Antibacterial action of penicillin against Mycobacterium avium complex.

INTRODUCTION: ß-lactam antibiotics are promising treatments for Mycobacterium avium complex (MAC) lung disease. We hypothesized that benzylpenicillin has efficacy against MAC. METHODS: Benzylpenicillin lung concentration-time profiles of seven doses in three dosing schedules were administered for 28 days using the hollow fiber system model of intracellular MAC (HFS-MAC). Data were analyzed using the inhibitory sigmoid maximal effect (Emax) model for each sampling day, while two ordinary differential equations (ODEs) were used for the wild-type and penicillin-resistant mutants. RESULTS: Benzylpenicillin killed >2.1 log10 colony-forming unit (CFU)/mL below Day 0, better than azithromycin, ethambutol, and rifabutin. Efficacy was terminated by acquired resistance. Sigmoid Emax parameter estimates significantly differed between sampling days and were a poor fit. However, ODE model parameter estimates vs. exposure were a better fit. The exposure mediating Emax was 84.6% (95% CI 76.91-82.98) of time concentration exceeded the minimum inhibitory concentration (MIC). In Monte Carlo experiments, 24 million international units of benzylpenicillin continuous infusion achieved the target exposure in lungs of >90% of 10,000 subjects until an MIC of 64 mg/L, designated the susceptibility breakpoint. CONCLUSIONS: Benzylpenicillin demonstrated a better bactericidal effect against MAC than guideline-recommended drugs before the development of resistance. Its role in combination therapy with other drugs with better efficacy than guideline-recommended drugs should be explored.

INTRODUCTION: Les ß-lactamines représentent des options thérapeutiques prometteuses pour le traitement de la maladie pulmonaire à complexe Mycobacterium avium (MAC). Notre hypothèse suggère que la benzylpénicilline pourrait être efficace contre cette maladie pulmonaire causée par M. avium. MÉTHODES: Les concentrations pulmonaires de benzylpénicilline ont été mesurées à différents moments après l'administration de sept doses selon trois schémas différents pendant 28 jours dans le modèle de MAC intracellulaire du système de fibres creuses (HFS-MAC). Les données ont été analysées en utilisant un modèle sigmoïde inhibiteur à effet maximal (Emax) pour chaque jour d'échantillonnage, et deux équations différentielles ordinaires (ODE) ont été appliquées pour les souches sauvages et les mutants résistants à la pénicilline. RÉSULTATS: La benzylpénicilline a provoqué une réduction de >2,1 log10 CFU/mL en dessous du jour 0, surpassant ainsi l'azithromycine, l'éthambutol et la rifabutine. Cependant, son efficacité a été compromise par l'émergence d'une résistance. Les estimations des paramètres de l'Emax sigmoïde ont montré des différences significatives entre les jours d'échantillonnage et étaient mal ajustées. En revanche, les estimations des paramètres du modèle ODE en fonction de l'exposition étaient plus précises. L'exposition médiane de l'Emax était de 84,6% (IC à 95% 76,91­82,98) du temps où la concentration dépassait la concentration minimale inhibitrice (MIC, pour l'anglais « minimum inhibitory concentration ¼). Dans les simulations de Monte Carlo, une perfusion continue de 24 millions d'unités internationales de benzylpénicilline a permis d'atteindre l'exposition cible dans les poumons de plus de 90% des 10 000 sujets, jusqu'à ce qu'une MIC de 64 mg/L soit atteinte, indiquant ainsi le point de rupture de la sensibilité. CONCLUSIONS: La benzylpénicilline a montré une efficacité bactéricide supérieure contre le MAC par rapport aux médicaments recommandés par les lignes directrices avant l'émergence de la résistance. Il convient d'explorer son utilisation dans une thérapie combinée avec des médicaments plus performants que ceux recommandés par les lignes directrices.

Tinospora cordifolia modulates the seminal parameters, leakage of intracellular enzymes and seminal antioxidants in equilibrated and cryopreserved semen of Sahiwal bulls.

The present study was undertaken to assess the effects of stem extract of Tinospora cordifolia (Giloy or Guduchi) in the semen extender on seminal parameters, leakage of intracellular enzymes and antioxidants in semen of Sahiwal bull. A total of 48 ejaculates from four bulls were selected for the study. Spermatozoa of 25 × 106 were incubated in 100, 300 and 500 µg of stem extract of Guduchi as Gr II, III and IV, respectively, and pre-freeze and post-thaw semen samples were analysed for seminal parameters [motility, viability, total sperm abnormality (TSA), plasma membrane integrity (PMI) and acrosomal integrity (AcI)], intracellular enzymes [aspartate aminotransferase (AST) and lactate dehydrogenase (LDH)] and seminal antioxidants [superoxide dismutase (SOD) and catalase] in comparison with an untreated control group (Gr I). The results revealed that stem extract-treated semen had significantly (p < .05) higher motility, viability, PMI, AcI, SOD and catalase and had significantly (p < .05) lower TSA, AST and LDH compared to those in untreated control group at pre-freeze and post-thaw stages. Semen treated with 100 µg stem extract/25 × 106 spermatozoa had significantly (p < .05) higher motility, viability, PMI, AcI, SOD and catalase and had significantly (p < .05) lower TSA, AST and LDH compared to those in control, 300- and 500-µg-treated groups at pre-freeze and post-thaw stages. Further, these seminal parameters and antioxidants were showing decreasing trend and TSA and leakage of intracellular enzymes were showing increasing trend from Gr II to Gr IV at pre-freeze and post-thaw stages. Thus, 100 µg/25 × 106 spermatozoa were optimum or suitable dose for cryopreservation of Sahiwal bull semen. The study concluded that T. cordifolia stem extract 100 µg/25 × 106 spermatozoa in the semen extender can be effectively utilized to reduce the oxidative stress and improve the pre-freeze and post-thaw seminal parameters in Sahiwal bull. However, further studies on effects of different concentrations of stem extract on in vitro or in vivo fertility trials are to be conducted to assess the impact of the stem extract supplementation in the semen extender on field pregnancy outcomes in bovine species.

An Audit for Radiotherapy Planning and Treatment Errors From a Low-Middle-Income Country Centre.

AIMS: To report the findings of an audit for radiotherapy errors from a low-middle-income country (LMICs) centre. This would serve as baseline data for radiotherapy error rates, their severity and causes, in such centres where modern error reporting and learning processes still do not exist. MATERIALS AND METHODS: A planned cross-sectional weekly audit of electronic radiotherapy charts at the radiotherapy planning and delivery step for all patients treated with curative intent was conducted. Detailed analysis was carried out to determine the step of origin of error, time and contributing factors. They were graded as per indigenous institutional (TMC) radiotherapy error grading (TREG) system and the contributing factors identified were prioritised using the product of frequency, severity and ease of detection. RESULTS: In total, 1005 consecutive radically treated patients' charts were audited, 67 radiotherapy errors affecting 60 patients, including 42 incidents and 25 near-misses were identified. Transcriptional errors (29%) were the most common type. Most errors occurred at the time of treatment planning (59.7%), with "plan information transfer to the radiation oncology information system" being the most frequently affected sub-step of the radiotherapy process (47.8%). More errors were noted at cobalt units (52/67; 77.6%) than at linear accelerators. Trend analysis showed an increased number of radiotherapy incidents on Fridays and near-misses on Mondays. Trend for increased radiotherapy errors noted in the evening over other shifts. On severity grading, most of the errors (54/60; 90%) were clinically insignificant (grade I/II). Inadequacies and non-adherence towards standard operating procedures, poor documentation and lack of continuing education were the three most prominent causes. CONCLUSION: Preliminary data suggest a vulnerability of LMIC set-up to radiotherapy errors and emphasises the need for the development of longitudinal prospective processes, such as voluntary reporting and a continued education system, to ensure robust and comprehensive safe practises on par with centres in developed countries.

Implementation of failure mode and effective analysis for high dose rate brachytherapy at Tata Memorial Hospital, Mumbai, India.

PURPOSE: To report our experience of failure mode and effective analysis for high dose rate brachytherapy of gynaecological cancer carried out in our hospital. MATERIALS AND METHODS: Failure mode and effective analysis process described in AAPM TG 100 was followed: a multidisciplinary team consisting of two physicians, physicists, dosimetrists, a medical resident, a nurse, and a secretary was formed. A weekly meeting was held for four months. A process tree was created based on the overview of the entire process, with the main branches as follows: procedure in the operating room, patient imaging, contouring, treatment planning, machine quality assurance and treatment delivery. Each team member assigned the risk probability numbers based on the predefined scoring system. For a particular failure mode, if the risk probability number assigned by one member differed from the other, the highest risk probability number was taken into consideration. RESULTS: The process tree consisted of 185 nodes, with risk probability numbers ranging from 1-220, with 77 possible failure modes. Four nodes were found with risk probability numbers greater than 200, which were considered for immediate process improvements. Twenty-four nodes were found to be with risk probability numbers ranging from 100 to 200. All 24 processes were considered for process improvement, out of which 12 were found effective and feasible, which includes failure nodes with high severity score at least 8. The processes with high-risk probability numbers (greater than 200) were reduced after the introduction of process improvements. For the other processes, standard procedures were modified. The common causes of failure, were found to be due to lack of attention, human error and work pressure. CONCLUSIONS: Failure mode and effective analysis is a useful tool that uses a systematic approach for quality management of a specific process.

Commissioning and validation of commercial deformable image registration software for adaptive contouring.

PURPOSE: To report the commissioning and validation of deformable image registration(DIR) software for adaptive contouring. METHODS: DIR (SmartAdapt®v13.6) was validated using two methods namely contour propagation accuracy and landmark tracking, using physical phantoms and clinical images of various disease sites. Five in-house made phantoms with various known deformations and a set of 10 virtual phantoms were used. Displacement in lateral, anterio-posterior (AP) and superior-inferior (SI) direction were evaluated for various organs and compared with the ground truth. Four clinical sites namely, brain (n = 5), HN (n = 9), cervix (n = 18) and prostate (n = 23) were used. Organs were manually delineated by a radiation oncologist, compared with the deformable image registration (DIR) generated contours. 3D slicer v4.5.0.1 was used to analyze Dice Similarity Co-efficient (DSC), shift in centre of mass (COM) and Hausdorff distances Hf95%/avg. RESULTS: Mean (SD) DSC, Hf95% (mm), Hfavg (mm) and COM of all the phantoms 1-5 were 0.84 (0.2) mm, 5.1 (7.4) mm, 1.6 (2.2) mm, and 1.6 (0.2) mm respectively. Phantom-5 had the largest deformation as compared to phantoms 1-4, and hence had suboptimal indices. The virtual phantom resulted in consistent results for all the ROIs investigated. Contours propagated for brain patients were better with a high DSC score (0.91 (0.04)) as compared to other sites (HN: 0.84, prostate: 0.81 and cervix 0.77). A similar trend was seen in other indices too. The accuracy of propagated contours is limited for complex deformations that include large volume and shape change of bladder and rectum respectively. Visual validation of the propagated contours is recommended for clinical implementation. CONCLUSION: The DIR algorithm was commissioned and validated for adaptive contouring.

Monte Carlo Investigation of Photon Beam Characteristics and its Variation with Incident Electron Beam Parameters for Indigenous Medical Linear Accelerator.

PURPOSE: A Monte Carlo model of a 6 MV medical linear accelerator (linac) unit built indigenously was developed using the BEAMnrc user code of the EGSnrc code system. The model was benchmarked against the measurements. Monte Carlo simulations were carried out for different incident electron beam parameters in the study. MATERIALS AND METHODS: Simulation of indigenously developed linac unit has been carried out using the Monte Carlo based BEAMnrc user-code of the EGSnrc code system. Using the model, percentage depth dose (PDD), and lateral dose profiles were studied using the DOSXYZnrc user code. To identify appropriate electron parameters, three different distributions of electron beam intensity were investigated. For each case, the kinetic energy of the incident electron was varied from 6 to 6.5 MeV (0.1 MeV increment). The calculated dose data were compared against the measurements using the PTW, Germany make RFA dosimetric system (water tank MP3-M and 0.125 cm3 ion chamber). RESULTS: The best fit of incident electron beam parameter was found for the combination of beam energy of 6.2 MeV and circular Gaussian distributed source in X and Y with FWHM of 1.0 mm. PDD and beam profiles (along both X and Y directions) were calculated for the field sizes from 5 cm × 5 cm to 25 cm × 25 cm. The dose difference between the calculated and measured PDD and profile values were under 1%, except for the penumbra region where the maximum deviation was found to be around 2%. CONCLUSIONS: A Monte Carlo model of indigenous linac (6 MV) has been developed and benchmarked against the measured data.

The Effect of the Canine ABCB1-1Δ Mutation on Sedation after Intravenous Administration of Acepromazine.

BACKGROUND: Dog breeds with the ABCB1-1Δ mutation have substantially truncated nonfunctional P-glycoprotein. Dogs homozygous for this mutation (mut/mut) are susceptible to the toxic adverse effects of ivermectin, loperamide, and vincristine. Anecdotal reports suggested ABCB1 mut/mut dogs showed increased depth and duration of acepromazine sedation. HYPOTHESIS/OBJECTIVES: That ABCB1 mut/mut dogs have increased depth and duration of sedation after acepromazine IV compared to normal dogs (nor/nor). ANIMALS: Twenty-nine rough-coated collies were divided into 3 groups of dogs based on their ABCB1 genotype: 10 mut/mut, 10 mut/nor, and 9 nor/nor. METHODS: Dogs were given 0.04 mg/kg of acepromazine IV. Level of sedation, heart rate, respiratory rate, and blood pressure were recorded for 6 hours after acepromazine administration. Area under the curves (AUCs) of the normalized sedation score results were calculated and compared. RESULTS: The median sedation scores for ABCB1 mut/mut dogs were higher than nor/nor dogs at all time points and were higher in mut/nor dogs for the first 2 hours. These differences were not found to be significant for any individual time point (P > .05). The median sedation score AUC for mut/mut dogs was significantly higher than nor/nor dogs (P = .028), but the AUC for mut/nor dogs was not (P = .45). There were no significant differences between groups for heart rate, respiratory rate, and blood pressure (P > .05). CONCLUSIONS AND CLINICAL IMPORTANCE: In ABCB1 mut/mut dogs acepromazine dose rates should be reduced and careful monitoring performed during sedation.

MicroRNA Regulation of Airway Inflammation and Airway Smooth Muscle Function: Relevance to Asthma.

Genetic and environmental factors contribute to the onset and severity of asthma. Molecular pathogenesis of asthma involves changes in gene expression by a variety of inflammatory mediators acting in autocrine and paracrine fashion on effector cells of the airways. Transcriptional regulation of gene expression in resident airway cells has been studied extensively. However, protein function in a target cell can be regulated at multiple levels starting from transcription followed by post-transcription, translation, and post-translation steps. In this context, small noncoding RNAs known as microRNAs (miRNAs) have evolved as one of the key regulators of gene expression post-transcriptionally. Most importantly, miRNA expression is dynamic in nature and can be regulated by a variety of external stimuli. Altered expression of individual or a group of miRNAs is thought to contribute to human diseases. Recent studies have implicated differential expression of miRNAs in the lungs during inflammation. Most importantly, advanced biochemical and molecular tools could be used to manipulate miRNA expression thereby effecting functional changes in target cells and organ systems. This review summarizes the current understanding of miRNA in the regulation of airway function in health and disease, and highlights the potential clinical utility of mRNAs as biomarkers of airway diseases and as potential therapeutic targets.

Probiotic and prebiotic-probiotic PEC microparticles for sustaining and enhancing intestinal probiotic growth.

The aim of the study was to develop and evaluate Polyelectrolyte complex (PEC) microparticles composing Lactobacillus Acidophilus (probiotic) and Fructo oligosaccharide-Lactobacillus Acidophilus (prebiotic-probiotic), for sustaining and enhancing intestinal growth of probiotic bacteria. Gum Karaya-Chitosan(GK-CH) was used to fabricate PEC microparticles by extrusion method. The prepared microparticles were characterized for FT-IR, DSC and particle size and evaluated for percentage yield, swelling, surface morphology, entrapment rate and further studied for influence of prebiotic over probiotic growth. The fabricated PEC microparticles composed of Probiotic and Prebiotic- Probiotic have exhibited sustainability of probiotic bacteria for 12 hrs in GIT conditions and presence of prebiotic in the preparation enhanced the probiotic cell growth. Hence, it can be concluded that PEC between GK-CH was found to be successful in sustaining cell release and presence of prebiotic was found to enhance the probiotic cell growth.

Acceptance criteria for flattening filter-free photon beam from standard medical electron linear accelerator: AERB task group recommendations.

Medical electron linear accelerators with the capability of generating unflat photon (flattening filter-free, FFF) beams are also available commercially for clinical applications in radiotherapy. However, the beam characteristics evaluation criteria and parameters are not yet available for such photon beams. Atomic Energy Regulatory Board (AERB) of India constituted a Task Group comprising experts from regulatory agency, advisory body/research and technical institutions, and clinical radiotherapy centers in the country to evolve and recommend the acceptance criteria for the flattening filter-free (FFF) photon beams. The Task Group thoroughly reviewed the literature and inputs of the manufactures/suppliers of the FFF linac and recommended a set of dosimetry parameters for evaluating the characteristics of the unflat photon beam. The recommendations included the evaluation of quality index, degree of unflatness, difference in percentage surface dose between flat and unflat photon beams, percentage depth dose at 10 cm depth, off-axis-ratios and radiation beam penumbra. The recommended parameters were evaluated for FFF photon beams generated by three different models of the linac, and it was observed that recommended evaluation methods are simple and easy to be implemented with the existing dosimetry and quality assurance infrastructure of the linac facilities of the radiotherapy departments. Recommendations were also made for periodic quality control check of the unflat photon beams and constancy evaluation in the beam characteristics.

Dose optimization in gynecological 3D image based interstitial brachytherapy using martinez universal perineal interstitial template (MUPIT) -an institutional experience.

The aim of this study was to evaluate the dose optimization in 3D image based gynecological interstitial brachytherapy using Martinez Universal Perineal Interstitial Template (MUPIT). Axial CT image data set of 20 patients of gynecological cancer who underwent external radiotherapy and high dose rate (HDR) interstitial brachytherapy using MUPIT was employed to delineate clinical target volume (CTV) and organs at risk (OARs). Geometrical and graphical optimization were done for optimum CTV coverage and sparing of OARs. Coverage Index (CI), dose homogeneity index (DHI), overdose index (OI), dose non-uniformity ratio (DNR), external volume index (EI), conformity index (COIN) and dose volume parameters recommended by GEC-ESTRO were evaluated. The mean CTV, bladder and rectum volume were 137 ± 47cc, 106 ± 41cc and 50 ± 25cc, respectively. Mean CI, DHI and DNR were 0.86 ± 0.03, 0.69 ± 0.11 and 0.31 ± 0.09, while the mean OI, EI, and COIN were 0.08 ± 0.03, 0.07 ± 0.05 and 0.79 ± 0.05, respectively. The estimated mean CTV D90 was 76 ± 11Gy and D100 was 63 ± 9Gy. The different dosimetric parameters of bladder D2cc, D1cc and D0.1cc were 76 ± 11Gy, 81 ± 14Gy, and 98 ± 21Gy and of rectum/recto-sigmoid were 80 ± 17Gy, 85 ± 13Gy, and 124 ± 37Gy, respectively. Dose optimization yields superior coverage with optimal values of indices. Emerging data on 3D image based brachytherapy with reporting and clinical correlation of DVH parameters outcome is enterprizing and provides definite assistance in improving the quality of brachytherapy implants. DVH parameter for urethra in gynecological implants needs to be defined further.

A new paradigm to understand and treat diabetic neuropathy.

The clinical symptoms of diabetic neuropathy (DN) manifest in a time dependent manner as a positive symptoms (i. e. pain, hypersensitivity, tingling, cramps, cold feet etc.) during its early stages and by a loss of function (i. e. loss of sensory perception, delayed wound healing etc.) predominating in the later stages. Elevated blood glucose alone cannot explain the development and progression of DN and the lowering of blood glucose is insufficient in preventing and/or reversing neuropathy in patients with type 2 diabetes. Recently it has been shown that the endogenous reactive metabolite methylglyoxal (MG) can contribute to the gain of function via post-translational modification in DN of neuronal ion channels involved in chemosensing and action potential generation in nociceptive nerve endings. Dicarbonyls, such as MG, that are elevated in diabetic patients, modify DNA as well as extra- and intracellular proteins, leading to the formation of advanced glycation endproducts (AGEs). Increased formation of AGEs leads to increased cellular stress, dysfunction and ultimately cell death. The interaction of AGE-modified proteins through cell surface receptors, such as RAGE, can lead to increased cellular activation and sustained inflammatory responses, which are the molecular hallmarks of the later, degenerative, stages of DN. The direct and indirect effects of dicarbonyls on nerves or neuronal microvascular network provides a unifying mechanism for the development and progression of DN. Targeting the accumulation of MG and/or prevention of RAGE interactions may therefore provide new, more effective, therapeutic approaches for the treatment of DN.

Investigation on the effect of sharp phantom edges on point dose measurement during patient-specific dosimetry with Rapid Arc.

The objective of this work was to investigate and quantify the effect of sharp edges of the phantom on the point dose measurement during patient-specific dosimetry with Rapid Arc (RA). Ten patients with carcinoma of prostate were randomly selected for this dosimetric study. Rapid Arc plans were generated with 6 MV X-rays in the Eclipse (v 8.6.14) with single arc (clockwise). Dosimetry verification plans were generated for two phantoms (cylindrical and rectangular). The cylindrical phantom was solid water (diameter 34 cm) and the rectangular phantom was a water phantom (25 cm × 25 cm × 10 cm). These phantoms were pre-scanned in computed tomography (CT) machine with cylindrical ionization chamber (FC65) in place. The plans were delivered with Novalis Tx linear accelerator with 6 MV X-rays for both the phantoms separately. The measured dose was compared with the planned dose for both the phantoms. Mean percentage deviation between measured and planned doses was found to be 4.19 (SD 0.82) and 3.63 (SD 0.89) for cylindrical and rectangular phantoms, respectively. No significant dosimetric variation was found due to the geometry (sharp edges) of the phantom. The sharp edges of the phantom do not perturb the patient specific Rapid Arc dosimetry significantly.

SU-E-T-424: Inter-Fraction Variation of High Dose Regions of OARS in MR Image Based Cervix Brachytherapy Using Rigid Registration.

PURPOSE: To quantify the inter fraction variation of spatial location of high dose regions of OARs in MR-image based cervix brachytherapy using rigid registration algorithm. METHODS: Retrospective analysis of 27 previously treated patients under EMBRACE multi-centric trial was evaluated. Each patient had two applications, API and AP2 with Vienna applicator. As part of the protocol, all patients underwent MR imaging for each application, followed by volume delineation (Oncentra v3.3) treatment planning & optimization (Plato sunrise, Nucletron), documentation of DVH parameters based on GEC-ESTRO recommendations. The volume receiving the dose D2cc from the plan with which the patient was treated was contoured in each of the image series for OARs rectum, bladder, sigmoid and small bowel region. Both the image series were exported to Eclipse planning system (v8.6.14, VMS) and were co-registered with applicator as the reference using rigid registration Results: Out of 27 patients, the overlapping D2cc volumes were found in 21, 20, 10 and 4 patients for rectum, bladder, sigmoid and small bowel respectively between AP1 and AP2. The mean(SD) volume of overlap of D2cc was 0.20(0.23), 0.17(0.20), 0.07(0.14), and 0.09(0.11) for rectum, bladder, sigmoid and small bowel respectively. The overlap volume had a wide range which is evident from its standard deviation. The mean(SD) difference of the absolute volumes between AP1 and AP2 was 22(20), 5(6), and 11(11) for bladder, rectum and sigmoid respectively. The uncertainties include the calculation of small overlapping volumes of D2cc, co-registration and variation between applications. CONCLUSIONS: The inter-fraction variation of spatial location of high dose regions were more consistent in rectum and bladder and less in sigmoid and much lesser in small bowel region.

SU-E-T-442: Assessing Vertex Beam with its Dosimetric Relevance for Intracranial Tumours: A Computational Exploration.

PURPOSE: To assess the selection of the minimal vertex beam angle for the avoidance of organs at risk (OARs) in radiotherapy planning of brain tumors. METHODS: Seventy patients with intracranial tumors were studied. Three field conformal plans with co-planar or non co-planar beam arrangements with an anterior vertex beam were used. Two methods were studied for determining the vertex angle for avoidance of eye as organ at risk. In the standard technique, the beam's eye view (BEV) was used to determine need of vertex beam. For the vertex beam, the angle was approximated to avoid eyes. In the second method, the angle from the baseplate to the posterior surface of the head and the angle from the posterior surface of the head to the inferior-most extent of the head were measured from sagital view. The minimum vertex angle required was calculated as the complement of the sum of these angles. The dose volume histogram parameters were maintained. RESULTS: Depending on the spatial location of the planning target volume with reference to the eyes, patients were classified into 4 types: no overlap; overlap with eye anteriorly; overlap with eye posteriorly, overlap with eye anteriorly and posteriorly. No additional angulation, positive vertex and negative vertex angles were needed for type 1, 2 and 3 respectively. The angle subtended by the isocenter to the neck rest apex was the required vertex angle for type 4. Of the 36 type 2, 3 and 4 patients the planned vertex angle was more than the calculated vertex angle by over 5 degrees in 10 patients, and less by over 5 degrees in 4 patients. CONCLUSIONS: A simple method for deriving the minimal vertex beam angle for OAR avoidance in radiotherapy planning of intracranial tumors was described and validated.

The GPCR OGR1 (GPR68) mediates diverse signalling and contraction of airway smooth muscle in response to small reductions in extracellular pH.

BACKGROUND AND PURPOSE: Previous studies have linked a reduction in pH in airway, caused by either environmental factors, microaspiration of gastric acid or inflammation, with airway smooth muscle (ASM) contraction and increased airway resistance. Neural mechanisms have been shown to mediate airway contraction in response to reductions in airway pH to < 6.5; whether reduced extracellular pH (pHo) has direct effects on ASM is unknown. EXPERIMENTAL APPROACH: Intracellular signalling events stimulated by reduced pHo in human cultured ASM cells were examined by immunoblotting, phosphoinositide hydrolysis and calcium mobilization assays. ASM cell contractile state was examined using magnetic twisting cytometry. The expression of putative proton-sensing GPCRs in ASM was assessed by real-time PCR. The role of ovarian cancer G protein-coupled receptor 1 (OGR1 or GPR68) in acid-induced ASM signalling and contraction was assessed in cultures subjected to siRNA-mediated OGR1 knockdown. KEY RESULTS: ASM cells responded to incremental reductions in pHo (from pH 8.0 to pH 6.8) by activating multiple signalling pathways, involving p42/p44, PKB, PKA and calcium mobilization. Coincidently, ASM cells contracted in response to decreased pHo with similar 'dose'-dependence. Real-time PCR suggested OGR1 was the only proton-sensing GPCR expressed in ASM cells. Both acid-induced signalling (with the exception of PKB activation) and contraction were significantly attenuated by knockdown of OGR1. CONCLUSIONS AND IMPLICATIONS: These studies reveal OGR1 to be a physiologically relevant GPCR in ASM cells, capable of pleiotropic signalling and mediating contraction in response to small reductions in extracellular pH. Accordingly, ASM OGR1 may contribute to asthma pathology and represent a therapeutic target in obstructive lung diseases.

Electron arc therapy for bilateral chest wall irradiation: treatment planning and dosimetric study.

AIMS: The treatment of patients with synchronous bilateral breast cancer is a challenge. We present a report of dosimetric data of patients with bilateral chest walls as the target treated with electron arc therapy. MATERIALS AND METHODS: Ten consecutive patients who had undergone electron arc therapy to the bilateral chest wall for breast cancer were analysed. After positioning and immobilisation, patients underwent computed tomography scans from the neck to the upper abdomen. Electron arc plans were generated using the PLATO RTS (V1.8.2 Nucletron) treatment planning system. Electron energy was chosen depending upon the depth and thickness of the planning target volume (PTV). For all patients, the arc angle ranged between 80 and 280° (start angle 80°, stop angle 280°). The homogeneity index, coverage index and doses to organs at risk were evaluated. The patient-specific output factor and thermoluminescence dosimetry (TLD) measurements were carried out for all patients. The total planned dose to the PTV was 50Gy/25 fractions/5 weeks. RESULTS: The mean PTV (± standard deviation) was 568.9 (±116)cm(3). The mean PTV coverage was 89 (±5.8)% of the prescribed dose. For the right lung, the mean values of D(1) and D(10) were 46 (±7.6) and 30 (±9)Gy, respectively. For the left lung, the mean values of D(1) and D(10) were 45 (±7) and 27 (±8)Gy, respectively. For the heart, the mean values of D(1), D(5) and D(10) were 21 (±15), 13.5 (±12) and 9 (±9)Gy, respectively. The mean values of TLD at various pre-specified locations on the chest wall surface were 1.84, 1.82, 1.82, 1.89 and 1.78Gy, respectively CONCLUSION: The electron arc technique for treating the bilateral chest wall is a feasible and pragmatic technique. This technique has the twin advantages of adequate coverage of the target volume and sparing of adjacent normal structures. However, compared with other techniques, it needs a firm quality assurance protocol for dosimetry and treatment delivery.

Radiation therapy with implanted cardiac pacemaker devices: a clinical and dosimetric analysis of patients and proposed precautions.

AIMS: To report the radiation planning dosimetric aspects and clinical outcomes of patients with implanted cardiac pacemakers. MATERIALS AND METHODS: Between 2005 and 2009, eight patients with in situ cardiac pacemakers of varied primary site were treated at our hospital. All patients underwent computed tomography-based treatment planning. The target volumes, organs at risk and pacemaker device were all contoured. A treatment plan optimally covering the target area and maximally sparing the pacemaker was generated. All patients were evaluated at baseline, during radiotherapy and after radiotherapy conclusion by a cardiologist as well as pacemaker company personnel. RESULTS: The median age at presentation was 67 (range 53-77) years. There were three men with head and neck primaries, two men with lung primaries and three women with breast primaries. The prescribed dose ranged from 45 to 70 Gy in 25-35 fractions with a daily dose of 1.8-2.0 Gy. Four patients had the pacemaker implanted on the same side as the radiotherapy target. The dose ranges for the minimum, mean and maximum doses to the pacemaker were 0.06-2.0, 0.07-20.6 and 0.14-60.0 Gy, respectively. Radiation therapy was safely delivered in all patients without any untoward effects. At 5 months of median follow-up, all patients were well with no malfunction of the pacemaker. CONCLUSION: A series of eight patients with in situ pacemakers treated with radiotherapy is reported. Radiotherapy can be safely delivered in patients with implanted cardiac pacemakers. However, it mandates a cautious approach in planning and treatment delivery to ensure the least possible dose to the pacemaker. Close liaison with the cardiologist and a pacemaker clinic before, during and after the course of treatment is essential to ensure patient safety.

Do all patients of breast carcinoma need 3-dimensional CT-based planning? A dosimetric study comparing different breast sizes.

Evaluation of dose distribution in a single plane (i.e., 2-dimensional [2D] planning) is simple and less resource-intensive than CT-based 3-dimensional radiotherapy (3DCRT) planning or intensity modulated radiotherapy (IMRT). The aim of the study was to determine if 2D planning could be an appropriate treatment in a subgroup of breast cancer patients based on their breast size. Twenty consecutive patients who underwent breast conservation were planned for radiotherapy. The patients were grouped in 3 different categories based on their respective chest wall separation (CWS) and the thickness of breast, as "small," "medium," and "large." Two more contours were taken at locations 5 cm superior and 5 cm inferior to the isocenter plane. Maximum dose recorded at specified points was compared in superior/inferior slices as compared to the central slice. The mean difference for small breast size was 1.93 (standard deviation [SD] = 1.08). For medium breas size, the mean difference was 2.98 (SD = 2.40). For the large breasts, the mean difference was 4.28 (SD = 2.69). Based on our dosimetric study, breast planning only on the single isocentric contour is an appropriate technique for patients with small breasts. However, for large- and medium-size breasts, CT-based planning and 3D planning have a definite role. These results can be especially useful for rationalizing treatment in busy oncology centers.