An overview of psychological and neurobiological mechanisms by which early negative experiences increase risk of mood disorders

Objective: Early life experiences are associated with severe and long-lasting effects on behavioural and emotional functioning, which in turn are thought to increase the risk for unipolar depression and other disorders of affect regulation. The neurobiological and psychological mechanisms through which adverse early life experiences confer risk are poorly understood. Method: Alterations in brain structure and function in limbic and prefrontal cortical regions have been linked to early negative experiences and to mood disorders. Results: There are a number of psychological domains that may be dysfunctional in people with mood disorders, and which, if the dysfunction occurs prior to onset of mood symptoms, may signify a risk factor for depression. Cognitive dysfunction has been examined in patients with mood disorders, with some suggestion that changes in cognitive function may antedate the onset of mood symptoms, and may be exacerbated in those who experienced early negative trauma. Social cognition, including emotion comprehension, theory of mind and empathy, represent under-studied domains of psychological function that may be negatively influenced by early adverse experience. Temperament and personality factors may also leave people vulnerable to mood instability. Conclusion: This review summarizes the evidence for dysfunction in each of these domains for people with mood disorders.

Independent neuronal oscillators of the rat globus pallidus

In vivo, neurons of the globus pallidus (GP) and subthalamic nucleus (STN) resonate independently around 70 Hz. However, on the loss of dopamine as in Parkinson's disease, there is a switch to a lower frequency of firing with increased bursting and synchronization of activity. In vitro, type A neurons of the GP, identified by the presence of Ih and rebound depolarizations, fire at frequencies (≤80 Hz) in response to glutamate pressure ejection, designed to mimic STN input. The profile of this frequency response was unaltered by bath application of the GABAA antagonist bicuculline (10 μM), indicating the lack of involvement of a local GABA neuronal network, while cross-correlations of neuronal pairs revealed uncorrelated activity or phase-locked activity with a variable phase delay, consistent with each GP neuron acting as an independent oscillator. This autonomy of firing appears to arise due to the presence of intrinsic voltage- and sodium-dependent subthreshold membrane oscillations. GABAA inhibitory postsynaptic potentials are able to disrupt this tonic activity while promoting a rebound depolarization and action potential firing. This rebound is able to reset the phase of the intrinsic oscillation and provides a mechanism for promoting coherent firing activity in ensembles of GP neurons that may ultimately lead to abnormal and pathological disorders of movement.

Frequency selectivity and dopamine-dependence of plasticity at glutamatergic synapses in the subthalamic nucleus

In Parkinson's disease, subthalamic nucleus (STN) neurons burst fire with increased periodicity and synchrony. This may entail abnormal release of glutamate, the major source of which in STN is cortical afferents. Indeed, the cortico-subthalamic pathway is implicated in the emergence of excessive oscillations, which are reduced, as are symptoms, by dopamine-replacement therapy or deep brain stimulation (DBS) targeted to STN. Here we hypothesize that glutamatergic synapses in the STN may be differentially modulated by low-frequency stimulation (LFS) and high-frequency stimulation (HFS), the latter mimicking deep brain stimulation. Recordings of evoked and spontaneous excitatory post synaptic currents (EPSCs) were made from STN neurons in brain slices obtained from dopamine-intact and chronically dopamine-depleted adult rats. HFS had no significant effect on evoked (e) EPSC amplitude in dopamine-intact slices (104.4±8.0%) but depressed eEPSCs in dopamine-depleted slices (67.8±6.2%). Conversely, LFS potentiated eEPSCs in dopamine-intact slices (126.4±8.1%) but not in dopamine-depleted slices (106.7±10.0%). Analyses of paired-pulse ratio, coefficient of variation, and spontaneous EPSCs suggest that the depression and potentiation have a presynaptic locus of expression. These results indicate that the synaptic efficacy in dopamine-intact tissue is enhanced by LFS. Furthermore, the synaptic efficacy in dopamine-depleted tissue is depressed by HFS. Therefore the therapeutic effects of DBS in Parkinson's disease appear mediated, in part, by glutamatergic cortico-subthalamic synaptic depression and implicate dopamine-dependent increases in the weight of glutamate synapses, which would facilitate the transfer of pathological oscillations from the cortex.

Aspects of health among an employed population

This survey collected information on aspects of health amongst an employed population, employees in 14 different organisations in the West Midlands Regional Health Authority; and was a stratified sample of senior managers, middle managers and operatives. Nine hundred and sixty questionnaires were distributed asking for both quantitative and qualitative information on 58 questions covering health, work, family, leisure activities and life-style. A response rate of 48% (459 returned questionnaires) came from 290 men (63%), 165 women (36%) and four people (1%) who did not answer the gender question. The initial findings from this study are unique in that there has not been a specific review of the health of people at work. In answer to the main research questions, 92% felt they were healthy. Compared to others of a similar age, 34% felt their health was `above average', 58% `average', and 7&37 `below average'. Thirty two percent of respondents had visited their GP in the past 1-2 months; the highest reason given was disorders of the respiratory system, 20%. People's perceptions on the effects of work on their health were: good effect, 13% fair effect, 20% no effect, 27% poor effect, 27% and bad effect, 7%. The effects of leisure activities on health were thought to be more positive: good effect, 46% fair effect, 20% no effect, 21% poor effect, 3% and bad effect, 2%. The perceptions of effects of life-style on health were considered to be: good effect, 32% fair effect, 32% no effect, 20% poor effect, 9% and bad effect, 1%.  In this survey, leisure and life-style were seen by employees to have more beneficial effects on health than work. Future implications include a review of occupational health as a major policy development area within primary care. There is a need to influence the education and training of health care practitioners in order to affect their ability to practise effectively in this new and challenging area of work.

Ceramide and reactive oxygen species (ROS) as signal transduction molecules in inflammation

Reactive oxygen species (ROS) and the sphingolipid ceramide are each partly responsible for the intracellular signal transduction of a variety of physiological, pharmacological or environmental agents. Furthermore, the enhanced production of many of these agents, that utilise ROS and ceramide as signalling intermediates, is associated with the aetiologies of several vascular diseases (e.g. atherosclerosis) or disorders of inflammatory origin (e.g. rheumatoid arthritis; RA). Excessive monocyte recruitment and uncontrolled T cell activation are both strongly implicated in the chronic inflammatory responses that are associated with these pathologies. Therefore the aims of this thesis are (1) to further elucidate the cellular responses to modulations in intracellular ceramide/ROS levels in monocytes and T cells, in order to help resolve the mechanisms of progression of these diseases and (2) to examine both existing agents (methotrexate) and novel targets for possible therapeutic manipulation. Utilising synthetic, short chain ceramide to mimic the cellular responses to fluctuations in natural endogenous ceramide or, stimulation of CD95 to induce ceramide formation, it is described here that ceramide targets and manipulates two discrete sites responsible for ROS generation, preceding the cellular responses of growth arrest in U937 monocytes and apoptosis in Jurkat T-cells. In both cell types, transient elevations in mitochondrial ROS generation were observed. However, the prominent redox altering effects appear to be the ceramide-mediated reduction in cytosolic peroxide, the magnitude of which dictates in part the cellular response in U937 monocytes, Jurkat T-cells and primary human peripheral blood resting or PHA-activated T-cells in vitro. The application of synthetic ceramides to U937 monocytes for short (2 hours) or long (16 hours) treatment periods reduced the membrane expression of proteins associated with cell-cell interaction. Furthermore, ceramide treated U937 monocytes demonstrated reduced adhesion to 5 or 24 hour LPS activated human umbilical vein endothelial cells (HUVEC) but not resting HUVEC. Consequently it is hypothesised that the targeted treatment of monocytes from patients with cardiovascular diseases with short chain synthetic ceramide may reduce disease progression. Herein, the anti-inflammatory and immunosuppressant drug, methotrexate, is described to require ROS production for the induction of cytostasis or cytotoxicity in U937 monocytes and Jurkat T-cells respectively. Further, ROS are critical for methotrexate to abrogate monocyte interaction with activated HUVEC in vitro. The histological feature of RA of enhanced infiltration, survivability and hyporesponsiveness of T-cells within the diseased synovium has been suggested to arise from aberrant signalling. No difference in the concentrations of endogenous T-cell ceramide, the related lipid diacylglycerol (DAG) and cytosolic peroxide ex vivo was observed. TCR activation following PHA exposure in vitro for 72 hours did not induced maintained perturbations in DAG or ceramide in T-cells from RA patients or healthy individuals. However, T-cells from RA patients failed to upregulate cytosolic peroxide in response to PHA, unlike those from normals, despite expressing identical levels of the activation marker CD25. This inability to upregulate cytosolic peroxide may contribute to the T-cell pathology associated with RA by affecting the signalling capacity of redox sensitive biomolecules. These data highlight the importance of two distinctive cellular pools of ROS in mediating complex biological events associated with inflammatory disease and suggest that modulation of cellular ceramides represents a novel therapeutic strategy to minimise monocyte recruitment.

The spalling of concrete in fires

The occurrence of spalling is a major factor in determining the fire resistance of concrete constructions. The apparently random occurrence of spalling has limited the development and application of fire resistance modelling for concrete structures. This Thesis describes an experimental investigation into the spalling of concrete on exposure to elevated temperatures. It has been shown that spalling may be categorised into four distinct types, aggregate spalling, corner spalling, surface spalling and explosive spalling. Aggregate spalling has been found to be a form of shear failure of aggregates local to the heated surface. The susceptibility of any particular concrete to aggregate spalling can be quantified from parameters which include the coefficients of thermal expansion of both the aggregate and the surrounding mortar, the size and thermal diffusivity of the aggregate and the rate of heating. Corner spalling, which is particularly significant for the fire resistance of concrete columns, is a result of concrete losing its tensile strength at elevated temperatures. Surface spalling is the result of excessive pore pressures within heated concrete. An empirical model has been developed to allow quantification of the pore pressures and a material failure model proposed. The dominant parameters are rate of heating, pore saturation and concrete permeability. Surface spalling may be alleviated by limiting pore pressure development and a number of methods to this end have been evaluated. Explosive spalling involves the catastrophic failure of a concrete element and may be caused by either of two distinct mechanisms. In the first instance, excessive pore pressures can cause explosive spalling, although the effect is limited principally to unloaded or relatively small specimens. A second cause of explosive spalling is where the superimposition of thermally induced stresses on applied load stresses exceed the concrete's strength.

Some clinical aspects of the eye in extended contact lens wear

The limbal vascular response to extended contact lens wear was examined in a group comparative study initially intended to last eighteen months. After six months all patients wearing contact lenses had presented with micro-epithelial cysts. This unanticipated occurrence of the micro-epithelial-cysts necessitated termination of the study, and limited the quantity of data collected. However, sufficient results were available to allow a limited description of •the vascular response to this form of contact lens wear. Interpretations of the date collected ore discussed in relation to suggested vasostimulating factors in the cornea. The micro-epithelial cysts observed after extended wear were classified and their rate of recovery recorded. A further clinical study was undertaken to observe cysts in both contact lens - and non contact lens-wearing eyes. Cysts were observed in every category of patient, although the characteristic patterns varied. These observations of micro-epithelial cysts are discussed with respect to the aetiopathogeneses of corneal epithelial cystic disorders. Subsequently, attempts were made to induce cysts in rabbit corneae by extended contact lens wear. Clinical observations revealed cyst-like appearances. Histological sections did not contain cysts but did exhibit signs characteristic •of cystic disorders of the corneal epithelium. In general, the results from the study indicate that extended wear is subjectively acceptable to contact lens wearers. However, the objective findings of significant vascular changes, micro-epithelial cysts and cases of acute red eye response cast considerable doubt on the recommendation of extended wear contact lenses for purely cosmetic applications.

Inhibition of collagen I accumulation reduces glomerulosclerosis by a Hic-5-dependent mechanism in experimental diabetic nephropathy

Glomerulosclerosis of any cause is characterized by loss of functional glomerular cells and deposition of excessive amounts of interstitial collagens including collagen I. We have previously reported that mesangial cell attachment to collagen I leads to upregulation of Hic-5 in vitro, which mediates mesangial cell apoptosis. Furthermore, glomerular Hic-5 expression was increased during the progression of experimental glomerulosclerosis. We hypothesized that reducing collagen I accumulation in glomerulosclerosis would in turn lower Hic-5 expression, reducing mesangial cell apoptosis, and thus maintaining glomerular integrity. We examined archive renal tissue from rats undergoing experimental diabetic glomerulosclerosis, treated with the transglutaminase-2 inhibitor NTU281. Untreated animals exhibited increased glomerular collagen I accumulation, associated with increased glomerular Hic-5 expression, apoptosis, and mesangial myofibroblast transdifferentiation characterized by a-smooth muscle actin (a-SMA) expression. NTU281 treatment reduced glomerular collagen I accumulation, Hic-5 and a-SMA expression, and apoptosis. Proteinurea and serum creatinine levels were significantly reduced in animals with reduced Hic-5 expression. In vitro studies of Hic-5 knockdown or overexpression show that mesangial cell apoptosis and expression of both a-SMA and collagen I are Hic-5 dependent. Together, these data suggest that there exists, in vitro and in vivo, a positive feedback loop whereby increased levels of collagen I lead to increased mesangial Hic-5 expression favoring not only increased apoptosis, but also mesangial myofibroblast transdifferentiation and increased collagen I expression. Prevention of collagen I accumulation interrupts this Hic-5-dependent positive feedback loop, preserving glomerular architecture, cellular phenotype, and function. © 2013 USCAP, Inc All rights reserved.

Rapid tonicity induced re-localisation of endogenous aquaporin 4 in primary rat astrocytes - a therapeutic target for cytotoxic brain oedema?

It is estimated that 69-75 million people worldwide will suffer a traumatic brain injury (TBI) or stroke each year. Brain oedema caused by TBI or following a stroke, together with other disorders of the brain cost Europe €770 billion in 2014. Aquaporins (AQP) are transmembrane water channels involved in many physiologies and are responsible for the maintenance of water homeostasis. They react rapidly to changes in osmolarity by transporting water through their highly selective central pore to maintain tonicity and aid in cell volume regulation. We have previously shown that recombinant AQP1-GFP trafficking occurs in a proteinkinase C-microtubule dependant manner in HEK-293 cells in response to hypotonicity. This trafficking mechanism is also reliant on the presence of calcium and its messenger-binding protein calmodulin and results in increased cell surface expression of AQP1 in a time-scale of ~30 seconds. There is currently very little research into the trafficking mechanisms of endogenous AQPs in primary cells. AQP4 is the most abundantly expressed AQP within the brain, it is localised to the astrocytic end-feet, in contact with the blood vessels at the blood-brain-barrier. In situations where the exquisitely-tuned osmotic balance is disturbed, high water permeability can become detrimental. AQP4-mediated water influx causes rapid brain swelling, resulting in death or long term brain damage. Previous research has shown that AQP4 knock-out mice were protected from the formation of cytotoxic brain oedema in a stroke model, highlighting AQP4 as a key drug target for this pathology. As there are currently no treatments available to restrict the flow of water through AQP4 as all known inhibitors are either cytotoxic or non-specific, controlling the mechanisms involved in the regulation of AQP4 in the brain could provide a therapeutic solution to such diseases. Using cell surface biontinylation of endogenous AQP4 in primary rat astrocytes followed by neutraavidin based ELISA we have shown that AQP4 cell surface localisation increases by 2.7 fold after 5 minutes hypotonic treatment at around 85 mOsm/kg H2O. We have also shown that this rapid relocalisation of AQP4 is regulated by PKA, calmodulin, extra-cellular calcium and actin. In summary we have shown that rapid translocation of endogenous AQP4 occurs in primary rat astrocytes in response to hypotonic stimuli; this mechanism is PKA, calcium, actin and calmodulin dependant. AQP4 has the potential to provide a treatment for the development of brain oedema.

When does leverage hurt productivity growth? A firm-level analysis:a firm-level analysis

In the wake of the global financial crisis, several macroeconomic contributions have highlighted the risks of excessive credit expansion. In particular, too much finance can have a negative impact on growth. We examine the microeconomic foundations of this argument, positing a non-monotonic relationship between leverage and firm-level productivity growth in the spirit of the trade-off theory of capital structure. A threshold regression model estimated on a sample of Central and Eastern European countries confirms that TFP growth increases with leverage until the latter reaches a critical threshold beyond which leverage lowers TFP growth. This estimate can provide guidance to firms and policy makers on identifying "excessive" leverage. We find similar non-monotonic relationships between leverage and proxies for firm value. Our results are a first step in bridging the gap between the literature on optimal capital structure and the wider macro literature on the finance-growth nexus. © 2012 Elsevier Ltd.

Psychosoziale Merkmale der Arbeit, Überforderungserleben und Depressivität

Die vorliegende Studie untersuchte die im Job-Demand-Control-Support-Modell und Effort-Reward-Imbalance-Modell beschriebenen Tätigkeitsmerkmale in Bezug auf Depressivität in einer Stichprobe von 265 Erwerbstätigen. Anhand konfirmatorischer Faktorenanalysen wurden Gemeinsamkeiten und Unterschiede beider Modelle geprüft. Anschließend wurde die Bedeutung der nachweisbaren Tätigkeitsmerkmale für die Vorhersage von Depressivität getestet und untersucht, inwieweit die Effekte durch Überforderungserleben mediiert werden. Die Analysen zeigten, dass die Modelle sowohl gemeinsame (Arbeitsintensität bzw. berufliche Anforderungen) als auch distinkte Arbeitsmerkmale (Tätigkeitsspielraum, Arbeitsplatzsicherheit, beruflicher Status, soziale Anerkennung) erfassen. Hohe Arbeitsintensität, geringe Arbeitsplatzsicherheit und fehlende soziale Anerkennung standen in signifikantem Zusammenhang mit Depressivität. Anders als erwartet war der berufliche Status positiv mit Depressivität assoziiert, während für den Tätigkeitsspielraum keine signifikanten Effekte nachweisbar waren. Das Pfadmodell bestätigte sowohl direkte als auch durch Überforderungserleben vermittelte Zusammenhänge zwischen den Tätigkeitsmerkmalen und Depressivität (39 % Varianzaufklärung). Die Ergebnisse bieten eine Grundlage für die Identifizierung potenzieller Risikofaktoren für das Auftreten depressiver Symptome am Arbeitsplatz. This study examined the job characteristics in the Job-Demand-Control-Support Model and in the Effort-Reward Imbalance Model with regard to depression in a sample of 265 employees. First, we tested by means of confirmatory factor analysis similarities and differences of the two models. Secondly, job characteristics were introduced as predictors in a path model to test their relation with depression. Furthermore, we examined whether the associations were mediated by the experience of excessive demands. Our analyses showed the demand/effort component to be one common factor, while decision latitude and reward (subdivided into the three facets of job security, social recognition, and status-related reward) remained distinctive components. Employees with high job demands/effort, low job security, low social recognition, but high status-related rewards reported higher depression scores. Unexpectedly, status-related rewards were positively associated with depression, while we found no significant effects for decision latitude. The path models confirmed direct as well as mediation effects (through experienced excessive demands) between job characteristics and depression (39 % explained variance in depression). Our results could be useful to identify possible job-related risk factors for depression.