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1.
Mol Biol Cell ; 34(3): br3, 2023 03 01.
Article in English | MEDLINE | ID: mdl-36598814

ABSTRACT

Coordination between the microtubule and actin networks is essential for cell motility, neuronal growth cone guidance, and wound healing. Members of the CLASP (cytoplasmic linker-associated protein) family of proteins have been implicated in the cytoskeletal cross-talk between microtubules and actin networks; however, the molecular mechanisms underlying the role of CLASP in cytoskeletal coordination are unclear. Here, we investigate CLASP2α's cross-linking function with microtubules and F-actin. Our results demonstrate that CLASP2α cross-links F-actin to the microtubule lattice in vitro. We find that the cross-linking ability is retained by L-TOG2-S, a minimal construct containing the TOG2 domain and serine-arginine-rich region of CLASP2α. Furthermore, CLASP2α promotes the accumulation of multiple actin filaments along the microtubule, supporting up to 11 F-actin landing events on a single microtubule lattice region. CLASP2α also facilitates the dynamic organization of polymerizing actin filaments templated by the microtubule network, with F-actin forming bridges between individual microtubules. Finally, we find that depletion of CLASPs in vascular smooth muscle cells results in disorganized actin fibers and reduced coalignment of actin fibers with microtubules, suggesting that CLASP and microtubules contribute to higher-order actin structures. Taken together, our results indicate that CLASP2α can directly cross-link F-actin to microtubules and that this microtubule-CLASP-actin interaction may influence overall cytoskeletal organization in cells.


Subject(s)
Actin Cytoskeleton , Actins , Microtubules , Actin Cytoskeleton/metabolism , Actin Cytoskeleton/ultrastructure , Actins/metabolism , Cytoskeleton/metabolism , Microtubule-Associated Proteins/metabolism , Microtubules/metabolism , Microtubules/ultrastructure , Protein Binding , Humans
2.
Biomed Phys Eng Express ; 7(6)2021 09 15.
Article in English | MEDLINE | ID: mdl-34488197

ABSTRACT

In previous works, we showed that incorporating individual airways as organs-at-risk (OARs) in the treatment of lung stereotactic ablative radiotherapy (SAbR) patients potentially mitigates post-SAbR radiation injury. However, the performance of common clinical dose calculation algorithms in airways has not been thoroughly studied. Airways are of particular concern because their small size and the density differences they create have the potential to hinder dose calculation accuracy. To address this gap in knowledge, here we investigate dosimetric accuracy in airways of two commonly used dose calculation algorithms, the anisotropic analytical algorithm (AAA) and Acuros-XB (AXB), recreating clinical treatment plans on a cohort of four SAbR patients. A virtual bronchoscopy software was used to delineate 856 airways on a high-resolution breath-hold CT (BHCT) image acquired for each patient. The planning target volumes (PTVs) and standard thoracic OARs were contoured on an average CT (AVG) image over the breathing cycle. Conformal and intensity-modulated radiation therapy plans were recreated on the BHCT image and on the AVG image, for a total of four plan types per patient. Dose calculations were performed using AAA and AXB, and the differences in maximum and mean dose in each structure were calculated. The median differences in maximum dose among all airways were ≤0.3Gy in magnitude for all four plan types. With airways grouped by dose-to-structure or diameter, median dose differences were still ≤0.5Gy in magnitude, with no clear dependence on airway size. These results, along with our previous airway radiosensitivity works, suggest that dose differences between AAA and AXB correspond to an airway collapse variation ≤0.7% in magnitude. This variation in airway injury risk can be considered as not clinically relevant, and the use of either AAA or AXB is therefore appropriate when including patient airways as individual OARs so as to reduce risk of radiation-induced lung toxicity.


Subject(s)
Bronchoscopy , Radiotherapy, Intensity-Modulated , Algorithms , Humans , Lung/diagnostic imaging , Radiotherapy Dosage , Radiotherapy Planning, Computer-Assisted , Radiotherapy, Intensity-Modulated/adverse effects
3.
Environ Monit Assess ; 193(2): 61, 2021 Jan 14.
Article in English | MEDLINE | ID: mdl-33443643

ABSTRACT

In view of increasing anthropogenic influences and global changes, quantification of carbon assimilation through photosynthesis has gained tremendous significance. Precise estimation of Gross Primary Productivity (GPP) is essential for several ecosystem models and is typically done using coarser scale satellite data. The mangrove ecosystem, which offers significant protection to the coastal environment, is one of the critical habitats from a global change point of view. Light use efficiency (LUE) was measured using diurnal in situ photosynthetic rate observations for 13 dominant mangrove species for 3 seasons at each of the three mangrove dominant test-sites situated along the east and west coast of India. Variations in photosynthetic rates among these species were studied for 3 seasons that indicated varying responses of mangrove ecosystem at each site. Among all species, Rhizophora mucronata and Sonneratia apetala indicated higher values at two of the test-sites. IRS Resourcesat-2 LISS-IV datasets were used for the estimation of GPP. Mean GPP for all the sites varied from 1.2 to 7.7 g C m-2 day-1 with maximum value of 14.4 g C m-2 day-1. Mean values of GPP varied across the sites, based on its maximum LUE values and available photosynthetically active radiation (PAR). The results provide GPP values at much better spatial resolution for a threatened habitat like mangroves that typically survive in a narrow habitat along the coasts.


Subject(s)
Ecosystem , Wetlands , Environmental Monitoring , India , Photosynthesis , Seasons
4.
Phys Med Biol ; 66(4): 045035, 2021 02 16.
Article in English | MEDLINE | ID: mdl-33207334

ABSTRACT

Many surrogate-based motion models (SMMs), proposed to guide motion management in radiotherapy, are constructed by correlating motion of an external surrogate and internal anatomy during CT-simulation. Changes in this correlation define model break down. We validate a methodology that incorporates fluoroscopic (FL) images acquired during treatment for SMM construction and update. Under a prospective IRB, 4DCT scans, VisionRT (VRT) surfaces, and orthogonal FLs were collected from five lung cancer patients. VRT surfaces and two FL time-series were acquired pre- and post-treatment. A simulated annealing optimization scheme was used to estimate optimal lung deformations by maximizing the mutual information (MI) between digitally reconstructed radiographs (DRRs) of the SMM-estimated 3D images and FLs. Our SMM used partial-least-regression and was trained using the optimal deformations and VRT surfaces from the first breathing-cycle. SMM performance was evaluated using the MI score between reference FLs and the corresponding SMM or phase-assigned 4DCT DRRs. The Hausdorff distance for contoured landmarks was used to evaluate target position estimation error. For four out of five patients, two principal components approximated lung surface deformations with submillimeter accuracy. Analysis of the MI score between more than 4000 pairs of FL and DRR demonstrated that our model led to more similarity between the FL and DRR images compared to 4DCT and DRR images from a model based on an a priori correlation model. Our SMM consistently displayed lower mean and 95th percentile Hausdorff distances. For one patient, 95th percentile Hausdorff distance was reduced by 11 mm. Patient-averaged reductions in mean and 95th percentile Hausdorff distances were 3.6 mm and 7 mm for right-lung, and 3.1 mm and 4 mm for left-lung targets. FL data were used to evaluate model performance and investigate the feasibility of model update. Despite variability in breathing, use of post-treatment FL preserved model fidelity and consistently outperformed 4DCT for position estimation.


Subject(s)
Fluoroscopy , Four-Dimensional Computed Tomography , Lung/diagnostic imaging , Lung/physiology , Models, Biological , Movement , Humans , Respiration
5.
Phys Med Biol ; 65(16): 165010, 2020 08 19.
Article in English | MEDLINE | ID: mdl-32575096

ABSTRACT

Recent changes to the guidelines for screening and early diagnosis of lung cancer have increased the interest in preserving post-radiotherapy lung function. Current investigational approaches are based on spatially mapping functional regions and generating regional avoidance plans that preferentially spare highly ventilated/perfused lung. A potentially critical, yet overlooked, aspect of functional avoidance is radiation injury to peripheral airways, which serve as gas conduits to and from functional lung regions. Dose redistribution based solely on regional function may cause irreparable damage to the 'supply chain'. To address this deficiency, we propose the functionally weighted airway sparing (FWAS) method. FWAS (i) maps the bronchial pathways to each functional sub-lobar lung volume; (ii) assigns a weighting factor to each airway based on the relative contribution of the sub-volume to overall lung function; and (iii) creates a treatment plan that aims to preserve these functional pathways. To evaluate it, we used four cases from a retrospective cohort of SAbR patients treated for lung cancer. Each patient's airways were auto-segmented from a diagnostic-quality breath-hold CT using a research virtual bronchoscopy software. A ventilation map was generated from the planning 4DCT to map regional lung function. For each terminal airway, as resolved by the segmentation software, the total ventilation within the sub-lobar volume supported by that airway was estimated and used as a function-based weighting factor. Upstream airways were weighted based on the cumulative volumetric ventilation supported by corresponding downstream airways. Using a previously developed model for airway radiosensitivity, dose constraints were determined for each airway corresponding to a <5% probability of airway collapse. Airway dose constraints, ventilation scores, and clinical dose constraints were input to a swarm optimization-based inverse planning engine to create a 3D conformal SAbR plan (CRT). The FWAS plans were compared to the patients' prescribed CRT clinical plans and the inverse-optimized clinical plans. Depending on the size and location of the tumour, the FWAS plan showed superior preservation of ventilation due to airflow preservation through open pathways (i.e. cumulative ventilation score from the sub-lobar volumes of open pathways). Improvements ranged between 3% and 23%, when comparing to the prescribed clinical plans, and between 3% and 35%, when comparing to the inverse-optimized clinical plans. The three plans satisfied clinical requirements for PTV coverage and OAR dose constraints. These initial results suggest that by sparing pathways to high-functioning lung subregions it is possible to reduce post-SAbR loss of respiratory function.


Subject(s)
Lung Neoplasms/radiotherapy , Lung/physiopathology , Organ Sparing Treatments/methods , Organs at Risk/radiation effects , Pulmonary Ventilation/physiology , Radiotherapy Planning, Computer-Assisted/methods , Radiotherapy, Conformal/methods , Aged , Algorithms , Female , Humans , Male , Middle Aged , Radiotherapy Dosage , Respiration , Retrospective Studies
6.
PDA J Pharm Sci Technol ; 74(4): 468-494, 2020.
Article in English | MEDLINE | ID: mdl-32467176

ABSTRACT

This article reviews currently available scientific literature related to the epidemiology, infectivity, survival, and susceptibility to disinfectants of Coronaviruses, in the context of the controls established to meet good manufacturing practice (GMP) regulations and guidance, and the public health guidance issued specifically to combat the COVID-19 pandemic. The possible impact of the COVID-19 pandemic on the pharmaceutical supply chain is assessed and recommendations are listed for risk mitigation steps to minimize supply disruption to pharmaceutical drug products. Areas addressed include a brief history of the COVID-19 viral pandemic, a description of the virus, the regulatory response to the pandemic, the screening of employees, the persistence of the virus on inanimate surfaces, cleaning and disinfection of manufacturing facilities, the use of GMP-mandated personal protective equipment to counter the spread of the disease, the role of air changes in viral clearance, and approaches to risk assessment and mitigation. Biological medicinal products have a great record of safety, yet the cell cultures used for production can be susceptible to viruses, and contamination events have occurred. Studies on SARS-CoV-2 for it ability to replicate in various mammalian cell lines used for biopharmaceutical manufacturing suggests that the virus poses a low risk and any contamination would be detected by currently used adventitious virus testing. The consequences of the potential virus exposure of manufacturing processes as well as the effectiveness of mitigation efforts are discussed. The pharmaceutical supply chain is complex, traversing many geographies and companies that range from large multinationals to mid- and small-size operations. This paper recommends practices that can be adopted by all companies, irrespective of their size, geographic location, or position in the supply chain.


Subject(s)
Coronavirus Infections/prevention & control , Disinfection/methods , Pandemics/prevention & control , Pharmaceutical Preparations/supply & distribution , Pneumonia, Viral/prevention & control , Animals , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Disinfectants/chemistry , Drug Contamination/prevention & control , Drug Industry/standards , Equipment Contamination/prevention & control , Humans , Pharmaceutical Preparations/standards , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Risk Management/methods , SARS-CoV-2 , Virus Replication
7.
Med Phys ; 46(12): 5407-5420, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31518437

ABSTRACT

PURPOSE: We develop and validate a motion model that uses real-time surface photogrammetry acquired concurrently with four-dimensional computed tomography (4DCT) to estimate respiration-induced changes within the entire irradiated volume, over arbitrarily many respiratory cycles. METHODS: A research, couch-mounted, VisionRT (VRT) system was used to acquire optical surface data (15 Hz, ROI = 15 × 20 cm2 ) from the thoraco-abdominal surface of a consented lung SBRT patient, concurrently with their standard-of-care 4DCT. The end-exhalation phase from the 4DCT was regarded as reference and for each remaining phase, deformation vector fields (DVFs) with respect to the reference phase were computed. To reduce dimensionality, the first two principal components (PCs) of the matrix of nine DVFs were calculated. In parallel, ten phase-averaged VRT surfaces were created. Surface DVFs and corresponding PCs were computed. A principal least squares regression was used to relate the PCs of surface DVF to those of volume DVFs, establishing a relationship between time-varying surface and the underlying time-varying volume. Proof-of-concept validation was performed during each treatment fraction by concurrently acquiring 30 s time series of real-time surface data and "ground truth" kV fluoroscopic data (FL). A ray-tracing algorithm was used to create a digitally reconstructed fluorograph (DRF), and motion trajectories of high-contrast, soft-tissue, anatomical features in the DRF were compared with those from kV FL. RESULTS: For five of the six fluoroscopic acquisition sessions, the model out-performed 4DCT in predicting contour Dice coefficient with respect to fluoroscopy-derived contours. Similarly, the model exhibited a marked improvement over 4DCT for patch positions on the diaphragm. Model patch position errors varied from 5 to -15 mm while 4DCT errors ranged between 5 and -22.4 mm. For one fluoroscopic acquisition, a marked change in the a priori internal-external correlation resulted in model errors comparable to those of 4DCT. CONCLUSIONS: We described the development and a proof-of-concept validation for a volumetric motion model that uses surface photogrammetry to correlate the time-varying thoraco-abdominal surface to the time-varying internal thoraco-abdominal volume. These early results indicate that the proposed approach can result in a marked improvement over 4DCT. While limited by the duration of the fluoroscopic acquisitions as well as the resolution of the acquired images, the DRF-based proof-of-concept technique developed here is model-agnostic, and therefore, has the potential to be used as an in-patient validation tool for other volumetric motion models.


Subject(s)
Four-Dimensional Computed Tomography , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/radiotherapy , Models, Biological , Movement , Photogrammetry , Aged , Dose Fractionation, Radiation , Humans , Lung Neoplasms/physiopathology , Male , Respiration , Time Factors
8.
Phys Med Biol ; 62(5): 1791-1809, 2017 03 07.
Article in English | MEDLINE | ID: mdl-28075331

ABSTRACT

Baseline shifts in respiratory patterns can result in significant spatiotemporal changes in patient anatomy (compared to that captured during simulation), in turn, causing geometric and dosimetric errors in the administration of thoracic and abdominal radiotherapy. We propose predictive modeling of the tumor motion trajectories for predicting a baseline shift ahead of its occurrence. The key idea is to use the features of the tumor motion trajectory over a 1 min window, and predict the occurrence of a baseline shift in the 5 s that immediately follow (lookahead window). In this study, we explored a preliminary trend-based analysis with multi-class annotations as well as a more focused binary classification analysis. In both analyses, a number of different inter-fraction and intra-fraction training strategies were studied, both offline as well as online, along with data sufficiency and skew compensation for class imbalances. The performance of different training strategies were compared across multiple machine learning classification algorithms, including nearest neighbor, Naïve Bayes, linear discriminant and ensemble Adaboost. The prediction performance is evaluated using metrics such as accuracy, precision, recall and the area under the curve (AUC) for repeater operating characteristics curve. The key results of the trend-based analysis indicate that (i) intra-fraction training strategies achieve highest prediction accuracies (90.5-91.4%); (ii) the predictive modeling yields lowest accuracies (50-60%) when the training data does not include any information from the test patient; (iii) the prediction latencies are as low as a few hundred milliseconds, and thus conducive for real-time prediction. The binary classification performance is promising, indicated by high AUCs (0.96-0.98). It also confirms the utility of prior data from previous patients, and also the necessity of training the classifier on some initial data from the new patient for reasonable prediction performance. The ability to predict a baseline shift with a sufficient look-ahead window will enable clinical systems or even human users to hold the treatment beam in such situations, thereby reducing the probability of serious geometric and dosimetric errors.


Subject(s)
Motion , Neoplasms/radiotherapy , Radiotherapy Planning, Computer-Assisted/methods , Respiration , Algorithms , Humans
9.
Phys Med Biol ; 61(16): 6181-202, 2016 08 21.
Article in English | MEDLINE | ID: mdl-27476472

ABSTRACT

A critical aspect of highly potent regimens such as lung stereotactic body radiation therapy (SBRT) is to avoid collateral toxicity while achieving planning target volume (PTV) coverage. In this work, we describe four dimensional conformal radiotherapy using a highly parallelizable swarm intelligence-based stochastic optimization technique. Conventional lung CRT-SBRT uses a 4DCT to create an internal target volume and then, using forward-planning, generates a 3D conformal plan. In contrast, we investigate an inverse-planning strategy that uses 4DCT data to create a 4D conformal plan, which is optimized across the three spatial dimensions (3D) as well as time, as represented by the respiratory phase. The key idea is to use respiratory motion as an additional degree of freedom. We iteratively adjust fluence weights for all beam apertures across all respiratory phases considering OAR sparing, PTV coverage and delivery efficiency. To demonstrate proof-of-concept, five non-small-cell lung cancer SBRT patients were retrospectively studied. The 4D optimized plans achieved PTV coverage comparable to the corresponding clinically delivered plans while showing significantly superior OAR sparing ranging from 26% to 83% for D max heart, 10%-41% for D max esophagus, 31%-68% for D max spinal cord and 7%-32% for V 13 lung.


Subject(s)
Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Four-Dimensional Computed Tomography/methods , Lung Neoplasms/diagnostic imaging , Models, Theoretical , Radiosurgery/methods , Radiotherapy Planning, Computer-Assisted/methods , Radiotherapy, Conformal/methods , Carcinoma, Non-Small-Cell Lung/surgery , Humans , Lung Neoplasms/surgery , Radiotherapy Dosage , Retrospective Studies
10.
Herz ; 40(3): 402-9, 2015 May.
Article in English | MEDLINE | ID: mdl-25963172

ABSTRACT

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a rare cardiomyopathy associated with life-threatening arrhythmias and an increased risk of sudden cardiac death. In addition to mutations in desmosomal genes, environmental factors such as exercise and sport have been implicated in the pathogenesis of the disease. Recent studies have shown that exercise may be associated with adverse outcomes in patients with ARVD/C. On the basis of current evidence, patients with ARVD/C are recommended to limit exercise irrespective of their mutation status. Some studies have suggested the presence of an entirely acquired form of the disease caused by exercise, which has been dubbed "exercise-induced ARVD/C."


Subject(s)
Arrhythmogenic Right Ventricular Dysplasia/diagnosis , Arrhythmogenic Right Ventricular Dysplasia/genetics , Death, Sudden, Cardiac/prevention & control , Desmosomes/genetics , Mass Screening/methods , Sports , Genetic Predisposition to Disease/genetics , Germany , Humans , Mandatory Testing/methods , Mutation , Physical Examination/methods
11.
Luminescence ; 29(6): 586-90, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24123997

ABSTRACT

A series of novel fluoroionophore bearing derivatives of benzo-15-crown-5 were synthesized by the amination of benzo-15-crown-5 followed by condensation with different quinones in the presence of titanium tetrachloride (TiCl4 ) and 1,4-diazabicyclo-[2.2.2]octane. The compounds were characterized by infrared, (1) H and (13) C nuclear magnetic resonance, mass spectroscopy and elemental analysis. Absorption and fluorescence spectral characteristics of these compounds were studied. It was observed that the anthraquinone derivative was acting as an Hg(2+) ion sensor.


Subject(s)
Crown Ethers/chemistry , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Imines/chemistry , Mercury/analysis , Quinones/chemistry , Imines/chemical synthesis , Molecular Structure , Quinones/chemical synthesis
12.
J Dairy Sci ; 95(1): 196-205, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22192198

ABSTRACT

The focus of the current research was to develop real-time PCR assays with improved sensitivity and the capacity to simultaneously speciate the 3 most common mycoplasma mastitis agents: Mycoplasma bovis, Mycoplasma californicum, and Mycoplasma bovigenitalium. Real-time PCR was chosen because it provides rapid results. Partial 16S rRNA gene sequencing was used as the gold standard for evaluating candidate real-time PCR assays. To ascertain the real-time PCR assay specificity, reference strains of Mycoplasma species, Acholeplasma axanthum, and common gram-positive and gram-negative mastitis pathogens were tested. No cross-reactions were observed. Mycoplasma spp. isolated from bovine milk samples (n=228) and other organ sites (n=40) were tested by the real-time PCR assays and the partial 16S rRNA gene sequencing assay. Overall accuracy of this novel real-time PCR was 98.51%; 4 of 228 isolates identified as M. bovis by the partial 16S rRNA gene sequencing assay were identified as both M. bovis and M. californicum by real-time PCR. Subsequent amplicon sequencing suggested the presence of both M. bovis and M. californicum in these 4 samples. Using a cycle threshold of 37, the detection limits for real-time PCR were 10 copies of DNA template for both M. bovis and M. bovigenitalium, and 1 copy for M. californicum. This real-time PCR assay is a diagnostic technique that may be used as a screening tool or as a confirmation test for mycoplasma mastitis.


Subject(s)
Mastitis, Bovine/microbiology , Mycoplasma Infections/veterinary , Mycoplasma bovigenitalium/genetics , Mycoplasma bovis/genetics , Mycoplasma/genetics , Real-Time Polymerase Chain Reaction/veterinary , Animals , Cattle , DNA, Bacterial/genetics , Female , Mastitis, Bovine/diagnosis , Milk/microbiology , Mycoplasma Infections/diagnosis , Mycoplasma Infections/microbiology , RNA, Ribosomal, 16S/genetics , Real-Time Polymerase Chain Reaction/methods
13.
Med Phys ; 39(6Part18): 3833, 2012 Jun.
Article in English | MEDLINE | ID: mdl-28518530

ABSTRACT

PURPOSE: We present a simple, practical framework for truly 4D lung IMRT planning based on a weighted individual-phase optimization paradigm. This strategy is specifically developed for use in real-time tumor tracking delivery systems so as to utilize respiratory motion as an additional degree of freedom rather than a constraint. METHODS: A 4D-CT scan from a lung SBRT patient was loaded into the Eclipse treatment planning system. The target and normal structures were manually contoured on each of the ten phases. For each phase, the total dose prescription was scaled by the number of phases and a seven-field plan was developed. An open-source deformable image and dose registration engine (DIRART) was used to deform the dose map at each phase to a reference phase. DVH data from the individually optimized phase plans were input into an in-house linear programming-based optimizer implemented in MATLAB, in order to determine dose-weighting factors for each phase. The objective function aimed to maintain PTV coverage while keeping normal structure dose as low as possible. This weighted-4D plan (W-4D) was compared to an ITV-based plan and a 4D plan with equal dose-weights to individual phases (E-4D). RESULTS: The W-4D dose fractions were determined to be 0.33, 0.01, 0.65 and 0.02 at phase 0%, 30%, 40%, and 90%, respectively (and zero elsewhere). PTV coverage (V95) was close to identical for all three strategies. The W-4D plan exhibited mean lung dose 18.8% and 8.5% lower and mean liver dose 23.3% and 5.7% lower than corresponding values from ITV-based and E-4D plans, respectively. CONCLUSIONS: By significantly improving normal structure sparing while maintaining PTV coverage, weighted 4D planning represents a more attractive solution than ITV-based planning for (currently investigational) real-time tumor tracking-based delivery systems.

14.
Xenobiotica ; 40(6): 400-14, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20334492

ABSTRACT

The metabolism and excretion of a GABA(A) partial agonist developed for the treatment of anxiety, CP-409,092; 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4-methylaminomethyl-phenyl)-amide, were studied in rats following intravenous and oral administration of a single doses of [(14)C]CP-409,092. The pharmacokinetics of CP-409,092 following single intravenous and oral doses of 4 and 15 mg kg(-1), respectively, were characterized by high clearance of 169 + or - 18 ml min(-1) kg(-1), a volume of distribution of 8.99 + or - 1.46 l kg(-1), and an oral bioavailability of 2.9% + or - 3%. Following oral administration of 100 mg kg(-1) [(14)C]CP-409,092, the total recovery was 89.1% + or - 3.2% for male rats and 89.3% + or - 0.58% for female rats. Approximately 87% of the radioactivity recovered in urine and faeces were excreted in the first 48 h. A substantial portion of the radioactivity was measured in the faeces as unchanged drug, suggesting poor absorption and/or biliary excretion. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or faeces. The major metabolic pathways of CP-409,092 were hydroxylation(s) at the oxo-tetrahydro-indole moiety and oxidative deamination to form an aldehyde intermediate and subsequent oxidation to form the benzoic acid. The minor metabolic pathways included N-demethylation and subsequent N-acetylation and oxidation. The present work demonstrates that oxidative deamination at the benzylic amine of CP-409,092 and subsequent oxidation to form the acid metabolite seem to play an important role in the metabolism of the drug, and they contribute to its oral clearance and low exposure.


Subject(s)
Anilides/pharmacokinetics , GABA-A Receptor Agonists , Indoles/pharmacokinetics , Administration, Oral , Anilides/administration & dosage , Anilides/metabolism , Animals , Carbon Radioisotopes/analysis , Chromatography, Liquid , Drug Evaluation, Preclinical , Feces/chemistry , Female , Indoles/administration & dosage , Indoles/metabolism , Injections, Intravenous , Male , Molecular Structure , Rats , Rats, Sprague-Dawley , Tandem Mass Spectrometry
15.
Vet Microbiol ; 144(1-2): 210-3, 2010 Jul 29.
Article in English | MEDLINE | ID: mdl-20053506

ABSTRACT

Mycoplasma species are fastidious microorganisms causing mastitis in dairy cows. Storage by freezing milk samples affects their viability. The purpose of this study was to compare the effect of alternative storage methods on their recoverability. In Experiment I, mycoplasma counts from fresh milk samples were compared to those same samples stored for 1, 3, and 5 days at refrigerated (5 degrees C) temperatures. Experiment II was done to compare the mycoplasma counts of fresh milk samples with those stored frozen (-20 degrees C) with addition of 0%, 10%, 30% and 50% glycerol (v/v). Two strains of each of 5 species: M. bovis, M. californicum, M. bovigenitalium, M. canadense and M. alkalescens, were selected and inoculated into bulk tank milk free of this pathogen. Compared to those in fresh milk samples, counts were approximately reduced by: 0.3 log(10)CFU/ml in 5 day refrigerated milk (P<0.05) and by 1.0 log(10)CFU/ml in milk frozen without glycerol (P<0.05). Addition of glycerol (10% and 30%, v/v) to milk samples increased the number of recovered Mycoplasma by up to 0.4 log(10)CFU/ml in frozen milk samples (P<0.05). No significant interactions were detected between either Mycoplasma species or starting concentration and survival as effected by storage method. Refrigerating milk samples for 5 days and freezing milk samples lowers the number of recovered Mycoplasma species. The addition of glycerol to achieve 10% and 30% v/v solutions improves the recovery of Mycoplasma species from frozen milk samples. To maximize detection of this pathogen, fresh milk samples should be cultured without storage.


Subject(s)
Milk/microbiology , Mycoplasma/isolation & purification , Animals , Bacterial Load , Cryopreservation/methods , Female , Freezing , Mycoplasma bovigenitalium/isolation & purification , Mycoplasma bovis/isolation & purification , Refrigeration
16.
Vet Microbiol ; 134(1-2): 73-81, 2009 Feb 16.
Article in English | MEDLINE | ID: mdl-18950969

ABSTRACT

Coagulase-negative Staphylococcus (CNS) isolates (n=168) obtained from milk from heifers and dairy cows were screened for minimum inhibitory concentration (MIC) to antimicrobials used commonly for mastitis therapy. Of the 10 CNS species included in the study, the predominant species were Staphylococcus chromogenes (n=61), Staphylococcus epidermidis (n=37), Staphylococcus hyicus (n=37), and Staphylococcus simulans (n=16). The majority of CNS was susceptible to ampicillin, oxacillin, cephalothin, and ceftiofur. Erythromycin and pirlimycin were also very effective in vitro inhibitors of CNS. The only exception was observed with S. epidermidis. Of 37 S. epidermidis evaluated, 13 (35%) exhibited efflux-based resistance to erythromycin (> or =16 microg/ml) encoded by msrA and one isolate carried ermC encoding ribosomal methylase-based resistance to both erythromycin (> or =64 microg/ml) and pirlimycin (> or =64 microg/ml). A total of 17 S. epidermidis, 11 S. chromogenes, and one S. hyicus exhibited phenotypic resistance to ampicillin (> or =0.5 microg/ml). Constitutive beta-lactamase production was observed in all ampicillin resistant isolates except 4 S. epidermidis that exhibited inducible beta-lactamase production. Induced beta-lactamase production was also observed in 13 S. epidermidis that were phenotypically susceptible to the entire MIC panel. All isolates that produced beta-lactamase either constitutively or by induction carried blaZ. S. epidermidis (n=12, 32%) that were resistant to methicillin (oxacillin > or =0.5 microg/ml) carried low affinity penicillin-binding protein encoded by mecA. Most multi-drug resistant (MDR) S. epidermidis (> or =2 resistance genes) were resistant to ampicillin, erythromycin and methicillin. All except one MDR S. epidermidis had icaAB, which encodes for polysaccharide intercellular adhesion. Based on pulsed field gel electrophoresis, MDR S. epidermidis were closely related genotypically, and were isolated from different cows on the same farm suggesting clonal dissemination. Bovine S. epidermidis share antimicrobial resistance patterns and virulence determinants of strains observed in human infections. Studying CNS at the species level can provide valuable information about species-specific differences that can be vital data for effective mastitis therapy and management.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial , Mastitis, Bovine/microbiology , Milk/microbiology , Staphylococcus/drug effects , Staphylococcus/enzymology , Animals , Cattle , Genetic Variation , Genotype , Microbial Sensitivity Tests , Phylogeny , Staphylococcal Infections/microbiology , Staphylococcal Infections/veterinary , Staphylococcus/classification , Staphylococcus/isolation & purification
17.
J Assoc Physicians India ; 56: 99-102, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18472509

ABSTRACT

BACKGROUND: Cardiovascular diseases (CVD) are the major cause of morbidity and mortality in our society with dyslipidemia contributing significantly to atherosclerosis. Thus measurement of plasma lipids would help in identifying people at risk for CVD. The goal of this study was to ascertain the prevalence of Dyslipidemia among young adult population in urban India. MATERIAL AND METHODS: The study was conducted for a period of one year--from 1st January 2006 to 31st December 2006. Around 1805 subjects with > or =40 age group were selected from a population of approximately 9000 urban dwellers who had attended annual general health check ups in P. D. Hinduja National Hospital and Medical research Center. Health status was evaluated by physical check ups, complete fasting lipid profiles and blood glucose levels. Dyslipidemia risk and impaired blood sugar levels were determined as per National Cholesterol Education Program (NCEP) - Adult Treatment Panel (ATP) III guidelines and American Diabetes Association (ADA) respectively. RESULTS: The prevalence of dyslipidemia was observed to be higher in males then in females. Among participants who had a total Cholesterol (TC) concentration > or = 200 mg/dl, 38.7% were males and 23.3% were females. High density lipoprotein cholesterol (HDL-C) was abnormally low in 64.2% males and 33.8% in females. The increase of prevalence of hypercholesterolemia and hypertriglyceridemia was more prominent in 31-40 age group than in < or =30 age group. CONCLUSION: The low percentage of adults with controlled lipid concentrations suggests that there is a need for awareness programs for the prevention and control of Dyslipidemia and impaired blood sugar levels.


Subject(s)
Dyslipidemias/epidemiology , Adult , Female , Humans , India/epidemiology , Male , Prevalence , Retrospective Studies , Sex Distribution
18.
Sens Actuators A Phys ; 140(2): 185-193, 2007 Nov 10.
Article in English | MEDLINE | ID: mdl-18159218

ABSTRACT

Megavoltage x-ray imaging performed during radiotherapy is the method of choice for geometric verification of patient localization and dose delivery. Presently, such imaging is increasingly performed using electronic portal imaging devices (EPIDs) based on indirect detection active matrix flat panel imagers (AMFPIs). These devices use a scintillating phosphor screen in order to convert incident x-rays into optical photons, which are then detected by the underlying active matrix photodiode array. The use of a continuous phosphor introduces a trade-off between x-ray quantum efficiency and spatial resolution, which limits current devices to use only ∼2% of the incident x-rays. This trade-off can be circumvented by "segmented phosphor screens", comprising a two-dimensional matrix of optically-isolated cell structures filled with scintillating phosphor. In this work we describe the fabrication of millimeter-thick segmented phosphor screens using the MEMS (micro-electro-mechanical-system) polymer SU-8. This method is capable of being extended to large-area substrates.

19.
J Environ Sci Eng ; 49(4): 283-6, 2007 Oct.
Article in English | MEDLINE | ID: mdl-18476376

ABSTRACT

Silica gel adsorption, strong base anion exchange IRA 400-OH form resin were evaluated for the treatment of trihalomethane precursors present in raw and drinking water. A powdered silica gel having 60 to 120 mesh size and a previously dried IRA 400-OH form resin having 20-50 mesh size have been applied to artificial water samples and a specific analytical approach was used for selective removal of humic acid present in the water. This study aims to evaluate the role of contact time, pH, adsorption dose, concentration of humic acid (H.A.), flow rate on the reduction of THM-precursors as a result of adsorption of H.A. while passing raw water through silica gel and IRA 400 OH form resin column. Freundlich adsorption isotherm constants K for silica gel and IRA 400-OH form resin were determined as 1.13 x 10(-3) and 4.2 x 10(-3) mg/g respectively and l/n were found to be 0.9927 and 1.069 respectively.


Subject(s)
Trihalomethanes/analysis , Water Purification/methods , Adsorption , Anions , Chromatography, Ion Exchange/methods , Humic Substances/analysis , Hydrogen-Ion Concentration , Silica Gel , Silicon Dioxide/chemistry , Temperature , Water/chemistry , Water Pollutants, Chemical , Water Pollution, Chemical , Water Supply
20.
Foodborne Pathog Dis ; 3(3): 222-33, 2006.
Article in English | MEDLINE | ID: mdl-16972770

ABSTRACT

The dairy farm environment and animals on the farm serve as important reservoirs of pathogenic and commensal bacteria that could potentially gain access to milk in the bulk tank via several pathways. Pathogenic gram-negative bacteria can gain access to bulk tank milk from infected mammary glands, contaminated udders and milking machines, and/or from the dairy farm environment. Contaminated raw milk when consumed by humans or fed to animals on the farm can result in gastroenteric infections in humans and animals and also provide an opportunity for organisms to colonize the farm environment. This scenario becomes much more complicated when pathogenic bacteria such as Salmonella, Shiga toxin-producing Escherichia coli, and commensal gram-negative enteric bacteria encode for antimicrobial resistance determinants. In recent years, the role of commensal bacteria as reservoirs of genetic determinants for antimicrobial resistance has come under closer scrutiny. Commensal bacteria in bulk tank milk can be a significant reservoir of antimicrobial determinants. Raw milk consumption can result in exposure to antimicrobial-resistant commensal gram-negative bacteria. This paper examines the prevalence and role of commensal gram-negative enteric bacteria in bulk tank milk and their public health significance.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial , Gram-Negative Bacteria/drug effects , Milk/microbiology , Public Health , Animals , Cattle , Consumer Product Safety , Disease Reservoirs/veterinary , Food Contamination/analysis , Food Contamination/prevention & control , Food Microbiology , Gram-Negative Bacteria/isolation & purification , Humans , Microbial Sensitivity Tests , Prevalence
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