Different responses to K-10 and CIDI suggest that complex structured psychiatric interviews underestimate rates of mental disorder in old people.

BACKGROUND: Epidemiological surveys based on complex diagnostic interviews, such as the Composite International Diagnostic Interview (CIDI), report very low rates of anxiety and depressive disorders in older age groups. Mental health checklists show much less change over the lifespan. This paper explores the possibility that complex interviews present a special challenge to older respondents and thereby exaggerate the decline in mental disorder with age. METHOD: Analysis of data from an Australian national mental health survey with 10,641 community-resident adult respondents. Measures of interest included ICD-10 anxiety and depression diagnoses, scores on the Kessler Psychological Distress Scale (K-10), agreement between K-10 and CIDI anxiety and depressive questions, and changes in agreement with age. RESULTS: Levels of inconsistency between simple and complex questions about anxiety and depression rose with age. CONCLUSIONS: Older people may have difficulty attending to and processing lengthy, complex questionnaires. When in doubt, their preferred response may be to deny having experienced symptoms, thus deflating rates of diagnosed mental disorder. We recommend that simple mental health scales be included in epidemiological studies involving older age groups.

Extracellular loops and ligand binding to a subfamily of Family A G-protein-coupled receptors.

GPCRs (G-protein-coupled receptors) are a large family of structurally related proteins which mediate their effects by coupling to G-proteins. The V(1a)R (V(1a) vasopressin receptor) is a member of a family of related GPCRs that are activated by vasopressin {AVP ([Arg(8)]vasopressin)}, OT (oxytocin) and related peptides. These receptors are members of a subfamily of Family A GPCRs called the neurohypophysial peptide hormone receptor family. GPCRs exhibit a conserved tertiary structure comprising a bundle of seven TM (transmembrane) helices linked by alternating ECLs (extracellular loops) and ICLs (intracellular loops). The cluster of TM helices is functionally important for ligand binding, and, furthermore, activation of GPCRs involves movement of these TM helices. Consequently, it might be assumed that the extracellular face of GPCRs is composed of peptide linkers that merely connect important TM helices. However, using a systematic mutagenesis approach and focusing on the N-terminus and the second ECL of the V(1a)R, we have established that these extracellular domains fulfil a range of important roles with respect to GPCR signalling, including agonist binding, ligand selectivity and receptor activation.

Pulmonary function, cognitive impairment and brain atrophy in a middle-aged community sample.

OBJECTIVE: To determine the relationship of lung function to brain anatomical parameters and cognitive function and to examine the mediating factors for any relationships. METHODS: A random sub-sample of 469 persons (men = 252) aged 60-64 years from a larger community sample underwent brain magnetic resonance imaging scans and pulmonary function tests (forced vital capacity, FVC, forced expiratory volume in the first second, FEV(1)). Subjects were assessed for global cognitive function, episodic memory, working memory, information processing speed, fine motor dexterity and grip strength. The magnetic resonance imaging scans were analysed for overall brain atrophy, subcortical atrophy (ventricle-to-brain ratio, VBR), hippocampal volume, and white matter hyperintensity (WMH) volume. RESULTS: FEV(1) had a significant negative correlation with overall brain atrophy and VBR in men. The FEV(1)/FVC ratio had a significant correlation with WMHs in both men and women. In regression models that controlled for sex, age, height, level of activity, smoking, chronic respiratory disease and education, FEV(1) and FVC were significant predictors of VBR but no other structural brain measure. Pulmonary function was also significantly related to information processing speed and fine motor dexterity. Male subjects with chronic respiratory disease had more deep WMHs. Path analyses to examine if structural measures mediated between lung function and cognition, and whether markers of inflammation and oxidative stress or cortisol mediated between lung function and brain measures were negative. CONCLUSIONS: Decreased lung function is related to poorer cognitive function and increased subcortical atrophy in mid-adult life. Presence of chronic respiratory disease may be related to deep WMHs in men.

Associations between plasma antioxidants and hypertension in a community-based sample of 415 Australians aged 60-64.

It has been suggested that increased oxidative stress may be both a cause as well as a consequence of hypertension. In vivo oxidation of low-density lipoproteins by oxygen-free radicals may increase hypertension-related atherogenesis, and antioxidants may be beneficial in this regard. Previous findings concerning associations between serum measures of antioxidants and hypertension have however been inconsistent. Plasma levels of beta-carotene, Vitamin A, E, uric acid, homocysteine and total antioxidant capacity, as well as two markers of oxidative stress, malondialdehyde (MDA) and protein carbonyls, were measured in morning fasting blood samples provided by 415 Australians aged 60-64 years, selected randomly from the community. Participants also provided information on sociodemographic attributes, mental and physical health, and provided two measures of resting blood pressure, allowing a diagnosis of definite or borderline hypertension. Those with hypertension had lower levels of beta-carotene and higher levels of uric acid and MDA compared to normotensive participants. The last two of these associations persisted when the analyses controlled for lifestyle and health factors. The findings from this study offer limited support for the proposition that lower antioxidant status and higher oxidative stress are associated with hypertension, and suggest the need for longitudinal studies to examine causality and intervention studies to determine the benefit of antioxidants in this group.

Actions taken to cope with depression at different levels of severity: a community survey.

BACKGROUND: Many people with symptoms of psychological distress do not seek professional help. Little is known about the actions taken by these people to reduce their symptoms. The present study aimed to assess, in a community sample, actions taken to cope with depression at different levels of psychological distress. METHOD: A postal survey was carried out with 6618 adults living in Canberra and south-east New South Wales, Australia. Measures covered psychological distress and a checklist of actions taken to cope with depression in the previous 6 months. RESULTS: Actions taken to cope with depression could be classified as: intensification of everyday strategies, initiation of new self-help (including complementary therapies, non-prescription medication and dietary changes) and seeking professional help. Use of everyday strategies peaked with mild psychological distress, new self-help showed a peak in moderate distress, while professional help-seeking peaked in severe distress. CONCLUSION: Self-help strategies are very commonly used, particularly in mild-moderate psychological distress. More evidence is needed to evaluate their effectiveness, so that optimal self-help can be encouraged.

Providing information about the effectiveness of treatment options to depressed people in the community: a randomized controlled trial of effects on mental health literacy, help-seeking and symptoms.

BACKGROUND: Many people who are depressed do not receive any professional help and their beliefs about the helpfulness of treatment do not always correspond with those of health professionals. To facilitate choices about treatment, the present study examined the effects of providing depressed people in the community with evidence on whether various treatment options work. METHOD: A randomized controlled trial was carried out with 1094 persons selected at random from the community who screened positive for depressive symptoms and agreed to participate. Participants were mailed either an evidence-based consumer guide to treatments for depression or, as a control, a general brochure on depression. Outcomes were the rated usefulness of the information provided, changes in attitudes to depression treatments, actions taken to reduce depression, and changes in depressive symptoms, anxiety symptoms and disability. RESULTS: Participants rated the evidence-based consumer guide as more useful than the control brochure. Attitudes to some treatments changed. Improvements in symptoms and disability did not differ significantly between interventions. CONCLUSION: Providing people who are depressed with evidence on which treatments work produces some changes in attitudes and behaviour. However, this intervention may need to be enhanced if it is to produce symptom change.

Agonist binding to peptide hormone receptors.

A fundamental issue in molecular pharmacology is to define how agonist-receptor interaction differs from that of antagonist-receptor interaction. The V(1a) vasopressin receptor (V(1a)R) is a member of a family of related G-protein-coupled receptors (GPCRs) that are activated by vasopressin, oxytocin (OT) and related peptides. A segment of the N-terminus that was required for agonist binding, but not antagonist binding, was identified by characterizing truncated V(1a)R constructs. Site-directed mutagenesis revealed that a single residue (Arg(46)) was critical for agonist binding and receptor activation. The N-terminus of the related OT receptor (OTR) could recover agonist binding in a chimaeric OTR(N)-V(1a)R construct. Furthermore, Arg(34) of the human OTR, which corresponds to Arg(46) of the rat V(1a)R, provided agonist-specific binding epitopes in the OTR, indicating a conserved function of this locus throughout this GPCR subfamily. Mutation of Arg(46) revealed that high-affinity agonist binding had an absolute requirement for arginine at this position.

Predictors of partially met or unmet need reported by consumers of mental health services: an analysis of data from the Australian National Survey of Mental Health and Wellbeing.

OBJECTIVE: We examined data from the 1997 National Survey of Mental Health and Wellbeing to identify factors associated with consumers of mental health help reporting that their needs were unmet or only partially met. Predictor factors included sociodemographic variables, psychological morbidity measures and type of health practitioner seen. METHOD: Five types of mental health help were considered: information, medication, psychological therapy, social interventions and skills training. A respondent's unmet need for each type of mental health help was given one of three values: 0: no unmet need reported; 1: some but not enough help of this type provided; and 2: no help of this type provided although it was needed. Multiple ordered logistic regressions were undertaken to identify predictor variables associated with reporting unmet need for each type of help. RESULTS: Few sociodemographic factors were found to be associated with consumers reporting unmet need for mental health help. Those with less education were more likely to report unmet need for medication. Being male, living alone and being unemployed were associated with unmet need for skills training. Having seen a general practitioner for mental health reasons was found to be associated with reporting unmet need for both information and social interventions. Self-identifying, or being diagnosed, as having an anxiety disorder was associated with reporting unmet need for four of the five types of help. CONCLUSIONS: In this exploratory analysis, we examined factors associated with consumers of mental health help reporting that their needs were unmet or partially met. We found that the needs of those with anxiety problems were not generally well met. Our findings also indicate there is a need to continue to improve collaboration between the medical and community services sectors.

Predictors of types of help provided to people using services for mental health problems: an analysis of the Australian National Survey of Mental Health and Wellbeing.

OBJECTIVE: Using the 1997 National Survey of Mental Health and Wellbeing, this study examined the types of mental health help provided to those Australians who use mental health services. We also sought to identify the extent to which sociodemographic factors, patterns of psychiatric morbidity and type of health practitioner seen were associated with receiving different types of mental health help. METHOD: Multiple logistic regressions were undertaken to identify predictor variables associated with receiving information, medication, psychological therapy, practical help and help looking after oneself or one's home. A total of 25 predictor variables provided in the National Survey were considered including age, sex, marital status, labour force status, geographical location, education, psychological symptoms, neuroticism, diagnoses of affective, anxiety and substance-abuse disorders and self-identified depression, anxiety and substance abuse. The type of practitioner seen for mental health reasons was also considered. RESULTS: Of the sociodemographic factors, age was the most consistently associated with receiving particular types of help. Younger respondents were more likely to have received information whereas older patients reported receiving more medication. As might be expected, the type and severity of psychiatric morbidity and the category of health professional seen were also associated with receiving particular types of mental health help. CONCLUSIONS: There are relatively few predictor variables that suggest possible bias in the types of help provided. Age group of recipient is an important exception. Our findings suggest that older recipients of mental health care are not provided the range of mental health treatments offered younger people who present with similar problems.

Who uses mental health services in Australia? An analysis of data from the National Survey of Mental Health and Wellbeing.

OBJECTIVE: This study sought to identify sociodemographic and psychological measures associated with utilisation of mental health services in Australia, using information collected through the 1997 National Survey of Mental Health and Wellbeing. METHOD: Twenty-one potential predictor variables were selected from the National Survey. Predisposing and enabling factors included age, sex, marital status, labour force status, geographical location and level of education. Predictor variables measuring need for services included the General Health Questionnaire score, a neuroticism scale, diagnoses of affective, anxiety and substance-abuse disorders from the Composite International Diagnostic Interview, and self-identified depression, anxiety and substance abuse. Simple and multiple logistic regressions were undertaken to identify predictor variables associated with use of mental health services from general practitioners, psychiatrists, psychologists and other health professionals. RESULTS: General practitioners were the most commonly reported providers of mental health services with 76% of those receiving any mental health care reporting using this type of service. Using multiple logistic regression, the predictor variables most associated with use of mental health services were measures of the need for such services, such as psychological distress and mental disorder. After controlling for need variables, the sociodemographic variables associated with using services provided by any health professional were being female, level of education and being separated. Living in a remote area was associated with lower use of specialist services, but not with general practitioner services. Older age was associated with less use of psychologists and other health professionals. Income and having a usual language other than English did not affect service use. CONCLUSIONS: The factors most strongly related to Australians' use of mental health services are their having a diagnosed affective, anxiety or substance-abuse disorder and their self-identifying as having depression or anxiety. Although there are regional inequalities in levels of utilisation of mental health services, these are seen more with specialist services than with those provided by general practitioners.

Critical role of a subdomain of the N-terminus of the V1a vasopressin receptor for binding agonists but not antagonists; functional rescue by the oxytocin receptor N-terminus.

A fundamental issue in molecular pharmacology is to define how agonist:receptor interaction differs from that of antagonist:receptor. The V(1a) receptor (V(1a)R) is a member of a family of related G-protein-coupled receptors that are activated by the neurohypophysial peptide hormone arginine-vasopressin (AVP). Here we define a short subdomain of the N-terminus of the V(1a)R from Glu(37) to Asn(47) that is an absolute requirement for binding AVP and other agonists. In marked contrast to the situation for agonists, deleting this segment has little or no effect on the binding of either peptide or non-peptide antagonists. In addition, we established that this subdomain was crucial for receptor activation and second messenger generation. The oxytocin receptor (OTR) also binds AVP with high affinity but exhibits a different pharmacological profile to the V(1a)R. Substitution of the N-terminus of the V(1a)R with the corresponding sequence from the OTR generated a chimeric receptor (OTR(N)-V(1a)R). The presence of the OTR N-terminus recovered high affinity agonist binding such that the OTR(N)-V(1a)R possessed almost wild-type V(1a)R pharmacology and signaling. Consequently, a domain within the N-terminus is required for agonist binding but it does not provide the molecular discriminator for subtype-selective agonist recognition. Cotransfection and peptide mimetic studies demonstrated that this N-terminal subdomain had to be contiguous with the receptor polypeptide to be functional. This study establishes that a segment of the V(1a)R N-terminus has a pivotal role in the mechanism of agonist binding and provides molecular insight into key differences between the interaction of agonists and antagonists with a peptide receptor family.

Distress experienced by participants during an epidemiological survey of posttraumatic stress disorder.

We examined the potential for epidemiological studies of mental disorders, specifically of posttraumatic stress disorder (PTSD), to cause further harm to participants involved. Of 1,000 randomly selected Australian Vietnam veterans, 641 agreed to participate in an epidemiological survey. Participants were asked about distress experienced during the interview when traumatic events were raised. Significant distress attributed to the interview was reported by 75.3% of those with current PTSD, 56.5% of those with past PTSD, and 20.6% of those with no PTSD diagnosis. Distress did not affect participants' use of medical services following the interview nor did it affect their willingness to continue participating in the study. We concluded that research interviews about PTSD may cause short-term distress, but found no evidence of long-term harm.

Studies of the Escherichia coli Trp repressor binding to its five operators and to variant operator sequences.

The Escherichia coli Trp repressor binds to promoters of very different sequence and intrinsic activity. Its mode of binding to trp operator DNA has been studied extensively yet remains highly controversial. In order to examine the selectivity of the protein for DNA, we have used electromobility shift assays (EMSAs) to study its binding to synthetic DNA containing the core sequences of each of its five operators and of operator variants. Our results for DNA containing sequences of two of the operators, trpEDCBA and aroH are similar to those of previous studies. Up to three bands of lower mobility than the free DNA are obtained which are assigned to complexes of stoichiometry 1 : 1, 2 : 1 and 3 : 1 Trp repressor dimer to DNA. The mtr and aroL operators have not been studied previously in vitro. For DNA containing these sequences, we observe predominantly one retarded band in EMSA with mobility corresponding to 2 : 1 complexes. We have also obtained retardation of DNA containing the trpR operator sequence, which has only been previously obtained with super-repressor Trp mutants. This gives bands with mobilities corresponding to 1 : 1 and 2 : 1 complexes. In contrast, DNA containing containing a symmetrized trpR operator sequence, trpRs, gives a single retarded band with mobility corresponding solely to a 1 : 1 protein dimer-DNA complex. Using trpR operator variants, we show that a change in a single base pair in the core 20 base pairs can alter the number of retarded DNA bands in EMSA and the length of the DNase I footprint observed. This shows that the binding of the second dimer is sequence selective. We propose that the broad selectivity of Trp repressor coupled to tandem 2 : 1 binding, which we have observed with all five operator sequences, enables the Trp repressor to bind to a limited number of sites with diverse sequences. This allows it to co-ordinately control promoters of different intrinsic strength. This mechanism may be of importance in a number of promoters that bind multiple effector molecules.

Rat testicular myoid cells express vasopressin receptors: receptor structure, signal transduction, and developmental regulation.

Detection of the neurohypophysial hormones vasopressin (AVP) and oxytocin (OT) in the testis of several species has led to the proposal that these peptides may have a physiological role in the regulation of testicular function. Therefore, we investigated whether the contractile myoid cells of rat seminiferous tubules express functional receptors for AVP or OT and, thus, constitute a target for these hormones. This study used primary cultures of purified peritubular myoid cells derived from rats both before and after puberty. By several criteria, myoid cells prepared from adult rats expressed vasopressin receptors (VPRs). We detected specific and saturable [3H]AVP binding to a single population of sites with a Kd of 7.5 nM and a binding capacity of 145 fmol/mg protein. AVP stimulated the accumulation of inositol phosphates in a dose-dependent manner with an EC50 of 1.7 nM. Cloning and sequencing of the myoid cell VPR confirmed it to be the V1a subtype of VPR. VPR expression by myoid cells is under developmental control, as the receptors are present in the adult rat, but absent before puberty. In contrast, OT receptors were not expressed at any stage of development. Peritubular myoid cells are also responsive to endothelin-1 (ET-1), which potently stimulated phosphoinositidase-C. However, unlike AVP, the ET-1 responses were observed both before and after sexual maturity, suggesting different roles for AVP and ET-1 in the control of myoid cell function. Our data establish that the myoid cells of the adult rat seminiferous tubule are a target for AVP. This indicates an additional role for AVP in the regulation of testicular function and male fertility in the adult rat.

1H-NMR assignments and secondary structure of dendroaspin, an RGD-containing glycoprotein IIb-IIIa (alpha IIb-beta 3) antagonist with a neurotoxin fold.

Dendroaspin, also referred to as mambin, was originally isolated from the venom of the Elapidae snake Dendroaspis jamesoni kaimose. It shares a high level of sequence similarity with the short-chain neurotoxins found in other Elapidae but displays approximately 1000-fold lower neurotoxin activity than the closely related protein erabutoxin b. However, unlike neurotoxins, it contains an RGD (Arg-Gly-Asp) motif and functions as an antagonist of platelet aggregation and cell-cell adhesion of comparable potency to the disintegrins from the venoms of Viperidae. We have determined the secondary structure of dendroaspin using 1H-NMR spectroscopy. Its structure resembles that of the short-chain neurotoxins, with three loops extending from a disulphide-bridged core; however, the strands of the triple-stranded beta-sheet are shorter and the loop containing the RGD sequence is moved away from this sheet. The structure bears little resemblance to that of the disintegrins, except in the RGD-containing loop, suggesting that this loop may be of prime importance in its inhibitory function. Comparison of this preliminary structure with that of the neurotoxins and disintegrins furthers our understanding of the mechanism of integrin antagonists and shows how the neurotoxin fold can be manipulated to give a variety of inhibitors.

Pharmacological characterization of linear analogues of vasopressin generated by the systematic substitution of positions 1 and 6 by L-amino acids.

Eighteen linear analogues of [Arg8]vasopressin (AVP) were synthesized by systematically substituting the cysteine residues at positions 1 and 6 with a range of L-amino acids. Screening by competition ligand binding revealed that the combinations of amino acid residues tolerated at these positions was very restricted with respect to retention of vasopressin receptor (VPR) binding. Consequently, only three of the eighteen analogues investigated, [Pro1,Met6]AVP, [Gly1,Met6]AVP and [Phe1,Lys6]AVP, bound to the V1a receptor. Furthermore, these three peptides were all selective for the V1a receptor rather than the V1b, V2 and vasotocin receptors. In addition, although very homologous to the natural agonist, these analogues were in fact antagonists at V1a receptors. These data provide insights into the biophysical requirements at positions 1 and 6 of linear ligands for binding to V1a receptors and furthermore, supply clues to the nature of the receptor:ligand interaction.