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.

Switching to tenofovir vs continuing entecavir for hepatitis B virus with partial virologic response to entecavir: a randomized controlled trial.

Entecavir 0.5 mg (ETV) is widely used among treatment-naïve chronic hepatitis B (CHB) patients. However, 10%-30% of patients show partial virologic response (PVR) to the drug. If the hepatitis B virus (HBV) continues to replicate, the underlying liver disease may progress. Herein, we compared the efficacy of switching to tenofovir disoproxil fumarate (TDF) with that of continuing ETV in CHB patients with PVR to ETV. This was an open-label randomized controlled trial including CHB patients who had been receiving 0.5 mg of ETV for >12 months, but who still had detectable HBV DNA levels of >60 IU/mL without known resistance to ETV. Sixty patients were enrolled and 45 qualified for the study: Twenty-two patients were randomly assigned into the TDF group and 23 into the ETV group. After 12 months of treatment, the virologic response rate (HBV DNA <20 IU/mL) was significantly higher in the TDF group than in the ETV group, as measured using per-protocol analysis (55% vs 20%; P = .022) and intention-to-treat analysis (50% vs 17.4%; P = .020). The reduction in HBV DNA was greater (-1.13 vs -0.67 log10 IU/mL; P = .024), and the mean HBV DNA level was lower (1.54 vs 2.01 log10 IU/mL; P = .011) in the TDF group than in the ETV group. In conclusion, to achieve optimal response in CHB patients with PVR to ETV, switching to TDF would be a better strategy than continuing ETV. Appropriate modification of therapy would further improve the outcome of chronic HBV infection.

Atypia of undetermined significance on thyroid fine needle aspiration - risk factors for malignancy.

OBJECTIVES: This study is designed to determine the clinical predictors of malignancy in the atypia of undetermined significance (AUS) category resulted from thyroid fine needle aspiration (FNA). DESIGN: Retrospective cohort study. SETTING: Dong-A University Medical Center, Busan, Korea. PARTICIPANTS: Sixty-two patients who underwent thyroid surgery from January 2010 to December 2013, following a diagnosis of AUS from preoperative thyroid FNA. MAIN OUTCOME MEASURES: We investigated the age, gender, maximum size and site of the nodules, ultrasonographic findings, cytological features, BRAF gene mutation, surgical method, number of AUS on repeated FNA and final pathologic results. RESULTS: Forty-one of sixty-two patients underwent total thyroidectomy and the rest had lobectomy. The final pathologic results were 41 malignancies and 21 benign diseases. Nodules less than 1.5 cm, ultrasonographic findings suggestive of malignancy were risk factors for malignancy on univariated analysis (P < 0.001). Multivariated analysis showed that nodules less than 1.5 cm, ultrasonographic findings suggestive of malignancy and more than 2 results of atypia from repeated FNAs were significant risk factors for malignancy (P < 0.001). A BRAF gene mutation analysis was performed in 38 patients, and 13 patients had the mutation. All patients with the BRAF gene mutation had been diagnosed with papillary thyroid cancer (P > 0.05). CONCLUSIONS: We recommend close observation or diagnostic surgery in patients with nodules <1.5 cm and with two or more malignant ultrasound feature and a BRAF mutation, or with two or more AUS findings on repeated FNAs.

The utility of intra-operative frozen section for the evaluation of microscopic extrathyroidal extension in papillary thyroid carcinoma.

OBJECTIVES: This study was designed to evaluate the usefulness of intra-operative frozen section for the evaluation of microscopic extrathyroidal extension (ETE) in papillary thyroid carcinoma (PTC). DESIGN: Retrospective cohort study. SETTING: Dong-A University Medical Center, Busan, Korea. PARTICIPANTS: Three hundred and sixty-four patients who underwent thyroid surgery from January 2000 to December 2010 with PTC confined to one unilateral lobe as diagnosed using preoperative ultrasonography were enrolled. MAIN OUTCOME MEASURES: The patients who had microscopic ETE on frozen section were classified into "group A," and those who did not have microscopic ETE on frozen section were classified into "group B." Clinicopathologic factors including age, gender, size of the tumour, extent of operation, ETE, multifocality, bilaterality, lymph node metastasis and recurrence were compared between the two groups. RESULTS: Of the 364 patients enrolled, ETE was confirmed in 100 patients (group A, 27.5%) on frozen biopsy. The nodule size in group A (0.94±0.87 cm) was larger than that in group B (0.86±0.79 cm) (P=.042). In group A, 15 patients (15%) showed multifocality and 11 patients (14.47%) showed bilaterality. In group B, 37 patients (14.02%) showed multifocality and seven patients (43.35%) showed bilaterality. They did not differ significantly between the two groups (P=.811, P=.182). There was a higher frequency of lymph node metastases in group A (52/86, 60.47%) than in group B (7/16, 43.75%, P=.214). Recurrence was observed in only two patients who had received thyroid lobectomy as the initial surgery in group A. CONCLUSIONS: Intra-operative frozen biopsy can be a useful method for identifying the microscopic ETE. During the surgery, it can also help the surgeon to decide the optimal extent of surgery and the need for central compartment neck dissection in PTC patients.

Continuous distraction-induced delayed spinal cord injury on motor-evoked potentials and histological changes of spinal cord in a porcine model.

STUDY DESIGN: Experimental study. OBJECTIVES: This study evaluated distraction-induced delayed spinal cord injury in a porcine model. SETTING: Department of Orthopedics, Korea University Guro Hospital, Seoul, Korea. METHODS: Global osteotomy of three columns was performed on the thirteenth thoracic vertebrae with 13 pigs. The osteotomized vertebrae were distracted to 57-103% of segmental vertebral height (SVH) length, which was less than the distraction length that induces prompt SCI. The vertebral height was maintained until the loss of motor-evoked potential (MEP) signals with continuous distraction. The distraction distance and the time at which SCI occurred were measured, and distraction was then released to observe MEP recovery patterns. RESULTS: We found delayed SCI in 8 of the 12 pigs, with a mean 20.9 mm (range 19-25 mm) and 10.7 min (range 8-12 min) of continuous spinal distraction, which was equivalent to 74.3% (68-84%) of SVH and 3.63% (3.42-4.31%) of thoracolumbar spinal length. A continuous 74.3% SVH distraction over an average of 10.7 min caused a delayed SCI, which was indicated by mild histologic changes in the spinal cord. Recovery patterns from SCI after distraction release were compatible with the degree of histological change; however, these patterns differed from the previously investigated prompt type of SCI. CONCLUSION: Late onset injury due to continuous spinal distraction, which is comparable to iatrogenic SCI in spinal correction surgery, is important for understanding the impact of corrective surgery.

Change in body surface temperature as an ancillary measurement to motor evoked potentials.

STUDY DESIGN: Experimental study. OBJECTIVES: To study the role of surface temperature as an adjunct to motor evoked potentials (MEPs) in rabbit spinal cord injury (SCI) model. SETTING: Department of Orthopedics, Korea University Guro Hospital, Seoul, Korea. METHODS: Rabbits (n =18) were divided into Complete (n = 9) and Incomplete (n = 9) SCI groups. Complete SCI was defined as being non-responsive to a wake-up test with loss of MEPs after transection of spinal cord. Incomplete SCI was defined as being responsive to a wake-up test with significant attenuation (⩾ 80%) of MEPs after impaction on spinal cord. Surface temperature of upper and lower extremities, core temperature and MEPs signals were checked before, during and after SCI for 20 min. A wake-up test was conducted and spinal cord was histologicaly evaluated. RESULTS: Experimental conditions between the two groups were statistically similar (P > 0.005 for all values). After SCI, upper extremity temperatures did not change in either group (P > 0.005); however, the surface temperature of the lower extremities in the Complete SCI Group elevated to 1.7 ± 0.5°C in comparison to 0.5 ± 0.1°C in the Incomplete SCI Group (P < 0.001). The scores of wake-up test in the Incomplete SCI Group were significantly different from that of the Complete SCI Group (P < 0.001), while white and gray matter damage was variable on histology. CONCLUSIONS: Monitoring of changes of body surface temperature of the lower extremities can be potentially used to identify the completeness of SCI in a rabbit model.

Internal herniation due to an omphalomesenteric duct cyst in a 69-year-old man.

Previous abdominal surgery is the most common cause of mechanical small bowel obstruction. However, in patients with no history of abdominal surgery, the diagnosis and treatment of mechanical small bowel obstruction is difficult. A persistent omphalomesenteric duct remnant is a rare finding that typically presents in the pediatric population and is extremely rare in patients aged > 60 years. In the present report, we describe the case of an omphalomesenteric duct cyst causing small bowel obstruction in a 69-year-old man with no history of a surgical procedure.

Entanglement tsunami: universal scaling in holographic thermalization.

We consider the time evolution of entanglement entropy after a global quench in a strongly coupled holographic system, whose subsequent equilibration is described in the gravity dual by the gravitational collapse of a thin shell of matter resulting in a black hole. In the limit of large regions of entanglement, the evolution of entanglement entropy is controlled by the geometry around and inside the event horizon of the black hole, resulting in regimes of pre-local-equilibration quadratic growth (in time), post-local-equilibration linear growth, a late-time regime in which the evolution does not carry memory of the size and shape of the entangled region, and a saturation regime with critical behavior resembling those in continuous phase transitions. Collectively, these regimes suggest a picture of entanglement growth in which an "entanglement tsunami" carries entanglement inward from the boundary. We also make a conjecture on the maximal rate of entanglement growth in relativistic systems.

Formation mechanism and red light emission photoluminescence of single-phase crystalline Eu2O2CO3 nanoplates compared with Y2O3:Eu phosphor.

The photoluminescence properties and formation mechanism of a novel stoichiometric phosphor are presented. Nanoplates of pure single-phase crystalline Eu2O2CO3 oxycarbonate (hexagonal type-II) were synthesized by dry autoclaving under autogenic pressure (under 3 MPa) using an efficient, high yield solid state green-chemistry route that can be extended to other rare-earth oxycarbonate and oxide systems, resulting in the full conversion of a simple commercial precursor in single-crystalline nanoplates with strong visible luminescence. Phosphors made of an oxide host and an active luminescent dopant ion are the commercial standard (i.e., Y2O3:Eu). It is generally considered that the activity of luminescent species, such as Eu3+, is quenched and disappears above a certain concentration of them in the lattice (concentration quenching). The truly stoichoimetric oxycarbonate phosphor without active dopant ions exhibits very strong red emission when excited by different excitations, in the UV and visible range, without any concentration quenching effect. The bright red light emission spectra of the of the photo-excited phosphor nanoplates under UV and visible light excitation is compared with that of a standard Y2O3:Eu commercial red phosphor powder, and the thermal conversion mechanism is proposed to obtain the single-phase stable stoichiometric oxycarbonate nanoplates.

Molecular methods used to estimate thermal inactivation of a prototype human norovirus: more heat resistant than previously believed?

Two molecular-based methods for estimating capsid integrity as a proxy for virus infectivity were used to produce thermal inactivation profiles of Snow Mountain virus (SMV), a prototype human norovirus (HuNoV). Monodispersed virus suspensions were exposed to 77, 80, 82 and 85 °C for various times, pre-treated with either propidium monoazide (PMA) or RNase, and subjected to RNA isolation followed by RT-qPCR amplification. D-values were 25.6 ± 2.8, 3.1 ± 0.1, 0.7 ± 0.04 and 0.2 ± 0.07 min at 77, 80, 82 and 85 °C, respectively for PMA-treated SMV; and 16.4 ± 0.4, 3.9 ± 0.2 0.9 ± 0.3 and 0.12 ± 0.00 min at 77, 80, 82 and 85 °C, respectively for RNase-treated SMV. Corresponding zD values were 3.80 °C and 3.71 °C for PMA and RNase-treated virus, respectively. Electron microscopy data applied to heat-treated virus-like particles supported this relatively high degree of thermal resistance. The data suggest that SMV is more heat resistant than common cultivable HuNoV surrogates. Standardized thermal inactivation methods (such as milk pasteurization) may not be stringent enough to eliminate this virus and perhaps other HuNoV.

Co-transplantation of bone marrow-derived endothelial progenitor cells improves revascularization and organization in islet grafts.

Bone marrow-derived early endothelial progenitor cells (BM-EPCs) are a clinical tool for enhancing revascularization. However, the therapeutic efficacy of co-transplantation of BM-EPC with islets has not been investigated. In this study, marginal mass islets were co-transplanted with or without BM-EPCs under the kidney capsules of syngeneic streptozotocin-induced diabetic mice. Using green fluorescent protein transgenic (GFP-Tg) mice as BM-EPC and islet donors or recipients, the role of EPCs in revascularization was assessed for graft morphology, vascular density and fate of EPCs by immunohistochemistry. Islet-EPC co-transplantation improved the outcome of islet transplantation as measured by glucose tolerance, serum insulin level and diabetes reversal rate, compared with transplantation of islets alone. Between groups, the morphology of islet grafts showed significant differences in size and composition of grafted endocrine tissues. Significantly more vessel density derived from donors and recipients was detected with islet-EPC co-transplantation. Abundant GFP-Tg mice-derived BM-EPCs (GFP-EPCs) were observed in or around islet grafts and incorporated into CD31-positive capillaries. Remaining GFP-EPCs expressed VEGF. In conclusion, co-transplantation of islets with BM-EPCs could improve the outcome of marginal mass islet transplantation by promoting revascularization and preserving islet morphology.

Counting small hypointense spots confounds the quantification of functional islet mass based on islet MRI.

Iron-containing fragmented islets or free iron released from dying cells could confound the interpretation of MRI of iron nanoparticle-labeled islets. Exclusion of small hypointense spots could be a useful strategy to avoid such artifact. We investigated whether this strategy could improve the estimation of functioning islet mass after islet transplantation. Using a rat syngeneic intraportal islet transplantation model, we quantitatively assessed the relationships between total area, number of hypointense spots on MRI that belong to each size quartile and glycemic control of the recipients. The total area of hypointense spots on MRI was greater in the recipients that achieved diabetes reversal (p = 0.002), whereas the total number of hypointense spots was not different (p = 0.757). Exclusion of small hypointense spots improved the association between the number of hypointense spots and the blood glucose level of the recipients (p < 0.001). Ex-vivo imaging and histologic study confirmed that some small hypointense spots represent the phagocytosed free iron. Exclusion of small hypointense spots improved the quantification of the functional islet mass based on islet MRI. This would be a useful principle in the development of an algorithm to estimate functioning islet mass based on islet MRI.

Quantum electron star.

We construct and probe a holographic description of a state of matter that results from coupling a Fermi liquid to a relativistic conformal field theory (CFT). The bulk solution is described by a quantum gas of fermions supported from collapse into the gravitational well of anti-de Sitter space by their own electrostatic repulsion. A physical interpretation of our result is that, in the probe limit studied here, the Landau quasiparticles survive this coupling to a CFT.

Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in TRP4-/- mice.

Agonist-induced Ca2+ entry into cells by both store-operated channels and channels activated independently of Ca2+-store depletion has been described in various cell types. The molecular structures of these channels are unknown as is, in most cases, their impact on various cellular functions. Here we describe a store-operated Ca2+ current in vascular endothelium and show that endothelial cells of mice deficient in TRP4 (also known as CCE1) lack this current. As a consequence, agonist-induced Ca2+ entry and vasorelaxation is reduced markedly, showing that TRP4 is an indispensable component of store-operated channels in native endothelial cells and that these channels directly provide an Ca2+-entry pathway essentially contributing to the regulation of blood vessel tone.

DNA barcodes for two scale insect families, mealybugs (Hemiptera: Pseudococcidae) and armored scales (Hemiptera: Diaspididae).

Although DNA barcode coverage has grown rapidly for many insect orders, there are some groups, such as scale insects, where sequence recovery has been difficult. However, using a recently developed primer set, we recovered barcode records from 373 specimens, providing coverage for 75 species from 31 genera in two families. Overall success was >90% for mealybugs and >80% for armored scale species. The G·C content was very low in most species, averaging just 16.3%. Sequence divergences (K2P) between congeneric species averaged 10.7%, while intra-specific divergences averaged 0.97%. However, the latter value was inflated by high intra-specific divergence in nine taxa, cases that may indicate species overlooked by current taxonomic treatments. Our study establishes the feasibility of developing a comprehensive barcode library for scale insects and indicates that its construction will both create an effective system for identifying scale insects and reveal taxonomic situations worthy of deeper analysis.

MRI-Visible Perivascular Spaces in the Centrum Semiovale Are Associated with Brain Amyloid Deposition in Patients with Alzheimer Disease-Related Cognitive Impairment.

BACKGROUND AND PURPOSE: The association of perivascular spaces in the centrum semiovale with amyloid accumulation among patients with Alzheimer disease-related cognitive impairment is unknown. We evaluated this association in patients with Alzheimer disease-related cognitive impairment and ß-amyloid deposition, assessed with [18F] florbetaben PET/CT. MATERIALS AND METHODS: MR imaging and [18F] florbetaben PET/CT images of 144 patients with Alzheimer disease-related cognitive impairment were retrospectively evaluated. MR imaging-visible perivascular spaces were rated on a 4-point visual scale: a score of ≥3 or <3 indicated a high or low degree of MR imaging-visible perivascular spaces, respectively. Amyloid deposition was evaluated using the brain ß-amyloid plaque load scoring system. RESULTS: Compared with patients negative for ß-amyloid, those positive for it were older and more likely to have lower cognitive function, a diagnosis of Alzheimer disease, white matter hyperintensity, the Apolipoprotein E ε4 allele, and a high degree of MR imaging-visible perivascular spaces in the centrum semiovale. Multivariable analysis, adjusted for age and Apolipoprotein E status, revealed that a high degree of MR imaging-visible perivascular spaces in the centrum semiovale was independently associated with ß-amyloid positivity (odds ratio, 2.307; 95% CI, 1.036-5.136; P = .041). CONCLUSIONS: A high degree of MR imaging-visible perivascular spaces in the centrum semiovale independently predicted ß-amyloid positivity in patients with Alzheimer disease-related cognitive impairment. Thus, MR imaging-visible perivascular spaces in the centrum semiovale are associated with amyloid pathology of the brain and could be an indirect imaging marker of amyloid burden in patients with Alzheimer disease-related cognitive impairment.

The functional significance of microRNA-145 in prostate cancer.

BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNAs that have important roles in numerous cellular processes. Recent studies have shown aberrant expression of miRNAs in prostate cancer tissues and cell lines. On the basis of miRNA microarray data, we found that miR-145 is significantly downregulated in prostate cancer. METHODS AND RESULTS: We investigated the expression and functional significance of miR-145 in prostate cancer. The expression of miR-145 was low in all the prostate cell lines tested (PC3, LNCaP and DU145) compared with the normal cell line, PWR-1E, and in cancerous regions of human prostate tissue when compared with the matched adjacent normal. Overexpression of miR-145 in PC3-transfected cells resulted in increased apoptosis and an increase in cells in the G2/M phase, as detected by flow cytometry. Investigation of the mechanisms of inactivation of miR-145 through epigenetic pathways revealed significant DNA methylation of the miR-145 promoter region in prostate cancer cell lines. Microarray analyses of miR-145-overexpressing PC3 cells showed upregulation of the pro-apoptotic gene TNFSF10, which was confirmed by real-time PCR and western analysis. CONCLUSION: One of the genes significantly upregulated by miR-145 overexpression is the proapoptotic gene TNFSF10. Therefore, modulation of miR-145 may be an important therapeutic approach for the management of prostate cancer.

Interictal metabolic changes in episodic migraine: a voxel-based FDG-PET study.

Whereas there are many H(2)(15)O-positron emission tomography (PET) studies demonstrating neuronal activation during acute migraine attacks, little information is available on the interictal (headache-free period) glucose metabolic changes in migraine. We therefore conducted voxel-based statistical parametric mapping analysis of (18)F-fluorodeoxyglucose-PET to evaluate interictal metabolic differences between 20 episodic migraine patients (four with aura; three men; mean age 34.0 +/- 6.4 years) and 20 control subjects. Separate correlation analyses were performed to delineate a possible relationship between regional glucose metabolism and disease duration or lifetime headache frequency in migraine patients. Group comparison showed that migraine patients had significant hypometabolism in several regions known to be involved in central pain processing, such as bilateral insula, bilateral anterior and posterior cingulate cortex, left premotor and prefrontal cortex, and left primary somatosensory cortex (uncorrected P < 0.001, corrected P < 0.05 with small volume corrections). Correlation analyses showed that regional metabolism of the insula and anterior cingulate cortex had significant negative correlations with disease duration and lifetime headache frequency (uncorrected P < 0.001, corrected P < 0.05 with small volume corrections). Our findings of progressive glucose hypometabolism in relation to increasing disease duration and increasing headache frequency suggest that repeated migraine attacks over time lead to metabolic abnormalities of selective brain regions belonging to the central pain matrix.

Intraoperative high-dose remifentanil increases post-anaesthetic shivering.

BACKGROUND: Remifentanil is associated with increased incidence of post-anaesthetic shivering (PAS). The aim of this study was to compare the effects of intraoperative high and low doses of remifentanil on PAS. METHODS: We investigated 50 consecutive patients, aged <60 yr, who underwent gynaecological laparotomy. Patients who underwent prolonged surgery (>4 h) were excluded from the study. Anaesthesia throughout surgery was maintained with i.v. propofol and remifentanil, and epidural ropivacaine, and no nitrous oxide was used. Fifty patients were randomly assigned to receive intraoperative remifentanil at 0.1 microg kg(-1) min(-1) (low-dose group, n=25) or 0.25 microg kg(-1) min(-1) (high-dose group, n=25) until the end of surgery. Intraoperative analgesia was achieved by a fixed infusion rate of remifentanil and titrated epidural ropivacaine. PAS was evaluated by nursing stuff over the first hour after surgery. RESULTS: PAS occurred more frequently in the high-dose group than in the low-dose group (60% vs 20%, P=0.009). None of the patients complained of pain during the observation period due to epidural analgesia. There were no significant differences in rectal or palm skin temperature after extubation between the two dose groups. CONCLUSIONS: Remifentanil-induced PAS is not a phenomenon of intraoperative hypothermia. The higher incidence of PAS with higher doses of remifentanil probably reflects acute opioid tolerance and stimulation of N-methyl-d-aspartate receptors, similar to hyperalgesia. We conclude that patients administered high doses of remifentanil are sensitive to shivering after sudden drug withdrawal.