Desynchronization of pathological low-frequency brain activity by the hypnotic drug zolpidem.

Reports of the beneficial effects of the hypnotic imidazopyridine, zolpidem, described in persistent vegetative state^1, 2^ have been replicated recently in brain-injured and cognitively impaired patients^3-7^. Previous single photon emission computed tomography (SPECT) studies have suggested that sub-sedative doses of zolpidem increased regional cerebral perfusion in affected areas^5, 8^, implying enhanced neuronal metabolic activity; which has led to speculation that zolpidem 'reawakens' functionally dormant cortex. However, a neuronal mechanism by which this hypnotic drug affords benefits to brain injured patients has yet to be demonstrated. Here, we report the action of sub-sedative doses of zolpidem on neuronal network oscillatory activity in human brain, measured using pharmaco-magnetoencephalography (pharmaco-MEG). Study participant JP suffered a stroke in 1996, causing major damage to the left hemisphere that impaired aspects of both motor and cognitive function. Pharmaco-MEG analyses revealed robust and persistent pathological theta (4-10Hz) and beta (15-30Hz) oscillations within the lesion penumbra and surrounding cortex. Administration of zolpidem (5mg) reduced the power of pathological theta and beta oscillations in all regions of the lesioned hemisphere. This desynchronizing effect correlated well with zolpidem uptake (occurring approximately 40 minutes after acute administration) and was coincident with marked improvements in cognitive and motor function. Control experiments revealed no effect of placebo, while a structurally unrelated hypnotic, zopiclone, administered at a comparable dose (3.5mg) elicited widespread increases in cortical oscillatory power in the beta (15-30Hz) band without functional improvement. These results suggest that in JP, specific motor and cognitive impairments are related to increased low-frequency oscillatory neuronal network activity. Zolpidem is unique amongst hypnotic drugs in its ability to desynchronize such pathological low-frequency activity, thereby restoring cognitive function

A cohort study of the recovery of health and wellbeing following colorectal cancer (CREW study): protocol paper

Background: the number of people surviving colorectal cancer has doubled in recent years. While much of the literature suggests that most people return to near pre-diagnosis status following surgery for colorectal cancer, this literature has largely focused on physical side effects. Longitudinal studies in colorectal cancer have either been small scale or taken a narrow focus on recovery after surgery. There is a need for a comprehensive, long-term study exploring all aspects of health and wellbeing in colorectal cancer patients. The aim of this study is to establish the natural history of health and wellbeing in people who have been treated for colorectal cancer. People have different dispositions, supports and resources, likely resulting in individual differences in restoration of health and wellbeing. The protocol described in this paper is of a study which will identify who is most at risk of problems, assess how quickly people return to a state of subjective health and wellbeing, and will measure factors which influence the course of recovery. Methods: this is a prospective, longitudinal cohort study following 1000 people with colorectal cancer over a period of two years, recruiting from 30 NHS cancer treatment centres across the UK. Questionnaires will be administered prior to surgery, and 3, 9, 15 and 24 months after surgery, with the potential to return to this cohort to explore on-going issues related to recovery after cancer. Discussion: outcomes will help inform health care providers about what helps or hinders rapid and effective recovery from cancer, and identify areas for intervention development to aid this process. Once established the cohort can be followed up for longer periods and be approached to participate in related projects as appropriate and subject to funding<br/

The differential regulation of the adiponectin system in response to lipopolysaccharide and sepsis

Background Sepsis is a condition characterised by a massive acute inflammatory response and insulin resistance. Several inflammatory mediators involved in the immune response during sepsis have been identified. Recently it has become clear that adipose tissue contributes to the production of pro- and anti-inflammatory mediators, which have been termed adipokines. Adiponectin is an adipokine that has anti-diabetic, anti-atherogenic and anti-inflammatory properties. Its role in chronic inflammatory diseases, such as type II diabetes mellitus (DM) and obesity has been extensively studied. Generally, adiponectin is down-regulated in these conditions which are characterised by insulin resistance. Adiponectin, previously thought to be exclusively expressed in and secreted from adipocytes, has now been shown to be released from other tissues such as skeletal muscle, cardiac muscle and bone. Adiponectin from adipose tissue is down-regulated in mouse models of sepsis, however, no information is available about the role of adiponectin receptors. In chronic insulin resistance, adiponectin receptor gene expression is decreased, suggesting a down-regulation of the ‘adiponectin system’. Adiponectin gene expression appears to be partially regulated by NFκB, a transcription factor co-ordinating the release of inflammatory mediators in response to an appropriate stimulus, such as lipopolysaccharide. Other signalling mechanisms may also be involved, in particular the HIF-1α pathway. HIF-1α is another transcription factor with a large number of target genes, many of which are involved in the inflammatory process. Although HIF-1α was initially discovered as a cellular regulator of hypoxia, the pathway has now been shown to be activated by other non-hypoxic mechanisms of up-regulation, including bacterial infection. HIF-1α is expressed in immune cells, however, its role in adipose tissue during sepsis remains unclear. Methods Three different lines of experiments used in this thesis. The animal model used high dose LPS injected intra-peritoneally (under general anaesthesia) into 8-10 week old male C57BL/6J mice. Mice were killed at 4 or 24 hours after injection and tissues (Peri-renal, subcutaneous and epididymal fat, liver, muscle, small bowel and spleen) were removed for analysis. Adiponectin and adiponectin receptor gene expression was determined by quantitative real-time PCR (qPCR). The cell culture model used cell lines, 3T3-L1 adipocytes and C2C12 myocytes, grown in culture and then treated with varying concentrations of LPS. Cells were harvested at 4 and 24 hours and qPCR was performed to ascertain adiponectin and adiponectin receptor gene expression. The same animal and cellular models were utilised for the HIF-1α investigations with protein determination carried out using ELISA. Finally, twenty-one septic patients were recruited from the Intensive care unit at the Royal Liverpool University Hospital, following ethical approval and written consent. Blood samples were taken on days 1 and 2 and day of discharge and serum levels of total and HMW adiponectin were determined by ELISA. Results Alterations in adiponectin and its receptors expression in murine endotoxaemia Adiponectin receptors were down-regulated following LPS injection. The greatest changes acutely were in muscle, liver and peri-renal fat (adipoR1) and liver, muscle, peri-renal and sub-cutaneous fat (adipoR2). There were no significant changes in the other tissue depots. After 24 hours, there were fewer changes in gene expression with adipoR1 being down-regulated in liver and skeletal muscle and AdipoR2 in skeletal muscle only. Down-regulation of adiponectin gene expression following LPS was confirmed in the adipose tissue depots. We demonstrated that the adiponectin gene was expressed in skeletal muscle and sequencing of the PCR product confirmed a 100% match for adiponectin mRNA. C2C12 myocytes were then used to verify the presence of adiponectin mRNA in skeletal muscle cells. In tissue depots, adiponectin gene expression was significantly reduced in skeletal muscle in both the 4 and 24 hour cohorts respectively. Alterations in adiponectin and its receptors expression in cell lines In the cell lines, the inflammatory response to LPS was confirmed using IL-6 as a reference gene. This also confirmed methodological success. Adiponectin gene expression from 3T3-L1 adipocytes was acutely reduced following treatment with high dose LPS but there were no changes in expression in cells treated with lower concentrations of LPS. There were no changes at 24 hours. Adiponectin receptors were down-regulated but not consistently with dose and these changes were only observed in the cells harvested after 4 hours. In C2C12 myocytes, there was a significant reduction in adiponectin gene expression following high doses of LPS but there were minimal changes in adiponectin receptor expression in the C2C12 myocytes. Human Study There was a significant increase in both total and HMW adiponectin between day 1 and day of discharge and the ratio of HMW adiponectin to total adiponectin also increased between admission and discharge. There were no changes in total or HMW adiponectin or their ratio between day 1 and day 2 of admission. HIF-1α HIF-1α gene expression was up-regulated in liver and spleen 4 hours post LPS injection. The changes persisted 24 hours after LPS treatment with increased expression in liver, small bowel and spleen. Protein levels were elevated in skeletal muscle after 4 hours and liver after 24 hours and spleen. Discussion These results increase the evidence that adipose tissue is not an inert storage medium for fatty acids but a sophisticated endocrine organ. The ‘adiponectin system’, including adiponectin and its two receptors, is down-regulated in-vivo and in-vitro models of sepsis. This may play a role in the metabolic derangements such as hyperglycaemia and insulin resistance. In addition, hypoadiponectinaemia may have a significant role in the disordered inflammatory process known to occur in sepsis, possibly impacting on mortality as shown in some animal studies. Adiponectin is not exclusively adipose tissue derived and interestingly we have demonstrated the presence of adiponectin mRNA in other tissue such as skeletal muscle. The effect of reduced gene expression from extra-adipose tissue depots is yet to be established but may have a paracrine or autocrine effect rather than an endocrine role. Low total and HMW adiponectin levels during human sepsis have also been identified. Whilst hypoadiponectinaemia in sepsis has been observed in previous studies, increases in HMW adiponectin associated with clinical improvement have not been previously demonstrated. A further signalling pathway investigated in these models was HIF-1α. These results demonstrate a global up-regulation of HIF-1α gene expression across tissue depots and cellular models. This may reflect tissue hypoxia but also may reflect non-hypoxic up-regulation by LPS and inflammatory mediators. HIF-1α is known to play a part in the inflammatory process and, like adiponectin, has links to the NFκB signalling pathways

Participants' use of enacted scenes in research interviews: a method for reflexive analysis in health and social care

In our study of a workforce intervention within a health and social care context we found that participants who took part in longitudinal research interviews were commonly enacting scenes from their work during one-to-one interviews. Scenes were defined as portions of the interviews in which participants directly quoted the speech of at least two actors. Our analysis in this paper focuses on these enacted scenes, and compares the content of them before and after the intervention. We found that, whilst the tensions between consistency and change, and change management, were common topics for scene enactment in both pre and post-intervention data, following the intervention participants were much more likely to present themselves as active agents in that change. Post-intervention enacted scenes also showed participants' reports of taking a service user perspective, and a focus on their interactions with service users that had been absent from pre-intervention data. In addition, descriptions of positive feeling and emotions were present in the post-intervention enacted scenes. We suggest that this analysis confirms the importance of enacted scenes as an analytic resource, and that this importance goes beyond their utility in identifying the impact of this specific intervention. Given the congruence between the themes prominent in enacted scenes, and those which emerged from a more extensive qualitative analysis of these data, we argue that enacted scenes may also be of wider methodological importance. The possibility of using scene enactment as an approach to the validation of inductive analysis in health and social care settings could provide a useful methodological resource in settings where longitudinal ethnographic observation of frontline care staff is impossible or impractical

Circulating anti-inflammatory adipokines High Molecular Weight Adiponectin and Zinc-α2-glycoprotein (ZAG) are inhibited in early sepsis, but increase with clinical recovery: a pilot study

BACKGROUND: Adipose tissue has been identified as an endocrine organ secreting adipokines involved in metabolic and inflammatory pathways. Adiponectin, an anti-inflammatory adipokine, is reduced in sepsis. High Molecular Weight (HMW) adiponectin, the biologically most relevant molecule, has been investigated very little in human sepsis. Zinc-alpha2-glycoprotein (ZAG) is a novel adipokine and its expression in adipose tissue is positively correlated with adiponectin expression. It is not yet known whether ZAG has a role in sepsis. In this study we assessed levels of HMW adiponectin and ZAG during different stages of sepsis. METHODS: A prospective observational pilot study was carried out on 21 septic patients. Serum samples were taken on day 1 and 2 post ICU admission and on day of discharge. Samples were analysed for total and HMW adiponectin, HMW/total adiponectin ratio, and ZAG. Results were correlated with clinical and metabolic data. RESULTS: There were no differences in total adiponectin, HMW adiponectin and ZAG plasma concentrations between day 1 (admission) and day 2 of the sepsis episode. Compared to admission, a significant increase in total and HMW adiponectin and ZAG was observed on the day of discharge when clinical improvement had been achieved. There was also an increase in the HMW/total adiponectin ratio at that time. CONCLUSIONS: Our data demonstrate an increase in both HMW adiponectin and total adiponectin in patients who had clinically recovered from sepsis. The increase in HMW/total adiponectin ratio with improvement of the clinical condition suggests that HMW adiponectin may have a greater role in the inflammatory process and insulin resistance seen in sepsis. In this pilot study, we have also demonstrated a significant increase in ZAG in critically ill patients temporally related to recovery from sepsis

How does social context influence appraisal and help-seeking for potential cancer symptoms in adults aged 50 and over? A qualitative interview study

Objective: To investigate how social context and social network activation influence appraisal and help-seeking for symptoms potentially indicative of cancer. Methods: Semi-structured telephone interview study. Community dwelling adults who had experienced at least one symptom potentially indicative of cancer within the last month were sampled from a national symptom survey. Results: Thirty-four interviews were conducted. Participants looked to peers and wider society to judge whether symptoms might be normal for their age. Involvement of others in symptom appraisal promoted an active management strategy, such as contacting a healthcare professional or trying a medication. There were practical, emotional, attitudinal, normative and moral barriers to involving others. Cancer narratives from significant others, public health campaigns and the media influenced symptom appraisal. Participants held mental representations of types of people who get cancer, for example, smokers and unfit people. This had two consequences. First, participants did not identify themselves as a candidate for cancer; impeding help-seeking. Second, social judgements about lifestyle introduced stigma. Conclusion: Involving friends/family in symptom appraisal facilitates help-seeking but barriers exist to involving others. Campaigns to promote earlier cancer diagnosis should incorporate age-appropriate narratives, address misconceptions about ‘types’ of people who get cancer and tackle stigma about lifestyle factors.</p

Kinesin-3 mediated axonal delivery of presynaptic neurexin stabilizes dendritic spines and postsynaptic components

The functional properties of neural circuits are defined by the patterns of synaptic connections between their partnering neurons, but the mechanisms that stabilize circuit connectivity are poorly understood. We systemically examined this question at synapses onto newly characterized dendritic spines of C. elegans GABAergic motor neurons. We show that the presynaptic adhesion protein neurexin/NRX-1 is required for stabilization of postsynaptic structure. We find that early postsynaptic developmental events proceed without a strict requirement for synaptic activity and are not disrupted by deletion of neurexin/nrx-1. However, in the absence of presynaptic NRX-1, dendritic spines and receptor clusters become destabilized and collapse prior to adulthood. We demonstrate that NRX-1 delivery to presynaptic terminals is dependent on kinesin-3/UNC-104 and show that ongoing UNC-104 function is required for postsynaptic maintenance in mature animals. By defining the dynamics and temporal order of synapse formation and maintenance events in vivo, we describe a mechanism for stabilizing mature circuit connectivity through neurexin-based adhesion

Genomic variant sharing: a position statement.

Sharing de-identified genetic variant data is essential for the practice of genomic medicine and is demonstrably beneficial to patients. Robust genetic diagnoses that inform medical management cannot be made accurately without reference to genetic test results from other patients, as well as population controls. Errors in this process can result in delayed, missed or erroneous diagnoses, leading to inappropriate or missed medical interventions for the patient and their family. The benefits of sharing individual genetic variants, and the harms of not sharing them, are numerous and well-established. Databases and mechanisms already exist to facilitate deposition and sharing of pseudonomised genetic variants, but clarity and transparency around best practice is needed to encourage widespread use, prevent inconsistencies between different communities, maximise individual privacy and ensure public trust. We therefore recommend that widespread sharing of a small number of individual genetic variants associated with limited clinical information should become standard practice in genomic medicine. Information robustly linking genetic variants with specific conditions is fundamental biological knowledge, not personal information, and therefore should not require consent to share. For additional case-level detail about individual patients or more extensive genomic information, which is often essential for clinical interpretation, it may be more appropriate to use a controlled-access model for data sharing, with the ultimate aim of making as much information as open and de-identified as possible with appropriate consent

‘They’re more like ordinary stroppy British women’: Attitudes and expectations of maternity care professionals to UK-born ethnic minority women

Objective To explore the attitudes and expectations of maternity care professionals to UK-born ethnic minority mothers. Methods Qualitative in-depth interviews with 30 professionals from eight NHS maternity units in England that provide services for large proportions of women of black Caribbean, black African, Indian, Pakistani and Irish descent. Results All the professionals reported providing care to both UK-born and migrant mothers from ethnic minorities. Most of them felt that they could differentiate between UK-born and migrant mothers based mainly on language fluency and accent. ‘Westernized dress’ and ‘freedom’ were also cited as indicators. Overall, professionals found it easier to provide services to UK-born mothers and felt that their needs were more like those of white English mothers than those of migrant mothers. UK-born mothers were generally thought to be assertive and expressive, and in control of care-related decision-making whereas some South Asian Muslim women were thought to be constrained by family influences. Preconceived ideas about ethnic minority mothers' tolerance of pain in labour, use of pharmacological pain relief measures and mode of delivery were recurring themes. Women's education and social class were felt to be major influences on the uptake of maternity care, regardless of ethnicity. Conclusions Professionals appeared to equate the needs of UK-born ethnic minority women with those of white English women. Overall, this has positive implications for care provision. Despite this, specific behavioural expectations and unconscious stereotypical views were evident and have the potential to affect clinical practice