Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome.

Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, psoriasis, and other conditions. Despite an apparent autosomal-dominant pattern of inheritance, the genetic background of SMS and information about its phenotypic heterogeneity remain unknown. Recently, we found a family affected by glaucoma, aortic calcification, and skeletal abnormalities. Unlike subjects with classic SMS, affected individuals showed normal dentition, suggesting atypical SMS. To identify genetic causes of the disease, we performed exome sequencing in this family and identified a variant (c.1118A>C [p.Glu373Ala]) of DDX58, whose protein product is also known as RIG-I. Further analysis of DDX58 in 100 individuals with congenital glaucoma identified another variant (c.803G>T [p.Cys268Phe]) in a family who harbored neither dental anomalies nor aortic calcification but who suffered from glaucoma and skeletal abnormalities. Cys268 and Glu373 residues of DDX58 belong to ATP-binding motifs I and II, respectively, and these residues are predicted to be located closer to the ADP and RNA molecules than other nonpathogenic missense variants by protein structure analysis. Functional assays revealed that DDX58 alterations confer constitutive activation and thus lead to increased interferon (IFN) activity and IFN-stimulated gene expression. In addition, when we transduced primary human trabecular meshwork cells with c.803G>T (p.Cys268Phe) and c.1118A>C (p.Glu373Ala) mutants, cytopathic effects and a significant decrease in cell number were observed. Taken together, our results demonstrate that DDX58 mutations cause atypical SMS manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies.

An atypical case involving real, ghost, and pseudo-ghost images on a panoramic radiograph.

Purpose: This report presents a unique case featuring real, ghost, and pseudo-ghost images on the panoramic radiograph of a patient wearing earrings. It also explains the formation of these images in an easy-to-understand manner. Material and Methods: One real image and two ghost images appeared on each side of a panoramic radiograph of a patient wearing earrings on both sides. Of the two ghost images on each side, one was considered a typical ghost image and the other was considered a ghost-like real image (pseudo-ghost image). The formation zones of the real, double, and ghost images were examined based on the path and angles of the X-ray beam from the Planmeca ProMax. To simulate the pseudo-ghost and typical ghost images on panoramic radiography, a radiopaque marker was affixed to the right mandibular condyle of a dry mandible, and the position of the mandible was adjusted accordingly. Results: The center of rotation of the Planmeca ProMax extended beyond the jaw area, and the area of double image formation also reached beyond the jaw. The radiopaque-marked mandibular condyle, situated in the outwardly extending area of double image formation, exhibited triple images consisting of real, double (pseudo-ghost), and ghost images. These findings helped to explain the image formation associated with the patient's earrings observed in the panoramic radiograph. Conclusion: Dentists must understand the characteristics and principles of the panoramic equipment they use and apply this understanding to taking and interpreting panoramic radiographs.

Whole-genome sequencing in clinically diagnosed Charcot-Marie-Tooth disease undiagnosed by whole-exome sequencing.

Whole-genome sequencing is the most comprehensive form of next-generation sequencing method. We aimed to assess the additional diagnostic yield of whole-genome sequencing in patients with clinically diagnosed Charcot-Marie-Tooth disease when compared with whole-exome sequencing, which has not been reported in the literature. Whole-genome sequencing was performed on 72 families whose genetic cause of clinically diagnosed Charcot-Marie-Tooth disease was not revealed after the whole-exome sequencing and 17p12 duplication screening. Among the included families, 14 (19.4%) acquired genetic diagnoses that were compatible with their phenotypes. The most common factor that led to the additional diagnosis in the whole-genome sequencing was genotype-driven analysis (four families, 4/14), in which a wider range of genes, not limited to peripheral neuropathy-related genes, were analysed. Another four families acquired diagnosis due to the inherent advantage of whole-genome sequencing such as better coverage than the whole-exome sequencing (two families, 2/14), structural variants (one family, 1/14) and non-coding variants (one family, 1/14). In conclusion, an evident gain in diagnostic yield was obtained from whole-genome sequencing of the whole-exome sequencing-negative cases. A wide range of genes, not limited to inherited peripheral neuropathy-related genes, should be targeted during whole-genome sequencing.

Highly Specific Loop-Mediated Isothermal Amplification Using Graphene Oxide-Gold Nanoparticles Nanocomposite for Foot-and-Mouth Disease Virus Detection.

Loop-mediated isothermal amplification (LAMP) is a molecular diagnosis technology with the advantages of rapid results, isothermal reaction conditions, and high sensitivity. However, this diagnostic system often produces false positive results due to a high rate of non-specific reactions caused by formation of hairpin structures, self-dimers, and mismatched hybridization. The non-specific signals can be due to primers used in the methods because the utilization of multiple LAMP primers increases the possibility of self-annealing of primers or mismatches between primers and templates. In this study, we report a nanomaterial-assisted LAMP method that uses a graphene oxide-gold nanoparticles (AuNPs@GO) nanocomposite to enable the detection of foot-and-mouth disease virus (FMDV) with high sensitivity and specificity. Foot-and-mouth disease (FMD) is a highly contagious and deadly disease in cloven-hoofed animals; hence, a rapid, sensitive, and specific detection method is necessary. The proposed approach exhibited high sensitivity and successful reduction of non-specific signals compared to the traditionally established LAMP assays. Additionally, a mechanism study revealed that these results arose from the adsorption of single-stranded DNA on AuNPs@GO nanocomposite. Thus, AuNPs@GO nanocomposite is demonstrated to be a promising additive in the LAMP system to achieve highly sensitive and specific detection of diverse diseases, including FMD.

Effective Diagnosis of Foot-And-Mouth Disease Virus (FMDV) Serotypes O and A Based on Optical and Electrochemical Dual-Modal Detection.

Foot-and-mouth disease virus (FMDV) is a highly contagious disease that affects cloven-hoofed animals. The traditional diagnostic methods for FMDV have several drawbacks such as cross-reactivity, low sensitivity, and low selectivity. To overcome these drawbacks, we present an optical and electrochemical dual-modal approach for the specific detection of FMDV serotypes O and A by utilizing a magnetic nanoparticle labeling technique with resorufin ß-d-glucopyranoside (res-ß-glc) and ß-glucosidase (ß-glc), without the use of typical lateral flow assay or polymerase chain reaction. FMDV serotypes O and A were reacted with pan-FMDV antibodies that recognize all seven FMDV serotypes (O, A, C, Asia 1, SAT 1, SAT 2, and SAT 3). The antigen-antibody complex was then immobilized on magnetic nanoparticles and reacted with ß-glc-conjugated FMDV type O or type A antibodies. Subsequently, the addition of res-ß-glc resulted in the release of fluorescent resorufin and glucose owing to catalytic hydrolysis by ß-glc. The detection limit of fluorescent signals using a fluorescence spectrophotometer was estimated to be log(6.7) and log(5.9) copies/mL for FMDV type O and A, respectively, while that of electrochemical signals using a glucometer was estimated to be log(6.9) and log(6.1) copies/mL for FMDV type O and A, respectively. Compared with a commercially available lateral flow assay diagnostic kit for immunochromatographic detection of FMDV type O and A, this dual-modal detection platform offers approximately four-fold greater sensitivity. This highly sensitive and accurate dual-modal detection method can be used for effective disease diagnosis and treatment, and will find application in the early-stage diagnosis of viral diseases and next-generation diagnostic platforms.

Effects of Graphene Oxide-Gold Nanoparticles Nanocomposite on Highly Sensitive Foot-and-Mouth Disease Virus Detection.

The polymerase chain reaction (PCR) has become a powerful molecular diagnostic technique over the past few decades, but remains somewhat impaired due to low specificity, poor sensitivity, and false positive results. Metal and carbon nanomaterials, quantum dots, and metal oxides, can improve the quality and productivity of PCR assays. Here, we describe the ability of PCR assisted with nanomaterials (nano-PCR) comprising a nanocomposite of graphene oxide (GO) and gold nanoparticles (AuNPs) for sensitive detection of the foot-and-mouth disease virus (FMDV). Graphene oxide and AuNPs have been widely applied as biomedical materials for diagnosis, therapy, and drug delivery due to their unique chemical and physical properties. Foot-and-mouth disease (FMD) is highly contagious and fatal for cloven-hoofed animals including pigs, and it can thus seriously damage the swine industry. Therefore, a highly sensitive, specific, and practical method is needed to detect FMDV. The detection limit of real-time PCR improved by ~1000 fold when assisted by GO-AuNPs. We also designed a system of detecting serotypes in a single assay based on melting temperatures. Our sensitive and specific nano-PCR system can be applied to diagnose early FMDV infection, and thus may prove to be useful for clinical and biomedical applications.

Contemporary alumina-on-alumina total hip arthroplasty performed in patients younger than forty years: a 5-year minimum follow-up study.

Ceramic-on-ceramic bearing surfaces in total hip arthroplasties (THAs) are an attractive alternative coupling and may offer a promising option for young active patients. We evaluated the clinical results of 72 contemporary primary cementless alumina-on-alumina THAs performed in 61 patients younger than 40 years (mean age, 30 years), after a 5-year minimum follow-up. Most patients (97%) were able to return to their prearthritic activity levels, and none changed occupation because of a postoperative hip joint problem. No implant loosened radiographically and no stem or cup was revised. Ceramic wear was undetectable in 24 hips, where differentiation of the femoral head from the cup was possible on radiographs and no osteolysis was observed. One ceramic fracture following a major motor vehicle accident and a recurrent subluxation-associated ceramic liner edge fracture attributed to inadequate hip muscle tone occurred. We believe that this alternative articulation offers a promising option for young active patients. However, our findings also suggest that contemporary ceramic implant fracture is not a potential, but a real danger. Careful preoperative patient evaluation, proper indications for ceramic bearings, and meticulous surgical techniques are recommended to minimize the possibility of modern ceramic failure.

Improvement in Trainees' Attitude and Resuscitation Quality With Repeated Cardiopulmonary Resuscitation Training: Cross-Sectional Simulation Study.

INTRODUCTION: This study investigated the effect of increasing numbers of training sessions in cardiopulmonary resuscitation (CPR) on trainees' attitude and CPR quality. METHODS: Cardiopulmonary resuscitation training for hospital employees was held every year from 2006 to 2010. Participants were recruited among the trainees in 2010. The trainees' attitudes toward CPR were surveyed by questionnaire, and the quality of their CPR was measured using 5-cycle 30:2 CPR on a manikin. Participants were categorized according to the number of consecutive CPR training sessions as T1 (only 2010), T2 (2009 and 2010), T3 (from 2008 to 2010) and T4-5 (from 2006 or 2007 to 2010). The trainee attitude and CPR quality were compared among the 4 groups. RESULTS: Of 923 CPR trainees, 267 were enrolled in the study. There was significant increase in willingness to start CPR and confidence in chest compression and mouth-to-mouth ventilation (MTMV) with increasing number of CPR training sessions attended (especially for ≥ 3 sessions). There was a significant increase in mean compression depth and decrease in percentage of chest compressions with depth of less than 38 mm in the T3 and T4-5 compared with the T1 and T2. No-flow time decreased significantly, and the percentage of MTMV with visible chest rise increased, as the number of training sessions increased. CONCLUSIONS: Repeated CPR training improved trainees' attitude and CPR quality. Because the number of training sessions increased (≥3), the willingness to start CPR and the confidence in skills increased significantly, and chest compression depth, no-flow time, and MTMV improved.

Video laryngoscopy vs. direct laryngoscopy: Which should be chosen for endotracheal intubation during cardiopulmonary resuscitation? A prospective randomized controlled study of experienced intubators.

AIM: This study compared endotracheal intubation (ETI) performance during cardiopulmonary resuscitation (CPR) between direct laryngoscopy (DL) and video laryngoscopy (VL) (GlideScope(®)) by experienced intubators (>50 successful ETIs). METHODS: This was a prospective randomized controlled study conducted in an emergency department between 2011 and 2013. Intubators who used DL or VL were randomly allocated to ETI during CPR. Data were collected from recorded video clips and rhythm sheets. The success, speed, complications, and chest compressions interruption were compared between the two devices. RESULTS: Total 140 ETIs by experienced intubators using DL (n=69) and VL (n=71) were analysed. There were no significant differences between DL and VL in the ETI success rate (92.8% vs. 95.8%; p=0.490), first-attempt success rate (87.0% vs. 94.4%; p=0.204), and median time to complete ETI (51 [36-67] vs. 42 [34-62]s; p=0.143). In both groups, oesophageal intubation and dental injuries seldom occurred. However, longer chest compressions interruption occurred using DL (4.0 [1.0-11.0]s) compared with VL (0.0 [0.0-1.0]s) and frequent serious no-flow (interruption>10s) occurred with DL (18/69 [26.1%]) compared with VL (0/71) (p<0.001). For highly experienced intubators (>80 successful ETIs), frequent serious no-flow occurred in DL (14/55 [25.5%] vs. 0/57 in VL). CONCLUSIONS: The ETI success, speed and complications during CPR did not differ significantly between the two devices for experienced intubators. However, the VL was superior in terms of completion of ETI without chest compression interruptions. TRIAL REGISTRATION: Clinical Research Information Service (CRIS) in South Korea KCT0000849.

Efficacy of various types of laryngoscope (direct, Pentax Airway Scope and GlideScope) for endotracheal intubation in various cervical immobilisation scenarios: a randomised cross-over simulation study.

OBJECTIVE: To compare the efficacy of direct laryngoscopy (DL), Pentax Airway Scope (PAWS) and GlideScope video laryngoscope (GVL) systems for endotracheal intubation (ETI) in various cervical immobilisation scenarios: manual in-line stabilisation (MILS), Philadelphia neck collar (PNC) (moderate limit of mouth opening) and Stifneck collar (SNC) (severe limit of mouth opening). DESIGN: Randomised cross-over simulation study. SETTING AND PARTICIPANTS: 35 physicians who had >30 successful ETI experiences at a tertiary hospital in Seoul, Korea. PRIMARY AND SECONDARY OUTCOME MEASURES: Participants performed ETI using PAWS, GVL and DL randomly in simulated MILS, PNC and SNC scenarios in our simulation centre. The end points were successful ETI and the time to complete ETI. In addition, modified Cormack-Lehane (CL) classification and pressure to teeth were recorded. RESULTS: In MILS, there were no significant differences in the rate of success of ETI between the three devices: 33/35(94.3%) for DL vs 32/35(91.4%) for GVL vs 35/35(100.0%) for PAWS; p=0.230). PAWS achieved successful ETI more quickly (19.8 s) than DL (29.6 s) and GVL (35.4 s). For the PNC scenario, a higher rate of successful ETI was achieved with GVL 33/35 (94.3%) than PAWS 29/35 (82.9%) or DL 25/35 (71.4%) (p=0.040). For the SNC scenario, a higher rate of successful ETI was achieved with GVL 28/35(80.0%) than with DL 14/35(40.0%) and PAWS 7/35(20.0%) (p<0.001). For the PNC and SNC scenarios, GVL provided a relatively good view of the glottis, but a frequent pressure to teeth occurred. CONCLUSIONS: All three devices are suitable for ETI in MILS. DL is not suitable in both neck collar scenarios. PAWS showed faster intubations in MILS, but was not suitable in the SNC scenario. GVL is most suitable in all cervical immobilisation scenarios, but may cause pressure to teeth more frequently.

A novel point mutation in PMP22 gene associated with a familial case of Charcot-Marie-Tooth disease type 1A with sensorineural deafness.

Charcot-Marie-Tooth disease with deafness is a clinically distinct entity and is associated with mutations or deletions in several genes including PMP22 gene. Here, we report a large family showing characteristic phenotypes of Charcot-Marie-Tooth type 1A along with deafness in an autosomal dominant fashion. We detected a sequence variation (c.68C>G) co-segregating with the disease phenotype and leading to a T23R missense mutation in PMP22.

Multiple Endocrine Neoplasia Type 2B: Early Diagnosis by Multiple Mucosal Neuroma and Its DNA Analysis.

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare disease caused by germline mutations in the RET proto-oncogene and is transmitted in an autosomal dominant fashion. It is characterized by medullary thyroid carcinoma, pheochromocytoma and mucosal neuroma developing in the tongue, lip, intestinal tract, palate etc. Among these neoplasias, mucosal neuroma generally develops from early childhood. Therefore, early detection and proper treatment can minimize the disease course. Here we describe a 9-year-old male who presented with multiple verrucous papules and nodules on his lips, tongue and gingiva that were there since birth. Histologic findings of his lips and tongue showed well-defined nerve bundles and DNA analysis revealed a M918T mutation at codon 918 of the RET oncogene. He was diagnosed early as having MEN 2B according to his genetic and phenotypic features.

Tracheal intubation without the use of muscle relaxant in severe burn patients using propofol and varying doses of remifentanil.

BACKGROUND: Severe burn patients often have a difficult airway. Tracheal intubation can be conducted safely in patients in a stable hemodynamic condition using a propofol in conjunction with remifentanil without employing muscle relaxant. However, no studies have been conducted to date to evaluate intubation of severe burn patients. Therefore, this study was conducted to evaluate the condition of tracheal intubation with propofol and varying doses of remifentanil without muscle relaxants in severe burn patients. METHODS: Eighty severe burn patients were divided into four groups at random. Anesthesia was intravenously induced by continuous infusion of propofol (4 microgram/ml of effect site concentration)and slowly injected remifentanil. Groups 1, 2, 3, and 4 received 1, 1.5, 2, and 2.5 microgram/kg of remifentanil, respectively. Ninety seconds after the administration of remifentanil, tracheal intubation was attempted. We used a scoring system in which jaw relaxation, the state when laryngoscopy was inserted, vocal cord opening, cough, limb movement, and difficulty with laryngoscopy were divided into < or = 2 (acceptable) or > or = 3 (not acceptable). In addition, the hemodynamic changes were measured at baseline, before intubation, and 1, 2, 3, 4, and 5 min after intubation. RESULTS: Clinically acceptable intubating conditions were observed in 35%, 40%, 55%, and 70% of the patients in groups 1-4, respectively. The mean arterial pressure and heart rate decreased immediately before intubation in all groups. One patient was treated for bradycardia however, no patients manifested hypotension. CONCLUSIONS: Propofol and slowly injected remifentanil (2.5 microgram/kg) without muscle relaxant can provide clinically acceptable intubating conditions and stable hemodynamic conditions in major burn patients. However, further studies should be conducted to evaluate the effects of increased doses of remifentanil.

A case report of a poor metabolizer of CYP2D6 presented with unusual responses to nortriptyline medication.

We present a case with decreased metabolic activity of CYP2D6, a cytochrome P450 enzyme catalyzing the metabolism of nortriptyline (NT). Conventional dosage regimen led to toxic plasma concentration of NT and adverse effects such as dry mouth, constipation, and dizziness in this case with genotype CYP2D6*5/*10B. This case suggests the clinical usefulness of pharmacogenetic testing in individualized dosage adjustments of NT.