Identification of rare coding variants associated with Kawasaki disease by whole exome sequencing

Kawasaki disease (KD) is an acute pediatric vasculitis that affects genetically susceptible infants and children. To identify coding variants that influence susceptibility to KD, we conducted whole exome sequencing of 159 patients with KD and 902 controls, and performed a replication study in an independent 586 cases and 732 controls. We identified five rare coding variants in five genes (FCRLA, PTGER4, IL17F, CARD11, and SIGLEC10) associated with KD (odds ratio [OR], 1.18–4.41; p = 0.0027–0.031). We also performed association analysis in 26 KD patients with coronary artery aneurysms (CAAs; diameter > 5 mm) and 124 patients without CAAs (diameter < 3 mm), and identified another five rare coding variants in five genes (FGFR4, IL31RA, FNDC1, MMP8, and FOXN1), which may be associated with CAA (OR, 3.89–37.3; p = 0.0058–0.0261). These results provide insights into new candidate genes and genetic variants potentially involved in the development of KD and CAA.

IgA Levels Are Associated with Coronary Artery Lesions in Kawasaki Disease

Background and Objectives@#Kawasaki disease (KD) is an acute systemic vasculitis that affects the coronary arteries. Abnormal immune reactions are thought to contribute to disease pathogenesis. The effect of immunoglobulin (Ig) isotype (IgG, IgA, IgM, and IgE) on inflammatory data and clinical outcomes of patients with KD was examined. @*Methods@#Ig levels in 241 patients with KD were measured during the acute, subacute, convalescent, and normal phases of the disease. @*Results@#Compared with reference Ig values, IgG, IgA, and IgM levels were significantly higher in the subacute phase, while IgE levels were elevated in 73.9% (178/241) of patients with KD in all clinical phases. However, high IgE levels were not associated with clinical outcomes, including intravenous immunoglobulin unresponsiveness and coronary artery lesions (CALs).Significantly more CALs were observed in the high IgA group than in the normal IgA group (44.7% vs. 20.8%, respectively; p<0.01). In addition, IgA levels in the acute phase (p=0.038) were 2.2-fold higher, and those in the subacute phase were 1.7-fold higher (p <0.001), in the CAL group than in the non-CAL group. IgA concentrations increased along with the size of the coronary artery aneurysm (p <0.001). Furthermore, there was a strong correlation between IgA levels and CAL size (r=0.435, p<0.001), with a high odds ratio of 2.58 (p=0.022). @*Conclusions@#High IgA levels in patients with KD are prognostic for the risk of CALs.

IgA Levels Are Associated with Coronary Artery Lesions in Kawasaki Disease

Background and Objectives@#Kawasaki disease (KD) is an acute systemic vasculitis that affects the coronary arteries. Abnormal immune reactions are thought to contribute to disease pathogenesis. The effect of immunoglobulin (Ig) isotype (IgG, IgA, IgM, and IgE) on inflammatory data and clinical outcomes of patients with KD was examined. @*Methods@#Ig levels in 241 patients with KD were measured during the acute, subacute, convalescent, and normal phases of the disease. @*Results@#Compared with reference Ig values, IgG, IgA, and IgM levels were significantly higher in the subacute phase, while IgE levels were elevated in 73.9% (178/241) of patients with KD in all clinical phases. However, high IgE levels were not associated with clinical outcomes, including intravenous immunoglobulin unresponsiveness and coronary artery lesions (CALs).Significantly more CALs were observed in the high IgA group than in the normal IgA group (44.7% vs. 20.8%, respectively; p<0.01). In addition, IgA levels in the acute phase (p=0.038) were 2.2-fold higher, and those in the subacute phase were 1.7-fold higher (p <0.001), in the CAL group than in the non-CAL group. IgA concentrations increased along with the size of the coronary artery aneurysm (p <0.001). Furthermore, there was a strong correlation between IgA levels and CAL size (r=0.435, p<0.001), with a high odds ratio of 2.58 (p=0.022). @*Conclusions@#High IgA levels in patients with KD are prognostic for the risk of CALs.

Assessment of the Clinical Heterogeneity of Kawasaki Disease Using Genetic Variants of BLK and FCGR2A

BACKGROUND AND OBJECTIVES@#Patients with Kawasaki disease (KD) are clinically heterogeneous because its diagnosis is based solely on clinical observation and there are no definitive biomarkers. We dissected the clinical heterogeneity of KD patients using the KD-associated genetic variants.@*METHODS@#We performed a genetic association analysis in several KD subgroups categorized by clinical characteristics using the KD-associated variants of the B lymphoid tyrosine kinase (BLK; rs6993775) and Fc gamma receptor II a (FCGR2A; rs1801274) in a large number of case (n=1,011) and control (n=4,533) samples.@*RESULTS@#BLK and FCGR2A were very significantly associated with KD in Korean KD patients (odds ratio [OR],1.48; p=4.63×10⁻¹¹ for BLK, and OR, 1.26; p=1.42×10⁻⁴ for FCGR2A). However, in KD subgroup analysis, we found that neither BLK nor FCGR2A were associated with either incomplete Kawasaki disease (iKD) type patients or those older than 5 years of age (p>0.2), suggesting that patients with iKD or those older than 5 years of age are a unique subgroup of KD. In genetic association analysis after excluding iKD patients and those older than 5 years old, we found that BLK was associated with all KD subgroups, whereas FCGR2A was specifically associated with male KD patients younger than 1 year of age (OR, 2.22; p=2.35×10⁻⁵).@*CONCLUSIONS@#KD is a clinically and genetically heterogeneous disease. These findings will provide new insights into the clinical and genetic heterogeneity of KD.

Assessment of the Clinical Heterogeneity of Kawasaki Disease Using Genetic Variants of BLK and FCGR2A

BACKGROUND AND OBJECTIVES: Patients with Kawasaki disease (KD) are clinically heterogeneous because its diagnosis is based solely on clinical observation and there are no definitive biomarkers. We dissected the clinical heterogeneity of KD patients using the KD-associated genetic variants. METHODS: We performed a genetic association analysis in several KD subgroups categorized by clinical characteristics using the KD-associated variants of the B lymphoid tyrosine kinase (BLK; rs6993775) and Fc gamma receptor II a (FCGR2A; rs1801274) in a large number of case (n=1,011) and control (n=4,533) samples. RESULTS: BLK and FCGR2A were very significantly associated with KD in Korean KD patients (odds ratio [OR],1.48; p=4.63×10⁻¹¹ for BLK, and OR, 1.26; p=1.42×10⁻⁴ for FCGR2A). However, in KD subgroup analysis, we found that neither BLK nor FCGR2A were associated with either incomplete Kawasaki disease (iKD) type patients or those older than 5 years of age (p>0.2), suggesting that patients with iKD or those older than 5 years of age are a unique subgroup of KD. In genetic association analysis after excluding iKD patients and those older than 5 years old, we found that BLK was associated with all KD subgroups, whereas FCGR2A was specifically associated with male KD patients younger than 1 year of age (OR, 2.22; p=2.35×10⁻⁵). CONCLUSIONS: KD is a clinically and genetically heterogeneous disease. These findings will provide new insights into the clinical and genetic heterogeneity of KD.

Biological and Genetic Characteristics of Clinically Isolated Enterobacter cloacae with Multidrug Resistance

BACKGROUND: From January 2014 to December 2015, 69 clones of Enterobacter cloacae showing multidrug resistance to six classes of antimicrobial agents were collected from two medical centers in Korea. METHODS: Minimum inhibitory concentrations were determined using the E-test method, and 17 genes were detected using polymerase chain reaction (PCR). The epidemiological relatedness of the strains was identified using repetitive element sequence-based PCR and multilocus sequence typing. RESULTS: The 69 E. cloacae clones produced extended spectrum β lactamase (ESBL) and AmpC and showed multidrug resistance to cefotaxime, ceftazidime, and aztreonam. We identified the following sequence types: ST56 of type VI for ESBL SHV (N=12, 17.4%); ST53, ST114, ST113, and ST550 of types I, IV, VI, and VII, respectively, for CTX-M (N=11, 15.9%); and ST668 of type III for the carbapenemase NDM gene (N=1, 1.5%). The AmpC DHA gene (N=2, 2.89%) was confirmed as ST134, although its type was not identified, whereas EBC (MIR/ACT; N=18, 26.1%) was identified as ST53, ST24, ST41, ST114, ST442, ST446, ST484, and ST550 of types V, I, III, IV, VII, and VI, respectively. The formed subclasses were bla CTX-M-3 and bla CTX-M-22 by CTX-M-1, bla CTX-M-9 and bla CTX-M-125 by CTX-M-9, bla DHA-1 by DHA, and bla MIR-7 and bla ACT-15,17,18,25,27,28 by EBC (MIR/ACT). CONCLUSIONS: There were no epidemiological relationships between the gene products and the occurrence of resistance among the strains.

Results of Total Hip Arthroplasty with 36-mm Metallic Femoral Heads on 1st Generation Highly Cross Linked Polyethylene as a Bearing Surface in Less than Forty Year-old Patients: Minimum Ten-year Results / 대한고관절학회지

PURPOSE: We evaluated long-term clinical and radiographic results in patients underwent primary total hip arthroplasty (THA) using 36-mm metallic femoral head and 1st generation highly cross-linked polyethylene among patients aged 40 years and less, with minimum 10 years follow-up. MATERIALS AND METHODS: We retrospectively reviewed 20 hips underwent primary THA by one hip surgeon using 36-mm femoral head and 1st generation highly cross-linked polyethylene from 2004 to 2006. Mean follow up was 131.55 months. Clinical follow-ups included functional measurements. And we evaluated post operative complications, prosthesis loosening, failure, and osteolysis. For radiologic evaluations, together with position of acetabular cup at 6 weeks later of postoperation, we separately calculated the penentrations of femoral heads into polyethylene liners during postoperation and one year later check-ups, and during one year later check-ups and final check-ups. Polywear pro3D 5.10 software was used to measure penetrations of femoral head. RESULTS: Mean acetabular cup inclination and anteversion were 49.02° and 10.19°, respectively. Mean thickness of the polyethylene liner at 45° was 6.44 mm. There were no major complications such as implant loosening or osteolysis, and one case of dislocation occurred. Average modified Harris hip score at final follow-up was 91, and Merle d'Aubigne and Postel scores 15 were or over. Average femoral head penetration of bedding wear was 0.170±0.039 mm/year. Steady-state wear rates was 0.059±0.006 mm/year. CONCLUSION: Results of THA with 36-mm metallic femoral heads on 1st generation highly cross linked as a bearing surface in less than 40 year-old patients were satisfactory.

Current Concepts of Using Large Femoral Heads in Total Hip Arthroplasty / 대한고관절학회지

Instability and dislocation after total hip arthroplasty are the most common causes of revisions and major complications for failure of inserted prostheses, leading to a reduction in quality of life. Because the use of artificial femoral head sizes smaller than patient's own size is the important cause for dislocation, the use of large femoral head have increased. Femoral head sizes greater than 32 mm offer multiple advantages in physical function and activity levels of patients by improving hip stability, decreasing dislocation rate and increasing range of motion. However, various concerns are encountered including wear debris generation at the trunnion-bore interface and increases in frictional torque and stress over the component-bone interface when using larger head sizes. So, the use of femoral head sizes less than 40 mm is recommended.

Endotracheal intubation-related vocal cord ulcer following general anesthesia / 대한마취과학회지

No abstract available.

Cardiac arrest due to coronary spasms in a patient in a lateral decubitus position and contralateral thoracotomy state during Ivor Lewis esophagogastrectomy: A case report

A coronary artery spasm (CAS) during noncardiac surgery is rare, but it can lead to catastrophic consequences. Furthermore, cardiac arrest caused by CAS, while a patient is in a lateral decubitus position and under contralateral thoracotomy conditions, represents a major challenge to both the anesthesiologist and the surgeon. We present a case of cardiac arrest due to CAS in a 69-year-old man undergoing Ivor Lewis esophagogastrectomy surgery for esophageal cancer in the left lateral decubitus position and the right thoracotomy state. The patient was successfully resuscitated with conventional cardiopulmonary resuscitation after repositioning him to a supine position.

Cardiac arrest due to coronary spasms in a patient in a lateral decubitus position and contralateral thoracotomy state during Ivor Lewis esophagogastrectomy: A case report

A coronary artery spasm (CAS) during noncardiac surgery is rare, but it can lead to catastrophic consequences. Furthermore, cardiac arrest caused by CAS, while a patient is in a lateral decubitus position and under contralateral thoracotomy conditions, represents a major challenge to both the anesthesiologist and the surgeon. We present a case of cardiac arrest due to CAS in a 69-year-old man undergoing Ivor Lewis esophagogastrectomy surgery for esophageal cancer in the left lateral decubitus position and the right thoracotomy state. The patient was successfully resuscitated with conventional cardiopulmonary resuscitation after repositioning him to a supine position.

Approach for Epiduroscopic Laser Neural Decompression in Case of the Sacral Canal Stenosis

Epiduroscopy is very useful in the treatment of not only low back pain caused by failed back surgery syndrome, epidural scar or herniated disc but also by chronic refractory low back pain which does not respond to interventional conservative treatment including fluoroscopically-directed epidural steroid injections and percutaneous adhesiolysis. Because cauterization using a laser fiber has become recently available, a wider opening is required to enter into the sacral canal in the case of epiduroscopic laser neural decompression (ELND). However, in a few patients, it is difficult to insert a device into the epidural space due to stenosis around the opening, and there is no alternative method. Herein, we report a case where a hiatus rasp specially designed for such patients was used to perform the operation.

Lack of Replication of Genetic Association with Body Mass Index Detected by Genome-wide Association Study

Obesity provokes many serious human diseases, including various cardiovascular diseases and diabetes. Body mass index (BMI) is a highly heritable trait that is broadly used to diagnose obesity. To identify genetic loci associated with obesity in Asians, we conducted a genome-wide association study (GWAS) of a population of Korean adults (n=6,742, age 40~60 years) and detected six BMI risk loci (TNR, FAM124B, RGS12, NFE2L3, MC4R and FTO) having p<1x10(-5). However, in the replication study, only melanocortin 4 receptor gene (MC4R) (rs9946888, p=4.58x10(-7)) was replicated with marginal significance (p<0.05) in the second cohort (n=5,102, age 40~60 years). This study indicates that each locus associated with BMI has very weak genetic effect.

Association of a c.1084A>G (p.Thr362Ala)Variant in the DCTN4 Gene with Wilson Disease

PURPOSE: Wilson disease is an autosomal recessive disorder which causes excessive copper accumulation in the hepatic region. So far, ATP7B gene is the only disease-causing gene of Wilson disease known to date. However, ATP7B mutations have not been found in ~15% of the patients. This study was performed to identify any causative gene in Wilson disease patients without an ATP7B mutation in either allele. MATERIALS AND METHODS: The sequence of the coding regions and exon-intron boundaries of the five ATP7B-interacting genes, ATOX1, COMMD1, GLRX, DCTN4, and ZBTB16, were analyzed in the 12 patients with Wilson disease. RESULTS: Three nonsynonymous variants including c.1084A>G (p.Thr362Ala) in the exon 12 of the DCTN4 gene were identified in the patients examined. Among these, only p.Thr362Ala was predicted as possibly damaging protein function by in silico analysis. Examination of allele frequency of c.1084A>G (p.Thr362Ala) variant in the 176 patients with Wilson disease and in the 414 normal subjects revealed that the variant was more prevalent in the Wilson disease patients (odds ratio [OR]=3.14, 95% confidence interval=1.36-7.22, P=0.0094). CONCLUSION: Our result suggests that c.1084A>G (p.Thr362Ala) in the ATP7B-interacting DCTN4 gene may be associated with the pathogenesis of Wilson disease.

Effect of Botulinum Toxin A on Capsule Formation in Submuscular Breast Implant Insertion: Rabbit Experimental Model

We examined the effects of botulinum toxin after submuscular implant insertion, observing the degree of capsule formation after restricting movement of muscle. 12 female Newzeland white rabbits weighing 2.5~3.0 kg were used in our study. A skin incision 5cm in length was made to above the Latissimus Dorsi muscle followed by a 4cm incision on the muscle. An implant was inserted under the muscle. Botulinum toxin was injected at the right side of the 12 rabbit Latissimus Dorsi muscles (experimental group). Then rabbits were dived in two group, 6 rabbits each. Saline was injected at the left side of the 6 rabbit Latissimus Dorsi muscles (control group) and nothing was given to the others (negative control group). The 12 rabbits were euthanized after 6 months and the capsule surrounding the implant was excised along with adjacent tissue. The thickness of the capsule was taken from 5 locations from the stained tissue and the results were statistically analyzed. There was no statistical significant difference among the groups. Restriction of muscular movement did not have a significant effect in the formation of capsule formation.

Orthotopic Cardiac Transplantation after Inter-caval Anastomosis in a Patient with Hypertrophic Cardiomyopathy and Persistent Left Superior Vena Cava / 대한흉부외과학회지

Cardiac transplantation in a patient with persistent left superior vena cava (SVC) necessitates unifocalization of the caval veins. Here we report a successful case of orthotopic heart transplantation in a patient with hypertrophic cardiomyopathy and persistent left SVC. Cardiac transplantation was done after the left SVC was anastomosed to the right SVC in an end to side fashion. The postoperative course was uneventful, and the patient is currently in an excellent clinical condition.

Identification and Characterization of Human Genes Targeted by Natural Selection

The human genome has evolved as a consequence of evolutionary forces, such as natural selection. In this study, we investigated natural selection on the human genes by comparing the numbers of nonsynonymous(NS) and synonymous (S) mutations in individual genes. We initially collected all coding SNP data of all human genes from the public dbSNP. Among the human genes, we selected 3 different selection groups of genes: positively selected genes (NS/S > or = 3), negatively selected genes (NS/S < or = 1/3) and neutral selection genes (0.9 < NS/S < 1.1). We characterized human genes targeted by natural selection. Negatively selected human genes were markedly associated with disease occurrence, but not positively selected genes. Interestingly, positively selected genes displayed an increase in potentially deleterious nonsynonymous SNPs with an increased frequency of tryptophan and tyrosine residues, suggesting a correlation with protective effects against human disease. Furthermore, our nonsynonymous/synonymous ratio data imply that specific human genes, such as ALMS1 and SPTBN5 genes, are differentially selected among distinct populations. We confirmed that inferences of natural selection using the NS/S ratio can be used extensively to identify functional genes selected during the evolutionary adaptation process.

A New Year's Greeting Message

No abstract available.

The Experience of the Treatment of Scapular and Midback Pain in a Patient with Gall Bladder Cancer: A case report / 대한마취과학회지

Gall bladder cancer is a very rare disease but most common in the biliary system. It has a poor prognosis because it is usually detected at an advanced stage due to no specific symptoms. So sometimes all that is needed is a proper pain control. It is important to remember that newly developed pain area can be a referred pain due to a cancer. We present a patient with a gall bladder cancer who suffered from right scapular and paravertebral pain. For his pain relief, we tried celiac plexus block and his pain was dramatically relieved.

The Efficacy and Safety of an Immunosuppressive Regimen Including the Use of Mycophenolate Mofetil and an Interleukin-2 Monoclonal Antibody in Heart Transplant Patients

BACKGROUND AND OBJECTIVES: An immunosuppressive regimen including the use of mycophenolate mofetil (MMF) and an interleukin-2 monoclonal antibody (IL2mAb) has shown promise to prevent acute rejection after heart transplantation. There has been a lack of report on the evaluation of the efficacy and safety of this regimen in patients receiving heart transplants in Korea. SUBJECTS AND METHODS: From November 1992 to December 2003, 111 consecutive patients who had received heart transplants in our institute were classified into two groups: patients who received the immunosuppressive regimen with MMF and an IL2mAb (group A, n=51) and patients who did not receive the regimen (group B, n=60). We compared the clinical outcomes of patients in each group including the survival rate and the occurrence of acute rejection and infection at 24 months post transplantation. RESULTS: Both drugs were tolearated in all patients except in 5 patients who complained of gastrointestinal side effects due to MMF. Despite a longer ischemic time (137.4+/-54.6 vs. 92.3+/-25.8 hours, p<0.05) and a lower serum level of cyclosporine (212.3+/-66.8 vs. 259.1+/-62.1 ng/mL, p<0.05), the rate of treatment for acute rejection was lower in group A than in group B (16% vs. 53%, p<0.05). In addition, the median time to the first treatment for acute rejection was almost twice as long for group A as for group B (91 vs. 43 days, p<0.05). The 2-year survival rate and the incidence of major infection requiring hospitalization in both groups were 94% vs. 88% and 26% vs. 21%, respectively, which were not statistically different. CONCLUSION: An immunosuppressive regimen including the use of MMF and an IL2mAb is efficacious and safe as a prophylaxis against acute rejection without the increased risk of major infection in patients who have received heart transplants in Korea.