Experimental demonstration of accurate Bragg peak localization with ionoacoustic tandem phase detection (iTPD).

Accurate knowledge of the exact stopping location of ions inside the patient would allow full exploitation of their ballistic properties for patient treatment. The localized energy deposition of a pulsed particle beam induces a rapid temperature increase of the irradiated volume and leads to the emission of ionoacoustic (IA) waves. Detecting the time-of-flight (ToF) of the IA wave allows inferring information on the Bragg peak location and can henceforth be used forin-vivorange verification. A challenge for IA is the poor signal-to-noise ratio at clinically relevant doses and viable machines. We present a frequency-based measurement technique, labeled as ionoacoustic tandem phase detection (iTPD) utilizing lock-in amplifiers. The phase shift of the IA signal to a reference signal is measured to derive theToF. Experimental IA measurements with a 3.5 MHz lead zirconate titanate (PZT) transducer and lock-in amplifiers were performed in water using 22 MeV proton bursts. A digital iTPD was performedin-silicoat clinical dose levels on experimental data obtained from a clinical facility and secondly, on simulations emulating a heterogeneous geometry. For the experimental setup using 22 MeV protons, a localization accuracy and precision obtained through iTPD deviates from a time-based reference analysis by less than 15µm. Several methodological aspects were investigated experimentally in systematic manner. Lastly, iTPD was evaluatedin-silicofor clinical beam energies indicating that iTPD is in reach of sub-mm accuracy for fractionated doses < 5 Gy. iTPD can be used to accurately measure theToFof IA signals online via its phase shift in frequency domain. An application of iTPD to the clinical scenario using a single pulsed beam is feasible but requires further development to reach <1 Gy detection capabilities.

Impact of Gaussian uncertainty assumptions on probabilistic optimization in particle therapy.

Range and setup uncertainties in charged particle therapy may induce a discrepancy between the planned and the delivered dose. Countermeasures based on probabilistic (stochastic) optimization usually assume a Gaussian probability density to model the underlying range and setup error. While this standard assumption is generally taken for granted, this study explicitly investigates the dosimetric consequences if the actual range and setup errors obey a different probability density function (PDF) over the course of treatment to the one used during the probabilistic treatment plan optimization. Discrete random sampling was performed for conventionally and probabilistically optimized proton and carbon ion treatment plans utilizing various PDFs that modeled the setup and range error. This method allowed us to assess the treatment plan robustness against different PDFs of conventional and probabilistic plans, which both explicitly assume Gaussian uncertainties. The induced uncertainty in dose was quantified by estimating the expectation value and standard deviation of the RBE-weighted dose for each PDF on the basis of 2500-5000 random dose samples. Probabilistic dose metrics and standard deviation volume histograms were computed to quantify treatment plan robustness of both optimization approaches. It was shown that the classical planning target volume margin extension concept did not compensate the influence of range and setup errors and consequently resulted in a non-negligible average standard deviation in dose of 7.3% throughout the clinical target volume (CTV). In contrast, probabilistic optimization on normally distributed errors yielded treatment plans that not only entailed a lower standard deviation against normally distributed errors accounted for during optimization, but also lower standard deviations for other symmetric PDFs. It was shown that the impact of an incorrect probability distribution assumption is of lower importance after probabilistic optimization as the average uncertainty in the CTV drops to 3.9%. Probabilistic optimization is an effective tool to create robust particle treatment plans. Normally distributed range and setup error assumptions for probabilistic optimization are a reasonable first approximation and yield treatment plans that are also robust against other PDFs.

Analytical probabilistic modeling of RBE-weighted dose for ion therapy.

Particle therapy is especially prone to uncertainties. This issue is usually addressed with uncertainty quantification and minimization techniques based on scenario sampling. For proton therapy, however, it was recently shown that it is also possible to use closed-form computations based on analytical probabilistic modeling (APM) for this purpose. APM yields unique features compared to sampling-based approaches, motivating further research in this context. This paper demonstrates the application of APM for intensity-modulated carbon ion therapy to quantify the influence of setup and range uncertainties on the RBE-weighted dose. In particular, we derive analytical forms for the nonlinear computations of the expectation value and variance of the RBE-weighted dose by propagating linearly correlated Gaussian input uncertainties through a pencil beam dose calculation algorithm. Both exact and approximation formulas are presented for the expectation value and variance of the RBE-weighted dose and are subsequently studied in-depth for a one-dimensional carbon ion spread-out Bragg peak. With V and B being the number of voxels and pencil beams, respectively, the proposed approximations induce only a marginal loss of accuracy while lowering the computational complexity from order [Formula: see text] to [Formula: see text] for the expectation value and from [Formula: see text] to [Formula: see text] for the variance of the RBE-weighted dose. Moreover, we evaluated the approximated calculation of the expectation value and standard deviation of the RBE-weighted dose in combination with a probabilistic effect-based optimization on three patient cases considering carbon ions as radiation modality against sampled references. The resulting global γ-pass rates (2 mm,2%) are [Formula: see text]99.15% for the expectation value and [Formula: see text]94.95% for the standard deviation of the RBE-weighted dose, respectively. We applied the derived analytical model to carbon ion treatment planning, although the concept is in general applicable to other ion species considering a variable RBE.

Efficiency of analytical and sampling-based uncertainty propagation in intensity-modulated proton therapy.

The sensitivity of intensity-modulated proton therapy (IMPT) treatment plans to uncertainties can be quantified and mitigated with robust/min-max and stochastic/probabilistic treatment analysis and optimization techniques. Those methods usually rely on sparse random, importance, or worst-case sampling. Inevitably, this imposes a trade-off between computational speed and accuracy of the uncertainty propagation. Here, we investigate analytical probabilistic modeling (APM) as an alternative for uncertainty propagation and minimization in IMPT that does not rely on scenario sampling. APM propagates probability distributions over range and setup uncertainties via a Gaussian pencil-beam approximation into moments of the probability distributions over the resulting dose in closed form. It supports arbitrary correlation models and allows for efficient incorporation of fractionation effects regarding random and systematic errors. We evaluate the trade-off between run-time and accuracy of APM uncertainty computations on three patient datasets. Results are compared against reference computations facilitating importance and random sampling. Two approximation techniques to accelerate uncertainty propagation and minimization based on probabilistic treatment plan optimization are presented. Runtimes are measured on CPU and GPU platforms, dosimetric accuracy is quantified in comparison to a sampling-based benchmark (5000 random samples). APM accurately propagates range and setup uncertainties into dose uncertainties at competitive run-times (GPU [Formula: see text] min). The resulting standard deviation (expectation value) of dose show average global [Formula: see text] pass rates between 94.2% and 99.9% (98.4% and 100.0%). All investigated importance sampling strategies provided less accuracy at higher run-times considering only a single fraction. Considering fractionation, APM uncertainty propagation and treatment plan optimization was proven to be possible at constant time complexity, while run-times of sampling-based computations are linear in the number of fractions. Using sum sampling within APM, uncertainty propagation can only be accelerated at the cost of reduced accuracy in variance calculations. For probabilistic plan optimization, we were able to approximate the necessary pre-computations within seconds, yielding treatment plans of similar quality as gained from exact uncertainty propagation. APM is suited to enhance the trade-off between speed and accuracy in uncertainty propagation and probabilistic treatment plan optimization, especially in the context of fractionation. This brings fully-fledged APM computations within reach of clinical application.

Wheat-dependent exercise-induced anaphylaxis.

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a rare, but potentially severe food allergy exclusively occurring when wheat ingestion is accompanied by augmenting cofactors. It is clinically characterized by anaphylactic reactions ranging from urticaria and angioedema to dyspnoea, hypotension, collapse, and shock. WDEIA usually develops after ingestion of wheat products followed by physical exercise. Other cofactors are acetylsalicylic acid and other non-steroidal anti-inflammatory drugs, alcohol, and infections. The precise mechanisms of WDEIA remain unclear; exercise and other cofactors might increase gastrointestinal allergen permeability and osmolality, redistribute blood flow, or lower the threshold for IgE-mediated mast cell degranulation. Among wheat proteins, ω5-gliadin and high-molecular-weight glutenin subunits have been reported to be the major allergens. In some patients, WDEIA has been discussed to be caused by epicutaneous sensitization with hydrolysed wheat gluten included in cosmetics. Diagnosis is made based on the patient's history in combination with allergy skin testing, determination of wheat-specific IgE serum antibodies, basophil activation test, histamine release test, and/or exercise challenge test. Acute treatment includes application of adrenaline or antihistamines. The most reliable prophylaxis of WDEIA is a gluten-free diet. In less severe cases, a strict limitation of wheat ingestion before exercise and avoidance of other cofactors may be sufficient.

Effects of elevated CO2 on grain yield and quality of wheat: results from a 3-year free-air CO2 enrichment experiment.

Spring wheat (Triticum aestivum L. cv. TRISO) was grown for three consecutive seasons in a free-air carbon dioxide (CO(2)) enrichment (FACE) field experiment in order to examine the effects on crop yield and grain quality. CO(2) enrichment promoted aboveground biomass (+11.8%) and grain yield (+10.4%). However, adverse effects were predominantly observed on wholegrain quality characteristics. Although the thousand-grain weight remained unchanged, size distribution was significantly shifted towards smaller grains, which may directly relate to lower market value. Total grain protein concentration decreased significantly by 7.4% under elevated CO(2), and protein and amino acid composition were altered. Corresponding to the decline in grain protein concentration, CO(2) enrichment resulted in an overall decrease in amino acid concentrations, with greater reductions in non-essential than essential amino acids. Minerals such as potassium, molybdenum and lead increased, while manganese, iron, cadmium and silicon decreased, suggesting that adjustments of agricultural practices may be required to retain current grain quality standards. The concentration of fructose and fructan, as well as amounts per area of total and individual non-structural carbohydrates, except for starch, significantly increased in the grain. The same holds true for the amount of lipids. With regard to mixing and rheological properties of the flour, a significant increase in gluten resistance under elevated CO(2) was observed. CO(2) enrichment obviously affected grain quality characteristics that are important for consumer nutrition and health, and for industrial processing and marketing, which have to date received little attention.

The Wada test in Austrian, Dutch, German, and Swiss epilepsy centers from 2000 to 2005: a review of 1421 procedures.

Twenty-six Austrian, Dutch, German, and Swiss epilepsy centers were asked to report on use of the Wada test (intracarotid amobarbital procedure, IAP) from 2000 to 2005 and to give their opinion regarding its role in the presurgical diagnosis of epilepsy. Sixteen of the 23 centers providing information had performed 1421 Wada tests, predominantly the classic bilateral procedure (73%). A slight nonsignificant decrease over time in Wada test frequency, despite slightly increasing numbers of resective procedures, could be observed. Complication rates were relatively low (1.09%; 0.36% with permanent deficit). Test protocols were similar even though no universal standard protocol exists. Clinicians rated the Wada test as having good reliability and validity for language determination, whereas they questioned its reliability and validity for memory lateralization. Several noninvasive functional imaging techniques are already in use. However, clinicians currently do not want to rely solely on noninvasive functional imaging in all patients.

Intestinal expression of cytochrome P450 enzymes and ABC transporters and carbamazepine and phenytoin disposition.

OBJECTIVES: Interindividual variability in intestinal absorption and bioavailability might contribute to inadequate control of seizures under treatment with carbamazepine and phenytoin. We therefore correlated intestinal expression levels and genetics of CYP3A4, CYP2C9/19, MDR1 and MRP2 with dose requirement and plasma levels of carbamazepine and phenytoin. MATERIALS AND METHODS: Epileptic patients on carbamazepine (n = 29) or phenytoin (n = 15) were stratified into a 'high'-dose (carbamazepine > or =800 mg/day, phenytoin > or =300 mg/day) and a 'low'-dose group (carbamazepine < or =600 mg/day, phenytoin < or =200 mg/day). Duodenal biopsies and DNA were obtained for Western blotting and genotyping studies. RESULTS: Low carbamazepine plasma levels showed a trend towards higher intestinal MDR1 expression (P = 0.06). Furthermore, carbamazepine dose was positively correlated with MRP2 expression (P = 0.1). Moreover, MDR1 expression and carbamazepine and phenytoin dose requirement was influenced by the genotype in position 2677 and 3435 of the MDR1 gene. CONCLUSION: Differences in intestinal MDR1 and MRP2 expression may influence carbamazepine and phenytoin disposition and may account for interindividual pharmacokinetic variability.

Transient epileptic opercular syndrome.

Ictal transient opercular syndrome is rarely observed in benign epilepsy with centro-temporal spikes in children, and even more rarely in epilepsia partialis continua and symptomatic focal status epilepticus in adults. Here we report the ictal and interictal neuroimaging and electrophysiological findings in an adult female suffering from discontinuous focal status epilepticus presenting as a transient opercular syndrome. This patient was unusual insofar as the discharges were strictly unilateral, i.e., that even with extensive neuroimaging no structural abnormalities could be found.

Transient MR changes and symptomatic epilepsy following gamma knife treatment of a residual GH-secreting pituitary adenoma in the cavernous sinus.

OBJECTIVE: To report a rare side effect of gamma knife treatment of pituitary macroadenoma. CASE REPORT: In a forty-one-year old female patient acromegaly was diagnosed due to a growth hormone secreting pituitary macroadenoma. Following transsphenoidal surgery the patient underwent gamma knife treatment for persistent uncontrolled acromegaly activity of residual tumor, infiltrating the left cavernous sinus. 15 months later, complex partial seizures were diagnosed and 17 months after gamma knife treatment a gadolinium enhancing lesion was detected in her left medial temporal lobe. Radiation induced changes, radiation necrosis or a glioma were considered. Neuropsychological testing indicated potentially significant post-surgical deficits. Therefore, surgical action was postponed and anti-epileptic treatment was started. Four months later she was free of seizures and an MR scan showed an almost complete regression of the gadolinium enhancing lesion, indicating that it had been due to radiation induced changes. CONCLUSION: Gamma knife surgery of a pituitary adenoma may cause radiation induced MR changes of the mesial temporal lobe mimicking glioma or radionecrosis and cause symptomatic epileptic seizures. The awareness of this rare complication is important to avoid unnecessary and potentially harmful diagnostic or therapeutic interventions.

The effect of manganese(II) on the structure of DNA/HMGB1/H1 complexes: electronic and vibrational circular dichroism studies.

The interactions were studied of DNA with the nonhistone chromatin protein HMGB1 and histone H1 in the presence of manganese(II) ions at different protein to DNA and manganese to DNA phosphate ratios by using absorption and optical activity spectroscopy in the electronic [ultraviolet (UV) and electronic circular dichroism ECD)] and vibrational [infrared (IR) and vibrational circular dichroism (VCD)] regions. In the presence of Mn2+, the protein-DNA interactions differ from those without the ions and cause prominent DNA compaction and formation of large intermolecular complexes. At the same time, the presence of HMGB1 and H1 also changed the mode of interaction of Mn2+ with DNA, which now takes place mostly in the major groove of DNA involving N7(G), whereas interactions between Mn2+ and DNA phosphate groups are weakened by histone molecules. Considerable interactions were also detected of Mn2+ ions with aspartic and glutamic amino acid residues of the proteins.

Barley and rye prolamins induce an mRNA interferon-gamma response in coeliac mucosa.

BACKGROUND: In coeliac disease, wheat, barley and rye are traditionally excluded in the gluten-free diet. However, few studies have examined the small intestinal immune response to barley and rye. AIM: To investigate the immunogenicity of barley and rye prolamins (hordein and secalin respectively) in comparison with wheat gliadin. METHODS: Duodenal biopsies from 22 coeliac patients and 23 disease controls were cultured for 4 h with gliadin, hordein or secalin and compared with culture medium alone. Proinflammatory cytokines, interferon-gamma and interleukin-2, were quantified by TaqMan polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Hordein caused the greatest increase in interferon-gamma mRNA in coeliac patients (median: 3.3-fold) in comparison with control subjects (median: 0.28-fold, P < 0.085). Secalin and gliadin induced similar levels of interferon-gamma mRNA with median fold-changes of 3.4 and 2.8, respectively, in coeliac patients in comparison with 1.6- and 1.1-fold increases in control subjects (P < 0.294 and P < 0.105, respectively). The median fold-changes for interleukin-2 mRNA did not differ between coeliac patients and controls. Cytokine protein was not upregulated. CONCLUSION: The findings of this study provide evidence that barley and rye cause immune activation in the mucosa of coeliac patients and support the practice that barley and rye should be excluded from the gluten-free diet.

Intestinal T cell responses to cereal proteins in celiac disease.

Celiac disease is caused by sensitivity to wheat gluten in genetically susceptible individuals. The etiological role of the other wheat-related cereals, barley, rye, and oats, is still debated. In order to investigate this issue further, in this study we examined the immune response of celiac mucosal T cell lines to fractions from all four cereals. Cell stimulation was assessed by measuring proliferation (employing (3)H-thymidine incorporation) or cytokine (IL-2, IFN-gamma) production. All five T cell lines demonstrated immunoreactivity to protein fractions from the four related cereals. In some cell lines, reactivity to wheat, barley, and rye was only evident when these cereal fractions had been pretreated with tissue transglutaminase. This study confirms the similar T cell antigenic reactivity of these four related cereals and has implications for their exclusion in the gluten-free diet. However, despite oats stimulation of T cell lines, this cereal does not activate a mucosal lesion in most celiac patients.

Cross linking to tissue transglutaminase and collagen favours gliadin toxicity in coeliac disease.

BACKGROUND AND AIMS: Intestinal inflammation in coeliac disease is driven by the gluten fraction of wheat proteins. Deamidation or cross linking of gluten peptides by tissue transglutaminase (tTG), the coeliac disease autoantigen, creates potent T cell stimulatory peptides. Therefore, our aim was to identify the reaction patterns of gluten peptides, intestinal extracellular matrix proteins, and tTG. METHODS: tTG activity was analysed by incorporation of monodansyl cadaverine into gliadins. Fluorescence labelled tTG reactive short gliadin peptides were used to demonstrate their deamidation and explore their cross linking patterns with tTG itself or extracellular matrix proteins. Patient sera and controls were checked for autoantibodies to matrix proteins. RESULTS: Gliadins alpha1-alpha11, gamma1-gamma6, omega1-omega3, and omega5 were substrates for tTG. tTG catalysed the cross linking of gliadin peptides with interstitial collagen types I, III, and VI. Coeliac patients showed increased antibody titres against the collagens I, III, V, and VI. CONCLUSIONS: tTG formed high molecular weight complexes with all tested gliadins. As all tested gliadins were substrates for tTG, the tTG catalysed modifications were not restricted to single gliadin types and epitopes. Furthermore, haptenisation and long term immobilisation of gliadin peptides by tTG catalysed binding to abundant extracellular matrix proteins could be instrumental in the perpetuation of intestinal inflammation and some associated autoimmune diseases in coeliac disease.

Intercalation of daunomycin into d(CG)4 oligomer duplex containing G x T mismatches by vibrational circular dichroism and infrared absorption spectroscopy.

The vibrational circular dichroism (VCD) and infrared absorption (IR) spectra of the mismatched octamer oligonucleotides d(CGTGCGCG)(2) (CGT) and d(CGCGTGCG)(2) (CGC) and their complexes with the antitumor drug daunomycin were measured in D(2)O, interpreted, and compared to the octamer d(CGCGCGCG)(2) (CG). The IR spectra of the mismatched octamers in the carbonyl-stretching region are similar to those of the parent CG, whereas the VCD spectra differ in several respects between each other. The main VCD feature due to carbonyl stretching is informative for the mismatches and CG. Vibrational modes in the sugar-phosphate region remain essentially unchanged especially for PO(2) (-) symmetric stretching. Differences between the free and complexed mismatch octamers occurred mainly in the carbonyl-stretching region (1,700-1,600 cm(-1)). The absorption intensity of the C==O peak of G is more prominent for CGC than CGT and resembles CG in this respect. The detailed composition of this doublet is clearly visible, indicating the geometric rearrangement of the base pairs in the presence of the mismatch and upon forming the daunomycin complex.

Vibrational circular dichroism signature of hemiprotonated intercalated four-stranded i-DNA.

The four-stranded intercalated DNA structure exemplified by the oligonucleotide 5'-d(CCCCCCCCCCCC) (d(C)12) was studied at acidic pH by infrared absorption (IR) and vibrational circular dichroism (VCD) spectroscopy and compared with spectra of the same oligonucleotide at neutral pH to establish distinct VCD markers for the intercalation motif. The most striking feature is a new absorption at 1694 cm(-1) and its corresponding VCD couplet with reversed sign. These are unique for the intercalated structure and have not been observed for other parallel stranded duplexes. Significant characteristic features resulting from the spatial arrangement of the sugar-phosphate backbone are also clearly present for d(C)12 at acidic pH. An extensive network of CH...O bonds twists the backbone such that multiple through-space vibrational coupling occurs among neighbouring sugar-phosphate residues resulting in unusual VCD signals.

H2(15)O or 13NH3 PET and electromagnetic tomography (LORETA) during partial status epilepticus.

The authors evaluated the feasibility and source localization utility of H2(15)O or 13NH3 PET and low-resolution electromagnetic tomography (LORETA) in three patients with partial status epilepticus (SE). Results were correlated with findings from intraoperative electrocorticographic recordings and surgical outcomes. PET studies of cerebral blood flow and noninvasive source modeling with LORETA using statistical nonparametric mapping provided useful information for localizing the ictal activity in patients with partial SE.

[Neurotoxic encephalopathy caused by neuroleptics and lithium]. / Neurotoxische Enzephalopathie unter Neuroleptika und Lithium.

Treatment of psychiatric patients often necessitates overlapping neuroleptic medication. We report a 60-year-old woman suffering from a schizoaffective disorder who received temporarily three neuroleptics, together with lithium. She developed neurotoxic encephalopathy with symptoms of a malignant neuroleptic syndrome. It is unclear if irreversible brain damage will remain. We recommend frequent electroencephalographic controls for early detection of neurotoxicity.

[The effect of Ca2+ ions on DNA compaction in the complex with non-histone chromosomal protein HMGB1]. / Vliianie ionov Ca2+ na kompaktizatsiiu DNK v komplekse s negistonovym khromosomnym belkov HMGB1.

The analysis of absorption and circular dichroism spectra in UV and IR regions showed that Ca2+ ions interact both with the phosphate groups of DNA and with the HMGB1 protein. Not only negatively charged C-terminal part of the protein molecule participates in interaction with metal ions but also its DNA-binding domains. The latter fact leads to the change of the mode of protein-DNA interaction. The presence of Ca2+ ions prevents formation of ordered supramolecular structures, specific for the HMGB1-DNA complexes, though promotes intermolecular aggregation. The structure of the complexes between DNA and the protein HMGB1 lacking C-terminal tail appears to be the most sensitive to the presence of Ca2+ ions. The data obtained allow to conclude that Ca2+ ions do not play a structural role in the HMGB1/DNA complexes and the presence of these ions is not necessary to DNA compaction in such systems.

The effect of manganese(II) on DNA structure: electronic and vibrational circular dichroism studies.

The interaction of DNA with Mn2+ was studied in absorbance and optical activity in the electronic and vibrational regions. Based on the data, several stages of the interaction were identified. Con formational transition towards the C-form of DNA was observed in solution at the molar ratio Mn2+/DNA-phosphates between 0.1 and 1.5. The exact ratio depended on the ionic strength and increased with increasing NaCl concentration. Although manganese interacted with the phosphates and bases of DNA at higher metal concentrations, it is unlikely that direct chelation occurred. A model for the interaction between manganese ions and DNA mediated by water is suggested destabilizing the double helix and partially breaking the hydrogen bonds between the base pairs. At high Mn2+ concentrations DNA aggregation was observed.