Hereditary paragangliomas : clinical studies

In this thesis we describe the genetic, biochemical and clinical characteristics of patients with head and neck paragangliomas (HNPGL). In the Netherlands, the majority of SDHx mutation carriers, harbor a mutation in the SDHD gene. Twenty-nine percent of patients with HNPGL have increased urinary excretion of 3-methoxytyramine, indicating dopaminergic activity. Test sensitivity of plasma 3MT measurement equals the measurement of urinary deconjugated 3MT excretion. Only a minority of HNPGL patients have increased plasma chromogranin A levels. Therefore, the practical implications of the measurement of plasma chromogranin A levels are limited in HNPGL patients. Patients screened for pheochromocytomas, because of a hereditary predisposition, present with less signs and symptoms, lower urinary excretion rates of catecholamines, and smaller tumors than patients presenting with symptomatic pheochromocytomas. Despite these differences in biochemical activity and the sizes of the tumors, there is no difference in patients regarding peri-operative complications. Patients with bilateral carotid body tumors are at risk for developing sleep disordered breathing. Sleep disordered breathing is associated with increased carotid body output, which is reflected by increased chemosensitivity.UBL - phd migration 201

Study protocol: effect of infection, Modic and inflammation on clinical outcomes in surgery for radiculopathy (EIMICOR)

Background: Evidence indicates that inflammatory processes are involved in radicular pain as well as in resorption of herniated disc tissue. Furthermore there are indications that the presence of vertebral end plate pathology (Modic changes; MC) is associated with a negative effect on inflammation. It is hypothesized that in patients with MC, the (possibly bacterial induced) inflammation will be accompanied by pro inflammatory cytokines that worsen the outcome, and that in patients without MC, the inflammation is accompanied by cytokines that induce a resorption process to accelerate recovery.Methods: This prospective cohort study will include 160 lumbar and 160 cervical patients (total of 320), which are scheduled for surgery for either a lumbar or cervical herniated disc with ages between 18 and 75. The main and interaction effects of local bacterial infection (culture), inflammatory cells in disc material (immunohistology), MC (MRI), and blood biomarkers indicating inflammation or infection (blood sample evaluation) will be evaluated. Clinical parameters to be evaluated are leg pain on the 11 point NRS pain scale, Oswestry (lumbar spine) or Neck (cervical spine) Disability Index, Global Perceived Recovery, Womac Questionnaire, and medication status, at baseline, and after 6, 16, 26 and 52 weeks.Discussion: Gaining insight in the aetiology of pain and discomfort in radiculopathy caused by a herniated disc could lead to more effective management of patients. If the type of inflammatory cells shows to be of major influence on the rate of recovery, new immunomodulating treatment strategies can be developed to decrease the duration and intensity of symptoms. Moreover, identifying a beneficial inflammatory response in the disc through a biomarker in blood could lead to early identification of patients whose herniations will resorb spontaneously versus those that require surgery.OV

Longitudinal assessment of Alzheimer's beta-amyloid plaquedevelopment in transgenic mice monitored by in vivo magnetic resonance microimaging

Solid state NMR/Biophysical Organic Chemistr

The XMM-Newton serendipitous ultraviolet source survey catalogue

The XMM-Newton Serendipitous Ultraviolet Source Survey (XMM-SUSS) is a catalogue of ultraviolet (UV) sources detected serendipitously by the Optical Monitor (XMM-OM) on-board the XMM-Newton observatory. The catalogue contains ultraviolet-detected sources collected from 2,417 XMM-OM observations in 1-6 broad band UV and optical filters, made between 24 February 2000 and 29 March 2007. The primary contents of the catalogue are source positions, magnitudes and fluxes in 1 to 6 passbands, and these are accompanied by profile diagnostics and variability statistics. The XMM-SUSS is populated by 753,578 UV source detections above a 3 sigma signal-to-noise threshold limit which relate to 624,049 unique objects. Taking account of substantial overlaps between observations, the net sky area covered is 29-54 square degrees, depending on UV filter. The magnitude distributions peak at 20.2, 20.9 and 21.2 in UVW2, UVM2 and UVW1 respectively. More than 10 per cent of sources have been visited more than once using the same filter during XMM-Newton operation, and > 20 per cent of sources are observed more than once per filter during an individual visit. Consequently, the scope for science based on temporal source variability on timescales of hours to years is broad. By comparison with other astrophysical catalogues we test the accuracy of the source measurements and define the nature of the serendipitous UV XMM-OM source sample. The distributions of source colours in the UV and optical filters are shown together with the expected loci of stars and galaxies, and indicate that sources which are detected in multiple UV bands are predominantly star-forming galaxies and stars of type G or earlier.Comment: Accepted for publication in MNRA

Bi-allelic <i>NIT1 </i>variants cause a brain small vessel disease characterized by movement disorders, massively dilated perivascular spaces, and intracerebral hemorrhage

Purpose: To describe a recessively inherited cerebral small vessel disease, caused by loss-of-function variants in Nitrilase1 (NIT1). Methods:We performed exome sequencing, brain magnetic resonance imaging, neuropathology, electron microscopy, western blotting, and transcriptomic and metabolic analyses in 7 NIT1-small vessel disease patients from 5 unrelated pedigrees. Results: The first identified patients were 3 siblings, compound heterozygous for the NIT1 c.727C&gt;T; (p.Arg243Trp) variant and the NIT1 c.198_199del; p.(Ala68∗) variant. The 4 additional patients were single cases from 4 unrelated pedigrees and were all homozygous for the NIT1 c.727C&gt;T; p.(Arg243Trp) variant. Patients presented in mid-adulthood with movement disorders. All patients had striking abnormalities on brain magnetic resonance imaging, with numerous and massively dilated basal ganglia perivascular spaces. Three patients had non-lobar intracerebral hemorrhage between age 45 and 60, which was fatal in 2 cases. Western blotting on patient fibroblasts showed absence of NIT1 protein, and metabolic analysis in urine confirmed loss of NIT1 enzymatic function. Brain autopsy revealed large electron-dense deposits in the vessel walls of small and medium sized cerebral arteries. Conclusion: NIT1-small vessel disease is a novel, autosomal recessively inherited cerebral small vessel disease characterized by a triad of movement disorders, massively dilated basal ganglia perivascular spaces, and intracerebral hemorrhage.</p

UV and EUV Instruments

We describe telescopes and instruments that were developed and used for astronomical research in the ultraviolet (UV) and extreme ultraviolet (EUV) regions of the electromagnetic spectrum. The wavelength ranges covered by these bands are not uniquely defined. We use the following convention here: The EUV and UV span the regions ~100-912 and 912-3000 Angstroem respectively. The limitation between both ranges is a natural choice, because the hydrogen Lyman absorption edge is located at 912 Angstroem. At smaller wavelengths, astronomical sources are strongly absorbed by the interstellar medium. It also marks a technical limit, because telescopes and instruments are of different design. In the EUV range, the technology is strongly related to that utilized in X-ray astronomy, while in the UV range the instruments in many cases have their roots in optical astronomy. We will, therefore, describe the UV and EUV instruments in appropriate conciseness and refer to the respective chapters of this volume for more technical details.Comment: To appear in: Landolt-Boernstein, New Series VI/4A, Astronomy, Astrophysics, and Cosmology; Instruments and Methods, ed. J.E. Truemper, Springer-Verlag, Berlin, 201

Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy.

Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism

The Galaxy Evolution Explorer: A Space Ultraviolet Survey Mission

We give an overview of the Galaxy Evolution Explorer (GALEX), a NASA Explorer Mission launched on April 28, 2003. GALEX is performing the first space UV sky-survey, including imaging and grism surveys in two bands (1350-1750 Angstroms and 1750-2750 Angstroms). The surveys include an all-sky imaging survey (m[AB] ~ 20.5), a medium imaging survey of 1000 square degrees (m[AB] ~ 23), a deep imaging survey of 100 square degrees (m[AB] ~ 25), and a nearby galaxy survey. Spectroscopic grism surveys (R=100-200) are underway with various depths and sky coverage. Many targets overlap existing or planned surveys. We will use the measured UV properties of local galaxies, along with corollary observations, to calibrate the UV-global star formation rate relationship in local galaxies. We will apply this calibration to distant galaxies discovered in the deep imaging and spectroscopic surveys to map the history of star formation in the universe over the redshift range 0 < z < 1.5, and probe the physical drivers of star formation in galaxies. The GALEX mission includes a Guest Investigator program supporting the wide variety of programs made possible by the first UV sky survey.Comment: This paper will be published as part of the Galaxy Evolution Explorer (GALEX) Astrophysical Journal Letters Special Issue. Links to the full set of papers will be available at http:/www.galex.caltech.edu/PUBLICATIONS/ after November 22, 200

The VASCERN PPL working group patient pathway for primary and paediatric lymphoedema.

Lymphoedema is caused by an imbalance between fluid production and transport by the lymphatic system. This imbalance can be either caused by reduced transport capacity of the lymphatic system or too much fluid production and leads to swelling associated with tissue changes (skin thickening, fat deposition). Its main common complication is the increased risk of developing cellulitis/erysipelas in the affected area, which can worsen the lymphatic function and can be the cause of raised morbidity of the patient if not treated correctly/urgently. The term primary lymphoedema covers a group of rare conditions caused by abnormal functioning and/or development of the lymphatic system. It covers a highly heterogeneous group of conditions. An accurate diagnosis of primary lymphoedema is crucial for the implementation of an optimal treatment plan and management, as well as to reduce the risk of worsening. Patient care is diverse across Europe, and national specialised centres and networks are not available everywhere. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) gathers the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. There are six different working groups in VASCERN, which focus on arterial diseases, hereditary haemorrhagic telangiectasia, neurovascular diseases, lymphoedema and vascular anomalies. The working group Paediatric and Primary Lymphedema (PPL WG) gathers and shares knowledge and expertise in the diagnosis and management of adults and children with primary and paediatric lymphoedema. The members of PPL WG have worked together to produce this opinion statement reflecting strategies on how to approach patients with primary and paediatric lymphoedema. The objective of this patient pathway is to improve patient care by reducing the time to diagnosis, define the best management and follow-up strategies and avoid overuse of resources. Therefore, the patient pathway describes the clinical evaluation and investigations that lead to a clinical diagnosis, the genetic testing, differential diagnosis, the management and treatment options and the patient follow up at expert and local centres. Also, the importance of the patient group participation in the PPL WG is discussed