Psychosocial adjustment to Mild Cognitive Impairment: The role of illness perceptions, cognitive fusion and cognitive impairment.

BACKGROUND AND OBJECTIVE: Receiving a Mild Cognitive Impairment diagnosis and adjusting to this condition is challenging, given the uncertain clinical trajectory surrounding progression to dementia. We aimed to explore the influence of illness perceptions and cognitive fusion on coping and emotional responses in a sample of people diagnosed with Mild Cognitive Impairment.Research design and method: A cross-sectional study of 34 participants with Mild Cognitive Impairment (47% female and 53% male; mean age 76.4 years) evaluated the relationships between cognitive impairment, illness perceptions and cognitive fusion on levels of distress and quality of life. Participants completed standardised measures for cognitive assessment, illness perceptions, cognitive fusion, depression, anxiety and quality of life. Relationships between variables were analysed using correlation, regression and conditional process analyses. RESULTS: At the group level, illness perceptions were found to be a stronger predictor of depression and quality of life in the current sample than objective cognitive impairment. Illness perceptions did not directly predict anxiety, rather cognitive fusion significantly mediated this relationship. Cognitive fusion also significantly mediated the relationship between illness perceptions and depression. Illness perceptions had a significant, direct effect on quality of life; however, there was no significant indirect effect via cognitive fusion. Greater fusion with threatening illness perceptions was significantly related to increased anxiety and depression.Discussion and implications: Data suggest multiple potential treatment targets in helping people diagnosed with Mild Cognitive Impairment to successfully adapt and adjust. Targeting appraisals (illness perceptions) using Cognitive Therapy is one potential treatment target. In addition, psychological treatments such as Acceptance and Commitment Therapy, which target cognitive fusion, could also warrant further investigation in this population, due to the significant indirect paths from illness perceptions to distress and quality of life, via cognitive fusion.

Evaluation of Aquacel Ag for Autogenous Skin Donor Sites.

An ongoing objective of burn research is to evaluate wound dressings and develop new treatments to expedite wound healing. This was a single-center, prospective, randomized, controlled study to evaluate the effectiveness of Aquacel Ag as a dressing for autogenous skin donor sites compared with Xeroform. We hypothesized that donor sites treated with Aquacel Ag would heal faster. Patients were considered for enrollment if they required skin grafting with two donor sites >100 cm at least 2 inches apart. Dressings were observed daily starting on post-op day #2 until discharge and then weekly in the outpatient burn clinic. Assessments evaluated pain, infection, and reapplication. Photographs were taken on post-op day #2, upon "90% re-epithelialization," and at post-op day #30-45. Scar assessments and blinded photographic reviews were completed to assess cosmetic healing. Twenty-nine patients completed the study. Re-epithelialization occurred faster with Xeroform (15.2 days vs. 17.6 days). Daily pain scores were higher with Xeroform (6.72 vs. 5.68) and Aquacel Ag needed to be replaced more often (1.72 times vs. 0.10 times). Three patients developed donor site infections with Aquacel Ag. Scar scores between the donor sites were not statistically significant. The blinded photo review concluded that Xeroform had a better cosmetic outcome (24 vs. 10%). Although patients complained of more pain with Xeroform, it demonstrated shorter healing times and better cosmetic outcomes. Aquacel Ag needed to be replaced more often and represented the only three donor site infections.

Setting global research priorities for integrated community case management (iCCM): Results from a CHNRI (Child Health and Nutrition Research Initiative) exercise.

AIMS: To systematically identify global research gaps and resource priorities for integrated community case management (iCCM). METHODS: An iCCM Child Health and Nutrition Research Initiative (CHNRI) Advisory Group, in collaboration with the Community Case Management Operational Research Group (CCM ORG) identified experts to participate in a CHNRI research priority setting exercise. These experts generated and systematically ranked research questions for iCCM. Research questions were ranked using a "Research Priority Score" (RPS) and the "Average Expert Agreement" (AEA) was calculated for every question. Our groups of experts were comprised of both individuals working in Ministries of Health or Non Governmental Organizations (NGOs) in low- and middle-income countries (LMICs) and individuals working in high-income countries (HICs) in academia or NGO headquarters. A Spearman's Rho was calculated to determine the correlation between the two groups' research questions' ranks. RESULTS: The overall RPS ranged from 64.58 to 89.31, with a median score of 81.43. AEA scores ranged from 0.54 to 0.86. Research questions involving increasing the uptake of iCCM services, research questions concerning the motivation, retention, training and supervision of Community Health Workers (CHWs) and concerning adding additional responsibilities including counselling for infant and young child feeding (IYCF) and treatment of severe acute malnutrition (SAM) ranked highly. There was weak to moderate, statistically significant, correlation between scores by representatives of high-income countries and those working in-country or regionally (Spearman's ρ = 0.35034, P < 0.01). CONCLUSIONS: Operational research to determine optimal training, supervision and modes of motivation and retention for the CHW is vital for improving iCCM, globally, as is research to motivate caregivers to take advantage of iCCM services. Experts working in-country or regionally in LMICs prioritized different research questions than those working in organization headquarters in HICs. Further exploration is needed to determine the nature of this divergence.

Depression in first episode psychosis: the role of subordination and shame.

Depression in early psychosis is linked to poor outcome, relapse and risk of suicide, yet remains poorly understood. This article aims to examine the development of depression in acute and post psychotic phases of first episode psychosis (FEP), and its relationship to persecutors, voices, insight, and recovery. Data were gathered on 92 patients with acute FEP on depression course, severity and experience of positive symptoms, insight and appraisals of illness using validated semi-structured interviews and questionnaires. Measures were repeated at 12 months. Malevolent voices, use of safety behaviours and subordination to persecutors were associated with depression and suicidal behaviour in acute FEP. Loss, Shame, low level continuing positive symptoms and longer duration of untreated psychosis were associated with post psychotic depression. Negative appraisals remained stable despite recovery in other symptom domains. Thus, depression and risk in early psychosis may be propagated by the personal significance and content of positive symptoms experienced. When in recovery, low level symptoms, longer period of illness and negative appraisals are significant factors.

Cognitive Biases Questionnaire for psychosis.

OBJECTIVE: The Cognitive Biases Questionnaire for psychosis (CBQp) was developed to capture 5 cognitive distortions (jumping to conclusions, intentionalising, catastrophising, emotional reasoning, and dichotomous thinking), which are considered important for the pathogenesis of psychosis. Vignettes were adapted from the Cognitive Style Test (CST),(1) relating to "Anomalous Perceptions" and "Threatening Events" themes. METHOD: Scale structure, reliability, and validity were investigated in a psychosis group, and CBQp scores were compared with those of depressed and healthy control samples. RESULTS: The CBQp showed good internal consistency and test-retest reliability. The 5 biases were not independent, with a 2-related factor scale providing the best fit. This structure suggests that the CBQp assesses a general thinking bias rather than distinct cognitive errors, while Anomalous Perception and Threatening Events theme scores can be used separately. Total CBQp scores showed good convergent validity with the CST, but individual biases were not related to existing tasks purporting to assess similar reasoning biases. Psychotic and depressed populations scored higher than healthy controls, and symptomatic psychosis patients scored higher than their nonsymptomatic counterparts, with modest relationships between CBQp scores and symptom severity once emotional disorders were partialled out. Anomalous Perception theme and Intentionalising bias scores showed some specificity to psychosis. CONCLUSIONS: Overall, the CBQp has good psychometric properties, although it is likely that it measures a different construct to existing tasks, tentatively suggested to represent a bias of interpretation rather than reasoning, judgment or decision-making processes. It is a potentially useful tool in both research and clinical arenas.

A prospective study of PTSD following recovery from first-episode psychosis: the threat from persecutors, voices, and patienthood.

OBJECTIVES: Approximately one third of people with early psychosis report post-traumatic symptoms, some of which are thought to arise from traumatic experiences associated with psychosis itself. This prospective study tested hypotheses based on retrospective findings that threat appraisals of voices, persecutors, or the new label of 'mental health patient' predict symptoms of post-traumatic stress disorder (PTSD). METHODS: Appraisals of power and threat from voices and other persecutors and appraisals of the threat posed to identity by the diagnosis were assessed during the first acute phase of psychosis. Eighteen months later, PTSD symptom levels and diagnosis were established. DESIGN: Prospective. RESULTS: Of 39 participants who completed the follow-up phase, 12 (31%) met criteria for PTSD diagnosis. Nineteen (49%) of the participants were still distressed by memories of their psychosis or the associated treatment. During the acute phase of psychosis, appraisals of threat from voices and persecutors were strongly associated with distress. With the exception of the perceived ability to cope with threat, none of these appraisals were predictive of subsequent post-traumatic stress however. Similarly, only one appraisal of the diagnosis (loss of control) was predictive of PTSD. CONCLUSION: It may be that retrospective studies have overestimated the influence of candidate appraisals in predicting PTSD. It might also be that assessments made during the acute phase of psychosis preceded a key phase of psychological processing that takes place during the immediate aftermath of the psychotic episode. A staged prospective design is required to uncover the true impact of psychosis on PTSD.

A randomized experimental investigation of reasoning training for people with delusions.

The present study aimed to investigate whether a brief reasoning training module changes the "jumping to conclusions" data gathering bias in people with delusions. A secondary aim was to examine whether improvements in reasoning would lead to greater flexibility in thinking about delusions. It was found that people with delusions and a diagnosis of schizophrenia (n = 34) requested less information on a reasoning task compared with a nonclinical control group (n = 34). The clinical group was then randomly allocated to a session of reasoning training or to an attention control condition. Following training, participants showed a significant increase in data gathering, and a small number reported more flexibility and less conviction in their delusions, although this finding was not significant. The presence at baseline of an extreme reasoning bias moderated the effect of training. The study provides further confirmation of the jumping to conclusions bias and shows that data gathering can be improved, though the severest form of the bias is resistant to change. It is recommended that lengthier, delusion-related reasoning packages be developed and evaluated.

Distinct roles of galactose-1P in galactose-mediated growth arrest of yeast deficient in galactose-1P uridylyltransferase (GALT) and UDP-galactose 4'-epimerase (GALE).

Galactose is metabolized in humans and other species by the three-enzyme Leloir pathway comprised of galactokinase (GALK), galactose 1-P uridylyltransferase (GALT), and UDP-galactose 4'-epimerase (GALE). Impairment of GALT or GALE in humans results in the potentially lethal disorder galactosemia, and loss of either enzyme in yeast results in galactose-dependent growth arrest of cultures despite the availability of an alternate carbon source. In contrast, loss of GALK in humans is not life-threatening, and in yeast has no impact on the growth of cultures challenged with galactose. Further, the growth of both GALT-null and GALE-null yeast challenged with galactose is rescued by loss of GALK, thereby implicating the GALK reaction product, gal-1P, for a role in the galactose-sensitivity of both strains. However, the nature of that relationship has remained unclear. Here we have developed and applied a doxycycline-repressible allele of galactokinase to define the quantitative relationship between galactokinase activity, gal-1P accumulation, and growth arrest of galactose-challenged GALT or GALE-deficient yeast. Our results demonstrate a clear threshold relationship between gal-1P accumulation and galactose-mediated growth arrest in both GALT-null and GALE-null yeast, however, the threshold for the two strains is distinct. Further, we tested the galactose-sensitivity of yeast double-null for GALT and GALE, and found that although loss of GALT barely changed accumulation of gal-1P, it significantly lowered the accumulation of UDP-gal, and also dramatically rescued growth of the GALE-null cells. Together, these data suggest that while gal-1P alone may account for the galactose-sensitivity of GALT-null cells, other factors, likely to include UDP-gal accumulation, must contribute to the galactose-sensitivity of GALE-null cells.

Mediators of galactose sensitivity in UDP-galactose 4'-epimerase-impaired mammalian cells.

UDP-galactose 4'-epimerase (GALE) catalyzes the final step in the Leloir pathway of galactose metabolism, interconverting UDP-galactose and UDP-glucose. Unlike its Escherichia coli counterpart, mammalian GALE also interconverts UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. Considering the key roles played by all four of these UDP-sugars in glycosylation, human GALE therefore not only contributes to the Leloir pathway, but also functions as a gatekeeper overseeing the ratios of important substrate pools required for the synthesis of glycosylated macromolecules. Defects in human GALE result in the disorder epimerase-deficiency galactosemia. To explore the relationship among GALE activity, substrate specificity, metabolic balance, and galactose sensitivity in mammalian cells, we employed a previously described GALE-null line of Chinese hamster ovary cells, ldlD. Using a transfection protocol, we generated ldlD derivative cell lines that expressed different levels of wild-type human GALE or E. coli GALE and compared the phenotypes and metabolic profiles of these lines cultured in the presence versus absence of galactose. We found that GALE-null cells accumulated abnormally high levels of Gal-1-P and UDP-Gal and abnormally low levels of UDP-Glc and UDP-GlcNAc in the presence of galactose and that human GALE expression corrected each of these defects. Comparing the human GALE- and E. coli GALE-expressing cells, we found that although GALE activity toward both substrates was required to restore metabolic balance, UDP-GalNAc activity was not required for cell proliferation in the presence of otherwise cytostatic concentrations of galactose. Finally, we found that uridine supplementation, which essentially corrected UDP-Glc and, to a lesser extent UDP-GlcNAc depletion, enabled ldlD cells to proliferate in the presence of galactose despite the continued accumulation of Gal-1-P and UDP-Gal. These data offer important insights into the mechanism of galactose sensitivity in epimerase-impaired cells and suggest a potential novel therapy for patients with epimerase-deficiency galactosemia.

Differential roles of the Leloir pathway enzymes and metabolites in defining galactose sensitivity in yeast.

The metabolism of galactose via enzymes of the Leloir pathway: galactokinase, galactose-1-P uridylyltransferase, and UDP galactose-4'-epimerase, is a process that has been conserved from Escherichia coli through humans. Impairment of this pathway in patients results in the disease galactosemia. Despite decades of study, the underlying pathophysiology in galactosemia remains unknown. Here we have defined the functional and metabolic implications of impaired galactose metabolism in yeast, by asking two questions: (1) What is the impact of loss of each of the three Leloir enzymes on the ability of cells to metabolize galactose, and on their sensitivity to galactose, and (2) what is the relationship between gal-1P and galactose-sensitivity in yeast? Our results demonstrate that only transferase-null cells are able to deplete their medium of galactose; deletion of kinase or epimerase halts this process. In contrast, only kinase-null cultures grow well in glycerol/ethanol medium despite the addition of galactose; both transferase and epimerase-null yeast arrest growth under these conditions. Indeed, epimerase-null yeast arrest growth at galactose concentrations 10-fold lower than do their transferase-null counterparts. Secondary deletion of kinase relieves growth arrest in both strains. Finally, rather than a continuous relationship between gal-1P and growth arrest, we observed a threshold level of gal-1P (approximately 10 nmol/mg cell DM) above which both transferase-null and epimerase-null cultures could not grow. These results both confirm and significantly extend prior knowledge of galactose metabolism in yeast, and set the stage for future studies into the mediators and mechanism of Leloir-impaired galactose sensitivity in eukaryotes.

Use of LeVeen pleuroperitoneal shunt for refractory high-volume chylothorax.

We present a case of intractable high-volume (> 2L/d) chylothorax after transhiatal esophagectomy treated successfully with the simultaneous insertion of both Denver (Denver Biomedical, Golden, CO) and LeVeen (Becton-Dickinson, Rutherford, NJ) pleuroperitoneal shunts. The patient initially had chemoradiotherapy for a T4N1 squamous cell carcinoma of the thoracic esophagus. Re-staging showed a dramatic shrinkage of tumor, and a transhiatal esophagectomy was performed. Sequential bilateral thoracotomies were performed on postoperative days 19 and 26 for attempted control of high-volume chylothorax, but these were unsuccessful. Subsequent pleuroperitoneal shunt insertion was used, which immediately controlled the effusion. A shunt study was performed shortly after hospital discharge, which showed an occluded Denver shunt and a patent LeVeen shunt. The patient succumbed to metastatic carcinoma 18 months after discharge, but no pleural effusion had recurred.

Determinants of function and substrate specificity in human UDP-galactose 4'-epimerase.

UDP-galactose 4'-epimerase (GALE) interconverts UDP-galactose and UDP-glucose in the final step of the Leloir pathway. Unlike the Escherichia coli enzyme, human GALE (hGALE) also efficiently interconverts a larger pair of substrates: UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. The basis of this differential substrate specificity has remained obscure. Recently, however, x-ray crystallographic data have both predicted essential active site residues and suggested that differential active site cleft volume may be a key factor in determining GALE substrate selectivity. We report here a direct test of this hypothesis. In brief, we have created four substituted alleles: S132A, Y157F, S132A/Y157F, and C307Y-hGALE. While the first three substitutions were predicted to disrupt catalytic activity, the fourth was predicted to reduce active site cleft volume, thereby limiting entry or rotation of the larger but not the smaller substrate. All four alleles were expressed in a null-background strain of Saccharomyces cerevisiae and characterized in terms of activity with regard to both UDP-galactose and UDP-N-acetylgalactosamine. The S132A/Y157F and C307Y-hGALE proteins were also overexpressed in Pichia pastoris and purified for analysis. In all forms tested, the Y157F, S132A, and Y157F/S132A-hGALE proteins each demonstrated a complete loss of activity with respect to both substrates. In contrast, the C307Y-hGALE demonstrated normal activity with respect to UDP-galactose but complete loss of activity with respect to UDP-N-acetylgalactosamine. Together, these results serve to validate the wild-type hGALE crystal structure and fully support the hypothesis that residue 307 acts as a gatekeeper mediating substrate access to the hGALE active site.

Cognitive therapy for command hallucinations: randomised controlled trial.

BACKGROUND: Command hallucinations are a distressing and high-risk group of symptoms that have long been recognised but little understood, with few effective treatments. In line with our recent research, we propose that the development of an effective cognitive therapy for command hallucinations (CTCH) would be enhanced by applying insights from social rank theory. AIMS: We tested the efficacy of CTCH in reducing beliefs about the power of voices and thereby compliance, in a single-blind, randomised controlled trial. METHOD: A total of 38 patients with command hallucinations, with which they had recently complied with serious consequences, were allocated randomly to CTCH or treatment as usual and followed up at 6 months and 12 months. RESULTS: Large and significant reductions in compliance behaviour were obtained favouring the cognitive therapy group (effect size 1.1). Improvements were also observed in the CTCH but not the control group in degree of conviction in the power and superiority of the voices and the need to comply, and in levels of distress and depression. No change in voice topography (frequency, loudness, content) was observed. The differences were maintained at 12 months' follow-up. CONCLUSIONS: The results support the efficacy of cognitive therapy for CTCH.

Novel roles for iron regulatory proteins in the adaptive response to iron deficiency.

Iron regulatory proteins (IRP) modulate the use of mRNA-encoding proteins that are involved in the transport, storage and use of iron. Several new potential mRNA targets for IRP were recently identified: divalent metal transporter-1 (DMT-1) and ferroportin, which are critical regulators of iron absorption in the gut and of iron cycling between various tissues of the body. Although this may extend the reach of IRP to other processes that are important for maintaining body iron homeostasis, the extent to which IRP modulate other physiological processes that are altered in response to changes in iron availability is not clear. However, in the past several years, targets for IRP and IRP-like proteins were identified in eukaryotes and prokaryotes in the tricarboxylic acid (TCA) cycle and electron-transport chain. In mammals, this includes the mRNA that encodes the TCA-cycle enzyme mitochondrial aconitase (m-acon). Recent work established that m-acon expression is translationally regulated by iron in a manner that is strongly correlated with IRP RNA-binding activity. Interestingly, these studies also demonstrate that IRP regulate their mRNA targets in a hierarchical manner. The changes in m-acon synthesis and abundance in liver during iron deficiency fail to affect TCA-cycle capacity but are associated with a significant upregulation of mitochondrial export of radiolabeled citrate. We conclude that IRP are required for the regulation of physiological pathways that include but are not limited to iron metabolism, and as such, IRP are critical factors in the adaptive response to iron deficiency.

Iron deficiency decreases mitochondrial aconitase abundance and citrate concentration without affecting tricarboxylic acid cycle capacity in rat liver.

Mitochondrial aconitase (m-acon) is the tricarboxylic acid (TCA) cycle enzyme that converts citrate to isocitrate. m-Acon mRNA is a potential target for regulation by iron regulatory proteins (IRPs), suggesting a link between dietary iron intake, m-acon synthesis, and energy metabolism. Our previous studies indicate that m-acon is one of a limited number of proteins that is down-regulated in iron-deficient liver. Here we use isolated hepatocytes to study the relationships among decreased m-acon abundance, TCA cycle function and cellular citrate concentration in iron deficiency. Rats were fed an iron-deficient (ID) (2 mg Fe/kg diet) diet, or they were pair-fed (PF) or freely fed (C) a control diet (50 mg Fe/kg diet) for up to 21 d. Hepatocyte total IRP activity was greater by d 2 in the ID group than in the C and PF groups and by d 10, the difference was maximal. Liver IRP activity was inversely correlated with m-acon abundance (r = -0.93, P < 0.0001). However, the decrease in m-acon abundance did not affect the ability of hepatocytes to oxidize 2-[(14)C]pyruvate or 1-[(14)C]acetate, indicating that TCA cycle capacity was not affected. Interestingly, by d 21, total liver citrate concentration was 40% lower in ID than in PF rats, suggesting enhanced utilization of citrate. However, the decrease in citrate concentration was not reflected in a change in liver total lipid concentration. Taken together, our results indicate that the iron-dependent regulation of m-acon in liver does not alter TCA cycle capacity but suggest that IRP-mediated changes in m-acon expression may modulate citrate use in other aspects of intermediary or iron metabolism.

Uroporphyria in mice: thresholds for hepatic CYP1A2 and iron.

In mice treated with 5-aminolevulinic acid (ALA) and polyhalogenated aromatic compounds, the levels of both hepatic cytochrome P450 (CYP)1A2 and iron-which can be quite different among inbred strains-are critical in causing experimental uroporphyria. Here we investigate the development of uroporphyria as a function of CYP1A2 and iron levels in the liver of mice having a common C57BL/6 genetic background. We compared Cyp1a2(-/-) knockout mice, Cyp1a2(+/-) heterozygotes, Cyp1a2(+/+) wild type, and Cyp1a2(+/+) mice pretreated with a low dose of 3,3',4,4',5-pentachlorobiphenyl (PCB126) (4 microg/kg). Cyp1a2(+/-) mice contain about 60% of the hepatic CYP1A2 content of Cyp1a2(+/+) mice, and the PCB126-pretreated Cyp1a2(+/+) mice have about twice the wild-type levels of CYP1A2. ALA- and iron-treated Cyp1a2(+/+) mice are known to accumulate hepatic uroporphyrin; this accumulation was increased 7-fold by pretreatment with the low dose of PCB126. ALA- and iron-treated Cyp1a2(+/-) heterozygote mice accumulated no uroporphyrin in 4 weeks, but by 8 weeks accumulated significant amounts of uroporphyrin. As previously reported, the ALA- and iron-treated Cyp1a2(-/-) knockout mouse has no CYP1A2 and exhibits no detectable uroporphyrin accumulation. Iron dose-response curves in ALA- and PCB126-treated Cyp1a2(+/+) mice showed that hepatic iron levels greater than 850 microg/g liver were required to produce significant uroporphyrin accumulation in the liver. Other measures of hepatic effects of iron (iron-response element-binding protein [IRP]-iron response element [IRE] binding activity and accumulation of protoporphyrin from ALA) decreased when the level of iron was considerably lower than 850 microg/g liver. At low iron doses, accumulation of iron was principally in Kupffer cells, whereas at the higher doses (required to stimulate uroporphyrin accumulation), more iron was found in parenchymal cells. We conclude that small changes in hepatic CYP1A2 levels can dramatically affect uroporphyria in C57BL/6 mice, providing the animals have been sufficiently loaded with iron; these data might be clinically relevant to acquired (sporadic) porphyria cutanea tarda, because humans show greater than 60-fold genetic differences in hepatic basal CYP1A2.