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Simple Summary: Active BNP-32, less active proBNP-108, and inactive N-terminal proBNP-76 all circulate in the blood. The circulating protease neprilysin has lower substrate specificity for BNP than ANP, while proBNP and N-terminal proBNP are not degraded by neprilysin. Currently available BNP immunoassays react with both mature BNP and proBNP; therefore, measured plasma BNP is mature BNP + proBNP. Because ARNI administration increases mature BNP, measured plasma BNP initially increases with ARNI administration by the amount of the increase in mature BNP. Later, ARNI administration reduces myocardial wall stress, and the resultant reduction in BNP production more than offsets the increase of mature BNP due to inhibition of degradation by neprilysin, resulting in lower plasma BNP levels. In the ARNI era, BNP remains a useful biomarker for heart failure, though mild increases early during ARNI administration should be taken into consideration. Myocardial wall stress, cytokines, hormones, and ischemia all stimulate B-type (or brain) natriuretic peptide (BNP) gene expression. Within the myocardium, ProBNP-108, a BNP precursor, undergoes glycosylation, after which a portion is cleaved by furin into mature BNP-32 and N-terminal proBNP-76, depending on the glycosylation status. As a result, active BNP, less active proBNP, and inactive N-terminal proBNP all circulate in the blood. There are three major pathways for BNP clearance: (1) cellular internalization via natriuretic peptide receptor (NPR)-A and NPR-C; (2) degradation by proteases in the blood, including neprilysin, dipeptidyl-peptidase-IV, insulin degrading enzyme, etc.; and (3) excretion in the urine. Because neprilysin has lower substrate specificity for BNP than atrial natriuretic peptide (ANP), the increase in plasma BNP after angiotensin receptor neprilysin inhibitor (ARNI) administration is much smaller than the increase in plasma ANP. Currently available BNP immunoassays react with both mature BNP and proBNP. Therefore, BNP measured with an immunoassay is mature BNP + proBNP. ARNI administration increases mature BNP but not proBNP, as the latter is not degraded by neprilysin. Consequently, measured plasma BNP initially increases with ARNI administration by the amount of the increase in mature BNP. Later, ARNI reduces myocardial wall stress, and the resultant reduction in BNP production more than offsets the increase in mature BNP mediated by inhibiting degradation by neprilysin, which lowers plasma BNP levels. These results suggest that even in the ARNI era, BNP can be used for diagnosis and assessment of the pathophysiology and prognosis of heart failure, though the mild increases early during ARNI administration should be taken into consideration. [ABSTRACT FROM AUTHOR]

Simple Summary: CNP is the third natriuretic peptide to be isolated and is widely expressed in the central nervous system, osteochondral system, and vascular system. The receptor that is mainly targeted by CNP is GC-B, which differs from GC-A, the receptor targeted by the other two natriuretic peptides, ANP and BNP. Consequently, the actions of CNP differ somewhat from those of ANP and BNP. Research into the actions of CNP has shown that CNP attenuates cardiac remodeling in animal models of cardiac hypertrophy, myocardial infarction, and myocarditis. Studies examining CNP/GC-B signaling showed that it contributes to the prevention of cardiac stiffness. Endogenous CNP, perhaps acting in part through CNP/NPR-C signaling, contributes to the regulation of vascular function and blood pressure. CNP regulates vascular remodeling and angiogenesis via CNP/GC-B/CGK signaling. CNP attenuates interstitial fibrosis and fibrosis-related gene expression in pressure overload and myocardial infarction models. The clinical application of CNP as a therapeutic agent for cardiovascular diseases is anticipated. The natriuretic peptide family consists of three biologically active peptides: ANP, BNP, and CNP. CNP is more widely expressed than the other two peptides, with significant levels in the central nervous system, osteochondral system, and vascular system. The receptor that is mainly targeted by CNP is GC-B, which differs from GC-A, the receptor targeted by ANP and BNP. Consequently, the actions of CNP differ somewhat from those of ANP and BNP. CNP knockout leads to severe dwarfism, and there has been important research into the role of CNP in the osteochondral system. As a result, a CNP analog is now available for clinical use in patients with achondroplasia. In the cardiovascular system, CNP and its downstream signaling are involved in the regulatory mechanisms underlying myocardial remodeling, cardiac function, vascular tone, angiogenesis, and fibrosis, among others. This review focuses on the roles of CNP in the cardiovascular system and considers its potential for clinical application in the treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: We previously reported that early alendronate administration accelerated bone formation and improved the quality of repaired cartilage in the donor site in rabbits. To investigate whether alendronate administration has effects in humans similar to those observed in rabbits.Methods: The study cohort included 35 patients over the age of 12-years old who underwent mosaicplasty without osteoporotic therapy from March 2011 to October 2012. The donor sites were medial or lateral in the patellofemoral joint. Placebo (P) or Bonalon containing 35 mg of alendronate (A) was administered orally every week for 8 weeks. The cohort comprised 15 male and 20 female, including 14 right and 21 left knees. The mean age at the time of surgery was 57.1 years. Bone formation was examined using computer tomography and lateral knee radiography, and cartilage formation was examined using magnetic resonance imaging (MRI), second-look assessment, and intraoperative acoustic evaluation. The clinical outcomes were assessed using the Japanese Orthopaedic Association knee score and visual analog scale (VAS). Bone and cartilage formation in the donor site and clinical outcomes were assessed at 3, 6, and 12 months after mosaicplasty.Results: The ratio of TRAP-5b in group A was significantly smaller than that in group P at 2 and 8 weeks after mosaicplasty. The extent of bone formation in the donor sites in group A was significantly greater than that in group P at 3 and 6 months after mosaicplasty. Cartilage formation did not differ significantly between the two groups as determined by MRI, macroscopic assessment, and intraoperative acoustic evaluation. Clinical outcomes did not differ significantly between the two groups, and no negative clinical outcomes were observed.Conclusion: Early alendronate administration accelerated bone formation but not cartilage formation in the mosaicplasty donor site in humans. [ABSTRACT FROM AUTHOR]

This study was aimed at investigating the use of ultrasound parameters obtained non-invasively through soft tissue (ST) to evaluate degeneration in cartilage and subchondral bone (SB) in the human knee. We developed a 3-D ultrasound system and introduced the ratio parameters Rcb and RcbT to suppress the attenuation effect in the ST or in both the ST and cartilage. As reference measurements, the grade for cartilage by visual judgment (Gsum) and ultrasound parameters for the cartilage and the SB were directly evaluated under arthroscopy. Rcb correlated significantly with Gsum (rs = -0.63) and with the corresponding parameter obtained directly under arthroscopy (r = 0.55). RcbT also correlated significantly with Gsum (rs = -0.46) but was not superior to Rcb. Rcb is considered to be an efficient parameter that reflects the total degeneration in both the cartilage and SB, including the information on cartilage thickness. [ABSTRACT FROM AUTHOR]

Background: We previously developed a surface-controlled water-dispersible form of curcumin that we called Theracurmin®. The area under the blood concentration-time curve (AUC) of Theracurmin in humans was 27-fold higher than that of curcumin powder. Previously, we reported on the anti-inflammatory effects of Theracurmin for knee osteoarthritis. Hypothesis/Purpose: We determined the clinical effects of orally administered Theracurmin in patients with knee osteoarthritis over a 6-month period. Study Design: Open prospective study. Methods: Fifty patients Kellgren-Lawrence grade II, III, or IV knee osteoarthritis who were above 40 years old were enrolled in this clinical study. Theracurmin containing 180 mg/day of curcumin was administered orally every day for 6 months. To monitor for adverse events, blood biochemistry analyses were performed before and after 6 months of each intervention. The patients' knee symptoms were evaluated at 0, 1, 2, 3, 4, 5, and 6 months based on the Japanese Knee Osteoarthritis Measure, the knee pain visual analog scale, and the knee scoring system of the Japanese Orthopedic Association. Results: Five cases dropped out during the study, but no cases dropped out because of major problems. No major side effects were observed with Theracurmin treatment, including the blood biochemistry analysis results. The effective group included 34 cases (75.6%), while the not-effective group included 11 cases. Conclusion: This study demonstrates the safety and good efficacy of Theracurmin for various types of knee osteoarthritis. Theracurmin shows great potential for the treatment of human knee osteoarthritis. [ABSTRACT FROM AUTHOR]

Background: We previously developed a surface-controlled water-dispersible form of curcumin that we called Theracurmin®. The area under the blood concentration-time curve (AUC) of Theracurmin in humans was 27-fold higher than that of curcumin powder. Previously, we reported on the anti-inflammatory effects of Theracurmin for knee osteoarthritis. Hypothesis/Purpose: We determined the clinical effects of orally administered Theracurmin in patients with knee osteoarthritis over a 6-month period. Study Design: Open prospective study. Methods: Fifty patients Kellgren-Lawrence grade II, III, or IV knee osteoarthritis who were above 40 years old were enrolled in this clinical study. Theracurmin containing 180 mg/day of curcumin was administered orally every day for 6 months. To monitor for adverse events, blood biochemistry analyses were performed before and after 6 months of each intervention. The patients' knee symptoms were evaluated at 0, 1, 2, 3, 4, 5, and 6 months based on the Japanese Knee Osteoarthritis Measure, the knee pain visual analog scale, and the knee scoring system of the Japanese Orthopedic Association. Results: Five cases dropped out during the study, but no cases dropped out because of major problems. No major side effects were observed with Theracurmin treatment, including the blood biochemistry analysis results. The effective group included 34 cases (75.6%), while the not-effective group included 11 cases. Conclusion: This study demonstrates the safety and good efficacy of Theracurmin for various types of knee osteoarthritis. Theracurmin shows great potential for the treatment of human knee osteoarthritis. [ABSTRACT FROM AUTHOR]

Highlights • ANP and BNP are secreted by the heart and act as cardiac hormones. • Human ANP has three molecular forms: α-ANP, β-ANP, and proANP (or γ-ANP). • ProANP and β-ANP are minor forms but are increased in patients with heart failure. • ProBNP is secreted by the heart and is increased in patients with heart failure. • MiR30-GALNTs-dependent O -glycosylation contributes to the secretion of proBNP. Abstract The natriuretic peptide family consists of three biologically active peptides: atrial natriuretic peptide (ANP), brain (or B-type) natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Among these, ANP and BNP are secreted by the heart and act as cardiac hormones. Both ANP and BNP preferentially bind to natriuretic peptide receptor-A (NPR-A or guanylyl cyslase-A) and exert similar effects through increases in intracellular cyclic guanosine monophosphate (cGMP) within target tissues. Expression and secretion of ANP and BNP are stimulated by various factors and are regulated via multiple signaling pathways. Human ANP has three molecular forms, α-ANP, β-ANP, and proANP (or γ-ANP), with proANP predominating in healthy atrial tissue. During secretion proANP is proteolytically processed by corin, resulting in secretion of bioactive α-ANP into the peripheral circulation. ProANP and β-ANP are minor forms in the circulation but are increased in patients with heart failure. The human BNP precursor proBNP is proteolytically processed to BNP 1-32 and N-terminal proBNP (NT-proBNP) within ventricular myocytes. Uncleaved proBNP as well as mature BNP 1-32 and NT-proBNP is secreted from the heart, and its secretion is increased in patients with heart failure. Mature BNP, its metabolites including BNP 3-32 , BNP 4-32 , and BNP 5-32 , and proBNP are all detected as immunoreactive-BNP by the current BNP assay system. We recently developed an assay system that specifically detects human proBNP. Using this assay system, we observed that miR30-GALNTs-dependent O -glycosylation in the N-terminal region of proBNP contributes to regulation of the processing and secretion of proBNP from the heart. [ABSTRACT FROM AUTHOR]

Background: There have been some reports of high tibial osteotomy combined with osteochondral autograft transfer for osteonecrosis of the medial femoral condyle of the knee. However, few of them have focused on the deep knee flexion needed to sit straight in the Japanese style.Purpose: To evaluate the clinical outcomes and the knee flexion of HTO combined with OAT for osteonecrosis of the medial femoral condyle of the knee, especially the ability to sit straight in the Japanese style.Methods: Between 1998 and 2012, valgus HTO combined with OAT was performed in 23 patients for stage IV osteonecrosis according to Koshino's radiological classification of the medial femoral condyle. The follow-up period was more than 2 years in all cases. The mean age at the time of the surgery was 65.8 years, and the mean follow-up period was 72.2 months. The function of the knee and the ability to sitting straight in the Japanese style were examined. Twenty-one knees were examined with second-look arthroscopy to assess the recipient and donor sites.Results: The JOA scale and IKDC subjective scores were significantly improved. Twelve patients were able to sit straight in the Japanese style after the surgery, compared to 3 patients who were able to do so before surgery. On second-look arthroscopy of 21 knees, the average ICRS score was 10.5 points. No patient needed additional surgery except for removal of the implants.Conclusion: Valgus HTO combined with OAT is one treatment option for osteonecrosis of the medial femoral condyle with osteoarthritis. In the present study, many of the patients regained good knee function, and 50% of the patients were able to sit straight in the Japanese style after surgery, which is a higher rate than after total knee arthroplasty and unilateral knee arthroplasty. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify ultrasound parameters reflecting subchondral porosity (Po), subchondral plate thickness (Tpl) and bone volume fraction at the trabecular bone region (BV/TVTb). Sixteen osteoarthritic human lateral femoral condyles were evaluated ex vivo using a 15-MHz pulsed-echo ultrasound 3-D scanning system. The cartilage-subchondral bone (C-B) surface region (layer 1) and inner subchondral bone region (layer 2) were analyzed; we newly introduced entropy (ENT) and correlation (COR) of ultrasound texture parameters of the parallel (x) or perpendicular (z) direction to the C-B interface for this analysis. Po, Tpl and BV/TVTb were evaluated as reference measurements using micro-computed tomography. ENTL1x (ENT of layer 1, x-direction) and ENTL1z were significantly correlated with Po (both r values = 0.58), CORL2x with Tpl (r = -0.73) and CORL2z with BV/TVTb (r = -0.66). These are efficient indicators of the characteristics of osteoarthritis-related subchondral bone; the other texture parameters were not significant. [ABSTRACT FROM AUTHOR]

Background: Plug protuberance occasionally occurs in osteochondral autologous transplantation (OAT). The incongruity of plugs results in poor clinical outcomes, especially in cases of protuberance. However, a surgical procedure to deal with this problem has not been reported. Purpose/Hypothesis: The purpose was to evaluate the efficacy and safety of cartilage resection of elevated plugs, with the hypothesis that patients whose elevated plugs were resected and leveled would achieve clinical outcomes equivalent to those of patients with flush plugs. Study Design: Cohort study; Level of evidence, 3. Methods: Cases (group P) included 22 patients who underwent OAT of the knee and whose plugs showed protuberance greater than 1 mm that was resected with a scalpel to obtain smooth congruity, while controls (group C) included 22 background-matched patients who did not require plug resection. The International Knee Documentation Committee (IKDC) subjective score, IKDC objective grade, and Japanese Orthopaedic Association score for knee osteoarthritis (JOA knee score) were used preoperatively and at the final follow-up (mean ± SD, 49.3 ± 18.1 months). International Cartilage Repair Society (ICRS) Cartilage Repair Assessment was used to evaluate lesion healing during the second-look arthroscopy. Results: IKDC subjective scores of group C (82.5 ± 11.8) and group P (82.1± 15.1) showed no difference at the final follow-up. On postoperative IKDC objective grading, 86% of group C and 82% of group P patients were graded as “nearly normal” or better (P = .639). The mean JOA knee scores of group C (90.9 ± 8.9) and group P (90.1 ± 9.5) did not differ significantly (P = .647). Nine second-look arthroscopies were performed in group C versus 8 in group P, and all patients had plugs that were graded as “nearly normal” or better by the ICRS Cartilage Repair Assessment. Larger plugs tended to be used in those patients who required resection. Conclusion: Resection of the elevated plug surface did not negatively affect patient outcomes in the midterm follow-up period. [ABSTRACT FROM AUTHOR]

B-type natriuretic peptide (BNP) is a cardiac hormone widely used as a biomarker for heart failure. Here, we present the first report of extremely high levels of immunoreactive BNP caused by formation of macro-proBNP. A 70-year-old woman with left ventricular hypertrophy and normal systolic function presented with extremely high plasma levels of BNP (35,374 pg/ml) and N-terminal proBNP (NT-proBNP; 30,600 pg/ml). Our recently developed proBNP immunoassay showed that nearly 100% of her immunoreactive BNP was proBNP. Polyethylene glycol precipitation tests reported extremely low BNP recovery (1.3%), while protein G addition tests also reported a remarkably low BNP fraction (3.3%). Gel filtration chromatography with normal elution buffer combined with BNP immunoassays showed a BNP peak with a retention time slightly shorter than that of IgG. With acidic elution buffer (pH 3.0), however this peak disappeared and a new BNP peak consistent with glycosylated human proBNP appeared. These results suggest that in this case most BNP immunoreactivity consisted of macro-proBNP, which is an immune complex composed of proBNP and an anti-proBNP autoantibody. Gel filtration chromatography combined with NT-proBNP immunoassays revealed that the NT-proBNP assay cross-reacts with both the proBNP-IgG complex and proBNP. In addition, with acidic buffer, a new large peak appeared with a retention time the same as that of glycosylated NT-proBNP. These results suggest spuriously high levels of BNP and NT-proBNP are caused by macro-proBNP. Macro-NT-proBNP is not detected by the currently available NT-proBNP assay system. [ABSTRACT FROM AUTHOR]

Background: It has been reported that the short-term results of mosaicplasty are good, but there have been no reports of the serial cartilage changes in the recipient sites and their mirror sites for mosaicplasty. Purpose: To examine the serial changes in cartilage in the recipient sites and their mirror sites using second-look imaging. Study Design: Case series; Level of evidence, 4. Methods: A total of 33 patients (37 knees, 40 sites) underwent mosaicplasty and second-look arthroscopy at a single institution over a 7-year period. There were 14 men and 19 women (12 right knees and 25 left knees). The recipient sites were the patella (n = 3), trochlea (n = 7), medial femoral condyle (n = 21), and lateral femoral condyle (n = 9). The mean patient age at surgery was 38.3 years; the mean period from mosaicplasty to second-look arthroscopy was 15.4 months; and the mean follow-up period was 34.9 months (range, 24-65 months). The results of second-look arthroscopy at the recipient site were categorized as cartilage with a smooth surface (group S) and fibrillation or an irregular surface (group I), and results of second-look arthroscopy at the mirror site were categorized as worse (group W), improved (group E), and unchanged (group U). Results: There were 30 sites in group S, 10 sites in group I, 3 sites in group W, 4 sites in group E, and 33 sites in group U. The age at operation was significantly greater in group S than in group I. There was a significant correlation between group S and groups E and U. The clinical outcome was significantly worse in group W when compared with groups E and U. Conclusion: If a smooth surface was seen in the recipient site during second-look arthroscopy, the cartilage degeneration in its mirror site did not become worse after mosaicplasty. [ABSTRACT FROM AUTHOR]

Background: We previously developed a surface-controlled water-dispersible form of curcumin and named it Theracurmin (Theracurmin; Theravalues, Tokyo, Japan). The area under the blood concentration-time curve of Theracurmin in humans was 27-fold higher than that of curcumin powder. We determined the clinical effects of orally administered Theracurmin in patients with knee osteoarthritis during 8 weeks of treatment. Methods: Fifty patients with knee osteoarthritis of Kellgren-Lawrence grade II or III and who were aged more than 40 years were enrolled in this randomized, double-blind, placebo-controlled, prospective clinical study. Placebo or Theracurmin containing 180 mg/day of curcumin was administered orally every day for 8 weeks. To monitor adverse events, blood biochemistry analyses were performed before and after 8 weeks of each intervention. The patients' knee symptoms were evaluated at 0, 2, 4, 6, and 8 weeks by the Japanese Knee Osteoarthritis Measure, the knee pain visual analog scale (VAS), the knee scoring system of the Japanese Orthopedic Association, and the need for nonsteroidal anti-inflammatory drugs. Results: At 8 weeks after treatment initiation, knee pain VAS scores were significantly lower in the Theracurmin group than in the placebo group, except in the patients with initial VAS scores of 0.15 or less. Theracurmin lowered the celecoxib dependence significantly more than placebo. No major side effects were observed with Theracurmin treatment. Conclusion: Theracurmin shows modest potential for the treatment of human knee osteoarthritis. [ABSTRACT FROM AUTHOR]

Background: Plasma BNP levels are predictive of prognosis in hemodialysis patients. However, recent studies showed that the current BNP immunoassay cross-reacts with glycosylated proBNP, and the NT-proBNP assay underestimates glycosylated NT-proBNP. In addition, the recently developed high performance dialyzer removes medium-sized molecular solutes such as β2-microgloburin. We therefore investigated the effects of high performance dialysis on measured levels of glycosylated proBNP, glycosylated NT-proBNP and other BNP-related peptides in end-stage renal disease (ESRD) patients on hemodialysis. Method: The relationships between clinical parameters and BNP-related molecule were also investigated. We used our newly developed immunoassay to measure plasma total BNP and proBNP in 105 normal subjects and 36 ESRD patients before and after hemodialysis. Plasma NT-proBNP was measured using Elecsys II after treatment with or without deglycosylating enzymes. We also measured plasma ANP and cGMP using radioimmunoassays. Results: All the measured BNP-related peptides were significantly higher in ESRD patients than healthy subjects. Total BNP (−38.9%), proBNP (−29.7%), glycoNT-proBNP (−45.5%), nonglycoNT-proBNP (−53.4%), ANP (−50.4%) and cGMP (−72.1%) were all significantly reduced after hemodialysis, and the magnitude of the reduction appeared molecular weight- dependent. Both the proBNP/total BNP and glycoNT-proBNP/nonglycoNT-proBNP ratios were increased after hemodialysis. The former correlated positively with hemodialysis vintage and negatively with systolic blood pressure, while the latter correlated positively with parathyroid hormone levels. Conclusion: These results suggest that hemodialysis using super-flux dialyzer removes BNP-related peptides in a nearly molecular weight-dependent manner. The ProBNP/total BNP and glycoNT-proBNP/nonglycoNT-proBNP ratios appear to be influenced by hemodialysis-related parameters in ESRD patients on hemodialysis. [ABSTRACT FROM AUTHOR]

Background: In response to socioeconomic pressure to cut budgets in medicine, single-use surgical instruments are often reprocessed despite potential biological hazard. Purpose: To evaluate the quality and contaminants of reprocessed shaver blades. Hypothesis: Reprocessed shaver blades have mechanical damage and chemical contamination. Study Design: Controlled laboratory study. Methods: Seven blades and 3 abraders were reprocessed 1 time or 3 times and then were assessed. In the first part of the study, structural damage on the blades after 3 reprocessings was compared to that after 1 reprocessing using optical microscopy. In the second part, surface damage was observed using optical microscopy and scanning electron microscopy; elemental and chemical analyses of contaminants found by the microscopy were performed using scanning electron microscopy/energy dispersive x-ray spectroscopy, scanning Auger microscopy, and Fourier transform infrared spectroscopy. Results: Optical microscopic examination revealed abrasion on the surface of the inner blade and cracks on the inner tube after 1 reprocessing. These changes were more evident after 3 reprocessings. Scanning electron microscopy/energy dispersive x-ray spectroscopy of the inner cutter of the blade reprocessed once showed contaminants containing calcium, carbon, oxygen, and silicon, and Fourier transform infrared spectroscopy demonstrated biological protein consisting mainly of collagen, some type of salts, and polycarbonate used in plastic molding. Scanning electron microscopy/energy dispersive x-ray spectroscopy of the inner cutter of the reprocessed abrader revealed contaminants containing carbon, calcium, phosphorous, and oxygen, and Fourier transform infrared spectroscopy showed H2O, hydroxyapatite, and hydroxyl proteins. Scanning Auger microscopy showed that the tin-nickel plating on the moving blade and abrader was missing in some locations. Conclusion: This is the first study to evaluate both mechanical damage and chemical contaminants containing collagen, hydroxyapatite, and salts on the reprocessed arthroscopic shaver blades. Clinical Relevance: Surgeons should keep in mind that mechanical damage and chemical contamination are found on reprocessed arthroscopic blades. [ABSTRACT FROM AUTHOR]

Although osteochondral grafting surgery is believed to replace damaged cartilage with healthy-looking normal cartilage, no study focuses on ultrasound quantification of those cartilage immediately after the surgery. It is unknown whether the ultrasound properties of damaged cartilage from trauma or osteonecrosis are same with each other. We have examined ultrasound properties of damaged cartilage, adjacent intact cartilage and plug cartilage during osteochondral grafting surgery for 15 knees of 15 patients, mean age of 43.4 (range, 14–61) years. Results showed that signal intensities of ultrasound (a measure of superficial cartilage integrity) of intact cartilage, damaged cartilage, and plug cartilage were 1.91 (arbitrary unit), 0.40, and 2.13, respectively, in 11 knees of 11 patients of traumatic cartilage lesions. Interval between signals of ultrasound (a parameter related to thickness) were 2.79 (μs), 1.90, and 2.85, respectively. The signal intensity and the interval between signals of plug cartilage were 533% ( P < 0.01) and 150% ( P < 0.01) of damaged cartilage, respectively. In four knees of four patients of osteonecrosis, the signal intensities of intact cartilage, damaged cartilage, and plug cartilage were 1.25, 0.30, and 1.39, respectively. The interval between signals were 2.36, 2.00, and 2.69, respectively. The signal intensity and the interval between signals of plug cartilage were 463% ( P < 0.01) and 135% ( P < 0.05) of damaged cartilage. We conclude that ultrasound properties of the damaged cartilage from trauma or osteonecrosis did not differ a lot especially in the late stages of osteonecrosis and that the osteochondral grafting surgery replaced the damaged cartilage with plug cartilage that had greater superficial cartilage integrity and greater thickness parameter immediately after the surgery. Long-term effect of the osteochondral grafting surgery should be verified in further study. [ABSTRACT FROM AUTHOR]

Background: Autologous osteochondral mosaicplasty for osteochondritis dissecans of the capitellum is being used increasingly in adolescent patients. Little research has been published on the material properties of living human cartilage of the elbow and knee. Hypothesis: The cartilage of the osteochondritis dissecans lesion is detected as degenerated by ultrasound. The material properties of the cartilage of the intact part of.the elbow are not different from those of the intact knee except in thickness. Study Design: Descriptive laboratory study. Methods: The authors studied 10 young male athletes with osteochondritis dissecans of the capitellum who underwent mosaicplasty. An acoustic probe was used for measurement, and the wavelet transform method was used. Three parameters were used: signal intensity (index of cartilage stiffness), signal duration (index of roughness), and signal interval (index of thickness). Results: The cartilage of the osteochondritis dissecans lesion had lower signal intensity than did the intact part of the capitellum. The cartilage of the radial head opposite the capitellum had significantly lower signal intensity and higher signal duration than did other sites. The signal intensity of the radial head was significantly higher in early-stage patients than in late-stage patients, although the macroscopic view was almost all intact. The signal intensity of the plug was decreased significantly after grafting. Conclusion: The osteochondritis dissecans lesion had lower signal intensity than did the intact part of the capitellum. Although the macroscopic view looked intact, the radial head cartilage was degenerated as measured acoustically. Clinical Relevance: Not only the cartilage of the capitellum but the cartilage of the radial head are acoustically degenerated in osteochondritis dissecans patients. Plugs might be damaged in the transplanting procedure, and further follow-up is necessary. [ABSTRACT FROM AUTHOR]

Although grafted osteochondral plugs should ideally have a smooth surface for mosaicplasty, surface incongruity is sometimes evident at the time of surgery. There may be no problem if there is depression of the grafted plugs, but graft protuberance may have an adverse effect. We studied five knees in five patients who had incongruity (protuberance or depression) of grafted osteochondral plugs at the time of mosaicplasty. The mean age at surgery was 36.6 years (range, 15–65 years), and the mean follow-up period was 32.9 months (range, 24–49 months). All patients underwent second-look arthroscopy after a mean post-surgical period of 14.8 months (range, 3–18 months). We divided the cases so that there were two in the protuberant group (P) and three in the depressed group (D). In P, all patients had a catching sensation about 4 months after surgery, and sometimes pain in the knee joint. Second-look arthroscopy revealed fissuring of the plugs and fibrillation around the recipient site. In D, there were no symptoms due to the depressed plugs. Second-look arthroscopy showed that the depressed areas were covered with fibrocartilage-like tissue, and that the joint surface was smooth. In conclusion, our clinical results and second-look arthroscopic evaluation suggest that isolated osteochondral plug depressions of not greater than 1 mm could still promote acceptable cartilage healing leading to good clinical outcomes. However, plug protuberance at mosaicplasty should always be avoided. [ABSTRACT FROM AUTHOR]

Abstract: We recently reported that a transcriptional repressor, neuron-restrictive silencer factor (NRSF), represses expression of fetal cardiac genes, including atrial and brain natriuretic peptide (ANP and BNP), by recruiting class I histone deacetylase (HDAC) and that attenuation of NRSF-mediated repression contributes to the reactivation of fetal gene expression during cardiac hypertrophy. The molecular mechanism by which the activity of the NRSF–HDAC complex is inhibited in cardiac hypertrophy remains unresolved, however. In the present study, we show that class II HDACs (HDAC4 and 5), which are Ca/calmodulin-dependent kinase (CaMK)-responsive repressors of hypertrophic signaling, associate with NRSF and participate in NRSF-mediated repression. Blockade of the CaMK-class II HDAC signaling pathway using a CaMK-resistant HDAC5 mutant, a CaMK inhibitor (KN62) or a dominant-negative CaMK mutant inhibited ET-1-inducible ANP and BNP promoter activity, but that inhibitory effect was abolished by mutation of the neuron-restrictive silencer element (NRSE) within the ANP and BNP promoter. In addition, adenovirus-mediated expression of a dominant-negative NRSF mutant abolished the inhibitory effect of KN62 on ET-1-inducible endogenous ANP gene expression in ventricular myocytes. Finally, the interaction between NRSF and class II HDACs was decreased in both in vitro and in vivo models of cardiac hypertrophy. These findings show that ET-1-induced CaMK signaling disrupts class II HDAC–NRSF repressor complexes, thereby enabling activation of ANP and BNP gene transcription in ventricular myocytes, and shed light on a novel mechanism by which the fetal cardiac gene program is reactivated. [Copyright &y& Elsevier]

Background: There are growing concerns about thermal chondroplasty using radiofrequency energy to treat partial-thickness cartilage defects. However, most studies emphasize effects on chondrocyte viability, and other factors such as mechanical properties are less studied. Hypothesis: Radiofrequency energy may cause significant effects on articular cartilage other than chondrocyte viability. Study Design: Controlled laboratory study. Methods; Human osteoarthritic cartilage samples were obtained from total knee arthroplasty, and monopolar radiofrequency energy was applied using commercially available equipment. Material properties (compressive stiffness, surface roughness, and thickness) just before and after thermal treatment were determined using ultrasound. A series of biochemical analyses were also performed after explant culture of the samples. Results: The cartilage surface became smoother by radiofrequency energy, whereas cartilage stiffness or thickness was not altered significantly. Collagen fibrils, especially in the superficial layers, were converted to denatured form, whereas proteoglycan contents released in the media as well as retained in the tissue remained unchanged. The concentrations of matrix metalloproteinases (MMP-1 and MMP-2) were reduced remarkably. Conclusion: Radiofrequency energy is able to create a smooth cartilage surface and reduce catabolic enzymes at the cost of collagen denaturation and chondrocyte death in the superficial layers. The stiffness of the cartilage is not changed at time zero. Clinical Relevance: Further animal as well as clinical studies will be necessary to fully evaluate the long-term effects of radiofrequency energy. [ABSTRACT FROM AUTHOR]

This article focuses on a study related to cervical spinal cord injury in sumo wrestling. Sumo has long been a traditional sport in Japan. But the first World Sumo Championship was held only as recently as 1992, when the International Sumo Federation was established. Since then, the World Sumo Championships have been held in Japan, Germany, and Brazil. In the present case a 19-year-old collegiate sumo wrestler, 166 cm tall and weighing 78 kg, had been practicing sumo for 10 years. During an intercollegiate sumo championship on October 31, 1999, he competed with an opponent whose weight was 120 kg.

Focuses on a study which examined a treatment for end-stage osteochondritis dissecans lesions of the humeral capitellum. Details of a case report about a boy suffering from pain in his right elbow; Information on osteochondritis dissecans of an elbow; History of the patient; Description of surgical treatments for osteochondritis.

Intraosseous ganglia of the glenoid are rare, and their etiology is unknown. This report describes a case of an intraosseous ganglion about to cause fracture of the glenoid. The patient was a 61-year-old woman with a painful left shoulder with a limited range of motion. Her symptoms did not improve after non-operative treatment. Arthroscopic examination showed a cartilage defect and erosion in the posteroinferior portion of the glenoid, behind which computed tomography (CT) showed a cystic lesion of the glenoid. There was no communication between the cyst and the joint space. The patient was treated by curettage and an autogenous cancellous bone graft from the iliac crest. Two years after the operation, the patient was almost free from pain, and CT showed good integration of the bone graft. [ABSTRACT FROM AUTHOR]

Presents the case of a recurrent throwing fracture of the humerus experienced by a baseball player. Clinical profile of the player; Risk factors associated with humerus fractures; Possible causes of recurrent fracture.

To assess the physiological and clinical implications of the C-type natriuretic peptide (CNP)/guanylyl cyclase B (GC-B) system in the human vasculature, we have examined gene expressions of CNP and its receptor, GC-B, in human vascular endothelial cells (ECs) and smooth muscle cells (SMCs) and have also compared the endothelin-1(ET-1)/endothelin receptor-A (ETR-A) and endothelin receptor-B (ETR-B) system in human aortic ECs (HAECs) and vascular SMCs (HSMCs) in vitro. We also examined these gene expressions in human embryonic stem (ES)/induced pluripotent stem cell (iPS)-derived ECs and mural cells (MCs). A little but significant amount of mRNA encoding CNP was detected in both human ES-derived ECs and HAECs. A substantial amount of GC-B was expressed in both ECs (iPS-derived ECs and HAECs) and SMCs (iPS-derived MCs and HSMCs). ET-1 was expressed solely in ECs. ETR-A was expressed in SMCs, while ETR-B was expressed in ECs. These results indicate the existence of a vascular CNP/GC-B system in the human vascular wall, indicating the evidence for clinical implication of the CNP/GC-B system in concert with the ET-1/ETR-A and ETR-B system in the human vasculature. [ABSTRACT FROM AUTHOR]

We aimed to quantitatively investigate the relationship between amplitude-based pulse-echo ultrasound parameters and early degeneration of the knee articular cartilage. Twenty samples from six human femoral condyles judged as grade 0 or 1 according to International Cartilage Repair Society grading were assessed using a 15-MHz pulsed-ultrasound 3-D scanning system ex vivo. Surface roughness (Rq), average collagen content (A1) and collagen orientation (A12) in the superficial zone of the cartilage were measured via laser microscopy and Fourier transform infrared imaging spectroscopy. Multiple regression analysis with a linear mixed-effects model (LMM) revealed that a time-domain reflection coefficient at the cartilage surface (Rc) had a significant coefficient of determination with Rq and A12 (RLMMm2=0.79); however, Rc did not correlate with A1. Concerning the collagen characteristic in the superficial zone, Rc was found to be a sensitive indicator reflecting collagen disorganization, not collagen content, for the early degeneration samples. [ABSTRACT FROM AUTHOR]

In this study, a two-stage absorption heat transformer was investigated, which can generate high-temperature steam of approximately 180°C driven by waste heat from hot water below 90°C. A model-scale (steam 14 kW) apparatus and a practical-scale (steam 200 kW) test apparatus were designed and built. Test operations of the apparatus were conducted, and the function and effectiveness of the heat transformers were verified. [ABSTRACT FROM PUBLISHER]

Myocardin-related transcription factor (MRTF)-A is a Rho signalling-responsive co-activator of serum response factor (SRF). Here, we show that induction of MRTF-A expression is key to pathological vascular remodelling. MRTF-A expression was significantly higher in the wire-injured femoral arteries of wild-type mice and in the atherosclerotic aortic tissues of ApoE?/? mice than in healthy control tissues, whereas myocardin expression was significantly lower. Both neointima formation in wire-injured femoral arteries in MRTF-A knockout (Mkl1?/?) mice and atherosclerotic lesions in Mkl1?/?; ApoE?/? mice were significantly attenuated. Expression of vinculin, matrix metallopeptidase 9 (MMP-9) and integrin ?1, three SRF targets and key regulators of cell migration, in injured arteries was significantly weaker in Mkl1?/? mice than in wild-type mice. In cultured vascular smooth muscle cells (VSMCs), knocking down MRTF-A reduced expression of these genes and significantly impaired cell migration. Underlying the increased MRTF-A expression in dedifferentiated VSMCs was the downregulation of microRNA-1. Moreover, the MRTF-A inhibitor CCG1423 significantly reduced neointima formation following wire injury in mice. MRTF-A could thus be a novel therapeutic target for the treatment of vascular diseases. [ABSTRACT FROM AUTHOR]

The article discusses the procedure of autogenous bone-cartilage transplantation. Among the measures for cartilage repair include marrow stimulation, correction osteotomy and chondrocyte or stem cell transplantation. An overview of the indications and contraindications of autogenous bone-cartilage transplantation is provided, along with technical data about osteonecrosis of the knee, and complications and rehabilitation of the procedure.

We previously developed a novel ultrasound assessment system featuring wavelet transform to evaluate the material properties of articular cartilage. We aimed in this study to demonstrate the feasibility of quantitative evaluation of meniscus using ultrasound and to elucidate the relationships between its acoustic, mechanical, and biochemical properties. Meniscal disc specimens from mature pigs were assessed by ultrasound and compression testing, and their correlation was analyzed. A positive correlation was found between the ultrasound signal intensity and apparent Young's modulus ( r = 0.61). Subsequently, the porcine meniscal discs were treated with various enzymes and then characterized by ultrasound, by compression tests, by biochemical analyses, and by histology and immunohistochemistry. The signal intensity was decreased not by hyaluronidase but by collagenase treatment. Hyaluronidase-treated menisci showed a discrepancy between acoustic and mechanical properties, suggesting that the ultrasound reflection could not detect a reduction in proteoglycan content. Also, ultrasound signal intensity could only reflect superficial layers of the material. Several limitations exist at present, and further studies and improvements of the device are required. However, given the noninvasive nature and the requirement of only small equipment, this ultrasound assessment system will be an instrumental diagnostic tool for meniscal function in both research and clinical fields. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:884-893, 2007 [ABSTRACT FROM AUTHOR]

Abstract: As a preclinical study, we evaluated the ability of hydroxyapatite and titanium on zirconia (HTOZ) to bond to bone under load-bearing conditions in animal experiments. HTOZ, HA, and Ti on Co–Cr alloy (HTOC) and Ti on Co–Cr alloy (TOC) were implanted into the weight-bearing portion of the femoral condyles of nine beagle dogs. Femurs were extracted 4, 12, and 52 weeks after implantation and examined mechanically by pullout testing, and histologically by toluidine blue staining, SEM, and calculation of the affinity index. The interfacial shear strengths (mean±SD) of the HTOZ, HTOC, and TOC groups were 4.42±0.453, 3.90±0.903, and 4.08±0.790MPa at 4 weeks; 6.82±2.64, 6.00±1.88, and 6.63±1.63MPa at 12 weeks; and 13.98±1.94, 11.95±1.51, and 10.78±0.83MPa at 52 weeks. There were no significant differences in the interfacial shear strengths between the three groups at any time. Affinity indices (mean±SD) obtained from SEM images of the HTOZ, HTOC, and TOC groups were 49.6±6.52%, 43.3±10.43%, and 23.7±3.95% at 4 weeks; 55.0±6.72%, 51.5±3.07%, and 28.6±4.09% at 12 weeks; and 59.1±6.73%, 63.0±6.40%, and 34.3±6.72% at 52 weeks. HA-coated implants (HTOZ, HTOC) had significantly higher affinity indices than non-HA-coated implants (TOC) at all times. HTOZ has the ability to bond to bone equivalent to HTOC and TOC. HTOZ is an excellent material for components of cementless joint prostheses. [Copyright &y& Elsevier]

Abstract: Low-intensity pulsed ultrasound (LIPUS) has been shown to accelerate fracture healing, but the precise mechanism is still unknown. We used aggregate chondrocyte culture system to analyze LIPUS-induced effects on chondrocytes. First, Northern analyses revealed that LIPUS maintained higher expression levels of type II collagen and aggrecan mRNA and delayed the appearance of type X collagen mRNA expression. We also showed that DNA content was increased and that alkaline phosphatase activity was maintained low by daily treatment. Moreover, LIPUS significantly promoted transforming growth factor (TGF)-β1 mRNA expression and the protein production at 2 h and 12 h after the treatment, respectively. Furthermore, recombinant TGF-β1 protein mimicked the LIPUS effect and anti-TGF-β1 neutralizing antibody reversed all these changes induced by the LIPUS treatment. These results indicate that LIPUS promotes the proliferation and retains the differentiation state of chondrocytes in the aggregate culture and that TGF-β1 plays an important role in mediating the LIPUS effects in chondrocytes. (E-mail: smukai@kyotolan.hosp.go.jp) [Copyright &y& Elsevier]

A domino osteochondral autograft transplantation enables the treatment of larger lesions compared to typical osteochondral autograft transplantation. Herein, we describe a case of steroid-induced knee osteonecrosis combined with osteonecrosis of the femoral head in which the knee was treated with domino osteochondral autograft transplantation. 4 Conclusion We reported a case in which we performed a domino osteochondral autograft transplantation using the resected femoral head as the donor for steroid-induced osteonecrosis of the knee that developed simultaneously with osteonecrosis of the hip. Since the necrotic lesion plus bone defect was larger in her left knee than in her right knee, we planned to operate on her left knee and right hip simultaneously so that we could use the resected femoral head as a donor site for the left knee surgery. [Extracted from the article]

The article discusses the molecular forms of B-type natriuretic peptide (BNP) in heart failure. It mentions that the molecular forms of BNP circulating in plasma of heart failure patients remain uncertain because aminopeptidases digest the N-terminal region of BNP and the current assay systems also cross-react with BNP altering is molecular form. It further states that in healthy individuals BNP metabolites is difficult because of the low level of BNP present.

We have previously reported that promoter polymorphism of myocardin-related transcription factor A (MRTF-A) is associated with coronary atherosclerosis. However, the contribution of MRTF-A to the development of atherosclerosis remains unknown. Macrophages are known to be important mediators of atherosclerosis. It has been demonstrated that local proliferation and survival of macrophages are atherogenic. In this study, we found that MRTF-A was highly expressed in lesional macrophages in human carotid atherosclerotic plaque. We then investigated the role of macrophagic MRTF-A in the pathogenesis of atherosclerosis. ApoE null MRTF-A transgenic mice (ApoE−/−/MRTF-Atg/+), in which human MRTF-A was specifically overexpressed in monocytes/macrophages, were established and fed with normal diet to examine the progression of atherosclerosis. We found that ApoE−/−/MRTF-Atg/+ aggravated atherosclerosis and lesional macrophages were more prominently accumulated in the aortic sinus of ApoE−/−/MRTF-Atg/+ than in that of ApoE−/− littermates. We also found that MRTF-A promoted proliferation and mitigated apoptosis of macrophages both in vitro and in vivo , and down regulated the expression of cyclin-dependent kinase inhibitors. From these findings, we conclude that MRTF-A modulates functional properties of pro-atherogenic macrophages. Our study may play a valuable role in understanding the pathological role of macrophagic MRTF-A in the progression of atherosclerosis. • Overexpression of MRTF-A in macrophages exacerbates atherosclerosis in ApoE knockout mice without altering plasma profile. • Overexpression of MRTF-A in macrophages facilitates local accumulation of lesional macrophages in atherosclerotic plaques. • MRTF-A mitigates apoptosis and promotes proliferation of macrophages. • MRTF-A regulates the expression level of cyclin-dependent kinase inhibitors. [ABSTRACT FROM AUTHOR]

Background: The blood pressure (BP) variability (BPV) is a predictor of cardiovascular disease, independently of the BP itself. In addition, visceral fat accumulation can trigger atherosclerotic disease through various mechanisms. Methods and results: We examined the association between fat accumulation and day-to-day BPV in 61 adult hypertensive patients. Visceral fat area (VFA) was measured using the dual bioelectrical impedance analysis method. Participants were divided into three groups based on VFA. The standard deviation (SD) in home systolic BP (SBP) for 7 consecutive days was significantly lower in the high VFA tertile (low VFA, 8.40±4.15 mmHg; intermediate VFA, 8.47±2.80 mmHg; and high VFA, 5.84±2.37 mmHg, p of One-way ANOVA = 0.017, p for trend = 0.0126). A similar association was observed between the coefficient of variance (CV) of home SBP and the VFA tertile. Multiple-regression analysis adjusted for age, sex, antihypertensive drug, diabetes, habitual drinking, and SBP level also showed a significant association between the VFA tertile and the SD or CV of home SBP. The adjusted coefficient of regression for the SD of home SBP was -3.28 (95%CI: -5.60 to -0.97, p = 0.008) and the CV of home SBP was -2.51 (95%CI: -4.31 to -0.71, p = 0.008) for the highest VFA tertile as compared to the lowest VFA tertile. Conclusions: These results show for the first time negative correlation between VFA and day-to-day BPV. The degree of obesity should be taken into account when evaluating the value of BPV. [ABSTRACT FROM AUTHOR]

Reports on the measurement of the high field magnetization in Sm[sub2]Fe[sub17]N[sub3.0]. Data on the observed magnetization curves; Calculation of the angle between the samarium moment and c axis.

Presents a high-resolution neutron powder diffraction study on nitrogenated Nd[sub2]Fe[sub17]. Determination of structural parameters and magnetic moments; Analysis of the magnetic moments of iron atoms; Measurement of neutron diffraction intensities.

Studies the crystal distortion and weak ferromagnetism of Mn[sub3+δ]Ga[sub1-x]Ge[subx] alloys. Hexagonal structure of the intermetallic compound Mn[sub3]Ga; Saturation magnetization of the compounds; Temperature dependence of saturation magnetization.

Presents a study which measured the magnetization and neutron diffraction of a single crystal of hexagonal yttrium iron manganese oxygen[sub4], a two dimensional Heisenberg triangular antiferromagnet. Experimental details; Results and discussion; Conclusion.

Presents a study that measured the upper critical field hydrogen (H)[subc2] of superconducting niobium[sub3]germanium films prepared by sputtering and chemical vapor deposition in a pulsed field. Relation of the H[subc2] of the films to their superconducting critical temperature; Linear increase of H[subc2] in sputtered films; Dependence of H[subc2] to temperature.

Deals with a study which investigated the composition dependence of the lattice constants, Curie temperature, remanent magnetization, coercivity, and magnetic annealing effect of manganese-gallium alloys. Discussion on ferrimagnetic structure; Methodology of the study; Results and discussion.

We conducted an open-label, randomized study to evaluate the clinical efficacy of cefozopran, meropenem or imipenem–cilastatin using cefepime as a control in febrile neutropenia (FN) patients. Three hundred and seventy-six patients received cefepime, cefozopran, meropenem or imipenem–cilastatinas initial therapy for FN. The primary endpoint was the non-inferiority of response rates including modification at day 7 in cefozopran, meropenem or imipenem–cilastatin patients compared with cefepime in the per-protocol population (delta = 10%). The response rates for cefozopran, meropenem and imipenem–cilastatin were not significantly different compared with cefepime (cefozopran: 54/90 (60%), meropenem: 60/92 (65%), and IPM/CS: 63/88 (72%) versus cefepime: 56/85 (66%) ( p = 0.44, 1.0 and 0.51, respectively)), and the differences in treatment success for cefozopran, meropenem and imipenem–cilastatin compared with cefepime were −5.9% (95% confidence interval (CI): −20.1–8.4), −0.7% (95% CI: −14.6–13.3), and 5.7% (95% CI: −8.1–19.4), respectively. The same tendency was seen in the modified intention-to-treat population. Based on the evaluation of initial drug efficacy performed on days 3–5, there was no significant difference between the four drugs. In the subgroup with an absolute neutrophil count ≤100 × 10 6 /L for longer than seven days, there was significantly better efficacy in the carbapenem arm compared to 4th generation beta-lactams (52% versus 27% at days 3–5, p = 0.006, and 76% versus 48% at day 7, p = 0.002). Our results suggest that the effects of these four drugs as empiric therapy were virtually the same for adult FN patients, although non-inferiority was shown only in imipenem–cilastatin compared with cefepime (clinical trial number: UMIN000000462 ). [ABSTRACT FROM AUTHOR]

Aims Dysregulation of autonomic nervous system activity can trigger ventricular arrhythmias and sudden death in patients with heart failure. N-type Ca2+ channels (NCCs) play an important role in sympathetic nervous system activation by regulating the calcium entry that triggers release of neurotransmitters from peripheral sympathetic nerve terminals. We have investigated the ability of NCC blockade to prevent lethal arrhythmias associated with heart failure. Methods and results We compared the effects of cilnidipine, a dual N- and L-type Ca2+ channel blocker, with those of nitrendipine, a selective L-type Ca2+ channel blocker, in transgenic mice expressing a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). In this mouse model of dilated cardiomyopathy leading to sudden arrhythmic death, cardiac structure and function did not significantly differ among the control, cilnidipine, and nitrendipine groups. However, cilnidipine dramatically reduced arrhythmias in dnNRSF-Tg mice, significantly improving their survival rate and correcting the imbalance between cardiac sympathetic and parasympathetic nervous system activity. A β-blocker, bisoprolol, showed similar effects in these mice. Genetic titration of NCCs, achieved by crossing dnNRSF-Tg mice with mice lacking CACNA1B, which encodes the α1 subunit of NCCs, improved the survival rate. With restoration of cardiac autonomic balance, dnNRSF-Tg;CACNA1B+/− mice showed fewer malignant arrhythmias than dnNRSF-Tg;CACNA1B+/+ mice. Conclusions Both pharmacological blockade of NCCs and their genetic titration improved cardiac autonomic balance and prevented lethal arrhythmias in a mouse model of dilated cardiomyopathy and sudden arrhythmic death. Our findings suggest that NCC blockade is a potentially useful approach to preventing sudden death in patients with heart failure. [ABSTRACT FROM PUBLISHER]

Recognizing subtle cartilage changes in the preclinical stage of osteoarthritis (OA) is essential for early diagnosis. To this end, the ability of the ultrasound signal intensity to detect macroscopically undetectable cartilage change was investigated. In this study, cartilage of rabbit OA model and human OA samples was examined by macroscopic evaluation, ultrasound signal intensity, histology with Mankin scores, and Fourier transform infrared imaging (FTIRI) analysis. Rabbit OA was induced by anterior cruciate ligament transection and evaluated at 1, 2, 4 and 12 weeks. Twenty human samples were harvested during total knee arthroplasty from OA patients who had macroscopically normal human cartilage (ICRS grade 0) on the lateral femoral condyle. In the animal study, there was no macroscopic OA change at 2 weeks, but histology detected degenerative changes at this time point. Ultrasound signal intensity also detected degeneration at 2 weeks. In human samples, all samples were obtained from macroscopically intact site, however nearly normal (0≤ Mankin score <2), early OA (2≤ Mankin score <6), and moderate OA (6≤ Mankin score <10) samples were actually intermixed. Ultrasound signal intensity was significantly different among these 3 stages and was well correlated with Mankin scores (R = −0.80) and FTIR parameters related to collagen and proteoglycan content in superficial zone. In conclusion, ultrasound can detect microscopic cartilage deterioration when such changes do not exist macroscopically, reflecting superficial histological and biochemical changes. [ABSTRACT FROM AUTHOR]

Background and Purpose Angiotensin II has been implicated in the development of various cardiovascular ailments, including cardiac hypertrophy and heart failure. The fact that inhibiting its signalling reduced the incidences of both sudden cardiac death and heart failure in several large-scale clinical trials suggests that angiotensin II is involved in increased cardiac arrhythmogenicity during the development of heart failure. However, because angiotensin II also promotes structural remodelling, including cardiomyocyte hypertrophy and cardiac fibrosis, it has been difficult to assess its direct contribution to cardiac arrhythmogenicity independently of the structural effects. Experimental Approach We induced cardiac hypertrophy in wild-type ( WT) and angiotensin II type 1a receptor knockout ( AT1aR- KO) mice by transverse aortic constriction ( TAC). The susceptibility to ventricular tachycardia ( VT) assessed in an in vivo electrophysiological study was compared in the two genotypes. The effect of acute pharmacological blockade of AT1 R on the incidences of arrhythmias was also assessed. Key Results As described previously, WT and AT1aR- KO mice with TAC developed cardiac hypertrophy to the same degree, but the incidence of VT was much lower in the latter. Moreover, although TAC induced an increase in tyrosine phosphorylation of connexin 43, a critical component of gap junctional channels, and a reduction in ventricular levels of connexin 43 protein in both genotypes, the effect was significantly ameliorated in AT1aR- KO mice. Acute pharmacological blockade of AT1R also reduced the incidence of arrhythmias. Conclusions and Implications Our findings demonstrate that AT1aR-mediated signalling makes a direct contribution to the increase in arrhythmogenicity in hypertrophied hearts independently of structural remodelling. [ABSTRACT FROM AUTHOR]

Background:Recent studies have shown that in addition to brain (or B-type) natriuretic peptide (BNP) and the N-terminal proBNP fragment, levels of intact proBNP are also increased in heart failure. Moreover, present BNP immunoassays also measure proBNP, as the anti-BNP antibody cross-reacts with proBNP. It is important to know the exact levels of proBNP in heart failure, because elevation of the low-activity proBNP may be associated with the development of heart failure. Methodology/Principal Findings: We therefore established a two-step immunochemiluminescent assay for total BNP (BNP+proBNP) and proBNP using monoclonal antibodies and glycosylated proBNP as a standard. The assay enables measurement of plasma total BNP and proBNP within only 7 h, without prior extraction of the plasma. The detection limit was 0.4 pmol/L for a 50-ml plasma sample. Within-run CVs ranged from 5.2%-8.0% in proBNP assay and from 7.0%-8.4% in total BNP assay, and between-run CVs ranged from 5.3-7.4% in proBNP assay and from 2.9%-9.5% in total BNP assay, respectively. The dilution curves for plasma samples showed good linearity (correlation coefficients = 0.998-1.00), and analytical recovery was 90-101%. The mean total BNP and proBNP in plasma from 116 healthy subjects were 1.4±1.2 pM and 1.0±0.7 pM, respectively, and were 80±129 pM and 42±70 pM in 32 heart failure patients. Plasma proBNP levels significantly correlate with age in normal subjects. Conclusions/Significance: Our immunochemiluminescent assay is sufficiently rapid and precise for routine determination of total BNP and proBNP in human plasma. [ABSTRACT FROM AUTHOR]

The aim was to use repeat delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) to estimate glycosaminoglycan (GAG) content in reparative cartilage after osteochondral autogenous transfer (OAT). The study group comprised 7 knees of 7 patients that were examined three times by dGEMRIC, at 3, 6, and 12 months using a 1.5 Tesla MRI system in both OAT operated and nonoperated condyles at 90 min after the injection. The gadolinium diethylene triamine pentaacetic acid (Gd-DTPA)2− containing contrast medium (0.2 mmols/kg) was injected intravenously. The mean T1 values of the plug cartilage at 3, 6, and 12 months after OAT was 230 ± 40, 213 ± 31, and 230 ± 23 ms (mean ± SD), respectively. There were differences between the plug and control cartilage at 3 ( p < 0.01) and 12 ( p < 0.05) months after OAT, but not at 6 months ( p = 0.089). No T1 changes were detected between the plug cartilage at the different time points after OAT. The fact that the GAG content of the OAT plugs were maintained for 12-month study period suggest that no major deterioration of load-bearing properties occurs in the cartilage after the OAT. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:221-225, 2012 [ABSTRACT FROM AUTHOR]

Objective Pro-brain natriuretic peptide (proBNP)-108 and N-terminal proBNP-76 (NT-BNP) contain seven sites for O-linked oligosaccharide attachment. Currently, levels of glycosylated NT-BNP are probably underestimated because it is not recognised by one antibody in the sandwich assay system. The pathophysiological significance of cardiac and plasma levels of non-glycosylated (nonglyNT-BNP) and glycosylated NT-BNP (glyNT-BNP) in heart failure (HF) and chronic renal failure (CRF) was investigated. Methods Plasma samples from 186 patients with HF and 76 patients with CRF on haemodialysis were studied, together with 11 atrial tissue samples. To measure nonglyNT-BNP and glyNT-BNP, samples were incubated with or without deglycosylating enzymes and NT-BNP was measured using Roche Elecsys proBNP I. The percentage glyNT-BNP was calculated as glyNT-BNP/ (glyNT-BNP + nonglyNT-BNP). Results In HF, plasma BNP, nonglyNT-BNP and glyNT-BNP levels all increased with increasing disease severity (New York Heart Association class; p<0.0001), though the molar ratio remained constant (molar ratio, BNP:nonglyNT-BNP:glyNT-BNP = 1:2.4:9.6). Before haemodialysis for CRF, plasma BNP and nonglyNT-BNP were somewhat elevated, and glyNT-BNP was markedly increased (molar ratio, BNP:nonglyNT-BNP:glyNT-BNP = 1:8.5:82). After haemodialysis, plasma BNP, nonglyNT- BNP, atrial natriuretic protein and cGMP all declined (p<0.0001), but glyNT-BNP was unchanged. Notably, the percentage of glyNT-BNP was elevated before haemodialysis, and was further increased after haemodialysis (p<0.0001). Atrial tissue levels of BNP, nonglyNT-BNP and glyNT-BNP were similar. Conclusion The findings suggest that most endogenous plasma NT-BNP is glycosylated and therefore undetectable with the current assay system, and that the relative glycosylation level is increased by haemodialysis. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to quantify rotational and antero-posterior instabilities using biplanar image-matching technique. Methods: Biplanar radiographs of both chronic ACL-deficient knees and contralateral uninjured knees were taken in the pivot shift test and in the 'giving way position' and lateral radiographs in stress arthrometer at 30° and 90°. Three-dimensional knee models were constructed using computed tomography. Using biplanar image-matching technique, the external rotational angle and the translation of the center of the both condyles of the femur were analyzed. Results: The external rotation angle of geometric center axis in the pivot shift test was 16.9° ± 5.6° and 10.9° ± 7.3° ( P = 0.004), and in the 'giving way position' was 16.1° ± 5.7° and 10.7° ± 6.6° ( P = 0.004) in ACL-deficient knees and intact knees, respectively. In the pivot shift test, the medial and the lateral femoral condylar centers of ACL-deficient knees were translated 1.2 ± 5.1 mm anteriorly and 3.9 ± 3.4 mm posteriorly, respectively, and in the 'giving way position,' 2.0 ± 3.7 mm anteriorly and 2.9 ± 2.6 mm posteriorly, respectively. In stress arthrometer at 30°, the medial and the lateral femoral condylar center translated 7.1 ± 6.0 and 6.6 ± 4.8 mm posteriorly (n.s.), respectively, and at 90° translated 2.7 ± 3.4 and 2.6 ± 3.5 mm posteriorly (n.s.), respectively. Conclusion: Rotational instability was evaluable in the pivot shift test and in the 'giving way position.' Translation of both condylar centers was similar in stress arthrometry. The image-matching technique is able to quantify dynamic rotational and antero-posterior instabilities with static parameters in ACL-deficient knees. Level of evidence: III. [ABSTRACT FROM AUTHOR]