Effect of prolonged intravenous glucose and essential amino acid infusion on nitrogen balance, muscle protein degradation and ubiquitin-conjugating enzyme gene expression in calves

Background: Intravenous infusions of glucose and amino acids increase both nitrogen balance and muscle accretion. We hypothesised that co-infusion of glucose ( to stimulate insulin) and essential amino acids (EAA) would act additively to improve nitrogen balance by decreasing muscle protein degradation in association with alterations in muscle expression of components of the ubiquitin-proteasome proteolytic pathway. Methods: We examined the effect of a 5 day intravenous infusions of saline, glucose, EAA and glucose + EAA, on urinary nitrogen excretion and muscle protein degradation. We carried out the study in 6 restrained calves since ruminants offer the advantage that muscle protein degradation can be assessed by excretion of 3 methyl-histidine and multiple muscle biopsies can be taken from the same animal. On the final day of infusion blood samples were taken for hormone and metabolite measurement and muscle biopsies for expression of ubiquitin, the 14-kDa E2 ubiquitin conjugating enzyme, and proteasome sub-units C2 and C8. Results: On day 5 of glucose infusion, plasma glucose, insulin and IGF-1 concentrations were increased while urea nitrogen excretion and myofibrillar protein degradation was decreased. Co-infusion of glucose + EAA prevented the loss of urinary nitrogen observed with EAA infusions alone and enhanced the increase in plasma IGF-1 concentration but there was no synergistic effect of glucose + EAA on the decrease in myofibrillar protein degradation. Muscle mRNA expression of the ubiquitin conjugating enzyme, 14-kDa E2 and proteasome sub-unit C2 were significantly decreased, after glucose but not amino acid infusions, and there was no further response to the combined infusions of glucose + EAA. Conclusion: Prolonged glucose infusion decreases myofibrillar protein degradation, prevents the excretion of infused EAA, and acts additively with EAA to increase plasma IGF-1 and improve net nitrogen balance. There was no evidence of synergistic effects between glucose + EAA infusion on muscle protein degradation or expression of components of the ubiquitin-proteasome proteolytic pathway.

Effect of plasma insulin and branched-chain amino acids on skeletal muscle protein synthesis in fasted lambs

The increase in fractional rate of protein synthesis (K-s) in the skeletal muscle of growing rats during the transition from fasted to fed state has been explained by the synergistic action of a rise in plasma insulin and branched-chain amino acids (BCAA). Since growing lambs Also exhibit an increase in K-s with level of feed intake, the objective of the present study was to determine if this synergistic relationship between insulin and BCAA also occurs in ruminant animals. Six 30 kg fasted (72 h) lambs (8 months of age) received each of four treatments, which were based on continuous infusion into the jugular vein for 6 h of: (1) saline (155 mmol NaCl/l); (2) a mixture of BCAA (0.778 mumol leucine, 0.640 mumol isoleucine and 0.693 mumol valine/min.kg); (3) 18.7 mumol glucose/min.kg (to induce endogenous insulin secretion): (4) co-infusion of BCAA and glucose. Within each period all animals received the same isotope of phenylalanine, (Phe) as follows: (1) L-[1-C-13]Phe; (2) L-phenyl-[ring H-2(5)]-alanine; (3) L-[N-15]Phe; (4) L-[ring 2,6-H-3]Phe. Blood was sampled serially during infusions to measure plasma concentrations of insulin, glucose and amino acids, and plasma free Phe isotopic activity; biopsies were taken 6 h after the beginning of infusions to determine K-s in in. longissimus dorsi and vastus muscle. Compared with control (saline-infused) lambs, K-s was increased by an average of 40% at the end of glucose infusion, but this effect was not statistically significant in either of the muscles sampled. BCAA infusion, alone or in combination with glucose, also had no significant effect on K-s compared with control sheep. K-s was approximately 60% greater for vastus muscle than for m. longissimus dorsi (P<0.01), regardless of treatment. It is concluded that there are signals other than insulin and BCAA that are responsible for the feed-induced increase in K-s in muscle of growing ruminant animals.

The exchange of radiotherapy data as part of an electronic patient-referral system

PURPOSE: To describe the implementation and use of an electronic patient-referral system as an aid to the efficient referral of patients to a remote and specialized treatment center. METHODS AND MATERIALS: A system for the exchange of radiotherapy data between different commercial planning systems and a specially developed planning system for proton therapy has been developed through the use of the PAPYRUS diagnostic image standard as an intermediate format. To ensure the cooperation of the different TPS manufacturers, the number of data sets defined for transfer has been restricted to the three core data sets of CT, VOIs, and three-dimensional dose distributions. As a complement to the exchange of data, network-wide application-sharing (video-conferencing) technologies have been adopted to provide methods for the interactive discussion and assessment of treatments plans with one or more partner clinics. RESULTS: Through the use of evaluation plans based on the exchanged data, referring clinics can accurately assess the advantages offered by proton therapy on a patient-by-patient basis, while the practicality or otherwise of the proposed treatments can simultaneously be assessed by the proton therapy center. Such a system, along with the interactive capabilities provided by video-conferencing methods, has been found to be an efficient solution to the problem of patient assessment and selection at a specialized treatment center, and is a necessary first step toward the full electronic integration of such centers with their remotely situated referral centers.

Introduction XXIX European Seminar in Ethnomusicology: Cultural Mapping and Musical Diversity

«Cultural mapping» has become a central keyword in the UNESCO strategy to protect world cultural and natural heritage. It can be described as a tool to increase the awareness of cultural diversity. As Crawhall (2009) pointed out, cultural mapping was initially considered to represent the «landscapes in two or three dimensions from the perspectives of indigenous and local peoples». It thus transforms the intangible cultural heritage to visible items by establishing profiles of cultures and communities, including music traditions. Cultural mapping is used as a resource for a variety of purposes as broad as peace building, adaptation to climate change, sustainability management, heritage debate and management, but can also become highly useful in the analysis of conflict points. Music plays a significant role in each of these aspects. This year’s symposium invites to highlight, yet also to critically reassess this topic from the following ethnomusicological perspectives: - The method of cultural mapping in ethnomusicology What approaches and research techniques have been used so far to establish musical maps in this context? What kinds of maps have been developed (and, for example, how far do these relate to indigenous mental maps that have only been transmitted orally)? How far do these modern approaches deviate from the earlier cultural mapping approaches of the cultural area approaches that were still evident with Alan P. Merriam and in Alan Lomax` Cantometrics? In how far are the methods of cultural mapping and of ethnomusicological fieldwork different and how can they benefit from each other? - Intangible cultural heritage and musical diversity As the 2003 UNESCO Convention for the Safeguarding of the Intangible Cultural Heritage pointed out in Article 12, each state signing the declaration «shall draw up, in a manner geared to its own situation, one or more inventories of the intangible cultural heritage, present in its territory and monitor these.» This symposium calls for a critical re-assessment of the hitherto established UNESCO intangible cultural heritage lists. The idea is to highlight the sensitive nature and the effects of the various heritage representations. «Heritage» is understood here as a selection from a selection – a small subset of history that relates to a given group of people in a particular place, at a specific time (Dann and Seaton 2001:26). This can include presentations of case studies, yet also a critical re-analysis of the selection process, e.g. who was included – or even excluded (and why)? Who were the decision makers? How can the role of ethnomusicology be described here? Where are the (existent and possible) conflict points (politically, socially, legally, etc.)? What kinds of solution strategies are available to us? How is the issue of diversity – that has been so strongly emphasized in the UNESCO declarations – reflected in the approaches? How might diversity be represented in future approaches? How does the selection process affect musical canonization (and exclusion)? What is the role of archives in this process? - Cultural landscape and music As defined by the World Heritage Committee, cultural landscapes can be understood as a distinct geographical area representing the «combined work of nature and man» (http://whc.unesco.org/en/culturallandscape/). This sub-topic calls for a more detailed – and general – exploration of the exact relation between nature/landscape (and definition of such) and music/sound. How exactly is landscape interrelated with music – and identified (and vice versa)? How is this interrelation being applied and exploited in a (inter-)national context?

The effect of surgical titanium rods on proton therapy delivered for cervical bone tumors: experimental validation using an anthropomorphic phantom.

To investigate the effect of metal implants in proton radiotherapy, dose distributions of different, clinically relevant treatment plans have been measured in an anthropomorphic phantom and compared to treatment planning predictions. The anthropomorphic phantom, which is sliced into four segments in the cranio-caudal direction, is composed of tissue equivalent materials and contains a titanium implant in a vertebral body in the cervical region. GafChromic® films were laid between the different segments to measure the 2D delivered dose. Three different four-field plans have then been applied: a Single-Field-Uniform-Dose (SFUD) plan, both with and without artifact correction implemented, and an Intensity-Modulated-Proton-Therapy (IMPT) plan with the artifacts corrected. For corrections, the artifacts were manually outlined and the Hounsfield Units manually set to an average value for soft tissue. Results show a surprisingly good agreement between prescribed and delivered dose distributions when artifacts have been corrected, with > 97% and 98% of points fulfilling the gamma criterion of 3%/3 mm for both SFUD and the IMPT plans, respectively. In contrast, without artifact corrections, up to 18% of measured points fail the gamma criterion of 3%/3 mm for the SFUD plan. These measurements indicate that correcting manually for the reconstruction artifacts resulting from metal implants substantially improves the accuracy of the calculated dose distribution.

Long-term outcomes and prognostic factors of skull-base chondrosarcoma patients treated with pencil-beam scanning proton therapy at the Paul Scherrer Institute

BACKGROUND Skull-base chondrosarcoma (ChSa) is a rare disease, and the prognostication of this disease entity is ill defined. METHODS We assessed the long-term local control (LC) results, overall survival (OS), and prognostic factors of skull-base ChSa patients treated with pencil beam scanning proton therapy (PBS PT). Seventy-seven (male, 35; 46%) patients with histologically confirmed ChSa were treated at the Paul Scherrer Institute. Median age was 38.9 years (range, 10.2-70.0y). Median delivered dose was 70.0 GyRBE (range, 64.0-76.0 GyRBE). LC, OS, and toxicity-free survival (TFS) rates were calculated using the Kaplan Meier method. RESULTS After a mean follow-up of 69.2 months (range, 4.6-190.8 mo), 6 local (7.8%) failures were observed, 2 of which were late failures. Five (6.5%) patients died. The actuarial 8-year LC and OS were 89.7% and 93.5%, respectively. Tumor volume > 25 cm(3) (P = .02), brainstem/optic apparatus compression at the time of PT (P = .04) and age >30 years (P = .08) were associated with lower rates of LC. High-grade (≥3) radiation-induced toxicity was observed in 6 (7.8%) patients. The 8-year high-grade TFS was 90.8%. A higher rate of high-grade toxicity was observed for older patients (P = .073), those with larger tumor volume (P = .069), and those treated with 5 weekly fractions (P = .069). CONCLUSIONS This is the largest PT series reporting the outcome of patients with low-grade ChSa of the skull base treated with PBS only. Our data indicate that protons are both safe and effective. Tumor volume, brainstem/optic apparatus compression, and age were prognosticators of local failures.

Pencil Beam Scanning Proton Therapy for Pediatric Parameningeal Rhabdomyosarcomas: Clinical Outcome of Patients Treated at the Paul Scherrer Institute

BACKGROUND Parameningeal rhabdomyosarcomas (PM-RMSs) represent approximately 25% of all rhabdomyosarcoma (RMS) cases. These tumors are associated with early recurrence and poor prognosis. This study assessed the clinical outcome and late toxicity of pencil beam scanning (PBS) proton therapy (PT) in the treatment of children with PM-RMS. PROCEDURES Thirty-nine children with PM-RMS received neoadjuvant chemotherapy followed by PBS-PT at the Paul Scherrer Institute, with concomitant chemotherapy. The median age was 5.8 years (range, 1.2-16.1). Due to young age, 25 patients (64%) required general anesthesia during PT. The median time from the start of chemotherapy to PT was 13 weeks (range, 3-23 weeks). Median prescription dose was 54 Gy (relative biologic effectiveness, RBE). RESULTS With a mean follow-up of 41 months (range, 9-106 months), 10 patients failed. The actuarial 5-year progression-free survival (PFS) was 72% (95% CI, 67-94%) and the 5-year overall survival was 73% (95% CI, 69-96%). On univariate analysis, a delay in the initiation of PT (>13 weeks) was a significant detrimental factor for PFS. Three (8%) patients presented with grade 3 radiation-induced toxicity. The estimated actuarial 5-year toxicity ≥grade 3 free survival was 95% (95% CI, 94-96%). CONCLUSIONS Our data contribute to the growing body of evidence demonstrating the safety and effectiveness of PT for pediatric patients with PM-RMS. These preliminary results are encouraging and in line with other combined proton-photon and photons series; observed toxicity was acceptable.

Robustness of the Voluntary Breath-Hold Approach for the Treatment of Peripheral Lung Tumors Using Hypofractionated Pencil Beam Scanning Proton Therapy.

PURPOSE The safe clinical implementation of pencil beam scanning (PBS) proton therapy for lung tumors is complicated by the delivery uncertainties caused by breathing motion. The purpose of this feasibility study was to investigate whether a voluntary breath-hold technique could limit the delivery uncertainties resulting from interfractional motion. METHODS AND MATERIALS Data from 15 patients with peripheral lung tumors previously treated with stereotactic radiation therapy were included in this study. The patients had 1 computed tomographic (CT) scan in voluntary breath-hold acquired before treatment and 3 scans during the treatment course. PBS proton treatment plans with 2 fields (2F) and 3 fields (3F), respectively, were calculated based on the planning CT scan and subsequently recalculated on the 3 repeated CT scans. Recalculated plans were considered robust if the V95% (volume receiving ≥95% of the prescribed dose) of the gross target volume (GTV) was within 5% of what was expected from the planning CT data throughout the simulated treatment. RESULTS A total of 14/15 simulated treatments for both 2F and 3F met the robustness criteria. Reduced V95% was associated with baseline shifts (2F, P=.056; 3F, P=.008) and tumor size (2F, P=.025; 3F, P=.025). Smaller tumors with large baseline shifts were also at risk for reduced V95% (interaction term baseline/size: 2F, P=.005; 3F, P=.002). CONCLUSIONS The breath-hold approach is a realistic clinical option for treating lung tumors with PBS proton therapy. Potential risk factors for reduced V95% are small targets in combination with large baseline shifts. On the basis of these results, the baseline shift of the tumor should be monitored (eg, through image guided therapy), and appropriate measures should be taken accordingly. The intrafractional motion needs to be investigated to confirm that the breath-hold approach is robust.

Improving 4D plan quality for PBS-based liver tumour treatments by combining online image guided beam gating with rescanning.

Pencil beam scanned (PBS) proton therapy has many advantages over conventional radiotherapy, but its effectiveness for treating mobile tumours remains questionable. Gating dose delivery to the breathing pattern is a well-developed method in conventional radiotherapy for mitigating tumour-motion, but its clinical efficiency for PBS proton therapy is not yet well documented. In this study, the dosimetric benefits and the treatment efficiency of beam gating for PBS proton therapy has been comprehensively evaluated. A series of dedicated 4D dose calculations (4DDC) have been performed on 9 different 4DCT(MRI) liver data sets, which give realistic 4DCT extracting motion information from 4DMRI. The value of 4DCT(MRI) is its capability of providing not only patient geometries and deformable breathing characteristics, but also includes variations in the breathing patterns between breathing cycles. In order to monitor target motion and derive a gating signal, we simulate time-resolved beams' eye view (BEV) x-ray images as an online motion surrogate. 4DDCs have been performed using three amplitude-based gating window sizes (10/5/3 mm) with motion surrogates derived from either pre-implanted fiducial markers or the diaphragm. In addition, gating has also been simulated in combination with up to 19 times rescanning using either volumetric or layered approaches. The quality of the resulting 4DDC plans has been quantified in terms of the plan homogeneity index (HI), total treatment time and duty cycle. Results show that neither beam gating nor rescanning alone can fully retrieve the plan homogeneity of the static reference plan. Especially for variable breathing patterns, reductions of the effective duty cycle to as low as 10% have been observed with the smallest gating rescanning window (3 mm), implying that gating on its own for such cases would result in much longer treatment times. In addition, when rescanning is applied on its own, large differences between volumetric and layered rescanning have been observed as a function of increasing number of re-scans. However, once gating and rescanning is combined, HI to within 2% of the static plan could be achieved in the clinical target volume, with only moderately prolonged treatment times, irrespective of the rescanning strategy used. Moreover, these results are independent of the motion surrogate used. In conclusion, our results suggest image guided beam gating, combined with rescanning, is a feasible, effective and efficient motion mitigation approach for PBS-based liver tumour treatments.

Dose-painting intensity-modulated proton therapy for intermediate- and high-risk meningioma.

BACKGROUND Newly diagnosed WHO grade II-III or any WHO grade recurrent meningioma exhibit an aggressive behavior and thus are considered as high- or intermediate risk tumors. Given the unsatisfactory rates of disease control and survival after primary or adjuvant radiation therapy, optimization of treatment strategies is needed. We investigated the potential of dose-painting intensity-modulated proton beam-therapy (IMPT) for intermediate- and high-risk meningioma. MATERIAL AND METHODS Imaging data from five patients undergoing proton beam-therapy were used. The dose-painting target was defined using [68]Ga-[1,4,7,10-tetraazacyclododecane tetraacetic acid]- d-Phe(1),Tyr(3)-octreotate ([68]Ga-DOTATATE)-positron emission tomography (PET) in target delineation. IMPT and photon intensity-modulated radiation therapy (IMRT) treatment plans were generated for each patient using an in-house developed treatment planning system (TPS) supporting spot-scanning technology and a commercial TPS, respectively. Doses of 66 Gy (2.2 Gy/fraction) and 54 Gy (1.8 Gy/fraction) were prescribed to the PET-based planning target volume (PTVPET) and the union of PET- and anatomical imaging-based PTV, respectively, in 30 fractions, using simultaneous integrated boost. RESULTS Dose coverage of the PTVsPET was equally good or slightly better in IMPT plans: dose inhomogeneity was 10 ± 3% in the IMPT plans vs. 13 ± 1% in the IMRT plans (p = 0.33). The brain Dmean and brainstem D50 were small in the IMPT plans: 26.5 ± 1.5 Gy(RBE) and 0.002 ± 0.0 Gy(RBE), respectively, vs. 29.5 ± 1.5 Gy (p = 0.001) and 7.5 ± 11.1 Gy (p = 0.02) for the IMRT plans, respectively. The doses delivered to the optic structures were also decreased with IMPT. CONCLUSIONS Dose-painting IMPT is technically feasible using currently available planning tools and resulted in dose conformity of the dose-painted target comparable to IMRT with a significant reduction of radiation dose delivered to the brain, brainstem and optic apparatus. Dose escalation with IMPT may improve tumor control and decrease radiation-induced toxicity.

The Diageotropica Gene Differentially Affects Auxin and Cytokinin Responses throughout Development in Tomato1

The interactions between the plant hormones auxin and cytokinin throughout plant development are complex, and genetic investigations of the interdependency of auxin and cytokinin signaling have been limited. We have characterized the cytokinin sensitivity of the auxin-resistant diageotropica (dgt) mutant of tomato (Lycopersicon esculentum Mill.) in a range of auxin- and cytokinin-regulated responses. Intact, etiolated dgt seedlings showed cross-resistance to cytokinin with respect to root elongation, but cytokinin effects on hypocotyl growth and ethylene synthesis in these seedlings were not impaired by the dgt mutation. Seven-week-old, green wild-type and dgt plants were also equally sensitive to cytokinin with respect to shoot growth and hypocotyl and internode elongation. The effects of cytokinin and the dgt mutation on these processes appeared additive. In tissue culture organ regeneration from dgt hypocotyl explants showed reduced sensitivity to auxin but normal sensitivity to cytokinin, and the effects of cytokinin and the mutation were again additive. However, although callus induction from dgt hypocotyl explants required auxin and cytokinin, dgt calli did not show the typical concentration-dependent stimulation of growth by either auxin or cytokinin observed in wild-type calli. Cross-resistance of the dgt mutant to cytokinin thus was found to be limited to a small subset of auxin- and cytokinin-regulated growth processes affected by the dgt mutation, indicating that auxin and cytokinin regulate plant growth through both shared and separate signaling pathways.

Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach.

The structural relationships between interstitial cells of Cajal (ICC), varicose nerve fibers, and smooth muscle cells in the gastrointestinal tract have led to the suggestion that ICC may be involved in or mediate enteric neurotransmission. We characterized the distribution of ICC in the murine stomach and found two distinct classes on the basis of morphology and immunoreactivity to antibodies against c-Kit receptors. ICC with multiple processes formed a network in the myenteric plexus region from corpus to pylorus. Spindle-shaped ICC were found within the circular and longitudinal muscle layers (IC-IM) throughout the stomach. The density of these cells was greatest in the proximal stomach. IC-IM ran along nerve fibers and were closely associated with nerve terminals and adjacent smooth muscle cells. IC-IM failed to develop in mice with mutations in c-kit. Therefore, we used W/W(V) mutants to test whether IC-IM mediate neural inputs in muscles of the gastric fundus. The distribution of inhibitory nerves in the stomachs of c-kit mutants was normal, but NO-dependent inhibitory neuro-regulation was greatly reduced. Smooth muscle tissues of W/W(V) mutants relaxed in response to exogenous sodium nitroprusside, but the membrane potential effects of sodium nitroprusside were attenuated. These data suggest that IC-IM play a critical serial role in NO-dependent neurotransmission: the cellular mechanism(s) responsible for transducing NO into electrical responses may be expressed in IC-IM. Loss of these cells causes loss of electrical responsiveness and greatly reduces responses to nitrergic nerve stimulation.

Método para análise da interação fluido-estrutura em travessas do pré-distribuidor de turbinas hidráulicas.

Um dos grandes desafios enfrentados pelos fabricantes de turbinas hidráulicas é prevenir o aparecimento de vibrações induzidas pelo escoamento nas travessas do pré-distribuidor e pás do rotor. Considerando apenas as travessas, e atribuídos a tais vibrações, foram relatados 28 casos de trincas ou ruídos anormais nas últimas décadas, que acarretaram enormes prejuízos associados a reparos, atrasos e perda de geração. O estado da arte na prevenção destes problemas baseia-se na utilização de sofisticados, e caros, programas comerciais de dinâmica dos fluidos computacional para o cálculo transiente do fenômeno. Este trabalho faz uma ampla revisão bibliográfica e levantamento de eventos de trincas ou ruídos ocorridos em travessas nos últimos 50 anos. Propõe, então, um enfoque alternativo, baseado exclusivamente em ferramentas de código aberto. A partir de hipóteses simplificadoras devidamente justificadas, o problema é formulado matematicamente de forma bidimensional, no plano da seção transversal da travessa, levando em conta a interação fluido-estrutura. Nesta estratégia, as equações de Navier-Stokes são resolvidas pelo método dos elementos finitos por meio da biblioteca gratuita oomph-lib. Um código especial em C++ é desenvolvido para o problema de interação fluido-estrutura, no qual o fenômeno de turbulência é levado em consideração por meio de um algoritmo baseado no modelo de Baldwin-Lomax. O método proposto é validado por meio da comparação dos resultados obtidos com referências e medições disponíveis na literatura, que tratam de problemas de barras retangulares suportadas elasticamente. O trabalho finaliza com a aplicação do método a um estudo de caso envolvendo uma travessa particular.

Trends in urban roadway congestion: 1982 to 1991. Volume 1: annual report.

Texas Department of Transportation, Austin

Trends in urban roadway congestion: 1982 to 1991. Volume 2: methodology and urbanized area data.

Texas Department of Transportation, Austin