Visualisation of tissue kallikrein, kininogen and kinin receptors in human skin following trauma and in dermal diseases

During dermal injury and inflammation the serine proteases kallikreins cleave endogenous, multifunctional substrates (kininogens) to form bradykinin and kallidin. The actions of kinins are mediated by preferential binding to constitutively expressed kinin-B2 receptors or inducible kinin-B1 receptors. A feature of the kinin-B1 receptors is that they show low levels of expression, but are distinctly upregulated following tissue injury and inflammation. Because recent evidence suggested that kinin-B1 receptors may perform a protective role during inflammation, we investigated the specific occurrence of the kallikrein-kinin components in skin biopsies obtained from normal skin, patients undergoing surgery, basalioma, lichenificated atopic eczema, and psoriasis. The tissue was immunolabelled in order to determine the localisation of tissue pro-kallikrein, kallikrein, kininogen and kinin receptors. The kinin components were visualised in normal, diseased and traumatised skin, except that no labelling was observed for kininogen in normal skin. Of the five types of tissue examined, upregulation of kinin-B1 receptors was observed only in skin biopsies obtained following surgery. In essence, the expression of kinin-B1 receptors did not appear to be enhanced in the other biopsies. Within the multiple steps of the inflammatory cascade in wound healing, our results suggest an important regulatory role for kinin-B1 receptors during the first phase of inflammation following injury

Setting ART initiation targets in response to changing guidelines : The importance of addressing both steady-state and backlog

PKBackground: Target setting is useful in planning, assessing and improving antiretroviral treatment (ART) programmes. In the past 4 years, the ART initiation environment has been transformed due to the change in eligibility criteria (starting ART at a CD4+ count <350 cells/μl v. <200 cells/μl) and the roll-out of nurse-initiated management of ART. Objective: To describe and illustrate the use of a target-setting model for estimating district-based targets in the era of an expanding ART programme and changing CD4+ count thresholds for ART initiation. Method: Using previously described models and data for annual new HIV infections, we estimated both steady-state need for ART initiation and backlog in a North West Province district, accounting for the shift in eligibility. Comparison of actual v. targeted ART initiations was undertaken. The change in CD4+ count threshold adds a once-off group of newly eligible patients to the pool requiring ART – the backlog. The steady-state remains unchanged as it is determined by the annual rate of new HIV infections in previous years. Results: The steady-state need for the district was 639 initiations/month, and the backlog was ~15 388 patients. After the shift in eligibility in September 2011, the steady-state target was exceeded over several months with some backlog addressed. Of the total backlog for this district, 72% remains to be cleared. Conclusion: South Africa has two pools of patients who need ART: the steady-state of HIV-infected patients entering the programme each year, determined by historical infection rates; and the backlog created by the shift in eligibility. The healthcare system needs to build longterm capacity to meet the steady-state need for ART and additional capacity to address the backlog

Adjusting Overall Survival Estimates after Treatment Switching: a Case Study in Metastatic Castration-Resistant Prostate Cancer

Background If patients in oncology trials receive subsequent therapy, standard intention-to-treat (ITT) analyses may inaccurately estimate the overall survival (OS) effect of the investigational product. In this context, a post-hoc analysis of the phase 3 PREVAIL study was performed with the aim to compare enzalutamide with placebo in terms of OS, adjusting for potential confounding from switching to antineoplastic therapies that are not part of standard metastatic castration-resistant prostate cancer (mCRPC) treatment pathways in some jurisdictions. Methods The PREVAIL study, which included 1717 chemotherapy-naïve men with mCRPC randomized to treatment with enzalutamide 160 mg/day or placebo, was stopped after a planned interim survival analysis revealed a benefit in favor of enzalutamide. Data from this cutoff point were confounded by switching from both arms and so were evaluated in terms of OS using two switching adjustment methods: the two-stage accelerated failure time model (two-stage method) and inverse probability of censoring weights (IPCW). Results Following adjustment for switching to nonstandard antineoplastic therapies by 14.8 (129/872 patients) and 21.3% (180/845 patients) of patients initially randomized to enzalutamide and placebo, respectively, the two-stage and IPCW methods both resulted in numerical reductions in the hazard ratio (HR) for OS [HR 0.66, 95% confidence interval (CI) 0.57–0.81 and HR 0.63, 95% CI 0.52–0.75, respectively] for enzalutamide compared to placebo versus the unadjusted ITT analysis (HR 0.71, 95% CI 0.60–0.84). These results suggest a slightly greater effect of enzalutamide on OS than originally reported. Conclusion In the PREVAIL study, switching to nonstandard antineoplastic mCRPC therapies resulted in the ITT analysis of primary data underestimating the benefit of enzalutamide on OS

Acceleration of Diffusional Jumps of Interstitial Fe with Increasing Ge Concentration in Si1 − x Ge x Alloys Observed by Mössbauer Spectroscopy

Radioactive 57Mn isotopes have been implanted into Si1 − x Ge x crystals (x ≤ 0.1) at elevated temperatures for Mössbauer studies of the diffusion of interstitial 57Fe daughter atoms. The atomic jump frequency is found to increase upon Ge alloying. This is attributed to a lowering of the activation energy, i.e. the saddle point energy at hexagonal interstitial sites with Ge neighbour atom

Globalisation, neo-liberalism and vocational learning: the case of English further education colleges

Further education (FE) has traditionally been a rather unspectacular activity. Lacking the visibility of schools or the prestige of universities, for the vast majority of its existence FE has had a relatively low profile on the margins of English education. Over recent years this situation has altered significantly and further education has undergone profound change. This paper argues that a combination of related factors – neo-liberalism, globalisation, and dominant discourses of the knowledge economy – has acted in synergy to transform FE into a highly performative and marketised sector. Against this backdrop, further education has been assigned a particular role based upon certain narrow and instrumental understandings of skill, employment and economic competitiveness. The paper argues that, although it has always been predominantly working class in nature, FE is now, more than ever, positioned firmly at the lower end of the institutional hierarchy in the highly class-stratified terrain of English education

AN INVESTIGATION INTO THE PERCEPTION OF CRICKETING PLAYERS AND OFFICIALS INTO THE QUOTA POLICY ON CRICKET

South Africa’s racially divided past has led to the institution of various remedial measures across all segments of life, whereby the imbalances of the past are being addressed. Of all the remedial measures employed, the quota policy in sport which is an extension of affirmative action, has been a source of debate and contention. The cricket authorities have struggled to achieve transformation targets but should not shoulder the burden of this under-achievement alone. Government has not provided the necessary infrastructure and facilities at schools to facilitate the development and transformation of cricket. This brings into question the effectiveness of the management and administration of the quota policy in cricket. The results of the quantitative study have shown that the respondents to the survey are discontented with the effectiveness of the management and administration of the quota policy. Furthermore, the respondents believed that the quota policy was unnecessary and responsible for players leaving the country. The authors recommend that the provision of facilities and infrastructure at schools become a high priority in order to stimulate participation in cricket and facilitate the development of cricketers at grassroots level. Furthermore, a synergistic relationship between cricket federations and schools must be fostered

Safeguarding children in dentistry: 1. Child protection training, experience and practice of dental professionals with an interest in paediatric dentistry

* Few dental professionals with child protection training have experience of making referrals. * There is a wide gap in practice between recognising signs of child abuse and neglect and responding effectively. * This may indicate missed opportunities to save children from continuing abuse. * There is a need for improved child protection information, support and training for dental professionals. Abstract Following several highly publicised inquiries into the deaths of children from abuse and neglect, there has been much recent interest in the role and responsibility of all health professionals to protect children at risk of maltreatment. The findings of a postal questionnaire, sent in March 2005 to 789 dentists and dental care professionals with an interest in paediatric dentistry working in varied settings in the UK, are presented in a two-part report and discussed in the context of current multi-agency good practice in safeguarding and promoting the welfare of children. This first part explores reported child protection training, experience and practice. There was a significant gap between recognising signs of abuse and responding effectively: 67% of respondents had suspected abuse or neglect of a child patient at some time in their career but only 29% had ever made a child protection referral. The dental profession is alerted to the need to ensure necessary appropriate action to safeguard children is always taken when child abuse or neglect are suspected

The potential role of GLUT4 transporters and insulin receptors in the hypoglycaemic activity of Ficus lutea acetone leaf extract

BACKGROUND: Some Ficus species have been used in traditional African medicine in the treatment of diabetes. The antidiabetic potential of certain species has been confirmed in vivo but the mechanism of activity remains uncertain. The aim was to investigate the hypoglycaemic potential of ten Ficus species focussing on glucose uptake, insulin secretion and the possible mechanism of hypoglycaemic activity. METHODS: The dried and ground leaves of ten Ficus species were extracted with acetone. The dried acetone extract was reconstituted with DMSO to a concentration of 100 mg/ml which was then serially diluted and used to assay for glucose uptake in muscle, fat and liver cells, and insulin secretion in pancreatic cells. RESULTS: Only the F. lutea extract was able to modulate glucose metabolism. In comparison to insulin in the primary muscle cells, the glucose uptake ability of the extract was 33% as effective. In the hepatoma cell line, the extract was as effective as metformin in decreasing extracellular glucose concentration by approximately 20%. In the pancreatic insulin secretory assay, the extract was 4 times greater in its secretory activity than commercial glibenclamide. With F. lutea extract significantly increasing glucose uptake in the primary muscle cells, primary fat cells, C2C12 muscle and H-4-II-E liver cells, the extract may act by increasing the activity of cell surface glucose transporters. When the 3T3-L1 pre-adipocytes were compared to the primary muscle, primary fat and C2C12 cells, the differences in the former’s ability to transport glucose into the cell may be due to the absence of the GLUT4 transporter, which on activation via the insulin receptor decreases extracellular glucose concentrations. Because the pre-adipocytes failed to show any active increase in glucose uptake, the present effect has to be linked to the absence of the GLUT4 transporter. CONCLUSION: Only F. lutea possessed substantial in vitro activity related to glucose metabolism. Based on the effect produced in the various cell types, F. lutea also appears to be a partial agonist/antagonist of the insulin cell membrane receptor. While the clinical effectiveness of F. lutea is not known, this plant species does possess the ability to modify glucose metabolism

Reflecting Upon Ethical Imperatives for Scholarly Research and The Case of a South African University

A university’s reputation is built on the quality of its research and teaching output. Often a university with an established track record on research and teaching output can more easily access external funding and further improve on its ranking and standing amongst peers.  This enables it to attract and retain better quality students, academics and researchers.  Ideally, these staff and students in turn increase the quality of its research and thus a virtuous circle is created.  Therefore, it is understandable that universities in South Africa, as in most parts of the world, are constantly scrambling to increase their research output and enhance their research quality.  However, whenever issues of compromised academic integrity and unethical research practices arise, university management has often been unable to deal adequately with these issues.  This article concurs with the emerging argument among research scholars that it is insufficient to focus on ethical policies and guidelines without considering the culture of the institution. It argues that the ethical researcher needs to be supported by a dominant culture of academic integrity. The article then uses the case of South African university to illustrate this argument.