Geographical variation in the penetrance of CDKN2A mutations for melanoma

Background: Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium Methods: We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14APF protein, and population melanoma incidence rates. All statistical tests were two-sided. Results: The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P = .003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia. Conclusions: This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance.

Apoptosis in the pathogenesis of renal disease with a focus on tubulointerstitial injury

Renal cell apoptosis is important not only in normal physiological conditions of the kidney but also in pathological processes. In normal renal development, it removes unwanted, damaged or harmful cells, and in the healthy adult kidney, it maintains cellular homeostasis by regulating the balance between cell proliferation and cell loss. The apoptotic process has now been described in the pathogenesis and prognosis of certain renal diseases with both beneficial and detrimental roles. It causes deletion of cells intrinsic to the kidney after, for example, toxic, ischaemic, immune or radiation damage, and this loss can be destructive and can cause significant reduction of renal function. In contrast, it can control and limit inflammatory processes in both the acute and chronic phases of renal disease. Information on the positive and negative outcomes of renal cell apoptosis, plus the thousands of publications on more general aspects of apoptosis mechanisms, have now presented real opportunities for the development of therapies that selectively delete or protect certain renal cell populations. This review will discuss some of the more general aspects of renal cell apoptosis and then concentrate on the detrimental or beneficial roles of apoptosis in the initiation, progression or resolution of selected, mainly tubulointerstitial, renal diseases.

Interacting roles of myofibroblasts, apoptosis and fibrogenic growth factors in the pathogenesis of renal tubulo-interstitial fibrosis

The interrelationship between myofibroblasts and fibrogenic growth factors in the pathogenesis of renal fibrosis is poorly defined. A temporal and spatial analysis of myofibroblasts, their proliferation and death, and presence of transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor-B (PDGF-B) was carried out in an established rodent model in which chronic renal scarring and fibrosis occurs after healed renal papillary necrosis (RPN), similar to that seen with analgesic nephropathy. Treated and control groups (N = 6 and 4, respectively) were compared at 2, 4, 8 and 12 weeks. A positive relationship was found between presence of tubulo-interstitial myofibroblasts and development of fibrosis. Apoptotic myofibroblasts were identified in the interstitium and their incidence peaked 2 weeks after treatment. Levels of interstitial cell apoptosis and fibrosis were negatively correlated over time (r = -0.57, p < 0.01 ), suggesting that as apoptosis progressively failed to limit myofibroblast numbers, fibrosis increased. In comparison with the diminishing apoptosis in the interstitium, the tubular epithelium had progressively increasing levels of apoptosis over time, indicative of developing atrophy of nephrons. TGF-beta1 protein expression had a close spatial and temporal association with fibrosis and myofibroblasts, whilst PDGF-B appeared to have a closer link with populations of other chronic inflammatory cells such as infiltrating lymphocytes. Peritubular myofibroblasts were often seen near apoptotic cells in the tubular epithelium, suggestive of a paracrine toxic effect of factor/s secreted by the myofibroblasts. In vitro , TGF-beta1 was found to be toxic to renal tubular epithelial cells. These findings suggest an interaction between myofibroblasts, their deletion by apoptosis, and the presence of the fibrogenic growth factor TGF-beta1 in renal fibrosis, whereby apoptotic deletion of myofibroblasts could act as a controlling factor in progression of fibrosis.

Oxidizing species in the mechanism of cytochrome P450

This review discusses the mechanisms of oxygen activation by cytochrome P450 enzymes, the possible catalytic roles of the various iron-oxygen species formed in the catalytic cycle, and progress in understanding the mechanisms of hydrocarbon hydroxylation, heteroatom oxidation, and olefin epoxidation. The focus of the review is on recent results, but earlier work is discussed as appropriate. The literature through to February 2002 is surveyed, and 175 referenced are cited.

Geographic variation in the behaviour of the cleaner fish Labroides dimidiatus (Labridae)

Geographical variation in the outcome of interspecific interactions has a range of proximate ecological causes. For instance, cleaning interactions between coral reef fishes can result in benefits for both the cleaner and its clients. However, because both parties can cheat and because the rewards of cheating may depend on the local abundance of ectoparasites on clients, the interaction might range from exploitative to mutualistic. In a comparative analysis of behavioural measures of the association between the cleaner fish Labroides dimidiatus and all its client species, we compared cleaning interactions between two sites on the Great Barrier Reef that differ with respect to mean ectoparasite abundance. At Heron Island, where client fish consistently harbour fewer ectoparasites, client species that tended to pose for cleaners were more likely to receive feeding bites by cleaners than client species that did not pose for cleaners. This was not the case at Lizard Island, where ectoparasites are significantly more abundant. Client fish generally spent more time posing for cleaners at Lizard Island than their conspecifics at Heron Island. However, fish at Heron Island were inspected longer on average by cleaners than conspecifics at Lizard Island, and they incurred more bites and swipes at their sides per unit time from cleaners. These and other differences between the two sites suggest that the local availability of ectoparasites as a food source for cleaners may determine whether clients will seek cleaning, and whether cleaners will feed on parasites or attempt to feed on client mucus. The results suggest that cleaning symbiosis is a mosaic of different outcomes driven by geographical differences in the benefits for both participants.

A hedging point strategy - balancing effluent quality, economy and robustness in the control of wastewater treatment plants

An operational space map is an efficient tool to compare a large number of operational strategies to find an optimal choice of setpoints based on a multicriterion. Typically, such a multicriterion includes a weighted sum of cost of operation and effluent quality. Due to the relative high cost of aeration such a definition of optimality result in a relatively high fraction of the effluent total nitrogen in the form of ammonium. Such a strategy may however introduce a risk into operation because a low degree of ammonium removal leads to a low amount of nitrifiers. This in turn leads to a reduced ability to reject event disturbances, such as large variations in the ammonium load, drop in temperature, the presence of toxic/inhibitory compounds in the influent etc. Hedging is a risk minimisation tool, with the aim to "reduce one's risk of loss on a bet or speculation by compensating transactions on the other side" (The Concise Oxford Dictionary (1995)). In wastewater treatment plant operation hedging can be applied by choosing a higher level of ammonium removal to increase the amount of nitrifiers. This is a sensible way to introduce disturbance rejection ability into the multi criterion. In practice, this is done by deciding upon an internal effluent ammonium criterion. In some countries such as Germany, a separate criterion already applies to the level of ammonium in the effluent. However, in most countries the effluent criterion applies to total nitrogen only. In these cases, an internal effluent ammonium criterion should be selected in order to secure proper disturbance rejection ability.

Apoptosis and cell proliferation in the development of gastric carcinomas: Associations with c-myc and p53 protein expression

Background and Aim: Patients with gastric carcinomas have a poor prognosis and low survival rates. The aim of the present paper was to characterize cellular and molecular properties to provide insight into aspects of tumor progression in early compared with advanced gastric cancers. Methods: One hundred and nine graded gastric carcinomas (early or advanced stage, undifferentiated or differentiated type) with paired non-cancer tissue were studied to define the correlation between apoptosis (morphology, terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling), cell proliferation (Ki-67 expression, morphology) and expression and localization of two proteins frequently having altered expression in cancers, namely p53 and c-myc. Results: Overall, apoptosis was lower in early stage, differentiated and undifferentiated gastric carcinomas compared with advanced-stage cancers. Cell proliferation was comparatively high in all stages. There was a high level of p53 positivity in all stages. Only the early- and advanced-stage undifferentiated cancers that were p53 positive had a significantly higher level of apoptosis (P< 0.05). Cell proliferation was significantly greater (P < 0.05) only in the early undifferentiated cancers that had either c-myc or p53-positivity. Conclusions: The results indicate that low apoptosis and high cell proliferation combine to drive gastric cancer development. The molecular controls for high cell proliferation of the early stage undifferentiated gastric cancers involve overexpression of both p53 and c-myc. Overexpression of p53 may also control cancer development in that its expression is associated with higher levels of apoptosis in early and late-stage undifferentiated, cancers. (C) 2002 Blackwell Publishing Asia Pty Ltd.

The role of Doppler left ventricular filling indexes and Doppler tissue echocardiography in the assessment of cardiac involvement in hereditary hemochromatosis

Although cardiac dysfunction in hereditary hemochromatosis (HHC) can be evaluated by conventional echocardiography, findings are often not specific. To test the hypothesis that the assessment of (1) conventional Doppler left ventricular filling indexes and (2) intrinsic elastic properties of the myocardium by Doppler tissue echocardiography can both enhance the accuracy of echocardiographic diagnosis of cardiac involvement in HHC, a group of 18 patients with HHC (mean age 50+/-7 years) and 22 age-matched healthy subjects were studied. The following indexes were characteristic for HHC: (1) the duration of atrial reversal measured from pulmonary venous flow (ms) was longer(118+/-20 vs 90+/-16; P

The role of the Eph-ephrin signalling system in the regulation of developmental patterning

The Eph and ephrin system, consisting of fourteen Eph receptor tyrosine kinase proteins and nine ephrin membrane proteins in vertebrates, has been implicated in the regulation of many critical events during development. Binding of cell surface Eph and ephrin proteins results in bi-directional signals, which regulate the cytoskeletal, adhesive and motile properties of the interacting cells. Through these signals Eph and ephrin proteins are involved in early embryonic cell movements, which establish the germ layers, cell movements involved in formation of tissue boundaries and the pathfinding of axons. This review focuses on two vertebrate models, the zebrafish and mouse, in which experimental perturbation of Eph and/or ephrin expression in vivo have provided important insights into the role and functioning of the Eph/ephrin system.

Hydrolytic kinetic resolution of terminal mono- and bis-epoxides in the synthesis of insect pheromones: routes to (-)-(R)- and (+)-(S)-10-methyldodecyl acetate, (-)-(R)-10-methyl-2-tridecanone, (-)-(R)-(Z)-undec-6-en-2-ol (Nostrenol), (-)-(1R,7R)-1,7-dime

Hydrolytic kinetic resolution (HKR) of functionalised epoxides using (salen)Co(OAc) complexes provides enantiomerically enriched epoxides and diols, which have been transformed into important insect sex pheromones. In this general approach, (-)-(R)- and (+)-(S)-10-methyldodecyl acetates from the smaller tea tortrix moth were obtained, as was (-)-(R)-10-methyltridecan-2-one from the southern corn rootworm. The (S)-epoxide obtained from undec-1-en-6-yne was transformed to (-)-(R)-(Z)-undec-6-en-2-ol (Nostrenol) from ant-lions. HKR of appropriate bisepoxides was also investigated, and transformations of the resulting bisepoxides and epoxydiols provided (-)-(1R,7R)-1,7-dimethylnonylpropanoate from corn rootworms, (-)-(6R,12R)-6,12-dimethylpentadecan-2-one from the female banded cucumber beetle, and (-)-(2S,11S)-2,11-diacetoxytridecane and (+)-(2S,12S)-2,12-diacetoxytridecane from female pea-midges. (C) 2002 Elsevier Science Ltd. All rights reserved.

Monooxygenase stereoselectivity in the biosynthesis of stereoisomeric spiroacetals in the cucumber fly, Bactrocera cucumis

The stereoselectivity of hydroxylation of alkyltetrahydropyran-2-ols (or their biological equivalents) in the formation of stereoisomers of 2,8-dimethyl-1,7-dioxaspiro[5.5]undecanes in male Bactrocera cucumis has been investigated. Racemic, (6R)-, and (6S)-6-methyl-2-[5-H-2(1)]-n-pentyltetrahydropyran-2-ol was administered under an [O-18(2)]-enriched atmosphere. The stereochemistry and isotopic composition of generated spiroacetals were monitored by combined enantioselective GC-MS. The monooxygenase(s) strongly prefers the (6S)-substrate and furnishes predominantly the (S)-alcohol and then the (2S,6R,8S)-2,8-dimethyl-1,7-dioxaspiro[5.5]undecane. The (2S,6S,8R) and (2R,6S,8S) (E,Z)-isomers appear to be derived in vivo predominantly from (R)-hydroxylation of the (6S)-tetrahydropyranol.

Global distribution and genetic discontinuities of mangroves - emerging patterns in the evolution of Rhizophora

Mangroves are often described as a group of plants with common features and common origins based mostly on their broad distributional patterns, together with an erroneous view of comparable abilities in long-distance dispersal. However, whilst mangroves have common needs to adapt to rigorous environmental constraints associated with regular seawater inundation, individual taxa have developed different strategies and characteristics. Since mangroves are a genetically diverse group of mostly flowering plants, they may also have evolved at quite different geological periods, dispersed at different rates from different locations and developed different adaptive strategies. Current distributions of individual taxa show numerous instances of unusual extant distribution which demonstrate finite dispersal limitations, especially across open water. Our preliminary assessment of broad distribution and discontinuities reveals important patterns. Discontinuities, in the absence of current dispersal barriers, may be explained by persistent past barriers. As we learn more about discontinuities, we are beginning to appreciate their immense implications and what they might tell us about past geological conditions and how these might have influenced the distribution and evolution of mangroves. In this article, we describe emerging patterns in genetic relationships and distributions based on both current knowledge and preliminary results of our studies of molecular and morphometric characteristics of Rhizophora species in the Indo West Pacific region.

Novel application of biological glue in the management of a complicated pneumothorax in cystic fibrosis

Spontaneous pneumothorax is a frequent complication in advanced lung disease of cystic fibrosis. We describe a case of a complicated pneumothorax in a 21-year old-woman with cystic fibrosis who was effectively treated with the application of biological glue via a minithoracotomy. (C) 2002 Wiley-Liss, Inc.