Wnt4 and LAP2alpha as pacemakers of Thymic Epithelial Senescence

Age-associated thymic involution has considerable physiological impact by inhibiting de novo T-cell selection. This impaired T-cell production leads to weakened immune responses. Yet the molecular mechanisms of thymic stromal adipose involution are not clear. Age-related alterations also occur in the murine thymus providing an excellent model system. In the present work structural and molecular changes of the murine thymic stroma were investigated during aging. We show that thymic epithelial senescence correlates with significant destruction of epithelial network followed by adipose involution. We also show in purified thymic epithelial cells the age-related down-regulation of Wnt4 (and subsequently FoxN1), and the prominent increase in LAP2α expression. These senescence-related changes of gene expression are strikingly similar to those observed during mesenchymal to pre-adipocyte differentiation of fibroblast cells suggesting similar molecular background in epithelial cells. For molecular level proof-of-principle stable LAP2α and Wnt4-over-expressing thymic epithelial cell lines were established. LAP2α over-expression provoked a surge of PPARγ expression, a transcription factor expressed in pre-adipocytes. In contrast, additional Wnt4 decreased the mRNA level of ADRP, a target gene of PPARγ. Murine embryonic thymic lobes have also been transfected with LAP2α- or Wnt4-encoding lentiviral vectors. As expected LAP2α over-expression increased, while additional Wnt4 secretion suppressed PPARγ expression. Based on these pioneer experiments we propose that decreased Wnt activity and increased LAP2α expression provide the molecular basis during thymic senescence. We suggest that these molecular changes trigger thymic epithelial senescence accompanied by adipose involution. This process may either occur directly where epithelium can trans-differentiate into pre-adipocytes; or indirectly where first epithelial to mesenchymal transition (EMT) occurs followed by subsequent pre-adipocyte differentiation. The latter version fits better with literature data and is supported by the observed histological and molecular level changes

Value of antibodies to free light chains in immunoperoxidase studies of renal biopsies

Aims Because immunoglobulin abnormalities may affect the kidney, investigation of renal biopsies requires immunohistological study of light chains. A problem is that most antibodies to light chains react with whole immunoglobulins as well as free light chains, and there are generally many more whole immunoglobulins than free light chains. The usefulness of antibodies that only detected free light chains was investigated. Methods Antibodies to free light chains were used in an immunoperoxidase method on paraffin sections of 198 renal biopsies, and compared with conventional antibodies against light chains examined by immunofluorescence on 13 frozen sections and by immunoperoxidase on 46 paraffin sections. Results Immunofluorescence and immunoperoxidase were concordant on 10 of 13 biopsies. Immunofluorescence detected slight deposition of light chains in three biopsies not shown by immunoperoxidase, of undetermined clinical significance. Using immunoperoxidase, the free light chain antibodies were more sensitive than conventional antibodies, giving much cleaner staining and better detection of deposits in AL amyloid, light chain deposition disease and cryoglobulinaemic glomerulonephritis. The free light chain antibodies showed discordance or ambiguity between immunohistological and clinical findings in seven (4%) of 185 patients with known immunoglobulin status. These included two of 28 cases of AL amyloid that showed no light chain deposition. The method was not designed for detection of light chain restriction in neoplastic plasma or lymphoplasmacytic cells. Conclusions Polyclonal antibodies to free light chains are an improvement on conventional antibodies in immunoperoxidase study of paraffin sections of renal biopsies and are useful in everyday practice

Feasibility of brief psychological distress screening by a community-based telephone helpline for cancer patients and carers

Background Up to one-third of people affected by cancer experience ongoing psychological distress and would benefit from screening followed by an appropriate level of psychological intervention. This rarely occurs in routine clinical practice due to barriers such as lack of time and experience. This study investigated the feasibility of community-based telephone helpline operators screening callers affected by cancer for their level of distress using a brief screening tool (Distress Thermometer), and triaging to the appropriate level of care using a tiered model. Methods Consecutive cancer patients and carers who contacted the helpline from September-December 2006 (n = 341) were invited to participate. Routine screening and triage was conducted by helpline operators at this time. Additional socio-demographic and psychosocial adjustment data were collected by telephone interview by research staff following the initial call. Results The Distress Thermometer had good overall accuracy in detecting general psychosocial morbidity (Hospital Anxiety and Depression Scale cut-off score ≥ 15) for cancer patients (AUC = 0.73) and carers (AUC = 0.70). We found 73% of participants met the Distress Thermometer cut-off for distress caseness according to the Hospital Anxiety and Depression Scale (a score ≥ 4), and optimal sensitivity (83%, 77%) and specificity (51%, 48%) were obtained with cut-offs of ≥ 4 and ≥ 6 in the patient and carer groups respectively. Distress was significantly associated with the Hospital Anxiety and Depression Scale scores (total, as well as anxiety and depression subscales) and level of care in cancer patients, as well as with the Hospital Anxiety and Depression Scale anxiety subscale for carers. There was a trend for more highly distressed callers to be triaged to more intensive care, with patients with distress scores ≥ 4 more likely to receive extended or specialist care. Conclusions Our data suggest that it was feasible for community-based cancer helpline operators to screen callers for distress using a brief screening tool, the Distress Thermometer, and to triage callers to an appropriate level of care using a tiered model. The Distress Thermometer is a rapid and non-invasive alternative to longer psychometric instruments, and may provide part of the solution in ensuring distressed patients and carers affected by cancer are identified and supported appropriately

Risk measures for direct real estate investments with non-normal or unknown return distributions

The volatility of returns is probably the most widely used risk measure for real estate. This is rather surprising since a number of studies have cast doubts on the view that volatility can capture the manifold risks attached to properties and corresponds to the risk attitude of investors. A central issue in this discussion is the statistical properties of real estate returns—in contrast to neoclassical capital market theory they are mostly non-normal and often unknown, which render many statistical measures useless. Based on a literature review and an analysis of data from Germany we provide evidence that volatility alone is inappropriate for measuring the risk of direct real estate. We use a unique data sample by IPD, which includes the total returns of 939 properties across different usage types (56% office, 20% retail, 8% others and 16% residential properties) from 1996 to 2009, the German IPD Index, and the German Property Index. The analysis of the distributional characteristics shows that German real estate returns in this period were not normally distributed and that a logistic distribution would have been a better fit. This is in line with most of the current literature on this subject and leads to the question which indicators are more appropriate to measure real estate risks. We suggest that a combination of quantitative and qualitative risk measures more adequately captures real estate risks and conforms better with investor attitudes to risk. Furthermore, we present criteria for the purpose of risk classification

Using a Stick Does Not Necessarily Alter Judged Distances or Reachability

Background It has been reported that participants judge an object to be closer after a stick has been used to touch it than after touching it with the hand. In this study we try to find out why this is so. Methodology We showed six participants a cylindrical object on a table. On separate trials (randomly intermixed) participants either estimated verbally how far the object is from their body or they touched a remembered location. Touching was done either with the hand or with a stick (in separate blocks). In three different sessions, participants touched either the object location or the location halfway to the object location. Verbal judgments were given either in centimeters or in terms of whether the object would be reachable with the hand. No differences in verbal distance judgments or touching responses were found between the blocks in which the stick or the hand was used. Conclusion Instead of finding out why the judged distance changes when using a tool, we found that using a stick does not necessarily alter judged distances or judgments about the reachability of objects

Unintentional asphyxia, SIDS, and medically explained deaths:A descriptive study of outcomes of child death review (CDR) investigations following sudden unexpected death in infancy

Background: A comprehensive Child Death Review (CDR) program was introduced in England and Wales in 2008 but as yet data have only been analysed at a local level, limiting the learning from deaths. The aim of this study is to describe the profile of causes and risk factors for Sudden Unexpected Death in Infancy (SUDI) as determined by the new CDR program. Methods: This was a descriptive outcome study using data from Child Death Overview Panel (CDOP) Form C for SUDI cases dying during 2010-2 in the West Midlands region of England. The main outcome measures were: cause of death, risk factors and potential preventability of death, and determination of deaths probably due to unintentional asphyxia. Results: Data were obtained for 65/70 (93%) SUDI cases. 20/65 (31%) deaths were initially categorised as due to medical causes; 21/65 (32%) as SIDS, and 24/65 (37%) as undetermined. Reanalysis suggested that 2/21 SIDS and 7/24 undetermined deaths were probably due to unintentional asphyxia, with 6 of these involving co-sleeping and excessive parental alcohol consumption. Deaths classified as ‘undetermined’ had significantly higher total family and environmental risk factor scores (mean 2.6, 95% CI 2.0– 3.3) compared to those classified as SIDS (mean 1.6, 95% CI 1.2-1.9), or medical causes for death (mean 1.1, 95% CI 0.8-1.3). 9/20 (47%) of medical deaths, 19/21 (90%) SIDS and 23/24 (96%) undetermined deaths were considered to be potentially preventable. There were inadequacies in medical provision identified in 5/20 (25%) of medically explained deaths. Conclusions: The CDR program results in detailed information about risk factors for SUDI cases but failed to recognise deaths probably due to unintentional asphyxia. The misclassification of probable unintentional asphyxial deaths and SIDS as ‘undetermined deaths’ is likely to limit learning from these deaths and inhibit prevention strategies. Many SUDI occurred in families with mental illness, substance misuse and chaotic lifestyles and most in unsafe sleep-environments. This knowledge could be used to better target safe sleep advice for vulnerable families and prevent SUDI in the future

Performance feedback: An exploratory study to examine the acceptability and impact for interdisciplinary primary care teams

Background - This mixed methods study was designed to explore the acceptability and impact of feedback of team performance data to primary care interdisciplinary teams. // Methods - Seven interdisciplinary teams were offered a one-hour, facilitated performance feedback session presenting data from a comprehensive, previously-conducted evaluation, selecting highlights such as performance on chronic disease management, access, patient satisfaction and team function. // Results - Several recurrent themes emerged from participants' surveys and two rounds of interviews within three months of the feedback session. Team performance measurement and feedback was welcomed across teams and disciplines. This feedback could build the team, the culture, and the capacity for quality improvement. However, existing performance indicators do not equally reflect the role of different disciplines within an interdisciplinary team. Finally, the effect of team performance feedback on intentions to improve performance was hindered by a poor understanding of how the team could use the data. // Conclusions - The findings further our understanding of how performance feedback may engage interdisciplinary team members in improving the quality of primary care and the unique challenges specific to these settings. There is a need to develop a shared sense of responsibility and agenda for quality improvement. Therefore, more efforts to develop flexible and interactive performance-reporting structures (that better reflect contributions from all team members) in which teams could specify the information and audience may assist in promoting quality improvement

"I'm not being rude, I'd want somebody normal" Adolescents' perception of their peers with Tourette's syndrome; an exploratory study

Background: Tourette’s syndrome (TS) is a highly stigmatised condition, and typically developing adolescents’ motives and reason for excluding individuals with TS have not been examined. Aims: The aim of the study was to understand how TS is conceptualised by adolescents and explore how individuals with TS are perceived by their typically developing peers. Method: Free text writing and focus groups were used to elicit the views of twenty-two year ten students from a secondary school in South East England. Grounded theory was used to develop an analytical framework. Result: Participants’ understanding about the condition was construed from misconceptions, unfamiliarity and unanswered questions. Adolescents who conceived TS as a disorder beyond the individual’s control perceived their peers as being deprived of agency and strength and as straying from the boundaries of normalcy. People with TS were viewed as individuals deserving pity, and in need of support. Although participants maintained they had feelings of social politeness towards those with TS, they would avoid initiating meaningful social relationships with them due to fear of “social contamination”. Intergroup anxiety would also inhibit a close degree of social contact. Participants that viewed those with TS as responsible for their condition expressed a plenary desire for social distance. However, these behavioural intentions were not limited to adolescents that elicited inferences of responsibility to people with TS, indicating that attributional models of stigmatisation may be of secondary importance in the case of TS. Implications for interventions to improve school belonging among youths with TS are discussed

Nationwide randomised trial evaluating elective neck dissection for early stage oral cancer (SEND study) with meta-analysis and concurrent real-world cohort

BACKGROUND: Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours. // METHODS: We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials. // RESULTS: Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001). // CONCLUSION: SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours. // CLINICAL TRIAL REGISTRATION: NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883

Fitness Cost of Resistance to Bt Cotton Linked with Increased Gossypol Content in Pink Bollworm Larvae

Fitness costs of resistance to Bacillus thuringiensis (Bt) crops occur in the absence of Bt toxins, when individuals with resistance alleles are less fit than individuals without resistance alleles. As costs of Bt resistance are common, refuges of non-Bt host plants can delay resistance not only by providing susceptible individuals to mate with resistant individuals, but also by selecting against resistance. Because costs typically vary across host plants, refuges with host plants that magnify costs or make them less recessive could enhance resistance management. Limited understanding of the physiological mechanisms causing fitness costs, however, hampers attempts to increase costs. In several major cotton pests including pink bollworm (Pectinophora gossypiella), resistance to Cry1Ac cotton is associated with mutations altering cadherin proteins that bind this toxin in susceptible larvae. Here we report that the concentration of gossypol, a cotton defensive chemical, was higher in pink bollworm larvae with cadherin resistance alleles than in larvae lacking such alleles. Adding gossypol to the larval diet decreased larval weight and survival, and increased the fitness cost affecting larval growth, but not survival. Across cadherin genotypes, the cost affecting larval growth increased as the gossypol concentration of larvae increased. These results suggest that increased accumulation of plant defensive chemicals may contribute to fitness costs associated with resistance to Bt toxins