2-mm surgical margins are adequate for most basal cell carcinomas in Japanese: a retrospective multicentre study on 1000 basal cell carcinomas.

BACKGROUND: Surgery is the gold standard for basal cell carcinomas (BCC). Current recommended surgical margins for BCCs are determined from studies in Caucasian populations. However, the appropriate surgical margins for BCCs in non-white races are unclear. OBJECTIVES: To investigate the accuracy of preoperative determination of clinical tumour borders and appropriate surgical margins in Japanese patients with BCC. METHODS: The maximum calculated differences in distance between the preoperatively determined surgical margins and the actual histologic tumour side margins were considered as 'accuracy gaps' of clinical tumour borders. Estimated side margin positivity rates (ESMPRs) with narrower (2 and 3 mm) surgical margins were calculated on the basis of the accuracy gaps. RESULTS: Overall, 1000 surgically excised BCCs from 980 Japanese patients were included. The most frequent histologic subtype was nodular BCC (67%). The median accuracy gap was 0.3 mm [interquartile range (IQR): -0.5 to +1 mm]. The ESMPRs with 2- and 3-mm surgical margins were 3.8% and 1.4%, respectively. Only the ESMPRs between the well-defined (n = 921) and poorly defined clinical tumour border groups (n = 79) showed statistical difference [2-mm margin: 3.1% vs. 11.7%, OR: 3.89, 95% confidential interval (CI): 1.41-10.71, P <0.01; 3-mm margin: 0.97% vs. 6.3%, OR: 6.58, 95% CI: 1.67-25.99, P <0.01]. No significant differences in ESMPRs were noted in other subgroups including risk classifications. CONCLUSIONS: The determined clinical tumour border accuracy gaps in this Japanese cohort were negligible. Dermatologic surgeons may use narrower surgical margins with acceptable margin positivity rates. The clarity of clinical tumour borders could be an appropriate guide for selection of different surgical margins in the Japanese cohort.

Emerging role of interleukin-31 and interleukin-31 receptor in pruritus in atopic dermatitis.

Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder associated with skin barrier dysfunction. The lesional skin of AD exhibits T helper 2 (TH 2)-deviated immune reactions. Interleukin-31 (IL-31), preferentially produced from TH 2 cells, is a potent pruritogenic cytokine, and its systemic and local administration induces scratching behavior in rodents, dogs and monkeys. Recent clinical trials have revealed that administration of an anti-IL-31 receptor antibody significantly alleviates pruritus in patients with AD. In this review, we summarize recent topics related to IL-31 and its receptor with special references to atopic itch.

Influence of cerebral fluid drainage on the pharmacokinetics of vancomycin in neurosurgical patients.

The objective of this study was to retrospectively investigate the influence of cerebral fluid drainage on the serum concentrations and pharmacokinetic parameters of vancomycin (VCM). We analyzed 55 patients with normal renal function who had been hospitalized in the neurosurgical ward and received intravenous infusions of VCM. We compared the daily doses of VCM, serum VCM concentrations, serum concentration/dose ratio (C/D ratio), and pharmacokinetic parameters calculated using the Sawchuk-Zaske method between patients who underwent cerebral fluid drainage (drainage group) and controls (non-drainage group). The patients in the drainage group showed a significantly lower trough concentration of VCM (5.8 ± 3.3 µg/mL) than that shown by the non-drainage group (9.9 ± 5.4 µg/mL, p = 0.017). Further, the patients in the drainage group showed a significantly lower trough C/D ratio (0.32 ± 0.17) than that shown by the non-drainage group (0.50 ± 0.31, p = 0.047). In conclusion, cerebral fluid drainage may influence VCM pharmacokinetics. Our findings strongly suggest that a high dose of VCM is required to maintain optimal serum concentrations of VCM in patients managed with cerebral fluid drainage.

Jaw movement-related primary somatosensory cortical area in the rat.

It has anatomically been revealed that the rostral part of the rat primary somatosensory cortex (S1) directly projects to the dorsal part of the trigeminal oral subnucleus (dorVo) and the dorsal part of juxtatrigeminal region (dorVjuxt), and that the dorVo and dorVjuxt contain premotoneurons projecting directly to the jaw-opening or jaw-closing motoneurons in the trigeminal motor nucleus (Vmo). However, little is known about how the rostral S1 regulates jaw movements in relation to its corticofugal projections. To address this issue, we performed intracortical microstimulation of the rat rostral S1 by monitoring jaw movements and electromyographic (EMG) activities. We for the first time found that low-frequency long-train stimulation of the rostral S1 induced single sustained opening of the jaw with elevated EMG activities of the anterior digastric muscles (jaw-opener). The effective sites for the low-frequency long-train stimulation overlapped the S1 sites where traditional high-frequency short-train stimulation was effective to induce single twitch-like jaw movement. We also found that the effective sites for the two kinds of train stimuli were included in the rostral S1 area, which has previously been identified to send direct projections to the dorVo or the dorVjuxt. Specifically, the most effective stimulation sites for the two kinds of train stimuli were located in the rostralmost part of S1 which has been reported to emanate strong direct projections to the dorVjuxt but less to the dorVo. Therefore, the present study suggests that the rat rostral S1, especially its rostralmost part, plays an important role in controlling jaw movements by activation of direct descending projections from the rostral S1 to the trigeminal premotoneuron pools, especially to the dorVjuxt.

Natural occurrence of mycotoxins in forage maize during crop growth in Japan: case study.

We investigated concentrations of mycotoxins during the growth of four cultivars of forage maize (Zea mays L.) in Nasushiobara, Tochigi prefecture, and their distribution in ears of maize grown in Morioka, Iwate prefecture, Japan. In experiment 1, we measured concentrations of naturally occurring fumonisin, nivalenol, deoxynivalenol and zearalenone at progressive crop growth stages. Concentrations of fumonisin in stems+leaves remained very low or not detectable, but those in ears became detectable at 40 days after heading and increased rapidly after 50 days after heading (DAH) (fumonisin B1+B2<3260 µg/kg; mean value at 50-74 days after heading). Concentrations varied widely within cultivars on the same day. Concentrations of nivalenol, deoxynivalenol and zearalenone in stems+leaves and in ears were low or not detectable throughout the experiment. In experiment 2, we collected three ears of each cultivar at the late yellow-ripe stage that showed extreme symptoms of Fusarium ear rot. Concentrations of fumonisin were extremely high in the upper half of ears in all cultivars (fumonisin B1+B2 18,000-25,900 µg/kg) but low in the lower half and bracts. Concentrations of nivalenol, deoxynivalenol and zearalenone were extremely low or not detectable. These results show that fumonisin concentrations in ears increased rapidly after 50 DAH, they were extremely high in ears of all cultivars with symptoms of Fusarium ear rot, and fumonisin was the most common contaminant. These results will help reduce mycotoxin contamination.

Three-dimensional surface figure measurement of high-accuracy spherical mirror with nanoprofiler using normal vector tracing method.

Processing technology using an extreme ultraviolet light source, e.g., next-generation lithography, requires next-generation high-accuracy mirrors. As it will be difficult to attain the degree of precision required by next-generation high-accuracy mirrors such as aspherical mirrors through conventional processing methods, rapid progress in nanomeasurement technologies will be needed to produce such mirrors. Because the measuring methods used for the surface figure measurement of next-generation mirrors will require high precision, we have developed a novel nanoprofiler that can measure the figures of high-accuracy mirrors without the use of a reference surface. Because the accuracy of the proposed method is not limited by the accuracy of a reference surface, the measurement of free-form mirrors is expected to be realized. By using an algorithm to process normal vectors and their coordinate values at the measurement point obtained by a nanoprofiler, our measurement method can reconstruct three-dimensional shapes. First, we measured the surface of a concave spherical mirror with a 1000-mm radius of curvature using the proposed method, and the measurement repeatability is evaluated as 0.6 nm. Sub-nanometer repeatability is realized, and an increase in the repeatability would be expected by improving the dynamic stiffness of the nanoprofiler. The uncertainty of the measurement using the present apparatus is estimated to be approximately 10 nm by numerical simulation. Further, the uncertainty of a Fizeau interferometer is also approximately 10 nm. The results obtained using the proposed method are compared with those obtained using a Fizeau interferometer. The resulting profiles are consistent within the range of each uncertainty over the middle portions of the mirror.

Observation of the spatial distribution of gravitationally bound quantum states of ultracold neutrons and its derivation using the Wigner function.

Ultracold neutrons (UCNs) can be bound by the potential of terrestrial gravity and a reflecting mirror. The wave function of the bound state has characteristic modulations. We carried out an experiment to observe the vertical distribution of the UCNs above such a mirror at the Institut Laue-Langevin in 2011. The observed modulation is in good agreement with that prediction by quantum mechanics using the Wigner function. The spatial resolution of the detector system is estimated to be 0.7 µm. This is the first observation of gravitationally bound states of UCNs with submicron spatial resolution.

Application of wireless inertial measurement units and EMG sensors for studying deglutition - Preliminary results.

Different types of sensors are being used to study deglutition and mastication. These often suffer from problems related to portability, cost, reliability, comfort etc. that make it difficult to use for long term studies. An inertial measurement based sensor seems a good fit in this application; however its use has not been explored much for the specific application of deglutition research. In this paper, we present a system comprised of an IMU and EMG sensor that are integrated together as a single system. With a preliminary experiment, we determine that the system can be used for measuring the head-neck posture during swallowing in addition to other parameters during the swallowing phase. The EMG sensor may not always be a reliable source of physiological data especially for small clustered muscles like the ones responsible for swallowing. In this case, we explore the possibility of using gyroscopic data for the recognition of deglutition events.

Phasic bursts of the antagonistic jaw muscles during REM sleep mimic a coordinated motor pattern during mastication.

Sleep-related movement disorders are characterized by the specific phenotypes of muscle activities and movements during sleep. However, the state-specific characteristics of muscle bursts and movement during sleep are poorly understood. In this study, jaw-closing and -opening muscle electromyographic (EMG) activities and jaw movements were quantified to characterize phenotypes of motor patterns during sleep in freely moving and head-restrained guinea pigs. During non-rapid eye movement (NREM) sleep, both muscles were irregularly activated in terms of duration, activity, and intervals. During rapid eye movement (REM) sleep, clusters of phasic bursts occurred in the two muscles. Compared with NREM sleep, burst duration, activity, and intervals were less variable during REM sleep for both muscles. Although burst activity was lower during the two sleep states than during chewing, burst duration and intervals during REM sleep were distributed within a similar range to those during chewing. A trigger-averaged analysis of muscle bursts revealed that the temporal association between the bursts of the jaw-closing and -opening muscles during REM sleep was analogous to the temporal association during natural chewing. The burst characteristics of the two muscles reflected irregular patterns of jaw movements during NREM sleep and repetitive alternating bilateral movements during REM sleep. The distinct patterns of jaw muscle bursts and movements reflect state-specific regulations of the jaw motor system during sleep states. Phasic activations in the antagonistic jaw muscles during REM sleep are regulated, at least in part, by the neural networks involving masticatory pattern generation, demonstrating that waking jaw motor patterns are replayed during sleep periods.

Topical application of PPARα (but not ß/δ or γ) suppresses atopic dermatitis in NC/Nga mice.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which regulate not only adipogenesis and proliferation/differentiation but also the immune response of cells. Because topical application of the activators of some PPAR isoforms improved clinical symptoms in patients with atopic dermatitis (AD), we investigated the role of PPAR activators using a murine AD model in NC/Nga mice; to the best of our knowledge, this has not been previously reported. METHODS: Activators of three PPAR isoforms (α, ß/δ, γ) were topically applied on inflamed skin in a murine AD model that was developed by repeated topical application of mite antigen in NC/Nga mice. The efficacy of each topical PPAR activator was evaluated immunologically and serologically. RESULTS: Topical application of the PPARα activator, but not of the activators of PPARß/δ or PPARγ, improved clinical dermatitis, reduced inflammatory cell infiltration in the dermis, and alleviated the elevation of serum IgE levels. In addition, PPARα expression was downregulated in the epidermis in our murine AD model, as is seen in patients with AD. CONCLUSIONS: Topical application of PPARα activator could be a potent therapeutic agent for patients with AD and could take the place of topical steroid treatments.

Antitumor efficacy of oncolytic herpes simplex virus adsorbed onto antigen-specific lymphocytes.

Although several studies have reported that locally administering oncolytic viruses effectively targets malignancies, the efficacy of systemically administered oncolytic viruses is restricted. Recently, however, it was reported that systemic administration of oncolytic vesicular stomatitis virus adsorbed onto antigen-specific lymphocytes was effective against malignancies. We hypothesized that intravenously administering such virus might have significant potential in treatment of the malignant tumors. We adsorbed oncolytic herpes simplex virus-1 mutant R3616 onto lymphocytes harvested from mice with acquired antitumor immunity. We administered adsorbed R3616 to peritoneally disseminated tumors and analyzed the efficacy of this treatment. Mice administered adsorbed R3616 survived significantly longer than mice administered R3616 adsorbed onto non-specific lymphocytes, or mice administered either virus or tumor antigen-specific lymphocytes alone. In this context, herpes oncolytic virus is a promising treatment not only for primary lesions, but also for multiple metastasizing lesions. This treatment strategy may become one of the most effective methods for systemic virus delivery.

Histo-blood group gene polymorphisms as potential genetic modifiers of the development of coronary artery lesions in patients with Kawasaki disease.

Abnormal immunological responses to certain microbial agents may play a crucial role in the pathogenesis of Kawasaki disease (KD). The association studies between histo-blood group genes (Lewis and ABO blood types) and various types of infectious diseases or vasculopathy have been carried out based on the fact that glycosylated antigens could directly mediate microbial infections. We attempted to clarify the role of blood type antigens in the development of KD and coronary artery lesions in KD patients. The subjects included 164 KD patients enrolled from 1998 to 2003 (1st group), 232 patients from 2004 to 2009 (2nd group), and 223 healthy children and 118 patients with growth hormone deficiency as controls. The genotyping of the FUT2 and FUT3 genes, and ABO genotypes, was determined with the TaqMan SNP assay and allele-specific polymerase chain reaction. No significant differences were observed in the genotypes and allele frequencies of the FUT2 and FUT3 genes between the groups. The frequency of the BB blood genotype was significantly higher in KD patients with coronary artery lesions in the 1st and 2nd groups than in the controls (17% and 14% vs. 5%, P = 0.0020). This is the first report to investigate the roles of ABO and Lewis blood types in the development of KD, and in the formation of coronary artery lesions in KD patients. These data suggest that the ABO blood type may play a role in the development of coronary artery lesions in KD patients.

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer.

Oncolytic viruses are a promising method of cancer therapy, even for advanced malignancies. HF10, a spontaneously mutated herpes simplex type 1, is a potent oncolytic agent. The interaction of oncolytic herpes viruses with the tumor microenvironment has not been well characterized. We injected HF10 into tumors of patients with recurrent breast carcinoma, and sought to determine its effects on the tumor microenvironment. Six patients with recurrent breast cancer were recruited to the study. Tumors were divided into two groups: saline-injected (control) and HF10-injected (treatment). We investigated several parameters including neovascularization (CD31) and tumor lymphocyte infiltration (CD8, CD4), determined by immunohistochemistry, and apoptosis, determined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Median apoptotic cell count was lower in the treatment group (P=0.016). Angiogenesis was significantly higher in treatment group (P=0.032). Count of CD8-positive lymphocytes infiltrating the tumors was higher in the treatment group (P=0.008). We were unable to determine CD4-positive lymphocyte infiltration. An effective oncolytic viral agent must replicate efficiently in tumor cells, leading to higher viral counts, in order to aid viral penetration. HF10 seems to meet this criterion; furthermore, it induces potent antitumor immunity. The increase in angiogenesis may be due to either viral replication or the inflammatory response.

Gene expression profiling: identification of genes with altered expression in Ayu17-449 knockout mice.

Ayu17-449, a novel gene in mice, has been identified as a tumor-suppressor gene in myeloid malignancy; its product catalyzes the conversion of 5-methylcytosine of DNA to 5-hydroxymethylcytosine. However, in vivo, its functional target genes and biological function have remained unclear. Based on the assumption that alterations in the expression of the Ayu17-449 gene affect the expression of other related genes, we screened a microarray of altered gene expression in Ayu17-449(-/-) and Ayu17-449(+/+) mice. We identified 4049 genes with altered expression, including 1296 up-regulated (fold change ≥2) and 2753 down-regulated (fold change ≤0.5) genes in knockout mice compared with control mice. We then used qRT-PCR and RT-PCR to validate the chip data. Gene ontology and pathway analysis were performed on these altered genes. We found that these altered genes are functional genes in the complement and coagulation cascades, metabolism, biosynthesis, transcriptional regulation, proteolysis, and intracellular signaling pathways, such as the peroxisome proliferator-activated-receptor signaling pathway, the TNF-α-NF-κB pathway, the Notch signaling pathway, the MAPK signaling pathway, and the insulin signaling pathway. The results of our genome-wide comprehensive study could be helpful for comprehending the underlying functional mechanisms of the Ayu17-449 gene in mammals.

Recurrent atrial fibrillation after high-dose methylprednisolone therapy in a girl with lupus-associated hemophagocytic syndrome.

Hemophagocytic syndrome (HPS) is a serious complication of systemic lupus erythematosus (SLE). A 15-year-old female with lupus-nephritis developed HPS. Bone marrow study showed florid thrombophagocytosis. There was no associated infection. High-dose methylprednisolone therapy ameliorated HPS. However, atrial fibrillation (Af) repeated after the infusion and required direct-current cardioversion. No underlying diseases were found in the heart and endocrine system. Chest roentgenogram and echocardiography were normal. Electrocardiogram showed slightly prolonged PR interval in sinus rhythm. Af occurred at high circulating levels of interferon-γ and interleukin (IL)-10, but not IL-6, IL-2, tumor necrosis factor-α, C-reactive protein or catecholamines. This is the first observation that high-dose corticosteroid induced Af in a case of lupus-HPS. Af is unusual in SLE children without cardiac disease, while conduction defect occurs associated with lupus-myocarditis. Lupus-HPS may be an aggressive SLE subset with cardiac involvement. High-dose corticosteroid infusion controls lupus activity, but could disclose the cardiac stress in lupus-HPS patients.

Sonic hedgehog is required for cardiac outflow tract and neural crest cell development.

The Hedgehog signaling pathway is critical for a significant number of developmental patterning events. In this study, we focus on the defects in pharyngeal arch and cardiovascular patterning present in Sonic hedgehog (Shh) null mouse embryos. Our data indicate that, in the absence of Shh, there is general failure of the pharyngeal arch development leading to cardiac and craniofacial defects. The cardiac phenotype results from arch artery and outflow tract patterning defects, as well as abnormal development of migratory neural crest cells (NCCs). The constellation of cardiovascular defects resembles a severe form of the human birth defect syndrome tetralogy of Fallot with complete pulmonary artery atresia. Previous studies have demonstrated a role for Shh in NCC survival and proliferation at later stages of development. Our data suggest that SHH signaling does not act directly on NCCs as a survival factor, but rather acts to restrict the domains that NCCs can populate during early stages (e8.5-10.5) of cardiovascular and craniofacial development.