The development of Kawasaki disease (KD) has been suggested to be associated with droplet- or contact-transmitted infection; however, its triggers and transmission modes remain to be determined. ...Under an epidemic of SARS-CoV-2, the COVID-19 state of emergency in Japan served as a nationwide social experiment to investigate the impact of quarantine or isolation on the incidence of KD.
To assess the role of droplet or contact transmission in the etiopathogenesis of KD.
This multicenter, longitudinal, cross-sectional study was conducted from 2015 to 2020 at Fukuoka Children's Hospital and 5 adjacent general hospitals. The number of admissions for KD and infectious diseases were analyzed. Participants were pediatric patients admitted to the participating hospitals for KD or infectious diseases.
Quarantine and isolation owing to the COVID-19 state of emergency.
The primary end points were the ratios of patients with KD to patients with respiratory tract or gastrointestinal infections admitted from April to May in 2015 to 2019 and 2020. A Poisson regression model was used to analyze them.
The study participants included 1649 patients with KD (median interquartile range age, 25 13-43 months; 901 boys 54.6%) and 15 586 patients with infectious disease (data on age and sex were not available for these patients). The number of admissions for KD showed no significant change between April and May in 2015 to 2019 vs the same months in 2020 (mean SD, 24.8 5.6 vs 18.0 4.0 admissions per month; 27.4% decrease; adjusted incidence rate ratio aIRR, 0.73; 95% CI, 0.48-1.10; P = .12). However, the number of admissions for droplet-transmitted or contact-transmitted respiratory tract infections (mean SD, 157.6 14.4 vs 39.0 15.0 admissions per month; 75.3% decrease; aIRR, 0.25; 95% CI, 0.17-0.35; P < .001) and gastrointestinal infections (mean SD, 43.8 12.9 vs 6.0 2.0 admissions per month; 86.3% decrease; aIRR, 0.14; 95% CI, 0.04-0.43; P < .001) showed significant decreases between April and May in 2015 to 2019 vs the same months in 2020 (total, 12 254 infections). Thus, the ratio of KD to droplet- or contact-transmitted respiratory tract and gastrointestinal infections incidence in April and May 2020 was significantly increased (ratio, 0.40 vs 0.12; χ21 = 22.76; P < .001).
In this study, the significantly increased incidence of KD compared with respiratory tract and gastrointestinal infections during the COVID-19 state of emergency suggests that contact or droplet transmission is not a major route for KD development and that KD may be associated with airborne infections in most cases.
Osmoregulation is an essential homeostatic process that requires constant release of vasopressin during sustained increases in plasma osmolality. The magnocellular neurosecretory cells (MNCs) respond ...to increases in external osmolality through increases in the activity of ΔN-TRPV1 channels, which leads to increased action potential firing and vasopressin release. We show that sustained exposure of acutely isolated rat and mouse MNCs to hypertonic solutions (90 min) causes a reversible translocation of ΔN-TRPV1 channels from internal stores to the plasma membrane that depends on the activation of phospholipase C and on SNARE-dependent exocytosis. ΔN-TRPV1 channel translocation is absent in MNCs isolated from transgenic mice lacking the PLCδ1 isoform, suggesting that PLCδ1 is essential for triggering this process. The translocation of ΔN-TRPV1 channels to the cell surface could contribute to the maintenance of MNC excitability during sustained increases in osmolality. Our data therefore have important implications for the mechanisms underlying mammalian osmoregulation.
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•Osmotic stimuli cause ΔN-TRPV1 channels to move to the surface of vasopressin neurons•This process is reversible and depends on exocytosis and activation of PLC and PKC•ΔN-TRPV1 translocation occurs in the VP neurons of water-deprived rats and mice•ΔN-TRPV1 translocation is absent in the VP neurons of mice that do not express PLCδ1
Cellular neuroscience; Cell biology
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
CD4⁺CD25⁺ regulatory T (Treg) cells are crucial mediators of autoimmune tolerance. The factors that regulate Treg cells, however, are largely unknown. Here, we show that deficiency in midkine (MK), a ...heparin-binding growth factor involved in oncogenesis, inflammation, and tissue repair, attenuated experimental autoimmune encephalomyelitis (EAE) because of an expansion of the Treg cell population in peripheral lymph nodes and decreased numbers of autoreactive T-helper type 1 (TH1) and TH17 cells. MK decreased the Treg cell population ex vivo in a dose-dependent manner by suppression of STAT5 phosphorylation that is essential for Foxp3 expression. Moreover, administration of anti-MK RNA aptamers significantly expanded the Treg cell population and alleviated EAE symptoms. These observations indicate that MK serves as a critical suppressor of Treg cell expansion, and inhibition of MK using RNA aptamers may provide an effective therapeutic strategy against autoimmune diseases, including multiple sclerosis.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The prevalence of overweight (body mass index (BMI)=25.0-29.9 kg m(-)(2)) and obesity (⩾30.0 kg m(-)(2)) has been increasing over the last several decades in Japan. We examined trends of the impact ...of overweight and obesity on hypertension (systolic/diastolic blood pressure ⩾140/90 mm Hg or antihypertensive drugs use) using four national surveys in Japan, from which the participants were randomly sampled from the entire population. Study participants aged 30-79 years were selected for each survey (10 370 in 1980, 8005 in 1990, 5327 in 2000 and 2547 in 2010). The results showed that the impact of overweight and obesity on hypertension had increased significantly (P=0.040 and 0.006 in men and women, respectively). From 1980 to 2010, the multivariable-adjusted odds ratios for hypertension, comparing overweight and obesity with normal weight (BMI =18.5-24.9 kg m(-)(2)), went from 1.94 (95% confidence intervals: 1.64, 2.28) to 2.82 (2.07, 3.83) in men, and from 2.37 (2.05, 2.73) to 3.48 (2.57, 4.72) in women. Most of the association was observed in overweight participants, as only 3% of the Japanese were obese. In addition to the relationship between excessive BMI and other adverse health conditions, the rise in the association with hypertension increases the urgency in addressing weight control. We need to address the overweight and obesity epidemic.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective
Few studies have reported the influence of clinical background factors on the outcome of Helicobacter pylori eradication therapy in primary care practice. We aimed to determine which ...clinical background factors influence the outcome of eradication therapy in a primary care setting.
Methods
This was a retrospective study of patients who received H pylori eradication therapy at Higashiohmi City Gamo Medical Center, Shiga, Japan, from January 2012 to December 2015. We investigated clinical background factors associated with success, failure, and self‐interruption of H pylori eradication therapy: patients’ age, gender, first‐ or second‐line treatment, reasons for receiving gastroenterological endoscopic examination, method of drug administration, and attending physicians’ age and their specialties.
Results
There were 369 patients (208 females, 161 male), with a mean age of 59 years (range 30‐88 years). The middle‐aged group (50‐69 years) was associated with successful eradication therapy compared with the young group (30‐49 years). The elderly group (>70 years) was associated with eradication therapy failure compared with the middle‐aged group. The young group was associated with self‐interruption of eradication therapy. There was a marginally significant association between male patients and self‐interruption. Older attending physicians (>50 years) were also associated with failure compared with younger physicians. There was no difference in outcome of eradication therapy between generalists and gastroenterology specialists.
Conclusion
We have identified clinical factors associated with success, failure, and self‐interruption of H pylori eradication therapy in a primary care setting.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Differentiation and proliferation of keratinocyte are controlled by various signalling pathways. The epidermal growth factor receptor (EGFR) is known to be an important regulator of multiple ...epidermal functions. Inhibition of EGFR signalling disturbs keratinocyte proliferation, differentiation and migration. Previous studies have revealed that one of the EGFR downstream signalling molecules, phospholipase Cγ1 (PLCγ1), regulates differentiation, proliferation and migration of keratinocytes in in vitro cell culture system. However, the role of PLCγ1 in the regulation of keratinocyte functions in animal epidermis remains unexplored. In this study, we generated keratinocyte‐specific PLCγ1 knockout (KO) mice (PLCγ1 cKO mice). Contrary to our expectations, loss of PLCγ1 did not affect differentiation, proliferation and migration of interfollicular keratinocytes. We further examined the role of PLCγ1 in irritant contact dermatitis (ICD), in which epidermal cells play a pivotal role. Upon irritant stimulation, PLCγ1 cKO mice showed exaggerated ICD responses. Further study revealed that epidermal loss of PLCγ1 induced sebaceous gland hyperplasia, indicating that PLCγ1 regulates homeostasis of one of the epidermal appendages. Taken together, our results indicate that, although PLCγ1 is dispensable in interfollicular keratinocyte for normal differentiation, proliferation and migration, it is required for normal ICD responses. Our results also indicate that PLCγ1 regulates homeostasis of sebaceous glands.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Familial Mediterranean Fever (FMF) has traditionally been considered to be an autosomal-recessive disease, however, it has been observed that substantial numbers of patients with FMF possess only 1 ...demonstrable MEFV mutation. The clinical profile of familial Mediterranean fever (FMF) may be influenced by MEFV allelic heterogeneity and other genetic and/or environmental factors.
In view of the inflammatory nature of FMF, we investigated whether serum amyloid A (SAA) and interleukin-1 beta (IL-1β) gene polymorphisms may affect the susceptibility of Japanese patients with FMF. The genotypes of the -13C/T SNP in the 5'-flanking region of the SAA1 gene and the two SNPs within exon 3 of SAA1 (2995C/T and 3010C/T polymorphisms) were determined in 83 Japanese patients with FMF and 200 healthy controls. The same samples were genotyped for IL-1β-511 (C/T) and IL-1 receptor antagonist (IL-1Ra) variable number of tandem repeat (VNTR) polymorphisms. There were no significant differences between FMF patients and healthy subjects in the genotypic distribution of IL-1β -511 (C/T), IL-1Ra VNTR and SAA2 polymorphisms. The frequencies of SAA1.1 allele were significantly lower (21.7% versus 34.0%), and inversely the frequencies of SAA1.3 allele were higher (48.8% versus 37.5%) in FMF patients compared with healthy subjects. The frequency of -13T alleles, associated with the SAA1.3 allele in the Japanese population, was significantly higher (56.0% versus 41.0%, p=0.001) in FMF patients compared with healthy subjects.
Our data indicate that SAA1 gene polymorphisms, consisting of -13T/C SNP in the 5'-flanking region and SNPs within exon 3 (2995C/T and 3010C/T polymorphisms) of SAA1 gene, are associated with susceptibility to FMF in the Japanese population.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Angiogenesis, a process of new blood vessel formation, is crucial not only for many physiological events but also for a number of diseases. The signaling pathways through members of the vesicular ...endothelial growth factor (VEGF) family play fundamental roles in angiogenesis. In this study, we identified inhibitory RNA aptamers against human Flt-1, a receptor of VEGF. One of the isolates, aptamer #38, showed a 50% inhibitory concentration (IC50) of 23 nM in the cell-based autophosphorylation assay, and the IC50 value was decreased to 6.3 nM upon removal of 32 dispensable nucleotides from parental #38 with a length of 72 nucleotides. Interestingly, the surface plasmon resonance-based or affinity resin-based binding study revealed that #38 and its shortened derivative, #38Jr, do not interfere with binding of VEGF or heparin, a functional cofactor, to Flt-1. Importantly, aptamer #38 does not affect the decoy activity of soluble Flt-1. These findings suggest that #38 prevents the conformational activation of Flt-1 associated with VEGF. Therefore, aptamer #38 might provide us with a unique tool for blocking the VEGF signaling specific to Flt-1, unlike most other known VEGF signaling blockers such as VEGF inhibitors, anti-Flt-1 antibodies, and decoy soluble receptors.
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IJS, KILJ, NUK, PNG, UL, UM
The prevalence and implications of vertebrobasilar dolichoectasia (VBD), a causative arteriopathy of stroke are unclear in Asian stroke patients. Through a comparative study of VBD and non-VBD stroke ...patients, we aimed to elucidate the clinicoradiologic features of VBD patients in Japan. A total of 481 consecutive patients (302 men and 179 women) with acute stroke were admitted to our department between 2007 and 2008. Of these 481 inpatients, 374 (231 men and 143 women) had brain infarct (BI), and 107 (71 men and 36 women) had brain hemorrhage (BH). We reviewed medical records, and VBD was diagnosed by magnetic resonance angiography. Cardiovascular disease (CVD) risk profile, modified Rankin scale score at 30 days poststroke, and stroke lesions were compared among 4 groups: the VBD BI group, the VBD BH group, the non-VBD BI group, and the non-VBD BH group. The diameter, height, and lateral displacement of the basilar artery (BA) were analyzed in the VBD patients. Statistical analyses used multivariate logistic regression analysis. VBD was found in 37 patients (34 men and 3 women). Mean age (± SD) was 64.4 ± 14.7 years (63.4 ± 14.6 years in men and 65.3 ± 6.1 years in women). Twenty-four patients (21 men and 3 women) had BI, and 13 men had BH. There were significant male preferences in VBD BI ( P < .01) and VBD BH patients ( P < .01). Mean age (± SD) was 67.7 ± 14.3 years in BI patients and 56.7 ± 12.7 years in BH patients. The VBD BH men were significantly younger than the non-VBD BH men ( P < .05) and VBD BI men ( P < .01). Frequency of current smoking was significantly greater in VBD BI patients compared with non-VBD BI patients ( P < .05). Other CVD risk factors did not differ among the 4 groups. Mean modified Rankin Scale score was significantly higher in VBD BH men compared with non-VBD BH men and VBD BI men ( P < .01). The height and lateral displacement of the BA were scored more severely in BH patients than in BI patients ( P < .01), but BA diameter did not differ between BH and BI patients. The frequency of pontine infarct and hemorrhage was 3-fold greater in VBD BI ( P < .05) and VBD BH patients ( P < .005) compared with non-VBD BI and BH patients. Our findings indicate a VBD prevalence of 7.7% in stroke patients, 6.4% in BI patients, and 12.1% in BH patients. Our clinicoradiologic analyses suggest male predominance, younger onset of BH, and higher frequency of pontine lesions in VBD patients. Significant BA changes and poor outcome of stroke were found in patients with hemorrhagic VBD rather than ischemic VBD. Thus, more attention should be paid to risk and care of BH in VBD patients, in addition to those of BI.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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