An Extensively Humanized Mouse Model to Predict Pathways of Drug Disposition and Drug/Drug Interactions, and to Facilitate Design of Clinical Trials.

Species differences in drug metabolism and disposition can confound the extrapolation of in vivo PK data to man and also profoundly compromise drug efficacy studies owing to differences in pharmacokinetics, in metabolites produced (which are often pharmacologically active), and in differential activation of the transcription factors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), which regulate the expression of such enzymes as P450s and drug transporters. These differences have gained additional importance as a consequence of the use of genetically modified mouse models for drug-efficacy testing and also patient-derived xenografts to predict individual patient responses to anticancer drugs. A number of humanized mouse models for cytochrome P450s, CAR, and PXR have been reported. However, the utility of these models has been compromised by the redundancy in P450 reactions across gene families, whereby the remaining murine P450s can metabolize the compounds being tested. To remove this confounding factor and create a mouse model that more closely reflects human pathways of drug disposition, we substituted 33 murine P450s from the major gene families involved in drug disposition, together with Car and Pxr, for human CAR, PXR, CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4, and CYP3A7. We also created a mouse line in which 34 P450s were deleted from the mouse genome. Using model compounds and anticancer drugs, we demonstrated how these mouse lines can be applied to predict drug-drug interactions in patients and discuss here their potential application in the more informed design of clinical trials and the personalized treatment of cancer.

Well-being in Chronic Fatigue Syndrome: Relationship to Symptoms and Psychological Distress.

OBJECTIVE: There is growing recognition in psychology that wellness is more than the absence of disease and distress. Well-being has been defined in numerous ways. Two dominant models include Diener, Eunkook, Suh, Lucas and Smith's (1999) model of subjective well-being (SWB) and Ryff's (1989) model of psychological well-being (PWB). In contrast to the abundance of research investigating negative constructs and psychopathology in chronic fatigue syndrome (CFS), there has been a paucity of positive psychology studies. This study had two aims: to examine PWB and SWB and their relationship to symptoms in CFS and to compare PWB scores in a subgroup of the CFS sample to a matched control group. METHOD: Chronic fatigue syndrome participants (n = 60) completed self-report scales of PWB, SWB, fatigue, anxiety and depression. PWB scores in a subgroup of the CFS sample (n = 42) were compared with those of a matched nonclinical control group (n = 42). RESULTS: Correlations between scales of symptoms and well-being were complex. Well-being dimensions were largely independent of physical components of fatigue but strongly related to psychological components of fatigue and psychological distress. Multiple regression indicated that five dimensions of well-being uniquely predicted symptomatology. Compared with the control group, the CFS group scored significantly lower on five of Ryff's six PWB dimensions, with particularly marked deficits in personal growth, environmental mastery and self-acceptance. CONCLUSION: This multidimensional assessment of well-being advances our understanding of CFS and offers new treatment targets. Future research must investigate whether interventions targeting theses well-being deficits can boost the efficacy of symptom-focused treatments. Copyright © 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGES: Previous psychological research into CFS has largely focused on the identification of negative constructs and CBT, a treatment that targets evidenced-based negative constructs, has demonstrated efficacy in reducing levels of fatigue and disability. However, the majority of people continue to experience psychiatric symptoms and excessive levels of fatigue post-treatment. Finding ways to enhance the efficacy of existing treatments is a clinical priority. There is evidence to suggest that in clinical populations, standard CBT is effective at reducing negative affect and thinking but fails to enhance low levels of positive affect and thinking, implying treatments may be more effective if they promote positive functioning alongside a reduction of negative functioning. Multidimensional models of well-being suggest that well-being is not a single phenomenon, and different psychological disorders may be characterized by varying well-being deficit profiles. Psychological well-being was found to be diminished in CFS participants compared with controls, with particularly marked deficits in personal growth, environmental mastery and self-acceptance, suggesting that these may be particularly important treatment targets. Well-being dimensions within the CFS group were largely independent of physical symptoms but strongly related to psychological symptoms, suggesting what may be causing low levels of well-being in CFS is largely psychological factors and the general impact of living with a chronic illness rather than symptom levels per se.

Some principles and practices of genetic biobanking studies.

Genetic biobanking studies are becoming increasingly common as researchers recognise the need for large samples to identify the genetic basis of susceptibility to complex disease. In the present review, the authors give a brief overview of some of the issues that should be considered when implementing such a large-scale project, from study design to sample management, data coding and storage to the statistical analysis and engagement with the public. Specific solutions to these issues are presented, as implemented in the Generation Scotland projects, but the general principles outlined are relevant to any biobanking study.

Cytokine gene polymorphisms in obstructive sleep apnoea/hypopnoea syndrome.

OBJECTIVE: The pro-inflammatory cytokines, TNF-α, IL-6, and IL-8 are elevated in obstructive sleep apnoea/hypopnoea syndrome (OSAHS). Cytokine gene interactions are complex and haplotype analysis may be more informative. We hypothesized that the effects of TNF-α in OSAHS might be due to linkage disequilibrium of the TNF-α (-308A) single nucleotide polymorphism (SNP) with other polymorphisms within the TNF-α gene, and that predisposition to elevated IL-6 and IL-8 levels in OSAHS might be attributable to pro-inflammatory IL-6 and IL-8 gene promoter polymorphisms. METHOD: 173 subjects were classified as having definite OSAHS or not on the basis of apnoea-hypopnoea frequency, sex, age, and symptoms. Population controls comprised 192 random UK blood donors. Genotyping was undertaken for the TNF-α promoter polymorphisms (-1031, -863, -857, -238), two lymphotoxin-α polymorphisms (intron 1 and Thr60Asn), the pro-inflammatory IL-6 gene promoter polymorphism (-174), and IL-8 gene promoter polymorphisms (-251; -781). RESULTS: There was no significant difference between groups re: genotype/allelic frequency in the genes investigated. Association between disease status and the TNF-α alleles independently (TNF-103, TNF-803, TNF-857, TNF-238) with five haplotypes of TNF-α was not significant (p > 0.05). There was no difference in allelic or genotypic frequencies between obese and non-obese subjects with OSAHS. The TNF-α (-863A) allele alone, was significantly associated with obesity (OR 2.4; CI95% 1.1-5; p = 0.025). CONCLUSION: Only the TNF-α (308A) SNP appears to be significantly associated with OSAHS. The impact of cytokine gene polymorphisms on phenotypic expression of inflammation in OSAHS is likely to be complex.

Anxiety, depression, and the anticipation of future positive and negative experiences.

An experiment is reported that attempts to distinguish between anxious and depressive future thinking in terms of anticipation of future positive and future negative experiences. Anxious, mixed (anxious-depressed), and control participants were given an adapted verbal fluency paradigm to examine the ease with which they could think of future positive and negative personal experiences. Anxious participants differed from controls only in anticipating more future negative experiences; mixed participants showed both greater anticipation of negative experiences and reduced anticipation of positive experiences. Self-report measures of hopelessness and worry followed a similar pattern to future positive and future negative anticipation, respectively. The results are discussed in terms of the distinction between positive affect and negative affect (D. Watson, L. A. Clark, & G. Carey, 1988).

Worry is reasonable: the role of explanations in pessimism about future personal events.

This experiment examines one component of worry, elevated subjective probabilities of negative events, and attempts to elucidate the cognitive processes on which this is based. The results suggest that the pessimistic subjective probabilities shown by chronic worriers can be understood using general theories of judgment, specifically, by the use of the availability heuristic (Tversky & Kahneman, 1973). However, it is the availability of a particular pattern of cognitions--an increased accessibility of explanations for why a negative event would occur, combined with a reduced accessibility of explanations for why it would not--that is important. The results are integrated within a description of the worry process, and possible clinical applications through the use of reason-generation techniques are discussed.

Explaining why negative events will happen to oneself: parasuicides are pessimistic because they can't see any reason not to be.

Parasuicides (N = 18) were compared with matched controls (N = 18) on their subjective probability judgements for nine future, negative, self-relevant events. Prior to the probability judgements, subjects were asked to think of reasons why the events would or would not happen. The ease with which they were able to think of reasons was assessed by time taken to think of the first reason, number of different reasons given in 90 seconds and a subjective rating of difficulty. Relative to controls, parasuicides judged negative events to be more likely. They also showed evidence of finding it more difficult to think of why those events might not happen, but were no different from controls in their ability to think of reasons why the events would happen. The effect of thinking of reasons against negative events happening was to reduce the pessimism of parasuicides. It is suggested that parasuicide subjects may not actively anticipate future negative outcomes, but when presented with the possibilities, they judge them to be likely because of an inability to think of positive aspects of themselves or their circumstances which would prevent those events happening.

Attributions and accessibility of explanations for future events in anxiety and depression.

OBJECTIVES: The research examined qualitative and quantitative aspects of future thinking in mood-disturbed participants. DESIGN: A cross-sectional, mixed design compared three groups of participants on measures of future thinking using an adapted fluency paradigm. METHODS: Participants who were either anxious (N = 25), anxious and depressed (mixed; N = 25), or neither anxious nor depressed (control; N = 25) were presented with a range of future positive and negative events and asked to provide explanations as to why those events would (pro reasons) or would not (con reasons) happen to them. Number of reasons given of each type was measured. The reasons were further analysed in terms of a number of attributional dimensions. RESULTS: Mood-disturbed participants (anxious and mixed) provided more pro relative to con reasons for negative events and more con relative to pro reasons for positive events. Compared to the control group, mood-disturbed participants also provided more internal and more global reasons for why negative events would happen and for why positive events would not happen. CONCLUSION: Mood-disturbed participants differ from controls on qualitative as well as quantitative aspects of future thinking.

Overgeneralization: an important but non-homogeneous construct.

Two self-report scales--the Cognitions Questionnaire (Fennell & Campbell, 1984) and the Attitudes to Self Scale (Carver & Ganellen, 1983)--which attempt to measure overgeneralization in depression are described. In line with previous research, both measures correlated with levels of depression, but the lack of a direct relationship between them implies that the construct of overgeneralization may not be a homogeneous one. Suggestions are made for future research which include elaboration of the construct and the development of new methods for measuring it.

Recovery of positive future thinking within a high-risk parasuicide group: results from a pilot randomized controlled trial.

OBJECTIVES: The research examined: (i) whether high risk parasuicide patients showed a deficit in positive future thinking but no increase in negative future thinking; and (ii) whether such a deficit could be remedied by a brief, manual-assisted psychological intervention (manual assisted cognitive-behaviour therapy; MACT). DESIGN: A cross-sectional, mixed model design was used to assess differences between a sample of high risk parasuicide patients and matched controls on future thinking. A longitudinal mixed model design was used to assess changes in future thinking in the different groups over time. METHODS: Parasuicide patients with a history of previous suicidal behaviour and personality disturbance were compared with a matched group of community controls on an adapted fluency measure of future thinking, which measured both quantitative and qualitative aspects of anticipated experiences. Patients were then randomly allocated to either the specific intervention (MACT) or treatment as usual (TAU) and assessed again at 6 month follow-up. RESULTS: Parasuicide patients showed reduced positive future thinking but no increased negative future thinking. Patients who received MACT showed a significant improvement in positive future thinking over the follow-up period whereas the TAU group showed no such improvement. However, interpretation of this finding was made more difficult by the control group also showing a significant improvement in positive future thinking. CONCLUSION: The results confirm that parasuicide patients exhibit a relative deficit in positive future thinking and suggest that this lack of positive future thinking may be remedied, at least partly, by a brief intervention.

Associations between phenomenal and objective aspects of concentration problems in depressed patients.

The paper explores a distinction between different kinds of lapse of concentration in depressed patients. The strategy is to begin with the phenomenological distinction between the mind (a) 'wandering' on to something else or (b) going 'blank'. Blanking, but not mind-wandering, is associated with longer planning times on the 'Tower of London' task. In contrast, mind-wandering but not blanking, is associated with poor memory for prose, at least under ordinary processing conditions. Different phenomenal forms of concentration problem thus have different task performance correlates. A tentative formulation is offered in terms of Shallice's model of the regulation of attention. Mind-wandering is seen as a problem of 'contention scheduling', and blanking as the result of generalized inhibition by the Supervisory Attentional System. It is evident that not all performance deficits in depression can be attributed to the cognitive capacity taken up by competing thoughts.

Drowning your sorrows? Attitudes towards alcohol in UK Jews and Protestants: a thematic analysis.

BACKGROUND: Jewish culturally supported beliefs may discourage drinking and drunkenness as ways of socialising and coping with stress. Thus Jewish men under stress may be relatively more likely to become depressed, and less likely to use and abuse alcohol. This study is the first qualitative comparison of Jews and Protestants, men and women. It examines whether alcohol-related beliefs are consistent with the alcohol-depression hypothesis, i.e. that positive beliefs about alcohol use and effects are associated with high alcohol use and low depression. MATERIAL AND DISCUSSION: A thematic (interpretive phenomenological) analysis on open-ended question responses, from 70 Jews and 91 Protestants, and on semi-structured interviews with five Jews and four Protestants, identified three salient themes: the importance of retaining self-control; the pleasures of losing inhibitions; and the relations of alcohol-related behaviour to identity. Compared to Protestants, Jews described alcohol-related behaviour as threatening to self-control, loss of inhibition as unenjoyable and dangerous and distinguished between the kinds of drinking behaviours appropriate for Jews and others. Sub-themes for Protestant men were denial that drinking threatens self-control, and appropriateness of going to the pub. CONCLUSIONS: The themes identified are not measurable using published research instruments. Alcohol-related behaviour may be a feature of Jewish identity. The beliefs identified are consistent with the alcohol-depression hypothesis.

Tolerance for depression: are there cultural and gender differences?

This study examined tolerance for depression among Jewish and Protestant men and women in the United Kingdom. A measure of tolerance for depression was developed, which examined willingness to admit to and seek help for depression. More specifically, the items in the measure (developed from extended interviews) covered empathy towards sufferers, potential virtues of the illness, hopes for treatment, seeing the illness as 'normal', and telling other people about it. Existing evidence suggested that tolerance for depression might be greater amongst Jews compared with Protestants, and women compared with men. Also, Jewish men were expected to be more tolerant than Protestant men, whereas Protestant and Jewish women were not expected to differ from each other. It was found that tolerance for depression was greater amongst Jews than Protestants, and this is consistent with the elevated levels of depression amongst Jewish men as compared with Protestant men. However, findings relating to gender were mixed and were not always consistent with our expectations. The findings suggest that there may be some cultural variations in willingness to admit to and seek help for depression, and this may be worth examining in other cultural-religious groups. Individual variations in tolerance for depression may be clinically significant.

Marker densities and the mapping of ancestral junctions.

In any partially inbred population, 'junctions' are the loci that form boundaries between segments of ancestral chromosomes. Here we show that the expected number of junctions per Morgan in such a population is linearly related to the inbreeding coefficient of the population, with a maximum in a completely inbred population corresponding to the prediction given by Stam (1980). We further show that high-density marker maps (fully informative markers with average densities of up to 200 per cM) will fail to detect a significant proportion of the junctions present in highly inbred populations. The number of junctions detected is lower than that which would be expected if junctions were distributed randomly along the chromosome, and we show that junctions are not, in fact randomly spaced. This non-random spacing of junctions significantly increases the number of markers that is required to detect 90% of the junctions present on any chromosome: a marker count of at least 12 times the number of junctions present will be needed to detect this proportion.

Moderate levels of chronic mood disturbance are associated with increased cognitive complexity about the self.

Despite its status as a general assumption, the idea that mood disturbance is associated with reduced complexity of cognitive representations has received little in the way of empirical support. It is suggested that this may arise because of a failure to make distinctions concerning the severity and type of mood disturbance, as well as not being specific about what the representations actually refer to. Using repertory grid methodology (Bieri et al., 1966) with a group of moderately mood-disturbed 'worriers', results showed that this group are significantly more complex than matched controls, but only for representations concerned with themselves. Moreover, this was related to chronic rather than current mood disturbance. The results are interpreted as indicating that cognitive complexity may follow an inverted-U pattern, where the self-representations of severely mood-disturbed and control subjects, although differing in valence, are similar in their lack of complexity. On the other hand, those who are chronically but moderately disturbed are, as a result of their ongoing tendency towards introspection, more complex in their self-representations. Possible implications for vulnerability to emotional disorder are discussed.

Parasuicide, depression and the anticipation of positive and negative future experiences.

BACKGROUND: Previous research has shown that parasuicides' view of the future is characterized by an absence of anticipation of positive experiences rather than the presence of anticipation of negative experiences. The present study aimed to replicate this finding and examine whether it would also be found in parasuicides who were not depressed. METHOD: Depressed parasuicides (N = 27), non-depressed parasuicides (N = 17) and matched controls (N = 34) were assessed on their anticipation of future positive and negative experiences using an adapted fluency paradigm, where they were given a set time to generate future positive and negative anticipated experiences. RESULTS: Consistent with previous findings, parasuicides showed an overall reduced anticipation of positive experiences and no overall increased anticipation of negative experiences. However, the parasuicides did show evidence of increased negative anticipation for the immediate future. The results for depressed and non-depressed parasuicides were essentially the same. CONCLUSION: Lack of positive anticipation in the absence of increased negative anticipation is a feature of parasuicide. Although this lack of positive anticipation can occur in depression, it appears to be an independent feature of parasuicide.

Attributions about common bodily sensations: their associations with hypochondriasis and anxiety.

BACKGROUND: Causal attributions about bodily sensations may determine help-seeking and influence patients' demands for medical treatment. The present study aimed to differentiate the causal attributions associated with health-related and non-health-related anxiety. METHODS: Anxious hypochondriacal, generally anxious, and non-anxious general practice attenders were compared on their propensity to give somatic, psychological or normalizing attributions for common bodily sensations, measured by number of each type of attribution in a given time period and the frequency of first response of each type. RESULTS: The groups differed in all three types of attributions. Giving more psychological and fewer normalizing attributions was related to general anxiety whereas giving more somatic attributions was related specifically to hypochondriasis. CONCLUSIONS: Anxiety and hypochondriasis can be distinguished in terms of their associated patterns of attributions for bodily sensations, reinforcing the importance of attributional processes and interventions which use reattributional training.

Causal attributions about common somatic sensations among frequent general practice attenders.

The causal attributions that people make about bodily symptoms or sensations are likely to influence their decisions whether or not to consult a doctor. Previous research has supported the model that people tend initially to look for external or environmental explanations for bodily sensations (normalizing attributions) and only if this process fails do they search for attributions internal to themselves (somatic or psychological attributions). This study tested two hypotheses about frequent general practice attenders: (1) compared with others, they are more likely to make somatic attributions and less likely to make normalizing ones; and (2) given a bodily symptom together with a somatic explanation, frequent attenders will have greater difficulty than others in finding reasons why the given (pathological) explanation is untrue. The frequent attenders' group had themselves initiated an average of 12 general practice visits in the 12 months before assessment, while a control group of infrequent attenders had not made appointments to see their general practitioner for an average of 24 months. The results provide partial support for the hypotheses. Frequent attenders generated significantly fewer normalizing explanations for a series of common bodily sensations than the comparison group, although the two groups did not differ in their somatic attributions. Given a common bodily sensation and an accompanying pathological explanation, the frequent attenders were less able than the control group to generate reasons why the given explanation might be untrue. Some associations were found between these measures and anxiety.