Cardiac Adverse Events Associated with Multiple Myeloma Patients Treated with Proteasome Inhibitors.

BACKGROUND: Proteasome inhibitors (PIs) are standard treatments for multiple myeloma (MM). The risk of cardiac adverse events (CAEs) with PIs has been documented with bortezomib and carfilzomib; however, only a few studies have been reported on ixazomib. Furthermore, the effects of concomitant medications including dexamethasone and lenalidomide remain unclear. OBJECTIVES: This study aimed to determine the safety signals of adverse events related to CAEs, the effect of concomitant medications, the time to the occurrence of CAEs, and the incidence of fatal clinical outcomes after the occurrence of CAEs for three PIs using the US Pharmacovigilance database. METHODS: We examined 1,567,240 cases of 231 drugs registered as anticancer drugs in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 1997 to March 2021. We compared the odds of developing CAEs between patients who received PIs and those who received non-PI anticancer drugs. RESULTS: Bortezomib treatment resulted in significantly higher reporting odds ratios (RORs) for cardiac failure, cardiac failure congestive, and atrial fibrillation. Carfilzomib treatment resulted in significantly higher RORs for cardiac failure, congestive cardiac failure, atrial fibrillation, and QT prolonged. However, no adverse event CAE signals were observed with ixazomib treatment. A signal was detected for the safety of cardiac failure with bortezomib or carfilzomib, regardless of the presence or absence of concomitant medications. Safety signals for cardiac failure congestive with bortezomib and for cardiac failure congestive, atrial fibrillation, and QT prolonged with carfilzomib were observed only with dexamethasone combination therapy. Co-administration of lenalidomide and its derivatives did not affect the safety of bortezomib and carfilzomib. CONCLUSION: We identified CAE safety signals for bortezomib and carfilzomib exposure when compared with 231 other anticancer agents. The safety signal for developing cardiac failure for both the drugs did not differ between patients with and without concomitantly administered medications.

Deep learning-based reconstruction can improve the image quality of low radiation dose head CT.

OBJECTIVES: To evaluate the image quality of deep learning-based reconstruction (DLR), model-based (MBIR), and hybrid iterative reconstruction (HIR) algorithms for lower-dose (LD) unenhanced head CT and compare it with those of standard-dose (STD) HIR images. METHODS: This retrospective study included 114 patients who underwent unenhanced head CT using the STD (n = 57) or LD (n = 57) protocol on a 320-row CT. STD images were reconstructed with HIR; LD images were reconstructed with HIR (LD-HIR), MBIR (LD-MBIR), and DLR (LD-DLR). The image noise, gray and white matter (GM-WM) contrast, and contrast-to-noise ratio (CNR) at the basal ganglia and posterior fossa levels were quantified. The noise magnitude, noise texture, GM-WM contrast, image sharpness, streak artifact, and subjective acceptability were independently scored by three radiologists (1 = worst, 5 = best). The lesion conspicuity of LD-HIR, LD-MBIR, and LD-DLR was ranked through side-by-side assessments (1 = worst, 3 = best). Reconstruction times of three algorithms were measured. RESULTS: The effective dose of LD was 25% lower than that of STD. Lower image noise, higher GM-WM contrast, and higher CNR were observed in LD-DLR and LD-MBIR than those in STD (all, p ≤ 0.035). Compared with STD, the noise texture, image sharpness, and subjective acceptability were inferior for LD-MBIR and superior for LD-DLR (all, p < 0.001). The lesion conspicuity of LD-DLR (2.9 ± 0.2) was higher than that of HIR (1.2 ± 0.3) and MBIR (1.8 ± 0.4) (all, p < 0.001). Reconstruction times of HIR, MBIR, and DLR were 11 ± 1, 319 ± 17, and 24 ± 1 s, respectively. CONCLUSION: DLR can enhance the image quality of head CT while preserving low radiation dose level and short reconstruction time. KEY POINTS: • For unenhanced head CT, DLR reduced the image noise and improved the GM-WM contrast and lesion delineation without sacrificing the natural noise texture and image sharpness relative to HIR. • The subjective and objective image quality of DLR was better than that of HIR even at 25% reduced dose without considerably increasing the image reconstruction times (24 s vs. 11 s). • Despite the strong noise reduction and improved GM-WM contrast performance, MBIR degraded the noise texture, sharpness, and subjective acceptance with prolonged reconstruction times relative to HIR, potentially hampering its feasibility.

Lung-Optimized Deep-Learning-Based Reconstruction for Ultralow-Dose CT.

RATIONALE AND OBJECTIVES: To evaluate the image properties of lung-specialized deep-learning-based reconstruction (DLR) and its applicability in ultralow-dose CT (ULDCT) relative to hybrid- (HIR) and model-based iterative-reconstructions (MBIR). MATERIALS AND METHODS: An anthropomorphic chest phantom was scanned on a 320-row scanner at 50-mA (low-dose-CT 1 [LDCT-1]), 25-mA (LDCT-2), and 10-mA (ULDCT). LDCT were reconstructed with HIR; ULDCT images were reconstructed with HIR (ULDCT-HIR), MBIR (ULDCT-MBIR), and DLR (ULDCT-DLR). Image noise and contrast-to-noise ratio (CNR) were quantified. With the LDCT images as reference standards, ULDCT image qualities were subjectively scored on a 5-point scale (1 = substantially inferior to LDCT-2, 3 = comparable to LDCT-2, 5 = comparable to LDCT-1). For task-based image quality analyses, a physical evaluation phantom was scanned at seven doses to achieve the noise levels equivalent to chest phantom; noise power spectrum (NPS) and task-based transfer function (TTF) were evaluated. Clinical ULDCT (10-mA) images obtained in 14 nonobese patients were reconstructed with HIR, MBIR, and DLR; the subjective acceptability was ranked. RESULTS: Image noise was lower and CNR was higher in ULDCT-DLR and ULDCT-MBIR than in LDCT-1, LDCT-2, and ULDCT-HIR (p < 0.01). The overall quality of ULDCT-DLR was higher than of ULDCT-HIR and ULDCT-MBIR (p < 0.01), and almost comparable with that of LDCT-2 (mean score: 3.4 ± 0.5). DLR yielded the highest NPS peak frequency and TTF50% for high-contrast object. In clinical ULDCT images, the subjective acceptability of DLR was higher than of HIR and MBIR (p < 0.01). CONCLUSION: DLR optimized for lung CT improves image quality and provides possible greater dose optimization opportunity than HIR and MBIR.

Radiation dose optimization potential of deep learning-based reconstruction for multiphase hepatic CT: A clinical and phantom study.

PURPOSE: This clinical and phantom study aimed to evaluate the impact of deep learning-based reconstruction (DLR) on image quality and its radiation dose optimization capability for multiphase hepatic CT relative to hybrid iterative reconstruction (HIR). METHODS: Task-based image quality was assessed with a physical evaluation phantom; the high- and low-contrast detectability of HIR and DLR images were computed from the noise power spectrum and task-based transfer function at five different size-specific dose estimate (SSDE) values in the range 5.3 to 18.0-mGy. For the clinical study, images of 73 patients who had undergone multiphase hepatic CT under both standard-dose (STD) and lower-dose (LD) examination protocols within a time interval of about four-months on average, were retrospectively examined. STD images were reconstructed with HIR, while LD with HIR (LD-HIR) and DLR (LD-DLR). SSDE, quantitative image noise, and contrast-to-noise ratio (CNR) were compared between protocols. The noise magnitude, noise texture, streak artifact, image sharpness, interface smoothness, and overall image quality were subjectively rated by two independent radiologists. RESULTS: In phantom study, the high- and low-contrast detectability of DLR images obtained at 5.3-mGy and 7.3-mGy, respectively, were slightly higher than those obtained with HIR at the STD protocol dose (18.0-mGy). In clinical study, LD-DLR yielded lower image noise, higher CNR, and higher subjective scores for all evaluation criteria than STD (all, p ≤ 0.05), despite having 52.8% lower SSDE (8.0 ± 2.5 vs. 16.8 ± 3.4-mGy). CONCLUSIONS: DLR improved the subjective and objective image quality of multiphase hepatic CT compared with HIR techniques, even at approximately half the radiation dose.

[Analysis of Information on Drug Adverse Reactions Using U.S. Food and Drug Administration Adverse Event Reporting System (FAERS)].

Nowadays, medical big data has been developed and made available in a variety of fields such as epidemiology and pharmacovigilance. Spontaneous reporting databases are one category of medical big data and that has been adequate for analysing events related to side effects that rarely occur in general practice. These data are freely available in several countries. In Japan, the Pharmaceuticals and Medical Devices Agency has developed the Japanese Adverse Drug Event Report (JADER), and the Food and Drug Administration (FDA) developed the FDA Adverse Events Reporting System (FAERS) in the United States. Since the release of these medical big data, many researchers in academic and research setting have accessed them, but it is still difficult for many medical professionals to analyse these data due to costs and operation of requisite statistical software. In this section, we give some tips to study spontaneous reporting databases resulting from our learning experiences.

Radiation Dose Reduction for 80-kVp Pediatric CT Using Deep Learning-Based Reconstruction: A Clinical and Phantom Study.

BACKGROUND. Deep learning-based reconstruction (DLR) may facilitate CT radiation dose reduction, but a paucity of literature has compared lower-dose DLR images with standard-dose iterative reconstruction (IR) images or explored application of DLR to low-tube-voltage scanning in children. OBJECTIVE. The purpose of this study was to assess whether DLR can be used to reduce radiation dose while maintaining diagnostic image quality in comparison with hybrid IR (HIR) and model-based IR (MBIR) for low-tube-voltage pediatric CT. METHODS. This retrospective study included children 6 years old or younger who underwent contrast-enhanced 80-kVp CT with a standard-dose or lower-dose protocol. Standard images were reconstructed with HIR, and lower-dose images were reconstructed with HIR, MBIR, and DLR. Size-specific dose estimate (SSDE) was calculated for both protocols. Image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were quantified. Two radiologists independently evaluated noise magnitude, noise texture, streak artifact, edge sharpness, and overall quality. Interreader agreement was assessed, and mean values were calculated. To evaluate task-based object detection performance, a phantom was imaged with 80-kVp CT at six doses (SSDE, 0.6-5.3 mGy). Detectability index (d') was calculated from the noise power spectrum and task-based transfer function. Reconstruction methods were compared. RESULTS. Sixty-five children (mean age, 25.0 ± 25.2 months) who underwent CT with standard- (n = 31) or lower-dose (n = 34) protocol were included. SSDE was 54% lower for the lower-dose than for the standard-dose group (1.9 ± 0.4 vs 4.1 ± 0.8 mGy). Lower-dose DLR and MBIR yielded lower image noise and higher SNR and CNR than standard-dose HIR (p < .05). Interobserver agreement on subjective features ranged from a kappa coefficient of 0.68 to 0.78. The readers subjectively scored noise texture, edge sharpness, and overall quality lower for lower-dose MBIR than for standard-dose HIR (p < .001), though higher for lower-dose DLR than for standard-dose HIR (p < .001). In the phantom, DLR provided higher d' than HIR and MBIR at each dose. Object detectability was greater for 2.0-mGy DLR than for 4.0-mGy HIR for low-contrast (3.67 vs 3.57) and high-contrast (1.20 vs 1.04) objects. CONCLUSION. Compared with IR algorithms, DLR results in substantial dose reduction with preserved or even improved image quality for low-tube-voltage pediatric CT. CLINICAL IMPACT. Use of DLR at 80 kVp allows greater dose reduction for pediatric CT than do current IR techniques.

Deep Learning-based Reconstruction for Lower-Dose Pediatric CT: Technical Principles, Image Characteristics, and Clinical Implementations.

Optimizing the CT acquisition parameters to obtain diagnostic image quality at the lowest possible radiation dose is crucial in the radiosensitive pediatric population. The image quality of low-dose CT can be severely degraded by increased image noise with filtered back projection (FBP) reconstruction. Iterative reconstruction (IR) techniques partially resolve the trade-off relationship between noise and radiation dose but still suffer from degraded noise texture and low-contrast detectability at considerably low-dose settings. Furthermore, sophisticated model-based IR usually requires a long reconstruction time, which restricts its clinical usability. With recent advances in artificial intelligence technology, deep learning-based reconstruction (DLR) has been introduced to overcome the limitations of the FBP and IR approaches and is currently available clinically. DLR incorporates convolutional neural networks-which comprise multiple layers of mathematical equations-into the image reconstruction process to reduce image noise, improve spatial resolution, and preserve preferable noise texture in the CT images. For DLR development, numerous network parameters are iteratively optimized through an extensive learning process to discriminate true attenuation from noise by using low-dose training and high-dose teaching image data. After rigorous validations of network generalizability, the DLR engine can be used to generate high-quality images from low-dose projection data in a short reconstruction time in a clinical environment. Application of the DLR technique allows substantial dose reduction in pediatric CT performed for various clinical indications while preserving the diagnostic image quality. The authors present an overview of the basic concept, technical principles, and image characteristics of DLR and its clinical feasibility for low-dose pediatric CT. ©RSNA, 2021.

Conditional generative adversarial networks to generate pseudo low monoenergetic CT image from a single-tube voltage CT scanner.

PURPOSE: To generate pseudo low monoenergetic CT images of the abdomen from 120-kVp CT images with cGAN. MATERIALS AND METHODS: We retrospectively included 48 patients who underwent contrast-enhanced abdominal CT using dual-energy CT. We reconstructed paired data sets of 120 kVp CT images and virtual low monoenergetic (55-keV) CT images. cGAN was prepared to generate pseudo 55-keV CT images from 120-kVp CT images. The pseudo 55 keV CT images in epoch 10, 50, 100, and 500 were compared to the 55 keV images generated using peak signal-to-noise ratio (PSNR) and structural similarity index (SSIM). RESULTS: The PSNRs were 28.0, 28.5, 28.6, and 28.8 at epochs 10, 50, 100, and 500, respectively. The SSIM was approximately constant from epochs 50 to 500. CONCLUSION: Pseudo low monoenergetic abdominal CT images were generated from 120-kVp CT images using cGAN, and the images had good quality similar to that of monochromatic images obtained with DECT software.

Myocardial Extracellular Volume Quantification Using Cardiac Computed Tomography: A Comparison of the Dual-energy Iodine Method and the Standard Subtraction Method.

RATIONALE AND OBJECTIVES: To clarify the accuracy of two measurement methods for myocardial extracellular volume (ECV) quantification (ie, the standard subtraction method [ECVsub] and the dual-energy iodine method [ECViodine]) with the use of cardiac CT in comparison to cardiac magnetic resonance imaging (CMR) as a reference standard. MATERIALS AND METHODS: Equilibrium phase cardiac images of 21 patients were acquired with a dual-layer spectral detector CT and CMR, and the images were retrospectively analyzed. CT-ECV was calculated using ECVsub and ECViodine. The correlation between the ECV values measured by each method was assessed. Bland-Altman analysis was used to identify systematic errors and to determine the limits of agreement between the CT-ECV and CMR-ECV values. Root mean squared errors and residual values for the ECVsub and ECViodine were also assessed. RESULTS: The correlations between ECVsub and ECViodine for both septal and global measurement were r = 0.95 (p < 0.01) and 0.91 (p < 0.01), respectively, while those between the mean ECVsub and CMR-ECV were r = 0.90 (septal, p < 0.01) and 0.84 (global, p < 0.01), and those between ECViodine and CMR-ECV were r = 0.94 (septal, p < 0.01) and 0.95 (global, p < 0.01). Bland-Altman plots showed lower 95% limits of agreement between ECViodine and CMR-ECV compared with that between ECVsub and CMR-ECV in both septal and global measurement. The root mean squared error of ECVsub was higher than that of ECViodine. The mean residual value of ECVsub was significantly higher than that of ECViodine. CONCLUSION: ECViodine yielded more accurate myocardial ECV quantification than ECVsub, and provided a comparable ECV value to that obtained by CMR.

Analysis of the Association of Administration of various glucocorticoids with development of acute pancreatitis using US Food and Drug Administration adverse event reporting system (FAERS).

BACKGROUND: There have been debates about the association between the administration of glucocorticoids and the development of acute pancreatitis, since many anecdotal cases of this adverse event were affected either by concomitant diseases (such as systemic lupus erythematosus, SLE) that may develop acute pancreatitis without glucocorticoid treatment or by co-administered drugs with high risk for the event. The aim of the present study was to explore whether disproportionally elevated signals of developing acute pancreatitis may be detected in patients receiving glucocorticoids as compared those receiving other drugs. METHODS: We retrieved spontaneously reported cases of acute pancreatitis and clinically related adverse events (target events) from the US Food and Drug Administration Adverse Event Reporting System (FAERS) using 18 preferred terms (PTs). Target drugs studied were cortisol, cortisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, and betamethasone. After cleaning the data, we calculated reporting odds ratios (RORs) and 95% confidence intervals (CIs) of acute pancreatitis in patients who received one of the glucocorticoids. RORs were calculated for each glucocorticoid using all reported cases irrespective of reporters' judgement about the contribution of the target drugs to events [i.e., primary suspected medication (PS), secondary suspected medication (SS), concomitant medication (C) and interacting (I)] and using cases with higher certainty of contribution (PS and SS), separately. When the lower limit of 95% CI of a ROR signal exceeded 1.0, the signal was considered statistically significant. RESULTS: The RORs (95% CIs) calculated using all reported cases (PS, SS, C, and I) for cortisol (1.68; 1.43-1.98), prednisolone (1.33; 1.19-1.47), methylprednisolone (1.77; 1.55-2.02) were significant, whereas those for other target drugs were insignificant. Using the cases in which target drugs were considered to contribute the events with higher certainty (PS or SS), RORs for prednisolone (1.31; 1.10-1.55), methylprednisolone (1.62; 1.30-2.01), and dexamethasone (1.27; 1.10-1.47) were considered significant, whereas those for others were insignificant. Regarding the performance of PTs for detecting signals (RORs) associated with acute pancreatitis from FAERS database, "pancreatitis acute" gave RORs with higher significance than others, whereas more specific PTs, "haemorrhagic necrotic pancreatitis", "ischaemic pancreatitis", "pancreatic necrosis" and "pancreatitis necrotising", gave RORs with greater magnitude. CONCLUSION: The present study demonstrated that the overrepresentation of signals for acute pancreatitis may be detected for prednisolone, methylprednisolone, and some others in the FAERS database.(372 words).

[Image Evaluation with Paired Comparison Method Using Automatic Analysis Software: Comparison of CT Images with Simulated Levels of Exposure Dose].

To simplify a procedure of the observer study with Ura's method of Scheffé's paired comparison and to improve experimental accuracy, we developed a software package to automatically analyze observer study data obtained by using a computer interface developed specially for the ROC observer study. Simulated low-dose CT images were used to demonstrate practical utility of this proposed method with a software package, in terms of a statistical analysis of the change of noise property due to the change of exposure dose. Six radiological technologists were participated in this observer study and compared each of six sample images selected at lower lung and liver slices with dose levels of 100, 80, 60, 40, 20, 10% per case. In the statistical analysis, the average psychological measures were highly correlated with the dose levels (lower lungs: R=0.95, liver: R=0.99). In addition, there were statistically significant differences in all combination of dose levels in liver slices. In conclusion, we demonstrated practical utility of this proposed method in terms of simplification of experimental procedure and the consistency of the analytic results.

Successful Cord Blood Transplantation in a Werner Syndrome Patient with High-risk Myelodysplastic Syndrome.

Werner syndrome (WS) confers a high risk of the development of neoplasias, including hematological malignancies, and curative treatment for these malignancies is difficult to achieve. A 44-year-old man with myelodysplastic syndrome was admitted to our hospital. He was diagnosed with mutation-proven WS. He underwent cord blood transplantation (CBT) following fludarabine, busulfan, and melphalan administration. A chimerism analysis of his marrow blood on day 62 showed a donor pattern >95%, which confirmed engraftment. The patient lived for 15 months while maintaining remission of MDS without treatment-related toxicity. Our case shows that CBT can be a treatment modality for WS patients with hematological malignancies.

Aging-associated latent herpes viral infection in normal Japanese individuals and patients with Werner syndrome.

A series of our "inflammageing" study examining serum samples from a maximum of 217 healthy Japanese individuals aged between 1 and 100 years and mutation-proven 40 patients with Werner syndrome (WS) indicated normal aging-associated elevations of highly sensitive CRP (hsCRP) and matrix metalloproteinase-9 (MMP-9). To further study the contribution of environmental factors such as persistent herpes viral infection to inflammageing, IgG antibodies against varicella/zoster virus (VZV) and cytomegalovirus (CMV) were examined in the same serum samples as has been done for hsCRP and MMP-9 analyses. The mean levels of serum IgG viral antibodies were comparable between normal (mean ± SE: 31.0 ± 4.3 unit) and WS (38.6 ± 7.6) for CMV, and between normal (42.0 ± 12.2) and WS (29.8 ± 3.8) for VZV, respectively. Significant associations of aging with IgG anti-CMV antibody were in normal aging (p = 0.023) and WS (p = 0.037), but not with IgG VZV in both conditions. Aging-associated change of IgG anti-CMV antibody titer in WS increased significantly (1.32 times higher) compared with normal aging (p = 0.037). IgG anti-CMV level was significantly elevated in the male gender than female in both conditions (p = 0.006). Elevated hsCRP level was significantly associated with IgG anti-CMV (p = 0.016) and IgG anti-VZV (p = 0.008) antibodies in normal aging, but not in WS. Serum MMP-9 was significantly associated with IgG anti-CMV level (p = 0.0002) in normal aging, but not in WS. Persistent herpes viral infection may constitute a part of "inflammageing" in normal aging and WS.

Saturation Recovery Myocardial T1 Mapping with a Composite Radiofrequency Pulse on a 3T MR Imaging System.

PURPOSE: To evaluate the effect of a composite radiofrequency (RF) pulse on saturation recovery (SR) myocardial T1 mapping using a 3T MR system. MATERIALS AND METHODS: Phantom and in vivo studies were performed with a clinical 3T MR scanner. Accuracy and reproducibility of the SR T1 mapping using conventional and composite RF pulses were first compared in phantom experiments. An in vivo study was performed of 10 healthy volunteers who were imaged with conventional and composite RF pulse methods twice each. In vivo reproducibility of myocardial T1 value and the inter-segment variability were assessed. RESULTS: The phantom study revealed significant differences in the mean T1 values between the two methods, and the reproducibility for the composite RF pulse was significantly smaller than that for the conventional RF pulse. For both methods, the correlations of the reference and measured T1 values were excellent (r2 = 0.97 and 0.98 for conventional and composite RF pulses, respectively). The in vivo study showed that the mean T1 value for composite RF pulse was slightly lower than that for conventional RF pulse, but this difference was not significant (P = 0.06). The inter-segment variability for the composite RF pulse was significantly smaller than that for conventional RF pulse (P < 0.01). Inter-scan correlations of T1 measurements of the first and second scans were highly and weakly correlated to composite RF pulses (r = 0.83 and 0.29, respectively). CONCLUSION: SR T1 mapping using composite RF pulse provides accurate quantification of T1 values and can lessen measurement variability and enable reproducible T1 measurements.

Quantification of hazard prediction ability at hazard prediction training (Kiken-Yochi Training: KYT) by free-response receiver-operating characteristic (FROC) analysis.

The ability to predict hazards in possible situations in a general X-ray examination room created for Kiken-Yochi training (KYT) is quantified by use of free-response receiver-operating characteristics (FROC) analysis for determining whether the total number of years of clinical experience, involvement in general X-ray examinations, occupation, and training each have an impact on the hazard prediction ability. Twenty-three radiological technologists (RTs) (years of experience: 2-28), four nurses (years of experience: 15-19), and six RT students observed 53 scenes of KYT: 26 scenes with hazardous points (hazardous points are those that might cause injury to patients) and 27 scenes without points. Based on the results of these observations, we calculated the alternative free-response receiver-operating characteristic (AFROC) curve and the figure of merit (FOM) to quantify the hazard prediction ability. The results showed that the total number of years of clinical experience did not have any impact on hazard prediction ability, whereas recent experience with general X-ray examinations greatly influenced this ability. In addition, the hazard prediction ability varied depending on the occupations of the observers while they were observing the same scenes in KYT. The hazard prediction ability of the radiologic technology students was improved after they had undergone patient safety training. This proposed method with FROC observer study enabled the quantification and evaluation of the hazard prediction capability, and the application of this approach to clinical practice may help to ensure the safety of examinations and treatment in the radiology department.

Inflammageing assessed by MMP9 in normal Japanese individuals and the patients with Werner syndrome.

Age-associated minor inflammation: inflammageing may explain human ageing mechanism(s). Our previous study reported a significant increase in the serum level of highly sensitive C-reactive protein (hsCRP) with normal ageing and the patients with Werner syndrome (WS). To further study the minor inflammatory condition associated with ageing, another possible ageing biomarker: matrix metalloproteinase-9 (MMP9) was examined in the sera from 217 normal Japanese individuals aged between 1 and 100 years and 41 mutation-proven Japanese WS aged between 32 and 70 years. MMP9 was assayed by ELISA. The serum level of MMP9 was elevated significantly (p < 0.001) with normal ageing from both sexes as hsCRP. In contrast to normal ageing, the serum MMP9 level in WS decreased significantly with calendar age (p < 0.05). The MMP9 level (ng/mL) in WS (147.2 ± 28.5) was not significantly different in comparison with those from age-matched normal adult population aged between 25 and 70 years (109.1 ± 9.4), nor normal elderly population aged between 71 and 100 years (179.9 ± 16.1). Although both normal ageing and WS were associated with minor inflammation, the inflammatory parameters such as serum MMP9 and hsCRP changed differently between normal ageing and WS. The WS-specific chronic inflammation including skin ulcer and diabetes mellitus may contribute the different behavior of both ageing biomarkers from normal ageing.

A computer simulation method for low-dose CT images by use of real high-dose images: a phantom study.

Practical simulations of low-dose CT images have a possibility of being helpful means for optimization of the CT exposure dose. Because current methods reported by several researchers are limited to specific vendor platforms and generally rely on raw sinogram data that are difficult to access, we have developed a new computerized scheme for producing simulated low-dose CT images from real high-dose images without use of raw sinogram data or of a particular phantom. Our computerized scheme for low-dose CT simulation was based on the addition of a simulated noise image to a real high-dose CT image reconstructed by the filtered back-projection algorithm. First, a sinogram was generated from the forward projection of a high-dose CT image. Then, an additional noise sinogram resulting from use of a reduced exposure dose was estimated from a predetermined noise model. Finally, a noise CT image was reconstructed with a predetermined filter and was added to the real high-dose CT image to create a simulated low-dose CT image. The noise power spectrum and modulation transfer function of the simulated low-dose images were very close to those of the real low-dose images. In order to confirm the feasibility of our method, we applied this method to clinical cases which were examined with the high dose initially and then followed with a low-dose CT. In conclusion, our proposed method could simulate the low-dose CT images from their real high-dose images with sufficient accuracy and could be used for determining the optimal dose setting for various clinical CT examinations.

Multiplex cytokine analysis of Werner syndrome.

We reported a minor inflammation-driven ageing (inflammageing) assessed by highly sensitive CRP (hsCRP) in normal individuals and patients with Werner syndrome (WS), followed by an ageing associated Th2-biased cytokine change in normal ageing in the previous papers. To further study the association of hsCRP and 26 cytokines/chemokines in 35 WS patients, a multiple cytokine array system was used in the same serum samples as were examined for hsCRP. The serum levels of Th2 cytokines (IL-4, IL-6, IL-10, and GM-CSF), Th1 products (IL-2, TNFα, IL-12, and IFNγ) and monocyte/macrophage products (MCP-1, basic FGF and G-CSF) in WS were significantly elevated compared with normal ageing. Elevated hsCRP level in WS was significantly correlated with IL-6, IL-12 and VEGF levels, if age and sex were taken into account. A pro-inflammatory cytokine/chemokine circuit-stimulated immunological shift to Th2 in WS was similar to normal ageing. These cytokine/chemokine changes may induce a systemic chronic inflammation monitored by hsCRP, though these immunological changes in WS were more complicated than normal ageing, possibly due to the WS-specific chronic inflammation such as skin ulcer, diabetes mellitus and central obesity with visceral fat deposition. Further study may warrant the pathophysiology of Th2 shift and Th2-biased inflammageing in normal ageing and WS.

Modulation transfer function measurement of CT images by use of a circular edge method with a logistic curve-fitting technique.

We propose a method for measuring the modulation transfer function (MTF) of a computed tomography (CT) system by use of a circular edge method with a logistic curve-fitting technique. An American College of Radiology (ACR) phantom was scanned by a Philips Brilliance system, and axial images were reconstructed by the filtered back projection algorithm with a standard reconstruction filter. The radial MTF was measured from a disk image of a rod or cylinder in the ACR phantom by use of the circular edge method. In this study, we applied a logistic curve-fitting technique to an edge-spread function (ESF) to eliminate noise because the edge method is very susceptible to noise in the ESF in a CT image. The circular edge method with the logistic curve-fitting technique provided the MTF without fluctuations due to noise for the entire spatial frequency range. The MTF was not affected by the tube current, the slice thickness, or the disk contrast, which were factors related to the amount of noise in the CT image. However, the MTF was affected by the location of the disk and by the disk size, depending on the average distance from the isocenter to the disk edge. Our results indicated that the MTF measured by the circular edge method with the logistic curve-fitting technique was not susceptible to noise in CT images. Therefore, this method is useful for MTF measurement for not only high-contrast objects, but also low-contrast objects with a large amount of noise.

WRN protein as a novel erythroblast immunohistochemical marker with applications for the diagnosis of Werner syndrome.

Genetic testing for mutations in the WRN gene is critical for the diagnosis of Werner syndrome (WS); however, these tests cannot be performed in a clinical setting. Nearly all of the WRN mutations result in expression of truncated WRN proteins that are missing the C-terminal nuclear localization signal. We evaluated the use of WRN protein immunohistochemistry for diagnosing WS using paraffin-embedded bone marrow sections. Using a well-defined commercially available polyclonal antibody against the C terminus of WRN, we found that of all the cell types tested, bone marrow erythroid precursors showed the strongest nuclear expression of WRN. Immunohistochemical analysis of bone marrow samples from 120 patients with non-WS hematological disorders (age range, 7 days-90 years) revealed WRN staining of the nuclei of CD71-positive early and late erythroid precursors. Erythroblasts negative for WRN immunostaining were only observed in two patients, both of whom were diagnosed with WS: one with concomitant myelodysplastic syndrome and the other with erythroleukemia with overexpression of TP53. Western blot analysis and immunocytochemistry indicated WRN was localized in the nuclei of the four positive control cell lines from non-WS patients but not in the five cell lines from WS patients, who had three different types of WRN mutations. Thus, immunohistochemical detection of WRN in erythroblasts from bone marrow paraffin sections could be useful in screening of WS cases and worthy of further molecular confirmation.