Effect of pregnancy on lower limb lymphedema in patients treated with multisite lymphaticovenular anastomoses (MLVAS).

Lymphaticovenular anastomosis (LVA) using supermicrosurgical techniques is effective for treating and preventing progression of lymphedema. We analyzed the influence of pregnancy on LVA in five patients from a total 2179 LVA cases. Previous studies offer conflicting reports on whether pregnancy worsens pre-existing lymphedema. This is the first report on the influence of pregnancy on lower limb lymphedema previously treated by multisite LVA (mLVA). Five patients with primary (n=4) and secondary (n=1) lower leg lymphedema were analyzed for this study. Patient age ranged from 18 to 31 (average 22.6) years old with 4 right and 1 left extremities involved. Duration of symptoms ranged from one to 19 (average 7.4) years and the periods of compression therapy were from 1 to 19 years (6.6 years). Four patients had single pregnancies and one patient was multiparous with 3 pregnancies. Final follow-up ranged from 5.8 to 18 years (average 8.9 years) after the primary mLVA. All patients had normal pregnancy, birth, and no serious complications after surgeries. Following pregnancy three patients had complete functional recovery (limb volume reduction and no compression requirement), one with functional improvement (limb volume reduction but required compression), and one with no change in symptoms (not worse and continued need for compression). There were no occurrences of infection following pregnancy. Based on this case series, it is suggested that pregnancy does not worsen the pre-existing lymphedema in patients who had previously undergone mLVA. Further studies with larger number of patients are needed to confirm these results.

Matrix changes in articular cartilage in the knee of patients with rheumatoid arthritis after biological therapy: 1-year follow-up evaluation by T2 and T1ρ MRI quantification.

AIM: To estimate the morphological changes in the articular cartilage of the knees of patients with rheumatoid arthritis treated with biological disease-modifying anti-rheumatic drugs (bDMARDs). MATERIALS AND METHODS: Cartilage-specific magnetic resonance imaging (MRI) results, including T2 and T1ρ mapping of the femorotibial joint of 17 patients, were obtained before and 1 year after starting treatment with bDMARDs. Regions of interest were selected on the sagittal images of the cartilage of the medial and lateral femoral condyles (MFC, LFC) and the tibial plateau (MTP, LTP). Cartilage thickness, T2, and T1ρ were measured, and the correlations of their changes were evaluated. RESULTS: The mean changes in cartilage thickness tended to decrease in all four condyles, and the rate was significant in the MFC. T2 and T1ρ tended to increase, and T2 in the MFC significantly increased. Changes in cartilage thickness after 1 year showed a moderate correlation with the baseline T2 in the MFC as well as changes in T2 in the MTP. CONCLUSIONS: Decreasing cartilage thickness and matrix changes appeared in the MFC after 1 year of treatment with bDMARDs. Microstructural damage of the cartilage at baseline is a predictor for further cartilage damage in the knee joint, even if treatment with bDMARDs is effective.

Angiopoietin-like protein 2 promotes chondrogenic differentiation during bone growth as a cartilage matrix factor.

OBJECTIVE: Chondrocyte differentiation is crucial for long bone growth. Many cartilage extracellular matrix (ECM) proteins reportedly contribute to chondrocyte differentiation, indicating that mechanisms underlying chondrocyte differentiation are likely more complex than previously appreciated. Angiopoietin-like protein 2 (ANGPTL2) is a secreted factor normally abundantly produced in mesenchymal lineage cells such as adipocytes and fibroblasts, but its loss contributes to the pathogenesis of lifestyle- or aging-related diseases. However, the function of ANGPTL2 in chondrocytes, which are also differentiated from mesenchymal stem cells, remains unclear. Here, we investigate whether ANGPTL2 is expressed in or functions in chondrocytes. METHODS: First, we evaluated Angptl2 expression during chondrocyte differentiation using chondrogenic ATDC5 cells and wild-type epiphyseal cartilage of newborn mice. We next assessed ANGPTL2 function in chondrogenic differentiation and associated signaling using Angptl2 knockdown ATDC5 cells and Angptl2 knockout mice. RESULTS: ANGPTL2 is expressed in chondrocytes, particularly those located in resting and proliferative zones, and accumulates in ECM surrounding chondrocytes. Interestingly, long bone growth was retarded in Angptl2 knockout mice from neonatal to adult stages via attenuation of chondrocyte differentiation. Both in vivo and in vitro experiments show that changes in ANGPTL2 expression can also alter p38 mitogen-activated protein kinase (MAPK) activity mediated by integrin α5ß1. CONCLUSION: ANGPTL2 contributes to chondrocyte differentiation and subsequent endochondral ossification through α5ß1 integrin and p38 MAPK signaling during bone growth. Our findings provide insight into molecular mechanisms governing communication between chondrocytes and surrounding ECM components in bone growth activities.

Tuneable strong optical absorption in a graphene-insulator-metal hybrid plasmonic device.

An optical device configuration allowing efficient electrical tuning of near total optical absorption in monolayer graphene is reported. This is achieved by combining a two-dimensional gold coated diffraction grating with a transparent spacer and a suspended graphene layer to form a doubly resonant plasmonic structure. Electrical tuneability is achieved with the inclusion of an ionic gel layer which plays the role of the gate dielectric. The underlying grating comprises a 2-dimensional array of inverted pyramids with a triple layer coating consisting of a reflective gold layer and two transparent dielectric spacers, also forming a vertical micro-cavity known as a Salisbury screen. Resonant coupling of plasmons between the gold grating and graphene result in strong enhancement of plasmon excitations in the atomic monolayer. Plasmon excitations can be dynamically switched off by lowering the chemical potential of graphene. Very high absorption values for an atomic monolayer and large tuning range, extremely large electrostatically induced changes in absorption over very small shifts in chemical potential are possible thus allowing for very sharp transitions in the optical behavior of the device. Overall this leads to the possibility of making electrically tunable plasmonic switches and optical memory elements by exploiting slow modes.

MRI T1ρ and T2 mapping for the assessment of articular cartilage changes in patients with medial knee osteoarthritis after hemicallotasis osteotomy.

OBJECTIVES: The purpose of this study was to clarify the appearance of the reparative tissue on the articular surface and to analyse the properties of the reparative tissue after hemicallotasis osteotomy (HCO) using MRI T1ρ and T2 mapping. METHODS: Coronal T1ρ and T2 mapping and three-dimensional gradient-echo images were obtained from 20 subjects with medial knee osteoarthritis. We set the regions of interest (ROIs) on the full-thickness cartilage of the medial femoral condyle (MFC) and medial tibial plateau (MTP) of the knee and measured the cartilage thickness (mm) and T1ρ and T2 relaxation times (ms). Statistical analysis of time-dependent changes in the cartilage thickness and the T1ρ and T2 relaxation times was performed using one-way analysis of variance, and Scheffe's test was employed for post hoc multiple comparison. RESULTS: The cartilage-like repair tissue appeared on the cartilage surface of the medial compartment post-operatively, and the cartilage thickness showed a significant increase between the pre-operative and one-year post-operative time points (MFC; p = 0.003, MTP; p < 0.001). The T1ρ values of the cartilage-like repair tissue showed no difference over time, however, the T2 values showed a significant decrease between the pre-operative and one-year post-operative time points (MFC; p = 0.004, MTP; p = 0.040). CONCLUSION: This study clarified that the fibrocartilage-like repair tissue appeared on the articular surface of the medial compartment after HCO as evidenced by MRI T1ρ and T2 mapping.Cite this article: H. Nishioka, E. Nakamura, J. Hirose, N. Okamoto, S. Yamabe, H. Mizuta. MRI T1ρ and T2 mapping for the assessment of articular cartilage changes in patients with medial knee osteoarthritis after hemicallotasis osteotomy. Bone Joint Res 2016;5:294-300. DOI: 10.1302/2046-3758.57.BJR-2016-0057.R1.

Strong modulation of plasmons in Graphene with the use of an Inverted pyramid array diffraction grating.

An optical device configuration allowing efficient electrical tuning of surface plasmon wavelength and absorption in a suspended/conformal graphene film is reported. An underlying 2-dimensional array of inverted rectangular pyramids greatly enhances optical coupling to the graphene film. In contrast to devices utilising 1D grating or Kretchman prism coupling configurations, both s and p polarization can excite plasmons due to symmetry of the grating structure. Additionally, the excited high frequency plasmon mode has a wavelength independent of incident photon angle allowing multidirectional coupling. By combining analytical methods with Rigorous Coupled-Wave Analysis, absorption of plasmons is mapped over near infrared spectral range as a function of chemical potential. Strong control over both plasmon wavelength and strength is provided by an ionic gel gate configuration. 0.04eV change in chemical potential increases plasmon energy by 0.05 eV shifting plasmon wavelength towards the visible, and providing enhancement in plasmon absorption. Most importantly, plasmon excitation can be dynamically switched off by lowering the chemical potential and moving from the intra-band to the inter-band transition region. Ability to electrically tune plasmon properties can be utilized in applications such as on-chip light modulation, photonic logic gates, optical interconnect and sensing applications.

Endoplasmic reticulum stress-induced apoptosis contributes to articular cartilage degeneration via C/EBP homologous protein.

OBJECTIVE: When endoplasmic reticulum (ER) stress, i.e., the excessive accumulation of unfolded proteins in ER, endangers homeostasis, apoptosis is induced by C/EBP homologous protein (Chop). In osteoarthritis (OA) cartilage, Chop expression and apoptosis increase as degeneration progresses. We investigated the role of Chop in murine chondrocyte apoptosis and in the progression of cartilage degeneration. METHOD: We induced experimental OA in Chop-knockout (Chop(-/-)) mice by medial collateral ligament transection and meniscectomy and compared cartilage degeneration, apoptosis, and ER stress in Chop(-/-)- and wild-type (Chop(+/+)) mice. In our in vitro experiments we treated murine Chop(-/-) chondrocytes with the ER stress inducer tunicamycin (TM) and evaluated apoptosis, ER stress, and chondrocyte function. RESULTS: In vivo, the degree of ER stress was similar in Chop(-/-)- and Chop(+/+) mice. However, in Chop(-/-) mice apoptosis and cartilage degeneration were lower by 26.4% and 42.4% at 4 weeks, by 26.8% and 44.9% at 8 weeks, and by 26.9% and 32.3% at 12 weeks after surgery than Chop(+/+) mice, respectively. In vitro, the degree of ER stress induction by TM was similar in Chop(-/-)- and Chop(+/+) chondrocytes. On the other hand, apoptosis was 55.3% lower and the suppression of collagen type II and aggrecan mRNA was 21.0% and 23.3% less, and the increase of matrix metalloproteinase-13 mRNA was 20.0% less in Chop(-/-)- than Chop(+/+) chondrocytes. CONCLUSION: Our results indicate that Chop plays a direct role in chondrocyte apoptosis and that Chop-mediated apoptosis contributes to the progression of cartilage degeneration in mice.

The long-term outcome of open-wedge osteotomy of the proximal tibia with hemicallotasis.

We report the long-term outcome of 33 patients (37 knees) who underwent proximal tibial open-wedge osteotomy with hemicallotasis (HCO) for medial osteoarthritis of the knee between 1995 and 2000. Among these, 29 patients with unilateral HCO were enrolled and 19 were available for review at a mean of 14.2 years (10 to 15.7) post-operatively. For these 19 patients, the mean Hospital for Special Surgery knee score was 60 (57 to 62) pre-operatively and 85 (82 to 87) at final follow-up (p < 0.001; paired t-test). The femorotibial angle and tibial inclination angle (IA) were measured at short-term follow-up, one to four years post-operatively, and showed no significant subsequent changes. The clinical scores and radiological measurements showed little change over time. One patient required conversion to total knee replacement during this time. These results suggest that the coronal angle achieved at operation is maintained at long-term follow up after HCO without alteration of the IA, providing a good long-term clinical outcome.

Multiple ovarian lipoprotein receptors in teleosts.

Recent investigations have revealed multiplicity in maternal yolk precursors and their corresponding ovarian lipoprotein receptors (LRs) in diverse oviparous vertebrates, including fishes. This mini-review describes further evidence for the system of fish egg yolk formation mediated by multiple ovarian LRs, which have been obtained by studies utilizing a combination of conventional molecular and biochemical analyses, and modern proteome and transcriptome technologies. A hypothetical "multiple ovarian LR" model is proposed based on our current and previous knowledge of fish yolk formation.

Cartilaginous repair of full-thickness articular cartilage defects is induced by the intermittent activation of PTH/PTHrP signaling.

OBJECTIVE: We studied the effects of the transient activation of parathyroid hormone (PTH)/PTH-related peptide (PTHrP) signaling during the repair of 5-mm-diameter full-thickness defects of articular cartilage in the rabbit. MATERIALS AND METHODS: Cylindrical full-thickness articular cartilage defects of 5mm in diameter were artificially created in the femoral trochlea of male adolescent Japanese white rabbits using a hand-drill. Recombinant human PTH(1-84) was then administered into the joint cavity continuously or intermittently for 2 weeks post-injury. The reparative tissues were histologically examined at 2, 4, and 8 weeks, and were also immunohistochemically examined for type II collagen. Double immunostaining analysis was also performed for the PTH/PTHrP receptor and proliferating cell nuclear antigen (PCNA) in the regenerating tissues. RESULTS: No evidence of cartilage formation was evident throughout the period of the experiments in injured animals administered saline alone. In contrast, cartilage formation occurred at 4 weeks in both the continuous and intermittent PTH-treated defects. At 8 weeks post-injury, for the intermittently treated defects, the regenerated cartilage successfully resurfaced the defects and the original bone-articular cartilage junction was recovered. In contrast, the defects were covered with fibrous or fibrocartilaginous tissues in the continuously administered group. PCNA and PTH/PTHrP receptor-double positive mesenchymal cells were significantly increased in both the continuous and intermittent PTH-treated defects at 2 weeks post-injury. CONCLUSIONS: The present results suggest that the transient activation and release from PTH/PTHrP signaling during the early stages of the cartilage repair process facilitates the induction of regenerative chondrogenesis in full-thickness articular cartilage defects.

Predictive factors for esophageal stenosis after endoscopic submucosal dissection for superficial esophageal cancer.

Endoscopic submucosal dissection (ESD) has been utilized as an alternative treatment to endoscopic mucosal resection for superficial esophageal cancer. We aimed to evaluate the complications associated with esophageal ESD and elucidate predictive factors for post-ESD stenosis. The study enrolled a total of 42 lesions of superficial esophageal cancer in 33 consecutive patients who underwent ESD in our department. We retrospectively reviewed ESD-associated complications and comparatively analyzed regional and technical factors between cases with and without post-ESD stenosis. The regional factors included location, endoscopic appearance, longitudinal and circumferential tumor sizes, depth of invasion, and lymphatic and vessel invasion. The technical factors included longitudinal and circumferential sizes of mucosal defects, muscle disclosure and cleavage, perforation, and en bloc resection. Esophageal stenosis was defined when a standard endoscope (9.8 mm in diameter) failed to pass through the stenosis. The results showed no cases of delayed bleeding, three cases of insidious perforation (7.1%), two cases of endoscopically confirmed perforation followed by mediastinitis (4.8%), and seven cases of esophageal stenosis (16.7%). Monovalent analysis indicated that the longitudinal and circumferential sizes of the tumor and mucosal defect were significant predictive factors for post-ESD stenosis (P < 0.005). Receiver operating characteristic analysis showed the highest sensitivity and specificity for a circumferential mucosal defect size of more than 71% (100 and 97.1%, respectively), followed by a circumferential tumor size of more than 59% (85.7 and 97.1%, respectively). It is of note that the success rate of en bloc resection was 95.2%, and balloon dilatation was effective for clinical symptoms in all seven patients with post-ESD stenosis. In conclusion, the most frequent complication with ESD was esophageal stenosis, for which the sizes of the tumor and mucosal defect were significant predictive factors. Although ESD enables large en bloc resection of esophageal cancer, practically, in cases with a lesion more than half of the circumference, great care must be taken because of the high risk of post-ESD stenosis.

The chondrogenic repair response of undifferentiated mesenchymal cells in rat full-thickness articular cartilage defects.

OBJECTIVE: The aim of this study is to develop a rat model of full-thickness articular cartilage defects that is suitable for detailed molecular analyses of the regenerative repair of cartilage. MATERIALS AND METHODS: The V-shaped full-thickness defects (width: 0.7 mm; depth: 0.8 mm; and length: 4mm) were created in the femoral patellar groove of 6 weeks old male rats using a custom-built twin-blade device. Prior to starting the repair experiments, our device was examined for its accuracy and reliability in generating defects. Then, the time course of the repair response in these cartilage defects was examined using a semi-quantitative histological grading scale. The expression of chondrogenic differentiation markers in the reparative regions was examined with immunohistochemistry and in situ hybridization. RESULTS: Our device creates full-thickness articular cartilage defects uniformly. In these defects, undifferentiated mesenchymal cells filled the defect cavities (4 days) and initiated chondrogenic differentiation at the center of the defect (7 days). Cartilage formation was observed in the same region (2 weeks). Finally, hyaline-like articular cartilage and subchondral bone layers were reconstituted in their appropriate locations (4 weeks). CONCLUSIONS: We have successfully developed a rat model containing identically sized full-thickness defects of articular cartilage that can undergo chondrogenic repair in a reproducible fashion.

Evaluation of estimation of physiologic ability and surgical stress (E-PASS) to predict the postoperative risk for hip fracture in elder patients.

INTRODUCTION: The Estimation of Physiologic Ability and Surgical Stress (E-PASS) scoring system is comprised of a preoperative risk score (PRS), a surgical stress score (SSS), and a comprehensive risk score (CRS) determined by both the PRS and SSS. E-PASS predicts the postoperative risk by quantifying the patient's reserve and surgical stress in general surgery. This study aims to evaluate the usefulness of this scoring system for the hospitalization outcomes in hip fracture. PATIENTS AND METHODS: A consecutive series of 419 elderly patients who underwent surgery with osteosynthesis or arthroplasty for hip fracture were prospectively assessed for the E-PASS scoring system, which was compared with their postoperative course. RESULTS: The postoperative morbidity and mortality rates in hospital increased linearly as the PRS and CRS increased, with significant correlation (rho = 0.2, P < 0.01) in both operations. The cost of hospital stay also related significantly to the SSS (r = 0.6, P < 0.0001) and CRS (r = 0.4, P < 0.0001). CONCLUSION: These results suggest that E-PASS may be useful for predicting postoperative risk and estimating medical expense for surgical cases with hip fracture.

T-wave vector alternans detection based on Holter ECG recordings.

This paper proposes a new method for detecting T-wave alternans (TWA) based on 3-channel Holter ECG recordings. The current standard method, based on spectral analysis of each signal lead, enables low amplitude alternans detection at the microvolt level. However, the method requires a controlled test environment where the mean heart rate is artificially increased. T Proposed method aims at realizing the reliable alternans detection from 24 hour Holter recordings during normal daily activities. To achieve this, the method utilizes singular value decomposition (SVD) for highly sensitive differentiation of T-wave morphology in noisy recording conditions. We propose the name T-wave Vector Alternance (TWVA) for TWA detected by SVD in decomposed ECG signals. The method was applied to three normal subjects and two subjects with TWA, and it correctly detected the TWA.

Healing of full-thickness defects of the articular cartilage in rabbits using fibroblast growth factor-2 and a fibrin sealant.

We have investigated in vitro the release kinetics and bioactivity of fibroblast growth factor-2 (FGF-2) released from a carrier of fibrin sealant. In order to evaluate the effects of the FGF-2 delivery mechanism on the repair of articular cartilage, full-thickness cylindrical defects, 5 mm in diameter and 4 mm in depth, which were too large to undergo spontaneous repair, were created in the femoral trochlea of rabbit knees. These defects were then filled with the sealant. Approximately 50% of the FGF-2 was released from the sealant within 24 hours while its original bioactivity was maintained. The implantation of the fibrin sealant incorporating FGF-2 successfully induced healing of the surface with hyaline cartilage and concomitant repair of the subchondral bone at eight weeks after the creation of the defect. Our findings suggest that this delivery method for FGF-2 may be useful for promoting regenerative repair of full-thickness defects of articular cartilage in humans.

Effect of common driving sources to the feedback analysis of heart rate variability.

OBJECTIVES: This paper examines the operational characteristics of the multivariate autoregressive analysis applied to the simultaneous recordings of the instantaneous heart rate (IHR) and the change in systolic blood pressure (SBP). METHODS: The multivariate autoregressive model has been utilized to reveal the feedback characteristics between IHR and SBP. The model assumes the presence of independent set of driving forces to activate the system. However, it is likely that the driving forces may have correlation due to the presence of a common fluctuation source. This paper examines the effect of the presence of correlated components in the driving forces to the estimation accuracy of impulse responses characterizing the feedback properties. The two-dimensional autoregressive model driven by two correlated 1/f noises was chosen for the analysis of operational characteristics. The driving force was generated by a moving average system which simulates non-integer order integration. RESULTS: Computer simulation revealed that the mean square estimation errors of impulse responses sharply increase as relative power of common driving force exceeds 50%. However, the estimation accuracy and bias are found to be in permissible range in practice. CONCLUSIONS: These findings ensure the practical validity of utilizing multivariate autoregressive models for the feedback analysis between IHR and SBP where both signals have the common driving force.

Expression of the PTH/PTHrP receptor in chondrogenic cells during the repair of full-thickness defects of articular cartilage.

OBJECTIVE: We studied the accumulation of parathyroid hormone (PTH)/PTHrP receptor-positive mesenchymal cells using double immunohistochemistry and examined whether this correlated with the subsequent regeneration of 3-mm-diameter full-thickness defects of articular cartilage. MATERIALS AND METHODS: Cylindrical full-thickness articular cartilage defects (3 mm) were artificially created in the femoral trochlea of male adolescent Japanese white rabbits (n = 210) with a hand-drill. Recombinant human PTH(1-84) was then administered into the defect cavities with an osmotic pump for either 2 or 4 weeks post-injury. Following PTH treatment, the repair processes in the cartilage defects were histologically examined. Double immunostaining analyses for the PTH/PTH-related peptide (PTHrP) receptor and proliferating cell nuclear antigen (PCNA) in the regenerating tissues were then performed. RESULTS: Activation of PTH/PTHrP receptor signaling by hPTH(1-84) results in the inhibition of chondrogenic differentiation in full-thickness articular cartilage defects. At the conclusion of the 2-week PTH treatment, the defect cavities were filled with undifferentiated mesenchymal cells, which were similar to the controls. In addition, almost all of these cells localized at the center of the injuries were both PTH/PTHrP receptor- and PCNA-positive. In contrast, after prolonged PTH treatment for 4 weeks, there was no indication of a cartilaginous repair response and cells that had migrated to the defect cavities were found to have irreversibly lost expression of the PTH/PTHrP receptor. CONCLUSIONS: The chondrogenic capacity of cells that had migrated to the area of these defect cavities is closely associated with their ability to express the PTH/PTHrP receptor. Moreover, these cells maintain their chondrogenic potential within only a limited time-span of 2 weeks.

An improved QT interval measurement based on singular value decomposition.

This paper proposes an improved method of automatic ECG QT interval measurement based on the singular value decomposition (SVD) of multiple lead ECG signals. SVD separates multiple lead ECG record into orthogonal signals. Major orthogonal signals associated with high singular values are selected first for subsequent analysis. Instantaneous norm of the major three orthogonal signals are used for estimating Q wave initiating time tQ. Two dimensional trajectory of the major orthogonal signals are utilized for T wave end time tTE estimation. The T wave trajectory stagnates at tTE. For the accurate tTE estimation, this stagnation of the trajectory is proposed to be detected by its change in tangential angle. The proposed method was applied to 17 ECG data from normal subjects, patients of long QT syndrome (LQTS) and left ventricular hypertrophy (LVH) to demonstrate its effectiveness. Good consistent agreement, mean relative error of 5.01%, between estimated QT intervals and those of manual measurement by an experienced cardiologist was achieved.