Lung nodules are reliably detectable on ultra-low-dose CT utilising model-based iterative reconstruction with radiation equivalent to plain radiography.

AIM: To determine if ultra-low-dose (ULD) computed tomography (CT) utilising model-based iterative reconstruction (MBIR) with radiation equivalent to plain radiography allows the detection of lung nodules. MATERIALS AND METHODS: Ninety-nine individuals undergoing surveillance of solid pulmonary nodules undertook a low-dose (LD) and ULD CT during the same sitting. Image pairs were read blinded, in random order, and independently by two experienced thoracic radiologists. With LD-CT as the reference standard, the number, size, and location of nodules was compared, and inter-rater agreement was established. RESULTS: There was very good inter-rater agreement with regards nodules ≥4mm for both the LD- (k=0.931) and ULD-CT (k=0.869). One hundred and ninety-nine nodules were reported on the LD-CT by both radiologists and 196 reported on the ULD-CT, with no nodules reported only on the ULD-CT. This gives a sensitivity of 98.5% and specificity of 100% for ULD-CT with MBIR. The effective dose of radiation was significantly different between the two scans (p<0.0001), 1.67 mSv for the LD-CT and 0.13 mSv for the ULD-CT. CONCLUSION: ULD-CT utilising MBIR and delivering radiation equivalent to plain radiography, allows detection of lung nodules with high sensitivity. The attendant 10-fold reduction in radiation may allow for dramatic reductions in cumulative radiation exposure.

Advanced biomaterial strategies to transplant preformed micro-tissue engineered neural networks into the brain.

OBJECTIVE: Connectome disruption is a hallmark of many neurological diseases and trauma with no current strategies to restore lost long-distance axonal pathways in the brain. We are creating transplantable micro-tissue engineered neural networks (micro-TENNs), which are preformed constructs consisting of embedded neurons and long axonal tracts to integrate with the nervous system to physically reconstitute lost axonal pathways. APPROACH: We advanced micro-tissue engineering techniques to generate micro-TENNs consisting of discrete populations of mature primary cerebral cortical neurons spanned by long axonal fascicles encased in miniature hydrogel micro-columns. Further, we improved the biomaterial encasement scheme by adding a thin layer of low viscosity carboxymethylcellulose (CMC) to enable needle-less insertion and rapid softening for mechanical similarity with brain tissue. MAIN RESULTS: The engineered architecture of cortical micro-TENNs facilitated robust neuronal viability and axonal cytoarchitecture to at least 22 days in vitro. Micro-TENNs displayed discrete neuronal populations spanned by long axonal fasciculation throughout the core, thus mimicking the general systems-level anatomy of gray matter-white matter in the brain. Additionally, micro-columns with thin CMC-coating upon mild dehydration were able to withstand a force of 893 ± 457 mN before buckling, whereas a solid agarose cylinder of similar dimensions was predicted to withstand less than 150 µN of force. This thin CMC coating increased the stiffness by three orders of magnitude, enabling needle-less insertion into brain while significantly reducing the footprint of previous needle-based delivery methods to minimize insertion trauma. SIGNIFICANCE: Our novel micro-TENNs are the first strategy designed for minimally invasive implantation to facilitate nervous system repair by simultaneously providing neuronal replacement and physical reconstruction of long-distance axon pathways in the brain. The micro-TENN approach may offer the ability to treat several disorders that disrupt the connectome, including Parkinson's disease, traumatic brain injury, stroke, and brain tumor excision.

Thermal conductivity and energetic recoils in UO2 using a many-body potential model.

Classical molecular dynamics simulations have been performed on uranium dioxide (UO2) employing a recently developed many-body potential model. Thermal conductivities are computed for a defect free UO2 lattice and a radiation-damaged, defect containing lattice at 300 K, 1000 K and 1500 K. Defects significantly degrade the thermal conductivity of UO2 as does the presence of amorphous UO2, which has a largely temperature independent thermal conductivity of ∼1.4 Wm(-1) K(-1). The model yields a pre-melting superionic transition temperature at 2600 K, very close to the experimental value and the mechanical melting temperature of 3600 K, slightly lower than those generated with other empirical potentials. The average threshold displacement energy was calculated to be 37 eV. Although the spatial extent of a 1 keV U cascade is very similar to those generated with other empirical potentials and the number of Frenkel pairs generated is close to that from the Basak potential, the vacancy and interstitial cluster distribution is different.

Density and structural effects in the radiation tolerance of TiO2 polymorphs.

The radiation response of TiO2 has been studied using molecular dynamics. The simulations are motivated by experimental observations that the three low-pressure polymorphs, rutile, brookite and anatase, exhibit vastly different tolerances to amorphization under ion-beam irradiation. To understand the role of structure we perform large numbers of simulations using the small thermal spike method. We quantify to high statistical accuracy the number of defects created as a function of temperature and structure type, and reproduce all the main trends observed experimentally. To evaluate a hypothesis that volumetric strain relative to the amorphous phase is an important driving force for defect recovery, we perform spike simulations in which the crystalline density is varied over a wide range. Remarkably, the large differences between the polymorphs disappear once the density difference is taken into account. This finding demonstrates that density is an important factor which controls radiation tolerance in TiO2.

Validation of Align Technology's Treat III digital model superimposition tool and its case application.

OBJECTIVE: An assessment of the efficacy and accuracy of three-dimensional computer-based predictive orthodontic systems requires that new methods of treatment analysis be developed and validated. DESIGN: Invisalign is a digitally fabricated, removable orthodontic appliance that has been commercially available since 1999. It is made up of two main components: 1) computerized graphical images of a patient's teeth moving through a series of stages from initial to final position; 2) pressure formed clear plastic appliances made from stereolithography models of the images in the first component. SETTING AND SAMPLE POPULATION: The manufacturer of Invisalign (Align Technology, Inc.) has created a software tool that can be used to superimpose digital models to evaluate treatment outcomes in three dimensions. Using this software, research was conducted to determine if a single operator could repeatedly superimpose two identical digital models using 12 selected points from the palatal rugae over 10 trials. The tool was then applied to one subject's orthodontic treatment. EXPERIMENT VARIABLES: The output from this tool includes rotations, translations and morphological changes. For this study, translations and rotations were chosen. RESULTS: The results showed that the digital superimposition was reproducible, and that after multiple trials, the superimposition error decreased. The average error in x, y, z, Rx, Ry and Rz after 10 trials was determined to approach approximately 0.2 mm in translation and less than 1 degree in rotation, with a standard deviation of 0.15 mm and 0.7 mm, respectively. The treatment outcome from a single Invisalign-treated bicuspid extraction case was also evaluated tooth-by-tooth in x, y, z, Rx, Ry and Rz dimensions. CONCLUSION: Using the palate, as a stable reference seemed to work well and the evaluation of the single case showed that many, but not all, of the planned movements occurred.

Impact of hospital volume on clinical and economic outcomes for esophagectomy.

BACKGROUND: Several complex surgical procedures had a reduction in mortality when they were performed at high volume centers. We hypothesized esophagectomy procedures for cancer performed at high volume hospitals in the state of Massachusetts would show a similar relationship. METHODS: Data were obtained from the Massachusetts Health Data Consortium on discharge information for all acute care hospitals in Massachusetts regardless of payer from 1992 to 2000. The influence of hospital volume was related to days in the intensive care unit, length of stay, discharge disposition, hospital mortality, and total cost. Hospitals were stratified to low volume hospitals (< 6 cases per year) and high volume hospitals (> 6 cases per year). RESULTS: One thousand one hundred ninety-three patients underwent esophagectomy during this 8-year study period in Massachusetts. Three high volume hospitals performed 56.5% of all resections (674 of 1,193). Sixty-one low volume hospitals performed 43.5% of the resections (519 of 1,193) with an average volume of only 1 case of esophagectomy per year. High volume hospitals were associated with a 2-day decrease in median length of stay (p < 0.001), a 3-day reduction in median intensive care unit stay (p < 0.001), an increased rate of home discharges (as opposed to rehabilitation hospitals) (p < 0.001), and a 3.7-fold decrease in hospital mortality (9.2% vs 2.5%; p < 0.001). The odds ratio of death at a low volume hospital was 4.3 (95% confidence interval, 2.3 to 7.7; p < 0.001). The median cost was $755 dollars greater at high volume hospitals (p = not significant). CONCLUSIONS: Hospitals that perform a high volume of esophagectomies have better results with early clinical outcomes and marked reductions in mortality compared with low volume hospitals.

Monocharged inhibitors of mast cell tryptase derived from potent and selective dibasic inhibitors.

Truncation of potent and selective dibasic inhibitors afforded monocharged inhibitors of human mast-cell tryptase. Using two classes of analogues as lead structures, several monocharged derivatives were identified with K(i) values ranging from 0.084 to 0.21 microM against the enzyme.

Dibasic inhibitors of human mast cell tryptase. Part 3: identification of a series of potent and selective inhibitors containing the benzamidine functionality.

A survey of charged groups and linkers for a series of symmetrical and unsymmetrical dibasic inhibitors is described, leading to several classes of potent and selective inhibitors. In particular, the benzamidine functionality was identified as the most potent charged group investigated.

Inhibition of stimulated Jurkat cell adenosine 3',5'-cyclic monophosphate synthesis by the immunomodulatory compound HR325.

HR325 (2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'(trifluoromethyl)-phenyl]-propenamide) is an immunomodulatory compound through pyrimidine biosynthesis inhibition with antiproliferative properties which was derived from the isoxazol compound A77 1726 [2-cyano-3-cyclopropyl-3-hydroxy-enoic acid (4-trifluoromethylphenyl)-amide]. During studies of the effects on early signal transduction events of this type of compound, it was found that HR325 dose-dependently inhibited adenosine 3',5'-cyclic monophosphate (cAMP) synthesis by Jurkat cells stimulated with prostaglandin E(2), (PGE(2)), cholera toxin (CTX), or forskolin (FKN). The potency of inhibition by HR325 of FKN-stimulated cells (IC(50) 30.4 microM) was approximately 3-fold higher than that of the other agonists (11.6 and 11.7 microM) and was independent of time of preincubation for both PGE(2) and FKN. Interestingly, A77 1726, an analogue of HR325, displayed a markedly different profile of stimulus-dependent potencies. The inhibition of cAMP synthesis by HR325 when stimulated by both PGE(2) and FKN was unaffected by glucose supplementation, in contrast to HR325-inhibited ATP levels, which were restored under such conditions. Further studies revealed that HR325 reduced intracellular ATP levels by uncoupling oxidative phosphorylation, albeit with a 1000-fold lower potency than the antihelmintic drug niclosamide. In addition, glucose supplementation experiments showed that, in contrast to HR325, the niclosamide-mediated reduction of ATP levels was wholly responsible for its inhibition of PGE(2)- and FKN-stimulated cAMP synthesis.

Comprehensive mutation screening in a cystic fibrosis center.

OBJECTIVES AND BACKGROUND: The identities of a cystic fibrosis (CF) patient's CFTR mutations can influence therapeutic strategies, but because >800 CFTR mutations exist, cost-effective, comprehensive screening requires a multistage approach. Single-strand conformation polymorphism and heteroduplex analysis (SSCP/HA) can be an important part of mutation detection, but must be calibrated within each laboratory. The sensitivity of a combined commercial-SSCP/HA approach to genotyping in a large, ethnically diverse US center CF population has not been established. STUDY DESIGN: We screened all 27 CFTR exons in 10 human participants who had an unequivocal CF diagnosis including a positive sweat chloride test and at least 1 unknown allele after commercial testing for the 70 most common mutations by SSCP/HA. These participants were compared with 7 participants who had negative sweat tests but at least 1 other CF-like symptom meriting complete genotyping. RESULTS: For the 10 CF participants, we detected 11 of 16 unknown alleles (69%) and all 4 of the known alleles (100%), for an overall rate of 75% inpatients not fully genotyped by conventional 70 mutation screen. For 7 participants with negative sweat tests, we confirmed 1 identified mutation in 14 alleles and detected 3 additional mutations. Mutations detected in both groups included 7 missense mutations (S13F, P67L, G98R, S492F, G970D, L1093P, N1303K) and 9 deletion, frameshift, nonsense or splicing mutations (R75X, G542X, DeltaF508, 451-458Delta8 bp, 5T, 663DeltaT, exon 13 frameshift, 1261+1G-->A and 3272-26A-->G). Three of these mutations were novel (G970D, L1093P, and 451-458Delta8 bp(1)). Thirteen other changes were detected, including the novel changes 1812-3 ins T, 4096-278 ins T, 4096-265 ins TG, and 4096-180 T-->G. CONCLUSION: When combined with the 70 mutation Genzyme test, SSCP/HA analysis allows for detection of >95% of the mutations in an ethnically heterogeneous CF center population. We discuss 5 possible explanations that could account for the few remaining undetected mutations.

Dibasic inhibitors of human mast cell tryptase. Part 1: synthesis and optimization of a novel class of inhibitors.

The synthesis and optimization of a novel class of reversible and active-site directed dibasic inhibitors of human mast cell tryptase are described. The compounds were shown to be both remarkably potent and selective for tryptase with Ki values for optimized inhibitors in the picomolar range.

Dibasic inhibitors of human mast cell tryptase. Part 2: structure-activity relationships and requirements for potent activity.

Detailed structure activity relationships (SARs) for a series of dibasic human tryptase inhibitors are presented. The structural requirements for potent inhibitory activity are remarkably broad with a range of core template modifications being well tolerated. Optimized inhibitors demonstrate potent anti-asthmatic activity in a sheep model of allergic asthma. APC-2059, a dibasic tryptase inhibitor with subnanomolar activity, has been advanced to phase II clinical trials for the treatment of both psoriasis and ulcerative colitis.

Long-segment colon interposition for acquired esophageal disease.

BACKGROUND: Long-segment colon interposition has been used for esophageal replacement for acquired esophageal disease. The indications for use, morbidity, and functional results of these conduits have been debated. METHODS: We reviewed the medical records, office visits, and operative reports of patients undergoing long colon interposition for acquired esophageal disease at our institution from 1956 to 1997. RESULTS: Long colon interposition was performed in 52 patients for caustic injury (n = 20), gastroesophageal disease (n = 16), previous irradiation (n = 8), primary motility disorders (n = 4), and acquired absence of the esophagus (n = 4). From 1976 to 1997, acquired diseases accounted for 62% of long colon interposition. The left colon was used in 46 patients and the right colon in 6. The in-hospital mortality rate was 4%. Early complications included graft ischemia in 5 patients, anastomotic leak in 3, and small bowel obstruction in 1. Late complications included anastomotic stenosis requiring dilation in 26 patients, with 2 requiring surgical revision, and bile reflux requiring surgical diversion in 1 patient. Swallowing function was excellent in 24% of patients, good in 66%, and poor in 10%. CONCLUSIONS: Long colon interposition can be performed safely, with acceptable long-term functional results in patients with acquired esophageal disease.

Purification of human dihydro-orotate dehydrogenase and its inhibition by A77 1726, the active metabolite of leflunomide.

Leflunomide is currently in phase-III clinical trials for the treatment of rheumatoid arthritis. In this study, we have focused our efforts on the study of the mechanism of action of the active metabolite of leflunomide, A77 1726, in cells and tissue of human origin. The human high-affinity binding protein for radiolabelled A77 1726 was purified from solubilized U937 membranes by following the binding activity through the purification process and was characterized as the mitochondrial enzyme dihydro-orotate dehydrogenase (DHO-DH). The human and murine enzyme displayed identical pI and molecular mass values on SDS/PAGE (43 kDa), which contrasts notably with previous reports suggesting a molecular mass of 50 kDa for the human enzyme. DHO-DH activity was inhibited by A77 1726 and its analogue HR325 with similar potency in U937 and human spleen membrane preparations. HR325 was found to be anti-proliferative for phytohaemagglutinin-stimulated human peripheral blood mononuclear cells, at the same concentrations that caused accumulation of DHO and depletion of uridine. Supplementation of the cultures with exogenous uridine led to partial abrogation of the anti-proliferative effect. This is in line with our recent demonstration that the anti-proliferative effect in vitro of A77 1726 on lipopolysaccharide-stimulated mouse spleen cells was mediated by DHO-DH inhibition [Williamson, Yea, Robson, Curnock, Gadher, Hambleton, Woodward, Bruneau, Hambleton, Moss et al., (1995) J. Biol. Chem. 270, 22467-22472]. Thus, DHO-DH inhibition by A77 1726 and its analogues is responsible for the anti-proliferative effects in vitro of the compounds on human cells and is likely to be responsible for some of its effects in vivo.

Inhaled nitric oxide for adult respiratory distress syndrome after pulmonary resection.

BACKGROUND: The adult respiratory distress syndrome (ARDS) developing after pulmonary resection is usually a lethal complication. The etiology of this serious complication remains unknown despite many theories. Intubation, aspiration bronchoscopy, antibiotics, and diuresis have been the mainstays of treatment. Mortality rates from ARDS after pneumonectomy have been reported as high as 90% to 100%. METHODS: In 1991, nitric oxide became clinically available. We instituted an aggressive program to treat patients with ARDS after pulmonary resection. Patients were intubated and treated with standard supportive measures plus inhaled nitric oxide at 10 to 20 parts/million. While being ventilated, all patients had postural changes to improve ventilation/perfusion matching and management of secretions. Systemic steroids were given to half of the patients. RESULTS: Ten consecutive patients after pulmonary resection with severe ARDS (ARDS score = 3.1+/-0.04) were treated. The mean ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen at initiation of treatment was 95+/-13 mm Hg (mean +/- SEM) and improved immediately to 128+/-24 mm Hg, a 31%+/-8% improvement (p<0.05). The ratio improved steadily over the ensuing 96 hours. Chest x-rays improved in all patients and normalized in 8. No adverse reactions to nitric oxide were observed. CONCLUSIONS: We recommend the following treatment regimen for this lethal complication: intubation at the first radiographic sign of ARDS; immediate institution of inhaled nitric oxide (10 to 20 parts per million); aspiration bronchoscopy and postural changes to improve management of secretions and ventilation/perfusion matching; diuresis and antibiotics; and consideration of the addition of intravenous steroid therapy.