Macroscopic and multiple metastases in sentinel lymph node biopsy are respectively associated with poor prognosis in early oral cancer.

BACKGROUND: A multicenter, randomized controlled phase III trial was conducted on sentinel lymph node biopsy (SLNB) and elective neck dissection for T1 (depth of invasion ≥ 4 mm)-T2N0M0 oral cavity squamous cell carcinoma. This study identified factors associated with poor prognosis in patients who underwent SLNB based on a subgroup analysis of this trial. METHODS: We analyzed 418 sentinel lymph nodes (SLNs) from 132 patients who underwent SLNB. The metastatic SLNs were classified into three categories based on size-isolated tumor cells: < 0.2 mm, micrometastasis: ≥ 0.2 mm and < 2 mm, and macrometastasis: ≥ 2 mm. Three groups were formed based on the number of metastatic SLNs: no metastasis, 1 metastatic node, and ≥ 2 metastatic nodes. The size and number of metastatic SLNs on survival were evaluated using Cox proportional hazard models. RESULTS: Patients with macrometastasis and ≥ 2 metastatic SLNs had worse overall survival (OS) and disease-free survival (DFS) after adjustment for potential confounders (HR for OS: macrometastasis, 4.85; 95% CI 1.34-17.60; ≥ 2 metastatic SLN, 3.63; 95% CI 1.02-12.89; HR for DFS: macrometastasis, 2.94; 95% CI 1.16-7.44; ≥ 2 metastatic SLN, 2.97; 95% CI 1.18-7.51). CONCLUSIONS: In patients who underwent SLNB, a poorer prognosis was associated with macrometastasis or having ≥ 2 metastatic SLNs.

Comparison of the Efficacy and Renal Safety of Bisphosphonate Between Low-Dose/High-Frequency and High-Dose/Low-Frequency Regimens in a Late-Stage Chronic Kidney Disease Rat Model.

The efficacy and renal safety of low-dose/high-frequency (LDHF) dosing and high-dose/low-frequency (HDLF) dosing of bisphosphonates (BPs) are comparable in patients with normal kidney function but might be different in patients with late-stage chronic kidney disease (CKD). This study aimed to compare the efficacy and renal safety of two different dosage regimens of a BP, alendronate (ALN), in stage 4 CKD using a rat model. Male, 10-week-old Sprague-Dawley rats were subjected to either 5/6 nephrectomy or sham surgery. The animals received subcutaneous administration of vehicle (daily) or ALN in LDHF dosage regimen (LDHF-ALN: 0.05 mg/kg/day) or HDLF dosage regimen (HDLF-ALN: 0.70 mg/kg/2 weeks). Medications commenced at 20 weeks of age and continued for 10 weeks. Micro-computed tomography, histological analysis, infrared spectroscopic imaging, and serum and urine assays were performed to examine the efficacy and renal safety of the ALN regimens. Both LDHF-ALN and HDLF-ALN increased bone mass, improved micro-structure, and enhanced mechanical properties, without causing further renal impairment in CKD rats. Histologically, however, HDLF-ALN more efficiently suppressed bone turnover, leading to more mineralized trabecular bone, than LDHF-ALN in CKD rats, whereas such differences between LDHF-ALN and HDLF-ALN were not observed in sham rats. Both LDHF-ALN and HDLF-ALN showed therapeutic effects on high bone turnover osteoporosis in CKD stage 4 rats without causing further renal impairment. However, as HDLF-ALN more efficiently suppressed bone turnover than LDHF-ALN in late-stage CKD, HDLF-ALN might be more appropriate than LDHF-ALN for fracture prevention in high bone turnover osteoporosis patients with late-stage CKD.

Ten years change in post-fracture care for hip fracture patients.

INTRODUCTION: This multicenter, retrospective study aimed to clarify the changes in postoperative care provided by orthopaedic surgeons after hip fractures and clarify the incidence of secondary fractures requiring surgery. MATERIALS AND METHODS: Subjects were patients with hip fracture treated surgically in seven hospitals during the 10-year period from January 2008 to December 2017. Data on patient demographics, comorbidities, preoperative and postoperative osteoporosis treatments, and secondary fractures were collected from the medical records. RESULTS: In total, 4764 new hip fractures in 982 men and 3782 women (mean age: 81.3 ± 10.0 years) were identified. Approximately 10% of patients had a history of osteoporosis drug treatment and 35% of patients received postoperative drug treatment. The proportion of patients receiving postoperative drug therapy increased by approximately 10% between 2009 and 2010, 10% between 2010 and 2011, and 10% between 2011 and 2013. Although the rate of secondary fractures during the entire period and within 3 years decreased from 2011, the rate of secondary fracture within 1 year remained at around 2% every year. CONCLUSIONS: The approval of new osteoporosis drugs and the establishment of osteoporosis liaison services have had a positive effect on the use of postoperative drug therapy in the orthopedic field. Our finding that the rate of secondary fracture within 1 year of the initial fracture remained around 2% every year, despite improvements in postoperative drug therapy, suggests that both rehabilitation for preventing falls and early postoperative drug therapy are essential to prevent secondary fractures.

Potential association with early changes in serum calcium level after starting or switching to denosumab combined with eldecalcitol.

The aims of this study are to investigate changes in serum calcium (Ca) level after switching from either non-therapy, bisphosphonate, selective estrogen receptor modulators (SERM) or teriparatide treatments to a combination therapy of denosumab (DMAb), and eldecalcitol, and the association between early changes in serum calcium and changes in bone metabolic markers and bone mineral density (BMD). 129 patients with postmenopausal osteoporosis (32 non-pretreatment, 50 bisphosphonates, 18 SERM, and 29 teriparatide) were recruited and switched to DMAb plus eldecalcitol. Serum calcium levels, bone metabolism markers, and BMD measurements of the lumbar spine and femoral neck were evaluated. All groups showed an increase in BMD 6 months and 1 year after DMAb administration compared to baseline via suppression of bone metabolism markers. The TPD group showed a significant decrease in serum calcium level 1 week after the first injection of DMAb and eldecalcitol compared to baseline and the bisphosphonate group. Changes in serum calcium level from baseline to 1 week after the first injection of DMAb trended to correlate with changes in bone metabolism markers and lumbar BMD. The risks of DMAb-induced hypocalcemia are different between starting and switching from bone resorption inhibitors and bone formation promoters. Therefore, appropriate assessment before administration of DMAb, including pretreatment therapy as well as serum Ca and bone metabolic markers will help identify the risk of hypocalcemia following DMAb in combination with eldecalcitol. Our findings also showed that early change in serum Ca level after DMAb initiation could potentially predict the efficacy for therapy reaction.

Assessment of valgus laxity after release of the medial structure in medial open-wedge high tibial osteotomy: an in vivo biomechanical study using quantitative valgus stress radiography.

BACKGROUND: To perform medial open-wedge high tibial osteotomy (OWHTO), surgeons expose the medial-proximal tibia by releasing or cutting the superficial layer of the medial collateral ligament (sMCL). Biomechanically, the sMCL provides primary restraint against valgus forces. Therefore, any release of the sMCL can cause valgus instability of the knee joint. The purpose of this study was to assess valgus laxity after release of the medial structure of the knee during OWHTO. METHODS: Between 2009 and 2015, 84 consecutive patients (93 knees) who underwent OWHTO using a locking plate were enrolled in this study. All patients underwent radiological examinations before surgery, during surgery, 1 year after surgery, and after plate removal to objectively assess valgus laxity. The medial joint space (MJS) and the joint line convergence angle (JLCA) of the knee were evaluated using quantitative valgus stress radiography. Clinical evaluation was performed 2 years after surgery. RESULTS: The mean functional knee score improved significantly, from 65.5 to 91.1 points (p < 0.0001). The mechanical axis percentage shifted to pass through a point 69.7% lateral from the medial edge of the tibial plateau. The MJS and JLCA increased significantly during OWHTO surgery (11.0 mm, 7.4 °, p < 0.0001). However, no significant differences were noted in the MJS and JLCA among preoperative, 1-year postoperative periods and after plate removal. CONCLUSION: Valgus laxity was significantly greater after release of the sMCL. However, no significant differences were noted in valgus laxity in preoperative, 1-year postoperative periods and after plate removal. Complete release of the sMCL did not cause postoperative valgus laxity after OWHTO surgery. TRIAL REGISTRATION: Trial registration number: No.012-0360.

Identification of Galectin-2-Mucin Interaction and Possible Formation of a High Molecular Weight Lattice.

Galectins comprise a group of animal lectins characterized by their specificity for ß-galactosides. Galectin-2 (Gal-2) is predominantly expressed in the gastrointestinal tract and has been identified as one of the main gastric mucosal proteins that are proposed to have a protective role in the stomach. As Gal-2 is known to form homodimers in solution, this may result in crosslinking of macromolecules with the sugar structures recognized by Gal-2. In this study, we report that Gal-2 could interact with mucin, an important component of gastric mucosa, in a ß-galactoside-dependent manner. Furthermore, Gal-2 and mucin could form an insoluble precipitate, potentially through the crosslinking of mucins via Gal-2 and the formation of a lattice, resulting in a large insoluble complex. Therefore, we suggest that Gal-2 plays a role in the gastric mucosa by strengthening the barrier structure through crosslinking the mucins on the mucosal surface.

Reliability of telecommunications systems following a major disaster: survey of secondary and tertiary emergency institutions in Miyagi Prefecture during the acute phase of the 2011 Great East Japan Earthquake.

INTRODUCTION: Telecommunication systems are important for sharing information among health institutions to successfully provide medical response following disasters. HYPOTHESIS/PROBLEM: The aim of this study was to clarify the problems associated with telecommunication systems in the acute phase of the Great East Japan Earthquake (March 11, 2011). METHODS: All 72 of the secondary and tertiary emergency hospitals in Miyagi Prefecture were surveyed to evaluate the telecommunication systems in use during the 2011 Great Japan Earthquake, including satellite mobile phones, multi-channel access (MCA) wireless systems, mobile phones, Personal Handy-phone Systems (PHS), fixed-line phones, and the Internet. Hospitals were asked whether the telecommunication systems functioned correctly during the first four days after the earthquake, and, if not, to identify the cause of the malfunction. Each telecommunication system was considered to function correctly if the hospital staff could communicate at least once in every three calls. RESULTS: Valid responses were received from 53 hospitals (73.6%). Satellite mobile phones functioned correctly at the highest proportion of the equipped hospitals, 71.4%, even on Day 0. The MCA wireless system functioned correctly at the second highest proportion of the equipped hospitals. The systems functioned correctly at 72.0% on Day 0 and at 64.0% during Day 1 through Day 3. The main cause of malfunction of the MCA wireless systems was damage to the base station or communication lines (66.7%). Ordinary (personal or general communication systems) mobile phones did not function correctly at any hospital until Day 2, and PHS, fixed-line phones, and the Internet did not function correctly at any area hospitals that were severely damaged by the tsunami. Even in mildly damaged areas, these systems functioned correctly at <40% of the hospitals during the first three days. The main causes of malfunction were a lack of electricity (mobile phones, 25.6%; the Internet, 54.8%) and damage to the base stations or communication lines (the Internet, 38.1%; mobile phones, 56.4%). CONCLUSION: Results suggest that satellite mobile phones and MCA wireless systems are relatively reliable and ordinary systems are less reliable in the acute period of a major disaster. It is important to distribute reliable disaster communication equipment to hospitals and plan for situations in which hospital telecommunications systems do not function.

Involvement of Siglec-15 in regulating RAP1/RAC signaling in cytoskeletal remodeling in osteoclasts mediated by macrophage colony-stimulating factor.

DNAX-associated protein 12 kD size (DAP12) is a dominant immunoreceptor tyrosine-based activation motif (ITAM)-signaling adaptor that activates costimulatory signals essential for osteoclastogenesis. Although several DAP12-associated receptors (DARs) have been identified in osteoclasts, including triggering receptor expressed on myeloid cells 2 (TREM-2), C-type lectin member 5 A (CLEC5A), and sialic acid-binding Ig-like lectin (Siglec)-15, their precise role in the development of osteoclasts and bone remodeling remain poorly understood. In this study, mice deficient in Trem-2, Clec5a, Siglec-15 were generated. In addition, mice double deficient in these DAR genes and FcεRI gamma chain (FcR)γ, an alternative ITAM adaptor to DAP12, were generated. Bone mass analysis was conducted on all mice. Notably, Siglec-15 deficient mice and Siglec-15/FcRγ double deficient mice exhibited mild and severe osteopetrosis respectively. In contrast, other DAR deficient mice showed normal bone phenotype. Likewise, osteoclasts from Siglec-15 deficient mice failed to form an actin ring, suggesting that Siglec-15 promotes bone resorption principally by modulating the cytoskeletal organization of osteoclasts. Furthermore, biochemical analysis revealed that Sigelc-15 activates macrophage colony-stimulating factor (M-CSF)-induced Ras-associated protein-1 (RAP1)/Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway through formation of a complex with p130CAS and CrkII, leading to cytoskeletal remodeling of osteoclasts. Our data provide genetic and biochemical evidence that Siglec-15 facilitates M-CSF-induced cytoskeletal remodeling of the osteoclasts.

Phase I study of nedaplatin prior to S-1 in patients with locally advanced head and neck squamous cell carcinoma.

BACKGROUND: We previously reported on the regimen of S-1 plus nedaplatin (NDP), with S-1 was administered orally for 14 days and NDP intravenously on day 8. The maximum tolerated dose (MTD) of NDP was determined to be 90 mg/m². The main toxicities were neutropenia and thrombocytopenia. This result was tolerated, but we believe there is a more effective and tolerable regimen. Thus, we investigated the S-1 regimen administered orally for 14 days, and NDP intravenously on day 1 in patients with locally advanced head and neck squamous cell carcinoma. PATIENTS AND METHODS: Oral administration of S-1 (days 1-14) and intravenous NDP (day 1) were tested for patients with advance head and neck cancer in a phase I setting. The dose of S-1 was fixed and the dose of NDP was escalated from 70 mg/m², with an increase of 10 mg/m² per step, to find the MTD. RESULTS: A total of 15 patients were registered. The MTD of NDP was determined to be 100 mg/m². The main toxicities were neutropenia and thrombocytopenia. The response rate (RR) was 57.1%. CONCLUSIONS: The recommended dose of NDP for a phase II study was determined to be 100 mg/m². We concluded that our regimen was well tolerated and that the RR was acceptable.

Effects of Preserving Anatomically Positioned and Adequate Remnant ACL Tissue in Double-Bundle ACL Reconstruction.

Background: The advantages of remnant tissue preservation in anterior cruciate ligament (ACL) reconstruction (ACLR) remain controversial. Hypothesis: It was hypothesized that a large amount of remnant tissue, especially if anatomically positioned, would improve patient-reported outcomes and second-look graft appearance after preserved double-bundle ACLR (DB-ACLR). Study Design: Cohort study; Level of evidence, 3. Methods: This retrospective study included 89 consecutive patients who underwent unilateral remnant-preserving DB-ACLR using 2 hamstring tendon autografts. The authors categorized the arthroscopic findings into 3 groups according to the location and volume of the ACL remnant tissue in the femoral notch: (1) anatomical attachment (group AA; n = 34); (2) nonanatomical attachment (group NA; n = 33); and (3) no remnant (group NR; n = 22). Based on second-look arthroscopy, the reconstructed graft was graded as excellent, fair, or poor. Patient-reported outcomes were evaluated at 2 years after surgery using the Knee injury and Osteoarthritis Outcome Score (KOOS) and the Japanese Anterior Cruciate Ligament Questionnaire-25 (JACL-25). Results: The AA and NA groups had a significantly shorter time from injury to surgery compared with the NR group (P = .0165). Considering the second-look arthroscopic findings, the authors found a significant difference in synovial coverage of the grafts between the 3 groups (P = .0018). There were no significant differences in the overall KOOS and JACL-25 score among the 3 groups; however, the KOOS-Sport and Recreation and KOOS-Quality of Life subscale scores were significantly higher in the AA group compared with the NA and NR groups (P = .0014 and .0039, respectively). The JACL-25 score for middle- to high-speed flexion and extension was significantly better in the AA group versus the NR group (P = .0261). Conclusion: This study showed that preserving anatomically positioned and adequate remnant tissue during DB-ACLR improved second-look graft appearance and KOOS-Sport and Recreation and KOOS-Quality of Life scores.

Chromatin remodeling factor, INO80, inhibits PMAIP1 in renal tubular cells via exchange of histone variant H2A.Z. for H2A.

Epigenetic modifications such as DNA methylation, histone modifications, and chromatin structures in the kidney contribute towards the progression of chronic kidney disease (CKD). In this study, the role of chromatin remodeling factor inositol requiring 80 (INO80) was investigated. Although INO80 regulates transcription by altering the chromatin structure at the nucleosome level, its role in the kidney remains unknown. We demonstrated that the expression of INO80 in impaired kidneys decreased in rats with unilateral urethral obstruction. We investigated INO80 expression in a proximal tubular cell line and observed that its expression decreased under hypoxic condition. Additionally, INO80 knockdown promoted apoptosis, suggesting that INO80 plays a role in inhibiting tubular cell apoptosis. We identified downstream target genes of INO80 via genome-wide analysis using RNA-sequences and found that the expression of apoptosis-related genes, such as TP53 and E2F1, and pro-apoptotic genes, such as PMAIP1, increased upon INO80 knockdown. ChIP-qPCR of the loci of PMAIP1 showed that the amount of H2A.Z. increased instead of decreasing the amount of H2A when INO80 was knocked down. These results indicated that INO80 plays a role in the exchange of H2A.Z. for H2A in the promoter region of PMAIP1 in tubular cells to inhibit apoptosis during CKD progression.

Differential effects of anti-RANKL monoclonal antibody and zoledronic acid on necrotic bone in a murine model of Staphylococcus aureus-induced osteomyelitis.

Osteomyelitis is characterized by progressive inflammatory bone destruction accompanied by severe pain and disability. However, with the exception of antibiotic therapies, there is no established therapy to protect the bone from infectious osteolysis. The anti-receptor activator of nuclear factor-kB ligand (RANKL) monoclonal antibody (anti-RANKL Ab) is a potential drug based on its proven effectiveness in preventing joint bone erosion in rheumatoid arthritis; however, the efficacy and adverse effects of anti-RANKL Ab in osteomyelitis remain to be investigated. In this study, we investigated the effects of anti-mouse RANKL Ab on acute osteomyelitis and compared them with those of zoledronic acid (ZA) using a murine model. Mice were inoculated with bioluminescent Staphylococcus aureus (Xen 29) on their left femur and then treated with ZA, anti-RANKL Ab, or phosphate-buffered saline as control. A 21-day longitudinal observational study using microcomputed tomography showed that both anti-RANKL Ab and ZA had an osteoprotective effect against infectious osteolysis. However, it was also demonstrated through bioluminescence imaging that ZA delayed the spontaneous reduction of bacterial load and through histology that it increased the amount of necrotic bone, while anti-RANKL Ab did not. Findings from histopathological and in vitro studies suggest that an intense inflammatory response around the necrotic bone could induce osteoclasts in a RANKL-independent manner, leading to the removal of necrotic bone, even after administration of the anti-RANKL Ab therapy. Collectively, anti-RANKL Ab may exert an osteoprotective effect without hampering the removal of the necrotic bone, which serves as a nidus for infection in osteomyelitis.

No patella resurfacing total knee arthroplasty leads to reduction in the thickness of patellar cartilage to less than half within 5 years: a quantitative longitudinal evaluation using MRI.

PURPOSE: Patellar resurfacing in total knee arthroplasty (TKA) remains controversial as recent meta-analyses have not shown its clear superiority; however, most authors recommend it because it is associated with less frequent anterior knee pain and need for reoperation. We aimed to clarify the changes in patellar cartilage thickness in no patellar resurfacing TKA using a ceramic femoral component on magnetic resonance imaging (MRI). METHODS: Between 2009 and 2014, 40 consecutive patients (59 knees) were included in this study. All patients underwent TKA using zirconia ceramic femoral implants without patellar resurfacing. Indications for no patellar resurfacing TKA were absence of anterior knee pain, patellar compression pain, and osteoarthritic changes in the patellofemoral joint on plain radiography. The mean postoperative follow-up duration was 81.5 months (range, 25-131 months). Clinical and radiological evaluations were performed preoperatively and 5 years after TKA. Patellar cartilage thickness was evaluated preoperatively and every year for 5 years after TKA using MRI T2-weighted imaging. The patellar cartilage was divided into three regions of interest: medial, central, and lateral. To standardise the variation in patellar thickness among patients, the percent cartilage thickness was calculated. RESULTS: The implant's position was appropriate in all cases. Compared to preoperative scores, 5 years postoperatively, the Japanese Orthopedic Association score and Oxford knee score significantly improved from 52.1 to 84.7; mean tilting angle and congruence angle did not change significantly; mean lateral shift ratio significantly increased from 7.1% to 14.6%; cartilage thickness significantly decreased (P < 0.05); and the percentage cartilage thickness of the central, medial, and lateral cartilage zones gradually thinned to less than half. Four patients underwent conversion to patellar resurfacing due to anterior knee pain, without loosening the femoral and tibial implants. CONCLUSION: The patellar cartilage thickness decreased to less than half its preoperative level within 5 years after no patellar resurfacing TKA; this would led to clinical problems and conversion to patellar resurfacing. LEVEL OF EVIDENCE: Level III.

Siglec-15-targeting therapy protects against glucocorticoid-induced osteoporosis of growing skeleton in juvenile rats.

Effective treatment of juvenile osteoporosis, which is frequently caused by glucocorticoid (GC) therapy, has not been established due to limited data regarding the efficacy and adverse effects of antiresorptive therapies on the growing skeleton. We previously demonstrated that sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) targeting therapy, which interferes with osteoclast terminal differentiation in the secondary, but not primary, spongiosa, increased bone mass without adverse effects on skeletal growth, whereas bisphosphonate, a first-line treatment for osteoporosis, increased bone mass but impaired long bone growth in healthy growing rats. In the present study, we investigated the efficacy of anti-Siglec-15 neutralizing antibody (Ab) therapy against GC-induced osteoporosis in a growing rat model. GC decreased bone mass and deteriorated mechanical properties of bone, due to a disproportionate increase in bone resorption. Both anti-Siglec-15 Ab and alendronate (ALN) showed protective effects against GC-induced bone loss by suppressing bone resorption, which was more pronounced with anti-Siglec-15 Ab treatment, possibly due to a reduced negative impact on bone formation. ALN induced histological abnormalities in the growth plate and morphological abnormalities in the long bone metaphysis but did not cause significant growth retardation. Conversely, anti-Siglec-15 Ab did not show any negative impact on the growth plate and preserved normal osteoclast and chondroclast function at the primary spongiosa. Taken together, these results suggest that anti-Siglec-15 targeting therapy could be a safe and efficacious prophylactic therapy for GC-induced osteoporosis in juvenile patients.

Breast cancer cells expressing cancer-associated sialyl-Tn antigen have less capacity to develop osteolytic lesions in a mouse model of skeletal colonization.

Breast cancer is one of the most prevalent malignancies in women, and approximately 75-80% of patients with advanced breast cancer develop bone metastasis. Expression of the cancer-associated carbohydrate antigen sialyl-Tn (STn) in breast cancer is associated with a poor prognosis; however, involvement of STn in the development of metastatic bone lesions remains unclear. We investigated whether STn expression on breast cancer cells influences intraosseous tumor growth and bone response in mice models of skeletal colonization. STn-positive (STn+) breast cancer cells were generated by stable transfection of an expression vector encoding ST6GaLNAc I into the breast cancer cell line MDA-MB-231. Parental MDA-MB-231 cells not expressing STn antigen were used as STn-negative (STn-) breast cancer cells. Contrary to expectations, STn expression attenuated the development of destructive bone lesions in the in vivo mice models. An in vitro study demonstrated that STn expression impaired adhesion of MDA-MB-231cells to bone marrow stromal cells. This finding in vitro was also confirmed by another breast cancer cell line MCF-7. Cell adhesion to fibronectin and type I collagen was also impaired in STn+ MDA-MB-231 cells compared to that in STn- MDA-MB-231 cells, suggesting integrin dysfunction. Given that the integrin ß1 subunit is the main carrier of the STn epitope, it is likely that changes in glycan structure impaired the adhesive capacity of ß1 integrin in the bone environment, leading to attenuation of tumor cell engraftment. In conclusion, breast cancer cells expressing STn antigen had less capacity for skeletal colonization, possibly due to impaired adhesive capability.

Crystallinity-Dependent Thermoelectric Properties of a Two-Dimensional Coordination Polymer: Ni3(2,3,6,7,10,11-hexaiminotriphenylene)2.

The evaluation of thermoelectric properties has recently become a standard method for revealing the electronic properties of conducting polymers. Herein we report on the thermoelectric properties of a two-dimensional coordination polymer pellets. The pellets of Ni3(2,3,6,7,10,11-hexaiminotriphenylene)2, which has recently been developed, show n-type thermoelectric transport, dependent on crystallinity. The present results provide systematic feedback to the guideline for high-performance molecular thermoelectric materials.

Paraneoplastic limbic encephalitis associated with mixed olfactory neuroblastoma and craniopharyngioma: A case report and literature review.

RATIONALE: Paraneoplastic limbic encephalitis (PLE) is a rare disorder of the nervous system associated with malignant disease. It has a subacute onset with the following symptoms: cognitive dysfunction, seizures, irritability, hallucinations, and short-term memory loss. Herein, we report the case of a 35-year-old man with PLE, an olfactory neuroblastoma (ONB) admixed with craniopharyngioma, and serum anti-Hu antibodies. PATIENT CONCERNS: The patient presented with generalized seizures, short-term memory loss, and a polypoid mass located high in the nasal cavity. INTERVENTIONS: He underwent surgical resection of the tumor and postoperative chemoradiotherapy with concurrent intra-arterial cisplatin administration. DIAGNOSIS: Pathological examination indicated an ONB admixed with craniopharyngioma. OUTCOMES: The patient's neurological symptoms gradually diminished after surgery. No evidence of recurrence was observed during a 4-year follow-up. LESSONS: We reported a histologically unusual heterogeneous tumor that comprised ONB and craniopharyngioma. This is the first reported case of PLE with anti-Hu antibodies possibly associated with ONB admixed with craniopharyngioma.

Drug therapy targeting pyrophosphate slows the ossification of spinal ligaments in twy mice.

The lack of an effective drug therapy against ossification of spinal ligament (OSL) warrants investigation into the therapeutic target of this disease. An endogenous inhibitor of biomineralization, pyrophosphate (PPi) is a potential therapy for ectopic ossification; however, exogenous PPi is rapidly hydrolyzed by tissue non-specific alkaline phosphatase (TNAP) present in body fluids. In this study, we examined whether a drug therapy targeting PPi is efficacious for the treatment of OSL using the Enpp1ttw/ttw (twy) mouse model. Twenty male twy mice were randomized into four groups: (i) vehicle (Control); (ii) alkaline phosphatase inhibitor levamisole (5 mg/kg/day sc continuously); (iii) levamisole + exogenous PPi (160 µmol/kg/day sc continuously); and (iv) nuclear retinoic acid receptor-γ (RARγ) agonist (6 µg/kg sc daily). The RARγ agonist, which is a proven inhibitor of ectopic endochondral ossification, was used as a positive control. Treatments commenced when the mice were 5 weeks of age and continued for 4 weeks. Longitudinal micro-computed tomography and postmortem histological analysis were performed. Administration of levamisole alone and in combination with PPi increased serum PPi concentration by 17% and 52%, respectively, compared to that in vehicle-treated mice. The development of OSL in twy mice was suppressed by levamisole + PPi and RARγ agonist treatments, but not by levamisole alone. The levamisole + PPi therapy did not cause osteoporosis, whereas RARγ agonist-treated mice developed osteoporosis. Treatment of twy mice with levamisole in combination with exogenous PPi increased serum PPi level, which slowed the progression of OSL without producing adverse effect on bone. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1256-1261, 2018.

Siglec-15-targeting therapy increases bone mass in rats without impairing skeletal growth.

The treatment of juvenile osteoporosis has not been established due to a lack of data regarding the efficacy and adverse effects of therapeutic agents. The possible adverse effects of the long-term use of antiresorptive therapies on skeletal growth in children is of particular concern. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption, and its deficiency suppresses bone remodeling in the secondary spongiosa, but not in the primary spongiosa, due to a compensatory mechanism of osteoclastogenesis. This prompted us to develop an anti-Siglec-15 therapy for juvenile osteoporosis because most anti-resorptive drugs have potential adverse effects on skeletal growth. Using growing rats, we investigated the effects of an anti-Siglec-15 neutralizing antibody (Ab) on systemic bone metabolism and skeletal growth, comparing this drug to bisphosphonate, a first-line treatment for osteoporosis. Male 6-week-old F344/Jcl rats were randomized into six groups: control (PBS twice per week), anti-Siglec-15 Ab (0.25, 1, or 4 mg/kg every 3 weeks), and alendronate (ALN) (0.028 or 0.14 mg/kg twice per week). Treatment commenced at 6 weeks of age and continued for the next 6 weeks. Changes in bone mass, bone metabolism, bone strength, and skeletal growth during treatment were analyzed. Both anti-Siglec-15 therapy and ALN increased bone mass and the mechanical strength of both the femora and lumbar spines in a dose-dependent manner. Anti-Siglec-15 therapy did not have a significant effect on skeletal growth as evidenced by micro-CT-based measurements of femoral length and histology, whereas high-dose ALN resulted in growth retardation with histological abnormalities in the growth plates of femurs. This unique property of the anti-Siglec-15 Ab can probably be attributed to compensatory signaling for Siglec-15 inhibition in the primary spongiosa, but not in the secondary spongiosa. Thus, anti-Siglec-15 therapy could be a safe and effective for juvenile osteoporosis.

Association of Urinary Neutrophil Gelatinase-Associated Lipocalin With Long-Term Renal Outcomes in ICU Survivors: A Retrospective Observational Cohort Study.

BACKGROUND: Epidemiological studies recently suggested that acute kidney injury (AKI) in intensive care units (ICUs) increases the risk of chronic kidney disease development and progression. However, whether any AKI biomarker can predict long-term renal outcomes in ICU survivors remains unclear. This study was undertaken to elucidate the role of urinary biomarkers for long-term renal outcome prediction after ICU discharge. METHODS: This retrospective observational study examined 495 adult patients who had been admitted to the ICU of the University of Tokyo Hospital. Major adverse kidney events (MAKE): death, incident end-stage renal disease (ESRD), and halving of estimated glomerular filtration rate (eGFR), at hospital discharge and long-term renal outcomes of 30% reduction of eGFR or incident ESRD were evaluated. RESULTS: Among all the enrolled 495 patients, 393 patients were discharged from the hospital without MAKE. Data of eGFR up to two years after ICU discharge were available for 173 patients; 63 patients (36.4%) were positive for long-term renal outcomes. Step-wise logistic regression analysis demonstrated that male sex and urinary neutrophil gelatinase-associated lipocalin (NGAL) measured at ICU admission showed significant associations with long-term renal outcomes. Receiver operating characteristic curve analysis showed the area under the curve of 0.66 (95% confidence interval 0.57-0.74) for prediction of long-term renal outcome by urinary NGAL. CONCLUSION: Urinary NGAL measured at ICU admission was significantly associated with long-term renal outcomes after hospital discharge in MAKE-free ICU survivors. Urinary NGAL measurements at ICU might be useful to identify a high risk population of kidney disease progression after intensive care.