Significantly increased CD70 up regulation on TEL-AML positive B cell precursor acute lymphoblastic leukemia cells following CD40 stimulation.

BACKGROUND: TEL-AML the most common genetic alteration in childhood precursor B acute lymphoblastic leukemia (BCP-ALL) is associated with a favorable prognosis. PATIENTS AND METHOD: We studied the expression of nerve growth factor/tumor necrosis factor receptor (NGFR/TNFR)/ligand family members on 108 primary BCP-ALL samples by flow cytometry and compared both their baseline expression and CD40-induced modulation on TEL-AML positive and negative leukemia samples. RESULTS: Our findings demonstrate that TEL-AML positive patients exhibit a significantly higher percentage of CD40, CD27 and p75NTR positive blasts at diagnosis. This might well contribute to the improved relapse-free survival of these patients assessed in Kaplan Meier analysis as CD27 and p75NTR directly mediate apoptotic signals. Furthermore CD40 ligation enhances antigen presenting and T cell stimulatory capacity via significant up regulation of CD70 while adequate response to physiological maturation signals as indicated by concomitant down regulation of CD27 is retained in TEL-AML positive leukemia. CONCLUSION: These data provide novel insights in immunological control mechanisms preserved in this leukemia subtype and suggest that not only treatment with chemicals such as HDAC inhibitors but also retained in vivo response to CD40 ligation contributes to improved immune surveillance in these patients which may add to a superior relapse-free survival observed particularly in the presence of other risk factors.

Exercise DVD effect on musculoskeletal disorders in professional orchestral musicians.

BACKGROUND: Professional musicians report a high prevalence of performance-related musculoskeletal disorders (PRMDs). Excessive muscle tension and fatigue have been reported as important factors contributing to PRMDs. AIMS: To evaluate feasibility and effectiveness of a specific exercise programme delivered via a digital video disc (DVD) targeting PRMDs and associated risk factors. METHODS: Volunteers from eight Australian symphony orchestras undertook two or more sessions per week over 12 weeks. Questionnaires were administered pre- and post-intervention with items including the frequency and severity of PRMDs, perceived exertion during different playing situations, per formance effects of the DVD and satisfaction rates. Musicians who had also participated in an equivalent face-to-face programme prior to this DVD trial compared the two interventions. RESULTS: One hundred and forty-four out of 576 musicians volunteered (25% uptake), and 50 participants completed a mean 2.1 (SD 0.42) sessions over the 12 week period (41% compliance). PRMD frequency and severity were significantly reduced post-intervention (P < 0.01). Participants reported benefits of the DVD on strengthening muscles, increasing ease of movement and improving flexibility related to playing. Despite this, perceived exertion levels during private practice, rehearsal and performance remained the same (not significant). Seventy-eight per cent of participants scored their overall experience of the use of the DVD as good or excellent. Owing to its convenience and detailed exercise demonstrations, the DVD was rated as better or much better overall than the face-to-face classes by 55% of participants who had experienced both. CONCLUSIONS: An exercise DVD was well received and appeared to be effective, convenient and safe in managing occupational-specific musculoskeletal disorders in musicians.

Prevalence of velopharyngeal insufficiency in woodwind and brass students.

BACKGROUND: Velopharyngeal insufficiency (VPI) is a disorder in which air leaks out through the nose, reducing performance quality and capacity in wind and brass players. There have been limited studies on the prevalence of this potentially career-threatening disorder. AIMS: To identify the prevalence of VPI in a sample of conservatorium level woodwind and brass student instrumentalists in Australia. METHODS: Wind and brass students from four music institutions were recruited by email invitation to complete an online survey. Results from 77 musicians were analysed for their knowledge and experience of VPI. Musicians who had experienced VPI provided information on the characteristics, symptoms and treatment or advice sought for the disorder. RESULTS: Of the 77 musicians included in the analysis, 44% had heard of VPI, 30% were aware of other musicians who had experienced VPI and 39% had personally experienced VPI. CONCLUSIONS: The results suggest that VPI may be a common occurrence in wind and brass players. Informal discussions with colleagues and music teachers also suggest that VPI is a frequent phenomenon. This group of musicians represents the largest sample surveyed about VPI to date.

Development of phantom materials with independently adjustable CT- and MR-contrast at 0.35, 1.5 and 3 T.

Quality assurance in magnetic resonance (MR)-guided radiotherapy lacks anthropomorphic phantoms that represent tissue-equivalent imaging contrast in both computed tomography (CT) and MR imaging. In this study, we developed phantom materials with individually adjustable CT value as well as [Formula: see text]- and [Formula: see text]-relaxation times in MR imaging at three different magnetic field strengths. Additionally, their experimental stopping power ratio (SPR) for carbon ions was compared with predictions based on single- and dual-energy CT. Ni-DTPA doped agarose gels were used for individual adjustment of [Formula: see text] and [Formula: see text] at [Formula: see text] and 3.0 T. The CT value was varied by adding potassium chloride (KCl). By multiple linear regression, equations for the determination of agarose, Ni-DTPA and KCl concentrations for given [Formula: see text] [Formula: see text] and CT values were derived and employed to produce nine specific soft tissue samples. Experimental [Formula: see text] [Formula: see text] and CT values of these soft tissue samples were compared with predictions and additionally, carbon ion SPR obtained by range measurements were compared with predictions based on single- and dual-energy CT. The measured CT value, [Formula: see text] and [Formula: see text] of the produced soft tissue samples agreed very well with predictions based on the derived equations with mean deviations of less than [Formula: see text] While single-energy CT overestimates the measured SPR of the soft tissue samples, the dual-energy CT-based predictions showed a mean SPR deviation of only [Formula: see text] To conclude, anthropomorphic phantom materials with independently adjustable CT values as well as [Formula: see text] and [Formula: see text] relaxation times at three different magnetic field strengths were developed. The derived equations describe the material specific relaxation times and the CT value in dependence on agarose, Ni-DTPA and KCl concentrations as well as the chemical composition of the materials based on given [Formula: see text] and CT value. Dual-energy CT allows accurate prediction of the carbon ion range in these materials.

Blood group AB increases risk for surgical necrotizing enterocolitis and focal intestinal perforation in preterm infants with very low birth weight.

Necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) are two of the most common emergencies of the gastrointestinal tract in preterm infants with very low birth weight (VLBW, birth weight < 1500 g). Identification of risk factors among these children is crucial for earlier diagnosis and prompt intervention. In this study, we investigated a relationship between ABO blood groups and the risk for surgical NEC/FIP. We genotyped the ABO locus (rs8176746 and rs8176719) in VLBW infants enrolled in a prospective, population-based cohort study of the German Neonatal Network (GNN). Of the 10,257 VLBW infants, 441 (4.3%) had surgical NEC/FIP. In univariate analyses, the blood group AB was more prevalent in VLBW infants with surgical NEC/FIP compared to non-AB blood groups (OR 1.51, 95% CI 1.07-2.13, p = 0.017; absolute risk difference 2.01%, 95% CI 0.06-3.96%). The association between blood group AB and surgical NEC/FIP was observed in a multivariable logistic regression model (OR of 1.58, 95% CI 1.10-2.26, p = 0.013) as well. In summary, our study suggests that the risk of surgical NEC and FIP is higher in patients with blood group AB and lower in those having non-AB blood groups.

Methodology paper: a novel phantom setup for commissioning of scanned ion beam delivery and TPS.

BACKGROUND: Commissioning of treatment planning systems (TPS) and beam delivery for scanned light ion beams is an important quality assurance task. This requires measurement of large sets of high quality dosimetric data in anthropomorphic phantoms to benchmark the TPS and dose delivery under realistic conditions. METHOD: A novel measurement setup is described, which allows for an efficient collection of a large set of accurate dose data in complex phantom geometries. This setup allows dose measurements based on a set of 24 small volume ionization chambers calibrated in dose to water and mounted in a holder, which can be freely positioned in a water phantom with various phantoms mounted in front of the water tank. The phantoms can be scanned in a CT and a CT-based treatment planning can be performed for a direct benchmark of the dose calculation algorithm in various situations. RESULTS: The system has been used for acceptance testing in scanned light ion beam therapy at Heidelberg Ion Beam Therapy Center for scanned proton and carbon ion beams. It demonstrated to be useful to collect large amounts of high quality data for comparison with the TPS calculation using various phantom geometries. CONCLUSION: The setup is an efficient tool for commissioning and verification of treatment planning systems. It is especially suited for dynamic beam delivery, as many data points can be obtained during a single plan delivery, but can be adapted also for other dynamic therapies, like rotational IMRT.

Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandin e synthase 1 inhibitor, with celecoxib.

To assess the safety, tolerability, and pharmacology of LY3023703, a microsomal prostaglandin E synthase 1 (mPGES1) inhibitor, a multiple ascending dose study was conducted. Forty-eight subjects received LY3023703, celecoxib (400 mg), or placebo once daily for 28 days. Compared with placebo, LY3023703 inhibited ex vivo lipopolysaccharide-stimulated prostaglandin E2 (PGE2 ) synthesis 91% and 97% on days 1 and 28, respectively, after 30-mg dosing, comparable to celecoxib's effect (82% inhibition compared to placebo). Unlike celecoxib, which also inhibited prostacyclin synthesis by 44%, LY3023703 demonstrated a maximal increase in prostacyclin synthesis of 115%. Transient elevations of serum aminotransferase were observed in one subject after 30-mg LY3023703 dosing (10× upper limit of normal (ULN)), and one subject after 15-mg dosing (about 1.5× ULN). Results from this study suggest that mPGES1 inhibits inducible PGE synthesis without suppressing prostacyclin generation and presents a novel target for inflammatory pain.

Central vasopressin in experimental aortic stenosis in the rat.

OBJECTIVE: In several forms of heart disease characterised by low cardiac output, activated neurohumoral systems including increased vasopressin plasma levels play a key role in the changes in cardiovascular function. The aim of this study was to test the hypothesis that under such conditions the central vasopressin system might also be altered, which could contribute to deranged cardiovascular control. METHODS: Aortic stenosis was produced in 22 rats by placing a Silver clip (inner diameter 0.6 mm) on the ascending aorta. After 12 weeks, haemodynamic and hormonal measurements were performed, and vasopressin content was determined in 20 microdissected brain areas (micropunch technique). Twenty two sham operated rats served as controls. RESULTS: Twelve weeks after placing the supravalvular clip, significant aortic stenosis was documented by left ventricular myocardial hypertrophy. Cardiac index was significantly reduced and the peripheral vascular resistance index was increased, while poststenotic aortic pressure was non-significantly decreased. Plasma renin concentration [6.8(SEM 0.9) v 2.1(0.2) ngAI.ml-1.h-1 in controls] and plasma vasopressin [32.9(12.5) v 18.4(6.0) pg.ml-1] were significantly increased, while plasma and urinary noradrenaline remained unaltered. The vasopressin content was significantly altered in eight out of 20 brain areas investigated. Concerning the vasopressin producing hypothalamic nuclei, concentrations were increased in the paraventricular [7494(360) v 4744(237) pg.mg-1 protein, P < 0.05] and suprachiasmatic [3613(170) v 1784(197) pg.mg-1 protein, P < 0.01], but not in the supraoptic nuclei. Rats with aortic stenosis showed significantly raised vasopressin concentrations in the median eminence [25 186(1682) v 37 367(1345) pg.mg-1 protein, P < 0.01], where the hormone is mainly concentrated in the hypothalamo-hypophysial tract. Vasopressin content was significantly decreased in locus coeruleus [49(5) v 89(6) pg.mg-1 protein], which is known to be involved in modulation of sympathetic activity. CONCLUSIONS: As well as showing increased secretion of vasopressin into the blood with consecutive peripheral antidiuretic and vasoconstrictive effects, these data suggest an alteration in the central vasopressin system in aortic stenosis which might transmit cardiovascular effects by neuromodulation and neuroregulation.

A motorized solid-state phantom for patient-specific dose verification in ion beam radiotherapy.

For regular quality assurance and patient-specific dosimetric verification under non-horizontal gantry angles in ion beam radiotherapy, we developed and commissioned a motorized solid state phantom. The phantom is set up under the selected gantry angle and moves an array of 24 ionization chambers to the measurement position by means of three eccentrically-mounted cylinders. Hence, the phantom allows 3D dosimetry at oblique gantry angles. To achieve the high standards in dosimetry, the mechanical and dosimetric accuracy of the phantom was investigated and corrections for residual uncertainties were derived. Furthermore, the exact geometry as well as a coordinate transformation from cylindrical into Cartesian coordinates was determined. The developed phantom proved to be suitable for quality assurance and 3D-dose verifications for proton- and carbon ion treatment plans at oblique gantry angles. Comparing dose measurements with the new phantom under oblique gantry angles with those in a water phantom and horizontal beams, the dose deviations averaged over the 24 ionization chambers were within 1.5%. Integrating the phantom into the HIT treatment plan verification environment, allows the use of established workflow for verification measurements. Application of the phantom increases the safety of patient plan application at gantry beam lines.

Evidence for a novel pentyl radical adduct of the cyclic nitrone spin trap MDL 101,002.

3,4-Dihydro-3,3-dimethyl-isoquinoline-2-oxide (MDL 101,002) is a conformationally constrained cyclic analog of the known spin trap alpha-phenyl N-tert-butyl nitrone (PBN). Because of PBN's ability to scavenge free radicals, MDL 101,002 is currently being evaluated in stroke models as a means to ameliorate the oxidative insult associated with reperfusion injury. To augment our understanding of the radical scavenging mechanism of this potential drug, MDL 101,002 was incubated with soybean lipoxygenase in the presence of linoleic acid to study the interaction between MDL 101,002 and free radicals formed during lipid peroxidation. Analysis of the reaction mixture was performed by high performance liquid chromatography using normal phase conditions with detection by atmospheric pressure chemical ionization mass spectrometry (APCI-MS). Similar to the work by Iwahashi et al. [Arch. Biochem. Biophys., 1991, 285, 172], who studied the spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone (4-POBN), an adduct that suggested the trapping of pentyl radicals by MDL 101,002 was observed. However, the apparent molecular ion for this adduct (246 Da) was 1 Da lower than would be predicted if a pentyl radical had simply added to MDL 101,002. In addition, the adduct exhibited significant absorbance at 304 nm, consistent with the unsaturated nitrone structure of MDL 101,002. To account for these observations, it is postulated that, after the initial capture of a pentyl radical, subsequent abstraction of a hydrogen atom by a neighboring radical occurs to regenerate a nitrone (1-pentyl analog of MDL 101,002). We present evidence for this adduct and offer a mechanism for its formation. These findings indicate that mass spectroscopic analysis of stable nitrone radical adducts may be useful in the identification of radical-dependent damage in vivo and possibly in clinical development of MDL 101,002 as an antioxidant pharmaceutical.

Specific targeting of cytokine-secreting cells: a bispecific diabody recognizing human interleukin-6 and CD3 induces T cell-mediated killing.

Cytokines have been implicated in the pathophysiology of many diseases. Although there have been many attempts to neutralize the activity of cytokines in vivo and in vitro, no strategies have been developed to specifically eliminate cells that overexpress cytokines. Considering the fact that cytokines in part remain cell associated on secretion, we have constructed a bispecific diabody consisting of a nonneutralizing scFv antibody recognizing human interleukin-6 (IL-6) and an scFv corresponding to the monoclonal antibody (mAb) OKT3, which recognizes and activates the human T cell receptor. Here we show that the diabody recognized both human IL-6 and human CD3. In the presence of human T cells, the diabody induced killing of human hepatoma cells that had been transfected with a human IL-6 cDNA. The extent of killing was dependent on the ratio of effector/target cells and increased with increasing concentrations of the diabody. Untransfected control cells or human hepatoma cells that secrete the IL-6-related cytokine leukemia inhibitory factor (LIF) remained unaffected. We conclude that diabodies recognizing cytokines can be used to specifically target cytokine-secreting cells.

Rapid analysis of antibiotic-containing mixtures from fermentation broths by using liquid chromatography-electrospray ionization-mass spectrometry and matrix-assisted laser desorption ionization-time-of-flight-mass spectrometry.

A crucial step in the isolation of antibiotic substances is establishing whether or not the isolated material represents a new chemical entity. Because of the importance of molecular weight to this process-known as dereplication-mass spectrometry has traditionally played an active role. In this communication a strategy for utilizing liquid chromatography-mass spectrometry (LC/MS) for novelty assessment is described. Crude extracts (20-50 µg) are chromatographed by conventional bore high-performance liquid chromatography (1 mL/min) after which a postcolumn split to divert roughly one-tenth of the sample to the mass spectrometer for molecular weight determination by electrospray ionization (ESI) mass spectrometry. The majority of the effluent is sent to a UV detector and ultimately collected as 1-min fractions for biological testing. As a secondary confirmation of molecular weight, an aliquot of each fraction (< 5%) is taken for analysis by matrix-assisted laser desorption ionization (MALDI). The improved efficiency of this approach over more traditional schemes utilizing off-line fraction collection and conventional ionization methods can be explained by several factors. First, the superior sensitivity of ESI and MALDI means that less material is required for successful analysis. Second, on-line LC/MS optimizes the efficiency of sample transfer and saves both time and labor. Furthermore, the concentration dependence of ESI allows a majority of the material injected for LC/MS to be recovered for biological testing without compromising the signal available for molecular weight determination. As a validation of the above method, crude extracts containing two well-characterized antibiotics-teicoplanin and phenelfamycin-were examined. Results from these analyses are presented along with data from the analysis of a potent unknown antifungal sample.

Application of packed capillary liquid chromatography/mass spectrometry with electrospray ionization to the study of the human biotransformation of the anti-emetic drug dolasetron.

Packed capillary liquid chromatography/mass spectrometry (LC/MS) using electrospray ionization (ESI) was used to study the human biotransformation of the anti-emetic drug dolasetron. Urine from subjects given a single 100 mg intravenous dose, containing 14C-labeled dolasetron (50 microCi), was de-salted and concentrated for LC/MS with minimal loss of radioactivity (97% recovery). Aliquots of the de-salted material were injected directly onto a C8 packed capillary column (25 cm x 0.32 mm i.d.) and eluted with an acetonitrile-water gradient, buffered with 1% acetic acid, at a flow rate of 2 microliters min-1. Five metabolites were detected by LC ESI-MS which, yielded molecular mass information but no fragmentation. The identity of each metabolite was confirmed in a subsequent analysis using product ion scans in conjunction with collisionally induced dissociation. Precursor ion scanning was also employed and did not reveal any new biotransformation products. In addition to defining the major routes of biotransformation, the data obtained were compared with a 14C radioprofile prepared in a separate experiment. Qualitative agreement in the two chromatographic profiles enabled the major clusters of radioactivity to be assigned to specific metabolites of dolasetron. An important observation in this comparison was that the signal obtained by ESI did not provide an accurate assessment of the quantity of each metabolite. This was especially true for acidic conjugates (i.e. glucuronides, sulfates), which in the case of dolasetron can exist as zwitterions (no net charge). The results demonstrate the power of packed capillary LC ESI-MS for use in drug biotransformation studies and suggest that caution should be exercised when interpreting relative metabolite abundances from ESI data in the absence of actual reference standards.

Synovial fluid MHC-unrestricted gamma delta-T lymphocytes contribute to antibacterial and anti-self cytotoxicity in the spondylarthropathies.

OBJECTIVE: In reactive arthritis (ReA), synovial fluid-derived bacteria-specific CD4+ and CD8+ T cells have been studied intensively in recent years. We have addressed the question whether gamma delta-TCR+ lymphocytes could contribute to antibacterial or anti-self cytotoxicity in the affected joints of patients, with spondylarthropathies. METHODS: T cell clones were derived by random cloning from the synovial fluids of one patient with Yersinia-induced ReA, one patient with a Yersinia-induced flare up of pre-existing ankylosing spondylitis, and one patient with ankylosing spondylitis. Eight clones with a CD3+, alpha beta-TCR-, CD4-, CD8- and gamma delta-TCR+ phenotype (all expressing V gamma 9) were tested in a standard 52Cr-release assay using autologous or allogeneic B cell lines, CIR-B27, Daudi cells, and RJ.225 cells. RESULTS: Four gamma delta-TCR+ clones killed both autologous and allogeneic target cells when infected with live Yersinia or Salmonella and also uninfected Daudi cells expressing GroEL heatshock protein. One clone was specific for Yersinia-infected targets. Three gamma delta-TCR+ clones were cytotoxic when uninfected autologous or allogeneic targets were employed. Polymorphic "classical" MHC class I or class II molecules were not used as restriction elements. CONCLUSION: We conclude that, upon in vivo contact with bacteria such as Yersinia and Salmonella, synovial gamma delta-T lymphocytes are activated and contribute to antibacterial immunity via specific target cell lysis. Furthermore, anti-self cytolytic gamma delta-T cells could participate in the clearance of stressed and detrimental cells in the arthritic joint or, alternatively, could support the chronicity of autoimmune arthritis.

Determination of olanzapine in human blood by liquid chromatography-tandem mass spectrometry.

A liquid chromatographic-tandem mass spectrometric (LC-MS-MS) assay was developed and validated to quantitatively determine olanzapine (OLZ) concentrations in human blood. Liquid-liquid extraction, using n-butanol:cyclohexane (3:47, v/v), was used to isolate OLZ and its internal standard, LY170158, from the biological matrix. Chromatographic resolution of OLZ from endogenous interferences and known metabolites was accomplished with a MetaChem Monochrom HPLC column (4.6 x 150 mm, d(p) 5 microm). Detection occurred using a Perkin-Elmer Sciex API III Plus triple quadrupole mass spectrometer using positive ion APCI and multiple reaction monitoring (MRM). The linear dynamic range was from 5 to 500 ng ml(-1) based on a 0.25-ml aliquot of human blood. The inter-day precision (%RSD) and accuracy (%RE) ranged from 3.65 to 10.64 and from -2.14 to 3.07, respectively. Modifications to an existing assay for the determination of OLZ in human plasma were necessary. A different structural analog was used as the internal standard due to instability observed for the original analog when using human blood as the matrix. A second modification was the addition of the anti-oxidant sodium ascorbate to inhibit degradation of OLZ in human blood, as has been noted by other investigators. Upon fortification of human blood with sodium ascorbate (final concentration, 0.33 mM), OLZ was found to be stable for at least 1 week at -70 degrees C as well as through two freeze-thaw cycles. This assay, which will be used to investigate the distribution of OLZ in human blood, grants insight into the proper sample handling conditions needed to perform valid determinations of OLZ in human blood.

Mutagenic effect of 1.1'-hexamethylene-bis-[(5-p-chlorophenyl)-biguanide].

The strongly effective bactericidal compound 1.1'-hexamethylene-bis-[(5-p-chlorophenyl)-biguanide] (HCG) induces mutations with a slight inactivation rate in the auxotrophic strains Salmonella typhimurium TA 1535 and TA 1538 in 0.4 microM solution. The mutagenic effect could be confirmed by using the plate incorporation test and the repair test. As phenylethylbiguanide at different inactivation rates does not show any mutagenic effect, the biguanide structure does not seem to be responsible for chemical mutagenesis. A hypothetic mutation mechanism is proposed and compared with the corresponding reaction mechanism of N-methyl-N'-nitro-N-nitro-soguanidine (MNNG).

[Visceral angiography with intra-arterial DSA and programmed 100-mm technic]. / Viszerale Angiographie mit intraarterieller DSA und programmierter 100-mm-Technik.

One hundred and seventy specially selected visceral angiograms were carried out on 96 patients using I-A DSA and 100 mm technique. 85.2% of the I-A DSA and 91.7% of the 100 mm images were of good quality. I-A DSA produced comparable or better quality than the 100 mm technique in 66% during the arterial phase, in 79% during the parenchymatous phase and in 70% during the venous phase. The 100 mm technique produced better quality in a third of the cases during the arterial phase and in a quarter of the cases during the parenchymal and venous phases. The indications for the 100 mm technique are failure of I-A DSA or the need for high spatial resolution.

The T cell receptor (TCR) in HLA-B27-restricted T cell responses--an introduction.

Recent data indicate that cytotoxic T lymphocytes (CTL) are involved in the pathogenesis of HLA-B27-associated spondylarthropathies. In the absence of clearly defined "arthritogenic" bacterial or self peptides that are presented by HLA-B27 and recognized by such CD8+CTL, one approach has been to investigate the T cell repertoire of lesional cellular infiltrates by determining T cell receptor (TCR) variable (V) gene segment frequencies. Furthermore, the TCR V alpha and V beta chains of HLA-B27-restricted CTL clones, notably the putative peptide-contacting CDR3-regions of these TCRs, have been sequenced. This article will give a short review of the current literature on the topology of the TCR and its hypervariable CDR3 region, TCR repertoire diversity in rheumatic diseases and will concentrate on TCR V alpha and V beta gene usage in HLA-B27-restricted T cell responses.

Integration and evaluation of automated Monte Carlo simulations in the clinical practice of scanned proton and carbon ion beam therapy.

Monte Carlo (MC) simulations of beam interaction and transport in matter are increasingly considered as essential tools to support several aspects of radiation therapy. Despite the vast application of MC to photon therapy and scattered proton therapy, clinical experience in scanned ion beam therapy is still scarce. This is especially the case for ions heavier than protons, which pose additional issues like nuclear fragmentation and varying biological effectiveness. In this work, we present the evaluation of a dedicated framework which has been developed at the Heidelberg Ion Beam Therapy Center to provide automated FLUKA MC simulations of clinical patient treatments with scanned proton and carbon ion beams. Investigations on the number of transported primaries and the dimension of the geometry and scoring grids have been performed for a representative class of patient cases in order to provide recommendations on the simulation settings, showing that recommendations derived from the experience in proton therapy cannot be directly translated to the case of carbon ion beams. The MC results with the optimized settings have been compared to the calculations of the analytical treatment planning system (TPS), showing that regardless of the consistency of the two systems (in terms of beam model in water and range calculation in different materials) relevant differences can be found in dosimetric quantities and range, especially in the case of heterogeneous and deep seated treatment sites depending on the ion beam species and energies, homogeneity of the traversed tissue and size of the treated volume. The analysis of typical TPS speed-up approximations highlighted effects which deserve accurate treatment, in contrast to adequate beam model simplifications for scanned ion beam therapy. In terms of biological dose calculations, the investigation of the mixed field components in realistic anatomical situations confirmed the findings of previous groups so far reported only in homogenous water targets. This work can thus be useful to other centers commencing clinical experience in scanned ion beam therapy.

Impact of bispectral index monitoring on postoperative delirium in patients undergoing aortic surgery.

BACKGROUND: Bispectral index monitoring can facilitate anesthesia care. We evaluated the association of Bispectral index with postoperative neurological outcome and delirium in patients undergoing aortic surgery. METHODS: From 2006 to 2009, 292 consecutive patients undergoing aortic surgery were retrospectively reviewed. Patients were classified into 5 groups according to Bispectral index reduction: Group I (≤15%), Group II (15-20%), Group III (20-25%), Group IV (25-30%), and Group V (>30%). RESULTS: The number of patients in each group was : 52 (17.8%), Group I; 125 (42.8%), Group II;68 (23.3%), Group III; 33 (11.3%), Group IV; 14 (4.8%), Group V. The incidence of delirium and neurological events was higher in Group IV and Group V(90.9% and 18.2% in Group IV, and 71% and 79% in Group V; both p<0.001). Only Group V showed a longer intensive care unit stay compared to Group I (13.5±10.3 vs 5.4±6.6 days; p=0.002), Group II (7.3±8.6 days, p=0.005) and Group III (6.7±6.5 days, p=0.015). Group V also showed a longer intubation time compared to Group I (228±211 vs 73±112 hours; p=0.008) and Group II (105±177 hours, p=0.002). CONCLUSIONS: Our data suggest a higher incidence of neurological deficits in patients with a Bispectral index reduction of >25% from baseline. Explanations for these findings are speculative with regard to the underlying mechanisms, and larger studies are warranted to clarify these issues.