Association between DIO2 Thr92Ala polymorphism and hypertension in patients with hypothyroidism: Korean Genome and Epidemiology Study

Background/Aims@#Recent evidence has identified the significance of type 2 iodothyronine deiodinase (DIO2) in various diseases. However, the role of DIO2 polymorphism in metabolic parameters in patients with hypothyroidism is not fully understood. @*Methods@#We assessed the polymorphism of the DIO2 gene and various clinical parameters in 118 patients who were diagnosed with hypothyroidism from the Ansan-Anseong cohort of the Korean Genome and Epidemiology Study. Furthermore, we systematically analyzed Genotype-Tissue Expression (GTEx) data. @*Results@#A total of 118 participants with hypothyroidism were recruited; 32 (27.1%) were homozygous for the Thr allele, 86 (73.9%) were homozygous for the Ala allele or heterozygous. Patients with hypothyroidism with DIO2 polymorphism without hypertension at baseline had higher incidence of hypertension compared to patients without DIO2 polymorphism. Analysis of the GTEx database revealed that elevation of DIO2 expression is associated with enhancement of genes involved in blood vessel regulation and angiogenesis. @*Conclusions@#Commonly inherited variation in the DIO2 gene is associated with high blood pressure and prevalence of hypertension in patients with hypothyroidism. Our results suggest that genetic variation in the hypothalamic-pituitary-thyroid pathway in influencing susceptibility to hypertension.

A Multicenter, Randomized, Controlled Trial for Assessing the Usefulness of Suppressing Thyroid Stimulating Hormone Target Levels after Thyroid Lobectomy in Low to Intermediate Risk Thyroid Cancer Patients (MASTER): A Study Protocol

Background@#Postoperative thyroid stimulating hormone (TSH) suppression therapy is recommended for patients with intermediate- and high-risk differentiated thyroid cancer to prevent the recurrence of thyroid cancer. With the recent increase in small thyroid cancer cases, the extent of resection during surgery has generally decreased. Therefore, questions have been raised about the efficacy and long-term side effects of TSH suppression therapy in patients who have undergone a lobectomy. @*Methods@#This is a multicenter, prospective, randomized, controlled clinical trial in which 2,986 patients with papillary thyroid cancer are randomized into a high-TSH group (intervention) and a low-TSH group (control) after having undergone a lobectomy. The principle of treatment includes a TSH-lowering regimen aimed at TSH levels between 0.3 and 1.99 μIU/mL in the low-TSH group. The high-TSH group targets TSH levels between 2.0 and 7.99 μIU/mL. The dose of levothyroxine will be adjusted at each visit to maintain the target TSH level. The primary outcome is recurrence-free survival, as assessed by neck ultrasound every 6 to 12 months. Secondary endpoints include disease-free survival, overall survival, success rate in reaching the TSH target range, the proportion of patients with major cardiovascular diseases or bone metabolic disease, the quality of life, and medical costs. The follow-up period is 5 years. @*Conclusion@#The results of this trial will contribute to establishing the optimal indication for TSH suppression therapy in low-risk papillary thyroid cancer patients by evaluating the benefit and harm of lowering TSH levels in terms of recurrence, metabolic complications, costs, and quality of life.

Hypoxia Regulates the Extracellular Matrix via Mitogen-Activated Protein Kinases Pathway in Cells Retrieved from the Human Intervertebral Disc

Purpose@#The present study aimed to identify the physiological characteristics of cells by investigating the change in gene expression and protein levels during extracellular matrix (ECM) synthesis in the intervertebral disc (IVD) under hypoxic conditions. @*Materials and Methods@#To test the effect of oxygen on cell growth and ECM synthesis of chondrocyte-like cells, the cells from IVD were separated and cultured in two hypoxia-mimicking systems: chemical hypoxic conditions using deferoxamine (DFO), and physiological hypoxic conditions using a hypoxic chamber for 7 days. Chondrocyte like cells cultured without DFO and under the normal oxygen concentration (21% O2 and 5% CO2, 37°C) served as the controls. @*Results@#Chondrocyte-like cells cultured in the presence of 6% oxygen demonstrated a 100% increase in cellular proliferation compared to the control. The cells treated with chemical hypoxic conditions demonstrated a dose-dependent increase in the mRNA expression of glucose transporter-1, GAPDH, aggrecan, and type II collagen on Day 1. When treated with 100 μM DFO, the cells showed a 50% increase in the levels of proteoglycan protein on Day 7. The cells treated with chemical hypoxic condition demonstrated increase in sulfated glycosaminoglycan (GAG) protein levels on Day 7. Moreover, the cells cultured in the presence of 6% oxygen showed a 120% increase in sulfated GAG levels on Day 7. @*Conclusion@#The oxygen concentration had an important role in the viability, proliferation, and maturation of chondrocyte-like cells in IVD. In addition, chondrocyte-like cells are sensitive to the concentration of oxygen.

A Multicenter, Randomized, Controlled Trial for Assessing the Usefulness of Suppressing Thyroid Stimulating Hormone Target Levels after Thyroid Lobectomy in Low to Intermediate Risk Thyroid Cancer Patients (MASTER): A Study Protocol

Background@#Postoperative thyroid stimulating hormone (TSH) suppression therapy is recommended for patients with intermediate- and high-risk differentiated thyroid cancer to prevent the recurrence of thyroid cancer. With the recent increase in small thyroid cancer cases, the extent of resection during surgery has generally decreased. Therefore, questions have been raised about the efficacy and long-term side effects of TSH suppression therapy in patients who have undergone a lobectomy. @*Methods@#This is a multicenter, prospective, randomized, controlled clinical trial in which 2,986 patients with papillary thyroid cancer are randomized into a high-TSH group (intervention) and a low-TSH group (control) after having undergone a lobectomy. The principle of treatment includes a TSH-lowering regimen aimed at TSH levels between 0.3 and 1.99 μIU/mL in the low-TSH group. The high-TSH group targets TSH levels between 2.0 and 7.99 μIU/mL. The dose of levothyroxine will be adjusted at each visit to maintain the target TSH level. The primary outcome is recurrence-free survival, as assessed by neck ultrasound every 6 to 12 months. Secondary endpoints include disease-free survival, overall survival, success rate in reaching the TSH target range, the proportion of patients with major cardiovascular diseases or bone metabolic disease, the quality of life, and medical costs. The follow-up period is 5 years. @*Conclusion@#The results of this trial will contribute to establishing the optimal indication for TSH suppression therapy in low-risk papillary thyroid cancer patients by evaluating the benefit and harm of lowering TSH levels in terms of recurrence, metabolic complications, costs, and quality of life.

Hypoxia Regulates the Extracellular Matrix via Mitogen-Activated Protein Kinases Pathway in Cells Retrieved from the Human Intervertebral Disc

Purpose@#The present study aimed to identify the physiological characteristics of cells by investigating the change in gene expression and protein levels during extracellular matrix (ECM) synthesis in the intervertebral disc (IVD) under hypoxic conditions. @*Materials and Methods@#To test the effect of oxygen on cell growth and ECM synthesis of chondrocyte-like cells, the cells from IVD were separated and cultured in two hypoxia-mimicking systems: chemical hypoxic conditions using deferoxamine (DFO), and physiological hypoxic conditions using a hypoxic chamber for 7 days. Chondrocyte like cells cultured without DFO and under the normal oxygen concentration (21% O2 and 5% CO2, 37°C) served as the controls. @*Results@#Chondrocyte-like cells cultured in the presence of 6% oxygen demonstrated a 100% increase in cellular proliferation compared to the control. The cells treated with chemical hypoxic conditions demonstrated a dose-dependent increase in the mRNA expression of glucose transporter-1, GAPDH, aggrecan, and type II collagen on Day 1. When treated with 100 μM DFO, the cells showed a 50% increase in the levels of proteoglycan protein on Day 7. The cells treated with chemical hypoxic condition demonstrated increase in sulfated glycosaminoglycan (GAG) protein levels on Day 7. Moreover, the cells cultured in the presence of 6% oxygen showed a 120% increase in sulfated GAG levels on Day 7. @*Conclusion@#The oxygen concentration had an important role in the viability, proliferation, and maturation of chondrocyte-like cells in IVD. In addition, chondrocyte-like cells are sensitive to the concentration of oxygen.

Follistatin Mitigates Myofibroblast Differentiation and Collagen Synthesis of Fibroblasts from Scar Tissue around Injured Flexor Tendons

Relaxin Modulates the Expression of MMPs and TIMPs in Fibroblasts of Patients with Carpal Tunnel Syndrome

PURPOSE: The aim of this study was to investigate the anti-fibrotic effect of relaxin in subsynovial fibroblasts activated by transforming growth factor beta (TGF-β). MATERIALS AND METHODS: To test the anti-fibrotic effect of an adenovirus-relaxin construct (Ad-RLN) on subsynovial fibroblasts in vitro, cells from subsynovial connective tissue of patients with carpal tunnel syndrome were activated with TGF-β1 and exposed to Ad-RLN (as a therapeutic gene) or adenovirus-lacZ construct (as a marker gene) for four hours. Subsynovial fibroblast cultures without adenoviral exposure served as controls. RESULTS: We observed induction of gene expressions of collagen I, III and IV, as well as the abatement of alpha-smooth muscle actin (a-SMA) synthesis, Smad2 phosphorylation, and fibronectin at the protein level, in comparison to controls. In addition, protein expressions of matrix metalloproteinase (MMP) I was significantly induced, whereas the protein expressions of tissue inhibitor of metalloproteinases (TIMP) I and IV were reduced due to relaxin expression. CONCLUSION: RLN prevents excessive synthesis of extracellular matrix by reducing the expressions of its components, such as fibronectin, a-SMA, and phosphorylated Smad2, by increasing the expression of MMPs; and by decreasing the expression of TIMPs.

Efficacy and Safety of Different Aceclofenac Treatments for Chronic Lower Back Pain: Prospective, Randomized, Single Center, Open-Label Clinical Trials

PURPOSE: Nonsteroidal anti-inflammatory drugs are a mainstay for medical treatment of chronic lower back pain (CLBP). Increased dose intervals for medication have been associated with increased patient adherence to prescriptions. The purpose of this clinical trial was to compare the efficacy and safety of a once daily dose of aceclofenac controlled release (CR) and a twice daily dose of aceclofenac for CLBP management. MATERIALS AND METHODS: A prospective, randomized, single center, open-label clinical trial was performed to compare the efficacy and safety of aceclofenac CR (200 mg once daily) to aceclofenac dose (100 mg twice daily). Fifty patients in each group were enrolled for the study. The primary end point was Visual Analogue Scale (VAS) change at baseline to that at 2 weeks after medication and safety profiles. Also, change in quality of life measured by EuroQoL 5D (EQ-5D) and Oswestry Disability Index (ODI) functional score for the lumbar spine were also assessed. RESULTS: Within groups at pre- and post-treatment, there were significant VAS reductions for aceclofenac CR and aceclofenac (p=0.028). EQ-5D increased significantly in both groups (p=0.037). ODI scores decreased significantly in both groups (p=0.012). However, there were no significant differences between aceclofenac CR and aceclofenac at pre- and post-treatment. Patients with aceclofenac CR showed significant increases in heartburn and indigestion and adverse gastrointestinal effects, compared to aceclofenac. CONCLUSION: In patients with CLBP, aceclofenac CR and aceclofenac demonstrated significant symptomatic pain relief, improvement in quality of life and functional scores. Aceclofenac CR slightly increased gastrointestinal adverse effects, such as heartburn and indigestion.

Pamidronate Down-regulates Tumor Necrosis Factor-alpha Induced Matrix Metalloproteinases Expression in Human Intervertebral Disc Cells

BACKGROUND: N-containing bisphosphonates (BPs), such as pamidronate and risedronate, can inhibit osteoclastic function and reduce osteoclast number by inducing apoptotic cell death in osteoclasts. The aim of this study is to demonstrate the effect of pamidronate, second generation nitrogen-containing BPs and to elucidate matrix metallo-proteinases (MMPs) mRNA expression under serum starvation and/or tumor necrosis factor alpha (TNF-α) stimulation on metabolism of intervertebral disc (IVD) cells in vitro. METHODS: Firstly, to test the effect of pamidronate on IVD cells in vitro, various concentrations (10⁻¹², 10⁻¹⁰, 10⁻⁸, and 10⁻⁶ M) of pamidronate were administered to IVD cells. Then DNA and proteoglycan synthesis were measured and messenger RNA (mRNA) expressions of type I collagen, type II collagen, and aggrecan were analyzed. Secondly, to elucidate the expression of MMPs mRNA in human IVD cells under the lower serum status, IVD cells were cultivated in full serum or 1% serum. Thirdly, to elucidate the expression of MMPs mRNA in IVD cells under the stimulation of 1% serum and TNF-α (10 ng/mL) In this study, IVD cells were cultivated in three dimensional alginate bead. RESULTS: Under the lower serum culture, IVD cells in alginate beads showed upregulation of MMP 2, 3, 9, 13 mRNA. The cells in lower serum and TNF-α also demonstrated upregulation of MMP-2, 3, 9, and 13 mRNA. The cells with various doses of pamidronate and lower serum and TNF-α were reveled partial down-regulation of MMPs. CONCLUSIONS: Pamidronate, N-containing second generation BPs, was safe in metabolism of IVD in vitro maintaining chondrogenic phenotype and matrix synthesis, and down-regulated TNF-α induced MMPs expression.

Mechanism of Ligamentum Flavum Hypertrophy / 대한정형외과연구학회지

Ligamentum flavum (LF) is yellowish ligament tissue connecting the lamina of adjacent vertebra. Degenerative changes in the spine cause the hypertrophy of LF and facet joint and disc bulging and herniation. These changes results in a narrowing of the spinal canal. Neural decompression surgery by removing the hypertrophied lamina, LF and disc pathologies has been considered as successful treatment method in lumbar spinal stenosis. This surgery has showed relatively satisfactory clinical results and has increased life-expectancy in elderly patients. However, issues about post spinal surgery syndrome and re-stenosis after the surgery also have been reported. Because LF is one of the main mechanisms of spinal stenosis, accurate understanding about pathologic mechanism on the LF hypertrophy may suggest alternative treatment methods such as medical treatment or less invasive treatment than surgical decompression can be considered. Hypertrophy of the ligamentum flavum is generated from increase of collagen synthesis, fibroblast proliferation, and fibrosis caused by 1) the expression of growth factors (TGF-beta1 etc.) stimulated by the repeated mechanical tension, 2) inflammatory cytokines from spinal facet joint structure and LF 3) delayed cell death, and 4) inflammatory cytokine from hypertrophied and degenerated LF itself. After the middle ages, gradual and partial inhibition of LF hypertrophy can be expected by administration NSAIDs or selective cyclo-oxygenase-2 inhibitors because these drugs may cause reduction of the increased cytokines. Also, relaxin can be another new treatment material for spinal stenosis by the mechanism of melting hypertrophied LF and reducing synthesis of collagen.

Sedative-Hypnotic and Receptor Binding Studies of Fermented Marine Organisms

This study was performed to investigate the sedative-hypnotic activity of gamma-aminobutyric acid (GABA)-enriched fermented marine organisms (FMO), including sea tangle (FST) and oyster (FO) by Lactobacillus brevis BJ20 (L. brevis BJ20). FST and FO were tested for their binding activity of the GABA(A)-benzodiazepine and 5-HT(2C) receptors, which are well-known molecular targets for sleep aids. We also measured the sleep latency and sleep duration during pentobarbital-induced sleep in mice after oral administration of FST and FO. In GABA(A) and 5-HT(2C) receptor binding assays, FST displayed an effective concentration-dependent binding affinity to GABA(A) receptor, similar to the binding affinity to 5-HT(2C) receptor. FO exhibited higher affinity to 5-HT(2C) receptor, compared with the GABA(A) receptor. The oral administration of FST and FO produced a dose-dependent decrease in sleep latency and increase in sleep duration in pentobarbital-induced hypnosis. The data demonstrate that FST and FO possess sedative-hypnotic activity possibly by modulating GABA(A) and 5-HT(2C) receptors. We propose that FST and FO might be effective agents for treatment of insomnia.

Anesthetic experiences of myxoma removal surgery in two patients with Carney complex: A report of two cases / 대한마취과학회지

Carney complex is an autosomal dominant disorder that occurs due to a mutation in PRKAR1A, which encodes protein kinase A. The clinical features are multiple endocrine gland neoplasms, skin tumors, pigmented skin lesions, myxomas, and schwannomas. In Carney complex, the cardiac myxoma is a common co-morbidity. It occurs in multiples, during young age, regardless of gender and cardiac chamber and is known to recur frequently. Therefore there are high risks of adhesion and massive bleeding due to repeated surgeries. Such surgical risks account for over 50% of disease-specific mortality of Carney complex patients. Here, we present anesthetic experiences of myxoma removal surgery in two patients with Carney complex.

Spinal cord stimulation in complex regional pain syndrome with severe epidural adhesions: A case report

Complex regional pain syndrome (CRPS) is often a devastating neuropathic condition that has been recognized with increasing frequency in the lower extremities. Patients with CRPS may worsen to such a degree that the individual may never return to a satisfactory and productive life. Spinal cord stimulation (SCS) is one of the most minimally invasive and effective treatments for intractable pain such as CRPS. The most important factor for successful stimulation of the spinal cord is proper lead position that stimulation and pain regions match completely. A 39-year-old male patient, suffering from CRPS type II in his lower extremity, visited our pain clinic. It was a difficult case that the electrode for spinal cord stimulation was positioned at the proper site due to the adhesion of the epidural space by frequent epidural blocks and procedures. We report the efficacy of a steerable epidural catheter for adhesiolysis on the setting the electrode to the proper site in the epidural space.

Probable Role of Beta 2-Adrenergic Receptor Gene Haplotype in Toluene Diisocyanate-Induced Asthma

PURPOSE: A genetic polymorphism of the beta 2-adrenergic receptor is a major factor associated with the asthmatic phenotype. The association of this polymorphism with toluene diisocyanate (TDI)-induced asthma has not been investigated. We examined 103 TDI-induced asthma patients (TDI-OA), 60 asymptomatic exposed controls (AEC), and 263 unexposed healthy controls (NC) in order to identify beta 2-adrenergic receptor gene (ADRB2) polymorphisms and the possible association with TDI-induced asthma. METHODS: Single nucleotide polymorphisms (SNPs) of ADRB2 were genotyped by direct sequencing. Serum-specific IgE and IgG levels were measured using an enzyme-linked immunosorbent assay. Phenotypes and clinical patient parameters were compared. RESULTS: SNPs were identified (-47 T>C, -20 T>C, Arg16Gly A>G, Gln27Glu C>G, Leu134Leu G>A, Arg175Arg C>A) during ADRB2 screening (from -231 to 793 bp). No significant differences in allelic and genotypic frequencies were noted for any of the six ADRB2 SNPs. The Arg16Gly A>G, Leu134Leu G>A, and Arg175Arg C>A SNPs and haplotype 1 [TTACGC] were significantly associated with specific IgE antibodies to the TDI-human serum albumin (HSA) conjugate in TDI-exposed subjects (P<0.05). Exposed workers with the ADRB2 ht1/ht1 homozygote had a significantly higher TDI-HSA conjugate-specific IgE sensitization rate than did those with the null ht1 haplotype (odds ratio, 15.40; 95% confidence interval, 1.81-131.06). CONCLUSIONS: ADRB2 polymorphisms may affect IgE-specific sensitization to TDI-HSA conjugate in TDI-exposed workers.

Notice of Retraction: IgE sensitization to the potato allergen in adult allergy patients and identification of IgE binding components: comparison between the wild and genetically modified potato / 대한내과학회지

No abstract available.

A Case of Aplastic Anemia in Pregnancy Refractory to Platelet Transfusion / 대한산부인과학회지

Aplastic anemia is a rare complication of pregnancy that is associated with significant maternal and fetal morbidity and mortality. The relationship between aplastic anemia and pregnancy is not yet clear. Aplastic anemia in pregnancy is difficult to manage because the risk of bleeding and infection is high, especially in refractory to platelet transfusion. There is no therapeutic guide-line and prognosis for aplastic anemia in pregnancy refractory to platelet transfusion. We recently experienced one case of aplastic anemia in pregnancy refractory to platelet transfusion without no peripartum complication. So we report this case with brief review of the literature.

Chronological Pattern of the Frequencies and Indications for Cesarean Section: Analysis of 6,051 Cesarean Section Cases at Busan Paik Hospital for 24 Years, 1980-2003 / 대한산부인과학회지

OBJECTIVE: To evaluate chronological pattern of the frequencies and indications for cesarean section performed at one university hospital for 24 years. METHODS: This study was carried out retrospectively based on the clinical records of 6,051 patients who had cesarean sections among total 28,836 delivery cases at our hospital from January, 1980 to December, 2003 to show the frequencies and indications for cesarean section. RESULTS: The relative frequencies of cesarean section among total delivery cases for 24 years was 21.0%. The frequencies was 16.6% in the 1980s, 21.9% in the 1990s and 34.3% in the 2000s, which shows a tendency to marked increment. The common indications of cesarean section for 24 years was previous cesarean section (40.9%) followed by abnormal presentation (16.3%), dystocia (12.2%), fetal distress (7.9%), placenta previa (6.8%). Repeat cesarean section showed increasing frequencies from 1980 to 1992 and dropped again from 2002. Dystocia and abnormal presentation showed decreasing frequencies, but multiple pregnancy, placenta previa and other indications showed increasing frequencies, especially in late 1990s and 2000s. CONCLUSION: The frequencies for cesarean section was increasing, especially from 1990s. There are many changes in indications for cesarean section. Recent changes was decreasing frequencies for repeat cesarean section, increasing for multiple pregnancy, placenta previa and other indications. This might be related to low birth rate and high elderly mother's proportion.

A Case of Conservative Management of Ectopic Pregnancy Embedded in the Myometrium of Previous Cesarean Section Scar / 대한주산의학회잡지

Intramural pregnancy, implanted in the previous cesarean section scar, is one of the rare and dangerous forms of ectopic pregnancies, because a delay in either diagnosis or treatment can lead to uterine rupture, hysterectomy, or significant maternal morbidity, due to severe hemorrhaging. With the development of transvaginal ultrasound and MRI, early diagnosis and conservative treatment of intramural pregnancy is possible. For young patients who wish to maintain their fertility, an earlier diagnosis and more conservative treatment are desirable. We experienced a case of intramural pregnancy developed in the previous cesarean section scar and successfully treated it with conservative management. So we report this case with a brief review of literature.

A Case of Arthrogryposis Multiplex Congenita Diagnosed by Prenatal Ultrasonography / 대한산부인과학회지

Arthrogryposis multiplex congenita is congenital disorder that characterized by multiple joint contractures. Although there are characteristic morphologic features, most of cases are diagnosed at birth and cases diagnosed by prenatal ultrasonography are rare. We describe a case of fetal arthrogryposis multiplex congenita seen prenatally with sonographic feature of multiple joint contractures including clubhands, clubfeet, and absent fetal movements in late second trimester. This report is the first case of arthrogryposis multiplex congenita that diagnosed by prenatal ultrasonography in Korean literature.

IgE sensitization to the potato allergen in adult allergy patients and identification of IgE binding components: comparison between the wild and genetically modified potato / 대한내과학회지

BACKGROUND: The aim of this study was to evaluate the prevalence of IgE sensitization and allergic risk of genetically modified (GM) potato compared with wild one in adult patients with various allergic diseases. METHODS: One thousand eight hundred eighty eight allergy patients visited Ajou University hospital and 38 healthy controls were enrolled. Skin prick tests were performed with wild and GM extracts. Phosphinothricin N-acetyltransferase (PAT) and neomycin phosphotransferase (NPT) gene was inserted in GM potato. Serum specific IgE level to the two potato extracts was measured by ELISA and their binding specificities were confirmed by ELISA inhibition test. IgE binding components in both wild and GM potato extracts were identified by SDS-PAGE and IgE-immunoblot. RESULTS: One hundred eight patients (5.7%) showed positive responses (A/H >or= 2+) on skin prick test to both wild and GM potatoes. Serum specific IgE was detectable in 50~88% among the positive reactors on skin prick test. ELISA inhibition tests showed similar inhibition pattern between wild and GM. Fourteen IgE binding components within wild potato and nine IgE binding components within GM potato with similar binding patterns, of which three major allergens in wild (26, 34, 45 kDa) and one (45 kDa) in GM one were noted.. CONCLUSIONS: The sensitization rates to wild and GM potato extracts were 5.7% respectively, in adult allergy patients and one common major allergen (45 kDa) was identified. It is speculated that genetic manipulation of the potato did not increase allergenic risk.