Changes in the incidence of cervical lesions owing to the development of rheumatoid arthritis treatment and the impact of cervical lesions on patients' quality of life.

Objectives: To clarify changes in the incidence of cervical lesions in rheumatoid arthritis (RA) patients with advanced treatment and the impact of cervical lesions on the patients' quality of life (QOL).Methods: Incidence of radiographic cervical lesions in 1333 RA patients in 2015 was compared with that in our 1999 survey. The association between cervical lesions and QOL evaluated using three different patient-based questionnaires was also analyzed.Results: The incidence of atlantoaxial subluxation (AAS), vertical subluxation (VS), and subaxial subluxation (SAS) in 2015 decreased by 50%, 75%, and 5%, respectively, compared to the 1999 survey. Although QOL, evaluated using the Japanese Orthopedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ; specific to myelopathy), deteriorated as the cervical lesion progressed, there was no association between cervical lesion progression and QOL evaluated using the Short Form-8™ (SF-8™; comprehensive health-related QOL). Cervical lesion progression was also associated with QOL deterioration evaluated using the Health Assessment Questionnaire Disability Index (HAQ-DI; specific to RA), but age and disease duration had stronger influences.Conclusion: The incidence of cervical lesions decreased in 2015 compared to 1999. Cervical lesion progression may be associated with QOL deterioration due to myelopathy. Age and disease duration have more impact on disease-specific QOL.

Tubulointerstitial nephritis with monotypic lympho-plasmacytic infiltrates in a patient with primary Sjögren's syndrome accompanied by IgA-type monoclonal gammopathy.

BACKGROUND: Although most cases of tubulointerstitial nephritis in paraproteinemia are monoclonal light chain deposition-mediated, interstitial nephritis as neoplastic interstitial cell infiltration has rarely been described. On the other hand, lympho-plasma-cell-rich tubulointerstitial nephritis, in which the infiltrative cells are usually polytypic, is often evident in primary Sjögren's syndrome (pSS). Herein we present a rare case of pSS in a patient who had been diagnosed as having IgA kappa-type monoclonal gammopathy of undetermined significance (MGUS) and developed tubulointerstitial nephritis with monotypic (IgA kappa) lympho-plasmacytic infiltrates. CASE PRESENTATION: A 74-year-old Japanese woman with pSS who had been diagnosed as having IgA kappa-type MGUS developed progressive renal dysfunction. Renal biopsy revealed tubulointerstitial nephritis with abundant plasma cell-rich mononuclear cell infiltrates without atypia. Immunohistochemical staining for immunoglobulins and light chains showed that most infiltrates were positive for IgA and kappa. Most of the infiltrative cells were positive for CD38 and CD138, and cells positive for CD 19 and CD 45 were also widely evident. Electron microscopy and immunofluorescence studies revealed no apparent immunological deposits in the glomeruli and tubules. Bone marrow and whole-body radiological examinations revealed no findings suggestive of multiple myeloma or lymphoma. Renal function improved rapidly with prednisolone 40 mg daily and has been maintained at the same level on low-dose prednisolone and azathioprine for 18 months. CONCLUSION: Tubulointerstitial nephritis with monotypic cell infiltrates, without immunological deposits, is a quite rare histological picture in MGUS, and might be a unique renal manifestation in patients with pSS.

Evaluation of pelvic morphology in female patients with developmental dysplasia of the hip using three-dimensional computed tomography: A cross-sectional study.

BACKGROUND: The purpose of this study is to measure pelvic morphology with respect to the pelvic incidence, pelvic tilt, and sacral slope using 3-dimensional measurement and to compare the pelvic morphology between the normal population and women with developmental dysplasia of the hip (center-edge angle, <25°). We hypothesized that the relationship between pelvic incidence, anatomical pelvic tilt, and anatomical sacral slope would be different between normal subjects and patients with developmental dysplasia of the hip. METHODS: We evaluated 61 healthy women without low back or knee pain and 71 patients with developmental dysplasia of the hip. We used the 3-dimensional pelvis model adjusted to the anterior pelvic plane and measured the pelvic parameters. To determine correlation, we used Pearson's coefficients. To evaluate variation, we used intraclass correlation coefficients. RESULTS: Pelvic incidence and anatomical pelvic tilt were significantly greater by 4° in the group with developmental dysplasia of the hip than in the normal group (p = 0.026 and < 0.001, respectively). The vertical distance from hip axis to the center of the S1 endplate was significantly greater in the group with developmental dysplasia of the hip than in normal group, that is, by 8 mm (p < 0.001). There was a strong correlation between pelvic incidence and anatomical sacral slope in both groups (R = 0.707 and 0.897, respectively). The intraobserver and interobserver mean absolute differences were about 2 mm and 2°, respectively, and the intraclass correlation coefficient was >0.88. CONCLUSION: Pelvic incidence and anatomical-pelvic tilt were significantly greater in patients with developmental dysplasia of the hip. We found a strong correlation between the pelvic incidence and anatomical sacral slope in both groups. Therefore, anatomical-sacral slope may be useful for estimating pelvic incidence because it is not easily measured, especially in patients with osteoarthritis of the hip joint.

Comparison of clinical and laboratory features of patients with and without allergic conditions in IgG4-related disease: A single-center experience in Japan.

OBJECTIVE: The objective of this study is to compare the clinical and laboratory features of Japanese patients with IgG4-related disease, with and without allergic conditions. METHODS: We retrospectively examined the clinical and laboratory features and clinical courses of 51 patients with definitively diagnosed IgG4-RD, collected from Nagaoka Red Cross Hospital between January 2004 and August 2017, with reference to the presence of allergic conditions. RESULTS: Among these patients, 43% had allergic conditions. In the allergy group, the proportion of females was significantly higher, the age at diagnosis was significantly lower, and upper body organ involvement was predominant in comparison with the non-allergy group. There was no significant inter-group difference in the absolute number of peripheral blood eosinophils, the levels of serum IgG4 and IgE, the response to steroid, or the proportion of patients who relapsed. CONCLUSION: The present findings suggest that there may be some differences in the clinical features of IgG4-RD patients according to the allergic conditions that are present, although eosinophilia and high serum levels of IgE and IgG4 are common features regardless of allergy.

Tubulointerstitial nephritis and Fanconi syndrome in a patient with primary Sjögren's syndrome accompanied by antimitochondrial antibodies: A case report and review of the literature.

We describe a 53-year-old woman with primary Sjögren's syndrome and tubulointerstitial nephritis showing distal renal tubular acidosis and Fanconi syndrome. The patient showed high serum IgM levels and positivity for antimitochondrial antibodies, although her liver function was in normal range. According to our literature review, 75% of patients with tubulointerstitial nephritis who were positive for antimitochondrial antibodies showed Fanconi syndrome, suggesting that these antibodies may directly be associated with the pathophysiology of Fanconi syndrome.

Manual calf massage and passive ankle motion reduce the incidence of deep vein thromboembolism after total hip arthroplasty.

BACKGROUND: Venous thromboembolism is one of the general complications following total hip arthroplasty, wherein various preventive treatments have been recommended. Several studies reported that venous thromboembolism incidence after total hip arthroplasty was similar in patients who were administered prophylaxis with a conventional mechanical procedure alone, and those who were administered pharmacological anticoagulation therapy. Therefore, the optimum methods of prophylaxis are still controversial. The purpose of this study was to investigate whether manual calf massage and passive ankle motion could lower the risk for venous thromboembolism after total hip arthroplasty. METHODS: We retrospectively reviewed the data of 126 consecutive patients undergoing elective primary unilateral total hip arthroplasty wherein manual calf massage and passive ankle motion were performed after the surgery at our hospitals between January and October 2014. The 138 patients of the control group underwent total hip arthroplasty using the same surgical approach and pre- and postoperative protocols without this mechanical prophylaxis between January and December 2013. This mechanical prophylaxis was performed simultaneously 30 times during approximately 10 s; these procedures were repeated thrice immediately after total hip arthroplasty. Duplex ultrasonography was performed to observe the veins of both legs in all the patients on postoperative day 7. RESULTS: The incidence of deep vein thrombosis was 6.52% and 0.79% in the control and manual calf massage and passive ankle motion groups, respectively. The odds ratio for the manual calf massage and passive ankle motion groups was 8.72. Performing this mechanical prophylaxis reduced the incidence of venous thromboembolism after total hip arthroplasty. This mechanical prophylaxis is not only simple and easy, but is also safe and inexpensive. CONCLUSIONS: We therefore recommend that manual calf massage and passive ankle motion be performed in patients who will undergo total hip arthroplasty, if deep vein thrombosis does not exist before the surgery.

The Application of a Modified d-ROMs Test for Measurement of Oxidative Stress and Oxidized High-Density Lipoprotein.

Reactive oxygen species (ROS) are involved in the initiation and progression of atherosclerosis. ROS-derived hydroperoxides, as an indicator of ROS production, have been measured by using the diacron reactive oxygen metabolites (d-ROMs) test, which requires iron-containing transferrin in the reaction mixture. In this study we developed a modified d-ROMs test, termed the Fe-ROMs test, where iron ions were exogenously added to the reaction mixture. This modification is expected to exclude the assay variation that comes from different blood iron levels in individuals. In addition, this Fe-ROMs test was helpful for determining the class of plasma lipoproteins that are hydroperoxidized. Low-density lipoprotein/very low-density lipoprotein (LDL/VLDL) and high-density lipoprotein (HDL) were purified by use of an LDL/VLDL purification kit and the dextran sulfate-Mg2+ precipitation method, respectively; their hydroperoxide contents were assessed by performing the Fe-ROMs test. The majority of the hydroperoxides were detected only in the HDL fraction, not in the LDL/VLDL. Further detailed analysis of HDLs by size-exclusion high-performance liquid chromatography revealed that the hydroperoxide-containing molecules were small-sized HDLs. Because HDL was shown to be the principal vehicle for the plasma hydroperoxides, this Fe-ROMs test is a beneficial method for the assessment of oxidized-HDL levels. Indeed, Fe-ROMs levels were strongly associated with the levels of oxidized HDL, which were determined by performing the malondialdehyde-modified HDL enzyme immunoassay. In conclusion, the Fe-ROMs test using plasma itself or the HDL fraction after dextran sulfate-Mg2+ precipitation is useful to assess the functionality of HDL, because the oxidation of HDL impairs its antiatherogenic capacity.

Mortality after hip fracture with vertebral compression fracture is poor.

Due to the increasing elderly population, the prevalence of osteoporotic hip fractures in Japanese patients continues to rise. It is well established that patients with either hip fracture or both symptomatic and asymptomatic morphometric vertebral compression fracture (VCF) have a poor health prognosis compared with the general population. The purpose of this study was to retrospectively investigate vertebral fracture rates among patients with hip fracture and their influence on mortality. We examined 182 cases of osteoporotic hip fracture in patients admitted to our institution between January 2009 and May 2011. The average age at the time of fracture was 85 years. Radiographs of the lumbar spine were obtained from all of the participants and the lateral spinal radiographs were examined for evidence of VCF. The patients were classified into two groups, those with VCF and those without. A VCF was identified in approximately 78 % of the patients. The mortality rate 1 year after the hip fracture was approximately 22 % and it was significantly higher in patients with VCF. Through multivariate statistics we found that VCF, post-operative complication, loss of ambulation after operation and medication for osteoporosis were statistically significant. In other words, VCF, post-operative complication and loss of ambulation were considered to be poor prognostic factors and medication for osteoporosis was likely to improve the prognosis. We concluded that the risk of mortality after hip fracture is significantly greater in patients who also have VCF compared to patients without VCF, and that medication for osteoporosis is likely to improve prognosis.

Recovery of renal function after glucocorticoid therapy for IgG4-related kidney disease with renal dysfunction.

BACKGROUND: Although renal dysfunction in IgG4-related kidney disease (IgG4-RKD) shows rapid resolution with glucocorticoid therapy, little is known about the appropriate initial glucocorticoid dose for induction therapy or long-term renal outcome. METHODS: We retrospectively examined the differences in recovery of renal function according to the dose of glucocorticoid used for induction therapy and the long-term renal outcome in 43 patients with definite IgG4-RKD (mostly IgG4-tubulointerstitial nephritis), in whom the estimated glomerular filtration rate (eGFR) before glucocorticoid therapy was <60 ml/min. RESULTS: Most patients were treated with glucocorticoid alone and had been maintained on glucocorticoid. The initial dose of prednisolone employed was ≤0.6 mg/kg/day (mean 0.47) in 27 patients (group L), and >0.6 mg/kg/day (mean 0.81) in 16 patients (group H). In both groups, the pretreatment eGFR was significantly improved at 1 month after the start of glucocorticoid therapy and the degree of improvement showed no significant inter-group difference. Relapse of IgG4-RKD occurred in 16.7% of the group L patients and 13.3% of the group H patients (p = 0.78). Among 29 patients who were followed up for over 36 months (mean 74 months) and had been maintained on glucocorticoid, none showed progression to end-stage renal disease and there was no significant difference between eGFR at 1 month after treatment and eGFR at the last review. CONCLUSION: In glucocorticoid monotherapy for IgG4-RKD, a moderate dose is sufficient for induction, and recovery of renal function can be maintained for a long period on low-dose maintenance, although relapse can occur even in patients receiving maintenance therapy.

The role of cardiac sympathetic innervation and skin thermoreceptors on cardiac responses during heat stress.

The mechanism(s) for the changes in cardiac function during heat stress remain unknown. This study tested two unique hypotheses. First, sympathetic innervation to the heart is required for increases in cardiac systolic function during heat stress. This was accomplished by comparing responses during heat stress between paraplegics versus tetraplegics, with tetraplegics having reduced/absent cardiac sympathetic innervation. Second, stimulation of skin thermoreceptors contributes to cardiovascular adjustments that occur during heat stress in humans. This was accomplished by comparing responses during leg only heating between paraplegic versus able-bodied individuals. Nine healthy able-bodied, nine paraplegics, and eight tetraplegics participated in this study. Lower body (i.e., nonsensed area for para/tetraplegics) was heated until esophageal temperature had increased by ~1.0°C. Echocardiographic indexes of diastolic and systolic function were performed before and at the end of heat stress. The heat stress increased cardiac output in all groups, but the magnitude of this increase was attenuated in the tetraplegics relative to the able-bodied (1.3 ± 0.4 vs. 2.3 ± 1.0 l/min; P < 0.05). Diastolic function was maintained in all groups. Indexes of left atrial and ventricular systolic function were enhanced in the able-bodied, but did not change in tetraplegics, while these changes in paraplegics were attenuated relative to the able-bodied. These data suggest that the cardiac sympathetic innervation is required to achieve normal increases in cardiac systolic function during heat stress but not required to maintain diastolic function during this exposure. Second, elevated systolic function during heat stress primarily occurs as a result of increases in internal temperature, although stimulation of skin thermoreceptors may contribute.

Three-dimensional Assessment of Femoral Head Coverage in Normal and Dysplastic Hips: A Novel Method.

The acetabular coverage of the femoral head has been assessed in two-dimensions as the projected covered area or the covered angle on plain radiographs. We present a novel method of the three-dimensional assessment of femoral head coverage obtained by evaluating the covered volume of the femoral head in both normal and dysplastic hips. We also assessed the covered angles on the vertical slices passing through the center of the femoral head. The mean covered volume of the femoral head was 57.4% in normal hips and 26.6% in dysplastic hips. In dysplastic hips, the L-CE, A-CE, and P-CE angles were 7.7°, 21.8°, and 95.8°, respectively, while the acetabular angle was 27.5°. In normal hips, the CE angles were 34.0°, 56.8°, and 109.4°, respectively, while the acetabular angle was 7.2°. Our study suggests the usefulness of a novel 3D assessment for acetabular coverage of the femoral head. This assessment provided the precise 3D information necessary to diagnose hip dysplasia and assess the deficiency of acetabular coverage in these patients. Moreover, we may detect a cut-off between normal and dysplastic hips in the 3D assessment by assessing a large number of dysplastic hips both morphologically and using the new assessment.

Extensive antibody search with whole spectrum black-box optimization.

In designing functional biological sequences with machine learning, the activity predictor tends to be inaccurate due to shortage of data. Top ranked sequences are thus unlikely to contain effective ones. This paper proposes to take prediction stability into account to provide domain experts with a reasonable list of sequences to choose from. In our approach, multiple prediction models are trained by subsampling the training set and the multi-objective optimization problem, where one objective is the average activity and the other is the standard deviation, is solved. The Pareto front represents a list of sequences with the whole spectrum of activity and stability. Using this method, we designed VHH (Variable domain of Heavy chain of Heavy chain) antibodies based on the dataset obtained from deep mutational screening. To solve multi-objective optimization, we employed our sequence design software MOQA that uses quantum annealing. By applying several selection criteria to 19,778 designed sequences, five sequences were selected for wet-lab validation. One sequence, 16 mutations away from the closest training sequence, was successfully expressed and found to possess desired binding specificity. Our whole spectrum approach provides a balanced way of dealing with the prediction uncertainty, and can possibly be applied to extensive search of functional sequences.

The clinical course of patients with IgG4-related kidney disease.

Long-term follow-up for IgG4-related kidney disease, including relapse information, is sparse. To gather data on this we retrospectively examined the clinical course of 43 patients with IgG4-related kidney disease, in which most patients were treated with, and maintained on, corticosteroids. One month after the start of treatment, most of the abnormal serology and radiology parameters had improved. In 34 of the steroid-treated patients whose follow-up period was more than 12 months (median 34 months), excluding one hemodialysis patient, the estimated glomerular filtration rate (eGFR) before treatment was over 60 ml/min in 14 patients (group A) and under 60 ml/min in 20 patients (group B). In group A, there was no difference between the eGFR before therapy and at the last review. In group B, the mean eGFR before treatment (34.1 ml/min) was significantly improved after 1 month (45.0 ml/min), and renal function was maintained at a similar level through last follow-up. Among 24 evaluated patients at the last review, however, renal atrophy had developed in 2 of 9 in group A and in 9 of 15 in group B. Relapse of IgG4-related lesions occurred in 8 of 40 treated patients. Thus, the response of IgG4-related kidney disease to corticosteroids is rapid, not total, and the recovery of renal function persists for a relatively long time under low-dose maintenance. A large-scale prospective study to formulate more useful treatment strategies is necessary.

Pelvic flexion measurement from lateral projection radiographs is clinically reliable.

BACKGROUND: Pelvic flexion affects orientation of the acetabular cup; however, pelvic position is not static in daily activities. During THA it is difficult to know the degree of pelvic flexion with the patient in the lateral position and that position is static. However, surgeons need to appropriately determine pelvic tilt to properly insert the acetabular component. QUESTIONS/PURPOSES: We investigated the reliability of pelvic flexion angle that was measured by manually identifying the location of the pubic symphysis and bilateral anterior superior iliac spines using synthesized lateral radiographs. METHODS: We synthesized 49 lateral radiographs based on CT data. Each of the 49 radiographs had a unique position: 7° of varying lateral tilt and rotation in each of seven selected pelvic flexion angles. The pelvic flexion angle was measured three times by three independent observers in each position and determined the accuracy (based on the true value from the reconstructions) and reliability of the measures. RESULTS: The measurement error was 0.1° (range, -4.8° to 4.0°). There was a tendency for errors when the pelvic flexion angle was 0° or ±5°; the errors were less when the pelvic flexion angle was ±10° or ±20°. Lateral tilt was associated with greater error than rotation. The intraclass correlation coefficient (ICC) of the average value was 0.967. For one observer, more than two measurements are necessary for the ICC to be greater than 0.8, and only one measurement was needed for two of the three observers. CONCLUSIONS: Our data suggest measurement of pelvic flexion angle using lateral radiographs is reliable. We recommend the measurement be performed once by two observers for better reliability.

Recurrence of pelvic abscess from Panton-Valentine leukocidin-positive community-acquired ST30 methicillin-resistant Staphylococcus aureus.

A 17-year-old female patient (a basketball player) suffered from recurrent pelvic abscesses from methicillin-resistant Staphylococcus aureus (MRSA). The first episode, from strain NN12, occurred in October 2004. Her cutaneous abscesses complicated into systemic progression to osteomyelitis and multifocal pelvic abscesses, adjacent to the sacroiliac joint. The second episode, abscesses at tissues adjacent to the sacroiliac joint from strain NN31A, occurred late in February 2005. The third episode, from strain NN31B, occurred on July 30, 2005, repeating the second episode. Three MRSA strains were identical in terms of genotypes (belonging to Panton-Valentine leukocidin [PVL]-positive ST30 community-acquired MRSA, CA-MRSA), pulsed-field gel electrophoresis patterns, and peptide cytolysin gene (psmα) expression levels. The three MRSA strains exhibited superior THP-1 cell invasion ability over hospital-acquired MRSA (New York/Japan clone). The data suggest that PVL-positive ST30 CA-MRSA, with high levels of cell invasion and peptide cytolysins, causes recurrence of pelvic abscesses in a healthy adolescent.

A case of aseptic abscesses syndrome treated with corticosteroids and TNF-alpha blockade.

Aseptic abscesses syndrome (AA) is an emerging clinicopathological entity characterized by visceral sterile collections of mature neutrophils that do not respond to antibiotics but regress quickly when treated with corticosteroids. Although most previous case reports of AA have been restricted to Europe, we present here a Japanese woman with AA showing recurrence of splenic abscesses, ileocolitis, pyoderma gangrenosum, and arthritis. Although both steroid therapy and tumor necrosis factor (TNF)-alpha blockade were effective, relapses remained frequent.

Selection of target-binding proteins from the information of weakly enriched phage display libraries by deep sequencing and machine learning.

Despite the advances in surface-display systems for directed evolution, variants with high affinity are not always enriched due to undesirable biases that increase target-unrelated variants during biopanning. Here, our goal was to design a library containing improved variants from the information of the "weakly enriched" library where functional variants were weakly enriched. Deep sequencing for the previous biopanning result, where no functional antibody mimetics were experimentally identified, revealed that weak enrichment was partly due to undesirable biases during phage infection and amplification steps. The clustering analysis of the deep sequencing data from appropriate steps revealed no distinct sequence patterns, but a Bayesian machine learning model trained with the selected deep sequencing data supplied nine clusters with distinct sequence patterns. Phage libraries were designed on the basis of the sequence patterns identified, and four improved variants with target-specific affinity (EC50 = 80-277 nM) were identified by biopanning. The selection and use of deep sequencing data without undesirable bias enabled us to extract the information on prospective variants. In summary, the use of appropriate deep sequencing data and machine learning with the sequence data has the possibility of finding sequence space where functional variants are enriched.

Recent research advances on non-linear phenomena in various biosystems.

All biological phenomena can be classified as open, dissipative and non-linear. Moreover, the most typical phenomena are associated with non-linearity, dissipation and openness in biological systems. In this review article, four research topics on non-linear biosystems are described to show the examples from various biological systems. First, membrane dynamics of a lipid bilayer for the cell membrane is described. Since the cell membrane separates the inside of the cell from the outside, self-organizing systems that form spatial patterns on membranes often depend on non-linear dynamics. Second, various data banks based on recent genomics analysis supply the data including vast functional proteins from many organisms and their variable species. Since the proteins existing in nature are only a very small part of the space represented by amino acid sequence, success of mutagenesis-based molecular evolution approach crucially depends on preparing a library with high enrichment of functional proteins. Third, photosynthetic organisms depend on ambient light, the regular and irregular changes of which have a significant impact on photosynthetic processes. The light-driven process proceeds through many redox couples in the cyanobacteria constituting chain of redox reactions. The fourth topic focuses on a vertebrate model, the zebrafish, which can help to understand, predict and control the chaos of complex biological systems. In particular, during early developmental stages, developmental differentiation occurs dynamically from a fertilized egg to divided and mature cells. These exciting fields of complexity, chaos, and non-linear science have experienced impressive growth in recent decades. Finally, future directions for non-linear biosystems are presented.