Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis.

Smac mimetic promotes apoptosis by neutralizing inhibitor of apoptosis (IAP) proteins and is considered as a promising cancer therapeutic. Although an autocrine/paracrine tumor necrosis factor-α (TNFα) loop has been implicated in Smac mimetic-induced cell death, little is yet known about additional factors that determine sensitivity to Smac mimetic. Using genome-wide gene expression analysis, we identify death receptor 5 (DR5) as a novel key mediator of Smac mimetic-induced apoptosis. Although several cell lines that are sensitive to the Smac mimetic BV6 die in a TNFα-dependent manner, A172 glioblastoma cells undergo BV6-induced apoptosis largely independently of TNFα/TNFR1, as the TNFα-blocking antibody Enbrel or TNFR1 knockdown provide little protection. Yet, BV6-stimulated nuclear factor-κB (NF-κB) activation is critically required for apoptosis, as inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor (IκBα-SR) blocks BV6-induced apoptosis. Unbiased genome-wide gene expression studies in IκBα-SR-overexpressing cells versus vector control cells reveal that BV6 increases DR5 expression in a NF-κB-dependent manner. Importantly, this BV6-stimulated upregulation of DR5 is critically required for apoptosis, as transient or stable knockdown of DR5 significantly inhibits BV6-triggered apoptosis. In addition, DR5 silencing attenuates formation of a RIP1/FADD/caspase-8 cytosolic cell death complex and activation of caspase-8, -3 and -9. By identifying DR5 as a critical mediator of Smac mimetic-induced apoptosis, our findings provide novel insights into the determinants that control susceptibility of cancer cells to Smac mimetic.

The influence of the type of filling gas on the response of ionisation chambers to a mixed high-energy radiation field.

Radiation protection dosimetry in radiation fields behind the shielding of high-energy accelerators such as CERN is a challenging task and the quantitative understanding of the detector response used for dosimetry is essential. Measurements with ionisation chambers are a standard method to determine absorbed dose (in the detector material). For applications in mixed radiation fields, ionisation chambers are often also calibrated in terms of ambient dose equivalent at conventional reference radiation fields. The response of a given ionisation chamber to the various particle types of a complex high-energy radiation field in terms of ambient dose equivalent depends of course on the materials used for the construction and the chamber gas used. This paper will present results of computational studies simulating the exposure of high-pressure ionisation chambers filled with different types of gases to the radiation field at CERN's CERN-EU high-energy reference field facility. At this facility complex high-energy radiation fields, similar to those produced by cosmic rays at flight altitudes, are produced. The particle fluence and spectra calculated with FLUKA Monte Carlo simulations have been benchmarked in several measurements. The results can be used to optimise the response of ionisation chambers for the measurement of ambient dose equivalent in high-energy mixed radiation fields.

Field calibration studies for ionisation chambers in mixed high-energy radiation fields.

The monitoring of ambient doses at work places around high-energy accelerators is a challenging task due the complexity of the mixed stray radiation fields encountered. At CERN, mainly Centronics IG5 high-pressure ionisation chambers are used to monitor radiation exposure in mixed fields. The monitors are calibrated in the operational quantity ambient dose equivalent H*(10) using standard, source-generated photon- and neutron fields. However, the relationship between ionisation chamber reading and ambient dose equivalent in a mixed high-energy radiation field can only be assessed if the spectral response to every component and the field composition is known. Therefore, comprehensive studies were performed at the CERN-EU high-energy reference field facility where the spectral fluence for each particle type has been assessed with Monte Carlo simulations. Moreover, studies have been performed in an accessible controlled radiation area in the vicinity of a beam loss point of CERN's proton synchrotron. The comparison of measurements and calculations has shown reasonable agreement for most exposure conditions. The results indicate that conventionally calibrated ionisation chambers can give satisfactory response in terms of ambient dose equivalent in stray radiation fields at high-energy accelerators in many cases. These studies are one step towards establishing a method of 'field calibration' of radiation protection instruments in which Monte Carlo simulations will be used to establish a correct correlation between the response of specific detectors to a given high-energy radiation field.

Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome.

Insulin resistance (IR) and central obesity are common features of the polycystic ovary syndrome (PCOS). Vitamin D is thought to play a role in the pathogenesis of type 2 diabetes by affecting insulin metabolism. The aim of our study was to investigate the effect of 25-hydroxyvitamin D (25-OH-VD) on metabolic parameters and IR in PCOS. In 120 untreated PCOS patients (median age 28 years) levels of 25-OH-VD (radioimmunoassay method provided by DiaSorin), calcium and anorganic phosphate were measured. In addition, endocrine and metabolic variables were evaluated and a glucose tolerance test was performed to assess indices of IR. In the entire PCOS cohort, 25-OH-VD concentrations were negatively correlated with body mass index (r=-0.2765), body fat (r=-0.2490), HOMA-IR (r=-0.1947), hyperinsulinemia (r=-0.1892) and leptin levels (r=-0.2834), and positively correlated with HDL cholesterol (r=0.2630) (all p<0.05). Subgroup analysis of lean, overweight and obese women revealed significant higher 25-OH-VD levels in lean women. Differences remained significant when women were divided according to their 25-OH-VD levels. Women with hypovitaminosis D (<9 ng/ml) had higher mean BMI, indices of IR and leptin levels compared to women with normal serum levels (all p<0.05). Analysis of vitamin D and biochemical endocrine PCOS features revealed a significant correlation only between 25-OH-VD and sex hormone-binding globulin as well as the free androgen index. In conclusion, in PCOS women, low 25-OH-VD levels are associated with obesity and insulin resistance but not with PCOS per se.

The combination of increased ovarian volume and follicle number is associated with more severe hyperandrogenism in German women with polycystic ovary syndrome.

The prevalence and relevance of polycystic ovaries (PCO) in German women with polycystic ovary syndrome has not been evaluated. This retrospective study included 212 PCOS patients (mean age 28 years) diagnosed by the NIH-criteria and consecutively recruited since 2003. Clinical features including anthropometric variables and the degree of hirsutism, family history, menstrual cyclicity as well as endocrine biochemical parameters were recorded. In addition, 3-h oral glucose tolerance testing for indices of insulin resistance and glucose metabolism was performed in each patient. Transvaginal ultrasound was used to detect polcystic ovaries, defined as the presence of at least one ovary > 10 ml or with at least 12 follicles of 2-9 mm diameter. In this German PCOS cohort, PCO were identified in 166 women (78%). Women with PCO (PXO+) had significantly higher LH/FSH ratios (median 2.1 vs. 1.7) and IGF-1 levels (median 182.5 vs. 160.5 ng/ml) compared to patients without PCO (PCO-). In addition, a significantly higher prevalence of acne (50% vs. 33%) and higher hirsutism scores (median 9 vs. 7) were found in PCO+ patients. Testosterone levels and the free androgen index (FAI) correlated significantly with ovarian volume and the number of ovarian follicles. Also, a subgroup of PCO+ women with a combination of increased ovarian volume and follicle number had higher testosterone levels (median 3.1 vs. 2.1 nmol/l) and FAI (median 7.6 vs. 4.5) compared to women with increased follicle count but normal volume. No differences were found in metabolic parameters or insulin resistance indices. PCO are common finding in German PCOS women. PCO appear to be associated with a more pronounced hyperandrogenemia, especially when both ovarian volume and follicle number are increased.

Remanent dose rates around the collimators of the LHC beam cleaning insertions.

The LHC will require an extremely powerful and unprecedented collimation system. As approximately 30% of the LHC beam is lost in the cleaning insertions, these will become some of the most radioactive locations around the entire LHC ring. Thus, remanent dose rates to be expected during later repair or maintenance interventions must be considered in the design phase itself. As a consequence, the beam cleaning insertions form a unique test bed for a recently developed approach to calculate remanent dose rates. A set of simulations, different in complexity, is used in order to evaluate methods for the estimation of remanent dose rates. The scope, as well as the restrictions, of the omega-factor method are shown and compared with the explicit simulation approach. The latter is then used to calculate remanent dose rates in the beam cleaning insertions. Furthermore, a detailed example for maintenance dose planning is given.

The FLUKA code: new developments and application to 1 GeV/n iron beams.

The modeling of ion transport and interactions in matter is a subject of growing interest, driven by the continuous increase of possible application fields. These include hadron therapy, dosimetry, and space missions, but there are also several issues involving fundamental research, accelerator physics, and cosmic ray physics, where a reliable description of heavy ion induced cascades is important. In the present work, the capabilities of the FLUKA code for ion beams will be briefly recalled and some recent developments presented. Applications of the code to the simulation of therapeutic carbon, nitrogen and oxygen ion beams, and of iron beams, which are of direct interest for space mission related experiments, will be also presented together with interesting consideration relative to the evaluation of dosimetric quantities. Both applications involve ion beams in the AGeV range.

Benchmark studies of induced radioactivity produced in LHC materials, Part I: Specific activities.

Samples of materials which will be used in the LHC machine for shielding and construction components were irradiated in the stray radiation field of the CERN-EU high-energy reference field facility. After irradiation, the specific activities induced in the various samples were analysed with a high-precision gamma spectrometer at various cooling times, allowing identification of isotopes with a wide range of half-lives. Furthermore, the irradiation experiment was simulated in detail with the FLUKA Monte Carlo code. A comparison of measured and calculated specific activities shows good agreement, supporting the use of FLUKA for estimating the level of induced activity in the LHC.

Benchmark studies of induced radioactivity produced in LHC materials, Part II: Remanent dose rates.

A new method to estimate remanent dose rates, to be used with the Monte Carlo code FLUKA, was benchmarked against measurements from an experiment that was performed at the CERN-EU high-energy reference field facility. An extensive collection of samples of different materials were placed downstream of, and laterally to, a copper target, intercepting a positively charged mixed hadron beam with a momentum of 120 GeV c(-1). Emphasis was put on the reduction of uncertainties by taking measures such as careful monitoring of the irradiation parameters, using different instruments to measure dose rates, adopting detailed elemental analyses of the irradiated materials and making detailed simulations of the irradiation experiment. The measured and calculated dose rates are in good agreement.

Characterisation of ionisation chambers for a mixed radiation field and investigation of their suitability as radiation monitors for the LHC.

Monitoring of the radiation environment is one of the key tasks in operating a high-energy accelerator such as the Large Hadron Collider (LHC). The radiation fields consist of neutrons, charged hadrons as well as photons and electrons with energy spectra extending from those of thermal neutrons up to several hundreds of GeV. The requirements for measuring the dose equivalent in such a field are different from standard uses and it is thus necessary to investigate the response of monitoring devices thoroughly before the implementation of a monitoring system can be conducted. For the LHC, it is currently foreseen to install argon- and hydrogen-filled high-pressure ionisation chambers as radiation monitors of mixed fields. So far their response to these fields was poorly understood and, therefore, further investigation was necessary to prove that they can serve their function well enough. In this study, ionisation chambers of type IG5 (Centronic Ltd) were characterised by simulating their response functions by means of detailed FLUKA calculations as well as by calibration measurements for photons and neutrons at fixed energies. The latter results were used to obtain a better understanding and validation of the FLUKA simulations. Tests were also conducted at the CERF facility at CERN in order to compare the results with simulations of the response in a mixed radiation field. It is demonstrated that these detectors can be characterised sufficiently enough to serve their function as radiation monitors for the LHC.

[Transumbilical laparoscopic-assisted "one-trocar" appendectomy -- TULAA -- as an alternative operation method in the treatment of appendicitis]. / Die transumbilikale laparoskopisch assistierte "one-trocar" Appendektomie -- TULAA -- als Alternative zu den bisher bekannten Operationsverfahren in der Behandlung der Appendizitis.

INTRODUCTION: Appendectomy is one of the most commonly performed surgical procedures in general surgery and laparoscopic appendectomy represents the beginning of minimal invasive era in visceral surgery. But until yet, laparoscopic appendectomy is not the standard method for removal of the appendix and the discussion about the value and the advantages of laparoscopic appendectomy is still going on between the opponents and advocates of this method. In this article we present the transumbilical laparoscopic assisted "one-trocar" appendectomy (TULAA) as an alternative procedure for appendectomy and our experiences with this technique, which is up to now not very well known in Germany. METHOD: From November 1, 2000 to December 31, 2002, we performed appendectomy in 350 patients. 163 patients (46.6 %) underwent TULAA in the technique of Begin. All of them were examined two weeks and three months after surgery. RESULTS: In 94.5 % the "one-trocar" appendectomy was successful and there were no intraoperative complications. The mortality was 0 %. Conversion to the open procedure was necessary in 3 patients (1.8 %), respectively introduction of accessory trocars was necessary in 6 patients (3.7 %). In 111 from 163 patients (68.1 %) appendectomy was performed because of acute appendicitis. In 14.1 % we detected additional secondary findings during the laparoscopy. The postoperative complication rate was 3.6 %. CONCLUSION: The transumbilical laparoscopic assisted "one-trocar" appendectomy complements the minimal invasive procedures in visceral surgery. The operating technique combines the simplicity and the safety of conventional appendectomy with the survey of laparoscopic appendectomy. It minimizes the trauma of surgery and shows a perfect cosmetic result.

Averaged particle dose conversion coefficients in air crew dosimetry.

The MCNPX Monte Carlo code was used to calculate energy-dependent fluence-to-effective dose conversion coefficients for neutrons, protons, electrons, photons, charged pions and muons. The FLUKA Monte Carlo code was used to calculate the spectral particle fluences of secondary cosmic rays for different altitudes, and for different combinations of solar modulation and vertical cut-off rigidity parameters. The energy-averaged fluence-to-dose conversion coefficients were obtained by folding the particle fluence spectra with the conversion coefficients for effective dose and ambient dose equivalent. They show a slight dependence on altitude, solar activity and location in the geomagnetic field.

The FLUKA code for space applications: recent developments.

The FLUKA Monte Carlo transport code is widely used for fundamental research, radioprotection and dosimetry, hybrid nuclear energy system and cosmic ray calculations. The validity of its physical models has been benchmarked against a variety of experimental data over a wide range of energies, ranging from accelerator data to cosmic ray showers in the earth atmosphere. The code is presently undergoing several developments in order to better fit the needs of space applications. The generation of particle spectra according to up-to-date cosmic ray data as well as the effect of the solar and geomagnetic modulation have been implemented and already successfully applied to a variety of problems. The implementation of suitable models for heavy ion nuclear interactions has reached an operational stage. At medium/high energy FLUKA is using the DPMJET model. The major task of incorporating heavy ion interactions from a few GeV/n down to the threshold for inelastic collisions is also progressing and promising results have been obtained using a modified version of the RQMD-2.4 code. This interim solution is now fully operational, while waiting for the development of new models based on the FLUKA hadron-nucleus interaction code, a newly developed QMD code, and the implementation of the Boltzmann master equation theory for low energy ion interactions.

Monte Carlo calculation of the radiation field at aircraft altitudes.

Energy spectra of secondary cosmic rays are calculated for aircraft altitudes and a discrete set of solar modulation parameters and rigidity cut-off values covering all possible conditions. The calculations are based on the Monte Carlo code FLUKA and on the most recent information on the interstellar cosmic ray flux including a detailed model of solar modulation. Results are compared to a large variety of experimental data obtained on the ground and aboard aircraft and balloons, such as neutron, proton, and muon spectra and yields of charged particles. Furthermore, particle fluence is converted into ambient dose equivalent and effective dose and the dependence of these quantities on height above sea level, solar modulation, and geographical location is studied. Finally, calculated dose equivalent is compared to results of comprehensive measurements performed aboard aircraft.

[Primary and secondary aortoiliac reconstructions in patients with coexistent horseshoe and pelvic kidney]. / Primäre und sekundäre aortoiliakale Rekonstruktionen bei Hufeisenniere und Beckenniere - Routine oder technische Herausforderung?

The coexistence of dystopic kidney and abdominal aortic aneurysm or aortoiliac occlusive arterial disease is uncommon (0.12-0.15 %) and constitutes a technical challenge to vascular surgeons. Between 1997 and 1999 we performed 249 aortoiliac reconstructions and encountered four patients (1.6 %) with dystopic kidneys. The aortoiliac reconstructions were performed successfully in all patients while maintaining renal blood supply. Aortoiliac reconstructions in patients with horseshoe or pelvic kidney show similar results as regular reconstructions on the condition that optimal preoperative diagnosis and operative technique are used considering atypical renal vessels. Nevertheless, pelvic kidneys can lead to serious complications as we describe in this report. On the basis of our patients anatomy, embryology and surgical management of this entity.

[Effect of preoperative preoperative visualization therapy on postoperative outcome after inguinal hernia surgery and thyroid resection]. / Einfluss einer präoperativen Visualisierungstherapie auf die postoperativen Ergebnisse nach Leistenherniotomie und Strumaresektion.

UNLABELLED: This randomized controlled trial aims to evaluate the influence of preoperative relaxation techniques on postoperative outcomes. From January 1997 to June 1998 208 patients were operated on for primary inguinal hernia or goiter. The patients were randomized into two groups: Group A (n = 103) underwent the surgical treatment with a preoperative visualization therapy. Group B (n = 105) underwent the surgical treatment without a preoperative therapy. Patients with age under 18 years, ASA-status IV-V, recurrent inguinal hernia or recurrent goiter and malignant neoplasms were excluded from the study. There were no differences in age, sex, duration of the operation, training of the surgeon, and preoperative blood parameters between the two groups. RESULTS: During the postoperative follow-up we observed more hematomas (group A with visualization therapy: 30.3%, group B without visualization therapy: 44.4%) as well as more pain (group A: 4.2, group B: 5.2) and analgesic consumption (group A: 59.7 mg Tramadol HCL, group B: 72.5 mg Tramadol HCL) in group B (p < 0.05). There were no significant differences in infections, nausea, hypocalcemia, tetania, recurrent nerve palsy, fever. CONCLUSIONS: Preoperative visualization therapy reduces significantly the number of postoperative hematomas after inguinal hernia repair. Furthermore a decrease of analgesic requirements after surgical treatment was observed.

Cosmic rays and dosimetry at aviation altitudes.

Recent concerns regarding the effects of the cosmic radiation field at aircraft altitudes on aircrew have resulted in a renewed interest in detailed measurements of the neutral and charged particle components in the atmosphere. CR-39 nuclear track detectors have been employed on a number of subsonic and supersonic aircraft to measure charge spectra and LET spectra at aircraft altitudes. These detectors are ideal for long term exposures required for these studies and their passive nature makes them suitable for an environment where interference with flight instrumentation could be a problem. We report here on measurements and analysis of short range tracks which were produced by high LET particles generated mainly by neutron interactions at aviation altitudes. In order to test the overall validity of the technique measurements were also carried out at the CERN-CEC field which simulates the radiation field at aviation altitudes and good agreement was found with dose values obtained using mainly heavy ion calibration.

Physics of cosmic radiation fields.

This paper glances at the knowledge of composition and energy spectra of galactic cosmic rays and briefly discusses the mechanism of solar modulation and of shielding against these particles by the earth's magnetic field. A short review of the properties of solar particle events is given, in which particles emitted from the sun enter the atmosphere. Particle production in the earth's atmosphere in hadronic and electromagnetic cascades is described and the altitude variations of the different particle components are investigated. Typical energy spectra in the atmosphere are presented for some types of particles.

Calculation of radiation fields in the atmosphere and comparison to experimental data.

In this paper the spectra of secondary hadrons are determined in the atmosphere at various depths down to sea level. The calculations are performed using the Monte Carlo code FLUKA together with cosmic-ray environmental models which describe the spectra of primary cosmic-ray particles. We discuss the details of the calculations and the dependence of the results on the primary cosmic-ray spectrum, the atmospheric depth and the geographical location. Special emphasis is put on comparisons of calculated and measured hadron spectra including an experiment which was recently performed at the mountain Zugspitze (47.4 degrees N, 11.0 degrees E, 2963 m), Germany. It is shown that FLUKA may serve as an important tool for the estimation of the radiation environment in the atmosphere.

Neutron spectra in the atmosphere from interactions of primary cosmic rays.

Spectra of neutrons from interactions of primary cosmic rays in the earth's atmosphere are calculated with the Monte Carlo model FLUKA for various depths down to sea level. We discuss the environmental models describing the primary cosmic ray spectrum and details of the calculations. Neutron energy spectra are presented for different depths in the atmosphere and for different geographical locations. By comparing results of calculations to measurements on neutron spectra it is shown that FLUKA may serve as an important tool for the estimation of the radiation environment in the atmosphere.