A coping self-insight scale for adults: development and preliminary psychometric properties.

BACKGROUND: Self-insights focused on the coping process are implicated in the refinement of capacities for resilience. To advance this research, we must identify key coping self-insights and develop a concise measurement tool. OBJECTIVE: The purpose of this paper is to develop evidence for the construct dimensionality and validity of a measure of coping self-insight. METHODS: Items measuring 13 coping self-insight dimensions were generated via consultation with theoretical work, subject matter experts, and pre-testing items for clarity. Thereafter, the dimensionality of items was assessed with undergraduate students (N = 232) and an online sample (N = 800) via exploratory and confirmatory analyses. Finally, a multi-trait, multi-method approach was used to test discriminant validity in a further sample of students (N = 228). RESULTS: The initial item list was reduced to five key dimensions that balanced data-driven and conceptual considerations. Confirmatory Factor Analysis revealed moderate-to-strong correlations (r = .47-.80) among dimensions. We also demonstrated evidence of internal reliability, convergent, criterion, and discriminant validity. Invariance tests for sub-groups of interest (e.g., sex, sample type) frequently demonstrated metric or scalar invariance, except for age sub-groups. CONCLUSIONS: Findings offer a starting point regarding the types of coping self-insights important for the emergence of resilience and a validated tool for future research.

Problem behaviours and psychotropic medication use in intellectual disability: a multinational cross-sectional survey.

BACKGROUND: Problem behaviours (PBs) are a common cause for clinician contact in people with disorders of intellectual development and may be a common cause for the prescription of psychotropic medication. We aimed to use a large, multinational sample to define the prevalence of PBs, the associations with psychotropic medication use, and to assess for any potential 'diagnostic overshadowing' by the label of PBs in a population of people with disorders of intellectual development. METHOD: A multinational, multi-setting, cross-sectional service evaluation and baseline audit was completed. Data were collected from UK hospitals, UK community settings, Sri Lanka and Hong Kong. A semi-structured questionnaire was completed by treating clinicians, capturing demographic details, prevalence rates of intellectual disability and psychotropic medication use, alongside psychiatric co-morbidity. RESULTS: A sample size of 358 was obtained, with 65% of included participants treated in an inpatient setting. Psychotropic use was prevalent (90%) in our sample, particularly antipsychotics (74%). The prevalence of PB was high (83%). There was no statistically significant association between psychotropic prescription and recorded psychiatric co-morbidity, suggesting prevalent 'off-label' use for PBs, or poor recording of psychiatric co-morbidity. There was some evidence of possible diagnostic overshadowing due to the PB classification. A higher dose of psychotropic medication was associated with aggression toward others (P = 0.03). CONCLUSIONS: We found evidence of prevalent potential 'off-label' use for psychotropic medication, which may be due to PBs. We also found evidence of potential diagnostic-overshadowing, where symptoms of psychiatric co-morbidity may have been attributed to PBs. Our findings provide renewed importance, across borders and health systems, for clinicians to consider a holistic approach to treating PBs, and attempting to best understand the precipitants and predisposing factors before psychotropic prescribing.

Pancreaticoduodenectomy: expected post-operative anatomy and complications.

Pancreaticoduodenectomy is a complex, high-risk surgical procedure performed for tumours of the pancreatic head and other periampullary structures. The rate of perioperative mortality has decreased in the past number of years but perioperative morbidity remains high. This pictorial review illustrates expected findings in early and late post-operative periods, including mimickers of pathology. It aims to familiarize radiologists with the imaging appearances of common and unusual post-operative complications. These are classified into early non-vascular complications such as delayed gastric emptying, post-operative collections, pancreatic fistulae and bilomas; late non-vascular complications, for example, biliary strictures and hepatic abscesses; and vascular complications including haemorrhage and ischaemia. Options for minimally invasive image-guided management of vascular and non-vascular complications are discussed. Familiarity with normal anatomic findings is essential in order to distinguish expected post-operative change from surgical complications or recurrent disease. This review summarizes the normal and abnormal radiological findings following pancreaticoduodenectomy.

IgE-mediated food allergy--diagnosis and management in New Zealand children.

AIM: To summarise the diagnosis and management of IgE-mediated food allergy (FA) in New Zealand children. METHOD: A review of the scientific literature and subsequent consensus development. RESULTS: FA is a common problem in New Zealand children with management necessitating accurate diagnosis, appropriate risk management, and reassessment over time. CONCLUSION: This paper highlights the importance of a structured approach to diagnosis and management of FA in New Zealand children, guided by appropriately skilled health professionals.

The use of δ¹5N signatures of translocated macroalgae to map coastal nutrient plumes: improving species selection and spatial analysis of metropolitan datasets.

The definition of the spatial footprint of land-derived nutrient plumes is a key element to the design of initiatives to combat eutrophication in urbanised coastal regions. These plumes, however, are difficult to monitor because of their inherent high-frequency temporal and spatial variability. Biomonitoring with macroalgae provides time-integration of bioavailable nitrogen inputs through the measurement of δ¹5N signatures in tissues, and adequate spatial coverage through translocation to desirable monitoring locations. In this study, we used laboratory incubations to compare three different species of macroalgae as bioindicators, and a field experiment to investigate the applicability of the technique for the large-scale mapping of nutrient plumes. Cladophora valonioides was selected for the field experiment as it showed rapid changes in δ¹5N values in the laboratory incubations, was abundant in shallow depths making collection cost-efficient, and had tough thalli capable of withstanding deployment in open water. Ecklonia radiata also performed well in the laboratory incubations, but field harvest from subtidal depths was comparatively more expensive. Ulva lactuca had fragile thalli, and large nitrogen reserves that acted to mask the isotopic signal of newly acquired nitrogen. Cladophora valonioides was translocated to 246 sites covering an area of ∼445 km² along the highly urbanized temperate coast of Adelaide, South Australia. The resulting isotopic signatures of nitrogen in tissues were spatially interpolated to produce maps of land-derived nutrient plumes, to model probability and standard error in the predictive surface, and to optimize sampling design.

Personality disorders in offenders with intellectual disability: a comparison of clinical, forensic and outcome variables and implications for service provision.

AIM: To establish any differences between patients with and without a diagnosis of personality disorders, being treated in a secure inpatient service for offenders with intellectual disability (ID) in the UK. METHOD: A cohort study involving a selected population of people with ID and offending behaviours. Results The study included a total of 138 patients, treated over a 6 year period - 77 with a dissocial or emotionally unstable personality disorder and 61 without. Women were more likely to be in the personality disorder group. Both groups had high prevalence of abuse with no significant differences. Depressive disorders and substance abuse were more common in the personality disorder group, while epilepsy and autistic spectrum disorders were more common in the non-personality disorder group. Rather than differences, what was more striking was the rate and range of these comorbidities across both groups. Although past histories of violence and institutional aggression were no different, compulsory detention under criminal sections and restriction orders were more common in the personality disorder group. There were no differences in treatment outcomes. CONCLUSIONS: Although about half of patients detained in secure units for offenders with ID have a personality disorder, there were more similarities than differences between this group and the rest. While good treatment outcomes supported the case for specialised secure treatment units for people with ID, the case for establishing a more specialised ID-personality disorder unit was less convincing. There is also a need to explore whether there are alternative diagnostic models that can delineate better the group with personality difficulties in this population.

High level of telomerase RNA gene expression is associated with chromatin modification, the ALT phenotype and poor prognosis in liposarcoma.

Telomere length is maintained by two known mechanisms, activation of telomerase or alternative lengthening of telomeres (ALT). The ALT pathway is more commonly activated in tumours of mesenchymal origin, although the mechanisms involved in the decision of a cell to activate either telomerase or ALT are unknown at present and no molecular markers exist to define the ALT phenotype. We have previously shown an association between chromatin remodelling, telomerase gene expression and ALT in cell line models. Here, we evaluate these findings and investigate their prognostic significance in a panel of liposarcoma tissue samples to understand the biology underlying the ALT phenotype. Liposarcoma samples were split into three groups: telomerase positive (Tel+); ALT positive; ALT-/Tel-. Differences in telomerase gene expression were evident between the groups with increased expression of hTR in ALT and Tel+ compared to ALT-/Tel- samples and increased hTERT in Tel+ samples only. Investigation of a small panel of chromatin modifications revealed significantly increased binding of acetyl H3 in association with hTR expression. We confirm that the presence of the ALT phenotype is associated with poor prognosis and in addition, for the first time, we show a direct association between hTR expression and poor prognosis in liposarcoma patients.

A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer.

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.

Hypoxic regulation of telomerase gene expression by transcriptional and post-transcriptional mechanisms.

Basal telomerase activity is dependent on expression of the hTERT and hTR genes and upregulation of telomerase gene expression is associated with tumour development. It is therefore possible that signal transduction pathways involved in tumour development and features of the tumour environment itself may influence telomerase gene regulation. The majority of solid tumours contain regions of hypoxia and it has recently been demonstrated that hypoxia can increase telomerase activity by mechanisms that are still poorly defined. Here, we show that hypoxia induces the transcriptional activity of both hTR and hTERT gene promoters. While endogenous hTR expression is regulated at the transcriptional level, hTERT is subject to regulation by alternative splicing under hypoxic conditions, which involves a switch in the splice pattern in favour of the active variant. Furthermore, analysis of the chromatin landscape of the telomerase promoters reveals dynamic recruitment of a transcriptional complex involving the hypoxia-inducible factor-1 transcription factor, p300, RNA polymerase II and TFIIB, to both promoters during hypoxia, which traffics along and remains associated with the hTERT gene as transcription proceeds. These studies show that hTERT and hTR are subject to similar controls under hypoxia and highlight the rapid and dynamic regulation of the telomerase genes in vivo.

Dysregulated expression of the major telomerase components in leukaemic stem cells.

Telomere loss is rapid during the progression of chronic myeloid leukaemia (CML) and correlates with prognosis. We therefore sought to measure expression of the major telomerase components (hTR and hTERT) in CD34+ cells from CML patients and normal controls, to determine if their altered expression may contribute to telomere attrition in vivo. High-purity (median 94.1%) BCR-ABL+ CD34+ cells from CML (n=16) and non-CML (n=14) patients were used. CML samples had a small increase in telomerase activity (TA) compared to normal samples (approximately 1.5-fold, P=0.004), which was inversely correlated with the percentage of G0 cells (P=0.02) suggesting TA may not be elevated on a cell-to-cell basis in CML. Consistent with this, hTERT mRNA expression was not significantly elevated; however, altered mRNA splicing appeared to play a significant role in determining overall full length, functional hTERT levels. Interestingly, Q-RT-PCR for hTR demonstrated a mean five-fold reduction in levels in the chronic phase (CP) CML samples (P=0.002), raising the possibility that telomere homeostasis is disrupted in CML. In summary, the molecular events regulating telomerase gene expression and telomere maintenance during the CP of CML may influence the disease progression observed in these patients.

A multicentre phase II trial of bryostatin-1 in patients with advanced renal cancer.

Protein kinase C (PKC) has a critical role in several signal transduction pathways, and is involved in renal cancer pathogenesis. Bryostatin-1 modulates PKC activity and has antitumour effects in preclinical studies. We conducted a multicentre phase II clinical trial in patients with advanced renal cancer to determine the response rate, immunomodulatory activity and toxicity of bryostatin-1 given as a continuous 24 h infusion weekly for 3 out of 4 weeks at a dose of 25 mug m(-2). In all, 16 patients were recruited (11 males and five females). The median age was 59 years (range 44-68). Patients had been treated previously with nephrectomy (8) and/or interferon therapy (9) and/or hormone therapy (4) and/or radiotherapy (6). Eight, five and three patients had performance statuses of 0, 1 and 2, respectively. A total of 181 infusions were administered with a median of 12 infusions per patient (range 1-29). Disease response was evaluable in 13 patients. Three patients achieved stable disease lasting for 10.5, 8 and 5.5 months, respectively. No complete responses or partial responses were seen. Myalgia, fatigue, nausea, headache, vomiting, anorexia, anaemia and lymphopenia were the commonly reported side effects. Assessment of biological activity of bryostatin-1 was carried out using the whole-blood cytokine release assay in six patients, two of whom had a rise in IL-6 levels 24 h after initiating bryostatin-1 therapy compared to pretreatment values. However, the IL-6 level was found to be significantly lower at day 28 compared to the pretreatment level in all six patients analysed.

Investigation for complement deficiency following meningococcal disease.

BACKGROUND AND AIMS: The incidence of complement abnormalities in the UK is not known. It is suggested in at least three major paediatric textbooks to test for abnormalities of the complement system following meningococcal disease (MCD). METHODS: Over a four year period, surviving children with a diagnosis of MCD had complement activity assessed. A total of 297 children, aged 2 months to 16 years were screened. RESULTS: All children except one had disease caused by B or C serogroups. One child, with group B meningococcal septicaemia (complicated by disseminated intravascular coagulation and who required ventilation and inotropic support) was complement deficient. C2 deficiency was subsequently diagnosed. She had other major pointers towards an immunological abnormality prior to her MCD. CONCLUSION: It is unnecessary to screen all children routinely following MCD if caused by group B or C infection. However, it is important to assess the previous health of the child and to investigate appropriately if there have been previous suspicious infections, abnormal course of infective illnesses, or if this is a repeated episode of neisserial infection.

The parathyroid hormone 2 (PTH2) receptor.

The human PTH2 receptor binds and is activated at high potency by PTH and by the recently discovered peptide tuberoinfundibular peptide of 39 residues (TIP39). Rat and zebrafish PTH2 receptors are more weakly activated by PTH, suggesting that TIP39 may be the natural ligand for the PTH2 receptor. Unlike the PTH1 receptor, the PTH2 receptor interacts extremely weakly with parathyroid hormone-related peptide (PTHrP). The PTH2 receptor is strongly coupled to stimulation of cAMP accumulation, and more weakly, in a cell-specific manner to increases in intracellular calcium concentration. A variety of evidence supports the general model of receptor amino terminal sequences binding ligand carboxyl terminal sequences with high affinity, and ligand amino terminal sequences activating the receptor through interaction with the "juxtamembrane" portion of the receptor. The receptor is present at greatest levels in the nervous system. It is expressed in scattered cells in the cerebral cortex and basal ganglia and at relatively high abundance in the septum, midline thalamic nuclei, several hypothalamic nuclei, and the dorsal horn of the spinal cord. Peripherally, expression in pancreatic islet somatostatin cells is most dramatic. Functional hypotheses based on the receptor's distribution are being tested. Recent data support involvement in hypothalamic releasing-factor secretion and pain.

Regions in rat and human parathyroid hormone (PTH) 2 receptors controlling receptor interaction with PTH and with antagonist ligands.

The parathyroid hormone (PTH) 2 receptor is potently activated by tuberoinfundibular peptide (TIP39). Rat and human PTH2 receptors differ considerably in their PTH responsiveness. PTH weakly stimulates cAMP accumulation via the rat receptor, and here we show it did not detectably increase intracellular calcium ([Ca2+]i) and bound with low affinity (450 nM). For the human PTH2 receptor PTH was a full agonist for increasing cAMP, a partial agonist for increasing [Ca2+]i, and bound with high affinity (18 nM). In addition, the antagonists PTH(7-34) and TIP(7-39) bound with 10- to 49-fold lower affinity to the rat receptor. We investigated the molecular basis of differential PTH and antagonist interaction with human and rat PTH2 receptors by using chimeric human/rat PTH2 receptors. PTH cAMP-signaling efficacy (Emax) was determined by extracellular loop (EL) 1 and a region including EL2 and EL3. The N-terminal domain determined PTH binding selectivity at the inactive receptor state. Multiple regions throughout the receptor are required for the PTH-PTH2 receptor complex to adopt a high-affinity active state: inserting the rat receptor's N-terminal domain, EL1 or EL2/3, into the human receptor increased PTH's EC50 and reciprocal exchanges did not reduce EC50. This suggests the global receptor conformation prevents the rat receptor from adopting a high-affinity state when in complex with PTH. N-terminal ligand truncation, producing the antagonists PTH(7-34) and TIP(7-39), altered ligand interaction with the membrane-embedded domain of the receptor, eliminating EL2/3 as a specificity determinant and lowering binding affinity. These insights should contribute to the development of a high-affinity PTH2 receptor antagonist, for investigating the receptor's physiological role.

Molecular mechanisms of ligand recognition by parathyroid hormone 1 (PTH1) and PTH2 receptors.

The mammalian parathyroid hormone (PTH) / PTH receptor family includes PTH1 and PTH2 receptors and three related ligands (PTH, PTH-related protein (PTHrP) an d tuberoinfundibular peptide of 39 residues (TIP39)). Here we comparatively and systematically review the pharmacological properties of PTH receptors and ligands, structure of the ligands, and molecular mechanisms of receptor-ligand interaction. The PTH1 receptor is activated by PTH and PTHrP but not by TIP39. The PTH2 receptor is activated by TIP39 but not by PTHrP. PTH strongly activates the human PTH2 receptor but is a weak partial agonist for rat and zebrafish PTH2 receptors. Receptor-G-protein interaction increases the receptor binding selectivity of PTHrP and TIP39. Despite different primary structures, the secondary structures of PTH, PTHrP and TIP39 are quite similar. Each ligand contains an N-terminal and a C-terminal alpha-helix in secondary structure-inducing conditions. Receptor-bound ligand structure is less well-characterized. The orientation of receptor-ligand interaction is highly similar for PTH and PTHrP binding to the PTH1 receptor and TIP39 interaction with the PTH2 receptor. Ligands bind according to a 'two-site' mechanism, in which the C-terminal portion of the ligand binds the extracellular N-terminal domain of the receptor (N-interaction), and the N-terminal ligand portion binds to the juxtamembrane receptor domain (J-interaction). The N-interaction provides most of the PTH1-receptor binding energy for PTH and PTHrP but provides less energy for PTH2 receptor-TIP39 interaction. The J-interaction stimulates G-protein activation. For the PTH-PTH1 receptor interaction, the efficacy-generating component of the J-interaction is independent of the N-domain of the receptor and C-terminal portion of the ligand. This finding suggests that it might be possible to design low molecular-weight PTH1 receptor agonists, which could be bone anabolic agents and used for the treatment of osteoporosis.

Molecular confirmation of the unique phenotype of epidermolysis bullosa simplex with mottled pigmentation.

BACKGROUND: A distinctive subtype of epidermolysis bullosa simplex, with the additional feature of mottled pigmentation (EBS-MP), was initially characterized in a Swedish family in 1979, and seven further families have been reported. Features of EBS-MP that are observed in most affected patients include acral blistering early in childhood, mottled pigmentation distributed in a number of sites, focal punctate hyperkeratoses of the palms and soles, and dystrophic, thickened nails. The genetic basis of EBS-MP has been ascribed in five unrelated families to a heterozygous point mutation, P25L, in the non-helical V1 domain of K5. OBJECTIVES: We report a clinical, ultrastructural and molecular study of two of the earliest families to be clinically characterized as EBS-MP. METHODS: The P25L mutation was identified in all affected members of each of these families, bringing the total number of EBS-MP families with this mutation to seven. RESULTS: This unusual recurrent mutation may uniquely cause EBS-MP. CONCLUSIONS: While the exact molecular mechanisms by which this mutation causes epidermolysis, palmoplantar keratoderma and pigmentation remain elusive, we suggest possible molecular mechanisms through which the P25L substitution could cause this unusual phenotype.

Lack of telomerase RNA gene hTERC expression in alternative lengthening of telomeres cells is associated with methylation of the hTERC promoter.

The immortal phenotype of most human cancers is attributable to telomerase expression. However, a number of immortal cell lines and tumors achieve telomere maintenance in the absence of telomerase via alternative mechanisms known as ALT (alternative lengthening of telomeres). Here we show that the promoter of the telomerase RNA gene (hTERC) is methylated in three of five ALT cell lines and is associated with a total absence of hTERC expression in the three lines. Treatment with 5-azacytidine in combination with trichostatin A resulted in partial demethylation of the hTERC promoter and expression of the gene. Partial methylation was detected in tumors (5%) and in immortal cell lines (27%). Cell lines with partial methylation express hTERC. Only in ALT cell lines does there appear to be a strong correlation between hTERC promoter hypermethylation and lack of hTERC expression.

Evaluating the signal transduction mechanism of the parathyroid hormone 1 receptor. Effect of receptor-G-protein interaction on the ligand binding mechanism and receptor conformation.

Ligand binding to the PTH1 receptor is described by a "two-site" model, in which the C-terminal portion of the ligand interacts with the N-terminal domain of the receptor (N interaction), and the N-terminal region of the ligand binds the juxtamembrane domain of the receptor (J interaction). Previous studies have not considered the dynamic nature of receptor conformation in ligand binding and receptor activation. In this study the ligand binding mechanism was compared for the G-protein-coupled (RG) and uncoupled (R) PTH1 receptor conformations. The two-site model was confirmed by demonstration of spatially distinct binding sites for PTH(3-34) and PTH(1-14): PTH(1-14), which binds predominantly to the J domain, only partially inhibited binding of 125I-PTH(3-34); and PTH(3-34), shown to bind predominantly to the N domain, only partially inhibited PTH(1-14)-stimulated cAMP accumulation. To assess the effect of R-G coupling, ligand binding to R was measured by displacement of 125I-PTH(3-34) with 30 microM guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) present, and binding to RG was measured by displacement of 125I-[MAP]PTHrP(1-36) (where MAP is model amphipathic peptide), a new radioligand that binds selectively to RG. Agonists bound with higher affinity to RG than R, whereas antagonists bound similarly to these states. The J interaction was responsible for enhanced agonist binding to RG: residues 1 and 2 were required for increased PTH(1-34) affinity for RG; residue 5 of MAP-PTHrP(1-36) was a determinant of R/RG binding selectivity, and PTH(1-14) bound selectively to RG. The N interaction was insensitive to R-G coupling; PTH(3-34) binding was GTPgammaS-insensitive. Finally, several observations suggest the receptor conformation is more "closed" at RG than R. At the R state, an open conformation is suggested by the simultaneous binding of PTH(1-14) and PTH(3-34). At RG PTH(1-14) better occluded binding of 125I-PTH(3-34) and agonist ligands bound pseudo-irreversibly, suggesting a more closed conformation of this receptor state. The results extend the two-site model to take into account R and RG conformations and suggest a model for differences of receptor conformation between these states.