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Round trip signal latency, or time delay, is an unavoidable constraint that currently stands as a major barrier to safe and efficient remote telesurgery. While there have been significant technological advancements aimed at reducing the time delay, studies evaluating methods of mitigating the negative effects of time delay are needed. Herein, we explored instrument motion scaling as a method to improve performance in time-delayed robotic surgery. This was a robotic surgery user study using the da Vinci Research Kit system. A ring transfer task was performed under normal circumstances (no added time delay), and with 250 ms, 500 ms, and 750 ms delay. Robotic instrument motion scaling was modulated across a range of values (− 0.15, − 0.1, 0, + 0.1, + 0.15), with negative values indicating less instrument displacement for a given amount of operator movement. The primary outcomes were task completion time and total errors. Three-dimensional instrument movement was compared against different motion scales using dynamic time warping to demonstrate the effects of scaling. Performance declined with increasing time delay. Statistically significant increases in task time and number of errors were seen at 500 ms and 750 ms delay (p

Introduction: Clinical studies of intra-articular injection of mesenchymal stem cells for osteoarthritis (OA) indicate its efficacy. Here, we retrospectively investigated the associations of pretherapeutic magnetic resonance imaging (MRI) findings with the clinical outcomes up to 6 months, after intra-articular administration of adipose-derived stem cells (ASCs) to knee OA patients. Methods: We first analyzed alterations of the visual analog scale (VAS) and knee injury and osteoarthritis outcome score (KOOS) in 57 knees of 34 patients from whom clinical scores were obtained before ASC therapy, and at 1, 3, and 6 months. Among the patients, we further examined MRI findings of 34 knees of 19 patients whose pretherapeutic MRI data were available. Results: The mean improvement of VAS and KOOS-total during 6 months was 2.6 ± 4.0 (from 6.1 ± 2.5 to 3.5 ± 2.9, P

Introduction: Paraesophageal hernias readily affect the elderly with a median age of presentation between 65 and 75 years. Laparoscopic paraesophageal hernia repair (PEHR) is a technically challeng...

Round trip signal latency, or time delay, is an unavoidable constraint that currently stands as a major barrier to safe and efficient remote telesurgery. While there have been significant technological advancements aimed at reducing the time delay, studies evaluating methods of mitigating the negative effects of time delay are needed. Herein, we explored instrument motion scaling as a method to improve performance in time-delayed robotic surgery.This was a robotic surgery user study using the da Vinci Research Kit system. A ring transfer task was performed under normal circumstances (no added time delay), and with 250 ms, 500 ms, and 750 ms delay. Robotic instrument motion scaling was modulated across a range of values (- 0.15, - 0.1, 0, + 0.1, + 0.15), with negative values indicating less instrument displacement for a given amount of operator movement. The primary outcomes were task completion time and total errors. Three-dimensional instrument movement was compared against different motion scales using dynamic time warping to demonstrate the effects of scaling.Performance declined with increasing time delay. Statistically significant increases in task time and number of errors were seen at 500 ms and 750 ms delay (p 0.05). Total errors were positively correlated with task time on linear regression (R = 0.79, p 0.001). Under 750 ms delay, negative instrument motion scaling improved error rates. Negative motion scaling trended toward improving task times toward those seen in non-delayed scenarios. Improvements in instrument path motion were seen with the implementation of negative motion scaling.Under time-delayed conditions, negative robotic instrument motion scaling yielded fewer surgical errors with slight improvement in task time. Motion scaling is a promising method of improving the safety and efficiency of time-delayed robotic surgery and warrants further investigation.

Osteoarthritis (OA), the most common aging-related joint disease, is caused by an imbalance between extracellular matrix synthesis and degradation. Here, we discover that both strands of microRNA-455 (miR-455), -5p and -3p, are up-regulated by Sox9, an essential transcription factor for cartilage differentiation and function. Both miR-455-5p and -3p are highly expressed in human chondrocytes from normal articular cartilage and in mouse primary chondrocytes. We generate miR-455 knockout mice, and find that cartilage degeneration mimicking OA and elevated expression of cartilage degeneration-related genes are observed at 6-months-old. Using a cell-based miRNA target screening system, we identify hypoxia-inducible factor-2α (HIF-2α), a catabolic factor for cartilage homeostasis, as a direct target of both miR-455-5p and -3p. In addition, overexpression of both miR-455-5p and -3p protect cartilage degeneration in a mouse OA model, demonstrating their potential therapeutic value. Furthermore, knockdown of HIF-2α in 6-month-old miR-455 knockout cartilage rescues the elevated expression of cartilage degeneration-related genes. These data demonstrate that both strands of a miRNA target the same gene to regulate articular cartilage homeostasis., Osteoarthritis is caused by an imbalance between extracellular matrix synthesis and degradation. Here, the authors show that both strands of microRNA-455, -5p and -3p, target HIF2α and regulate cartilage homeostasis, and show that overexpression of these miRNAs is protective against osteoarthritis in mice.

Summary Deposition of amyloid is a common aging-associated phenomenon in several aging-related diseases. Osteoarthritis (OA) is the most prevalent joint disease, and aging is its major risk factor. Transthyretin (TTR) is an amyloidogenic protein that is deposited in aging and OA-affected human cartilage and promotes inflammatory and catabolic responses in cultured chondrocytes. Here, we investigated the role of TTR in vivo using transgenic mice overexpressing wild-type human TTR (hTTR-TG). Although TTR protein was detected in cartilage in hTTR-TG mice, the TTR transgene was highly overexpressed in liver, but not in chondrocytes. OA was surgically induced by destabilizing the medial meniscus (DMM) in hTTR-TG mice, wild-type mice of the same strain (WT), and mice lacking endogenous Ttr genes. In the DMM model, both cartilage and synovitis histological scores were significantly increased in hTTR-TG mice. Further, spontaneous degradation and OA-like changes in cartilage and synovium developed in 18-month-old hTTR mice. Expression of cartilage catabolic (Adamts4, Mmp13) and inflammatory genes (Nos2, Il6) was significantly elevated in cartilage from 6-month-old hTTR-TG mice compared with WT mice as was the level of phospho-NF-κB p65. Intra-articular injection of aggregated TTR in WT mice increased synovitis and significantly increased expression of inflammatory genes in synovium. These findings are the first to show that TTR deposition increases disease severity in the murine DMM and aging model of OA.

Objective Regulated in development and DNA damage response 1 (REDD1) is an endogenous inhibitor of mechanistic target of rapamycin (mTOR) that regulates cellular stress responses. REDD1 expression is decreased in aged and osteoarthritic (OA) cartilage, and it regulates mTOR signaling and autophagy in articular chondrocytes in vitro. This study was undertaken to investigate the effects of REDD1 deletion in vivo using a mouse model of experimental OA. Methods OA severity was histologically assessed in 4-month-old wild-type and REDD1−/− mice subjected to surgical destabilization of the medial meniscus (DMM). Chondrocyte autophagy, apoptosis, mitochondrial content, and expression of mitochondrial biogenesis markers were determined in cartilage and cultured chondrocytes from wild-type and REDD1−/− mice. Results REDD1 deficiency increased the severity of changes in cartilage, menisci, subchondral bone, and synovium in the DMM model of OA. Chondrocyte death was increased in the cartilage of REDD1−/− mice and in cultured REDD1−/− mouse chondrocytes under oxidative stress conditions. Expression of key autophagy markers (microtubule-associated protein 1A/1B light chain 3 and autophagy protein 5) was markedly reduced in cartilage from REDD1−/− mice and in cultured human and mouse chondrocytes with REDD1 depletion. Mitochondrial content, ATP levels, and expression of the mitochondrial biogenesis markers peroxisome proliferator–activated receptor γ coactivator 1α (PGC-1α) and transcription factor A, mitochondrial (TFAM) were also decreased in REDD1-deficient chondrocytes. REDD1 was required for AMP-activated protein kinase–induced PGC-1α in chondrocytes. Conclusion Our findings suggest that REDD1 is a key mediator of cartilage homeostasis through regulation of autophagy and mitochondrial biogenesis and that REDD1 deficiency exacerbates the severity of injury-induced OA.

Aging is a main risk factor for intervertebral disc (IVD) degeneration, the main cause of low back pain. FOXO transcription factors are important regulators of tissue homeostasis and longevity. Here, we determined the expression pattern of FOXO in healthy and degenerated human IVD and the associations with IVD degeneration during mouse aging. FOXO expression was assessed by immunohistochemistry in normal and degenerated human IVD samples and in cervical and lumbar IVD from 6-, 12-, 24-, and 36-month-old C57BL/6J mice. Mouse spines were graded for key histological features of disc degeneration in all the time points and expression of two key FOXO downstream targets, sestrin 3 (SESN3) and superoxide dismutase (SOD2), was assessed by immunohistochemistry. Histological analysis revealed that FOXO proteins are expressed in all compartments of human and mouse IVD. Expression of FOXO1 and FOXO3, but not FOXO4, was significantly deceased in human degenerated discs. In mice, degenerative changes in the lumbar spine were seen at 24 and 36 months of age whereas cervical IVD showed increased histopathological scores at 36 months. FOXO expression was significantly reduced in lumbar IVD at 12-, 24-, and 36-month-old mice and in cervical IVD at 36-month-old mice when compared with the 6-month-old group. The reduction of FOXO expression in lumbar IVD was concomitant with a decrease in the expression of SESN3 and SOD2. These findings suggest that reduced FOXO expression occurs in lumbar IVD during aging and precedes the major histopathological changes associated with lumbar IVD degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

The objective of this study was to examine FoxO expression and FoxO function in meniscus. In menisci from human knee joints with osteoarthritis (OA), FoxO1 and 3 expression were significantly reduced compared with normal menisci from young and old normal donors. The expression of FoxO1 and 3 was also significantly reduced in mouse menisci during aging and OA induced by surgical meniscus destabilization or mechanical overuse. Deletion of FoxO1 and combined FoxO1, 3, and 4 deletions induced abnormal postnatal meniscus development in mice and these mutant mice spontaneously displayed meniscus pathology at 6 mo. Mice with Col2Cre-mediated deletion of FoxO3 or FoxO4 had normal meniscus development but had more severe aging-related damage. In mature AcanCreERT2 mice, the deletion of FoxO1, 3, and 4 aggravated meniscus lesions in all experimental OA models. FoxO deletion suppressed autophagy and antioxidant defense genes and altered several meniscus-specific genes. Expression of these genes was modulated by adenoviral FoxO1 in cultured human meniscus cells. These results suggest that FoxO1 plays a key role in meniscus development and maturation, and both FoxO1 and 3 support homeostasis and protect against meniscus damage in response to mechanical overuse and during aging and OA.

Chronic anemia is a common, coinciding or presenting diagnosis in patients with paraesophageal hernia (PEH). Presence of endoscopically identified ulcerations frequently prompts surgical consultation in the otherwise asymptomatic patient with anemia. Rates of anemia resolution following paraesophageal hernia repair (PEHR) often exceed the prevalence of such lesions in the study population. A defined algorithm remains elusive. This study aims to characterize resolution of anemia after PEHR with respect to endoscopic diagnosis. Retrospective review of a prospectively maintained database of patients with PEH and anemia undergoing PEHR from 2007 to 2018 was performed. Anemia was determined by preoperative labs: Hgb

Background: Repair of an avascular meniscus is challenging because of its low capacity for healing. Several reports have shown that simvastatin stimulates the anabolic activity of intervertebral fibrochondrocytes, suggesting that simvastatin may be used for the treatment of meniscal defects. Purpose: To test whether the local administration of simvastatin stimulates healing of an avascular meniscus in rabbits. Study Design: Controlled laboratory study. Methods: In 30 Japanese White rabbits, a cylindrical defect (1.5-mm diameter) was introduced into the avascular zone of the anterior part of the medial meniscus in bilateral knees. Either a gelatin hydrogel (control group) or simvastatin-conjugated gelatin hydrogel (simvastatin group) was implanted into the defect. Histological assessments were performed using qualitative scoring systems, and immunohistochemical analysis was performed at 12 weeks after surgery. The occupation ratio (OR) and safranin O staining occupation ratio (SOR) were evaluated quantitatively at each time point. Stiffness of the regenerated tissue was analyzed biomechanically at 12 weeks after surgery. Rabbit meniscal cells were cultured in the presence or absence of 0.5 μM simvastatin, and then real-time polymerase chain reaction was performed to evaluate gene expression. Results: The qualitative score was significantly higher in the simvastatin group after 8 and 12 weeks ( P = .031 and .035, respectively). The mean OR and SOR were also significantly higher in the simvastatin group (OR at 8 weeks: 0.396 ± 0.019 [control] vs 0.564 ± 0.123 [simvastatin], P = .008; OR at 12 weeks: 0.451 ± 0.864 [control] vs 0.864 ± 0.035 [simvastatin], P = .001; SOR at 8 weeks: 0.071 ± 0.211 [control] vs 0.487 ± 0.430 [simvastatin], P = .009; SOR at 12 weeks: 0.093 ± 0.088 [control] vs 0.821 ± 0.051 [simvastatin], P = .006). Immunohistochemical analysis showed that at 12 weeks, the reparative tissue was more strongly positive for type I collagen (COL1), type II collagen (COL2), bone morphogenetic protein 2 (BMP-2), and BMP-7 in the simvastatin group than in the control group. Biomechanical analysis showed significantly higher stiffness in the simvastatin group (2.417 ± 1.593 N/ms [control] vs 5.172 ± 1.078 N/ms [simvastatin]; P = .005). In rabbit meniscal cells, BMP-2 and BMP-7 were upregulated after 4 and 8 hours and after 7 and 14 days, whereas COL1A1 and COL2A1 were significantly upregulated by simvastatin after 7 and 14 days. Conclusion: The local administration of simvastatin promotes the regeneration of an avascular meniscus in the rabbit model of a meniscal defect. The mechanism may involve the upregulation of BMPs and the subsequent upregulation of COL1 and COL2. Clinical Relevance: This study suggests that simvastatin stimulated intrinsic healing of an avascular meniscus. The local administration of simvastatin is safe and inexpensive and seems to be a promising treatment of meniscal injuries.

UNSTRUCTURED Japan is undergoing a major population health transition as its society ages, and it continues to experience low birth rates. An aging Japan will bring new challenges to its public health system, highlighted as a model for universal health coverage (UHC) around the world. Specific challenges Japan’s health care system will face include an increase in national public health expenditures, higher demand for health care services, acute need for elder and long-term care, shortage of health care workers, and disparities between health care access in rural versus urban areas. Blockchain technology has the potential to address some of these challenges, but only if a health blockchain is conceptualized, designed, localized, and deployed in a way that is compatible with Japan’s centralized UHC-centric public health system. Blockchain solutions must also be adaptive to opportunities and barriers unique to Japan’s national health and innovation policy, including its regulatory sandbox system, while also seeking to learn from blockchain adoption in the private sector and in other countries. This viewpoint outlines the major opportunities and potential challenges to blockchain adoption for the future of Japan’s health care.

Objectives Amyloid deposits are prevalent in osteoarthritis (OA)-affected joints. This study defined the dominant precursor and determined if the deposits affect chondrocyte functions.

Aging is a main risk factor for osteoarthritis (OA). FoxO transcription factors protect against cellular and organismal aging and FoxO expression in cartilage is reduced with aging and in OA. To investigate FoxO in cartilage function, single and triple FoxO1/3/4 floxed mice were crossed with Col2-Cre mice to generate Col2Cre-FoxO1, 3, and 4 single knockout (KO) and triple KO mice (Col2Cre-TKO). Articular cartilage in Col2Cre-TKO and Col2Cre-FoxO1 KO mice was significantly thicker than in control mice at 1 or 2 months. This was associated with increased proliferation of chondrocytes of Col2Cre-TKO mice in vivo and in vitro. OA-like changes developed in cartilage, synovium and subchondral bone between 4 and 6 months of age in Col2Cre-TKO and Col2Cre-FoxO1 KO mice. Col2Cre-FoxO3 and FoxO4 KO mice showed no cartilage abnormalities until 18 months when Col2Cre-FoxO3 KO mice had more severe spontaneous OA. Autophagy and anti-oxidant defense genes were reduced in Col2Cre-TKO mice. Deletion of triple FoxO1/3/4 in mature mice using Aggrecan(Acan)-CreERT2 (AcanCreERT-TKO) also led to spontaneous cartilage degradation and increased severity of OA induced by surgical knee instability or treadmill running. The superficial zone of Col2Cre-TKO and AcanCreERT-TKO mice exhibited reduced cell density and markedly decreased Prg4. In vitro, ectopic FoxO1 expression increased Prg4 and synergized with TGFβ stimulation. In OA chondrocytes, overexpression of FoxO1 reduced inflammatory mediators, cartilage-degrading enzymes, increased protective genes and antagonized IL-1β effects. Our observations suggest that FoxOs play a key role in postnatal cartilage development, maturation and homeostasis and protects against OA-associated cartilage damage.

Japan is undergoing a major population health transition as its society ages, and it continues to experience low birth rates. An aging Japan will bring new challenges to its public health system, highlighted as a model for universal health coverage (UHC) around the world. Specific challenges Japan’s health care system will face include an increase in national public health expenditures, higher demand for health care services, acute need for elder and long-term care, shortage of health care workers, and disparities between health care access in rural versus urban areas. Blockchain technology has the potential to address some of these challenges, but only if a health blockchain is conceptualized, designed, localized, and deployed in a way that is compatible with Japan’s centralized UHC-centric public health system. Blockchain solutions must also be adaptive to opportunities and barriers unique to Japan’s national health and innovation policy, including its regulatory sandbox system, while also seeking to learn from blockchain adoption in the private sector and in other countries. This viewpoint outlines the major opportunities and potential challenges to blockchain adoption for the future of Japan’s health care.

To investigate whether intraoperative kinematics obtained by navigation systems can be divided into several kinematic patterns and to assess the correlation between the intraoperative kinematics with maximum flexion angles before and after total knee arthroplasty (TKA).Fifty-four posterior-stabilised (PS) TKA implanted using an image-free navigation system were evaluated. At registration and after implantation, tibial internal rotation angles at maximum extension, 30°, 45°, 60°, 90°, and maximum flexion were collected. The rotational patterns were divided into four groups and were examined the correlation with maximum flexion before and after operation.Tibial internal rotation from 90° of flexion to maximum flexion at registration was correlated with maximum flexion angles pre- and postoperatively. The four groups showed statistically different kinematic patterns. The group with tibial external rotation up to 90° of flexion, following tibial internal rotation at registration, achieved better flexion angles, compared to those of another groups (126.7° ± 12.0°, p0.05). The group with tibial external rotation showed the worst flexion angles (80.0° ± 40.4°, p0.05). Furthermore, the group with limited extension showed worse flexion angles (111.6° ± 8.9°, p0.05).Navigation-based kinematic patterns found at registration predict postoperative maximum flexion angle in PS TKA. Navigation-based kinematics can be useful information during TKA surgery.Diagnostic studies, development of diagnostic criteria in a consecutive series of patients and a universally applied "gold" standard, Level II.

The present study aimed to examine the results of total knee arthroplasty (TKA) with the NexGen Legacy posterior-stabilized (LPS)-Flex system for osteoarthritis in the valgus knee. Between 2003 and 2011, 27 valgus knees in 26 patients who underwent TKA with the NexGen LPS-Flex implant were clinically and radiologically evaluated after a minimum follow-up of 2 years. The original diagnosis was osteoarthritis. Knee Society Knee Score (KSKS), Knee Society Function Score (KSFS), maximum flexion angle, maximum extension angle, and radiological femorotibial angle (FTA) were evaluated pre- and postoperatively. The mean KSKS improved from 42.6 before surgery to 82.2 by the final follow-up (p < 0.01), and the mean KSFS improved from 41.1 to 80.9 (p < 0.01). The mean maximum flexion angle changed from 109.1° to 117.3° (no statistical significance) and the maximum extension angle improved from -9.7° to -3.6° (p < 0.05) postoperatively. The postoperative radiological FTA was 172.4°, which was closer to a neutral angle (174°) than the preoperative FTA (166.4°) (p < 0.01). None of the patients had undergone revision surgery by the final follow-up. As a conclusion, TKA with the NexGen LPS-Flex implant for osteoarthritis in the valgus knee resulted in satisfactory improvement regarding objective outcomes, although a longer term follow-up with a greater number of cases is necessary to verify these results.

In this study, we examined the effects of overexpression of SIRT1 on IL-1β-induced gene expression changes in human chondrocytes to explore a protective role of SIRT1 in human chondrocytes. SIRT1 was overexpressed in human chondrocytes by expression plasmid under stimulation with IL-1β. SIRT1 was also inhibited by siRNA under stimulation with IL-1β. Gene expression changes were examined by real-time PCR. The interaction of SIRT1 and p65 (NF-κB) were examined by Western blotting. SIRT1, MMP-13, and ADAMTS-5 expressions in human cartilage were examined by immunohistochemistry. IL-1β stimulation significantly up-regulated MMP-1, 2, 9, and 13 and ADAMTS-5. Overexpression of SIRT1 significantly inhibited the up-regulation of those genes caused by IL-1β while the inhibition of SIRT1 further increased them. In addition, the overexpression of SIRT1 markedly reduced the IL-1β-induced acetylation of p65. SIRT1 expression was clearly detected in the non-OA cartilage while MMP-13 and ADAMTS-5 were undetectable. In contrast, in the OA cartilage, SIRT1 expression was decreased while MMP-13 and ADAMTS-5 were increased. Our observations suggested that SIRT1 can play a protective role by suppressing IL-1β-induced expressions of cartilage-degrading enzymes partially through the modulation of the NF-κB pathway. SIRT1 overexpression might be a new therapeutic approach for OA.

A 40-year-old man with macrodactyly of the left great toe presented with progressive enlargement of the ipsilateral ankle and increasing pain after minor trauma. Radiographs and computed tomographic scans of the foot and ankle revealed macrodactyly of the great toe and a large heterotopic ossified mass in the anteromedial aspect of the ankle. The large osseous lesion in the ankle was operatively excised. The lesion was easily excised en bloc after releasing the adhesion and histologically diagnosed as normal mature bone with osteoarthritic changes. Massive heterotopic ossification developing around the ankle in a patient with macrodactyly has not been previously reported. The current case was classified as hyperostotic macrodactyly. Operative treatment relieved the pain and improved the range of the motion of the ankle.

A 20-year-old man presented with pain and recurrent hemarthrosis in the right knee. Magnetic resonance imaging of the knee showed a lesion with homogeneous low signal intensity on T1-weighted images and a heterogeneous, low to high signal intensity on T2-weighted images. At arthroscopy, the mass was located between the posterior cruciate ligament and the posterior knee joint capsule. The tumor was excised through a posterior approach and histologically diagnosed as a nodular fasciitis. Intra-articular nodular fasciitis is a very rare clinicopathologic entity. The current case showed the unique clinical feature of recurrent hemarthrosis at initial presentation, which has not been previously reported.

Intervertebral disk (IVD) degeneration is a prevalent age‐associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age‐related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO‐deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.

Aging is a main risk factor for intervertebral disc (IVD) degeneration, the main cause of low back pain. FOXO transcription factors are important regulators of tissue homeostasis and longevity. Here, we determined the expression pattern of FOXO in healthy and degenerated human IVD and the associations with IVD degeneration during mouse aging. FOXO expression was assessed by immunohistochemistry in normal and degenerated human IVD samples and in cervical and lumbar IVD from 6-, 12-, 24-, and 36-month-old C57BL/6J mice. Mouse spines were graded for key histological features of disc degeneration in all the time points and expression of two key FOXO downstream targets, sestrin 3 (SESN3) and superoxide dismutase (SOD2), was assessed by immunohistochemistry. Histological analysis revealed that FOXO proteins are expressed in all compartments of human and mouse IVD. Expression of FOXO1 and FOXO3, but not FOXO4, was significantly deceased in human degenerated discs. In mice, degenerative changes in the lumbar spine were seen at 24 and 36 months of age whereas cervical IVD showed increased histopathological scores at 36 months. FOXO expression was significantly reduced in lumbar IVD at 12-, 24-, and 36-month-old mice and in cervical IVD at 36-month-old mice when compared with the 6-month-old group. The reduction of FOXO expression in lumbar IVD was concomitant with a decrease in the expression of SESN3 and SOD2. These findings suggest that reduced FOXO expression occurs in lumbar IVD during aging and precedes the major histopathological changes associated with lumbar IVD degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2682-2691, 2017.

Amyloid deposits are prevalent in osteoarthritic (OA) joints. We undertook this study to define the dominant precursor and to determine whether the deposits affect chondrocyte functions.Amyloid deposition in human normal and OA knee cartilage was determined by Congo red staining. Transthyretin (TTR) in cartilage and synovial fluid was analyzed by immunohistochemistry and Western blotting. The effects of recombinant amyloidogenic and nonamyloidogenic TTR variants were tested in human chondrocyte cultures.Normal cartilage from young donors did not contain detectable amyloid deposits, but 7 of 12 aged normal cartilage samples (58%) and 12 of 12 OA cartilage samples (100%) had Congo red staining with green birefringence under polarized light. TTR, which is located predominantly at the cartilage surfaces, was detected in all OA cartilage samples and in a majority of aged normal cartilage samples, but not in normal cartilage samples from young donors. Chondrocytes and synoviocytes did not contain significant amounts of TTR messenger RNA. Synovial fluid TTR levels were similar in normal and OA knees. In cultured chondrocytes, only an amyloidogenic TTR variant induced cell death as well as the expression of proinflammatory cytokines and extracellular matrix-degrading enzymes. The effects of amyloidogenic TTR on gene expression were mediated in part by Toll-like receptor 4, receptor for advanced glycation end products, and p38 MAPK. TTR-induced cytotoxicity was inhibited by resveratrol, a plant polyphenol that stabilizes the native tetrameric structure of TTR.These findings are the first to suggest that TTR amyloid deposition contributes to cell and extracellular matrix damage in articular cartilage in human OA and that therapies designed to reduce TTR amyloid formation might be useful.

Autophagy is a cellular homeostasis mechanism that may have a protective role against osteoarthritis (OA). The present study investigated the therapeutic effect of local administration of rapamycin, a potent activator of autophagy, against OA. To achieve controlled intra-articular administration of rapamycin, gelatin hydrogels incorporating rapamycin-micelles were created and the release profile was evaluated in vitro. The therapeutic effects of gelatin hydrogels incorporating rapamycin-micelles were then tested in a murine OA model. Mice were divided into four groups: Group 1, gelatin hydrogels alone; Group 2, single injection of 1 μg rapamycin; and Groups 3 and 4, gelatin hydrogels incorporating 100 ng or 1 μg rapamycin-micelles, respectively. Immunohistochemical analysis revealed that autophagic marker-positive chondrocytes were increased in the rapamycin-treated mice at 10 weeks after surgery. The histologic score was better in Groups 3 and 4 than in Groups 1 and 2, and Group 2 had a better score than Group 1. Delayed OA progression was maintained even at 16 weeks after surgery in Group 4. Microarray and real-time polymerase chain reaction analysis indicated that OA mediator genes were downregulated in the rapamycin-treated mice. Our novel system for intra-articular administration of rapamycin could be a novel therapeutic approach for treating patients with OA.

Summary Objective SIRT6, a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD + )-dependent protein deacetylases, has been implicated as a key factor in aging-related diseases. However, the role of SIRT6 in chondrocytes has not been fully explored. The purpose of this study was to examine the role of SIRT6 in human chondrocytes by inhibiting SIRT6 in vitro . Design First, the localization of SIRT6 and proliferation cell nuclear antigen (PCNA) in human cartilages was examined by immunohistochemistry. Next, SIRT6 was depleted by RNA interference (RNAi), and the effect of SIRT6 depletion on changes in gene expression, protein levels, proliferation, and senescence in human chondrocytes was assessed. Furthermore, to detect DNA damage and telomere dysfunction, γH2AX foci and telomere dysfunction-induced foci (TIFs) were examined using immunofluorescence microscopy. The protein levels of two mediators for DNA damage induced-senescence, p16 and p21, were examined by western blotting. Results Immunohistochemical analysis showed SIRT6 was preferentially expressed in the superficial zone chondrocytes and PCNA-positive cluster-forming chondrocytes in the osteoarthritic cartilage tissue samples. Real-time PCR analysis showed that matrix metalloproteinase 1 ( MMP-1 ) and MMP-13 mRNA were significantly increased by SIRT6 inhibition. Moreover, SIRT6 inhibition significantly reduced proliferation and increased senescence associated β-galactosidase (SA-β-Gal)-positive chondrocytes; it also led to increased p16 levels. Immunofluorescence microscopy showed that γH2AX foci and TIFs were increased by SIRT6 inhibition. Conclusion Depletion of SIRT6 in human chondrocytes caused increased DNA damage and telomere dysfunction, and subsequent premature senescence. These findings suggest that SIRT6 plays an important role in the regulation of senescence of human chondrocytes.

Summary Objective This study aimed to investigate alignment based on age in normal knees and alignment based on deformity in osteoarthritis (OA) knees using detailed radiographic parameters. Design Various parameters were measured from weight-bearing long leg radiographs of 1251 legs (797 normal and 454 OA knees) as a cross-sectional study. Normal knees were classified by age (young, middle aged, aged, and elderly) and symptomatic OA knees on the basis of the alignment (femorotibial angle (FTA): mild, moderate, severe and profound). The mean measurements in each group were calculated and compared within each group. Results The femoral shaft showed medially bowed curvature ( femoral bowing ) of approximately 2° in the young normal group, which shifted to lateral bowing with age. However, OA knees showed larger lateral bowing with OA grade, which might reduce the condylar-shaft angle and subsequently shifted the mechanical axis medially. Progression of mild to moderate OA might be associated with a decreasing condylar-shaft angle ( femoral condylar orientation ) and widening condylar-plateau angle ( joint space narrowing ) rather than decreasing tibial plateau flattering. Steeping of the tibial plateau inclination due to increasing tibial plateau shift ( tibial plateau compression ) rather than medial tibial bowing might be the main contributor to worsening of varus deformity in knees with severe and profound OA. Conclusions This cross-sectional study might provide the possibility of OA initiation and progression. The lateral curvature of the femoral shaft associated with aging may contribute to the initiation of varus-type OA of the knee. These changes in the femur may be followed by secondary signs of OA progression including varus femoral condylar orientation, medial joint space narrowing, and tibial plateau compression.

Given the knee kinematics and soft tissue balance in unicompartmental knee arthroplasty (UKA), it was hypothesised that intraoperative medial compartment stability will result in good functional outcome. The purpose of this study was to test the influence of soft tissue balance on post-operative knee flexion in UKA. The influence of soft tissue balance on post-operative knee flexion in UKA was first examined retrospectively by using a newly developed tensor device in 30 consecutive patients diagnosed with either isolated medial compartmental osteoarthritis or idiopathic necrosis. The intraoperative component gap of the medial compartment was measured by using the tensor while applying a 20-lb joint distraction force at 0°, 10°, 30°, 45°, 60°, 90°, 120°, and 135° of knee flexion, with calculation of the joint looseness. Correlations between the soft tissue parameters and post-operative knee flexion angles were analysed 1 year after surgery. The post-operative knee flexion angle was negatively correlated with the component gap at 45°, 60°, and 90° of flexion (R = −0.41, P

Background The success of unicompartmental knee arthroplasty relies on a lot of factors such as correct osteotomy and proper soft-tissue tensioning. A selection of insert thickness depends solely on the surgeon's subjective feeling. Recently, a tensor that is designed to assess soft tissue balance during unicompartmental knee arthroplasty has been developed. The purpose of this study was to compare the component gap throughout the range of motion among different distraction forces and examine the correlation between the component gap and the insert thickness. Methods 30 cases of 29 patients were included. All the patients received a conventional medial Zimmer Unicompartmental High Flex Knee System. Using a tensor under 10, 20, 30, and 40 lb distraction forces, after femoral component placement, the component gaps were assessed throughout the range of motion. The correlations between the component gap and the insert thickness selected were examined. Findings The component gap showed the same kinematic pattern among the different distraction forces and the value increased in proportion to the increase of the distraction force in unicompartmental knee arthroplasty. The insert thickness in unicompartmental knee arthroplasty was found to have a strong positive correlation with the component gap from 10 to 45° of knee flexion with a distraction force of more than 20 lb Interpretation With the use of the tensor, surgeons can quantify the component gap and objectify their insert thickness decision compared with the use of tension gauge.

The sagittal fibular axis serves as an intra-operative landmark during conventional total knee arthroplasty (TKA); however, only a few relevant anatomical studies have been published regarding its use as an extramedullary guide. Furthermore, the correlation between the coronal fibular and tibial mechanical axes in osteoarthritic knees has been only reported once. Here, the hypothesis of this study is that the fibula can be a reliable intra-operative landmark, in the sagittal and coronal planes, among patients with osteoarthritis who have undergone TKA. Osteoarthritic knees (n = 62) after TKA were evaluated using three-dimensional image-matching software. The angles between the tibial mechanical axis and the fibular shaft axis were measured in the sagittal and coronal planes. Moreover, correlations between the angles and patient-specific factors were evaluated. The mean angle between the tibial mechanical and fibular shaft axes was 2.6° ± 2.3° for posterior inclination in the sagittal plane and 0.9° ± 2.0° for varus inclination in the coronal plane. The percentage of subjects with the fibular shaft axis within 2° of the tibial mechanical axis was 17.7 and 69.3 % in the sagittal and coronal planes, respectively. No patient-specific factors were correlated with the angle between the tibial mechanical and fibular shaft axes. The angle between the tibial mechanical and fibular shaft axes differed among patients, independent of patient-specific factors, and did not appear to be a reliable intra-operative landmark. Surgeons should use values from individual pre-operative evaluations of the axis as reference for conventional TKA. Case series with no comparison group, Level IV.

Objectives Important roles for SIRT1 are implicated in ageing and age-related diseases. The role of SIRT1 in osteoarthritis (OA), however, remains partially unknown. To investigate the role of SIRT1 in chondrocytes in vivo, cartilage-specific Sirt1- conditional knockout (CKO) mice were analysed using an experimental OA model. Methods OA was surgically induced in 8-week-old C57BL6/J (wild-type) mice and Sirt1 -CKO ( Sirt1 flox / flox ; Col2a1-Cre ) mice generated using the Cre- lox P system. We examined changes in Sirt1 protein during the development of surgically-induced OA and during ageing in wild-type mice. OA progression in Sirt1 -CKO mice was evaluated histologically at 2, 4 and 8 weeks after surgery, and at 1 year of age without surgery compared with control ( Sirt1 flox / flox ) mice. Results The number of Sirt1-positive chondrocytes decreased during ageing, and although it was increased at 2 weeks after surgery, then gradually decreased to the presurgical level during the progression of OA in wild-type mice. Sirt1 -CKO mice showed no obvious skeletal abnormalities. The histological OA score was significantly higher in 1-year-old Sirt1 -CKO mice than in control mice. Sirt1 -CKO mice showed accelerated OA progression at 2 and 4 (but not 8) weeks compared with control mice. Immunohistochemical analysis revealed increases in type X collagen, matrix metalloproteinase 13, a disintegrin and metalloproteinase with thrombospondin motifs-5, apoptotic markers, and acetylated nuclear factor-κB p65 in Sirt1 -CKO mice compared with control mice 2 weeks after surgery. Conclusions Loss of Sirt1 in chondrocytes led to the accelerated development of OA in mice. Our observations suggest that SIRT1 has a preventive role against the development of OA.

The purpose of this study was to investigate kinematic factors affecting postoperative knee flexion after cruciate-retaining (CR) total knee arthroplasty (TKA) by analysing pre- and postoperative knee kinematics.We retrospectively analysed 58 patients with osteoarthritis who received the same implant series. Pre- and postoperative kinematics were measured intraoperatively using a navigation system. As a clinical outcome, we measured the knee flexion angle before and one year after surgery. Correlations among pre- and postoperative kinematics and postoperative flexion were analysed using simple linear regression analyses.Preoperative knee kinematics, including tibial internal rotation and anterior translation (R = 0.87, P 0.001; R = 0.53, P 0.001, respectively), were significantly correlated with postoperative kinematics. Preoperative varus-valgus movements improved significantly postoperatively; however, tibial internal rotation remained unchanged. Furthermore, postoperative knee flexion angle was significantly correlated with postoperative tibial internal rotation (R = 0.45, P 0.001).Preoperative knee kinematics were unchanged even after CR-TKA. Postoperative tibial internal rotation is one of the most important factors affecting postoperative knee flexion.

Anterior cruciate ligament (ACL) reconstruction with the hamstring tendon graft takes a long time, as the tendon graft needs to heal at the site of the bone-tendon integration in the created bone tunnels. Several reports have shown the therapeutic effects of simvastatin on bone formation with neovascularization. The aim of this study was to test the hypothesis that enhanced angiogenesis and osteogenesis by locally applied simvastatin promotes tendon-bone healing after ACL reconstruction. Rabbits received ACL reconstruction with hamstring tendon graft and were implanted with either simvastatin-conjugated gelatin hydrogel or gelatin hydrogel alone in their bone tunnels, and then bone regeneration and neovascularization at tendon-bone interface and biomechanical properties were assessed. Histological analysis at week 2 demonstrated that tendon-bone healing was significantly greater with angiogenesis and osteogenesis in the simvastatin-treated group than in the control group. Computed tomography at weeks 2 and 4 showed a significantly smaller tibial bone tunnel in the simvastatin-treated group. Biomechanical testing at week 2 demonstrated a significant increase in ultimate failure load in the simvastatin-treated group. This study suggested that local administration of low-dose simvastatin-conjugated gelatin hydrogel promotes the tendon-bone healing via its effect on both angiogenesis and osteogenesis at an early phase in a rabbit model, but does not affect biomechanical property in long-term after ACL reconstruction.

The purpose of this study was to test the hypothesis that intraoperative soft-tissue balance assessed by an offset-type tensor influences post-operative knee kinematics after cruciate-retaining (CR) total knee arthroplasty (TKA).The influence of intraoperative soft-tissue balance on knee kinematics in CR-TKA was retrospectively analysed in 30 patients. Intraoperative soft-tissue balance parameters such as varus angle (varus ligament balance), joint component gap (centre gap), and medial and lateral compartment gaps were measured in the navigation system while applying 40-lb joint distraction force at 0°, 10°, 30°, 60°, 90°, and 120° of knee flexion using an offset-type tensor with the patella reduced. Tibial internal rotation and tibial anterior translation were measured as the differences between the values at 60° and 120° of flexion using the navigation system. Correlations between the soft-tissue parameters and post-operative knee kinematics were analysed.The varus ligament balance was positively correlated with tibial internal rotation at 60° and 90° of flexion (R = 0.54, P 0.05; R = 0.60, P 0.01, respectively). Furthermore, the joint component gap was positively correlated with tibial internal rotation at 90° of flexion (R = 0.44, P 0.05), and the lateral compartment gap was positively correlated with tibial internal rotation at 60°, 90°, and 120° of knee flexion.The intraoperative varus ligament balance and joint component gap values were factors that predicted post-operative knee kinematics after CR-TKA. Lateral laxity at mid-to-deep knee flexion plays a significant role in tibial internal rotation.III.

Although the patella reduced or everted position has recently been recognised as an important factor influencing soft tissue balance during assessment in total knee arthroplasty (TKA), the influence of patella height on soft tissue balance has not been well addressed. Therefore, the relationship between soft tissue balance and patella height was investigated and differences between cruciate-retaining (CR) and posterior-stabilised (PS) TKA were compared.Forty consecutive patients blinded to the type of implant received, were randomised prospectively. Using lateral radiographs, pre-operative patella height was measured. Using an offset-type tensor designed to measure the soft tissue balance with a reduced patellofemoral (PF) joint and femoral component in place, soft tissue balance was intra-operatively assessed in CR TKA (n = 20) and PS TKA (n = 20) in osteoarthritic patients. The joint component gap and varus ligament balance at zero, ten, 45, 90 and 135° of knee flexion with the patella reduced were measured.In PS TKA, the joint component gap positively correlated with patella height at 90 and 135° of knee flexion. However, there was no correlation between joint component gap and patella height at other flexion angles in PS TKA and any flexion angle in CR TKA. Varus ligament balance showed no significant correlation with patella height in either CR or PS TKA.Analysis of soft tissue balance and patella height only showed a positive correlation in joint component gap at a high flexion angle (90 and 135°) in PS TKA but not in other parameters examined. Pre-operative measurement of patella height may be an important factor for predicting an intra-operative flexion gap in PS TKA.

In order to permit soft tissue balance under more physiological conditions during total knee arthroplasties (TKAs), an offset-type tensor was developed to obtain soft tissue balancing throughout the range of motion with reduced patello-femoral (PF) and aligned tibiofemoral joints. The main purpose of the present study was to assess intra-operative soft tissue balance using a navigation system with the offset-type tensor in both cruciate-retaining (CR) and posterior-stabilized (PS) TKAs. One hundred and twenty TKAs—80 CR and 40 PS—were performed in patients with varus-type osteoarthritis using a computed tomography–free navigation system. The offset-type TKA tensor with a reduced and repaired PF joint and femoral component in place was used with the tibia first gap technique to balance soft tissues (joint component gap and ligament balance) at 0°, 10°, 30°, 60°, 90°, and 120° of flexion. The achievement in equalized rectangular gap at extension and flexion—joint component gap within ±3 mm between extension and flexion and ligament balance within ±3° at extension and flexion—was assessed retrospectively. Both types of implants showed similar patterns of soft tissue balance throughout the range of motion, whereas PS TKA had larger values especially at 60° or 90° of flexion than did CR TKA. In the achievement of equalized rectangular gaps at extension and flexion, CR TKA was superior to PS TKA. Using the tibia first gap technique with the tensor allows appropriate soft tissue balancing, especially in CR TKA. Therapeutic studies, Level II.

In this study, we examined the effects of overexpression of SIRT1 on IL-1β-induced gene expression changes in human chondrocytes to explore a protective role of SIRT1 in human chondrocytes. SIRT1 was overexpressed in human chondrocytes by expression plasmid under stimulation with IL-1β. SIRT1 was also inhibited by siRNA under stimulation with IL-1β. Gene expression changes were examined by real-time PCR. The interaction of SIRT1 and p65 (NF-κB) were examined by Western blotting. SIRT1, MMP-13, and ADAMTS-5 expressions in human cartilage were examined by immunohistochemistry. IL-1β stimulation significantly up-regulated MMP-1, 2, 9, and 13 and ADAMTS-5. Overexpression of SIRT1 significantly inhibited the up-regulation of those genes caused by IL-1β while the inhibition of SIRT1 further increased them. In addition, the overexpression of SIRT1 markedly reduced the IL-1β-induced acetylation of p65. SIRT1 expression was clearly detected in the non-OA cartilage while MMP-13 and ADAMTS-5 were undetectable. In contrast, in the OA cartilage, SIRT1 expression was decreased while MMP-13 and ADAMTS-5 were increased. Our observations suggested that SIRT1 can play a protective role by suppressing IL-1β-induced expressions of cartilage-degrading enzymes partially through the modulation of the NF-κB pathway. SIRT1 overexpression might be a new therapeutic approach for OA.

An 83-year-old woman, subsequently diagnosed with Parkinson's disease, fell on her right shoulder. Radiographs showed the humeral head dislocated anterosuperiorly. The supraspinatus tendon was massively disrupted and judged irreparable. The subscapularis tendon was repaired, however re-dislocation of the humeral head was confirmed after the surgery but further treatment was rejected as she was almost pain free and had a low activity level. The patient was followed up for one year after surgery and her shoulder became almost pain-free, but range of motion with active elevation was limited. In such cases a goal of absence or reduction of pain rather than real repair might be considered appropriate.