The public sector in Australia, as in other western countries, has been accused in recent times of being too costly, too rigid, inefficient and ineffective. What is apparently needed is a public sector that is smaller, less costly, more efficient and more effective. The search for alternative and better ways to organise and undertake work to meet these reform objectives is at the heart of the rapid expansion of Competitive Tendering and Contracting (CTC) within the public sector in the last two decades. But increased reliance on government contracting does not always lead to outsourcing. Some government agencies allow, indeed encourage, their current employees to also bid for the work on offer by including an In-House Option (IHO) within their CTC processes. In a number of cases these IHOs have been selected ahead of their commercial competitors. IHOs are effectively internal tenders that, if selected, must be implemented by work areas within the confines of the policies and practices of their parent organisation. The reasons commonly expressed in support of IHOs are to do with addressing the potentially problematic aspects of organisational review and possible outsourcing, and to assist the parent organisation achieve its reform intentions in the most effective and least disruptive manner possible. This research examined the achievements of six IHOs within the Australian Defence Organisation. It also asked what can be learned from their experiences? The findings show that IHOs can contribute to reform and enhance the effectiveness of CTC processes but that these achievements come at a price�borne primarily by the staff who work within selected IHOs. IHOs add to the competition of CTC exercises. They also act as an insurance policy against being caught with no reasonable bids and offer a benchmark against which to assess unknown bids. But competition can also focus bidders on doing what is necessary to win rather than what is best for an organisation or its staff. Having IHOs increases the uncertainty for staff about their future employment while at the same times raising expectations that if they can be successful they will be able to make changes and improve their work areas. This research has shown that this does not always occur and staff can find the whole experience frustrating and demoralising. Organisations that include IHOs within their CTC methodologies need to assist them if they are to have the best opportunity to propose new and innovative ways of working. And they must be prepared for the possibility that their IHOs could win. Selected IHOs need support to successfully implement changes, and as the IHOs examined here have shown, they can make significant improvements in work practices and more efficient use of resources if given the chance.

Abstract It is a generally accepted dogma that sepsis disturbs skin function and wound healing, but surprisingly there is only remote pathophysiological evidence available behind that presumption. As the skin is the largest defensive barrier, the skin dysfunction in severe sepsis deserves more attention. In this study, the suction blister model was used to create experimental wounds. The study population included 44 patients with severe sepsis and 15 controls. The blister fluid was collected to analyse cytokine profile of the skin. The transepidermal water loss and blood flow from the wound were measured. A 4mm biopsy was taken under local anaesthesia on the first and the eighth day of the study from the healthy looking skin. Then 15 healing suction blisters were excised. Serum samples were also collected on the first day of the study. The barrier restoration was diminished, and the inflammation in the wound was more intense in severe sepsis than in the controls. The expression of the basement membrane components Laminin-332 and type IV collagen decreased during the septic disease, but increased over the next 3 months without achieving the level oft he controls. The expression of tight junction proteins remained nearly intact in the healing wound in severe sepsis compared to the controls. The expression of occludin on the leading edge of the migrating keratinocytes was more restricted and late in severe sepsis compared to the controls. The levels of the tumour necrosis factor (TNF), interleukin-10 (IL-10) and IL-6 in skin blister fluid were higher in the sepsis compared to controls. The blister fluid and serum cytokine response in the sepsis differed since the levels of epidermal growth factor, vascular endothelial growth factor, TNF and basic fibroblastic growth factor (bFGF) in the blister fluid did not correlate with the levels of serum. The septic patients with multiple organ failure had higher levels of several cytokines than patients without organ failure. Survivors had lower levels of IL-10 and bFGF in blister fluid than the non-survivors. This study offers novel findings for skin and wound healing in sepsis. Together, all the findings suggest that skin dysfunction in severe sepsis exists even when the most profound structures remain intact. Understanding these mechanisms of impaired wound healing can improve future treatments, such as the timing of surgery. / Tiivistelmä Sepsiksen ajatellaan heikentävän haavanparanemista, mutta tieteellistä näyttöä on niukasti. Iholla on keskeinen osa elimistön puolustuksessa ja tasapainon ylläpidossa, joten sen toiminnan häiriintyminen systeemisessä tulehduksessa ansaitsee suuremman huomion. Imurakkulahaavat tehtiin 44 septiselle potilaalle ja 15 kontrollille. Haavoista mitattiin veden haihtumista ja veren virtausta sekä otettiin imurakkulaneste näytteeksi sytokiinimäärityksiä varten. Tutkimuksen ensimmäisenä ja kahdeksantena päivänä otettiin 4mm biopsiat terveeltä iholta ja 15 potilaalta poistettiin näytteeksi paraneva imurakkulahaava. Seeruminäytteet otettiin tutkimuksen ensimmäisenä päivänä. Veden haihtuminen haavalta oli voimakkaampaa eli ihon barrierin palautuminen oli hidastunut septisillä potilailla verrattuna kontrolleihin. Haavassa havaittu tulehdus oli sepsiksessä voimakkaampi. Tyvikalvon komponenttien Laminiini-332:n ja tyypin IV kollageenin ilmentyminen oli vähäisempää sepsiksen aikana ja lisääntyi 3kk kohdalla, mutta ei kuitenkaan saavuttanut kontrollien tasoa. Tiivisliitosproteiinien ilmentyminen oli lähes muuttumatonta sepsiksessä kontrolleihin verrattuna. Okludiinin ilmentyminen sen sijaan paranevassa haavassa vaeltavien keratinosyyttien etureunassa oli rajoittuneempaa ja myöhäisempää sepsiksessä kuin kontrolleilla. Sytokiineistä tuumorinekroositekijä (TNF), interleukiini-10 (IL-10) ja IL-6 olivat koholla imurakkulanesteessä verrattuna kontrolleihin. Epidermaalinen kasvutekijä, verisuonten endoteelikasvutekijä, TNF ja perusfibroplastinen kasvutekijä (bFGF) pitoisuudet rakkulanesteessä erosivat seerumin pitoisuuksista eli ihon sytokiiniprofiili erosi systeemisestä sytokiiniprofiilista. Potilailla, joilla oli monielinvaurio, todettiin korkeampia sytokiinipitoisuuksia. Potilailla, jotka menehtyivät 30 vrk kuluessa, oli korkeammat pitoisuudet IL-10 ja bFGF rakkulanesteessä. Tämä tutkimus tarjoaa uutta tietoa ihosta ja haavanparanemisesta sepiksessä. Tulosten perusteella voidaan todeta, että ihon toimintahäiriö on sepsiksessä todellinen, vaikka kaikkein perustavimmat rakenteet säilyvät muuttumattomina. Toimintahäiriön mekanismien ymmärtäminen voisi auttaa septisen potilaan hoidossa, kuten kirurgisten toimenpiteiden ajoittamisessa paranemisen kannalta mahdollisimman otolliseen aikaan.

Thesis (Ph.D.)--University of Waikato, 2008. / Title from PDF cover (viewed April 7, 2009) Includes bibliographical references (p. 281-296)

Fundação de Amparo a Pesquisa no Estado do Rio Grande do Sul / Soil compaction is closed related to agriculture as well as animal production management. Soil quality improvement has not been always achieved with use of soil conservation practice as no-tillage or use of animal production integrated to agriculture management. Agricultural traffic and soil management effects on soil compaction are not well known, specially associated to wet soils, and in many cases, has induced to compaction states which restrict crop growth and productivity, which in turn, has lead farmers to break the compaction using mechanical tools as plow or chisel. To better understand compaction effects and critical values of soil physical properties on black beans growth and productivity four studies were set up out in the field. Another field study were performed in five typical dairy farms in Rio Grande do Sul plateau which use systems with agriculture integrated with animal production, including forage management and time of grazing. The objective of this study was to study animal trampling effects on soil physical properties, bulk density, porosity and soil resistance. The first experiment cultivated black beansi in a clayey Oxisol with the following treatments: a) immediate compaction caused by traffic of 16.6 Mg front buck loader; b) chiseling and; c)residual compaction from six years no-tillage. The additional compaction affected mass-volume relations, soil moisture and resistance, a well as black beans growth and productivity. The other three experiments were carried out in an Alfisol from central depression of Rio Grande do Sul with objectives to compare effects of immediate and residual compaction and soil chiseled on soil physical properties and black beans growth and productivity. The immediate compaction was obtained by traffic of a 9 Mg buck loader on present soil condition and on soil compacted with 10 Mg one year ago. For studied Alfisol the bulk density which restricted crop growth and productivity had value higher than 1.7 Mg m-3. The state of compaction with bulk density higher than 1.8 Mg m-3 and macroporority lower than 0.1 m3 m-3 reduced black beans height, leaf area index and crop productivity in abou 50%. The negative effects of additional compaction were maintained after twelve months and succession of three crops (soybeans, oats and black beans), reducing the black benas productivity in 61.8 %. Breaking compaction of a Oxisol under six no-tillage or Alfisol under twelve years no-tillage by soil chiseling did not improve soil quality which induce significant black benas productivity. The bulk density expressed the increase of soil compaction caused by animal trampling, reaching values of 1.77 Mg m-3, measured immediately after animal trampling and, was more significant at superficial layers where the effects on macroporosity were greater. / A compactação dos solos está intimamente relacionada com o manejo da agricultura e da pecuária na propriedade rural. A adoção de práticas conservacionistas como o plantio direto e a integração pecuária e agricultura não tem refletido em segurança aos agricultores quanto à melhoria permanente de aspectos físicos, químicos e biológicos do solo. O desconhecimento de ideais condições de trafegabilidade e manejo dos solos, associado à umidade inadequada às práticas agrícolas, tem aumentado a compactação do solo, podendo comprometer a produtividade e o desenvolvimento de plantas exigindo a adoção de medidas extremas como a escarificação do solo para melhorar a condição presente. Foram realizados quatro experimentos a campo, onde os efeitos da compactação causada pelo tráfego de máquinas foram avaliados pelos atributos do solo e no crescimento e produtividade da cultura do feijão. Outro estudo, realizado a campo, em cinco propriedades típicas de produção leiteira do planalto riograndense, que adotavam como sistema de produção a integração lavoura e pecuária, com distintos manejos de forrageiras e tempo de permanência dos animais nas glebas, teve por objetivo estudar o impacto do pisoteio animal nos atributos físicos do solo como: densidade, porosidade e resistência do solo a penetração. No primeiro experimento foi cultivado feijão em Latossolo argiloso do Planalto Gaúcho e se estabeleceu comparação entre: a) compactação imediata aplicada por tráfego de máquina com 16,6 Mg, b) compactação residual de 6 anos de plantio direto, e c) escarificação. A compactação adicional afetou as relações massa-volume, a umidade e a resistência do solo à penetração, assim como, a produtividade e o crescimento do feijoeiro. Os outros experimentos foram desenvolvidos em Argissolo da Depressão Central do RS, com o objetivo de comparar estados de compactação imediata, compactação residual aplicada em ano anterior e residual de compactação de 12 anos de plantio direto com a escarificação nas propriedades físicas do solo, na umidade e no crescimento e produtividade do feijoeiro. A compactação imediata foi obtida pelo tráfego de máquina com 9 Mg sobre o solo na condição presente e sobre resíduo de compactação de tráfego de 10 Mg aplicada em ano anterior. No Latossolo a densidade restritiva a produtividade do feijão e do trigo foi de 1,4 a 1,5 Mg m-3. Para o Argissolo, a densidade do solo restritiva a produtividade do feijoeiro foi superior a 1,7 Mg m-3. Os estados de compactação com densidade do solo maior que 1,8 Mg m-3 e macroporosidade menor que 0,1 m3 m-3, reduziram a altura de planta, a área foliar e a produtividade do feijoeiro em torno de 50 %. Os efeitos negativos da compactação adicional mantiveram-se após doze meses e sucessão de três cultivos (soja, aveia e feijão), reduzindo a produtividade de feijão em 61,8 %. O valor da densidade crítica baseada no intervalo hídrico ótimo (IHO) foi de 1,75 Mg m-3. A escarificação não representou ganho em qualidade do solo para áreas com seis anos de plantio direto em Latossolo e doze anos de plantio direto em Argissolo que implicasse em aumento de produtividade. A densidade do solo expressou o aumento da compactação do solo provocada pelo pisoteio animal, atingindo o valor de 1,77 Mg m-3 medida imediatamente após o pisoteio animal e mostrando-se mais significativa nas camadas superficiais do solo e, nessas, os efeitos na macroporosidade foram mais evidentes.

Abstract Skin stem cells are essential for maintaining epidermal homeostasis by providing new cells to replace those that are lost during normal tissue turnover and repair after injury. Adult epidermal stem cells serve also as the cells of origin for different types of skin cancers. This PhD study investigates the hair follicle (HF) stem cells and skin cancer, and the microenviromental factors that regulate the initiation of tumors and their progression to malignancy. Collagen XVIII is a common basement membrane multidomain proteoglycan highly expressed in HF stem cells (HFSCs) and in malignant skin squamous carcinoma cells. It is known to be essential for the development of the eye, and mutations in the COL18A1 gene cause a rare disease, Knobloch syndrome, with severe eye defects. However, the roles of collagen XVIII in other tissues and diseases are not well understood. Using genetically modified mice, we show here that collagen XVIII is important for the structure and formation of hemidesmosomes, the junctional complexes between epidermal cells and basement membrane. We propose that the disturbed adhesion of the HFSCs to the underlying BM in mice with collagen XVIII ablation leads to defects in stem cell viability and HF cycling. Overexpression of the N-terminal noncollageous sequences of collagen XVIII were sufficient to rescue the abnormal HF phenotype observed in the absence of collagen XVIII. We also found that mice lacking this collagen develop fewer chemical-induced skin tumors, which we suggest is due to increased apoptosis in skin stem cells upon carcinogen-induced DNA damage, and to reduced stemness of tumor cells. In another project we studied the functions of Bmx, a cytoplasmic protein tyrosine kinase, which is upregulated in different types of cancer. However, little is known about the pathways that Bmx regulates in tumors. Therefore, we investigated its roles in cancer using syngeneic tumor assays, and chemical and genetic experimental tumor models. We show here that Bmx promotes tumor growth and progression and induces tumor angiogenesis by contributing to the transduction of VEGF signals. / Tiivistelmä Ihon kantasoluilla on tärkeä tehtävä ihon epidermiksen tasapainon (homeostaasin) ylläpitämisessä. Kantasolut jakautuvat tarvittaessa ja tuottavat uusia erilaistuneita soluja sekä ihon pintasolukon normaalin uusiutumisen että vahingoittuneen kudoksen korjaamisen yhteydessä. Ihon kantasoluilla uskotaan olevan myös tärkeä rooli erilaisten ihosyöpien synnyssä. Tässä tutkimuksessa tutkittiin ihon karvatupen kantasoluja ja ihosyöpää, ja selvitettiin kantasoluja ympäröivän kudoksen, mikroympäristön (kantasolulokero), merkitystä ihosyövän synnyssä ja etenemisessä. Kollageeni XVIII on useista toiminnallisista osista koostuva tyvikalvojen proteoglykaani, joka ilmenee voimakkaasti ihon karvatupen kantasoluissa, sekä ihon pahanlaatuisissa levyepiteelikarsinoomasoluissa. Vaikka kollageeni XVIII:n biologiset tehtävät elimistössä ovat vielä jokseenkin epäselviä, sen tiedetään olevan välttämätön silmän kehittymiselle. Kollageeni XVIII:n geenimutaatioiden on osoitettu aiheuttavan Knoblochin oireyhtymän, jota sairastavilla potilailla on muutoksia silmän rakenteessa. Tässä väitöskirjatyössä hyödynnettiin useita muuntogeenisiä hiirimalleja ja osoitettiin, että kollageeni XVIII säätelee merkittävästi ihon karvatupen erilaistuvien solujen elinkykyä ja karvojen kasvukiertoa. Kollageeni XVIII:n puutos aiheutti muutoksia karvatupen pullistuma-alueen (bulge) liitoskomplekseissa (hemidesmosomi), jotka ankkuroivat alueen tyvisolut karvatuppea ympäröivään tyvikalvoon. Tulokset viittaavat siihen, että puutteelliset liitokset solujen ja tyvikalvon välillä ja niistä johtuvat signaalinvälityksen häiriöt voivat aiheuttaa muutoksia karvatupen solujen ominaisuuksissa. Kollageenin XVIII:n aminoterminaalisen osan tuottaminen poistogeenisen hiiren ihossa riitti palauttamaan hemidesmosomit, karvatupen solujen elinkyvyn ja karvasyklin normaaliksi. Työssä havaittiin myös, että kollageeni XVIII puute vähensi kemikaalikäsittelyillä aiheutettujen ihokasvainten määrää hiirillä, mitä voidaan osaltaan selittää sillä, että kollageeni XVIII:n puutos lisäsi DNA-vaurioista kärsivien erilaistuvien solujen ohjelmoitua solukuolemaa (apoptoosi) ja vähensi kasvainsolujen kantasoluominaisuuksia. Tässä työssä tutkittiin myös monissa syövissä voimakkaasti ilmenevän solunsisäisen signaalinvälittäjän tyrosiinikinaasi Bmx:n tehtäviä syövässä hyödyntäen istutettavia kasvainsoluja sekä kemiallista ja geneettisiä kokeellisia syöpämalleja muuntogeenisillä hiirillä. Tutkimuksessa ositettiin Bmx:n osallistuvan verisuonikasvutekijän signaalinvälitykseen ja täten edistävän syöpäkasvainten verisuonten uudismuodostusta sekä syövän kasvua ja etenemistä.

Abstract Heterotopic ossification is a pathological condition in which bone forms outside the skeletal system. It can also occur in skin, which is the case in some genetic disorders. In multiple miliary osteoma cutis (MMOC), tiny bone fragments develop in the dermis and nearby subcutaneous tissue of the face and upper chest region during middle age. The etiology of the disease is poorly understood. The origin of the osteoma-forming cells is not known and also unknown are the signaling factors that direct the skin cells towards an osteogenic lineage. The purpose of this study was to investigate MMOC and the pathogenesis of ectopic bone formation by combining patient study and cell biology methods. The results from an extensive review of the literature and five new cases revealed MMOC as a distinct disease entity, where heterotopic bone formation is intramembranous. No correlation was found between MMOC and acne scars, hormonal disturbances or GNAS gene mutations. In cell culture studies mouse and human dermal fibroblasts and mouse dermal papilla (DP) cells were found to differentiate into osteoblast-like matrix mineralizing cells. The bone morphogenetic protein 4 (BMP-4) homodimer and BMP-2/7 heterodimer had significant effects on the osteogenic differentiation of the above mentioned cells. Interestingly, the BMPs enhanced the differentiation of mouse cells but reduced it in human cells. In mouse DP cells and human fibroblasts BMP-2/7 was more potent than BMP-4. The skin area affected by osteomas in patients was compared to their unaffected skin and also to the corresponding skin areas in controls with regard to osteogenic differentiation and gene expression studies. MMOC patients’ skin differs from controls both in osteoma and unaffected skin areas, which suggests MMOC is not only a local but also a systemic skin disease. The results confirm the previous findings that gene expression in skin is different in different parts of the body, which could explain why the osteomas develop in certain skin areas. The results of this study provide new information about MMOC and heterotopic ossification in skin and could be useful when developing treatments for MMOC. This study also presents new information about BMPs and their different effects in mouse and human cells, which may stimulate discussion about the generalization of mouse studies in humans and the clinical use of BMPs. / Tiivistelmä Virhesijaintinen luutuminen on patologinen tila, jossa luuta muodostuu luisen tukirangan ulkopuolelle. Tätä voi tapahtua myös ihossa, kuten käy tietyissä sairauksissa. Ihon lukuisat jyvämäiset osteoomat on tauti, jossa pieniä luujyväsiä ilmaantuu verinahkaan ja ihonalaiskudokseen keski-iässä. Taudin syytä, osteoomia muodostavien solujen alkuperää tai sitä, mitkä viestinvälittäjät saavat esiastesolut siirtymään luusolulinjalle, ei tiedetä. Tässä työssä tutkittiin ihon lukuisia jyvämäisiä osteoomia ja virhesijaintista luutumista yhdistämällä kliinisiä ja solubiologisia menetelmiä. Laajasta kirjallisuuteen perehtymisestä ja viidestä omasta potilaasta saadut tulokset osoittivat ihon lukuisten jyvämäisten osteoomien olevan oma erillinen tautinsa, jossa virhesijaintinen luutuminen tapahtuu suoran luutumisen mekanismilla. Tauti ei näytä olevan yhteydessä aknearpiin, hormonihäiriöihin tai GNAS-geenin mutaatioihin. Soluviljelykokeissa hiiren ja ihmisen verinahan fibroblastien ja hiiren karvatupen nystyn solujen havaittiin erilaistuvan osteoblastityyppisiksi soluväliainetta mineralisoiviksi soluiksi. Luun morfogeneettisillä proteiineilla (BMP) 4 ja 2/7 oli merkitsevä vaikutus yllä mainittujen solujen erilaistumisessa. Yllättävää kyllä, ne edistivät hiiren solujen, mutta vähensivät ihmisen solujen erilaistumista. Hiiren karvatupen soluille ja ihmisen fibroblasteille BMP-2/7 oli tehokkaampi kuin BMP-4. Potilaiden osteoma-aluetta verrattiin heidän terveeseen ihoalueeseensa samoin kuin vastaaviin ihoalueisiin kontrollihenkilöillä käyttäen menetelminä solujen erilaistamista luuta muodostavaan suuntaan sekä geenien ilmentymisen tutkimista. Potilaiden iho erosi kontrollien ihosta sekä osteooma-alueella että terveellä ihoalueella, mikä viittaa taudin olevan koko elimistöön vaikuttava. Tulokset vahvistavat aikaisempia löydöksiä siitä, että geenien ilmentyminen ihossa on erilaista eri puolilla kehoa. Tämä voisi selittää osteoomien esiintymisen vain tietyllä alueella. Tämän tutkimuksen tulokset antavat uutta tietoa ihon lukuisista jyvämäisistä osteoomista ja virhesijaintisesta luutumisesta ja saattavat olla hyödyksi kehitettäessä taudin hoitoa. Tutkimus antaa uutta tietoa luun morfogeneettisten proteiinien erilaisesta käyttäytymisestä hiirellä ja ihmisellä, mikä herättänee keskustelua hiirikokeiden yleistämisestä ihmiseen ja luun morfogeneettisten proteiinien kliinisestä käytöstä.