748 research outputs found
Towards Genetic Prediction of Coronary Heart Disease in Familial Hypercholesterolemia
No full textFamilial hypercholesterolemia (FH) is an autosomal dominant disorder of lipid metabolism caused by mutations in the gene coding for the low-density lipoprotein (LDL) receptor. The LDL receptor is a transmembrane protein that regulates plasma cholesterol levels by uptake of LDL particles from the blood circulation (Figure). Mutations in the LDL receptor gene cause insufficient uptake of circulating LDL particles, which raises the endogenous cholesterol production by the hepatocytes, resulting in twofold increased plasma concentrations of LDL cholesterol in patients with the heterozygous form of FH. The rare (1/million) homozygous FH patients have severely reduced or completely absent residual function of the LDL receptor causing extremely raised plasma LDL cholesterol concentrations. These patients develop tendon
xanthomas in childhood and massive atherosclerosis occurs frequently at a very young age. This thesis, however, focuses on patients with heterozygous FH, which is more common with a prevalence of 1/500 in Western societies. The typical heterozygous FH patients develop
tendon xanthomas and have accelerated atherosclerosis and coronary heart disease (CHD) at a young age. Nevertheless, substantial variation is seen in the age of onset of CHD among patients with heterozygous FH
Potato leafroll virus, its purification from its vector Myzus persicae
No full textExperiments were described on the purification of potato leafroll virus (PLRV) from its vector Myzus persicae. Preliminary experiments demonstrated that much non- viral material had to be removed from aphid macerates to obtain a pure virus preparation. This was achieved by a multistep procedure, in which the aphid macerates were emulsified with chloroform at pH 5.0. The virus present in the interphase between the chloroform and water phases was extracted from the interphase, and concentrated by high-speed centrifuging. The virus suspension obtained was subjected to a phase system of butoxy-ethanol, ethoxy-ethanol and 2.5 M phosphate buffer pH 7.5, and centrifuged in a sucrose density gradient column.A fairly pure virus preparation was obtained when the material from the infective zone of the gradient was concentrated at 90,000 g for 3 h. Particles with a diameter of 23 mμand with a hexagonal outline were found in each preparation by electron- microscopy. The PLRV isolate purified was free of any contaminating virus when its biological purity was tested. One of the PLRV isolates used in the preliminary experiments, was contaminated with other, presumable persistent, viruses. Their properties and some studies on their host range were described. These viruses were referred to as virus-like particles
Insulin sensitivity of hepatic glucose and lipid metabolism in animal models of hepatic steatosis
No full textDe lever is betrokken bij de regulatie van zowel het koolhydraat als het vet metabolisme. De lever slaat glucose op als glycogeen, scheidt glucose uit, kan glucose maken uit bijvoorbeeld melkzuur en aminozuren (‘gluconeogenese’), zet glucose om in vet (‘de novo lipogenese’), verbrandt vetzuren in de beta-oxidatie (levert energie voor de gluconeogenese) en scheidt triglycerides uit in de circulatie in ‘very low density lipoprotein’ (VLDL) deeltjes. Insuline remt de glucoseproductie door de lever en stimuleert de omzetting van glucose in glycogeen, vetzuren en vet (triglycerides). Daarnaast onderdrukt insuline de uitscheiding van triglyceride-rijke VLDL-deeltjes. Indirect remt insuline ook de beta-oxidatie omdat het de vrijmaking van vetzuren uit triglycerides remt.
Een verhoogde triglyceride concentratie in de lever (vette lever of hepatische steatose) is geassocieerd met diverse componenten van het metabool syndroom (dyslipidemie, insulineresistentie, obesitas, hypertensie) en kan een voorloper zijn van bijvoorbeeld levercirrose. Uit de klinische praktijk is gebleken dat hepatische steatose is geassocieerd met insulineresistentie en diabetes mellitus type 2. In de studies beschreven in het proefschrift van Aldo Grefhorst werd met behulp van muismodellen het effect van hepatische steatose op de insulinegevoeligheid van het glucose- en vetmetabolisme onderzocht. Op deze manier is getracht de onderliggende moleculaire processen behorende bij deze associatie op te helderen. De gebruikte modellen waren de leptine-deficiënte ob/ob muis, activering van de novo lipogenese met synthetische agonisten van de liver X receptor, farmacologische remming van de beta-oxidation met TDGA en farmacologische remming van glucose-6-phosphatase met S4048. Insulinegevoeligheid werd onder andere gemeten met behulp van hyperinsulinemische euglycemische clamps in combinatie met infusies van stabiele isotopen.
In alle onderzochte muismodellen is sprake van ernstige hepatische steatose. Met uitzondering van de ob/ob muis, werd in geen van de modellen een afgenomen insulinegevoeligheid waargenomen. Aan de hand van deze studies kan dan ook geconcludeerd worden dat de hoeveelheid triglycerides in de lever op zich weinig zegt over de mate van hepatische insulinegevoeligheid. Andere factoren zijn waarschijnlijk belangrijke determinanten voor het optreden van insulineresistentie bij hepatische steatose. Te denken valt bijvoorbeeld aan de oorsprong van de triglycerides, de duur van de hepatische steatose, de locatie van de triglycerides in de lever, de grootte van de vetdruppels in de cellen en verhoogde concentraties van andere soorten lipiden.
Interspecies Translation of Disease Networks Increases Robustness and Predictive Accuracy
No full text© 2011 Anvar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Gene regulatory networks give important insights into the mechanisms underlying physiology and pathophysiology. The derivation of gene regulatory networks from high-throughput expression data via machine learning strategies is problematic as the reliability of these models is often compromised by limited and highly variable samples, heterogeneity in transcript isoforms, noise, and other artifacts. Here, we develop a novel algorithm, dubbed Dandelion, in which we construct and train intraspecies Bayesian networks that are translated and assessed on independent test sets from other species in a reiterative procedure. The interspecies disease networks are subjected to multi-layers of analysis and evaluation, leading to the identification of the most consistent relationships within the network structure. In this study, we demonstrate the performance of our algorithms on datasets from animal models of oculopharyngeal muscular dystrophy (OPMD) and patient materials. We show that the interspecies network of genes coding for the proteasome provide highly accurate predictions on gene expression levels and disease phenotype. Moreover, the cross-species translation increases the stability and robustness of these networks. Unlike existing modeling approaches, our algorithms do not require assumptions on notoriously difficult one-to-one mapping of protein orthologues or alternative transcripts and can deal with missing data. We show that the identified key components of the OPMD disease network can be confirmed in an unseen and independent disease model. This study presents a state-of-the-art strategy in constructing interspecies disease networks that provide crucial information on regulatory relationships among genes, leading to better understanding of the disease molecular mechanisms.This work was funded in part by the European Commission (PolyALA LSHM-CT-2005018675) and Muscular Dystrophy Association (68016) to SMvdM and MDA, European Community’s Seventh Framework Programme (FP7/2007–2013), ENGAGE project, grant agreement HEALTH-F4-2007-201413, and the Centre for Medical Systems Biology within the framework of the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO)
Eine epidemiologische Untersuchung der Suizidversuche im Kanton Basel-Stadt : Resultate der WHO/EURO-Multizenterstudie über Suizidversuche
No full textDie WHO anerkannte Ende der 1980er-Jahre die zunehmende Häufigkeit der Suizide auf dem europäischen Kontinent als Problem und berichtete über grosse Unterschiede in der Anzahl suizidaler Handlungen in den verschiedenen Ländern. Daher lancierte die WHO im Rahmen der „Health for all by the year 2000“-Strategie die WHO/EURO-Multizenterstudie über suizidales Verhalten. Ziel dieser Studie war es, die epidemiologischen Trends bezüglich der Häufigkeit der Suizidversuche zu monitorieren und Voraussagen treffen zu können, welche Bevölkerungsgruppen besonders gefährdet waren, damit spezifische Präventionsmassnahmen entwickelt werden können.
Die WHO/EURO-Multizenterstudie fokussierte auf Suizidversuche, da bekannt ist, dass ein erfolgter Suizidversuch der stärkste Prädiktor für einen vollendeten Suizid in der Zukunft darstellt (Isometsa & Lonnqvist, 1998; Harris & Barraclough, 1997) und Suizidversuche in den Ländern bisher nicht systematisch dokumentiert wurden. Da das Schweizer Studienzentrum in Bern die Datenerfassung 1999 sistierte, konnte das neue Zentrum in Basel stattdessen als Repräsentant der Schweiz die Erfassung ab 2003 fortführen. Erstmals konnten im ganzen Kanton Basel-Stadt für vier Jahre Suizidversuche dokumentiert werden, die dem medizinischen Versorgungssystem bekannt wurden. Einzigartig war, dass es sich beim Einzugsgebiet um einen ganzen Kanton handelt. Auch wurden Suizidversuche klar operationalisiert und dadurch bisherige methodische Schwächen früherer Studien behoben.
Artikel 1 beschreibt die Suizidversuchsraten/100'000 Einwohner der wichtigsten soziodemografischen Gruppen und gibt klinische Details (z.B. über bestehende psychiatrische Erkrankungen oder verwendete Intoxikationssubstanzen) bekannt. Die mittlere Suizidversuchsrate lag bei 164/100'000 Einwohner. Frauen unternahmen doppelt so häufig Suizidversuche wie Männer. Präventionsmassnahmen sollten auf Risikogruppen abzielen, welche die höchsten Prävalenzraten zeigten: Es waren dies junge Erwachsene im Alter von 20–24 Jahren, Alleinstehende, Menschen mit Migrationshintergrund oder wenig Bildung sowie Erwerbslose. Über 90% weisen psychische Störungen auf, am häufigsten Depression. Der Zugang zu vorwiegend Benzodiazepinen und nichtsteroidalen Antirheumatika sollte erschwert werden, da sie die am häufigsten verbreiteten Substanzen der Selbstvergiftungen darstellen. Auch Diagnostik und Behandlung von affektiven Störungen sollte verbessert werden.
Artikel 2 lehnte sich an die bisher im Kanton Basel-Stadt etablierte Migrationsforschung an (Yilmaz & Riecher-Rössler, 2008, 2012) und fokussierte auf die Unterschiede zwischen Schweizern und der gefährdeten Gruppe der türkisch-stämmigen Migranten. Es konnte repliziert werden, dass die Raten der Migranten fast dreimal so hoch waren wie die der Schweizer und, dass Frauen doppelt so oft Suizidversuche begingen wie Männer. Besonders hervorstechend waren erneut die Suizidversuchsraten der jüngeren Altersklassen. Im Gegensatz zur lokalen Bevölkerung litten die türkischen Migranten öfters an Anpassungsstörungen und verwendeten öfters Medikamente, v.a. Analgetika. Präventionsmassnahmen sollten daher die Medikamentenabgabe von Schmerzmitteln (auch der frei verkäuflichen) stärker kontrollieren, und Ärzte sollten bei der Verordnung auf Präparate mit geringer Toxizität achten.
Artikel 3 widmete sich dem in der Suizidologie spärlich behandelten Thema der Kosten von Suizidversuchen. Suizidversuche verursachen substanzielle direkte medizinische Kosten, die neben den indirekten Kosten nur einen Teil der finanziellen Belastungen für das Allgemeinwesen darstellen. Deshalb wurden die jährlichen direkten medizinischen Kosten aufgrund von Suizidversuchen im Kanton Basel-Stadt berechnet und analysiert, welche Variablen die Zugehörigkeit zur Hochkostengruppe bedingen. 2003 fielen Behandlungskosten für die Suizidversucher von 3'373'025 CHF an, die hauptsächlich auf die psychiatrische Versorgung zurückzuführen waren. Der Kostenmittelwert pro Fall lag bei 19'165 CHF und der entsprechende Kostenmedian bei 6'108 CHF. Für die Schweiz hochgerechnet ergaben sich jährliche Behandlungskosten von 191 Millionen Franken. Variablen, die die Chance erhöhten, ein Hochkostenfall zu sein, waren: Depressionsbetroffen, älter als 64 Jahre, Intensivpflege erhaltend, tödliche Absichten äussernd und harte Methoden verwendend. Daher sollten kosten-effektive Präventionsmassnahmen v.a. auf Menschen mit affektiven Störungen und Senioren abzielen.
Ein geeignetes Präventionsprogramm, das auf mehreren Interventionsebenen operiert und die einzelnen genannten Risikogruppen der Artikel 1 bis 3 miteinbeziehen könnte, wäre ein „Bündnis gegen Depression“ nach dem Beispiel von Hegerl, Althaus, Schmidtke und Niklewski aus Würzburg (2006)
A first genome assembly of the barley fungal pathogen Pyrenophora teres f. teres
No full textBackground: Pyrenophora teres f. teres is a necrotrophic fungal pathogen and the cause of one of barley's most important diseases, net form of net blotch. Here we report the first genome assembly for this species based solely on short Solexa sequencing reads of isolate 0-1. The assembly was validated by comparison to BAC sequences, ESTs, orthologous genes and by PCR, and complemented by cytogenetic karyotyping and the first genome-wide genetic map for P. teres f. teres.
Results: The total assembly was 41.95 Mbp and contains 11,799 gene models of 50 amino acids or more. Comparison against two sequenced BACs showed that complex regions with a high GC content assembled effectively. Electrophoretic karyotyping showed distinct chromosomal polymorphisms between isolates 0-1 and 15A, and cytological karyotyping confirmed the presence of at least nine chromosomes. The genetic map spans 2477.7 cM and is composed of 243 markers in 25 linkage groups, and incorporates simple sequence repeat markers developed from the assembly. Among predicted genes, non-ribosomal peptide synthetases and efflux pumps in particular appear to have undergone a P. teres f. teres-specific expansion of non-orthologous gene families.
Conclusions: This study demonstrates that paired-end Solexa sequencing can successfully capture coding regions of a filamentous fungal genome. The assembly contains a plethora of predicted genes that have been implicated in a necrotrophic lifestyle and pathogenicity and presents a significant resource for examining the bases for P. teres f. teres pathogenicity
Biosystematic studies on the Muellerianella complex (Delphacidae Homoptera Auchenorrhyncha)
No full textThe genus Muellerianella comprises the species: M. farmairei, M. brevipennis, M. relicta and one pseudogamous all-female biotype M. fairmairei (3n). The bisexual species M. fairmairei and M. brevipennis as well as the unisexual M. fairmairei (3n) were investigated from a biosystematic point of view. The males of the two bisexual species are morphologically distinct but their females, the female hybrids of both way-crossings between the two bisexual species and the unisexual biotype are morphologically indistinguishable.The bisexual species M. fairmairei and M. brevipennis are diploid (2n = 28) and their sex determination system is XY. F1 hybrids also have 28 chromosomes. The pseudogamous unisexual biotype is triploid (3n = 41) reproducing apomictically, but it requires sperm derived from the males of the two bisexual species to initiate embryogenesis (pseudogamy).The host plants of the Muellerianella complex are Holcuslanatus or H.mollis for the bisexual and unisexual M. fairmairei, and Deschampsia caespitosa for M. brevipennis.The distributions of the two species and their host plants overlap widely in West and Central Europe. M. fairmairei and its host plant are distributed more to the south, while M. brevipennis and its host extend more to the north. There is evidence that the unisexual M. fairmairei (3n) occurs in the overlapping area of the two bisexual species, but is absent from the peripheral areas where one of the other species is also absent.In the area of Leersum-Langbroek (prov. of Utrecht) in Holland both species are common, and their respective host plants grow in reasonable numbers. In a few localities where the two hosts are closely intermixed both delphacid species occur syntopically.Samples of the two species were taken bij the sweep-net and suction methods. M. fairmairei is more frequent in wet biotopes of noncultivated meadows in West Europe. M. brevipennis is more frequent in the north of Europe and is a stenotopic species typical of fresh biotopes of wooded areas.In Northern Europe both species are univoltine while in West and Central Europe M. fairmairei has two distinct generations in contrast to M. brevipennis which has an incomplete second generation. However, there is no important seasonal isolation between the two species. In Southern Europe M. fairmairei is probably polyvoltine.Populations of M. fairmairei from regions where M. brevipennis does not occur (S. Greece, S. France?, Ireland) have a sex ratio of 1 : 1, while populations occurring sympatrically with M. brevipennis (England, France, Holland) have a high proportion of females, comprising a mixture of diploid and triploid individuals. In Holland M. brevipennis has a sex ratio of1 : 1, while populations of this species in Finland have a high proportion of females.Both diploid species maintained a 1:1 sex ratio in the laboratory rearings. Crossings between triploid females and males of M. fairmairei resulted in absolute all-female triploid progenies. Diploid and triploid females of M. fairmairei coexist in Holland. In one biotope (in Leersum), the proportion of the two female biotypes of M.fairmairei was 1:1, while in others triploid females were more numerous than the diploid ones. It is not clear, whether both female populations of M. fairmairei occupy exactly the same ecological niche.Regarding the wing form of the two bisexual species and the unisexual biotope, long photoperiod (L:D = 18:6) favors the development of the long wings, while short photoperiod (L:D = 10:14) completely suppresses it. Under long photoperiod the macropterous form of M. brevipennis was more common than that of M. fairmairei. Under long photoperiod, when the larval density was increased M. fairmairei (2n) had proportionately more macropterous adults than M. fairmairei (3n).Summer and winter eggs of the two species were parasitized by Anagrus sp. However, eggs of the second generation were more frequently parasitized (up to 40%) that those of the first.The higher population densities of M. fairmairei than of M. brevipennis in the field were interpreted from laboratory observations by the fact that M. fairmairei has higher egg production than M. brevipennis. The triploid females of M. fairmairei are assumed to be more prolific than the diploid ones. Also, the rate of egg production of M. fairmairei was higher than that of M. brevipennis. Females of M. fairmairei mated once produced a few unfertile eggs at the end of their oviposition period, in contrast to M. brevipennis which always produced fertile eggs. Males of M. fairmairei appeared to have greater longevity than the females.During the first generation and in colonies under long photoperiod M. fairmairei oviposits in its food plant H. lanatus, while during the second generation and in colonies under short photoperiod in Juncus effusus. M. brevipennis was found to oviposit in the field only in its food plant, namely D. caespitosa, but in the laboratory it also oviposited in J. effusus. The egg-group size of both species depends upon the oviposition substrate.Embryonic development of both species is continuous during the first generation and in colonies under long photoperiod, but embryonic diapause (arrest of development before blastokinesis) takes place during the second generation and in laboratory rearings under short photoperiod. The intensity of diapause is higher in M. brevipennis as compared to M. fairmairei. Continuous rearings of the unisexual and bisexual M. fairmairei were possible under short photoperiod.The rate of larval development of both species under long photoperiod at 20- 25°C was approximately the same. Under short photoperiod the duration of the last instar larva of females is longer than that under long photoperiod. Temperature, humidity and crowding had an influence upon the rate of larval development.In laboratory experiments, development and reproduction of M. fairmairei occurred on several grass species, in contrast to M. brevipennis which appeared to be monophagous. Mature grasses were more suitable as food plants than seedlings.Some unmated females of M. fairmairei (2n) placed in cages containing H. lanatus and D. caespitosa, and males of M. brevipennis ultimately produced a few male and female hybrids. The reciprocal cross resulted in more female hybrids than males. Egg-fertility of these crosses was variable (0-100%) during the course of the oviposition period. Hybrid larvae can develop on both grass species, but they prefer D. caespitosa to H. lanatus. Males were sterile but females were often fertile and some of them crossed back with M. fairmairei produced a triploid pseudogamous biotype very similar to that collected in the field. The all-female progeny of the triploid M. fairmairei was greater when it was crossed with M. fairmairei males than with M. brevipennis males. Hybrids were obtained even when unmated females (2n + 3n) of both species together were caged with males of one species.In conformity with these results it is proposed that the two bisexual species should be called 'allomorphic-related species' instead of 'sibling species'. Allopatric speciation is considered as the most probable cause of divergence between both species. It is suggested that M. brevipennis originated from an isolated population of M. fairmairei during a period of glaciation and has survived on D. caespitosa.It is proposed to call the unisexual biotype M.2 fairmairei-brevipennis, following the nomenclatorial system of hybrids. In this context, it has been demonstrated that in insects hybridization may lead to unisexuality followed by polyploidy.<br/
Sulfide induced phosphate release from iron phosphates and its potential for phosphate recovery
No full textSulfide is frequently suggested as a tool to release and recover phosphate from iron phosphate rich waste streams, such as sewage sludge, although systematic studies on mechanisms and efficiencies are missing. Batch experiments were conducted with different synthetic iron phosphates (purchased Fe(III)P, Fe(III)P synthesized in the lab and vivianite, Fe(II)3(PO4)2*8H2O), various sewage sludges (with different molar Fe:P ratios) and sewage sludge ash. When sulfide was added to synthetic iron phosphates (molar Fe:S = 1), phosphate release was completed within 1 h with a maximum release of 92% (vivianite), 60% (purchased Fe(III)P) and 76% (synthesized Fe(III)P). In the latter experiment, rebinding of phosphate to Fe(II) decreased net phosphate release to 56%. Prior to the re-precipitation, phosphate release was very efficient (P released/S input) because it was driven by Fe(III) reduction and not by, more sulfide demanding, FeSx formation. This was confirmed in low dose sulfide experiments without significant FeSx formation. Phosphate release from vivianite was very efficient because sulfide reacts directly (1:1) with Fe(II) to form FeSx, without Fe(III) reduction. At the same time vivianite-Fe(II) is as efficient as Fe(III) in binding phosphate. From digested sewage sludge, sulfide dissolved maximally 30% of all phosphate, from the sludge with the highest iron content which was not as high as suggested in earlier studies. Sludge dewaterability (capillary suction test, 0.13 ± 0.015 g2(s2m4)−1) dropped significantly after sulfide addition (0.06 ± 0.004 g2(s2m4)−1). Insignificant net phosphate release (1.5%) was observed from sewage sludge ash. Overall, sulfide can be a useful tool to release and recover phosphate bound to iron from sewage sludge. Drawbacks -deterioration of the dewaterability and a net phosphate release that is lower than expected-need to be investigated.</p
- …
