A specific pathway can be identified between genetic characteristics and behaviour profiles in Prader-Willi syndrome via cognitive, environmental and physiological mechanisms

Behavioural phenotypes associated with genetic syndromes have been extensively investigated in order to generate rich descriptions of phenomenology, determine the degree of specificity of behaviours for a particular syndrome, and examine potential interactions between genetic predispositions for behaviour and environmental influences. However, relationships between different aspects of behavioural phenotypes have been less frequently researched and although recent interest in potential cognitive phenotypes or endophenotypes has increased, these are frequently studied independently of the behavioural phenotypes.

Taking Prader-Willi syndrome (PWS) as an example, we discuss evidence suggesting specific relationships between apparently distinct aspects of the PWS behavioural phenotype and relate these to specific endophenotypic characteristics.

The framework we describe progresses through biological, cognitive, physiological and behavioural levels to develop a pathway from genetic characteristics to behaviour with scope for interaction with the environment at any stage.

We propose this multilevel approach as useful in setting out hypotheses in order to structure research that can more rapidly advance theory.

Molecular mechanism and physiological role of active-deactive transition of mitochondrial complex I

The unique feature ofmitochondrial complex I is the so-called A/D transition (active-deactive transition). The A-form catalyses rapid oxidation of NADH by ubiquinone (k ~10 min) and spontaneously converts into the D-form if the enzyme is idle at physiological temperatures. Such deactivation occurs in vitro in the absence of substrates or in vivo during ischaemia, when the ubiquinone pool is reduced. The D-form can undergo reactivation given both NADH and ubiquinone availability during slow (k ~1-10 min) catalytic turnover(s). We examined known conformational differences between the two forms and suggested a mechanism exerting A/D transition of the enzyme. In addition, we discuss the physiological role of maintaining the enzyme in the D-form during the ischaemic period. Accumulation of the D-form of the enzyme would prevent reverse electron transfer from ubiquinol to FMN which could lead to superoxide anion generation. Deactivation would also decrease the initial burst of respiration after oxygen reintroduction. Therefore the A/D transition could be an intrinsic protective mechanism for lessening oxidative damage during the early phase of reoxygenation. Exposure of Cys of mitochondrially encoded subunit ND3 makes the Dform susceptible for modification by reactive oxygen species and nitric oxide metabolites which arrests the reactivation of the D-form and inhibits the enzyme. The nature of thiol modification defines deactivation reversibility, the reactivation timescale, the status of mitochondrial bioenergetics and therefore the degree of recovery of the ischaemic tissues after reoxygenation.

Using extended contact to improve physiological responses and behavior toward people with schizophrenia

Extended contact has been shown to improve explicit and implicit attitudes toward a number of outgroups, but not yet toward people with mental health conditions. Using people with schizophrenia as the target group, this experiment is the first to demonstrate that extended contact can reduce explicit prejudice, buffer stress responses to future interactions, improve non-verbal behavior, and improve the quality of interactions in a manner detectable by the target group member. Participants watched a video of a brief, positive interaction between two strangers, one of whom they were led to believe had schizophrenia. Control participants watched the same video without being told that the person had schizophrenia. They then participated in a social interaction with a confederate whom they were led to believe had the disorder. Participants' cardiovascular and electrodermal activity were monitored immediately before the interaction. The interaction was also secretly recorded to allow independent judges to assess the participants' non-verbal behaviors. The confederate also rated the positivity of each interaction. Participants in the extended contact condition reported more positive attitudes toward people with schizophrenia, displayed more positive non-verbal behaviors, and had a more positive interaction with the confederate. Moreover, just prior to the interaction, participants in the extended contact condition displayed smaller anticipatory stress responses, as reflected in smaller changes in interbeat interval and non-specific skin conductance responses during this phase. Together, these findings support the use of the extended contact as an intervention that could lead to genuine changes in attitudes toward and treatment of people with severe mental health disorders.

Uniformity of visual acuity measures in published studies

PURPOSE. To investigate the methods used in contemporary ophthalmic literature to designate visual acuity (VA). METHODS. Papers in all 2005 editions of five ophthalmic journals were considered. Papers were included if (1) VA, vision, or visual function was mentioned in the abstract and (2) if the study involved age-related macular degeneration, cataract, or refractive surgery. If a paper was selected on the basis of its abstract, the full text of the paper was examined for information on the method of refractive correction during VA testing, type of chart used to measure VA, specifics concerning chart features, testing protocols, and data analysis and means of expressing VA in results. RESULTS. One hundred twenty-eight papers were included. The most common type of charts used were described as logMAR-based. Although most (89.8%) of the studies reported on the method of refractive correction during VA testing, only 58.6% gave the chart design, and less than 12% gave any information whatsoever on chart features or measurement procedures used. CONCLUSIONS. The methods used and the approach to analysis were rarely described in sufficient detail to allow others to replicate the study being reported. Sufficient detail should be given on VA measurement to enable others to duplicate the research. The authors suggest that charts adhering to Bailey-Lovie design principles always be used to measure vision in prospective studies and their use encouraged in clinical settings. The distinction between the terms logMAR, an acuity notation, and Bailey-Lovie or ETDRS as chart types should be adhered to more strictly. Copyright © Association for Research in Vision and Ophthalmology.

Proteomic analysis reveals oxidative stress response as the main adaptative physiological mechanism in cows under different production systems

Three groups of cows representing three ranges of welfare in the production system were included in the study: two groups of Bruna dels Pirineus beef cattle maintained under different management systems (good and semiferal conditions) and a group of Alberes cows, a breed that lives in the mountains (hardest conditions).

In order to identify new stress/welfare biomarkers, serum from Bruna cows living in both environments was subjected to DIGE labelling, two-dimensional electrophoresis and MALDI-MS or ion trap MS. Identification was achieved for 15 proteins, which mainly belonged to three biological functions, the oxidative stress pathway (glutathione peroxidase (GPx) and paraoxonase (PON-1)), the acute phase protein family (Heremans Schmid glycoprotein alpha2 (α2-HSG)) and the complement system.

Biological validation included the Alberes breed. GPx and PON-1 were validated by an enzymatic assay and found to be higher and lower, respectively, in cows living in hard conditions. α2-HSG was validated by ELISA and found to be reduced in hard conditions. Other biomarkers of the redox status were also altered by living conditions: protein carbonyl content, superoxide dismutase (SOD) and glutathione reductase (GR).

Our results show that changes in the redox system are the main adaptation of cows living in challenging environmental conditions. This article is part of a Special Issue entitled: “Farm animal proteomics”.

Overview of clinical outcome measures used in glaucoma randomised controlled trials (RCTs)

Background: In clinical trials the selection of appropriate outcomes is crucial to the assessment of whether one intervention is better than another. Glaucoma is a chronic eye disease and the leading cause of irreversible blindness in the world. A variety of outcomes has been used and reported in glaucoma RCTs.

Objectives: The purpose of this review is to identify different clinical outcome measures used in glaucoma RCTs between January 2006 and March 2012.

Methods: A systematic review was conducted using standard methodology. We searched for RCTs in glaucoma published in English with no restrictions on the population type or size, or applied interventions. All clinical outcomes were included. Patient-reported, pharmacokinetic and economic outcomes were excluded.

Results: The search strategy identified 4288 potentially relevant abstracts. There were 315 publications retrieved, of which 233 RCTs were included. A total of 967 clinical measures were reported. There were large variations in the definitions used to describe different outcomes and their measures. Intraocular pressure (IOP) was the most commonly reported outcome (used in 201 RCTs, 86%) with a total of 422 measures (44%). Amongst the IOPrelated measures, the most commonly used was mean IOP (n=143, 15% of all measures). Safety outcomes were commonly reported, in 145 RCTs (62%) whereas visual field outcomes were utilized in 38 RCTs (16%).

Conclusions: There is a large variability in clinical outcomes used for glaucoma RCTs and in the way each outcome is reported. This lack of standardisation may impair the ability to evaluate the evidence of glaucoma interventions.

Repeated measures of body mass index and C-reactive protein in relation to all-cause mortality and cardiovascular disease: Results from the consortium on health and ageing network of cohorts in Europe and the United States (CHANCES)

Obesity has been linked with elevated levels of C-reactive protein (CRP), and both have been associated with increased risk of mortality and cardiovascular disease (CVD). Previous studies have used a single ‘baseline’ measurement and such analyses cannot account for possible changes in these which may lead to a biased estimation of risk. Using four cohorts from CHANCES which had repeated measures in participants 50 years and older, multivariate time-dependent Cox proportional hazards was used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) to examine the relationship between body mass index (BMI) and CRP with all-cause mortality and CVD. Being overweight (≥25–<30 kg/m2) or moderately obese (≥30–<35) tended to be associated with a lower risk of mortality compared to normal (≥18.5–<25): ESTHER, HR (95 % CI) 0.69 (0.58–0.82) and 0.78 (0.63–0.97); Rotterdam, 0.86 (0.79–0.94) and 0.80 (0.72–0.89). A similar relationship was found, but only for overweight in Glostrup, HR (95 % CI) 0.88 (0.76–1.02); and moderately obese in Tromsø, HR (95 % CI) 0.79 (0.62–1.01). Associations were not evident between repeated measures of BMI and CVD. Conversely, increasing CRP concentrations, measured on more than one occasion, were associated with an increasing risk of mortality and CVD. Being overweight or moderately obese is associated with a lower risk of mortality, while CRP, independent of BMI, is positively associated with mortality and CVD risk. If inflammation links CRP and BMI, they may participate in distinct/independent pathways. Accounting for independent changes in risk factors over time may be crucial for unveiling their effects on mortality and disease morbidity.

Family-based associations in measures of psychological distress and quality of life in a cardiac screening clinic for inheritable cardiac diseases: a cross-sectional study

BACKGROUND: Family-based cardiac screening programmes for persons at risk for genetic cardiac diseases are now recommended. However, the psychological wellbeing and health related quality of life (QoL) of such screened patients is poorly understood, especially in younger patients. We sought to examine wellbeing and QoL in a representative group of adults aged 16 and over in a dedicated family cardiac screening clinic.

METHODS: Prospective survey of consecutive consenting patients attending a cardiac screening clinic, over a 12 month period. Data were collected using two health measurement tools: the Short Form 12 (version 2) and the Hospital Anxiety and Depression Scale (HADS), along with baseline demographic and screening visit-related data. The HADS and SF-12v.2 outcomes were compared by age group. Associations with a higher HADS score were examined using logistic regression, with multi-level modelling used to account for the family-based structure of the data.

RESULTS: There was a study response rate of 86.6%, with n=334 patients providing valid HADS data (valid response rate 79.5%), and data on n=316 retained for analysis. One-fifth of patients were aged under 25 (n=61). Younger patients were less likely than older to describe significant depression on their HADS scale (p<0.0001), although there were overall no difference between the prevalence of a significant HADS score between the younger and older age groups (18.0% vs 20.0%, p=0.73). Significant positive associates of a higher HADS score were having lower educational attainment, being single or separated, and being closely related to the family proband. Between-family variance in anxiety and depression scores was greater than within-family variance.

CONCLUSIONS: High levels of anxiety were seen amongst patients attending a family-based cardiac screening clinic.Younger patients also had high rates of clinically significant anxiety. Higher levels of anxiety and depression tends to run in families, and this has implications for family screening and intervention programmes.