Ultrasound measurement of fetal arterial pulse pressure using phased-tracking methods: A phantom study and clinical experience with antenatal corticosteroid therapy.

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 < 0.01). The estimated pulse pressure was significantly correlated with gestational age in normal fetuses (r = 0.74, P < 0.01). In steroid-treated pregnant women, fetal pulse pressure was observed to increase significantly on the second day of administration (P < 0.01). CONCLUSION: A noninvasive and accurate estimation model of fetal pulse pressure could be established using phased-tracking method, and this method has the potential to improve the assessment of human fetal hemodynamics.

Autoantibodies reactive to PEP08 are clinically related with morbidity and severity of interstitial lung disease in connective tissue diseases.

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.

Low-Intensity Pulsed Ultrasound Enhances Angiogenesis and Ameliorates Left Ventricular Dysfunction in a Mouse Model of Acute Myocardial Infarction.

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 ß1-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.

Fast decomposition of two ultrasound longitudinal waves in cancellous bone using a phase rotation parameter for bone quality assessment: Simulation study.

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.

Fast characterization of two ultrasound longitudinal waves in cancellous bone using an adaptive beamforming technique.

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.

Pseudo-Behçet's disease associated with tuberculosis: a case report and review of the literature.

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.

Cytophagic histiocytic panniculitis in a 74-year-old man.

Cytophagic histiocytic panniculitis is a chronic histiocytic disease of the subcutaneous adipose tissue characterised by lobular panniculitis with histiocytes containing blood cell fragments. It is also associated with marked systemic features such as fever, pancytopenia, hepatosplenomegaly, liver abnormalities and coagulopathy. We report a case of cytophagic histiocytic panniculitis in a 74-year-old man successfully treated using combination therapy with prednisolone and cyclosporine A.

Recurrence of IgG4-related disease following treatment with rituximab.

A 54-year-old woman with suspected low-grade B-cell lymphoma of mucosa-associated lymphoid tissue type of the eyelids underwent rituximab-containing chemotherapy. She initially responded to the rituximab therapy, but later experienced two recurrences over a 3-year period. Biopsy specimens and a review of her previous histology revealed that she had had immunoglobulin G4-related disease at the initial presentation. Although IgG4-related disease seems to respond well to rituximab therapy, long-term follow up, including disease monitoring, is needed to evaluate disease remission.

Clinical characteristics and risk factors for Pneumocystis jirovecii pneumonia in patients with rheumatoid arthritis receiving adalimumab: a retrospective review and case-control study of 17 patients.

OBJECTIVES: To investigate the clinical characteristics and risk factors of Pneumocystis jirovecii pneumonia (PCP) in rheumatoid arthritis (RA) patients treated with adalimumab. METHODS: We conducted a multicenter, retrospective, case-control study to compare RA patients treated with adalimumab with and without PCP. Data from 17 RA patients who were diagnosed with PCP and from 89 RA patients who did not develop PCP during adalimumab treatment were collected. RESULTS: For the PCP patients, the median age was 68 years old, with a median RA disease duration of eight years. The median length of time from the first adalimumab injection to the development of PCP was 12 weeks. At the onset of PCP, the median dosages of prednisolone and methotrexate were 5.0 mg/day and 8.0 mg/week, respectively. The patients with PCP were significantly older (p < 0.05) and had more structural changes (p < 0.05) than the patients without PCP. Computed tomography of the chest revealed ground-glass opacity without interlobular septal boundaries in the majority of the patients with PCP. Three PCP patients died. CONCLUSIONS: PCP may occur early in the course of adalimumab therapy in patients with RA. Careful monitoring, early diagnosis, and proper management are mandatory to secure a good prognosis for these patients.

Respiratory involvement in IgG4-related Mikulicz's disease.

'Immunoglobulin G4 (IgG4)-related disease' is a new clinical concept of multi-organ diseases, with Mikulicz's disease (MD) being a clinical phenotype of IgG4-related disease. To clarify the clinical characteristics of respiratory involvement associated with IgG4-related MD, we retrospectively assessed 25 patients with MD, 11 (44%) of whom had allergic symptoms, and 7 (28%) of whom complained of respiratory problems. Thirteen patients (52%) presented with pulmonary and/or mediastinal lesions (P-MD) on chest computed tomography (CT), and 11 (44%) had lesions limited to the lacrimal and/or salivary glands (L-MD). Mean serum total protein, IgG, and IgG4 concentrations were significantly higher and CH50 was significantly lower in the P-MD than in the L-MD group. Immune complex was present only in the P-MD group. Chest CT images showed bronchial wall thickening, consolidation, nodule(s), interlobular thickening, ground glass opacity, pleural thickening/effusion, and mediastinal lymphadenopathy. Five of seven patients who underwent histological examination of the lungs had abundant IgG4-positive plasma cell infiltrates (IgG4/IgG-positive plasma cells >40%), but the other two did not. These findings suggest that respiratory lesions are not rare in patients with IgG4-related MD, and that they present with various manifestations. IgG4-related MD should be differentiated from similar diseases, such as sarcoidosis, bronchial asthma, Sjögren's syndrome, and malignant lymphoma.

Small calcification indicator in ultrasonography using correlation of echoes with a modified Wiener filter.

PURPOSE: The purpose of this study is to improve the calcification depiction ability in ultrasonography using correlation of echoes with a modified Wiener filter. METHODS: 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. RESULTS: 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. CONCLUSION: This study suggests the potential of the proposed method to improve the performance of calcification depiction by ultrasound devices.

Small calcification depiction in ultrasound B-mode images using decorrelation of echoes caused by forward scattered waves.

PURPOSE: The purpose of this study is to propose a novel method to depict small calcifications in ultrasound B-mode images using decorrelation of forward scattered waves with no decrease in the frame rate. METHODS: Since the waveform of an ultrasound pulse changes when it passes through a calcification location, the echo waveform from regions behind the calcification is quite different from that without a calcification. This indicates that the existence of a calcification is predictable based upon the waveform difference between adjacent scan lines by calculating cross-correlation coefficients. In addition, a high-intensity echo should return from the calcification itself. Therefore, the proposed method depicts the high-intensity echo positions with posterior low correlation coefficient regions. RESULTS: Eleven of 15 wires 0.2-0.4 mm in diameter were depicted using this method, yielding a sensitivity of 73.3% and a specificity of 100%, even though they might go undetected under clinical inspection of ultrasound B-mode images. CONCLUSION: This study suggests that an US device could perform well in terms of calcification detection.

Treatment of Glucocorticoid-Induced Osteoporosis and Risk Factors for New Vertebral Fractures in Female Patients with Autoimmune Diseases.

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.

Inhibition of tumor progression locus 2 protein kinase decreases lipopolysaccharide-induced tumor necrosis factor alpha production due to the inhibition of the tip-associated protein induction in RAW264.7 cells.

The activation of mitogen-activated protein kinases (MAPKs) is critically involved in inflammatory events through mediation of the production of various inflammatory cytokines. The Tpl2 (tumor progression locus 2)-MEK (MAPK/ERK kinase)-ERK (extracellular signal-regulated kinase) signaling pathway plays an essential role in the production of tumor necrosis factor alpha (TNFalpha) in macrophages stimulated with lipopolysaccharide (LPS). Here, we studied the molecular mechanisms of Tpl2-mediated TNFalpha production using a potent Tpl2 kinase inhibitor, 1,7-naphtyridine-3-carbonitrile, and LPS-stimulated RAW264.7 cells. This inhibitor was effective in suppressing the in vitro Tpl2 kinase activity, and caused a significant reduction in TNFalpha production via specific suppression of the phosphorylation of MEK and ERK but not that of p38 and c-Jun N-terminal kinase (JNK). A p38 inhibitor, SB203580, also inhibited the TNFalpha production dose-dependently. Although the TNFalpha mRNA level was not altered by either inhibitor, the Tpl2 inhibitor increased the nuclear TNFalpha mRNA level, while decreasing that in the cytoplasm. Tip-associated protein (TAP), a key molecule in the nucleocytoplasmic transport of TNFalpha mRNA, was up-regulated by LPS, but this increase was impaired by the Tpl2 inhibitor. In all cases, SB203580 was without effect in the presence of LPS. These results suggest that the LPS-induced TNFalpha production via the Tpl2-MEK-ERK signaling pathway is regulated by changing the TAP level at the nucleocytoplasmic transport level. These results improve understanding of TNFalpha regulatory mechanisms and might provide a new therapeutic strategy against inflammatory diseases.

Inhibition of tumor progression locus 2 protein kinase suppresses receptor activator of nuclear factor-kappaB ligand-induced osteoclastogenesis through down-regulation of the c-Fos and nuclear factor of activated T cells c1 genes.

Whether tumor progression locus 2 (Tpl2)/cancer Osaka thyroid (Cot) protein kinase participates in osteoclastogenesis from receptor activator of nuclear factor-kappaB ligand (RANKL)-stimulated monocytes/macrophages remains elusive. To clarify this, a selective and potent inhibitor of Tpl2, 1,7-naphtyridine-3-carbonitrile, was used. When RAW264.7 cells were stimulated with RANKL, Tpl2 was found to be activated. Under this condition, the Tpl2 inhibitor suppressed osteoclastogenesis in a dose-dependent manner. This was due to the blockade of the phosphorylation of mitogen activated protein kinase/ERK kinase (MEK) and extracellular signal-regulated kinase (ERK), but not c-Jun N-terminal kinase (JNK) or p38, concomitant with the down-regulation of the c-Fos and nuclear factor of activated T cells (NFAT)c1 genes. A long period of RANKL-stimulated cell exposure to the inhibitor suppressed osteoclastogenesis as assessed by tartrate-resistant acid phosphatase (TRAP) staining and pit formation on dentin slices. Almost identical results were obtained with macrophage colony-stimulating factor (M-CSF) and RANKL-stimulated bone marrow cells. These findings suggest the possibility that Tpl2 plays a pivotal role in osteoclastogenesis and thus that its inhibitor is useful for investigating the differentiation of monocytes/macrophages to osteoclasts after treatment with RANKL or other stimuli.

Presenting manifestations of hemophagocytic syndrome in a male patient with systemic lupus erythematosus.

Hemophagocytic syndrome (HPS) is an unusual but sometimes fatal disorder. We reported a case of 21-year-old man who developed HPS and SLE simultaneously. Febrile pancytopenia, hyperferritinemia, and abnormal liver function tests were observed. Hemophagocytic cells were observed by means of bone marrow biopsy and diagnosed as HPS. The patient was treated with high-dose prednisolone, resulting in an excellent outcome. Early diagnosis of HPS by bone marrow biopsy is important for the successful treatment.

Calculus detection for ultrasonography using decorrelation of forward scattered wave.

PURPOSE: The purpose of this paper is to propose a novel strategy to detect small calculi efficiently. METHODS: The proposed calculus detection strategy focuses on decorrelation of forward scattered waves caused by the failure of Born's approximation. A calculus causes waveform changes of transmit pulses, resulting in a decrease in the cross-correlation coefficients calculated from IQ signals scattered near the calculus position. Therefore, we can detect calculi from the appearance of dips in correlation coefficients. RESULTS: When a calculus exists in a digital tissue map, sharp and deep dips in cross-correlation coefficients between acoustic IQ signals appear around the calculus. By contrast, no apparent dip exists when a tissue map contains no calculus. A scan line interval of 0.2 mm or less is appropriate for the conditions simulated in this paper, and the proper transmit focal range for the proposed method is at a calculus range. CONCLUSION: These results imply that the proposed strategy can improve the efficiency of US devices for small calculus detection.

[Pleiotropic effects of PPARgamma agonists on bone remodeling].

Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates both glucose and bone mass. PPARgamma activation has been shown to affect bone through an increased in bone marrow adiposity and decreased in osteoblastogenesis, resulting in reduced bone formation. In fact, clinical studies have reported that PPARgamma agonists may cause increased risk of bone fractures and decreased bone mineral density. On the other hand, PPARgamma agonists may have protective effect on inflammatory bone resorption through inhibition of RANKL- or TNFalpha-induced osteoclastogenesis. In this report, we review recent studies showing pleiotropic effects of PPARgamma agonists on bone formation and inflammatory bone resorption observed at joints in rheumatoid arthritis.

Physiologic Target, Molecular Evolution, and Pathogenic Functions of a Monoclonal Anti-Citrullinated Protein Antibody Obtained From a Patient With Rheumatoid Arthritis.

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.