Lens ER-stress response during cataract development in Mip-mutant mice

AbstractMajor intrinsic protein (MIP) is a functional water-channel (AQP0) that also plays a key role in establishing lens fiber cell architecture. Genetic variants of MIP have been associated with inherited and age-related forms of cataract; however, the underlying pathogenic mechanisms are unclear. Here we have used lens transcriptome profiling by microarray-hybridization and qPCR to identify pathogenic changes during cataract development in Mip-mutant (Lop/+) mice. In postnatal Lop/+ lenses (P7) 99 genes were up-regulated and 75 were down-regulated (>2-fold, p=<0.05) when compared with wild-type. A pathway analysis of up-regulated genes in the Lop/+ lens (P7) was consistent with endoplasmic reticulum (ER)-stress and activation of the unfolded protein response (UPR). The most up-regulated UPR genes (>4-fold) in the Lop/+ lens included Chac1>Ddit3>Atf3>Trib3>Xbp1 and the most down-regulated genes (>5-fold) included two anti-oxidant genes, Hspb1 and Hmox1. Lop/+ lenses were further characterized by abundant TUNEL-positive nuclei within central degenerating fiber cells, glutathione depletion, free-radical overproduction, and calpain hyper-activation. These data suggest that Lop/+ lenses undergo proteotoxic ER-stress induced cell-death resulting from prolonged activation of the Eif2ak3/Perk-Atf4-Ddit3-Chac1 branch of the UPR coupled with severe oxidative-stress

How head and neck consultants manage patients’ emotional distress during cancer follow-up consultations : a multilevel study

Head and neck cancer (HNC) patients suffer substantial emotional problems. This study aimed to explore how utterance-level variables (source, type and timing of emotional cues) and patient-level variables (e.g. age, gender and emotional well-being) relate to consultants’ responses (i.e. reducing or providing space) to patient expressions of emotional distress. Forty-three HNC outpatient follow-up consultations were audio recorded and coded, for patients’ expressions of emotional distress and consultants’ responses, using the Verona Coding Definitions of Emotional Sequence. Multilevel logistic regression modelled the probability of the occurrence of consultant reduce space response as a function of patient distress cue expression, controlling for consultation and patient-related variables. An average of 3.5 cues/concerns (range 1–20) was identified per consultation where 84 out of 152 total cues/concerns were responded by reducing space. Cue type did not impact on response; likewise for the quality of patient emotional well-being. However, consultants were more likely to reduce space to cues elicited by patients, as opposed to those initiated by themselves. This reduced space response was more pronounced as the consultation continued. However, about 6 min into the consultation, this effect (i.e. tendency to block patients) started to weaken. Head and neck consultants’ responses to negative emotions depended on source and timing of patient emotional expressions. The findings are useful for training programme development to encourage consultants to be more flexible and open in the early stages of the consultation.PostprintPeer reviewe

How are emotional distress and reassurance expressed in medical consultations for people with long-term conditions who were unable to receive curative treatment? A pilot observational study with huntington’s disease and prostate cancer

Objective It is unclear whether how people with long-term conditions express distress, and how clinicians respond, influences perceptions of consultation outcomes. The pilot study examined emotional distress and reassurance in consultations with people whose long-term conditions (at the time of consultations) were treated using active surveillance or symptom management (as no curative treatment was suitable). Methods An observational pilot study was conducted involving consultations between people with long-term conditions and their respective clinician. Consultations between three clinicians (two Huntington’s Disease; one Prostate Cancer) and 22 people with long-term conditions (11 Huntington’s Disease; 11 Prostate Cancer) were audio-recorded. Participants also completed an expanded Consultation and Relational Empathy (CARE) Measure. Two researchers coded sessions using Verona Coding Definitions of Emotional Sequences (VR-CoDES/VR-CoDES-P). Code frequencies were calculated, t tests performed between conditions, and Pearson’s correlations performed for associations between CARE responses and clinician utterances. Results People with long-term conditions expressed emotional distress on average 4.45 times per session, averaging 1.09 Concern and 3.36 Cue utterances. Clinicians responded with more explicit (2.59) and space-providing (3.36), than non-explicit (1.86) and space-reducing (1.09), responses per session. Clinicians expressed spontaneous reassurance on average 5.18 times per session, averaging 3.77 Cognitive and 1.5 Affective reassurance utterances. Huntington’s Disease consultations featured significantly more 'Cues', 'Concerns' and 'Overall' 'Emotional Distress', and 'Cognitive' and 'Overall' ‘Reassurance'. Conclusion Emotional distress was expressed more using hints than explicit concern utterances. Clinicians predominantly explicitly explored distress rather than providing information/advice and provided advice using spontaneous cognitive reassurance. People with Huntington’s Disease expressed more concerns and received more reassurance, indicating different needs between conditions. Future research is required to explore emotional distress and reassurance in a larger sample of participants and long-term condition types, and how the practical implications of these findings may be used to enhance outcomes of consultations.Publisher PDFPeer reviewe

Using fundamental frequency of cancer survivors’ speech to investigate emotional distress in out-patient visits

Objective Emotions, are in part conveyed by varying levels of fundamental frequency of voice pitch (f0). This study tests the hypothesis that patients display heightened levels of emotional arousal (f0) during Verona Coding Definitions of Emotional Sequences (VR-CoDES) cues and concerns versus during neutral statements. Methods The audio recordings of sixteen head and neck cancer survivors’ follow-up consultations were coded for patients’ emotional distress. Pitch (f0) of coded cues and concerns, including neutral statements was extracted. These were compared using a hierarchical linear model, nested for patient and pitch range, controlling for statement speech length. Utterance content was also explored. Results Clustering by patient explained 30% of the variance in utterances f0. Cues and concerns were on average 13.07 Hz higher than neutral statements (p = 0.02). Cues and concerns in these consultations contained content with a high proportion of recurrence fears. Conclusion The present study highlights the benefits and challenges of adding f0 and potential other prosodic features to the toolkit of coding emotional distress in the health communication setting. Practice implications The assessment of f0 during clinical conversations can provide additional information for research into emotional expression.PostprintPeer reviewe

Mutation of the EPHA2 tyrosine-kinase domain dysregulates cell pattern formation and cytoskeletal gene expression in the lens

Genetic variations in ephrin type-A receptor 2 (EPHA2) have been associated with inherited and age-related forms of cataract in humans. Here, we have characterized the eye lens phenotype and transcript profile of germlin

Mimicking non-verbal emotional expressions and empathy development in simulated consultations : an experimental feasibility study

The authors are grateful to the Carnegie Trust (RIG 70156), who generously funded this project.Objective : To explore the feasibility of applying an experimental design to study the relationship between non-verbal emotions and empathy development in simulated consultations. Method : In video-recorded simulated consultations, twenty clinicians were randomly allocated to either an experimental group (instructed to mimic non-verbal emotions of a simulated patient, SP) or a control group (no such instruction). Baseline empathy scores were obtained before consultation, relational empathy was rated by SP after consultation. Multilevel logistic regression modelled the probability of mimicry occurrence, controlling for baseline empathy and clinical experience. ANCOVA compared group differences on relational empathy and consultation smoothness. Results : Instructed mimicry lasted longer than spontaneous mimicry. Mimicry was marginally related to improved relational empathy. SP felt being treated more like a whole person during consultations with spontaneous mimicry. Clinicians who displayed spontaneous mimicry felt consultations went more smoothly. Conclusion : The experimental approach improved our understanding of how non-verbal emotional mimicry contributed to relational empathy development during consultations. Further work should ascertain the potential of instructed mimicry to enhance empathy development. Practice implications : Understanding how non-verbal emotional mimicry impacts on patients' perceived clinician empathy during consultations may inform training and intervention programme development.PostprintPeer reviewe

Applying the Verona Coding Definitions of Emotional Sequences (VR-CoDES) in the dental context involving patients with complex communication needs : an exploratory study

This study was conducted as part of a larger collaborative study funded by the EPSRC, between the University of St Andrews and the University of Dundee.Objective The VR-CoDES has been previously applied in the dental context. However, we know little about how dental patients with intellectual disabilities (ID) and complex communication needs express their emotional distress during dental visits. This is the first study explored the applicability of the VR-CoDES to a dental context involving patients with ID. Methods Fourteen dental consultations were video recorded and coded using the VR-CoDES, assisted with the additional guidelines for the VR-CoDES in a dental context. Both inter- and intra-coder reliabilities were checked on the seven consultations where cues were observed. Results Sixteen cues (eight non-verbal) were identified within seven of the 14 consultations. Twenty responses were observed (12 reducing space) with four multiple responses. Cohen's Kappa were 0.76 (inter-coder) and 0.88 (intra-coder). Conclusion With the additional guidelines, cues and responses were reliably identified. Cue expression was exhibited by non-verbal expression of emotion with people with ID in the literature. Further guidance is needed to improve the coding accuracy on multiple providers’ responses and to investigate potential impacts of conflicting responses on patients. Practice implications The findings provided a useful initial step towards an ongoing exploration of how healthcare providers identify and manage emotional distress of patients with ID.PostprintPeer reviewe

Charged multivesicular body protein 4b forms complexes with gap junction proteins during lens fiber cell differentiation

Charged multivesicular body protein 4b (CHMP4B) is a core sub-unit of the endosomal sorting complex required for transport III (ESCRT-III) machinery that serves myriad remodeling and scission processes of biological membranes. Mutation of the human CHMP4B gene underlies rare forms of early-onset lens opacities or cataracts, and CHMP4B is required for lens growth and differentiation in mice. Here, we determine the sub-cellular distribution of CHMP4B in the lens and uncover a novel association with gap junction alpha-3 protein (GJA3) or connexin 46 (Cx46) and GJA8 or Cx50. Immunofluorescence confocal microscopy revealed that CHMP4B localized to cell membranes of elongated fiber cells in the outer cortex of the lens-where large gap junction plaques begin to form-particularly, on the broad faces of these flattened hexagon-like cells in cross-section. Dual immunofluorescence imaging showed that CHMP4B co-localized with gap junction plaques containing Cx46 and/or Cx50. When combined with the in situ proximity ligation assay, immunofluorescence confocal imaging indicated that CHMP4B lay in close physical proximity to Cx46 and Cx50. In Cx46-knockout (Cx46-KO) lenses, CHMP4B-membrane distribution was similar to that of wild-type, whereas, in Cx50-KO lenses, CHMP4B localization to fiber cell membranes was lost. Immunoprecipitation and immunoblotting analyses revealed that CHMP4B formed complexes with Cx46 and Cx50 in vitro. Collectively, our data suggest that CHMP4B forms plasma membrane complexes, either directly and/or indirectly, with gap junction proteins Cx46 and Cx50 that are often associated with ball-and-socket double-membrane junctions during lens fiber cell differentiation

Multimorbidity and socioeconomic deprivation in primary care consultations

Purpose: The influence of multimorbidity on the clinical encounter is poorly understood, especially in areas of high socioeconomic deprivation where burdensome multimorbidity is concentrated. The aim of the current study was to examine the effect of multimorbidity on general practice consultations, in areas of high and low deprivation. Methods: We conducted secondary analyses of 659 video-recorded routine consultations involving 25 general practitioners (GPs) in deprived areas and 22 in affluent areas of Scotland. Patients rated the GP’s empathy using the Consultation and Relational Empathy (CARE) measure immediately after the consultation. Videos were analyzed using the Measure of Patient-Centered Communication. Multilevel, multi-regression analysis identified differences between the groups. Results: In affluent areas, patients with multimorbidity received longer consultations than patients without multimorbidity (mean 12.8 minutes vs 9.3, respectively; P = .015), but this was not so in deprived areas (mean 9.9 minutes vs 10.0 respectively; P = .774). In affluent areas, patients with multimorbidity perceived their GP as more empathic (P = .009) than patients without multimorbidity; this difference was not found in deprived areas (P = .344). Video analysis showed that GPs in affluent areas were more attentive to the disease and illness experience in patients with multimorbidity (P &lt; .031) compared with patients without multimorbidity. This was not the case in deprived areas (P = .727). Conclusions: In deprived areas, the greater need of patients with multimorbidity is not reflected in the longer consultation length, higher GP patient centeredness, and higher perceived GP empathy found in affluent areas. Action is required to redress this mismatch of need and service provision for patients with multimorbidity if health inequalities are to be narrowed rather than widened by primary care