JMJD6 Autoantibodies as a Potential Biomarker for Inflammation-Related Diseases.

Inflammation is closely associated with cerebrovascular diseases, cardiovascular diseases, diabetes, and cancers, and it is accompanied by the development of autoantibodies in the early stage of inflammation-related diseases. Hence, it is meaningful to discover novel antibody biomarkers targeting inflammation-related diseases. In this study, Jumonji C-domain-containing 6 (JMJD6) was identified by the serological identification of antigens through recombinant cDNA expression cloning. In particular, JMJD6 is an antigen recognized in serum IgG from patients with unstable angina pectoris (a cardiovascular disease). Then, the serum antibody levels were examined using an amplified luminescent proximity homogeneous assay-linked immunosorbent assay and a purified recombinant JMJD6 protein as an antigen. We observed elevated levels of serum anti-JMJD6 antibodies (s-JMJD6-Abs) in patients with inflammation-related diseases such as ischemic stroke, acute myocardial infarction (AMI), diabetes mellitus (DM), and cancers (including esophageal cancer, EC; gastric cancer; lung cancer; and mammary cancer), compared with the levels in healthy donors. The s-JMJD6-Ab levels were closely associated with some inflammation indicators, such as C-reactive protein and intima-media thickness (an atherosclerosis index). A better postoperative survival status of patients with EC was observed in the JMJD6-Ab-positive group than in the negative group. An immunohistochemical analysis showed that JMJD6 was highly expressed in the inflamed mucosa of esophageal tissues, esophageal carcinoma tissues, and atherosclerotic plaques. Hence, JMJD6 autoantibodies may reflect inflammation, thereby serving as a potential biomarker for diagnosing specific inflammation-related diseases, including stroke, AMI, DM, and cancers, and for prediction of the prognosis in patients with EC.

Fracture risk assessment of vascularized medial femoral condylar bone graft: A finite element analysis.

BACKGROUND: Vascularized medial femoral condyle (MFC) bone graft is useful for pseudarthrosis and osteonecrosis, but has the risk of fracture as a complication. This study aimed to create multiple three-dimensional (3D) finite element (FE) femur models to biomechanically evaluate the fracture risk in the donor site of a vascularized MFC bone graft. METHODS: Computer tomography scans of the femurs of nine patients (four males and five females) with no left femur disease were enrolled in the study. A 3D FE model of the left femur was generated based on the CT images taken from the patients. The descending genicular artery (DGA), the main nutrient vessel in vascularized MFC bone grafts, divides into the proximal transversal branch (TB) and the distal longitudinal branch (LB) before entering the periosteum. Thirty-six different bone defect models with different sizes and locations of the harvested bone were created. RESULTS: The highest stress was observed in the proximal medial and metaphyseal portions under axial and external rotation, respectively. In the bone defect model, the stress was most elevated in the extracted region's anterior or posterior superior part. Stress increased depending on proximal location and harvested bone size. CONCLUSION: Increasing the size of the bone graft proximally raises the stress at the site of bone extraction. For bone grafting to non-load-bearing areas, bone grafting distally using LB can reduce fracture risk. If TB necessitates a larger proximal bone extraction, it is advisable to avoid postoperative rotational loads.

Serum anti-PCK1 antibody levels are a prognostic factor for patients with diabetes mellitus.

BACKGROUND: Autoantibodies develop in autoimmune diseases, cancer, diabetes mellitus (DM), and atherosclerosis-related diseases. However, autoantibody biomarkers have not been successfully examined for diagnosis and therapy. METHODS: Serological identification of antigens through recombinant cDNA expression cloning (SEREX) was used for primary screening of antigens. The cDNA product was expressed in bacteria and purified. Amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) was used to evaluate antibody levels in serum samples. RESULTS: Phosphoenolpyruvate carboxykinase 1 (PCK1) was recognized as an antigen by serum IgG antibodies in the sera of patients with atherosclerosis. AlphaLISA showed significantly higher serum antibody levels against recombinant PCK1 protein in patients with DM and cardiovascular disease than in healthy donors, but not in those with acute ischemic stroke, transient ischemic attack, or obstructive sleep apnea syndrome. The area under the receiver operating characteristic curve for anti-PCK1 antibodies was 0.7024 for DM. The serum anti-PCK1 antibody levels were associated with age, platelet count, and blood pressure. Anti-PCK1-antibody-positive patients showed significantly lower overall survival than the negative patients. CONCLUSIONS: Serum anti-PCK1 antibody levels were found to be associated with DM. The anti-PCK1 antibody marker is useful for predicting the overall survival of patients with DM.

Association of high proprotein convertase subtilisin/kexin type 9 antibody level with poor prognosis in patients with diabetes: a prospective study.

In addition to pathogenic autoantibodies, polyclonal autoantibodies with unknown physiological roles and pathogenicity are produced in the body. Moreover, serum antibodies against the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein, which is integral to cholesterol metabolism, have also been observed. PCSK9 was also reported to be associated with insulin secretion and diabetes mellitus (DM). Therefore, we aimed to examine the clinical significance of PCSK9 antibodies (PCSK9-Abs) levels. We measured blood PCSK9-Abs and PCSK9 protein levels in 109 healthy donors (HDs) and 274 patients with DM (type 2 DM: 89.8%) using an amplified luminescence proximity homogeneous assay-linked immunosorbent assay. Subsequently, patients with DM were followed up (mean: 4.93 years, standard deviation: 2.77 years, maximum: 9.58 years, minimum: 0.07 years) to examine associations between antibody titers and mortality, myocardial infarction, stroke onset, and cancer. The primary endpoint of this study was to examine whether PCSK9-Abs can be a prognostic marker for overall mortality among the patients with diabetes. The secondary endpoint was to examine the relationship between PCSK9-Abs and clinical parameters. Although both PCSK9-Abs and PCSK9 protein levels were significantly higher in the DM group than in the HD group (p < 0.008), PCSK9-Abs and PCSK9 protein levels showed no correlation in either group. Mortality was significantly associated with higher PCSK9-Ab levels, but unrelated to PCSK9 protein levels. After investigating for potential confounding factors, higher PCSK9-Ab levels were still associated with increased mortality among the patients with DM. PCSK9-Abs may be a novel prognostic marker for overall mortality in patients with diabetes, and further studies are warranted to verify its usefulness.

Iatrogenic distal femur fracture following medial femoral supracondylar bone graft harvest: a case report and finite element analysis.

Objective: This report presents a case of supracondylar femur fracture with finite element analysis and discusses its causes and prevention. Patient and Methods: A 53-year-old man presented with right talar osteonecrosis after osteosynthesis for a talus fracture. A medial femoral condyle-free vascularized bone graft (size, 20 × 12 × 17 mm) from the contralateral femur was performed, including the posteromedial cortical corner. The patient suffered a donor-site supracondylar femoral fracture while standing up from a cross-legged sitting position on the bed on postoperative day 6. The fracture was treated with intramedullary nailing. We analyzed the effects of the location of the bone graft harvest in an intact model using the three-dimensional finite element method (FEM). Results: The talar necrosis and the femur fracture healed. The FEM result revealed that the longitudinal axial pressure had minimal effect on the femur; however, the stress around the bone defect increased with rotation, especially in the posteromedial bone defect model. Conclusion: Harvesting the bone graft should not include the posteromedial corner of the supracondylar femur. The patient should strictly limit the motion of torsional stress, such as standing from a cross-legged sitting position or pivoting turn.

The Incidence and Risk Factors of Hyponatremia in Pulmonary Tuberculosis.

Context: The syndrome of inappropriate antidiuresis (SIAD) with euvolemic hyponatremia may occur in patients with pulmonary tuberculosis (PTB), but little is known about the clinical characteristics of SIAD-associated hyponatremia in PTB patients. Objective: This study aimed to investigate the frequency and risk factors of hyponatremia in PTB patients. Methods: In this retrospective chart review, we examined the incidence and severity of hyponatremia in PTB patients. Multivariate analysis was conducted to identify risk factors for hyponatremia in PTB patients. Results: Of the 161 patients who were screened, after excluding patients with hyperglycemia and renal failure, we enrolled and analyzed data from 113 participants. Hyponatremia occurred in 40.7% patients (<135 mEq/L). Univariate analysis revealed that the presence of hyponatremia was associated with old age, female sex, low body mass index, high glycosylated hemoglobin, C-reactive protein (CRP), and N-terminal pro-brain natriuretic peptide. Multivariable analysis indicated that hyponatremia was strongly associated with old age (odds ratio, 1.06; 95% CI, 1.03-1.09 for every 1-year age increase) and CRP values (odds ratio, 1.15; 95% CI, 1.03-1.30 for every 1-mg/dL increase in CRP). For 86 patients with blood cortisol measurements, the cortisol level was significantly high in the hyponatremia group. Conclusions: Hyponatremia was less frequently associated with hyperglycemia, heart failure, renal failure, and other diseases that cause euvolemic hyponatremia; thus, PTB patients may have euvolemic hyponatremia due to SIAD. Administration of hypertonic saline or fluid restriction should be considered in PTB patients with hyponatremia.

A radiographic and physical analysis of factors affecting seat belt position in sitting car seat.

The characteristic subcutaneous hemorrhage along the seat belt in motor vehicle accidents is called the seat belt sign (SBS). The risk of organ injuries is especially high when abdominal SBS is located above the anterior superior iliac spine (ASIS). The purpose of this study analyzed the physical and radiographic factors of healthy volunteers sit on car seat that affect initial position of abdominal seat belt, namely "lap belt", related to the seat belt injury. This study was examined prospectively relation between physical characteristics of one hundred healthy volunteers and lap belt position sitting the car seat. Physical findings were clarified age, sex, height, body mass index (BMI), and waist circumference. Radiographical findings were measured lumber lordosis (LL), sacral slope (SS), and initial lap belt position by marking with lead tape for the center and ASIS of the lap belt installed on the driver's car seat. In the lateral X-ray image, we measured the horizontal distance (X-value) and vertical distance (Z-value) from the ASIS to the central marker. The lap belt angle was determined to measure the angle between the horizontal line and the straight line connecting the upper edges of the markers. Statistical analysis of the relationships between physical characteristics and radiological findings was performed. X-value and Z-value were positively correlated with body weight, BMI, and waist circumference, while the lap belt angle was negatively correlated with body weight, BMI, and waist circumference. The relationship between physical characteristics and the initial position of seat belt was analyzed. Since the lap belt is positioned higher than the ASIS in occupants with a high BMI, it is likely to cause seat belt injury. This analysis can help to develop safer seat belts and to enlighten car occupants.

Continuous Scanning and Inching in Ultrasonographic Localisation of Ulnar Neuropathy: A Comparative Study of Sensitivity.

Background: This study compares the sensitivity of continuous ultrasonographic scanning and ultrasonographic inching in the localisation of ulnar neuropathy at the elbow to diagnose the two common entrapment sites: retroepicondylar groove and cubital tunnel. Methods: The charts of 30 patients who were diagnosed with ulnar neuropathy of the elbow and underwent ultrasonographic examinations using the inching and the continuous technique between April 2015 and September 2019 were reviewed. Sensitivities of ultrasonographic inching and continuous scanning were compared. Results: A total of 34 elbows from 30 patients were examined. The sensitivities of continuous ultrasonographic scanning method and ultrasonographic inching were 85% and 71%, respectively, but this was not significant (p = 0.06). The maximum cross-sectional areas (CSAs) in continuous scanning were mainly found within the area from the medial epicondyle to the 2-cm distal point in the cubital tunnel entrapment, while a majority of the largest CSAs in ultrasonographic inching was observed at the medial epicondyle level in both entrapment sites. The mean of the maximum CSAs in continuous scanning (17.04 ± 6.75 mm2) was higher than that in ultrasonographic inching (14.13 ± 6.63 mm2), although this difference remained non-significant (p = 0.08). However, continuous scanning differed more significantly (p < 0.0001) from the cut-off value than the ultrasonographic inching (p < 0.0066). Conclusions: Continuous scanning might be more suitable than ultrasonographic inching to localise ulnar neuropathy, which inherently has variations in the cubital tunnel anatomy and its entrapment points, when selecting optimal treatment based on the entrapment site. Level of Evidence: Level III (Diagnostic).

Association of Serum Anti-PCSK9 Antibody Levels with Favorable Postoperative Prognosis in Esophageal Cancer.

BACKGROUND: Esophageal cancer often appears as postoperative metastasis or recurrence after radical surgery. Although we had previously reported that serum programmed cell death ligand 1 (PD-L1) level correlated with the prognosis of esophageal cancer, further novel biomarkers are required for more precise prediction of the prognosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with the cholesterol metabolism. But there was no report of relationship between serum PCSK9 antibody and cancer. Therefore, we investigated whether anti-PCSK9 antibodies could be a novel biomarker for solid cancer. METHODS: Serum levels of anti-PCSK9 antibodies and antigens in patients with solid cancer were analyzed using amplified luminescence proximity homogeneous assay-linked immunosorbent assay (AlphaLISA). The reactivity of serum antibodies against recombinant PCSK9 protein was investigated by Western blotting, and the expression of PCSK9 antigens in esophageal cancer tissues was examined by immunohistochemical staining. RESULTS: AlphaLISA showed that serum anti-PCSK9 antibody (s-PCSK9-Ab) levels were significantly higher in patients with esophageal cancer, gastric cancer, colorectal cancer, lung cancer, and breast cancer than in healthy donors, and patients with esophageal cancer had the highest levels. The presence of serum antibody in patients was confirmed by Western blotting. There was no apparent correlation between s-PCSK9-Ab and PCSK9 antigen levels. Immunohistochemical staining demonstrated the expression of PCSK9 antigen in both the cytoplasm and nuclear compartments of esophageal squamous cell carcinoma tissue but not in normal tissue. Compared with patients with low s-PCSK9-Ab levels, those with high s-PCSK9-Ab levels had a favorable postoperative prognosis after radical surgery for esophageal cancer. In the multivariate analysis, tumor depth and s-PCSK9-Ab level were identified as independent prognostic factors. In the univariate analysis of clinicopathological features, high PCSK9 antibody levels were not associated with sex, age, location, tumor depth, lymph node status, squamous cell carcinoma antigen, or p53-Ab, whereas they correlated significantly with PD-L1 levels, which were associated with unfavorable prognosis. Correlation between s-PCSK9-Ab and PD-L1 levels was also confirmed in the logistic regression analysis; therefore, low s-PCSK9-Ab levels could discriminate another poor prognosis group other than high-PD-L1 group. CONCLUSIONS: Patients with solid cancer had higher s-PCSK9-Ab levels than healthy donors. High s-PCSK9-Ab levels indicated better prognosis for overall survival after surgery in patients with esophageal cancer.

Analysis of individual differences in pelvic and spine alignment in seated posture and impact on the seatbelt kinematics using human body model.

Analysis using human body models has been performed to reduce the impact of accidents; however, no analysis has shown a relationship between lumbar and pelvic/spine angle and seat belts in reducing human damage from accidents. Lumbar and pelvic/spine angles were measured in 75 individuals and the measurements were used to create three different angles for the Total Human Model for Safety model. In the present study, we focused on lumber lordosis (LL) and pelvic angle (PA). A normal distribution and histogram were used for analysis of PA (01, 10, and 50). The Total Human Model for Safety, including LL and PA, was corrected using finite element software. Simulations were conducted under the conditions of the Japan New Car Assessment Programme (JNCAP) 56 kph full lap frontal impact. Using the results of the FEM, the amount of lap-belt cranial sliding-up, anterior movement of the pelvis, posterior tilt of the pelvis, head injury criterion (HIC), second cervical vertebrae (C2) compressive load, C2 moment, chest deflectiou (upper, middle, and lower), left and right femur load, and shoulder belt force were measured. The lap-belt cranial sliding-up was 1.91 and 2.37 for PA10 and PA01, respectively, compared to PA50; the anterior movement of the pelvis was 1.08 and 1.12 for PA10 and PA01, respectively; and the posterior tilt of the pelvis was 1.1 and 1.18 for PA10 and PA01, respectively. HIC was 1.13 for PA10 and 1.58 for PA01; there was no difference in C2 compressive load by PA, but C2 moment increased to 1.59 for PA10 and 2.72 for PA01. It was found that as LL increases and the PA decreases, the seat belt becomes likely to catch the iliac bone, making it harder to cause injury. This study could help to reconsider the safe seat and seatbelt position in the future.

Changes in the global spine alignment in the sitting position in an automobile.

BACKGROUND CONTEXT: Studies of the changes in spine alignment in the sitting position have been limited to specific spine segments. Because there have been few studies of global spinopelvic alignment in the sitting position, it is important to assess the changes associated with this position for such settings as developing future design of seats and achieving appropriate restoration of spine alignment. PURPOSE: This study aimed to measure changes in global spine alignment when people are sitting in car seats and to analyze the characteristics of those changes. STUDY DESIGN: This was a prospective, collaborative study of the radiological evaluation of changes in global spine alignment. PATIENT SAMPLE: The study included 113 asymptomatic adult participants (56 men and 57 women) without a history of spine disease or lower limb surgery, and with no current lower back or leg pain. OUTCOME MEASURES: Radiographic findings were assessed by measurement of various angles: cervical lordosis (CL), thoracic kyphosis (TK), thoracolumbar kyphosis (TLK), lumbar lordosis (LL), sacral slope (SS), pelvic tilt (PT), pelvic incidence (PI), C7 sagittal vertical axis (C7-SVA), T1 spinopelvic inclination (T1SPI), and T1 pelvic angle (TPA). METHODS: Radiographs were obtained in the standing and sitting positions. The objective variables analyzed statistically were spine alignments (CL, TK, TLK, LL, C7-SVA, T1SPI, TPA, SS, PT, and PI) measured in the standing position, body alignments (CL, TK, TLK, LL, C7-SVA, T1SPI, TPA, SS, and PT) measured in the sitting position, and stand-to-sit changes (∆CL, ∆TK, ∆TLK, ∆LL, ∆C7-SVA, ∆T1SPI, ∆TPA, ∆SS, and ∆PT). Explanatory variables were sex, age, body height, and body mass index. RESULTS: Changing posture from standing to sitting decreased CL by an average of 5.3°, slightly decreased TK by an average of 1.3°, increased TLK by an average of 6.8°, decreased LL by an average of 35°, decreased SS by an average of 49.2°, increased PT by an average of 49.2°, shifted C7-SVA backward by an average of 106.7 mm, decreased T1SPI by an average of 18.8°, and increased TPA by an average of 21.1°. Statistical analysis revealed that ΔLL was significantly decreased in elderly participants. After the stand-to-sit change, ΔTLK and ∆TPA were significantly increased in taller participants and ΔT1SPI was significantly decreased in taller participants. CONCLUSIONS: Among other changes, most notably LL is decreased and the pelvic tilt is increased when a person is sitting in a car seat. However, these changes in spine alignment differ with age and height. These findings may be useful for the development of future design of seats and for achieving appropriate surgical restoration of spine alignment.

Bisphenol A inhibits compound action potentials in the frog sciatic nerve in a manner independent of estrogen receptors.

Although the endocrine disruptor bisphenol A (BPA) is reported to inhibit nerve conduction, the underlying mechanisms are unclear. Therefore, in the present study, we examined the effect of BPA on compound action potentials (CAPs) recorded from the frog sciatic nerve using the air-gap method. Treatment of the sciatic nerve with BPA (0.5 mM) for 20 min reduced the peak amplitude of the CAP by approximately 60% in a partially reversible manner. The reduction in the CAP peak amplitude was concentration-dependent, with a half-maximal inhibitory concentration (IC50) value of 0.31 mM. This effect of BPA was unaffected by an estrogen-receptor antagonist, 4-hydroxytamoxifen, which by itself reduced CAP peak amplitude, with an IC50 value of 0.26 mM (comparable to that of BPA). The natural estrogen 17ß-estradiol, at the highest dissolvable concentration (0.05 mM), had an effect similar to that of BPA. The IC50 value of BPA was comparable to those of some local anesthetics in inhibiting frog CAPs. Our findings suggest that BPA inhibits nerve conduction in a manner independent of estrogen receptors. This action of BPA may underlie, at least in part, the neurotoxicity of the compound.

[Latent malignant lymphoma diagnosed at autopsy in a patient with cold agglutinin disease coexisting thrombotic thrombocytopenic purpura].

An 89-year-old woman presented to our hospital with hemolytic anemia and a high titer of cold agglutinins. Red cell agglutination was observed on a blood smear. Agglutination visibly decreased after warming the blood; therefore, the patient was diagnosed with cold agglutinin disease (CAD). Bone marrow aspiration revealed no infiltration of malignant cells. Computed tomography indicated moderate splenomegaly. The patient had neither an infection nor autoimmune disease. Initial steroid therapy was ineffective and hemolysis worsened. Meanwhile, thrombocytopenia, delirium, fever, and schistocytes in the blood were observed. The progression of hemolysis was attributed not only to CAD but also to coexisting thrombotic thrombocytopenic purpura (TTP) because of the decreased ADAMTS 13 level. Autopsy revealed mild paraaortic lymphadenopathy and splenomegaly. Microscopic examination revealed lymphoma cell infiltration in the spleen, liver, bone marrow, and paraaortic lymph nodes. These observations suggested that TTP and CAD were both secondary complications. This case highlights the importance of an autopsy for the detection of latent lymphoma, which can be difficult to diagnose before the patient's death. Careful examination to exclude lymphomas is important in patients with CAD at the time of diagnosis.

Assessment of current status of zinc in wastewater treatment plants to set effluent standards for protecting aquatic organisms in Japan.

New environmental standards for protecting aquatic organisms for zinc (e.g., 0.03 mg/L) in surface waters were set in Japan in 2003. Although wastewater effluent might be one of the major pathways of zinc to public water bodies in Japan, current status of concentration of zinc in wastewater effluent was not clear due to higher detection limits (e.g., 0.5 mg/L) than the level required by the new regulations. This study aims at assessing current status of zinc in wastewater effluent in Japan to revise wastewater effluent standards for protecting aquatic organisms. Survey of zinc in wastewater treatment plants (WWTPs) was carried out in Japan in 2005, setting the detection limits at least 0.01 mg/L. The results of the survey suggested the difficulty to remove zinc (especially dissolved zinc) with conventional activated sludge treatment if concentration of zinc in influent was relatively low. And it was suggested that high concentration of dissolved zinc might be derived from some industries discharging high concentration of zinc. The concentration of zinc in wastewater influent without industrial discharges was about 0.1 mg/L which might be lower than that in wastewater from industries discharging high concentration of zinc. Finally, effluent standards for point sources including WWTPs to public water bodies were set at 2 mg/L in 2006. Based on the results of the survey that it was difficult to remove dissolved zinc discharged from industries at WWTPs, the effluent standards from industries to sewerage were set at the same value of the effluent standards from WWTPs to public water bodies.