The first Dutch SDHB founder deletion in paraganglioma – pheochromocytoma patients

Contains fulltext : 81280.pdf (publisher's version ) (Open Access)BACKGROUND: Germline mutations of the tumor suppressor genes SDHB, SDHC and SDHD play a major role in hereditary paraganglioma and pheochromocytoma. These three genes encode subunits of succinate dehydrogenase (SDH), the mitochondrial tricarboxylic acid cycle enzyme and complex II component of the electron transport chain. The majority of variants of the SDH genes are missense and nonsense mutations. To date few large deletions of the SDH genes have been described. METHODS: We carried out gene deletion scanning using MLPA in 126 patients negative for point mutations in the SDH genes. We then proceeded to the molecular characterization of deletions, mapping breakpoints in each patient and used haplotype analysis to determine whether the deletions are due to a mutation hotspot or if a common haplotype indicated a single founder mutation. RESULTS: A novel deletion of exon 3 of the SDHB gene was identified in nine apparently unrelated Dutch patients. An identical 7905 bp deletion, c.201-4429_287-933del, was found in all patients, resulting in a frameshift and a predicted truncated protein, p.Cys68HisfsX21. Haplotype analysis demonstrated a common haplotype at the SDHB locus. Index patients presented with pheochromocytoma, extra-adrenal PGL and HN-PGL. A lack of family history was seen in seven of the nine cases. CONCLUSION: The identical exon 3 deletions and common haplotype in nine patients indicates that this mutation is the first Dutch SDHB founder mutation. The predominantly non-familial presentation of these patients strongly suggests reduced penetrance. In this small series HN-PGL occurs as frequently as pheochromocytoma and extra-adrenal PGL

The effects of high frequency subthalamic stimulation on balance performance and fear of falling in patients with Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>Balance impairment is one of the most distressing symptoms in Parkinson's disease (PD) even with pharmacological treatment (levodopa). A complementary treatment is high frequency stimulation in the subthalamic nucleus (STN). Whether STN stimulation improves postural control is under debate. The aim of this study was to explore the effects of STN stimulation alone on balance performance as assessed with clinical performance tests, subjective ratings of fear of falling and posturography.</p> <p>Methods</p> <p>Ten patients (median age 66, range 59–69 years) with bilateral STN stimulation for a minimum of one year, had their anti-PD medications withdrawn overnight. Assessments were done both with the STN stimulation turned OFF and ON (start randomized). In both test conditions, the following were assessed: motor symptoms (descriptive purposes), clinical performance tests, fear of falling ratings, and posturography with and without vibratory proprioceptive disturbance.</p> <p>Results</p> <p>STN stimulation alone significantly (p = 0.002) increased the scores of the Berg balance scale, and the median increase was 6 points. The results of all timed performance tests, except for sharpened Romberg, were significantly (p ≤ 0.016) improved. The patients rated their fear of falling as less severe, and the total score of the Falls-Efficacy Scale(S) increased (p = 0.002) in median with 54 points. All patients completed posturography when the STN stimulation was turned ON, but three patients were unable to do so when it was turned OFF. The seven patients with complete data showed no statistical significant difference (p values ≥ 0.109) in torque variance values when comparing the two test situations. This applied both during quiet stance and during the periods with vibratory stimulation, and it was irrespective of visual input and sway direction.</p> <p>Conclusion</p> <p>In this sample, STN stimulation alone significantly improved the results of the clinical performance tests that mimic activities in daily living. This improvement was further supported by the patients' ratings of fear of falling, which were less severe with the STN stimulation turned ON. Posturography could not be performed by three out of the ten patients when the stimulation was turned OFF. The posturography results of the seven patients with complete data showed no significant differences due to STN stimulation.</p

ICGA Journal 24(2): special issue on Ken Thompson

This special issue of the ICGA_J focuses on Ken Thompson on the occasion of his retirement from Bell Labs in December 2000. The contents touch on Unix and cover ken's contribution to computer games, computer chess and 'ICCA', the International Computer Chess Association

An improved model to study tumor cell autonomous metastasis programs using MTLn3 cells and the Rag2−/− γc−/− mouse

The occurrence of metastases is a critical determinant of the prognosis for breast cancer patients. Effective treatment of breast cancer metastases is hampered by a poor understanding of the mechanisms involved in the formation of these secondary tumor deposits. To study the processes of metastasis, valid in vivo tumor metastasis models are required. Here, we show that increased expression of the EGF receptor in the MTLn3 rat mammary tumor cell-line is essential for efficient lung metastasis formation in the Rag mouse model. EGFR expression resulted in delayed orthotopic tumor growth but at the same time strongly enhanced intravasation and lung metastasis. Previously, we demonstrated the critical role of NK cells in a lung metastasis model using MTLn3 cells in syngenic F344 rats. However, this model is incompatible with human EGFR. Using the highly metastatic EGFR-overexpressing MTLn3 cell-line, we report that only Rag2−/−γc−/− mice, which lack NK cells, allow efficient lung metastasis from primary tumors in the mammary gland. In contrast, in nude and SCID mice, the remaining innate immune cells reduce MTLn3 lung metastasis formation. Furthermore, we confirm this finding with the orthotopic transplantation of the 4T1 mouse mammary tumor cell-line. Thus, we have established an improved in vivo model using a Rag2−/− γc−/− mouse strain together with MTLn3 cells that have increased levels of the EGF receptor, which enables us to study EGFR-dependent tumor cell autonomous mechanisms underlying lung metastasis formation. This improved model can be used for drug target validation and development of new therapeutic strategies against breast cancer metastasis formation

A Mass-Selective Neutral Particle Energy Analyzer with Background Rejection

A mass-discriminating neutral particle spectrometer has been developed for the Rutherford scattering diagnostic at the TEXTOR tokamak. The analyzer is equipped with a momentum preselector and a triple-coincidence time-of-flight detection system providing a rejection capability for background events. Entering neutral particles are stripped by means of a thin carbon foil. Electrons emitted from a second carbon foil are used to give the time-zero signal. Calibration has been performed for hydrogen and helium particles in the energy range from 10 to 90 keV. The energy loss inside the carbon foils, the absolute efficiency, and the resolution of the analyzer have been investigated. The momentum preselector has a bandwidth of +/- 12.5% with respect to its adjustable central momentum. For both hydrogen and helium, the energy resolution is 2.5% for energies above 30 keV. Calculations show that the analyzer can still operate in the highly radiative environments of nuclear fusion devices

Continuous localization of cardiac activation sites using a database of multichannel ECG recordings

Monomorphic ventricular tachycardia and ventricular extrasystoles have a specific exit site that can be localized using the multichannel surface electrocardiogram (ECG) and a database of paced ECG recordings. An algorithm is presented that improves on previous methods by providing a continuous estimate of the coordinates of the exit site instead of selecting one out of 25 predetermined segments. The accuracy improvement is greatest, and most useful, when adjacent pacing sites in individual patients are localized relative to each other. Important advantages of the new method are the objectivity and reproducibility of the localization result