Giant coronary artery aneurysms in juvenile polyarteritis nodosa: a case report

Juvenile polyarteritis nodosa (PAN) is a rare, necrotizing vasculitis, primarily affecting small to medium-sized muscular arteries. Cardiac involvement amongst patients with PAN is uncommon and reports of coronary artery aneurysms in juvenile PAN are exceedingly rare. We describe a 16 year old girl who presented with fever, arthritis and two giant coronary artery aneurysms, initially diagnosed as atypical Kawasaki disease and treated with IVIG and methylprednisolone. Her persistent fevers, arthritis, myalgias were refractory to treatment, and onset of a vasculitic rash suggested an alternative diagnosis. Based on angiographic abnormalities, polymyalgia, hypertension and skin involvement, this patient met criteria for juvenile PAN. She was treated with six months of intravenous cyclophosphamide and high dose corticosteroids for presumed PAN related coronary vasculitis. Maintenance therapy was continued with azathioprine and the patient currently remains without evidence of active vasculitis. She remains on anticoagulation for persistence of the aneurysms. This case illustrates a rare and unusual presentation of giant coronary artery aneurysms in the setting of juvenile PAN

Variation of selfing rate and inbreeding depression among individuals and across generations within an admixed Cedrus population

[EN] We investigated the variation and short-term evolution of the selfing rate and inbreeding depression (ID) across three generations within a cedar forest that was established from admixture ca 1860. The mean selfing rate was 9.5%, ranging from 0 to 48% among 20 seed trees (estimated from paternally inherited chloroplast DNA). We computed the probability of selfing for each seed and we investigated ID by comparing selfed and outcrossed seeds within progenies, thus avoiding maternal effects. In all progenies, the germination rate was high (88-100%) and seedling mortality was low (0-12%). The germination dynamics differed significantly between selfed and outcrossed seeds within progenies in the founder gene pool but not in the following generations. This transient effect of selfing could be attributed to epistatic interactions in the original admixture. Regarding the seedling growth traits, the ID was low but significant: 8 and 6% for height and diameter growth, respectively. These rates did not vary among generations, suggesting minor gene effects. At this early stage, outcrossed seedlings outcompeted their selfed relatives, but not necessarily other selfed seedlings from other progenies. Thus, purging these slightly deleterious genes may only occur through within-family selection. Processes that maintain a high level of genetic diversity for fitness-related traits among progenies also reduce the efficiency of purging this part of the genetic load. © 2011 Macmillan Publishers Limited All rights reserved. Guardar / Salir Siguiente >This work has been partially supported by Grant PPI-00-04 from the Polytechnic University of Valencia (Spain). We thank B Fady and E Klein as well as two anonymous reviewers for their helpful comments on a previous version of the paper. We acknowledge B Jouaud, W Brunetto, F Jean and H Picot for seed collection and processing and laboratory assistance, as well as P Brahic and staff from the Experimental Nursery of Aix-Les Milles for nursery cares.Ferriol Molina, M.; Pichot, C.; Lefevre, F. (2011). Variation of selfing rate and inbreeding depression among individuals and across generations within an admixed Cedrus population. Heredity. 106(1):146-157. https://doi.org/10.1038/hdy.2010.451461571061Barret SH, Eckert CG (1990). Variation and evolution of mating systems in seed plants. In: Kawano S (ed). Biological Approaches and Evolutionary Trends in Plants. Academic Press: London. pp 230–254.Benton TG, Plaistow SJ, Coulson TN (2006). Complex population dynamics and complex causation: devils, details and demography. Proc R Soc B Biol Sci 273: 1173–1181.Bower AD, Aitken SN (2007). Mating system and inbreeding depression in whitebark pine (Pinus albicaulis Engelm.). Tree Genet Genomes 3: 379–388.Byers DL, Waller DM (1999). Do plant populations purge their genetic load? Effects of population size and mating history on inbreeding depression. Annu Rev Ecol Syst 30: 479–513.Cointat M (1996). Le roman du cèdre. Revue Forestière Française 48: 503–526.Collevatti RG, Grattapaglia D, Duvall J (2001). High resolution microsatellite based analysis of the mating system allows the detection of significant biparental inbreeding in Caryocar brasiliense, an endangered tropical tree species. Heredity 86: 60–67.Cottrell JE, White IMS (1995). The use of isozyme genetic markers to estimate the rate of outcrossing in a Sitka pruce (Picea sitchensis (Bong.) Carr.) seed orchard in Scotland. New Forests 10: 111–122.Coulson T, Benton TG, Lundberg P, Dall SRX, Kendall BE (2006). Putting evolutionary biology back in the ecological theatre: a demographic framework mapping genes to communities. Evol Ecol Res 8: 1155–1171.Durel CE, Bertin P, Kremer A (1996). Relationship between inbreeding depression and inbreeding coefficient in maritime pine (Pinus pinaster). Theor Appl Genet 92: 347–356.Eriksson E (2006). Thinning operations and their impact on biomass production in stands of Norway spruce and Scots pine. Biomass Bioenergy 30: 848–854.Fady B, Lefèvre F, Reynaud M, Vendramin GG, Bou Dagher-Karrat M, Anzidei M et al. (2003). Gene flow among different taxonomic units: evidence from nuclear and cytoplasmic markers in Cedrus plantation forests. Theor Appl Genet 107: 1132–1138.Farris MA, Mitton JB (1984). Population density, outcrossing rate, and heterozygote superiority in ponderosa pine. Evolution 38: 1151–1154.Favre-Duchartre M (1970). Des Ovules Aux Graines. Monographie 8. Masson et Cie.: Paris.Franklin EC (1969). Inbreeding Depression in Metrical Traits of Loblolly Pine (Pinus taeda L.) as a Result of Self-pollination. North Carolina State University: Raleigh, NC. Technical report No 40, School of Forest Resources.Gregorius HR, Ziehe M, Ross MD (1987). Selection caused by self-fertilization I. Four measures of self-fertilization and their effects on fitness. Theor Popul Biol 31: 91–115.Hamrick JL, Godt MJ (1989). Allozyme diversity in plant species. In: Brown AHD, Al Kahler MC, Weir BS (eds). Plant Population Genetics, Breeding, and Genetic Resources. Sinauer: Sunderland, MA. pp 43–63.Holsinger KE (1991). Mass-action models of plant mating systems—the evolutionary stability of mixed mating systems. Am Nat 138: 606–622.Husband BC, Schemske DW (1996). Evolution of the magnitude and timing of inbreeding depression in plants. Evolution 50: 54–70.Jones FA, Hamrick JL, Peterson CJ, Squiers ER (2006). Inferring colonization history from analyses of spatial genetic structure within populations of Pinus strobus and Quercus rubra. Mol Ecol 15: 851–861.Kärkkäinen K, Savolainen O (1993). The degree of early inbreeding depression determines the selfing rate at the seed stage: model and results from Pinus sylvestris (Scots pine). Heredity 71: 160–166.Keller LF, Waller DM (2002). Inbreeding effects in wild populations. Trends Ecol Evol 17: 230–241.Klein EK, Lavigne C, Gouyon PH (2006). Mixing of propagules from discrete sources at long distance: comparing an exponential tail to an exponential. BMC Ecol 6: 3.Knowles P, Furnier GR, Aleksiuk MK, Perry DJ (1987). Significant levels of self-fertilization in natural populations of tamarack. Can J Bot 65: 1087–1091.Koelewijn HP, Koski V, Savolainen O (1999). Magnitude and timing of inbreeding depression in Scots pine (Pinus sylvestris L.). Evolution 53: 758–768.Kremer A (1994). Genetic diversity and phenotypic variability of forest trees. Genet Sel Evol 26: s105–s123.Krouchi F, Derridj A, Lefèvre F (2004). Year and tree effect on reproductive organisation of Cedrus atlantica in a natural forest. For Ecol Manage 197: 181–189.Lande R (1988). Genetics and demography in biological conservation. Science 241: 1455–1460.Ledig FT (1986). Heterozygosity, heterosis, and fitness in outbreeding plants. In: Soulé ME (ed). Conservation Biology: the Science of Scarcity and Diversity. Sinauer Ass: Sunderland. pp 77–104.Lee JK, Nordheim EV, Kang H (1996). Inference for lethal gene estimation with application in plants. Biometrics 52: 451–462.Lefèvre F, Fady B, Fallour-Rubio D, Ghosn D, Bariteau M (2004). Impact of founder population, drift and selection on the genetic diversity of a recently translocated tree population. Heredity 93: 542–550.Marquardt PE, Epperson BK (2004). Spatial and population genetic structure of microsatellites in white pine. Mol Ecol 13: 3305–3315.Morgante M, Vendramin GG, Rossi P (1991). Effects of stand density on outcrossing rate in two Norway spruce (Picea abies) populations. Can J Bot 69: 2704–2708.Mosseler A, Major JE, Simpson JD, Daigle B, Lange K, Park YS et al. (2000). Indicators of population viability in red spruce, Picea rubens. I. Reproductive traits and fecundity. Can J Bot 78: 928–940.Naydenov KD, Tremblay FM, Alexandrov A, Fenton NJ (2005). Structure of Pinus sylvestris L. populations in Bulgaria revealed by chloroplast microsatellites and terpenes analysis : provenance tests. Biochem Syst Ecol 33: 1226–1245.Neale DB, Adams WT (1985). The mating system in natural and shelterwood stands of Douglas-fir. Theor Appl Genet 71: 201–207.Notivol E, Garcia-Gil MR, Alia R, Savolainen O (2007). Genetic variation of growth rhythm traits in the limits of a latitudinal cline in Scots pine. Can J For Res 37: 540–551.O’Connell LM, Russell J, Ritland K (2004). Fine-scale estimation of outcrossing in western redcedar with microsatellite assay of bulked DNA. Heredity 93: 443–449.Parducci L, Szmidt AE, Madaghiele A, Anzidei M, Vendramin GG (2001). Genetic variation at chloroplast microsatellites (CpSSRs) in Abies nebrodensis (Lojac.) Mattei and three neighboring Abies species. Theor Appl Genet 102: 733–740.Parraguirre-Lezama C, Vargas-Hernández JJ, Ramirez-Vallejo P, Ramirez Herrera C (2004). Mating system in four natural populations of Pinus greggii Engelm. Agrociencia 38: 107–119.Petit RJ, Hampe A (2006). Some evolutionary consequences of being a tree. Annu Rev Ecol Evol Syst 37: 187–214.Pichot C, Bastien C, Courbet F, Demesure-Musch B, Dreyfus P, Fady B et al. (2006). Déterminants et conséquences de la qualité génétique des graines et semis lors de la phase initiale de régénération naturelle des peuplements forestiers. In: 6e Colloque National du BRG ; La Rochelle 2006/10/02-04. Les Actes du Bureau des Ressources Génétiques 6: 277–297.Remington DL, O’Malley DM (2000a). Whole-genome characterization of embryonic stage inbreeding depression in a selfed loblolly pine family. Genetics 155: 337–348.Remington DL, O’Malley DM (2000b). Evaluation of major genetic loci contributing to inbreeding depression for survival and early growth in a selfed family of Pinus taeda. Evolution 54: 1580–1589.Restoux G, Silva DE, Sagnard F, Torre F, Klein E, Fady B (2008). Life at the margin: the mating system of Mediterranean conifers. Web Ecol 8: 94–102.Ribeiro MM, Mariette S, Vendramin GG, Szmidt AE, Plomion C, Kremer A (2002). Comparison of genetic diversity estimates within and among populations of maritime pine using chloroplast simple-sequence repeat and amplified fragment length polymorphism data. Mol Ecol 11: 869–877.Ritland K, El-Kassaby YA (1985). The nature of inbreeding in a seed orchard of Douglas fir as shown by an efficient multi-locus model. Theor Appl Genet 71: 375–384.Ritland K, Travis S (2004). Inferences involving individual coefficients of relatedness and inbreeding in natural populations of Abies. For Ecol Manage 197: 171–180.Robledo-Arnuncio JJ, Alia R, Gil L (2004). Increased selfing and correlated paternity in a small population of a predominantly outcrossing conifer, Pinus sylvestris. Mol Ecol 13: 2567–2577.Rouault G, Turgeon J, Candau JN, Roques A, Aderkas P (2004). Oviposition strategies of conifer seed chalcids in relation to host phenology. Naturwissenschaften 91: 472–480.Savolainen O, Kärkkäinen K, Kuittinen H (1992). Estimating numbers of embryonic lethals in conifers. Heredity 69: 308–314.Scofield DG, Schultz ST (2006). Mitosis, stature and evolution of plant mating systems: low-Phi and high-Phi plants. Proc R Soc B Biol Sci 273: 275–282.Shaw DV, Allard RW (1982). Estimation of outcrossing rates in douglas-fir using isoenzyme markers. Theor Appl Genet 62: 113–120.Skrøppa T (1996). Diallel crosses in Picea abies. II. Performance and inbreeding depression of selfed families. For Genet 3: 69–79.Sorensen FC (1997). Effects of sib mating and wind pollination on nursery seedling size, growth components, and phenology of Douglas-fir seed-orchard progenies. Can J For Res 27: 557–566.Sorensen FC (1999). Relationship between self-fertility, allocation of growth, and inbreeding depression in three coniferous species. Evolution 53: 417–425.Sorensen FC (2001). Effect of population outcrossing rate on inbreeding depression in Pinus contorta var. murrayana seedlings. Scand J For Res 16: 391–403.Sorensen FC, Adams WT (1993). Self fertility and natural selfing in three Oregon Cascade populations of lodgepole pine. In: Lindgren D (ed). Pinus contorta—From Untamed Forest to Domesticated Crop. Department of Forest Genetics and Plant Physiology, Sweden University of Agricultural Science: Umea, Sweden. Report 11, pp 358–374.Sorensen FC, Miles RS (1974). Self-pollination effects on Douglas fir and ponderosa pine seeds and seedlings. Silvae Genet 23: 135–138.Sorensen FC, Miles RS (1982). Inbreeding depression in height, height growth, and survival of Douglas-fir, ponderosa pine, and noble fir to 10 years of age. For Sci 28: 283–292.Terrab A, Paun O, Talavera S, Tremetsberger K, Arista M, Stuessy TF (2006). Genetic diversity and population structure in natural populations of Moroccan Atlas cedar (Cedrus atlantica; Pinaceae) determined with cpSSR markers. Am J Bot 93: 1274–1280.Vendramin GG, Lelli L, Rossi P, Morgante M (1996). A set of primers for the amplification of 20 chloroplast microsatellites in Pinaceae. Mol Ecol 5: 595–598.White TL, Adams WT, Neale DB (2007). Forest Genetics. CABI Publisher: Cambridge, MA. pp 149–186.Wilcox MD (1983). Inbreeding depression and genetic variances estimated from self- and cross- pollinated families of Pinus radiata. Silvae Genet 32: 89–96.Williams CG (2007). Re-thinking the embryo lethal system within the Pinaceae. Can J Bot 85: 667–677.Williams CG (2008). Selfed embryo death in Pinus taeda: a phenotypic profile. New Phytol 178: 210–222.Williams CG, Auckland LD, Reynolds MM, Leach KA (2003). Overdominant lethals as part of the conifer embryo lethal system. Heredity 91: 584–592.Wilson R (1923). Life history of Cedrus atlantica. Bot Gaz 75: 203–208.Yazdani R, Muona O, Rudin D, Szmidt AE (1985). Genetic structure of a Pinus sylvestris L. seed-tree stand and naturally regenerated understory. For Sci 31: 430–436

Modulation of γ-Secretase Activity by Multiple Enzyme-Substrate Interactions: Implications in Pathogenesis of Alzheimer's Disease

BACKGROUND: We describe molecular processes that can facilitate pathogenesis of Alzheimer's disease (AD) by analyzing the catalytic cycle of a membrane-imbedded protease γ-secretase, from the initial interaction with its C99 substrate to the final release of toxic Aβ peptides. RESULTS: The C-terminal AICD fragment is cleaved first in a pre-steady-state burst. The lowest Aβ42/Aβ40 ratio is observed in pre-steady-state when Aβ40 is the dominant product. Aβ42 is produced after Aβ40, and therefore Aβ42 is not a precursor for Aβ40. The longer more hydrophobic Aβ products gradually accumulate with multiple catalytic turnovers as a result of interrupted catalytic cycles. Saturation of γ-secretase with its C99 substrate leads to 30% decrease in Aβ40 with concomitant increase in the longer Aβ products and Aβ42/Aβ40 ratio. To different degree the same changes in Aβ products can be observed with two mutations that lead to an early onset of AD, ΔE9 and G384A. Four different lines of evidence show that γ-secretase can bind and cleave multiple substrate molecules in one catalytic turnover. Consequently depending on its concentration, NotchΔE substrate can activate or inhibit γ-secretase activity on C99 substrate. Multiple C99 molecules bound to γ-secretase can affect processive cleavages of the nascent Aβ catalytic intermediates and facilitate their premature release as the toxic membrane-imbedded Aβ-bundles. CONCLUSIONS: Gradual saturation of γ-secretase with its substrate can be the pathogenic process in different alleged causes of AD. Thus, competitive inhibitors of γ-secretase offer the best chance for a successful therapy, while the noncompetitive inhibitors could even facilitate development of the disease by inducing enzyme saturation at otherwise sub-saturating substrate. Membrane-imbedded Aβ-bundles generated by γ-secretase could be neurotoxic and thus crucial for our understanding of the amyloid hypothesis and AD pathogenesis

The modular systems biology approach to investigate the control of apoptosis in Alzheimer's disease neurodegeneration

Apoptosis is a programmed cell death that plays a critical role during the development of the nervous system and in many chronic neurodegenerative diseases, including Alzheimer's disease (AD). This pathology, characterized by a progressive degeneration of cholinergic function resulting in a remarkable cognitive decline, is the most common form of dementia with high social and economic impact. Current therapies of AD are only symptomatic, therefore the need to elucidate the mechanisms underlying the onset and progression of the disease is surely needed in order to develop effective pharmacological therapies. Because of its pivotal role in neuronal cell death, apoptosis has been considered one of the most appealing therapeutic targets, however, due to the complexity of the molecular mechanisms involving the various triggering events and the many signaling cascades leading to cell death, a comprehensive understanding of this process is still lacking. Modular systems biology is a very effective strategy in organizing information about complex biological processes and deriving modular and mathematical models that greatly simplify the identification of key steps of a given process. This review aims at describing the main steps underlying the strategy of modular systems biology and briefly summarizes how this approach has been successfully applied for cell cycle studies. Moreover, after giving an overview of the many molecular mechanisms underlying apoptosis in AD, we present both a modular and a molecular model of neuronal apoptosis that suggest new insights on neuroprotection for this disease

Adding a third dimension to the edge of a species’ range: altitude and genetic structuring in mountainous landscapes

In addition to the topographical and ecological barriers, other landscape features may also subtly influence the patterns of gene flow and spatial genetic structuring at species’ borders. This paper focuses on the role played by altitudinal gradients that characterize mountainous landscapes. We formulate and test the hypothesis that when the distribution boundaries of plant species intersect mountainous landscapes, altitudinal gradients in ecological conditions may considerably enhance population subdivision and genetic structuring at the regional level. Using amplified fragment length polymorphism markers, we studied genetic diversity and differentiation in a set of 21 peripheral populations of the evergreen shrub Lavandula latifolia Med. (Labiatae) at its southernmost distribution limit in the Betic mountain ranges of southern Spain. Population size and abundance, and within-population genetic diversity, varied predictably with altitude, being highest at middle elevations and declining steadily towards both the upper and lower altitudinal distribution margins. Genetic differentiation tended to follow the opposite trend. These altitudinal patterns result from variation with elevation in the relative influence of gene flow and drift on the distribution of genetic variation. Genetic drift prevails around the upper and lower altitudinal limits, whereas a situation closer to a drift-gene flow equilibrium exists at the center of the altitudinal distribution. Altitudinal variation in the relative influences of gene flow and drift appears as an essential element in the interpretation of regional genetic structuring of L. latifolia at its mountainous distribution edge, and a factor which may influence the evolutionary potential of peripheral populations and the likelihood of local adaptation.Peer reviewe