Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma

The last 10 years have seen enormous progress in the field of paraganglioma and pheochromocytoma genetics. The identification of the first gene related to paraganglioma, SDHD, encoding a subunit of mitochondrial succinate dehydrogenase (SDH), was quickly followed by the identification of mutations in SDHC and SDHB. Very recently several new SDH-related genes have been discovered. The SDHAF2 gene encodes an SDH co-factor related to the function of the SDHA subunit, and is currently exclusively associated with head and neck paragangliomas. SDHA itself has now also been identified as a paraganglioma gene, with the recent identification of the first mutation in a patient with extra-adrenal paraganglioma. Another SDH-related co-factor, SDHAF1, is not currently known to be a tumor suppressor, but may shed some light on the mechanisms of tumorigenesis. An entirely novel gene associated with adrenal pheochromocytoma, TMEM127, suggests that other new paraganglioma susceptibility genes may await discovery. In addition to these recent discoveries, new techniques related to mutation analysis, including genetic analysis algorithms, SDHB immunohistochemistry, and deletion analysis by MLPA have improved the efficiency and accuracy of genetic analysis. However, many intriguing questions remain, such as the striking differences in the clinical phenotype of genes that encode proteins with an apparently very close functional relationship, and the lack of expression of SDHD and SDHAF2 mutations when inherited via the maternal line. Little is still known of the origins and causes of truly sporadic tumors, and the role of oxygen in the relationships between high-altitude, familial and truly sporadic paragangliomas remains to be elucidated

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Guidance document on leptospirosis in relation to swimming in surface waters

Leptospirose is een verzamelnaam voor verschillende ziekten die worden veroorzaakt door Leptospira-bacteriën, zoals modderkoorts of de ziekte van Weil. Deze bacteriën kunnen met de urine van de bruine rat in het oppervlaktewater terechtkomen. Mensen kunnen hier ziek van worden door bijvoorbeeld in of rond oppervlaktewater te recreëren. In Nederland komt het erg weinig voor dat mensen leptospirose krijgen door te zwemmen in oppervlaktewater. Áls het gebeurt, is het niet altijd duidelijk wie waarvoor verantwoordelijk is en actie moet ondernemen. Ook hebben de betrokken overheden vaak vragen over te nemen maatregelen en de wetten en regels. Daarom heeft het RIVM met betrokken partijen een handreiking gemaakt die informatie geeft over leptospirose, wetgeving en welke acties en maatregelen mogelijk zijn. Het is niet bekend van welke hoeveelheid Leptospira-bacteriën in zwemwater mensen ziek kunnen worden. De handreiking beschrijft daarom drie scenario’s om maatregelen te nemen na (mogelijke) besmettingen: als het gerucht gaat dat er iemand op een zwemlocatie is besmet, als er één persoon is besmet, en als er meerdere personen zijn besmet. Zwemwaterbeheerders kunnen uitzoeken of op een zwemlocatie risico’s door ratten te verwachten zijn. Zij kunnen hiervoor, naast het verplichte zwemwaterprofiel, een zogeheten plaagdier risico-inventarisatie laten opstellen. Zo kunnen ze te weten komen of maatregelen nodig zijn. Er zijn twee soorten maatregelen mogelijk om besmettingen op een zwemlocatie te voorkomen: ratten bestrijden en zwemmers informeren. Goede informatie voor de zwemmers kan ervoor zorgen dat er geen besmettingen optreden. Zwemmers moeten op hun gedrag worden gewezen. Ze moeten bijvoorbeeld geen afval achterlaten op een zwemlocatie, want dat trekt ratten aan. En als ze een wondje hebben, kunnen ze beter niet in het water gaan. Ze kunnen namelijk besmet raken doordat hun slijmvliezen of wondjes in de huid in contact komen met oppervlaktewater waarin Leptospira-bacteriën zitten.Leptospirosis is an umbrella term for a variety of conditions caused by Leptospira bacteria, such as fever and Weil's disease. These bacteria can end up in surface water with the urine of brown rats. People can contract the disease during recreational activities in or around surface water. In the Netherlands, very few people get leptospirosis from swimming in surface water. If this does happen, it is not always clear who is responsible and who should take action. In addition, the authorities involved are often uncertain about what the rules are and what measures to take. This is why RIVM and a number of parties involved have drawn up a guidance document with information about leptospirosis, the relevant laws and regulations and possible measures. It is not known how much Leptospira bacteria in bathing water can make people ill. For that reason, the guidance document describes three scenarios for measures following a (possible) infection: when a person is thought to have been infected at a particular bathing site, when one person has been infected and when several persons have been infected. Bathing water managers can then find out whether a particular bathing site poses a risk of infection by rats. They can commission a pest risk inventory for that site, in addition to the obligatory bathing water profile. This will tell them whether any measures are required. Infections at bathing sites can be prevented in two ways: by controlling rat populations and by informing swimmers. Good information for swimmers can help to prevent infections. Swimmers need to be made aware of their own behaviour. For example, they should not leave any litter at bathing sites, to avoid attracting rats. And even with a small wound it is better not to go into the water. Swimmers can get infected when mucous membranes or small cuts in the skin come into contact with surface water that contains Leptospira bacteria

Validity, reliability and discriminative capacity of an electronic quality of life instrument (Pelican) for childhood asthma in the Netherlands

Item does not contain fulltextPURPOSE: To assess psychometric properties of the Pelican instrument, an online Dutch self-administered Quality of Life instrument for childhood asthma for scientific and clinical use. METHODS: A cohort study was done in two asthma populations and healthy children. One asthma population had assessment at start, 4 and 8 weeks. The other asthma population and healthy children had one assessment. All children were aged 6-12 years. Children completed the Pelican instrument, Paediatric Asthma Quality of Life Questionnaire, feeling thermometer and Childhood Asthma Control Test. Lung function and fraction exhaled nitric oxide were measured. Parents completed Functional Status II, Asthma Control Questionnaire, Childhood Asthma Control Test questionnaires and symptom diaries. We assessed interpretability, structural validity, internal consistency, reliability, construct and discriminative validity of the Pelican instrument. RESULTS: Eighty-five asthmatic (mean age 8.5 years) and 49 healthy children (mean age 8.4 years) participated. The Pelican instrument has 5 domains with 21 items after factor analysis. Internal consistency was 0.89 (CI 0.85-0.92), domain reliability showed Cronbach's alpha's from 0.64 to 0.76 and item-to-scale correlations from 0.61 to 0.81. Test-retest reliability was confirmed ICC = 0.88 (CI 0.79-0.93). Construct validity was demonstrated by significant moderate correlations with other relevant asthma outcomes like PAQLQ (r = -0.59, p < 0.01). Discriminative capacity between controlled or uncontrolled asthma (t = 3.20, p < 0.01, Delta = 0.64) and asthma versus healthy subjects (t = 6.31, p < 0.01, Delta = 0.94) was found. CONCLUSIONS: The psychometric properties of the Pelican instrument were acceptable in Dutch paediatric asthma patients between 6 and 12 years old

The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family

Germline mutations in SDHD predispose to the development of head and neck paragangliomas, and phaeochromocytomas. The risk of developing a tumor depends on the sex of the parent who transmits the mutation: paragangliomas only arise upon paternal transmission. In this study, both the risk of paraganglioma and phaeochromocytoma formation, and the risk of developing associated symptoms were investigated in 243 family members with the SDHD.D92Y founder mutation. By using the Kaplan–Meier method, age-specific penetrance was calculated separately for paraganglioma formation as defined by magnetic resonance imaging (MRI) and for paraganglioma-related signs and symptoms. Evaluating clinical signs and symptoms alone, the penetrance reached a maximum of 57% by the age of 47 years. When MRI detection of occult paragangliomas was included, penetrance was estimated to be 54% by the age of 40 years, 68% by the age of 60 years and 87% by the age of 70 years. Multiple tumors were found in 65% and phaeochromocytomas were diagnosed in 8% of paraganglioma patients. Malignant paraganglioma was diagnosed in one patient (3%). Although the majority of carriers of a paternally inherited SDHD mutation will eventually develop head and neck paragangliomas, we find a lower penetrance than previous estimates from studies based on predominantly index cases. The family-based study described here emphasizes the importance of the identification and inclusion of clinically unaffected mutation carriers in all estimates of penetrance. This finding will allow a more accurate genetic counseling and warrants a ‘wait and scan' policy for asymptomatic paragangliomas, combined with biochemical screening for catecholamine excess in SDHD-linked patients