Discovery of small molecule inhibitors against the NS3/4A serine protease of Hepatitis C virus genotype 3 via highthroughput virtual screening and in vitro evaluations.

The hepatitis C virus (HCV) consists of eight genotypes and 90 subtypes, with genotype (GT) 3 being the second most common globally and is linked to higher incidences of steatosis and rapid development of fibrosis and cirrhosis. The NS3/4A serine protease, a heterodimer complex of two HCV non-structural proteins, is an effective target for pharmaceutical intervention due to its essential roles in processing HCV polyproteins and inhibiting innate immunity. This study combines structure-based virtual screening (SBVS) of predefined compound libraries, pharmacokinetic prediction (ADME/T) and in vitro evaluation to identify potential low molecular weight (<500 Dalton) inhibitors of the NS3/4A serine protease (GT3). In silico screening of ZINC and PubChem libraries yielded five selected compounds as potential candidates. Dose-dependent inhibition of the NS3/4A serine protease and HCV replication in HuH-7.5 cells revealed that compound A (PubChem ID No. 16672637) exhibited inhibition towards HCV GT3 with an IC50 of 106.7µM and EC50 of 25.8µM, respectively. Thus, compound A may be developed as a potent, low molecular weight drug against the HCV NS3/4A serine protease of GT3.

Functional Outcomes of Fragility Fracture Integrated Rehabilitation Management in Sarcopenic Patients after Hip Fracture Surgery and Predictors of Independent Ambulation.

OBJECTIVES: To compare the changes in the functional level of patients with versus without sarcopenia who received by fragility fracture integrated rehabilitation management (FIRM) after hip fracture (HF) surgery over a 6-month follow-up period and to identify variables influencing independent ambulation (IA) at 6 months after HF. DESIGN: Prospective observational study. SETTING: Three in-hospital rehabilitation setting. PARTICIPANTS: Patients older than 65 years of age (N=80) categorized by the presence of sarcopenia. INTERVENTION: The FIRM program during the-2 week hospital stay after surgery. MEASUREMENTS: Main outcomes for ambulatory function (Koval score, Functional Ambulatory Category) and other secondary outcomes were measured at rehabilitation admission, at discharge, at 3 months and 6 months after surgery. Other secondary outcomes were measured. The possibility of IA at 6 months after surgery were also investigated. RESULTS: Sarcopenia and non-sarcopenia patients did not differ significantly in terms of changes in ambulation or other functions over a 6-month follow-up (p < 0.001 or p = 0.001). The two groups did not differ significantly in terms of final functional status (6 months). The IA ratios of the two groups did not significantly differ at 6 months after surgery (sarcopenia [54.3%] and non-sarcopenia [64.5%]). IA before fracture (p = 0.039) and age (≥80 years) (p = 0.03) were independent predictors and sarcopenia was not a predictor for the possibility of IA at 6-months after surgery. CONCLUSIONS: The FIRM program was effective for promoting functional recovery in older patients with fragility HF, either with or without sarcopenia. The present findings provide evidence of the pressing need for integrated rehabilitation management in fragility fracture care to improve functional recovery in patients with sarcopenia.

Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration.

OBJECTIVE: Clinical and animal studies have demonstrated the efficacy of mesenchymal stem cell (MSC) therapies in cartilage repair. As the efficacy of many MSC-based therapies has been attributed to paracrine secretion, particularly extracellular vesicles/exosomes, we determine here if weekly intra-articular injections of human embryonic MSC-derived exosomes would repair and regenerate osteochondral defects in a rat model. METHODS: In this study, osteochondral defects were created on the trochlear grooves of both distal femurs in 12 adult rats. In each animal, one defect was treated with 100 µg exosomes and the contralateral defect treated with phosphate buffered saline (PBS). Intra-articular injections of exosomes or PBS were administered after surgery and thereafter weekly for a period of 12 weeks. Three unoperated age-matched animals served as native controls. Analyses were performed by histology, immunohistochemistry, and scoring at 6 and 12 weeks after surgery. RESULTS: Generally, exosome-treated defects showed enhanced gross appearance and improved histological scores than the contralateral PBS-treated defects. By 12 weeks, exosome-treated defects displayed complete restoration of cartilage and subchondral bone with characteristic features including a hyaline cartilage with good surface regularity, complete bonding to adjacent cartilage, and extracellular matrix deposition that closely resemble that of age-matched unoperated control. In contrast, there were only fibrous repair tissues found in the contralateral PBS-treated defects. CONCLUSION: This study demonstrates for the first time the efficacy of human embryonic MSC exosomes in cartilage repair, and the utility of MSC exosomes as a ready-to-use and 'cell-free' therapeutic alternative to cell-based MSC therapy.

Distinctive role of 6-month teriparatide treatment on intractable bisphosphonate-related osteonecrosis of the jaw.

UNLABELLED: The administration of teriparatide (TPTD) in conjunction with periodontal care could provide faster and more favorable clinical outcomes in previously refractory bisphosphonate-related osteonecrosis of the jaws (BRONJ) cases compared to conventional dental care, combination of surgery and antimicrobial treatment. We also found that underlying vitamin D levels might influence the response to TPTD treatment. INTRODUCTION: Treatment of BRONJ is quite challenging and there are no standard treatment modalities. In this retrospective, longitudinal study, we examined whether additional TPTD administration could be beneficial for the resolution of BRONJ lesions compared to conservative management, such as antimicrobial treatment with or without surgery, and also studied the factors influencing the response to TPTD. METHODS: Twenty-four cases of intractable BRONJ were included: 15 subjects were assigned to the TPTD group and the other 9 subjects, who refused TPTD administration, were assigned to the non-TPTD group. All subjects in both groups continued calcium and vitamin D supplementation and the TPTD group additionally received a daily subcutaneous injection of 20 µg TPTD for 6 months. RESULTS: While 60.0% of the non-TPTD group showed one stage of improvement in BRONJ, 40.0% of the group did not show any improvement in disease status. In the TPTD group, 62.5% of the treated subjects showed one stage of improvement and the other 37.5% demonstrated a marked improvement, including two stages of improvement or complete healing, and there was not a single case that did not improve. The clinical improvement of BRONJ was statistically better in the TPTD group after the 6-month treatment (p < 0.05). Moreover, patients with higher baseline serum 25(OH)D levels showed better clinical therapeutic outcomes with TPTD. CONCLUSIONS: We observed the beneficial effects of TPTD on BRONJ, and subjects with optimal serum vitamin D concentrations seemed to reap the maximum therapeutic effects of TPTD. A prospective, randomized, controlled trial should be needed to further evaluate the therapeutic efficacy of TPTD in the resolution of BRONJ.

A rare case of interparietal incisional hernia from 8 mm trocar site after robot-assisted laparoscopic prostatectomy.

Trocar site hernia arising from 8 mm robotic port is very rare despite the increasing prevalence of robot-assisted surgeries. To date, there had been only a single case reported in the literature. We report a case of small bowel obstruction secondary to an interparietal trocar site incisional hernia after robot-assisted laparoscopic prostatectomy. Meticulous closure of 8 mm robotic trocar sites associated with large peritoneal defect at the end of surgery should be performed.

Clinical characteristics predicting early clinical failure after 72 h of antibiotic treatment in women with community-onset acute pyelonephritis: a prospective multicentre study.

In patients with community-onset acute pyelonephritis (CO-APN), assessing the risk factors for poor clinical response after 72 h of antibiotic treatment (early clinical failure) is important. The objectives of this study were to define those risk factors, and to assess whether early clinical failure influences mortality and treatment outcomes. We prospectively collected the clinical and microbiological data of women with CO-APN in South Korea from March 2010 to February 2012. The numbers of cases in the early clinical success and early clinical failure groups were 840 (79.1%) and 222 (20.9%), respectively. Final clinical failure and mortality were higher in the early clinical failure group than in the early clinical success group (14.9% vs 2.3%, p <0.001; 6.8% vs 0.1%, p 0.001, respectively). In a multiple logistic regression model, the risk factors for early clinical failure among the total 1062 patients were diabetes mellitus (OR 1.5; 95% CI 1.1-2.1), chronic liver diseases (OR 3.3; 95% CI 1.6-6.7), malignancy (OR 2.2; 95% CI 1.1-4.4), Pitt score ≥2 (OR 2.5; 95% CI 1.6-3.8), presence of azotaemia (OR 1.8; 95% CI 1.2-2.7), white blood cell count ≥20 000/mm(3) (OR 2.5; 95% CI 1.6-4.0), serum C-reactive protein level ≥20 mg/dL (OR 1.7; 95% CI 1.2-2.4), and history of antibiotic usage within the previous year (OR 1.5; 95% CI 1.1-2.2). Analysing the subgroup of 743 patients with CO-APN due to Enterobacteriaceae, fluoroquinolone resistance of the uropathogen was another factor associated with early clinical failure (OR 1.7; 95% CI 1.1-2.5). Simple variables of underlying diseases, previous antibiotic usage and initial laboratory test outcomes can be used to decide on the direction of treatment in CO-APN.

Plasma extracellular vesicle protein content for diagnosis and prognosis of global cardiovascular disease.

Cardiovascular disease is a major public health problem worldwide. Its growing burden is particularly ominous in Asia, due to increasing rates of major risk factors such as diabetes, obesity and smoking. There is an urgent need for early identification and treatment of individuals at risk of adverse cardiovascular events. Plasma extracellular vesicle proteins are novel biomarkers that have been shown to be useful in the diagnosis, risk stratification and prognostication of patients with cardiovascular disease. Ongoing parallel biobank initiatives in European (the Netherlands) and Asian (Singapore) populations offer a unique opportunity to validate these biomarkers in diverse ethnic groups.

Detection of microscopic particles present as contaminants in latent fingerprints by means of synchrotron radiation-based Fourier transform infra-red micro-imaging.

Synchrotron radiation-based Fourier transform infra-red (SR-FTIR) micro-imaging has been developed as a rapid, direct and non-destructive technique. This method, taking advantage of the high brightness and small effective source size of synchrotron light, is capable of exploring the molecular chemistry within the microstructures of microscopic particles without their destruction at high spatial resolutions. This is in contrast to traditional "wet" chemical methods, which, during processing for analysis, often caused destruction of the original samples. In the present study, we demonstrate the potential of SR-FTIR micro-imaging as an effective way to accurately identify microscopic particles deposited within latent fingerprints. These particles are present from residual amounts of materials left on a person's fingers after handling such materials. Fingerprints contaminated with various types of powders, creams, medications and high explosive materials (3-nitrooxy-2,2-bis(nitrooxymethyl)propyl nitrate (PETN), 1,3,5-trinitro-1,3,5-triazinane (RDX), 2-methyl-1,3,5-trinitrobenzene (TNT)) deposited on various - daily used - substrates have been analysed herein without any further sample preparation. A non-destructive method for the transfer of contaminated fingerprints from hard-to-reach areas of the substrates to the place of analysis is also presented. This method could have a significant impact on forensic science and could dramatically enhance the amount of information that can be obtained from the study of fingerprints.

Rectal culture screening for vancomycin-resistant enterococcus in chronic haemodialysis patients: false-negative rates and duration of colonisation.

Infection or colonisation with vancomycin-resistant enterococci (VRE) is common in chronic haemodialysis (HD) patients. However, there is limited information on the duration of VRE colonisation or on the reliability of consecutive negative rectal cultures to determine the clearance of VRE in chronic HD patients. Chronic HD patients from whom VRE was isolated were examined retrospectively. Rectal cultures were collected more than three times, at least one week apart, between 1 June 2003 and 1 March 2010. The results of the sequential VRE cultures and patients' data were analysed. Among 812 patients from whom VRE was isolated, 89 were chronic HD patients and 92 had three consecutive negative cultures. It took 60.7 ± 183.9 and 111.4 ± 155.4 days to collect three consecutive negative cultures in the 83 non-chronic haemodialysis patients and nine chronic HD patients, respectively (P = 0.011). The independent risk factors for more than three negative sequential rectal cultures were glycopeptide usage [odds ratio (OR): 2.155; P = 0.003] and length of hospital stay (OR: 1.009; P = 0.001). After three consecutive negative rectal cultures, two of six chronic HD patients and 10 of 36 non-HD patients were culture positive again. In conclusion, a significant proportion of patients colonised with VRE cannot be detected by three-weekly rectal cultures, and the duration of VRE colonisation in chronic haemodialysis patients tends to be prolonged. These results may be contributing to the continued increase in the prevalence of VRE.

Cannabinoid receptor 1 mediates palmitic acid-induced apoptosis via endoplasmic reticulum stress in human renal proximal tubular cells.

The endocannabinoid system (ECS) is activated at the onset of obesity and diverse metabolic diseases. Endocannabinoids mediate their physiological and behavioral effects by activating specific cannabinoid receptors, mainly cannabinoid receptor 1 (CB(1)R). Diabetic nephropathy (DN) is induced by hyperlipidemia, and renal proximal tubule cells are an important site for the onset of DN. However, the pathophysiology of CB(1)R, especially in the hyperlipidemia of DN, has not been elucidated. Therefore, we examined the effect of palmitic acid (PA) on CB(1)R expression and its related signal pathways in human renal proximal tubular cells (HK-2 cells). PA significantly increased CB(1)R mRNA and protein levels and induced CB(1)R internalization. PA-induced activation of CB(1)R is prevented by the treatment of AACOCF(3) (a cPLA(2) inhibitor), indomethacin and NS398 (a COX 2 inhibitors). Indeed, PA increased cPLA(2), and COX-2 but not COX-1. We also investigated whether the PA-induced activation of CB(1)R is linked to apoptosis. As a result, AM251 (a CB(1)R antagonist) attenuated PA-mediated apoptosis in a concentration-dependent manner. Furthermore, PA decreased GRP78 expression and induced increases in the endoplasmic reticulum (ER) stress signaling pathways p-PERK, p-eIF2α, p-ATF4, and CHOP, which were blocked by AM251 treatment. Moreover, PA increased the Bax/Bcl-2 ratio, cleaved PARP, and caspase-3 levels. The PA-induced apoptotic effects were decreased with CB(1)R-specific antagonist (AM251) treatment and CB1 si-RNA transfection. In conclusion, PA induced apoptosis through ER stress via CB(1)R expression in human proximal tubule cells. Our results provide evidence that CB(1)R blockade may be a potential anti-diabetic therapy for the treatment of DN.

Oral bisphosphonate-related osteonecrosis of the jaw: the first report in Asia.

UNLABELLED: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side effect of bisphosphonate therapy. The incidence of BRONJ is known to be low among patients treated with oral bisphosphonates. We investigated the prevalence, demographics, clinical manifestations, and treatment outcome of 24 patients with oral BRONJ in Asian populations. INTRODUCTION: The long-term safety of oral bisphosphonates is clinically important considering the rare but potentially serious complications such as bisphosphonate-related osteonecrosis of the jaw (BRONJ) versus the effect of reducing and preventing osteoporotic fracture. The incidence of BRONJ is known to be low among patients treated with oral bisphosphonates around the world. However, the prevalence in those taking oral bisphosphonates for osteoporosis in Asian populations is unknown. Moreover, a recent article, showing that the majority of reported patients who received alendronate were Asian American, raised concern about the prevalence of oral BRONJ in Asian populations. The objective of this study was to investigate the estimated prevalence, clinical characteristics, and treatment outcome of oral BRONJ in Asian populations. METHODS: From October 2005 to December 2008, a retrospective review of medical charts identified 24 patients receiving oral bisphosphonates diagnosed as BRONJ at the Department of Oral and Maxillofacial Surgery, Yonsei University Dental Hospital, Seoul, South Korea. RESULTS: The estimated prevalence of oral BRONJ was 0.05-0.07%. The average oral bisphosphonate treatment duration was 43.1 months (range, 5-120 months). Treatment with oral antibiotics and/or surgery including sequestrectomy or alveolectomy showed relatively favorable results. CONCLUSIONS: The prevalence of oral BRONJ in Korea is similar to that reported previously in Western populations. We suggest that recognition of BRONJ and appropriate management pre- and post-dental surgery might reduce the frequency of BRONJ among patients receiving oral bisphosphonates.

Grossly delayed graft function in a living related kidney transplant recipient: a case report.

Delayed graft function is a potentially challenging problem especially in cadaveric kidney transplant recipients. It adversely impacts long-term graft survival. It is rarely seen in living kidney transplants. Recovery of graft function usually occurs within a month. The chances of recovery of graft function diminish with further prolongation of delayed function. In fact, recovery of graft function after 3 months has rarely been described, we report herein recovery of graft function after 132 days of nonfunction in a living related kidney transplant.

Serum parathyroid hormone is associated with carotid intima-media thickness in postmenopausal women.

OBJECTIVES: To test whether parathyroid hormone (PTH) might be related to the development of atherosclerosis in postmenopausal women, we measured serum levels of PTH, the carotid intima-media thickness (IMT), and other clinical and biochemical parameters. METHODS: One hundred and seven postmenopausal women were recruited for this study. The serum level of PTH was measured by immunoradiometric assay, and carotid IMT was measured with high resolution B-mode ultrasonography. RESULTS: On the basis of bivariate correlation analyses or unpaired t-tests, the body mass index (BMI), waist circumference, estimated glomerular filtration rate, and 25-hydroxyvitamin D were not associated with carotid IMT. In contrast, age (r = 0.414, p < 0.001), serum level of PTH (r = 0.304, p = 0.001), hypertension (p < 0.001), and hypercholesterolaemia (p = 0.004) were related to carotid IMT. On the basis of multiple regression analysis, the serum level of PTH (beta = 0.198, p = 0.029), as well as age (beta = 0.309, p = 0.001) and hypertension (beta = 0.262, p = 0.006), were independent predictors of carotid IMT. CONCLUSIONS: Our results have demonstrated that serum PTH is an independent determinant of carotid IMT in postmenopausal women. This result suggests that serum PTH, even in the reference range, might be associated with the development of atherosclerosis or cardiovascular diseases in postmenopausal women. Further study is necessary in males and premenopausal women to fully elucidate the clinical significance of this finding.

Vitamin D inadequacy in postmenopausal women in Eastern Asia.

OBJECTIVE: To review data on the prevalence of vitamin D inadequacy and its causes in postmenopausal women in Eastern Asia. RESEARCH DESIGN AND METHOD: Data were obtained from the published biomedical literature as well as abstracts and posters presented at scientific meetings. Using MEDLINE, EMBASE and BIOSIS databases (to July 2007), epidemiological studies were identified using the search terms: 'human', 'vitamin D', 'vitamin D deficiency', 'vitamin D inadequacy', 'vitamin D insufficiency' and 'hypovitaminosis D', 'osteomalacia' and 'osteoporosis'. Additional references were also identified from the bibliographies of published articles. RESULTS: The prevalence of vitamin D inadequacy in studies of postmenopausal women (ambulatory or with osteoporosis or related musculoskeletal disorders) in Eastern Asia ranged from 0 to 92%, depending on the cut-off level of serum 25-hydroxycholecalciferol [25(OH)D] that was applied (range < or =6-35 ng/mL [< or = 15-87 nmol/L]). One large international study found that 71% of postmenopausal women with osteoporosis in Eastern Asia had vitamin D inadequacy, defined as serum levels of 25(OH)D < 30 ng/mL (75 nmol/L). Prevalence rates using this cut-off level were 47% in Thailand, 49% in Malaysia, 90% in Japan and 92% in South Korea. High prevalences of vitamin D inadequacy were evident in two studies using a lower 25(OH)D level cut-off value of < 12 ng/mL (30 nmol/L) - 21% in China and 57% in South Korea. Dietary deficiency and inadequate exposure or reactivity to sunlight (due to lifestyle choices, cultural customs and/or aging) were identified as important risk factors for vitamin D inadequacy. CONCLUSIONS: Non-uniform, epidemiological studies indicate a high prevalence of vitamin D inadequacy in postmenopausal women in Eastern Asia. Recommended remedial approaches are education campaigns and broad-based provision of vitamin D supplementation.

Antizyme1 mediates AURKAIP1-dependent degradation of Aurora-A.

Overexpression of Aurora-A oncogene has been shown to induce genomic instability and tumorigenesis. Cellular levels of Aurora-A are regulated by multiple mechanisms including the proteasome-dependent degradation of Aurora-A protein. Cell-cycle-dependent turnover of Aurora-A protein is mediated by cdh1 through ubiquitin (Ub)- and proteasome-dependent pathway. However, Aurora-A kinase interacting protein 1 (AURKAIP1), a negative regulator of Aurora-A, also promotes proteasome-dependent Aurora-A degradation through an Ub-independent mechanism. In an attempt to understand how AURKAIP1 promotes Aurora-A degradation through Ub-independent pathway, we demonstrate here that antizyme1 (Az1), a well-studied mediator of Ub-independent protein degradation pathway, regulates Aurora-A protein stability. We show that ectopic or polyamine-induced expression of Az1 can lower the steady-state levels of Aurora-A. The effect of Az1 on Aurora-A turnover was shown to be proteasome-dependent, but Ub-independent. Az1 interacts with Aurora-A in vivo and the interaction between Aurora-A and Az1 is essential for the Az1-mediated Aurora-A degradation. Furthermore, we observed that AURKAIP1 could not promote degradation of Aurora-A mutant, which is defective in Az1 interaction. Coexpression of the Az inhibitor (AzI), which downregulates Az1 functions, also abrogated AURKAIP1-mediated degradation of Aurora-A. We further demonstrated that AURKAIP1, Az1 and Aurora-A could exist as a ternary complex and AURKAIP1 enhances the interaction between Az1 and Aurora-A. We propose that AURKAIP1 might function upstream of the Az1 by enhancing the binding affinity of Az1 to Aurora-A to promote recognition, targeting to proteasome and subsequent degradation.

Analysis of adrenal masses by 18F-FDG positron emission tomography scanning.

This study aimed to analyse the characteristics of adrenal masses visible in the computerised tomography (CT) scans which have been also evaluated by 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET), and to characterise the features of 18F-FDG PET scans associated with various adrenal endocrine tumours, especially benign functional tumours. 18F-FDG PET scans of 105 patients with adrenal masses on the CT scan were analysed. Positive uptakes in the 18F-FDG PET scans were seen in 60 malignant tumours (54 metastasic lesions, six primary adrenal cancers) and seven benign tumours. The positive predictive value of 18F-FDG PET imaging to characterise an adrenal mass as a malignant tumour was 90%; the corresponding negative predictive value to rule out malignancy was also 90%. Benign adrenal tumours were smaller than that of malignant lesions (p<0.05). The mean standardised uptake value max (SUVmax) of the metastatic lesions [8.4+/-6.5 (microCi/g)/microCi/kg] was significantly higher than that of the benign adrenal tumours [2.4+/-1.2 (microCi/g)/microCi/kg, p<0.001]. Examination of only the primary adrenal lesions revealed that all adrenocortical carcinomas, two of three cases of pheochromocytomas, three of five neuroblastomas and two of four cases of primary aldosteronism showed positive 18F-FDG uptake. In conclusion, for patients presenting adrenal masses with a high probability of malignancy, 18F-FDG PET can be used to differentiate malignant from benign adrenal lesions. However, the 18F-FDG PET uptake did not show an always consistent pattern for endocrine tumours, which was probably due to the variability inherent in 18F-FDG uptake. This study suggests that 18F-FDG PET scanning can offer supporting data to localise and characterise adrenal tumours.

Ectopic Cushing's syndrome due to concurrent corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secreted by malignant gastrinoma.

Ectopic Cushing's syndrome due to various malignancies is not uncommon. However, a few cases of ectopic Cushing's syndrome caused by corticotropin-releasing hormone (CRH), or CRH with adrenocorticotropic hormone (ACTH) have been reported. A 28-year-old woman presented with acute upper gastrointestinal bleeding caused by an active ulcer, located atypically in the 2nd portion of duodenum. Further work-up revealed high gastrin levels and abdominal computed tomography (CT) scans showed a large pancreatic head mass with multiple liver metastases. The serum cortisol and ACTH levels were checked due to hypokalemia with metabolic alkalosis and recent amenorrhea. Cortisol and ACTH were both highly elevated with pituitary hyperplasia and elevated CRH. The existence of ectopic ACTH and CRH in the liver biopsy was also demonstrated immunohistochemically. Since an operation was not feasible, chemotherapy was conducted using paclitaxel and etoposide. These two drugs were chosen according to the IN VITRO chemotherapy response assay to maximize the treatment. This report demonstrates concurrent ACTH- and CRH-related ectopic Cushing's syndrome caused by malignant gastrinoma with multiple liver metastases that was treated with marginal success using a multidisciplinary medical approach.

Effects of a combined alendronate and calcitriol agent (Maxmarvil) on bone metabolism in Korean postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study.

INTRODUCTION: A randomized, double-blind, prospective, 24-week clinical trial was performed to evaluate the effects of a combinative agent, Maxmarvil, of calcitriol (0.5 mug) and alendronate (5 mg) on bone metabolism in postmenopausal women. METHODS: A total of 217 postmenopausal women with osteoporosis were enrolled; 199 patients were randomly assigned to one of two treatment groups (Maxmarvil group or alfacalcidol group). None of the patients were vitamin-D-deficient, as assessed by serum 25-hydroxyvitamin D (25(OH)D), nor had they received any drugs affecting bone metabolism before enrollment. Bone mineral densities (BMD) of L1-L4 and the femur were measured by dual-energy X-ray absorptiometry (DXA) at the initial assessment and after 6 months of treatment. Serum biochemical assays, including serum calcium, 24-h urinary calcium excretion, and bone turnover markers (both bone-specific alkaline phosphatase [bsALP] and urine N-telopeptide [NTx]), were performed at the baseline and after 3 and 6 months of treatment. RESULTS: In the Maxmarvil group, the BMD of the lumbar spine increased up to 2.42+/-0.5% from the baseline after 6 months (p<0.05). On the other hand, the change in BMD in the alfacalcidol group was 0.28+/-0.5% after 6 months. There was no significant difference in femoral BMD between the two groups. The levels of bsALP and NTx were significantly lower in the Maxmarvil group than in the alfacalcidol group (-22.04+/-3.9% vs. -11.42+/-2.8% [p<0.05] and -25.46+/-5.2% vs. 1.24+/-6.2% [p<0.001], respectively). Interestingly, there was a significantly smaller amount of 24-h urinary calcium in the Maxmarvil group (p<0.05). CONCLUSIONS: Our study demonstrates that a combination of calcitriol and alendronate is quite effective in preventing bone loss, with the advantage of lesser hypercalciuric effect of calcitriol in the postmenopausal osteoporotic women.

Mutational analysis of OGG1, MYH, MTH1 in FAP, HNPCC and sporadic colorectal cancer patients: R154H OGG1 polymorphism is associated with sporadic colorectal cancer patients.

MYH, OGG1 and MTH1 are members of base excision repair (BER) families, and MYH germline mutations were recently identified in patients with multiple adenomas or familial adenomatous polyposis (FAP). A total of 20 APC-negative Korean FAP patients were analyzed for OGG1, MYH and MTH1 germline mutations. A total of 19 hereditary nonpolyposis colorectal cancer (HNPCC), 86 suspected HNPCC, and 246 sporadic colorectal cancer cases were investigated for OGG1 and MYH mutations. A total of 14 R154H OGG1 polymorphisms were identified in hereditary, sporadic colorectal cancers, and normal controls. For the case-control analysis of OGG1 R154H, a total of 625 hereditary or sporadic colorectal cancer patients and 527 normal controls were screened. R154H was a rare polymorphism associated with sporadic colorectal cancer patents (OR: 3.586, P= 0.053). R154H does not segregate with cancer phenotypes. Upon examining the possibility of recessive inheritance of R154H, we could not identify any complementary mutations in OGG1, MYH or MTH1. Samples with R154H were further screened for mutations of K-ras, beta-catenin, APC, p53, BRAF and the microsatellite instability (MSI) status. Eight somatic mutations were identified in these genes and G:C to T:A transversion mutations were not dominant in samples harboring R154H. This result raises the possibility that OGG1 R154H may function as a low/moderate-penetrance modifier for colorectal cancer development.

The 10th and 11th residues of short length N-terminal PTH(1-12) analogue are important for its optimum potency.

The 10th and 11th residues of parathyroid hormone PTH(1-12) analogues were substituted to study the structure and function of PTH analogues. The substitution of Ala(10) of [Ala(3,10,12)(Leu(7)/Phe(7))Arg(11)]rPTH(1-12)NH(2) with Glu(10) and/or the Arg(11) with Ile(11) markedly decreased cAMP generating activity. Data from circular dichroism (CD) and the nuclear magnetic resonance (NMR) structural analysis of [Ala(3,10,12)(Leu(7)/Phe(7))Arg(11)]rPTH(1-12)NH(2) revealed tight alpha-helical structures, while the Glu(10) and/or Ile(11) substituted analogues showed unstable alpha-helical structures. We conclude that 10th and 11th residues are important for stabilizing its helical conformation and that destabilization of the alpha-helical structure, induced by substituting the above residues, remarkably affect its biological potency.