Different changes in the biomarker C-terminal telopeptides of type II collagen (CTX-II) following intra-articular injection of high molecular weight hyaluronic acid and oral non-steroidal anti-inflammatory drugs in patients with knee osteoarthritis: a multi-center randomized controlled study.

OBJECTIVES: We previously reported, based on a multicenter randomized-control study, that the efficacy of intra-articular injections of hyaluronic acid (IA-HA) was not inferior to that of oral non-steroidal anti-inflammatory drugs (NSAIDs) in patients with knee osteoarthritis (OA). However, the molecular effects on the pathophysiology of knee OA remain unclear. C-terminal telopeptides of type II collagen (CTX-II) is reported to primarily originate from the interface between articular cartilage and subchondral bone, which is a site of potential remodeling in OA. We performed a predefined sub-analysis of the previous study to compare the changes of urinary CTX-II (uCTX-II) in response to IA-HA to those in response to NSAID for knee OA. DESIGN: A total of 200 knee OA patients were registered from 20 hospitals and randomized to receive IA-HA (2,700 kDa HA, 5 times at 1-week intervals) or NSAID (loxoprofen sodium, 180 mg/day) for 5 weeks. The uCTX-II levels were measured before and after treatment. RESULTS: The uCTX-II levels were significantly increased by IA-HA treatment (337.7 ± 193.8 to 370.7 ± 234.8 ng/µmol Cr) and were significantly reduced by NSAID treatment (423.2 ± 257.6 to 370.3 ± 250.9 ng/µmol Cr). The %changes of uCTX-II induced by IA-HA (11.6 ± 29.5%) and NSAID (-9.0 ± 26.7%) was significantly different (between-group difference: 20.6, 95% confidence intervals: 10.6 to 30.6). CONCLUSIONS: While both IA-HA and NSAID improved symptoms of knee OA, uCTX-II levels were increased by IA-HA and reduced by NSAIDs treatment, suggesting these treatments may improve symptoms of knee OA through different modes of action.

Epidemiology of long-stay patients in the pediatric intensive care unit: prevalence, characteristics, resource consumption and complications.

Background: The impact of pediatric intensive care unit (PICU) utilization and resource consumption among long-stay patients has not been characterized recently. This study aimed to describe the resource consumption and characteristics of long-stay patients in a PICU. Methods: This was a single-center descriptive cohort study of 1309 patients admitted to a PICU in 2017. The main outcome was ICU length of stay (LOS). Patients were divided into prolonged LOS (PLS) and non-PLS groups if they had an LOS of ≥ 28 or < 28 days, respectively. Two groups were compared to characterize PLS. Results: Thirty-two (2.4%) patients had a PLS and utilized 33% of PICU bed days. Factors associated with PLS with odds ratio [95% confidence interval (CI)] were being a neonate (7.8 [2.5-25.4], p = <0.001), being an infant (2.9 [1.0-9.0], p = 0.04), admission for a respiratory ailment (7.3 [1.6-44.2], p = 0.003), cardiovascular dysfunction (24.1 [4.8-152.1], p = <0.001), post-cardiac operation (8.0 [1.7-50.1], p = 0.003), post-cardiopulmonary arrest (22.8 [1.7-211.9], p = 0.01), and transfer from another facility (4.2 [1.8-10.7], p = 0.001). PLS patients developed more nosocomial infections and disproportionately received monitoring and therapeutic resources. Conclusions: A PLS was associated with substantial PICU utilization and complication rates. Future studies should aim to alleviate both institutional and patient-related issues in the affected population harboring possible risk factors for PLS.

The correlation of urinary podocytes and podocalyxin with histological features of lupus nephritis.

Objectives The objective of this study was to test the correlation of urinary podocyte number (U-Pod) and urinary podocalyxin levels (U-PCX) with histology of lupus nephritis. Methods This was an observational, cross-sectional study. Sixty-four patients were enrolled: 40 with lupus nephritis and 24 without lupus nephritis (12 lupus nephritis patients in complete remission and 12 systemic lupus erythematosus patients without lupus nephritis). Urine samples were collected before initiating treatment. U-Pod was determined by counting podocalyxin-positive cells, and U-PCX was measured by sandwich ELISA, normalized to urinary creatinine levels (U-Pod/Cr, U-PCX/Cr). Results Lupus nephritis patients showed significantly higher U-Pod/Cr and U-PCX/Cr compared with patients without lupus nephritis. U-Pod/Cr was high in proliferative lupus nephritis (class III±V/IV±V), especially in pure class IV (4.57 (2.02-16.75)), but low in pure class V (0.30 (0.00-0.71)). U-Pod/Cr showed a positive correlation with activity index ( r=0.50, P=0.0012) and was independently associated with cellular crescent formation. In contrast, U-PCX/Cr was high in both proliferative and membranous lupus nephritis. Receiver operating characteristic analysis revealed significant correlation of U-Pod/Cr with pure class IV, class IV±V and cellular crescent formation, and the combined values of U-Pod/Cr and U-PCX/Cr were shown to be associated with pure class V. Conclusions U-Pod/Cr and U-PCX/Cr correlate with histological features of lupus nephritis.

Proteasome inhibitors exert cytotoxicity and increase chemosensitivity via transcriptional repression of Notch1 in T-cell acute lymphoblastic leukemia.

The Notch signaling pathway has been recognized as a key factor for the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), because of the high incidence of activating mutations of Notch1. Notch inhibition could serve as a new treatment strategy for T-ALL; however, the attempts to perturb Notch signaling pathways have been unsuccessful so far. In this study, we found that proteasome inhibitors exert cytotoxic effects on T-ALL cells with constitutive activation of Notch1 to a similar extent as myeloma cells. The proteasome inhibitor bortezomib repressed the transcription of Notch1 and downstream effectors including Hes1, GATA3, RUNX3 and nuclear factor-κB (NF-κB) (p65 and p50), coincided with downregulation of the major transactivator Sp1 and its dissociation from Notch1 promoter. Overexpression of the Notch1 intracellular domain (NICD) significantly ameliorated bortezomib-induced cytotoxicity against T-ALL cells. Drug combination studies revealed that bortezomib showed synergistic or additive effects with key drugs for the treatment of T-ALL such as dexamethasone (DEX), doxorubicin and cyclophosphamide, which were readily abolished by NICD overexpression. The synergy of bortezomib and DEX was confirmed in vivo using a murine xenograft model. Our findings provide a molecular basis and rationale for the inclusion of proteasome inhibitors in treatment strategies for T-ALL.

The factors associated with pain severity in patients with knee osteoarthritis vary according to the radiographic disease severity: a cross-sectional study.

OBJECTIVES: Knee osteoarthritis (OA) pain is suggested to be associated with inflammation and detrimental mechanical loading across the joint. In this cross-sectional study, we simultaneously examined the inflammation and alignment of the lower limb and examined how the pain components varied depending on the disease progression. DESIGN: One-hundred sixty female medial type of early- [n = 74 in Kellgren-Lawrence (K/L) 2] to advanced-stage (n = 96 in K/L >2) knee OA subjects (70.5 years on average) were enrolled. Knee pain was evaluated using a pain visual analog scale (VAS) and the pain-related subcategory of the Japanese Knee Osteoarthritis Measure (JKOM-pain). The serum interleukin (sIL)-6 level reflecting synovitis, and the high sensitivity C-reactive protein (hs-CRP) level were measured to evaluate the severity of inflammation. The anatomical axis angle (AAA) was measured as an alignment index. The ß-coefficient was estimated after adjusting for age and the body mass index (BMI) using a multiple linear regression analysis. RESULTS: Multiple linear regression analyses showed that the sIL-6 levels, but not AAA, associated with the pain VAS [ß = 10.77 (95% confidence interval (CI): 4.14-17.40), P < 0.01] and JKOM-pain scores [ß = 3.19 (95% CI: 1.93-4.44), P < 0.001] in the early stage. Conversely, AAA, but not the sIL-6 levels, was found to be associated with the pain VAS [ß = -1.29 (95% CI: -2.51 to -0.08), P < 0.05] and JKOM-pain scores [ß = -0.49 (95% CI: -0.82 to -0.16), P < 0.01] in the advanced stage. CONCLUSIONS: The presence of a higher level of sIL-6 and the varus alignment of the joint is associated with pain in early- and advanced-stage knee OA patients, respectively.

Urinary podocalyxin is an early marker for podocyte injury in patients with diabetes: establishment of a highly sensitive ELISA to detect urinary podocalyxin.

AIMS/OBJECTIVE: Nephropathy, a major complication of diabetes, is the leading cause of end-stage renal disease. Recent studies have demonstrated that podocyte injury is involved in the onset of and progression to renal insufficiency. Here, we describe a novel, highly sensitive ELISA for detecting urinary podocalyxin, a glycoconjugate on the podocyte apical surface that indicates podocyte injury, particularly in the early phase of diabetic nephropathy. METHODS: Urine samples from patients with glomerular diseases (n = 142) and type 2 diabetes (n = 71) were used to quantify urinary podocalyxin by ELISA. Urine samples were obtained from 69 healthy controls for whom laboratory data were within normal values. Podocalyxin was detected in urine by immunofluorescence, immunoelectron microscopy and western blotting. RESULTS: Morphologically, urinary podocalyxin was present as a vesicular structure; western blotting showed it as a positive band at 165-170 kDa. Levels of urinary podocalyxin were elevated in patients with various glomerular diseases and patients with diabetes. In patients with diabetes, urinary podocalyxin was higher than the cut-off value in 53.8% patients at the normoalbuminuric stage, 64.7% at the microalbuminuric stage and 66.7% at the macroalbuminuric stage. Positive correlations were observed between urinary podocalyxin levels and HbA(1c), urinary ß(2) microglobulin, α(1) microglobulin and urinary N-acetyl-ß-D-glucosaminidase, although urinary podocalyxin levels were not correlated with other laboratory markers such as blood pressure, lipid level, serum creatinine, estimated GFR or proteinuria. CONCLUSIONS/INTERPRETATION: Urinary podocalyxin may be a useful biomarker for detecting early podocyte injury in patients with diabetes.

Oncogenic fusion E2A-HLF sensitizes t(17;19)-positive acute lymphoblastic leukemia to TRAIL-mediated apoptosis by upregulating the expression of death receptors.

t(17;19)-acute lymphoblastic leukemia (ALL) shows extremely poor prognosis. E2A-HLF derived from t(17;19) blocks apoptosis induced by the intrinsic mitochondrial pathway and has a central role in leukemogenesis and chemoresistance. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expressed on cytotoxic T cells and natural killer cells and binds with death receptors (DR4/DR5), inducing apoptosis by dual activation of intrinsic and extrinsic pathways, and TRAIL mediates the graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT). We found that cell lines and patients' samples of t(17;19)-ALL expressed death receptors for TRAIL, and recombinant soluble TRAIL immediately induced apoptosis into t(17;19)-ALL cell lines. E2A-HLF induced gene expression of DR4/DR5, which was dependent on the DNA-binding and transactivation activities of E2A-HLF through the 5' upstream region of the start site at least in the DR4 gene. Introduction of E2A-HLF into non-t(17;19)-ALL cell line upregulated DR4 and DR5 expression, and sensitized to proapoptotic activity of recombinant soluble TRAIL. Finally, a newly diagnosed t(17;19)-ALL patient underwent allo-SCT immediately after induction of first complete remission, and the patient has survived without relapse for over 3-1/2 years after allo-SCT. These findings suggest that E2A-HLF sensitizes t(17;19)-ALL to the GVL effect by upregulating death receptors for TRAIL.

[Surgical results of Konno and Ross procedures in children and Bentall and David procedures in adults].

The surgical management of complex aortic root lesions has developed over 3 decades both in pediatric and adults patients. To avoid permanent anticoagulation and prosthetic materials as much as possible, we had introduced Ross procedure as an alternative to Konno procedure in pediatric patients and David procedures in adults patients. We sought to evaluate the surgical results of Konno, Ross, Bentall and David procedures. The Konno procedure has excellent long term results and anticoagulation-related complication and endocarditis were major causes of re-operation. Ross procedure has excellent long term results, and autograft failure and right ventricular outflow tract (RVOT) obstruction were causes of re-opertion Bentall procedure is certainly effective and has excellent long term results. Pseudoaneurysmal formation in coronary reconstruction was a major cause of reoperation. David procedure is certainly an attractive option especially for young patients. Early result was satisfactory but durability of this operation should be reevaluated.

Combinatory effects of androgen receptor deficiency and hind limb unloading on bone.

Male sex hormones play a critical role in regulation of bone metabolism. In male mice lacking androgen receptor (AR), osteopenia and high turnover state in bone remodeling have been reported. However, androgen receptor's role in disuse-induced osteopenia is not known. Therefore, we examined the effects of AR deficiency on unloading-induced bone loss. Wild type or androgen receptor deficient mice (ARKO) were subjected to hind limb unloading (HU) or normal housing (Control). The groups of mice were as follows; wild type control mice (Group WT-Cont), ARKO control mice (Group ARKO-Cont), wild type HU mice (Group WT-HU), and ARKO-HU mice (Group ARKO-HU). HU reduced cancellous bone mass in ARKO (ARKO-HU) by about 70% compared to ARKO-Cont and this reduction rate was over two-fold more than that of wild type (WT-HU) (reduction by less than 30% compared to WT-Cont). Combination of ARKO and HU (ARKO-HU) resulted in the least levels of cortical bone mass and bone mineral density among the four groups. ARKO-HU group indicated the highest levels of systemic bone resorption marker, deoxypyridinoline. Osteoclast development levels in the cultures in ARKO-HU derived bone marrow cells were the highest among the four groups. These data suggest that combination of androgen receptor deficiency and hind limb unloading results in exacerbation of disuse-induced osteopenia due to the enhanced levels of bone resorption.

[Ross procedure with aortic replacement for aortic stenosis with ascending aortic aneurysm: report of a case].

Bicuspid aortic valve (BAV) is a common congenital heart disease, and it is well known to be a risk factor for ascending aortic dilatation and dissection. We here report a case of 34-year-old woman who underwent Ross procedure with ascending aortic replacement under the diagnosis of subaortic stenosis and ascending aortic aneurysm. She was pointed out to have heart murmur soon after the birth diagnosed as patent ductus arteriosus. The ductus was ligated when she was 3-years-old, however, heart murmur remained. Further examinations revealed that she also had aortic stenosis with BAV. During her 20-year-follow-up, subaortic stenosis and ascending aorta ectasia were also progressed. Pathological examinations of resected ascending aortic wall showed mucoid degeneration and laceration of collagen fibers, suggesting the fragility of dilated aortic wall with BAV.

Involvement of TWEAK/Fn14 interaction in the synovial inflammation of RA.

OBJECTIVE: TWEAK, TNF-like weak inducer of apoptosis, induces not only apoptosis of some tumour cells, but also proliferation of endothelial cells, and angiogenesis. It is known that TWEAK induces production of cytokines that are involved in the pathogenesis of RA. However, it is not clear how TWEAK takes part in the synovitis of RA. In this study, we investigated the role of TWEAK/fibroblast growth factor-inducible 14 (Fn14) interaction in the synovitis of RA. METHODS: TWEAK and Fn14 expression on RA and OA synovial cells (SCs) were analysed by FACS. Synovial fibroblasts (SFs) or freshly isolated SCs were cultured in the presence or absence of recombinant TWEAK (rTWEAK) and anti-TWEAK or anti-Fn14 mAbs. Cell proliferation, cytokine/chemokine production and intercellular adhesion molecule (ICAM-1) expression were measured by WST-8 [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)-2H-tetrazolium monosodium salt], ELISA and FACS, respectively. RESULTS: TWEAK expression was detected on CD45-positive population in RA synovium, whereas Fn14 was detected on both CD45-positive and CD45-negative populations. Cultured RA and OA SFs showed higher proliferation and produced IL-6, IL-8 and MCP-1 in response to rTWEAK. Cell proliferation and cytokine production of freshly isolated SCs from RA patients were suppressed by anti-TWEAK and anti-Fn14 mAbs. ICAM-1 expression on RA, but not OA, SFs was up-regulated by rTWEAK. CONCLUSIONS: These data suggest that TWEAK/Fn14 interaction plays a substantial role in the synovitis of RA, by directly inducing the proliferation of SFs, and by up-regulating the production of inflammatory cytokines/chemokines as well as the expression of ICAM-1.

Evaluation of the suppressive actions of glucosamine on the interleukin-1beta-mediated activation of synoviocytes.

OBJECTIVE: Recently, we found that administration of glucosamine to adjuvant arthritis, a model for rheumatoid arthritis, suppressed the progression of arthritis in rats. To clarify its anti-inflammatory mechanism, we evaluated the actions of glucosamine on the activation of synoviocytes in vitro. MATERIALS AND METHODS: Synoviocytes isolated from human synovial tissues were stimulated with interleukin (IL)-1beta in the presence of 0.01-1 mM glucosamine. IL-8 and prostaglandin (PG) E(2) were measured by ELISA, and nitric oxide was quantitated by Griess assay. IL-8 mRNA was detected by RT-PCR. Furthermore, the effect of glucosamine on the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and the binding of [(125)I] IL-1beta to its receptors were examined using a primary human synovial cell line (CSABI- 479). RESULTS: Glucosamine significantly suppressed the IL-1beta-induced IL-8 production as well as its mRNA expression (p < 0.05) at 1 mM. Furthermore, glucosamine (1 mM) inhibited the IL-1beta-induced nitric oxide and PGE(2) production (p < 0.05). Moreover, glucosamine suppressed the IL-1beta-induced phosphorylation of p38 MAPK (p < 0.05 at >0.1 mM) and the IL-1beta-binding to its receptors (p < 0.05 at 1 mM). CONCLUSIONS: These observations suggest that glucosamine can suppress the IL-1beta-mediated activation of synoviocytes (such as IL-8-, nitric oxide- and PGE(2)-production, and phosphorylation of p38 MAPK), thereby possibly exhibiting antiinflammatory actions in arthritis.

[Dissection of descending aorta with spinal paralysis].

A 56-year-old man had undergone ascending aorta and total arch replacement because of aortic dissection (Stanford type A) in 1997. He had onset of diplegia of the lower limb and vesicorectal disability. Computed tomography (CT) showed serpentine aneurysm in the descending aorta, it was seen between the left subclavian artery and diaphragm level. It was 80 mm of maximum diameter. Magnetic resonance imaging (MRI) was performed for identified Adamkiewicz artery, but we could not identify it. We performed a graft replacement. The 8th intercostal artery was reconstructed with a branch graft. The postoperative course was uneventful. We conclude that graft replacement for spinal ischemia can be effective.

Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19.

Hypercalcemia is relatively rare but clinically important complication in childhood leukemic patients. To clarify the clinical characteristics, mechanisms of hypercalcemia, response to management for hypercalcemia, incidence of t(17;19) and final outcome of childhood acute lymphoblastic leukemia (ALL) accompanied by hypercalcemia, clinical data of 22 cases of childhood ALL accompanied by hypercalcemia (>12 mg/dl) reported in Japan from 1990 to 2005 were retrospectively analyzed. Eleven patients were 10 years and older. Twenty patients had low white blood cell count (<20 x 10(9)/l), 15 showed hemoglobin> or =8 g/dl and 14 showed platelet count > or =100 x 10(9)/l. Parathyroid hormone-related peptide (PTHrP)-mediated hypercalcemia was confirmed in 11 of the 16 patients in whom elevated-serum level or positive immunohistochemistry of PTHrP was observed. Hypercalcemia and accompanying renal insufficiency resolved quickly, particularly in patients treated with bisphosphonate. t(17;19) or add(19)(p13) was detected in five patients among 17 patients in whom karyotypic data were available, and the presence of E2A-HLF was confirmed in these five patients. All five patients with t(17;19)-ALL relapsed very early. Excluding the t(17;19)-ALL patients, the final outcome of ALL accompanied by hypercalcemia was similar to that of all childhood ALL patients, indicating that the development of hypercalcemia itself is not a poor prognostic factor.

[Mitral valvuloplasty utilizing a posterior leaflet patch for healed infective endocarditis; report of a case].

A 63-year-old man was diagnosed as having grade IV mitral regurgitation (MR). Intraoperative examination revealed perforation (13x7 mm) of the anterior mitral leaflet (AML) and prolapse of the posterior mitral leaflet (PML). The prolapsing part of the PML was resected as a rectangle and the AML perforation was covered with this resected PML patch. A Carpentier-Edwards rigid ring (30 mm) was used to secure the mitral valve annulus after suturing the PML. The patient had an uneventful course after surgery and postoperative echocardiography showed no regurgitation.

[Modified Komeda-David operation for postinfarction ventricular septal perforation].

The infarct exclusion technique with a xeno-pericardial patch which Komeda and associates firstly reported in 1990 is one of the best procedure to close ventricular septal perforation. A large patch can protect the perforation and the surrounding weak tissue from the internal left ventricular pressure. However, suturing this large patch to the left ventricular wall through the small incision is not technically easy because of the patch design in the ventricle. We modified the design of the patch. This round shaped bovine pericardial patch was sutured continuously to the left ventricular wall. Then, excessive part of the patch was trimmed to make a corn shape. Finally, the corn shaped patch fit the left ventricular wall naturally.

[Mitral regurgitation due to sole punched out lesion of the mitral anterior leaflet in infective endocarditis; report of a case].

Mitral regurgitation (MR) due to only punched out lesion is extremely rare in infective endocarditis. A 31-year-old male was admitted to our hospital due to unusual cause of MR. Echocardiography showed MR due to punched out lesion of the mitral anterior leaflet, which is extremely rare. A round shape punched out lesion (about 16 mm in size) was found intraoperatively in the anterior leaflet of the mitral valve. The surface around the punched out lesion was smooth, and the leaflet displayed good movability. Neither vegetation nor calcification was found. Punched out lesion was successfully closed with autologous pericardial patch and annuloplasty was performed.