The role of GRK6 in animal models of Parkinson's disease and L-DOPA treatment.

G protein-coupled Receptor Kinase 6 (GRK6) belongs to a family of kinases that phosphorylate GPCRs. GRK6 levels were found to be altered in Parkinson's Disease (PD) and D(2) dopamine receptors are supersensitive in mice lacking GRK6 (GRK6-KO mice). To understand how GRK6 modulates the behavioral manifestations of dopamine deficiency and responses to L-DOPA, we used three approaches to model PD in GRK6-KO mice: 1) the cataleptic response to haloperidol; 2) introducing GRK6 mutation to an acute model of absolute dopamine deficiency, DDD mice; 3) hemiparkinsonian 6-OHDA model. Furthermore, dopamine-related striatal signaling was analyzed by assessing the phosphorylation of AKT/GSK3β and ERK1/2. GRK6 deficiency reduced cataleptic behavior, potentiated the acute effect of L-DOPA in DDD mice, reduced rotational behavior in hemi-parkinsonian mice, and reduced abnormal involuntary movements induced by chronic L-DOPA. These data indicate that approaches to regulate GRK6 activity could be useful in modulating both therapeutic and side-effects of L-DOPA.

Venus infers

These poems mark the fault lines of myth, dream and memory, of a doubled identity emerging from the clash of war, desire and the cacophony of the city. 1974/Dead Sister , a narrative poem with a cast that includes Lewis Carroll’s Alice, Freud’s Dora, the Lady of Shalott, Ophelia, Esther, female cowboys and other deposed goddesses is ‘an autobiography’ of an imaginary dead twin. Alev Adil delineates the traces of a sense of displacement, but while the poems mark those frenetic uncertainties and erasures they celebrate the plenitude of new stories, epistemologies and possibilities born out of falling into fracture (the fracture of memory, gender, identity, culture) more than they mourn any loss. Venus Infers is haunted by the deities of ancient Greek myths and their contemporary manifestations. Eurydice is hiding out in Hackney, sometimes glimpsed on the Jubilee Line; Ariadne remembers her ancient palace as she prowls the endless corridors of a London hotel; Penelope still waits for peace in the ruins of Marash/Varosha. Cyprus often features in these poems, both as a landscape for myth and as a site for contemporary, and contested, memories. [From the Author]

Induction of apoptosis in host cells: a survival mechanism for Leishmania parasites?

Leishmania parasites invade host macrophages, causing infections that are either limited to skin or spread to internal organs. In this study, 3 species causing cutaneous leishmaniasis, L. major, L. aethiopica and L. tropica, were tested for their ability to interfere with apoptosis in host macrophages in 2 different lines of human monocyte-derived macrophages (cell lines THP-1 and U937) and the results confirmed in peripheral blood mononuclear cells (PBMC). All 3 species induced early apoptosis 48 h after infection (expression of phosphatidyl serine on the outer membrane). There were significant increases in the percentage of apoptotic cells both for U937 and PBMC following infection with each of the 3 species. Early apoptotic events were confirmed by mitochondrial membrane permeabilization detection and caspase activation 48 and 72 h after infection. Moreover, the percentage of infected THP-1 and U937 macrophages increased significantly (up to 100%) following treatment with an apoptosis inducer. Since phosphatidyl serine externalization on apoptosing cells acts as a signal for engulfment by macrophages, induction of apoptosis in the parasitized cells could actively participate in spreading the infection. In summary, parasite-containing apoptotic bodies with intact membranes could be released and phagocytosed by uninfected macrophages.

Individual crisis episodes and cultural transition: finding the macrocosm in the microcosm

According to dialogical self theory (Hermans, 2001), individual identities reflect cultural and subcultural values, and appropriate voices and discourses from the social environment. Bronfenbrenner’s (1979) systemic theory of human development similarly postulates that individual and social development occur in a symbiotic and interdependent fashion. It would therefore be predicted that individual changes in identity reflect macrocosmic changes in cultural values and social structures. The current study investigated narratives of crisis transitions within adults aged 25-40, by way of interviews with 22 participants. An intensive qualitative analysis showed that the narratives of crisis could indeed be viewed as individual manifestations of contemporary cultural changes. National statistics and academic research have documented in the UK substantial cultural shifts over the last twenty years including the lessening popularity of marriage, the rise of freelance and portfolio careers and the growth of accepted alternative gender roles. In individual crises, changes made over the course of the episode were invariably in the same direction as these social changes; towards flexible work patterns, non-marital relationships and redefined gender identities. Before the crisis, participants described their identity as bound into an established discourse of conventionality, a traditional sense of masculinity or feminitity and a singular career role, while after the crisis alternative and fluid identities are explored, and identity is less defined by role and institution. These findings show that changes in the social macrocosm can be found in the individual microcosm, and therefore support dialogical self theory.

Spatial variability of marine climate change impacts in the North Atlantic

There is an accumulating body of evidence to suggest that many marine ecosystems in the North Atlantic, both physically and biologically are responding to changes in regional climate caused predominately by the warming of air and sea surface temperatures (SST) and to a varying degree by the modification of oceanic currents, precipitation regimes and wind patterns. The biological manifestations of rising SST and oceanographic changes have variously taken the form of biogeographical, phenological, physiological and community changes. For example, during the last 40 years there has been a northerly movement of warmer water plankton by 10 degree latitude in the north-east Atlantic and a similar retreat of colder water plankton to the north. This geographical movement is much more pronounced than any documented terrestrial study, presumably due to advective processes playing an important role. Other research has shown that the plankton community in the North Sea has responded to changes in SST by adjusting their seasonality (in some cases a shift in seasonal cycles of over six weeks has been detected), but more importantly the response to climate warming varied between different functional groups and trophic levels, leading to mismatch. Therefore, while it has been documented that marine ecosystems in certain regions of the Atlantic have undergone some conspicuous changes over the last few decades it is not known whether this is a pan-oceanic homogenous response. Using these two most prominent responses and/or indicative signals of pelagic ecosystems to hydro-climatic change, changes in species phenology and the biogeographical movement of populations, we attempt to identify vulnerable regional areas in terms of particularly rapid and marked change.

Challenges for implementing the Marine Strategy Framework Directive in a climate of macroecological change

Unprecedented basin-scale ecological changes are occurring in our seas. As temperature and carbon dioxide concentrations increase, the extent of sea ice is decreasing, stratification and nutrient regimes are changing and pH is decreasing. These unparalleled changes present new challenges for managing our seas, as we are only just beginning to understand the ecological manifestations of these climate alterations. The Marine Strategy Framework Directive requires all European Member States to achieve good environmental status (GES) in their seas by 2020; this means management towards GES will take place against a background of climate-driven macroecological change. Each Member State must set environmental targets to achieve GES; however, in order to do so, an understanding of large-scale ecological change in the marine ecosystem is necessary. Much of our knowledge of macroecological change in the North Atlantic is a result of research using data gathered by the Continuous Plankton Recorder (CPR) survey, a near-surface plankton monitoring programme that has been sampling in the North Atlantic since 1931. CPR data indicate that North Atlantic and North Sea plankton dynamics are responding to both climate and human-induced changes, presenting challenges to the development of pelagic targets for achievement of GES in European Seas. Thus, the continuation of long-term ecological time series such as the CPR survey is crucial for informing and supporting the sustainable management of European seas through policy mechanisms.

Why is it so hard to set MSFD indicators and targets? Messages from the plankton

Unprecedented basin-scale ecological changes are occurring in our seas. As temperature and carbon dioxide concentrations increase, the extent of sea ice is decreasing, stratification and nutrient regimes are changing, and pH is decreasing. These unparalleled changes present new challenges for managing our seas as we are only just beginning to understand the ecological manifestations of these climate alterations. The Marine Strategy Framework Directive requires all European Member States to achieve Good Environmental Status (GES) in their seas by 2020; this means management toward GES will take place against a background of climate-driven macroecological change. Each Member State must set environmental targets to achieve GES; however, in order to do so an understanding of large-scale ecological change in the marine ecosystem is necessary. Much of our knowledge of macroecological change in the North Atlantic is a result of research using data gathered by the Continuous Plankton Recorder (CPR) survey, a near-surface plankton monitoring program which has been sampling in the North Atlantic since 1931. CPR data indicate that North Atlantic and North Sea plankton dynamics are responding to both climate and human-induced changes, presenting challenges to the development of pelagic targets for achievement of GES in European seas. Thus the continuation of long-term ecological time-series such as the CPR is crucial for informing and supporting the sustainable management of European seas through policy mechanisms.

Variaciones termométricas en la planta del pie y piernas valorada en corredores antes y después de correr 30 km

La termometría es una técnica no invasiva que permite cuantificar los cambios en la temperatura cutánea y evaluarla de forma cuantitativa. El aumento significativo de la temperatura puede indicar la existencia de patología. Se ha demostrado que la actividad muscular induce procesos de transferencia de calor entre los músculos y las capas superficiales de tejido. En este estudio queremos cuantificar los cambios de temperatura que se producen en los músculos del pie y miembro inferior tras una carrera de 30 km, para ello hemos utilizado una cámara termográfica de alta resolución. Contamos con la colaboración voluntaria de 32 sujetos sanos a los que procedimos a tomar fotografías de la planta del pie, parte anterior de la pierna, parte posterior de la pierna, parte anterior del muslo y parte posterior del muslo en dos etapas, primero antes de la carrera y segunda toma después de la carrera de 30 km, de esta manera pudimos valorar si había o no variación de temperatura en las zonas seleccionadas. Tras el análisis de los datos obtenidos encontramos significativas variaciones térmicas en Talón, cabeza primer metatarsiano, cabeza segundo metatarsiano, cabeza tercer metatarsiano, cabeza cuarto metatarsiano, cabeza quinto metatarsiano, apófisis estiloides quinto metatarsiano, arco longitudinal interno, maléolo interno, maléolo externo, peroneo lateral largo, vasto interno, vasto externo, recto femoral, tensor de la fascia lata, inserción cuádriceps, gemelo interno, tendón de Aquiles y Biceps femoral.

Los diferentes tipos de láser y sus aplicaciones en podología

Los diferentes tipos de láseres, sobre todo el láser de diodo, irrumpen en la terapéutica podológica para proporcionar una alternativa más de tratamiento en muchas patologías que son el día a día de las consultas. El buen manejo y el conocimiento de sus características son requisitos imprescindibles para no tener efectos secundarios indeseados y poder llevar a cabo tratamientos poco dolorosos, minimizando el tiempo total, y muchas veces proporcionando una solución a diversas patologías.

The Cult of 'Maria Regina' in Early Medieval Rome

This paper examines the importance of the cult of Mary to religious practice in early medieval Rome, with a particular focus on the manifestations of devotion to Mary in the decoration of churches such as S. Maria Antiqua and San Clemente.

The role of cathepsin C in Papillon-Lefèvre syndrome, prepubertal periodontitis, and aggressive periodontitis

We have previously reported that loss-of-function mutations in the cathepsin C gene (CTSC) result in Papillon Lefevre syndrome, an autosomal recessive condition characterized by palmoplantar keratosis and early,onset, severe periodontitis. Others have also reported CTSC mutations in patients with severe prepubertal periodontitis, but without any skin manifestations. The possible role of CTSC variants in more common types of non-mendelian, early-onset, severe periodontitis ("aggressive periodontitis") has not been investigated. In this study, we have investigated the role of CTSC in all three conditions. We demonstrate that PLS is genetically homogeneous and the mutation spectrum that includes three novel mutations (c.386T>A/p. V129E, c.935A>G/p.Q312R, and c.1235A>G/p.Y412C) in 21 PLS families (including eight from our previous study) provides an insight into structure-function relationships of CTSC. Our data also suggest that a complete loss-of-function appears to be necessary for the manifestation of the phenotype, making it unlikely that weak CTSC mutations are a cause of aggressive periodontitis. This was confirmed by analyses of the CTSC activity in 30 subjects with aggressive periodontitis and age-sex matched controls, which demonstrated that there was no significant difference between these two groups (1,728.7 +/- SD 576.8 mu moles/mg/min vs. 1,678.7 +/- SD 527.2 mu moles/mg/min, respectively, p = 0.73). CTSC mutations were detected in only one of two families with prepubertal periodontitis; these did not form a separate functional class with respect to those observed in classical PLS. The affected individuals in the other prepubertal periodontitis family not only lacked CTSC mutations, but in addition did not share the haplotypes at the CTSC locus. These data suggest that prepubertal periodontitis is a genetically heterogeneous disease that, in some families, just represents a partially penetrant PLS. (C) 2004 Wiley-Liss, Inc.

Stability of 5-aminolevulinic acid in novel non-aqueous gel and patch-type systems intended for topical application.

Aminolevulinic acid (ALA) stability within topical formulations intended for photodynamic therapy (PDT) is poor due to dimerisation to pyrazine-2,5-dipropionic acid (PY). Most strategies to improve stability use low pH vehicles, which can cause cutaneous irritancy. To overcome this problem, a novel approach is investigated that uses a non-aqueous vehicle to retard proton-induced charge separation across the 4-carbonyl group on ALA and lessen nucleophilic attack that leads to condensation dimerisation. Bioadhesive anhydrous vehicles based on methylvinylether-maleic anhydride copolymer patches and poly(ethyleneglycol) or glycerol thickened poly(acrylic acid) gels were formulated. ALA stability fell below pharmaceutically acceptable levels after 6 months, with bioadhesive patches stored at 5°C demonstrating the best stability by maintaining 86.2% of their original loading. Glycerol-based gels maintained 40.2% in similar conditions. However, ALA loss did not correspond to expected increases in PY, indicating the presence of another degradative process that prevented dimerisation. Nuclear magnetic resonance (NMR) analysis was inconclusive in respect of the mechanism observed in the patch system, but showed clearly that an esterification reaction involving ALA and both glycerol and poly(ethyleneglycol) was occurring. This was especially marked in the glycerol gels, where only 2.21% of the total expected PY was detected after 204 days at 5°C. Non-specific esterase hydrolysis demonstrated that ALA was recoverable from the gel systems, further supporting esterified binding within the gel matrices. It is conceivable that skin esterases could duplicate this finding upon topical application of the gel and convert these derivatives back to ALA in situ, provided skin penetration is not affected adversely.

Hope in the Most Unlikely Spaces: Thawra and the Contemporary Arabic Novel

In the early to mid-twentieth century, many novelists in the Arab world championed Arab nationalism in their literary reflections on the social and political struggles of their countries, depicting these struggles primarily in terms of spatial binaries that pitted the Arab world against the West, even as they imported Western literary models of progress and modernity into their own work. The intense experience of national awakening that infused their writing often placed these authors at a literary disadvantage, for in their literature, all too often the depth and diversity of Arabic cultures and the complexity of socio-political struggles across the Arab world were undermined by restrictive spatial discourses that tended to focus only on particular versions of Arab history and on a seemingly unifying national predicament. Between the Arab defeat of 1967 and the present day, however, an increasing number of Arab authors have turned to less restrictive forms of spatial discourse in search of a language that might offer alternative narratives of hope beyond the predictable, and seemingly thwarted, trajectories of nationalism. This study traces the ways in which contemporary Arab authors from Egypt and the Sudan have endeavoured to re-think and re-define the Arab identity in ever-changing spaces where elements of the local and the global, the traditional and the modern, interact both competitively and harmoniously. I examine the spatial language and the tropes used in three Arabic novels, viewing them through the lens of thawra (revolution) in both its socio-political and artistic manifestations. Linking the manifestations of thawra in each text to different scenes of revolution in the Arab world today, in Chapter Two, I consider how, at a stage when the Sudan of the sixties was both still dealing with colonial withdrawal and struggling to establish itself as a nation-state, the geographical and textual landscapes of Tayeb Salih‟s Season of Migration to the North depict the ongoing dilemma of the Sudanese identity. In Chapter Three, I examine Alaa iii al-Aswany‟s The Yacoubian Building in the context of a socially diseased and politically corrupt Egypt of the nineties: social, political, modern, historical, local, and global elements intertwine in a dizzyingly complex spatial network of associations that sheds light on the complicated reasons behind today‟s Egyptian thawra. In Chapter Four, the final chapter, Gamal al-Ghitani‟s approach to his Egypt in Pyramid Texts drifts far away from Salih‟s anguished Sudan and al-Aswany‟s chaotic Cairo to a realm where thawra manifests itself artistically in a sophisticated spatial language that challenges all forms of spatial hegemony and, consequently, old and new forms of social, political, and cultural oppression in the Arab world.

MARKERS OF CARDIOVASCULAR DYSFUNCTION AFTER PREGNANCIES COMPLICATED BY PRE-ECLAMPSIA

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy characterized by maternal systemic endothelial dysfunction. While the clinical manifestations resolve soon after delivery, a large body of epidemiological evidence indicates significant long-term maternal risk for cardiovascular disease (CVD) after PE. The mechanisms by which PE and future CVD are associated are unclear, although shared constitutional risk factors likely contribute to the features of endothelial dysfunction characteristic to both. We postulate that PE offers a window of opportunity for the identification of unique markers of dysfunction in the earliest stages of disease that may be used to validate cardiovascular risk screening in the early postpartum period. The studies presented in this thesis provide evidence of changes in circulating factors in women with a recent history of PE. Using blood samples collected within the first year of pregnancy, unique patterns of microRNA expression, enrichment of coagulation system proteins and endothelial progenitor cell dysfunction were described. Many of the described changes appear to be independent of cardiovascular risk. In addition to alterations in circulating factors however, longitudinal postpartum assessments demonstrated that microvascular and cardiac abnormalities were evident in the early periods postpartum after a pre-eclamptic pregnancy. Collectively, the data presented in this thesis reveal that physiological alterations in women with a recent history of PE are not necessarily dependent on clinical parameters of cardiovascular risk, and that resulting dysfunction may be demonstrated within the first year postpartum. Importantly, the biomarkers presented herein are all demonstrated elsewhere in the literature to benefit from lifestyle modification and risk reduction. In closing, the findings of this thesis support a need for cardiovascular risk screening based on obstetrical history, namely after pregnancies complicated by PE.

Transient receptor potential melastatin 8 (TRPM8) channel involvement in the regulation of vascular tone

The transient receptor potential melastatin 8 (TRPM8) channel has been characterized as a cold and menthol receptor expressed in a subpopulation of sensory neurons but was recently identified in other tissues, including the respiratory tract, urinary system, and vasculature. Thus TRPM8 may play multiple functional roles, likely to be in a tissue- and activation state-dependent manner. We examined the TRPM8 channel presence in large arteries from rats and the functional consequences of their activation. We also aimed to examine whether these channels contribute to control of conscious human skin blood flow. TRPM8 mRNA and protein were detected in rat tail, femoral and mesenteric arteries, and thoracic aorta. This was confirmed in single isolated vascular myocytes by immunocytochemistry. Isometric contraction studies on endothelium-denuded relaxed rat vessels found small contractions on application of the TRPM8-specific agonist menthol (300 microM). However, both menthol and another agonist icilin (50 microM) caused relaxation of vessels precontracted with KCl (60 mM) or the alpha-adrenoceptor agonist phenylephrine (2 microM) and a reduction in sympathetic nerve-mediated contraction. These effects were antagonized by bromoenol lactone treatment, suggesting the involvement of Ca(2+)-independent phospholipase A(2) activation in TRPM8-mediated vasodilatation. In thoracic aorta with intact endothelium, menthol-induced inhibition of KCl-induced contraction was enhanced. This was unaltered by preincubation with either N(omega)-nitro-l-arginine methyl ester (l-NAME; 100 nM), a nitric oxide synthase inhibitor, or the ACh receptor antagonist atropine (1 microM). Application of menthol (3% solution, topical application) to skin caused increased blood flow in conscious humans, as measured by laser Doppler fluximetry. Vasodilatation was markedly reduced or abolished by prior application of l-NAME (passive application, 10 mM) or atropine (iontophoretic application, 100 nM, 30 s at 70 microA). We conclude that TRPM8 channels are present in rat artery vascular smooth muscle and on activation cause vasoconstriction or vasodilatation, dependent on previous vasomotor tone. TRPM8 channels may also contribute to human cutaneous vasculature control, likely with the involvement of additional neuronal mechanisms.