20 research outputs found
Clinical predictors for germline mutations in Head and neck paraganglioma patients: cost reduction strategy in Genetic diagnostic process as fail-out
No full textGrant 107995 (H.P.H. Neumann), the Deutsche Forschungsgemeinschaft (NE 571/5-3; H.P.H. Neumann), and the European Union (LSHC-CT-2005-518200; H.P.H. Neumann). C. Eng is the recipient of a Doris Duke Distinguished Clinical Scientist Award, and is the Sondra J. and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic. C. Suarez is supported by a grant from the Fondo de Investigaciones Sanitarias (FIS; PI052071) and Red Tematica de Investigacio ́n Cooperativa en Ca ́ncer (RD06/0020/0034). M. Robledo is supported by a grant from FIS (PI042154) and Centro de Investigacio ́n Biome ́dica En Red de Enfermedades Raras.Neumann, H.P.H., Erlic, Z., Boedeker, C.C., Rybicki, L.A., Robledo, M., Hermsen, M., Schiavi, F., Falcioni, M., Kwok, P., Bauters, C., Lampe, K., Fischer, M., Edelman, E., Benn, D.E., Robinson, B.G., Wiegand, S., Rasp, G., Stuck, B.A., Hoffmann, M.M., Sullivan, M., Sevilla, M.A., Weiss, M.M., Peczkowska, M., Kubaszek, A., Pigny, P., Ward, R.L., Learoyd, D., Croxson, M., Zabolotny, D., Yaremchuk, S., Dra, W., Muresan, M., Lorenz, R.R., Knipping, S., Strohm, M., Dyckhoff, G., Matthias, C., Reisch, N., Preuss, S.F., Eßer, D., Walter, M.A., Kaftan, H., Stöver, T., Fottner, C., Gorgulla, H., Malekpour, M., Zarandy, M.M., Schipper, J., Brase, C., Glien, A., Kühnemund, M., Koseielny, S., Schwerdtfeger, P., Välimäki, M., Szyfter, W., Finckh, U., Zerres, K., Cascon, A., Opocher, G., Ridder, G.J., Januszewicz, A., Suarez, C., Eng, C
Carotid body paragangliomas: a systematic study on management with surgery and radiotherapy
No full textGrant support: Carlos Suarez is supported by grants from the FIS (PI08/0531 and PI11/00929)and Red Tematica de Investigacion Cooperativa en Cancer (RD12/0036/0015).Suarez, C., Rodrigo, J.P., Mendenhall, W.M., Hamoir, M., Silver, C.E., Gregoire, V., Strojan, P., Neumann, H.P.H., Obholzer, R., Offergeld, C., Langendijk, J.A., Rinaldo, A., Ferlito, A
Ikat from Timor and its outer islands: insular and interwoven
No full textThis dissertation investigates ikat from the eastern Indonesian islands from a uniquely technical perspective, including design analysis of asymmetry and microscopy. Paradoxically, this technical perspective highlights the human factor. We see 19th- and early 20th-century weavers’ decisions in close-up, as if sitting next to them. This yields rich insights in both materiality and creativity. It also allowed the differentiation of 21 weave types and their distribution across 41 regions in the Indonesian archipelago.Asymmetry is widely distributed, yet has largely been ignored. Ten Hoopen discriminates seven techniques to achieve asymmetry, including visual tricks and illusions. Sumbanese royal weavers made thrilling efforts to hide their virtuosity, using tiny visual devices, secret keys, to reveal that their creations were far more labour-intensive than apparent. Ironically, because they were such great masters at hiding their virtuosity, it remained overlooked by generations of scholars.In his final chapter the author analyses what may have spurred the weavers of the region to create their most time-consuming feats of artistry, and develops a view of these women as more inventive and intelligent than they have been credited with before – and more assertive, using ikat’s prestige to spin their men into a web of taboos and prescriptions.Archaeological heritage management, heritage of indigenous people and museum studie
SDHB variant type impacts phenotype and malignancy in pheochromocytoma-paraganglioma
No full textBackground Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHB variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHD variants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations for SDHD variants. In the present study we zoom in on the genotype-phenotype associations of SDHB gene variants, considering the impact of individual gene variants on disease risk and risk of malignancy. Methods We analysed two large independent data sets, including a total of 448 patients with PPGL and HNPGL, and studied the association of missense or truncating SDHB variants with tumour incidence, age of onset and malignancy risk using binomial testing and Kaplan-Meier analysis. Results Compared with missense variants, truncating SDHB variants were significantly and consistently more common in patients with PPGL, by a 20 percentage point margin. Malignancy was also significantly more common in truncating versus missense variant carriers. No overall differences in age of PPGL onset were noted between carriers of the two variant types, although some individual variants may differ in certain cases. Missense variants were marginally over-represented among patients with HNPGL, but the difference was not statistically significant. Conclusion SDHB truncating variants convey an elevated risk for development of both PPGL and malignancy compared with missense variants. These results further support earlier robust associations between truncating variants and PPGL, and also suggest that the two variant types differ in their impact on complex II function, with PPGL/HNPGL tissues displaying differing sensitivities to changes in complex II function.Genome Instability and Cance
Prognostic factors of functional outcome in acute ischemic stroke
No full textTrombolyse is een behandeling waarbij een stolsel in een bloedvat wordt opgelost door het gebruik van anti-bloedstollingsmiddelen. Irene Miedema deed onderzoek naar veiligheidsaspecten van trombolyse.
Door de ontwikkeling van trombolyse is de zorg aan patiënten met een acuut herseninfarct de afgelopen decennia sterk verbeterd. De behandeling is echter alleen voor een selecte groep beschikbaar en is niet zonder risico’s.
Miedema bestudeerde een groep van ruim 700 patiënten. Zij vond dat trombolyse na drie maanden geen verbeterde klinische uitkomst gaf, wanneer deze patiënten voor het herseninfarct een bepaald soort antidepressivum (SSRI), een cholesterolverlagend middel (statine) of urinezuur gebruikten. De promovenda constateert dat dat ook het geval was wanneer de bloedsuikerspiegel bij aanvang van de behandeling te hoog was. Tot slot ontdekte ze dat behandeling met een vitamine K antagonist (een anti-bloedstollingsmiddel) bij patiënten met een normale of licht verhoogde bloedstollingswaarde leidde tot een verhoogd risico op het ontwikkelen van een hersenbloeding.
Omdat trombolyse nog steeds de eerste keus behandeling is, is het voor de veiligheid van patiënten extra van belang dat artsen daarvoor de juiste patiënten selecteren. Deze uitkomsten kunnen daarbij helpen.
In the last decades, the development of revascularisation therapy with intravenous recombinant tissue plasminogen antigen (tPA) has greatly improved the outcome of acute ischemic stroke patients, but this therapy is only available for a selected group of patients and has safety concerns. In this thesis several possible neuroprotective agents in acute ischemic stroke and some safety aspects of tPA-treatment are discussed. In a cohort of patients with acute ischemic stroke treated with intravenous tPA no improvement of functional outcome at 3 months after the event was found in patients using selective serotonin re-uptake inhibitor (SSRI) or statin. Serum uric acid levels were also unrelated to improvement outcomes in patients with acute ischemic stroke. Concerning safety, for all stroke subtypes, hyperglycemia during admission was associated with a poor functional outcome in patients treated with tPA. Using vitamin-K-antagonist in patients with normal or slightly elevated International Normalized Ratio (INR) who are treated with tPA, is associated with the risk of symptomatic intracranial hemorrhage (SICH), but not with the actual functional outcome at 3 months after ischemic stroke. In conclusion, the studies in this thesis do not support a neuroprotective effect of SSRIs, statins and serum uric acid levels in patients with acute ischemic stroke. Treatment with tPA is still the most effective therapy for acute ischemic stroke and selection of patients to reduce treatment risks is important. Use of vitamin-K-antagonist with elevated INR and admission hyperglycemia are associated with the occurrence of SICH and poor functional outcome respectively.
Caractérisation qualitative de pesticides et produits de transformations ultra-polaires dans les eaux potables par échantillonnage passif couplé à la HRMS
No full textInternational audienceLes pesticides font partie intégrante de l'agriculture intensive et servent à garantir des rendements de production élevés en combattant divers ravageurs tels que des insectes, des champignons ou des adventices indésirables. Toutefois, en raison de leur usage intensif et de leurs caractéristiques physico-chimiques, une partie de ces molécules se retrouve dans les sols et les eaux de ruissellement, avant de rejoindre les écosystèmes aquatiques, qui sont les réceptacles ultimes des contaminants organiques anthropiques. Au cours du transport, les substances actives peuvent être progressivement dégradées en produits de transformation et ces derniers peuvent parfois se révéler plus toxiques et plus mobiles que les molécules mères. Malgré des concentrations environnementales faibles allant de la trace (μg/L) à l'ultra-trace (ng/L), ils sont souvent présents dans les eaux de surface ou les eaux souterraines. Or ces eaux sont potabilisées pour la consommation humaine, et la présence de substances actives ou de produits de transformation à des taux supérieurs aux normes en vigueur [1] est actuellement un des principaux facteurs de non-conformité. Parmi ces contaminants, les PMOCs (Composés Organiques Persistants et Mobiles) se distinguent par leur caractère hydrophile et polaire (logP 2500 substances contenues dans les bases de données utilisées (PesticideScreener 2.1 & ToxScreener 2.1). Avec 11 à 36 molécules selon les échantillons, les fréquences de détections sont généralement plus importantes dans les eaux brutes en lien avec les usages anthropiques. Il est également possible de mettre en évidence que les traitements multi-barrières sont à priori plus efficaces à réduire les contaminations dissoutes que les simples chlorations, et que et l’on observe généralement moins de substances actives à l’issue de la potabilisation.Mots-clés : molécules ultrapolaires, HILIC, échantillonneurs passifs, suspect screening, eaux potables[1]Directive(UE) 2020/2184 du parlement Européen et du conseil du 16 décembre 2020 relative à la qualité des eaux destinées à la consommation humaine, n.d.[2]T. Reemtsma, U. Berger, H.P.H. Arp, H. Gallard, T.P. Knepper, M. Neumann, J.B. Quintana, P. de Voogt, Mind the Gap: Persistent and Mobile Organic Compounds—Water Contaminants That Slip Through, Environ Sci Technol 50 (2016) 10308–10315. https://doi.org/10.1021/acs.est.6b03338.[3]L. Pinasseau, L. Wiest, A. Fildier, L. Volatier, G.R. Fones, G.A. Mills, F. Mermillod-Blondin, E. Vulliet, Use of passive sampling and high resolution mass spectrometry using a suspect screening approach to characterise emerging pollutants in contaminated groundwater and runoff, Science of The Total Environment 672 (2019) 253–263. https://doi.org/10.1016/j.scitotenv.2019.03.489.[4]E.L. Schymanski, J. Jeon, R. Gulde, K. Fenner, M. Ruff, H.P. Singer, J. Hollender, Identifying Small Molecules via High Resolution Mass Spectrometry: Communicating Confidence, Environ Sci Technol 48 (2014) 2097–2098. https://doi.org/10.1021/es5002105
Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma-paraganglioma
No full textBackground Pathogenic germline variants in subunits of succinate dehydrogenase (SDHB, SDHC and SDHD) are broadly associated with disease subtypes of phaeochromocytoma-paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype.Methods Three independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk. All patients were carriers of pathogenic germline variants in the SDHB, SDHC or SDHD genes.Results Truncating SDH variants were significantly over-represented in clinical cases compared with missense variants, and carriers of SDHD truncating variants had a significantly higher risk for PPGL (p<0.001), an earlier age of diagnosis (p<0.0001) and a greater risk for PPGL/HNPGL comorbidity compared with carriers of missense variants. Carriers of SDHB truncating variants displayed a trend towards increased risk of PPGL, and all three SDH genes showed a trend towards over-representation of missense variants in HNPGL cases. Overall, variant types conferred PPGL risk in the (highest-to-lowest) sequence SDHB truncating, SDHB missense, SDHD truncating and SDHD missense, with the opposite pattern apparent for HNPGL (p<0.001).Conclusions SDHD truncating variants represent a distinct group, with a clinical phenotype reminiscent of but not identical to SDHB. We propose that surveillance and counselling of carriers of SDHD should be tailored by variant type. The clinical impact of truncating SDHx variants is distinct from missense variants and suggests that residual SDH protein subunit function determines risk and site of disease.Diabetes mellitus: pathophysiological changes and therap
The Kidney and Von Hippel-Lindau Disease: Impact of Molecular Genetic Analysis of the VHL Gene for Clinical Management
No full textSupplementary Material for: Co-Inheritance of Autosomal Dominant Polycystic Kidney Disease and Naevoid Basal Cell Carcinoma Syndrome: Effects on Renal Progression
No full textThe calcium signalling and hedgehog (HH) signalling pathways operate in the primary cilium. Abnormalities in these pathways cause autosomal dominant polycystic kidney disease (ADPKD) and naevoid basal cell carcinoma syndrome (NBCCS) respectively. Several reports have proposed that hyperactivation of the HH pathway in animal models of polycystic kidney disease affects normal renal development and renal cyst phenotype. A family with 2 cases (a proband and her sister) of ADPKD and NBCCS coinheritance led us to investigate whether interactions may be present in the 2 pathways. The effect of HH pathway hyperactivation (due to c.573C>G mutation on PTCH1 gene that cause NBCCS) on renal ADPKD progression in the proband was compared to 18 age- and sex-matched ADPKD patients in a 9-year, prospective, follow-up study. Blood pressure, total kidney volume, estimated glomerular filtration rate, plasma copeptin, urine excretion of albumin, total protein and monocyte chemoattractant protein-1 (MCP-1) were analysed. Data for the sibling was not available. In the ADPKD group, blood pressure and estimated glomerular filtration rate were within normal values, and total kidney volume and MCP-1 increased (p < 0.01) throughout the study. In comparison, during the 9-year follow-up, the proband showed persistent hypertension (from 125/85 to 140/95 mm Hg), low total kidney volume (75 and 61% of median ADPKD), and a ninefold increase in urine MCP-1. We found no differences in urine excretion of albumin or plasma copeptin values. These results suggest that HH hyperactivation may play a minimal role in ADPKD progression. These observations can help to clarify the clinical impact of affected pathways in renal development and cystogenesis in humans
Maternal and fetal outcomes in phaeochromocytoma and pregnancy:a multicentre retrospective cohort study and systematic review of literature
No full textBackground: Phaeochromocytoma or paraganglioma (collectively known as PPGL) in pregnant women can lead to severe complications and death due to associated catecholamine excess. We aimed to identify factors associated with maternal and fetal outcomes in women with PPGL during pregnancy. Methods: We did a multicentre, retrospective study of patients with PPGL and pregnancy between Jan 1, 1980, and Dec 31, 2019, in the International Pheochromocytoma and Pregnancy Registry and a systematic review of studies published between Jan 1, 2005, and Dec 27, 2019 reporting on at least five cases. The inclusion criteria were pregnancy after 1980 and PPGL before or during pregnancy or within 12 months post partum. Eligible patients from the retrospective study and systematic review were included in the analysis. Outcomes of interest were maternal or fetal death and maternal severe cardiovascular complications of catecholamine excess. Potential variables associated with these outcomes were evaluated by logistic regression. Findings: The systematic review identified seven studies (reporting on 63 pregnancies in 55 patients) that met the eligibility criteria and were of adequate quality. A further 197 pregnancies in 186 patients were identified in the International Pheochromocytoma and Pregnancy Registry. After excluding 11 pregnancies due to potential overlap, the final cohort included 249 pregnancies in 232 patients with PPGL. The diagnosis of PPGL was made before pregnancy in 37 (15%) pregnancies, during pregnancy in 134 (54%), and after delivery in 78 (31%). Of 144 patients evaluated for genetic predisposition for phaeochromocytoma, 95 (66%) were positive. Unrecognised PPGL during pregnancy (odds ratio 27·0; 95% CI 3·5–3473·1), abdominal or pelvic tumour location (11·3; 1·5–1440·5), and catecholamine excess at least ten-times the upper limit of the normal range (4·7; 1·8–13·8) were associated with adverse outcomes. For patients diagnosed during pregnancy, α-adrenergic blockade therapy was associated with fewer adverse outcomes (3·6; 1·1–13·2 for no α-adrenergic blockade vs α-adrenergic blockade), whereas surgery during pregnancy was not associated with better outcomes (0·9; 0·3–3·9 for no surgery vs surgery). Interpretation: Unrecognised and untreated PPGL was associated with a substantially higher risk of either maternal or fetal complications. Appropriate case detection and counselling for premenopausal women at risk for PPGL could prevent adverse pregnancy-related outcomes. Funding: US National Institutes of Health.</p
