Presenteeism in academic employees-occupational and individual factors.

Background: There is growing evidence that presenteeism can be damaging for individuals and organizations. It is, therefore, important to identify the prevalence of working while sick in different working environments and the factors that contribute to such behaviour. Aims: To examine the prevalence of self-reported presenteeism in academic staff working in UK universities and colleges and the extent to which job demands, control, support and work engagement are risk factors. Methods: Scales from the Health and Safety Executive Management Standards Indicator Tool were used to measure job demands, control and support from managers and co-workers. Work engagement was assessed using a validated measure and the frequency of self-reported presenteeism was measured. The effects of demands, control, support and engagement on presenteeism were examined with ordinal regression analysis. Results: The study sample comprised 6874 people working in academic roles in UK colleges and universities (59% female). Most respondents (88%) reported working while sick at least sometimes. The risk factors for presenteeism were job demands, control, support from managers and work engagement. Conclusions: The findings of this study indicate that presenteeism is commonplace in UK colleges and universities. Some of the features of the job that might encourage employees to work while sick are highlighted, whereas engagement in work was an additional risk factor.

Review: Induced pluripotent stem cell models of frontotemporal dementia.

The increasing prevalence of dementia in the ageing population combined with the lack of treatments and the burden on national health care systems globally make dementia a public health priority. Despite the plethora of important research findings published over the past two decades, the mechanisms underlying dementia are still poorly understood and the progress in pharmacological interventions is limited. Recent advances in cellular reprogramming and genome engineering technologies offer an unprecedented new paradigm in disease modeling. Induced pluripotent stem cells (iPSCs) have enabled the study of patient-derived neurons in vitro, a significant progress in the field of dementia research. The first studies using iPSCs to model dementia have recently emerged, holding promise for elucidating disease pathogenic mechanisms and accelerating drug discovery. In this review, we summarize the major findings of iPSC-based studies in frontotemporal dementia (FTD) and FTD overlapping with amyotrophic lateral sclerosis (FTD/ALS). We also discuss some of the main challenges in the use of iPSCs to model complex, late-onset neurodegenerative diseases such as dementias.

Review: Insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation: unifying theories.

Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by dystonia, parkinsonism and spasticity. Iron accumulates in the basal ganglia and may be accompanied by Lewy bodies, axonal swellings and hyperphosphorylated tau depending on NBIA subtype. Mutations in 10 genes have been associated with NBIA that include Ceruloplasmin (Cp) and ferritin light chain (FTL), both directly involved in iron homeostasis, as well as Pantothenate Kinase 2 (PANK2), Phospholipase A2 group 6 (PLA2G6), Fatty acid hydroxylase 2 (FA2H), Coenzyme A synthase (COASY), C19orf12, WDR45 and DCAF17 (C2orf37). These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy. A greater understanding of the cellular pathways that link these genes and the disease mechanisms leading to iron dyshomeostasis is needed. Additionally, the major overlap seen between NBIA and more common neurodegenerative diseases may highlight conserved disease processes. In this review, we will discuss clinical and pathological findings for each NBIA-related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis, and speculate the potential overlap between NBIA subtypes.

Progress in understanding electro-mechanical signalling in the myometrium.

In this review, we give a state-of-the-art account of uterine contractility, focussing on excitation-contraction (electro-mechanical) coupling (ECC). This will show how electrophysiological data and intracellular calcium measurements can be related to more modern techniques such as confocal microscopy and molecular biology, to advance our understanding of mechanical output and its modulation in the smooth muscle of the uterus, the myometrium. This new knowledge and understanding, for example concerning the role of the sarcoplasmic reticulum (SR), or stretch-activated K channels, when linked to biochemical and molecular pathways, provides a clearer and better informed basis for the development of new drugs and targets. These are urgently needed to combat dysfunctions in excitation-contraction coupling that are clinically challenging, such as preterm labour, slow to progress labours and post-partum haemorrhage. It remains the case that scientific progress still needs to be made in areas such as pacemaking and understanding interactions between the uterine environment and ion channel activity.

Oxytocin: its mechanism of action and receptor signalling in the myometrium.

Oxytocin is a nonapeptide hormone that has a central role in the regulation of parturition and lactation. In this review, we address oxytocin receptor (OTR) signalling and its role in the myometrium during pregnancy and in labour. The OTR belongs to the rhodopsin-type (Class 1) of the G-protein coupled receptor superfamily and is regulated by changes in receptor expression, receptor desensitisation and local changes in oxytocin concentration. Receptor activation triggers a number of signalling events to stimulate contraction, primarily by elevating intracellular calcium (Ca(2+) ). This includes inositol-tris-phosphate-mediated store calcium release, store-operated Ca(2+) entry and voltage-operated Ca(2+) entry. We discuss each mechanism in turn and also discuss Ca(2+) -independent mechanisms such as Ca(2+) sensitisation. Because oxytocin induces contraction in the myometrium, both the activation and the inhibition of its receptor have long been targets in the management of dysfunctional and preterm labours, respectively. We discuss current and novel OTR agonists and antagonists and their use and potential benefit in obstetric practice. In this regard, we highlight three clinical scenarios: dysfunctional labour, postpartum haemorrhage and preterm birth.

Rebif(®) Quality of Life (RebiQoL): A randomized, multicenter, Phase IIIb study evaluating quality-of-life measures in patients receiving the serum-free formulation of subcutaneous interferon beta-1a for the treatment of relapsing forms of multiple sclerosis.

BACKGROUND: In clinical studies, treatment with subcutaneous interferon beta-1a (IFNß-1a) has been shown to reduce relapse rates and slow the progression of physical disability in patients with relapsing forms of multiple sclerosis (MS). A formulation of subcutaneous IFNß-1a has been developed that is free of fetal bovine serum and human serum albumin. OBJECTIVE: To evaluate (a) the impact on quality of life (QoL) and treatment satisfaction of transitioning from the original formulation of subcutaneous IFNß-1a to the serum-free formulation in patients with relapsing forms of MS; and (b) the impact of dose titration versus non-titration during the transition on tolerability and patterns of analgesic use. QoL was measured by the Multiple Sclerosis Treatment Concerns Questionnaire Global Side Effects (GSE) score. METHODS: Patients who had received the original formulation of IFNß-1a subcutaneously for ≥24 weeks were randomized to receive the serum-free formulation of IFNß-1a 44µg subcutaneously three times weekly for 12 weeks, with or without a dose titration over a 4-week period. After week 12, patients continued to receive serum-free subcutaneous IFNß-1a during a safety extension phase until they completed between 84 and 112 weeks of treatment. The primary endpoint was the percentage change from baseline to week 12 in GSE score in all patients. RESULTS: A total of 232 patients were randomized (titrated n=113; non-titrated n=119). The mean percent change (improvement) from baseline to week 12 in the GSE score was 5.0% (p<0.001 for mean change in GSE score from baseline); this change was similar between titrated and non-titrated patients and met criteria for non-inferiority to the original formulation. Adverse event (AE) incidence and use of analgesics for the treatment of flu-like symptoms (FLS) were less common in the titrated group. Few patients (<2%) discontinued due to AEs during weeks 0 to 12. CONCLUSION: Patients with relapsing forms of MS who transitioned from original-formulation subcutaneous IFNß-1a to serum-free subcutaneous IFNß-1a had overall improved QoL scores at 12 weeks of treatment. Titration during the transition resulted in a lower requirement for analgesic treatment of FLS and fewer AEs.

Patient-rated ease of use and functional reliability of an electronic autoinjector for self-injection of subcutaneous interferon beta-1a for relapsing multiple sclerosis.

BACKGROUND: For patients with multiple sclerosis (MS), electronic autoinjectors may improve convenience and reduce discomfort associated with chronic injections. OBJECTIVE: To assess ease of use, patient satisfaction, and functional reliability of an investigational electronic autoinjector for self-injection of subcutaneous interferon beta-1a (IFNß-1a). METHODS: This prospective, multicenter, open-label, single-arm, 12-week, Phase IIIb study enrolled patients aged 18-65 years with relapsing MS receiving IFNß-1a 44µg subcutaneously 3 times weekly for ≥12 weeks before enrollment. Thereafter, patients continued their regimen using an electronic autoinjector. The primary endpoint was the proportion of patients rating the autoinjector 'easy to use' or 'very easy to use' on a User Trial Questionnaire at week 12. Secondary endpoints included patient responses to questions regarding device reliability, patient satisfaction, and convenience. RESULTS: Of 103 patients enrolled, 88 completed the study. The primary objective was met, with most patients (78%) indicating the device was 'easy to use' or 'very easy to use' at week 12 (worst-case imputation). In an analysis of secondary endpoints, over 60% of patients responded favorably to each of the User Trial questions regarding device ease-of-use and their satisfaction with the device. Overall convenience was judged the most important benefit of the device. Adverse events reported were consistent with the known safety profile of IFNß-1a, with injection site reactions the most frequently reported. CONCLUSION: These data show that patients found the electronic autoinjector for delivery of subcutaneous IFNß-1a reliable and easy to use, suggesting the device may help patients with relapsing MS to administer self-injections.

Diabetes is associated with impairment of uterine contractility and high Caesarean section rate.

AIMS/HYPOTHESIS: The prevalence of births worldwide complicated by diabetes mellitus is increasing. In the UK, for example, <25% of diabetic women have a non-instrumental vaginal delivery. Strikingly, more than half the Caesarean sections (CS) in these patients are non-elective, but the reasons for this are not understood. We have tested the hypothesis that poor myometrial contractility as a consequence of the disease contributes to this high CS rate. METHODS: We compared spontaneous, high K depolarisation and oxytocin-induced contractions from diabetic and matched control patients having an elective CS. To investigate the mechanism of any differences we measured intracellular Ca, and performed western blotting and compared the tissues histologically. RESULTS: There was significantly decreased contraction amplitude and duration in uteri from diabetic compared with control patients, even when possible confounders such as BMI were analysed. Reduced intracellular calcium signals and expression of calcium entry channels were found in uteruses from diabetic patients, which, along with a reduction in muscle content found on histological examination, could explain the reduced force. Myometrium from diabetic patients was responsive to oxytocin, but still did not reach the levels found in non-diabetic patients. CONCLUSIONS/INTERPRETATIONS: These are the first data investigating myometrium in diabetic patients and they support the hypothesis that there is poorer contractility even in the presence of oxytocin. The underlying mechanism is related to reduced Ca channel expression and intracellular calcium signals and a decrease in muscle mass. We conclude that these factors significantly contribute to the increased emergency CS rate in diabetic patients.

In vitro myometrial contractility reflects indication for caesarean section.

OBJECTIVE: To assess the extent to which in vitro measurements of myometrial contractility reflect the clinical indication for caesarean section. DESIGN: A prospective, observational hypothesis-generating study. SETTING: Women were recruited from Liverpool Women's NHS Foundation Trust and experiments were performed in the Physiology Department at the University of Liverpool. POPULATION: Myometrial samples were taken from women undergoing a caesarean section during labour (n = 50) or from women having a repeat nonlabouring caesarean section (n = 70). METHODS: The demographic characteristics of the women and indications for current and previous caesarean sections were recorded. The force, frequency and duration of spontaneous contractions of myometrial strips, and changes in the intracellular calcium concentration of the strips, were measured. Kruskall-Wallis and post hoc tests were used to assess the significance of differences between groups. RESULTS: Samples from women whose caesarean section was for fetal distress/acidosis (scalp pH <7.2) contracted with more force than those from women whose caesarean section was for delay in the first stage of labour (P < 0.001). For repeat, nonlabouring caesarean sections, samples from women whose first caesarean section was for fetal distress/acidosis also contracted with more force than did samples from women whose first caesarean section was for delay in the first stage of labour (P = 0.03). CONCLUSIONS: These findings suggest that the myometrium contracts with greater force in women who have a caesarean section for fetal distress.

Maternal obesity and labour complications following induction of labour in prolonged pregnancy.

OBJECTIVE: To investigate the effect of maternal obesity on mode of delivery following induction of labour (IOL) for prolonged pregnancy and subsequent intrapartum and neonatal complications. DESIGN: Retrospective (historical) cohort study. SETTING: Liverpool Women's Hospital NHS Foundation Trust, UK. POPULATION: A total of 29, 224 women with singleton pregnancies between 2004 and 2008 of whom 3076 had a prolonged pregnancy (defined as ≥290 days or 41(+3) weeks of gestation) and received IOL. METHODS: Kruskal-Wallis test, chi-square test and multivariable logistic regression. MAIN OUTCOME MEASURES: Mode of delivery and risk of delivery and neonatal complications in obese verses non-obese women following IOL. RESULTS: Obese women had a significantly higher rate of IOL ending in caesarean section compared with women of normal weight following IOL (38.7% versus 23.8% primiparous; 9.9% versus 7.9% multiparous women, respectively); however, length of labour, incidence of postpartum haemorrhage and third-degree tear, rate of low cord blood pH, low Apgar scores and shoulder dystocia were similar in all body mass index categories. Complications included a higher incidence of fetal macrosomia and second-degree, but not third-degree, tear in primiparous women. CONCLUSIONS: Higher maternal body mass index at booking is associated with an increased risk of prolonged pregnancy and increased rate of IOL. Despite this, more than 60% of obese primiparous and 90% of multiparous women with prolonged pregnancies who were induced achieved vaginal delivery and labour complications in the obese women with prolonged pregnancies were largely comparable to those of normal weight women with prolonged pregnancies. Our data suggest that IOL for prolonged pregnancy in obese women is a reasonable and safe management option.

From nose to brain: development of gonadotrophin-releasing hormone-1 neurones.

Gonadotrophin-releasing hormone-1 (GnRH-1) is essential for mammalian reproduction, controlling release of gonadotrophins from the anterior pituitary. GnRH-1 neurones migrate from the nasal placode into the forebrain during development. Although first located within the nasal placode, the embryonic origin/lineage of GnRH-1 neurones is still unclear. The migration of GnRH-1 cells is the best characterised example of neurophilic/axophilic migration, with the cells using a subset of olfactory-derived vomeronasal axons as their pathway and numerous molecules to guide their movement into the forebrain. Exciting work in this area is beginning to identify intersecting pathways that orchestrate the movement of these critical neuroendocrine cells into the central nervous system, both spatially and temporally, through a diverse and changing terrain. Once within the forebrain, little is known about how the axons target the median eminence and ultimately secrete GnRH-1 in a pulsatile fashion.

Male and female Fmr1 knockout mice on C57 albino background exhibit spatial learning and memory impairments.

Impaired spatial learning is a prominent deficit in fragile X syndrome (FXS). Previous studies using the Fmr1 knockout (KO) mouse model of FXS have not consistently reported a deficit in spatial learning. Fmr1 KO mice bred onto an albino C57BL/6J-Tyr(c-Brd) background showed significant deficits in several primary measures of performance during place navigation and probe trials in the Morris water maze. Fmr1 KO mice were also impaired during a serial reversal version of the water maze task. We examined fear conditioning as an additional cognitive screen. Knockout mice exhibited contextual memory deficits when trained with unsignaled shocks; however, deficits were not found in a separate group of KO mice trained with signaled shocks. No potentially confounding genotypic differences in locomotor activity were observed. A decreased anxiety-like profile was apparent in the open field, as others have noted, and also in the platform test. Also as previously reported, startle reactivity to loud auditory stimuli was decreased, prepulse inhibition and social interaction increased in KO mice. Female Fmr1 KO mice were tested along with male KO mice in all assays, except for social interaction. The female and male KO exhibited very similar impairments indicating that sex does not generally drive the behavioral symptoms of the disorder. Our results suggest that procedural factors, such as the use of albino mice, may help to reliably detect spatial learning and memory impairments in both sexes of Fmr1 KO mice, making it more useful for understanding FXS and a platform for evaluating potential therapeutics.

Effect of i.v. phenylephrine or ephedrine on the ED50 of intrathecal bupivacaine with fentanyl for caesarean section.

BACKGROUND: Prophylactic infusion of phenylephrine to prevent hypotension at Caesarean section has been shown to decrease the rostral spread of intrathecal plain levobupivacaine and intrathecal hyperbaric bupivacaine by a median of two dermatomes compared with ephedrine. The aim of this study was to determine the median effective dose (ED50) of intrathecal bupivacaine required to achieve a block to touch at the xiphisternum in patients undergoing Caesarean section when phenylephrine or ephedrine are used to prevent hypotension. METHODS: Seventy women were randomized in two groups to receive either phenylephrine at a rate of 16.6 microg min(-1) (concentration 1microg ml(-1)) or ephedrine at a rate of 1.5 mg min(-1) (concentration 90 microg ml(-1)). Patients received varying doses of hyperbaric bupivacaine with fentanyl 25 microg using a double-blinded, up-down sequential allocation design. Effective doses were defined as anaesthesia to touch with ethyl chloride spray to the xiphisternum within 20 min. RESULTS: The ED50 estimates of bupivacaine were similar in the two groups: 7.8 mg [95% confidence interval (CI) 6.7-8.9] with phenylephrine and 7.6 mg (95% CI 6.8-8.4) with ephedrine. Systolic blood pressure control was similar (P=0.18) with vasopressors but heart rate was higher with ephedrine (P=0.0014). CONCLUSIONS: Under the conditions of this study, we have shown that when phenylephrine or ephedrine were used to prevent post-spinal hypotension, the dosing requirement of hyperbaric bupivacaine was similar for intrathecal anaesthesia.

Sex hormones and excitation-contraction coupling in the uterus: the effects of oestrous and hormones.

In this review, we examine how far the increased understanding that we have of the events in excitation contraction can explain the effects of the oestrous cycle and sex hormones on uterine function. Observational studies of electrical and mechanical activity in the rat myometrium have shown a relative quiescence during pro-oestrous, with little propagation of any electrical events. Thus, uterine activity can be said to approximately inversely reflect plasma 17beta-oestradiol concentrations. We show that Ca(2+) signalling and mechanical activity are greatest in metoestrous and dioestrous compared to pro-oestrous and oestrous. These data are discussed in terms of hormonal effects on Ca(2+) and K(+) channels. Finally, the influence of sex hormones on lipid rafts and caveolae are considered and discussed in relation to recent findings on their role in uterine signalling and contractility, and cholesterol levels and obesity.

Temporal migration of gonadotrophin-releasing hormone-1 neurones is modified in GAD67 knockout mice.

Gonadotrophin-releasing hormone (GnRH-1) neurones reside in the forebrain and regulate gonadal function via the hypothalamic-pituitary-gonadal axis. Disruption of this axis results in reproductive dysfunction. During embryonic development, GnRH-1 neurones migrate from the nasal pit through the nasal/forebrain junction (NFJ) into the developing brain. Prenatally gamma-aminobutyric acid (GABA) is excitatory and has been shown to play a role in nervous system development. Both in vivo and in vitro experiments suggest that GABA inhibits migration of GnRH-1 neurones. The present study examines the migration of GnRH-1 neurones in GAD67 knockout (KO) mice to further elucidate the role of GABA on GnRH-1 neuronal development. Three stages were examined, embryonic day (E)12.5, E14.5 and E17.5. GnRH-1 cell number and location were analysed by immunocytochemistry and in situ hybridisation histochemistry. The total number of GnRH-1 immunopositive cells was similar between wild-type (WT) and KO mice. However, significant differences were found in the overall distribution of GnRH-1 immunopositive cells in GAD67 KO compared to WT mice at all stages. Subsequent analysis by area revealed differences occurred at the NFJ with an increase in GnRH-1 cells in GAD67 KO at E14.5 and a decrease in GnRH-1 cells in GAD67 KO at E17.5. Comparable counts for cells expressing GnRH-1 transcript and protein were obtained. These data indicate that attenuated levels of GABA accelerate GnRH-1 cell migration in nasal areas as well as movement of GnRH-1 cells into the central nervous system at the NFJ.

Intravenous conscious sedation in children for outpatient dentistry.

The use of general anaesthesia for dental treatment in the NHS outside hospitals has changed over time. Although deaths are uncommon during or immediately after general anaesthesia for dental treatment, they are more likely to occur than with other methods of pain and anxiety reduction, such as local anaesthesia and conscious sedation. Inquiries into recent anaesthetic deaths in dental practice have been critical of the standard of care provided in areas such as pre-operative assessment, monitoring, resuscitation and transfer to specialist critical care facilities.

Poor uterine contractility in obese women.

OBJECTIVE: The aim of the study was to elucidate the reason for the high rate of caesarean section in obese women. We examined the following hypotheses: (1) obese women have a high incidence of complications related to poor uterine contractility--caesarean section for dysfunctional labour and postpartum haemorrhage. 2) The myometrium from obese women has less ability to contract in vitro. DESIGN: First, a clinical retrospective analysis of data from 3913 completed singleton pregnancies was performed. Secondly, in a prospective study the force, frequency and intracellular [Ca(2+)] flux of spontaneously contracting myometrium were related to the maternal body mass index. SETTING: Liverpool Women's Hospital and University of Liverpool. POPULATION: The clinical study involved all women who delivered in one hospital in 2002. The in vitro study myometrial biopsies were obtained from 73 women who had elective caesarean section at term. RESULTS: Maternal obesity carried significant risk of caesarean section in labour that was highest for delay in the first stage of labour (OR 3.54). The increased risk of caesarean section in obese women largely occurred in women with normal- and not with high-birthweight infants. Obese women delivering vaginally had increased risk of prolonged first stage of labour and excessive blood loss. Myometrium from obese women contracted with less force and frequency and had less [Ca(2+)] flux than that from normal-weight women. CONCLUSIONS: We suggest that these findings indicate that obesity may impair the ability of the uterus to contract in labour.

Developmental changes in GABA receptor subunit composition within the gonadotrophin-releasing hormone-1 neuronal system.

It is becoming increasingly evident that GABA plays an important role in the regulation of gonadotrophin-releasing hormone (GnRH)-1 neurones via the GABAA receptor. The aim of the present study was to characterise expression of the GABAA receptor within the GnRH-1 system across development. The expression pattern of five GABAAalpha subunits and one GABAAbeta subunit was first examined within individual GnRH-1 neurones by the polymerase chain reaction. A significant increase in the expression of GABAAalpha2 and a significant decrease in the expression of GABAAalpha6 over time were found. Of the other subunits examined, two (alpha1 and alpha3) showed no differences in expression and two (alpha4 and beta3) showed variable low incidence of expression. Given the reciprocal relationship of alpha2 and alpha6 expression, we hypothesised that there is a developmental switch in the expression of these subunits in GnRH-1 neurones. To investigate this hypothesis, single- and double-label immunocytochemistry for GABAAalpha2 and alpha6 and GnRH-1 was performed in tissue from ages E12.5 to adulthood, as well as in nasal explants. We show that GABAAalpha2 and alpha6 are present in the GnRH-1 neuronal system both in vivo and in vitro and that the levels of expression are altered as a function of age.

Distribution of AQP2 and AQP3 water channels in human tissue microarrays.

The objective of this investigation was to use semi-quantitative immunohistochemistry to determine the distribution and expression levels of AQP2 and AQP3 proteins in normal human Tissue MicroArrays. Expression of the vasopressin regulated AQP2 was observed in a limited number of tissues. AQP2 was prominent in the apical and subapical plasma membranes of cortical and medullary renal collecting ducts. Surprisingly, weak AQP2 immunoreactivity was also noted in pancreatic islets, fallopian tubes and peripheral nerves. AQP2 was also localized to selected parts of the central nervous system (ependymal cell layer, subcortical white matter, hippocampus, spinal cord) and selected cells in the gastrointestinal system (antral and oxyntic gastric mucosa, small intestine and colon). These findings corroborate the restricted tissue distribution of AQP2. AQP3 was strongly expressed in many of the human tissues examined particularly in basolateral membranes of the distal nephron (medullary collecting ducts), distal colon, upper airway epithelia, transitional epithelium of the urinary bladder, tracheal, bronchial and nasopharyngeal epithelium, stratified squamous epithelial cells of the esophagus, and anus. AQP3 was moderately expressed in basolateral membranes of prostatic tubuloalveolar epithelium, pancreatic ducts, uterine endometrium, choroid plexus, articular chondrocytes, subchondral osteoblasts and synovium. Low AQP3 levels were also detected in skeletal muscle, cardiac muscle, gastric pits, seminiferous tubules, lymphoid vessels, salivary and endocrine glands, amniotic membranes, placenta and ovary. The abundance of basolateral AQP3 in epithelial tissues and its expression in many non-epithelial cells suggests that this aquaglyceroporin is a major participant in barrier hydration and water and osmolyte homeostasis in the human body.