for prolonged times may offer lower toxicity and should be well-suited for growth factor therapeutics. We investigated the potency of plasmid gene delivery from genes physically entrapped in a polymer matrix (gene activated matrix) using bone regeneration as the endpoint in vivo. Implantation of gene activated matrices at sites of bone injury was associated with retention and expression of plasmid DNA for at least 6 weeks, and with the induction of centimeters of normal new bone in a stable, reproducible, dose- and time-dependent manner.

DNA delivery from polymer matrices for tissue engineering.

We have proposed engineering tissues by the incorporation and sustained release of plasmids encoding tissue-inductive proteins from polymer matrices. Matrices of poly(lactide-co-glycolide) (PLG) were loaded with plasmid, which was subsequently released over a period ranging from days to a month in vitro. Sustained delivery of plasmid DNA from matrices led to the transfection of large numbers of cells. Furthermore, in vivo delivery of a plasmid encoding platelet-derived growth factor enhanced matrix deposition and blood vessel formation in the developing tissue. This contrasts with direct injection of the plasmid, which did not significantly affect tissue formation. This method of DNA delivery may find utility in tissue engineering and gene therapy applications.

Alternative splicing of LTBP-3.

LTBPs bind the 100-kDa latent TGF-beta complex and thereby regulate TGF-beta assembly, tissue localization, and function. However, the 100-kDa complex is not always associated with LTBP, and, conversely, evidence suggests that LTBP has a distinct role in the extracellular matrix. As yet, there are no data to explain how the binding interaction between LTBP and the 100-kDa complex is regulated. This report provides the first direct evidence of alternative splicing of an LTBP gene. Two alternative splice sites in the mouse LTBP-3 gene have been identified based on in vivo and in vitro studies. Alternative splicing at one site in particular was found to disrupt a structural motif involved in the binding interaction with the 100-kDa latent TGF-beta complex. Therefore, alternative splicing may represent a molecular mechanism by which the uncomplexed form of LTBP-3 is produced, and, as a corollary, by which the 100-kDa latent TGF-beta 1 complex is produced.

8-Cysteine TGF-BP structural motifs are the site of covalent binding between mouse LTBP-3, LTBP-2, and latent TGF-beta 1.

The small latent TGF-beta complex often is associated with the latent TGF-beta binding protein (LTBP). Three LTBPs (LTBP-1, -2, and -3) have been isolated to date. Previous studies have shown that LTBP-1 binds the small latent TGF-beta 1 complex through a disulfide bond between an 8-cysteine structural motif of LTBP-1 (TGF-bp repeat) and the propeptide dimer of latent TGF-beta 1 (TGF-beta 1 latency associated peptide). There is indirect evidence that LTBP-2 and LTBP-3 also bind the latent TGF-beta complex, but the nature and location of the binding interaction are unknown. We have used immunoprecipitation, SDS-PAGE, and autoradiography to characterize the association between mouse LTBP-3 and the small latent TGF-beta 1 complex. We report that the second and third TGF-bp repeats of LTBP-3 covalently bind the latent complex, and we show a similar capability for the homologous TGF-bp repeats of mouse LTBP-2. The second TGF-bp repeat of LTBP-3 is unusual in that it has 9 cysteine residues instead of 8, and our results provide the first evidence that a TGF-bp repeat with an odd number of cysteine residues can covalently bind latent TGF-beta 1. Altogether, these results have important implications for TGF-beta biosynthesis and the regulation of TGF-beta activity.

Genes coding for mouse activin beta C and beta E are closely linked and exhibit a liver-specific expression pattern in adult tissues.

Five activin beta subunits have been isolated to date, and a comparative analysis of amino acid identity has suggested that the activin beta C, beta D and beta E subunits represent a distinct subset. Based on genomic cloning studies, we now report that the mouse activin beta C and beta E genetic loci are closely linked-i.e, the coding sequences are separated by 5.5-kbp. These genes also show similarities in structural organization as well as a unique liver-restricted pattern of expression in adult mice. Our results suggest that tandem duplication of an ancestral gene generated the mouse activin beta C and beta E genetic loci, and they provide further evidence for the postulate that the beta C-beta E subunits form a distinct subset of related activins. To our knowledge, this report is the first to demonstrate close chromosomal linkage between members of the TGF-beta superfamily as well as a liver-restricted expression pattern for a TGF-beta-like gene.

Mouse latent TGF-beta binding protein-2: molecular cloning and developmental expression.

The molecular cloning and developmental expression of mouse LTBP-2 are presented here. We established the identity of the cDNA by sequence comparison (80% identity with human LTBP-2) and by chromosome localization (mouse chromosome 12, band D, a region of conserved synteny with the human LTBP-2 gene). In contrast to LTBP-1 and LTBP-3, mouse LTBP-2 apparently is a more modular protein, with proline/glycine-rich sequences always alternating with clusters of cysteine-rich structural motifs. We found for the first time that LTBP-2 gene expression in mouse embryos was restricted to cartilage perichondrium and blood vessels, a somewhat surprising result since other LTBP genes are widely expressed in rodent tissues. Therefore, mouse LTBP-2 may play a critical role in the assembly of latent TGF-beta complexes in developing elastic tissues such as cartilage and blood vessel.

Molecular cloning of the mouse activin beta E subunit gene.

cDNA clones encoding a novel activin beta subunit have been isolated from mouse liver cDNA library. An amino acid homology comparison among members of the TGF-beta superfamily indicates that the open reading frame codes for a new activin/inhibin beta subunit. The predicted mature region of the subunit shows > 60% identity with activin beta C and beta D and > or = 45% identity with activin beta A and beta B, but only 20-40% amino acid sequence identity with other TGF-beta superfamily members. Therefore, the novel subunit has been designated activin beta E. Alignment of the mature growth factor region of the five activin beta subunits revealed that activin beta A and beta B share 63% amino acid identity, while activin beta C, beta D, and beta E share 62% identity. Therefore, activin beta A and beta B are most related to one another, while activin beta C, beta D, and beta E may represent a subset of related sequences.

Stimulation of new bone formation by direct transfer of osteogenic plasmid genes.

Degradable matrices containing expression plasmid DNA [gene-activated matrices (GAMs)] were implanted into segmental gaps created in the adult rat femur. Implantation of GAMs containing beta-galactosidase or luciferase plasmids led to DNA uptake and functional enzyme expression by repair cells (granulation tissue) growing into the gap. Implantation of a GAM containing either a bone morphogenetic protein-4 plasmid or a plasmid coding for a fragment of parathyroid hormone (amino acids 1-34) resulted in a biological response of new bone filling the gap. Finally, implantation of a two-plasmid GAM encoding bone morphogenetic protein-4 and the parathyroid hormone fragment, which act synergistically in vitro, caused new bone to form faster than with either factor alone. These studies demonstrate for the first time that repair cells (fibroblasts) in bone can be genetically manipulated in vivo. While serving as a useful tool to study the biology of repair fibroblasts and the wound healing response, the GAM technology may also have wide therapeutic utility.

Isolation of a novel latent transforming growth factor-beta binding protein gene (LTBP-3).

This paper reports the molecular cloning of a novel gene in the mouse that shows structural similarities to the microfibril protein fibrillin and to the latent transforming growth factor-beta (TGF-beta) binding protein (LTBP), a component of the latent TGF-beta complex. The gene was initially isolated during a low stringency polymerase chain reaction screen of a NIH 3T3 cell cDNA library using primers that amplify a human fibrillin-1 epidermal growth factor-like repeat. Three lines of evidence suggest that the mouse gene is a third member of the LTBP gene family, which we designate LTBP-3. First, the deduced polypeptide, which consists of 15 epidermal growth factor-like repeats, 3 TGF binding protein repeats, and 2 proline- and glycine-rich sequences, shows 38.4% identity with LTBP-1 but only 27% identity with fibrillin-1. Second, the gene appears to be co-expressed in developing mouse tissues with TGF-beta. Third, immunoprecipitation studies using mouse preosteoblast MC3T3-E1 cells and a specific anti-peptide polyclonal antiserum reveal that the mouse polypeptide forms a complex with the TGF-beta 1 precursor. Finally, we note that the LTBP-3 gene was recently localized to a distinct genetic locus (Li, X., Yin, W., Perez-Jurado, L., Bonadio, J., and Francke, U. (1995) Mamm. Genome 6, 42-45). Identification of a third binding protein provides further insight into a mechanism by which latent TGF-beta complexes can be targeted to connective tissue matrices and cells.

Primary structure and developmental expression of Fbn-1, the mouse fibrillin gene.

Previous studies have reported > 10 kilobases of human fibrillin-1 cDNA sequence, but a consensus regarding the 5' end of the transcript remains to be worked out. One approach to developing a clear consensus would be to search for regions of evolutionary conservation in transcripts from a related species such as mouse. As reported here, the mouse fibrillin-1 transcript encodes a highly conserved polypeptide of 2,871 amino acids. The upstream sequence that flanks the ATG is considerably less well conserved, however. Indeed, the ATG codon (which occurs in the context of a Kozak consensus sequence and is located just upstream of a consensus signal peptide) signals the point where human and mouse fibrillin-1 sequences cease to be nearly identical. Together, these results are consistent with previous efforts by Pereira et al. (Pereira, L., D'Alessio, M., Ramirez, F., Lynch, J. R., Sykes, B., Pangilinan, T., and Bonadio, J. (1993) Human Mol. Genet. 2, 961-968) to identify the human fibrillin-1 translational start site. Sequences immediately upstream of the ATG are GC-rich and devoid of TATA and CCAAT boxes, which suggests that the mouse fibrillin-1 gene will be broadly expressed. A survey of expression in mouse embryo tissues is consistent with this hypothesis and suggests two novel functions for fibrillin-associated microfibrils in non-elastic connective tissues.