Japanese guidelines for atopic dermatitis 2017

Given the importance of appropriate diagnosis and appropriate assessment of cutaneous symptoms in treatment of atopic dermatitis, the basics of treatment in this guideline are composed of (1) investigation and countermeasures of causes and exacerbating factors, (2) correction of skin dysfunctions (skin care), and (3) pharmacotherapy, as three mainstays. These are based on the disease concept that atopic dermatitis is an inflammatory cutaneous disease with eczema by atopic diathesis, multi-factorial in onset and aggravation, and accompanied by skin dysfunctions. These three points are equally important and should be appropriately combined in accordance with the symptoms of each patient. In treatment, it is important to transmit the etiological, pathological, physiological, or therapeutic information to the patient to build a favorable partnership with the patient or his/her family so that they may fully understand the treatment. This guideline discusses chiefly the basic therapy in relation to the treatment of this disease. The goal of treatment is to enable patients to lead an uninterrupted social life and to control their cutaneous symptoms so that their quality of life (QOL) may meet a satisfactory level.The basics of treatment discussed in this guideline are based on the “Guidelines for the Treatment of Atopic Dermatitis 2008” prepared by the Health and Labour Sciences Research and the “Guidelines for the Management of Atopic Dermatitis 2015 (ADGL2015)” prepared by the Atopic Dermatitis Guidelines Advisory Committee, Japanese Society of Allergology in principle. The guidelines for the treatment of atopic dermatitis are summarized in the “Japanese Guideline for the Diagnosis and Treatment of Allergic Disease 2016” together with those for other allergic diseases.     

Analysis of systemic and airway inflammation in obstructive sleep apnea

Purpose

The presence of both systemic and airway inflammation has been suggested in obstructive sleep apnea (OSA) by increased levels of inflammatory biomarkers in the circulation and respiratory specimens. We aimed to investigate the relationship between systemic and airway inflammation in OSA.

Methods

This study was conducted by simultaneously measuring various biomarkers both in serum and induced sputum of 43 patients. We compared the relationships of these biomarker levels with polysomnographic data and obesity measurements and also investigated their interrelationships between systemic and local compartments. We also assessed the relation of inflammatory markers with proximal airway resistance measured by impulse oscillometry.

Results

In multiple regression analyses, each measured serum biomarker [leptin, interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF)] significantly correlated with waist circumference or fat area determined by computed tomography. In contrast, regarding airway inflammation, sputum IL-6, IL-8, TNF-α, and VEGF significantly correlated with OSA severity as indicated by the respiratory disturbance index or oxygen desaturation indices. Sputum IL-6, IL-8, TNF-α, and VEGF were significantly related to sputum neutrophil number, and sputum IL-8 and TNF-α were related to proximal airway resistance independently of body mass index. There were no significant interrelationships between the same biomarkers in serum and induced sputum.

Conclusions

Systemic and airway inflammation in OSA might be differently regulated by OSA itself and comorbid obesity, depending on the type of cytokine. Although we did not find apparent interrelationships between systemic and local compartments, further studies are needed to clarify this concept.     

Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN

High-fidelity replication of the large RNA genome of coronaviruses (CoVs) is mediated by a 3′-to-5′ exoribonuclease (ExoN) in nonstructural protein 14 (nsp14), which excises nucleotides including antiviral drugs misincorporated by the low-fidelity viral RNA-dependent RNA polymerase (RdRp) and has also been implicated in viral RNA recombination and resistance to innate immunity. Here, we determined a 1.6-Å resolution crystal structure of severe acute respiratory syndrome CoV 2 (SARS-CoV-2) ExoN in complex with its essential cofactor, nsp10. The structure shows a highly basic and concave surface flanking the active site, comprising several Lys residues of nsp14 and the N-terminal amino group of nsp10. Modeling suggests that this basic patch binds to the template strand of double-stranded RNA substrates to position the 3′ end of the nascent strand in the ExoN active site, which is corroborated by mutational and computational analyses. We also show that the ExoN activity can rescue a stalled RNA primer poisoned with sofosbuvir and allow RdRp to continue its extension in the presence of the chain-terminating drug, biochemically recapitulating proofreading in SARS-CoV-2 replication. Molecular dynamics simulations further show remarkable flexibility of multidomain nsp14 and suggest that nsp10 stabilizes ExoN for substrate RNA binding to support its exonuclease activity. Our high-resolution structure of the SARS-CoV-2 ExoN–nsp10 complex serves as a platform for future development of anticoronaviral drugs or strategies to attenuate the viral virulence.

The 29.9-kb single-stranded RNA genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the global COVID-19 pandemic, is replicated and transcribed by the viral RNA-dependent RNA polymerase (RdRp, nsp12) (1–3). Unlike the high-fidelity cellular replicative DNA polymerases, viral RdRp enzymes, including the CoV RdRp, do not contain a proofreading exonuclease domain to ensure high fidelity. The resulting higher mutation rate (10⁻⁴ to 10⁻⁶ substitutions per nucleotide per round of replication) is generally thought to promote rapid viral adaptation in response to selective pressure (4–6). However, the lack of proofreading activity in RdRp poses a particular challenge for the replication of CoVs, which feature the largest known RNA virus genomes (27 to 32 kb, up to twice the length as the next-largest nonsegmented RNA viral genomes) (7, 8). It has been reported that SARS-CoV nsp12 is the fastest viral RdRp known but with an error rate more than one order of magnitude higher than the generally admitted error rate of viral RdRps (9), clearly necessitating a unique proofreading mechanism.To mitigate the low fidelity of RdRp, all coronaviruses encode a 3′-to-5′ exoribonuclease (ExoN) in multifunctional nsp14 (10–12), which forms a complex with nsp10 critical for the ExoN activity, and additionally contains a C-terminal guanine N7 methyl transferase (N7-MTase) domain. Mutations of SARS-CoV-2 nsp14 exhibit strong association with increased genome-wide mutation load (13, 14), and genetic inactivation of ExoN in engineered SARS-CoV and murine hepatitis virus (MHV) leads to 15- to 20-fold increases in mutation rates (7, 15, 16). Furthermore, in a mouse model, SARS-CoV with inactivated ExoN shows a mutator phenotype with decreased fitness and lower virulence over serial passage, suggesting a potential strategy for generating a live, impaired-fidelity coronavirus vaccine (17). Alternatively, recent studies show that ExoN inactivation abrogates replication of SARS-CoV-2 and Middle East Respiratory Syndrome CoV (18), hinting at additional functions for ExoN in viral replication. Indeed, ExoN activity has been reported to mediate the extensive viral RNA recombination required for subgenomic messenger RNA (mRNA) synthesis during normal replication of CoVs, including SARS-CoV-2 (19), and it was shown to be required for resistance to the antiviral innate immune response for MHV (20). ExoN inactivation also significantly increases the sensitivity of CoVs to nucleoside analogs that target RdRp, which is consistent with the biochemical activity of ExoN to excise mutagenic or chain-terminating nucleotides misincorporated by RdRp (21–23). These observations combine to suggest that chemical inhibition of ExoN could be an effective antiviral strategy against CoVs. In this study, we determined high-resolution crystal structures of the SARS-CoV-2 ExoN–nsp10 complex and studied its biochemical activities. Furthermore, we used molecular dynamics (MD) simulations to better understand the dynamics of nsp14, nsp10, and their interaction with RNA.     

Ossification of the ligamentum flavum of the thoracic spine in adult kyphosis

Summary Ossification of the ligamentum flavum has been recognised as a definite clinical entity as is ossification of the posterior longitudinal ligament. The incidence of both is high in Japan. This study demonstrates that the incidence of ossification of the ligamentum flavum in persons who have a kyphosis of the thoracic or lumbar spine is higher than in those who do not. It is considered that localised mechanical stress affecting the ligamentum flavum is a contributing factor to the development of ossification, together with the generalised factors which may favour bone formation. However, the aetiology of this lesion is still obscure as is that of ossification of the posterior longitudinal ligament.

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Résumé L'ossification du ligament jaune représente une entité clinique définie, de même que celle du ligament longitudinal postérieur. Les deux affections sont fréquentes au Japon. Cette étude montre que l'ossification du ligament jaune s'observe plus souvent chez les sujets qui présentent une cyphose dorsale ou lombaire. On peut penser que les contraintes mécaniques localisées au ligament jaune constituent un facteur contribuant au développement de l'ossification, et s'ajoutant aux facteurs généraux susceptibles de favoriser la formation osseuse. Cependant, l'étiologie de cette affection demeure mystérieuse de même que l'ossification du ligament longitudinal postérieur.

     

Laparoscopy-assisted proximal gastrectomy with gastric tube reconstruction for early gastric cancer

Background  

In this report, laparoscopy-assisted proximal gastrectomy (LAPG) and gastric tube reconstruction using a mini-loop retractor (MLR) is described for the treatment of early gastric cancer.     

Idiopathic sustained left ventricular tachycardia: clinical and electrophysiologic characteristics

Electrophysiologic studies were performed in 16 patients 11 to 45 years old (mean 33 years) with idiopathic sustained (lasting more than 5 min) ventricular tachycardia (VT) originating from the left ventricle. Endocardial mapping during VT showed that the earliest site of activation was at the apical inferior portion of the left ventricle in 14 patients whose QRS morphology during VT showed a right bundle branch block pattern and left-axis deviation, but at the apical anterosuperior portion of the left ventricle in two patients whose QRS morphology during VT showed a right bundle branch block and right-axis deviation. Single programmed ventricular stimulation induced VT in 13 patients, and rapid ventricular pacing induced VT in the remaining three patients. Rapid ventricular pacing terminated VT in all patients. The relationship between the coupling interval and the echo interval was inverse in all eight patients with a wide VT inducible zone. Entrainment was recognized in three of six patients. The initiation of VT by constant pacing depended on the number of pacing beats but not the duration of pacing in all four patients tested. Intravenous verapamil terminated the VT in 13 of 14 patients. Long-term oral verapamil was also effective in all five patients who required long-term oral therapy for their symptoms associated with VT. In conclusion (1) idiopathic left ventricular tachycardia has unique electrocardiographic, electrophysiologic, and electropharmacological properties, (2) the electrophysiologic characteristics suggest that the mechanism is reentry, and (3) verapamil is effective in both the short- and long-term treatment of VT.     

DNA ploidy and clonal selection in ras + myc – Induced mouse prostate cancer

An important goal in prostate cancer research is to define specific molecular and cellular alterations that are associated with malignant progression. The mouse prostate reconstitution model is a relevant and useful system as it allows the study of early events in cancer progression under conditions where oncogene-initiated cells are surrounded by normal tissue. Using this model, activated ras and myc oncogenes are introduced into urogenital sinus cells via the recombinant retrovirus Zipras/myc 9. After 4 weeks' growth as subcapsular renal grafts, poorly differentiated carcinomas are produced in C57BL/6 mice. In this study we examined the temporal relationships between morphological alterations, growth, DNA ploidy status and clonal selection as determined by Southern blotting in ras + myc-initiated carcinomas. Nuclear image analysis demonstrated that the emergence of a cycling DNA tetraploid cell population strongly correlated with growth and histologic progression. These tightly linked events culminated in the outgrowth of mono- or oligoclonal cancer. © 1995 Wiley-Liss, Inc.     

Intracisternal sodium nitroprusside fails to prevent vasospasm in nonhuman primates

OBJECTIVE: Hemoglobin contributes to vasospasm after subarachnoid hemorrhage. One mechanism may involve binding of nitric oxide, destruction of nitric oxide, or both. Support for this mechanism would be evidence that nitric oxide donors prevent vasospasm. This study attempted to provide such evidence. METHODS: A randomized, blinded study was conducted in which 13 monkeys underwent cerebral angiography and creation of a right subarachnoid hemorrhage. Subcutaneous osmotic pumps were implanted to deliver sodium nitroprusside (n = 7) or vehicle (n = 6) via catheters into the right basal cisterns. Seven days later, angiography was repeated, and the animals were humanely killed. Levels of cyclic nucleotides, hemoglobins, and thiocyanate were measured. RESULTS: Significant vasospasm of the right middle cerebral artery was present in animals treated with sodium nitroprusside (35 +/- 22% reduction in diameter, P < 0.05, paired t test) and placebo (28 +/- 20% reduction, P < 0.05, not significantly different from nitroprusside group by unpaired t test). Adequate delivery of sodium nitroprusside was supported by the finding of a significant increase in cyclic guanosine monophosphate levels in the cerebral arteries of treated animals compared with placebo (P < 0.05, unpaired t test). Thiocyanate was not present in significantly increased amounts in animals treated with nitroprusside, although this group did display elevated concentrations of nitrosyl hemoglobin (measured by electron paramagnetic resonance spectroscopy) and cyanomethemoglobin (measured by spectrophotometry) in the cerebrospinal fluid on Day 7. CONCLUSION: The lack of effect of sodium nitroprusside was not the result of inadequate drug delivery because cyclic guanosine monophosphate levels were significantly increased in vasospastic arteries. Vasospasm may not have been prevented because of a toxic effect of sodium nitroprusside metabolites, involvement of smooth muscle relaxation or contraction processes downstream of cyclic guanosine monophosphate, or both.