Distinct osteogenic mechanisms of bones of distinct origins

Mammalian bones have three distinct origins (paraxial mesoderm, lateral plate mesoderm, and neural crest) and undergo two different modes of formation (intra-membranous and endochondral). Bones derived from the paraxial mesoderm and lateral plate mesoderm mainly form through the endochondral process. During this process, hypertrophic chondrocytes play a vital role in inducing both osteogenesis and angiogenesis. One of the essential osteogenic factors secreted from hypertrophic chondrocytes is Indian hedgehog (Ihh). In contrast, bones derived from the neural crest mainly form through the intramembranous pro-cess and do not require Ihh. Thus, depending on their origin, bones have distinct signaling properties, which need to be considered in the research and application of bone biology.Presented at the 18th Annual Research Meeting of the Japanese Orthopaedic Association, Kitakyushu, Japan, October 17, 2003     

Differences in arrhythmogenicity between the canine right ventricular outflow tract and anteroinferior right ventricle in a model of Brugada syndrome

BACKGROUND: The Brugada syndrome is characterized by ST-segment elevation on the ECG, especially in the right precordial leads sensitive to the right ventricular outflow tract (RVOT). OBJECTIVES: The purpose of this study was to evaluate the hypothesis that right ventricular electrophysiologic heterogeneity caused arrhythmogenicity in the Brugada syndrome. METHODS: Action potentials (APs) were mapped on the epicardium of 14 RVOT preparations and on the transmural surfaces of 15 pairs of RVOT and right ventricular anteroinferior (RVAI) preparations isolated from canine hearts. Brugada ECG and arrhythmias were induced with pilsicainide (2.5-12.5 micromol/L), pinacidil (1.25-12.5 micromol/L), and terfenadine (2.0 micromol/L). RESULTS: Low doses of drugs elevated the J-ST segment and induced APs with both short and long action potential durations (APDs) in contiguous RVOT epicardial regions. In addition, APs in the RVOT had a larger phase 1 notch and longer APD than in RVAI. The longest APDs were in the epicardium in RVOT but in the endocardium in RVAI regions. High doses of drugs eliminated the phase 2 dome of the AP and abbreviated APDs in the epicardium but not in endocardium and reduced the epicardial heterogeneity of APs but increased the transmural gradient of APD in 14 (93%) of the RVOT preparations. In contrast, abbreviations of epicardial APDs occurred in only 4 (27%) of the RVAI preparations. Ventricular tachycardia occurred more frequently in the RVOT (47%) than in paired RVAI preparations (7%). Blocking the transient outward current reduced the heterogeneity of APs and eliminated arrhythmogenicity in all preparations. CONCLUSION: Compared with the RVAI region, the RVOT has greater electrophysiologic heterogeneity that contributes to arrhythmogenicity in this model of Brugada syndrome.     

Preparation of two-drug composite microparticles to improve the dissolution of insoluble drug in water for use with a 4-fluid nozzle spray drier.

In this study, we used a novel 4-fluid nozzle spray drier to prepare composite microparticles of a water-insoluble drug, flurbiprofen (FP), and a water-soluble drug, sodium salicylate (SS), for the purpose of improving the water solubility of FP. An ethanol solution of FP and an aqueous SS solution were simultaneously introduced through different liquid passages in the 4-fluid nozzle spray drier and then spray-dried. Quantitative elemental analysis suggested that the FP/SS ratio in each composite microparticle was nearly the same as the formulation ratio. We also found that SS and FP exist in a low crystallinity state in the composite particles. Release of FP from dissolved composite microparticles was markedly improved because of an increase in the effective surface area following rapid dissolution of SS. This study shows that it is possible to prepare FP-SS composite microparticles using a 4-fluid nozzle spray drier in single process and that this can improve the ability of FP to dissolve in water.     

Carpentier-Edwards pericardial aortic valve in middle-aged patients comparison with the St. Jude medical valve

Objective The objective of the present study was to compare long-term results of single aortic valve replacement (AVR) with mechanical (St. Jude Medical valves: standard) and biologic (the Carpentier-Edwards pericardial) prostheses. Method: Between 1995 and 2002, 95 patients who underwent single AVR with mechanical (n=46) or biologic (n=49) prostheses were enrolled in this study. The mean age at the operation was 54.0±9.6 years (range: 20 to 69 years) with the mechanical and 68.8±7.1 years (range: 44 to 85 years) with the biologic prosthesis. Results: The 9-year actuarial survival rate, which was calculated by taking perioperative mortality into account, was 90.3±4.6% for patients with mechanical valves and 87.6 ±4.8% for patients with bioprostheses, with no difference between the two groups (p=0.342). The 9-year freedom rate from thromboembolism, reoperation, endocarditis was 94.8+3.6%, 100% and 97.8 ±2.2% for patients with mechanical valves and 98.0 ±2.0%, 97.5 ±3.4% and 95.0 ±3.4% for those with bioprostheses, respectively. After 9 years, freedom from cardiac death averaged 97.8% in the group with mechanical valves compared with 95.3% in those with bioprostheses (p=0.541). Conclusion: We conclude that the mid-term durability of the Carpentier-Edwards pericardial valve in the aortic position for the elderly is excellent. Nevertheless, the risk of tissue valve reoperation progressively increases with time, and a longer follow-up may be necessary to provide its value compared with the mechanical valves in a country like Japan with a high life expectancy. (Jpn J Thorac Cardiovasc Surg 2005; 53:465-469)     

Effects of hypertension and type 2 diabetes mellitus on the risk of total cardiovascular events in Japanese patients with hypercholesterolemia: implications from the Japan Lipid Intervention Trial (J-LIT).

Hyperlipidemia, hypertension, and diabetes mellitus (DM) are well-established risk factors for cardiovascular disease. We analyzed the cardiovascular events in hyperlipidemic patients with or without DM who were administered open-labeled simvastatin in groups stratified by blood pressure level using data from the Japan Lipid Intervention Trial (J-LIT). Hyperlipidemic patients with DM (n=6,288) had significantly more cardiovascular events than those without DM (n=33,933). The incidence rates of total cardiovascular events in the Non-DM and DM groups were 15.40 and 25.76 per 1,000 patients for the 6-year period, respectively. The relative risk of total cardiovascular events in the DM vs. the Non-DM group was 1.68, and the relative risk was significantly higher in the DM than in the Non-DM group. The relative risks of total cardiovascular events were significantly higher in DM and Non-DM patients whose systolic blood pressure (SBP) was greater than or equal to 130 mmHg compared to that of Non-DM patients whose SBP was less than 130 mmHg, and in DM and Non-DM patients whose diastolic blood pressure (DBP) was greater than or equal to 80 mmHg compared to that of Non-DM patients whose DBP was less than 80 mmHg. In all groups stratified by SBP and DBP, relative risks of total cardiovascular events were higher in DM patients than in Non-DM patients. For patients with hypercholesterolemia and DM, blood pressure should be strictly controlled in order to prevent both coronary events and stroke. These results are in good agreement with the JNC 7 and the ESH/ESC guidelines for DM patients, which recommended that the SBP and DBP be less than 130 and 80 mmHg, respectively.     

Dorsal inlay graft urethroplasty for primary hypospadiac repair

OBJECTIVE: Tubularized incised plate urethroplasty has become a popular technique for repairing distal and proximal hypospadias in many institutions. Dorsal inlay graft urethroplasty has been used in our institution since 2003 to reduce the risk of meatal stenosis. In the present study, we evaluated the results of the dorsal inlay graft procedure. METHODS: A total of 28 patients with no deep groove and no severe curvature underwent one-stage urethroplasty using an inner preputial-based dorsal inlay graft. The medical records of all patients were retrospectively reviewed with regard to complication rate and cosmetic appearance. RESULTS: Mean patient age at surgery was 21 months (range, 14 months to 4.6 years). Preoperatively the urethral meatus was coronal in two cases, distal shaft in 17, proximal shaft in six and penoscrotal in three. Nine patients required testosterone therapy before surgery. Mean operative time was 200 min (range, 154-249 min). Mean length of inlay graft was 20.9 mm (range, 12-30 mm). In all patients, a straight penis was achieved without dorsal plication of the corposa cavernosa, and the neomeatus with a slit-like appearance was positioned at the glans tip. At a mean of 22 months of follow up, a urethrocutaneous fistula developed in only one patient (3.6%), requiring repair surgery 6 months after urethroplasty. No patient had meatal stenosis, neourethral stricture or urethral diverticulum along the inlay graft. CONCLUSION: Dorsal inlay graft urethroplasty is an effective method for hypospadiac repair and leads to good cosmetic outcome with low risk of complications.     

Cardiac tamponade due to intrapericardial rupture of an amebic liver abscess

Pericardial abscess is rare in healthy individuals, especially the amebic type. We report a case of pericardial abscess and cardiac tamponade due to intrapericardial rupture of an amebic liver abscess. A 31-year old Japanese male complained of fever to a local hospital. A liver mass was discovered in his left hepatic lobe by an abdominal echogram. He was referred to the internal department of our hospital and was treated with quinolone antibiotics. Two weeks after medication, he suddenly complained of epigastralgia and severe orthopnea and was admitted. Abdominal computed tomographic scan showed an enlarged liver mass, and massive pericardial effusion suggested cardiac tamponade. He underwent an emergency subxiphoid partial pericardiectomy under local anesthesia. 1,000 ml of light brownish fluid was removed and his condition improved. Although no ameba was cultivated from the pus, the amebic serological test was positive. Metronidazole was administered and the patients was discharged 31 days after surgery.     

Effect of Inflammation on Costimulation Blockade-Resistant Allograft Rejection

Previously, we reported that allogeneic skin grafts were rapidly rejected by CD28 and CD40 ligand double deficient mice mediated by CD8⁺ T cells. These results indicated that some elements in addition to CD28- and CD40-mediated costimulation provide stimulatory signals for the activation of donor-specific CD8⁺ T cells. In this report, we investigated the role of inflammation associated with transplantation on costimulation-independent priming of CD8⁺ T cell during graft rejection. B6 RAG1 KO mice were transplanted with BALB/c-skin and adoptively transferred with syngeneic CD8⁺ T cells the same day or 50 days after transplantation. When blockade of CD28- and CD40-mediated costimulation failed to prevent acute rejection of freshly transplanted skin grafts, it efficiently delayed rejection of well-healed skin grafts. These results showed that factors associated with transplantation have essential roles in inducing costimulation blockade-resistant allograft rejection. Costimulation blockade failed to prevent acute graft-infiltration of NK cells and increasing expression of intragraft IL-12 and IL-15. These factors may trigger the graft-infiltration and priming of CD8⁺ T cells to induce costimulation blockade-resistant allograft rejection.