Differences between primary care physicians and specialised neurotologists in the diagnosis of dizziness and vertigo in Japan.

OBJECTIVE: Vertigo and dizziness are frequent symptoms in patients at out-patient services. An accurate diagnosis for vertigo or dizziness is essential for symptom relief; however, it is often challenging. This study aimed to identify differences in diagnoses between primary-care physicians and specialised neurotologists. METHOD: In total, 217 patients were enrolled. To compare diagnoses, data was collected from the reference letters of primary-care physicians, medical questionnaires completed by patients and medical records. RESULTS: In total, 62.2 per cent and 29.5 per cent of the patients were referred by otorhinolaryngologists and internists, respectively. The cause of vertigo or dizziness and diagnosis was missing in 47.0 per cent of the reference letters. In addition, 67.3 per cent of the diagnoses by previous physicians differed from those reported by specialised neurotologists. CONCLUSION: To ensure patient satisfaction and high quality of life, an accurate diagnosis for vertigo or dizziness is required; therefore, methods or materials to improve the diagnostic accuracy are needed.

Reduced induction of human ß-defensins is involved in the pathological mechanism of cutaneous adverse effects caused by epidermal growth factor receptor monoclonal antibodies.

Epidermal growth factor receptor inhibitors (EGFRIs) frequently cause cutaneous adverse effects such as papulopustular eruptions. However, the mechanism of the reactions remains unclear. To assess the pathological mechanism of cutaneous adverse reactions caused by EGFRIs, we investigated whether EGFRIs have an influence on the innate immune response of the skin. Levels of human ß-defensins (hBDs), which serve as the first line of defence against infection by pathogenic microorganisms, in the stratum corneum samples of patients treated with EGFR. monoclonal antibodies were measured before and after starting therapy. There were no obvious trends in hBD production in patients without eruptions, whereas a significant decrease in hBD1 and hBD3 production and a nonsignficant decrease in hBD2 production were observed in patients who developed papulopustular eruptions. Our results suggest that a reduction in hBD contributes to the increased incidence of papulopustular eruptions.

Basic evaluation of a novel 4D target and human body phantom.

Stereotactic body radiation therapy (SBRT) is usually verified with a dynamic phantom or solid phantom, but there is a demand for phantoms that can accurately simulate tumor dynamics within an individual that would allow customized validation in every patient. We developed a new 4D dynamic target phantom (multi-cell 4D phantom) that allows simulation of tumor movement in patients. The basic quality and dynamic reproducibility of this new phantom was verified in this investigation. The newly developed multi-cell 4D phantom comprises four main components: soft tissue, bones, lungs, and tumor (target). The phantom structure was based on computed tomography (CT) data of a male. In this study, we investigated the basic performance of a multi-cell 4D phantom. All the CT numbers of the phantom were very close to those of human data. The geometric maximum amplitudes were 4.57 mm in the lateral direction, 4.59 mm in the ventrodorsal direction, and 3.68 mm in the cranio-caudal direction. Geometric errors were 0.84, 0.58, and 0.40 mm, respectively. Movements of the abdominal surface were stable for 60 s. Repeated measurements show no actual differences in target movements between multiple measurements and indicated high reproducibility (r > 0.97). End-to-end tests using Gafchromic film revealed a gamma pass rate of 98% or above (2 mm/3%). Although our phantom performed limited reproducibility in the movement of the patient tumor at present, a satisfactory level of precision was confirmed in general. This is a very promising device for use in the verification of radiation therapy for moving targets.

International consensus (ICON) on treatment of Ménière's disease.

OBJECTIVE: To present the international consensus for recommendations for Ménière's disease (MD) treatment. METHODS: Based on a literature review and report of 4 experts from 4 continents, the recommendations have been presented during the 21st IFOS congress in Paris, in June 2017 and are presented in this work. RESULTS: The recommendation is to change the lifestyle, to use the vestibular rehabilitation in the intercritic period and to propose psychotherapy. As a conservative medical treatment of first line, the authors recommend to use diuretics and Betahistine or local pressure therapy. When medical treatment fails, the recommendation is to use a second line treatment, which consists in the intratympanic injection of steroids. Then as a third line treatment, depending on the hearing function, could be either the endolymphatic sac surgery (when hearing is worth being preserved) or the intratympanic injection of gentamicin (with higher risks of hearing loss). The very last option is the destructive surgical treatment labyrinthectomy, associated or not to cochlear implantation or vestibular nerve section (when hearing is worth being preserved), which is the most frequent option.

Ceramide synthase 4 is highly expressed in involved skin of patients with atopic dermatitis.

BACKGROUND: Ceramide is a crucial lipid in the stratum corneum (SC) which maintains the barrier function and hydration of the skin. In atopic dermatitis (AD) patients who have defective skin barrier function, ceramide levels are altered. We previously reported that although the amount of total ceramide was lower in involved skin compared with uninvolved skin of AD patients and with healthy control skin, the amounts of smaller ceramide species of Cer[NS] (<40 total carbons, which are total carbons of both sphingoid base and amide-linked fatty acid), especially Cer[NS] with 34 total carbons (C34-Cer[NS]), were higher. However, the enzyme(s) that produces the higher levels of smaller ceramide species in involved skin of AD patients was unclear. OBJECTIVE: To identify the enzyme(s) that produces higher levels of smaller ceramide species of Cer[NS] in the involved skin of AD patients. METHODS: Eight female Caucasian subjects who were diagnosed with AD on their arms (age range: 21-45 years) were enroled in this study. We compared ceramide levels in the SC and the expression levels of enzymes involved in ceramide metabolism using real-time PCR and immunohistochemistry between involved and uninvolved skin of AD patients. RESULTS: Level of mRNA encoding ceramide synthase 4 (CERS4), which is one of the enzymes that synthesize ceramide from a sphingoid base and an amide-linked fatty acid, was significantly higher in involved skin than in uninvolved skin (P < 0.01). Additionally, the protein expression level of CERS4 in the epidermis was also higher in involved skin compared with uninvolved skin. The expression level of CERS4 correlated with the amount of C34-Cer[NS] (P < 0.01) and the skin hydration value (P < 0.05). CONCLUSIONS: The elevated expression level of CERS4 contributes to the increase of C34-Cer[NS] and the impaired SC barrier function in involved skin of AD patients.

Post-operative infection of endoscopic submucosal dissection of early colorectal neoplasms: a case-controlled study using a Japanese database.

WHAT IS KNOWN AND OBJECTIVE: Endoscopic submucosal dissection of early colorectal neoplasms (ESD-ECN) is known to be an operation with risk of contamination, possibly requiring pre-operative antimicrobial prophylaxis for the prevention of post-operative infection. However, an evaluation of the need for pre-operative antimicrobial prophylaxis for ESD-ECN has yet to be reported. The objective of this study was to determine whether pre-operative antimicrobial prophylaxis is associated with a reduced incidence of post-operative infection following ESD-ECN. METHODS: The present retrospective case-controlled study utilized a database built from the medical records of 14 university hospitals throughout Japan. Patients who were admitted and discharged from the hospital from April 2012 to October 2013 and who had undergone ESD-ECN were included in the study. Patients who had been undergone any other operation during their course of hospitalization, and patients who were prescribed antimicrobial agents for reasons other than post-operative infection or for prophylaxis were excluded. Characteristics of the study population, pre-operative antimicrobial prophylaxis and antimicrobial therapy for post-operative infection were investigated. In addition, we compared the characteristics of patients with post-operative infection (PI) and those with no post-operative infection (NPI). Univariate analyses were used to estimate the odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS AND DISCUSSION: We obtained the records of 522 patients who had undergone ESD-ECN from the database. After application of exclusion criteria, 421 patients were enrolled. The post-operative infection rate was 1·2%. Peritonitis was found most to be the most common post-operative infection (44%). Pre-operative antimicrobial prophylaxis was used for 314 patients (75%), with a median duration of 3·0 (range 1-11) days. Cefotiam was most frequently prescribed for pre-operative antimicrobial prophylaxis (56%). Antimicrobial therapies were started 1-10 days after ESD-ECN for a duration of 1-14 days. Pre-operative antimicrobial prophylaxis was not associated with post-operative infection rate, with an OR (95% CI) of 0·73 (0·08-6·61). However, digestive tract perforation was shown to be associated with post-operative infection and had an OR (95% CI) of 17·1 (1·66-176·45). WHAT IS NEW AND CONCLUSION: Post-operative infection is an exceedingly rare event following ESD-ECN. Pre-operative antimicrobial prophylaxis had no significant effect on post-operative infection following ESD-ECN and thus may be unnecessary. Instead, prevention of digestive tract perforation may be more critical for the decrease in post-operative infections.

Human herpesvirus 6 reactivation on the 30th day after allogeneic hematopoietic stem cell transplantation can predict grade 2-4 acute graft-versus-host disease.

BACKGROUND: Viral infections and their occult reactivation occasionally cause not only organ damage, but also exacerbation of acute graft-versus-host disease (aGVHD), which may increase transplantation-related mortality synergistically. To determine correlations between viral reactivation and transplantation-related complications, we performed various viral screening tests on the 30th day after allogeneic hematopoietic stem cell transplantation (HSCT), and assessed the clinical implications. PATIENTS AND METHODS: Between August 2007 and January 2013, 49 patients (37 men, 12 women) underwent HSCT in our hospital. The stem cell sources were bone marrow (n = 21), peripheral blood (n = 13), and cord blood (n = 15). The presence of cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpesvirus (HHV) 6, and HHV7 in plasma samples prospectively collected from HSCT recipients on day 30 after HSCT was assayed by quantitative polymerase chain reaction, and the correlations with transplantation-related complications were evaluated. RESULTS: The positivities of CMV, EBV, HHV6, and HHV7 were 44.9%, 22.4%, 53.1%, and 18.3%, respectively. We analyzed transplantation-related complications, and a significant correlation was found only between HHV6 and grade 2-4 aGVHD from day 30 to day 100 (P < 0.001). Using a receiver operating characteristic curve, the area under the curve was calculated as 0.86 (95% confidence interval [CI], 0.74-0.98) between the viral load (VL) of HHV6 and grade 2-4 aGVHD. The sensitivity and specificity were 79% and 93%, respectively, when a cutoff value of 87 copies/mL was used. In multivariate analysis using the Fine and Gray proportional hazards model, the clinically determined high-risk patients (P = 0.004; hazard ratio [HR], 3.69; 95% CI, 1.52-9.00) and the positivity of HHV6 (P < 0.001; HR, 9.957; 95% CI, 2.68-37.06) were extracted as independent risk factors for the cumulative incidence of grade 2-4 aGVHD on or after post-HSCT day 30. The only risk factor extracted for the elevation of HHV6 VL >87 copies/mL was cord blood transplantation (P = 0.0032; odds ratio, 7.10; 95% CI, 1.98-30.00). CONCLUSION: All of the risk factors previously reported to predict severe aGVHD were obtained only during, but not after, HSCT. Our study suggests that the reactivation of HHV6 (≥ 87 copies/mL) at 30 days after HSCT is a possible predictive marker for grade 2-4 aGVHD on or after post-HSCT day 30.

A novel reduced-intensity umbilical cord blood transplantation using a recombinant G-CSF combined with high-dose Ara-C for active myeloid malignancies.

Non-remitting patients with hematologic myeloid malignancies have poor prognosis. To overcome this problem, we investigated the use of reduced-intensity preconditioning umbilical cord blood transplantation (RICBT) combined with recombinant G-CSF (rG-CSF) with high-dose Ara-C, fludarabine, melphalan, and 4 Gy of TBI in a phase I/II study in patients with non-remitting myeloid hematologic malignancies. Thirteen patients were enrolled, including 12 with non-remitting AML and one patient with blastic crisis CML (CML-BC). The patients' median age was 45 years, with a median comorbidity index of 4. All patients received 4/6 serological HLA-antigen matched unrelated umbilical cord blood. All patients were engrafted within 30 days after RICBT (median, 20 days; range, 14-29) and achieved complete remission without prior hematopoiesis. Common grade III non-hematologic toxicities included eight cases of transient mucositis (62%) and six cases of febrile neutropenia (46%). Transplant-related mortality was 7.7%. The 1-year overall survival was 28.6% in cases without post-RICBT treatment and 83.3% in cases with post-RICBT treatment. These data suggest that in active AML and CML-BC, the combination of rG-CSF with high-dose Ara-C and fludarabine/melphalan/4 Gy TBI with a reduced-intensity preconditioning regimen is well tolerated, secures engraftment and has significant anti-leukemia activity. In addition, performing post-RICBT treatment may provide high-quality long-term survival and remission.

Age-related changes of stratum corneum functions of skin on the trunk and the limbs.

BACKGROUND/AIMS: Despite our understanding that the care of back and buttock skin is important for elderly nursing patients, the stratum corneum (SC) functions of the skin on the trunk of elderly patients have not been well investigated. METHODS: Overall, 41 elderly subjects (average age: 75.9 years, 20 male and 21 female) and 20 middle-aged subjects (average age: 41.3 years, 10 male and 10 female) residing in Tokyo were recruited. Hydration of the SC, transepidermal water loss (TEWL), skin surface pH, total bacteria and inflammatory cytokines in the SC of skin on the buttocks, back, lower leg and inner forearm were measured. RESULTS AND CONCLUSION: The hydration of the SC decreased only on the lower leg with age. TEWL showed no change with age at any site. The pH was significantly higher in elderly skin than in middle-aged skin at all sites. The number of total bacteria on the forearm and back increased with age. The ratio of interleukin-1α (IL-1α) and IL-1α receptor antagonist was only higher on the middle-aged forearm compared to the elderly. No remarkable gender difference was found in these parameters without pH values. We clarified that most of the SC functional parameters change with age on both the trunk and the limbs in a similar manner, suggesting that the limbs are acceptable sites to estimate the SC functions of the trunk of elderly patients. Our study may be useful as basic data for future work to maintain the SC function of elderly patients.

Nationwide surveillance of antimicrobial consumption and resistance to Pseudomonas aeruginosa isolates at 203 Japanese hospitals in 2010.

PURPOSE: In Japan, a national surveillance study of antimicrobial consumption has never been undertaken. This study aimed to describe antimicrobial consumption and resistance to Pseudomonas aeruginosa in 203 Japanese hospitals, to identify targets for quality improvement. METHODS: We conducted an ecological study using retrospective data (2010). Antimicrobial consumption was collected in the World Health Organization (WHO) anatomical therapeutic chemical/defined daily dose (ATC/DDD) format. Rates of imipenem (IPM), meropenem (MEPM), ciprofloxacin (CPFX), or amikacin (AMK) resistance were expressed as the incidence of non-susceptible isolates. Additionally, hospitals were asked to provide data concerning hospital characteristics and infection control policies. Hospitals were classified according to functional categories of the Medical Services Act in Japan. RESULTS: Data were collected from 203 Japanese hospitals (a total of 91,147 beds). The total antimicrobial consumption was 15.49 DDDs/100 bed-days (median), with consumptions for penicillins, carbapenems, quinolones, and glycopeptides being 4.27, 1.60, 0.41, and 0.49, respectively. The median incidences of IPM, MEPM, CPFX, and AMK resistance were 0.15, 0.10, 0.13, and 0.03 isolates per 1,000 patient-days, respectively. Antimicrobial notification and/or approval systems were present in 183 hospitals (90.1 %). In the multivariate analysis, the piperacillin/tazobactam, quinolones, and/or total consumptions and the advanced treatment hospitals showed a significant association with the incidence of P. aeruginosa resistant to IPM, MEPM, CPFX, and AMK [adjusted R (2) (aR (2)) values of 0.23, 0.30, 0.22, and 0.35, respectively). CONCLUSION: This is the first national surveillance study of antimicrobial consumption in Japan. A continuous surveillance program in Japan is necessary in order to evaluate the association among resistance, antimicrobial restriction, and consumption.

Eucalyptus increases ceramide levels in keratinocytes and improves stratum corneum function.

The objectives of this study were to identify a plant extract that would improve stratum corneum functions and to elucidate the mechanism(s) involved. Based on the information that stratum corneum functions depend on the level of ceramide in the stratum corneum, we identified a Eucalyptus extract that was able to increase the level of ceramide in human keratinocytes in culture and in human stratum corneum and that improves the stratum corneum water holding and barrier functions. Addition of the Eucalyptus extract to human keratinocytes in culture increased the level of ceramide in a dose-dependent manner and also increased the biosynthesis of ceramide, glucosylceramide and sphingomyelin. Topical application of the Eucalyptus extract on the dry skin of human subjects induced by acetone and diethylether treatment resulted in a significant increase in ceramide level in the stratum corneum, a significant improvement in its water-holding function and an improvement in its barrier function. The addition of macrocarpal A, one of the main components of the Eucalyptus extract, to human keratinocytes in culture increased the level of ceramide and the mRNA expression of serine palmitoyltransferase, acid sphingomyelinase, neutral sphingomyelinase, glucosylceramide synthase and glucocerebrosidase in a dose-dependent manner. Our results indicate that the increased content of ceramides in the stratum corneum may underlie the therapeutic effect of the Eucalyptus extract. Our results also indicate the possibility that macrocarpal A is the key component that stimulates the synthesis of ceramide in the stratum corneum.

Real-life use of underwear treated with fabric softeners improves skin dryness by decreasing the friction of fabrics against the skin.

Scientific evaluation of fabric softener use on the friction of fabrics and on dry skin in real life is very limited. The coefficient of friction of fabrics was measured with a surface tester using model skin and cotton fabrics. The effects and safety of fabric softener-treated T-shirts on subjects with dry skin were evaluated in real-life conditions in the cold and arid environment. Twenty male volunteers with dry skin used T-shirts without softener for 1 week before day 0 and then wore softener-treated T-shirts for 14 days. Effects were evaluated by clinical grading, subjective symptoms, stratum corneum water content (SCWC) and transepidermal water loss (TEWL). A significant decrease in the coefficient of friction of fabrics was detected. A significant improvement in SCWC was observed on the torso, waist and shoulder, but no improvement was found on the inner forearm. There was a slight change in TEWL. The visual grading of dryness improved significantly at all sites, but no significant change was found in subjective symptoms. Our results suggest that fabric softener provides benefits to individuals with dry skin because of the decreased friction of the garments against the skin. It is possible that the softener treatment of fabrics contributes to the state of moisturization of the skin and may work in collaboration with the application of moisturizers.

Outcomes analysis of ruptured distal anterior cerebral artery aneurysms treated by endosaccular embolization and surgical clipping.

Although endovascular surgery is now widely used to treat intracranial aneurysms, no comparative studies of clipping versus endovascular surgery to address distal ACA aneurysms at the same institution are available. We compared the results of these treatment modalities to address distal ACA aneurysms at our institution. We treated 68 patients with ruptured distal ACA aneurysms (endovascular surgery, n=13; clipping surgery, n=55). We performed a retrospective comparison of the treatment outcomes. To study the efficacy of endovascular surgery we classified all our cases into three types: type A were small-necked aneurysms, type B were wide-necked aneurysms on the parent artery, and type C were aneurysms in which the A3 portion of the ACA arose from the aneurysmal dome near the neck. Intraoperative hemorrhage occurred in 7.7% of aneurysms treated by endovascular surgery and in 34.5% treated by clipping surgery. In 7.7% of the endovascularly-treated aneurysms we noted coil migration during embolization surgery; venous infarction due to cortical vein injury occurred in 7.3% of clipped aneurysms. Of the endovascularly-treated aneurysms, 7.7% manifested post-embolization hemorrhage; 23.1% manifested coil compaction. In clipping surgery, postoperative rerupture occurred in 1.8% of the aneurysms; one patient presented with postoperative acute epidural hematoma. Clip dislocation was noted in 1.8% of aneurysms. Angiography was indicative of post-treatment vasospasm in 7.7% of aneurysms treated endovascularly and in 50.9% of the clipped aneurysms. The clinical outcome showed no significant difference between endovascular surgery and clipping surgery.

Serum levels of IGF-1 are related to human skin characteristics including the conspicuousness of facial pores.

Conspicuous facial pores are one type of serious aesthetic defects for many women. However, the mechanism(s) that underlie the conspicuousness of facial pores remains unclear. We previously characterized the epidermal architecture around facial pores that correlates with the appearance of those pores in various ethnic groups including Japanese. The goal of this study was to evaluate the possible relationships between facial pore size, the severity of impairment of epidermal architecture around facial pores and sebum output levels to investigate the possible role of IGF-1 in the pathogenesis of conspicuous facial pores. The subjects consisted of 38 healthy Japanese women (aged 22-41 years). IGF-1 was measured using immunoradiometric assay. Surface replicas were collected to compare pore sizes of cheek skin and horizontal cross-section images of cheek skin were obtained non-invasively from the same subjects using in vivo confocal laser scanning microscopy and the severity of impairment of epidermal architecture around facial pores was determined. The skin surface lipids of each subject were collected from their cheeks and lipid classes were determined using gas chromatography/flame ionization detection. The serum level of IGF-1 correlated significantly with total pore area (R = 0.36, P < 0.05), with the severity of impairment of epidermal architecture around facial pores (R = 0.43, P < 0.05) and with sebum output levels (R = 0.41, P < 0.01). The sebum output levels correlated with total pore area (R = 0.32, P < 0.05). Our study found that serum levels of IGF-1 are correlated with facial skin characteristics including facial pore size and with the severity of impairment of epidermal architecture around facial pores.

Expression and translocation of aquaporin-2 in the endolymphatic sac in patients with Meniere's disease.

Meniere's disease, characterised by episodic vertigo, fluctuating hearing loss and tinnitus, can occur under conditions of stress. Its pathology was first revealed to be inner ear hydrops through temporal bone studies in 1938. Although its pathogenesis has been proposed to be a disorder of water transport in the inner ear, subsequently, it remains unsolved, until now. A recent study revealed that both plasma stress hormone, vasopressin (pAVP) and its receptor, V2 (V2R) expression in the inner ear endolymphatic sac were significantly higher in Meniere's patients. In the present study, to link V2R-related molecules and inner ear hydrops, we examined V2R-linked water channel molecule, aquaporin-2 (AQP2) expression and translocation in human endolymphatic sac. AQP2 mRNA expression in the endolymphatic sac was significantly higher in Meniere's patients by using real-time polymerase chain reaction, as further confirmed by western blotting. AQP2-like immunoreactivity (-LIR) was translocated from luminal to basolateral side with endosomal trapping in the endolymphatic sac at the time of AVP exposure in human endolymphatic sac tissue culture. The similar AQP2-LIR translocation was also demonstrated by forskolin and blocked by vasopressin/V2R specific antagonist, OPC31260 and protein kinase A (PKA) specific antagonists, H-89 and KT-5720. We concluded that in the pathogenesis of inner ear hydrops resulting in Meniere's attacks, pAVP elevation as a result of stress and subsequent V2R-cAMP-PKA-AQP2 activation and endosomal trapping of AQP2 in the endolymphatic sac, might be important as a basis of this disease. Further experimental and clinical studies are needed to better clarify the neuroscientific relationship between stress and Meniere's disease.

Behavioral assessment and identification of a molecular marker in a salicylate-induced tinnitus in rats.

Tinnitus is a non-observable phantom sensation. As such, it is a difficult condition to investigate and, to date, no effective treatment has been developed. To approach this phantom sensation, we aimed to develop a rat behavioral model of tinnitus using salicylate, an active component of aspirin known to induce tinnitus. We also aimed to establish a molecular marker of tinnitus by assessing the expression of transient receptor potential cation channel superfamily V-1 (TRPV1) in the rat auditory pathway during salicylate-induced tinnitus. Animals were trained to perform "an active avoidance task": animals were conditioned by electrical footshock to move to the other side of the conditioning box when hearing a sound. Animals received a single injection of saline or salicylate (400 mg/kg i.p.) and false positive responses were measured 2 h after injection as the number of movements during a silent period. The number of responses in salicylate-treated animals was highest when the conditioned stimulus was 60 dB sound pressure level (SPL) and 16 kHz. This indicates that animals could feel tinnitus 2 h after salicylate injection, equivalent to that induced by 60 dB SPL and 16 kHz. By means of real-time PCR and western blot analysis, TRPV1 expression was significantly upregulated in spiral ganglion cells 2 h after salicylate injection and this upregulation together with the increase in the number of false positive responses was significantly suppressed by capsazepine (10 mg/kg i.p.), a specific antagonist of TRPV1. This suggests that salicylate could induce tinnitus through activation of TRPV1 in the rat auditory pathway.