'The terrible twos': Gaining control in the nursery?

'The terrible twos' are often described as a time of 'gaining control', usually thought of as adults asserting control over children, who learn to control themselves. However, toddlerhood is as much about children learning to take control for themselves. This paper is an attempt to detail something of the social geography in the toddler room of a Scottish nursery, considering both styles of adult control and the ways in which toddlers attempt to appropriate and reconfigure space and time for themselves. That is, the ways in which space and time are negotiated in the course of day-to-day nursery life

The impact of NHS based primary care complementary therapy services on health outcomes and NHS costs: a review of service audits and evaluations

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to review evaluations and audits of primary care complementary therapy services to determine the impact of these services on improving health outcomes and reducing NHS costs. Our intention is to help service users, service providers, clinicians and NHS commissioners make informed decisions about the potential of NHS based complementary therapy services.</p> <p>Methods</p> <p>We searched for published and unpublished studies of NHS based primary care complementary therapy services located in England and Wales from November 2003 to April 2008. We identified the type of information included in each document and extracted comparable data on health outcomes and NHS costs (e.g. prescriptions and GP consultations).</p> <p>Results</p> <p>Twenty-one documents for 14 services met our inclusion criteria. Overall, the quality of the studies was poor, so few conclusions can be made. One controlled and eleven uncontrolled studies using SF36 or MYMOP indicated that primary care complementary therapy services had moderate to strong impact on health status scores. Data on the impact of primary care complementary therapy services on NHS costs were scarcer and inconclusive. One controlled study of a medical osteopathy service found that service users did not decrease their use of NHS resources.</p> <p>Conclusion</p> <p>To improve the quality of evaluations, we urge those evaluating complementary therapy services to use standardised health outcome tools, calculate confidence intervals and collect NHS cost data from GP medical records. Further discussion is needed on ways to standardise the collection and reporting of NHS cost data in primary care complementary therapy services evaluations.</p

Disconnection between the default mode network and medial temporal lobes in post-traumatic amnesia

Post-traumatic amnesia is very common immediately after traumatic brain injury. It is characterised by a confused, agitated state and a pronounced inability to encode new memories and sustain attention. Clinically, post-traumatic amnesia is an important predictor of functional outcome. However, despite its prevalence and functional importance, the pathophysiology of post-traumatic amnesia is not understood. Memory processing relies on limbic structures such as the hippocampus, parahippocampus and parts of the cingulate cortex. These structures are connected within an intrinsic connectivity network, the Default Mode Network. Interactions within the Default Mode Network can be assessed using resting state functional magnetic resonance imaging, which can be acquired in confused patients unable to perform tasks in the scanner. Here we used this approach to test the hypothesis that the mnemonic symptoms of post-traumatic amnesia are caused by functional disconnection within the Default Mode Network. We assessed whether the hippocampus and parahippocampus showed evidence of transient disconnection from cortical brain regions involved in memory processing. 19 traumatic brain injury patients were classified into post-traumatic amnesia and traumatic brain injury control groups, based on their performance on a paired associates learning task. Cognitive function was also assessed with a detailed neuropsychological test battery. Functional interactions between brain regions were investigated using resting-state functional magnetic resonance imaging. Together with impairments in associative memory patients in post-traumatic amnesia demonstrated impairments in information processing speed and spatial working memory. Patients in post-traumatic amnesia showed abnormal functional connectivity between the parahippocampal gyrus and posterior cingulate cortex. The strength of this functional connection correlated with both associative memory and information processing speed and normalised when these functions improved. We have previously shown abnormally high posterior cingulate cortex connectivity in the chronic phase after traumatic brain injury, and this abnormality was also observed in patients with post-traumatic amnesia. Patients in post-traumatic amnesia showed evidence of widespread traumatic axonal injury measured using diffusion magnetic resonance imaging. This change was more marked within the cingulum bundle, the tract connecting the parahippocampal gyrus to the posterior cingulate cortex. These findings provide novel insights into the pathophysiology of post-traumatic amnesia and evidence that memory impairment acutely after traumatic brain injury results from altered parahippocampal functional connectivity, perhaps secondary to the effects of axonal injury on white matter tracts connecting limbic structures involved in memory processing

Assessment of alcohol problems using AUDIT in a prison setting: more than an 'aye or no' question

&lt;br&gt;Background: Alcohol problems are a major UK and international public health issue. The prevalence of alcohol problems is markedly higher among prisoners than the general population. However, studies suggest alcohol problems among prisoners are under-detected, under-recorded and under-treated. Identifying offenders with alcohol problems is fundamental to providing high quality healthcare. This paper reports use of the AUDIT screening tool to assess alcohol problems among prisoners.&lt;/br&gt; &lt;br&gt;Methods: Universal screening was undertaken over ten weeks with all entrants to one male Scottish prison using the AUDIT standardised screening tool and supplementary contextual questions. The questionnaire was administered by trained prison officers during routine admission procedures. Overall 259 anonymised completed questionnaires were analysed.&lt;/br&gt; &lt;br&gt;Results: AUDIT scores showed a high prevalence of alcohol problems with 73% of prisoner scores indicating an alcohol use disorder (8+), including 36% having scores indicating ‘possible dependence’ (20-40). AUDIT scores indicating ‘possible dependence’ were most apparent among 18-24 and 40-64 year-olds (40% and 56% respectively). However, individual questions showed important differences, with younger drinkers less likely to demonstrate habitual and addictive behaviours than the older age group. Disparity between high levels of harmful/hazardous/dependent drinking and low levels of ‘treatment’ emerged (only 27% of prisoners with scores indicating ‘possible dependence’ reported being ‘in treatment’). Self-reported associations between drinking alcohol and the index crime were identified among two-fifths of respondents, rising to half of those reporting violent crimes.&lt;/br&gt; &lt;br&gt;Conclusions: To our knowledge, this is the first study to identify differing behaviours and needs among prisoners with high AUDIT score ranges, through additional analysis of individual questions. The study has identified high prevalence of alcohol use, varied problem behaviours, and links across drinking, crime and recidivism, supporting the argument for more extensive provision of alcohol-focused interventions in prisons. These should be carefully targeted based on initial screening and assessment, responsive, and include care pathways linking prisoners to community services. Finally, findings confirm the value and feasibility of routine use of the AUDIT screening tool in prison settings, to considerably enhance practice in the detection and understanding of alcohol problems, improving on current more limited questioning (e.g. ‘yes or no’ questions).&lt;/br&gt

Modulation of Cellular Hsp72 Levels in Undifferentiated and Neuron-Like SH-SY5Y Cells Determines Resistance to Staurosporine-Induced Apoptosis

Increased expression of Hsp72 accompanies differentiation of human neuroblastoma SH-SY5Y cells to neuron-like cells. By modulating cellular levels of Hsp72, we demonstrate here its anti-apoptotic activity both in undifferentiated and neuron-like cells. Thermal preconditioning (43°C for 30 min) induced Hsp72, leading to cellular protection against apoptosis induced by a subsequent treatment with staurosporine. Preconditioned staurosporine-treated cells displayed decreased Bax recruitment to mitochondria and subsequent activation, as well as reduced cytochrome c redistribution from mitochondria. The data are consistent with Hsp72 blocking apoptosis upstream of Bax recruitment to mitochondria. Neuron-like cells (with elevated Hsp72) were more resistant to staurosporine by all measured indices of apoptotic signaling. Use of stable transfectants ectopically expressing moderately elevated levels of Hsp72 revealed that such cells in the undifferentiated state showed enhanced resistance to staurosporine-induced apoptosis, which was even more robust after differentiation to neuron-like cells. Overall, the protective effects of differentiation, thermal preconditioning and ectopic Hsp72 expression were additive. The strong inverse correlation between cellular Hsp72 levels and susceptibility to apoptosis support the notion that Hsp72 acts as a significant neuroprotective factor, enabling post-mitotic neurons to withstand potentially lethal stress that induces apoptosis

High and Low Molecular Weight Hyaluronic Acid Differentially Regulate Human Fibrocyte Differentiation

Following tissue injury, monocytes can enter the tissue and differentiate into fibroblast-like cells called fibrocytes, but little is known about what regulates this differentiation. Extracellular matrix contains high molecular weight hyaluronic acid (HMWHA; ∼2×10(6) Da). During injury, HMWHA breaks down to low molecular weight hyaluronic acid (LMWHA; ∼0.8-8×10(5) Da).In this report, we show that HMWHA potentiates the differentiation of human monocytes into fibrocytes, while LMWHA inhibits fibrocyte differentiation. Digestion of HMWHA with hyaluronidase produces small hyaluronic acid fragments, and these fragments inhibit fibrocyte differentiation. Monocytes internalize HMWHA and LMWHA equally well, suggesting that the opposing effects on fibrocyte differentiation are not due to differential internalization of HMWHA or LMWHA. Adding HMWHA to PBMC does not appear to affect the levels of the hyaluronic acid receptor CD44, whereas adding LMWHA decreases CD44 levels. The addition of anti-CD44 antibodies potentiates fibrocyte differentiation, suggesting that CD44 mediates at least some of the effect of hyaluronic acid on fibrocyte differentiation. The fibrocyte differentiation-inhibiting factor serum amyloid P (SAP) inhibits HMWHA-induced fibrocyte differentiation and potentiates LMWHA-induced inhibition. Conversely, LMWHA inhibits the ability of HMWHA, interleukin-4 (IL-4), or interleukin-13 (IL-13) to promote fibrocyte differentiation.We hypothesize that hyaluronic acid signals at least in part through CD44 to regulate fibrocyte differentiation, with a dominance hierarchy of SAP>LMWHA≥HMWHA>IL-4 or IL-13

Patient-reported outcome measures of the impact of cancer on patient’s everyday lives: a systematic review

Purpose: Patients with advanced disease are living longer and commonly used patient-reported outcome measures (PROMs) may miss relevant elements of the quality of extended survival. This systematic review examines the measures used to capture aspects of the quality of survival including impact on patients’ everyday lives such as finances, work and family roles. Methods: Searches were conducted in MEDLINE, EMBASE, CINAHL and PsycINFO restricted to English language articles. Information on study characteristics, instruments and outcomes was systematically extracted and synthesised. A predefined set of criteria was used to rate the quality of studies. Results: From 2761 potentially relevant articles, 22 met all inclusion criteria, including 10 concerning financial distress, 3 on roles and responsibilities and 9 on multiple aspects of social well-being. Generally, studies were not of high quality; many lacked bias free participant selection, had confounding factors and had not accounted for all participants. High levels of financial distress were reported and were associated with multiple demographic factors such as age and income. There were few reports concerned with impacts on patients’ roles/responsibilities in everyday life although practical and emotional struggles with parenting were identified. Social difficulties were common and associated with multiple factors including being a caregiver. Many studies were single time-point surveys and used non-validated measures. Exceptions were employment of the COST and Social Difficulties Inventory (SDI), validated measures of financial and social distress respectively. Conclusions: Impact on some important parts of patients’ everyday lives is insufficiently and inconsistently captured. Further PROM development focussing on roles and responsibilities, including work and caring for dependents, is warranted. Implications for Cancer Survivors: Factors such as finances, employment and responsibility for caring for dependents (e.g. children and elderly relatives) can affect the well-being of cancer survivors. There is a need to ensure that any instruments used to assess patients’ social well-being are broad enough to include these areas so that any difficulties arising can be better understood and appropriately supported

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies