Objectives: The main histological change in rheumatoid arthritis (RA) is the villous proliferation of synovial lining cells, an important source of cytokines and chemokines, which are associated with inflammation. The aim of this study was to evaluate gene expression in the microdissected synovial lining cells of RA patients, using those of osteoarthritis (OA) patients as the control. Methods: Samples were obtained during total joint replacement from 11 RA and five OA patients. Total RNA from the synovial lining cells was derived from selected specimens by laser microdissection (LMD) for subsequent cDNA microarray analysis. In addition, the expression of significant genes was confirmed immunohistochemically. Results: The 14 519 genes detected by cDNA microarray were used to compare gene expression levels in synovial lining cells from RA with those from OA patients. Cluster analysis indicated that RA cells, including low- and high-expression subgroups, and OA cells were stored in two main clusters. The molecular activity of RA was statistically consistent with its clinical and histological activity. Expression levels of signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor 1 (IRF1), and the chemokines CXCL9, CXCL10, and CCL5 were statistically significantly higher in the synovium of RA than in that of OA. Immunohistochemically, the lining synovium of RA, but not that of OA, clearly expressed STAT1, IRF1, and chemokines, as was seen in microarray analysis combined with LMD. Conclusions: Our findings indicate an important role for lining synovial cells in the inflammatory and proliferative processes of RA. Further understanding of the local signalling in structural components is important in rheumatology.

For successful total knee arthroplasty (TKA), it is very important to gain an accurate grasp of the mechanical axis of the lower limb and establish a suitable ligament balance. Recently, TKA using navigation systems has been developed to accomplish more accurate component placement and to achieve a better understanding of the mechanical axis. The purpose of this study was to compare the radiological results of computer-navigated TKA with those of conventional TKA. We prospectively evaluated 75 primary TKAs (75 subjects) that were performed using a cruciate-retaining prosthesis of the same model at our institution. The subjects were allocated alternately to a navigation group (37 knees) and a conventional group (38 knees). Postoperative radiographs were taken in the standing position at 12 weeks after surgery, and were evaluated in accordance with the report of Bäthis et al.[1]. No significant difference in preoperative profiles was observed between the two groups. At the postoperative radiographic evaluation, significantly better results were obtained in the navigation group with regard to the mechanical axis and the component, but the results were less conclusive in the lateral femoral component position. Our findings suggest that computer-navigated TKA is useful for obtaining more accurate results. However, the present study was limited by the small number of subjects and short follow-up period, and therefore further study involving more subjects and a longer-term follow-up will be needed.

Here we report a metastatic brain carcinosarcoma from the uterus that posed a problem on diagnosis by containing an extensive gliomatous component. A 56-year woman developed motor aphasia 3 months after hysterectomy for a uterine tumor. Magnetic resonance imaging (MRI) demonstrated a left frontal cystic tumor, which was treated by stereotactic radiosurgery. The lesion recurred 5 months later and was resected. Histological examination demonstrated neoplastic cells that were positive for glial fibrillary acidic protein (GFAP), leading to the diagnosis of high-grade glioma. This lesion recurred again after 9 months, and was resected again. The tumor tissue mostly consisted of GFAP-positive gliomatous cells, but close examination identified a sarcomatous component compatible with the metastatic lesion from the uterine sarcoma. This sarcoma component contained GFAP-negative-CD10-positive cells and GFAP-positive-CD10-negative cells. There was no clear border between those components, and, therefore, the lesion was considered to be a metastatic tumor from the uterus showing extensive neural differentiation. Although rare, uterine tumors are known to show such neural differentiation, and the histological diagnosis in such cases can be challenging.

PURPOSE The purpose was to evaluate the correlation between messenger RNA (mRNA) expression of collagen at the edge of the ruptured rotator cuff tendon and postoperative cuff integrity. METHODS The edge of the ruptured tendon was sampled during open rotator cuff surgery in 12 patients with full-thickness rotator cuff tears (mean age, 58.2 years). The mean period from symptom onset was 9.3 months (range, 1 to 36 months), and the mean tear size was 4.1 cm. As controls, rotator cuff tendons with no gross rupture were taken from 5 fresh cadavers. Production of type I and type III collagen was examined by real-time reverse transcription polymerase chain reaction. By use of magnetic resonance imaging, postoperative cuff integrity was evaluated based on the classification of Sugaya et al. and then scored, ranging from 5 points for type I to 1 point for type V. RESULTS Looking at the mRNA of type I and type III collagen in tendons, we found that the expression of mRNA for both collagen types in ruptured tendons was significantly greater than in control tendons (P =.0462 for type I collagen and P =.0306 for type III collagen). Correlating the mRNA of type I and type III collagen with repaired cuff integrity on postoperative magnetic resonance imaging, we found a close relation between expression of mRNA for both collagen types and postoperative rotator cuff integrity (r = 0.63 [P =.038] for type I collagen and r = 0.626 [P =.03] for type III collagen). Furthermore, expression of type I collagen mRNA showed a significant inverse correlation with the period from symptom onset (r =-0.845, P <.0005). CONCLUSIONS This study showed that expression of mRNA for type I and type III collagen at the edge of the ruptured rotator cuff tendon was significantly correlated with postoperative cuff integrity and that mRNA expression for type I collagen was significantly associated with the period from symptom onset. These results may suggest that conservative treatment should not be prolonged if patients do not respond within a certain period. LEVEL OF EVIDENCE Level III, prognostic case-control study.

Aberrant transcriptional regulation may be one of the key components of the pathophysiology of mood disorders. DNA methylation generally acts as an epigenetic gene silencing mechanism and is catalyzed by a group of enzymes known as DNA methyltransferases (DNMTs). Several lines of evidence have suggested aberrant DNA methylation in patients with neuropsychiatric disorders and in animal models for psychiatric disorders. However, the involvement of DNMTs in the pathophysiology of mood disorders is not completely understood. In this study, we aimed to determine whether there are alterations in the expression of DNMTs mRNA in mood disorder patients. We used quantitative real-time PCR to measure the mRNA expression of four DNMT isoforms in the peripheral white blood cells of major depressive disorder (MDD) and bipolar disorder (BPD) patients during a depressive and a remissive episode. We found that the levels of DNMT1 mRNA were significantly decreased in a depressive but not in a remissive state of MDD and BPD. In addition, the levels of DNMT3B mRNA in MDD were significantly increased in a depressive but not in a remissive state. Thus, our data suggest that the altered expression of DNMTs is state dependent and that the aberrant epigenetic gene regulations caused by the altered expression of DNMT1 and DNMT3B may be associated with the pathophysiology of mood disorders.

Expression and function of megalin, an endocytic receptor in proximal tubule cells (PTCs), are reduced in diabetic nephropathy, involved in the development of proteinuria/albuminuria. Lipopolysaccharide (LPS) is chronically increased in diabetic sera, by the mechanism called metabolic endotoxemia. We investigated low-level LPS-mediated signaling that regulates megalin expression in immortalized rat PTCs (IRPTCs). Incubation of the cells with LPS (10 ng/ml) for 48 h suppressed megalin protein expression and its endocytic function. TNF-α mRNA expression was increased by LPS treatment, and knockdown of the mRNA with siRNA inhibited LPS-mediated downregulation of megalin mRNA expression at the 24-h time point. Incubation of IRPTCs with exogenous TNF-α also suppressed megalin mRNA and protein expression at the 24- and 48-h time points, respectively. MEK1 inhibitor PD98059 competed partially but significantly TNF-α-mediated downregulation of megalin mRNA expression. Collectively, low-level LPS-mediated TNF-α-ERK1/2 signaling pathway is involved in downregulation of megalin expression in IRPTCs.

Sirtuins are a family of NAD+-dependent enzymes that regulate cellular functions through deacetylation of various proteins. Although recent reports have suggested an important role of deacetylases (i.e., histone deacetylases) in mood disorders and antidepressant action, the involvement of sirtuins in the pathophysiology of mood disorders is largely unknown. In this study, we aimed to determine whether there are alterations in sirtuin mRNA expression in peripheral white blood cells of patients with a mood disorder. Also, to examine whether the altered sirtuin mRNA expression is state- or trait-dependent, mood disorder patients who were in a remissive state were assessed. We used quantitative real-time polymerase chain reaction to measure the mRNA levels of seven sirtuin isoforms (SIRT1-7) in peripheral white blood cells of patients with major depressive disorder (MDD) or bipolar disorder (BPD) during depressive and remissive states and in normal healthy subjects. The SIRT1, 2 and 6 mRNA levels in MDD and BPD patients decreased significantly in those who were in a depressive state compared to healthy controls, whereas the expression of those mRNAs in both MDD and BPD of patients in a remissive state were comparable to those in healthy controls. Thus, our data suggest that altered SIRT1, 2 and 6 expression is state-dependent and might be associated with the pathogenesis and/or pathophysiology of mood disorders.

Aberrant transcriptional regulation in the brain is thought to be one of the key components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Heat shock factors (HSFs) modulate cellular homeostasis through the control of gene expression. However, the roles of HSFs in brain function have yet to be elucidated fully. In the present study, we attempted to clarify the role of HSF1-mediated gene regulation in neuronal and behavioral development using HSF1-deficient (HSF1(-/-)) mice. We found granule neurons of aberrant morphology and impaired neurogenesis in the dentate gyrus of HSF1(-/-) mice. In addition, HSF1(-/-) mice showed aberrant affective behavior, including reduced anxiety and sociability but increased depression-like behavior and aggression. Furthermore, HSF1 deficiency enhanced behavioral vulnerability to repeated exposure to restraint stress. Importantly, rescuing the HSF1 deficiency in the neonatal but not the adult hippocampus reversed the aberrant anxiety and depression-like behaviors. These results indicate a crucial role for hippocampal HSF1 in neuronal and behavioral development. Analysis of the molecular mechanisms revealed that HSF1 directly modulates the expression of polysialyltransferase genes, which then modulate polysialic acid-neural cell adhesion molecule (PSA-NCAM) levels in the hippocampus. Enzymatic removal of PSA from the neonatal hippocampus resulted in aberrant behavior during adulthood, similar to that observed in HSF1(-/-) mice. Thus, these results suggest that one role of HSF1 is to control hippocampal PSA-NCAM levels through the transcriptional regulation of polysialyltransferases, a process that might be involved in neuronal and behavioral development in mice.

Two patients underwent arthroscopy-guided injections of autologous fibrin sealants to treat ganglion cysts causing suprascapular nerve palsies. After at least 2 years of follow-up, both patients had no suprascapular nerve symptoms and their external rotation strength had returned to normal. Magnetic resonance imaging revealed no evidence of ganglion cyst recurrence.

There is a growing body of evidence supporting the use of hyaluronan (HA) in patients with adhesive capsulitis of the shoulder, although the mechanisms of the effect have not yet been clarified. This in vitro study examined the effects of HA on glenohumeral synovial/capsular fibroblasts (GSCFs) from patients with adhesive capsulitis of the shoulder. The study subjects were seven patients with primary or secondary adhesive capsulitis of the shoulder (average age: 55 years; range: 42-65). Synovial/capsular specimens were obtained from the rotator interval of each patient during arthroscopy. Part of the tissue specimen was used for histological analysis. The remainder of the tissue was prepared for cell culture. Various concentrations of HA (0.0-4.0 mg/mL) were added to the monolayer-cultured GSCFs from these patients. Histological analysis consistently demonstrated chronic nonspecific inflammation with synovial hyperplasia, proliferation of vessels and fibroblasts, and increased amount of extracellular matrix. Treatment with HA at various concentrations significantly and dose-dependently inhibited cell proliferation and decreased the expression levels of mRNA for adhesion-related procollagens and cytokines. Pretreatment with OS/37 did not reverse the inhibitory effect of HA. These results suggest that HA modulates cell proliferation and expression of the mRNA of adhesion-related procollagens and cytokines in GSCFs, preventing the progression of adhesion formation in patients with adhesive capsulitis of the shoulder.