Enzymatic removal of O6-ethylguanine from mitochondrial DNA in rat tissues exposed to N-ethyl-N-nitrosourea in vivo

DNA repair is essential for maintaining the integrity of the genetic material, and a number of DNA repair mechanisms have been fairly well characterized for the nuclear DNA of eukaryotic cells as well as prokaryotes. However, little is known about DNA repair in mitochondria. Using highly sensitive immunoanalytical methods to detect specific DNA alkylation products, we found active removal of O6-ethyl-2'-deoxyguanosine (O6-EtdGuo) from rat liver mitochondrial DNA after pulse-exposure to N-ethyl-N-nitrosourea in vivo. In the kidney, O6-EtdGuo was removed from mitochondrial DNA with moderate efficiency, but nearly no removal was observed from the DNA of brain mitochondria. Among the rat tissues examined, the kinetics of O6-EtdGuo elimination from mitochondrial DNA was very similar to the kinetics of removal from nuclear DNA. O4-Ethyl-2'-deoxythymidine, another premutagenic DNA ethylation product, was stable in both mitochondrial and nuclear DNA of rat liver.     

A Prospective Study of Fatty Liver Index and Incident Hypertension: The KoGES-ARIRANG Study

Background

Although non-alcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, its influence on hypertension development is poorly understood. We investigated whether fatty liver disease, as assessed by the fatty liver index, could predict the development of hypertension independently of systemic insulin resistance, inflammatory status and adipokine levels.

Methods

Prospective cohort study of 1,521 adults (484 men and 1037 women) aged 40 to 70 years without baseline hypertension examined. An equation was used to calculate fatty liver index and classify patients as follows: fatty liver index <30, no non-alcoholic fatty liver disease; fatty liver index ≥60, non-alcoholic fatty liver disease; and 30≤ fatty liver index <60, intermediate fatty liver index.

Results

During an average of 2.6 years of follow-up, 153 subjects (10.06%) developed hypertension. Fatty liver index was positively associated with baseline blood pressure, homeostasis model assessment of insulin resistance, urinary albumin/creatinine excretion, and high sensitivity C-reactive protein. After adjustment for confounding factors, including markers of insulin resistance, systemic inflammation and adiponectin levels, the odds ratio [95% confidence interval] for the incident hypertension increased in a graded manner with fatty liver index (<30 vs. 30–59 vs. ≥60 = 1 vs. 1.83 [1.16~2.88] vs. 2.09 [1.08~4.055], respectively).

Conclusions

Non-alcoholic fatty liver disease assessed by fatty liver index was an independent risk factor for hypertension. Our findings suggest that fatty liver index, a simple surrogate indicator of fatty liver disease, might be useful for identifying subjects at high risk for incident hypertension in clinical practice.     

A Significant Increase in the Incidence of Central Precocious Puberty among Korean Girls from 2004 to 2010

Background

Few studies have explored the trends in central precocious puberty (CPP) in Asian populations. This study assessed the prevalence and annual incidence of CPP among Korean children.

Methods

Using data from the Korean Health Insurance Review Agency from 2004 to 2010, we reviewed the records of 21,351 children, including those registered with a diagnosis of CPP for the first time and those diagnosed with CPP who were treated with gonadotropin-releasing hormone analogs.

Results

The prevalence of CPP was 55.9 per 100,000 girls and 1.7 per 100,000 boys, respectively. The overall incidence of CPP was 15.3 per 100,000 girls, and 0.6 per 100,000 boys. The annual incidence of CPP in girls significantly increased from 3.3 to 50.4 per 100,000 girls; whereas in boys, it gradually increased from 0.3 to 1.2 per 100,000 boys. The annual incidence of CPP in girls consistently increased at all ages year by year, with greater increases at older ages (≥6 years of age), and smaller increases in girls aged < 6 years. In contrast, the annual incidence remained relatively constant in boys aged < 8 years, while a small increase was observed only in boys aged 8 years. The increase of annual incidence showed significant differences depending on age and gender (P <0.0001).

Conclusions

The annual incidence of CPP has substantially increased among Korean girls over the past 7 years. Continued monitoring of CPP trends among Korean children will be informative.     

Changes in the Pulmonary Function Test after Radioactive Iodine Treatment in Patients with Pulmonary Metastases of Differentiated Thyroid Cancer

ObjectivePulmonary function test (PFT) is a useful tool for an objective assessment of respiratory function. Impaired pulmonary function is critical for the survival and quality of life in patients with pulmonary metastases of solid cancers including thyroid cancer. This study aimed to evaluate clinical factors associated with severely impaired pulmonary function by serial assessment with PFT in patients with pulmonary metastasis of differentiated thyroid cancer (DTC) who received radioactive iodine treatment (RAIT).PatientsThis retrospective study enrolled 31 patients who underwent serial PFTs before and after RAIT for pulmonary metastasis of DTC. We evaluated the risk factors for severe impairment of pulmonary function.ResultsThe median age of the patients was 44.1 years and 18 of them were female patients. Severe impairment of pulmonary function was observed in five patients (16%) after a median of three RAITs (cumulative I-131 activity = 20.4 GBq). These patients were older and more frequently had mild impairment of baseline pulmonary function, respiratory symptoms, or progressive disease compared with patients with stable pulmonary function. Neither cumulative dose nor number of RAIT was associated with decreased pulmonary function. Coexisting pulmonary diseases, presence of respiratory symptoms, and metastatic disease progression were significantly associated with severe decrease in forced vital capacity during follow-up (p =.047, p =.011, and p =.021, respectively).ConclusionsPulmonary function was severely impaired during follow-up in some patients with pulmonary metastasis of DTC after a high-dose RAITs. Neither the number of RAIT nor the cumulative I-131 activity was associated with decreased pulmonary function. Serial PFT might be considered for some high-risk patients during follow-up.     

Utility of the Rio Score and Modified Rio Score in Korean Patients with Multiple Sclerosis

Objectives

Early identification of suboptimal responders to multiple sclerosis (MS) treatment is critical for optimizing therapeutic decisions. The Rio score (RS) and modified Rio score (MRS) were developed to discriminate the responses to interferon-beta (IFNB) treatment in MS patients. This study was performed to evaluate the utility of RS and MRS in daily clinical practice in Korea.

Methods

This was a real-world setting, multicenter, retrospective study of MS patients treated with IFNB from 10 hospitals in Korea. We investigated whether the RS and MRS at the early stage of IFNB therapy could predict treatment responses over 3 years. Suboptimal treatment responses at 3 years were defined as the presence of clinical relapse and/or EDSS progression and/or patients who had been treated with INFB for at least for 1 year and therapy was switched due to perceived treatment failure during the 2 years of follow-up.

Results

Seventy patients (50 females and 20 males) were enrolled; 92% (12/13) of patients with high RS and 86% (12/14) of patients with high MRS (score 2 or 3) were suboptimal responders, whereas 93% (53/57) of patients with low RS and 93% (52/56) patients with low MRS (score 0 or 1) showed optimal responses. New active lesions on MRI with clinical relapse in high RS and MRS were the most common combination in suboptimal responders.

Conclusions

We confirmed that RS and MRS at 6–15 months of IFNB therapy were useful for predicting poor responders over 3 years.     

Lipid-Overloaded Enlarged Adipocytes Provoke Insulin Resistance Independent of Inflammation

In obesity, adipocyte hypertrophy and proinflammatory responses are closely associated with the development of insulin resistance in adipose tissue. However, it is largely unknown whether adipocyte hypertrophy per se might be sufficient to provoke insulin resistance in obese adipose tissue. Here, we demonstrate that lipid-overloaded hypertrophic adipocytes are insulin resistant independent of adipocyte inflammation. Treatment with saturated or monounsaturated fatty acids resulted in adipocyte hypertrophy, but proinflammatory responses were observed only in adipocytes treated with saturated fatty acids. Regardless of adipocyte inflammation, hypertrophic adipocytes with large and unilocular lipid droplets exhibited impaired insulin-dependent glucose uptake, associated with defects in GLUT4 trafficking to the plasma membrane. Moreover, Toll-like receptor 4 mutant mice (C3H/HeJ) with high-fat-diet-induced obesity were not protected against insulin resistance, although they were resistant to adipose tissue inflammation. Together, our in vitro and in vivo data suggest that adipocyte hypertrophy alone may be crucial in causing insulin resistance in obesity.