Angiopoietin-Like Protein 2 Induces Synovial Inflammation in the Facet Joint Leading to Degenerative Changes via Interleukin-6 Secretion.

STUDY DESIGN: Experimental human study. PURPOSE: To determine whether angiopoietin-like protein 2 (ANGPTL2) is highly expressed in the hyperplastic facet joint (FJ) synovium and whether it activates interleukin-6 (IL-6) secretion in FJ synoviocytes. OVERVIEW OF LITERATURE: Mechanical stress-induced synovitis is partially, but significantly, responsible for degenerative and subsequently osteoarthritic changes in the FJ tissues in patients with lumbar spinal stenosis (LSS). However, the underlying molecular mechanism remains unclear. IL-6 is highly expressed in degenerative FJ synovial tissue and is responsible for local chronic inflammation. ANGPTL2, an inflammatory and mechanically induced mediator, promotes the expression of IL-6 in many cells. METHODS: FJ tissues were harvested from five patients who had undergone lumbar surgery. Immunohistochemistry for ANGPTL2, IL-6, and cell markers was performed in the FJ tissue samples. After cultured synoviocytes from the FJ tissues were subjected to mechanical stress, ANGPTL2 expression and secretion were measured quantitatively using real-time quantitative reverse-transcription-polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA), respectively. Following ANGPTL2 administration in the FJ synoviocytes, anti-nuclear factor-κB (NF-κB) activation was investigated using immunocytochemistry, and IL-6 expression and secretion were assayed quantitatively with or without NF-κB inhibitor. Moreover, we assessed whether ANGPTL2-induced IL-6 modulates leucocyte recruitment in the degenerative process by focusing on the monocyte chemoattractant protein-1 (MCP-1) expression. RESULTS: ANGPTL2 and IL-6 were highly expressed in the hyperplastic FJ synovium samples. ANGPTL2 was co-expressed in both, fibroblast-like and macrophage-like synoviocytes. Further, the expression and secretion of ANGPTL2 in the FJ synoviocytes increased in response to stimulation by mechanical stretching. ANGPTL2 protein promoted the nuclear translocation of NF-κB and induced IL-6 expression and secretion in the FJ synoviocytes. This effect was reversed following treatment with NF-κB inhibitor. Furthermore, ANGPTL2-induced IL-6 upregulated the MCP-1 expression in the FJ synoviocytes. CONCLUSIONS: Mechanical stress-induced ANGPTL2 promotes chronic inflammation in the FJ synovium by activating IL-6 secretion, leading to FJ degeneration and subsequent LSS.

Matrix metalloproteinase promotes elastic fiber degradation in ligamentum flavum degeneration.

Ligamentum flavum (LF) hypertrophy in lumbar spinal canal stenosis (LSCS) is characterized by a loss of elastic fibers and fibrosis. Chronic inflammation is thought to be responsible for the histological change but the mechanism underlying elastic fiber degradation remains unclear. Given that matrix metalloproteinase (MMP)-2 and -9 have elastolytic activity and are partly regulated by inflammatory cytokines such as interleukin (IL)-6, in this study, we investigated whether MMPs mediate LF degeneration using 52 LF samples obtained during lumbar surgery, including 31 LSCS and 21 control specimens. We confirmed by histological analysis that the LSCS samples exhibited severe degenerative changes compared with the controls. We found that MMP-2 was upregulated in LF tissue from patients with LSCS at the mRNA and protein levels, whereas MMP-9 expression did not differ between the two groups. The MMP-2 level was positively correlated with LF thickness and negatively correlated with the area occupied by elastic fibers. IL-6 mRNA expression was also increased in LF tissue from patients with LSCS and positively correlated with that of MMP-2. Signal transducer and activator of transcription (STAT)3, a component of the IL-6 signaling pathway, was activated in hypertrophied LF tissues. Our in vitro experiments using fibroblasts from LF tissue revealed that IL-6 increased MMP-2 expression, secretion, and activation via induction of STAT3 signaling, and this effect was reversed by STAT3 inhibitor treatment. Moreover, elastin degradation was promoted by IL-6 stimulation in LF fibroblast culture medium. These results indicate that MMP-2 induction by IL-6/STAT3 signaling in LF fibroblasts can degrade elastic fibers, leading to LF degeneration in LSCS.

Accelerated (99m)Tc-sestamibi clearance associated with mitochondrial dysfunction and regional left ventricular dysfunction in reperfused myocardium in patients with acute coronary syndrome.

BACKGROUND: Accelerated clearance of (99m)technetium-sestamibi (MIBI) has been observed after reperfusion therapy in patients with acute coronary syndrome (ACS), but the mechanisms have not been fully investigated. MIBI retention may depend on mitochondrial function. The clearance rate of (11)carbon-acetate reflects such mitochondrial functions as oxidative metabolism. The purpose of this study was to examine the mechanisms of accelerated MIBI clearance in ACS. We therefore compared it to oxidative metabolism estimated using (11)C-acetate positron emission tomography (PET). METHODS: Eighteen patients [mean age 69.2 ± 8.7 years, 10 males (56 %)] with reperfused ACS underwent MIBI single-photon emission computed tomography (SPECT), echocardiography, and (11)C-acetate PET within 3 weeks of the onset of ACS. MIBI images were obtained 30 min and 3 h after MIBI administration. Regional left ventricular (LV) function was evaluated by echocardiography. The measurement of oxidative metabolism was obtained through the mono-exponential fitting of the (11)C-acetate time-activity curve (k mono). RESULTS: Among 95 segments of reperfused myocardium, MIBI SPECT showed 64 normal segments (group N), 14 segments with accelerated MIBI clearance (group AC), and 17 segments with fixed defect (group F). Group AC showed lower k mono than group N (0.041 ± 0.009 vs 0.049 ± 0.010, p = 0.02). Group F showed lower k mono than group N (0.039 ± 0.012 vs 0.049 ± 0.010, p = 0.01). However, k mono was similar in group AC and group F (p = 0.99). CONCLUSIONS: Segments with accelerated MIBI clearance showed reduced oxidative metabolism in ACS. Loss of MIBI retention may be associated with mitochondrial dysfunction.

Angiopoietin-like protein 2 promotes inflammatory conditions in the ligamentum flavum in the pathogenesis of lumbar spinal canal stenosis by activating interleukin-6 expression.

PURPOSE: Chronic inflammation is thought to cause ligamentum flavum (LF) degeneration and hypertrophy in lumbar spinal canal stenosis (LSCS). Angiopoietin-like protein 2 (Angptl2) is highly expressed in hypertrophied LF. Because Angptl2 regulates interleukin-6 (IL-6) expression in various tissues, we investigated whether IL-6 is expressed in hypertrophied LF and, if so, does Angptl2 induce IL-6 expression in LF fibroblasts. METHODS: LF tissue was obtained from LSCS patients and non-LSCS patients. Polymerase chain reaction (PCR) for Angptl2 and IL-6 genes and immunohistochemistry for IL-6 protein were performed in LF tissue. Fibroblasts from LF tissue were used for in vitro experiments. Expression of integrin α5ß1 (an Angptl2 receptor) and Angptl2 binding to receptors on LF fibroblasts were examined by fluorescence-activated cell sorter analysis and cell adhesion assays. After Angptl2 recombinant protein treatment, NF-κB activation and IL-6 expression in LF fibroblasts were investigated by immunocytochemistry, PCR, and enzyme-linked immunosorbent assay. RESULTS: IL-6 mRNA expression was increased in hypertrophied LF tissue from LSCS patients and positively correlated with LF thickness and Angptl2 mRNA expression. IL-6 protein was highly expressed in LF fibroblasts in hypertrophied LF tissue. In vitro experiments demonstrated integrin α5ß1 expression on LF fibroblasts and Angptl2 binding to cells via receptors. Angptl2 stimulation promoted NF-κB nuclear translocation and induced IL-6 expression and secretion in LF fibroblasts. CONCLUSIONS: Angptl2 promotes inflammation in LF tissue by activating IL-6 expression, leading to LF degeneration and hypertrophy.

Evaluation of the relationship between T1ρ and T2 values and patella cartilage degeneration in patients of the same age group.

OBJECTIVE: The aim of this study was to investigate the association between the T1ρ and T2 values and the progression of cartilage degeneration in patients of the same age group. MATERIALS AND METHODS: Sagittal T1ρ and T2 mapping and three-dimensional (3D) gradient-echo images were obtained from 78 subjects with medial knee osteoarthritis (OA). The degree of patella cartilage degeneration was classified into four groups using MRI-based grading: apparently normal cartilage, mild OA, moderate OA, and severe OA group. We measured the T1ρ and T2 values (ms) in the regions of interest set on the full-thickness patella cartilage. Then, we analyzed the relationship between the T1ρ and T2 values and the degree of patella cartilage degeneration. RESULTS: There were no significant differences in age among the four groups. Both the T1ρ and T2 values showed a positive correlation with the degree of OA progression (ρ=0.737 and ρ=0.632, respectively). By comparison between the apparently normal cartilage and the mild OA groups, there were significant differences in the T1ρ mapping, but not in the T2 mapping. CONCLUSIONS: Our study confirmed that T1ρ and T2 mapping can quantitatively evaluate the degree of patella cartilage degeneration in patients within the same age group.

Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis.

Amyloidosis is a protein conformational disorder with the distinctive feature of extracellular accumulation of amyloid fibrils that come from different proteins. In the ligamentum flavum of the lumbar spine, amyloid deposits were frequently found in elderly patients with lumbar spinal canal stenosis and were at least partially formed by wild-type transthyretin. However, how amyloid deposits in the ligamentum flavum affect lumbar spinal canal stenosis has remained unclear. In this study, we analyzed clinical, pathologic, and radiologic findings of patients with lumbar spinal canal stenosis who had amyloid deposits in the ligamentum flavum. We studied 95 ligamentum flavum specimens obtained from 56 patients with lumbar spinal canal stenosis and 21 ligamentum flavum specimens obtained from 19 patients with lumbar disk herniation. We evaluated histopathologic findings and clinicoradiologic manifestations, such as thickness of the ligamentum flavum and lumbar spinal segmental instability. We found that all 95 ligamentum flavum specimens resected from patients with lumbar spinal canal stenosis had amyloid deposits, which we classified into two types, transthyretin-positive and transthyretin-negative, and that transthyretin amyloid formation in the ligamentum flavum of patients with lumbar spinal canal stenosis was an age-associated phenomenon. The amount of amyloid in the ligamentum flavum was related to clinical manifestations of lumbar spinal canal stenosis, such as thickness of the ligamentum flavum and lumbar spinal segmental instability, in the patients with lumbar spinal canal stenosis with transthyretin-positive amyloid deposits. To our knowledge, this report is the first to show clinicopathologic correlations in transthyretin amyloid deposits of the ligamentum flavum. In conclusion, transthyretin amyloid deposits in the ligamentum flavum may be related to the pathogenesis of lumbar spinal canal stenosis in elderly patients.

Effects of the water-holding capability of polyvinyl formal sponges on osteogenic ability in in vivo experiments.

In this study, dextran-coated polyvinyl formal (PVF) sponges with high water-holding capability were developed to increase the osteogenic response in the PVF sponge. The study aimed to estimate the effect of the increased water-holding capability of the sponges on osteogenic capacity at a bone defect site in the rabbit femur epiphysis. Bone formation was evaluated using radiography, microcomputed tomography (CT), and histological analysis at 2, 4, and 6 weeks after implantation. As shown by radiography and micro-CT findings, the dextran-coated PVF sponge without water-holding capability showed little bone formation at all evaluated time points. However, the dextran-coated PVF sponge with high water-holding capability showed increasing bone formation around the implant at 4 and 6 weeks after implantation. Furthermore, as shown by micro-CT quantitative analysis, the grafted PVF sponge with high water-holding capability showed significantly greater values for percentage of bone volume per total volume and mean bone mineral density compared with the grafted PVF sponge without water-holding capability at 4 and 6 weeks after implantation. These results suggest that the dextran-coated PVF sponge with high water-holding capability promoted osteogenesis in vivo. The PVF sponge might be a new biomaterial to be used as a fill material for bone defects.

Validity of E-PASS System for Postoperative Morbidity of Spinal Surgery.

STUDY DESIGN: A single-center retrospective cohort study. OBJECTIVE: To evaluate the ability of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) system to predict postoperative risk in patients scheduled for spinal surgery. SUMMARY OF BACKGROUND DATA: The E-PASS system is a surgical audit to predict postoperative morbidity and mortality in general surgery. It is currently not applied in patients with spinal disorders. METHODS: The E-PASS system is comprised of a preoperative risk score (PRS), a surgical stress score (SSS), and a comprehensive risk score (CRS). The latter reflects both the PRS and SSS. We calculated the E-PASS scores for 275 consecutive patients who underwent spinal surgery and evaluated the relationship between the incidence of postoperative complications and each score of the E-PASS system and their ability to predict postoperative morbidity. RESULTS: Postoperative complications developed in 31 patients (11.3%). All E-PASS scores were significantly higher in patients with postoperative complications and they were linearly correlated with the overall incidence of postoperative complications. In particular, PRS was correlated with complications at nonsurgical sites and SSS with surgical site complications. The area under the receiver operating characteristic curve (AUC) for PRS and SSS was higher in patients with complications at nonsurgical and surgical sites, respectively. The AUC for CRS exhibited good predictive power for both types of complication. CONCLUSIONS: The E-PASS system correctly predicted morbidity. The predictive ability of CRS was good for overall morbidity. The E-PASS system is useful for the accurate prediction of the risk for in-hospital morbidity in individual patients scheduled for spinal surgery.

In vivo kinematic comparison between mobile-bearing and fixed-bearing total knee arthroplasty during step-up activity.

Mobile-bearing total knee arthroplasty (TKA) expects high conformity and low contact stress. It is designed to correct the rotational mismatch between femoral and tibial components. We examined the difference in weight-bearing knee kinematics in patients with mobile-bearing and fixed-bearing TKA performing step-up activities. We randomly assigned 40 knees (37 patients) to mobile-bearing TKA (n=20) or fixed-bearing TKA (n=20). Using fluoroscopic imaging we evaluated knee kinematics during step-up activity one year after surgery. The total extent of rotation was not different for the two TKAs. Due to the axial rotation of the polyethylene insert, patients with mobile-bearing TKA had a wider range of absolute axial rotation. The position of the medial and the lateral condyles was significantly more posterior in the fixed-bearing TKA. There were only minor kinematic differences between the two TKAs. The polyethylene insert in the mobile-bearing TKA moved as designed especially with respect to the self-alignment feature.

Angiopoietin-like protein 2 induced by mechanical stress accelerates degeneration and hypertrophy of the ligamentum flavum in lumbar spinal canal stenosis.

Chronic inflammation and subsequent fibrosis induced by mechanical stress play an important role in ligamentum flavum (LF) hypertrophy and degeneration in patients with lumbar spinal canal stenosis (LSCS). Angiopoietin-like protein 2 (Angptl2) is a chronic inflammatory mediator induced under various pathological conditions and increases the expression of TGF-ß1, which is a well-characterized mediator in LF hypertrophy. We investigated whether Angptl2 is induced by mechanical stress, and whether it contributes to LF hypertrophy and degeneration by activating the TGF-ß1 signaling cascade. In this study, we investigated human LF tissue and LF fibroblasts isolated from patients who underwent lumbar surgery. We found that Angptl2 was abundantly expressed in fibroblasts of hypertrophied LF tissues at both the mRNA and protein levels. This expression was not only positively correlated with LF thickness and degeneration but also positively correlated with lumbar segmental motion. Our in vitro experiments with fibroblasts from hypertrophied LF tissue revealed that mechanical stretching stress increases the expression and secretion of Angptl2 via activation of calcineurin/NFAT pathways. In hypertrophied LF tissue, expression of TGF-ß1 mRNA was also increased and TGF-ß1/Smad signaling was activated. Angptl2 expression in LF tissue was positively correlated with the expression of TGF-ß1 mRNA, suggesting cooperation between Angptl2 and TGF-ß1 in the pathogenesis of LF hypertrophy. In vitro experiments revealed that Angptl2 increased levels of TGF-ß1 and its receptors, and also activated TGF-ß1/Smad signaling. Mechanical stretching stress increased TGF-ß1 mRNA expression, which was partially attenuated by treatment with a calcineurin/NFAT inhibitor or Angptl2 siRNA, indicating that induction of TGF-ß1 expression by mechanical stretching stress is partially mediated by Angptl2. We conclude that expression of Angptl2 induced by mechanical stress in LF fibroblasts promotes LF tissue degeneration by activation of TGF-ß1/Smad signaling, which results in LF hypertrophy in patients with LSCS.

Effects of water-holding capability of the PVF sponge on the adhesion and differentiation of rat bone marrow stem cell culture.

The aim of the study is to estimate the effects of the water-holding capability of the polyvinyl formal (PVF) sponges on osteogenic response in vitro experiments. The rat bone marrow stem cells (BMCs) were seeded and cultured for up to 4 weeks under static conditions in osteogenic media to evaluate the adhesion, proliferation, differentiation, and mineralization on the Dextran-coated PVF sponges with or without water-holding capability. The BMCs seeded onto the PVF sponges with water-holding capability showed more significant increases in DNA content, alkaline phosphatase (ALP) activity, osteocalcin content, and calcium deposition than those without water-holding capability. These results suggest that the Dextran-coated PVF sponges with high water-holding capability would have potential uses as both a new scaffold to bone tissue engineering and as a new biomaterial.

Predictive value of E-PASS and POSSUM systems for postoperative risk assessment of spinal surgery.

OBJECT: The Estimation of Physiological Ability and Surgical Stress (E-PASS) and Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM) systems are surgical risk scoring systems that take into account both the patient's preoperative condition and intraoperative variables. While they predict postoperative morbidity and mortality rates for several types of surgery, spinal surgeries are currently not included. The authors assessed the usefulness of E-PASS and POSSUM algorithms and compared the predictive ability of both systems in patients with spinal disorders considered for surgery. METHODS: The E-PASS system includes a preoperative risk score, a surgical stress score, and a comprehensive risk score that is determined by both the preoperative risk score and surgical stress score. The POSSUM system is composed of a physiological score and an operative severity score; its total score is based on both the physiological score and operative severity score. The authors calculated the E-PASS and POSSUM scores for 601 consecutive patients who had undergone spinal surgery and investigated the relationship between the individual scores of both systems and the incidence of postoperative complications. They also assessed the correctness of the predicted morbidity rate of both systems. RESULTS: Postoperative complications developed in 64 patients (10.6%); there were no in-hospital deaths. All EPASS scores (p ≤ 0.001) and the operative severity score and total score of the POSSUM (p < 0.03) were significantly higher in patients with postoperative complications than in those without postoperative complications. The morbidity rates correlated linearly and significantly with all E-PASS scores (p ≤ 0.001); their coefficients (preoperative risk score, ρ = 0.179; surgical stress score, ρ = 0.131; and comprehensive risk score, ρ = 0.198) were higher than those for the POSSUM scores (physiological score, ρ = 0.059; operative severity score, ρ = 0.111; and total score, ρ = 0.091). The area under the receiver operating characteristic curve for the predicted morbidity rate was 0.668 for the E-PASS and 0.588 for the POSSUM system. CONCLUSIONS: As E-PASS predicted morbidity more correctly than POSSUM, it is useful for estimating the postoperative risk of patients considered for spinal surgery.

Detecting ICRS grade 1 cartilage lesions in anterior cruciate ligament injury using T1ρ and T2 mapping.

OBJECTIVE: The purpose of this study was to clarify the detectability of the International Cartilage Repair Society (ICRS) grade 1 cartilage lesions in anterior cruciate ligament (ACL)-injured knees using T1ρ and T2 mapping. MATERIALS AND METHODS: We performed preoperative T1ρ and T2 mapping and 3D gradient-echo with water-selective excitation (WATS) sequences on 37 subjects with ACL injuries. We determined the detectability on 3D WATS based on arthroscopic findings. The T1ρ and T2 values (ms) were measured in the regions of interest that were placed on the weight-bearing cartilage of the femoral condyle. The receiver operating characteristic (ROC) curve based on these values was constructed using the arthroscopic findings as a reference standard. The evaluation of cartilage was carried out only in the weight-bearing cartilage. The cut-off values for determining the presence of a cartilage injury were determined using each ROC curve, and the detectability was calculated for the T1ρ and T2 mapping. RESULTS: The cut-off values for the T1ρ and T2 were 41.6 and 41.2, respectively. The sensitivity and specificity of T1ρ were 91.2% and 89.5%, respectively, while those of T2 were 76.5% and 81.6%, respectively. For the 3D WATS images, the same values were 58.8% and 78.9%, respectively. CONCLUSIONS: Our study demonstrated that the T1ρ and T2 values were significantly higher for ICRS grade 1 cartilage lesions than for normal cartilage and that the two mappings were able to non-invasively detect ICRS grade 1 cartilage lesions in the ACL-injured knee with a higher detectability than were 3D WATS images.

Intracellular accumulation of advanced glycation end products induces apoptosis via endoplasmic reticulum stress in chondrocytes.

Mammalian cells attempt to maintain their homeostasis under endoplasmic reticulum (ER) stress. If the stress cannot be alleviated, cells are led to apoptosis through induction of C/EBP homologous protein (CHOP). ER stress is provoked in osteoarthritis chondrocytes, and intracellular accumulation of advanced glycation end products (AGEs) in chondrocytes is a possible cause. To clarify the role of intracellular AGE accumulation in chondrocytes, the present study investigated the effect of intracellular AGE accumulation on ER stress and apoptosis by in vitro and in vivo analysis. Intracellular AGE accumulation induced by AGE precursors caused apoptosis, induced expression of ER stress markers, and led to co-localization of AGEs with glucose-regulated protein 78, leading to formation of high-molecular-weight complexes in cultured chondrocytes. These reactions were inhibited by an AGE formation inhibitor. CHOP deletion inhibited apoptosis induced by intracellular AGE accumulation. In vivo intracellular AGE accumulation induced by intra-articular injection of AGE precursors caused ER stress and apoptosis in chondrocytes and led to degradation of articular cartilage. Additionally, intracellular AGE accumulation increased the degree of cartilage degradation in an osteoarthritis model. These data indicate that intracellular accumulation of AGEs induces modification of unfolded protein response-related protein by AGEs and apoptosis via ER stress in chondrocytes. Moreover, the in vivo study showed that intracellular AGE accumulation in chondrocytes is involved in the occurrence and progression of osteoarthritis through ER stress. Thus, research on mechanisms of apoptosis via ER stress induced by intracellular AGE accumulation in chondrocytes will lead to a new understanding of osteoarthritis pathology.

A reduced linezolid dosage maintains favorable efficacy with minimal hematologic toxicity in a methicillin-resistant Staphylococcus aureus-infected patient with renal insufficiency.

The optimal dosage of linezolid to avoid hematologic toxicity is unknown. We report the case of an 87-y-old woman with renal insufficiency who developed a surgical site infection with refractory methicillin-resistant Staphylococcus aureus. The standard dosage of linezolid (1200 mg daily) was not initially tolerated by the patient due to severe thrombocytopenia, but she was successfully treated when the dose was reduced by half (600 mg daily) based on a population pharmacokinetic-pharmacodynamic model. Appropriate dose adjustments can be made to optimize linezolid therapy especially in cases with preexisting renal dysfunction.

Indeterminacy in the WHO classification of tumors: an example of the histopathological diagnosis of brain tumors.

The WHO classifications of tumors are the global standards of tumor diagnosis. In spite of the detailed descriptions of the histopathological features of tumors in the classifications, tumors may be difficult to diagnose or the diagnosis can be improper. One of the reasons is that the diagnostic criteria have indeterminacy. In this article, we clarify this indeterminacy and discuss the diagnostic problems associated with indeterminacy. Indeterminacy of the histopathological features is classified according to the following three points: specificity, constancy, and exclusiveness. We consider an oblique (ambiguous description), variable (not always present), or duplicative feature as an indeterminate feature. Under indeterminacy, pathologists make their diagnosis on the basis of their experience and heuristic reasoning, which can lead to improper diagnosis. Not only the histopathological features, but also the diagnostic criterion, will have indeterminacy, which may be the direct influence of the indeterminacy of the features. Also, it is possible for there to be too many combinations of findings that satisfy a criterion, preventing an exhaustive description. The diagnostic criteria of the WHO classification have indeterminacy. Users should therefore verify their diagnosis. Further efforts by WHO editors to improve the diagnostic criteria also are desirable.

Synoviocyte-derived angiopoietin-like protein 2 contributes to synovial chronic inflammation in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by symmetrical polyarticular synovitis of the diarthrodial joints. Several proinflammatory cytokines derived from both infiltrating inflammatory cells and activated resident cells within the RA joint play a fundamental role in the processes that cause inflammation. However, anticytokine treatment is beneficial but not curative, the effects are only partial, and nonresponses are common. Therefore, an effort has been made to identify other key regulators of inflammation in articular structures to develop new therapies to suppress synovial inflammation and joint destruction in RA. Adipose tissue-derived angiopoietin-like protein 2 (Angptl2) activates an inflammatory cascade in endothelial cells and induces chemotaxis of monocytes/macrophages in obesity, resulting in initiation and propagation of inflammation within adipose tissues and obesity-related metabolic diseases. Angptl2 mRNA and protein are abundantly expressed in hyperplastic rheumatoid synovium of RA patients, especially in fibroblast-like and macrophage-like synoviocytes, but not in B and T lymphocytes. Angptl2 concentration in joints of RA patients was also significantly increased in comparison with patients with osteoarthritis, which in comparison with RA represents a significantly lower inflammatory grade form of arthritis. Notably, Angptl2 promoted increased chemotactic activities of CD14+CD16- monocytes from synovial fluid of RA patients. Therefore, Angptl2 acts as an important rheumatoid synovium-derived inflammatory mediator in RA pathogenesis.

[Case of bilateral pneumothorax observed during the administration of gefitinib for lung adenocarcinoma with multiple pulmonary metastases].

A 61-year-old woman who had never smoked was given a diagnosis of adenocarcinoma of the lung with multiple pulmonary metastases. Systemic chemotherapy consisting of carboplatin and paclitaxel was not effective, thereafter daily oral administration of gefitinib was initiated. Six days later, bilateral pneumothorax was found. The extent of the pneumothorax was slight and she recovered without drainage within about one month although treatment of gefitinib was restarted. Gefitinib was effective for lung cancer in this case. Bilateral pneumothorax is a rare complication of chemotherapy for lung cancer. Only 3 such cases under treatment with gefitinib were reported in Japan.

[A case of lung adenocarcinoma effectively treated with sivelestat and corcicosteroid for drug-induced lung disease due to gefitinib].

A 70-year-old Japanese man was re-admitted because of relapse of adenocarcinoma of the lung. He received daily administration of gefitinib as second-line chemotherapy. He was given a diagnosis of drug-induced lung disease due to gefitinib on day 6 because of hypoxemia and ground glass opacities in the bilateral lung fields. There was no response to corticosteroid pulse therapy. Continuous administration of sivelestat was intravenously added from day 9. Although mechanical ventilation was required for 10 days, lung infiltrates and hypoxia gradually improved. Sivelestat and corcicosteroid was apparently effective in this case and may be useful treatment for drug-induced lung disease due to gefitinib.

Regulated motion of glycoproteins revealed by direct visualization of a single cargo in the endoplasmic reticulum.

The quality of cargo proteins in the endoplasmic reticulum (ER) is affected by their motion during folding. To understand how the diffusion of secretory cargo proteins is regulated in the ER, we directly analyze the motion of a single cargo molecule using fluorescence imaging/fluctuation analyses. We find that the addition of two N-glycans onto the cargo dramatically alters their diffusion by transient binding to membrane components that are confined by hyperosmolarity. Via simultaneous observation of a single cargo and ER exit sites (ERESs), we could exclude ERESs as the binding sites. Remarkably, actin cytoskeleton was required for the transient binding. These results provide a molecular basis for hypertonicity-induced immobilization of cargo, which is dependent on glycosylation at multiple sites but not the completion of proper folding. We propose that diffusion of secretory glycoproteins in the ER lumen is controlled from the cytoplasm to reduce the chances of aggregation.