CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages

CTLA4-Ig (cytotoxic T-lymphocyte antigen 4-immunoglobulin; Abatacept) is a biologic drug for rheumatoid arthritis. CTLA4 binds to the CD80/86 complex of antigen-presenting cells and blocks the activation of T cells. Although previous reports showed that CTLA4-Ig directly inhibited osteoclast differentiation, the whole inhibitory mechanism of CTLA4-Ig for osteoclast differentiation is unclear. Bone marrow macrophages (BMMs) from WT mice were cultured with M-CSF and RANKL with or without the recombinant mouse chimera CTLA4-Ig. Intracellular calcium oscillations of BMMs with RANKL were detected by staining with calcium indicator fura-2 immediately after administration of CTLA4-Ig or after one day of treatment. Calcium oscillations were analyzed using Fc receptor gamma- (FcRγ-) deficient BMMs. CTLA4-Ig inhibited osteoclast differentiation and reduced the expression of the nuclear factor of activated T cells NFATc1 in BMMs in vitro. Calcium oscillations in BMMs were suppressed by CTLA4-Ig both immediately after administration and after one day of treatment. CTLA4-Ig did not affect osteoclastogenesis and did not cause remarkable changes in calcium oscillations in FcRγ-deficient BMMs. Finally, to analyze the effect of CTLA4-Ig in vivo, we used an LPS-induced osteolysis model. CTLA4-Ig suppressed LPS-induced bone resorption in WT mice, not in FcRγ-deficient mice. In conclusion, CTLA4-Ig inhibits intracellular calcium oscillations depending on FcRγ and downregulates NFATc1 expression in BMMs. © 2019 American Society for Bone and Mineral Research.     

Large blunt scleral rupture without retinal detachment

Eyes with scleral rupture after blunt trauma are often complicated by proliferative vitreoretinopathy. A 56-year-old man sustained blunt trauma to his left eye. Visual acuity was light perception. The fundus was obscured by hyphema. Computed tomography imaging and the presence of extensive subconjunctival hemorrhage suggested scleral rupture. Prompt primary surgery to repair a 25-mm scleral rupture was performed under general anesthesia. No retinal detachment developed. Two years postoperatively, visual acuity increased to 12/20. This case shows that retinal detachment and proliferative vitreoretinopathy may not complicate extensive scleral ruptures under certain circumstances.     

Differentiation of spinal giant cell tumors from chordomas by using a scoring system

Introduction

Few reports have compared the clinical features and imaging characteristics of giant cell tumor and chordoma of the spine. The aim of the present study was to investigate whether the two types of tumors could be differentially diagnosed, by comparing clinical characteristics as well as magnetic resonance imaging (MRI) or computed tomography (CT) findings and then scoring the characteristic findings.

Methods

A total of 18 patients were retrospectively assessed. To elucidate the characteristic findings, we investigated the following 10 items: age at diagnosis, sex, and site of occurrence; for MRI findings, the pattern of tumor expansion, T1-weighted images, T2-weighted images, septal structure, and cystic changes; and for CT findings, calcification or residual bone fragments and incomplete bone shells. Then, we developed a unique scoring system and investigated whether the two tumors could be differentiated by this scoring system.

Results

Six items, including, age, site of occurrence, tumor expansion pattern, T2-weighted images, septal structure, and incomplete bone shells, were significantly different between giant cell tumor and chordoma patients. By using newly developed scoring system, the mean scores of 0.9 ± 0.6 (range 0–2) for giant cell tumor and 4.8 ± 1.5 (range 3–6) for chordoma patients were significantly different (P < 0.001), thereby allowing the differential diagnosis by setting the cutoff value to three.

Conclusions

We found that the six items were useful for differentially diagnosing giant cell tumor and chordoma. These results indicate that it may be possible to distinguish the two types of tumor by scoring these items.

     

Time-dependent risk factors associated with the decline of estimated GFR in CKD patients

Background

Targeting the modifiable risk factors may help halt the progression of CKD, thus risk factor analysis is better performed using the parameters in the follow-up. This study aimed to examine the time-dependent risk factors for CKD progression using time-averaged values and to investigate the characteristics of rapid progression group.

Methods

This is a retrospective cohort study enrolling 770 patients of CKD stage 3–4. Time-dependent parameters were calculated as time-averaged values by a trapezoidal rule. % decline of estimated GFR (eGFR) per year from entry was divided to three groups: <10 % (stable), 10–25 % (moderate progression), and ≥25 % (rapid progression). Multivariate regression analyses were employed for the baseline and the time-averaged datasets.

Results

eGFR decline was 2.83 ± 4.04 mL/min/1.73 m²/year (8.8 ± 12.9 %) in male and 1.66 ± 3.23 mL/min/1.73 m²/year (5.4 ± 11.0 %) in female (p < 0.001). % decline of eGFR was associated with male, proteinuria, phosphorus, and systolic blood pressure as risk factors and with age, albumin, and hemoglobin as protective factors using either dataset. Baseline eGFR and diabetic nephropathy appeared in the baseline dataset, while uric acid appeared in the time-averaged dataset. The rapid progression group was associated with proteinuria, phosphorus, albumin, and hemoglobin in the follow-up.

Conclusion

These results suggest that time-averaged values provide insightful clinical guide in targeting the risk factors. Rapid decline of eGFR is strongly associated with hyperphosphatemia, proteinuria, and anemia indicating that these risk factors should be intervened in the follow-up of CKD.

     

Idiopathic left atrial appendage rupture

Cardiac rupture is mainly caused by myocardial infarction or blunt chest trauma. We present a case of idiopathic left atrial appendage rupture.     

High preoperative hemoglobin A1c is a risk factor for surgical site infection after posterior thoracic and lumbar spinal instrumentation surgery

Background

Diabetes mellitus (DM) is reported to be a risk factor for surgical site infection (SSI), which is a serious complication after spinal surgery. The effect of DM on SSI after instrumented spinal surgery remains to be clarified. The aim was to elucidate perioperative risk factors for infection at the surgical site after posterior thoracic and lumbar spinal arthrodesis with instrumentation in patients with DM.

Methods

Consecutive patients who underwent posterior instrumented thoracic and lumbar spinal arthrodesis during the years 2005–2011, who could be followed for at least 1 year after surgery, were included. These included 36 patients with DM (19 males and 17 females; mean age 64.3 years). The patients’ medical records were retrospectively reviewed to determine the SSI rate. The characteristics of the DM patients were examined in detail, including the levels of serum glucose and HbA1c, which indicate the level of diabetes control.

Results

Patients with DM had a higher rate of SSI (6 of 36 patients, 16.7 %) than patients without DM (10 of 309 patients, 3.2 %). Although the perioperative serum glucose level did not differ between DM patients that did or did not develop SSI, the preoperative HbA1c value was significantly higher in the patients who developed SSI (7.6 %) than in those who did not (6.9 %). SSI developed in 0.0 % of the patients with controlled diabetes (HbA1c <7.0 %) and in 35.3 % of the patients with uncontrolled diabetes (HbA1c ≥7.0 %).

Conclusions

DM patients whose blood glucose levels were poorly controlled before surgery were at high risk for SSI. To prevent SSI in DM patients, we recommend lowering the HbA1c to <7.0 % before performing surgery.     

Factors contributing to improvement of syringomyelia after foramen magnum decompression for Chiari type I malformation

Background

Although various surgical approaches have been proposed for treating syringomyelia associated with Chiari type I malformation, a standard method has yet to be established. we prospectively investigated the results of our surgical method: foramen magnum decompression combined with C1 laminectomy and excision of the outer layer of the dura mater.

Methods

Twenty patients underwent surgery between 2000 and 2010 at our hospital. After surgery, the size of the syrinx decreased in 11 patients (decreased group) but remained unchanged in nine patients (unchanged group). The following parameters were compared: age at the time of surgery, duration of morbidity, improvement of preoperative symptoms, morphological type and length of the syrinx, presence or absence of scoliosis, cervical alignment, basal and clivo-axial angles, and postoperative subarachnoid space at the foramen magnum level.

Results

Preoperative symptoms improved in all patients in the decreased group but in only one patient in the unchanged group. The average duration of morbidity was significantly shorter in the decreased group. Morphological examination revealed that the size of all central-type syrinxes decreased after surgery, whereas in all cases of deviated-type syrinx, size was unchanged. The average length of preoperative syrinx was significantly shorter in the decreased group. The postoperative subarachnoid space at the foramen magnum was enlarged in the entire decreased group, whereas residual narrowing of the space was observed in 44 % of patients in the unchanged group. No significant intergroup differences were observed in the other factors.

Conclusions

In patients with syringomyelia, a longer and deviated type of syrinx, a longer duration of morbidity, and postoperative residual narrowing of the subarachnoid space are associated with a poor prognosis after the surgical procedure. The pathogenesis of syringomyelia is inconsistent, and the choice of surgical technique for each pathological condition is important.