Minimally Invasive Paraesophageal Hernia Repair in the Elderly: Is Age Really Just a Number?

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 challenging operation with potential for dire complications. Advanced age and medical comorbidities may heighten perioperative risk and limit surgical candidacy, potentially refusing patients an opportunity toward symptom resolution. Given the increased prevalence in the elderly and associated surgical risks, we aim to assess age as an independent risk factor for perioperative morbidity and mortality after PEHR. Methods: A retrospective analysis using a prospectively maintained database assessed patients undergoing PEHR from 2007 to 2018. Patients were stratified by age: Group A (age <65 years), Group B (65≤ age <80 years), and Group C (age ≥80 years). Patient demographics, preoperative symptoms, postoperative outcomes, and mortality rate were analyzed. Barium esophagram was performed on symptomatic postsurgical patients. Recurrence was confirmed radiologically. Results: In total, 143 patients underwent laparoscopic (94.4%) or robotic-assisted (5.6%) PEHR. Average age per group was Group A (n = 49) 55.4 years (standard deviation [SD] ±8.91), Group B (n = 76) 71.4 years (SD ±4.40), and Group C (n = 17) 84.1 (years) (SD ±3.37). Group C had significantly higher rates of nonelective surgery (P = .018), preoperative weight loss (P = .014), hypertension (P = .031), ischemic heart disease (P = .001), and cancer (P = .039); preoperative body mass index was significantly lower (P = .048). Charlson comorbidity index differences between groups were significant (2.00 versus 3.61 versus 5.28, P < .001). Median follow-up was 426 days (6-3199). Symptom improvement was seen in 78.3% of patients. Recurrence and reoperation rates were not significantly different between groups. No differences were seen in mortality, length of stay, or postoperative complications between groups. Conclusions: PEHR in elderly patients proved to be safe and effective. Avoidance of emergent intervention may be achieved through a judicious elective approach to this anatomic problem. Symptom resolution and quality-of-life improvement can be safely achieved with surgical repair in this patient population, demonstrating that age is truly just a number for PEHR.

Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis.

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.

Compensatory motion scaling for time-delayed robotic surgery.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Associations of clinical outcomes and MRI findings in intra-articular administration of autologous adipose-derived stem cells for knee osteoarthritis.

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 < 0.001) and 10.2 ± 12.4 (from 54.4 ± 12.7 to 64.6 ± 13.8, P < 0.01), respectively. Scales related to pain and symptoms improved earlier than those related to activities of daily living (ADL) and sports/recreation. Improvement of VAS and KOOS-sports/recreation was significantly higher in patients with more severe cartilage lesions. Similarly, osteophyte lesions were associated significantly with improvement of VAS and KOOS-ADL, and BML was associated with KOOS-ADL and KOOS-sports/recreation. CONCLUSIONS: In intra-articular administration of autologous ASCs for knee OA, improvement of VAS and KOOS-sports/recreation was significantly higher in patients with more severe cartilage lesions. Similarly, osteophyte lesions were associated significantly with improvement of VAS and KOOS-ADL, and BML was associated with KOOS-ADL and KOOS-sports/recreation. Clinical studies with larger numbers of patients and various kinds of data are necessary to predict therapeutic effects.

FOXO1 and FOXO3 transcription factors have unique functions in meniscus development and homeostasis during aging and osteoarthritis.

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.

Examining the Potential of Blockchain Technology to Meet the Needs of 21st-Century Japanese Health Care: Viewpoint on Use Cases and Policy.

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.

Paraesophageal hernia repair: a curative consideration for chronic anemia?

INTRODUCTION: 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. MATERIALS AND METHODS: 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 < 12 mg/dl in females, Hgb < 13 mg/dl in males, or patients with ongoing iron supplementation. Improvement of post-operative anemia was assessed by post-operative hemoglobin values and continued necessity of iron supplementation. RESULTS: Among 56 identified patients, 45 were female (80.4%). Forty patients (71.4%) were anemic by hemoglobin value, 16 patients (28.6%) required iron supplementation. Mean age was 65.1 years, with mean BMI of 27.7 kg/m2. One case was a Type IV PEH and the rest Type III. 32 (64.0%) had potential source of anemia: 16 (32.0%) Cameron lesions, 6 (12.0%) gastric ulcers, 12 (24.0%) gastritis. 10 (20.0%) had esophagitis and 4 (8%) Barrett's esophagus. 18 (36%) PEH patients had normal preoperative EGD. Median follow-up was 160 days. Anemia resolution occurred in 46.4% of patients. Of the 16 patients with pre-procedure Cameron lesions, 10 (63%) had resolution of anemia. Patients with esophagitis did not achieve resolution. 72.2% (13/18) of patients with no lesions on EGD had anemia resolution (p = 0.03). CONCLUSION: Patients with PEH and identifiable ulcerations showed 50% resolution of anemia after hernia repair. Patients without identifiable lesions on endoscopy demonstrated statistically significant resolution of anemia in 72.2% of cases. Anemia associated with PEH adds an indication for surgical repair with curative intent.

Wwp2 maintains cartilage homeostasis through regulation of Adamts5.

The WW domain-containing protein 2 (Wwp2) gene, the host gene of miR-140, codes for the Wwp2 protein, which is an HECT-type E3 ubiquitin ligases abundantly expressed in articular cartilage. However, its function remains unclear. Here, we show that mice lacking Wwp2 and mice in which the Wwp2 E3 enzyme is inactivated (Wwp2-C838A) exhibit aggravated spontaneous and surgically induced osteoarthritis (OA). Consistent with this phenotype, WWP2 expression level is downregulated in human OA cartilage. We also identify Runx2 as a Wwp2 substrate and Adamts5 as a target gene, as similar as miR-140. Analysis of Wwp2-C838A mice shows that loss of Wwp2 E3 ligase activity results in upregulation of Runx2-Adamts5 signaling in articular cartilage. Furthermore, in vitro transcribed Wwp2 mRNA injection into mouse joints reduces the severity of experimental OA. We propose that Wwp2 has a role in protecting cartilage from OA by suppressing Runx2-induced Adamts5 via Runx2 poly-ubiquitination and degradation.

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration.

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.

FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis.

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 the role of FoxO in cartilage, Col2Cre-FoxO1, 3, and 4 single knockout (KO) and triple KO mice (Col2Cre-TKO) were analyzed. Articular cartilage in Col2Cre-TKO and Col2Cre-FoxO1 KO mice was thicker than in control mice at 1 or 2 months of age. 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 of age when Col2Cre-FoxO3 KO mice had more severe OA than control mice. Autophagy and antioxidant defense genes were reduced in Col2Cre-TKO mice. Deletion of FoxO1/3/4 in mature mice using Aggrecan(Acan)-CreERT2 (AcanCreERT-TKO) also led to spontaneous cartilage degradation and increased OA severity in a surgical model or treadmill running. The superficial zone of knee articular cartilage 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 transforming growth factor-ß stimulation. In OA chondrocytes, overexpression of FoxO1 reduced inflammatory mediators and cartilage-degrading enzymes, increased protective genes, and antagonized interleukin-1ß effects. Our observations suggest that FoxO play a key role in postnatal cartilage development, maturation, and homeostasis and protect against OA-associated cartilage damage.

Transthyretin deposition promotes progression of osteoarthritis.

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.

Age-related reduction in the expression of FOXO transcription factors and correlations with intervertebral disc 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.

Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of Experimental Osteoarthritis.

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.

The contribution of intraoperative medial compartment stability to post-operative knee flexion angle in unicompartmental knee arthroplasty.

PURPOSE: 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. METHODS: 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. RESULTS: The post-operative knee flexion angle was negatively correlated with the component gap at 45°, 60°, and 90° of flexion (R = -0.41, P < 0.05; R = -0.44, P < 0.05; and R = -0.44, P < 0.05, respectively). Furthermore, the post-operative knee flexion angle was negatively correlated with joint looseness at 45°, 60°, and 90° of flexion (R = -0.40, P < 0.05; R = -0.41, P < 0.05; and R = -0.36, P < 0.05, respectively). CONCLUSIONS: The intraoperative medial compartment stability of knee flexion in midrange resulted in increasing post-operative knee flexion angle in UKA. Medial soft tissue release should be minimised, and assessment of soft tissue balance using a tensor can be performed to predict the post-operative knee flexion angle during surgery for UKA. LEVEL OF EVIDENCE: III.

Local Administration of Simvastatin Stimulates Healing of an Avascular Meniscus in a Rabbit Model of a Meniscal Defect.

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.

Navigation-based femorotibial rotation pattern correlated with flexion angle after total knee arthroplasty.

PURPOSE: 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). METHOD: 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. RESULTS: 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°, p < 0.05). The group with tibial external rotation showed the worst flexion angles (80.0° ± 40.4°, p < 0.05). Furthermore, the group with limited extension showed worse flexion angles (111.6° ± 8.9°, p < 0.05). CONCLUSION: 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. LEVEL OF EVIDENCE: Diagnostic studies, development of diagnostic criteria in a consecutive series of patients and a universally applied "gold" standard, Level II.

Anterior cruciate ligament remnant tissue harvested within 3-months after injury predicts higher healing potential.

BACKGROUND: No study has examined the possible factors associated with different characteristics of stem-like cells derived from anterior cruciate ligament (ACL) remnants. And the purpose of the study is to elucidate whether demographic factors are associated with healing potential of stem-like cells derived from the ACL remnants tissue. METHODS: Thirty-six ACL remnants were harvested from patients who received primary arthroscopic ACL reconstruction. Interval from injury to surgery, age, sex, and combined meniscal or chondral injuries were analyzed. Cells were isolated from remnant tissues and their healing potential was evaluated by: 1) characterization of surface markers (CD34, CD44, CD45, CD146, CD29, and Stro-1), 2) cell expansion, 3) osteogenic differentiation, and 4) endothelial differentiation. Finally, using multivariable logistic regression to evaluate the relation between demographic factors and healing potential parameters. Adjusted odds ratios (OR) were calculated, and the significant difference was set at p < 0.05. RESULTS: ACL remnant tissue harvested less than 90 days after injury predicted higher fractions of stem-like cells [CD34+ (OR = 6.043, p = 0.025), CD44 + (OR = 8.440, p = 0.011), CD45+ (OR = 16.144, p = 0.015), and CD146+ (OR = 9.246, p = 0.015)] and higher expansion potential (passage 3: OR = 9.755, p = 0.034; passage 10: OR = 33.245, p = 0.003). Regarding osteogenic differentiation, higher gene expression of Osteocalcin (OR = 22.579, p = 0.009), Alkaline phosphatase (OR = 6.527, p = 0.022), and Runt-related transcription factor 2 (OR = 5.247, p = 0.047) can also be predicted. Younger age predicted higher CD34+ levels (20 ≤ age < 30 years, OR = 2.020, p = 0.027) and higher expansion potential at passage 10 (10 ≤ age < 20 years, OR = 25.141, p = 0.026). There was no significant relation found between meniscal or chondral injuries and ACL healing potential. CONCLUSION: Our results indicated that the ACL remnant tissue harvested within 3-months after injury yields higher healing potential, suggesting early surgical intervention may achieve better clinical results.

Transthyretin deposition in articular cartilage: a novel mechanism in the pathogenesis of osteoarthritis.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Fibular axes are not a reliable landmark for tibial mechanical axes of osteoarthritic knees that underwent total knee arthroplasty.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. LEVEL OF EVIDENCE: Case series with no comparison group, Level IV.