Imiquimod for the treatment of oral leukoplakia: A two-center retrospective study.

OBJECTIVES: We aimed to assess the effectiveness of the use of topical imiquimod for the management of oral leukoplakia (OL). METHODS: This was a retrospective study. Medical chart reviews were conducted to identify patients with biopsy-proven OL treated with topical 5% imiquimod. Data included OL characteristics, histopathological diagnosis, treatment outcome, and adverse events (AEs). Treatment response was assessed by measuring the percentage reduction in the size of OL lesions. RESULTS: 33 patients (51.5% females; median age: 65 years) with 38 lesions were included. OLs were either localized (23.7%) or multifocal lesions (76.3%), with the majority on the gingiva (86.8%). Pretreatment histopathological diagnoses were dysplasia in 84.2% and nonreactive hyperkeratosis in 15.8%. Most regimens consisted of 60-minute applications, 5-days-a-week, for 6 weeks. At the end of treatment, 81.6% of 38 lesions showed a reduction in size with 68.4% exhibiting ≥50% reduction in size, and 42.1% exhibiting complete resolution. Application site reactions were the most common with pain/soreness/sensitivity occurring in 86.8%. Fatigue was the most frequently reported systemic AE (28.9%). CONCLUSION: Two-thirds of OL lesions had ≥50% reduction in size. Most AEs were temporary and resolved upon treatment discontinuation. Prospective studies are needed to further assess Imiquimod's effectiveness in OL management.

Discovery of non-proteinogenic amino acids inhibiting biofilm formation by S. aureus and methicillin-resistant S. aureus.

Bacterial biofilms often cause medical complications and there has been a great deal of interest in the discovery of small-molecule agents that can inhibit the formation of biofilms. Among these agents, it has been reported that several d-amino acids, such as d-Leu, d-Trp, d-Tyr, and d-Met, exhibit weak inhibitory activity toward bacterial biofilm formation. In this study, we have screened a library of 332 non-proteinogenic amino acids for new biofilm inhibitory agents and discovered several compounds exhibiting biofilm-inhibitory activity against Gram-positive bacteria. In particular, H-DL-ß-(3,4-dihydroxyphenyl)-dl-Ser-OH (253) showed potent activity against S. aureus, including methicillin-resistant S. aureus.

Amine skeleton-based c-di-GMP derivatives as biofilm formation inhibitors.

Bacteria can form a biofilm composed of diverse bacterial microorganism, which work as a barrier to protect from threats, such as antibiotics and host immunity system. The formation of biofilms significantly impairs the efficacy of antibiotics against pathogenic bacteria. It is also a serious problem to be solved that the emergence of multidrug-resistant bacteria (such as methicillin-resistant Staphylococcus aureus, MRSA) accelerated by the overuse of antibiotics. Therefore, the usage of biofilm inhibition agents has attracted immense interest as a novel strategy for treatment of diseases related to bacterial infection. From the difference of mode of action against bacterial cells, biofilm inhibition agents are expected to circumvent the emergence of multidrug-resistant bacteria. In this study, we have developed the derivatives of c-di-GMP, a kind of cyclic dinucleotide that is expected to have the effect of inhibiting bacterial biofilm formation. Some of the synthesized derivatives were found to inhibit biofilm formation of Gram-positive bacteria.

Multiple arrhythmic and cardiomyopathic phenotypes associated with an SCN5A A735E mutation.

BACKGROUND: SCN5A mutations are associated with multiple arrhythmic and cardiomyopathic phenotypes including Brugada syndrome (BrS), sinus node dysfunction (SND), atrioventricular block, supraventricular tachyarrhythmias (SVTs), long QT syndrome (LQTS), dilated cardiomyopathy and left ventricular noncompaction. Several single SCN5A mutations have been associated with overlap of some of these phenotypes, but never with overlap of all the phenotypes. OBJECTIVE: We encountered two pedigrees with multiple arrhythmic phenotypes with or without cardiomyopathic phenotypes, and sought to identify a responsible mutation and reveal its functional abnormalities. METHODS: Target panel sequencing of 72 genes, including inherited arrhythmia syndromes- and cardiomyopathies-related genes, was employed in two probands. Cascade screening was performed by Saner sequencing. Wild-type or identified mutant SCN5A were expressed in tsA201 cells, and whole-cell sodium currents (INa) were recorded using patch-clamp techniques. RESULTS: We identified an SCN5A A735E mutation in these probands, but did not identify any other mutations. All eight mutation carriers exhibited at least one of the arrhythmic phenotypes. Two patients exhibited multiple arrhythmic phenotypes: one (15-year-old girl) exhibited BrS, SND, and exercise and epinephrine-induced QT prolongation, the other (4-year-old boy) exhibited BrS, SND, and SVTs. Another one (30-year-old male) exhibited all arrhythmic and cardiomyopathic phenotypes, except for LQTS. One male suddenly died at age 22. Functional analysis revealed that the mutant did not produce functional INa. CONCLUSIONS: A non-functional SCN5A A735E mutation could be associated with multiple arrhythmic and cardiomyopathic phenotypes, although there remains a possibility that other unidentified factors may be involved in the phenotypic variability of the mutation carriers.

Abnormal cardiac axis as a prenatal marker of left pulmonary artery sling.

Left pulmonary artery sling (LPAS) is a rare vascular anomaly. The left pulmonary artery arises distally from the right pulmonary artery on the right side of the trachea and passes between the trachea and esophagus towards the left lung, compressing the lower trachea. LPAS is associated with congenital tracheal stenosis, which frequently requires early surgical intervention and has a poor prognosis due to severe airway obstruction after birth. Therefore, LPAS should be prenatally diagnosed to prepare for surgical intervention for tracheal stenosis. To the best of our knowledge, there are few reports on prenatal echocardiographic findings in LPAS. We report three prenatal cases of LPAS, which resulted in respiratory symptoms. We discuss fetal ultrasound findings and highlight the abnormal rotation of the fetal cardiac axis to the right as a useful sign in the prenatal screening of LPAS.

Ridaifen G, tamoxifen analog, is a potent anticancer drug working through a combinatorial association with multiple cellular factors.

Ridaifen-G (RID-G), a tamoxifen analog that we previously synthesized, has potent growth inhibitory activity against various cancer cell lines. Tamoxifen is an anticancer drug known to act on an estrogen receptor (ER) and other proteins. However, our previous studies interestingly suggested that the mechanism of action of RID-G was different from that of tamoxifen. In order to investigate the molecular mode of action of RID-G, we developed a novel chemical genetic approach that combined a phage display screen with a statistical analysis of drug potency and gene expression profiles in thirty-nine cancer cell lines. Application of this method to RID-G revealed that three proteins, calmodulin (CaM), heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1), and zinc finger protein 638 (ZNF638) were the candidates of direct targets of RID-G. Moreover, cell lines susceptible to RID-G show similar expression profiles of RID-G target genes. These results suggest that RID-G involves CaM, hnRNP A2/B1, and ZNF638 in its growth inhibitory activity.

Total synthesis and anti-hepatitis C virus activity of MA026.

The first total synthesis of MA026 and the identification of its candidate target protein for anti-hepatitis C virus activity are presented. MA026, a novel lipocyclodepsipeptide isolated from the fermentation broth of Pseudomonas sp. RtIB026, consists of a cyclodepsipeptide, a chain peptide, and an N-terminal (R)-3-hydroxydecanoic acid. The first subunit, side chain 2, was prepared by coupling fatty acid moiety 4 with tripeptide 5. The key macrocyclization of the decadepsipeptide at L-Leu(10)-D-Gln(11) provided the second subunit, cyclodepsipeptide 3. Late-stage condensation of the two key subunits and final deprotection afforded MA026. This convergent, flexible, solution-phase synthesis will be invaluable in generating MA026 derivatives for future structure-activity relationship studies. An infectious hepatitis C virus (HCV) cell culture assay revealed that MA026 suppresses HCV infection into host hepatocytes by inhibiting the entry process in a dose-dependent manner. Phage display screening followed by surface plasmon resonance (SPR) binding analyses identified claudin-1, an HCV entry receptor, as a candidate target protein of MA026.

Efficacy of intravenous immunoglobulin combined with prednisolone following resistance to initial intravenous immunoglobulin treatment of acute Kawasaki disease.

OBJECTIVES: To determine the most effective first-line rescue therapy for intravenous immunoglobulin (IVIG) nonresponders, using IVIG, prednisolone, or both, to prevent coronary artery abnormalities (CAAs). STUDY DESIGN: We retrospectively reviewed the clinical records of 359 consecutive patients with Kawasaki disease who failed to respond to initial IVIG. RESULTS: CAAs up to 1 month after treatment were less common in the IVIG+prednisolone group (15.9%) than in the IVIG group (28.7%, P = .005) and the prednisolone group (30.6%, P = .01). The IVIG+prednisolone group had significantly lower risks of failing to respond to first-line rescue therapy (aOR 0.16, 95% CI 0.09-0.31), CAAs up to 1 month (aOR 0.46, 95% CI 0.27-0.90), and CAAs at 1 month (aOR 0.40, 95% CI 0.18-0.91) than the IVIG group. In the prednisolone and IVIG+prednisolone groups, risk score, day of illness at first-line rescue therapy, prednisolone monotherapy, and resistance to first-line rescue therapy were independent risk factors for CAA. Sex and resistance to first-line rescue therapy were independent risk factors in the IVIG group. CONCLUSIONS: IVIG+prednisolone may be superior to IVIG or prednisolone as first-line rescue therapy in the treatment of IVIG nonresponders. To establish the efficacy of rescue therapy with IVIG+prednisolone following nonresponse to initial IVIG, a prospective randomized trial is warranted.

Oxytocin cells in the supraoptic nucleus receive excitatory synaptic inputs from the contralateral supraoptic and paraventricular nuclei in the lactating rat.

The present experiments were undertaken to examine whether oxytocin cells in the supraoptic nucleus receive synaptic inputs from the contralateral supraoptic nucleus or paraventricular nucleus. Using urethane-anesthetized lactating rats, extracellular action potentials were recorded from single oxytocin or vasopressin cells in the supraoptic nucleus. Electrical stimulation was applied to the contralateral supraoptic nucleus or paraventricular nucleus, and responses of oxytocin or vasopressin cells were analyzed by peri-stimulus time histogram or by change in firing rate of oxytocin or vasopressin cells. Electrical stimulation of the contralateral supraoptic nucleus or paraventricular nucleus did not cause antidromic excitation in oxytocin or vasopressin cells but caused orthodromic responses. Although analysis by peri-stimulus time histogram showed that electrical stimulation of the contralateral supraoptic nucleus or paraventricular nucleus caused orthodromic excitation in both oxytocin and vasopressin cells, the proportion of excited oxytocin cells was greater than that of vasopressin cells. Train stimulation applied to the contralateral supraoptic nucleus or paraventricular nucleus at 10 Hz increased firing rates of oxytocin cells and decreased those of vasopressin cells. The results of the present experiments suggest that oxytocin cells in the supraoptic nucleus receive mainly excitatory synaptic inputs from the contralateral supraoptic nucleus and paraventricular nucleus. Receipt these synaptic inputs to oxytocin cells may contribute to the synchronized activation of oxytocin cells during the milk ejection reflex.

Maternal Effects of Japanese Shorthorn Cows on the Growth of Embryo-transferred Japanese Black Calves in a Cow-calf Grazing System.

The growth performance of embryo-transferred Japanese Black calves that were born from, and suckled by, Japanese Shorthorn cows in a cow-calf grazing system (BS-group, n = 5) was compared to that of Japanese Black calves from Japanese Black cows in a cowshed (BB-group, n = 5). The daily weight gain from birth to 1 month was higher in the BS-group than in the BB-group (p<0.01), and the same trend (p<0.05) was observed at 2 and 3 months of age. This resulted in body weight that was significantly higher for the BS-group between 1 and 3 months of age than what was observed for the BB-group (p<0.05). Heart girth was significantly greater in the BS-group than in the BB-group throughout the experimental period (p<0.01), and chest depth and withers height in the BS-group were significantly greater from 2 to 4 months of age (p<0.05) and at 4 months of age only (p<0.05). No difference in body length (p>0.05) was observed between the groups. These results suggest that the maternal effect of Japanese Shorthorn cows was positive for embryo-transferred Japanese Black calf growth during the early suckling stage. As Japanese Black calves are traded at a high price on the Japanese market, we conclude that this proposed production system is likely to improve the profitability of herd management in upland Japan.

Efficacy of SubcutAneous implantable cardioVErter-defibrillators in ≤18 year-old CHILDREN: SAVE-CHILDREN registry.

BACKGROUND: In adult patients, subcutaneous implantable cardioverter defibrillators (S-ICDs) have been reported to be non-inferior to transvenous ICDs with respect to the incidence of device-related complications and inappropriate shocks. Only a few reports have investigated the efficacy of S-ICDs in the pediatric field. This study aimed to investigate the utility and safety of S-ICDs in patients ≤18 years old. METHODS: This study was a multicenter, observational, retrospective study on S-ICD implantations. Patients <18 years old who underwent S-ICD implantations were enrolled. The detailed data on the device implantations and eligibility tests, incidence of appropriate- and inappropriate shocks, and follow-up data were assessed. RESULTS: A total of 62 patients were enrolled from 30 centers. The patients ranged in age from 3 to 18 (median 14 years old [IQR 11.0-16.0 years]). During a median follow up of 27 months (13.3-35.8), a total of 16 patients (26.2%) received appropriate shocks and 13 (21.3%) received inappropriate shocks. The common causes of the inappropriate shocks were sinus tachycardia (n = 4, 30.8%) and T-wave oversensing (n = 4, 30.8%). In spite of the physical growth, the number of suitable sensing vectors did not change during the follow up. No one had any lead fractures or device infections in the chronic phase. CONCLUSIONS: Our study suggested that S-ICDs can prevent sudden cardiac death in the pediatric population with a low incidence of lead complications or device infections. The number of suitable sensing vectors did not change during the patients' growth.

A large amount of microscopic precipitates are inevitably injected during infusion therapy without an in-line filter.

Infusion route problems can have a significant impact on hemodynamics in children with severe heart failure. Here, we report the case of a 13-year-old girl with dilated cardiomyopathy. Her condition fluctuated due to frequent occlusion of the central venous catheter (CVC) route. However, a quick check revealed no apparent abnormalities in the CVC, infusion route, in-line filter or infusion pump. Scanning electron microscopy revealed that dobutamine and heparin had crystallized and that the in-line filter membrane was occluded. This case emphasizes the importance of proper infusion route management in pediatric patients with severe heart failure. Even drugs that are used daily may form microscopic crystals at several concentrations and administration rates. Without an in-line filter, microscopic particles are injected into the body, and there is no evidence that the injected crystals do not cause permanent damage.

Predicting disease occurrence of cabbage Verticillium wilt in monoculture using species distribution modeling.

BACKGROUND: Although integrated pest management (IPM) is essential for conservation agriculture, this method can be inadequate for severely infected fields. The ability to predict the potential occurrence of severe infestation of soil-borne disease would enable farmers to adopt suitable methods for high-risk areas, such as soil disinfestation, and apply other options for lower risk areas. Recently, researchers have used species distribution modeling (SDM) to predict the occurrence of target plant and animal species based on various environmental variables. In this study, we applied this technique to predict and map the occurrence probability of a soil-borne disease, Verticillium wilt, using cabbage as a case study. METHODS: A disease survey assessing the distribution of Verticillium wilt in cabbage fields in Tsumagoi village (central Honshu, Japan) was conducted two or three times annually from 1997 to 2013. Road density, elevation and topographic wetness index (TWI) were selected as explanatory variables for disease occurrence potential. A model of occurrence probability of Verticillium wilt was constructed using the MaxEnt software for SDM analysis. As the disease survey was mainly conducted in an agricultural area, the area was weighted as "Bias Grid" and area except for the agricultural area was set as background. RESULTS: Grids with disease occurrence showed a high degree of coincidence with those with a high probability occurrence. The highest contribution to the prediction of disease occurrence was the variable road density at 97.1%, followed by TWI at 2.3%, and elevation at 0.5%. The highest permutation importance was road density at 93.0%, followed by TWI at 7.0%, while the variable elevation at 0.0%. This method of predicting disease probability occurrence can help with disease monitoring in areas with high probability occurrence and inform farmers about the selection of control measures.

Visual liver assessment using Gd-EOB-DTPA-enhanced magnetic resonance imaging of patients in the early post-Fontan period.

No imaging modality can be used to evaluate Fontan-associated liver disease (FALD). We retrospectively reviewed hepatic gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) characteristics of patients within 1 year post-Fontan procedure, and we evaluated the association between hepatic imaging abnormalities and clinical parameters, including follow-up cardiac catheterization and laboratory test findings. The EOB-MR images were graded, based on the extent of the decreased enhancement, as "normal" (Grade 1), "segmental" (Grade 2), "regional" (Grade 3), and "diffuse" (Grade 4). We enrolled 37 patients (mean age, 3.5 ± 1.0 years): 9 patients had Grade 1 or 2; 14 patients, Grade 3; and 14 patients, Grade 4. EOB-MRI revealed characteristic reticular or mosaic patterns of diminished enhancement (i.e. "frog spawn" appearance). Ultrasonography did not detect diminished enhancement or "frog spawn" appearance. A trend existed toward increased grade severity in imaging with increased central venous pressure, pulmonary vascular resistance, and gamma-glutamyltransferase levels. Noninvasive EOB-MRI revealed the characteristic pattern of diminished enhancement, which was correlated with certain clinical parameters indicative of Fontan physiology and liver dysfunction. Early-stage FALD may occur soon after the Fontan procedure and is associated with increased pressure in the inferior vena cava and hepatic veins.

Randomized comparison of contact force-guided versus conventional circumferential pulmonary vein isolation of atrial fibrillation: prevalence, characteristics, and predictors of electrical reconnections and clinical outcomes.

PURPOSE: We prospectively investigated the differences in pulmonary vein reconnections (PVRs) and clinical outcomes between contact force (CF)-guided and conventional circumferential PV isolation (CPVI) of atrial fibrillation (AF). METHODS: One hundred twenty consecutive AF patients (63 ± 10 years; 88 males) undergoing an initial CPVI were randomized to ablation with a target CF of 20 g (CF group; n = 60) or that with operators blinded to the CF information (blind group; n = 60). RESULTS: The CF group had fewer PVRs (0.67 ± 0.91/patient vs. 1.16 ± 1.16/patient; P = 0.007), a lower incidence of persistent PVRs (13.2 vs. 41.2%; P < 0.001), and a shorter procedural time for the CPVI (50 vs. 56 min; P = 0.019) than the blind group. The mean CF was higher in the CF group than the blind group (18.0 vs. 16.1 g; P < 0.001), with the most significant difference observed along the posterior right-sided PVs (P-RPVs) and anterior left-sided PVs (A-LPVs). In logistic regression models, the mean CF was a negative predictor of PVRs along the P-RPVs and A-LPVs in the blind group (odds ratios, 0.728 and 0.786; P < 0.001 and 0.007), while no significant predictor was identified in the CF group or elsewhere in the blind group. In the Kaplan-Meier analysis, the arrhythmia-free survival rate at 12 months was 89.9% in the CF group and 88.2% in the blind group, respectively (P = 0.624). CONCLUSIONS: CF-guided CPVI can reduce PVRs and the procedural time and be particularly beneficial along regions where a relatively low CF tends to be applied: the P-RPVs and A-LPVs. The comparable clinical outcomes may be due to the learning curve effect obtained by the CF-guided technique and repeated provocation of dormant PV conduction.

Zero mortality of continuous veno-venous hemodiafiltration with PMMA hemofilter after pediatric cardiac surgery.

OBJECTIVE: Continuous veno-venous hemodiafiltration (CVVH) is used as one of the modalities of continuous renal replacement therapy (CRRT) in pediatric intensive units. The aim of our study was to investigate the use of CVVH in small children with acute renal failure (ARF) after cardiac surgery. PATIENT AND METHODS: Between June 2005 and June 2008, 7 patients who required dialysis after pediatric cardiac surgery without ECMO underwent CVVH with polymethylmethacrylate membrane (PMMA) treatment. The definition of ARF was based on a 100% rise in serum creatinine (Cr) concentration, oliguria. On the other hand, PMMA-CVVH was weaned in patients with satisfactory urine output, stable biochemical markers of renal function and adequate fluid balance. RESULTS: All patients treated with PMMA-CVVH alone (4 boys, 3 girls) had a median age of 36 months and a median body weight of 11 kg. The averaged established time from cardiac operation to CVVH was 2.6 days. There was a significant decrease in the post-filter compared with pre-filter levels of BUN, Cr, potassium concentration. There were no significant changes in systolic blood pressure, lactate level and CRP; however, it was unnecessary for all patients to use epinephrine. CONCLUSIONS: Continuous veno-venous hemodiafiltration with PMMA-CVVH without ECMO achieved a surprisingly Zero mortality.

External validation of a risk score to predict intravenous immunoglobulin resistance in patients with kawasaki disease.

BACKGROUND: we previously developed a new risk score to predict intravenous immunoglobulin (IVIG) resistance in Kawasaki disease. However, the IVIG dosage used in that study (1 g/kg/d for 2 consecutive days) differs from the single infusion of 2 g/kg recommended in the United States and elsewhere. Our aim was to assess the validity and applicability of our risk score in patients treated with a single infusion. METHODS: we used a database of 1626 patients with Kawasaki disease given initial IVIG treatment at a dose of 1 g/kg/d for 2 consecutive days (n = 990; IVIG- 1 g/kg × 2) or 2 g/kg/d for 1 day (n = 636; IVIG- 2 g/kg × 1) across 17 hospitals in Japan. Patients received the total IVIG dose within 36 hours in IVIG- 1 g/kg × 2 and 24 hours in IVIG- 2 g/kg × 1. We stratified the patients according to a risk scoring system developed to predict IVIG unresponsiveness, based on scores of ≥ 5 points. We compared the accuracy of prediction between the 2 groups using receiver operating characteristic analysis. RESULTS: baseline characteristics and clinical outcomes were similar between both groups. The areas under the receiver operating characteristic curve in IVIG- 2 g/kg × 1 were similar to those of IVIG- 1 g/kg × 2. Using a cut-off risk score of ≥ 5 points, we could identify IVIG resistance in terms of coronary artery abnormalities within 1 month and coronary artery abnormalities at 1 month with equivalent sensitivity and specificity in both groups. CONCLUSION: our risk score can be used to predict IVIG unresponsiveness to a regimen based on a single infusion of 2 g/kg IVIG.

Staged repair of truncus arteriosus with interrupted aortic arch: adjustable pulmonary artery banding.

We report a successful two-stage treatment for an infant with truncus arteriosus with aortic arch interruption. The treatment consisted of flow-adjustable bilateral pulmonary artery banding using clipping and postoperative balloon dilation, followed by staged repair. The merits of this strategy are as follows: (1) bilateral pulmonary artery banding is less invasive than neonatal one-stage repair; (2) use of cardiopulmonary bypass can be avoided in the newborn period; and (3) control of pulmonary blood flow adjusted for body size is possible. Although further studies are needed, our therapeutic strategy might provide a clinically important option for managing severe congenital heart disease.