A couple stress model of blood flow in the microcirculation

A simple mathematical model depicting blood flow in the capillary is developed with an emphasis on the permeability property of the blood vessel based on Starling's hypothesis. In this study the effect of inertia has been neglected in comparison with the viscosity on the basis of the smallness of the Reynolds number of the flow in the capillary. The capillary blood vessel is approximated by a circular cylindrical tube with a permeable wall. The blood is represented by a couple stress fluid. With such an ideal model the velocity and pressure fields are determined. It is shown that an increase in the couple stress parameter increases the resistance to the flow and thereby decreases the volume rate flow. A comparison of the results with those of the Newtonian case has also been made.

Lysozyme: A model protein for amyloid research

Ever since lysozyme was discovered by Fleming in 1922, this protein has emerged as a model for investigations on protein structure and function. Over the years, several high-resolution structures have yielded a wealth of structural data on this protein. Extensive studies on folding of lysozyme have shown how different regions of this protein dynamically interact with one another. Data is also available from numerous biotechnological studies wherein lysozyme has been employed as a model protein for recovering active recombinant protein from inclusion bodies using small molecules like L-arginine. A variety of conditions have been developed in vitro to induce fibrillation in hen lysozyme. They include (a) acidic pH at elevated temperature, (b) concentrated solutions of ethanol, (c) moderate concentrations of guanidinium hydrochloride at moderate temperature, and (d) alkaline pH at room temperature. This review aims to bring together similarities and differences in aggregation mechanisms, morphology of aggregates, and related issues that arise using the different conditions mentioned above to improve our understanding. The alkaline pH condition (pH 12.2), discovered and studied extensively in our lab, shall receive special attention. More than a decade ago, it was revealed that mutations in human lysozyme can cause accumulation of large quantities of amyloid in liver, kidney, and other regions of gastrointestinal tract. Understanding the mechanism of lysozyme aggregation will probably have therapeutic implications for the treatment of systemic nonneuropathic amyloidosis. Numerous studies have begun to focus attention on inhibition of lysozyme aggregation using antibody or small molecules. The enzymatic activity of lysozyme presents a convenient handle to quantify the native population of lysozyme in a sample where aggregation has been inhibited. The rich information available on lysozyme coupled with the multiple conditions that have been successful in inducing/inhibiting its aggregation in vitro makes lysozyme an ideal model protein to investigate amyloidogenesis.

Establishing the C. elegans uterine seam cell (utse) as a novel model for studying cell behavior

The molecular inputs necessary for cell behavior are vital to our understanding of development and disease. Proper cell behavior is necessary for processes ranging from creating one’s face (neural crest migration) to spreading cancer from one tissue to another (invasive metastatic cancers). Identifying the genes and tissues involved in cell behavior not only increases our understanding of biology but also has the potential to create targeted therapies in diseases hallmarked by aberrant cell behavior.

A well-characterized model system is key to determining the molecular and spatial inputs necessary for cell behavior. In this work I present the C. elegans uterine seam cell (utse) as an ideal model for studying cell outgrowth and shape change. The utse is an H-shaped cell within the hermaphrodite uterus that functions in attaching the uterus to the body wall. Over L4 larval stage, the utse grows bidirectionally along the anterior-posterior axis, changing from an ellipsoidal shape to an elongated H-shape. Spatially, the utse requires the presence of the uterine toroid cells, sex muscles, and the anchor cell nucleus in order to properly grow outward. Several gene families are involved in utse development, including Trio, Nav, Rab GTPases, Arp2/3, as well as 54 other genes found from a candidate RNAi screen. The utse can be used as a model system for studying metastatic cancer. Meprin proteases are involved in promoting invasiveness of metastatic cancers and the meprin-likw genes nas-21, nas-22, and toh-1 act similarly within the utse. Studying nas-21 activity has also led to the discovery of novel upstream inhibitors and activators as well as targets of nas-21, some of which have been characterized to affect meprin activity. This illustrates that the utse can be used as an in vivo model for learning more about meprins, as well as various other proteins involved in metastasis.

Percentile growth charts for biomedical studies using a porcine model

Increasing rates of obesity and heart disease are compromising quality of life for a growing number of people. There is much research linking adult disease with the growth and development both in utero and during the first year of life. The pig is an ideal model for studying the origins of developmental programming. The objective of this paper was to construct percentile growth curves for the pig for use in biomedical studies. The body weight (BIN) of pigs was recorded from birth to 150 days of age and their crown-to-rump length was measured over the neonatal period to enable the ponderal index (Pl; kg/m(3)) to be calculated. Data were normalised and percentile curves were constructed using Cole's lambda-mu-sigma (LMS) method for BW and PI. The construction of these percentile charts for use in biomedical research will allow a more detailed and precise tracking of growth and development of individual pigs under experimental conditions.

Temperature and concentration dependence of heat capacity of model aqueous solutions

Heat capacities of binary aqueous solutions of different concentrations of sucrose, glucose, fructose, citric acid, malic acid, and inorganic salts were measured with a differential scanning calorimeter in the temperature range from 5degreesC to 65degreesC. Heat capacity increased with increasing water content and increasing temperature. At low concentrations, heat capacity approached that of pure water, with a less pronounced effect of temperature, and similar abnormal behavior of pure water with a minimum around 30degreesC-40degreesC. Literature data, when available agreed relatively well with experimental values. A correction factor, based on the assumption of chemical equilibrium between liquid and gas phase in the Differential Scanning Calorimeter, was proposed to correct for the water evaporation due to temperature rise. Experimental data were fitted to predictive models. Excess molar heat capacity was calculated using the Redlich-Kister equation to represent the deviation from the additive ideal model.

Intrauterine dentistry: an integrated model of prevention.

Intrauterine Dentistry is a highly relevant subject of our time. The use of preventive measures in the intrauterine stage can avoid several diseases, among these, dental caries. The WHO advises that from the 4th month of pregnancy, women should avoid the intake of sugar, so that the fetus, future child, does not develop an exaggerated attraction for these types of foods, thus being susceptible to caries. Through questionnaires sent to gynecologist-obstetricians and dentists, this research investigated the information they have about this subject and how they instruct their patients. Questionnaires were also sent to pregnant women requesting information about the instructions they had received for the prevention of oral diseases of their fetus. Seventy-one percent of the dentists and 80% of the gynecologist-obstetricians reported having instructed the pregnant women to reduce the intake of sugar. However, only 13.6% of the dentists and no gynecologist-obstetrician instructed the reduction of sugar intake between the 12th and 18th week of pregnancy. A total of 42.2% of the pregnant women referred to these instructions, but none received instruction as to the specific period of the 12th and 18th week. An ideal model of treatment for pregnant women must include integrated and multiprofessional treatment, in which general dentists and gynecologist-obstetricians work together with the participation of the patient.

Molecular basis of salt tolerance in Physcomitrella Patens model plant: potassium homeostasis and physiological roles of chx transporters

El suelo salino impone un estrés abiótico importante que causa graves problemas en la agricultura ya que la mayoría de los cultivos se ven afectados por la salinidad debido a efectos osmóticos y tóxicos. Por ello, la contaminación y la escasez de agua dulce, la salinización progresiva de tierras y el aumento exponencial de la población humana representan un grave problema que amenaza la seguridad alimentaria mundial para las generaciones futuras. Por lo tanto, aumentar la tolerancia a la salinidad de los cultivos es un objetivo estratégico e ineludible para garantizar el suministro de alimentos en el futuro. Mantener una óptima homeostasis de K+ en plantas que sufren estrés salino es un objetivo importante en el proceso de obtención de plantas tolerantes a la salinidad. Aunque el modelo de la homeostasis de K+ en las plantas está razonablemente bien descrito en términos de entrada de K+, muy poco se sabe acerca de los genes implicados en la salida de K+ o de su liberación desde la vacuola. En este trabajo se pretende aclarar algunos de los mecanismos implicados en la homeostasis de K+ en plantas. Para ello se eligió la briofita Physcomitrella patens, una planta no vascular de estructura simple y de fase haploide dominante que, entre muchas otras cualidades, hacen que sea un modelo ideal. Lo más importante es que no sólo P. patens es muy tolerante a altas concentraciones de Na+, sino que también su posición filogenética en la evolución de las plantas abre la posibilidad de estudiar los cambios claves que, durante el curso de la evolución, se produjeron en las diversas familias de los transportadores de K+. Se han propuesto varios transportadores de cationes como candidatos que podrían tener un papel en la salida de K+ o su liberación desde la vacuola, especialmente miembros de la familia CPA2 que contienen las familias de transportadores KEA y CHX. En este estudio se intenta aumentar nuestra comprensión de las funciones de los transportadores de CHX en las células de las plantas usando P. patens, como ya se ha dicho. En esta especie, se han identificado cuatro genes CHX, PpCHX1-4. Dos de estos genes, PpCHX1 y PpCHX2, se expresan aproximadamente al mismo nivel que el gen PpACT5, y los otros dos genes muestran una expresión muy baja. La expresión de PpCHX1 y PpCHX2 en mutantes de Escherichia coli defectivos en el transporte de K+ restauraron el crecimiento de esta cepa en medios con bajo contenido de K+, lo que viii sugiere que la entrada de K+ es energizada por un mecanismo de simporte con H+. Por otra parte, estos transportadores suprimieron el defecto asociado a la mutación kha1 en Saccharomyces cerevisiae, lo que sugiere que podrían mediar un antiporte en K+/H+. La proteína PpCHX1-GFP expresada transitoriamente en protoplastos de P. patens co-localizó con un marcador de Golgi. En experimentos similares, la proteína PpCHX2-GFP localizó aparentemente en la membrana plasmática y tonoplasto. Se construyeron las líneas mutantes simples de P. patens ΔPpchx1 y ΔPpchx2, y también el mutante doble ΔPpchx2 ΔPphak1. Los mutantes simples crecieron normalmente en todas las condiciones ensayadas y mostraron flujos de entrada normales de K+ y Rb+; la mutación ΔPpchx2 no aumentó el defecto de las plantas ΔPphak1. En experimentos a largo plazo, las plantas ΔPpchx2 mostraron una retención de Rb+ ligeramente superior que las plantas silvestres, lo que sugiere que PpCHX2 promueve la transferencia de Rb+ desde la vacuola al citosol o desde el citosol al medio externo, actuando en paralelo con otros transportadores. Sugerimos que transportadores de K+ de varias familias están involucrados en la homeostasis de pH de orgánulos ya sea mediante antiporte K+/H+ o simporte K+-H+.ix ABSTRACT Soil salinity is a major abiotic stress causing serious problems in agriculture as most crops are affected by it. Moreover, the contamination and shortage of freshwater, progressive land salinization and exponential increase of human population aggravates the problem implying that world food security may not be ensured for the next generations. Thus, a strategic and an unavoidable goal would be increasing salinity tolerance of plant crops to secure future food supply. Maintaining an optimum K+ homeostasis in plants under salinity stress is an important trait to pursue in the process of engineering salt tolerant plants. Although the model of K+ homeostasis in plants is reasonably well described in terms of K+ influx, very little is known about the genes implicated in K+ efflux or release from the vacuole. In this work, we aim to clarify some of the mechanisms involved in K+ homeostasis in plants. For this purpose, we chose the bryophyte plant Physcomitrella patens, a nonvascular plant of simple structure and dominant haploid phase that, among many other characteristics, makes it an ideal model. Most importantly, not only P. patens is very tolerant to high concentrations of Na+, but also its phylogenetic position in land plant evolution opens the possibility to study the key changes that occurred in K+ transporter families during the course of evolution. Several cation transporter candidates have been proposed to have a role in K+ efflux or release from the vacuole especially members of the CPA2 family which contains the KEA and CHX transporter families. We intended in this study to increase our understanding of the functions of CHX transporters in plant cells using P. patens, in which four CHX genes have been identified, PpCHX1-4. Two of these genes, PpCHX1 and PpCHX2, are expressed at approximately the same level as the PpACT5 gene, but the other two genes show an extremely low expression. PpCHX1 and PpCHX2 restored growth of Escherichia coli mutants on low K+-containing media, suggesting they mediated K+ uptake that may be energized by symport with H+. In contrast, these genes suppressed the defect associated to the kha1 mutation in Saccharomyces cerevisiae, which suggest that they might mediate K+/H+ antiport. PpCHX1-GFP protein transiently expressed in P. patens protoplasts co-localized with a Golgi marker. In similar experiments, the PpCHX2-GFP protein appeared to localize to tonoplast and plasma x membrane. We constructed the ΔPpchx1 and ΔPpchx2 single mutant lines, and the ΔPpchx2 ΔPphak1 double mutant. Single mutant plants grew normally under all the conditions tested and exhibited normal K+ and Rb+ influxes; the ΔPpchx2 mutation did not increase the defect of ΔPphak1 plants. In long-term experiments, ΔPpchx2 plants showed a slightly higher Rb+ retention than wild type plants, which suggests that PpCHX2 mediates the transfer of Rb+ from either the vacuole to the cytosol or from the cytosol to the external medium in parallel with other transporters. We suggest that K+ transporters of several families are involved in the pH homeostasis of organelles by mediating either K+/H+ antiport or K+-H+ symport.

Ficciones urbanas vernáculas diseñadas según principios artísticos. Permanencia y poder simbólico del ideal urbano tradicional

The theoretical contributions of John Ruskin, the analysis and proposals in Camillo Sitte?s City Planning According to Artistic Principles or the urban environment defense by Gustavo Giovannoni involved important restrictions on the destruction of this heritage and on the progressive Haussmanization of many European cities. But this interest on the endangered traditional city also caused the birth of a wide range of urban proposals which aimed at recreating or reproducing an ideal model of it. Erected under different circumstances and with multiple purposes, they did not only define new urban developments, but also succeeded in the context of the mentioned international fairs and exhibitions, appearing a whole family of them in diverse countries.

Non-ideal monitoring of a qubit state using a quantum tunnelling device

We propose a model for non-ideal monitoring of the state of a coupled quantum dot qubit by a quantum tunnelling device. The non-ideality is modelled using an equivalent measurement circuit. This allows realistically available measurement results to be related to the state of the quantum system (qubit). We present a quantum trajectory that describes the stochastic evolution of the qubit state conditioned by tunnelling events (i.e. current) through the device. We calculate and compare the noise power spectra of the current in an ideal and a non-ideal measurement. The results show that when the two qubit dots are strongly coupled the non-ideal measurement cannot detect the qubit state precisely. The limitation of the ideal model for describing a realistic system maybe estimated from the noise spectra.

Women, computing and the 'ideal worker': A comparison of professional occupations

In this paper we use recent census data supplemented with case study evidence to investigate the extent to which professional computing occupations in Australia are constructed around the notion of an ‘ideal’ worker. Census data are used to compare computer professionals with other selected professional occupational groups, illustrating different models of accommodating (or not accommodating) workers who do not fit the ideal model. The computer professionals group is shown to be distinctive in combining low but consistent levels of female representation across age groups, average rates of parenthood and minimal provisions for working-time flexibility. One strategy employed by women in this environment is selection of relatively routine technical roles over more time intensive consultancy based work.

Crosstalk between developmental and tumour-specific signalling pathways : kallikrein-related serine peptidases and nodal in prostrate cancer

Prostate cancer is an important male health issue. The strategies used to diagnose and treat prostate cancer underscore the cell and molecular interactions that promote disease progression. Prostate cancer is histologically defined by increasingly undifferentiated tumour cells and therapeutically targeted by androgen ablation. Even as the normal glandular architecture of the adult prostate is lost, prostate cancer cells remain dependent on the androgen receptor (AR) for growth and survival. This project focused on androgen-regulated gene expression, altered cellular differentiation, and the nexus between these two concepts. The AR controls prostate development, homeostasis and cancer progression by regulating the expression of downstream genes. Kallikrein-related serine peptidases are prominent transcriptional targets of AR in the adult prostate. Kallikrein 3 (KLK3), which is commonly referred to as prostate-specific antigen, is the current serum biomarker for prostate cancer. Other kallikreins are potential adjunct biomarkers. As secreted proteases, kallikreins act through enzyme cascades that may modulate the prostate cancer microenvironment. Both as a panel of biomarkers and cascade of proteases, the roles of kallikreins are interconnected. Yet the expression and regulation of different kallikreins in prostate cancer has not been compared. In this study, a spectrum of prostate cell lines was used to evaluate the expression profile of all 15 members of the kallikrein family. A cluster of genes was co-ordinately expressed in androgenresponsive cell lines. This group of kallikreins included KLK2, 3, 4 and 15, which are located adjacent to one another at the centromeric end of the kallikrein locus. KLK14 was also of interest, because it was ubiquitously expressed among the prostate cell lines. Immunohistochemistry showed that these 5 kallikreins are co-expressed in benign and malignant prostate tissue. The androgen-regulated expression of KLK2 and KLK3 is well-characterised, but has not been compared with other kallikreins. Therefore, KLK2, 3, 4, 14 and 15 expression were all measured in time course and dose response experiments with androgens, AR-antagonist treatments, hormone deprivation experiments and cells transfected with AR siRNA. Collectively, these experiments demonstrated that prostatic kallikreins are specifically and directly regulated by the AR. The data also revealed that kallikrein genes are differentially regulated by androgens; KLK2 and KLK3 were strongly up-regulated, KLK4 and KLK15 were modestly up-regulated, and KLK14 was repressed. Notably, KLK14 is located at the telomeric end of the kallikrein locus, far away from the centromeric cluster of kallikreins that are stimulated by androgens. These results show that the expression of KLK2, 3, 4, 14 and 15 is maintained in prostate cancer, but that these genes exhibit different responses to androgens. This makes the kallikrein locus an ideal model to investigate AR signalling. The increasingly dedifferentiated phenotype of aggressive prostate cancer cells is accompanied by the re-expression of signalling molecules that are usually expressed during embryogenesis and foetal tissue development. The Wnt pathway is one developmental cascade that is reactivated in prostate cancer. The canonical Wnt cascade regulates the intracellular levels of β-catenin, a potent transcriptional co-activator of T-cell factor (TCF) transcription factors. Notably, β-catenin can also bind to the AR and synergistically stimulate androgen-mediated gene expression. This is at the expense of typical Wnt/TCF target genes, because the AR:β-catenin and TCF:β-catenin interactions are mutually exclusive. The effect of β-catenin on kallikrein expression was examined to further investigate the role of β-catenin in prostate cancer. Stable knockdown of β-catenin in LNCaP prostate cancer cells attenuated the androgen-regulated expression of KLK2, 3, 4 and 15, but not KLK14. To test whether KLK14 is instead a TCF:β-catenin target gene, the endogenous levels of β-catenin were increased by inhibiting its degradation. Although KLK14 expression was up-regulated by these treatments, siRNA knockdown of β-catenin demonstrated that this effect was independent of β-catenin. These results show that β-catenin is required for maximal expression of KLK2, 3, 4 and 15, but not KLK14. Developmental cells and tumour cells express a similar repertoire of signalling molecules, which means that these different cell types are responsive to one another. Previous reports have shown that stem cells and foetal tissues can reprogram aggressive cancer cells to less aggressive phenotypes by restoring the balance to developmental signalling pathways that are highly dysregulated in cancer. To investigate this phenomenon in prostate cancer, DU145 and PC-3 prostate cancer cells were cultured on matrices pre-conditioned with human embryonic stem cells (hESCs). Soft agar assays showed that prostate cancer cells exposed to hESC conditioned matrices had reduced clonogenicity compared with cells harvested from control matrices. A recent study demonstrated that this effect was partially due to hESC-derived Lefty, an antagonist of Nodal. A member of the transforming growth factor β (TGFβ) superfamily, Nodal regulates embryogenesis and is re-expressed in cancer. The role of Nodal in prostate cancer has not previously been reported. Therefore, the expression and function of the Nodal signalling pathway in prostate cancer was investigated. Western blots confirmed that Nodal is expressed in DU145 and PC-3 cells. Immunohistochemistry revealed greater expression of Nodal in malignant versus benign glands. Notably, the Nodal inhibitor, Lefty, was not expressed at the mRNA level in any prostate cell lines tested. The Nodal signalling pathway is functionally active in prostate cancer cells. Recombinant Nodal treatments triggered downstream phosphorylation of Smad2 in DU145 and LNCaP cells, and stably-transfected Nodal increased the clonogencity of LNCaP cells. Nodal was also found to modulate AR signalling. Nodal reduced the activity of an androgen-regulated KLK3 promoter construct in luciferase assays and attenuated the endogenous expression of AR target genes including prostatic kallikreins. These results demonstrate that Nodal is a novel example of a developmental signalling molecule that is reexpressed in prostate cancer and may have a functional role in prostate cancer progression. In summary, this project clarifies the role of androgens and changing cellular differentiation in prostate cancer by characterising the expression and function of the downstream genes encoding kallikrein-related serine proteases and Nodal. Furthermore, this study emphasises the similarities between prostate cancer and early development, and the crosstalk between developmental signalling pathways and the AR axis. The outcomes of this project also affirm the utility of the kallikrein locus as a model system to monitor tumour progression and the phenotype of prostate cancer cells.

Isolation and characterisation of novel microsatellite and mitochondrial DNA markers for the Eastern Water Dragon (Physignathus lesueurii)

Habitat fragmentation as a result of urbanisation is a growing problem for native lizard species. The Eastern Water Dragon (Physignathus lesueurii) is a social arboreal agamid lizard, native to Australia. This species represents an ideal model species to investigate the effect of urbanisation because of their prominent abundance in the urban landscape. Here we describe the isolation and characterisation of a novel set of 74 di-, tri-, and tetramicrosatellites from which 18 were selected and optimised into two multiplexes. The 18 microsatellites generated a total 148 alleles across the two populations. The number of alleles per locus varied from 2 to 18 alleles and measures of Ho and He varied from 0.395 to 0.877 and from 0.441 to 0.880, respectively. We also present primers for four novel mitochondrial DNA (mtDNA) markers. The combined length of the four mtDNA marker pairs was 2,528 bp which included 15 nucleotides changes. In comparison to threatened species, which are generally characterised by small population sizes, the Eastern Water Dragon represents an ideal model species to investigate the effect of urbanisation on their behavioural ecology and connectivity patterns among populations.

Functional monoecy due to delayed anther dehiscence : a novel mechanism in pseuduvaria mulgraveana (annonaceae)

Unlike most genera in the early-divergent angiosperm family Annonaceae, Pseuduvaria exhibits a diversity of floral sex expression. Most species are structurally andromonoecious (or possibly androdioecious), although the hermaphroditic flowers have been inferred to be functionally pistillate, with sterile staminodes. Pseuduvaria presents an ideal model for investigating the evolution of floral sex in early-divergent angiosperms, although detailed empirical studies are currently lacking. The phenology and pollination ecology of the Australian endemic species Pseuduvaria mulgraveana are studied in detail, including evaluations of floral scent chemistry, pollen viability, and floral visitors. Results showed that the flowers are pollinated by small diurnal nitidulid beetles and are protogynous. Pollen from both hermaphroditic and staminate flowers are shown to be equally viable. The structurally hermaphroditic flowers are nevertheless functionally pistillate as anther dehiscence is delayed until after petal abscission and hence after the departure of pollinators. This mechanism to achieve functional unisexuality of flowers has not previously been reported in angiosperms. It is known that protogyny is widespread amongst early-divergent angiosperms, including the Annonaceae, and is effective in preventing autogamy. Delayed anther dehiscence represents a further elaboration of this, and is effective in preventing geitonogamy since very few sexually mature flowers occur simultaneously in an individual. We highlight the necessity for field-based empirical interpretations of functional floral sex expression prior to evaluations of evolutionary processes.

Morphometry and abnormalities of the feet of Kaimanawa feral horses in New Zealand

Objective: The present study investigated the foot health of the Kaimanawa feral horse population and tested the hypotheses that horses would have a large range of foot morphology and that the incidence of foot abnormality would be significantly high. Procedures: Abnormality was defined as a variation from what the two veterinarian assessors considered as optimal morphology and which was considered to impact negatively on the structure and/or function of the foot. Fifteen morphometric variables were measured on four calibrated photographic views of all four feet of 20 adult Kaimanawa feral horses. Four morphometric variables were measured from the lateromedial radiographs of the left forefoot of each horse. In addition, the study identified the incidence of gross abnormality observed on the photographs and radiographs of all 80 feet. Results: There was a large variation between horses in the morphometric dimensions, indicating an inconsistent foot type. Mean hoof variables were outside the normal range recommended by veterinarians and hoof care providers; 35% of all feet had a long toe conformation and 15% had a mediolateral imbalance. Abnormalities included lateral (85% of horses) and dorsal (90% of horses) wall flares, presence of laminar rings (80% of horses) and bull-nose tip of the distal phalanx (75% of horses). Both hypotheses were therefore accepted. Conclusions: The Kaimanawa feral horse population demonstrated a broad range of foot abnormalities and we propose that one reason for the questionable foot health and conformation is lack of abrasive wearing by the environment. In comparison with other feral horse populations in Australia and America there may be less pressure on the natural selection of the foot of the Kaimanawa horses by the forgiving environment of the Kaimanawa Ranges. Contrary to popular belief, the feral horse foot type should not be used as an ideal model for the domestic horse foot.

Multifocal urothelial cancers with the mutator phenotype are of monoclonal origin and require panurothelial treatment for tumor clearance

Purpose: UC is a disease of the entire urothelium, characterized by multiplicity and multifocality. The clonal relationship among multiple UCs has implications regarding adjuvant chemotherapy. It has been investigated in studies of chromosomal alteration and single gene mutation. However, these genetic changes can occur in unrelated tumors under similar carcinogenic selection pressures. Tumors with high MSI have numerous DNA mutations, of which many provide no selection benefit. While these tumors represent an ideal model for studying UC clonality, their low frequency has prevented their previous investigation. Materials and Methods: We investigated 32 upper and lower urinary tract UCs with high MSI and 4 nonUC primary cancers in 9 patients. We used the high frequency and specificity of individual DNA mutations in these tumors (MSI at 17 loci) and the early timing of epigenetic events (methylation of 7 gene promoters) to investigate tumor clonality. Results: Molecular alterations varied among tumors from different primary organs but they appeared related in the UCs of all 9 patients. While 7 patients had a high degree of concordance among UCs, in 2 the UCs shared only a few similar alterations. Genetic and epigenetic abnormalities were frequently found in normal urothelial samples. Conclusions: Multiple UCs in each patient appeared to arise from a single clone. The molecular order of tumor development varied from the timing of clinical presentation and suggested that residual malignant cells persist in the urinary tract despite apparent curative surgery. These cells lead to subsequent tumor relapse and new methods are required to detect and eradicate them.