Skin delivery potency and antitumor activities of temozolomide ester prodrugs

Clinical trials have shown temozolomide to be an effective agent for treatment of malignant melanoma. In order to investigate its suitability for delivery via the skin, a series of temozolomide esters was synthesized as prodrugs. In vitro assays demonstrated temozolomide, temozolomide acid and the hexyl ester equi-effective against selected cancer cell lines. The susceptibility of the esters to enzyme hydrolysis and their effectiveness for application to the skin were investigated. The esters effectively diffuse through rat skin and the hexyl ester demonstrated profound potency for penetrating through skin. Topical application of 5% (w/v) hexyl ester in DMSO solution on a mouse model demonstrated a significant inhibition of tumor growth. These results suggest that temozolomide esters could be an effective alternative to temozolomide in the treatment of skin cancer. © 2005 Elsevier Ireland Ltd. All rights reserved.

Sparkling fountains or stagnant ponds:An integrative model of creativity and innovation implementation in work groups

In this article I synthesise research and theory that advance our understanding of creativity and innovation implementation in groups at work. It is suggested that creativity occurs primarily at the early stages of innovation processes with innovation implementation later. The influences of task characteristics, group knowledge diversity and skill, external demands, integrating group processes and intragroup safety are explored. Creativity, it is proposed, is hindered whereas perceived threat, uncertainty or other high levels of demands aid the implementation of innovation. Diversity of knowledge and skills is a powerful predictor of innovation, but integrating group processes and competencies are needed to enable the fruits of this diversity to be harvested. The implications for theory and practice are also explored.

Generic experiments at the sump model "Zittauer Strömungswanne" (ZSW) for the behaviour of mineral wool in the sump and the reactor core

The investigation of insulation debris transport, sedimentation, penetration into the reactor core and head loss build up becomes important to reactor safety research for PWR and BWR, when considering the long-term behaviour of emergency core cooling systems during loss of coolant accidents. Research projects are being performed in cooperation between the University of Applied Sciences Zittau/Görlitz and the Helmholtz-Zentrum Dresden-Rossendorf. The projects include experimental investigations of different processes and phenomena of insulation debris in coolant flow and the development of CFD models. Generic complex experiments serve for building up a data base for the validation of models for single effects and their coupling in CFD codes. This paper includes the description of the experimental facility for complex generic experiments (ZSW), an overview about experimental boundary conditions and results for upstream and down-stream phenomena as well as for the long-time behaviour due to corrosive processes. © Carl Hanser Verlag, München.

Mechanisms of drying of skin forming materials

The literature relating to evaporation from single droplets of pure liquids, and to the drying of droplets containing solids and of droplet sprays has been reviewed. The heat and mass transfer rates for a single droplet suspended from a nozzle were studied within a 42mm I.D. horizontal wind tunnel designed to supply hot dry air, to simulate conditions encountered in a practical spray dryer. A novel rotating glass nozzle was developed to facilitate direct measurements of droplet weight and core temperature. This design minimised heat conduction through the nozzle. Revised correlations were obtained for heat and mass transfer coefficients, for evaporation from pure water droplets suspended from a rotating nozzle. Nu = 2.0 + 0.27 (l/B)°-18Re°-5Pr°-83 Sh = 2.0 + 0.575 ((T0-T.)/Tomfc) -o.o4Reo.5 ^0.33 Experimental drying studies were carried out on single droplets of different types of skin-forming materials, namely, custard, gelatin, skim milk and fructose at air temperatures ranging from 19°C to 198°C. Dried crusts were recovered and examined by Scanning Electron Microscopy. Skin-forming materials were classified into three types according to the mechanisms of skin formation. In the first type (typified by droplets of custard and starch) skin formed due to gelatinisation at high temperatures. Increasing the drying temperature resulted in increased crust resistance to mass transfer due to increased granule swelling and the crust resistance was completely transferred to a skin resistance at drying temperatures > 150°C. In the second type e.g. gelatin droplets the skin formed immediately drying had taken place at any drying temperature. At drying temperature > 60° C a more resistant skin was formed. In the third type (typified by droplets of skim milk and fructose) the skin appeared on the droplet surface at a certain stage of the drying process under any drying conditions. As the drying temperature was increased the resistance of the skin to mass transfer increased. The drying rate history of any material depended upon the nature of the skin formed which, in turn, depended upon the drying conditions. A mathematical model was proposed for the drying of the first type of skin-forming material. This was based on the assumption that, once all the granules gelatinised at the gelatinisation temperature, a skin appeared instantaneously on the droplet surface. The experimentally-observed times at which the skin appeared on the droplets surfaces were in excellent agreement with those predicted from the model. The work should assist in understanding the fundamentals of paniculate drying processes, particularly when skin-formation occurs and may be a crucial factor in volatiles retention.

Tissue engineering of co-cultured skin substitutes using biocomposite membranes based on collagen and polycaprolactone

The preparation and characterisation of collagen: PCL, gelatin: PCL and gelatin/collagen:PCL biocomposites for manufacture of tissue engineered skin substitutes are reported. Films of collagen: PLC, gelatin: PCL (1:4, 1:8 and 1:20 w/w) and gelatin/collagen:PCL (1:8 and 1:20 w/w) biocomposites were prepared by impregnation of lyophilised collagen and/or gelatin mats by PCL solutions followed by solvent evaporation. In vitro assays of total protein release of collagen:PCL and gelatin: PCL biocomposite films revealed an expected inverse relationship between the collagen release rate and the content of synthetic polymer in the biocomposite samples that may be exploited for controlled presentation and release of biopharmaceuticals such as growth factors. Good compatibility of all biocomposite groups was proven by interaction with 3T3 fibroblasts, normal human epidermal keratinocytes (NHEK), and primary human epidermal keratinocytes (PHEK) and dermal fibroblasts (PHDF) in vitro respectively. The 1:20 collagen: PCL materials exhibiting good cell growth curves and mechanical characteristics were selected for engineering of skin substitutes in this work. The tissue-engineered skin model based on single-donor PHEK and PHDF with differentiated confluent epidermal layer and fibrous porous dermal layer was then developed successfully in vitro proven by SEM and immunohistochemistry assay. The following in vivo animal study on athymic mice revealed early complete wound healing in 10 days and good integration of co-cultured skin substitutes with adjacent mice skin structures. Thus the co-cultured skin substitutes based on 1:20 collagen: PCL biocomposite membranes was proven in principle. The approach to skin modelling reported here may find application in wound treatment, gene therapy and screening of new pharmaceuticals.

The interaction between the implementation of an occupational health and safety management system and safety culture:a case study in the rubber industry

A prominent theme emerging in Occupational Health and Safety (OSH) is the development of management systems. A range of interventions, according to a prescribed route detailed by one of the management systems, can be introduced into an organisation with some expectation of improved OSH performance. This thesis attempts to identify the key influencing factors that may impact upon the process of introducing interventions, (according to B88800: 1996, Guide to Implementing Occupational Health and Safety Management Systems) into an organisation. To help identify these influencing factors a review of possible models from the sphere of Total Quality Management (TQM) was undertaken and the most suitable TQM model selected for development and use in aSH. By anchoring the aSH model's development in the reviewed literature a range ofeare, medium and low level influencing factors were identified. This model was developed in conjunction with the research data generated within the case study organisation (rubber manufacturer) and applied to the organisation. The key finding was that the implementation of an OSH intervention was dependant upon three broad vectors of influence. These are the Incentive to introduce change within an organisation which refers to the drivers or motivators for OSH. Secondly the Ability within the management team to actually implement the changes refers to aspects, amongst others, such as leadership, commitment and perceptions of OSH. Ability is in turn itself influenced by the environment within which change is being introduced. TItis aspect of Receptivity refers to the history of the plant and characteristics of the workforce. Aspects within Receptivity include workforce profile and organisational policies amongst others. It was found that the TQM model selected and developed for an OSH management system intervention did explain the core influencing factors and their impact upon OSH performance. It was found that within the organisation the results that may have been expected from implementation of BS8800:1996 were not realised. The OSH model highlighted that given the organisation's starting point, a poor appreciation of the human factors of OSH, gave little reward for implementation of an OSH management system. In addition it was found that general organisational culture can effectively suffocate any attempts to generate a proactive safety culture.

Hearing protectors: a dilemma involving acoustics and personal safety

This thesis is concerned with the optimising of hearing protector selection. A computer model was used to estimate the reduction in noise exposure and risk of occupational deafness provided by the wearing of hearing protectors in industrial noise spectra. The model was used to show that low attenuation hearing protectors con provide greater protection than high attenuation protectors if the high attenuation protectors ore not worn for the total duration of noise exposure; or not used by a small proportion of the population. The model was also used to show that high attenuation protectors will not necessarily provide significantly greater reduction in risk than low attenuation protectors if the population has been exposed to the noise for many years prior to the provision of hearing protectors. The effects of earplugs and earmuffs on the localisation of sounds were studied to determine whether high attenuation earmuffs are likely to have greater potential than the lower attenuation earplugs for affecting personal safety. Laboratory studies and experiments at a foundry with normal-hearing office employees and noise-exposed foundrymen who had some experience of wearing hearing protectors showed that although earplugs reduced the ability of the wearer to determine the direction of warning sounds, earmuffs produced more total angular error and more confusions between left and right. !t is concluded from the research findings that the key to the selection of hearing protectors is to be found in the provision of hearing protectors that can be worn for a very high percentage of the exposure time by a high percentage of the exposed population with the minimum effect on the personal safety of the wearers - the attenuation provided by the protection should be adequate but not a maximum value.

Safety and health in mines: the rise of bureaucracy in the coal mining industry and its results as evidenced by the public enquiry into an accident at Houghton Main Colliery

This thesis is concerned with certain aspects of the Public Inquiry into the accident at Houghton Main Colliery in June 1975. It examines whether prior to the accident there existed at the Colliery a situation in which too much reliance was being placed upon state regulation and too Iittle upon personal responsibility. I study the phenomenon of state regulation. This is done (a) by analysis of selected writings on state regulation/intervention/interference/bureaucracy (the words are used synonymously) over the last two hundred years, specifically those of Marx on the 1866 Committee on Mines, and (b) by studying Chadwick and Tremenheere, leading and contrasting "bureaucrats" of the mid-nineteenth century. The bureaucratisation of the mining industry over the period 1835-1954 is described, and it is demonstrated that the industry obtained and now possesses those characteristics outlined by Max Weber in his model of bureaucracy. I analyse criticisms of the model and find them to be relevant, in that they facilitate understanding both of the circumstances of the accident and of the Inquiry . Further understanding of the circumstances and causes of the accident was gained by attendance at the lnquiry and by interviewing many of those involved in the Inquiry. I analyse many aspects of the Inquiry - its objectives. structure, procedure and conflicting interests - and find that, although the Inquiry had many of the symbols of bureaucracy, it suffered not from " too much" outside interference. but rather from the coal mining industry's shared belief in its ability to solve its own problems. I found nothing to suggest that, prior to the accident, colliery personnel relied. or were encouraged to rely, "too much" upon state regulation.

The use of expert manpower in health and safety in France

The thesis examines the system of occupational health and safety in France. It analyses the use of expert manpower in the field with a view to establishing the possibility of a profession in health and safety. An input-output model is developed to bring together the necessary elements of prevention of accidents and occupational diseases. The role of institutions concerned with health and safety is analysed with reference to this model. The research establishes the need for a health and safety specialist role. The recognition and status of this role are found to be subject to other criteria including the acceptance by institutions of such a specialist role. The model is also used to define the role of this specialist as expected by the various institutions intervening in the field.

Self-regulation of health and safety in a Local Authority with particular reference to safety representatives, supervisors and safety committees

The Report of the Robens Committee (1972), the Health and Safety at Work Act (1974) and the Safety Representatives and Safety Committees Regulations (1977) provide the framework within which this study of certain aspects of health and safety is carried out. The philosophy of self-regulation is considered and its development is set within an historical and an industrial relations perspective. The research uses a case study approach to examine the effectiveness of self-regulation in health and safety in a public sector organisation. Within this approach, methodological triangulation employs the techniques of interviews, questionnaires, observation and documentary analysis. The work is based in four departments of a Scottish Local Authority and particular attention is given to three of the main 'agents' of self-regulation - safety representatives, supervisors and safety committees and their interactions, strategies and effectiveness. A behavioural approach is taken in considering the attitudes, values, motives and interactions of safety representatives and management. Major internal and external factors, which interact and which influence the effectiveness of joint self-regulation of health and safety, are identified. It is emphasised that an organisation cannot be studied without consideration of the context within which it operates both locally and in the wider environment. One of these factors, organisational structure, is described as bureaucratic and the model of a Representative Bureaucracy described by Gouldner (1954) is compared with findings from the present study. An attempt is made to ascertain how closely the Local Authority fits Gouldner's model. This research contributes both to knowledge and to theory in the subject area by providing an in-depth study of self-regulation in a public sector organisation, which when compared with such studies as those of Beaumont (1980, 1981, 1982) highlights some of the differences between the public and private sectors. Both empirical data and hypothetical models are used to provide description and explanation of the operation of the health and safety system in the Local Authority. As data were collected during a dynamic period in economic, political and social terms, the research discusses some of the effects of the current economic recession upon safety organisation.

Studies of skin antisepsis and enhanced penetration of chlorhexidine

Current evidence-based guidelines recommend that 2% (w/v) chlorhexidine digluconate (CHG), preferentially in 70% (v/v) isopropyl alcohol (IIPA), is used for skin antisepsis prior to incision of the skin. In this current study, the antimicrobial efficacy of CHG, six essential oils [tea tree oil (TTO), thymol, eucalyptus oil (EO), juniper oil, lavender oil and citronella] and novel benzylidenecarboxamidrazone and thiosemicarbazone compounds were determined against a panel of microorganisms commonly associated with skin infection (Staphylococcus epidermidis, S. aureus, meticillin-resistant S. aureus, Propionibacterium acnes, Acinetobacter spp., Pseudomonas aeruginosa and Candida albicans) The results demonstrated synergistic activity of CHG in combination with EO against biofilm cultures of S. epidermidis, with significantly reduced concentrations of CHG and EO required to inhibit biofilm growth compared to CHG or EO alone. Skin permeation of CHG was subsequently investigated using an in vitro human skin model (Franz cell) and the penetration profile was determined by serial sectioning of the full thickness human skin. Two percent (w/v) CHG in aqueous solution and in 70% (v/v) IPA demonstrated poor skin permeation; however, the skin permeation was significantly enhanced in combination with 5% - 50% (v/v) EO. Detectable levels of CHG did not permeate through full thickness skin in 24 h. Skin permeation of 2% (w/v) CHG in 70% (v/v) IPA in the presence of 10% (v/v) EO was subsequently studied. The results demonstrated a significantly enhanced skin penetration of CHG after a 2 min application, with CHG detected at significant levels to a depth of 600 m with CHG in combination with EO and IPA compared to 100 m with IPA alone. Combination antisepsis comprising CHG and EO may be beneficial for skin antisepsis prior to invasive procedures to reduce the number of microorganisms on and within the skin due to enhanced skin penetration of CHG and improved efficacy against S. epidermidis in a biofilm mode of growth.

The evolution and design of safety management systems

Research in safety management has been inhibited by lack of consensus as to the definitions of the terms with which it is concerned and, in general, the lack of an agreed theoretical framework within which to collate and contrast empirical findings. This thesis sets out definitions of key terms (hazard, risk, accident, incident and safety) and provides a theoretical framework. This framework has been informed by many sources but especially the Management Oversight and Risk Tree (MORT), cybernetics and the Viable System Model (VSM). Fieldwork designs are proposed for the empirical development of an analytical framework and its use to assist study of the development of safety management in organisations.

Performance analysis of DSRC priority mechanism for road safety applications in vehicular networks

Dedicated short range communications (DSRC) has been regarded as one of the most promising technologies to provide robust communications for large scale vehicle networks. It is designed to support both road safety and commercial applications. Road safety applications will require reliable and timely wireless communications. However, as the medium access control (MAC) layer of DSRC is based on the IEEE 802.11 distributed coordination function (DCF), it is well known that the random channel access based MAC cannot provide guaranteed quality of services (QoS). It is very important to understand the quantitative performance of DSRC, in order to make better decisions on its adoption, control, adaptation, and improvement. In this paper, we propose an analytic model to evaluate the DSRC-based inter-vehicle communication. We investigate the impacts of the channel access parameters associated with the different services including arbitration inter-frame space (AIFS) and contention window (CW). Based on the proposed model, we analyze the successful message delivery ratio and channel service delay for broadcast messages. The proposed analytical model can provide a convenient tool to evaluate the inter-vehicle safety applications and analyze the suitability of DSRC for road safety applications.

Human single-donor composite skin substitutes based on collagen and polycaprolactone copolymer

The development and characterization of an enhanced composite skin substitute based on collagen and poly(e-caprolactone) are reported. Considering the features of excellent biocompatibility, easy-manipulated property and exempt from cross-linking related toxicity observed in the 1:20 biocomposites, skin substitutes were developed by seeding human single-donor keratinocytes and fibroblasts alone on both sides of the 1:20 biocomposite to allow for separation of two cell types and preserving cell signals transmission via micro-pores with a porosity of 28.8 ± 16.1 µm. The bi-layered skin substitute exhibited both differentiated epidermis and fibrous dermis in vitro. Less Keratinocyte Growth Factor production was measured in the co-cultured skin model compared to fibroblast alone condition indicating a favorable microenvironment for epidermal homeostasis. Moreover, fast wound closure, epidermal differentiation, and abundant dermal collagen deposition were observed in composite skin in vivo. In summary, the beneficial characteristics of the new skin substitutes exploited the potential for pharmaceutical screening and clinical application.