Short-term outcomes of a multicentre randomized clinical trial comparing laparoscopic pylorus-preserving gastrectomy with laparoscopic distal gastrectomy for gastric cancer (the KLASS-04 trial).

BACKGROUND: There remain concerns about the safety and functional benefit of laparoscopic pylorus-preserving gastrectomy (LPPG) compared with laparoscopic distal gastrectomy (LDG). This study evaluated short-term outcomes of a randomized clinical trial (RCT) comparing LPPG with LDG for gastric cancer. METHODS: The Korean Laparoendoscopic Gastrointestinal Surgery Study (KLASS)-04 trial was an investigator-initiated, open-label, parallel-assigned, superiority, multicentre RCT in Korea. Patients with cT1N0M0 cancer located in the middle third of the stomach at least 5 cm from the pylorus were randomized to undergo LPPG or LDG. Participants, care givers and those assessing the outcomes were not blinded to group assignment. Outcomes were 30-day postoperative morbidity rate and death at 90 days. RESULTS: Some 256 patients from nine institutions were randomized (LPPG 129 patients, LDG 127 patients) between July 2015 and July 2017 and outcomes for 253 patients were analysed. Postoperative complications within 30 days were seen in 19.3 and 15.5 per cent in the LPPG and LDG groups respectively (P = 0·419). Postoperative pyloric stenosis was observed in nine (7.2 per cent) and two (1·5 per cent) patients in the LPPG and LDG groups (P = 0·026) respectively. In multivariable analysis higher BMI was a risk factor for postoperative complications (odds ratio 1·17, 95 per cent c.i. 1·04 to 1·32; P = 0·011). Death at 90 days was zero in both groups. CONCLUSION: Postoperative complications and mortality was comparable in patients undergoing LPPG and LDG. Registration number: NCT02595086 (http://www.clinicaltrials.gov).

The effects of cortisol and adrenal androgen on bone mass in Asians with and without subclinical hypercortisolism.

Analyses using the largest Korean cohort of adrenal incidentaloma (AI) revealed that subtle cortisol excess in premenopausal women and reduced dehydroepiandrosterone-sulfate (DHEA-S) in postmenopausal women and men are associated with bone mineral density (BMD) reduction in Asian patients with subclinical hypercortisolism (SH). INTRODUCTION: Few studies evaluated bone metabolism in Asians with SH. We investigated associations of cortisol and DHEA-S, an adrenal androgen, with BMD in Asians with AI, with or without SH. METHODS: We used cross-sectional data of a prospective multicenter study from Korea. We measured BMD, bone turnover markers, cortisol levels after 1-mg dexamethasone suppression test (1-mg DST), DHEA-S, and baseline cortisol to DHEA-S ratio (cort/DHEA-S) in 109 AI patients with SH (18 premenopausal, 38 postmenopausal women, and 53 men) and 686 with non-functional AI (NFAI; 59 premenopausal, 199 postmenopausal women, and 428 men). RESULTS: Pre- and postmenopausal women, but not men, with SH had lower BMDs at lumbar spine (LS) than those with NFAI (P = 0.008~0.016). Premenopausal women with SH also had lower BMDs at the hip than those with NFAI (P = 0.009~0.012). After adjusting for confounders, cortisol levels after 1-mg DST demonstrated inverse associations with BMDs at all skeletal sites only in premenopausal women (ß = - 0.042~- 0.033, P = 0.019~0.040). DHEA-S had positive associations with LS BMD in postmenopausal women (ß = 0.096, P = 0.001) and men (ß = 0.029, P = 0.038). The cort/DHEA-S had inverse associations with LS BMD in postmenopausal women (ß = - 0.081, P = 0.004) and men (ß = - 0.029, P = 0.011). These inverse associations of cort/DHEA-S remained significant after adjusting for cortisol levels after 1-mg DST (ß = - 0.079~- 0.026, P = 0.006~0.029). In postmenopausal women, the odds ratios of lower BMD by DHEA-S and cort/DHEA-S was 0.26 (95% CI, 0.08-0.82) and 3.40 (95% CI, 1.12-10.33), respectively. CONCLUSION: Subtle cortisol excess in premenopausal women and reduced DHEA-S in postmenopausal women and men may contribute to BMD reduction in Asians with SH.

Association of blood n-3 fatty acid with bone mass and bone marrow TRAP-5b in the elderly with and without hip fracture.

The plasma n-3 fatty acid level was 26.2% lower in patients with osteoporotic hip fracture than in those with osteoarthritis. In all patients, n-3 fatty acid was positively associated with bone mineral density and inversely associated with tartrate-resistant acid phosphatase-5b level in bone marrow aspirates, reflecting the bone microenvironment. INTRODUCTION: Despite the potential beneficial role of n-3 fatty acid (FA) on bone metabolism, the specific mechanisms underlying these effects in humans remain unclear. Here, we assessed whether the plasma n-3 level, as an objective indicator of its status, is associated with osteoporosis-related phenotypes and bone-related markers in human bone marrow (BM) samples. METHODS: This was a case-control and cross-sectional study conducted in a clinical unit. n-3 FA in the blood and bone biochemical markers in the BM aspirates were measured by gas chromatography/mass spectrometry and immunoassay, respectively. BM fluids were collected from 72 patients who underwent hip surgery because of either osteoporotic hip fracture (HF; n = 28) or osteoarthritis (n = 44). RESULTS: After adjusting for confounders, patients with HF had 26.2% lower plasma n-3 levels than those with osteoarthritis (P = 0.006), and each standard deviation increment in plasma n-3 was associated with a multivariate-adjusted odds ratio of 0.40 for osteoporotic HF (P = 0.010). In multivariate analyses including all patients, a higher plasma n-3 level was associated with higher bone mass at the lumbar spine (ß = 0.615, P = 0.002) and total femur (ß = 0.244, P = 0.045). Interestingly, the plasma n-3 level was inversely associated with the tartrate-resistant acid phosphatase-5b level (ß = - 0.633, P = 0.023), but not with the bone-specific alkaline phosphatase level, in BM aspirates. CONCLUSIONS: These findings provide clinical evidence that n-3 FA is a potential inhibitor of osteoclastogenesis that favors human bone health.

Questionable correlation of the apparent diffusion coefficient with the histological grade and microvascular invasion in small hepatocellular carcinoma.

AIM: To evaluate the correlation between the apparent diffusion coefficient (ADC) and various histopathological parameters in small hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: In 143 surgically resected small HCCs, the mean and minimum ADC values, tumour-to-liver ADC ratio, and normalised ADC (ADC of the HCC/ADC of the spleen) were correlated to the tumour grade, microvascular invasion (MVI), cellularity, fatty change, degree of fibrosis, and lymphocytic infiltration using linear regression analysis, the Wilcoxon rank sum test, or Spearman's rank correlation. RESULTS: No significant correlation was found between the ADC parameters and tumour grade. In the univariate analysis, the ADC ratio of the tumour was significantly correlated with MVI as well as the degree of fibrosis and lymphocyte infiltration of the HCC (p=0.017, 0.042, and 0.002, respectively). The ADC of the tumour was significantly correlated with the degree of lymphocyte infiltration of the HCC (p=0.049). In the multivariate analysis, the ADC ratio of the tumour was an independent parameter for MVI and the degree of lymphocyte infiltration of the HCC (p=0.034 and <0.001, respectively), and the ADC of the tumour was an independent parameter for the degree of lymphocyte infiltration of the HCC (p=0.009). There was no significant correlation between the other ADCs and pathological tumour parameters. CONCLUSION: The tumour grade of small HCCs was not correlated with ADC parameters. The tumour-to-liver ADC ratio was a significant independent parameter for the degree of lymphocyte infiltration and MVI of small HCCs.

Evolution and persistence of resistance-associated substitutions of hepatitis C virus after direct-acting antiviral treatment failures.

Daclatasvir plus asunaprevir (DCV+ASV) treatment is an all-oral direct-acting antiviral (DAA) therapy for the genotype 1b HCV-infected patients. In this study, we investigated how resistance-associated substitutions (RASs) evolved after treatment failures and assessed the effect of those substitutions on viral fitness. Sequencing of NS5A and NS3 revealed typical RASs after treatment failures. Interestingly, the RASs of NS3 reverted to the wild-type amino acid within 1 year after treatment failures. However, the RASs of NS5A were stable and did not change. The effect of NS5A and NS3 RASs on viral RNA replication was assessed after mutagenic substitution in the genotype 1b HCV RNA. Among single substitutions, the effect of D168V was more substantial than the others and the effect of the triple mutant combination (D168V+L31V+Y93H) was the most severe. The RAS at NS5A Y93 affected both viral RNA replication and virus production. Finally, the effect of trans-complementation of NS5A was demonstrated in our co-transfection experiments and these results suggest that such a trans-complementation effect of NS5A may help maintain the NS5A RASs for a long time even after cessation of the DAA treatment. In conclusion, the results from this investigation would help understand the emergence and persistence of RASs.

Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment.

Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.

The relationship between fatty liver index and bone mineral density in Koreans: KNHANES 2010-2011.

Analyses using a nationally representative cohort have revealed that high fatty liver index (FLI) is associated with low bone mineral density (BMD) regardless of insulin resistance in men, thereby supporting the deteriorated bone metabolism in nonalcoholic fatty liver disease (NAFLD). INTRODUCTION: NAFLD is linked to deteriorated bone health. We investigated the association of FLI, a scoring model for NAFLD, with BMD. METHODS: This was a population-based, cross-sectional study from the Korea National Health and Nutrition Examination Surveys including 4264 Koreans (1908 men and 2356 women). FLI was calculated using body mass index, waist circumference, serum triglyceride, and gamma-glutamyltranspeptidase level. Insulin resistance was evaluated using the homeostasis model assessment-estimated insulin resistance (HOMA-IR) index. BMD was measured using dual-energy X-ray absorptiometry at the lumbar spine, total hip, femoral neck, and whole body. RESULTS: Men had a higher FLI than women, while the HOMA-IR index was similar between men and women. The significant association between FLI and BMD was observed only in men, but not in women. FLI was negatively correlated with total hip, femoral neck, and whole body BMD in men after adjusting for all potential confounders, including HOMA-IR (P < 0.001 to 0.010). Lumbar spine, total hip, femoral neck, and whole body BMD in men showed a decreasing trend as the FLI tertile increased after adjusting for all potential confounders, including HOMA-IR (P for trends < 0.001 to 0.034). In men aged 50 years or older, odds ratios for combined osteopenia and osteoporosis increased across increasing FLI tertiles after adjusting for confounders (P for trends < 0.011 to 0.029). CONCLUSION: NAFLD is associated with low bone density regardless of insulin resistance in men. These findings suggest an undiscovered direct link between liver and bone that increases the risk of osteoporosis in men with NAFLD.

The association of cortisol and adrenal androgen with trabecular bone score in patients with adrenal incidentaloma with and without autonomous cortisol secretion.

Despite ethnic differences in cortisol sensitivity, only one study in Caucasians has assessed trabecular bone score (TBS) in patients with subclinical hypercortisolism (SH). We showed that both subtle cortisol excess and reduced adrenal androgen may contribute to impaired bone quality in Asian women with SH. INTRODUCTION: One study in Caucasians has assessed trabecular bone score (TBS), an index of bone microstructure, in adrenal incidentaloma (AI) patients with subclinical hypercortisolism (SH). There are ethnic differences in cortisol sensitivities between Caucasian and Asian populations. We investigated the associations of cortisol and the adrenal androgen dehydroepiandrosterone-sulfate (DHEA-S) with TBS in AI patients with SH, adrenal Cushing's syndrome (CS), and nonfunctional AI (NFAI). METHODS: We measured TBS, cortisol levels after the overnight 1 mg dexamethasone suppression test (1 mg DST), and cortisol/DHEA-S in 61 patients with SH (30 men; 31 women), 19 with adrenal CS (4 men; 15 women), and 355 with NFAI (213 men; 142 women). RESULTS: After adjusting for confounders, the serum cortisol level after 1 mg DST was inversely correlated with TBS in men (ß = -0.133, P = 0.045) and women (ß = - 0.140, P = 0.048). Higher cortisol/DHEA-S ratio was associated with lower TBS in women (ß = - 0.252, P < 0.001), but not men. This inverse association of cortisol/DHEA-S ratio in women remained statistically significant after adjusting for the serum cortisol level after 1 mg DST (ß = - 0.221, P = 0.008). Compared with women with NFAI, women with SH had 2.2% lower TBS (P = 0.040). Deteriorated bone microstructure (TBS < 1.230) was associated with the serum cortisol level after 1 mg DST (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.04-4.53) and cortisol/DHEA-S ratio (OR, 2.05; 95% CI, 1.03-4.08). CONCLUSIONS: Subtle cortisol excess in both genders and reduced DHEA-S, especially in women, may contribute to impaired bone quality in Asian patients with SH.

Tenofovir versus tenofovir plus entecavir for chronic hepatitis B with lamivudine resistance and entecavir resistance.

We compared the viral suppressive efficacy of tenofovir disoproxil fumarate (TDF) mono-rescue therapy (TDF group) and TDF plus entecavir (ETV) combination-rescue therapy (TDF + ETV group) in chronic hepatitis B (CHB) patients with lamivudine resistance and entecavir resistance. One hundred and thirty-three CHB patients with lamivudine and entecavir resistance were investigated. Ninety-six patients were treated with TDF and 37 with TDF + ETV for at least 6 months. We compared the virologic response rate (HBV DNA level <20 IU/mL) between the two groups and identified the predictive factors of treatment outcome. There were no significant differences between the two groups in demographic characteristics. Up to 24 months [median: 18 (range 6-24) months], 85.4% and 89.2% of the TDF group and TDF + ETV group, respectively, achieved a virologic response (P=.068). Only the HBV DNA level at baseline was significantly associated with a virologic response in the multivariate analysis. In a subanalysis of patients with HBV DNA levels ≥4 log (IU/mL) at baseline, a higher proportion of patients in the TDF + ETV group than the TDF group achieved a virologic response (92.9% vs 68.3%; P<.001), while 90% of patients with HBV DNA (IU/mL) levels <4 log in all both TDF and TDF + ETV groups achieved a virologic response. TDF mono-rescue therapy is a reasonable option in patients with lamivudine resistance and entecavir resistance. However, the combination strategy should be considered in patients with high baseline HBV DNA levels.

Association of circulating dipeptidyl-peptidase 4 levels with osteoporotic fracture in postmenopausal women.

Postmenopausal women with osteoporotic fracture (OF) had higher plasma dipeptidyl-peptidase 4 (DPP4) levels than those without. Furthermore, higher plasma DPP4 levels were significantly associated with higher bone turnover and a higher prevalence of OF. These results indicated that DPP4 may be associated with OF by mediating bone turnover rate. INTRODUCTION: Evidence indicates that dipeptidyl-peptidase 4 (DPP4) plays a distinct role in bone metabolism. However, there has been no report on the association, if any, between circulating DPP4 levels and osteoporosis-related phenotypes, including osteoporotic fracture (OF). Therefore, we performed a case-control study to investigate these associations in postmenopausal women. METHODS: This study was conducted in multiple centers in Korea. We enrolled 178 cases with OF and 178 age- and body mass index-matched controls. OF was assessed by an interviewer-assisted questionnaire and lateral thoracolumbar radiographs. Bone turnover markers (BTMs), bone mineral density (BMD), and plasma DPP4 levels were obtained in all subjects. RESULTS: After adjustment for potential confounders, subjects with OF had significantly higher DPP4 levels than those without (P = 0.021). Higher DPP4 levels were significantly positively associated with higher levels of all BTMs, but not with BMD at all measured sites. The differences in DPP4 levels according to OF status disappeared after an additional adjustment for each BTM, but not after adjustment for any BMD values. BTMs explained approximately half of the relationship between DPP4 and OF. The risk of OF was 3.80-fold (95% confidence interval = 1.53-9.42) higher in subjects in the highest DPP4 quartile than in those in the lowest quartile after adjustment for potential confounders, including femoral neck BMD. CONCLUSIONS: DPP4 may be associated with OF by at least partly mediating the bone turnover rate. Circulating DPP4 levels may be a potential biomarker that could increase the predictive power of current fracture risk assessment models.

Comparison of reversal with neostigmine of low-dose rocuronium vs. reversal with sugammadex of high-dose rocuronium for a short procedure.

Some short procedures require deep neuromuscular blockade, which needs to be reversed at the end of the procedure. Forty-four patients undergoing elective laryngeal micro-surgery were randomly allocated into two groups: rocuronium 0.45 mg.kg-1 with neostigmine (50 µg.kg-1 with glycopyrrolate 10 µg.kg-1 ) reversal (moderate block group) vs. rocuronium 0.90 mg.kg-1 with sugammadex (4 mg.kg-1 ) reversal (deep block group). The primary outcome was the intubating conditions during laryngoscopy secondary outcomes included recovery of neuromuscular block; conditions for tracheal intubation; satisfaction score as determined by the surgeon; onset of neuromuscular block; and postoperative sore throat. The onset of neuromuscular block was more rapid, and intubation conditions and ease of intra-operative laryngoscopy were more favourable, and the satisfaction score was lower in the moderate block group compared with the deep block group. No difference was found in the incidence of postoperative sore throat. In laryngeal micro-surgery, the use of rocuronium 0.9 mg.kg-1 with sugammadex for reversal was associated with better surgical conditions and a shorter recovery time than rocuronium 0.45 mg.kg-1 with neostigmine.

groEL is a suitable genetic marker for detecting Vibrio parahaemolyticus by loop-mediated isothermal amplification assay.

A groEL gene-based loop-mediated isothermal amplification (LAMP) assay was developed to detect Vibrio parahaemolyticus in contaminated seafood and water. The assay was optimized and conducted at 63°C for 40 min using Bacillus stearothermophilus (Bst) DNA polymerase, large fragment. Amplification was analysed via multiple detection methods, including opacity, formation of white precipitate, DNA intercalating dyes (ethidium bromide and SYBR Green I), metal ion-binding indicator dye, calcein, and 2% agarose gel electrophoresis. A characteristic ladder-like band pattern on agarose gel and the desired colour changes when using different dyes were observed in positive cases, and these were species-specific for V. parahaemolyticus when compared with other closely related Vibrio spp. The limit of detection (LoD) of this assay was 100 fg per reaction, 100-fold higher than that for conventional polymerase chain reaction (PCR). When tested on artificially contaminated seafood and seawater, the LoDs of the LAMP assay were 120 and 150 fg per reaction respectively, and those of conventional PCR were 120 and 150 pg per reaction respectively. Based on our results, the groEL gene-based LAMP assay is rapid, specific, sensitive, and reliable for detecting V. parahaemolyticus, and it could be used in field diagnosis. SIGNIFICANCE AND IMPACT OF THE STUDY: The loop-mediated isothermal amplification (LAMP) assay using groEL gene (an abundant, highly conserved gene and member of the groESL chaperone gene family) provided rapid, species-specific and highly sensitive method for detecting Vibrio parahaemolyticus, the leading causal agent of seafood-borne diseases worldwide. Moreover, groEL LAMP revealed high efficiency than conventional PCR assay for V. parahaemolyticus using template both from pure culture and artificially contaminated seafood and water, which indicated the applicability in the field and environmental screening purpose for the organism.

Toll-IL1 receptor-mediated innate immune responses vary across HBV genotype and predict treatment response to pegylated-IFN in HBeAg-positive CHB patients.

Patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) have suppressed TLR2 expression, function and cytokine production. The aim of this study was to explore the importance of hepatitis B virus (HBV) genotype in innate immune responses and investigate whether Toll-like receptor (TLR) expression/function has potential roles as predictive biomarkers of successful therapy with pegylated interferon (Peg-IFN) therapy of HBeAg seroconversion in HBeAg-positive patients. We showed that as early as 4 weeks after initiation of Peg-IFN, future HBeAg seroconverters had significantly elevated levels of TLR2 expression on monocytes. TLR2-associated IL-6 production at baseline and week 4 of therapy and TLR4 IL-6 production at week 4 were also markedly elevated in HBeAg seroconverters. HBV genotype also influenced treatment response, with genotypes A and B more likely to seroconvert than D. We were able to demonstrate that these differences were due in part to the interaction of the specific HBeAg proteins with TLR pathway adaptor molecules, and these interactions were genotype dependent. HBeAg-mediated modulation of TLR signalling was also observed in Huh7 cells, following stimulation with Pam3Cys. Importantly, the addition of IFN-α to TLR2-stimulated cells cotransfected with an HBeAg expression plasmid reversed HBeAg-mediated suppression of hepatocytes. These findings demonstrate that patients with an activated inflammatory response are much more likely to respond to IFN therapy, with TLR responses showing promise as potential biomarkers of HBeAg seroconversion in this setting. Furthermore, our findings suggest there is differential genotype-specific HBeAg suppression of innate signalling pathways which may account for some of the clinical differences observed across the CHB spectrum.

A phase 3b study of sofosbuvir plus ribavirin in treatment-naive and treatment-experienced Korean patients chronically infected with genotype 2 hepatitis C virus.

In Korea, patients with chronic hepatitis C virus (HCV) infection are typically treated with pegylated interferon-alpha plus ribavirin, but interferons are contraindicated in many patients and are often poorly tolerated, particularly by the elderly and those with advanced liver disease. No interferon-free treatment regimens are approved in Korea. Sofosbuvir is an oral nucleotide analog inhibitor of the HCV nonstructural 5B RNA polymerase. It is approved in the USA, European Union and Japan for treating a number of HCV genotypes, including genotype 2. Genotype 2 has a seroprevalence of 38-46% in Korea. This single-arm, phase 3b study (NCT02021643) examined the efficacy and safety of sofosbuvir plus ribavirin (12-week duration) in chronic genotype 2 HCV-infected treatment-naive and treatment-experienced Korean patients with and without cirrhosis. The proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12) was 97% (125/129), with 96% (101/105) of treatment-naive and 100% (24/24) of treatment-experienced patients achieving SVR12. Two patients experienced virologic failure (n = 1, on-treatment failure; n = 1, relapse). No patient discontinued study treatment due to an adverse event (AE). The most common treatment-emergent AEs were headache (18%, 23/129) and pruritus (15%, 19/129). Few patients had grade 3 AEs (5%, 6/129) or grade 3 laboratory abnormalities (12%, 15/129). No grade 4 AE was reported. These data suggest that 12 weeks of treatment with the all-oral, interferon-free regimen of sofosbuvir plus ribavirin is effective and well tolerated in Korean patients with chronic genotype 2 HCV infection.

The circulating sphingosine-1-phosphate level predicts incident fracture in postmenopausal women: a 3.5-year follow-up observation study.

UNLABELLED: A high level of circulating sphingosine-1-phosphate (S1P) is associated with a high incidence of osteoporotic fracture and a high rate of an insufficient response to bisphosphonate therapy. INTRODUCTION: Sphingosine-1-phosphate (S1P) is a significant regulator of bone metabolism. Recently, we found that a high plasma S1P level is associated with low bone mineral density (BMD), high levels of bone resorption markers (BRMs), and a high risk of prevalent vertebral fracture in postmenopausal women. We investigated the possibility that S1P is a predictor of incident fracture. METHODS: A total of 248 postmenopausal women participated in this longitudinal study and were followed up for a mean duration of 3.5 years (untreated [n = 76] or treated with bisphosphonate or hormone replacement therapy [n = 172]). The baseline plasma S1P level and prevalent and incident fracture occurrence were assessed. RESULTS: A high S1P level was significantly associated with a higher rate of prevalent fracture after adjusting for femoral neck (FN) BMD, BRM, and potential confounders (odds ratio = 2.05; 95 % confidence interval [CI] = 1.03-4.00). Incident fractures occurred more frequently in the highest S1P tertile (T3) than in the lower two tertiles (T1-2) after adjusting for confounders, including baseline FN BMD, prevalent fracture, antiosteoporotic medication, annualized changes in FN BMD, BRM, and potential confounders (hazard ratio = 5.52; 95 % CI = 1.04-56.54). Insufficient response to bisphosphonate therapy occurred more frequently in T3 than T1-2 (odds ratio = 4.43; 95 % CI = 1.02-21.25). CONCLUSIONS: The plasma S1P level may be a potential predictor of fracture occurrence and an insufficient response to bisphosphonate therapy in postmenopausal women.

Gut microbiota-associated bile acid deconjugation accelerates hepatic steatosis in ob/ob mice.

AIM: Nonalcoholic hepatic fat accumulation has been hypothesized to be associated with alterations in gut microbiota composition, although mechanistic explanations for this link are largely insufficient. The aim of this study was to elucidate the microbiota-driven mechanisms involved in the development of nonalcoholic hepatic steatosis. METHODS AND RESULTS: Ob/ob mice and their wild-type lean control mice were fed an AIN-93G diet for 12 weeks. Faecal microbiota composition, faecal bile acid (BA) profile and intestinal and hepatic markers of BA metabolism were analysed. Ob/ob mice had significantly less faecal taurine-conjugated BAs compared to their lean controls. The proportions of butyrate-producing bacteria were lower in ob/ob mice compared to those in lean mice. Intestinal expression of farnesoid X receptor (FXR) mRNA was significantly higher, whereas hepatic expression of cholesterol-7α-hydroxylase 1 (CYP7A1) and small heterodimer partner (SHP) were significantly lower in ob/ob mice compared to those in control mice. CONCLUSION: Microbiota-associated BAs deconjugation may induce nonalcoholic fatty liver disease (NAFLD) by activating intestinal FXR signalling and blocking hepatic FXR-SHP pathway, thereby accelerating fat synthesis. SIGNIFICANCE AND IMPACT OF THE STUDY: We provided evidences that changes in the gut microbiota and their metabolites can alter the profile of BAs, thereby providing a mechanism by which an altered microbiota profile contributes to the development of NAFLD.

The effect of sphingosine-1-phosphate on bone metabolism in humans depends on its plasma/bone marrow gradient.

BACKGROUND: Although recent studies provide clinical evidence that sphingosine-1-phosphate (S1P) may primarily affect bone resorption in humans, rather than bone formation or the osteoclast-osteoblast coupling phenomenon, those studies could not determine which bone resorption mechanism is more important, i.e., chemorepulsion of osteoclast precursors via the blood to bone marrow S1P gradient or receptor activator of NF-κB ligand (RANKL) elevation in osteoblasts via local S1P. AIM: To investigate how S1P mainly contributes to increased bone resorption in humans, we performed this case-control study at a clinical unit in Korea. METHODS: Blood and bone marrow samples were contemporaneously collected from 70 patients who underwent hip surgery due to either osteoporotic hip fracture (HF) (n = 10) or other causes such as osteoarthritis (n = 60). RESULTS: After adjusting for sex, age, BMI, smoking, alcohol, previous fracture, diabetes, and stroke, subjects with osteoporotic HF demonstrated a 3.2-fold higher plasma/bone marrow S1P ratio than those without HF, whereas plasma and bone marrow S1P levels were not significantly different between these groups. Consistently, the risk of osteoporotic HF increased 1.38-fold per increment in the plasma/bone marrow S1P ratio in a multivariate adjustment model. However, the odds ratios for prevalent HF according to the increment in the plasma and bone marrow S1P level were not statistically significant. CONCLUSION: Our current results using simultaneously collected blood and bone marrow samples suggest that the detrimental effects of S1P on bone metabolism in humans may depend on the S1P gradient between the peripheral blood and bone marrow cavity.

Pure non-gestational choriocarcinoma arising in the ovary.

Non-gestational choriocarcinoma (NGCO) is a rare primary ovarian cancer with poor prognosis. It is important to distinguish it from gestational ovarian choriocarcinoma (GCO), because there are different treatment options. However, it is difficult to distinguish the two types by routine histologic, ultrastructural, or immunohistochemical examination. The authors present NGCO in a 41-year-old woman, which was confirmed by DNA polymorphism analysis. All tested microsatellite markers had identical DNA profiles with the same allelic sizes between tumor and normal myometrium of the patient, indicating that both tissues originated from the same person. The results confirmed that the tumor was non-gestational in origin. Although the tumor was large, the authors performed hand- assisted laparoscopic surgical (HALS) staging. After three cycles of combination chemotherapy and surgery, the patient has not had any evidence of disease 48 months after treatment. This case demonstrates the usefulness of HALS staging and DNA polymorphism analysis in NGCO.

Downregulation of interleukin-18-mediated cell signaling and interferon gamma expression by the hepatitis B virus e antigen.

UNLABELLED: The mechanisms by which hepatitis B virus (HBV) establishes and maintains chronic hepatitis B infection (CHB) are poorly defined. Innate immune responses play an important role in reducing HBV replication and pathogenesis. HBV has developed numerous mechanisms to escape these responses, including the production of the secreted hepatitis B e antigen (HBeAg), which has been shown to regulate antiviral toll-like receptor (TLR) and interleukin-1 (IL-1) signaling. IL-18 is a related cytokine that inhibits HBV replication in hepatoma cell lines and in the liver through the induction of gamma interferon (IFN-γ) by NK cells and T cells. We hypothesized that HBV or HBV proteins inhibit IFN-γ expression by NK cells as an accessory immunomodulatory function. We show that HBeAg protein inhibits the NF-κB pathway and thereby downregulates NK cell IFN-γ expression. Additionally, IFN-γ expression was significantly inhibited by exposure to serum from individuals with HBeAg-positive but not HBeAg-negative chronic HBV infection. Further, we show that the HBeAg protein suppresses IL-18-mediated NF-κB signaling in NK and hepatoma cells via modulation of the NF-κB pathway. Together, these findings show that the HBeAg inhibits IL-18 signaling and IFN-γ expression, which may play an important role in the establishment and/or maintenance of persistent HBV infection. IMPORTANCE: It is becoming increasingly apparent that NK cells play a role in the establishment and/or maintenance of chronic hepatitis B infection. The secreted HBeAg is an important regulator of innate and adaptive immune responses. We now show that the HBeAg downregulates NK cell-mediated IFN-γ production and IL-18 signaling, which may contribute to the establishment of infection and/or viral persistence. Our findings build on previous studies showing that the HBeAg also suppresses the TLR and IL-1 signaling pathways, suggesting that this viral protein is a key regulator of antiviral innate immune responses.

Low skeletal muscle mass associates with low femoral neck strength, especially in older Korean women: the Fourth Korea National Health and Nutrition Examination Survey (KNHANES IV).

SUMMARY: Data gathered from a nationally representative cohort demonstrated that subject with low skeletal muscle mass had consistently low femoral neck composite strength indices for compression, bending, and impact, especially in older women, supporting the highly integrated nature of skeletal muscle and bone. INTRODUCTION: Skeletal muscle and bone interact mechanically and functionally. The present study was performed to investigate the association between muscle mass and femoral neck composite strength indices using a nationally representative cohort. METHODS: This is a population-based, cross-sectional study from Korea National Health and Nutrition Examination Surveys, including 1,275 Koreans (674 women and 601 men) aged 50 years or older. Femoral neck axis length and width were measured by hip DXA scans and were combined with BMD, body weight, and height to create composite indices of femoral neck strength relative to load in three different failure modes: compression, bending, and impact. Presarcopenia was defined as an appendicular skeletal muscle mass (ASM) divided by body weight that was less than 1 SD below the sex-specific mean for young adults. RESULTS: After adjusting for confounders, women with presarcopenia had consistently lower indices for compression strength (CSI), bending strength (BSI), and impact strength (ISI) than women without this condition. Men with presarcopenia had a lower ISI value than men without presarcopenia. Multiple regression analyses revealed that lower relative skeletal muscle mass (ASM/weight) associated significantly with lower values for all three femoral neck composite indices in women and with lower CSI and ISI in men. CONCLUSIONS: These findings provide the first clinical evidence for the notion that age-related low muscle mass may increase the risk of osteoporotic hip fractures by decreasing femoral neck strength relative to load, especially in older women, and support the highly integrated nature of skeletal muscle and bone.