Dimeric but not monomeric soluble CD40 prolongs allograft survival and generates regulatory T cells that inhibit CTL function

BACKGROUND: We previously reported that adenovirus mediated CD40Ig gene therapy (AdCD40Ig) induced long-term acceptance of fully allogeneic rat cardiac allografts, however, the underlying mechanism has not been fully clarified. To address this we have compared the ability of dimeric and monomeric soluble CD40 to prolong allograft survival in vivo and generate regulatory T cells in vitro. METHODS: The ability of CD40Ig (soluble dimmer, containing an Fc region) or CD40/Myc/His (soluble monomer, lacking an Fc region) therapy to generate CD4CD25 regulatory T cells in vitro and to prevent rejection of rat cardiac allografts (ACI to LEWIS) was compared. Immunoregulatory capacity of regulatory T cells generated was determined by suppression of alloantigen specific proliferation and cytotoxicity. RESULTS: Dimeric soluble CD40Ig did not inhibit CD4 T cell proliferation but rather promoted IL-2 production and the generation of CD4CD25 T cells, which regulated alloantigen-specific cytotoxic T lymphocyte activity. Treatment with either AdCD40Ig or purified soluble CD40Ig prolonged the survival of rat cardiac allografts. In contrast, although monomeric soluble CD40/Myc/His suppressed IL-12 production in a similar manner to that achieved by CD40Ig, it did not augment IL-2 production. Moreover, while CD40/Myc/His also generated CD4CD25 T cells, they did not exhibit regulatory activity and administration of soluble CD40/Myc/His failed to prolong cardiac allograft survival. CONCLUSIONS: These results suggest signaling through CD154 in addition to blocking of CD154-CD40 interaction is important for the immunomodulatory effects of soluble CD40Ig. Taken together, our results provide new insight into the mechanism of immunomodulation by soluble CD40 constructs.     

Clinical remission and pathological progression after tonsillectomy in a renal transplant patient with recurrent IgA nephropathy

Abstract:  We discuss a renal transplant patient with recurrent IgA nephropathy (IgAN) before and after tonsillectomy. A 36-year-old man started on hemodialysis support in 1996 due to biopsy-proven IgAN, living related renal transplantation was then performed in 1997. Six years after transplantation, the patient presented with microhematuria and proteinuria. Graft biopsy for these urinary abnormalities showed recurrent IgAN. Tonsillectomy was subsequently performed in December 2003, proteinuria remitted 6 months after the tonsillectomy and microhematuria disappeared three years later. Protocol graft biopsy was subsequently performed twice, at 2 yr after the tonsillectomy (2005) and 4 yr after (2008). Comparing the findings of the pre-tonsillectomy biopsy and the two post-tonsillectomy biopsies, an increase in mesangial cells and matrix in 2005, and an expansion of the mesangial matrix and proliferation of mesangial interposition in 2008. In addition, global sclerosis of glomeruli increased over time, the area of tubulointerstitial damage has extended as well. While the tonsillectomy led to clinical remission of recurrent IgAN, the chronicity progressed on these protocol biopsies. This is the first report of the efficacy and the limitations of tonsillectomy in a case of recurrent IgAN in a transplant patient.     

Postoperative hip motion and functional recovery after simultaneous bilateral total hip arthroplasty for bilateral osteoarthritis

Background  Simultaneous bilateral total hip arthroplasty (THA) can offer a potential benefit of greater postoperative hip motion without the negative influence of contralateral hip disabilities, compared to two-stage THA. However, postoperative changes in hip motion after simultaneous bilateral THA have rarely been reported. The purpose of this study was to clarify the efficacy of simultaneous procedures on postoperative hip motion and functional recovery. Methods  We retrospectively compared hip motion in 27 patients treated with simultaneous bilateral THA to those in 11 patients with two-stage bilateral THA, 35 patients with unilateral THA for unilateral disease, and 15 patients with unilateral THA for bilateral disease. We also evaluated the clinical manifestations according to the Japanese Orthopaedic Association (JOA) hip scores and compared the outcomes among the groups. All of the THA surgeries were primarily performed through a posterolateral approach using cement-less prostheses. The diagnosis at surgery was dysplastic osteoarthritis in all patients, and the patients were followed up for at least 4 years. Results  The postoperative improvement of motion in hip flexion was significantly greater in patients treated with simultaneous procedures compared to patients with two-stage THA and unilateral THA for bilateral disease. The differences in improvement of motion in hip abduction were less marked than the improvement in hip flexion among the groups. Although there were no significant differences in pain scores among the groups, the values for activity of daily living were significantly greater in patients treated with simultaneous bilateral THA and patients with unilateral THA for unilateral disease than in patients with unilateral and two-stage bilateral THA for bilateral disease. Conclusions  The simultaneous procedure was considered to be more effective in patients with bilateral hip osteoarthritis and demonstrated a substantial improvement in hip motion and functional recovery after THA.     

Chondroblastic osteosarcoma arising from the pleura: Report of a case

Extraskeletal osteosarcoma is an uncommon malignant neoplasm. The origin of osteosarcoma in the pleura is extremely rare, with only four such cases so far documented in the literature to the best of our knowledge. We herein report the case of a 64-year-old Japanese man in whom a left pneumonectomy and pleurectomy were carried out to remove a huge tumor. The pathological examination confi rmed a diagnosis of chondroblastic osteosarcoma that had originally arisen from the pleura.     

Development of a compact laparoscope manipulator (P-arm)

Background

Laparoscope manipulating robots are useful for maintaining a stable view during a laparoscopic operation and as a substitute for the surgeon who controls the laparoscope. However, there are several problems to be solved. A large apparatus sometimes interferes with the surgeon. The setting and repositioning is awkward. Furthermore, the initial and maintenance costs are expensive. This study was designed to develop a new laparoscope manipulating robot to overcome those problems.

Methods

We developed a compact robot applicable for various types of laparoscopic surgery with less expensive materials. The robot was evaluated by performing an in vitro laparoscopic cholecystectomy using extracted swine organs. Then, the availability of the robot to various operations was validated by performing a laparoscopic cholecystectomy, anterior resection of the rectum, and distal gastrectomy using a living swine. The reliability of the system was tested by long-time continuous running.

Results

A compact and lightweight laparoscope manipulating robot by the name of P-arm was developed. The surgical time of an in vitro laparoscopic cholecystectomy with and without the P-arm was not different. The three types of operations were accomplished successfully. During the entire procedure, the P-arm worked without trouble and did not interfere with the surgeons. Continuous 8-h operating tests were performed three times and neither discontinuance nor trouble occurred with the system.

Conclusions

The P-arm worked steadily for various swine operations, without interfering with surgeon’s work.     

Nonlinear stress analysis of the supraspinatus tendon using three-dimensional finite element analysis

Purpose

No studies have used stress analysis with finite element analysis (FEA) to determine the causes of and mechanisms underlying rotator cuff tears. Therefore, we performed a biomechanical evaluation of the changes in stress distribution on the rotator cuff using three-dimensional (3-D) FEA.

Methods

The 3-D FEA model of shoulder joint allowed for abduction angles of 0°, 45° and 90° from the plane of the scapula and included the anatomical insertion points of the three major rotator cuff tendons and the middle fibres of the deltoid muscle. Stress distribution of the supraspinatus tendon on 3-D FEA was validated by a comparison with cadaveric and two-dimensional finite element model.

Results

The principal stress peaked in the region approximately 1 cm proximal to the insertion of the supraspinatus tendon. Furthermore, the stress on the joint side increased at the anterior edge of the supraspinatus tendon at abduction angles of 45° and 90°.

Conclusion

There are differences in stress changes between the joint side and bursal side of the supraspinatus tendon within the angles of abduction. The maximal tensile stress was observed on the articular side of the anterior edge of the supraspinatus tendon at 90° abduction. Our results indicate that the difference in tensile stress between the two layers results in delamination and causes partial-thickness tears.

Level of evidence

Decision analysis, Level II.     

Respiratory-gated F-FDG PET/CT for the diagnosis of liver metastasis

Purpose

To ascertain the role of respiratory-gated PET/CT with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) for accurate diagnosis of liver metastasis.

Materials and methods

Forty patients with suspected liver metastasis underwent conventional whole-body PET/CT scan initially, followed by respiratory-gated PET/CT scan covering the liver. Visual detectability (using a 5-point confidence scale), maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) of hepatic metastatic lesions were assessed for three data sets including ordinary whole-body (WB) scan, and non-respiratory-gated (nRG) and respiratory-gated (RG) scans. Results of enhanced CT and/or MRI, or clinical and radiological follow-up were used for reference.

Results

Sixteen of the patients were found to have 53 metastatic lesions in the liver. Patient-based accuracy of WB, nRG, and RG was 92.5%, 95.0%, and 97.5%, respectively, with a lesion-based detection rate of 67.9%, 73.6%, and 73.6%, respectively. The average SUVmax of 34 liver metastatic lesions for WB, nRG, and RG was 6.60 ± 2.34, 7.19 ± 2.66, and 8.08 ± 3.24, respectively. SUVmax for RG was significantly higher than that for WB (p = 0.0069). The average MTV of these 40 lesions for the three protocols was 5.32 ± 4.78 cm³, 5.07 ± 4.73 cm³, and 4.73 ± 4.67 cm³, respectively. Among the three protocols, RG showed the best visual and quantitative evaluation for diagnosis of liver metastasis.

Conclusion

Respiratory-gated PET/CT allows more accurate identification of liver metastases than non-respiratory-gated PET/CT.     

In vitro production of functionally mature hepatocytes from prospectively isolated hepatic stem cells

Hepatocyte transplantation and artificial organ hepatic support require a number of functionally mature hepatocytes. However, their growth activity and functional behaviors are much smaller in culture after isolation from the liver. We examined whether continuously differentiating hepatocytes from multipotent hepatic stem cells that were isolated by using flow cytometry and propagated clonally in culture could be a source of clinical application. They actually gave rise to cells that were functionally equal to mature hepatocytes found in the adult liver, which secreted albumin into culture medium and metabolized harmful ammonium into urea. These data suggest that stem cell-derived hepatocytes are a useful cell source for developing therapeutic strategies, such as cell transplantation, gene therapy, and artificial liver organ to treat various liver disorders.     

Comparison of grey matter and metabolic reductions in frontotemporal dementia using FDG-PET and voxel-based morphometric MR studies

Purpose  The aim of this study was to investigate the regional differences between the morphologic and functional changes in the same patients with frontotemporal dementia (FTD) using statistical parametric mapping and voxel-based morphometry (VBM). Methods  Thirteen FTD patients (mean age, 64.9 years old; mean MMSE score, 17.7), 20 sex-matched Alzheimer’s disease (AD) patients (mean age, 65.0 years old; mean MMSE score, 17.5), and 20 normal volunteers (mean age, 65.2 years old; mean MMSE score, 29.0) underwent both [¹⁸F]FDG positron emission tomography and three-dimensional spoiled gradient echo MRI. Statistical parametric mapping was used to conduct a VBM analysis of the morphologic data, which were compared voxel by voxel with the results of a similar analysis of glucose metabolic data. Results  FTD patients showed decreased grey matter volume and decreased glucose metabolism in the frontal lobe and anterior temporal lobe. In addition, there was a clear asymmetry in grey matter volume in FTD patients by the VBM analysis while the glucose metabolic data showed little asymmetry. In AD patients, glucose metabolic reduction occurred in the bilateral posterior cingulate gyri and parietal lobules while grey matter density decreased the least in the same patients. Conclusion  In FTD, metabolic and morphologic changes occur in the bilateral frontal lobe and temporal lobe with a limited asymmetry whereas there was considerable discordance in the AD group.     

Rosai-Dorfman disease presenting with multiple intracranial and intraspinal masses: a case report

Rosai-Dorfman disease (RDD), a systemic histioproliferative disorder, was first described by Rosai and Dorfman in 1969. However, only 41 cases involving the central nervous system have been reported. The authors present a rare case of RDD with multiple intracranial and spinal lesions mimicking multiple meningioma. A 59-year-old woman was admitted to our hospital with a history of bilateral visual impairment. MRI demonstrated multiple central nervous system lesions in the suprasellar region, right temporal convexity, left frontal convexity, left cerebello-pontine angle and C5 level of the spinal cord. Preoperative neuro-imaging studies suggested multiple meningioma. Subtotal removal of the suprasellar lesion was performed, followed by gamma knife radiosurgery to the residual lesion and the other intracranial lesions. All intracranial lesions disappeared following gamma knife radiotherapy. The spinal lesion, however, was completely excised one year after the initial operation following the appearance of sensory disturbance. Both intracranial and spinal lesions were diagnosed as RDD on histological examination. No recurrences have been detected on MRI two years after the initial operation. Seeing the good results already achieved by surgical removal of RDD, this case suggests that the combination of surgery and gamma knife radiotherapy might improve further.