MC1R genotype modifies risk of melanoma in families segregating CDKN2A mutations

Mutations in the exons of the cyclin-dependent kinase inhibitor gene CDKN2A are melanoma-predisposition alleles which have high penetrance, although they have low population frequencies. In contrast, variants of the melanocortin-1 receptor gene, MC1R, confer much lower melanoma risk but are common in European populations. Fifteen Australian CDKN2A mutation-carrying melanoma pedigrees were assessed for MC1R genotype, to test for possible modifier effects on melanoma risk. A CDKN2A mutation in the presence of a homozygous consensus MC1R genotype had a raw penetrance of 50%, with a mean age at onset of 58.1 years. When an MC1R variant allele was also present, the raw penetrance of the CDKN2A mutation increased to 84%, with a mean age at onset of 37.8 years (P=0.1). The presence of a CDKN2A mutation gave a hazard ratio of 13.35, and the hazard ratio of 3.72 for MC1R variant alleles was also significant. The impact of MC1R variants on risk of melanoma was mediated largely through the action of three common alleles, Arg151Cys, Arg160Trp, and Asp294His, that have previously been associated with red hair, fair skin, and skin sensitivity to ultraviolet light.

City profile - Colombo

Rooted in a history that dates back 1500 years, the concentration of economic activity and infrastructure in Colombo represents an extreme case of urban primacy within the national context of Sri Lanka. Located on the West Coast of the country, the Colombo metropolitan area accommodates a quarter of the country's 18.6 million population, and is the economic and political core of the country. However, Colombo is a city of extremes. Its modem and well-serviced core stands in stark contrast to the circumstances of more than half of its population, who live in poorly serviced shack and shanty settlements. The proportion of the population living in these areas continues to expand, notwithstanding a history of innovative and participatory approaches to development planning and management. Complicating these development challenges, the potential of the city is undermined by a civil war that has been under way since the early 1980s, taking an immense toll in loss of life, political polarization, and economic opportunity costs. This paper traces Colombo's historical development, provides a description of contemporary characteristics and challenges faced by the city, and examines the evolution of plans and programmes designed to improve the conditions of low-income settlements in the city. (C) 2002 Elsevier Science Ltd. All rights reserved.

Latent inhibition and schizophrenia: Pavlovian conditioning of autonomic responses

Latent inhibition (LI) is an important model for understanding cognitive deficits in schizophrenia, Disruption of LI is thought to result from an inability to ignore irrelevant stimuli. The study investigated LI in schizophrenic patients by using Pavlovian conditioning of electrodermal responses in a complete within-subject design. Thirty-two schizophrenic patients, ( 16 acute. unmedicated and 16 medicated patients) and 16 healthy control subjects (matched with respect to age and gender) participated in the study. The experiment consisted of two stages: preexposure and conditioning. During preexposure two visual stimuli were presented, one of which served as the to-be-conditioned stimulus (CSp +) and the other one was the not-to-be-conditioned stimulus (CSp -) during the following conditioning ( = acquisition). During acquisition. two novel visual stimuli (CSn + and CSn -) were introduced. A reaction time task was used as the unconditioned stimulus (US). LI was defined as the difference in response differentiation observed between proexposed and non-preexposed sets of CS + and CS -. During preexposure. the schizophrenic patients did not differ in electrodermal responding from the control subjects, neither concerning the extent of orienting nor the course of habituation. The exposure to novel stimuli at the beginning of the acquisition elicited reduced orienting responses in unmedicated patients compared to medicated patients and control subjects, LI was observed in medicated schizophrenic patients and healthy controls. but not in acute unmedicated patients. Furthermore LI was found to be correlated with the duration of illness: it was attenuated in patients who had suffered their first psychotic episode. (C) 2002 Elsevier Science B.V. All rights reserved.

Peroxisome proliferator-activated receptor alpha in the human breast cancer cell lines MCF-7 and MDA-MB-231

Peroxisome proliferator-activated receptor (PPAR) alpha is a ligand-activated transcription factor that has been linked with rodent hepatocarcinogenesis. It has been suggested that PPARalpha mRNA expression levels are an important determinant of rodent hepatic tumorigenicity. Previous work in rat mammary gland epithelial cells showed significantly increased PPARalpha mRNA expression in carcinomas, suggesting the possible role of this isoform in rodent mammary gland carcinogenesis. In this study we sought to determine whether PPARalpha is expressed and dynamically regulated in human breast cancer MCF-7 and MDA-MB-231 cells. Having established the presence of PPARalpha in both cell types, we then examined the consequence of PPARa activation, by its ligands Wy-14,643 and clofibrate, on proliferation. With real-time reverse transcriptase-polymerase chain reaction, we showed that PPARalpha mRNA was dynamically regulated in MDA-MB-231 cells and that PPARalpha activation significantly increased proliferation of the cell line. In contrast, PPARalpha expression in MCF-7 cells did not change with proliferation during culture and was present at significantly lower levels than in MDA-MB-231 cells. However, PPARalpha ligand activation still significantly increased the proliferation of MCF-7 cells. The promotion of proliferation in breast cancer cell lines following PPARalpha activation was in stark contrast to the effects of PPARgamma-activating ligands that decrease proliferation in human breast cancer cells. our results established the presence of PPARalpha in human breast cancer cell lines and showed for the first time that activation of PPARalpha in human breast cancer cells promoted proliferation. Hence, this pathway may be significant in mammary gland tumorigenesis. (C) 2002 Wiley-Liss, Inc.

Pulse-exposure effects of selected insecticides to juvenile Australian crimson-spotted rainbowfish (Melanotaenia duboulayi)

Laboratory toxicity studies were conducted in southeastern Queensland, Australia, to determine the acute lethal effects of a 1-h pulse exposure of selected insecticides to adult and juvenile (

Ocular melanoma is not associated with CDKN2A or MC1R variants - a population-based study

Germline variants in the melanocortin 1 receptor gene (MC1R) and the p16 gene (CDKN2A) are associated with an increased risk of cutaneous melanoma. The frequency of these germline variants was examined in a population-based, incident series of 62 ocular melanoma cases and ethnicity-matched population controls. In both cases and controls, 59% of individuals carried at least one MC1R variant and there were no significant differences in the frequency of any of the five most common variants of MC1R. We also found no significant differences between cases and controls in the frequency of any of the four most common variants of CDKN2A, and no melanoma case carried a deleterious germline CDKN2A mutation. Our findings argue against an important predisposing effect of the MC1R and CDKN2A genes for ocular melanoma.

Localization of a novel melanoma susceptibility locus to 1p22

Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta = 0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores 13 in this subset, with the highest parametric LOD score, 4.95 (theta = 0) ( nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.

High frequency of BRAF mutations in nevi

To evaluate the timing of mutations in BRAF (v-raf murine sarcoma viral oncogene homolog B1) during melanocytic neoplasia, we carried out mutation analysis on microdissected melanoma and nevi samples. We observed mutations resulting in the V599E amino-acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi. These data suggest that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.

Dobras estruturais: ruptura generativa em grupos sobrepostos

Os grupos empresariais enfrentam um desafio duplo: reconhecer e implementar novas ideias. O presente artigo sugere que o empreendedorismo está mais relacionado com a geração de novos conhecimentos, por meio da recombinação de recursos, do que com a importação de ideias. Em contraste com a perspectiva "intermediação mais fechamento", enfocamos a sobreposição de estruturas coesas de grupos. Ao analisar processos de intercoesão de redes, identificamos uma topologia de rede distinta: a dobra estrutural. Os atores de uma dobra estrutural são membros de múltiplos grupos, o que facilita o acesso familiar a diversos recursos. Nosso conjunto de dados permite observar laços pessoais entre as 1.696 maiores empresas húngaras de 1987 a 2001. Primeiro, testamos se dobras estruturais contribuem para o desempenho de grupos. Segundo, como o empreendedorismo é um processo de ruptura generativa, testamos a contribuição das dobras estruturais para a instabilidade do grupo. Terceiro, passamos de métodos dinâmicos à análise histórica de redes, e demonstramos que a coerência é uma propriedade de genealogias entrelaçadas de coesão, construídas por meio de repetidas separações e reunificações.

Princípios para a reabilitação sustentável low cost de edifícios antigos: estudo de um quarteirão no centro da cidade do Porto

Dissertação de mestrado em Construção e Reabilitação Sustentável

User expectations for media sharing practices in open display networks

Open Display Networks have the potential to allow many content creators to publish their media to an open-ended set of screen displays. However, this raises the issue of how to match that content to the right displays. In this study, we aim to understand how the perceived utility of particular media sharing scenarios is affected by three independent variables, more specifically: (a) the locativeness of the content being shared; (b) how personal that content is and (c) the scope in which it is being shared. To assess these effects, we composed a set of 24 media sharing scenarios embedded with different treatments of our three independent variables. We then asked 100 participants to express their perception of the relevance of those scenarios. The results suggest a clear preference for scenarios where content is both local and directly related to the person that is publishing it. This is in stark contrast to the types of content that are commonly found in public displays, and confirms the opportunity that open displays networks may represent a new media for self-expression. This novel understanding may inform the design of new publication paradigms that will enable people to share media across the display networks.

Relevanz von Änderungen für Datenbestände mobiler Clients

Aufgrund der Entwicklungen auf dem Sektor der Mobiletelefone ist davon auszugehen, dass die Anzahl kleiner, leichtgewichtiger mobiler Endgeräte, welche als Clients von Datenbanksystemen genutzt werden, weiter ansteigt. Ein wesentliches Problem in diesem Szenario ist die langsame und teure Datenübertragung in Funknetzwerken. Aus Sicht der Nutzer derartiger Technologien ist es somit nicht sinnvoll bzw. wünschenswert, Daten, welche keinen direkten Nutzen für sie bieten, auf das Mobilgerät zu übertragen. Des Weiteren werden einmal empfangene Daten lokal gespeichert und wiederverwendet (Caching). Ändern sich Daten auf dem Server des Informationssystems, müssen die mobilen Clients, welche von einer Änderung betroffen sind, ermittelt und darüber informiert werden. Im Rahmen dieser Dissertation wird gezeigt, dass eine derartige exakte Relevanzprüfung nur mithilfe der Daten in der Datenbank realisiert werden kann. Andere Verfahren, welche das Problem auf semantischer Ebene adressieren, funktionieren nur, wenn die unterstützte Anfragesprache stark eingeschränkt wird und können selbst dann zur falschen Feststellung einer Relevanz führen. Insbesonderen in Informationssystemen mit einer großen Anzahl mobiler Clients kommt es dazu, dass verschiedene Nutzer gleiche oder zumindest ähnliche Anfragen stellen. Diese Eigenschaft wird hier genutzt, um basierend auf einer speziellen Anfragenotation syntaktisch gleiche Teile mehrerer Anfragen gemeinsam auf Relevanz zu testen. Hierzu werden die Anfragen in einem Anfragebaum gespeichert, welcher die IDs der Clients referenziert. Die Relevanzprüfung erfolgt durch Traversieren des Baumes. In der vorliegenden Arbeit werden verschiedene Anfrageindexstrukturen diskutiert und die Menge der notwendigen Relevanztest formal auf der Basis der Relationenmodells hergeleitet. Abschließend werden die theoretisch erarbeiteten Techniken evaluiert und Vorschläge für ihre Optimierung diskutiert.

Experimentos com os nematicidas D. D., E. D. B. e brometo de metilo no combate aos nematódeos causadores de galhas em raízes de plantas (Meloidogyne spp.)

Tomato roots heavily disfigured by root-knot nematodes were throughly mixed with soil. At various time intervals, samples were taken from the mixture and treated in closed containers by each of the folio wing nematicides: D.D., E.D.B. and M.B. The efficacy of the treatment was tested by setting indicator plants in the treated soil and by examining their roots for the presence of galls two months later. In other words, the ability of the three nematicides to penetrate nematode galls after various periods of rotting, which varied from 5 to 30 days was studied. The main conclusions drawn are as follows: a) no nematicide among the three listed above showed the ability for complete destruction of the nematodes protected inside the roots, for a number of small galls developed on the root system of the indicator plant in all treatments; b) smaller and less numerous galls were present on the roots of the indicator plants grown in soil treated after a rotting period of 30 days; c) however, the control obtained seems to be quite satisfactory economically, since the check plants grew poorly and have developed a very unhealthy root system. This is in accordance with STARK & LEAR (1947), LEAR (1951) and CICCARONE's (1951) statements. The results of the present experiments show again that awaiting for the rotting of galls of the root-knot nematodes is not indispensable for an economically convenient soil fumigation. Fields in which many fleshy infected roots from previous crops have been buried can be economically fumigated immediately, without any loss of time. Notwithstanding, when thick woody roots are present in the soil, the above statements may not hold true. This should constitute a new problem calling for further experiments. Another essay dealing with methyl bromide alone, consisted in treating cotton roots heavily disfigured by Meloidogyne incognita in a container (diameter = 28cm, height = 32 cm), which remained closed for five days. After the treatment, the roots were mixed with soil, in which tomato seedlings were planted. After a growing period of two months, the roots of the tomato plants were washed in running water and examined for the presence of galls. As an early infeccion was present in the root system of all plants, the inefficacy of the treatment has been proved.

Vermittlung von herrschaftskritischem Wissen : Kindheitswissenschaftlich relevante diskursiv-reflexive Interventionen in sexistischen und rassistischen Gesellschaftsverhältnissen

[s.c.]

Selbstparametrierende Steuerung für den Guss von Sanitärkeramik

In der Firma KERAMAG wird für den Guss von Sanitärkeramik das Hohlgussverfahren angewendet. Bei diesem Gießverfahren treten Fehlerbilder auf, die die Qualität negativ beeinflussen. Ziel der vorliegenden Arbeit ist den Gießprozess zu optimieren, damit sich die komplexen physikalischen Eigenschaften des Schlickers weniger stark auf den technologischen Ablauf des Gießprozesses auswirken. Dazu wird eine intelligente Softwarelösung (automatische Eingießsteuerung)erarbeitet, die die herkömmliche elektromechanische Steuerung ablöst. Als erstes werden der Aufbau und die Funktionsweise der herkömmlichen Gießanlage analysiertund die Einflüsse auf den technologischen Ablauf des Gießprozess untersucht. Aus dengewonnenen Erkenntnissen der Analyse werden Lösungsansätze zur Optimierung desGießprozesses abgeleitet. Mit den Anforderungen die sich aus den Lösungsansätzen ergebenen, wird eine geeigneteHardware für die Steuerungskomponenten des Automatisierungssytems ausgewählt. Auf Grundlage der ermittelten Steuerungsaufgaben wird mit SIMATIC-STEP7 ein Automatisierungsprojekt erstellt. Dabei sind die behandelten Schwerpunkte die „Selbstparametrierung und Optimierung der Eingießkurve“ und die „gleitende Skalierung der Analogausgangsgröße des Proportional-Druckregelventils“. Die vorgeschlagenen Lösungen werden an einer Gießanlage installiert und es wird der Nachweis erbracht, dass die Aufgabenstellung vollständig umgesetzt werden konnte.