Identification and In Vivo Functional Characterization of Novel Compound Heterozygous BMP1 Variants in Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal‐dominant inheritance, but many autosomal‐recessive genes have been reported. We applied whole‐exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypofunctional nature of the two variants was demonstrated in a zebrafish assay.     

Intrahepatic bile duct adenoma in a patient with chronic hepatitis B accompanied by elevation of alpha-fetoprotein

A 51-year-old male patient with chronic hepatitis B was referred to our hospital due to a 1-cm liver nodule on ultrasonography. Alpha-fetoprotein (AFP) was slightly elevated. The nodule showed prolonged enhancement on dynamic liver magnetic resonance imaging and appeared as a hyperintensity on both diffusion-weighted and T2-weighted imaging. The nodule was followed up because it was small and typical findings of hepatocellular carcinoma (HCC) were not observed in the dynamic imaging investigations. However, liver contrast-enhanced ultrasonography performed 1 month later showed enhancement during the arterial phase and definite washout during the delayed phase. Also, AFP had increased to over 200 ng/mL even though AST and ALT were decreased after administering an antiviral agent. He was presumptively diagnosed as HCC and underwent liver segmentectomy. Microscopy findings of the specimen indicated bile duct adenoma. After resection, the follow-up AFP had decreased to within the normal range. This patient represents a case of bile duct adenoma with AFP elevation mimicking HCC on contrast-enhanced ultrasonography.     

Dexmedetomidine-Induced Contraction in the Isolated Endothelium-Denuded Rat Aorta Involves PKC-δ-mediated JNK Phosphorylation

Vasoconstriction mediated by the highly selective alpha-2 adrenoceptor agonist dexmedetomidine leads to transiently increased blood pressure and severe hypertension. The dexmedetomidine-induced contraction involves the protein kinase C (PKC)-mediated pathway. However, the main PKC isoform involved in the dexmedetomidine-induced contraction remains unknown. The goal of this in vitro study was to examine the specific PKC isoform that contributes to the dexmedetomidine-induced contraction in the isolated rat aorta. The endothelium-denuded rat aorta was suspended for isometric tension recording. Dexmedetomidine dose-response curves were generated in the presence or absence of the following inhibitors: the pan-PKC inhibitor, chelerythrine; the PKC-α and -β inhibitor, Go6976; the PKC-α inhibitor, safingol; the PKC-β inhibitor, ruboxistaurin; the PKC-δ inhibitor, rottlerin; the c-Jun NH₂-terminal kinase (JNK) inhibitor, SP600125; and the myosin light chain kinase inhibitor, ML-7 hydrochloride. Western blot analysis was used to examine the effect of rottlerin on dexmedetomidine-induced PKC-δ expression and JNK phosphorylation in rat aortic vascular smooth muscle cells (VSMCs) and to investigate the effect of dexmedetomidine on PKC-δ expression in VSMCs transfected with PKC-δ small interfering RNA (siRNA) or control siRNA. Chelerythrine as well as SP600125 and ML-7 hydrochloride attenuated the dexmedetomidine-induced contraction. Go6976, safingol, and ruboxistaurin had no effect on the dexmedetomidine-induced contraction, whereas rottlerin inhibited the dexmedetomidine-induced contraction. Dexmedetomidine induced PKC-δ expression, whereas rottlerin and PKC-δ siRNA transfection inhibited dexmedetomidine-induced PKC-δ expression. Dexmedetomidine also induced JNK phosphorylation, which was inhibited by rottlerin. Taken together, these results suggest that the dexmedetomidine-induced contraction involves PKC-δ-dependent JNK phosphorylation in the isolated rat aorta.     

Steep Decrease of Gender Difference in DSM-IV Alcohol Use Disorder: A Comparison of Two Nation-wide Surveys Conducted 10 Years Apart in Korea

While decreasing trend in gender differences in alcohol use disorders was reported in Western countries, the change in Asian countries is unknown. This study aims to explore the shifts in gender difference in alcohol abuse (AA) and dependence (AD) in Korea. We compared the data from two nation-wide community surveys to evaluate gender differences in lifetime AA and AD by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Face-to-face interviews using the Composite International Diagnostic Interview (CIDI) were applied to all subjects in 2001 (n=6,220) and 2011 (n=6,022). Male-to-female ratio of odds was decreased from 6.41 (95% CI, 4.81-8.54) to 4.37 (95% CI, 3.35-5.71) for AA and from 3.75 (95% CI, 2.96-4.75) to 2.40 (95% CI, 1.80-3.19) for AD. Among those aged 18-29, gender gap even became statistically insignificant for AA (OR, 1.59; 95% CI, 0.97-2.63) and AD (OR, 1.18; 95% CI, 0.80-2.41) in 2011. Men generally showed decreased odds for AD (0.55; 95% CI, 0.45-0.67) and women aged 30-39 showed increased odds for AA (2.13; 95% CI 1.18-3.84) in 2011 compared to 2001. Decreased AD in men and increased AA in women seem to contribute to the decrease of gender gap. Increased risk for AA in young women suggests needs for interventions.     

Congenital cytomegalovirus infection in Korean population with very high prevalence of maternal immunity.

In order to asses congenital cytomegalovirus (CMV) infection in Korea, five hundred and seventy five pregnant women (mean age 29.5 +/- 3.8 yrs., mean gestational age at test 37.5 +/- 6.7 weeks) visiting the prenatal clinic at Severance Hospital, Seoul, Korea were studied. CMV IgG antibody was present in 96% (552/575) and IgM antibody was present in 0.7% (4/575) of the pregnant women by the third trimester. Four of 445 cord sera were positive for CMV IgM antibody (0.9%). Urine samples from 514 newborns were tested for the evaluation of congenital CMV infection. Six (1.2%) of 514 newborns excreted CMV in their urine. All the congenitally infected infants had subclinical involvement at birth and during the 12 months of the follow-up period. These results indicate that Korean pregnant women were highly immunized against CMV by the third trimester. Furthermore this study suggests that the rate of congenital CMV infection is relatively as high as rates previously reported from other countries, although there is a very high prevalence of maternal immunity. The incidence of maternal primary infection during pregnancy seems to be rare and therefore most congenital infections in Korea might be following by maternal reactivation or reinfection.     

Impact of a cervical dysplasia and its treatment on quality of life and sexual function

Purpose

In this case–control study, the impact on quality of life and sexual function in women with cervical dysplasia and conization will be evaluated, in order to address coping with such a premalignant lesion and to improve strategies for salutogenesis.

Methods

This multicenter case–control study evaluates women at special dysplasia outpatient clinic (T1) as well as 3 (T2) and 6 (T3) months after the diagnosis of a dysplasia. The women were subgrouped upon dysplasia only (S2) or dysplasia with conization (S1). Sexual function as well as cervix-related and general quality of life was assessed using validated instruments (FSFI-d, EORTC-QLQ-CX24, SF-36).

Results

Women with dysplasia had a lower sexual functioning than controls (FSFI: S1: 23.8?±?9.7 (p?<?0.003); S2: 25.3?±?7.5 (p?<?0.03); K: 29.1?±?4.5) as well as a lower physical component score (SF-36: S1: 51.3?±?8.6 (p?<?0.02); S2: 51.7?±?7.8 (p?<?0.05); K: 54.2?±?6.6) and had a significantly reduced body image (EORTC-QLQ-CX24: S1: 75.7 (p?<?0.001); S2: 76.5 (p?<?0.001), K:89.2). Sexual functioning was not affected by conization in the observational period over 6 months; however, sexual worry was impacted. Over temporal progression women who underwent conization worried more. Regression analysis revealed a cervical dysplasia to impact sexual function.

Conclusion

Data suggest that women with the diagnosis of a cervical dysplasia are impaired in their sexual function as well as general and cervix-related quality of life, mostly independent of conization or further observation. To improve salutogenesis in the long run, the communication on dysplasia and its treatment strategy at the beginning, as well as part of aftercare, or psychosomatic intervention, might be treatment options for women at risk.

     

Value and feasibility of LLETZ procedures for pregnant women with suspected high-grade squamous intraepithelial lesions and microinvasive cervical cancer

ObjectiveTo evaluate the efficacy, safety, and feasibility of large loop excision of the transformation zone (LLETZ) procedures during pregnancy.MethodsA retrospective study included 27 patients who underwent LLETZ during pregnancy for suspected high-grade squamous intraepithelial lesions (HSIL) where microinvasion could not be excluded. The study investigated intraoperative and postoperative complications, and compared preoperative and postoperative results. Questionnaires were used to obtain information about peripartum and postpartum data.ResultsThree (11.1%) women had invasive or microinvasive cancer, 22 (81.5%) had cervical intraepithelial neoplasia (CIN) 3, and 1 (3.7%) had CIN 2. Twenty-four were positive for high-risk human papillomavirus. All cervical cancers were classified as HSIL or CIN 3 before LLETZ. There were positive resection margins in 15 (55.6%) cases. No intraoperative complications occurred. One (3.7%) patient had a postoperative missed abortion. Major complications such as premature labor or cervical incompetence without influence on delivery occurred after LLETZ in 4 (14.8%) patients.ConclusionLLETZ during pregnancy can be performed if invasive cancer cannot be excluded by colposcopy, cytology, or biopsy. The procedure has a diagnostic intention but can also be a curative therapy in pregnancy, with low intraoperative, postoperative, and peripartum complication rates.     

Use of vaccine in the era of antimicrobial resistance: need of effective pneumococcal vaccines

Streptococcus pneumoniae is an important pathogen causing invasive infections particularly in children. Penicillin-nonsusceptible pneumococci are very prevalent in Korea and a difficult problem in antimicrobial treatment. Immunization with effective vaccines including viral and bacterial vaccines has proven to be the most effective and reliable method to prevent the target disease. Universal immunization to infants with Haemophilus influenzae type b conjugate vaccine has dramatically proven to be very effective in reducing invasive Hib diseases and also the carriage rate. The 23-valent pneumococcal polysaccharide vaccine is effective in preventing invasive diseases in young adults and covers most of the penicillin-nonsusceptible types. It has not proven very effective in the prevention of otitis media, and is unable to elicit adequate antibody response in children younger than 2 years of age. Recently a new polysaccharide-protein conjugate vaccine was developed which can elicit antibody response in children younger than 2 years of age. However, the vaccine is only 8-valent at the moment. Studies are required to determine the possible idiotypic modulation and nonproductive immune response when polysaccharide vaccine is administered to infants. Part of the problem of antimicrobial-resistant pneumococcal infection may be solved in the future with the use of improved vaccine. Preventing pneumococcal infections with safe and effective vaccines will not only reduce the development of antibiotic resistance, but could also be the most cost-effective method to control pneumococcal disease.     

Sputum TWEAK expression correlates with severity and degree of control in non‐eosinophilic childhood asthma

Background

Tumor necrosis factor‐like weak inducer of apoptosis (TWEAK) is known to play a role in the pathogenesis of various inflammatory diseases. However, no study has been performed on childhood asthma.

Methods

Ninety‐five children with asthma and 78 controls aged 5‐18 years were included. Sputum induction, pulmonary function test (PFT), and methacholine challenge test were performed. The subjects were divided into the eosinophilic airway (EA) and non‐EA (NEA) groups based on sputum analysis and into the high and low TWEAK groups according to the TWEAK cutoff level (263.0 pg/mL). TWEAK in induced sputum supernatant was measured through enzyme‐linked immunosorbent assay.

Results

Children with asthma had higher TWEAK levels than healthy controls (493.0 [157.1‐904.3] vs 118.2 (67.5‐345.5) pg/mL, P < .001). Sputum TWEAK levels were significantly correlated with PFT parameters reflecting airway obstruction. This association was particularly prominent in subjects with NEA inflammation. Significant differences in FEF_25‐75 (maximum mid‐expiratory flow, % predicted; P = .017), AX (reactance area; P < .001), R5‐R20 (difference between resistance at 5 and 20 Hz; P = .025), and X5 (reactance at 5 Hz, % predicted; P < .001) were noted between the high and low TWEAK groups within the NEA group. Sputum TWEAK level also showed significant positive correlations with asthma severity (r = .358, P = .001) and control status (r = .470, P < .001), distinctively in subjects with NEA inflammation.

Conclusions

Airway TWEAK may play a role in small airway inflammation especially in children with non‐eosinophilic asthma.