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OBJECTIVE In plasma from a patient with rheumatoid arthritis (RA), we previously isolated a human monoclonal anti-citrullinated protein antibody (ACPA), CCP-Ab1, that recognizes various citrullinated antigens. In this study, we aimed to explore the physiologic target of CCP-Ab1 and the role of molecular evolution, through affinity maturation, of this ACPA in the onset and the exacerbation of RA. METHODS The target protein of CCP-Ab1 was identified in the plasma of a patient with RA and purified under native conditions. Germline-reverted (GL-rev) CCP-Ab1 was generated, and its reactivity was compared to that of mature CCP-Ab1. The functions of CCP-Ab1 and GL-rev CCP-Ab1 in the onset or exacerbation of autoimmune arthritis were analyzed using autoimmune arthritis-prone SKG mice. RESULTS CCP-Ab1 bound citrullinated fibrinogen under native conditions. In cultures with GL-rev CCP-Ab1, the binding affinity to citrullinated fibrinogen was drastically reduced (P < 0.05). The elements implicated in GL-rev CCP-Ab1 binding to a citrullinated peptide, cfc1-cyc, were almost identical to those implicated in CCP-Ab1 binding. In arthritis-prone SKG mice, CCP-Ab1, but not GL-rev CCP-Ab1, induced significant exacerbation of experimental arthritis (P < 0.05). Increased production of interleukin-6, both in the joint tissue and in the serum, was observed in SKG mice treated with CCP-Ab1 compared to those treated with GL-rev CCP-Ab1 (P < 0.05). Furthermore, the immune complex formed by CCP-Ab1 and fibrinogen was detected at higher concentrations in the synovial tissue of SKG mice administered CCP-Ab1 (P < 0.05 versus control treatment groups). CONCLUSION These data show that germline-encoded CCP-Ab1, which binds weakly to citrullinated fibrinogen, undergoes hypermutation through the activation of naive B cells by citrullinated peptides/proteins, thereby stimulating high reactivity to citrullinated fibrinogen. These findings deepen our understanding of the role of molecular evolution of ACPAs in the onset and exacerbation of RA.

During the economic crises in the years following 2008, policymakers of various governments regularly hit the alarm bells about the dire situation of marginalized youth in various European countries. Early-career inactivity turns Not in Education, Employment, or Training (NEETs) into the most likely candidates for long-term socioeconomic marginalization, criminal careers, and grave mental and physical health problems. Japanese NEET who have completely retreated from society, are from different social backgrounds and face different circumstances from German immigrant children who have trouble finding a job, who in turn differ from Dutch low-ability adolescents who fail to graduate from vocational education. Since the 1990s, various alternative concepts emerged in labour market research as well as among policymakers.

AIM This study aimed to compare the accuracy of fetal pulse pressure estimated with a vascular simulator with that obtained by a manometer (reference) and evaluate the pulse pressure in normal human fetuses and fetuses whose mothers received corticosteroids. METHODS Fetal pulse pressure was estimated as the product of blood flow velocity and pulse wave velocity, based on the water hammer equation. Ultrasonic raw radiofrequency signals for blood flow velocity were captured from the fetal descending aortas at the diaphragm level, and pulse wave velocity was simultaneously measured from different directions using the phased-tracking method. First, the precision and accuracy of pulse pressure in the estimated method were verified by a circulatory phantom simulator, which reproduced fetal blood flow using a pulsating pump. Then, the pulse pressure of 98 normal human fetuses after 17 weeks of gestation and the fetal pulse pressure in 21 mothers who received antenatal corticosteroids for fetal maturation were measured. RESULTS A significant correlation between the estimated pulse pressure values and the actual values was found in the phantom simulation (r = 0.99, P

We aimed to evaluate the compliance of physicians with the 2014 guidelines of the Japanese Society for Bone and Mineral Research, for the prevention and treatment of glucocorticoid (GC) induced osteoporosis (GIO) and to investigate the risk of fracture and other associated risk factors in bisphosphonate-treated patients. We evaluated 90 female patients with nonrheumatoid arthritis autoimmune diseases who received long-term GC treatment (≥12 months). Clinical characteristics, including age, GC dose, history of fragility fractures, osteoporosis treatments, as well as lumbar (L2–L4) and femoral neck bone mineral density, were collected from the patients’ medical charts. New vertebral fractures during the study period were evaluated using thoracic and lumbar spine radiographs by quantitative measurements. The GIO score was calculated for each patient according to 2014 Japanese guidelines. Of the 90 patients evaluated, 60 were indicated for osteoporosis treatment, based on the 2014 guidelines of Japan. We observed a high compliance rate, with 93% of patients receiving osteoporosis treatment and 50% receiving bisphosphonates. In total, eight patients developed new vertebral fractures during the study, six of whom received bisphosphonates. In bisphosphonate-treated patients, fracture risk was associated with GC treatment and a lack of active vitamin D3 supplementation. The compliance rate with the updated Japanese 2014 guidelines at our institution was very high. Large randomized controlled trials are needed to confirm our findings that suggest that active vitamin D3 should be used in combination with bisphosphonates for the treatment of GIO to reduce fracture risk.

Early diagnosis of sleep-apnea-related breathing problems helps to avoid the increased risk they can cause. In this study, we performed simultaneous radar measurements and polysomnography on patients with sleep apnea. A support vector machine algorithm was applied to the radar data to automatically detect sleep apnea events. Support vector machine parameters were optimized using the relationship between the radar and polysomnography data. The support vector machine was found to be effective in noncontact detection of central/mixed sleep apnea events using radar data. The proposed approach achieved an accuracy of 79.5%, a recall of 71.2%, and a precision of 71.2%.

Background Therapeutic focused-ultrasound to the hippocampus has been reported to exert neuroprotective effects on dementia. In the present study, we examined whether the whole-brain LIPUS (low-intensity pulsed ultrasound) therapy is effective and safe in 2 mouse models of dementia (vascular dementia, VaD and Alzheimer's disease, AD), and if so, to elucidate the common underlying mechanism(s) involved. Methods We used bilateral carotid artery stenosis (BCAS) model with micro-coils in male C57BL/6 mice as a VaD model and 5XFAD transgenic mice as an AD model. We applied the LIPUS therapy (1.875 MHz, 6.0 kHz, 32cycles) to the whole brain. Results In both models, the LIPUS therapy markedly ameliorated cognitive impairments (Y-maze test and/or passive avoidance test) associated with improved cerebral blood flow (CBF). Mechanistically, the LIPUS therapy significantly increased CD31-positive endothelial cells and Olig2-positive oligodendrocyte precursor cells (OPCs) in the VaD model, while it reduced Iba-1-positive microglias and amyloid-β (Aβ) plaque in the AD model. In both models, endothelium-related genes were significantly upregulated in RNA-sequencing, and expressions of endothelial nitric oxide synthase (eNOS) and neurotrophins were upregulated in Western blotting. Interestingly, the increases in glia cells and neurotrophin expressions showed significant correlations with eNOS expression. Importantly, these beneficial effects of LIPUS were absent in eNOS-knockout mice. Conclusions These results indicate that the whole-brain LIPUS is an effective and non-invasive therapy for dementia by activating specific cells corresponding to each pathology, for which eNOS activation plays an important role as a common mechanism.

A noncontact measurement of the heart rate of a specific person using an ${X}$ -band radar system with a four-element antenna array is presented. The system comprises a 2-D planar wide-beam antenna array with a four-channel network analyzer. The direction of arrival is estimated using the Capon method, and the directionally constrained minimization-of-power algorithm is then applied to the received signals. Signals from the four channels are adaptively combined to enhance the accuracy in estimating the instantaneous heart rate in a multi-person scenario. Measurement results indicate that the proposed system with the adaptive array processing technique is effective for the noncontact measurement of the heart rate of a specific person when there is more than one person in the scene.

Objective— Left ventricular (LV) remodeling after acute myocardial infarction still remains an important issue in cardiovascular medicine. We have recently demonstrated that low-intensity pulsed ultrasound (LIPUS) therapy improves myocardial ischemia in a pig model of chronic myocardial ischemia through enhanced myocardial angiogenesis. In the present study, we aimed to demonstrate whether LIPUS also ameliorates LV remodeling after acute myocardial infarction and if so, to elucidate the underlying molecular mechanisms involved in the beneficial effects of LIPUS. Approach and Results— We examined the effects of LIPUS on LV remodeling in a mouse model of acute myocardial infarction, where the heart was treated with either LIPUS or no-LIPUS 3 times in the first week (days 1, 3, and 5). The LIPUS improved mortality and ameliorated post–myocardial infarction LV remodeling in mice. The LIPUS upregulated the expression of vascular endothelial growth factor, endothelial nitric oxide synthase, phosphorylated ERK, and phosphorylated Akt in the infarcted area early after acute myocardial infarction, leading to enhanced angiogenesis. Microarray analysis in cultured human endothelial cells showed that a total of 1050 genes, including those of the vascular endothelial growth factor signaling and focal adhesion pathways, were significantly altered by the LIPUS. Knockdown with small interfering RNA of either β1-integrin or caveolin-1, both of which are known to play key roles in mechanotransduction, suppressed the LIPUS-induced upregulation of vascular endothelial growth factor. Finally, in caveolin-1–deficient mice, the beneficial effects of LIPUS on mortality and post–myocardial infarction LV remodeling were absent. Conclusions— These results indicate that the LIPUS therapy ameliorates post–myocardial infarction LV remodeling in mice in vivo, for which mechanotransduction and its downstream pathways may be involved.

We investigate the potential of through-transmission ultrasound in noninvasive aspiration detection for bedside rehabilitation. In the present study, we used through- transmission ultrasound to investigate the waveform change in received signals caused by an aspirated object located at the posterior wall of the larynx, the most difficult type of case in the detection of aspiration. In a simulation study based on an X-ray CT image of the neck of a patient, the aspirated object adhered at the posterior wall of the larynx resulted in the waveform change of the received signal with a maximum amplitude of 4.3% compared with that of the received signal with aspiration. In an experimental study using a swine larynx ex vivo, an aspirated object resulted in the waveform change of the received signal with a maximum amplitude of 43.3%. These results indicate the high potential of through-transmission ultrasound in aspiration detection.

Quantitative ultrasound techniques for assessment of bone quality have been attracting significant research attention. The axial transmission technique, which involves analysis of ultrasonic guided waves propagating along cortical bone, has been proposed for assessment of cortical bone quality. Because the frequency-dependent wavenumbers reflect the elastic parameters of the medium, high-resolution estimation of the wavenumbers is required at each frequency with low computational cost. We use an adaptive array signal processing method and propose a technique that can be used to estimate the numbers of propagation modes that exist at each frequency without the need for time-consuming calculations. An experimental study of 4-mm-thick copper and bone-mimicking plates showed that the proposed method estimated the wavenumbers accurately with estimation errors of less than 4% and a calculation time of less than 0.5 s when using a laptop computer.

Ultrasound signals that pass through cancellous bone may be considered to consist of two longitudinal waves, which are called fast and slow waves. Accurate decomposition of these fast and slow waves is considered to be highly beneficial in determination of the characteristics of cancellous bone. In the present study, a fast decomposition method using a wave transfer function with a phase rotation parameter was applied to received signals that have passed through bovine bone specimens with various bone volume to total volume (BV/TV) ratios in a simulation study, where the elastic finite-difference time-domain method is used and the ultrasound wave propagated parallel to the bone axes. The proposed method succeeded to decompose both fast and slow waves accurately; the normalized residual intensity was less than −19.5 dB when the specimen thickness ranged from 4 to 7 mm and the BV/TV value ranged from 0.144 to 0.226. There was a strong relationship between the phase rotation value and the BV/TV value. The ratio of the peak envelope amplitude of the decomposed fast wave to that of the slow wave increased monotonically with increasing BV/TV ratio, indicating the high performance of the proposed method in estimation of the BV/TV value in cancellous bone.Ultrasound signals that pass through cancellous bone may be considered to consist of two longitudinal waves, which are called fast and slow waves. Accurate decomposition of these fast and slow waves is considered to be highly beneficial in determination of the characteristics of cancellous bone. In the present study, a fast decomposition method using a wave transfer function with a phase rotation parameter was applied to received signals that have passed through bovine bone specimens with various bone volume to total volume (BV/TV) ratios in a simulation study, where the elastic finite-difference time-domain method is used and the ultrasound wave propagated parallel to the bone axes. The proposed method succeeded to decompose both fast and slow waves accurately; the normalized residual intensity was less than −19.5 dB when the specimen thickness ranged from 4 to 7 mm and the BV/TV value ranged from 0.144 to 0.226. There was a strong relationship between the phase rotation value and the BV/TV value. The ra...

Anti-Ro52 autoantibodies (Ro52-autoAbs) appear in the sera of connective tissue disease (CTD) patients with interstitial lung disease (ILD). Studies using patient sera have shown a correlation between the generation of Ro52-autoAbs and the clinical morbidity and severity of CTD with ILD. In this study, we used a single B-cell manipulating technology and obtained 12 different monoclonal Ro52-autoAbs (mRo52-autoAbs) from the selected four patients suffering from severe ILD with a high titer of Ro52-autoAbs in their sera. Western blot analysis revealed that 11 of 12 mRo52-autoAbs bound to the coiled-coil domain of Ro52. Competitive ELISA demonstrated that mRo52-autoAbs competed with each other to bind to Ro52. Epitope mapping showed that two of them specifically bound to a peptide (PEP08) in the coiled-coil domain. We then examined the titer of Ro52-autoAbs in the sera of 192 CTD patients and assessed the relationship between the serum levels of Ro52-autoAbs that were reactive to PEP08 peptide and the clinical morbidity and severity of ILD. Statistical analysis revealed that the production of PEP08-reactive Ro52-autoAbs correlated with the morbidity and severity of ILD in CTD. Assessment of the production of PEP08-reactive Ro52-autoAbs in autoimmune diseases is useful for predicting the clinical morbidity of ILD.

Objective To investigate the reactivity of monoclonal anti–citrullinated protein antibody (ACPA) obtained from peripheral blood B cells of rheumatoid arthritis (RA) patients with human autoantigens as well as environmental proteins by determining the essential epitope for the ACPA. Methods A human monoclonal ACPA (cyclic citrullinated peptide antibody 1 [CCP-Ab1]) was obtained by screening peripheral blood lymphocytes from 31 patients with RA using a novel monoclonal antibody–secreting cell (ASC) screening system, the immunospot-array assay on a chip. The essential epitope for CCP-Ab1 was determined using epitope mapping. Then, human, microbial, and plant proteins that share the essential epitope identified were searched using BLAST. Finally, representative proteins identified by the search were produced in vitro, and their reactivity with CCP-Ab1 was examined. Results CCP-Ab1 bound CCP in a citrulline-indispensable manner. In CCP, the 6 amino acid residues required for CCP-Ab1 binding were identified. In the BLAST search, 38 human, 56 viral, 1,383 fungal, 547 bacterial, and 1,072 plant proteins were found to share the essential epitope, and CCP-Ab1 reacted with all of the recombinant citrullinated proteins tested, which included the various environmental factors, such as various plant proteins that are part of the daily diet. Conclusion Our findings demonstrate, for the first time, that a monoclonal ACPA (CCP-Ab1) derived from RA patients cross-reacts not only with various autoantigens but also with numerous plant and microbial proteins. We propose that countless environmental factors, including microbes and diet, may trigger the generation of ACPAs that then cross-react with various citrullinated human autoantigens through molecular mimicry to induce RA.

The received signal in through-transmission ultrasound measurements of cancellous bone consists of two longitudinal waves, called the fast and slow waves. Analysis of these fast and slow waves may reveal characteristics of the cancellous bone that would be good indicators of osteoporosis. Because the two waves often overlap, decomposition of the received signal is an important problem in the characterization of bone quality. This study proposes a fast and accurate decomposition method based on the frequency domain interferometry imaging method with a modified wave transfer function that uses a phase rotation parameter. The proposed method accurately characterized the fast and slow waves in the experimental study, and the residual intensity, which was normalized with respect to the received signal intensity, was less than -20 dB over the bone specimen thickness range from 6 to 15 mm. In the simulation study, the residual intensity was less than -20 dB over the specimen thickness range from 3 to 8 mm. Decomposition of a single received signal takes only 5 s using a laptop personal computer with a single central processing unit. The proposed method has great potential to provide accurate and rapid measurements of indicators of osteoporosis in cancellous bone.

The non-invasive cortical bone quality assessments using ultrasound axial transmission technique have attracted strong attention. The estimation of phase velocity and attenuation of absorbing plate should help the assessment. To get the high-resolution estimation, we employ an adaptive beamforming technique that uses an eigenvalue decomposition. The technique can estimate not only the phase velocities but also intensities of the multiple propagation modes separately. We situate two arrays in the whole array and compare the estimated intensities at the adjacent arrays. To remove unreliable estimates, we also situate sub-arrays with multiple sizes in the two arrays and evaluate the correspondences between the results with different sub-array sizes. The proposed method was evaluated by using numerical simulation. We used one transmitter and 28 receivers and a 5-mm-thick plate with longitudinal and shear wave velocities of 4430 m/s and 2120 m/s, respectively. The attenuations of the longitudinal and shear waves were 320 dB/MHz/m and 400 dB/MHz/m, respectively. The estimation error of the phase velocity and attenuation was 3.6 m/s and 2.4 dB/m, respectively. The proposed method accurately estimated the phase velocity and attenuation. We believe the method is suitable for bone quality assessments.

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Orogenital ulcer is one of the clinical manifestations of Behçet's disease (BD). However, orogenital ulcer may be observed in various conditions, such as complex aphthous dermatitis and herpes simplex virus infections. Therefore, orogenital ulcer along with skin lesions, including acne or erythema nodosum, may be misdiagnosed as BD, but is actually pseudo-BD instead. We report here a case of pseudo-BD due to Mycobacterium tuberculosis infection in which anti-tuberculous treatment resulted in complete resolution. Furthermore, we review the literature regarding the association of BD and M. tuberculosis infection.

Axial transmission technique is useful in assessing bone quality. Most conventional techniques require multiple transmitters and receivers. Decreasing the number of elements and computational complexity are desired for low-cost diagnosis. We propose a technique that characterizes the Lamb wave using one transmitter and two receivers. Because the transfer function of the Lamb wave is mainly determined by the longitudinal wave velocity (LWV), shear wave velocity (SWV), and bone thickness, these parameters may be determined in a fitting procedure using the transfer function. The number of combinations of these parameters is enormous, and we thus select the candidates for these parameters using spatial domain interferometry. The method estimates the phase velocity of zero-th order anti-symmetric mode. We applied the proposed method to numerical simulation data generated by the semi-analytical finite element method. We employed a viscoelastic plate with LWV, SWV, and thickness of 2120 m/s, 4430 m/s, and 1.0 mm...

Minimum variance beamformer has high potential in improving image quality through an adaptive apodization weight optimization approach, but its impact is conventionally limited to lateral resolution enhancements. Recently, we reported a high range resolution technique that applies minimum variance beamformer to the frequency components of the RF signal after a delay-and-sum process. The technique has high performance in the improvement of the range resolution when a target has flat interfaces, such as a longitudinal section of an artery. In the present study, we report further advance of this technique to enhance image quality of a normal swine eye whose anatomy is marked by multiple layers of curved interfaces. The reference signal is acquired by the coherent integration of the echoes from isolated interfaces to take account of the attenuation and the interface shape. The proposed technique succeeded to offer a sharp rendering of the cornea boundaries of the swine eye, where the center frequency of the transmit ultrasound pulse was 12 MHz. Computationally, it required 5 seconds using a laptop PC with a single CPU for the depiction of an image in the ROI that consists of 422,528 pixels. We reckon that, if the proposed technique is implemented using GPUs, high-quality images of the eye (with both lateral and range resolution enhancements) can be readily achieved in real time.

The characterization of Lamb waves propagating in cortical bone is important for diagnosing bone quality. Using fewer transmitters and receivers is desirable for low-cost diagnosis. Thus, in this study, we propose a method based on an adaptive beamforming technique to characterize Lamb waves using a single transmitter-receiver pair. We begin by estimating the longitudinal and shear wave velocities as these are the primary determinants of the Lamb wave transfer function. The frequency domain interferometry (FDI) with Capon method, which is one of the adaptive signal processing methods, accurately estimates the position of the wave having the same frequency components as the reference wave. The high-frequency components of the zeroth-order modes of the Lamb wave are almost non-dispersive. Therefore, we use the transmitted wave as the reference and apply the Capon method to the high-frequency components where the phase velocity is converge to the Rayleigh wave velocity. Because the Rayleigh wave velocity is determined by the longitudinal and shear wave velocities, we can estimate candidates of the velocities by using estimated Rayleigh wave velocity. Finally, we calculate the transfer function using a least squares method (LSM) applied to the estimated velocities. We conduct 2-D numerical simulations using a semi-analytical finite element method. The center frequency of the transmitted wave is 1.0 MHz, the thickness of cortical bone is 5.0 mm, signal-to-noise ratio is 20 dB, longitudinal and shear wave velocities are 4430 and 2120 m/s, respectively, and the distance from the transmitter to the receiver is 21 mm. We use eight candidates in the fitting process using LSM. The predicted longitudinal and shear wave velocities were 4458 and 2116 m/s, respectively, and the residue normalized with respect to the received signal intensity was −16 dB. The proposed method accurately predicts the waveforms and longitudinal and shear wave velocities.

Several adaptive beamforming techniques have been proposed to improve the quality of medical ultrasound images. The beamspace (BS) Capon method is one common method used to depict high-resolution images with low computational complexity. However, the complexity is not low enough for real-time imaging in clinical situations because the conventional BS Capon method employs a time-delay process and a transition process from elementspace signal processing to BS signal processing at all points of interest. Thus, we propose a technique that replaces the time-delay process using a steering vector. In addition, the Capon method employs a spatial averaging (SA) technique to stabilize the estimation in intensity. However, when the averaging size is not adequate, the estimated intensity might be smaller than that given by the delay-and-sum (DAS) method. Because most medical diagnoses are presented based on the estimation of intensity acquired by the DAS beamformer, accurate estimation of intensity is also required. Therefore, we propose a compensation technique that uses both small and large sizes for SA. In an experiment, the −6 dB beam width, sidelobe level, and estimation error in the intensity of the proposed method were 0.17 mm, −27 dB, and 0.92 dB, respectively, where those of the conventional BS Capon method were 0.29 mm, −22 dB, and 8.1 dB. The complexity of the proposed method is one-fourteenth that of the conventional method. Compared with conventional methods, the proposed method succeeded in depicting a higher-contrast image with accurate intensity estimation and lower computational complexity.

The purpose of this study is to improve the calcification depiction ability in ultrasonography using correlation of echoes with a modified Wiener filter. The waveform of an ultrasound pulse changes when it passes through the location of a calcification. Since the change in echo waveform caused by a calcification decreases the correlation of waveforms in adjacent scan lines, we have proposed a calcification depiction method using the decorrelation of echoes. However, the low signal-to-noise ratio of echoes also decreases the correlation of the echoes. In this study, we employ the correlation of echoes with a modified Wiener filter to suppress the effect of noise, as an indicator of a calcification. The proposed calcification indicator depicted copper cylindrical rods 0.2 mm in size at a depth of 2 cm with a sensitivity of 80% and a positive predictive value of 80%, despite being hardly depicted at all on B-mode ultrasound imaging. This study suggests the potential of the proposed method to improve the performance of calcification depiction by ultrasound devices.