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Plasma levels of angiopoietin-2 are increased in patients with chronic kidney disease (CKD). Moreover, mouse models of progressive kidney disease also demonstrate increased angiopoietin-2 in both plasmas and kidneys. The role of dysregulated angiopoietins in the progression of kidney disease has not been thoroughly investigated. Here, we found in a cohort of 319 patients with CKD that plasma angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratios were positively associated with the development of kidney failure. In mice with progressive kidney disease induced by either ureteral obstruction or ischemia-reperfusion injury, overexpression of human angiopoietin-1 in the kidney tubules not only reduced macrophage infiltration in the initial stage post-injury but also attenuated endothelial cell apoptosis, microvascular rarefaction, and fibrosis in the advanced disease stage. Notably, angiopoietin-1 attenuated chemokine C-C motif ligand 2 (CCL2) expression in the endothelial cells of the fibrosing kidneys, and these protective effects led to attenuation of functional impairment. Mechanistically, angiopoietin-1 reduced CCL2-activated macrophage migration and protected endothelial cells against cell apoptosis induced by angiopoietin-2 and Wnt ligands. Based on this, we applied L1-10, an angiopoietin-2 inhibitor, to the mouse models of progressive kidney disease and found inhibitory effects on macrophage infiltration, microvascular rarefaction, and fibrosis. Thus, we defined the detrimental impact of increased angiopoietin-2 on kidney survival of patients with CKD which appears highlighted by angiopoietin-2 induced endothelial CCL2-activated macrophage infiltration and endothelial cell apoptosis in their kidneys undergoing fibrosis.

An elegant and precise method to fabricate asymmetrical structures and/or gradient structures was developed based on a vapor-phase sublimation and deposition process. The fabricated materials exhib...

Bottom–up approaches using building blocks of modules to fabricate scaffolds for tissue engineering applications have enabled the fabrication of structurally complex and multifunctional materials allowing for physical and chemical flexibility to better mimic the native extracellular matrix. Here we report a vapor-phased fabrication process for constructing three-dimensional modulated scaffold materials via simple steps based on controlling mass transport of vapor sublimation and deposition. We demonstrate the fabrication of scaffolds comprised of multiple biomolecules and living cells with built-in boundaries separating the distinct compartments containing defined biological configurations and functions. We show that the fabricated scaffolds have mass production potential. We demonstrate overall >80% cell viability of encapsulated cells and that modulated scaffolds exhibit enhanced cell proliferation, osteogenesis, and neurogenesis, which can be assembled into various geometric configurations. We perform cell co-culture experiments to show independent osteogenesis and angiogenesis activities from separate compartments in one scaffold construct., Current methods for the modular assembly of biomaterials are associated with limitations. Here the authors implement vapor-phase deposition to fabricate 3D polymeric materials that permit biomolecule functionalization, tunable mass transport and mechanical properties, as well as control over boundaries between compartments, and analyze the behavior of 3D encapsulated cells.

Background We developed a porous Ti alloy/PEEK composite interbody cage by utilizing the advantages of polyetheretherketone (PEEK) and titanium alloy (Ti alloy) in combination with additive manufacturing technology. Methods Porous Ti alloy/PEEK composite cages were manufactured using various controlled porosities. Anterior intervertebral lumbar fusion and posterior augmentation were performed at three vertebral levels on 20 female pigs. Each level was randomly implanted with one of the five cages that were tested: a commercialized pure PEEK cage, a Ti alloy/PEEK composite cage with nonporous Ti alloy endplates, and three composite cages with porosities of 40, 60, and 80%, respectively. Micro-computed tomography (CT), backscattered-electron SEM (BSE-SEM), and histological analyses were performed. Results Micro-CT and histological analyses revealed improved bone growth in high-porosity groups. Micro-CT and BSE-SEM demonstrated that structures with high porosities, especially 60 and 80%, facilitated more bone formation inside the implant but not outside the implant. Histological analysis also showed that bone formation was higher in Ti alloy groups than in the PEEK group. Conclusion The composite cage presents the biological advantages of Ti alloy porous endplates and the mechanical and radiographic advantages of the PEEK central core, which makes it suitable for use as a single implant for intervertebral fusion.

Background: We developed a porous Ti alloy/PEEK composite interbody cage by utilizing the advantages of polyetheretherketone (PEEK) and titanium alloy (Ti alloy) in combination with additive manufacturing technology. Methods: Porous Ti alloy/PEEK composite cages were manufactured using various controlled porosities. Anterior intervertebral lumbar fusion and posterior augmentation were performed at three vertebral levels on 20 female pigs. Each level was randomly implanted with one of the five cages that were tested: a commercialized pure PEEK cage, a Ti alloy/PEEK composite cage with nonporous Ti alloy endplates, and three composite cages with porosities of 40%, 60%, and 80%, respectively. Micro-computed tomography (CT), backscattered-electron SEM (BSE-SEM), and histological analyses were performed.Results: Micro-CT and histological analyses revealed improved bone growth in high-porosity groups. Micro-CT and BSE-SEM demonstrated that structures with high porosities, especially 60% and 80%, facilitated more bone formation inside the implant but not outside the implant. Histological analysis also showed that bone formation was higher in Ti alloy groups than in the PEEK group. Conclusion: The composite cage presents the biological advantages of Ti alloy porous endplates and the mechanical and radiographic advantages of the PEEK central core, which makes it suitable for use as a single implant for intervertebral fusion.

Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFβ1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFβ1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF., Pulmonary fibrosis is a major public health problem with unclear mechanism and limited therapeutic options. Here the authors show that a fibroblast-enriched endoplasmic reticulum protein, TXNDC5, promotes pulmonary fibrosis by stabilizing TGFBR1 and show the potential of TXNDC5 as a therapeutic target against pulmonary fibrosis.

Osteoarthritis (OA) is a chronic inflammatory and progressive joint disease that results in cartilage degradation and subchondral bone remodeling. The proinflammatory cytokine interleukin 1 beta (IL-1&beta, ) is abundantly expressed in OA and plays a crucial role in cartilage remodeling, although its role in the activity of chondrocytes in cartilage and subchondral remodeling remains unclear. In this study, stimulating chondrogenic ATDC5 cells with IL-1&beta, increased the levels of bone morphogenetic protein 2 (BMP-2), promoted articular cartilage degradation, and enhanced structural remodeling. Immunohistochemistry staining and microcomputed tomography imaging of the subchondral trabecular bone region in the experimental OA rat model revealed that the OA disease promotes levels of IL-1&beta, BMP-2, and matrix metalloproteinase 13 (MMP-13) expression in the articular cartilage and enhances subchondral bone remodeling. The intra-articular injection of Noggin protein (a BMP-2 inhibitor) attenuated subchondral bone remodeling and disease progression in OA rats. We also found that IL-1&beta, increased BMP-2 expression by activating the mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and specificity protein 1 (Sp1) signaling pathways. We conclude that IL-1&beta, promotes BMP-2 expression in chondrocytes via the MEK/ERK/Sp1 signaling pathways. The administration of Noggin protein reduces the expression of IL-1&beta, and BMP-2, which prevents cartilage degeneration and OA development.

The interference screw is a widely used fixation device in the anterior cruciate ligament (ACL) reconstruction surgeries. Despite the generally satisfactory results, problems of using interference screws were reported. By using additive manufacturing (AM) technology, we developed an innovative titanium alloy (Ti6 Al4 V) interference screw with rough surface and inter-connected porous structure designs to improve the bone-tendon fixation. An innovative Ti6 Al4 V interference screws were manufactured by AM technology. In vitro mechanical tests were performed to validate its mechanical properties. Twenty-seven New Zealand white rabbits were randomly divided into control and AM screw groups for biomechanical analyses and histological analysis at 4, 8, and 12 weeks postoperatively; while micro-CT analysis was performed at 12 weeks postoperatively. The biomechanical tests showed that the ultimate failure load in the AM interference screw group was significantly higher than that in the control group at all tested periods. These results were also compatible with the findings of micro-CT and histological analyses. In micro-CT analysis, the bone-screw gap was larger in the control group; while for the additive manufactured screw, the screw and bone growth was in close contact. In histological study, the bone-screw gaps were wider in the control group and were almost invisible in the AM screw group. The innovative AM interference screws with surface roughness and inter-connected porous architectures demonstrated better bone-tendon-implant integration, and resulted in stronger biomechanical characteristics when compared to traditional screws. These advantages can be transferred to future interference screw designs to improve their clinical performance. The AM interference screw could improve graft fixation and eventually result in better biomechanical performance of the bone-tendon-screw construct. The innovative AM interference screws can be transferred to future interference screw designs to improve the performance of implants. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2633-2640, 2018.

This study evaluated the biocompatibility and biological performance of novel additive-manufactured bioabsorbable iron-based porous suture anchors (iron_SAs). Two types of bioabsorbable iron_SAs, with double- and triple-helical structures (iron_SA_2_helix and iron_SA_3_helix, respectively), were compared with the synthetic polymer-based bioabsorbable suture anchor (polymer_SAs). An in vitro mechanical test, MTT assay, and scanning electron microscope (SEM) analysis were performed. An in vivo animal study was also performed. The three types of suture anchors were randomly implanted in the outer cortex of the lateral femoral condyle. The ultimate in vitro pullout strength of the iron_SA_3_helix group was significantly higher than the iron_SA_2_helix and polymer_SA groups. The MTT assay findings demonstrated no significant cytotoxicity, and the SEM analysis showed cells attachment on implant surface. The ultimate failure load of the iron_SA_3_helix group was significantly higher than that of the polymer_SA group. The micro-CT analysis indicated the iron_SA_3_helix group showed a higher bone volume fraction (BV/TV) after surgery. Moreover, both iron SAs underwent degradation with time. Iron_SAs with triple-helical threads and a porous structure demonstrated better mechanical strength and high biocompatibility after short-term implantation. The combined advantages of the mechanical superiority of the iron metal and the possibility of absorption after implantation make the iron_SA a suitable candidate for further development.

Long-term opioid therapy for chronic pain may lead to analgesic tolerance, especially when administered intrathecally, thus preventing adequate pain relief. Discovering drug targets to treat opioid tolerance using a mechanism-based approach targeting opioid-induced neuroinflammation provides new therapeutic opportunities. In this study, we provide translational evidence that CXCL12/CXCR4 signaling contributes to the pathogenesis of opioid tolerance.The CXCL12 levels in the cerebrospinal fluid of opioid-tolerant patients were compared with those of opioid-naive subjects. For further investigation, a rodent translational study was designed using 2 clinically relevant opioid delivery paradigms: daily intraperitoneal morphine injections and continuous intrathecal morphine infusion. We measured rats' tail flick responses and calculated the percentage of maximum possible effects (%MPE) to demonstrate opioid acute antinociception and the development of analgesic tolerance. The effects of exogenous CXCL12, CXCL12 neutralizing antibody, and receptor antagonist AMD3100 were investigated by intrathecal administration. Data were presented as mean ± SEM.CXCL12 was significantly upregulated in the cerebrospinal fluid of opioid-tolerant patients for 892 ± 34 pg/mL (n = 27) versus 755 ± 33 pg/mL (n = 10) in naive control subjects (P = .03). Furthermore, after 2 and 5 days of intrathecal morphine infusion, rat lumbar spinal cord dorsal horn CXCL12 messenger RNA levels were significantly upregulated by 3.2 ± 0.7 (P = .016) and 3.4 ± 0.3 (P = .003) fold, respectively. Results from the daily intraperitoneal morphine injection experiments revealed that administering an intrathecal infusion of CXCL12 for 24 hours before the first morphine injection did not decrease antinociception efficacy on day 1 but accelerated tolerance after day 2 (%MPE 49.5% vs 88.1%, P = .0003). In the intrathecal morphine coinfusion experiments, CXCL12 accelerated tolerance development (%MPE 9.4% vs 43.4% on day 1, P.0001), whereas coadministration with CXCL12 neutralizing antibody attenuated tolerance (72.5% vs 43.4% on day 1, P.0001; 47.6% vs 17.5% on day 2, P.0001). Coadministration of receptor antagonist AMD 3100 can persistently preserve morphine analgesic effects throughout the study period (27.9% ± 4.1% vs 0.9% ± 1.6% on day 5, P = .03).The CXCL12/CXCR4 pathway contributes to the pathogenesis of opioid tolerance. Our study indicates that intervening with CXCL12/CXCR4 signaling has therapeutic potential for opioid tolerance.

Objective: The aim of this retrospective observational study was to determine the efficacy of carbetocin in reducing blood loss and primary postpartum hemorrhage (PPH) in vaginal and cesarean deliveries in a tertiary hospital in Taiwan. Materials and methods: Eligible gravid women (27–41 weeks) with available data were categorized into those treated prophylactically with and without carbetocin. The primary outcome was blood loss and incidence of primary PPH as measured by intrapartum/intraoperative and postpartum (recovery room) blood loss. Results: A total of 1069 deliveries were evaluated. Maternal age (∼31 years of age), body mass index (∼27 kg/m2) and parity (∼1.4) were similar among those treated with and without carbetocin for both vaginal and cesarean deliveries. The majority [749/1069 (70.1%)] of deliveries were vaginal; a similar proportion of women undergoing vaginal [221/749 (29.5%)] and cesarean [110/320 (34.4%)] deliveries received prophylactic carbetocin for prevention of PPH. Among vaginal deliveries, there was no significant difference in intrapartum (p = 0.083) or postpartum (p = 0.925) blood loss, or incidence of PPH (p = 0.092) between women with versus without carbetocin prophylaxis. However, there was a significant reduction in the intraoperative and total blood loss among cesarean deliveries with versus without carbetocin prophylaxis (p

Objective: To examine the factors affecting pregnant women's decisions to accept or decline the prenatal pertussis (Tdap) vaccination in Taiwan. Materials and methods: We conducted a cross-sectional survey, recruiting pregnant women who had received prenatal care from eight maternity hospitals between January and December 2018. We examined the participants’ demographic characteristics, perceptions of pertussis disease risk and vaccination effectiveness, beliefs regarding vaccine information, physician recommendation, and other potential factors affecting decision-making regarding prenatal vaccination. Results: The complete survey response rate among eligible women was 78%. Among the participants, 74% accepted and 26% declined prenatal Tdap vaccination. Most women accepted Tdap during pregnancy because of perceived severity of pertussis in their infants, perceived effectiveness of the prenatal Tdap in preventing neonatal pertussis, and perceived safety of the prenatal Tdap vaccine for the fetus, as well as a provider's recommendation, which was the factor strongly associated with actual Tdap reception. Most of the participants who accepted Tdap vaccination during pregnancy and who believed that the Tdap vaccine could protect their infants from pertussis reported the receiving sufficient information to make an informed decision and trust in the information. By contrast, a large proportion of the participants who declined Tdap and who did not want to experience possible fetal side effects of Tdap reported not getting sufficient information to make an informed decision and a lack of trust in the information. Conclusion: Developing a comprehensive strategy involving government policy, the health care system, public media, health professionals, and pregnant women to launch a successful campaign may improve the nationwide acceptance of the prenatal pertussis vaccination. Keywords: Pertussis, Vaccine, Prenatal

This study presents a simple but high performance vector quantisation (VQ) codebook search algorithm for line spectral frequency quantisation in ITU-T G.729 speech codec, designated as the binary search space-structured VQ (BSS-VQ) algorithm. This is done through a combined use of a fast locating technique and lookup tables, such that an input vector, ahead of VQ encoding, is assigned efficiently to a subspace where merely a small number of codeword searches are required to be performed. As a consequence, the computational load is reduced remarkably. A trade-off can be made easy to meet a user's requirement when performing VQ encoding. It is experimentally validated that a search accuracy is well maintained at 99% approximately for a threshold of quantisation accuracy of 0.99. More importantly, with a full search algorithm as a benchmark for search load comparison, this proposal provides a 85% search load reduction, a figure far beyond 43% in multiple triangular inequality elimination approach, 47% in TIE with dynamic and intersection rules and 59% in quasi-binary search VQ algorithm.

Applied to analgebraic codebook search conducted on an algebraic code-excitedlinear-prediction (ACELP) speech coder, two improved versions of reducedcandidate mechanism (RCM), designated as Fixed-G1-RCM and Fixed-2Track-RCM, arepresented in this study for further search performance improvement. It ismainly derived from two major research findings in a piece of our prior work.The first finding is that a pulse with a high contribution in a track is morelikely to serve as the optimal pulse in the optimal vector pertaining to thetrack, and the second is that the speech quality can be well maintained at asearch accuracy above 50%. In this proposal, the trade off can be tuned betweenthe search accuracy and the search complexity so as to reach a nearlyconsistent speech quality. It is experimentally demonstrated that either Fixed-G1-RCM(N = 3), or Fixed-2Track-RCM (M = 2, N = 3, or M = 3, N = 4) can provide ahighly superior search performance relative to a global pulse replacementmethod (iteration = 2) and an iteration-freepulse replacement method.DOI: http://dx.doi.org/10.5755/j01.itc.44.4.9847

NC-8 (ent-16-oxobeyeran-19-N-methylureido) is an isosteviol-derived analogue with multiple biological effects, including anti-inflammation and anti-bacterial activities and inhibition of HBV viral surface antigen gene expression. In this study, we explored the effects of NC-8 on the formation of osteoclasts from RAW 264.7 cells. We found that NC-8 exerts the novel effect of inhibiting osteoclast-like cell formation. Our experiments showed that RANKL-induced ERK, p38, and JNK phosphorylation were inhibited by NC-8. An ovariectomy-induced osteoporosis animal model was used to examine the protective effects of oral treatment with NC-8. Serum analysis was used to examine markers of osteoblasts, osteoclasts, and renal and hepatic function in rats. Micro CT scanning and histological analysis were used to measure bone loss in ovariectomized rats. Oral administration of NC-8 effectively decreased excess bone resorption and significantly antagonized trabecular bone loss in ovariectomized rats. Serum analysis of C-terminal telopeptide of type-I collagen, an osteoclast marker, also showed that NC-8 administration inhibited excess bone resorption. Furthermore, serum analysis showed that renal and liver function were not affected by these doses of NC-8 during long-term treatment. Our results demonstrate that NC-8 inhibits osteoclast differentiation and effectively ameliorates ovariectomy-induced osteoporosis.

Background: Pulmonary sequestration is a rare disease whose development begins in the embryonic stage. Surgery is the definitive treatment for eliminating respiratory symptoms and preventing complications. Reports of uniportal video-assisted thoracoscopic surgery (VATS) lobectomy and segmentectomy for pulmonary sequestration are limited in the literature. This study analyzes the perioperative results of the uniportal approach and compared them with those of the multiportal approach for pulmonary sequestration. Methods: We collected a VATS series in a single institute from 2007 to 2017. Adult patients diagnosed with pulmonary sequestration and who had received surgical intervention were included. The use of uniportal VATS began from 2016. The perioperative outcomes for uniportal and multiportal approaches were compared. Results: A total of 19 patients (7 in the uniportal group and 12 in the multiportal group) were included. VATS segmentectomy was performed significantly more in the uniportal group (P=0.033). Shorter operative time, less intraoperative blood loss, shorter pleural drainage time, and shorter postoperative hospital stay were found for the uniportal group; however, the differences compared with the multiportal group were not significant. There was also no significant difference in perioperative parameters among patients who underwent wedge resection, segmentectomy and lobectomy, respectively. All patients were symptom-free in the follow-up. Conclusions: The perioperative results for a series of uniportal VATS anatomical resections for pulmonary sequestration were found to be better than those obtained with the multiportal approach. Although a challenging procedure, uniportal VATS segmentectomy can be performed safely for pulmonary sequestration to preserve more healthy pulmonary parenchyma.

As human beings live longer, age-related diseases such as osteoporosis will become more prevalent. Intolerant side effects and poor responses to current treatments are observed. Therefore, novel effective therapeutic agents are greatly needed. Here, pyrazole derivatives were designed and synthesized, and their osteoclastogenesis inhibitory effects both in vitro and in vivo were evaluated. The most promising compound 13 with a 2-(dimethylamino)ethyl group inhibited markedly in vitro osteoclastogenesis as well as the bone resorption activity of osteoclasts. Compound 13 affected osteoclast's early proliferation and differentiation more than later fusion and maturation stages. In ovariectomized (OVX) mice, compound 13 can inhibit the loss of trabecular bone volume, trabecular bone number, and trabecular thickness. Moreover, compound 13 can antagonize OVX-induced reduction of serum bone resorption marker and then compensatory increase of the bone formation marker. To sum up, compound 13 has high potential to be developed into a novel therapeutic agent for treating osteoporosis in the future.

Background: The pivotal role of glial activation and up-regulated inflammatory mediators in the opioid tolerance has been confirmed in rodents but not yet in humans. Here, the authors investigated the intraspinal cytokine and chemokine profiles of opioid-tolerant cancer patients; and to determine if up-regulated chemokines could modify opioid tolerance in rats. Methods: Cerebrospinal fluid samples from opioid-tolerant cancer patients and opioid-naive subjects were compared. The cerebrospinal fluid levels of tumor necrosis factor-alpha, CXCL1, CXCL10, CCL2, and CX3CL1 were assayed. The rat tail flick test was utilized to assess the effects of intrathecal CXCL1 on morphine-induced acute antinociception and analgesic tolerance. Results: CXCL1 level in cerebrospinal fluid was significantly up-regulated in the opioid-tolerant group (n = 30, 18.8 pg/ml vs. 13.2 pg/ml, P = 0.02) and was positively correlated (r2 = 0.49, P < 0.01) with opioid dosage. In rat experiment, after induction of tolerance by morphine infusion, the spinal cord CXCL1 messenger RNA was up-regulated to 32.5 ± 11.9-fold. Although CXCL1 infusion alone did not affect baseline tail-flick latency, the analgesic efficacy of a single intraperitoneal injection of morphine dropped significantly on day 1 to day 3 after intrathecal infusion of CXCL1. After establishing tolerance by intrathecal continuous infusion of morphine, its development was accelerated by coadministration of CXCL1 and attenuated by coadministration of CXCL1-neutralizing antibody or CXCR2 antagonist. Conclusions: CXCL1 is up-regulated in both opioid-tolerant patients and rodents. The onset and extent of opioid tolerance was affected by antagonizing intrathecal CXCL1/CXCR2 signaling. Therefore, the CXCL1/CXCR2 signal pathway may be a novel target for the treatment of opioid tolerance.

This study provides a method to mitigate the effect of packet loss and congestion for a real-time transport protocol (RTP) [1] for video streaming. The sequence number of the RTP [2] was used to detect packet loss such that retransmission [3] and flow control [4] [5] could be addressed. Retransmission ensures that an entire frame can be appropriately decoded. Users do not see the broken image, and do not waste bandwidth. Flow control addresses the rate of data transmission that is adjusted dependent on the available network bandwidth. Frames per second are reduced by low bandwidth, but an image can still be viewed appropriately, without a black screen or freeze-frame occurring.

BACKGROUND CONTEXT Several materials have been used to manufacture the cages, the most common being polyetheretherketone (PEEK) and titanium (Ti) alloy (Ti–6Al–4V). Each material has its advantages and disadvantages. PURPOSE The purpose is to utilize the advantages of each material in combination with additive manufacturing technology to develop a new porous Ti alloy/PEEK composite interbody cage. STUDY DESIGN/SETTING In vitro mechanical tests and cell biocompatibility study; in vivo posterior instrumented interbody fusion porcine model. PATIENT SAMPLE In vitro cell culture analysis for Porous Ti alloy/PEEK composite cages. In vivo animal study used 20 female pigs through an anterior intervertebral lumbar fusion and posterior pedicle screws augmentation. Each level was randomly implanted with one of five testing cages. OUTCOME MEASURES In vitro mechanical tests for shear strength of the interface layer. In vitro cell culture analysis for alkaline phosphatase (ALP) activity, ALP and osteocalcin mRNA expression for in vitro study. Micro–computed tomography (CT), back-scattered-electrons SEM (BSE-SEM) and histological analyses for in vivo study. METHODS In vitro and in vivo study compared 5 groups of cages. The first was a commercialized pure PEEK cage (group 1). The second was a Ti alloy/PEEK composite cage with nonporous Ti alloy end plates (group 2). The third, fourth, and fifth groups were composite cages with porosity of 40%, 60%, and 80% (groups 3, 4, and 5), respectively. Mechanical tests, alkaline phosphatase activity and mRNA expression, osteocalcin mRNA expression, SEM were performed for in vitro study. Micro–computed tomography (CT), back-scattered-electrons SEM (BSE-SEM) and histological analyses were performed for in vivo study. RESULTS The shear strength reached 33.4 MPa at the Ti alloy/PEEK interface. ALP activity and ALP mRNA expression were positively correlated with the porosity rate and peaked at 60% porosity. Micro-CT and BSE-SEM demonstrated that structures with high porosities, especially 60% and 80%, facilitated more bone formation inside the implant but not outside the implants. Histological analysis also showed that bone formation was better in Ti alloy groups than in the PEEK group. CONCLUSIONS In vitro cell culture showed higher porous structure exhibited superior bone growth. Micro-CT and histological analyses showed improved bone growth in high-porosity composite cage groups. Composite cage implant takes the biological advantages of Ti alloy porous end plates and the mechanical and radiographic advantages of PEEK central core to incorporate as a single implant suitable for intervertebral fusion. FDA DEVICE/DRUG STATUS Unavailable from authors at time of publication.

ObjectiveWe describe a prenatal molecular diagnosis of hypochondroplasia (HCH) in a pregnancy not at risk of HCH and review the literature on prenatal diagnosis of HCH.Case reportA 28-year-old primigravid woman was referred for genetic counseling at 30 weeks of gestation because of short-limbed dwarfism in the fetus. The woman had a body height of 152 cm. Her husband had a body height of 180 cm. Level II ultrasound showed a normal amount of amniotic fluid and a singleton fetus with fetal biometry equivalent to 30 weeks except for short limbs. Fetal biometry measurements were as follows: biparietal diameter = 7.38 cm (30 weeks); head circumference = 28.14 cm (30 weeks); abdominal circumference (AC) = 24.64 cm (30 weeks); femur length (FL) = 3.97 cm ( 0.18); humerus = 3.64 cm ( G, TAC > TGC transversion in exon 7 leading to a p.Tyr278Cys (Y278C) mutation in the FGFR3 protein. aCGH analysis revealed no genomic imbalance in cord blood. After delivery, the fetus had short limbs, a narrow thorax, brachydactyly, and relative macrocephaly. Cytogenetic analysis of cultured placental cells revealed a karyotype of 46,XX.ConclusionPrenatal diagnosis of abnormal ultrasound findings suspicious of ACH should include a differential diagnosis of HCH by molecular analysis of FGFR3.

Osteoarthritis (OA) is a degenerative joint disease involving a combination of cartilage degradation and inflammation. EGb761, a standardized extract of Ginkgo biloba leaves, holds an anti-inflammatory potency. Here, we determined whether EGb761 could inhibit lipopolysaccharide (LPS)- and IL-1β-induced inflammatory responses in human articular chondrocytes and apply the chondroprotection in OA rats. We found that LPS markedly induced the productions of PGE2 and NO and the protein expressions of COX-2 and iNOS in human chondrocytes. LPS was also seen to up-regulate the expressions of toll-like receptor-4 (TLR4), its downstream signal TNF receptor-associated factor 6 (TRAF6), and nuclear factor (NF)-κB signaling. These LPS-induced inflammatory responses were efficaciously reversed by EGb761 and its active components quercetin and kampferol. The similar results could be observed by using IL-1β as an in vitro model to mimic an inflammatory response. In an OA rat model, PGE2 and NO levels in blood, the histological alterations, and COX-2 and nitrotyrosine expressions in cartilages were markedly increased, which were effectively reversed by EGb761. Our results suggested that EGb761 exerts the anti-inflammatory effects on human articular chondrocytes and OA rats.

Dextromethorphan (DXM), a commonly used antitussive, is a dextrorotatory morphinan. Here, we report that DXM inhibits the receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and bone resorption by abrogating the activation of NF-κB signalling in vitro. Oral administration of DXM ameliorates ovariectomy (OVX)-induced osteoporosis in vivo. DXM was reported to possess anti-inflammatory properties through inhibition of the release of pro-inflammatory factors. However, the potential role and action mechanism of DXM on osteoclasts and osteoblasts remain unclear. In this study, in vitro and in vivo studies were performed to investigate the potential effects of DXM on osteoclastogenesis and OVX-induced bone loss. Osteoclastogenesis was examined by the TRAP staining, pit resorption, TNF-α release, and CCR2 and CALCR gene expression. Osteoblast differentiation was analyzed by calcium deposition. Osteogenic and adipogenic genes were measured by real-time PCR. Signaling pathways were explored using Western blot. ICR mice were used in an OVX-induced osteoporosis model. Tibiae were measured by µCT and serum markers were examined with ELISA kits. DXM inhibited RANKL-induced osteoclastogenesis. DXM mainly inhibited osteoclastogenesis via abrogation of IKK-IκBα-NF-κB pathways. However, a higher dosage of DXM antagonized the differentiation of osteoblasts via the inhibition of osteogenic signals and increase of adipogenic signals. Oral administration of DXM (20 mg/kg/day) partially reduced trabecular bone loss in ovariectomized mice. DXM inhibits osteoclast differentiation and activity by affecting NF-κB signaling. Therefore, DXM at suitable doses may have new therapeutic applications for the treatment of diseases associated with excessive osteoclastic activity.

Oncostatin M (OSM) belongs to IL-6 subfamily and is mostly produced by T lymphocytes. High levels of OSM are detected in the pannus of rheumatoid arthritis (RA) patients and it may arouse the inflammation responses in joints and eventually leads to bone erosion. Placenta growth factor (PLGF) is an angiogenic factor and highly homologous with vascular endothelial growth factor (VEGF). It has been recently reported that PLGF is highly expressed in synovial tissue and enhances the production of proinflammatory cytokines including TNF-α and IL-6. Here, we demonstrated that OSM increased mRNA and protein levels of PLGF in a time- and concentration-dependent manner in RA synovial fibroblasts. Inhibitors of JAK3 and PI3K antagonized OSM-induced production of PLGF. OSM enhanced the phosphorylation of Tyr705-STAT3, Ser727-STAT3, Ser473-Akt, and increased the nuclear translocation of phosphorylated STAT3 time-dependently. Transfection of dominant negative Akt or application of PI3K inhibitorLY294002 significantly inhibited p-Tyr705-STAT3, p-Ser727-STAT3, and PLGF expression, indicating that Akt is involved in JAK3/STAT3/PLGF signaling cascade. To further examine whether STAT3 binds to the promoter region of PLGF, Chip assay was used and it was found that OSM could bind with PLGF promoter, which was inhibited by JAK3 and PI3K inhibitors. Accumulation of PLGF in the pannus may contribute to the inflammation, angiogenesis and joints destruction in RA patients. These findings demonstrated the important role of OSM in the pathology network of RA and provided novel therapeutic drug targets for RA treatment.

Integrins are heterodimeric cell surface receptors that mediate cell-cell and cell-matrix interaction. The vitronectin and osteopontin receptor αvβ3 integrin has increased expression levels and is implicated in the adhesion, activation, and migration of osteoclasts on the bone surface as well as osteoclast polarization. αvβ3 integrin plays an important role in osteoclast differentiation and resorption. In addition, Arg-Gly-Asp (RGD)-containing peptides, small molecular inhibitors, and antibodies to αvβ3 integrin have been shown to inhibit bone resorption in vitro and in vivo. Here we examined the effects of a disintegrin HSA-ARLDDL a genetically modified mutant of rhodostomin conjugated with human serum albumin, which is highly selective of αvβ3, on RANKL-induced osteoclastogenesis and ovariectomy (OVX)-induced osteoporosis. In RANKL-induced osteoclastogenesis, HSA-ARLDDL significantly inhibited osteoclast formation, and IC50 was at nM range. Post-treatment HSA-ARLDDL also inhibits osteoclast formation. Furthermore, weekly administration of HSA-ARLDDL significantly inhibits the increase in serum bone resorption marker levels and decrease in cancellous bone loss in tibia and femur induced by OVX. On the other hand, HSA-ARLDDL did not affect the differentiation and calcium deposition of osteoblasts. These results indicate that the highly selective and long-acting αvβ3 integrin antagonists could be developed as effective drugs for postmenopausal osteoporosis.