A spatially-averaged mathematical model of kidney branching morphogenesis.

Kidney development is initiated by the outgrowth of an epithelial ureteric bud into a population of mesenchymal cells. Reciprocal morphogenetic responses between these two populations generate a highly branched epithelial ureteric tree with the mesenchyme differentiating into nephrons, the functional units of the kidney. While we understand some of the mechanisms involved, current knowledge fails to explain the variability of organ sizes and nephron endowment in mice and humans. Here we present a spatially-averaged mathematical model of kidney morphogenesis in which the growth of the two key populations is described by a system of time-dependant ordinary differential equations. We assume that branching is symmetric and is invoked when the number of epithelial cells per tip reaches a threshold value. This process continues until the number of mesenchymal cells falls below a critical value that triggers cessation of branching. The mathematical model and its predictions are validated against experimentally quantified C57Bl6 mouse embryonic kidneys. Numerical simulations are performed to determine how the final number of branches changes as key system parameters are varied (such as the growth rate of tip cells, mesenchyme cells, or component cell population exit rate). Our results predict that the developing kidney responds differently to loss of cap and tip cells. They also indicate that the final number of kidney branches is less sensitive to changes in the growth rate of the ureteric tip cells than to changes in the growth rate of the mesenchymal cells. By inference, increasing the growth rate of mesenchymal cells should maximise branch number. Our model also provides a framework for predicting the branching outcome when ureteric tip or mesenchyme cells change behaviour in response to different genetic or environmental developmental stresses.

The spectrum of patched mutations in a collection of Australian basal cell carcinomas.

Inactivating mutations in the human patched (PTCH) gene have been identified in both familial and sporadic basal cell carcinomas (BCCs). In some tumors mutations have been detected in both alleles thereby supporting the role of PTCH as a tumor suppressor gene. We have analyzed 22/23 coding exons of PTCH for mutations in 44 sporadic BCCs, and detected 10 novel mutations in nine tumors. In two of the mutant tumors the remaining allele was inactivated by loss of heterozygosity. Five novel PTCH polymorphisms were also identified. Most of the variations found were C>T substitutions at dipyrimidine sites, supporting previous studies which indicate a role for ultraviolet-B in the genesis of sporadic BCCs.

Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene inbasal cell carcinoma and medulloblastoma on chromosome 1p32.

Mutations of the human Patched gene ( PTCH ) have been identified in individuals with the nevoid basal cell carcinoma syndrome (NBCCS) as well as in sporadic basal cell carcinomas and medulloblastomas. We have isolated a homologue of this tumour suppressor gene and localized it to the short arm of chromosome 1 (1p32.1-32.3). Patched 2 ( PTCH2 ) comprises 22 coding exons and spans approximately 15 kb of genomic DNA. The gene encodes a 1203 amino acid putative transmembrane protein which is highly homologous to the PTCH product. We have characterized the genomic structure of PTCH2 and have used single-stranded conformational polymorphism analysis to search for mutations in PTCH2 in NBCCS patients, basal cell carcinomas and in medulloblastomas. To date, we have identified one truncating mutation in a medulloblastoma and a change in a splice donor site in a basal cell carcinoma, suggesting that the gene plays a role in the development of some tumours.

The hedgehog signalling pathway in tumorigenesis and development.

The hedgehog signalling pathway is responsible for the embryonic patterning of a range of tissues, and it is now known that dysregulation of this pathway can result in the formation of several tumour types. This cascade is regulated at the cell surface by the opposing actions of the patched and smoothened molecules which together form a receptor complex for hedgehog. The discovery that inactivation of the human patched gene is responsible for familial and sporadic forms of basal cell carcinoma firmly established a role for dysregulation of hedgehog signalling in tumorigenesis. Other key members of this pathway have also been shown to be involved in tumour formation, as have more distal downstream targets of hedgehog signalling. Since it appears that tumorigenesis results from constitutive activation of hedgehog responsive genes, the identification of novel downstream targets of hedgehog signalling in given cell types is likely to increase our understanding of the molecular processes underlying tumour formation.

The need for reliable systems: gendered work in Oxfam's Uganda programme.

PIP: This paper considers the results of a gender review of Oxfam/Great Britain's work in Uganda that sought to determine what gender approaches had been adopted (theoretically and actually) and how they could be improved. After a desk review in the UK, a team conducted a field visit to Uganda where an initial conventional approach that "targeted" women had given way to efforts to conduct an in-depth gender analysis of programs. The team noted that the post of Gender and Development Program Officer in Uganda had been eliminated so that the entire staff would be responsible for addressing gender concerns. The review revealed that the staff exhibited a poor understanding of key concepts, was unwilling to challenge traditional roles and attitudes, deployed ad hoc initiatives, and failed to interact with appropriate local organizations. This situation occurred because of a lack of systematic procedures for planning and evaluation. Also, the fact that there was no extra compensation for staff living in harsh and insecure conditions discouraged female staff from seeking or maintaining positions in the field. Oxfam needs to develop a clear and binding strategy that will spell out the type of social change the Uganda program is seeking, integrate gender concerns, and implement monitoring and evaluation mechanisms. There is also a need to adopt a more political approach to gender concerns by taking advantage of opportunities and confronting attendant risks.^ieng

Education in conflict.

PIP: The provision of education is affected in many different ways by political and civil unrest and armed conflict. During armed conflict, the lack of adequate financial support for the maintenance of school buildings, supplies and teacher's salaries becomes particularly acute. Other factors include the destruction of school buildings and other infrastructures in time of war, and the targeting of teachers by acts of violence. This paper explores the impact of conflict on the educational opportunities of men and women. Interventions to address the educational needs of children are also discussed. Among these programs are the Oxfam programs in Bhutan, Sri Lanka, Nicaragua, Bosnia, and Eritrea which have provided psychosocial support and human rights education to refugee and displaced women and children through the provision of educational material and by training teachers.^ieng

The effects of splice site mutations in patients with naevoid basal cell carcinoma syndrome.

We have previously identified the human homologue of the Drosophila patched gene and have described, in this gene, mutations that give rise to naevoid basal cell carcinoma syndrome (NBCCS). Here, we have analysed the effects of three splice site mutations within human PATCHED (PTCH) by the reverse transcription/polymerase chain reaction method in cultured patient lymphocyte cell lines. Two alterations, a point mutation in intron 7 and an insertion in intron 10, lead to premature truncation of the PATCHED protein. Another point mutation in intron 17 results in the skipping of exon 18 and the subsequent in-frame deletion of 46 amino acids. Additionally, in all lymphocyte and keratinocyte cell lines examined, exon 10 of PTCH is alternatively spliced leading to an in-frame deletion of 52 amino acids.

Gender training for development practitioners: only a partial solution.

PIP: This article considers gender training for Oxfam staff working on a development program or project in a particular context where their experience of gender relations and ability to seek gender equality is informed by their hierarchial position, by their national culture, and by the fact that institutions are also gendered. Thus, the article focuses on contextualizing gender training and on the potential of such training to transform institutions. The first section looks at gender training in the Oxfam head office and notes that, although Oxfam identifies itself as a learning organization, the former Training Department has been devolved into separate divisions, so there is no longer any centrally available gender training. The next section describes gender training in the field context where hierarchial positions that may influence the effectiveness of training are created by the age and sex of the trainer and where it is important to distinguish between gender frameworks (what is taught) from pedagogy (how it is taught). Oxfam's present gender training is limited by a lack of documentation of gender training efforts, by trainees' personal resistance to concepts of gender, by language barriers, and by logistical problems. The article then explores Oxfam's use of gender training as a transformative tool and notes that Oxfam focuses on individual rather than internal organizational transformation. It is concluded that gender training is only a partial solution unless its potential for personal and political transformational is recognized and fostered.^ieng

Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident.

The human homologue of the Drosophila segment polarity gene patched is implicated in the development of nevoid basal cell carcinoma syndrome (NBCCS) and in the genesis of sporadic basal cell carcinomas. In order to examine the phenotypic variability in NBCCS and to highlight functionally important domains of the PTCH protein, we have now screened 71 unrelated NBCCS individuals for mutations in the PTCH exons. We identified 28 mutations that are distributed throughout the entire gene, and most (86%) cause protein truncation. As part of this analysis, we demonstrate that failure of one NBCCS family to show clear linkage to chromosome 9q22.3-31 is most likely due to germinal mosaicism. We have identified three families bearing identical mutations with variable phenotypes, suggesting phenotypic variability in NBCCS is a complex genetic event. No phenotype genotype correlation between the position of truncation mutations and major clinical features was evident. Two missense mutations have been identified, and their location within transmembrane domains supports the notion that PTCH may have a transport function. The preponderance of truncation mutants in the germ line of NBCCS patients suggests that the developmental defects associated with the disorder are most likely due to haploinsufficiency.

De novo mutations of the Patched gene in nevoid basal cell carcinoma syndrome help to define the clinical phenotype.

The demonstration that mutations in the Patched (PTCH) gene cause nevoid basal cell carcinoma syndrome (NBCCS) has led to the identification of the exact molecular lesion in a percentage of individuals with the syndrome. In addition, it has been possible to determine, through molecular analysis of parents and other relatives of these individuals, if the mutation is inherited or has arisen de novo. We have previously reported 28 mutations in individuals with NBCCS, and here we present an additional 4 novel mutations. We have also analyzed relatives of a number of the individuals in whom we have found mutations. In total we have identified 8 individuals who carry a de novo mutation in the PTCH gene. In 5 of these cases, clinical and radiological examination had not unequivocally ruled out a diagnosis in one of the parents. This helps to define the clinical phenotype and suggests that diagnostic criteria in this complex syndrome may require review.

Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.

An investigation into the possible use of hydrocyclones for the removal of yeast from beer.

This investigation has focused on the importance of hydrocyclone design and running conditions for the removal of yeast from suspensions. Experiments have been carried out using both a model system of yeast grown in suspension cultures and rough beer. It appeared that the most important factor was the design of the hydrocyclone with a positive correlation between higher residence times and acceleration with the efficiency of separation. The other factor that affected the separation efficiency was the concentration of the yeast suspension and a new phenomenon of a lower efficiency of hydrocyclones at very low feed concentrations has been observed. The separation efficiency was also affected by temperature with lower temperatures giving poorer separations.

"Safe motherhood", family planning and maternal mortality: an Indonesian case study.

PIP: This case study in Indonesia examined some assumptions about the outcome of family planning services. Safe Motherhood programs were flawed, because of the misplaced emphasis on family planning as a strategy to reduce maternal mortality. Family planning programs reduce the exposure to the risks of child-bearing, but they do not reduce the actual risks. Reproductive health should not be linked so tightly to demographic concerns and family planning. That cost saving occurs from family planning is insufficient to justify inattention to the needs of high quality obstetric care. Family planning should be viewed as just one component of a larger, comprehensive set of measures designed to assure the health of women at all stages in the life cycle: as citizens and workers, as mothers, and as adolescents. Interventions must begin before childbearing and include growth in economic, educational, and health opportunities. The aim of reducing maternal mortality by 50% by the year 2000 was included in Indonesia's five-year development plan: Repelita V. The example of Indonesia was important, because of its achievements in reducing poverty and increasing the standard of living of the population, and because of its large population size. Estimated maternal mortality in Indonesia was 450/100,000 live births in 1989, up from 390/100,000 in 1982. There was evidence from other studies that maternal mortality has increased. Criticism has been directed to the misplaced emphasis on family planning and the top-down delivery of professional services for ignoring local health-enhancing practices and the role of families, fathers, and communities as health providers. The realized cost effectiveness of family planning is an abstraction. Fertility has declined with an increase in family planning from 5.6 children to 3.0 children in 1990, but, for example, Bali has both high levels of contraception use and high maternal mortality. Integrated programs and the high risk approach have not been particularly successful.^ieng

The Indonesian Family Planning Programme: a success story for women?

PIP: Many family planning specialists worldwide are praising the success of the family program of Indonesia because fertility rates have fallen considerably in many parts of the country. Yet, others question the reliability of the data collected and distributed by the National Family Co-ordinating Board (BKKBN), whether the publicized fertility rates are real, and whether the program or socioeconomic changes are responsible for the decline. Further, no one has assessed whether the program is sensitive to women's needs and desires. Overall, the program does not meet women's needs or consider women's health. Specifically, it deems population control more important than family planning, uses provider-dependent, long-acting hormonal contraceptives, and delivers poor quality service. The BKKBN is a prestigious group and accountable to Indonesia's president because its primary objective is to reduce population growth so socioeconomic development can occur. Even though the program originally stressed maternal and child health as a means for women to accept family planning methods, it no longer promotes maternal and child health as evidenced by the continuously high maternal mortality rates (lowest rate, 450/100,000 lives births). In fact, the maternal mortality rate for 15-19 year old women (1100) is so very high that it is second only to Ethiopia. The Indonesian Planned Parenthood Association agrees that the family planning program of Indonesia does not provide means for women to autonomously control their fertility and has taken as assembly line approach. Moreover, the administrative officials coerce subordinates to meet the ambitious targets who then coerce eligible couples and individuals to accept contraceptives. This violates their basic rights. The program has realized the significant role women play in demographic dynamics, but not as leader of socioeconomic development but as tools to rapidly and effectively implement population policies.^ieng