The farnesoid X receptor negatively regulates osteoclastogenesis in bone remodeling and pathological bone loss

Farnesoid X receptor (FXR, NR1H4) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. Since the role of FXR in osteoclast differentiation remains ill-defined, we investigated the biological function of FXR on osteoclastogenesis, using FXR-deficient mice. We demonstrated that FXR deficiency increases osteoclast formation in vitro and in vivo. First, FXR deficiency was found to accelerate osteoclast formation via down-regulation of c-Jun N-terminal kinase (JNK) 1/2 expression. Increased expression of peroxisome proliferator-activated receptor (PPAR)γ and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC- 1)β seems to mediate the pro-osteoclastogenic effect of FXR deficiency via the JNK pathway. In addition, we found that FXR deficiency downregulated the expression of interferon-β (IFN-β), a strong inhibitor of osteoclastogenesis, via receptor activator of nuclear factor-kappaB ligand (RANKL). We further suggested that interference of IFN-β expression by FXR deficiency impaired the downstream JAK3-STAT1 signaling pathways, which in turn increased osteoclast formation. Finally, FXR deficiency accelerated unloading- or ovariectomy-induced bone loss in vivo. Thus, our findings demonstrate that FXR is a negative modulator in osteoclast differentiation and identify FXR as a potential therapeutic target for postmenopausal osteoporosis and unloadinginduced bone loss

Nonpalpable Breast Masses: Evaluation by US Elastography

OBJECTIVE: To compare the diagnostic performances of conventional ultrasound (US) and US elastography for the differentiation of nonpalpable breast masses, and to evaluate whether elastography is helpful at reducing the number of benign biopsies, using histological analysis as a reference standard. MATERIALS AND METHODS: Conventional US and real-time elastographic images were obtained for 100 women who had been scheduled for a US-guided core biopsy of 100 nonpalpable breast masses (83 benign, 17 malignant). Two experienced radiologists unaware of the biopsy and clinical findings analyzed conventional US and elastographic images by consensus, and classified lesions based on degree of suspicion regarding the probability of malignancy. Results were evaluated by receiver operating characteristic curve analysis. In addition, the authors investigated whether a subset of lesions was categorized as suspicious by conventional US, but as benign by elastography. RESULTS: Areas under the ROC curves (Az values) were 0.901 for conventional US and 0.916 for elastography (p = 0.808). For BI-RADS category 4a lesions, 44% (22 of 50) had an elasticity score of 1 and all were found to be benign. CONCLUSION: Elastography was found to have a diagnostic performance comparable to that of conventional US for the differentiation of nonpalpable breast masses. The authors conclude that BI-RADS category 4a lesions with an elasticity score of 1 probably do not require biopsy

Downregulated miR-18b-5p triggers apoptosis by inhibition of calcium signaling and neuronal cell differentiation in transgenic SOD1 (G93A) mice and SOD1 (G17S and G86S) ALS patients

Abstract Background MicroRNAs (miRNAs) are endogenous non-coding RNAs that regulate gene expression at the post-transcriptional level and are key modulators in neurodegenerative diseases. Overexpressed miRNAs play an important role in ALS; however, the pathogenic mechanisms of deregulated miRNAs are still unclear. Methods We aimed to assess the dysfunction of RNAs or miRNAs in fALS (SOD1 mutations). We compared the RNA-seq of subcellular fractions in NSC-34 WT (hSOD1) and MT (hSOD1 (G93A)) cells to find altered RNAs or miRNAs. We identified that Hif1α and Mef2c were upregulated, and Mctp1 and Rarb were downregulated in the cytoplasm of NSC-34 MT cells. Results SOD1 mutations decreased the level of miR-18b-5p. Induced Hif1α which is the target for miR-18b increased Mef2c expression as a transcription factor. Mef2c upregulated miR-206 as a transcription factor. Inhibition of Mctp1 and Rarb which are targets of miR-206 induces intracellular Ca2+ levels and reduces cell differentiation, respectively. We confirmed that miR-18b-5p pathway was also observed in G93A Tg, fALS (G86S) patient, and iPSC-derived motor neurons from fALS (G17S) patient. Conclusions Our data indicate that SOD1 mutation decreases miR-18b-5p, which sequentially regulates Hif1α, Mef2c, miR-206, Mctp1 and Rarb in fALS-linked SOD1 mutation. These results provide new insights into the downregulation of miR-18b-5p dependent pathogenic mechanisms of ALS

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Initial Clinical Practicum Stress among Nursing Students: A Cross-Sectional Study on Coping Styles

Nursing students experience various stressors during their initial clinical practicum. As these stressors negatively affect learning and performance, coping strategies are essential. Therefore, this research study explored the relationship between coping styles and stress levels using a cross-sectional study with a convenience sample of 184 nursing students. Clinical practicum stress and coping styles were assessed via electronic questionnaires, and the data were analyzed using descriptive statistics, t-tests, and variance analyses. The highest score for clinical practice stress was for the practical education environment and practical work burden. The total stress score differed significantly according to coping style (t = −2.36, p = 0.020), and the total stress score of the passive coping group was higher. Among the sub-categories of stress, the scores of the education environment (t = −2.68, p = 0.008) and having undesirable role models (t = −2.14, p = 0.034) were significantly higher in the passive coping group. Although practical work burden was the highest stress factor in the active coping style group, the stress on the environment was highest in the passive coping group. The findings show that professors and clinical educators should recognize the various coping styles and incorporate different teaching methods in the clinical setting

Chronic Pain and Mood Disorders in Asian Americans.

Purpose: Pain and mood disorder frequently coexist. Yet, for Asian Americans (AAs), scant information about pain and mood disorder is available. Our aims were to compare (1) the rates of pain and mood disorders and (2) the magnitude of associations between pain and mood disorders between AAs and European Americans (EAs), and across different Asian subgroups. Methods: An analytical data was constructed from the Collaborative Psychiatric Epidemiology Studies (CPES), a representative sample of community-residing U.S. adults (n = 9,871). Pain morbidity was assessed by self-report. Mood disorders, including major depression and anxiety disorders, were assessed using the diagnostic interview. Analysis included descriptive statistics and multivariate logistic regression modeling. All analyses were weighted to approximate the U.S. populations, and controlled for sociodemographic and immigration characteristics. Results: Greater proportion of EAs, compared to AAs, endorsed lifetime pain (56.8% vs. 35.8%). Having life pain disorders elevated the likelihood of lifetime mood disorder by more than 2-folds (weight adjusted odds ratio (WAOR): 2.12, 95% CI: 1.77, 2.55). Having pain disorders over the past 12 months elevated the likelihood of mood disorder in the same time period by more than 3-folds (WAOR: 3.29, 95% CI: 2.02, 5.37) among AAs. The magnitude of the association between pain and psychiatric morbidity were greater in Vietnamese Americans compared to other AAs and EAs. Discussion: The conventional belief that rates of pain and mood disorders are greater in AAs than EAs may need to be further examined. Vietnamese Americans may be particularly vulnerable for experience of comorbid pain and mood disorders

Chronic Pain and Mood Disorders in Asian Americans.

Purpose: Pain and mood disorder frequently coexist. Yet, for Asian Americans (AAs), scant information about pain and mood disorder is available. Our aims were to compare (1) the rates of pain and mood disorders and (2) the magnitude of associations between pain and mood disorders between AAs and European Americans (EAs), and across different Asian subgroups. Methods: An analytical data was constructed from the Collaborative Psychiatric Epidemiology Studies (CPES), a representative sample of community-residing U.S. adults (n = 9,871). Pain morbidity was assessed by self-report. Mood disorders, including major depression and anxiety disorders, were assessed using the diagnostic interview. Analysis included descriptive statistics and multivariate logistic regression modeling. All analyses were weighted to approximate the U.S. populations, and controlled for sociodemographic and immigration characteristics. Results: Greater proportion of EAs, compared to AAs, endorsed lifetime pain (56.8% vs. 35.8%). Having life pain disorders elevated the likelihood of lifetime mood disorder by more than 2-folds (weight adjusted odds ratio (WAOR): 2.12, 95% CI: 1.77, 2.55). Having pain disorders over the past 12 months elevated the likelihood of mood disorder in the same time period by more than 3-folds (WAOR: 3.29, 95% CI: 2.02, 5.37) among AAs. The magnitude of the association between pain and psychiatric morbidity were greater in Vietnamese Americans compared to other AAs and EAs. Discussion: The conventional belief that rates of pain and mood disorders are greater in AAs than EAs may need to be further examined. Vietnamese Americans may be particularly vulnerable for experience of comorbid pain and mood disorders

NMR structural studies of interactions of a small, nonpeptidyl Tpo mimic with the thrombopoietin receptor extracellular juxtamembrane and transmembrane domains.

Thrombopoietin (Tpo) is a glycoprotein growth factor that supports hematopoietic stem cell survival and expansion and is the principal regulator of megakaryocyte growth and differentiation. Several small, nonpeptidyl molecules have been identified as selective human Tpo receptor (hTpoR) agonists. To understand how the small molecule Tpo mimic SB394725 interacts and activates hTpoR, we performed receptor domain swap and mutagenesis studies. The results suggest that SB394725 interacts specifically with the extracellular juxtamembrane region (JMR) and the transmembrane (TM) domain of hTpoR. Solution and solid-state NMR structural studies using a peptide containing the JMR-TM sequences showed that this region of hTpoR, unexpectedly, consists of two alpha-helices separated by a few nonhelical residues. SB394725 interacts specifically with His-499 in the TM domain and a few distinct residues in the JMR-TM region and affects several specific C-terminal TM domain residues. The unique structural information provided by these studies both sheds light on the distinctive mechanism of action of SB394725 and provides valuable insight into the mechanism of ligand-induced cytokine receptor activation