Cost-effectiveness analysis of surgical proximal femur fracture prevention in elderly: a Markov cohort simulation model.

BACKGROUND: Hip fractures are a common and costly health problem, resulting in significant morbidity and mortality, as well as high costs for healthcare systems, especially for the elderly. Implementing surgical preventive strategies has the potential to improve the quality of life and reduce the burden on healthcare resources, particularly in the long term. However, there are currently limited guidelines for standardizing hip fracture prophylaxis practices. METHODS: This study used a cost-effectiveness analysis with a finite-state Markov model and cohort simulation to evaluate the primary and secondary surgical prevention of hip fractures in the elderly. Patients aged 60 to 90 years were simulated in two different models (A and B) to assess prevention at different levels. Model A assumed prophylaxis was performed during the fracture operation on the contralateral side, while Model B included individuals with high fracture risk factors. Costs were obtained from the Centers for Medicare & Medicaid Services, and transition probabilities and health state utilities were derived from available literature. The baseline assumption was a 10% reduction in fracture risk after prophylaxis. A sensitivity analysis was also conducted to assess the reliability and variability of the results. RESULTS: With a 10% fracture risk reduction, model A costs between $8,850 and $46,940 per quality-adjusted life-year ($/QALY). Additionally, it proved most cost-effective in the age range between 61 and 81 years. The sensitivity analysis established that a reduction of ≥ 2.8% is needed for prophylaxis to be definitely cost-effective. The cost-effectiveness at the secondary prevention level was most sensitive to the cost of the contralateral side's prophylaxis, the patient's age, and fracture treatment cost. For high-risk patients with no fracture history, the cost-effectiveness of a preventive strategy depends on their risk profile. In the baseline analysis, the incremental cost-effectiveness ratio at the primary prevention level varied between $11,000/QALY and $74,000/QALY, which is below the defined willingness to pay threshold. CONCLUSION: Due to the high cost of hip fracture treatment and its increased morbidity, surgical prophylaxis strategies have demonstrated that they can significantly relieve the healthcare system. Various key assumptions facilitated the modeling, allowing for adequate room for uncertainty. Further research is needed to evaluate health-state-associated risks.

Structures and internal dynamics of diphenylether and its aggregates with water.

We report on a detailed multi-spectroscopic analysis of the structures and internal dynamics of diphenylether and its aggregates with up to three water molecules by employing molecular beam experiments. The application of stimulated Raman/UV and IR/UV double resonance methods as well as chirped-pulse Fourier transform microwave spectroscopy in combination with quantum-chemical computations yield the energetically preferred monomer and cluster geometries. Furthermore, the complex internal dynamics of the diphenylether monomer and the one-water clusters are analysed. In the cluster with three water molecules, water forms a cyclic structure similar to the isolated water trimer. The interactions ruling the structures of the higher-order water clusters are a combination of the ones identified for the two monohydrate isomers, with dispersion being a decisive contribution for systems that have a delicate energetic balance between different hydrogen-bonded arrangements of similar energy.

Dispersion-controlled docking preference: multi-spectroscopic study on complexes of dibenzofuran with alcohols and water.

The structural preferences within a series of dibenzofuran-solvent complexes have been investigated by electronic, vibrational, and rotational spectroscopic methods probing supersonic jet expansions. The experimental study is accompanied by a detailed theoretical analysis including dispersion-corrected density functional theory, symmetry adapted perturbation theory, as well as coupled cluster approaches. The complementary, multi-spectroscopic results reveal a preferred OHO structure for the smallest complex of dibenzofuran-water, whereas for the methanol complex an OHπ isomer is simultaneously observed. For the largest complex, dibenzofuran-tert-butyl alcohol, only a π-bound structure is found. These comprehensive investigations show that a completely inverse trend regarding the docking preference is observed by comparing the present results with the ones for analogous diphenyl ether complexes. This can be rationalized on the basis of the planarity/non-planarity and rigidity/flexibility of the different systems, providing valuable insight into the interplay between different non-covalent interactions. This analysis is a further step towards a quantitative description of very delicate energetic balances with the overall goal of yielding reliable structural predictions for non-covalently bound systems.

Mid-term development of the right ventricle in competitive athletes.

BACKGROUND: Long-term intensive training induces physiological, morphological, and functional adaption of the athlete's heart. PURPOSE: To evaluate the development of athlete's heart during a mid-term follow-up of competitive athletes using cardiac magnetic resonance (CMR). MATERIAL AND METHODS: Eighteen competitive long-distance runners and triathletes (age 43 ± 13 years, 3 women) were prospectively examined in a longitudinal follow-up study 5.05 ± 0.6 years after baseline. CMR at 1.5-T was performed for functional and late gadolinium enhancement (LGE) imaging. Left ventricular (LV) and right ventricular (RV) end-diastolic volume (LVEDV, RVEDV) as well as ejection fraction (LVEF, RVEF), LV myocardial mass (LVMM), and atrial sizes were determined and compared to baseline in matched pairs statistics for paired difference. RESULTS: LVEDV (197 ± 38 mL vs. 196 ± 38 mL, paired difference -0.9 mL, P = 0.7) and LVEF (62 ± 7% vs. 62 ± 5%, paired difference 0.1%, P = 0.9) did not change during the follow-up period, whereas LVMM increased significantly (149 ± 31 g vs.164 ± 32 g, paired difference 14 g, P < 0.0001). RVEDV significantly increased from 221 ± 47 mL at baseline to 230 ± 52 mL (paired difference 10 mL, P = 0.0033). RVEF decreased from baseline 57 ± 8% to 53 ± 7% (paired difference -3%, P = 0.0234). Left atrial size showed no significant changes (24 ± 5 cm2 vs. 25 ± 6 cm2, paired difference 0.5 cm2, P = 0.17) and right atrial size increased significantly (30 ± 5 cm2 vs. 32 ± 4 cm2, paired difference 2 cm2, P = 0.0054). CONCLUSION: This study supports the theory of ongoing remodeling in an athlete's heart. Predominantly the right heart can further enlarge in a mid-term period. This response seems not linearly dependent on a steady, decreased, or increased training volume.

Combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with stage IV melanoma-safety and efficacy in a phase II study.

Treatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis. The primary endpoint was the disease control rate according to immune-related response criteria at week 12; tolerability according to Common Terminology Criteria for Adverse Events criteria was secondary endpoint. No objective responses were observed in the 15 enrolled patients. Three patients had stable disease 12 weeks after starting treatment, yielding a disease control rate of 20%. Tolerability of this combination treatment was acceptable. Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred. Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone.

Cardiovascular magnetic resonance patterns of biopsy proven cardiac involvement in systemic sclerosis.

BACKGROUND: To determine morphological and functional cardiovascular magnetic resonance (CMR) patterns in histopathologically confirmed myocardial involvement in patients with systemic sclerosis (SSc). METHODS: Twenty patients (6 females; mean age 41 ± 11 years) with histopathologically proven cardiac involvement in SSc in the years 2008-2016 were retrospectively evaluated. Morphological, functional and late gadolinium enhancement (LGE) images were acquired in standard angulations at 1.5 T CMR. Pathologies were categorized: 1) Pericardial effusion; 2) pathologic left (LV) or right ventricular (RV) contractility (hypokinesia, dyssynchrony, and diastolic restriction); 3) reduced left (LV-EF) and right ventricular ejection fraction (RV-EF); 4) fibrosis and/or inflammation (positive LGE); 5) RV dilatation. 95 % confidence intervals (CI) were calculated for appearance of pathologic EF and RV dilatation. RESULTS: Seven patients (35 %) had positive CMR findings in three categories, 9 patients (45 %) in four categories and 4 patients (20 %) in five categories. The distribution of pathologic findings was: minimal pericardial effusion in 7 patients (35 %), moderate pericardial effusion >5 mm in nine patients (45 %); abnormal LV or RV contractility in 19 patients (95 %), reduced LV or RV function in 14 patients (70 %; 95 % CI: 51-88 %), pathologic LGE in all patients, RV dilatation in 6 patients (30 %; 95 % CI: 15-54 %). CONCLUSIONS: CMR diagnosis of myocardial involvement in SSc requires increased attention to subtle findings. Pathologic findings in at least three of five categories indicate myocardial involvement in SSc.

Structural investigations on a linear isolated depsipeptide: the importance of dispersion interactions.

In this paper we present the first investigations on an isolated linear depsipetide CyCO-Gly-Lac-NH-PhOMe (cyclohexylcarbonyl-glycine-lactate-2-anisidine abbreviated as MOC) in a molecular beam experiment. Depsipeptides are a special subclass of peptides which contain at least one ester bond replacing a peptide bond. This leads to a different folding behavior and a different biological activity compared to a "normal" peptide. In order to analyze the folding of an isolated depsipeptide on a molecular level a variety of combined IR/UV methods including IR/IR/UV experiments are applied to MOC. Three different isomers are identified in combination with DFT calculations using the hybrid functional B3LYP-D3 with a TZVP basis set. The most stable structure shows a tweezer-like arrangement between the aromatic chromophore and the aliphatic cyclohexyl ring. A characteristic feature of this structure is that it is stabilized by dispersion interactions resulting from CH/π interactions. If dispersion is not taken into account this structural arrangement is no longer a minimum on the potential energy surface indicating the importance of dispersion interactions.

High resolution myocardial magnetic resonance stress perfusion imaging at 3 T using a 1 M contrast agent.

OBJECTIVE: Stress perfusion magnetic resonance imaging (MSPMRI) is an established technique for the assessment of myocardial perfusion. Shortcomings at 1.5 T are low signal to noise ratio (SNR) and contrast to noise ratio (CNR). One approach to overcome these shortcomings is to increase field strength and contrast concentration. The aim of our study was to investigate the diagnostic capability of high resolution MSPMRI at 3-T field strength using a 1 M contrast agent. MATERIAL AND METHODS: Fifty-seven patients (62.3 +/- 11.0 years) with symptoms of coronary artery disease (CAD) were examined at 3 T. MMRSPI was assessed using a 2D saturation recovery gradient echo (SR GRE) sequence in short axis orientation (TR 1.9 ms, TE 1.0 ms, flip 12 degrees , 0.1 mmol gadobutrol/kg body weight (bw), 140 microg adenosine/kg bw/min). Perfusion images were assessed visually and semiquantitatively (upslope, peak signal intensity (SI), and myocardial perfusion reserve index (MPRI)). Standard of reference was invasive coronary angiography. RESULTS: Stress-induced hypoperfusion was found in 43 patients. Sensitivity for hemodynamically relevant CAD (stenoses greater than 70%) was 95%/98%, specificity 80%/87%, diagnostic accuracy 91%/95% (reader 1/reader 2). The MPRI was significantly lower in hypoperfused myocardium (1.3 +/- 0.2) compared with normal myocardium (2.6 +/- 0.7). CONCLUSION: High resolution MMRSPI at 3 T using 1 M contrast agent under daily routine conditions provides reliable detection of stress-induced myocardial hypoperfusion with higher diagnostic accuracy than 1.5-T conditions.

Cigarette smoke facilitates allergen penetration across respiratory epithelium.

BACKGROUND: The association between cigarette smoke exposure and allergic airway disease is a matter for debate. We sought to investigate in an in vitro system whether active smoking reduces the integrity and barrier function of the respiratory epithelium and thus facilitates allergen penetration. METHODS: We cultured the human bronchial epithelial cell line 16HBE14o- in a transwell culture system as a surrogate for the intact respiratory epithelium. The cell monolayer was exposed to standardized cigarette smoke extract (CSE). The extent and effects of trans-epithelial allergen penetration were measured using 125I-labelled purified major respiratory allergens (rBet v 1, rPhl p 5 and rDer p 2) and histamine release experiments. RESULTS: Exposure of cells to concentrations of CSE similar to those found in smokers induced the development of para-cellular gaps and a decrease in trans-epithelial resistance. CSE exposure induced a more than threefold increase in allergen penetration. Increased subepithelial allergen concentrations provoked a substantial augmentation of histamine release from sensitized basophils. CONCLUSIONS: Our results indicate that cigarette smoke is a potent factor capable of reducing the barrier function of the respiratory epithelium for allergens and may contribute to increased allergic inflammation, exacerbation of allergic disease and boosting of IgE memory.

Intraindividual comparison of myocardial delayed enhancement MR imaging using gadobenate dimeglumine at 1.5 T and 3 T.

For contrast-enhanced imaging techniques relying on strong T1 weighting, 3 T provides increased contrast compared with 1.5 T. The aim of our study was the intraindividual comparison of delayed enhancement MR imaging at 1.5 T and at 3 T. Twenty patients with myocardial infarction were examined at 1.5 T and 3 T. Fifteen minutes after injection of contrast agent (0.1 mmol gadobenate dimeglumine per kg body weight), inversion recovery gradient recalled echo (IR-GRE) sequences were acquired (1.5 T/3 T: TR 11.0/9.9 ms, TE 4.4/4.9 ms, flip 30 degrees /30 degrees , slice thickness 6/6 mm) to assess myocardial viability. Two observers rated image quality (Wilcoxon signed rank test). Quantification of hyperenhanced myocardium and standardized SNR/CNR measurements were performed (Student's t test). There was no significant difference with respect to image quality (1.5 T/3 T: 3.5/3.3, p = 0.34, reader 1; 2.4/2.7, p = 0.12, reader 2) and infarction size (760 +/- 566/828 +/- 677 mm(2) at 1.5 T, 808 +/- 639/826 +/- 726 mm(2) at 3 T, reader 1/reader 2, p > 0.05). Mean SNR in hyperenhanced/normal myocardium was 19.2/6.2 at 1.5 T and 29.5/8.8 at 3 T (p < 0.05). Mean CNR was 14.3 at 1.5 T and 26.0 at 3 T (p < 0.05). Delayed enhancement MR imaging at 3 T is a robust procedure yielding superior tissue contrast at 3 T compared with 1.5 T which is, however, not reflected by increased image quality.

An integral quality monitoring system for real-time verification of intensity modulated radiation therapy.

PURPOSE: To develop an independent and on-line beam monitoring system, which can validate the accuracy of segment-by-segment energy fluence delivery for each treatment field. The system is also intended to be utilized for pretreatment dosimetric quality assurance of intensity modulated radiation therapy (IMRT), on-line image-guided adaptive radiation therapy, and volumetric modulated arc therapy. METHODS: The system, referred to as the integral quality monitor (IQM), utilizes an area integrating energy fluence monitoring sensor (AIMS) positioned between the final beam shaping device [i.e., multileaf collimator (MLC)] and the patient. The prototype AIMS consists of a novel spatially sensitive large area ionization chamber with a gradient along the direction of the MLC motion. The signal from the AIMS provides a simple output for each beam segment, which is compared in real time to the expected value. The prototype ionization chamber, with a physical area of 22 x 22 cm2, has been constructed out of aluminum with the electrode separations varying linearly from 2 to 20 mm. A calculation method has been developed to predict AIMS signals based on an elementwise integration technique, which takes into account various predetermined factors, including the spatial response function of the chamber, MLC characteristics, beam transmission through the secondary jaws, and field size factors. The influence of the ionization chamber on the beam has been evaluated in terms of transmission, surface dose, beam profiles, and depth dose. The sensitivity of the system was tested by introducing small deviations in leaf positions. A small set of IMRT fields for prostate and head and neck plans was used to evaluate the system. The ionization chamber and the data acquisition software systems were interfaced to two different types of linear accelerators: Elekta Synergy and Varian iX. RESULTS: For a 10 x 10 cm2 field, the chamber attenuates the beam intensity by 7% and 5% for 6 and 18 MV beams, respectively, without significantly changing the depth dose, surface dose, and dose profile characteristics. An MLC bank calibration error of 1 mm causes the IQM signal of a 3 x 3 cm2 aperture to change by 3%. A positioning error in a single 5 mm wide leaf by 3 mm in 3 X 3 cm2 aperture causes a signal difference of 2%. Initial results for prostate and head and neck IMRT fields show an average agreement between calculation and measurement to within 1%, with a maximum deviation for each of the smallest beam segments to within 5%. When the beam segments of a prostate IMRT field were shifted by 3 mm from their original position, along the direction of the MLC motion, the IQM signals varied, on average, by 2.5%. CONCLUSIONS: The prototype IQM system can validate the accuracy of beam delivery in real time by comparing precalculated and measured AIMS signals. The system is capable of capturing errors in MLC leaf calibration or malfunctions in the positioning of an individual leaf. The AIMS does not significantly alter the beam quality and therefore could be implemented without requiring recommissioning measurements.

Evaluation of the effect of patient dose from cone beam computed tomography on prostate IMRT using Monte Carlo simulation.

The aim of this study is to evaluate the impact of the patient dose due to the kilovoltage cone beam computed tomography (kV-CBCT) in a prostate intensity-modulated radiation therapy (IMRT). The dose distributions for the five prostate IMRTs were calculated using the Pinnacle treatment planning system. To calculate the patient dose from CBCT, phase-space beams of a CBCT head based on the ELEKTA x-ray volume imaging system were generated using the Monte Carlo BEAMnr code for 100, 120, 130, and 140 kVp energies. An in-house graphical user interface called DOSCTP (DOSXYZnrc-based) developed using MATLAB was used to calculate the dose distributions due to a 360 degrees photon arc from the CBCT beam with the same patient CT image sets as used in Pinnacle. The two calculated dose distributions were added together by setting the CBCT doses equal to 1%, 1.5%, 2%, and 2.5% of the prescription dose of the prostate IMRT. The prostate plan and the summed dose distributions were then processed in the CERR platform to determine the dose-volume histograms (DVHs) of the regions of interest. Moreover, dose profiles along the x- and y-axes crossing the isocenter with and without addition of the CBCT dose were determined. It was found that the added doses due to CBCT are most significant at the femur heads. Higher doses were found at the bones for a relatively low energy CBCT beam such as 100 kVp. Apart from the bones, the CBCT dose was observed to be most concentrated on the anterior and posterior side of the patient anatomy. Analysis of the DVHs for the prostate and other critical tissues showed that they vary only slightly with the added CBCT dose at different beam energies. On the other hand, the changes of the DVHs for the femur heads due to the CBCT dose and beam energy were more significant than those of rectal and bladder wall. By analyzing the vertical and horizontal dose profiles crossing the femur heads and isocenter, with and without the CBCT dose equal to 2% of the prescribed dose, it was found that there is about a 5% increase of dose at the femur head. Still, such an increase in the femur head dose is well below the dose limit of the bone in our IMRT plans. Therefore, under these dose fractionation conditions, it is concluded that, though CBCT causes a higher dose deposited at the bones, there may be no significant effect in the DVHs of critical tissues in the prostate IMRT.

The aging cardiomyocyte: a mini-review.

BACKGROUND: Aging per se is a risk factor for reduced cardiac function and heart diseases, even when adjusted for aging-associated cardiovascular risk factors. Accordingly, aging-related biochemical and cell-biological changes lead to pathophysiological conditions, especially reduced heart function and heart disease. OBJECTIVE: In this review, we summarize the changes that occur as the heart ages from youth to old age on the basis of the cardiac myocyte. Aging phenotypes and underlying mechanisms shall be discussed that affect cardiomyocyte repair, signaling, structure, and function. METHODS: Review of the literature. RESULTS: The following factors play vital roles in the aging of cardiomyocytes: oxidative stress, inflammation, cellular protection and repair, telomere integrity, survival and death, metabolism, post-translational modifications, and altered gene expression. Importantly, non-cardiomyocyte-based aging processes (vascular, fibroblast, extracellular matrix, etc.) in the heart will interfere with cardiomyocyte aging and cardiac function. CONCLUSION: Based on our analyses, we postulate that the physiological aging process of the heart and of the cardiomyocyte is primarily driven by intrinsic aging factors. However, extrinsic aging factors, e.g. smoking, also make an important contribution to pathologically accelerated aging of the heart.

Impact of graft and tunnel orientation on patient-reported outcome in anterior cruciate ligament reconstruction using bone-patellar tendon-bone autografts.

BACKGROUND: The optimal positioning of anterior cruciate ligament graft is still controversially discussed. We therefore wanted to determine the tunnel-to-joint (TJA), tunnel-to-shaft (TSA), and graft-tunnel divergence angles which would provide the best outcome, determined by the KOOS (Knee Injury and Osteoarthritis Outcome Score). This study evaluated the clinical influence of graft orientation as measured with the KOOS questionnaire in patients with anterior cruciate ligament reconstruction with bone-patellar tendon-bone autografts. METHODS: We designed a prospective cohort study, with a 1 » year recruitment phase from March 2011 to July 2012 and a minimal follow-up period of 1 year. Inclusion criteria were patients ≥ 18 years of age receiving an ACL reconstruction with bone-patellar tendon-bone autografts at our institution after having suffered an acute ACL rupture. The primary outcome was the KOOS. Independent variables were patient age, gender, laterality of rupture, mechanism of trauma, and type of femoral and tibial fixation, as well as sagittal graft-tunnel divergence, TJA, and TSA, the latter two being assessed on coronal slices of magnetic resonance imaging. Equations modeling the relationship between TJA, TSA, and graft-tunnel divergence with the KOOS overall score were fitted, and the optimum angles were mathematically determined. RESULTS: In total, 31 patients were included in our study. Our cohort with a median age of 28 years was predominantly male. The mathematically determined optimal placement of the implant in the coronal plane was a TJA of 74.8°, a TSA of 80.1°, and a graft-tunnel divergence angle of 8.5°. CONCLUSION: With regard to patient-reported outcome, the optimal graft orientation is provided by a coronal tunnel-to-shaft angle of 80° and tunnel-to-joint angle of 75°, respectively. Interestingly, in our series, patients reported best clinical outcomes with a sagittal graft-tunnel divergence. These results should be validated in larger studies.

Smoking, oxidative stress and cardiovascular diseases--do anti-oxidative therapies fail?

Oxidative reactions caused by cigarette smoke (CS) chemicals have been shown to initiate crucial events in atherogenesis. However, physicians and scientists are confronted with the paradoxical situation that an antioxidative treatment of smokers improves acute smoking effects but hardly has any impact on long term outcome of cardiovascular diseases (CVD). In this review we make an attempt to explain this paradox. First, smoke-derived free radicals and oxidants are part of CS causing a pro-oxidative state in the circulatory system. Further, smoke chemicals down-regulate antioxidant defence enzymes that would counteract the oxidative burden by cigarette smoke. With the prolonged exposure to smoke, oxidation catalysing metals accumulate in the vessel wall and mediate local oxidation reactions. Therefore, pharmacological intervention relying on non-selective antioxidants often appears to be ineffective. Consequently a novel strategy for the prevention and treatment of CVD caused by smoking is suggest, relying on a combined application of antioxidants, substitution of factors important for physiological oxidant defence, and metal-detoxifying agents.

Single-Breath-Hold Evaluation of Cardiac Function with Use of Time-Resolved Parallel Cardiac Magnetic Resonance.

Using cardiac magnetic resonance, we tested whether a single-breath-hold approach to cardiac functional evaluation was equivalent to the established multiple-breath-hold method. We examined 39 healthy volunteers (mean age, 31.9 ± 11.4 yr; 22 men) by using 1.5 T with multiple breath-holds and our proposed single breath-hold. Left ventricular and right ventricular ejection fractions (LVEF and RVEF), LV and RV end-diastolic volumes (LVEDV and RVEDV), and LV myocardial mass (LVMM) were compared by using Bland-Altman plots; LVEF and RVEF were tested for equivalence by inclusion of 95% confidence intervals (CIs). Equivalence of the methods was assumed within the range of -5% to 5%. In the multiple- versus the single-breath-hold method, LVEF was 0.62 ± 0.05 versus 0.62 ± 0.04, and RVEF was 0.59 ± 0.06 versus 0.59 ± 0.07. The mean difference in both methods was -0.2% (95% CI, -1 to 0.6) for LVEF and 0.3% (95% CI, -0.8 to 1.5) for RVEF. The mean differences between methods fit within the predetermined range of equivalence, including the 95% CI. The mean relative differences between the methods were 3.8% for LVEDV, 4.5% for RVEDV, and 1.6% for LVMM. Results of our single-breath-hold method to evaluate LVEF and RVEF were equivalent to those of the multiple-breath-hold technique. In addition, LVEDV, RVEDV, and LVMM showed low bias between methods.

Patient dose from kilovoltage cone beam computed tomography imaging in radiation therapy.

Kilovoltage cone-beam computerized tomography (kV-CBCT) systems integrated into the gantry of linear accelerators can be used to acquire high-resolution volumetric images of the patient in the treatment position. Using on-line software and hardware, patient position can be determined accurately with a high degree of precision and, subsequently, set-up parameters can be adjusted to deliver the intended treatment. While the patient dose due to a single volumetric imaging acquisition is small compared to the therapy dose, repeated and daily image guidance procedures can lead to substantial dose to normal tissue. The dosimetric properties of a clinical CBCT system have been studied on an Elekta linear accelerator (Synergy RP, XVI system) and additional measurements performed on a laboratory system with identical geometry. Dose measurements were performed with an ion chamber and MOSFET detectors at the center, periphery, and surface of 30 and 16-cm-diam cylindrical shaped water phantoms, as a function of x-ray energy and longitudinal field-of-view (FOV) settings of 5,10,15, and 26 cm. The measurements were performed for full 360 degrees CBCT acquisition as well as for half-rotation scans for 120 kVp beams using the 30-cm-diam phantom. The dose at the center and surface of the body phantom were determined to be 1.6 and 2.3 cGy for a typical imaging protocol, using full rotation scan, with a technique setting of 120 kVp and 660 mAs. The results of our measurements have been presented in terms of a dose conversion factor fCBCT, expressed in cGy/R. These factors depend on beam quality and phantom size as well as on scan geometry and can be utilized to estimate dose for any arbitrary mAs setting and reference exposure rate of the x-ray tube at standard distance. The results demonstrate the opportunity to manipulate the scanning parameters to reduce the dose to the patient by employing lower energy (kVp) beams, smaller FOV, or by using half-rotation scan.

Vein graft thrombi, a niche for smooth muscle cell colonization - a hypothesis to explain the asymmetry of intimal hyperplasia.

UNLABELLED: Essentials Vein graft failure is the most frequent late onset complication of coronary artery bypass grafting. Cuff technique-based interposition mouse model including new anticoagulation regime was conducted. Early vein graft thrombi may serve as a niche for smooth muscle cell colonization. The focal character of early thrombi may form the basis for the asymmetry of intimal hyperplasia. SUMMARY: Background Autologous saphenous veins are widely used in coronary artery bypass grafting; however, 10 years after surgery, 40% of grafts are completely occluded, and another 30% show reduced blood flow. Objective In the past, the central processes and signaling pathways responsible for this loss of patency have been identified. However, one central finding in the process of graft failure is so far not understood: the asymmetric character of intimal hyperplasia. It was the goal of the present study to address this aspect. Methods By the use of a cuff technique-based vein interposition mouse model with a new anticoagulation regime, alterations in vein grafts were analyzed 1 h, 1 day, 2 days, 3 days, 7 days and 21 days after reperfusion by means of immunolabeling, histochemistry, and high-resolution ultrasound. Results The novel and major finding of this study is that the vein graft thrombus may serve as a niche that is infiltrated and colonized by smooth muscle cells (SMCs). Fibroblast growth factor-1 and platelet-derived growth factor-B may be the SMC-attracting factors in the thrombus. The focal character of early thrombi may define the focal and asymmetric character of vein graft intimal hyperplasia. Conclusions Inhibiting the formation and reducing the size of early thrombi is an old concept for reducing vein graft failure. However, in light of the present new findings obtained under a clinic-like anticoagulation regime, early vein graft thrombus prevention/size reduction should be revisited in the prevention of graft failure.

p53-induced apoptosis in the human T-ALL cell line CCRF-CEM.

The tumor suppressor p53 has been implicated in apoptosis induction and is mutated in human T-ALL CCRF-CEM cells. To investigate possible consequences of wild-type p53 loss, we reconstituted CEM-C7H2, a subclone of CCRF-CEM, with a temperature-sensitive p53 allele (p53ts). Stably transfected lines expressed high levels of p53ts and shift to the permissive temperature (32 degrees C) caused rapid induction of p53-regulated genes, such as p21(CIP1/WAF1), mdm-2 and bax. This was followed by extensive apoptosis within 24 h to 36 h, supporting the notion that mutational p53 inactivation contributed to the malignant phenotype. p53-dependent apoptosis was preceded by digestion of poly(ADP-ribose) polymerase, a typical target of interleukin-1beta-converting enzyme (ICE)-like proteases/caspases, and was markedly resistant to the ICE/caspase-1 and FLICE/caspase-8 inhibitor acetyl-Tyr-Val-Ala-Asp.chloromethylketone (YVAD), but sensitive to the CPP32/caspase-3 inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp.fluoromethylketone (DEVD) and benzyloxycarbonyl-Val-Ala-Asp.fluoromethylketone (zVAD), a caspase inhibitor with broader specificity. This indicated an essential involvement of caspases, but argued against a significant role of ICE/caspase-1 or FLICE/caspase-8. Actinomycin D or cycloheximide prevented cell death, suggesting that, in this system, p53-induced apoptosis depends upon macromolecule biosynthesis. Introduction of functional p53 into CEM cells enhanced their sensitivity to the DNA-damaging agent doxorubicin, but not to the tubulin-active compound vincristine. Thus, mutational p53 inactivation in ALL might entail relative resistance to DNA-damaging, but not to tubulin-destabilizing, chemotherapy.

c-Myc does not prevent glucocorticoid-induced apoptosis of human leukemic lymphoblasts.

Due to their growth arrest- and apoptosis-inducing ability, glucocorticoids (GC) are widely used in the therapy of various lymphoid malignancies. The signal transduction pathways leading to this clinically-relevant form of apoptosis have, however, not been sufficiently elucidated. GC bind to their specific receptor, a ligand-activated transcription factor of the Zn-finger type, that activates or represses transcription of GC-responsive genes. Previous studies in leukemia cells suggested that transcriptional repression of c-myc expression might be the crucial event in GC-induced apoptosis, although in other systems, c-Myc apparently increased the sensitivity to cell-death inducers. To address this controversy, we stably transfected the GC-sensitive human T-ALL cell line CEM-C7H2 with constructs allowing tetracycline-regulated expression of c-Myc. Subsequent analyses of these cell lines showed that overexpression of c-Myc per se had little, if any, effect on cell viability, although it rendered the cells more sensitive to apoptosis induced by low serum, confirming the functionality of the expressed transgene. More importantly, however, when the cells were treated with GC in the presence of exogenous c-Myc, they underwent apoptosis exceeding that in cells treated in the absence of transgenic c-Myc. The data indicate that c-myc downregulation is not critical for induction of cell-death by GC in this system, and support the notion that c-Myc sensitizes cells to apoptosis-inducing agents.