Search

Objective: To investigate the incidence of coronary artery abnormalities (CAAs) by fever pattern after intravenous immunoglobulin (IVIG) therapy in patients with Kawasaki disease.Study Design: This retrospective cohort study included 172 patients with Kawasaki disease aged ≤12 years who underwent IVIG therapy and had no CAAs before treatment. Resistance to initial IVIG was defined as persistent fever ≥37.5 °C for ≥24 hours after therapy or the recurrence of Kawasaki disease after initial defervescence. The patients were divided into 3 groups: IVIG responders, nonresponders with persistent fever, and nonresponders with recurrent fever. CAAs were evaluated 2 or 4 weeks and 12 months after onset and were defined by a coronary artery z-score ≥2.5.Results: The incidence of CAAs within 12 months after onset was significantly higher in nonresponders with persistent fever (27%) compared with the other 2 groups. On multivariate logistic regression analysis, being a nonresponder with persistent fever was an independent risk factor for having CAAs within 12 months after the onset of Kawasaki disease (OR, 6.48; P = .007).Conclusions: In patients with Kawasaki disease resistant to IVIG therapy, persistent fever, but not recurrent fever, was found to be a risk factor for the incidence of CAAs. Aggressive additional therapy may be beneficial to prevent CAA formation in patients with Kawasaki disease with persistent fever. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate the etiologies and diagnostic errors of early-phase pediatric fever without an obvious cause. This single-center, retrospective, descriptive study included 1334 febrile children hospitalized at Beppu Medical Center in Japan between 2014 and 2018. Eligibility criteria were age ≤12 years, axillary temperature ≥38.0°C, and fever duration ≤7 days at admission. Initial diagnoses on the day of admission and final diagnoses at defervescence were divided into initial fever with identified source (FIS) and initial fever without source (FWS) and final FIS and final FWS, respectively. The etiology of initial FWS and diagnostic discordance between initial FIS and final FIS were investigated. Of the 1334 participants, 94 (7.0%) were diagnosed with initial FWS. Among patients with initial FWS, final diagnoses were confirmed in 40 (43%), including Kawasaki disease in 17, urinary tract infection in 5, bacteremia in 4, exanthem subitum in 3, and the others in 11. Among the 1275 patients diagnosed with final FIS, diagnostic discordances between initial and final diagnoses were observed in 131 patients (10%). The multiple logistic regression analysis identified increased serum C-reactive protein value at admission (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.06–1.13), exanthem subitum (OR: 409; 95% CI: 119–1399), and Kawasaki disease (OR: 14.3; 95% CI: 8.7–23.3) as independent risk factors for diagnostic discordance. Exanthem subitum and Kawasaki disease may be undiagnosed or misdiagnosed in febrile children with fever duration ≤7 days. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the association between reduced prophylactic diazepam usage and short-term recurrence of febrile seizures (FSs) after the FS practice guideline was updated in Japan.Method: In this single-center, retrospective study, children (6-60 months of age) with FS who were transported to our center by ambulance from January 2011 through December 2018 were included. Rectal administration of diazepam (0.3-0.5 mg/kg) after the first seizure and seizure recurrence within 24 h were compared between 2011-2015 (pre-guideline revision) and 2016-2018 (post-guideline revision).Results: Among the total of 509 children, 297 were transported to our hospital in 2011-2015 and 212 in 2016-2018. Rectal diazepam administration was decreased in 2016-2018 (17 %) compared to 2011-2015 (53 %, P < 0.0001), while seizure recurrence was increased in 2016-2018 (20 %) compared to 2011-2015 (12 %, P = 0.0087). Similarly, hospital revisits (23 %) and hospital admissions (26 %) were increased in 2016-2018 compared to 2011-2015 (15 %, P = 0.031 and 18 %, P = 0.026, respectively). Multiple logistic regression analyses showed that prophylactic diazepam administration was the only factor related to preventing seizure recurrence. FS recurrence after the initial seizure was significantly less frequent with diazepam use (6 %) than without diazepam use (21 %, P < 0.0001; relative risk reduction, 70 %; number needed to treat, 6.8 children).Conclusion: The FS practice guideline revision was associated with reduced prophylactic diazepam usage and increased FS recurrence within 24 h in Japan. Prophylactic diazepam use should be determined based on clinical safety, local health infrastructure, and parental anxiety. [ABSTRACT FROM AUTHOR]

Background: Studies on the epidemiology of pediatric fractures have been scarce in recent years although fractures are very common in childhood. Boys have a higher incidence of fractures than girls. Currently, societal trends have seemed to influence the difference in activity patterns between boys and girls, but the sex difference regarding longitudinal changes in fracture incidence is not well known.Methods: We analyzed the school accident report in Niigata city, Japan and compared the incidence of fractures in elementary and junior high school students and the sex-related risk ratio between two 9-year periods separated by 20 years from their start and end points (1999-2007 and 1979-1987).Results: The study included 383,273 students from 1999 to 2007 and 561,109 students from 1979 to 1987. Comparing these periods, the fracture incidence increased significantly by 2.4 times in boys vs 2.1 times in girls from elementary school and by 2.2 times in boys vs 2.9 times in girls from junior high school (all p ＜ 0.001). The sex-related risk ratio of boys to girls increased significantly from 1.47 to 1.64 in elementary school students. In contrast, it decreased significantly from 3.29 to 2.52 in junior high school students and the change was markedly significant because of the drastic increase in fracture incidence in junior high school girls.Conclusions: The reasons proposed for the increase in schoolchildren's fractures were an improvement in diagnosis owing to social background and increased participation in sports activities despite the general decline in children's physical fitness and exercise ability. In junior high school girls, in particular, there was an increase in fracture risk due to increased participation in sports activities. [ABSTRACT FROM AUTHOR]

Risk of subsequent short stature remains unclear among mild small-for-gestational-age (SGA) infants with birthweight <10th percentile and ≥−2 standard deviations. In this multicenter cohort study in Japan, height was found to be <−2 standard deviations at 3 years old even in 18 % of mild-SGA infants. • Mild small-for-gestational-age (SGA) infants are commonly not indicated for growth hormone therapy. • The incidence of short stature or non-catch-up growth has not been well studied in this population. • Even among mild-SGA infants, short stature at 3 years of age was observed in 18 %. • Our findings provide basic data on the development of mild-SGA infants and risk factors for subsequent short stature. [ABSTRACT FROM AUTHOR]

Background Many case reports have described the coexistence of autoimmune bullous diseases (AIBDs) and psoriasis. Among them, anti-laminin γ1 (p200) pemphigoid is the best known. Objectives We sought to characterize patients with AIBDs and psoriasis and to investigate common AIBDs occurring in these patients. Methods This retrospective study included 145 patients with coexisting AIBD and psoriasis given a diagnosis from January 1, 1996, to July 31, 2013, at an academic dermatology department. Of these, 134 were consultation cases regarding AIBD diagnosis. Results Ratio of male to female patients was 5.7:1. Psoriasis onset preceded AIBD onset in most patients. Mean age at AIBD onset was 65.4 years, and mean duration between psoriasis and AIBD onset was 14.6 years. Most cases had single AIBD, whereas 16 cases had combined AIBDs. Bullous pemphigoid was the most prevalent (63.4%) followed by anti-laminin γ1 pemphigoid (37.2%). Limitations Consultation cases may not have included mild AIBD cases. Conclusion This study confirmed the association of psoriasis and anti-laminin γ1 pemphigoid. However, because bullous pemphigoid is a much more common disease, it is seen more frequently in patients with psoriasis than anti-laminin γ1 pemphigoid. [ABSTRACT FROM AUTHOR]

Abstract: Background: We recently reported that the autoantibodies of anti-p200 pemphigoid sera react with laminin γ1 and renamed this entity as anti-laminin γ1 pemphigoid. However, it has not been clarified whether the anti-laminin γ1 autoantibodies, particularly those to the C-terminal integrin binding site, affect the dermoepidermal junction and cause subepidermal blisters. Objective: The aim of this study was to develop animal models for anti-laminin γ1 pemphigoid. Methods: We attempted to produce two mouse models for anti-laminin γ1 pemphigoid; (1) a passive transfer model: injection of rabbit IgG to shorter bacterial recombinant protein of the murine laminin γ1 C-terminal 107 amino acids, and (2) an active disease model: direct immunization to mice with this recombinant protein. Results: Immunoblotting revealed that 70% of patient sera reacted with the shorter recombinant protein of human laminin γ1 C-terminus. In the passive transfer model, rabbit IgG to the murine laminin γ1 C-terminus was deposited, without C3 deposition, at the epidermal basement membrane zone. In contrast, in the active disease model, direct immunofluorescence of mouse skin sections showed no deposition of either murine IgG or C3. Blister formation was not seen in either model both phenotypically and histopathologically. Conclusion: In the two different mouse animal models for anti-laminin γ1 pemphigoid, although rabbit IgG to the recombinant laminin γ1 C-terminus bound to the epidermal basement membrane zone in passive transfer model, no obvious blister formation was seen. To reproduce skin lesions in mouse models for anti-laminin γ1 pemphigoid, further improvement should be needed. [Copyright &y& Elsevier]

• During the COVID-19 pandemic, infectious disease epidemiology has changed worldwide. • In Japan, 75% of infectious diseases decreased in incidence. • In contrast, 17% of those increased, particularly vector-borne diseases. • Respiratory syncytial virus infection and hand-foot-and-mouth disease showed unique epidemiological changes. • These changes can occur even in countries applying mitigation policies. To elucidate the impact of the COVID-19 pandemic on the epidemiology of other infectious diseases. We investigated the epidemiology of 36 communicable diseases during 2015-2021 in Japan and compared the number of cases in each disease between the prepandemic (2015-2019) and intrapandemic (2020-2021) periods. Relationships between the incidence of the infectious diseases and the COVID-19 pandemic were also investigated. Of 36 communicable diseases, the number of cases in the 27 diseases (75%) mainly caused by pathogens transmitted by droplet or contact was lower intrapandemic than prepandemic, and the cases of 21 diseases (58%) continued to decrease intrapandemic. The number of cases of six diseases (17%) was higher intrapandemic than prepandemic, and the cases of two diseases (5.6%), Japanese spotted fever and syphilis, continued to increase intrapandemic. Time trend analyses revealed a positive correlation between case numbers of communicable diseases and the COVID-19 pandemic, whereas the case numbers of hand-foot-and-mouth disease and respiratory syncytial virus infection rebounded in 2021 after decreasing in 2020. The COVID-19 pandemic has greatly impacted the epidemiology of communicable diseases, suggesting that countermeasures against COVID-19 and lifestyle changes might be involved in these epidemiological changes. [Display omitted] [ABSTRACT FROM AUTHOR]

Summary: Skeletal muscle atrophy induced by aging (sarcopenia), inactivity, and prolonged fasting states (starvation) is predominantly restricted to glycolytic type II muscle fibers and typical spares oxidative type I fibers. However, the mechanisms accounting for muscle fiber-type specificity of atrophy have remained enigmatic. In the current study, although the Fyn tyrosine kinase activated the mTORC1 signaling complex, it also induced marked atrophy of glycolytic fibers with relatively less effect on oxidative muscle fibers. This was due to inhibition of macroautophagy via an mTORC1-independent but STAT3-dependent reduction in Vps34 protein levels and decreased Vps34/p150/Beclin1/Atg14 complex 1. Physiologically, in the fed state endogenous Fyn kinase activity was increased in glycolytic but not oxidative skeletal muscle. In parallel, Y705-STAT3 phosphorylation increased with decreased Vps34 protein levels. Moreover, fed/starved regulation of Y705-STAT3 phosphorylation and Vps34 protein levels was prevented in skeletal muscle of Fyn null mice. These data demonstrate a Fyn/STAT3/Vps34 pathway that is responsible for fiber-type-specific regulation of macroautophagy and skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

Abstract: All cells count on precise mechanisms that regulate protein homeostasis to maintain a stable and functional proteome. A progressive deterioration in the ability of cells to preserve the stability of their proteome occurs with age and contributes to the functional loss characteristic of old organisms. Molecular chaperones and the proteolytic systems are responsible for this cellular quality control by assuring continuous renewal of intracellular proteins. When protein damage occurs, such as during cellular stress, the coordinated action of these cellular surveillance systems allows detection and repair of the damaged structures or, in many instances, leads to the complete elimination of the altered proteins from inside cells. Dysfunction of the quality control mechanisms and intracellular accumulation of abnormal proteins in the form of protein inclusions and aggregates occur in almost all tissues of an aged organism. Preservation or enhancement of the activity of these surveillance systems until late in life improves their resistance to stress and is sufficient to slow down aging. In this work, we review recent advances on our understanding of the contribution of chaperones and proteolytic systems to the maintenance of cellular homeostasis, the cellular response to stress and ultimately to longevity. [Copyright &y& Elsevier]

The aim of our study was to investigate the effects of silent brain lesions on cognitive function of community-dwelling elderly individuals. Brain magnetic resonance imaging and other medical examinations were performed on 350 nondemented elderly individuals (121 male and 229 female, average age 72.4 years) who resided in the rural community of Sefuri Village, Saga, Japan. The mini mental state examination and modified Stroop test (MST) were used to identify cognitive impairment. White matter lesions (WMLs) and cerebral atrophy on magnetic resonance imaging were measured quantitatively. Multivariate analyses were done using a logistic regression model with a software package. Cognitive impairment defined by mini mental state examination score less than 24 was present in 55 individuals (15.7%). They had a lower educational level, significantly larger quantity of WMLs, and more remarkable cerebral atrophy. Frontal lobe dysfunction was detected in 52 individuals (14.9%) through prolonged MST score (>36 seconds). Impaired frontal lobe function was related to number of silent lacunar infarcts, larger WMLs, and more prominent cerebral atrophy. MST score in individuals with two or more infarcts was significantly more prolonged compared with MST score in those without infarction. These results suggest that WMLs may cause rather diffuse cognitive decline, whereas multiple lacunar infarcts are specifically involved in frontal lobe dysfunction. Silent ischemic lesions in apparently healthy elderly individuals seem to form a distinctive group of people with vascular cognitive impairment without dementia. This group should be the primary target of prevention of vascular dementia. [Copyright &y& Elsevier]

Rationale and Objectives: An automated method for identification of patients with cerebral atrophy due to Alzheimer’s disease (AD) was developed based on three-dimensional (3D) T1-weighted magnetic resonance (MR) images. Materials and Methods: Our proposed method consisted of determination of atrophic image features and identification of AD patients. The atrophic image features included white matter and gray matter volumes, cerebrospinal fluid (CSF) volume, and cerebral cortical thickness determined based on a level set method. The cortical thickness was measured with normal vectors on a voxel-by-voxel basis, which were determined by differentiating a level set function. The CSF spaces within cerebral sulci and lateral ventricles (LVs) were extracted by wrapping the brain tightly in a propagating surface determined with a level set method. Identification of AD cases was performed using a support vector machine (SVM) classifier, which was trained by the atrophic image features of AD and non-AD cases, and then an unknown case was classified into either AD or non-AD group based on an SVM model. We applied our proposed method to MR images of the whole brains obtained from 54 cases, including 29 clinically diagnosed AD cases (age range, 52−82 years; mean age, 70 years) and 25 non-AD cases (age range, 49−78 years; mean age, 62 years). Results: As a result, the area under a receiver operating characteristic (ROC) curve (Az value) obtained by our computerized method was 0.909 based on a leave-one-out test in identification of AD cases among 54 cases. Conclusion: This preliminary result showed that our method may be promising for detecting AD patients. [Copyright &y& Elsevier]

Rationale and Objectives: A method of estimating and mapping the cortical damage resulting from neurodegenerative diseases based on diffusion-weighted imaging was recently proposed. We improved on this method to visualize the cortical damage in Alzheimer’s disease (AD) in the lateral and medial aspects of the cerebral hemispheres and to provide anatomic references. Materials and Methods: Damage in the cerebral cortex was estimated based on diffusivity in the subcortical white matter according to a previously published method. A map of subcortical mean diffusivity (MD) was superimposed on the corresponding anatomic image so that the spatial extent of the abnormality could be anatomically localized. The right and left hemispheres were separated to evaluate the medial and lateral aspects of each hemisphere. This method was applied to 10 healthy subjects and 11 AD patients. MDs within 20 cortical regions were visually evaluated and statistically compared between AD and healthy subjects at a significance level of P < .01. Results: In addition to the involvement of the lateral aspects of the bilateral parietal and temporal lobes and clear sparing of the bilateral pericentral regions that were previously reported, significant MD elevation was observed in the medial aspects of the right frontal, bilateral parietal, and right temporal lobes. The extent of MD abnormalities was easily identified by the background anatomic image. Conclusions: Results suggested that AD damage in the lateral and medial cerebral cortex can be visualized with an anatomic reference using our method. [Copyright &y& Elsevier]

Rationale and Objectives: White matter (WM) abnormality in Alzheimer’s disease (AD) has been less well characterized than cortical damage. We studied the spatial distribution of the subcortical WM abnormality using diffusion-weighted magnetic resonance imaging (DWI). Materials and Methods: Twenty-one AD patients and seven healthy, elderly subjects were included. DWIs were obtained using a cerebrospinal fluid (CSF)-nulled pulse sequence to reduce the partial volume contamination of CSF signal. Diffusivity in the subcortical WM voxels was mapped onto the cortical surface using original software so that the spatial distribution of subcortical WM damage, which was visualized as an area of increased diffusivity, could be viewed in a three-dimensional map. The damages in the lateral surface of the bilateral cerebral hemispheres were visually evaluated, and severities of the damages in five brain regions were compared with each other. In addition, the severity of the damage in each region was correlated with patient’s mini-mental state examination (MMSE) score. Results: In both hemispheres, clear sparing of the pericentral regions and predominant involvement of the parietal and temporal regions were revealed with statistical significance (P < .05, respectively). Marginal correlation (P < .05 uncorrected for multiple comparisons) was observed between the damage severity in the bilateral frontal and right temporal regions and patient’s MMSE score. Conclusion: We demonstrated a subcortical WM abnormality over the parietal and temporal regions with clear sparing of the pericentral region using our mapping method, which supported the hypothesis that the subcortical WM abnormality in AD originates in Wallerian degeneration. [Copyright &y& Elsevier]

Rationale and Objective: Brain tissue damage in frontotemporal dementia (FTD) has never been systematically studied using diffusion-weighted imaging (DWI). We studied FTD patients using DWI to determine whether microstructural changes in white matter can be detected in vivo. Materials and Methods: Thirteen FTD patients and 15 aged healthy subjects were studied. Mean diffusivity (MD) abnormalities in 28 white matter regions were visually evaluated. In addition, MD values in 10 white matter regions relative to that in the ipsilateral postcentral gyrus were measured. The results were compared between healthy subjects and FTD patients. Results: The visual rating resulted in a significant MD elevation in FTD patients in the bilateral high superior frontal gyri, right orbitofrontal gyrus, bilateral anterior temporal lobes, and left middle temporal lobe (P < .01, respectively). Relative MD comparison revealed a significant MD elevation in FTD patients in the bilateral high superior frontal gyri, bilateral orbitofrontal gyri, and bilateral anterior temporal lobes (P < .05 after Bonferroni correction, respectively). Conclusion: Our results demonstrated white matter MD abnormalities in FTD patients. It was suggested that the observed white matter MD abnormalities are secondary to damage in the overlying cortex. [Copyright &y& Elsevier]

Background: Anatomical and histopathologic correlates of the unique dermoscopic patterns seen in melanocytic nevi on acral volar skin is yet to be clarified. Objective: Our aim was to investigate the relation between the dermoscopic patterns and anatomical and histopathological characteristics of melanocytic nevi on the sole. Methods: The precise locations of 298 melanocytic nevi on the sole from 278 patients were retrospectively investigated, with attention paid to each dermoscopic pattern. In addition, 35 nevi showing each typical dermoscopic pattern were excised and evaluated histopathologically. Results: Melanocytic nevi showing the parallel furrow pattern or the fibrillar pattern were located on the portions of the sole with regular parallel skin markings and were not found on the arch areas of the foot. Moreover, a subtle but distinctive difference in the distribution was observed between nevi of the two patterns; the nevi with the fibrillar pattern showed a tendency for the sites directly pressed by the body''s weight. Melanocytic nevi of the lattice-like pattern were mostly located on the arch areas. Histopathologically, irrespective of the dermoscopic patterns, nests of nevus cells were mainly located in the epidermal rete ridges underlying the surface sulci. In the nevi with a fibrillar pattern, the cornified layer showed a slanting arrangement, which is considered to be a histopathological background of the fibrillar pattern. Conclusion: Dermoscopic patterns seen in acral melanocytic nevi could be explained by the unique anatomical and histopathological characteristics of the acral skin. [Copyright &y& Elsevier]

Tax, a protein encoded by the env-pX gene of human T-cell leukemia virus type I (HTLV-I), interacts with various host cell transcription factors. Tax activates transcription from the long terminal repeat (LTR) of HTLV-I through association with cyclic AMP-responsive element-binding protein (CREB). Here, we present evidence that transducer of regulated cyclic AMP-response element-binding protein 3 (TORC3), a co-activator of CREB, is involved in Tax-induced transcriptional activation from the HTLV-I LTR. By using a luciferase assay system, we show that TORC3 alone can enhance transcription from the HTLV-I LTR, as well as from a cellular cyclic AMP-response element (CRE). Interestingly, we find that co-expression of TORC3 and Tax dramatically increased transcriptional activation at the HTLV-I LTR. We also show by glutathione S-transferase pull-down and co-immunoprecipitation experiments that TORC3 interacts with Tax. Using deletion mutant analysis, we identify the Tax interaction domain of TORC3 as a region spanning from amino acid i to 103, which contains a coiled-coil domain. These results provide important clues toward understanding the molecular mechanism of Tax-dependent transcriptional activation of the HTLV-I LTR. [ABSTRACT FROM AUTHOR]

Covalent modification of many transcription factors with SUMO-1 is emerging as a key role of trans-activational regulation. Here, we demonstrate that peroxisome proliferator-activated receptor (PPAR) γ, which is a ligand-activated nuclear receptor, is modified by SUMO-1. Sumoylation of PPARγ mainly occurs at a lysine residue within the activation function 1 domain. Furthermore, we show that the PIAS family proteins, PIAS1 and PIASxβ, function as E3 ligases (ubiquitin-protein isopeptide ligase) for PPARγ. PPARγ interacts directly with PIASxβ in a ligand-independent manner. Analysis using a PPARγ mutant with a disrupted sumoylation site shows that modification of PPARγ by SUMO-1 represses its transcriptional activity. Interestingly, PIASxβ and Ubc9 enhance the transcriptional activity of PPARγ independent of PPARγ sumoylation. Furthermore, PPARγ ligand-induced apoptosis in a human hepatoblastoma cell line, HepG2, is significantly enhanced by ectopic production of the sumoylation-mutant PPARγ. These results suggest that the PPARγ-dependent transactivation pathway seems to be modulated by SUMO-1 modification and may serve as a novel target for apoptosis-induction therapy in cancer cells. [ABSTRACT FROM AUTHOR]

Identifying indicators of early knee osteoarthritis is important for preventing the onset and/or progression of the disease. Although low quadriceps strength and changes in stride and knee kinematics during gait have been suggested as possible indicators, their relevance and relationships have not been fully examined. This study aimed to analyze the association of quadriceps strength with stride and knee kinematics during gait in adults with normal knee or early knee osteoarthritis. A total of 881 knees from 474 community dwelling adults (238 males and 236 females) were included. Radiographic images of the knee in standing position were obtained, and grading of knee osteoarthritis was classified. Isometric quadriceps strength was measured using a force detector device. Three-dimensional knee kinematics during gait was obtained by a motion capture system. Sex-based difference of quadriceps strength, stride and knee kinematics during gait was evaluated by multiple comparison among grades by sex and multiple regression of quadriceps strength was analyzed by stride and knee kinematics during gait. Stride length and quadriceps strength were significantly reduced with higher grade in both sexes, and changes in knee kinematics during gait differed by sex from early knee osteoarthritis. Quadriceps strength in both sexes was significantly correlated with changes in stride length and knee kinematics during gait. Improving quadriceps strength in early knee osteoarthritis was related with maintaining gait ability and restraining abnormal knee kinematics during gait. This may help to develop clinical approaches to prevent the onset and/or progression of knee osteoarthritis. • Quadriceps strength and stride length reduced from early knee osteoarthritis. • Knee kinematics during gait was altered from early knee osteoarthritis. • Knee kinematics during gait had a sex difference in early knee osteoarthritis. • Quadriceps strength was associated with change in stride and knee kinematics. • Improving quadriceps strength may be important to maintain knee kinematics. [ABSTRACT FROM AUTHOR]

Abstract: X-linked myotubular myopathy is a severe congenital myopathy that can involve multiple organs. We report on a 10-month-old boy who manifested X-linked myotubular myopathy with subdural hemorrhage. The diagnosis of X-linked myotubular myopathy was based on typical muscle pathology and MTM1 missense mutation. The patient had undergone no traumatic episodes or bleeding diathesis. Axial growth acceleration is known to occur in X-linked myotubular myopathy, potentially leading to dolichocephaly. In our patient, an enlarged subdural space apparently stretched the bridging veins, increasing susceptibility to subdural hemorrhage. Patients who manifest X-linked myotubular myopathy with typical dolichocephaly are at increased risk for subdural hemorrhage. [Copyright &y& Elsevier]

Autophagy is a conserved cellular process involving intracellular membrane trafficking and degradation. Pathogens, including hepatitis C virus (HCV), often exploit this process to promote their own survival. The aim of this study was to determine the mechanism by which HCV increases steady-state autophagosome numbers while simultaneously inhibiting flux through the autophagic pathway. Using the lysosomal inhibitor bafilomycin A1, we showed that HCV-induced alterations in autophagy result from a blockage of autophagosome degradation rather than an increase in autophagosome generation. In HCV-infected cells, lysosome function was normal, but a tandem RFP--GFP--LC3 failed to reach the lysosome even under conditions that activate autophagy. Autophagosomes and lysosomes isolated from HCV-infected cells were able to fuse with each other normally in vitro, suggesting that the cellular fusion defect resulted from trafficking rather than an inability of vesicles to fuse. Arl8b is an Arf-like GTPase that specifically localizes to lysosomes and plays a role in autophagic flux through its effect on lysosomal positioning. At basal levels, Arl8b was primarily found in a perinuclear localization and co-localized with LC3-positive autophagosomes. HCV infection increased the level of Arl8b 3-fold and redistributed Arl8b to a more diffuse, peripheral pattern that failed to co-localize with LC3. Knockdown of Arl8b in HCV-infected cells restored autophagosome--lysosome fusion and autophagic flux to levels seen in control cells. Thus, HCV suppresses autophagic flux and increases the steady-state levels of autophagosomes by increasing the expression of Arl8b, which repositions lysosomes and prevents their fusion with autophagosomes. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to elucidate whether H1 antihistamine administration increases susceptibility to febrile convulsions in children.Methods: A single-center, retrospective observational study was conducted in Japan. The study included 380 children with febrile convulsions between the ages of six months and five years transported via ambulance from 2011 through 2016. They were divided into the preseizure H1 antagonist "use group" and the "nonuse group." The former consisted of children who took H1 antagonists within 24 hours before the seizure onset. The primary outcome (seizure duration) and the secondary outcome (interval from fever to seizure onset) were compared between the two groups.Results: Of the 380 study patients, 70 (18%) were identified as the use group. None of the patients was taking excessive doses of H1 antagonists. The prevalence of seizures lasting 15 minutes or longer was not different between the use group and the nonuse group (11% versus 8%, prevalence ratio 1.47 [95% confidence interval, 0.63 to 3.42], P = 0.37). The prevalence of fever to seizure onset less than six hours was significantly lower in the use group (26% versus 52%, prevalence ratio 0.33 [95% confidence interval 0.19 to 0.60], P < 0.001). Similar results were obtained when analyses were conducted separately by different generations (first and second) of H1 antagonists.Conclusions: Prolonged seizure duration and shortened interval from fever to seizure were not observed in children who received H1 antagonists. This study provides evidence that H1 antagonists at optimal doses could be safely used in febrile children with allergic symptoms. [ABSTRACT FROM AUTHOR]

Arfaptins (arfaptin-1 and arfaptin-2/POR1) were originally identified as binding partners of the Arf small GTPases. Both proteins contain a BAR (Bin/Amphiphysin/Rvs) domain, which participates in membrane deformation. Here we show that arfaptins associate with trans-Golgi membranes. Unexpectedly, Arl1 (Arf-like 1), but not Arfs, determines the trans-Golgi association of arfaptins. We also demonstrate that arfaptins interact with Arl1 through their BAR domain-containing region and compete for Arl1 binding with golgin-97 and golgin-245/p230, both of which also bind to Arl1 through their GRIP (golgin-97/RanBP2/Imh1p/p230) domains. However, arfaptins and these golgins show only limited colocalization at the trans-Golgi. Time-lapse imaging of cells overexpressing fluorescent protein-tagged arfaptins and golgin-97 reveals that arfaptins, but not golgin-97, are included in vesicular and tubular structures emanating from the Golgi region. These observations indicate that arfaptins are recruited onto trans-Golgi membranes by interacting with Arl1, and capable of inducing membrane deformation via their BAR domains. [ABSTRACT FROM AUTHOR]

Abstract Aim The aim of the study was to evaluate the efficacy and safety of nivolumab combined with ipilimumab in treatment-naïve Japanese patients with advanced melanoma. Methods In this multicentre, single-arm study, treatment-naïve Japanese patients with unresectable stage III/IV or recurrent melanoma received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for four doses, followed by biweekly doses of nivolumab (3 mg/kg). The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included overall survival (OS), progression-free survival (PFS), disease control rate and safety. Results The subtypes of the thirty patients enrolled were: 12, mucosal; eight, non-acral cutaneous; seven, acral; two, uveal and one, unknown primary melanoma. The ORR was 43.3% (95% confidence interval [CI]: 25.5, 62.6) with central and local assessment. The centrally and locally assessed disease control rate (95% CI) were 73.3% (54.1, 87.7) and 86.7% (69.3, 96.2), respectively. At the median follow-up period of 14.1 months (range 5.2–27.7), median OS and centrally assessed PFS were not reached. OS (95% CI) at 6, 12, 18 and 24 months was 93.3% (75.9, 98.3), 83.3% (64.5, 92.7), 72.9% (50.0, 86.5) and 65.6% (40.4, 82.2), respectively. Treatment-related adverse events (AEs) occurred in all patients. Grade III–IV and serious AEs occurred, mostly during the combination phase, in 23 (76.7%) and 20 (66.7%) patients, respectively. No treatment-related deaths occurred. Conclusions This study confirmed the efficacy and safety of nivolumab plus ipilimumab in treatment-naïve Japanese patients with advanced melanoma including rare subtypes. Incidence rates for grade III–IV AEs were high but manageable with appropriate medical attention and treatment. Trial registration JapicCTI-152869. Highlights • This study tested the efficacy and safety of nivolumab plus ipilimumab. • Participants were treatment-naïve Japanese patients with advanced melanoma including rare subtypes. • Survival outcomes were consistent with previous studies in Western populations. • The safety profile was similar to previous reports. • Nivolumab plus ipilimumab is a viable option for Japanese melanoma patients. [ABSTRACT FROM AUTHOR]

Mutations in the X-linked gene CDKL5 cause early-onset epileptic encephalopathy and severe developmental delay. Because this disorder predominantly affects females, the full clinical spectrum of male patients remains elusive. We herein report a 16-year-old boy, who suffered from intractable seizures 20 days after birth. Serial electroencephalograms detected recurrent focal epileptiform discharges from age 4 months, which evolved to hypsarrhythmia later in infancy. Mass-spectrometric analyses revealed increase in urinary excretion of methylmalonic acid without perturbed concentrations of propionic acid, homocystein and methionine. Whole-exome sequencing identified a de novo , truncating mutation in CDKL5 (NM_003159.2:c.419dupA, p.Asn140Lysfs*8). Targeted sequencing excluded concomitant mutations in methylmalonic academia-associated genes. No methylmalonic acidemia has been reported in children with CDKL5 disorder. Extensive analyses on organic acid metabolism for males with CDKL5 mutations will gain more insight into their biochemical profiles in infancy. [ABSTRACT FROM AUTHOR]

Background: We investigated features and responses to treatment in patients with febrile and afebrile convulsions with mild gastroenteritis and characterized convulsions with rotavirus and norovirus gastroenteritis.Methods: We conducted a prospective, observational study to evaluate patients with febrile and afebrile convulsions with mild gastroenteritis who were hospitalized between November 2011 and March 2014 at 13 facilities in the National Hospital Organization. We classified the patients into two groups: presence or absence of fever. We investigated the background, clinical and laboratory characteristics, viral antigen in stool, and efficacy of anticonvulsant drugs.Results: Of 126 patients enrolled in this study, 50 were febrile (Fc group) and 76 were afebrile (aFc group). A family history of febrile seizures was significantly more frequent in the Fc group than in the aFc group (28.0% vs 9.2%, P = 0.005). Clinical characteristics were similar between the rotavirus and norovirus groups, but fever was significantly more frequent in the rotavirus group (46.2% vs 8.3%, P < 0.001). Serum sodium levels were significantly negatively related to the number of seizures in the aFc group (β = -0.13; 95% confidence interval, -0.24, -0.03; P = 0.01). Carbamazepine was significantly more efficacious than diazepam suppositories in the aFc group (odds ratio = 49.3, 95% confidence interval, 2.35, 1037; P = 0.01).Conclusion: Febrile convulsions with mild gastroenteritis show characteristics of both febrile seizures and convulsions with mild gastroenteritis. Carbamazepine is optimal for convulsions with mild gastroenteritis. Clinical features of convulsions with rotavirus and norovirus gastroenteritis are similar, except for fever. Serum sodium levels may play a major role in the onset of convulsions with mild gastroenteritis. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a study of immunoglobulin G (IgG) anti-BP180 antibodies in patients with paraneoplastic pemphigus (PNP).

Paraneoplastic pemphigus (PNP) shows autoantibodies mainly to plakin and desmosomal cadherin family proteins. We have recently identified alpha-2-macroglobulin-like-1 (A2ML1), a broad range protease inhibitor, as a unique PNP antigen. In this study, we tested a large number of PNP sera by various methods. Forty (69.0%) of 58 PNP sera recognized A2ML1 recombinant protein expressed in COS7 cells by immunofluorescence (IF) and/or immunoprecipitation (IP)/immunoblotting (IB). IP/IB showed higher sensitivity than IF. In addition, 22 (37.9%) PNP sera reacted with A2ML1 by IB of cultured normal human keratinocytes (NHKs) under non-reducing conditions. Statistical analyses using various clinical and immunological data showed that the presence of anti-A2ML1 autoantibodies was associated with early disease onset and absence of ocular lesions. Next, to investigate the pathogenic role of anti-A2ML1 antibody, we performed additional functional studies. Addition of anti-A2ML1 polyclonal antibody to culture media decreased NHK cell adhesion examined by dissociation assay, and increased plasmin activity detected by casein zymography, suggesting that anti-A2ML1 antibody may decrease NHK cell adhesion through plasmin activation by inhibition of A2ML1. This study demonstrates that autoantibodies to A2ML1 are frequently and specifically detected and may have a pathogenic role in PNP. [ABSTRACT FROM AUTHOR]

Abstract: Background: Plectin, a member of the plakin family proteins, is a high molecular weight protein that is ubiquitously expressed. It acts as a cytolinker for the three major components of the cyotoskeleton, namely actin microfilaments, microtubules and intermediate filaments. Objective: The aim of our experiments was to identify new binding sites for intermediate filaments on plectin and to specify these sites. Methods: We introduced truncated forms of plectin into several cell lines and observe interaction between plectin and intermediate filaments. Results: We found that a linker region in the COOH-terminal end of plectin was required for the association of the protein with intermediate filaments. In addition, we also demonstrated that a serine residue at position 4645 of plectin may have a role on binding of plectin to intermediate filaments. Conclusion: A linker region in the COOH-terminal end and serine residue at position 4645 may be important for the binding of plectin to intermediate filaments. [Copyright &y& Elsevier]

Epitope spreading is involved in inducing and maintaining self-reactivity. Epitope spreading in pemphigus vulgaris (PV), caused by IgG autoantibodies to desmoglein 3 (Dsg3) and Dsg1, was previously analyzed using Dsg3/Dsg1 extracellular domain-swapped molecules. However, precise identification of the responsible epitopes in each molecule by using only this method was problematic. In this study, we studied epitope spreading in PV by a novel immunoprecipitation-immunoblot method using Dsg3 (or Dsg1)/Dsg2 domain-swapped molecules, which overcomes the problems associated with the previous approaches. We analyzed the antigenic epitopes recognized by 212 sera collected from 53 PV patients at multiple disease stages. The major epitopes were present at the N-terminal region of Dsgs and were unchanged over the course of the disease in both anti-Dsg3 mucosal dominant-type PV and anti-Dsg3/Dsg1 mucocutaneous-type PV. These N-terminal epitopes were calcium dependent. Circulating antibodies in paraneoplastic pemphigus and pemphigus herpetiformis had unique epitope distributions, although the Dsg N-termini still contained the major epitopes. These results suggest that, after onset, intramolecular and intermolecular epitope spreading among extracellular domains on Dsg3 and Dsg1 is rare in PV and has no correlation with disease course. [ABSTRACT FROM AUTHOR]

Abstract: Pemphigus is a life-threatening autoimmune blistering disease. Pemphigus is divided into 4 major types; pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, and IgA pemphigus. Among them, IgA pemphigus is characterized by tissue-bound and circulating IgA antibodies targeting desmosomal or nondesmosomal cell surface components in the epidermis. Histopathologically, slight epidermal acantholysis and extensive neutrophilic infiltration in either the upper part or all layers of the epidermis were observed. IgA pemphigus is subdivided into intraepidermal neutrophilic IgA dermatosis-type (IEN-type), whose target antigen is still unknown (probably nondesmosomal cell surface protein), and subcorneal pustular dermatosis-type (SPD-type), whose target antigen is desmocollin 1 (Dsc1). We summarize reported cases of IgA pemphigus and describe current knowledge including epidemiology, clinical manifestations, pathology, laboratory tests, pathophysiology, associated diseases, prognosis and treatment, and future perspectives of IgA pemphigus. [Copyright &y& Elsevier]

We describe a fully automated system for the classification of acral volar melanomas. We used a total of 213 acral dermoscopy images (176 nevi and 37 melanomas). Our automatic tumor area extraction algorithm successfully extracted the tumor in 199 cases (169 nevi and 30 melanomas), and we developed a diagnostic classifier using these images. Our linear classifier achieved a sensitivity (SE) of 100%, a specificity (SP) of 95.9%, and an area under the receiver operating characteristic curve (AUC) of 0.993 using a leave-one-out cross-validation strategy (81.1% SE, 92.1% SP; considering 14 unsuccessful extraction cases as false classification). In addition, we developed three pattern detectors for typical dermoscopic structures such as parallel ridge, parallel furrow, and fibrillar patterns. These also achieved good detection accuracy as indicated by their AUC values: 0.985, 0.931, and 0.890, respectively. The features used in the melanoma–nevus classifier and the parallel ridge detector have significant overlap.Journal of Investigative Dermatology (2008) 128, 2049–2054; doi:10.1038/jid.2008.28; published online 6 March 2008 [ABSTRACT FROM AUTHOR]

One of the most attractive clinical targets for melanoma is the mitogen-activated protein kinase (MAPK) signaling pathway. In this study, we examined MAPK signaling activation in a total of 28 acral melanoma samples, consisting of 13 primary tumors and 15 metastases. In line with the previous reports, NRAS/BRAF mutations were rare; only one metastatic tumor had an NRAS E61R mutation, and one primary tumor and two metastases harbored BRAF V599E mutations. Western blot analyses, however, revealed phosphorylated extracellular signal-regulated kinase (ERK)1/2 proteins in 11 of 14 (78.5%) of the acral melanoma tumors. Furthermore, fluorescence in situ hybridization analyses revealed the prominent amplification of the cyclin D1 ( CCND1) gene, which is an important down-stream effecter of the MAPK pathway, in 5 of 21 (23.8%) tumors examined. Interestingly, two of three tumors that were negative for phosphorylated ERK proteins according to western blot harbored CCND1 amplifications, suggesting that the increased gene dosage of CCND1 may exert effects similar to phosphorylated ERK proteins in cell growth. We conclude that, despite the low frequency of BRAF/NRAS mutations, the MAPK signaling pathway is constitutively activated in the majority of acral melanomas. This provides a rational basis to include acral melanomas into the clinical trials with MAPK inhibitors. [ABSTRACT FROM AUTHOR]