TGF-β1 Promotes Lymphangiogenesis during Peritoneal Fibrosis

Peritoneal fibrosis (PF) causes ultrafiltration failure (UFF) and is a complicating factor in long-term peritoneal dialysis. Lymphatic reabsorption also may contribute to UFF, but little is known about lymphangiogenesis in patients with UFF and peritonitis. We studied the role of the lymphangiogenesis mediator vascular endothelial growth factor-C (VEGF-C) in human dialysate effluents, peritoneal tissues, and peritoneal mesothelial cells (HPMCs). Dialysate VEGF-C concentration correlated positively with the dialysate-to-plasma ratio of creatinine (D/P Cr) and the dialysate TGF-β1 concentration. Peritoneal tissue from patients with UFF expressed higher levels of VEGF-C, lymphatic endothelial hyaluronan receptor-1 (LYVE-1), and podoplanin mRNA and contained more lymphatic vessels than tissue from patients without UFF. Furthermore, mesothelial cell and macrophage expression of VEGF-C increased in the peritoneal membranes of patients with UFF and peritonitis. In cultured mesothelial cells, TGF-β1 upregulated the expression of VEGF-C mRNA and protein, and this upregulation was suppressed by a TGF-β type I receptor (TGFβR-I) inhibitor. TGF-β1–induced upregulation of VEGF-C mRNA expression in cultured HPMCs correlated with the D/P Cr of the patient from whom the HPMCs were derived (P<0.001). Moreover, treatment with a TGFβR-I inhibitor suppressed the enhanced lymphangiogenesis and VEGF-C expression associated with fibrosis in a rat model of PF. These results suggest that lymphangiogenesis associates with fibrosis through the TGF-β–VEGF-C pathway.The decrease in ultrafiltration capacity that is associated with the high peritoneal solute transport that is observed after prolonged peritoneal dialysis (PD) treatment is a major reason for its discontinuation.^1–4 Several studies have shown that a higher peritoneal solute transport rate is associated with reduced survival of PD patients.^1,2,5 The characteristic features of chronic peritoneal damage in PD treatment are associated with submesothelial fibrosis and neoangiogenesis.^6,7 Analyses of the surface peritoneum showed no significant changes in vessel density with duration of PD.^6,8 In addition, the vessel density in patients with ultrafiltration failure (UFF) was significantly higher than the vessel density in normal individuals or non-PD patients, but it was not higher than the vessel density in patients undergoing PD.⁶ These findings suggest that factors other than increased vascular density may be involved in disease states associated with increased transport of peritoneal membranes. In addition, the relationship between peritoneal fibrosis and UFF remains obscure.Blood capillaries have a continuous basal lamina with tight interendothelial junctions and are supported by pericytes and smooth muscle cells. In contrast, lymphatic capillaries are thin-walled with a wide lumen and do not contain pericytes or basement membrane. The structures of lymphatic vessels are suitable for the removal of tissue fluid, cells, and macromolecules from the interstitium.^9–11 If lymphangiogenesis develops in the peritoneal membrane, absorption of the PD fluid could be increased and lead to UFF. An increase in the number of lymphatic vessels has recently been reported in several disease conditions, including tumor metastasis,^12–15 chronic respiratory inflammatory diseases,^16–18 wound healing,¹⁹ and renal transplant rejection.^20,21 We recently reported that lymphangiogenesis had developed in tubulointerstitial fibrosis of human renal biopsy specimens,²² and we also reported the mechanisms of lymphangiogenesis in rat unilateral ureteral obstruction models.²³The lymphatic absorption rate, which is measured by the rate at which intraperitoneally administered radioactive serum albumin or macromolecule dextran 70 disappears, is significantly higher in patients with UFF, and lymphatic reabsorption is considered to be one of the causes of UFF.^24–27 However, the results from these clinical approaches have been controversial.^28,29 In addition, little is known about the pathology and the process of lymphangiogenesis in patients with UFF and peritonitis.In this study, we investigated lymphangiogenesis and the expression of vascular endothelial growth factor-C (VEGF-C), which is a potentially important mediator of lymphangiogenesis, in human peritoneal tissues, PD effluent, and peritoneal mesothelial cells. We also explored VEGF-C induction by TGF-β1 in the human mesothelial cell line (Met-5A) and cultured human peritoneal mesothelial cells (HPMCs) from the spent PD effluent of patients with varying rates of peritoneal transport. Finally, we explored the relationship between peritoneal fibrosis and lymphangiogenesis in rats that were administered chlorhexidine gluconate (CG) into the abdominal cavity, which provides a model of chemically induced peritoneal inflammation/fibrosis.^30–32 This work is the first report to show that lymphangiogenesis is linked to the peritoneal fibrosis that is often associated with a high peritoneal transport rate.     

Posterior Femoral Condylar Offset After Total Knee Replacement in The Risk of Knee Flexion Contracture

The aim of this study was to clarify the risk of knee flexion contracture associated with a posterior femoral condylar offset after total knee replacement (TKR). Radiographs from 100 healthy Japanese volunteers were included in the study. We evaluated femoral component posterior offset in various implants and compared them with the normal Japanese knee. Posterior offset of the femoral condyle is up to a maximum of 4.7 times greater than that of the healthy Japanese knee in all knee implants. Excess posterior offset of the femoral condyle in TKR prostheses may cause knee joint flexion contracture due to the relative shortening of the posterior soft tissue.     

Degree of biological apatite c‐axis orientation rather than bone mineral density controls mechanical function in bone regenerated using recombinant bone morphogenetic protein‐2

The aim of the present study was to assess the bone regeneration process in defects introduced into rabbit long bones, which were regenerated with controlled release of recombinant bone morphogenetic protein‐2 (rBMP‐2). The orientation of the biological apatite (BAp) c‐axis and bone mineral density (BMD) were compared as predictors of bone mechanical function. A 20‐mm‐long defect was introduced in rabbit ulnas, and 17 µg of rBMP‐2 was controlled‐released into the defect using a biodegradable gelatin hydrogel as the carrier. In the bone regeneration process, two characteristic phases may have been governed by different factors. First, new bone formation actively occurred, filling the bone defect with newly formed bone tissue and increasing the BMD. This process was regulated by the strong osteoinductive capacity of rBMP‐2. Second, after filling of the defect and moderate BMD restoration, preferential BAp c‐axis orientation began to increase, coincident with initiation of remodeling. In addition, the BAp c‐axis orientation, rather than BMD, was strongly correlated with Young's modulus, an important index of bone mechanical function, particularly in the later stage of bone regeneration. Thus, preferential BAp c‐axis orientation is a strong determinant and predictor of the mechanical function of tissue‐engineered bone. Therefore, analysis of BAp preferential c‐axis orientation in addition to measurement of BMD is crucial in assessment of bone mechanical function. © 2013 American Society for Bone and Mineral Research © 2013 American Society for Bone and Mineral Research     

Maxillary sensory nerve responses induced by different types of dentures

PurposeThe purpose of this study was to investigate whether different types of dentures induced different responses to stimulations in sensory nerve underlying the denture-supporting mucosa using current perception threshold (CPT).Materials and methodsThe study population comprised 45 complete denture wearers with a mean age of 69.7 years (CD), 30 partial denture wearers (PD) with a mean age of 67.1 years, and 40 dentulous participants with a mean age of 69.0 years (Dent). Current perception threshold (CPT) on the greater palatine nerve at 2000 Hz, 250 Hz, and 5 Hz, corresponding to A-beta, A-delta, and C fibers respectively, were measured by the Neurometer^® NS3000 device. The differences CPTs among CD, PD, and Dent groups were analyzed by Kruskal–Wallis test and Mann–Whitney U test with adjusting the multiple comparisons’ inflation of type 1 error rate by a Bonferroni correction.ResultsCPTs of CD, PD, and Dent group at 2000 Hz were 61.5 ± 45.8, 53.5 ± 25.3, 33.0 ± 11.4 (10^?2 mA) respectively. CPTs of CD, PD, and Dent group at 250 Hz were 29.2 ± 28.2, 20.1 ± 13.2, 14.3 ± 5.9 (10^?2 mA) respectively. CPTs of CD, PD, and Dent group at 5 Hz were 28.9 ± 23.4, 17.8 ± 12.2, 12.2 ± 5.6 (10^?2 mA) respectively. The CPTs at all frequencies increased in the following order: Dent < PD < CD wearer. The statistical analyses showed that the different types of dentures significantly affected CPTs at 2000 Hz (p < 0.0001), 250 Hz (p < 0.0001), and 5 Hz (p < 0.0001).ConclusionThe different types of dentures induce different responses to stimulations in the sensory nerve underlying the denture-supporting mucosa.     

Secondary pouchitis in a pediatric patient successfully treated by salvage surgery

Apart from primary pouchitis, patients with secondary pouchitis caused by surgical complications require surgical management. The use of abdomino‐anal salvage surgery to treat secondary pouchitis caused by surgical complications in pediatric patients with ulcerative colitis (UC) has not been reported in detail. A girl was diagnosed with UC at 8 years old. She underwent restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) at 9 years old. She presented at 12 years old because of chronic antibiotic‐refractory pouchitis. The fistula and stricture failed to improve despite multiple local salvage surgeries and ileostomy construction. At 15 years old, she underwent redo IPAA. The patient was well at 20 years old with no signs of pouchitis. Early treatment by abdomino‐anal salvage surgery might be indicated to improve quality of life in pediatric patients with secondary pouchitis caused by surgical complication unresponsive to defunctioning and local salvage surgery.