Distinct clinical trajectories of gastrointestinal progression among patients with systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is heterogeneous in its clinical presentation. Common manifestations cluster together, defining unique subgroups. This investigation aims to characterize gastrointestinal (GI) phenotypes and determine whether they can be distinguished by temporal progression. METHODS: We examine a well-established SSc patient cohort with a modified Medsger GI severity score measured over time to determine heterogeneity in disease progression. Growth mixture models estimate each patient's phenotype and disease severity trajectory over time. We compare the characteristics of estimated phenotypes using non-parametric statistics and linear and logistic regression to compare patient characteristics between phenotypes while adjusting for disease duration. RESULTS: We examined 2696 SSc patients with at least two Medsger GI scores, identifying four unique phenotypes. The most common phenotype (n = 2325) ("Stable") had an average score of 1 that was consistent over time. Two phenotypes were progressive ["Early Progressive" (n = 142) and "Late Progressive" (n = 115)] with an initial average score of 1. The Early Progressive group increased initially and stabilized, and the Late Progressive group worsened slowly over time. A fourth phenotype ["Early Severe GI"; (n = 114)] had an initial average Medsger GI score just below 3 with high mortality and improving GI severity over time. CONCLUSIONS: Clinically distinct GI phenotypes exist among patients with SSc. These phenotypes are not only distinguished by GI and extra-intestinal SSc clinical complications, but they are also temporally distinct. Distinct autoantibody profiles are associated strongly with more severe GI disease.

A meta-analysis of the association between body mass index and risk of vertebral fracture.

We conducted a meta-analysis of prospective studies to assess the association between BMI and incident vertebral fracture. We found that as body mass index (BMI) increases, the risk of vertebral fracture decreases in men, but not in women, suggesting possible gender differences in the relationship of BMI with risk of vertebral fracture. INTRODUCTION: Recent evidence suggests that the relationship between BMI and fracture risk may be site-specific. We conducted a systematic review and meta-analysis of prospective studies to investigate the association between BMI and risk of incident vertebral fracture. METHODS: PubMed and Embase were searched for relevant articles published from inception through February 15, 2017. Extracted relative risks (RR) from the prospective studies were pooled using random-effects meta-analysis. RESULTS: Six studies were included, with a total of 105,129 participants followed for 3 to 19 years. The pooled RR (95% confidence interval [CI]) for vertebral fracture per each standard deviation increase in BMI was 0.94 (95% CI = 0.80-1.10) with significant heterogeneity (I 2 = 88.0%, p < 0.001). In subgroup analysis by gender, we found a significant inverse association between BMI and risk of vertebral fracture in men (RR = 0.85, 95% CI = 0.73-0.98, n = 25,617 participants) but not in women (RR = 0.98, 95% CI = 0.81-1.20, n = 79,512 participants). Across studies of women not adjusting for bone mineral density (BMD), there was no significant association between BMI and risk of vertebral fracture (RR = 0.91, 95% CI = 0.80-1.04, p = 0.18, n = 72,755 participants). However, BMI was associated with an increased risk of vertebral fracture in studies of women that adjusted for BMD (RR = 1.28, 95% CI = 1.17-1.40, p < 0.001, n = 6757 participants). Substantial heterogeneity was found among studies of women (I 2 = 90.1%, p < 0.001), which was partly explained by the adjustment for BMD (adjusted R 2 = 61%). We found no evidence of publication bias (p = 0.40). CONCLUSIONS: In conclusion, our findings suggest that there might be gender differences in the relationship of BMI with risk of vertebral fracture. Further research is needed, including the assessment of other measures of adiposity, such as visceral adiposity, on the risk of vertebral fracture.

Clinicopathologic and prognostic significance of c-MYC copy number gain in lung adenocarcinomas.

BACKGROUND: c-MYC copy number gain (c-MYC gain) has been associated with aggressive behaviour in several cancers. However, the role of c-MYC gain has not yet been determined in lung adenocarcinomas classified by genetic alterations in epidermal growth factor receptor (EGFR), KRAS, and anaplastic lymphoma kinase (ALK) genes. We investigated the clinicopathologic and prognostic significance of c-MYC gain for disease-free survival (DFS) and overall survival (OS) according to EGFR, KRAS, and ALK gene status and stages in lung adenocarcinomas. METHODS: In 255 adenocarcinomas resected in Seoul National University Bundang Hospital from 2003 to 2009, fluorescence in situ hybridisation (FISH) with c-MYC probe and centromeric enumeration probe 8 (CEP8) was analysed using tissue microarray containing single representative core per each case. EGFR (codon 18 to 21) and KRAS (codon 12, 13, and 61) mutations were analysed by polymerase chain reaction and direct sequencing method from formalin-fixed, paraffin-embedded tissue sections. ALK rearrangement was determined by FISH method. c-MYC gain was defined as >2 copies per nucleus, chromosome 8 gain as ⩾3 copies per nucleus, and gain of c-MYC:CEP8 ratio (hereafter, c-MYC amplification) as ⩾2. RESULTS: We observed c-MYC gain in 20% (51 out of 255), chromosome 8 gain in 5.5% (14 out of 255), c-MYC amplification in 2.4% (6 out of 255), EGFR mutation in 49.4% (118 out of 239), KRAS mutation in 5.7% (7 out of 123), and ALK rearrangement in 4.9% (10 out of 205) of lung adenocarcinomas. c-MYC gain was observed in 19% (22 out of 118) of patients with lung adenocarcinomas with an EGFR mutation, but not in any patients with a KRAS mutation, or an ALK rearrangement. c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor in the full cohort of lung adenocarcinoma (P=0.022, hazard ratio (HR)=1.71, 95% confidence interval (CI), 1.08-2.69 for DFS; P=0.032, HR=2.04, 95% CI, 1.06-3.91 for OS), as well as in stage I subgroup (P=0.023, HR=4.70, 95% CI, 1.24-17.78 for DFS; P=0.031, HR=4.65, 95% CI, 1.15-18.81 for OS), and in EGFR-mutant subgroup (P=0.022; HR=2.14; 95% CI, 1.11-4.10 for DFS). CONCLUSIONS: c-MYC gain (but not chromosome 8 gain or c-MYC amplification) was an independent poor-prognostic factor for DFS and OS in lung adenocarcinomas, both in full cohort and stage I cancer, and possibly for DFS in EGFR-mutant adenocarcinomas. Additional studies are required to determine if patients with lung adenocarcinoma with c-MYC gain are candidates for additional first-line treatment to mitigate their increased risk for disease progression and death.

Calcium supplement intake and risk of cardiovascular disease in women.

UNLABELLED: Some recent reports suggest that calcium supplement use may increase risk of cardiovascular disease. In a prospective cohort study of 74,245 women in the Nurses' Health Study with 24 years of follow-up, we found no independent associations between supplemental calcium intake and risk of incident coronary heart disease (CHD) and stroke. INTRODUCTION: Some recent reports suggest that calcium supplements may increase cardiovascular disease (CVD) risk. The objective was to examine the independent associations between calcium supplement use and risk of CVD. METHODS: We conducted a prospective cohort study of supplemental calcium use and incident CVD in 74,245 women in the Nurses' Health Study (1984-2008) free of CVD and cancer at baseline. Calcium supplement intake was assessed every 4 years. Outcomes were incident CHD (nonfatal or fatal MI) and stroke (ischemic or hemorrhagic), confirmed by medical record review. RESULTS: During 24 years of follow-up, 4,565 cardiovascular events occurred (2,709 CHD and 1,856 strokes). At baseline, women who took calcium supplements had higher levels of physical activity, smoked less, and had lower trans fat intake compared with those who did not take calcium supplements. After multivariable adjustment for age, body mass index, dietary calcium, vitamin D intake, and other CVD risk factors, the relative risk of CVD for women taking >1,000 mg/day of calcium supplements compared with none was 0.82 (95% confidence interval [CI] 0.74 to 0.92; p for trend <0.001). For women taking >1,000 mg/day of calcium supplements compared with none, the multivariable-adjusted relative risk for CHD was 0.71 (0.61 to 0.83; p for trend < 0.001) and for stroke was 1.03 (0.87 to 1.21; p for trend = 0.61). The relative risks were similar in analyses limited to non-smokers, women without hypertension, and women who had regular physical exams. CONCLUSIONS: Our findings do not support the hypothesis that calcium supplement intake increases CVD risk in women.

Effect of age on atherogenicity of LDL and inflammatory markers in healthy women.

BACKGROUND AND AIM: Since using LDL level alone is insufficient as a method to identify individuals with incident coronary artery disease (CAD), other factors may be implicated in the pathogenesis of CAD. Additionally, controversy still remains regarding whether there is an age-related increase in circulating cytokines in healthy individuals. We investigated the influence of age on atherogenicity of LDL and inflammatory markers in healthy women. METHODS AND RESULTS: Two thousand nine hundred forty four healthy women form 30-79 years old (23.3 ± 0.05 kg/m²) were categorized into 5 age groups: 30-39, 40-49, 50-59, 60-69 and 70-79 years. BMI, smoking, drinking, and metabolic syndrome prevalence adjusted mean values of total-cholesterol progressively increased from the group age 30-39 years to the group age 40-49 and 50-59 years and thereafter decreased in the group age 60-69 and 70-79 years. Serum concentrations of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were higher in women aged 60-79 years than women aged 30-59 years. Plasma ox-LDL levels increased in the group age 50-59 years compared with the group age 30-39 and 40-49 years and further increased in the group age 60-69 and 70-79 years. Mean values of LDL particle size were smaller in women aged 60-79 years than those in women aged 30-59 years. After adjustment for BMI, smoking, drinking, and metabolic syndrome status, age was positively correlated with LDL-cholesterol (r = 0.095, P < 0.001), oxidized LDL (r = 0.305, P < 0.001), hs-CRP (r = 0.150, P < 0.001), TNF-α (r = 0.171, P < 0.001) and IL-6 (r = 0.294, P < 0.001) and negatively with LDL particle size (r = -0.239, P < 0.001). CONCLUSION: Our results indicate that LDL atherogenicity and inflammatory mediators can be better markers of CAD risk than known risk factors such as elevated concentrations of total- and LDL-cholesterol, decreased HDL-cholesterol levels and smoking in old healthy women.

An open-label, rater-blinded, 8-week trial of bupropion hydrochloride extended-release in patients with major depressive disorder with atypical features.

The present study aimed at investigating the effectiveness and tolerability of -bupropion hydrochloride extended release (XL) in major depressive disorder (MDD) patients with atypical features (AF).51 patients were prescribed bupropion XL for 8 weeks (6 visits: screening, baseline, weeks 1, 2, 4 and 8). The primary efficacy measure was a change of the Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (SIGH-SAD) from baseline to endpoint. Secondary efficacy measures included the SIGH-SAD atypical symptoms subscale, Clinical Global Impression-Severity (CGI-S), Sheehan Disability Scale (SDS) and Epworth Sleepiness Questionnaire (ESQ). Response or remission was defined as ≥50% reduction or ≤7 in SIGH-SAD total scores, respectively, at end of treatment.The HAM-D-29 total score reduced by 55.3% from baseline (27.3±6.5) to end of treatment (12.2±6.3) (p<0.001). Atypical symptom subscale scores also reduced by 54.5% from baseline (9.2±3.0) to end of treatment (4.2±2.8) (p<0.001). At the end of treatment, 24.4% (n=10) and 51.2% (n=21) subjects were classified as remitters and responders, respectively. The most frequently reported AEs were headache (13.7%), dry mouth (11.8%), dizziness (9.8%), and dyspepsia (9.8%).Our preliminary study indicates that bupropion XL may be beneficial in the treatment of MDD with atypical features. Adequately powered, randomized, double-blind, placebo-controlled trials are necessary to determine our results.

Screening for cytotoxic activity of ovotransferrin and its enzyme hydrolysates.

The aim of this study was to investigate the cytotoxic activities of ovotransferrin (OTF) from egg white and its enzyme hydrolysates (OTH). The OTF was hydrolyzed at 45°C for 3 h using neutrase, alcalase, acid (0.03 N HCl, pH 2.5), protamex, protex 6L, flavorzyme, α-chymotrypsin, trypsin, and collupulin MG. The enzyme to substrate ratio was 1:25 (wt/wt) in all experiments. Using the 3-(4,5-dimethylthizol-2-yl)-2,5-diphenylatetetrazolium bromide (MTT) assay, the cytotoxicity of OTF and OTH was evaluated in human cancer cell lines of various tissue origins, including the lung (A549 and SK-MES-1), stomach (AGS), breast (MCF-7), larynx (Hep-2), cervix (HeLa), and liver (HepG2). The growth of all cancer cell lines was inhibited by both OTF and OTH in a dose-dependent manner. In particular, OTF displayed relatively high cytotoxicity (≤60% inhibition effects) at 40 mg/mL. At lower concentrations (≤5 mg/mL), however, OTF- and OTH-mediated cytotoxic effects were not significant in all cancer cell lines tested. The MCF-7 cells were the least sensitive to all treatments among all cancer cell lines tested. The OTH-trypsin and OTH-neutrase showed a potent cytotoxicity (over 90% cytotoxicity) to HeLa cells at the 10 mg/mL level. The OTH-trypsin, OTH-protamex, OTH-protex 6L, and OTH-collupulin MG caused 95, 96, 86, and 87% growth inhibition, respectively, in AGS cells. These results indicated there are possibilities that OTF and OTH can be used as natural growth inhibitors of human cancer cell lines.

Demographic, dietary, and serum factors and parathyroid hormone in the National Health and Nutrition Examination Survey.

UNLABELLED: Many determinants of parathyroid hormone (PTH) are unknown. In the National Health and Nutrition Examination Survey (NHANES), numerous factors not classically associated with calcium-phosphorus homeostasis, such as uric acid and smoking, are independently associated with PTH in adults without chronic kidney disease. Associations between serum phosphorus and PTH may vary by race. INTRODUCTION: Although PTH may be an important biomarker for osteoporosis and cardiovascular disease, many determinants of PTH are unknown. We investigated associations between demographic, dietary, and serum factors and PTH level. METHODS: We studied 4,026 white, 1,792 black, and 1,834 Mexican-American adult participants without chronic kidney disease from the 2003-2004 and 2005-2006 NHANES. RESULTS: The mean serum PTH level was 38.3 pg/ml for whites, 42.6 pg/ml for blacks, and 41.3 pg/ml for Mexican-Americans. After adjusting for diet, body mass index, serum levels of calcium, phosphorus, 25-hydroxyvitamin D, creatinine, and other factors, smokers compared to non-smokers had lower PTH, ranging from -4.2 pg/ml (95% confidence interval (CI) -7.3 to -1.1) in Mexican-Americans to -6.1 pg/ml (95% CI -8.7 to -3.5) in blacks. After multivariate adjustment, PTH was higher in females compared to males, ranging from 1.1 pg/ml (95% CI -1.2 to 3.4) in Mexican-Americans to 4.5 pg/ml (95% CI 1.9 to 7.0) in blacks, and in older (>60 years) compared to younger participants (<30 years), ranging from 3.7 pg/ml (95% CI 1.3 to 6.1) in Mexican-Americans to 8.0 pg/ml (95% CI 5.4 to 10.7) in blacks. Higher uric acid was associated with higher PTH. In whites only, lower serum phosphorus and lower serum retinol were associated with higher PTH. CONCLUSIONS: Numerous factors not classically associated with calcium-phosphorus homeostasis are independently associated with PTH and should be considered in future studies of PTH and chronic disease. Additional research is needed to elucidate mechanisms underlying identified associations with PTH and to explore possible racial differences in phosphorus handling.

Myositis due to the microsporidian Anncaliia (Brachiola) algerae in a lung transplant recipient.

Microsporidia are obligate intracellular parasites, more closely related to fungi than protozoa on molecular phylogenetic analysis, and are known to be a rare cause of opportunistic infection in immune compromised patients including human immunodeficiency virus-positive patients and solid organ transplant recipients. We report the first case to our knowledge of microsporidial myositis in a lung transplant recipient. He was 49 years old and had received a lung transplant in 2000 for cystic fibrosis. He presented in 2009 with fevers, chronic diarrhea, myalgia, and pancytopenia, and developed progressive weakness and neurological symptoms before his death 35 days after hospital admission. Multiple investigations, including stool culture, rectal biopsy, colonoscopy, cerebrospinal fluid examination, bone marrow biopsy, lung biopsy, and bronchoalveolar lavage, failed to reveal a definite cause for the patient's deterioration. The diagnosis of microsporidial infection was made on post-mortem light microscopic examination of tissue sections of the tongue and deltoid muscle. Light microscopy diagnosed a microsporidial myositis, confirmed by transmission electron microscopy, which suggested that the organism was Brachiola species. The identity of the organism was confirmed by polymerase chain reaction as Brachiola algerae (recently renamed Anncaliia algerae). The case highlights the need to consider protozoal organisms in the differential diagnosis of myalgia and multisystemic infections in immune compromised patients.

Successfully treated multicentric Castleman's disease with renal thrombotic microangiopathy using rituximab and corticosteroid.

Thrombotic microangiopathy (TMA) is a rare renal complication accompanied with Castleman's disease. We report the first case of TMA combined plasma cell type multicentric Castleman's disease (MCD) which was successfully treated with rituximab and corticosteroid. A previously healthy 60-year-old Korean man was admitted due to acute renal failure, thrombocytopenia, and multiple lymphadenopathies. The result of lymph node biopsy was plasma cell type Castleman's disease and TMA was revealed by kidney biopsy. After treatment with rituximab, prednisolone and temporary hemodialysis, complete remission was achieved. The combination of corticosteroid and rituximab was associated with improvement for this patient.

Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta.

Activated mouse peritoneal macrophages produce nitric oxide (NO) via a nitric oxide synthase that is inducible by interferon gamma (IFN-gamma): iNOS. We have studied the mechanisms by which transforming growth factor beta 1 (TGF-beta) suppresses IFN-gamma-stimulated NO production. TGF-beta treatment reduced iNOS specific activity and iNOS protein in both cytosolic and particulate fractions as assessed by Western blot with monospecific anti-iNOS immunoglobulin G. TGF-beta reduced iNOS mRNA without affecting the transcription of iNOS by decreasing iNOS mRNA stability. Even after iNOS was already expressed, TGF-beta reduced the amount of iNOS protein. This was due to reduction of iNOS mRNA translation and increased degradation of iNOS protein. The potency of TGF-beta as a deactivator of NO production (50% inhibitory concentration, 5.6 +/- 2 pM) may reflect its ability to suppress iNOS expression by three distinct mechanisms: decreased stability and translation of iNOS mRNA, and increased degradation of iNOS protein. This is the first evidence that iNOS is subject to other than transcriptional regulation.

Malignant struma ovarii with a robust response to radioactive iodine.

SUMMARY: Struma ovarii is a rare, usually benign ovarian tumour with malignancy occurring in <5% of cases. Metastases, particularly seeding to bone, are extremely rare. Presentation is variable but often features local pain and/or ascites and hyperthyroidism may occur. It is not established how to best treat and follow patients with extensive disease. Case reports of radioiodine (I131) ablative therapy following thyroidectomy have shown reduced recurrence. We describe the case of a 33-year-old woman who presented with bone pain and was diagnosed with skeletal metastases with features of follicular thyroid carcinoma. However, thyroid pathology was benign. She recalled that 5 years prior, an ovarian teratoma was excised, classified at that time as a dermoid cyst. Retrospective review of this pathology confirmed struma ovarii without obvious malignant features. The patient was found to have widespread metastases to bone and viscera and her thyroglobulin was >3000 µg/L following recombinant TSH administration prior to her first dose of I131. At 25 months following radioiodine treatment, she is in remission with an undetectable thyroglobulin and clear I131 surveillance scans. This case demonstrates an unusual presentation of malignant struma ovarii together with challenges of predicting metastatic disease, and demonstrates a successful radioiodine regimen inducing remission. LEARNING POINTS: Malignant transformation of struma ovarii (MSO) is extremely rare and even rarer are metastatic deposits in bone and viscera. MSO can be difficult to predict by initial ovarian pathology, analogous to the difficulty in some cases of differentiating between follicular thyroid adenoma and carcinoma. No consensus exists on the management for post operative treatment of MSO; however, in this case, three doses of 6Gbq radioiodine therapy over a short time period eliminated metastases to viscera and bone. Patients should continue to have TSH suppression for ~5 years. Monitoring thyroglobulin levels can predict recurrence.

Lysophospholipids--receptor revelations.

Upon cell activation, membrane phospholipids are metabolized into potent lysophospholipid (LP) mediators, such as sphingosine 1-phosphate and lysophosphatidic acid. LPs fulfill signaling roles in organisms as diverse as yeast and humans. The recent discovery of G protein-coupled receptors for LPs in higher eukaryotes, and their involvement in regulating diverse processes such as angiogenesis, cardiac development, neuronal survival, and immunity, has stimulated growing interest in these lipid mediators. LP receptor biology has generated insights into fundamental cellular mechanisms and may provide therapeutic targets for drug development.

Altering category-level beliefs: the impact of level of representation at belief formation and belief disconfirmation.

This research program investigates whether representational level of information underlying initial beliefs (individual vs. category) and disconfirming information (individual vs. category) influence the magnitude of belief and attitude change regarding categories of objects. In 3 experiments, 2 key effects emerged. A main effect of type of disconfirming information indicated that category-level information produced more belief and attitude change than did individual-level information. Also, a significant interaction between type of information at formation and disconfirmation indicated a relative matching effect, with category-level disconfirmation producing substantially more belief and attitude change than individual-level disconfirmation when initial beliefs were based on category-level information but only slightly greater change when initial beliefs were based on individual-level information.

Long-term treatment with human immunoglobulin for antisynthetase syndrome-associated interstitial lung disease.

BACKGROUND: Interstitial lung disease-associated antisynthetase syndrome (AS-ILD) carries significant morbidity and mortality. Corticosteroids and immunosuppressive drugs are the mainstay of treatment. Human immunoglobulin (IVIg), an immunomodulator without immunosuppressive properties, is effective in myositis but the evidence supporting its use in ILD is scarce. OBJECTIVE: To describe clinical outcomes of AS-ILD patients receiving IVIg. METHODS: Retrospective analysis of AS-ILD patients. Linear mixed models using restricted maximum likelihood estimation was used to estimate the change in lung function and corticosteroid dose over time. RESULTS: Data from 17 patients was analyzed. Median follow-up was 24.6 months. Fourteen patients had refractory disease. The mean percent-predicted forced vital capacity (FVC%) (p = 0.048) and percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (p = 0.0223) increased over time, while the mean prednisone dose (p < 0.001) decreased over time. Seven patients achieved a >10% increase in FVC%, including two who used IVIg as initial treatment. Five patients showed a >10% increase in DLCO% and TLC%. Nine (53%) patients experienced side effects. CONCLUSIONS: IVIg may be a useful complementary therapy in active progressive AS-ILD but is associated with potential side effects. Fssssurther investigation is required to determine the value of IVIg as an initial treatment in AS-ILD.

MYC translocation and an increased copy number predict poor prognosis in adult diffuse large B-cell lymphoma (DLBCL), especially in germinal centre-like B cell (GCB) type.

AIMS: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with various genetic alterations. The aim was to investigate MYC, Bcl-2 and Bcl-6 translocations and copy number changes in adult DLBCLs to evaluate their clinicopathological features and prognostic implications. METHODS AND RESULTS: Gene status was examined using fluorescence in situ hybridization (FISH), and the results were analysed in the context of germinal centre B-cell (GCB) and non-GCB type of DLBCL based on immunohistochemistry. MYC translocation was observed in 9% (14 of 156), and an increased copy number (ICN) in 7.1% (11 of 156). MYC translocation was more common in GCB type (22%) than in non-GCB type (4.9%), and associated with advanced International Prognostic Index (IPI). MYC aberration, i.e. translocation or increased copy number (ICN), was significantly associated with shorter overall survival, especially for the GCB type. Bcl-2 translocation was rare (3.4%, five of 145), and ICN was observed in 11.7% (17 of 145), more frequently in non-GCB type (16%) than in GCB type (2.5%). Bcl-2 aberration tended to have an adverse effect on survival. In multivariate analysis, MYC ICN was an independent poor prognostic factor. CONCLUSIONS: Analyses of MYC and Bcl-2 status, i.e. translocation and ICN, in the context of DLBCL phenotype might help predict prognosis and determine therapeutic strategies.

Lower urinary cotinine level is associated with a trend toward more myopic refractive errors in Korean adolescents.

PurposeTo investigate the association between urinary cotinine levels as an objective biological marker for exposure to nicotine and refractive status.Patients and methodsThis cross-sectional study analyzed data from the Korea National Health and Nutrition Examination Survey between 2008 and 2011. A total of 1139 Korean adolescents aged 12-18 years were enrolled. Urinary cotinine concentrations and other potential risk factors for myopia were examined. Correlation analyses and multivariate regression analysis were performed to investigate the association between urinary cotinine level and refractive error.ResultsSpherical equivalent correlated significantly with urinary cotinine concentration (r=0.104, P=0.011). Lower urinary cotinine level was associated with a trend toward more myopic refractive errors (P for trend=0.003). After adjusting for age, sex, area of residence, physical activity, serum 25-hydroxyvitamin D level, parental income level, and receipt of basic livelihood security, subjects with a low urinary cotinine level had a significantly increased risk of myopia <-0.5 D (odds ratio (OR) 1.95, 95% confidence interval (CI) 1.18-3.21), <-3.0 D (OR 2.03, 95% CI 1.29-3.2), and <-6.0 D (OR 2.2, 95% CI, 1.15-4.23) when compared with subjects with a high urinary cotinine level. As urinary cotinine level decreased, the risks of myopia <-0.5 D, <-3.0 D, and <-6.0 D increased significantly (P for trend <0.05).ConclusionA trend toward less myopic refractive error was observed among Korean adolescents with higher urinary cotinine levels. This result provides the epidemiologic evidence implying nicotine as a potential modulator related with refractive development. Further studies with full consideration for myopia-associated risk factors are required to yield clear answers on the direct effect of smoking to the refractive status.

Forkhead box O transcription factors in chondrocytes regulate endochondral bone formation.

The differentiation of embryonic mesenchymal cells into chondrocytes and the subsequent formation of a cartilaginous scaffold that enables the formation of long bones are hallmarks of endochondral ossification. During this process, chondrocytes undergo a remarkable sequence of events involving proliferation, differentiation, hypertrophy and eventually apoptosis. Forkhead Box O (FoxO) transcription factors (TFs) are well-known regulators of such cellular processes. Although FoxO3a was previously shown to be regulated by 1,25-dihydroxyvitamin D3 in osteoblasts, a possible role for this family of TFs in chondrocytes during endochondral ossification remains largely unstudied. By crossing Collagen2-Cre mice with FoxO1lox/lox;FoxO3alox/lox;FoxO4lox/lox mice, we generated mice in which the three main FoxO isoforms were deleted in growth plate chondrocytes (chondrocyte triple knock-out; CTKO). Intriguingly, CTKO neonates showed a distinct elongation of the hypertrophic zone of the growth plate. CTKO mice had increased overall body and tail length at eight weeks of age and suffered from severe skeletal deformities at older ages. CTKO chondrocytes displayed decreased expression of genes involved in redox homeostasis. These observations illustrate the importance of FoxO signaling in chondrocytes during endochondral ossification.

Is c-Met oncoprotein expression an adverse prognosticator in extrahepatic bile duct cancer treated with curative resection followed by adjuvant chemoradiotherapy?

PURPOSE: To analyze the expression of c-Met, and to investigate correlations between the expression of c-Met, clinicopathologic variables, and survival in patients undergoing curative surgery followed by adjuvant chemoradiotherapy for extrahepatic bile duct (EHBD) cancer. METHODS: Ninety EHBD cancer patients who underwent curative resection followed by adjuvant chemoradiotherapy were enrolled. Expression of c-Met was assessed with immunohistochemical staining on tissue microarray. The correlation between clinicopathologic variables and survival outcomes was evaluated using Kaplan-Meier method and Cox proportional hazard model. RESULTS: On univariate analysis, 66 patients (76.7 %) showed c-Met expression. c-Met expression had a significant impact on 5-year overall survival (OS) (43.0 % in c-Met(+) vs. 25.0 % in c-Met(-), p = 0.0324), but not on loco-regional relapse-free survival or distant metastasis-free survival (DMFS). However, on multivariate analysis incorporating tumor location and nodal involvement, survival difference was not maintained (p = 0.2940). Tumor location was the only independent prognostic factor predicting OS (p = 0.0089). Hilar location tumors, nodal involvement, and poorly differentiated tumors were all identified as independent prognostic factors predicting inferior DMFS (p = 0.0030, 0.0013, and 0.0037, respectively). CONCLUSIONS: This study showed that c-Met expression was not associated with survival outcomes in EHBD cancer patients undergoing curative resection followed by adjuvant chemoradiotherapy. Further studies are needed to fully elucidate the prognostic value of c-Met expression in these patients.