The regenerative treatment of costal osteochondral graft implantation for partial growth arrest using a rabbit model.

PURPOSE: To investigate the feasibility of cylindrical costal osteochondral graft transplantation as a novel regenerative treatment in growth arrest. METHODS: The medial portion of the proximal tibial growth plate of 6-week-old male New Zealand White rabbits was resected to establish an experimental model of partial growth plate injury. The rabbits were divided into four groups: no-treatment, bone wax transplantation, costal chondral graft, and costal osteochondral graft groups. Radiographic and micro-computed tomography scan results were analyzed to evaluate angular deformity of the tibia and bony bridge formation at the injury site. In addition, repair of the injured growth plate cartilage was assessed histologically at 4, 8, and 12 weeks postoperatively. RESULTS: Radiographic examination revealed that bone wax transplantation continuously decreased the medial proximal tibial angle (MPTA) while the costal chondral graft implantation reduced the decrease of MPTA at 12 weeks postoperatively. The costal osteochondral graft implantation recovered the MPTA, close to the normal. Histologically, the costal osteochondral grafts retained the MPTA in the injured site compared to costal chondral grafts. Additionally, hypertrophic chondrocytes were observed at the graft site in the costal osteochondral graft group at 12 weeks, suggesting that endochondral ossification may occur at the graft site similar to normal ossification. The fluorescence in situ hybridization analysis of osteochondral grafts transplanted from male to female rabbits indicated that they were replaced by cells of host origin. CONCLUSION: The costal osteochondral graft can achieve regeneration without bony bridge formation in partial growth plate injury.

Development of new colloid osmotic pressure measurement method using ultrafiltration membrane during cardiopulmonary bypass.

BACKGROUND: Clinical practice of measuring colloid osmotic pressure (COP) was abandoned after correcting hypoosmolarity did not improve overall patient outcomes. However, the use of albumin and colloidal solutions has contributed to maintaining intraoperative and postoperative fluid balance at lower levels. Reduced perioperative fluid balance is consistently reported to have positive effects on clinical outcomes. Priming solutions for cardiopulmonary bypass typically include colloids; however, the optimal type of priming solution has not yet been determined. Stricter COP management may further improve postoperative courses. To achieve this, the widespread adoption of a measurement method suitable for COP monitoring during cardiopulmonary bypass is required. METHODS: A test circuit was made which measured COP using an ultrafiltration membrane method based on the changes in hydrostatic pressure that occurs across a semipermeable membrane. We then compared the measurements obtained using this method with colloidal osmometer measurements. RESULTS: COP measurements were obtained for a total of 100 tests (10 times each for 10 test solutions). The evaluation parameters included simultaneous reproducibility, correlation with the colloid osmometer, and measurement time. The results demonstrated high accuracy of the ultrafiltration membrane method, simultaneous reproducibility within 3%, a high positive correlation with the colloid osmometer (correlation coefficient: R2 = 0.99; p < 0.01), and equal time required for measurement. CONCLUSION: Measuring COP using ultrafiltration membranes solves problems within existing measurement methods. Although further improvements in the method are necessary, it has implications for future research and clinical applications.

Antithrombotic Therapy for Patients With Atrial Fibrillation and Bioprosthetic Valves　- Real-World Data From the Multicenter, Prospective, Observational BPV-AF Registry.

BACKGROUND: Although bioprosthetic valve (BPV) replacements are becoming more common within our aging society, there are limited prospective data on the appropriate antithrombotic therapy for East Asian patients with atrial fibrillation (AF) and BPV replacement. Antithrombotic therapy and thrombotic and hemorrhagic event rates in Japanese patients with AF and BPV replacement are investigated.Methods and Results:This multicenter, prospective, observational study enrolled patients with BPV replacement and AF. The primary efficacy outcome was stroke or systemic embolism, and the primary safety outcome was major bleeding. Of the 894 patients analyzed, 54.7%, 29.4%, and 9.6%, were treated with warfarin-based therapy, direct oral anticoagulant (DOAC)-based therapy, or antiplatelet therapy without anticoagulants, respectively; 6.3% did not receive any antithrombotic drugs. The mean observation period was 15.3±4.0 months. The event rates for stroke or systemic embolism and major bleeding were 1.95%/year and 1.86%/year, respectively. The multivariate adjusted hazard ratios for DOAC vs. warfarin were 1.02 (95% confidence intervals [CI], 0.30-3.41 [P=0.979]) for systemic embolic events and 0.96 (95% CI, 0.29-3.16 [P=0.945]) for major bleeding. CONCLUSIONS: Approximately 30% of patients with AF and BPV replacement were treated with DOAC. The risks of major bleeding and stroke or systemic embolism were similar between warfarin- and DOAC-treated patients with AF who had BPV replacement. Treatment with DOACs could be an alternative to warfarin in this population.

Comparison of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and an Aortic Bioprosthetic Valve.

BACKGROUND: Current guidelines equally recommend direct oral anticoagulants (DOACs) and warfarin for atrial fibrillation (AF) patients with a bioprosthetic valve (BPV); however, there are limited data comparing DOACs and warfarin in AF patients with an aortic BPV.Methods and Results: This post-hoc subgroup analysis of a multicenter, prospective, observational registry (BPV-AF Registry) aimed to compare DOACs and warfarin in AF patients with an aortic BPV. The primary outcome was a composite of stroke, systemic embolism, major bleeding, heart failure requiring hospitalization, all-cause death, or BPV reoperation. The analysis included 479 patients (warfarin group, n=258; DOAC group, n=221). Surgical aortic valve replacement was performed in 74.4% and 36.7% of patients in the warfarin and DOAC groups, respectively. During a mean follow up of 15.5 months, the primary outcome occurred in 45 (17.4%) and 32 (14.5%) patients in the warfarin and DOAC groups, respectively. No significant difference was found in the primary outcome between the 2 groups (adjusted hazard ratio: 0.88, 95% confidence interval: 0.51-1.50). No significant multiplicative interaction was observed between the anticoagulant effects and type of aortic valve procedure (P=0.577). CONCLUSIONS: Among AF patients with an aortic BPV, no significant difference was observed in the composite outcome of adverse clinical events between patients treated with warfarin and those treated with DOACs, suggesting that DOACs can be used as alternatives to warfarin in these patients.

Extracorporeal shock wave therapy accelerates endochondral ossification and fracture healing in a rat femur delayed-union model.

Extracorporeal shock wave therapy (ESWT) has been demonstrated to accelerate bone healing; however, the mechanism underlying ESWT-induced bone regeneration has not been fully elucidated. This study aimed to examine the effects of ESWT and the process of fracture healing. A rat model of femur delayed-union was established by cauterizing the periosteum. ESWT treatment at the fracture site was performed 2 weeks after the operation and the site was radiographically and histologically evaluated at weeks 4, 6, and 8. The bone union rate and radiographic score of the ESWT group were significantly higher than those of the control group at 8 weeks. Histological evaluation revealed enhanced endochondral ossification at the fracture site. The effects of ESWT on ATDC5 cells were examined in vitro. ESWT promoted chondrogenic differentiation without inhibiting the proliferation of ATDC5 cells. ESWT may induce significant bone healing by promoting endochondral ossification at the fracture site.

Assessment of the talar deformity and alignment in congenital clubfoot using three-dimensional MRI after Ponseti method.

BACKGROUND: Ponseti method have been widely accepted as the initial treatment of congenital idiopathic clubfoot because its excellent primary result. On the other hand, relapses after Ponseti method are not uncommon and the cause of relapses have not been fully elucidated. We investigated detailed morphology and alignment of tarsal bones in clubfoot after Ponseti method using three-dimensional MRI analysis. METHODS: We performed MRI with 10 patients of unilateral clubfoot at three months after Achilles tenotomy. Based on the MRI volume data, we reconstructed three-dimensional bone surface model using the marching cubes method. We evaluated the volume of the talus and navicular bone, medial and planter deviation of the talar head and neck, medial deviation of the navicular bone, and internal rotation angle of the distal tibiofibular joint. RESULTS: In clubfoot, the volume of talus and navicular bone were significantly smaller compared with the contralateral side. Deviation of the talar head and neck varied from medially to almost the same as that on the contralateral side. The degree of deformity of the talus and alignment of the navicular bone and distal tibiofibular joint showed correlations. CONCLUSIONS: Patients with the medial deviated talar neck might have the alignment change of navicular bone and distal tibiofibular joint. Deformity of talar neck might to be compensated by talonavicular joint and distal tibiofibular joint through the manipulation of Ponseti method.

Relations of Augmented Systolic Annular Expansion and Leaflet/Papillary Muscle Dynamics in Late-Systolic Mitral Valve Prolapse Evaluated by Echocardiography with a Speckle Tracking Analysis.

The mechanism of systolic annular expansion in mitral valve prolapse (MVP) is not clarified. Since annular expansion is systolic outward shift of MV leaflet/chorda tissue complex at superior and outer ends, annular expansion could be related to inward (superior) shift of the complex at another inferior and inner end of the papillary muscle (PM) tip and/or systolic lengthening of the tissue complex, especially MV leaflets.MV annulus systolic expansion, PMs' systolic superior shift, and MV leaflets' systolic lengthening were evaluated by echocardiography with a speckle tracking analysis in 25 normal subjects, 25 subjects with holo-systolic MVP and 20 subjects with late-systolic MVP.PMs' superior shift, MV leaflets' lengthening, MV annular area at the onset of systole and subsequent MV annulus expansion were significantly greater in late-systolic MVP than in holo-systolic MVP (4.6 ± 1.6 versus 1.5 ± 0.7 mm/m2, 2.5 ± 1.4 versus 0.6 ± 2.0 mm/m2, 6.8 ± 2.5 versus 5.7 ± 1.0 cm2/m2 and 1.6 ± 0.8 versus 0.1 ± 0.5 cm2/m2, P < 0.001, respectively). Multivariate analysis identified MV leaflets' lengthening and PMs' superior shift as independent factors associated with MV annular expansion.Conclusions: These results suggest that systolic MV annular expansion in MVP is related to abnormal MV leaflets' lengthening and PMs' superior shift.

Achieving LDL cholesterol target levels <1.81 mmol/L may provide extra cardiovascular protection in patients at high risk: Exploratory analysis of the Standard Versus Intensive Statin Therapy for Patients with Hypercholesterolaemia and Diabetic Retinopathy study.

AIMS: To assess the benefits of intensive statin therapy on reducing cardiovascular (CV) events in patients with type 2 diabetes complicated with hyperlipidaemia and retinopathy in a primary prevention setting in Japan. In the intension-to-treat population, intensive therapy [targeting LDL cholesterol <1.81 mmol/L (<70 mg/dL)] was no more effective than standard therapy [LDL cholesterol ≥2.59 to <3.10 mmol/L (≥100 to <120 mg/dL)]; however, after 3 years, the intergroup difference in LDL cholesterol was only 0.72 mmol/L (27.7 mg/dL), and targeted levels were achieved in <50% of patients. We hypothesized that the intergroup difference in CV events would have been statistically significant if more patients had been successfully treated to target. MATERIALS AND METHODS: This exploratory post hoc analysis focused on intergroup data from patients who achieved their target LDL cholesterol levels. The primary endpoint was the composite incidence of CV events. A Cox proportional hazards model was used to estimate hazard ratios (HRs) for incidence of the primary endpoint in patients who achieved target LDL cholesterol levels in each group. RESULTS: Data were analysed from 1909 patients (intensive: 703; standard: 1206) who achieved target LDL cholesterol levels. LDL cholesterol at 36 months was 1.54 ± 0.30 mmol/L (59.7 ± 11.6 mg/dL) in the intensive group and 2.77 ± 0.46 mmol/L (107.1 ± 17.8 mg/dL) in the standard group (P < 0.05). After adjusting for baseline prognostic factors, the composite incidence of CV events or deaths associated with CV events was significantly lower in the intensive than the standard group (HR 0.48; 95% confidence interval 0.28-0.82; P = 0.007). CONCLUSIONS: This post hoc analysis suggests that achieving LDL cholesterol target levels <1.81 mmol/L may more effectively reduce CV events than achieving target levels ≥2.59 to <3.10 mmol/L in patients with hypercholesterolaemia and diabetic retinopathy.

Visit-to-Visit B-Type Natriuretic Peptide Variability during the Previous Year Has Independent Prognostic Value in Patients with Stable Chronic Heart Failure.

BACKGROUND: There is wide variability of visit-to-visit (V2V) B-type natriuretic peptide (BNP) in patients with chronic heart failure (CHF), even when they are stable. The prognostic significance of V2V-BNP variability has not been investigated. We aimed to test whether V2V-BNP variability during the stable period of CHF has prognostic value regardless of BNP level. METHODS: In 278 stable outpatients (75 ± 10 years, 65% male) with CHF, we studied V2V-BNP variability, which was defined as the coefficient of variance of BNP values measured during 1 year before enrollment. All-cause death and rehospitalization due to HF were considered the primary endpoint. RESULTS: The median V2V-BNP variability was 25.7% (IQR: 19.2-34.4%). During the follow-up period (median 3.2 years), 100 patients reached the endpoint and those with high V2V-BNP variability (≥25.7%) had a significantly higher rate of events (p = 0.001). CHF severity in terms of BNP level and MAGGIC risk score was not significantly different between those with high and low V2V-BNP variability. Multivariable analysis showed that high V2V-BNP variability was independently associated with increased event rates even after adjustment for other known prognostic predictors, including BNP (hazard ratio 1.90, p = 0.003), or for MAGGIC risk score and BNP (hazard ratio 1.72, p = 0.010). The hazard for the outcome consistently increased as V2V-BNP variability increased, with a marked increase up to about 30%. CONCLUSIONS: Even in the stable phase of CHF, V2V-BNP variability was associated with worse long-term outcomes, independent of BNP level.

Surgical as Opposed to Transcatheter Aortic Valve Replacement Improves Basal Interventricular Septal Hypertrophy.

BACKGROUND: Basal interventricular septum (IVS) hypertrophy (BSH) with reduced basal IVS contraction and IVS-aorta angle is frequently associated with aortic stenosis (AS). BSH shape suggests compression by the longitudinally elongated ascending aorta, causing basal IVS thickening and contractile dysfunction, further suggesting the possibility of aortic wall shortening to improve the BSH. Surgical aortic valve replacement (SAVR), as opposed to transcatheter AVR (TAVR), includes aortic wall shortening by incision and stitching on the wall and may potentially improve BSH. We hypothesized that BSH configuration and its contraction improves after SAVR in patients with AS. Methods and Results: In 32 patients with SAVR and 36 with TAVR for AS, regional wall thickness and systolic contraction (longitudinal strain) of 18 left ventricular (LV) segments, and IVS-aorta angle were measured on echocardiography. After SAVR, basal IVS/average LV wall thickness ratio, basal IVS strain, and IVS-aorta angle significantly improved (1.11±0.24 to 1.06±0.17; -6.2±5.7 to -9.1±5.2%; 115±22 to 123±14°, P<0.001, respectively). Contractile improvement in basal IVS was correlated with pre-SAVR BSH (basal IVS/average LV wall thickness ratio or IVS-aorta angle: r=0.47 and 0.49, P<0.01, respectively). In contrast, BSH indices did not improve after TAVR. CONCLUSIONS: In patients with AS, SAVR as opposed to TAVR improves associated BSH and its functional impairment.

Association of Primary Hemodilution and Retrograde Autologous Priming with Transfusion in Cardiac Surgery: Analysis of the Perfusion Case Database of the Japanese Society of Extra-Corporeal Technology in Medicine.

It is important to avoid unnecessary blood cell transfusion. However, the associations of hemodilution and retrograde autologous priming with red blood cell transfusion during and after cardiopulmonary bypass (CPB) in cardiac surgery in Japan are currently unclear. We analyzed these associations using data for 3,090 adults from the Perfusion Case Database of the Japanese Society of Extra-Corporeal Technology in Medicine. Percent hemodilution was calculated by total priming volume and weight. Logistic regression models were used to adjust for covariates including type of surgery, gender, age, hemoglobin concentration before CPB, CPB time, urine volume during CPB, and institution. The percentages of red blood cell transfusions during CPB for patients with <15, 15 to <20, 20 to <25, 25 to <30, and ≥30% hemodilution were 43.0, 51.5, 68.9, 77.3, and 87.7%, respectively. This increase in line with increasing dilution was significant after adjusting for covariates. The percentage of red blood cell transfusion after CPB also increased slightly between 39.0 and 49.4% with percent hemodilution, but the trend after adjusting for covariates was not significant. Use of retrograde autologous priming was significantly associated with blood cell transfusion during CPB after adjusting for covariates, but was not significantly related to blood cell transfusion after CPB. These results suggest that optimizing the percent hemodilution and use of retrograde autologous priming might reduce the use of red blood cell transfusion during CPB in clinical practice in Japan.

Natural history of scoliosis in cerebral palsy and risk factors for progression of scoliosis.

BACKGROUND: Scoliosis in cerebral palsy (CP) often occurs and causes a disturbance in daily life. The purpose of this study was to investigate the natural history of scoliosis in cerebral palsy and determine risk factors for the progression of scoliosis using multivariate analyses. METHODS: We revised 113 patients with CP (47 males and 66 females) who had scoliosis with a curve of at least 10° were reviewed and retrospectively investigated these cases of scoliosis and analyzed the risk factors for the progression of this condition. RESULTS: The mean follow-up period was 16.5 years and the mean age at onset of scoliosis was 6.6 years (range: 1-16 years). In 59 patients (52%), the age at onset of scoliosis was under 6 years. On the final radiographs, the mean Cobb angle was 55.1° (range: 10° to 169°). After the age of 20 years, 13 of 40 patients (32.5%) had a progression of over 10° in scoliosis. Multivariate analyses showed the risk factors for the progression of scoliosis to be hip displacement (p = 0.0038), the onset of scoliosis before the age of 6 years (p = 0.0024), and 30° of the Cobb angle before the age of 10 years (p < 0.001). A subtype of CP (spastic quadriplegia) was identified as a potential risk factor. CONCLUSIONS: After the age of 20 years, 32.5% patients had a progression of over 10° in scoliosis. Risk factors for the progression of scoliosis in CP included hip displacement, early-onset scoliosis, and Cobb angle of 30° before the age of 10 years. LEVEL OF EVIDENCE: Prognostic level IV - case series.

Acute improvement of endothelial functions after oral ingestion of isohumulones, bitter components of beer.

Isohumulones, principal components of the bitter taste of beers, have antioxidant capacity. We studied i) the effects of oral ingestion of isomerized hop extract (IHE) on the endothelial functions in smokers as well as non-smokers and ii) the effects of IHE on cultured endothelial cells in high oxidative stress state. Twelve cigarette smokers and eleven non-smokers ingested IHE and placebo in a randomized crossover design. Flow-mediated vasodilatation (FMD) was measured using ultrasonography. We also studied the effects of isohumulones on i) the cell viability under hypoxia and ii) the levels of angiotensin II (AT-II)-induced reactive oxygen species (ROS) in the cultured human aortic endothelial cells (HAECs). At baseline, the FMDs of the smokers were significantly lower than those of the non-smokers. The FMDs increased significantly after 30 min and 120 min of IHE ingestion in both the smokers and the non-smokers. IHE protected the HAECs from hypoxia-induced cell death as assessed by cell viability. IHE also reduced the AT-II-induced intracellular ROS level. Oral ingestion of IHE appears to exert acute beneficial effects on the endothelial functions in both the smokers and non-smokers, and the in vitro experiments using HAECs suggested that the effect be through reducing intracellular oxidative stress.

Prolapse Volume to Prolapse Height Ratio for Differentiating Barlow's Disease From Fibroelastic Deficiency.

BACKGROUND: As mitral valve (MV) repair for Barlow's disease remains surgically challenging, it is important to distinguish Barlow's disease from fibroelastic deficiency (FED) preoperatively. We hypothesized that the prolapse volume to prolapse height ratio (PV-PH ratio) may be useful to differentiate Barlow's disease and FED.Methods and Results:In 76 patients with MV prolapse who underwent presurgical transesophageal echocardiography, the 3D MV morphology was quantified: 19 patients were diagnosed with Barlow's disease and 57 with FED. The patients with Barlow's disease had greater prolapse volume and height than the patients with FED, as well as greater PV-PH ratio (0.61±0.35 vs. 0.17±0.10, P<0.001). Receiver-operating characteristic analysis revealed that with a cutoff value of 0.27, the PV-PH ratio differentiated Barlow's disease from FED with 84.2% sensitivity and 84.2% specificity. Net reclassification improvement showed that the differentiating ability of the PV-PH ratio was significantly superior to prolapse volume (1.30, P<0.001). After being adjusted by each of prolapse volume and height, annular area and shape, and the number of prolapsed segments, the PV-PH ratio had an independent association with Barlow's disease. CONCLUSIONS: The PV-PH ratio was able to differentiate Barlow's disease from FED with high accuracy. 3D quantification including this value should be performed before MV repair.

Left ventricular myocardial function assessed by three-dimensional speckle tracking echocardiography in Takotsubo cardiomyopathy.

BACKGROUND: We aimed to investigate left ventricular (LV) functional recovery in Takotsubo cardiomyopathy (TC) using three-dimensional (3D) speckle tracking echocardiography. METHODS: Twenty-one patients with TC who underwent routine and 3D echocardiography as well as electrocardiography were enrolled. 3D images were analyzed to measure 3D radial strain and area tracking (area change of each LV segment). Postsystolic shortening (PSS) or thickening (PST) was defined as a further shortening or thickening occurred after the end-systole. 3D echocardiography and ECG were repeated at 4 weeks and 6 months later. RESULTS: Mean age was 70.9±11.1 years, and 18 (86%) patients were female. All patients presented classical type of TC with apical ballooning. LV ejection fraction (EF) improved from 49.9±7.2 to 64.9±6.0% (P<.001) at 4 weeks without segmental wall-motion abnormality. However, PSS or PST still existed in 43% of LV segments, and electrocardiographic abnormality was also observed in 51% at 4 weeks and disappeared at 6 months. Mean 3D radial strain decreased from baseline to 6 months at base (36.1±19.6 vs 28.0±12.6%, P=.04), whereas it increased at mid (16.2±7.2 vs 28.7±9.1%, P=.03) and the apex (8.0±4.4 vs 21.2±7.9%, P<.001). Mean area tracking increased from baseline to 6 months at mid and apex (-28.5±9.5 vs -44.5±9.6%, P<.001 for mid, and -24.2±13.0 vs -42.9±16.8%, P=.002 for the apex), while it did not change at base (-37.0±8.9 vs -41.9±9.6%, P=NS). CONCLUSIONS: Patients with TC show abnormal wall motion during acute phase. Even after LV wall-motion recovery, subtle abnormalities of regional LV function appear to persist at 4 weeks followed by normalization at 6 months.

Long-term prognostic impact of the attenuated plaque in patients with acute coronary syndrome.

Several intravascular ultrasound studies have reported that culprit lesion-attenuated plaque (AP) is related to slow flow/no reflow after percutaneous coronary intervention (PCI). Long-term prognostic impact of the AP is unknown. The aim of this study was to investigate acute and long-term clinical impact of the AP in patients with acute coronary syndrome (ACS). A total of 110 ACS patients who underwent successful PCI were enrolled. Acute and long-term clinical outcomes were compared between patients with AP (AP group: n = 73) and those without AP (non-AP group: n = 37). Long-term cardiac event was defined as a composite of death and ACS. Baseline characteristics in 2 groups were similar. AP was associated with higher TIMI frame count immediately after the first balloon inflation. After thrombectomy and intracoronary drug administration, final TIMI frame count became similar between AP and non-AP group. Although AP was associated with higher incidence of fatal arrhythmia during hospitalization, in-hospital mortality did not differ between the 2 groups. During follow-up (median 6.2 years), cardiac event-free survival did not differ between the 2 groups. Despite the initial unfavorable effect on coronary reflow, presence of AP did not affect acute as well as long-term clinical outcome in patients with ACS.

Renal function on admission modifies prognostic impact of diuretics in acute heart failure: a propensity score matched and interaction analysis.

Although intravenous diuretics have been mainstay drugs in patients with acute heart failure (AHF), they have been suggested to have some deleterious effects on prognosis. We postulated that renal function may modify their deleterious effects in AHF patients. The study population consisted of 1094 AHF patients from three hospitals. Renal dysfunction (RD) was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 on admission, and the cohort was divided into a high-dose furosemide (≥100 mg/48 h) and low-dose furosemide group according to the amount of intravenous furosemide used within 48 h from admission. In the whole cohort, in-hospital mortality rate was higher in the high-dose furosemide group than the low-dose furosemide group (12.5 vs. 6.6 %, respectively, P = 0.001). However, this difference in the in-hospital mortality rates was significant only in the RD subgroup (15.6 vs. 7.0 %, respectively, P < 0.001), and not in the non-RD subgroup (2.5 vs. 5.9 %, respectively, P = 0.384). Propensity score-matched analysis was performed to evaluate the impact of high-dose furosemide on prognosis. After propensity score matching, high-dose furosemide was not associated with in-hospital mortality (OR 1.25, 95 % CI 0.73-2.16, P = 0.408). However, there was a qualitative difference in OR for in-hospital mortality between AHF with RD (OR 1.77, 95 % CI 0.96-3.28, P = 0.068) and without RD (OR 0.23, 95 % CI 0.05-1.10, P = 0.064), and there was a significant interaction between eGFR and prognostic impact of high-dose furosemide (P for OR interaction = 0.013). An inverse relationship was observed between eGFR and OR for in-hospital death in the group treated with high-dose furosemide (decreasing OR with better eGFR). The deleterious effect of diuretics was significantly modified with renal function in AHF. This association may be one reason for poorer prognosis of AHF patients complicated with renal impairment.

Efficacy and Accuracy of Novel Automated Mitral Valve Quantification: Three-Dimensional Transesophageal Echocardiographic Study.

BACKGROUND: Previous studies indicated that the three-dimensional features of the mitral valve (MV) have a significant impact on MV disease. However, quantification of MV with manual tracing software was too time-consuming for routine clinical practice. This study was performed to investigate the efficacy and accuracy of MV quantification with a novel highly automated commercially available software package developed for this purpose. METHODS: Using the manual tracing and automated package, two expert sonographers and one cardiologist individually analyzed three-dimensional datasets acquired with transesophageal echocardiography from 74 patients (15 with functional mitral regurgitation, 32 with MV prolapse, and 27 normal subjects) retrospectively. Time for analysis and inter-observer agreement were compared between the two methods, and agreement of measurements was analyzed using Cronbach's α. RESULTS: Time for analysis using the automated package was significantly shorter than manual tracing (whole cohort, 260 ± 65 vs. 381 ± 68 seconds, P < 0.001; functional mitral regurgitation, 234 ± 42 vs. 378 ± 64 seconds, P < 0.001; MV prolapse, 293 ± 69 vs. 407 ± 67 seconds, P < 0.001; normal controls, 235 ± 52 vs. 351 ± 60 seconds, P < 0.001). There was good agreement among all three observers using both methods, and measurements with the automated package agreed well with the manual tracing values. CONCLUSIONS: The novel automated software package reduced time for quantification of MV with similar accuracy compared to the manual method. Automated quantification is useful and may be a key to widespread adoption of three-dimensional quantification in clinical practice.

Is hip dysplasia a common deformity in skeletally mature patients with hereditary multiple exostoses?

BACKGROUND: Various deformities appear in hereditary multiple exostoses (HMEs). Deformities around the knee or ankle joints are easy to detect in this disease because such deformities are visible in appearance. However, deformities in the hip joints of skeletally mature patients are not well understood because their tumors are invisible. METHODS: To understand deformities around the hip joint in HMEs, we investigated 36 hip joints in 19 skeletally mature patients (12 males, 7 females). The mean age at last X-ray imaging investigation was 29.2 years (14.5-66.5 years). We evaluated the lesions of exostoses around the acetabulum and proximal femur, Wiberg's center-edge angle (CEA), neck-shaft angle (NSA), acetabular depth-width ratio (ADR), and Sharp's acetabular angle. RESULTS: No exostoses were present in four hips of three cases. Thirty-one hip joints had exostoses on the medial side of the femoral neck. Exostoses existed on the lateral side of the femoral neck in 16 hips. None of the patients had acetabuluar tumors. One patient experienced pain because of impingement between the acetabular rim and medial tumors of the femoral neck. The increase in NSA, which is an index of proximal femoral deformity, was common with a mean NSA of 147.3 °. Two indices of acetabular deformity, Sharp's angle and ADR, were within normal limits with a mean Sharp's angle of 41.3 ° and mean ADR of 269. The average CEA was 29.9 °. CONCLUSIONS: Hip dysplasia is not necessarily common in skeletally mature patients with HMEs. To determine the possibility of hip dysplasia in skeletally immature patients with HMEs, ADR may be a useful reference index.

MEK5 suppresses osteoblastic differentiation.

Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family and is activated by its upstream kinase, MAPK kinase 5 (MEK5), which is a member of the MEK family. Although the role of MEK5 has been investigated in several fields, little is known about its role in osteoblastic differentiation. In this study, we have demonstrated the role of MEK5 in osteoblastic differentiation in mouse preosteoblastic MC3T3-E1 cells and bone marrow stromal ST2 cells. We found that treatment with BIX02189, an inhibitor of MEK5, increased alkaline phosphatase (ALP) activity and the gene expression of ALP, osteocalcin (OCN) and osterix, as well as it enhanced the calcification of the extracellular matrix. Moreover, osteoblastic cell proliferation decreased at a concentration of greater than 0.5 µM. In addition, knockdown of MEK5 using siRNA induced an increase in ALP activity and in the gene expression of ALP, OCN, and osterix. In contrast, overexpression of wild-type MEK5 decreased ALP activity and attenuated osteoblastic differentiation markers including ALP, OCN and osterix, but promoted cell proliferation. In summary, our results indicated that MEK5 suppressed the osteoblastic differentiation, but promoted osteoblastic cell proliferation. These results implied that MEK5 may play a pivotal role in cell signaling to modulate the differentiation and proliferation of osteoblasts. Thus, inhibition of MEK5 signaling in osteoblasts may be of potential use in the treatment of osteoporosis.