Juntendo Medical Journal
Online ISSN : 2188-2126
Print ISSN : 2187-9737
ISSN-L : 2187-9737
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Research of the 3rd Alumni Scientific Award for Medical Student, Juntendo University School of Medicine [1]
    2020 Volume 66 Issue 6 Pages 476-477
    Published: 2020
    Released: December 31, 2020

     Sleep disordered breathing (SDB) is defined by episodes of apneas and hypopneas during sleep and this condition is widely prevalent to potential in the general population. The prevalence of SDB (apnea-hypopnea index (AHI)≥15) among United States was 13% of men and 6% of women, and 27.1 % of men and 11.1 % of women among Japan. Several studies have concluded that SDB is a risk factor for motor vehicle crashes (MVCs), and a meta-analysis demonstrated that patients with SDB have a crash risk about 2.5 times that of individuals without SDB. Moreover, the treatment by continuous positive airway pressure therapy could reduce the risk of MVCs. Thus, early detection, treatment and prevention of SDB carries safety on driving significance. Also, subjective excessive daytime sleepiness (EDS) is widely known as a risk factor for MVCs, and it is included in one of the diagnostic criteria of sleep apnea syndrome (SAS). However, a previous study reported that there is no significant difference in AHI score between the SDB patients with and without EDS. Other study also suggested that there are comparatively many SDB patients who do not feel subjective EDS. The cause of this discrepancy is that assessment of subject EDS might be underestimated by chronic sleep deprivation and differs in each individual. While ample studies have conducted the association between SDB and MVC, only a prospective cohort study presumed the association of SDB with or without subjective EDS on the risk of MVC. Therefore, we conducted a prospective cohort study among 1,047 Japanese community residents to examine whether individuals with SDB were at increased risk of MVCs, independent of subjective EDS. The participants in this study completed a general sleep questionnaire and screening of SDB. SDB was assessed by a single-channel portable monitor; “Somnie” (NGK Spark Plug Co., Nagoya, Japan) which measured the respiratory disturbance index (RDI) during one-night sleep at home. Participants were classified into the SDB group (RDI ≥10) and non-SDB group (RDI <10). Subjective EDS was defined by Japanese version of Epworth Sleepiness Scale (JESS) scores ≥11. A follow-up questionnaire five years after the baseline ascertained history of MVC over the period. Sex-specific multivariable logistic regression analysis examined the association between SDB and MVC after stratification by subjective EDS. The multivariable-adjusted odds ratios (95% confidence interval) for MVC among the female SDB group were 1.66 (1.05-2.63) compared with the non-SDB group (Figure-1), and this association was more evident in females without subjective EDS, but not among those with subjective EDS (Figure-1). There was no significant association in males. The major finding of the present study is to demonstrate the significant association between SDB and risk of MVC in female participants, and this association was more evident among those without subjective EDS, suggesting that SDB is a risk factor for MVC, irrespective of subjective EDS, and therefore, screening for SDB even among individuals without subjective EDS might be significant for prevention of MVC among community dwelling population. More details are described in our article: Matsuo R, et al: Sleep disordered breathing and subjective excessive daytime sleepiness in relation to the risk of motor vehicle crash: the Toon Health Study. Sci Rep, 2020; 10 (1): 17050. doi: 10.1038/s41598-020-74132-7.

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    2020 Volume 66 Issue 6 Pages 478-479
    Published: 2020
    Released: December 31, 2020

     Recently, much attention has been focused on the role of autophagy in osteoarthritis (OA), a disease associated with cartilage degeneration, since autophagy is reduced in chondrocytes of subjects with OA 1), and the chondrocyte-specific induction of autophagy improves the pathological change of OA in mice 2). Furthermore, it has been reported that sirtuin (SIRT) 1, known as a longevity gene, induces autophagy 3). Previously, we revealed that glucosamine, a functional food, which is widely used for the treatment of OA, enhances the expression of SIRT1 in human chondrocyte line 4). Based on these findings, we have hypothesized that glucosamine induces autophagy in chondrocytes via the expression of SIRT1 and may exhibit a chondroprotective action on OA 5).

     When human chondrocytes (Hs819.T) were incubated with glucosamine, the expression of LC3-II, Beclin-1, ATG5 and ATG7 (autophagy markers) was increased, indicating that glucosamine induces autophagy in chondrocytes. Moreover, we confirmed that glucosamine induces the expression of SIRT1 in Hs819.T cells. Next, to examine the action of SIRT1 on the glucosamine-induced autophagy, Hs819.T cells were incubated with glucosamine in the presence of EX527, a SIRT1 inhibitor. The result indicated that EX527 inhibited the glucosamine-induced expression of LC3-II, suggesting that glucosamine induces autophagy in chondrocytes via the action of SIRT1.

     SIRT1 functions as a deacetylase and regulates the action of target proteins by deacetylation 6). In this context, it has been reported that p53, a target protein of SIRT1, is negatively regulating autophagy 7), and when p53 is deacetylated (inactivated), autophagy is induced 8). Thus, the effect of glucosamine on the deacetylation of p53 was evaluated. The results indicated that in the presence of glucosamine p53 was deacetylated in Hs819.T cells, and the deacetylation was inhibited by EX527, a SIRT1 inhibitor, suggesting that glucosamine induces the expression of SIRT1, a deacetylase, and SIRT1 deacetylates (inactivates) p53, a negative regulator of autophagy.

     Interestingly, it has been reported that when autophagy is induced in chondrocytes, the expression of cartilage matrix components such as type II collagen is increased 9), while the expression of matrix metalloproteinases (MMPs), cartilage matrix degrading enzymes, is suppressed 10).

     It is unclear how glucosamine induces the expression of SIRT1 in chondrocytes. Interestingly, however, it has been reported that glucosamine alters glucose metabollism by reducing glucose transport/phpsophorylation and storage of glycogen in skeletal muscle cells 11), and lowers blood glucose level in mice 12). Importantly, SIRT1 is upregulated by fasting and caloric restriction 13). Thus, it is tempting to speculate that glusocomine induces the expression of SIRT1 via the action on glucose metabolism that may mimic the states of fasting and caloric restriction.

     Together these observations suggest that glucosamine induces autophagy in chondrocytes via the expression of SIRT1, which deacetylates (inactivates) p53, a negative regulator of autophagy, and possibly exhibits a chondroprotective action on OA by increasing the expression of cartilage matrix components and suppressing the expression of cartilage matrix degrading enzymes (Figure-1).

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Health Topics for Tokyoites: “Atopic Dermatitis: The Latest Clinical Trials and Treatments”
    2020 Volume 66 Issue 6 Pages 480-486
    Published: 2020
    Released: December 31, 2020

     Atopic dermatitis (AD) is a multifactorial, chronic inflammatory skin disease that is caused by a combination of both genetic conditions and environmental factors. Mutations in the gene encoding filaggrin, which is a natural moisturizer, represent the most significant genetic factors that predispose an individual to the development of AD, as they are associated with the breakdown of the skin barrier, which leads to an increased risk of severe, early onset AD, skin infections, allergen sensitization, and food allergies, as well as the development of asthma and allergic rhinitis. In addition, abnormalities in both the adaptive and innate immune responses play a critical role in the pathogenesis of AD. The acute phase of AD is mainly characterized by the overactivation of type 2 helper T cells, while the chronic phase is characterized by the activation of type 1 helper T cells. Furthermore, environmental factors, allergens, the use of soap and detergents, and microbial infections exacerbate the breakdown of the epidermal barrier and contribute to aberrations of the immune system, further aggravating the manifestations of AD. Our understanding of AD pathophysiology will enable the better use of certain topical products, the development of new products that repair the skin barrier, and the design of new approaches for the prevention and treatment of AD.

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    2020 Volume 66 Issue 6 Pages 487-491
    Published: 2020
    Released: December 31, 2020

     The Japanese Dermatological Association (JDA) and the Japanese Society of Allergology (JSA) worked in cooperation to compile a single 2018 Clinical Practice Guidelines for Atopic Dermatitis. This paper provides an explanation of the 2018 for Clinical Practice Guidelines AD, published at the end of 2018, along with some of the changes made to the traditional Clinical Practice Guidelines from among the 26 clinical questions regarding said guidelines.

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    2020 Volume 66 Issue 6 Pages 492-496
    Published: 2020
    Released: December 31, 2020

     Atopic dermatitis (AD) is a chronic pruritic and eczematous skin condition that is characterized by repeated exacerbations and remissions. In recent years, its pathogenesis has been more clearly elucidated, and treatments targeting molecules that are important for its progression have been developed. In 2018, dupilumab, which blocks the common receptor of interleukin (IL)-4 and IL-13, was introduced as a new treatment for AD, representing a significant turning point in the treatment of AD. Since the pathogenesis of AD is complicated, other biological and molecularly targeted agents are also expected to be introduced in the future. In this article, we report our experience in treating atopic dermatitis patients with dupilumab at our hospital, describe the efficacy and safety of drugs used for AD and provide a review of the recent literature on new drugs that are expected to be approved in the future.

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    2020 Volume 66 Issue 6 Pages 497-506
    Published: 2020
    Released: December 31, 2020

     Most infants are immunologically active to develop a tolerance to oligoclonal antigens by producing IgA and introducing regulatory T cells in early infancy. Cytokines and their signalling molecules are important mediators in the intestine regulating both oral tolerance and mucosal inflammation. This system works efficiently in most individuals, but for an undefined reason, some people react to food and other proteins as though they were pathogens and induce chronic inflammation as food allergy/intolerance.

     The adverse reaction caused by ingested foods is defined as food intolerance. The clinical features of food intolerance include vomiting, diarrhea, bloody stool, eczema, failure to thrive, and a protean range of other symptoms. Intolerance can be divided into two categories depending on whether they are immunologically mediated. The one immunologically mediated is known as “Food allergy”. Food allergy and mucosal inflammation are deeply related since tolerance cannot be introduced when there is an inflammation in the intestinal mucosa. Mast cells, eosinophils, mucosal lymphocytes, and epithelial cells are deeply involved and related each other to cause mucosal inflammation.

     Meanwhile, it is known that tolerance can be introduced by keep eating antigenic foods, such as oral desensitization therapy. Feeding lower doses of antigen introduce “active suppression” by inducing TGF-β, IL-4 and IL-10 producing regulatory T (Th3) cells. At higher doses, “clonal anergy” occurs by deleting antigen-specific Th1 and Th2 cells by apoptosis, although TGF-β producing Th3 cells seen spared. These mechanisms are very important for infants to prevent/treat food allergy.

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Original Articles
    2020 Volume 66 Issue 6 Pages 507-511
    Published: 2020
    Released: December 31, 2020
    [Advance publication] Released: August 01, 2020

    Objectives: To examine the effects of (1) trunk constraint and (2) the entry angle on the cervical spine in response to a head-first impact.

    Materials: The AM50 Total HUman Model for Safety (THUMS ®) v4.02, pedestrian finite element model, was subjected to head-first impacts.

    Methods: The impact speed was 3.2 m/s. The following patterns were simulated: entry angle (0°, 15° to the sagittal plane) and trunk constraint (constraint, unconstraint).

    Results: As a result of head-first impact, the upper cervical spine was extended and the lower cervical spine was markedly flexed when the trunk was constrained. The mean stress applied to the cervical spine was significantly increased when the trunk was constrained, as indicated by the Mann-Whitney U test.

    Conclusions: In a head-first impact, the mean stress on the cervical spine increases significantly when the trunk is constrained. In order to reduce the risk of cervical spine injuries, it is desirable not to bind with teammates before a head-first impact.

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    2020 Volume 66 Issue 6 Pages 512-518
    Published: 2020
    Released: December 31, 2020
    [Advance publication] Released: October 09, 2020

    Objective: Although some parameters have been defined for predicting late-onset tricuspid regurgitation (TR) after mitral valve (MV) repair, few studies have focused on the early TR progression. The aim of this study was to evaluate the changes in unrepaired TR early after isolated MV repair for degenerative MR, and investigate the predictors of TR progression.

    Methods: We retrospectively identified 236 patients who underwent isolated MV repair in our institute between 2014 and 2019. Patients with severe preoperative TR, non-degenerative etiology, without echocardiography reports were excluded from the study. Early TR progression was defined as an increase in TR of at least one grade on pre-discharge echocardiography compared to preoperatively. Baseline characteristics were compared between patients with and without early TR progression.

    Results: A total of 214 patients were analyzed. Mean age was 59 years and 32.7% were female. At baseline, 77.6% had no TR, 20.6% had mild TR, and 1.9% had moderate TR. At follow-up before discharge, 15.4% (n=33) had TR progression. The TR progression group was older and showed lower body mass index (BMI) than the no-TR progression group. Although not significant, renal function tended to be lower in the TR progression group than in the no-TR progression group. Multivariable analysis revealed higher age and lower BMI as independent predictors of TR progression early after MV repair.

    Conclusions: Despite appropriate surgical correction of degenerative MR, progression of TR early after MV repair was observed in 15% of the patients. High age and low BMI were independently associated with TR progression early after MV repair. Further studies are necessary to examine the significance of early TR progression on long-term prognosis after MV repair.

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    2020 Volume 66 Issue 6 Pages 519-526
    Published: 2020
    Released: December 31, 2020
    [Advance publication] Released: December 08, 2020

    Objective: We conducted a survey to investigate the specialties selected by graduates of Juntendo University following the completion of clinical training, and compared the results obtained before and after the introduction of the mandatory clinical training system.

    Materials: Subjects were 1,115 graduates (male: 743, female: 372) who participated in the new clinical training system between 2004 and 2015. Controls were 1,068 graduates (male: 786, female: 282) who participated in the old clinical training system between 1992 and 2003.

    Methods: The specialties selected were classified into “internal medicine”, “surgery”, “required specialties (emergency medicine, pediatrics, obstetrics and gynecology, and psychiatry, which are compulsory for the clinical training system)”, other specialties, so-called “minor specialties”, and “basic medicine”. The percentage of graduates in each specialty was compared before and after the introduction of the mandatory clinical training system.

    Results: The percentage of graduates increased in internal medicine (from 32.8 to 34.1%), required specialties (from 18.0 to 20.7%), and basic medicine (from 0.6 to 1.5%, p=0.0276), but decreased in surgery (from 14.9 to 11.0%, p=0.0071) and minor specialties (from 33.7 to 32.7%). When surgery was included as a required specialty, the ratio of graduates who selected internal medicine, required specialties, and minor specialties was approximately the same (one third for each), with no significant differences being observed from before the introduction of the mandatory system.

    Conclusions: Our University graduates who selected internal medicine, required specialties (including surgery), and minor specialties accounted for approximately one third each, with the remainder selecting basic medicine.

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