Comparison of the skeletal stability after mandibular counter-clockwise rotation in three surgical procedures.

The treatment of mandibular deformities with an anterior open bite is challenging. In this study, skeletal stability after mandibular osteotomies was evaluated to determine the best treatment for mandibular prognathism with an anterior open bite in three procedures: intraoral vertical ramus osteotomy (IVRO), conventional sagittal split ramus osteotomy (conv-SSRO), and SSRO without bone fixation (nonfix-SSRO). Patients who underwent mandibular osteotomy to correct skeletal mandibular protrusion were included. Changes in skeletal and soft tissues were assessed using lateral cephalograms taken before (T1), 3 ± 2 days (T2), and 12 ± 3 months (T3) after surgery. Thirty-nine patients were included: nine in the IVRO group and 11 and 19 in the conv- and nonfix-SSRO groups, respectively. The mandibular plane angles (MPAs) of the T2-T1 were - 2.7 ± 2.0 (p = 0.0040), - 3.7 ± 1.7 (p < 0.0001), and - 2.3 ± 0.7 (p < 0.0001) in the IVRO, conv-SSRO, and nonfix-SSRO groups, respectively. The skeletal relapse of the MPAs was not related to the MPA at T2-T1, and it was approximately 1.3° in the conv-SSRO group. The skeletal relapse of the MAPs was significantly correlated with the MPA of T2-T1 in the IVRO (p = 0.0402) and non-fix-SSRO (p = 0.0173) groups. When the relapse of the MPAs was less than 1.3°, the MPA of T2-T1 was calculated as 2.5° in the nonfix-SSRO group. When the MPA of T2-T1 is less than 2.5°, non-fix SSRO may produce a reliable outcome, and when it is more than 2.5°, conv-SSRO may produce better outcomes.

Occlusal Plane Angle as a Key Factor for Chin Protrusion After Mandibular Osteotomy in Skeletal Class III.

There is no treatment algorithm to decide whether maxillomandibular or mandibular osteotomy alone should be performed in borderline cases. This study assessed the factors that affect the changes in soft tissue after mandibular setback. Patients who underwent mandibular osteotomy alone to correct mandibular protrusion were included in this study. Hard and soft tissue analyses were performed on lateral cephalograms before and 12±3 months after surgery. The popular points were set for referencing hard and soft tissues on the lateral cephalogram. Nasolabial, labiomental, and soft tissue facial plane angles were measured for the soft tissue assessment. To assess the mandibular setback amount, SNB was calculated. Twenty-one patients were included in this study. The nasolabial angle was increased after surgery and its change significantly correlated with the change in SNB ( P =0.00815). The change in soft tissue facial plane angle after surgery per change in SNB significantly correlated with the occlusal plane angle ( P =0.0009). An occlusal plane angle of at least 15.45 degrees was required for the SNB and soft tissue facial plane angle to change to the same degree. The occlusal plane angle (whether or not it was ≥15.45 degrees) may help in determining the surgical approach in borderline cases, specifically on whether maxillomandibular or mandibular osteotomy alone should be performed if the mandibular setback is simple.

Effect of masseter muscle mass on the rate of experimental tooth movement in rats.

BACKGROUND: Previous clinical observational studies have suggested that orthodontic tooth movement (OTM) is related, at least partly, to the mass and/or capabilities of the masticatory muscles. OBJECTIVES: Our study aimed to examine the influence of masticatory muscle mass on the OTM in an animal experimental model in which the masseter muscle was modulated by botulinum neurotoxin type A (BTX) injection. METHODS: Eighteen Wistar rats were equally divided into two groups: BTX injection and control. BTX was injected bilaterally into the masseter muscles. Three days after the injection, the maxillary left first molars were orthodontically moved for 14 days. At the end of the experiment, micro-computed tomography was performed to evaluate the rate of OTM and bone morphometry. The masseter muscles were weighed and prepared for histological analyses. RESULTS: The masseter muscle mass in the BTX group was less than that in the control group, and histological findings showed atrophy of muscle fibres. The rate of OTM was significantly higher in the BTX group than in the control group. Furthermore, a negative correlation was detected between masseter muscle mass and OTM in the BTX group. Bone morphometry showed no difference between the control and BTX groups. CONCLUSION: Decreased masseter muscle mass was found to be closely related to an increase in the rate of OTM in rats using BTX injection to modify the masseter muscle mass. Masseter muscle mass could be a predictive factor for OTM in rats injected with BTX.

Prognostic role of bronchial asthma in patients with heart failure.

There are few reports investigating the relationship between bronchial asthma (BA) and heart failure (HF). We hypothesized BA may have impact on prognosis in patients with HF. Among 323 consecutive outpatients with HF, 191 patients without chronic obstructive pulmonary disease were analyzed. Twenty patients had BA, most of whom (80.0%) had preserved left ventricular ejection fraction (LVEF ≥ 50%). The use of ß-blockers was less frequent (55.0% vs 83.0%. p = 0.01), systolic blood pressure (133 ± 22 vs 120 ± 17 mmHg, p = 0.003), and heart rate (83 ± 14 vs 74 ± 15 bpm, p = 0.02) were higher in patients with BA than those without BA. During median follow up of 24 months, 45 (23.6%) experienced primary outcome defined as a composite of all-cause death, nonfatal myocardial infarction, nonfatal ischemic stroke, and unexpected hospitalization due to HF. Multivariate Cox regression analysis revealed that the presence of BA was independently associated with the occurrence of primary outcome (hazard ratio 3.08, 95% CI 1.42-6.71, p = 0.004). In the subgroup analysis of patients with preserved LVEF, patients with BA exhibited worse outcomes (p = 0.03 by log-rank). Patients with HF complicated by BA, most of whom had preserved LVEF, exhibited worse outcomes than those without BA.

Comparison of anti-inflammatory effects of rivaroxaban vs. dabigatran in patients with non-valvular atrial fibrillation (RIVAL-AF study): multicenter randomized study.

Some experimental studies have shown that direct oral anticoagulants (DOACs) have anti-inflammatory effects. However, the interval changes in inflammatory markers in patients with non-valvular atrial fibrillation (AF) who receive DOACs remain unknown. Between July 2013 and April 2014, a total of 187 AF patients randomly assigned to receive rivaroxaban (n = 91) or dabigatran (n = 96) were assessed for eligibility. The levels of the following inflammatory markers were serially evaluated: high-sensitivity C-reactive protein, pentraxin-3, interleukin (IL)-1ß, IL-6, IL-18, tumor necrosis factor-α, monocyte chemotactic protein-1, growth and differentiation factor-15, and soluble thrombomodulin (sTM). The aim in this study was to evaluate the anti-inflammatory effects of rivaroxaban and dabigatran in patients with AF, in addition to the impact of markers on bleeding events. Finally, 117 patients (rivaroxaban: n = 55, dabigatran: n = 62) were included in the analysis at 12 months. Although the interval changes in sTM levels tended to be greater in the dabigatran group [0.3 (0-0.7) vs. 0.5 (0-1.0) FU/ml, p = 0.061], there were no significant differences in the interval changes in any inflammatory marker between 2 groups. There were no significant differences in bleeding events between 2 groups. The interval changes in sTM levels were significantly greater in patients with bleeding compared with those without [0.8 (0.5-1.3) vs. 0.4 (- 0.1-0.8) FU/ml, p = 0.017]. There were no significant differences in the interval changes in any inflammatory marker between rivaroxaban and dabigatran treatments in patients with AF. The increased levels of sTM after DOACs treatment might be related to bleeding events.

Late gadolinium enhancement on cardiac magnetic resonance imaging is associated with coronary endothelial dysfunction in patients with dilated cardiomyopathy.

Myocardial fibrosis and coronary endothelial dysfunction are important determinants of outcome in patients with heart failure. However, the relationship of these factors in patients with dilated cardiomyopathy (DCM) is not fully understood. This study aimed to investigate the relationship between endothelium-dependent coronary vasomotor abnormality and late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) in patients with DCM. We examined 38 consecutive patients with DCM. All patients underwent CMR and the acetylcholine (ACh) provocation test using cardiac catheterization. During the ACh provocation test, we sampled blood simultaneously from the coronary sinus and aortic root to compare lactate concentrations, and quantified coronary blood flow volume using an intracoronary Doppler-tipped guidewire. LGE was detected in 17 (44.7%) patients. The lactate extraction ratio (LER) in the ACh provocation test was significantly decreased in the LGE-positive group (before vs after ACh, 18.6 ± 13.6 vs - 13.3 ± 24.8%; p < 0.001) and in the LGE-negative group (before vs after ACh, 14.2 ± 19.5 vs 3.3 ± 16.2%; p = 0.02). The rate of patients with an LER < 0% (indicating myocardial lactate production due to myocardial ischemia) was significantly higher in the LGE-positive group than in the LGE-negative group [12 (70.6%) vs 7 (33.3%); p = 0.02]. Multivariable logistic regression analysis showed that a post-ACh LER < 0% was a significant predictor of LGE positivity (odds ratio 7.75; 95% confidence interval 1.37-43.68; p = 0.02). In conclusion, ACh-provoked coronary vasomotor abnormality is associated with myocardial fibrosis in patients with DCM. These results suggest that coronary endothelial dysfunction is involved in myocardial fibrosis and worsening heart failure concomitant with DCM.

Does Treatment of Impaired Glucose Tolerance Improve Cardiovascular Outcomes in Patients with Previous Myocardial Infarction?

PURPOSE: We evaluated the effects of an alpha-glucosidase inhibitor, voglibose, on cardiovascular events in patients with a previous myocardial infarction (MI) and impaired glucose tolerance (IGT). METHODS: This prospective, randomized, open, blinded-endpoint study was conducted in 112 hospitals and clinics in Japan in 3000 subjects with both previous MI and IGT receiving voglibose (0.6 mg/day, n = 424) or no drugs (n = 435) for 2 years. The Data and Safety Monitoring Board (DSMB) recommended discontinuation of the study in June 2012 after an interim analysis when the outcomes of 859 subjects were obtained. The primary endpoint was cardiovascular events including cardiovascular death, nonfatal MI, nonfatal unstable angina, nonfatal stroke, and percutaneous coronary intervention/coronary artery bypass graft. Secondary endpoints included individual components of the primary endpoint in addition to all-cause mortality and hospitalization due to heart failure. RESULTS: The age, ratio of males, and HbA1C were 65 vs. 65 years, 86 vs. 87%, and 5.6 vs. 5.5% in the groups with and without voglibose, respectively. Voglibose improved IGT; however, Kaplan-Meier analysis showed no significant between-group difference with respect to cardiovascular events [12.5% with voglibose vs. 10.1% without voglibose for the primary endpoint (95% confidence interval, 0.82-1.86)]; there were no significant differences in secondary endpoints. CONCLUSION: Although voglibose effectively treated IGT, no additional benefits for cardiovascular events in patients with previous MI and IGT were observed. Voglibose may not be a contributing therapy to the secondary prevention in patients with MI and IGT. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT00212017.

Probiotic Lactobacillus gasseri SBT2055 improves glucose tolerance and reduces body weight gain in rats by stimulating energy expenditure.

Probiotic Lactobacillus gasseri SBT2055 (LG2055) reduces postprandial TAG absorption and exerts anti-obesity effects in rats and humans; however, the underlying mechanisms are not fully understood. In the present study, we addressed the mechanistic insights of the anti-obesity activity of LG2055 by feeding Sprague-Dawley rats diets containing skimmed milk fermented or not by LG2055 for 4 weeks and by analysing energy expenditure, glucose tolerance, the levels of SCFA in the caecum and serum inflammatory markers. Rats fed the LG2055-containing diet demonstrated significantly higher carbohydrate oxidation in the dark cycle (active phase for rats) compared with the control group, which resulted in a significant increase in energy expenditure. LG2055 significantly reduced cumulative blood glucose levels (AUC) compared with the control diet after 3 weeks and increased the molar ratio of butyrate:total SCFA in the caecum after 4 weeks. Furthermore, the LG2055-supplemented diet significantly reduced the levels of serum amyloid P component - an indicator of the inflammatory process. In conclusion, our results demonstrate that, in addition to the inhibition of dietary TAG absorption reported previously, the intake of probiotic LG2055 enhanced energy expenditure via carbohydrate oxidation, improved glucose tolerance and attenuated inflammation, suggesting multiple additive and/or synergistic actions underlying the anti-obesity effects exerted by LG2055.

[Evaluation of Iris Morphology Viewed through Stromal Edematous Corneas by Infrared Camera].

BACKGROUND: We reported that the application of infrared camera enables us to observe iris morphology in Peters' anomaly through edematous corneas. PURPOSE: To observe the iris morphology in bullous keratopathy or failure grafts with an infrared camera. SUBJECTS AND METHODS: Eleven bullous keratopathy or failure grafts subjects (6 men and 5 women, mean age ± SD; 72.7 ± 13.0 years old) were enrolled in this study. The iris morphology was observed by applying visible light mode and near infrared light mode of infrared camera (MeibomPen). The detectability of pupil shapes, iris patterns and presence of iridectomy was evaluated. RESULTS: Infrared mode observation enabled us to detect the pupil shapes in 11 out of 11 cases, iris patterns in 3 out of 11 cases, and presence of iridetomy in 9 out of 11 cases although visible light mode observation could not detect any iris morphological changes. CONCLUSION: Applying infrared optics was valuable for observation of the iris morphology through stromal edematous corneas.

Inhibition of 12/15-lipoxygenase reduces orthodontically induced root resorption in rats.

OBJECTIVES: To investigate whether the inhibition of 12/15-lipoxygenase (12/15-LOX), one of the core enzymes of the arachidonic acid cascade, suppresses orthodontically induced root resorption (OIRR), and examine the involvement of the hyaline degeneration of periodontal ligament cells and odontoclast differentiation. MATERIALS AND METHODS: The left maxillary first molars of 10-week-old male Wistar rats were moved mesially for 14 days using a closed-coil spring (25 cN) inserted between the first molar and incisor. The rats were intraperitoneally administered with a 12/15-LOX specific inhibitor (ML-351; 0.05 mmol/kg) daily in the experimental group or vehicle (dimethyl sulfoxide) in the control group. Tooth movement was measured using microcomputed tomography on day 14. The appearance of OIRR, hyaline degeneration, osteoclasts, and odontoclasts was evaluated via histological analysis. Immunohistochemical staining for receptor-activated NF-kB ligand (RANKL) and osteoprotegerin was performed. RESULTS: OIRR observed on day 14 in the control group was strongly suppressed by ML-351 treatment. Hyaline degeneration observed on the compression side on day 3 and the appearance of osteoclasts and odontoclasts on days 3 and 14 were significantly suppressed by ML-351. RANKL expression on day 3 was significantly suppressed by ML-351. These key processes in OIRR were substantially suppressed by ML-351 treatment. CONCLUSIONS: Inhibition of 12/15-LOX reduced OIRR by suppressing hyaline degeneration and subsequent odontoclast differentiation.

Effects of anti-mouse RANKL antibody on orthodontic tooth movement in mice.

Background/purpose: Orthodontic tooth movement is achieved by alveolar bone remodeling, and therefore the balance of bone resorption and formation is important. Receptor activator of nuclear factor-κB ligand (RANKL) plays a crucial role in bone resorption. We previously reported that tumor necrosis factor-α (TNF-α) is also important in bone resorption during tooth movement. In this study, we focused on bone and root resorption during orthodontic tooth movement in mice using anti-mouse RANKL antibody (anti-mRANKL ab). Materials and methods: Anti-mRANKL ab was administered intraperitoneally to mice that subsequently underwent orthodontic tooth movement. After 10 days, tissues around the moved teeth were histologically evaluated. To confirm the effects of anti-mRANKL ab on TNF-α induced bone resorption, TNF-α was administered with and without anti-mRANKL ab into the supracalvaria and the sutures of the calvaria were histologically evaluated. Results: Orthodontic tooth movement was suppressed in mice treated with anti-mRANKL ab. Root resorption was observed after orthodontic tooth movement, but not in mice treated with anti-mRANKL ab. In the calvarial experiment, the number of TRAP-positive cells in the calvarial sutures was lower in mice administered TNF-α with anti-mRANKL ab than in mice administered TNF-α alone. Conclusion: Our findings suggest that anti-mRANKL ab suppressed orthodontic tooth movement. This needs to be considered when orthodontic tooth movement is required in patients using anti-RANKL antibody.

Impact of Chronic Kidney Disease on the Associations of Cardiovascular Biomarkers With Adverse Outcomes in Patients With Suspected or Known Coronary Artery Disease: The EXCEED-J Study.

Background The impact of chronic kidney disease (CKD) on the prognostic utility of cardiovascular biomarkers in high-risk patients remains unclear. Methods and Results We performed a multicenter, prospective cohort study of 3255 patients with suspected or known coronary artery disease (CAD) to investigate whether CKD modifies the prognostic utility of cardiovascular biomarkers. Serum levels of cardiovascular and renal biomarkers, including soluble fms-like tyrosine kinase-1 (sFlt-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin-I (hs-cTnI), cystatin C, and placental growth factor, were measured in 1301 CKD and 1954 patients without CKD. The urine albumin to creatinine ratio (UACR) was measured in patients with CKD. The primary outcome was 3-point MACE (3P-MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. The secondary outcomes were all-cause death, cardiovascular death, and 5P-MACE defined as a composite of 3P-MACE, heart failure hospitalization, and coronary/peripheral artery revascularization. After adjustment for clinical confounders, sFlt-1, NT-proBNP, and hs-cTnI, but not other biomarkers, were significantly associated with 3P-MACE, all-cause death, and cardiovascular death in the entire cohort and in patients without CKD. These associations were still significant in CKD only for NT-proBNP and hs-cTnI. NT-proBNP and hs-cTnI were also significantly associated with 5P-MACE in CKD. The UACR was not significantly associated with any outcomes in CKD. NT-proBNP and hs-cTnI added incremental prognostic information for all outcomes to the model with potential clinical confounders in CKD. Conclusions NT-proBNP and hs-cTnI were the most powerful prognostic biomarkers in patients with suspected or known CAD and concomitant CKD.

123I-MIBG imaging detects cardiac involvement and predicts cardiac events in Churg-Strauss syndrome.

PURPOSE: In Churg-Strauss syndrome (CSS) it is important to detect cardiac involvement, which predicts poor prognosis. This study evaluated whether (123)I-metaiodobenzylguanidine (MIBG) scintigraphy could detect cardiac damage and predict cardiac events in CSS. METHODS: (123)I-MIBG scintigraphy was performed in 28 patients with CSS, 12 of whom had cardiac involvement. The early and delayed heart to mediastinum ratio (early H/M and delayed H/M) and washout rate were calculated by using (123)I-MIBG scintigraphy and compared with those in control subjects. RESULTS: Early H/M and delayed H/M were significantly lower and the washout rate was significantly higher in patients with cardiac involvement than in those without and in controls (early H/M, p = 0.0024, p = 0.0001; delayed H/M, p = 0.0002, p = 0.0001; washout rate, p = 0.0012, p = 0.0052 vs those without and vs controls, respectively). Accuracy for detecting cardiac involvement was 86% for delayed H/M and washout rate and 79% for early H/M and B-type natriuretic peptide (BNP). Kaplan-Meier analysis showed significantly lower cardiac event-free rates in patients with early H/M ≤ 2.18 and BNP > 21.8 pg/ml than those with early H/M > 2.18 and BNP ≤ 21.8 pg/ml (log-rank test p = 0.006). CONCLUSION: Cardiac sympathetic nerve function was damaged in CSS patients with cardiac involvement. (123)I-MIBG scintigraphy was useful in detecting cardiac involvement and in predicting cardiac events.

IL-12- and IL-18-mediated, nitric oxide-induced apoptosis in TNF-α-mediated osteoclastogenesis of bone marrow cells.

TNF-α has been recognized as an important factor for osteoclastogenesis and plays an important role in bone resorption under pathological conditions. IL-12 and IL-18, which are T-cell mediators, are also important inflammatory cytokines. We have reported that IL-12 and IL-18 induce apoptosis in bone marrow cells treated with TNF-α in vitro and that osteoclastogenesis is inhibited by the interaction of TNF-α-induced Fas and the IL-12-induced Fas ligand (FasL). However, the anti-FasL antibody could not completely inhibit apoptosis. Therefore, it is possible that IL-12 and IL-18 may also trigger some other apoptotic mechanisms. Nitric oxide (NO) may act as a mediator of the apoptotic effect. In this study, we examined whether NO causes the IL-12- and IL-18-induced apoptosis of bone marrow cells in TNF-α-mediated osteoclast formation. We found that NO production was induced in bone marrow cells cultured with IL-12 and IL-18 in the presence of TNF-α. When bone marrow cells were cultured with TNF-α, osteoclasts were formed. In contrast, when bone marrow cells were cultured with both TNF-α and IL-12 or IL-18, the adherent cells were induced to undergo apoptosis. Apoptosis was partially inhibited when bone marrow cells were treated with NO synthase inhibitors. Furthermore, IL-12 and IL-18 synergistically induced cell death and upregulated NO production in the presence of TNF-α. These results indicate that the simultaneous effects of TNF-α and IL-12 or IL-18 on bone marrow cells induce apoptosis and that apoptosis is induced by the production of NO.

Clinical usefulness of additional treatment with ezetimibe in patients with coronary artery disease on statin therapy. - From the viewpoint of cholesterol metabolism.-.

BACKGROUND: Ezetimibe-plus-statin therapy has been reported to provide greater reduction in low-density lipoprotein cholesterol (LDL-C) level than statin monotherapy. The aim of the present study was to evaluate the relationship between LDL-C lowering effect and baseline cholesterol absorption and synthesis markers in patients with coronary artery disease (CAD). METHODS AND RESULTS: A total of 171 patients with CAD whose LDL-C level was ≥ 100 mg/dl after treatment with atorvastatin (10mg/day) or rosuvastatin (2.5 mg/day) for 4 weeks were assigned to additionally receive ezetimibe (10mg/day) plus a statin or a double dose of statin for 12 weeks. The decreases in LDL-C (-30.0 ± 15.6 mg/dl vs. -19.2 ± 14.2 mg/dl) and the ratio of campesterol, an absorption marker, to total cholesterol levels (-1.35 ± 0.90 µg/mg vs. 0.33 ± 0.74 µg/mg) were greater in the ezetimibe-plus-statin group (P<0.05, respectively). The decrease in LDL-C level in the ezetimibe-plus-statin group was greatest in patients with baseline levels of higher absorption and lower synthesis markers and smallest in patients with baseline levels of lower absorption and higher synthesis markers (-34.3 ± 15.6 mg/dl vs. -21.5 ± 16.7 mg/dl, P<0.05). The decrease in LDL-C did not differ, irrespective of baseline levels of cholesterol absorption and synthesis markers, in the double-dose statin group, and was similar to that in patients with lower absorption and higher synthesis markers in the ezetimibe-plus-statin group. CONCLUSIONS: Ezetimibe-plus-statin therapy may be useful for lowering LDL-C level, irrespective of baseline levels of cholesterol absorption and synthesis markers.

Correction of frameshift mutations with tailed duplex DNAs.

Tailed duplex (TD) DNAs, prepared by annealing an oligonucleotide to a several-hundred-base single-stranded (ss) DNA fragment, correct a base-substitution mutation with high efficiency. In the present study, the abilities of TD fragments to correct single-base insertion and deletion mutations were examined, using hygromycin-resistance and enhanced green fluorescent protein fusion (Hyg-EGFP) genes inactivated by +G and -C frameshift mutations. The 5'-TD and 3'-TD DNA fragments were co-transfected with plasmid DNA containing the inactivated Hyg-EGFP gene into CHO-K1 cells, and the gene correction efficiencies were determined by introducing the plasmid DNA recovered from the transfected cells into Escherichia coli cells. In contrast to their efficiencies for the substitution mutation, the gene correction abilities of the TD fragments were relatively low. The correction efficiencies by the TD fragments were apparently higher than that by a ss DNA fragment, one of the DNA fragments employed for gene correction. These results suggest that the TD fragments have the potential to correct frameshift mutations, although further improvement is required.

Predisposing conditions for condylar sag after intraoral vertical ramus osteotomy.

Intraoral vertical ramus osteotomy (IVRO) is used to treat mandibular prognathism and temporomandibular disorders. However, the improvement of temporomandibular disorders after IVRO is considered to be due to the anterior and downward movement of the mandibular condyle, which may lead to condylar sag, and in the worst case, condylar luxation. In this retrospective cohort study, we examined factors potentially associated with condylar sag. Univariate analysis indicated that condylar sag was significantly associated with the following factors: magnitude of setback (P = 0.001), less than 3 mm setback (P < 0.001), presence of temporomandibular joint (TMJ) symptoms (P = 0.002), Wilkes classification (P = 0.039), occlusal cant correction ≥ 2 mm (P = 0.018), and mandibular condyle deformation (P < 0.001). Setback magnitude (P = 0.032) and TMJ symptoms (P = 0.007) remained significant in the multivariate analysis. In the receiver operating characteristic curve, the setback magnitude cut-off value for condylar sag after IVRO was 3.25 mm. Thus, the incidence of condylar sag after IVRO is increased with a smaller setback magnitude (≤ 3.25 mm) and the presence of TMJ symptoms. These factors should be evaluated by surgeons during treatment planning for IVRO to estimate condylar sag, and it may be possible to predict the risk of condylar luxation.

Soluble vascular endothelial growth factor receptor 2 and prognosis in patients with chronic heart failure.

AIMS: Endothelial cell vascular endothelial growth factor receptor 2 (VEGFR-2) plays a pivotal role in angiogenesis, which induces physiological cardiomyocyte hypertrophy via paracrine signalling between endothelial cells and cardiomyocytes. We investigated whether a decrease in circulating soluble VEGFR-2 (sVEGFR-2) levels is associated with poor prognosis in patients with chronic heart failure (HF). METHODS AND RESULTS: We performed a multicentre prospective cohort study of 1024 consecutive patients with HF, who were admitted to hospitals due to acute decompensated HF and were stabilized after initial management. Serum levels of sVEGFR-2 were measured at discharge. Patients were followed up over 2 years. The outcomes were cardiovascular death, all-cause death, major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death and HF hospitalization, and HF hospitalization. The mean age of the patients was 75.5 (standard deviation, 12.6) years, and 57% were male. Patients with lower sVEGFR-2 levels were older and more likely to be female, and had greater proportions of atrial fibrillation and anaemia, and lower proportions of diabetes, dyslipidaemia, and HF with reduced ejection fraction (<40%). During the follow-up, 113 cardiovascular deaths, 211 all-cause deaths, 350 MACE, and 309 HF hospitalizations occurred. After adjustment for potential clinical confounders and established biomarkers [N-terminal B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin I, and high-sensitivity C-reactive protein], a low sVEGFR-2 level below the 25th percentile was significantly associated with cardiovascular death [hazard ratio (HR), 1.79; 95% confidence interval (CI), 1.16-2.74] and all-cause death (HR, 1.43; 95% CI, 1.04-1.94), but not with MACE (HR, 1.11; 95% CI, 0.86-1.43) or HF hospitalization (HR, 1.03; 95% CI, 0.78-1.35). The stratified analyses revealed that a low sVEGFR-2 level below the 25th percentile was significantly associated with cardiovascular death (HR, 1.76; 95% CI, 1.07-2.85) and all-cause death (HR, 1.49; 95% CI, 1.03-2.15) in the high-NT-proBNP group (above the median), but not in the low-NT-proBNP group. Notably, the patients with high-NT-proBNP and low-sVEGFR-2 (below the 25th percentile) had a 2.96-fold higher risk (95% CI, 1.56-5.85) for cardiovascular death and a 2.40-fold higher risk (95% CI, 1.52-3.83) for all-cause death compared with those with low-NT-proBNP and high-sVEGFR-2. CONCLUSIONS: A low sVEGFR-2 value was independently associated with cardiovascular death and all-cause death in patients with chronic HF. These associations were pronounced in those with high NT-proBNP levels.

Expression of semaphorin 3A in the rat corneal epithelium during wound healing.

The neural guidance protein semaphorin 3A (Sema3A) is expressed in corneal epithelial cells of the adult rat. We have now further investigated the localization of Sema3A in the normal rat corneal epithelium as well as changes in its expression pattern during wound healing after central corneal epithelial debridement. The expression pattern of Sema3A was compared with that of the tight-junction protein zonula occludens-1 (ZO-1), the gap-junction protein connexin43 (Cx43), or the cell proliferation marker Ki67. Immunofluorescence analysis revealed that Sema3A was present predominantly in the membrane of basal and wing cells of the intact corneal epithelium. The expression of Sema3A at the basal side of basal cells was increased in the peripheral epithelium compared with that in the central region. Sema3A was detected in all layers at the leading edge of the migrating corneal epithelium at 6h after central epithelial debridement. The expression of Sema3A was markedly up-regulated in the basal and lateral membranes of columnar basal cells apparent in the thickened, newly healed epithelium at 1 day after debridement, but it had largely returned to the normal pattern at 3 days after debridement. The expression of ZO-1 was restricted to superficial epithelial cells and remained mostly unchanged during the wound healing process. The expression of Cx43 in basal cells was down-regulated at the leading edge of the migrating epithelium but was stable in the remaining portion of the epithelium. Ki67 was not detected in basal cells of the central epithelium at 1 day after epithelial debridement, when Sema3A was prominently expressed. Immunoblot analysis showed that the abundance of Sema3A in the central cornea was increased 1 day after epithelial debridement, whereas that of ZO-1 or Cx43 remained largely unchanged. This increase in Sema3A expression was accompanied by up-regulation of the Sema3A coreceptor neuropilin-1. Our observations have thus shown that the expression of Sema3A is increased markedly in basal cells of the newly healed corneal epithelium, and that this up-regulation of Sema3A is not associated with cell proliferation. They further suggest that Sema3A might play a role in the regulation of corneal epithelial wound healing.

Hepatitis C virus infection in a Japanese leprosy sanatorium for the past 67 years.

Oku-Komyo-En is one of the national leprosy sanatoria, located on a small island in Setouchi city, Okayama prefecture of Japan since 1938. Since autopsies were carried out routinely on almost all patients who had died in the sanatorium up to 1980, approximately 1,000 formalin-fixed autopsy tissue samples were available for analysis. When these samples were reviewed, the pathological data indicated a sharp rise in the death rate caused by cirrhosis of the liver and hepatocellular carcinoma (HCC) since 1960 and 1970, respectively. Hepatitis C virus (HCV) infection is a common cause of HCC in Japan. The presence of HCV RNA was demonstrated in paraffin sections prepared from the autopsied liver tissue fixed in formalin for a prolonged period of time, by employing nested RT-PCR using type-specific primers. The data showed that HCV RNA was detectable in samples of the liver archived as early as 1940, representing the liver tissues kept in formalin for up to 67 years. HCV genotypes 1b and 2a were found by RT-PCR at 85.7% and 14.3%, respectively, in patients with leprosy.