Surveillance as an Option for the Treatment of Small Renal Masses

OBJECTIVES. To review the natural history and biological potential of small renal masses in order to evaluate surveillance as a treatment option. METHODS. Literature search of Medline and additional references from non-Medline-indexed publications concerning surveillance of small renal masses. RESULTS. The natural history and biological potential of small renal masses can still not be unambiguously predicted at present. There seems to be no clear correlation between tumour size and presence of benign histology. The majority of small renal masses grow and the majority are cancer, but one cannot safely assume that a lack of growth on serial CT scans is the confirmation of absence of malignancy. Needle core biopsies could be used to help in decision making. They show a high accuracy for histopathological tumour type but are less accurate in evaluating Fuhrman grade. CONCLUSIONS. At present, surveillance of small renal masses should only be considered in elderly and/or infirm patients with competing health risks, in those with a limited life expectancy, and in those for whom minimal invasive treatment or surgery is not an option. In all other patients, active surveillance should only be considered in the context of a study protocol. Long-term, prospective studies are needed to provide a more accurate assessment of the natural history and metastastic potential of small renal masses

Presenilins and the γ-secretase: still a complex problem

The presenilins form part of a complex of membrane proteins that are involved in the proteolytic cleavage of cell-surface molecules. This article reviews the history of the discovery of the presenilins, their role in the pathogenesis of Alzheimer's disease and in the metabolism of the amyloid-β precursor protein. Unanswered questions about their biochemical mechanism of action and their effects on Ca2+ homeostasis are examined

Effects of Heparin and Enoxaparin on APP Processing and Aβ Production in Primary Cortical Neurons from Tg2576 Mice

BACKGROUND Alzheimer's disease (AD) is caused by accumulation of Aβ, which is produced through sequential cleavage of β-amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE1) and γ-secretase. Enoxaparin, a low molecular weight form of the glycosaminoglycan (GAG) heparin, has been reported to lower Aβ plaque deposition and improve cognitive function in AD transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS We examined whether heparin and enoxaparin influence APP processing and inhibit Aβ production in primary cortical cell cultures. Heparin and enoxaparin were incubated with primary cortical cells derived from Tg2576 mice, and the level of APP and proteolytic products of APP (sAPPα, C99, C83 and Aβ) was measured by western blotting. Treatment of the cells with heparin or enoxaparin had no significant effect on the level of total APP. However, both GAGs decreased the level of C99 and C83, and inhibited sAPPα and Aβ secretion. Heparin also decreased the level of β-secretase (BACE1) and α-secretase (ADAM10). In contrast, heparin had no effect on the level of ADAM17. CONCLUSIONS/SIGNIFICANCE The data indicate that heparin and enoxaparin decrease APP processing via both α- and β-secretase pathways. The possibility that GAGs may be beneficial for the treatment of AD needs further study.This work was funded by a project grant (490031) from the National Health and Medical Research Council of Australia (http://www.nhmrc.gov.au). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Women and Work in Contemporary Japan: Deconstructing the "Crisis" of the Gender Order

ABSTRACT The 1990s saw important developments in the employment practices of Japanese women as necessitated by economic recession. Japanese women are increasingly postponing their traditional roles of wife and mother in lieu of expanding education and employment opportunities, suggesting that we are approaching or witnessing a period of redefinition of the prevailing gender structure. This thesis offers a theoretical exposition of this “crisis” in the gender structure utilising Connell’s concept of “hegemonic masculinity” and Finnemore and Sikkink’s “norm life cycle model”. This thesis will be presented as follows: i) hegemonic masculinity will be applied to the Japanese context to argue for the centrality of masculinity defined through the corporation, and for its significance in an understanding of femininity; ii) discussion of the “feminisation” of part-time work in Japan will test whether a challenge to the gender order from within of this nature represents a profound redefinition of the hegemonic gender structure; and iii) discursive study of Japanese state legislation and policy will reveal government commitment to ensuring continuity in gender norm dynamics. The findings suggest that we are not witnessing a period of “crisis” or profound transformation in the gender structure for greater gender equality. The pervasiveness of gender norm ideology in Japan is such that once established these norms have maintained an internal momentum so that changes in the material sphere are constrained by these ideational structures and not vice versa. The current period is marked by cooptation of gender norm challenges by corporations and government in an effort to neutralise gender norm challenge.N/ADepartment of Government and International Relation

T Cell Maturation Stage Prior to and During GMP Processing Informs on CAR T Cell Expansion in Patients

textabstractAutologous T cells were genetically modified to express a chimeric antigen receptor (CAR) directed toward carboxy-anhydrase-IX (CAIX) and used to treat patients with CAIX-positive metastatic renal cell carcinoma. In this study, we questioned whether the T cell maturation stage in the pre-infusion product affected CAIX CAR expression and function in vitro as well as in vivo CAR T cell numbers and expansion. During the 14 days expansion of CAR T cells prior to administration, we observed shifts from a predominant CD4 to a CD8 T cell phenotype and from a significant fraction of naïve to central effector T cells. Surface expression of the CAR was equally distributed among different T cell subsets and T cell maturation stages. During T cell culture days 14-18 (which covered patient treatment days 1-5), T cells demonstrated a decline in CAR expression level per cell irrespective of T cell maturation stage, although the proportion of CAR-positive T cells and CAR-mediated T cell effector functions remained similar for both CD4 and CD8 T cell populations. Notably, patients with a higher fraction of naïve CD8 T cells at baseline (prior to genetic modification) or central effector CD8 T cells at 2 weeks of CAR T cell culture demonstrated a higher fold expansion and absolute numbers of circulating CAR T cells at 1 month after start of therapy. We conclude that the T cell maturation stage prior to and during CAR T cell expansion culture is related to in vivo CAR T cell expansion

'The medical gaze and the watchful eye' : the treatment, prevention and epidemiology of venereal diseases in New South Wales c.1901 - 1925

From Federation in 1901 through the first three decades of the twentieth century there was a perceptible shift in modes of rule in New South Wales (NSW) related to the management of venereal diseases. At the beginning of the twentieth century a medicopenal approach was central. By 1925, persuasion and ‘responsibilisation’ were becoming important modes, and young people rather than ‘case-hardened prostitutes' were assessed as being a ‘venereal’ risk. Framing this period were three important legislative developments which informed, and were informed by, these shifts: the NSW Prisoners Detention Act 1909, the NSW Select Committee into the Prevalence of Venereal Diseases 1915 and the NSW Venereal Diseases Act 1918. At its core this thesis is concerned with examining shifting modes of rule. This thesis closely examines each. I suggest that these modes of rule can be viewed through the lens of biopolitics, and following Foucault, deploy the ‘medical gaze’ and the ‘watchful eye’ as constructs to examine the relationship between the government of self, government of others and government of the state. I use the medical gaze to describe not only the individual venereal patient attending a hospital and the body of the patient diagnosed with syphilis and/or gonorrhoea, but most importantly to describe the power relationship between the medical practitioner, the teaching hospital and the patient. I use the watchful eye in a more overarching way to suggest the suite of techniques and apparatus deployed by government to monitor and regulate the venereal body politic, both the populations perceived to be posing a venereal risk, and populations at risk of venereal infection. In relation to the venereal body and the venereal body politic, I analyse three fundamental aspects of the management of venereal diseases: treatment, prevention and epidemiology. Treatment: Over this period, treatment moved from lock institutions to outpatient clinics. Embodied in this change was a widespread institutional ambivalence towards treating venereal patients. I contend that treatment of venereal diseases was painful, prolonged and punitive precisely because of the moral sickness perceived to be at the iv heart of venereal infection. I track this ambivalence to a systemic fear of institutional ‘venerealisation’, which decreased perceptibly across the period. Closely analysing surviving patient records, I argue that in their conduct, venereal patients were often compliant, conscientious and responsible. Prevention: I argue that preventative approaches to venereal diseases became increasingly complex, and operated in three domains – preventative medicine (diagnosis, treatment and vaccination); public health prevention (notification, isolation and disinfection); and prevention education (social purity campaigns and sex hygiene). An emerging plethora of community-based organisations and campaigns began to shift the sites and practices of power. Epidemiology: I suggest that there was a shift from danger to risk in the conceptualisation of venereal diseases. This shift necessitated a focus on factors affecting populations, as opposed to factors affecting individuals. This in turn led to the deployment of various techniques to monitor the conduct of venereal populations. The NSW Venereal Diseases Act 1918 created two important new venereal categories: the ‘notified person’ and the ‘defaulter,’ both of which came to permeate renditions of venereal patients throughout the 20th century

Repurposing the GNAT Fold in the Initiation of Polyketide Biosynthesis.

Natural product biosynthetic pathways are replete with enzymes repurposed for new catalytic functions. In some modular polyketide synthase (PKS) pathways, a GCN5-related N-acetyltransferase (GNAT)-like enzyme with an additional decarboxylation function initiates biosynthesis. Here, we probe two PKS GNAT-like domains for the dual activities of S-acyl transfer from coenzyme A (CoA) to an acyl carrier protein (ACP) and decarboxylation. The GphF and CurA GNAT-like domains selectively decarboxylate substrates that yield the anticipated pathway starter units. The GphF enzyme lacks detectable acyl transfer activity, and a crystal structure with an isobutyryl-CoA product analog reveals a partially occluded acyltransfer acceptor site. Further analysis indicates that the CurA GNAT-like domain also catalyzes only decarboxylation, and the initial acyl transfer is catalyzed by an unidentified enzyme. Thus, PKS GNAT-like domains are re-classified as GNAT-like decarboxylases. Two other decarboxylases, malonyl-CoA decarboxylase and EryM, reside on distant nodes of the superfamily, illustrating the adaptability of the GNAT fold

Exposure to challenging behaviours and burnout symptoms among care staff:the role of psychological resources

Background Staff supporting individuals with intellectual disabilities are at risk of burnout symptoms. Evidence suggests an association between exposure to challenging behaviours of individuals with intellectual disabilities and burnout symptoms of staff, but the protective role of staff psychological resources in this relation has been understudied. Method We investigated the association between exposure to challenging behaviours and burnout symptoms of staff and the direct and moderating effects of several psychological resources. Staff (N = 1271) completed an online survey concerning burnout symptoms (subscale Emotional Exhaustion of the Maslach Burnout Inventory), exposure to challenging behaviours and a range of potential psychological resources. We examined main and moderating effects with multilevel analyses. In order to control for the multiple comparisons, P values corrected for false discovery rate (P-FDR) were reported. Results We found a direct relation between exposure to challenging behaviours and increased levels of burnout symptoms in staff (b = .15, t(670) = 4.466, P-FDR <.0001). Perceived supervisor social support (b = -.97, t(627) = -7.562, P-FDR <.0001), staff self-efficacy (b = -.23, t(673) = -3.583, P-FDR <.0001), resilience (b = -.19, t(668) = -2.086, P-FDR <.05) and extraversion (b = -.20, t(674) = -3.514, P-FDR <.05) were associated with reduced burnout symptoms. None of the proposed psychological resources moderated the association between exposure to challenging behaviours and burnout symptoms of staff. Conclusions Of the psychological resources found to be associated with reduced risk of burnout symptoms, staff self-efficacy and access of staff to supervisor social support seem to be the factors that can be influenced best. These factors thus may be of importance in reducing the risk of developing burnout symptoms and improving staff well-being, even though the current study was not designed to demonstrate causal relations between psychological resources and burnout symptoms

Reliability of detrital marine sediments as proxy for continental crust composition: the effects of hydrodynamic sorting on Ti and Zr isotope systematics

The isotopic composition of the detrital sediment record harbours a valuable proxy for estimating the composition of the erodible upper crust since the Archaean. Refractory elements such as titanium (Ti) and zirconium (Zr) can display systematic variations in their isotopic composition as a result of magmatic differentiation. Hence, for such elements, the isotope composition of detrital sediments could potentially be used to infer the average composition (e.g., SiO₂ content) of their source region, even when elemental systematics are obfuscated by weathering and diagenetic processes. A key premise of this approach is that the isotopic composition of sediments remains unbiased relative to their protolith. To what extent isotopic fractionation can occur during sedimentary processes, notably the hydrodynamic sorting of heavy mineral assemblages with contrasting isotopic compositions, remains poorly understood. We investigate the effects of such processes on the Ti and Zr isotope composition of a suite of detrital sediments from the Eastern Mediterranean Sea (EMS). These sediments are binary mixtures of two main provenance components, Saharan dust and Nile sediment, with strongly contrasting mineralogical and geochemical signatures. The EMS sediments display clear evidence for hydrodynamic sorting of zircon, expressed as a large variation in Zr/Al₂O₃ and deviation of εHf relative to the terrestrial εNd-εHf array. Our new data, however, do not show pronounced Zr isotope variation resulting from either hydrodynamic sorting of zircon or sediment provenance. Although this agrees with theoretical models that predict negligible equilibrium zircon-melt Zr isotope fractionation, it contrasts with recent observations suggesting that kinetic Zr isotope fractionation might be a common feature in igneous rocks. For the EMS sediments, the negligible shift in Zr isotope composition through hydrodynamic sorting means that fine-grained samples accurately reflect the composition of their source. The nearly overlapping Zr isotope compositions of Sahara- and Nile-derived sediment, however, means that Zr isotopes, in this case, have insufficient resolution to be a useful provenance proxy. Titanium behaves differently. A small but resolvable, systematic difference in Ti isotope composition is observed between the Sahara and Nile provenance components. Samples with a strong Saharan dust signature show some Ti isotope evidence for hydrodynamic sorting of oxides in tandem with zircon, but a much stronger effect is inferred for Nile sediment. Regression of the EMS sediment samples shows that the Ti isotope composition of the Nile-derived component is strongly fractionated compared to its protolith, the Ethiopian flood basalts. Whereas Ti in Nile sediment is carried in essentially unmodified concentration, and by inference isotope composition, from its sources to the delta, large-scale hydrodynamic sorting of Fe-Ti oxides occurs in the delta. This process decreases TiO₂/Al₂O₃ of the residual fine-grained sediment fraction and shifts its Ti isotope composition to heavier compositions. The potential of such an “oxide effect” in detrital sediments has implications for crustal evolution models that use Ti isotopes as a proxy for the proportion of felsic crust and can account for the observed scatter in the shale record

Natuurontwikkeling in de EHS, nu zorgen voor kwaliteit!

Momenteel werken de provincies aan het nieuwe subsidiestelsel voor (agrarisch) natuurbeheer, dat het huidige Programma Beheer gaat vervangen. Het streven is het nieuwe stelsel geïmplementeerd te krijgen in 2009. Met het stelsel is veel bereikt, maar er zijn zeker ook kansen gemist, namelijk om de ecologische kwaliteit van de EHS te realiseren. In dit artikel wordt een voorzet gegeven voor het inbedden van het realiseren van ecologische kwaliteit in een nieuwe regelgeving. Er valt namelijk een kwaliteitsslag te behalen bij het omvormen van landbouwgrond naar natuu