Evidence for the early clinical relevance of hallucinatory-delusional states in the general population

OBJECTIVE: To analyze, in a general population sample, clustering of delusional and hallucinatory experiences in relation to environmental exposures and clinical parameters. METHOD: General population-based household surveys of randomly selected adults between 18 and 65 years of age were carried out. SETTING: 52 countries participating in the World Health Organization's World Health Survey were included. PARTICIPANTS: 225 842 subjects (55.6% women), from nationally representative samples, with an individual response rate of 98.5% within households participated. RESULTS: Compared with isolated delusions and hallucinations, co-occurrence of the two phenomena was associated with poorer outcome including worse general health and functioning status (OR = 0.93; 95% CI: 0.92-0.93), greater severity of symptoms (OR = 2.5 95% CI: 2.0-3.0), higher probability of lifetime diagnosis of psychotic disorder (OR = 12.9; 95% CI: 11.5-14.4), lifetime treatment for psychotic disorder (OR = 19.7; 95% CI: 17.3-22.5), and depression during the last 12 months (OR = 11.6; 95% CI: 10.9-12.4). Co-occurrence was also associated with adversity and hearing problems (OR = 2.0; 95% CI: 1.8-2.3). CONCLUSION: The results suggest that the co-occurrence of hallucinations and delusions in populations is not random but instead can be seen, compared with either phenomenon in isolation, as the result of more etiologic loading leading to a more severe clinical state.

Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction?

Background: Widespread use of automated sensitive assays for thyroid hormones and thyroid-stimulating hormone (TSH) has increased identification of mild thyroid dysfunction, especially in elderly patients. The clinical significance of this dysfunction, however, remains uncertain, and associations with cognitive impairment, depression, and anxiety are unconfirmed. Objective: To determine the association between mild thyroid dysfunction and cognition, depression, and anxiety in elderly persons. Design: Cross-sectional study. Associations were explored through mixed-model analyses. Setting: Primary care practices in central England. Patients: 5865 patients 65 years of age or older with no known thyroid disease who were recruited from primary care registers. Measurements: Serum TSH and free thyroxine (T4) were measured. Depression and anxiety were assessed by using the Hospital Anxiety and Depression Scale (HADS), and cognitive functioning was established by using the Middlesex Elderly Assessment of Mental State and the Folstein Mini-Mental State Examination. Comorbid conditions, medication use, and sociodemographic profiles were recorded. Results: 295 patients met the criteria for subclinical thyroid dysfunction (127 were hyperthyroid, and 168 were hypothyroid). After confounding variables were controlled for, statistically significant associations were seen between anxiety (HADS score) and TSH level (P = 0.013) and between cognition and both TSH and free T4 levels. The magnitude of these associations lacked clinical relevance: A 50-mIU/L increase in the TSH level was associated with a 1-point reduction in the HADS anxiety score, and a 1-point increase in the Mini-Mental State Examination score was associated with an increase of 50 mIU/L in the TSH level or 25 pmol/L in the free T4 level. Limitations: Because of the low participation rate, low prevalence of subclinical thyroid dysfunction, and other unidentified recruitment biases, participants may not be representative of the elderly population. Conclusions: After the confounding effects of comorbid conditions and use of medication were controlled for, subclinical thyroid dysfunction was not associated with depression, anxiety, or cognition. © 2006 American College of Physicians.

The effect of R-plasmid RP1 on the properties of Proteus mirabilis

A clinical isolate of Proteus mirabilis containing R-plasmid RP1 (R+ cells), grown in both iron- and carbon- limited chemically defined media in mixed culture with plasmid-free (R- cells), did not disappear as expected, due to adherence of R+ cells to the wall of the chemostat vessel. Plasmid RP1 promoted adherence to glass and to medical prostheses. The hydrophobicity and surface charge of R+ cells were different from those of R- cells and both factors may contribute to the adherence of R+ cells to surfaces. The mode of cultivation of the cells, whether batch or continuous culture, were also found to affect the result. Antibodies raised against homologous cells increased the surface hydrophobicity of both R+ and R- cells and eliminated the differences between them. Results for surface hydrophobicity varied with the method used for measuring it. R+ cells were more sensitive than R- cells to tbe bacteridical action of normal serum and whole blood and to phagocytosis as measured by chemiluminescence. No clear differences were revealed in the protein antigens of R+ and R- cells by both SDS PAGE gels and immunoblots reacted with homologous antibodies. However, lectins revealed differences in the sugars exposed on the cell surfaces. Chemical analysis of R&43 and R- cells also revealed differences in the content of 2-keto-3-deoxy-D-manno-2-octulosonate, lipopolysaccharide and total fatty acids, when cells were grown in media containing added iron; however, no qualitative differences in the lipopolysaccharide were found. Removal of iron from the medium was found to have considerable effects on the chemical structure of R+ cells but not of R- ones. Adhesion to prostheses and to leucocytes is discussed in the light of the results and the clinical relevance outlined with respect to the initiation of infection and the association of virulence with antibiotic resistance.

Bioequivalence of sustained release theophylline formulations

The bioequivalence of sustained release theophylline formulations, marketed in the United Kingdom, has been investigated in relation to the co-administration of food in both single dose and steady state volunteer studies. The effect of food on pharmacokinetic parameters and their clinical relevance was researched. Experimentation using drug induced modification of gastric motility to ascertain the component influences of the rate of gastric emptying on the absorption of theophylline from sustained release formulations was conducted. Prolongation of time to maximum plasma theophylline concentration by food reported in the literature and its clinical importance was investigated in once daily compared with twice daily administration of sustained release theophylline formulations and smoking habit. The correlation between saliva and plasma theophylline concentrations as a means of developing a non-invasive sampling techniques was examined. Data obtained from in vitro dissolution studies was compared with in vivo results. This thesis has shown no significant differences occurred in the pharmacokinetic parameters measured between sustained release formulations available in the United Kingdom. The investigations into the influence of food on prolongation of time to maximum plasma theophylline concentration and other measured pharmacokinetic parameters demonstrated no important pharmacokinetic or clinical effects. Smoking adults taking sustained release theophylline formulations had similar drug clearances to those reported in the literature for smokers taking plain uncoated theophylline formulations. KEY WORDS Bioequivalence Theophylline Sustained Release Food Pharmacokinetics RONALD PURKISS SUBMITTED FOR

Impact of cholinesterase inhibitors on behavioral and psychological symptoms of Alzheimer's disease:a meta-analysis

Objective: To determine the efficacy of cholinesterase inhibitors (ChEIs) in improving the behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer’s disease (AD). Data sources: We searched MEDLINE, Cochrane Registry, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1966 to 2007. We limited our search to English Language, full text, published articles and human studies. Data extraction: We included randomized, double-blind, placebo-controlled trials evaluating the efficacy of donepezil, rivastigmine, or galantamine in managing BPSD displayed by AD patients. Using the United States Preventive Services Task Force (USPSTF) guidelines, we critically appraised all studies and included only those with an attrition rate of less than 40%, concealed measurement of the outcomes, and intention to treat analysis of the collected data. All data were imputed into pre-defined evidence based tables and were pooled using the Review Manager 4.2.1 software for data synthesis. Results: We found 12 studies that met our inclusion criteria but only nine of them provided sufficient data for the meta-analysis. Among patients with mild to severe AD and in comparison to placebo, ChEIs as a class had a beneficial effects on reducing BPSD with a standard mean difference (SMD) of -0.10 (95% confidence interval [CI]; -0.18, -0.01) and a weighted mean difference (WMD) of -1.38 neuropsychiatry inventory point (95% CI; -2.30, -0.46). In studies with mild AD patients, the WMD was -1.92 (95% CI; -3.18, -0.66); and in studies with severe AD patients, the WMD was -0.06 (95% CI; -2.12, +0.57). Conclusion: Cholinesterase inhibitors lead to a statistical significant reduction in BPSD among patients with AD, yet the clinical relevance of this effect remains unclear.

How checking breeds doubt:reduced performance in a simple working memory task

A paradox of memory research is that repeated checking results in a decrease in memory certainty, memory vividness and confidence [van den Hout, M. A., & Kindt, M. (2003a). Phenomenological validity of an OCD-memory model and the remember/know distinction. Behaviour Research and Therapy, 41, 369–378; van den Hout, M. A., & Kindt, M. (2003b). Repeated checking causes memory distrust. Behaviour Research and Therapy, 41, 301–316]. Although these findings have been mainly attributed to changes in episodic long-term memory, it has been suggested [Shimamura, A. P. (2000). Toward a cognitive neuroscience of metacognition. Consciousness and Cognition, 9, 313–323] that representations in working memory could already suffer from detrimental checking. In two experiments we set out to test this hypothesis by employing a delayed-match-to-sample working memory task. Letters had to be remembered in their correct locations, a task that was designed to engage the episodic short-term buffer of working memory [Baddeley, A. D. (2000). The episodic buffer: a new component in working memory? Trends in Cognitive Sciences, 4, 417–423]. Of most importance, we introduced an intermediate distractor question that was prone to induce frustrating and unnecessary checking on trials where no correct answer was possible. Reaction times and confidence ratings on the actual memory test of these trials confirmed the success of this manipulation. Most importantly, high checkers [cf. VOCI; Thordarson, D. S., Radomsky, A. S., Rachman, S., Shafran, R, Sawchuk, C. N., & Hakstian, A. R. (2004). The Vancouver obsessional compulsive inventory (VOCI). Behaviour Research and Therapy, 42(11), 1289–1314] were less accurate than low checkers when frustrating checking was induced, especially if the experimental context actually emphasized the irrelevance of the misleading question. The clinical relevance of this result was substantiated by means of an extreme groups comparison across the two studies. The findings are discussed in the context of detrimental checking and lack of distractor inhibition as a way of weakening fragile bindings within the episodic short-term buffer of Baddeley's (2000) model. Clinical implications, limitations and future research are considered.

A novel dried blood spot-LCMS method for the quantification of methotrexate polyglutamates as a potential marker for methotrexate use in children

Objective: Development and validation of a selective and sensitive LCMS method for the determination of methotrexate polyglutamates in dried blood spots (DBS). Methods: DBS samples [spiked or patient samples] were prepared by applying blood to Guthrie cards which was then dried at room temperature. The method utilised 6-mm disks punched from the DBS samples (equivalent to approximately 12 μl of whole blood). The simple treatment procedure was based on protein precipitation using perchloric acid followed by solid phase extraction using MAX cartridges. The extracted sample was chromatographed using a reversed phase system involving an Atlantis T3-C18 column (3 μm, 2.1x150 mm) preceded by Atlantis guard column of matching chemistry. Analytes were subjected to LCMS analysis using positive electrospray ionization. Key Results: The method was linear over the range 5-400 nmol/L. The limits of detection and quantification were 1.6 and 5 nmol/L for individual polyglutamates and 1.5 and 4.5 nmol/L for total polyglutamates, respectively. The method has been applied successfully to the determination of DBS finger-prick samples from 47 paediatric patients and results confirmed with concentrations measured in matched RBC samples using conventional HPLC-UV technique. Conclusions and Clinical Relevance: The methodology has a potential for application in a range of clinical studies (e.g. pharmacokinetic evaluations or medication adherence assessment) since it is minimally invasive and easy to perform, potentially allowing parents to take blood samples at home. The feasibility of using DBS sampling can be of major value for future clinical trials or clinical care in paediatric rheumatology. © 2014 Hawwa et al.

Can certain genotypes predispose to poor asthma control in children? A pharmacogenetic study of 9 candidate genes in children with difficult asthma

Objective - We tested the hypothesis that patients with difficult asthma have an increased frequency of certain genotypes that predispose them to asthma exacerbations and poor asthma control. Methods - A total of 180 Caucasian children with confirmed asthma diagnosis were selected from two phenotypic groups; difficult (n = 112) versus mild/moderate asthma (n = 68) groups. All patients were screened for 19 polymorphisms in 9 candidate genes to evaluate their association with difficult asthma. Key Results - The results indicated that LTA4H A-9188>G, TNFα G-308>A and IL-4Rα A1727>G polymorphisms were significantly associated with the development of difficult asthma in paediatric patients (p<0.001, p = 0.019 and p = 0.037, respectively). Haplotype analysis also revealed two haplotypes (ATA haplotype of IL-4Rα A1199>C, IL-4Rα T1570>C and IL-4Rα A1727>G and CA haplotype of TNFα C-863>A and TNFα G-308>A polymorphisms) which were significantly associated with difficult asthma in children (p = 0.04 and p = 0.018, respectively). Conclusions and Clinical Relevance - The study revealed multiple SNPs and haplotypes in LTA4H, TNFα and IL4-Rα genes which constitute risk factors for the development of difficult asthma in children. Of particular interest is the LTA4H A-9188>G polymorphism which has been reported, for the first time, to have strong association with severe asthma in children. Our results suggest that screening for patients with this genetic marker could help characterise the heterogeneity of responses to leukotriene-modifying medications and, hence, facilitate targeting these therapies to the subset of patients who are most likely to gain benefit.

Parental confidence in managing food allergy:development of the Food Allergy Self-Efficacy Scale for parents (FASE-P)

Background: Food allergy is often a life-long condition that requires constant vigilance in order to prevent accidental exposure and avoid potentially life-threatening symptoms. Parents’ confidence in managing their child’s food allergy may relate to the poor quality of life anxiety and worry reported by parents of food allergic children. Objective: The aim of the current study was to develop and validate the first scale to measure parental confidence (self-efficacy) in managing food allergy in their child. Methods: The Food Allergy Self-Efficacy Scale for Parents (FASE-P) was developed through interviews with 53 parents, consultation of the literature and experts in the area. The FASE-P was then completed by 434 parents of food allergic children from a general population sample in addition to the General Self-Efficacy Scale (GSES), the Food Allergy Quality of Life Parental Burden Scale (FAQL-PB), the General Health Questionnaire (GHQ12) and the Food Allergy Impact Measure (FAIM). A total of 250 parents completed the re-test of the FASE-P. Results: Factor and reliability analysis resulted in a 21 item scale with 5 sub-scales. The overall scale and sub-scales has good to excellent internal consistency (α’s of 0.63-0.89) and the scale is stable over time. There were low to moderate significant correlations with the GSES, FAIM and GHQ12 and strong correlations with the FAQL-PB, with better parental confidence relating to better general self-efficacy, better quality of life and better mental health in the parent. Poorer self-efficacy was related to egg and milk allergy; self-efficacy was not related to severity of allergy. Conclusions and clinical relevance: The FASE-P is a reliable and valid scale for use with parents from a general population. Its application within clinical settings could aid provision of advice and improve targeted interventions by identifying areas where parents have less confidence in managing their child’s food allergy.

Innovative biomarkers for predicting type 2 diabetes mellitus:relevance to dietary management of frailty in older adults

Type 2 diabetes mellitus (T2DM) increases in prevalence in the elderly. There is evidence for significant muscle loss and accelerated cognitive impairment in older adults with T2DM; these comorbidities are critical features of frailty. In the early stages of T2DM, insulin sensitivity can be improved by a “healthy” diet. Management of insulin resistance by diet in people over 65 years of age should be carefully re-evaluated because of the risk for falling due to hypoglycaemia. To date, an optimal dietary programme for older adults with insulin resistance and T2DM has not been described. The use of biomarkers to identify those at risk for T2DM will enable clinicians to offer early dietary advice that will delay onset of disease and of frailty. Here we have used an in silico literature search for putative novel biomarkers of T2DM risk and frailty. We suggest that plasma bilirubin, plasma, urinary DPP4-positive microparticles and plasma pigment epithelium-derived factor merit further investigation as predictive biomarkers for T2DM and frailty risk in older adults. Bilirubin is screened routinely in clinical practice. Measurement of specific microparticle frequency in urine is less invasive than a blood sample so is a good choice for biomonitoring. Future studies should investigate whether early dietary changes, such as increased intake of whey protein and micronutrients that improve muscle function and insulin sensitivity, affect biomarkers and can reduce the longer term complication of frailty in people at risk for T2DM.