Regional heritability mapping identifies several novel loci (STAT4, ULK4, and KCNH5) for primary biliary cholangitis in the Japanese population

While the advent of GWAS more than a decade ago has ushered in remarkable advances in our understanding of complex traits, the limitations of single-SNP analysis have also led to the development of several other approaches. Simulation studies have shown that the regional heritability mapping (RHM) method, which makes use of multiple adjacent SNPs jointly to estimate the genetic effect of a given region of the genome, generally has higher detection power than single-SNP GWAS. However, thus far its use has been mostly limited to agricultural settings, and its potential for the discovery of new genes in human diseases is yet to be fully exploited. In this study, by applying the RHM method to primary biliary cholangitis (PBC) in the Japanese population, we identified three novel loci (STAT4, ULK4, and KCNH5) at the genome-wide significance level, two of which (ULK4 and KCNH5) have not been found associated with PBC in any population previously. Notably, these genes could not be detected by using conventional single-SNP GWAS, highlighting the potential of the RHM method for the detection of new susceptibility loci in human diseases. These findings thereby provide strong empirical evidence that RHM is an effective and practical complementary approach to GWAS in this context. Also, liver tissue mRNA microarray analysis revealed higher gene expression levels in ULK4 in PBC patients (P < 0.01). Lastly, we estimated the common SNP heritability of PBC in the Japanese population (0.210 ± 0.026).Subject terms: Quantitative trait, Genome informatics     

EGFR Protein Expression Relates with Tumor Histology,Methylation Status of EGFR and HPV16 E6 Viral Load in Oropharyngeal Carcinoma

The epidermal growth factor receptor (EGFR) pathway is important in tumorigenesis of oropharyngeal carcinoma (OPC). However, the molecular mechanisms contributing to EGFR expression in OPC are not well-known. To detect relating factors and clinicopathological impact of EGFR protein expression in OPC, gene amplification/loss, point mutations including synonymous mutations, and promoter methylation of EGFR, and the viral genome load of human papillomavirus type 16 (HPV16)-E5, -E6, and -E7, after extracting HPV16-related OPCs with qPCR of HPV16-E6 and E7, were investigated in 74 OPC surgical cases, including 52 HPV-related (HPV-OPC) and 22 HPV-unrelated (nHPV-OPC). Immunohistochemical (IHC) data of EGFR expression (high, weak, and negative), validated by the qPCR of EGFR mRNA, were compared with molecular, viral, and clinicopathological data of patients. All nHPV-OPC cases were EGFR-IHC-high, whereas 21.2%, 65.4%, and 13.5% of HPV-OPC cases showed EGFR-IHC-high, -weak, -negative (p < 0.01), respectively. In HPV-OPC cases, EGFR-IHC-weak/negative status was related to promoter methylation of EGFR (p = 0.009), but not with gene amplification/loss or the point mutation of EGFR and was more often seen in HPV16-OPC cases (p = 0.049). Among HPV16-OPC cases, EGFR-IHC-weak/negative was related to high E6 expression. EGFR protein-loss was related to the tumor histology of non-keratinizing squamous cell carcinoma (SCC) (p = 0.035) but not with patient prognosis. In conclusion, decreased EGFR protein expression was more frequent in HPV-OPC than in nHPV-OPC and was related to EGFR methylation, infection of HPV16, and the viral genome load of HPV16-E6. Clinicopathologically, it was related to the tumor histology of non-keratinizing SCC.Supplementary informationThe online version of this article (10.1007/s12105-020-01261-w) contains supplementary material, which is available to authorized users.     

Mild hypohydration induced by exercise in the heat attenuates autonomic thermoregulatory responses to the heat, but not thermal pleasantness in humans

Hypohydration caused by exercise in the heat attenuates autonomic thermoregulation such as sweating and skin blood flow in humans. In contrast, it remains unknown if behavioral thermoregulation is modulated during hypohydration. We assume that thermal unpleasantness could drive the behavioral response, and would also be modulated during hypohydration. Nine healthy young men participated in the present study. Body and skin temperatures were monitored. Ratings of thermal sensation and pleasantness were conducted. After ∼ 45 min rest at 27 °C, they performed 50-min cycling exercise, which was at the level of 40% of heart rate range at 35 °C (hypohydration trial) or at the level of 10% of heart rate range at 23 °C (control trial), respectively. Subjects returned to the rest at 27 °C, and the ambient temperature was then changed from 22 to 38 °C. Body weight decreased by 0.9 ± 0.1% immediately after exercise in the hypohydration trial and 0.3 ± 0.1% in the control trial. In the cold, no significant difference in thermal sensation or pleasantness was observed between trials. There was no significant difference in thermal pleasantness between trials in the heat, although thermal sensation in the heat (32.5-36 °C) was significantly lower in the hypohydration trial than in the control trial. In addition, laser Doppler flow of the skin and sweat rate were attenuated in the heat in the hypohydration trial. These results may indicate that mild hypohydration after exercise in the heat has no influence on behavioral responses to the heat.     

Moderate hypercapnia-induced anesthetic effects and endogenous opioids

The purpose of this report is to explore the mechanisms of hypercapnia-induced antinociception. We carried out three experiments, the first to confirm whether moderate hypercapnia induces anesthetic effects, the second to determine whether naloxone reverses the anesthetic effects, and the third to evaluate whether beta-endorphin is related to the anesthetic effects. In a pre-test, we determined the optimal CO(2) concentration in a chamber which would cause moderate hypercapnia in rats. Eighteen rats were divided into control, hypercapnia, and hypercapnia plus naloxone groups in experiment 1. The naloxone group rats were injected with naloxone (10 mg/kg) intraperitoneally before gas inhalation. After 60 min gas inhalation, 10% formalin was injected into the left rear paw of all rats, and nociceptive behaviors were observed for 1 h. In experiment 2, 11 rats were divided into control and hypercapnia groups. The brain was removed and fixed under pentobarbital anesthesia. Sections were immunostained for c-Fos and beta-endorphin (ACTH) with the ABC method. All neurons double-labeled for c-Fos and beta-endorphin (ACTH) in the arcuate nucleus were counted by blinded investigators. Moderate hypercapnia (PaCO(2) 83+/-7 mmHg) reduced nociceptive behavior in the formalin test and naloxone pre-treatment attenuated this phenomenon. However, beta-endorphin-producing neurons were not activated by CO(2) inhalation. Endogenous opioids are related to moderate, hypercapnia-induced anesthetic effects, but, beta-endorphin-producing neurons in the hypothalamus were not activated by the CO(2) inhalation stress.     

Chemical surface modification of high-strength porous Ti compacts by spark plasma sintering

The biological properties of a titanium (Ti) implant depend on its surface oxide film. The aims of the present study were to increase the specific surface oxide area on Ti using a porous structure and to study the relationship between the amount of apatite coating in simulated body fluid (SBF) and the actual surface area on titanium powders. Ti powders of 110 microm average diameter were sintered by spark plasma sintering. The sintered compacts had a porosity of 28%, a compressive elastic modulus of 7.9 GPa and an ultimate strength of 112 MPa. The compressive strength of the compacts was increased to 588 MPa by subsequent annealing in a vacuum furnace at 1000 degrees C for 24 h. The sintered compacts were treated with aqueous NaOH solution and subsequently heated at 600 degrees C. The pretreated compacts showed apatite crystal precipitation in SBF. The amounts of precipitates through the compacts were compared with those of the Ti plate substrates subjected to the same chemical pretreatment. It was confirmed that the amounts of precipitates through the compacts were more than one hundred times higher than those on the Ti plates. It was concluded that the metal porous compacts developed may be used as functional materials for immobilizing functional proteins and/or drugs, because the precipitated apatite can adsorbed these substances.     

Vertical control by combining a monoblock appliance in adult class III overclosure treatment

Monoblock appliances were used in combination with intermaxillary elastics for treatment of adult skeletal Class III patients. The patients showed predisposing upper incisors problems, significant mobility in patient 1 and root resorption in patient 2, which contraindicated direct intrusion of the incisors. Using the monoblock with selective extrusion of the molars, a clockwise rotation was induced to reduce overbite and to achieve a better profile. It was also possible to reduce the excessive force to the upper incisors during and after treatment, which improved incisor mobility to a physiologic extent (patient 1) and prevented further progression of root resorption (patient 2). Stability was high after the 2-year follow-up, which suggests a stable vertical control approach by using the monoblock appliance in combination with a fixed appliance in adults.     

Education of dentists in China

China is geographically located in the east of Asia and its population exceeds 1.3 billion. An understanding of dental education in China is thus of interest. However, as there is little published information on this topic, this paper provides information about China regarding its dental history, dental school system including curriculum and dental licensure. High school graduates take a nationwide entrance examination to apply for dental school, of which there are more than 50 in China. A five year dental education leads to the BDS degree. Dental school graduates must then pass the nationwide licensure examination to practise dentistry. Currently, there are not adequate numbers of dentists to provide the necessary oral health care for people living outside metropolitan areas.     

Development of a compact and simple gas chromatography for oral malodor measurement

BACKGROUND: Volatile sulfur compounds (VSCs) in oral air are the only type of gases correlated with the strength of oral malodor. We developed a compact and simple gas chromatograph (GC) equipped with a newly invented indium oxide semiconductor gas sensor (SCS) for measuring the concentrations of VSCs in mouth air. We have assessed the correlation between measurements with a GC-SCS and those with a regular GC. METHODS: Oral air samples from randomly selected volunteers were analyzed with both a GC-SCS and a GC with a flame photometric detector (FPD), which is specific to VSCs, and GC-SCS measurements were compared to those obtained by GC-FPD. Subsequently, oral air samples before and after mouthrinsing with 5% ethanol mouthwash were analyzed to determine the effect of ethanol on VSC measurements by GC-SCS. RESULTS: There were strong correlations between VSC concentrations determined using these two gas chromatography methods (hydrogen sulfide, R=0.821, P<0.0001; methyl mercaptan, R=0.870, P<0.0001; and dimethyl sulfide, R=0.770, P<0.0001). Although GC-SCS can differentiate ethanol and VSCs in oral air samples after mouthrinsing, GC-SCS measurements demonstrated higher values than those obtained by GC-FPD; however, this discrepancy improved over time due to the reduced effect of ethanol. CONCLUSION: The results suggest that GC-SCS may be useful for the diagnosis of halitosis.     

Temporomandibular joint internal derangement in mandibular asymmetry. What is the relationship?

The purpose of this study was to clarify the contributing factors and their influences on temporomandibular joint internal derangement (TMJ ID) symptoms in subjects with mandibular asymmetry. Postero-anterior (PA) cephalograms of 187 pre-orthodontic treatment subjects (aged 18-45 years, mean 23.9 years) were used to investigate the inclination of the frontal occlusal (FOP) and frontal mandibular (FMP) planes to determine vertical asymmetry. Mandibular dental midline shift (DMS) and mandibular midline shift (MMS) were studied to determine transverse asymmetry. The degree of asymmetry was analysed in conjunction with the results from self-administered TMJ ID history forms. A prevalence of TMJ ID was most related to the inclination of the FMP (P < 0.01), with the symptoms being notably higher when the cant was greater than 3 degrees. The symptomatic side was related only to the inclination of the FOP and FMP. Symptoms confined to the ipsilateral side were primarily found in subjects with mild asymmetry, whereas symptoms on both sides and those on the contralateral side were greater in those with moderate and severe asymmetry, respectively. No significant correlation was found for DMS and MMS. The results suggest that the degree of asymmetry in the vertical dimension is significantly correlated with TMJ ID symptoms.     

Intravascular ultrasound guided wiring for chronic total occlusions

The success of percutaneous intervention for chronic total occlusion depends mainly on crossing the lesion with a wire. This report deals with the principles and the technical tips of intravascular ultrasound-guided wiring for chronic total occlusion, which can be divided into two trategies.The first is "identification of the site of entry." When the abrupt type chronic total occlusion with a side branch is treated, it is possible to identify the occlusion and the entry point by pulling back the intravascular ultrasound catheter from the distal part of the side branch.The second is "returning to the true lumen after entering a false lumen." If hematoma is caused by manipulating a wire in the false lumen that impairs visualization of the distal true lumen, an intravascular ultrasound catheter can be advanced into the false lumen.An attempt to make a successful re-entry into the true lumen can be achieved under intravascular ultrasound guidance.