New concepts for distinguishing the hidden patterns of linkage disequilibrium which underlie association between genotypes and complex phenotypes

A disappointing feature of conventional methods for detecting association between DNA variation and a phenotype of interest is that they tell us little about the hidden pattern of linkage disequilibrium (LD) with the functional variant that is actually responsible for the association. This limitation applies to case-control studies and also to the transmission/disequilibrium test (TDT) and other family-based association methods. Here we present a fresh perspective on genetic association based on two novel concepts called 'LD squares' and 'equi-risk alleles'. These describe and characterize the different patterns of gametic LD which underlie genetic association. These concepts lead to a general principle - the Equi-Risk Allele Segregation Principle - which captures the way in which underlying LD patterns affect the transmission patterns of genetic variants associated with a phenotype. This provides a basis for distinguishing the hidden LD patterns and might help to locate the functional variants responsible for the association.

Altitudinal variation in behavioural thermoregulation: Local adaptation vs. plasticity in California grasshoppers

We investigated the adaptive significance of behavioural thermoregulation in univoltine populations of the grasshopper Melanoplus sanguinipes along an altitudinal gradient in California using laboratory tests of animals raised under different temperatures. Trials consisted of continuous body temperature measurements with semi-implanted microprobes in a test arena, and observation and simultaneous recording of behavioural responses. These responses included mobility, basking and orientation of the body axes (aspect angle) towards a radiation source. Mobility and basking are determined by the altitudinal origin of the parental generation and not by the temperature treatments. With increasing altitude, individuals tend increasingly to raise body temperatures via mobility and increased basking. In contrast, body orientation towards the radiation source is influenced by the temperature treatments but not by the altitude of origin. Individuals experiencing higher temperatures during rearing show a lower tendency to lateral flanking. We conclude that body orientation responses are not adapted locally. In contrast other components of the behavioural syndrome that increase body temperature, such as mobility and basking, are adaptive in response to local selection pressure. The thermoregulatory syndrome of these grasshoppers is an important contribution to life-history adaptations that appropriately match season lengths.

The complexity of drinking: Interactions between the cognitive and behavioural determinants of alcohol consumption

This study expanded the earlier work conducted by this laboratory ( Hasking, P.A. and Oei, T.P.S. (2002a) . The differential role of alcohol expectancies, drinking refusal self-efficacy and coping resources in predicting alcohol consumption in community and clinical samples. Addiction Research and Theory , 10 , 465-494), by examining the independent and interactive effects of avoidant coping strategies, positive and negative expectancies and self-efficacy, in predicting volume and frequency of alcohol consumption in a sample of community drinkers. Differential relationships were found between the variables when predicting the two consumption measures. Specifically, while self-efficacy, seeking social support for emotional reasons and using drugs or alcohol to cope were independently related to both volume and frequency of drinking, complex interactions with positive and negative alcohol expectancies were also found. These interactions are discussed in terms of the cognitive and behavioural mechanisms thought to underlie drinking behaviour.

Explaining landholders' decisions about riparian zone management: The role of behavioural, normative, and control beliefs

Water quality is a key concern in the current global environment, with the need to promote practices that help to protect water quality, such as riparian zone management, being paramount. The present study used the theory of planned behaviour as a framework for understanding how beliefs influence decisions about riparian zone management. Respondents completed a survey that assessed their behavioural, normative, and control beliefs in relation to intentions to manage riparian zones on their property. The results of the study showed that, overall, landholders with strong intentions to manage their riparian zones differed significantly in terms of their beliefs compared to landholders who had weak intentions to manage their riparian zones. Strong intentions to manage riparian zones were associated with a favourable cost-benefit analysis, greater perceptions of normative support for the practice and lower perceptions of the extent to which barriers would impede management of riparian zones. It was also evident that willingness to comply with the recommendations of salient referents, beliefs about the benefits of riparian zone management and perceptions of the extent to which barriers would impede riparian zone management were most important for determining intentions to manage riparian zones. Implications for policy and extension practice are discussed. (c) 2005 Elsevier Ltd. All rights reserved.

Objective and behavioural assessment of the emergence from post-traumatic amnesia (PTA)

Primary objective: To determine the profile of resolution of typical PTA behaviours and describe new learning and improvements in self-care during PTA. Research design: Prospective longitudinal study monitoring PTA status, functional learning and behaviours on a daily basis. Methods and procedures: Participants were 69 inpatients with traumatic brain injury who were in PTA. PTA was assessed using the Westmead or Oxford PTA assessments. Functional learning capability was assessed using a routine set of daily tasks and behaviour was assessed using an observational checklist. Data was analysed using descriptive statistics. Main outcomes and results: Challenging behaviours that are typically associated with PTA, such as agitation, aggression and wandering resolved in the early stages of PTA and incidence rates of these behaviours were less than 20%. Independence in self-care and bowel and bladder continence emerged later during resolution of PTA. New learning in functional situations was demonstrated by patients in PTA. Conclusions: It is feasible to begin active rehabilitation focused on functional skills-based learning with patients in the later stages of PTA. Formal assessment of typically observed behaviours during PTA may complement memory-based PTA assessments in determining emergence from PTA.

Habitat type and density influence vocal signal design in satin bowerbirds

This study provided a thorough test of the acoustic adaptation hypothesis using a within-species comparison of call structure involving a wide range of habitat types, an objective measure of habitat density and direct measures of habitat-related attenuation. The structure of the bower advertisement call of the satin bowerbird was measured in 16 populations from throughout the species' range and related to the habitat type and density at each site. Transmission of white noise, pure tones and different bowerbird dialects was measured in five of six habitat types inhabited by satin bowerbirds. Bowerbird advertisement call structure converged in similar habitats but diverged among different habitats; this pattern was apparent at both continent-wide and local geographical scales. Bowerbirds' call structures differed with changes in habitat density, consistent with the acoustic adaptation hypothesis. Lower frequencies and less frequency modulation were utilized in denser habitats such as rainforest and higher frequencies and more frequency modulation were used in the more open eucalypt-dominated habitats. The white noise and pure tone transmission measurements indicated that different habitats varied in their sound transmission properties in a manner consistent with the observed variation in satin bowerbird vocalizations. There was no effect of geographical proximity of recording locations, nor was there the predicted inverse relationship between frequency and body size. These findings indicate that the transmission qualities of different habitats have had a major influence on variation in vocal phenotypes in this species. In addition, previously published molecular data for this species suggest that there is no effect of genetic relatedness on call similarity among satin bowerbird populations.

Liver fluke-associated and sporadic cholangiocarcinoma: an immunohistochemical study of bile duct, peribiliary gland and tumour cell phenotypes

Aim: To compare cell phenotypes displayed by cholangiocarcinomas and adjacent bile duct lesions in patients from an area endemic in liver-fluke infestation and those with sporadic cholangiocarcinoma. Methods: 65 fluke-associated and 47 sporadic cholangiocarcinomas and 6 normal livers were studied. Serial paraffin-wax sections were stained immunohistochemically with monoclonal antibodies characterising a Brunner or pyloric gland metaplasia cell phenotype (antigens D10 and 1F6), intestinal goblet cells (antigen 17NM), gastric foveolar apomucin (MUC5AC), a gastrointestinal epithelium cytokeratin (CK20) and the p53 protein. Results: 60% of the 112 cholangiocarcinomas expressed antigen D10, 68% MUC5AC, 33% antigen 17NM and 20% CK20; 37% showed overexpression of p53. When present together in a cholangiocarcinoma, cancer cells expressing D10 were distinct from those displaying 17NM or MUC5AC. Many more fluke-associated cholangiocarcinomas than sporadic cholangiocarcinomas displayed 17NM and p53 expression. Most cases of hyperplastic and dysplastic biliary epithelium expressed D10 strongly. Pyloric gland metaplasia and peribiliary glands displayed D10 and 1F6, with peribiliary gland hyperplasia more evident in the livers with fluke-associated cholangiocarcinoma; goblet cells in intestinal metaplasia stained for 17NM. No notable association of expression between any two antigens (including p53) was found in the cancers. Conclusions: Most cases of dysplastic biliary epithelium and cholangiocarcinoma display a Brunner or pyloric gland cell phenotype and a gastric foveolar cell phenotype. The expression of D10 in hyperplastic and dysplastic epithelium and in cholangiocarcinoma is consistent with a dysplasia-carcinoma sequence. Many more fluke-associated cholangiocarcinomas than sporadic cholangiocarcinoma display an intestinal goblet cell phenotype and overexpress p53, indicating differences in the aetiopathology of the cancers in the two groups of patients.

Macrophage-specific expression of human lysosomal acid lipase corrects inflammation and pathogenic phenotypes in lal(-/-) mice

Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in the cell. The downstream metabolites of these compounds serve as hormonal ligands for nuclear receptors and transcription factors. Genetic ablation of the lal gene in the mouse caused malformation of macrophages and inflammation-triggered multiple pathogenic phenotypes in multiple organs. To assess the relationship between macro phages and lal(-/-) pathogenic phenotypes, a macrophage-specific doxycycline-inducible transgenic system was generated to induce human LAL (hLAL) expression in the lal(-/-) genetic background under control of the 7.2-kb c-fins promoter/intron2 regulatory sequence. Doxycycline-induced hLAL expression in macrophages significantly ameliorated aberrant gene expression, inflammatory cell (neutrophil) influx, and pathogenesis in multiple organs. These studies strongly support that neutral lipid metabolism in macrophages contributes to organ inflammation and pathogenesis.

Use of latent profile analysis to identify eating disorder phenotypes in an adult Australian twin cohort

Context: The relationships among the different eating disorders that exist in the community are poorly understood, especially for residual disorders in which bingeing or purging occurs in the absence of other behaviors. Objective: To examine a community sample for the number of mutually exclusive weight and eating profiles. Design: Data regarding lifetime eating disorder symptoms and weight range were submitted to a latent profile analysis. Profiles were compared regarding personality, current eating and weight, retrospectively reported life events, and lifetime depressive psychopathology. Setting: Longitudinal study among female twins from the Australian Twin Registry in whom eating was assessed by a telephone interview. Participants: A community sample of 1002 twins (individuals) who had participated in earlier waves of data collection. Main Outcome Measures: Number and clinical character of latent profiles. Results: The best fit was a 5-profile solution with women who were (1) of normal weight with few lifetime eating disorders (4.3%), (2) overweight (10.6% had a lifetime eating disorder), (3) underweight and generally had no eating disorders except for 5.3% who had restricting anorexia nervosa, (4) of low to normal weight (89.0% had a lifetime eating disorder), and (5) obese (37.0% had a lifetime eating disorder). Each profile contained more than 1 type of lifetime eating disorder except for the third profile. Women in the first and third profiles had the best functioning, with women in the fourth and fifth profiles having similarly poorer functioning. The women in the fourth group had a symptom profile distinctive from the other 4 groups in terms of severity; they were also more likely to have had lifetime major depression and suicidality. Conclusion: Lifetime weight ranges and the severity of eating disorder symptoms affected clustering more than the type of eating disorder symptom.

The Queensland Cancer Risk Study: Behavioural risk factor results

Objective: To describe the population prevalence of key cancer risk behaviours in Queensland. Methods: The Queensland Cancer Risk Study was a population-based survey of 9,419 Queensland residents aged 20-75 years. Information was collected through an anonymous, computer-assisted telephone interview between February and November 2004. Outcome measures included tobacco smoking, alcohol consumption, sun-tanning and sunburn, obesity physical inactivity and poor diet, weighted by age, gender and geographic region. Results: Prevalence of current smoking was 25.2% for males and 20.8% for females and was highest in the 20-39 year age group and in rural/remote areas. Two-thirds of participants regularly drank alcohol; of these, 63% consumed excessive amounts of alcohol. Excessive sun exposure is still a problem; 70% of Queenslanders reported an episode of sunburn and 12% reported attempting to get a suntan in the past year. More than half of the respondents (53.9%) were above the healthy weight range, and 17.1% of males and 18.4% of females were obese. Just over 40% of Queensland adults reported having insufficient levels of physical activity. Fewer than half of the participants met recommended levels of fruit or vegetable consumption. Conclusions and implications: The majority of Queensland adults exhibit known, modifiable cancer risk behaviours. These results suggest that continuing efforts to reduce the prevalence of these risk factors are warranted. Specifically, significant gains could be made by targeting behaviour change programs at younger Queenslanders (aged 20-39 years), men, and those living in remote/ very remote areas of Queensland.

Combined acamprosate and naltrexone, with cognitive behavioural therapy is superior to either medication alone for alcohol abstinence: A single centres' experience with pharmacotherapy

Aims: To compare treatment outcomes amongst patients offered pharmacotherapy with either naltrexone or acamprosate used singly or in combination, in a 12-week outpatient cognitive behavioural therapy (CBT) programme for alcohol dependence. Methods: We matched 236 patients across gender, age group, prior alcohol detoxification, and dependence severity and conducted a cohort comparison study of three medication groups (CBT+acamprosate, CBT+naltrexone, CBT+combined medication) which included 59 patients per group. Outcome measures included programme attendance, programme abstinence and for those who relapsed, cumulative abstinence duration (CAD) and days to first breach (DFB). Secondary analyses compared the remaining matched 59 subjects who declined medication with the pharmacotherapy groups. Results: Across medication groups, CBT+ combined medication produced the greatest improvement across all outcome measures. Although a trend favoured the CBT+ combined group, differences did not reach statistical significance. Programme attendance: CBT + Acamprosate group (66.1%), CBT + Naltrexone group (79.7%), and in the CBT + Combined group (83.1%). Abstinence rates were 50.8, 66.1, and 67.8%, respectively. For those that did not complete the programme abstinent, the average number of days abstinent (CAD) were 45.07, 49.95, and 53.58 days, respectively. The average numbers of days to first breach (DFB) was 26.79, 26.7, and 37.32 days. When the focal group (CBT + combined) was compared with patients who declined medication (CBT-alone), significant differences were observed across all outcome indices. Withdrawal due to adverse medication effects was minimal. Conclusions: The addition of both medications (naltrexone and acamprosate) resulted in measurable benefit and was well tolerated. In this patient population naltrexone with CBT is as effective as combined medication with CBT, but the trend favours combination medication.