ABSTRACT
BACKGROUND: The diagnosis of secondary upper limb lymphedema (LE) is complicated by the lack of an agreed-upon measurement tool and diagnostic threshold. The aim of this study was to determine which of the many commonly used and normatively determined clinical diagnostic thresholds has the best diagnostic accuracy of secondary upper limb LE, when compared to diagnosis by an appropriate reference standard, lymphoscintigraphy. MATERIAL AND METHODS: The arms of women treated for breast cancer with and without a previous diagnosis of LE, as well as healthy controls, were assessed using lymphoscintigraphy, bioimpedance spectroscopy (BIS) and perometry. Dermal backflow score determined from lymphoscintigraphy imaging assessment (reference standard) was compared with diagnosis by both commonly used and normatively determined diagnostic thresholds for volume and circumference measurements as well as BIS. RESULTS: For those with established dermal backflow, all commonly used and normatively determined diagnostic thresholds accurately identified presence of LE compared with lymphoscintigraphy diagnosis. In participants with mild to moderate changes in dermal backflow, only a normatively determined diagnostic threshold, set at two standard deviations above the norm, for arm circumference and full arm BIS were found to have both high sensitivity (81% and 76%, respectively) and specificity (96% and 93%, respectively). For this group, strong, and clinically useful, positive (23 and 10, respectively) and negative likelihood (0.2 and 0.3) ratios were found for both the circumference and bioimpedance diagnostic thresholds. CONCLUSION: For the first time, evidence-based clinical diagnostic thresholds have been established for secondary LE. With mild LE, normatively determined circumference and BIS thresholds are superior to the commonly used thresholds.
Subject(s)
Breast Neoplasms/complications , Combined Modality Therapy/adverse effects , Evidence-Based Medicine , Lymphedema/diagnosis , Upper Extremity/pathology , Breast Neoplasms/therapy , Case-Control Studies , Female , Follow-Up Studies , Humans , Lymphedema/etiology , Middle Aged , Neoplasm Staging , PrognosisABSTRACT
Objectives: The spatial resolution of emission tomographic imaging systems can lead to a significant underestimation in the apparent radioactivity concentration in objects of size comparable to the resolution volume of the system. The aim of this study was to investigate the impact of the partial volume effect (PVE) on clinical imaging in PET and SPECT with current state-of-the-art instrumentation and the implications that this has for radionuclide dosimetry estimates. Methods: Using the IEC Image Quality Phantom we have measured the underestimation in observed uptake in objects of various sizes for both PET and SPECT imaging conditions. Both single pixel measures (i.e., SUVmax) and region of interest mean values were examined over a range of object sizes. We have further examined the impact of the PVE on dosimetry estimates in OLINDA in 177Lu SPECT imaging based on a subject with multiple somatostatin receptor positive paragangliomas in the head and neck. Results: In PET, single pixel estimates of uptake are affected for objects less than approximately 18 mm in minor axis with existing systems. In SPECT imaging with medium energy collimators (e.g., for 177Lu imaging), however, the underestimates are far greater, where single pixel estimates in objects less than 2-3×the resolution volume are significantly impacted. In SPECT, region of interest mean values are underestimated in objects less than 10 cm in diameter. In the clinical case example, the dosimetry measured with SPECT ranged from more than 60% underestimate in the largest lesion (28×22 mm in maximal cross-section; 10.2 cc volume) to >99% underestimate in the smallest lesion (4×5 mm; 0.06 cc). Conclusion: The partial volume effect remains a significant factor when estimating radionuclide uptake in vivo, especially in small volumes. Accurate estimates of absorbed dose from radionuclide therapy will be particularly challenging until robust solutions to correct for the PVE are found.
ABSTRACT
AIM: To summarise our centre's experience managing patients with neuroendocrine tumours (NETs) in the first 5 years after the introduction of peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-octreotate (LUTATE). The report emphasises aspects of the patient management related to functional imaging and use of radionuclide therapy. METHODS: We describe the criteria for treatment with LUTATE at our centre, the methodology for patient selection, and the results of an audit of clinical measures, imaging results and patient-reported outcomes. Subjects are treated initially with four cycles of ~ 8 GBq of LUTATE administered as an outpatient every 8 weeks. RESULTS: In the first 5 years offering LUTATE, we treated 143 individuals with a variety of NETs of which approx. 70% were gastroentero-pancreatic in origin (small bowel: 42%, pancreas: 28%). Males and females were equally represented. Mean age at first treatment with LUTATE was 61 ± 13 years with range 28-87 years. The radiation dose to the organs considered most at risk, the kidneys, averaged 10.6 ± 4.0 Gy in total. Median overall survival (OS) from first receiving LUTATE was 72.5 months with a median progression-free survival (PFS) of 32.3 months. No evidence of renal toxicity was seen. The major long-term complication seen was myelodysplastic syndrome (MDS) with a 5% incidence. CONCLUSIONS: LUTATE treatment for NETs is a safe and effective treatment. Our approach relies heavily on functional and morphological imaging informing the multidisciplinary team of NET specialists to guide appropriate therapy, which we suggest has contributed to the favourable outcomes seen.
Subject(s)
Neuroendocrine Tumors , Male , Female , Humans , Adult , Middle Aged , Aged , Aged, 80 and over , Neuroendocrine Tumors/pathology , Precision Medicine , Octreotide/therapeutic use , Molecular Imaging , Receptors, Peptide , RadioisotopesABSTRACT
INTRODUCTION: The identification of unknown radionuclides is an authentic practical activity for students that provides the foundations for clinical problem solving, especially in the storage and management of radioactive waste. As different radionuclides have different half-lives, some of which are quite long, the storage of waste material has to accommodate the longest of these. Cross contamination requires a method of identifying the radionuclide samples in a mixed sample to safely and appropriately manage disposal. Similarly, identifying a single unknown sample of a radionuclide allows correct handling and disposal. METHODS: Performing a systematic investigation of the physical properties of unknown radioactive samples is a rich learning opportunity to instil understanding of important physics principles among students in nuclear medicine. RESULTS: This manuscript outlines an investigation developed that would allow students to identify single unknown radionuclides based on physical properties and identify the constituent radionuclides of a mixed sample using some additional mathematical curve stripping. CONCLUSION: The processes and solutions are provided with real data and this practical activity can be replicated by students generating their own data. IMPLICATIONS FOR PRACTICE: This paper provides a template and analysis/interpretation guideline for educators and clinicians to deepen understanding of foundation physics. Enhanced and deeper understanding are a vehicle for improved problem solving in clinical and research practice.
Subject(s)
Nuclear Medicine , Radioactive Waste , Humans , Learning , Physics , Problem Solving , Radioactive Waste/analysisABSTRACT
BACKGROUND: SPECT-derived dose estimates in tissues of diameter less than 3× system resolution are subject to significant losses due to the limited spatial resolution of the gamma camera. Incorporating resolution modelling (RM) into the SPECT reconstruction has been proposed as a possible solution; however, the images produced are prone to noise amplification and Gibbs artefacts. We propose a novel approach to SPECT reconstruction in a theranostic setting, which we term SPECTRE (single photon emission computed theranostic reconstruction); using a diagnostic PET image, with its superior resolution, to guide the SPECT reconstruction of the therapeutic equivalent. This report demonstrates a proof in principle of this approach. METHODS: We have employed the hybrid kernelised expectation maximisation (HKEM) algorithm implemented in STIR, with the aim of producing SPECT images with PET-equivalent resolution. We demonstrate its application in both a dual 68Ga/177Lu IEC phantom study and a clinical example using 64Cu/67Cu. RESULTS: SPECTRE is shown to produce images comparable in accuracy and recovery to PET with minimal introduction of artefacts and amplification of noise. CONCLUSION: The SPECTRE approach to image reconstruction shows improved quantitative accuracy with a reduction in noise amplification. SPECTRE shows great promise as a method of improving SPECT radioactivity concentrations, directly leading to more accurate dosimetry estimates in small structures and target lesions. Further investigation and optimisation of the algorithm parameters is needed before this reconstruction method can be utilised in a clinical setting.
ABSTRACT
Obesity is associated with reduced operating lung volumes that may contribute to increased airway closure during tidal breathing and abnormalities in ventilation distribution. We investigated the effect of obesity on the topographical distribution of ventilation before and after methacholine-induced bronchoconstriction using single-photon emission computed tomography (SPECT)-computed tomography (CT) in healthy subjects. Subjects with obesity (n = 9) and subjects without obesity (n = 10) underwent baseline and postbronchoprovocation SPECT-CT imaging, in which Technegas was inhaled upright and followed by supine scanning. Lung regions that were nonventilated (Ventnon), low ventilated (Ventlow), or well ventilated (Ventwell) were calculated using an adaptive threshold method and were expressed as a percentage of total lung volume. To determine regional ventilation, lungs were divided into upper, middle, and lower thirds of axial length, derived from CT. At baseline, Ventnon and Ventlow for the entire lung were similar in subjects with and without obesity. However, in the upper lung zone, Ventnon (17.5 ± 10.6% vs. 34.7 ± 7.8%, P < 0.001) and Ventlow (25.7 ± 6.3% vs. 33.6 ± 5.1%, P < 0.05) were decreased in subjects with obesity, with a consequent increase in Ventwell (56.8 ± 9.2% vs. 31.7 ± 10.1%, P < 0.001). The greater diversion of ventilation to the upper zone was correlated with body mass index (rs = 0.74, P < 0.001), respiratory system resistance (rs = 0.72, P < 0.001), and respiratory system reactance (rs = -0.64, P = 0.003) but not with lung volumes or basal airway closure. Following bronchoprovocation, overall Ventnon increased similarly in both groups; however, in subjects without obesity, Ventnon only increased in the lower zone, whereas in subjects with obesity, Ventnon increased more evenly across all lung zones. In conclusion, obesity is associated with altered ventilation distribution during baseline and following bronchoprovocation, independent of reduced lung volumes.NEW & NOTEWORTHY Using ventilation SPECT-computed tomography imaging in healthy subjects, we demonstrate that ventilation in obesity is diverted to the upper lung zone and that this is strongly correlated with body mass index but is independent of operating lung volumes and of airway closure. Furthermore, methacholine-induced bronchoconstriction only occurred in the lower lung zone in individuals who were not obese, whereas in subjects who were obese, it occurred more evenly across all lung zones. These findings show that obesity-associated factors alter the topographical distribution of ventilation.
Subject(s)
Bronchial Hyperreactivity/pathology , Bronchoconstriction , Methacholine Chloride/pharmacology , Obesity/complications , Pulmonary Ventilation , Adolescent , Adult , Aged , Bronchial Hyperreactivity/etiology , Bronchial Provocation Tests , Female , Humans , Lung Volume Measurements , Male , Middle Aged , Obesity/diagnostic imaging , Respiratory Physiological Phenomena , Single Photon Emission Computed Tomography Computed Tomography , Young AdultABSTRACT
This study investigated, using digital bitewing radiography, the progression and regression of approximal caries in adolescent subjects chewing a sugar-free gum containing 54 mg CPP-ACP relative to the identical gum without CPP-ACP. 2,720 subjects from 29 schools were randomly assigned to one of the two gums and were instructed to chew their assigned gum for 3 x 10 min/day, with one session supervised on school days, over the 24-month study period. Standardized digital bitewing radiographs were taken at the baseline and 24-month clinical examinations for each subject. The radiographs, scored by a single examiner, were assessed for approximal surface dental caries at both the enamel and dentine level. Surface level transitions were scored using a transition matrix. Caries progression or regression was analysed using proportional-odds ordered logistic regression modelling of the transition scores at the tooth surface level. There was a statistically significant difference in the frequency distributions of the transition scores between the two gum groups (OR = 0.82, p = 0.03). For subjects chewing the CPP-ACP gum the odds of a surface experiencing caries progression were 18% less than those of a surface experiencing caries progression for subjects chewing the control gum. In conclusion, the 54 mg CPP-ACP sugar-free gum significantly slowed progression and enhanced regression of approximal caries relative to a control sugar-free gum in a 24-month clinical trial.
Subject(s)
Cariostatic Agents/therapeutic use , Caseins/therapeutic use , Chewing Gum , Dental Caries/prevention & control , Adolescent , Chewing Gum/analysis , Child , Dental Caries/diagnostic imaging , Disease Progression , Double-Blind Method , Female , Humans , Logistic Models , Male , Odds Ratio , Radiography, Bitewing , Radiography, Dental, Digital , Sample Size , Sorbitol , Sweetening Agents , Tooth Remineralization/methodsABSTRACT
The 6th annual meeting to address key issues in positron emission tomography (PET)/magnetic resonance imaging (MRI) was held again in Tübingen, Germany, from March 27 to 29, 2017. Over three days of invited plenary lectures, round table discussions and dialogue board deliberations, participants critically assessed the current state of PET/MRI, both clinically and as a research tool, and attempted to chart future directions. The meeting addressed the use of PET/MRI and workflows in oncology, neurosciences, infection, inflammation and chronic pain syndromes, as well as deeper discussions about how best to characterise the tumour microenvironment, optimise the complementary information available from PET and MRI, and how advanced data mining and bioinformatics, as well as information from liquid biomarkers (circulating tumour cells and nucleic acids) and pathology, can be integrated to give a more complete characterisation of disease phenotype. Some issues that have dominated previous meetings, such as the accuracy of MR-based attenuation correction (AC) of the PET scan, were finally put to rest as having been adequately addressed for the majority of clinical situations. Likewise, the ability to standardise PET systems for use in multicentre trials was confirmed, thus removing a perceived barrier to larger clinical imaging trials. The meeting openly questioned whether PET/MRI should, in all cases, be used as a whole-body imaging modality or whether in many circumstances it would best be employed to give an in-depth study of previously identified disease in a single organ or region. The meeting concluded that there is still much work to be done in the integration of data from different fields and in developing a common language for all stakeholders involved. In addition, the participants advocated joint training and education for individuals who engage in routine PET/MRI. It was agreed that PET/MRI can enhance our understanding of normal and disrupted biology, and we are in a position to describe the in vivo nature of disease processes, metabolism, evolution of cancer and the monitoring of response to pharmacological interventions and therapies. As such, PET/MRI is a key to advancing medicine and patient care.
Subject(s)
Magnetic Resonance Imaging , Positron-Emission Tomography , Humans , Liquid Biopsy , Radiotherapy, Image-Guided , Tumor MicroenvironmentABSTRACT
BACKGROUND: Despite the prevalence of periodontitis in Australia, there are few reports regarding periodontal diagnosis and therapies in the general dental practice setting. This study aimed to assess the degree of diagnostic accuracy in periodontal cases of Victorian general dental practitioners. METHODS: Following ethics approval, dentists were invited to complete a scenario-based questionnaire on the Australian Dental Association Victorian Branch (ADAVB) website. Five text-based clinical scenarios (from a total of 10) were randomly presented, representing patients with a range of disease levels from periodontal health/gingivitis to severe periodontitis, and respondents were asked what examinations they would usually perform. Based upon the presented results of periodontal and radiographic examinations, a periodontal diagnosis was requested. RESULTS: One hundred and thirty-five dentists attempted the survey. Most were in group practice and based in Melbourne; 22.5% of respondents worked in a practice employing a hygienist. The clinical parameters most commonly measured to diagnose periodontal disease were pocket depth and mobility. The majority of respondents diagnosed health, gingivitis and mild periodontitis correctly compared to American Academy of Periodontology guidelines. However, moderate periodontitis tended to be diagnosed as severe. CONCLUSIONS: Dentists in Victoria used appropriate clinical parameters when assessing periodontal disease and were generally accurate in their diagnoses. There is a need for consensus regarding diagnostic definitions.
Subject(s)
General Practice, Dental/standards , Periodontal Diseases/diagnosis , Private Practice/standards , Adult , Female , Gingivitis/diagnosis , Humans , Male , Middle Aged , Periodontitis/diagnosis , Surveys and Questionnaires , VictoriaABSTRACT
This article provides a collaborative perspective of the discussions and conclusions from the fifth international workshop of combined positron emission tomorgraphy (PET)/magnetic resonance imaging (MRI) that was held in Tübingen, Germany, from February 15 to 19, 2016. Specifically, we summarise the second part of the workshop made up of invited presentations from active researchers in the field of PET/MRI and associated fields augmented by round table discussions and dialogue boards with specific topics. This year, this included practical advice as to possible approaches to moving PET/MRI into clinical routine, the use of PET/MRI in brain receptor imaging, in assessing cardiovascular diseases, cancer, infection, and inflammatory diseases. To address perceived challenges still remaining to innovatively integrate PET and MRI system technologies, a dedicated round table session brought together key representatives from industry and academia who were engaged with either the conceptualisation or early adoption of hybrid PET/MRI systems. Discussions during the workshop highlighted that emerging unique applications of PET/MRI such as the ability to provide multi-parametric quantitative and visual information which will enable not only overall disease detection but also disease characterisation would eventually be regarded as compelling arguments for the adoption of PET/MR. However, as indicated by previous workshops, evidence in favour of this observation is only growing slowly, mainly due to the ongoing inability to pool data cohorts from independent trials as well as different systems and sites. The participants emphasised that moving from status quo to status go entails the need to adopt standardised imaging procedures and the readiness to act together prospectively across multiple PET/MRI sites and vendors.
Subject(s)
Magnetic Resonance Imaging , Multimodal Imaging , Positron-Emission Tomography , Animals , Disease , Germany , HumansABSTRACT
Succinyl-CoA synthetase (SCS) catalyzes the substrate-level phosphorylation step of the citric acid cycle. The enzyme from Escherichia coli is an (alphabeta)2-heterotetramer with two active sites, one in each alphabeta-dimer. To determine whether the two active sites could function independently, mutations were made to split the tetramer into alphabeta-dimers. Because two choices for the tetramer (I and II) were possible from the X-ray crystallographic analyses, mutations were made at two different interfaces. All mutations based on tetramer I resulted in an intact tetramer. Of the two mutants based on tetramer II, one was insoluble and the other, where M156beta, Y158beta, R161beta and E162beta were changed to D, D, E and R, respectively, was a dimer. This quaternary structure was confirmed by fast protein liquid chromatography, blue native PAGE and ultracentrifugation. The DDER mutant has kinetic parameters similar to the tetrameric E. coli enzyme. Like the tetrameric enzyme, it shows ATP-facilitated dethiophosphorylation, proving that this property is a single-site effect. The ATP-facilitated dethiophosphorylation is inhibited by phosphate. It is concluded that dimerization of alphabeta-dimers is not a prerequisite for catalytic competency nor for alternating sites cooperativity in the tetramer. The rationale behind the dimer-of-dimers in E. coli SCS is still not known, but increased solubility, increased stability and in vivo interactions of the tetramer with other proteins are still possibilities.
Subject(s)
Escherichia coli/enzymology , Escherichia coli/genetics , Succinate-CoA Ligases/chemistry , Succinate-CoA Ligases/genetics , Amino Acid Sequence , Animals , Base Sequence , Binding Sites/genetics , Coenzyme A/metabolism , Dimerization , Kinetics , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Myocardium/enzymology , Oligonucleotide Probes/genetics , Protein Conformation , Sequence Homology, Amino Acid , Succinate-CoA Ligases/metabolism , Swine , Tryptophan/chemistryABSTRACT
High-resolution cardiac PET imaging with emphasis on quantification would benefit from eliminating the problem of respiratory movement during data acquisition. Respiratory gating on the basis of list-mode data has been employed previously as one approach to reduce motion effects. However, it results in poor count statistics with degradation of image quality. This work reports on the implementation of a technique to correct for respiratory motion in the area of the heart at no extra cost for count statistics and with the potential to maintain ECG gating, based on rigid-body transformations on list-mode data event-by-event. A motion-corrected data set is obtained by assigning, after pre-correction for detector efficiency and photon attenuation, individual lines-of-response to new detector pairs with consideration of respiratory motion. Parameters of respiratory motion are obtained from a series of gated image sets by means of image registration. Respiration is recorded simultaneously with the list-mode data using an inductive respiration monitor with an elasticized belt at chest level. The accuracy of the technique was assessed with point-source data showing a good correlation between measured and true transformations. The technique was applied on phantom data with simulated respiratory motion, showing successful recovery of tracer distribution and contrast on the motion-corrected images, and on patient data with C15O and 18FDG. Quantitative assessment of preliminary C15O patient data showed improvement in the recovery coefficient at the centre of the left ventricle.
Subject(s)
Heart/diagnostic imaging , Image Enhancement , Motion , Respiratory Mechanics , Algorithms , Carbon Monoxide , Carbon Radioisotopes , Fluorodeoxyglucose F18 , Heart/physiology , Humans , Phantoms, Imaging , Positron-Emission Tomography , RadiopharmaceuticalsABSTRACT
This paper summarises key themes and discussions from the 4th international workshop dedicated to the advancement of the technical, scientific and clinical applications of combined positron emission tomography (PET)/magnetic resonance imaging (MRI) systems that was held in Tübingen, Germany, from February 23 to 27, 2015. Specifically, we summarise the three days of invited presentations from active researchers in this and associated fields augmented by round table discussions and dialogue boards with specific topics. These include the use of PET/MRI in cardiovascular disease, paediatrics, oncology, neurology and multi-parametric imaging, the latter of which was suggested as a key promoting factor for the wider adoption of integrated PET/MRI. Discussions throughout the workshop and a poll taken on the final day demonstrated that attendees felt more strongly that PET/MRI has further advanced in both technical versatility and acceptance by clinical and research-driven users from the status quo of last year. Still, with only minimal evidence of progress made in exploiting the true complementary nature of the PET and MRI-based information, PET/MRI is still yet to achieve its potential. In that regard, the conclusion of last year's meeting "the real work has just started" still holds true.
Subject(s)
Magnetic Resonance Imaging , Multimodal Imaging , Positron-Emission Tomography , Germany , HumansABSTRACT
This paper summarises the proceedings and discussions at the third annual workshop held in Tübingen, Germany, dedicated to the advancement of the technical, scientific and clinical applications of combined PET/MRI systems in humans. Two days of basic scientific and technical instructions with "hands-on" tutorials were followed by 3 days of invited presentations from active researchers in this and associated fields augmented by round-table discussions and dialogue boards with specific themes. These included the use of PET/MRI in paediatric oncology and in adult neurology, oncology and cardiology, the development of multi-parametric analyses, and efforts to standardise PET/MRI examinations to allow pooling of data for evaluating the technology. A poll taken on the final day demonstrated that over 50 % of those present felt that while PET/MRI technology underwent an inevitable slump after its much-anticipated initial launch, it was now entering a period of slow, progressive development, with new key applications emerging. In particular, researchers are focusing on exploiting the complementary nature of the physiological (PET) and biochemical (MRI/MRS) data within the morphological framework (MRI) that these devices can provide. Much of the discussion was summed up on the final day when one speaker commented on the state of PET/MRI: "the real work has just started".
Subject(s)
Magnetic Resonance Imaging/methods , Multimodal Imaging/methods , Positron-Emission Tomography/methods , Animals , Cardiology/methods , Germany , Humans , Image Processing, Computer-Assisted/methods , Medical Oncology/methods , Neurology/methodsABSTRACT
The form of succinyl-CoA synthetase found in mammalian mitochondria is known to be an alpha beta dimer. Both GTP- and ATP-specific isozymes are present in various tissues. We have isolated essentially identical complementary DNA clones encoding the beta subunit of pig heart succinyl-CoA synthetase from both newborn and adult tissues. These cDNAs include a 1.4-kb sequence encoding the cytoplasmic precursor to the beta subunit comprised of 417 amino acid residues including a 22-residue mitochondrial targeting sequence. The cDNA encoding the 395-amino acid, 42,502-Da mature protein was confirmed to be the succinyl-CoA synthetase beta subunit by agreement with the N-terminal protein sequence and by high homology to prokaryotic forms of the beta subunit that were previously cloned (about 45% identical to beta from Escherichia coli). In contrast to a previous report (Nishimura, J.S., Ybarra, J., Mitchell, T., & Horowitz, P.M., 1988, Biochem. J. 250, 429-434), we found no tryptophan residue to be encoded in the sequence for the mature beta subunit, and this finding is corroborated by the fact that highly purified pig heart succinyl-CoA synthetase shows no tryptophan fluorescence or tryptophan content in amino acid compositional analysis. The cDNA clones encoding the mature pig heart beta subunit and its counterpart alpha subunit were coexpressed in a deletion mutant strain of E. coli. Recovery of succinyl-CoA synthetase activity demonstrated that this combination of subunits forms a productive enzymatic complex having GTP specificity.
Subject(s)
Mitochondria, Heart/enzymology , Succinate-CoA Ligases/genetics , Swine/genetics , Aging/metabolism , Amino Acid Sequence , Animals , Animals, Newborn , Base Sequence , Cloning, Molecular , Escherichia coli , Gene Expression , Macromolecular Substances , Molecular Sequence Data , Oligodeoxyribonucleotides , Polymerase Chain Reaction , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolism , Sequence Homology, Amino Acid , Succinate-CoA Ligases/isolation & purification , Succinate-CoA Ligases/metabolismABSTRACT
A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit 1a led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead 1a. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS, 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.
Subject(s)
Anticoagulants/chemical synthesis , Pyrrolidines/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Thiophenes/chemical synthesis , Thrombin/antagonists & inhibitors , Animals , Anticoagulants/chemistry , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Binding Sites , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , In Vitro Techniques , Models, Molecular , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Rats , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacokinetics , Thiophenes/pharmacology , Thrombosis/blood , Thrombosis/metabolismABSTRACT
UNLABELLED: A method of scatter compensation has been developed that incorporates planar transmission measurements in the estimation of photopeak scatter in SPECT. METHODS: The scatter distribution is first estimated by convolving the planar projections with a monoexponential scatter function. The number of scattered events that subsequently reach the detector as a proportion of total events (i.e., scatter fraction) is then determined for each point in the projections based on narrow-beam transmission values, obtained using an external source. The assumptions of the method were tested using 99mTc and 201Tl point and line sources. The quantitative and qualitative impact of transmission-dependent scatter correction was assessed in realistic phantom experiments simulating blood-pool, lung and myocardial perfusion studies. RESULTS: The method accurately predicts the scatter distribution from 99mTc and 201Tl line sources in a phantom with variable density. Reconstructed counts are artificially enhanced in regions of high tissue density when scattered events are not removed from the projections prior to attenuation correction. Using convolution-subtraction with a constant scatter fraction (k = 0.4), scatter is underestimated in the heart and overestimated in the lungs, whereas transmission-dependent scatter correction enables activity to be quantified with > or = 95% accuracy in heart and lung regions. CONCLUSION: We conclude that incorporating transmission data enables accurate scatter compensation in objects with nonuniform density.
Subject(s)
Heart/diagnostic imaging , Technetium , Thallium Radioisotopes , Tomography, Emission-Computed, Single-Photon/methods , Female , Humans , Middle Aged , Models, StructuralABSTRACT
A method is proposed to simultaneously record single photon emission and transmission tomographic (SPECT) studies to produce a map of attenuation coefficients (mu) for the body. A dual radionuclide SPECT acquisition is performed with a transmission source attached to a rotating gamma camera of lower energy than the emission radionuclide. Scatter from the emission source into the transmission window is removed by subtracting the predicted scatter distribution. The transmission image is then reconstructed to yield the map of attenuation coefficients for anatomic display or attenuation correction purposes. Experimental work has shown that the method can accurately derive mu values to +/- 2.5% in both phantom and patient studies, without increasing acquisition time. Preliminary attenuation correction experiments have demonstrated an accuracy of better than 5% for estimated activity.
Subject(s)
Tomography, Emission-Computed/methods , Gadolinium , Humans , Radioisotopes , Technetium , Tomography, X-Ray ComputedABSTRACT
A technique for acquiring dynamic geometric mean studies utilizing a single-headed rotating gamma camera has been developed. The camera head is repeatedly rotated between opposed views under computer control. A single data set results, from which a dynamic sequence of geometric mean images can be produced. Software has been developed to accomplish data acquisition and the reformatting required. The accuracy of the geometric mean data formed using this technique has been studied experimentally, and compared with results obtained from anterior and posterior sequences. In a simple clearance experiment of a 1-I volume with a known clearance of 20 ml.min-1, the geometric mean data resulted in estimates of volume remaining in the container with a mean error or +2.0 ml (s.d. = 5.7 ml, range -4.5 +/- 15.3 ml), while the anterior and posterior images yielded volume estimates with mean errors of -10.1 ml (s.d. = 16.6 ml, range -47.4 +/- 10.5 ml) and +35.5 ml (s.d. = 22.6 ml, range -3.2 +/- 51.6, ml), respectively. The technique is easy to implement and does not require modification of existing hardware. An application of the technique to a clinical study of gastric emptying is also included.
Subject(s)
Gamma Cameras , Tomography, Emission-Computed, Single-Photon/methods , Mathematics , SoftwareABSTRACT
Simultaneous emission and transmission tomography was performed after the injection of [99mTc]MAA in 30 patients undergoing intra-arterial chemotherapy to nonhepatic sites to determine the accuracy of catheter placement. The transmission and emission data were reconstructed in transverse, and optionally, coronal and sagittal planes. The correlation of the emission scan with the reconstructed transmission data allowed accurate anatomical localization of the infusate distribution. In seven patients, catheter placement resulted in perfusion to nontumor sites, and hence required repositioning. MAA accumulation was seen in the lungs of all patients, regardless of tumor site, indicating arterio-venous shunting of the MAA. The degree of uptake in the lungs was quantified from planar anterior/posterior thorax images in terms of injected dose in ten patients, with values of 5-50% of injected dose present in the lungs. The technique provides a noninvasive means of accurately determining regional perfusion of chemotherapeutic agents delivered intra-arterially.