Hyperinsulinemic hypoglycemia subtype glucokinase V91L mutant induces necrosis in β-cells via ATP depletion.
Hyperinsulinemic hypoglycemia subtype glucokinase (GCK-HH) is caused by an activating mutation in glucokinase (GCK) and has been shown to increase β-cell death. However, the mechanism of β-cell death in GCK-HH remains poorly understood. Here, we expressed the GCK-HH V91L GCK mutant in INS-1 832/13 cells to determine the effect of the mutation on β-cell viability and the mechanisms of β-cell death. We showed that expression of the V91L GCK mutant in INS-1 832/13 cells resulted in a rapid glucose concentration-dependent loss of cell viability. At 11 mM D-glucose, INS-1 832/13 cells expressing V91L GCK showed increased cell permeability without significant increases in Annexin V staining or caspase 3/7 activation, indicating that these cells are primarily undergoing cell death via necrosis. Over-expression of SV40 large T antigen, which inhibits the p53 pathway, did not affect the V91L GCK-induced cell death. We also found that non-phosphorylatable L-glucose did not induce rapid cell death. Of note, glucose phosphorylation coincided with a 90% loss of intracellular ATP content. Thus, our data suggest that the GCK V91L mutant induces rapid necrosis in INS-1 cells through accelerated glucose phosphorylation, ATP depletion, and increased cell permeability.


A summertime peak of Down's syndrome in Franklin County, Ohio.
In June, July, and August of 1984, more infants than usual were born with Down's syndrome in Franklin County, Ohio. A direct physician survey was done, and chromosome reports were reviewed, resulting in the identification of 11 infants with Down's syndrome born during that period. Using a chi 2 analysis, the expected number of affected newborns was five, making the actual number of 11 significant. Although a summertime peak was observed, the yearly incidence of 1.09 per 1000 live births was within the expected range.


Dengue-associated kidney disease.
A mosquito-borne viral illness highly prevalent in the tropics and subtropics, dengue is considered a major global health threat by the World Health Organization. Directory of Open Access Journals (DOAJ), Google Scholar, PubMed (NLM), LISTA (EBSCO) and Web of Science have been searched. An RNA virus from the genus Flavivirus, dengue virus is transmitted by Aedes aegypti,the yellow fever mosquito. Dengue is asymptomatic in as many as one half of infected individuals. Dengue fever is an acute febrile illness accompanied by constitutional symptoms. Dengue hemorrhagic fever and dengue shock syndrome are the severe forms of dengue infection.Dengue infection has been associated with a variety of renal disorders. Acute renal failure is a potential complication of severe dengue infection and is typically associated with hypotension, rhabdomyolysis, or hemolysis. Acute renal failure complicates severe dengue infection in 2-5% of the cases and carries a high mortality rate. Proteinuria has been detected in as high as 74% of patients with severe dengue infection. Hematuria has been reported in up to 12.5% of patients. Various types of glomerulonephritis have been reported during or shortly after dengue infection in humans and mouse models of dengue infection. Mesangial proliferation and immune complex deposition are the dominant histologic features of dengue-associated glomerulonephritis. On a rare occasion, dengue infection is associated with systemic autoimmune disorders involving the kidneys. In the vast majority of cases, dengue infection and associated renal disorders are self-limited.


Study on antiviral activities, drug-likeness and molecular docking of bioactive compounds of Punica granatum L. to Herpes simplex virus - 2 (HSV-2).
Herpes simplex virus - 2 (HSV-2) causes lifelong persisting infection in the immunocompromised host and intermittent in healthy individuals with high morbidity in neonatals and also increase the transmission of HIV. Acyclovir is widely used drug to treat HSV-2 infection but it unable to control viral latency and recurrent infection and prolonged usage lead to drug resistance. Plant-based bioactive compounds are the lead structural bio-molecules play an inevitable role as a potential antiviral agent with reduced toxicity. Therefore, there is an urgent need to develop anti-HSV-2 bioactive molecules to prevent viral resistance and control of latent infection. Punica granatum fruit is rich in major bioactive compounds with potential antimicrobial properties. Hence, we evaluated the anti-HSV-2 efficacy of lyophilized extracts and bioactive compounds isolated from fruit peel of P. granatum. As a result, ethanolic peel extract showed significant inhibition at 62.5 μg/ml. Hence, the fruit peel ethanolic extract was subjected for the isolation of bioactive compounds isolation by bioactivity-guided fractionation. Among isolated bioactive compounds, punicalagin showed 100% anti-HSV-2 activity at 31.25 μg/ml with supportive evidence of desirable in silico ADMET properties and strong interactions to selected protein targets of HSV-2 by docking analysis.


Small cell carcinoma of gall bladder: An uncommon histologic entity.
Introduction: Gall bladder (GB) small cell carcinoma (SCC) comprises 0.5% of all gall bladder cancers. It carries a poor prognosis in view of its aggressive nature.
Case report: We here report a case of small cell carcinoma of GB in a female who presented with obstructive jaundice. Examination revealed a hard lump in the right upper abdomen. Tumour markers showed raised CA 19-9. Staging CECT of the thorax and abdomen reported polypoidal enhancing wall thickening of the gall bladder with multiple metastatic deposits close to the pancreatic head encasing the main portal vein and common bile duct. Histopathology report was suggestive of small cell carcinoma, which was confirmed by immunohistochemistry. Patient was referred to the Oncology Department for palliative chemotherapy.


Role of Na(+)-K+ pump and Na+ channel concentrations in the contractility of rat soleus muscle.
The dependence of contractile performance on the leak-to-pump ratio for Na+ has been examined. In isolated rat soleus muscle the concentration of Na(+)-K+ pumps was shown to decrease with age (-57%) or K+ deficiency (-69%), whereas Na+ channel concentration remained constant. This relative increase in the ratio between Na+ channels and Na(+)-K+ pumps was associated with a markedly faster rate of force decline (58 and 97%, respectively; both P < 0.001) during stimulation at 90 Hz and reduced subsequent force recovery (-34 and -38%, respectively; both P < 0.001). Similar effects were elicited by acute inhibition of Na(+)-K+ pump activity with ouabain. Preincubation with aconitine and veratridine, resulting in a 91 and 118% increase in Na+ influx per contraction, respectively (both P < 0.05), significantly hastened the initial rate of force decline (19%; P < 0.05 for aconitine and 69%; P < 0.001 for veratridine) and slowed recovery (-59 and -86%, respectively, both P < 0.001). It is concluded that the ratio between excitation-induced Na+ influx and Na(+)-K+ pump capacity is an important determinant for endurance and rate of recovery of force in skeletal muscle.


[Knowledge and evaluation of health-system reforms as reflected in social determinants].
Significant reforms have been instituted in Germany's health system in recent years. Although a number of studies have examined the population's knowledge of and attitudes towards the new regulations, little information is available on status-specific differences. This article examines the extent to which knowledge and evaluation of health policy measures is influenced by social determinants. The analysis draws on a survey conducted by the National Association of Statutory Health Insurance Physicians (Kassenärztliche Bundesvereinigung, 2009) based on a sample representative of the German population. In this context, 2 032 respondents aged between 18 and 79 years were interviewed on health-care policy issues. Results of bivariate analysis and logistic regression show that knowledge of the reform measures is significantly associated with educational level, age, and nationality. For example, respondents with the lowest level of formal education have an approximately four times higher risk as those with a higher level of formal education of not knowing about the health fund, and non-Germans have around twice the risk as Germans of not knowing about the reform measures. The main difference to emerge in respondents' EVALUATION of the reform measures is between East and West Germans. West Germans are significantly more likely than East Germans to evaluate the reform measures in negative terms. These status-specific differences in respondent knowledge can be attributed at least to some extent to the information asymmetry between patients and physicians/health-care providers. There is an urgent need for policy makers and care providers to render the reform measures transparent, accessible and comprehensible - especially to disadvantaged groups - to facilitate their effective implementation and positive evaluation.


Umbilical cord blood-derived mesenchymal stem cells inhibit, but adipose tissue-derived mesenchymal stem cells promote, glioblastoma multiforme proliferation.
Mesenchymal stem cells (MSCs) possess self-renewal and multipotential differentiation abilities, and they are thought to be one of the most reliable stem cell sources for a variety of cell therapies. Recently, cell therapy using MSCs has been studied as a novel therapeutic approach for cancers that show refractory progress and poor prognosis. MSCs from different tissues have different properties. However, the effect of different MSC properties on their application in anticancer therapies has not been thoroughly investigated. In this study, to characterize the anticancer therapeutic application of MSCs from different sources, we established two different kinds of human MSCs: umbilical cord blood-derived MSCs (UCB-MSCs) and adipose-tissue-derived MSCs (AT-MSCs). We used these MSCs in a coculture assay with primary glioblastoma multiforme (GBM) cells to analyze how MSCs from different sources can inhibit GBM growth. We found that UCB-MSCs inhibited GBM growth and caused apoptosis, but AT-MSCs promoted GBM growth. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling assay clearly demonstrated that UCB-MSCs promoted apoptosis of GBM via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL was expressed more highly by UCB-MSCs than by AT-MSCs. Higher mRNA expression levels of angiogenic factors (vascular endothelial growth factor, angiopoietin 1, platelet-derived growth factor, and insulin-like growth factor) and stromal-derived factor-1 (SDF-1/CXCL12) were observed in AT-MSCs, and highly vascularized tumors were developed when AT-MSCs and GBM were cotransplanted. Importantly, CXCL12 inhibited TRAIL activation of the apoptotic pathway in GBM, suggesting that AT-MSCs may support GBM development in vivo by at least two distinct mechanisms-promoting angiogenesis and inhibiting apoptosis. The opposite effects of AT-MSCs and UCB-MSCs on GBM clearly demonstrate that differences must be considered when choosing a stem cell source for safety in clinical application.


Drosophila topoisomerase I: isolation, purification and characterization.
We have purified and characterized topoisomerase I from Drosophila melanogaster. The molecular weight of the enzyme is 135,000; 100,000, 90,000, and 65,000 molecular weight products result from degradation of the enzyme. The enzyme relaxes both positive and negative supercoiled DNA. Mg++ is not absolutely required, but stimulates the enzymatic activity considerably.


Gene structure and expression of nanos (nos) and oskar (osk) orthologues of the vector mosquito, Culex quinquefasciatus.
The products of the maternal-effect genes, nanos (nos) and oskar (osk), are important for the development of germ cells in insects. Furthermore, these genes have been proposed as candidates for donating functional DNA regulatory sequences for use in gene drive systems to control transmission of mosquito-borne pathogens. The nos and osk genes of the cosmopolitan vector mosquito, Culex quinquefasciatus, encode proteins with domains common to orthologues found in other mosquitoes. Expression analyses support the conclusion that the role of these genes is conserved generally among members of the nematocera. Hybridization in situ analyses reveal differences in mRNA distribution in early embryos in comparison with the cyclorraphan, Drosophila melanogaster, highlighting a possible feature in the divergence of the clades each insect represents.


A case report of hereditary spherocytosis with concomitant chronic myelocytic leukemia.
Hereditary spherocytosis (HS) and Chronic myelocytic leukemia (CML) are both life threatening hemotologic diseases. They are rarely seen to occur simultaneously in one individual patient. Here we demonstrate a case of HS associated with CML in this study. The patient is a young female, diagnosed with HS in 2005, and was given partial embolization of the splenic artery. She got significant remission after the procedure. In 2008, she was found abnormal in blood routine test, after bone marrow routine, chromosome and fusion gene tests, she was diagnosed with CML (chronic phase). She did not receive regular treatment until 3 months prior, and is currently being treated with Dasatimib. She achieved hematological remission, but had no significant improvement in chromosome and fusion gene figures. Due to her severe condition of hemolysis, a splenectomy or an allogeneic hematopoietic stem cell transplantation is considered.


[Characteristics of the terminal segments of the lymphatic system of microcirculation according to the data of scanning electron microscopy].
Lymphatic capillaries and postcapillaries in the system of the connective tissue were studied by the method of scanning (raster) electron microscopy. It was shown that these capillaries consisted of chains of ballon-shaped structures-sinuses. Lymphatic capillaries represent an open system which is communicated with the intercellular matter of the connective tissue by means of openings ensuring filtration of the tissue liquid. Impairment of the absorbing function in the fibrous process in the lungs led to deposition in connective tissue cells of cellular detritus and foreign particles with formation around the walls of lymphatic capillaries and postcapillaries of residue-collector zones. Overgrowth of a rough fibrous tissue around these zones brought about atrophy and obliteration of vessels, gradual attenuation of the drenage function in the given region of microcirculation.


Innovative Antimicrobial Chitosan/ZnO/Ag NPs/Citronella Essential Oil Nanocomposite-Potential Coating for Grapes.
New packaging materials based on biopolymers are gaining increasing attention due to many advantages like biodegradability or existence of renewable sources. Grouping more antimicrobials agents in the same packaging can create a synergic effect, resulting in either a better antimicrobial activity against a wider spectrum of spoilage agents or a lower required quantity of antimicrobials. In the present work, we obtained a biodegradable antimicrobial film that can be used as packaging material for food. Films based on chitosan as biodegradable polymer, with ZnO and Ag nanoparticles as filler/antimicrobial agents were fabricated by a casting method. The nanoparticles were loaded with citronella essential oil (CEO) in order to enhance the antimicrobial activity of the nanocomposite films. The tests made on Gram-positive, Gram-negative, and fungal strains indicated a broad-spectrum antimicrobial activity, with inhibition diameters of over 30 mm for bacterial strains and over 20 mm for fungal strains. The synergic effect was evidenced by comparing the antimicrobial results with chitosan/ZnO/CEO or chitosan/Ag/CEO simple films. According to the literature and our preliminary studies, these formulations are suitable as coating for fruits. The obtained nanocomposite films presented lower water vapor permeability values when compared with the chitosan control film. The samples were characterized by SEM, fluorescence and UV-Vis spectroscopy, FTIR spectroscopy and microscopy, and thermal analysis.


Suppressive Effects of Aspirin for Postthoracotomy Pleural Adhesion in Rats.
Postoperative adhesion is one of major concerns at re-thoracotomy. Aspirin has both the anti-platelet and anti-inflammatory effects, and decreases several cytokines production. We investigated that aspirin could reduce postoperative adhesion formation in a rat model. We cauterised the lung visceral pleural to make postoperative adhesion in rats. The animals were allocated to a control group and an aspirin administration group (100 mg/kg/day for 14 days). We performed re-thoracotomy and evaluated the adhesion lengths on day 14. We also investigated the cytokine expression in the adhesion region and the peripheral tissue with platelet-derived growth factor (PDGF), platelet-derived growth factor receptor (PDGFR), alpha smooth muscle actin (α-SMA), transforming growth factor beta 1 (TGF-β1), and vascular endothelial growth factor-A (VEGF-A), sequentially. The adhesion lengths were significantly shorter in the aspirin group than that in the control group (8.7±2.0 mm vs 11.2±1.1 mm, p=0.024). The expressions of PDGF and PDGFR were lower in the aspirin group than that in the control group on day 3. The expression of α-SMA on fibroblasts decreased in the aspirin group on day 3. There was no significant difference in the expressions of TGF-β1 and VEGF-A with administration of aspirin. Aspirin could reduce postoperative pleural adhesion by inhibiting the expression of PDGF.


Recognition of IgG by Fcgamma receptor. The role of Fc glycosylation and the binding of peptide inhibitors.
Recently determined crystal structures of the complex between immunoglobulin constant regions (Fc) and their Fc-respective receptors (FcR) have revealed the detailed molecular interactions of this receptor-ligand pair. Of particular interest is the contribution of a glycosylation at Asn(297) of the C(H)2 domain of IgG to receptor recognition. The carbohydrate moieties are found outside the receptor.Fc interface in all receptor.Fc complex structures. To understand the role of glycosylation in FcR recognition, the receptor affinities of a deglycosylated IgG1 and its Fc fragment were determined by solution binding studies using surface plasmon resonance. The removal of carbohydrates resulted in a non-detectable receptor binding to the Fc alone and a 15- to 20-fold reduction of the receptor binding to IgG1, suggesting that the carbohydrates are important in the function of the FcgammaRIII. Structurally, the carbohydrates attached to Asn(297) fill the cavity between the C(H)2 domains of Fc functioning equivalently as a hydrophobic core. This may stabilize a favorable lower hinge conformation for the receptor binding. The structure of the complex also revealed the dominance of the lower hinge region in receptor.Fc recognition. To evaluate the potential of designing small molecular ligands to inhibit the receptor function, four lower hinge peptides were investigated for their ability to bind to the receptor FcgammaRIII. These peptides bind specifically to FcgammaRIII with affinities 20- to 100-fold lower than IgG1 and are able to compete with Fc in receptor binding. The results of peptide binding illustrate new ways of designing therapeutic compounds to block Fc receptor activation.


Inhibition, enhancement, and control of spontaneous emission in photonic nanowires.
We experimentally investigate the spontaneous emission (SE) rates of single InAs quantum dots embedded in GaAs photonic nanowires. For a diameter leading to the optimal confinement of the fundamental guided mode HE11, the coupling to HE11 dominates the SE process and an increase of the SE rate by a factor of 1.5 is achieved. When the diameter is decreased, the coupling to this mode vanishes rapidly, thus allowing the coupling to the other radiation modes to be probed. In these conditions, a SE inhibition factor of 16, equivalent to the one obtained in state-of-the-art photonic crystals, is measured. These results, which are supported by fully vectorial calculations, confirm the potential of photonic nanowires for a nearly perfect, broadband SE control.


Validation of a miniature thermochron for monitoring thoracolumbosacral orthosis wear time.
Prospective validation study. To establish the accuracy of miniature thermochrons for estimating thoracolumbosacral orthosis (TLSO) wear time in patients with adolescent idiopathic scoliosis. There has been an emphasis in recent years on measuring wear time as opposed to using subjective methods such as relying on the patient or parent estimation. By measuring the amount of time that was spent in the orthosis, uncertainty is reduced and the validity of the research is improved. Several types of devices have been employed for direct monitoring of orthosis wear time including strap tension monitors, pressure sensors, and temperature-time sensors (thermochrons). Direct monitoring studies have shown that relying on patient or parent report is inaccurate; the patient/parent report is clearly biased towards overestimation of wear time. Three miniature thermochrons (DS1922L iButton, Maxim Integrated Products, Inc., Sunnyvale, CA) were mounted underneath padding in the TLSOs of 7 participants diagnosed with adolescent idiopathic scoliosis. The participants wore their TLSO for 1 month. During this time, participants kept meticulous records of wear time in diaries. An algorithm was developed to automatically detect donning/doffing of the orthosis, and the results of the data reduction algorithm were compared with the diary (gold standard). Total wear time accuracy was 98.5% (0.37 hours/day), while the precise timing of donning/doffing was 92% accurate. An inexpensive, commercially available miniature thermochron and a simple robust algorithm can estimate TLSO wear time to a high degree of accuracy. This method is suitable for large-scale prospective studies examining the efficacy of bracing in adolescent idiopathic scoliosis, which remains a topic of controversy.


Patients with spinal deformity over the age of 75: a retrospective analysis of operative versus non-operative management.
The goal of the present study was to compare the outcomes of operative and non-operative patients with adult spinal deformity (ASD) over 75 years of age. A retrospective review of a multicenter prospective adult spinal deformity database was conducted examining patients with ASD over the age of 75 years. Demographics, comorbidities, operation-related variables, complications, radiographs, and Health-related quality of life (HRQOL) measures collected included Oswestry Disability Index, Short Form-36, and Scoliosis Research Society-22 preoperatively, and at 1 and 2 years later. Minimum clinically important difference (MCID) was calculated and also compared. 27 patients (12 operative, 15 non-operative) were studied. There were no significant differences (p > 0.05) between operative and non-operative patients for age, body mass-index, and comorbidities, but operative patients had worse baseline HRQOL than non-operative patients. Operative patients had a significant improvement in radiographic parameters in 2-year HRQOL, whereas non-operative patients did not (p > 0.05). Operative patients were significantly more likely to reach MCID (range 41.7-81.8 vs. 0-33.3 %, p < 0.05). In the surgical group, 9 (75 %) patients had at least 1 complication (24 total complications). In the largest series to date comparing operative and non-operative management of adult spinal deformity in elderly patients greater than 75 years of age, reconstructive surgery provides significant improvements in pain and disability over a 2-year period. Furthermore, operative patients were more likely to reach MCID than non-operative patients. When counseling elderly patients with ASD, such data may be helpful in the decision-making process regarding treatment.


Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an endogenous secreted peptide and, in preclinical studies, preferentially induces apoptosis in tumor cells rather than in normal cells. The acquisition of resistance in cells exposed to TRAIL or its mimics limits their clinical efficacy. Because kinases are intimately involved in the regulation of apoptosis, we systematically characterized kinases involved in TRAIL signaling. Using RNA interference (RNAi) loss-of-function and cDNA overexpression screens, we identified 169 protein kinases that influenced the dynamics of TRAIL-induced apoptosis in the colon adenocarcinoma cell line DLD-1. We classified the kinases as sensitizers or resistors or modulators, depending on the effect that knockdown and overexpression had on TRAIL-induced apoptosis. Two of these kinases that were classified as resistors were PX domain-containing serine/threonine kinase (PXK) and AP2-associated kinase 1 (AAK1), which promote receptor endocytosis and may enable cells to resist TRAIL-induced apoptosis by enhancing endocytosis of the TRAIL receptors. We assembled protein interaction maps using mass spectrometry-based protein interaction analysis and quantitative phosphoproteomics. With these protein interaction maps, we modeled information flow through the networks and identified apoptosis-modifying kinases that are highly connected to regulated substrates downstream of TRAIL. The results of this analysis provide a resource of potential targets for the development of TRAIL combination therapies to selectively kill cancer cells.


Long-term Outcome of Primary Closure After Laparoscopic Common Bile Duct Exploration Combined With Choledochoscopy.
Primary closure after laparoscopic common bile duct exploration (LCBDE) is considered to be a safe alternative to T-tube drainage on the basis of the short-term outcome. However, little published data exist regarding the biliary complications at the long-term follow-up of primary closure versus T-tube drainage following LCBDE. Hence, the aim of this study is to assess the long-term outcome of primary closure after LCBDE. This is a retrospective study of 142 consecutive patients who underwent LCBDE combined with choledochoscopy for CBD stones. After LCBDE, the choledochotomy was closed by primary closure (group P) in 91 patients (64.1%) and with T-tube drainage (group T) in 51 patients (35.9%). The data on operative outcome and long-term biliary complications were compared between the 2 groups. The mean operation time was significantly shorter in group P than group T (168.9 ± 50.1 min for group P vs. 198.0 ± 59.6 min for group T, P = 0.002). The hospital stay was significantly shorter in group P than in group T (8.59 ± 6.0 d for group P vs. 14.96 ± 5.4 d for group T, P = 0.001). Postoperative bile leak occurred in 2 patients (2.2%) in group P and 1 patient (2.0%) in group T. With a mean follow-up of 48.8 months, the stone recurrence rate in group P and group T were 4.4% and 5.9%, respectively (P = 0.722). During the follow-up period, there was no sign of biliary stricture or other biliary complications in both groups. The long-term follow-up data on primary closure after LCBDE indicated a low incidence of recurrent stones, and no biliary strictures. Thus, primary closure after LCBDE with choledochoscopy is considered to be a safe and effective alternative to T-tube drainage in terms of long-term outcome.


Diffraction-biased shear wave fields generated with longitudinal magnetic resonance elastography drivers.
Magnetic resonance elastography (MRE) is a technique for quantifying the acoustic response of biological tissues to propagating waves applied at low frequencies in order to evaluate mechanical properties. Application-specific MRE drivers are typically required to effectively deliver shear waves within the tissue of interest. Surface MRE drivers with transversely oriented vibrations have often been used to directly generate shear waves. These drivers may have disadvantages in certain applications, such as poor penetration depth and inflexible orientation. Therefore, surface MRE drivers with longitudinally oriented vibrations are used in some situations. The purpose of this work was to investigate and optimize a longitudinal driver system for MRE applications. A cone-like hemispherical distribution of shear waves being generated by these drivers and the wave propagation being governed by diffraction in the near field are shown. Using MRE visualization of the vector displacement field, we studied the properties of the shear wave field created by longitudinal MRE drivers of various sizes to identify optimum shear wave imaging planes. The results offer insights and improvements in both experimental design and imaging plane selection for 2-D MRE data acquisition.


Novel solution route synthesis of low thermal conductivity nanocrystalline bismuth telluride.
A novel synthesis approach based on a solution route has been developed for the fabrication of nanocrystalline bismuth telluride. The method consists of dissolving both bismuth and tellurium into the same organic solvent with the assistance of complexing agents and one-step coprecipitation of bismuth telluride. The synthesized nanocrystalline bismuth telluride powders possess rhombohedral crystal structure and are nanosheet/nanorod-like with an average size of between 30 and 40 nm. The thermal conductivity of the hot-pressed compact consolidated from the as-synthesized nanopowders is 0.39-0.45 Wm(-1)K(-1) in the temperature range of 323 to 523 K, which is at most one third of that of bulk bismuth telluride-based materials reported in the literature. Such low thermal conductivity of the investigated bismuth telluride is mainly attributed to substantially high concentration of grain boundaries provided by nanostructuring to scatter phonons intensively.


Effect of magnesium, high altitude and acute mountain sickness on blood flow velocity in the middle cerebral artery.
Cerebral blood flow is thought to increase at high altitude and in subjects suffering from acute mountain sickness (AMS); however, data from the literature are contentious. Blood flow velocity in the middle cerebral artery (MCAv) may be used as a proxy measure of cerebral blood flow. Using transcranial Doppler sonography, MCAv was measured during normo- and hyper-ventilation in subjects who participated in a trial that tested the effect of magnesium supplementation on the prevention of AMS. First, MCAv was recorded at 353 m (baseline). Subjects were then randomized to receive oral magnesium citrate and matching placebo. A second measurement was taken after a 24 +/- 2 h ascent from 1130 m to 4559 m (altitude I), and a third after a 20-24 h stay at 4559 m (altitude II). Using multivariate linear regression, an association was sought between MCAv and magnesium supplementation, subjects' age and gender, altitude itself, a temporary stay at altitude, and the presence of AMS (Lake Louise Score >6 with ataxia, nausea and/or headache). Subjects with AMS had additional Doppler recordings immediately before and after rescue medication (oxygen, dexamethasone and acetazolamide). Forty-seven subjects had measurements at baseline, 39 (21 receiving magnesium and 18 placebo) at altitude I and 26 (13 receiving magnesium and 13 placebo) at altitude II. During hyperventilation, MCAv decreased consistently (for each measurement, P<0.001). Magnesium significantly increased MCAv by 8.4 cm.s(-1) (95% confidence interval, 1.8-15), but did not prevent AMS. No other factors were associated with MCAv. Eleven subjects had severe AMS [median score (range), 11 (8-16)] and, after rescue medication, the median score decreased to 3 (range, 0-5; P=0.001), but MCAv remained unchanged (65 +/- 18 cm.s(-1) before compared with 67 +/- 16 cm.s(-1) after rescue medication; P=0.79). MCAv was increased in subjects who received magnesium, but was not affected by exposure to high altitude or by severe AMS.


Synthesis of L-iduronic acid derivatives via [3.2.1] and [2.2.2] L-iduronic lactones from bulk glucose-derived cyanohydrin hydrolysis: a reversible conformationally switched superdisarmed/rearmed lactone route to heparin disaccharides.
L-Idofuranoside cyanohydrin 1 is converted on large scale into a mixture of L-IdoA methyl pyranosides and furanosides, which is converged to provide short 2-step routes to bicyclic [3.2.1] or [2.2.2] L-iduronate lactones. The former is obtained via a 100 g scale synthesis of 3-OBn L-IdoA. A two-step conversion of this mixture provides either pure anomer of the novel [2.2.2] l-iduronate thioglycoside lactones. Both [3.2.1] and [2.2.2] lactones are converted into GlcN-IdoA heparin precursor disaccharides. The [2.2.2] lactone enables a scalable 3-step route from 1 to a new type of highly disarmed O-4 iduronate thioglycoside, which is an effective acceptor with glucoazide thioglycoside donors. The resulting new iduronic [2.2.2] lactone disaccharides are readily rearmed by mild methanolysis to provide GlcN-IdoA thiophenyl disaccharide donors, intercepting their established utility for the assembly of both heparin- and heparan sulfate-like oligosaccharides. The [2.2.2] lactonization acts as a conformational switch to superdisarm iduronate components, reversible by lactone ring opening. In addition, the separated 2,4-diacetates also provide short access to all four anomeric and ring size isomers of l-iduronic acid methyl glycosides, including the first syntheses of the parent idofuranosides. X-ray structures are reported for a [2.2.2] iduronate lactone and examples of both methyl L-idopyranoside and novel methyl-L-idofuranoside systems.


Epidemiological and clinical characteristics of scorpionism in Colima, Mexico (2000-2001).
We analyzed 13,223 clinical records of patients treated for scorpion sting in hospitals of the Mexican Institute of Public Health and the Ministry of Health in the state of Colima, Mexico, during the years 2000-2001. A database containing demographic, epidemiological and clinical information was constructed and analyzed retrospectively. Patients were classified in the categories as mild (49.2%), moderate (33.8%) and severe (17.0%) according to commonly accepted standards. Most common symptoms recorded were local pain (94.7%), local paresthesia (67.2%), pruritus/itching (54.3%), sensation of a lump or hair in the throat (47.3%), and sialorrhoea (27.7%). The median time from sting to admission to the emergency room (patient delay) was 33min (interquartile range: 12-60). We found that older and clinically severe patients were significantly associated with longer times of admission to the emergency room. Age was significantly associated with clinical severity: the age group 0-10 years included a higher proportion of severe cases than the group 11 years and older. In four cases, patients died. An educational campaign to inform the population about the importance of receiving prompt attention following a scorpion sting has potential value in reducing complications in the emergency room.


Update on Eluxadoline for the Treatment of Irritable Bowel Syndrome with Diarrhea: Patient Selection and Perspectives.
Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by chronic abdominal pain associated with changes in bowel habits. It is the most common GI problem seen by gastroenterologists. IBS is a heterogenous disorder encompassing a spectrum of underlying mechanisms and clinical presentations. The pathophysiology of diarrhea-predominant form of IBS (IBS-D) remains poorly understood, and current available therapeutic options for IBS-D are limited. Eluxadoline is a novel, locally acting mixed μ- and κ-opioid receptor agonist and δ-receptor antagonist approved by the Food and Drug Administration (FDA) for treatment of adults with IBS-D. Data from two phase III clinical trials showed that approximately 25-30% of the eluxadoline-treated patients achieved composite clinical response, defined by a reduction of abdominal pain and improvement in stool consistency. Patients who achieve composite response during the first month of therapy were significantly more likely to demonstrate sustained clinical response. The most common adverse events reported with eluxadoline use were constipation, nausea and abdominal pain. The risk of abuse, dependence, or withdrawal is low. Serious adverse events associated with eluxadoline include sphincter of Oddi spasm (SOS) and pancreatitis particularly in patients without a gallbladder. Development of pancreatitis is likely secondary to SOS, but it remains unclear why pancreatitis occurs so quickly after initial doses. This adverse event profile helps guide proper selection of IBS-D patients for eluxadoline use, with important contraindications including absence of a gallbladder, biliary duct obstruction or sphincter of Oddi dysfunction, alcoholism, history of pancreatitis, or structural diseases of the pancreas. With the recent clinical trials demonstrating its efficacy, eluxadoline provides an additional option to the few existing pharmacologic interventions available for IBS-D. In this review, we discuss the drug development, efficacy and safety of eluxadoline, as well as selection criteria for identifying appropriate candidates for this medication.


Visual grouping on binocular rivalry in a split-brain observer.
We studied the effects of visual grouping on binocular rivalry in the left and right hemispheres of a split-brain observer, JW. In Experiments 1 and 2, we compared responses to traditional rivalry stimuli (e.g., a red vertical grating presented to the left eye and a green horizontal grating presented to the right eye) with responses to Diaz-Caneja stimuli (i.e., half of each grating was presented to one eye and the other half to the other eye). As found for intact-brain observers, JW reported episodes of exclusive visibility of coherent stimuli (e.g., of a red vertical grating alternating with a green horizontal grating) with Diaz-Caneja stimuli that were fewer and briefer than with traditional stimuli. This occurred in both hemispheres, demonstrating that during binocular rivalry, contours from one eye can be grouped with those of the opposite eye to create a coherent percept, even in the isolated hemispheres of the split-brain observer. In Experiment 3, we studied the tendency of rivalry in adjacent patches to synchronize. When both patches were in one of JW's hemifields, rivalry synchronized for similarly oriented stimuli, the same as happened for intact-brain observers. When the patches were in JW's opposite hemifields, there was no synchronizing of rivalry, unlike what happened for intact-brain observers. This suggests that rivalry processed in JW's two hemispheres is independent. We conclude that rivalry is processed fully within each hemisphere.


Spatial organization of silybin biosynthesis in milk thistle [Silybum marianum (L.) Gaertn].
Silymarin is a collection of compounds extracted from the medicinal herb milk thistle, among which silybin is the major flavonolignan. However, the biosynthesis pathway of silybin remains unclear. In this study, biomimetic reactions demonstrated that silybin can be synthesized from coniferyl alcohol and taxifolin by the action of peroxidase. The concentration profiles of silybin and its precursors and RNA-Seq analysis of gene expression revealed that the amount of taxifolin and the activity of peroxidase serve as the limiting factors in silybin biosynthesis. Hierarchical clustering of the expression profile of genes of the flavonoid biosynthesis pathway distinguished flowers from other organs. RNA-Seq revealed five candidates for the peroxidase involved in silybin production, among which APX1 (ascorbate peroxidase 1) showed a distinct peroxidase activity and the capacity to synthesize silybin. The spatial organization of silybin biosynthesis in milk thistle was elucidated, which could help our understanding of the biosynthesis of silybin and other flavonolignans.


[Method of assessing the functional activity of tumor-associated suppressor cells].
A relatively simple and easily reproducible method is presented for testing the activity of tumour-associated suppressor cells in the syngeneic system. It includes adoptive transfer and radioactive assay of the inhibition degree of the specific proliferative response to tumour cells of syngeneic recipients.


Development and characterization of Triticum turgidum - Aegilops comosa and T. turgidum - Ae. markgrafii amphidiploids.
Aegilops comosa and Ae. markgrafii are diploid progenitors of polyploidy species of Aegilops sharing M and C genomes, respectively. Transferring valuable genes/traits from Aegilops into wheat is an alternative strategy for wheat genetic improvement. The amphidiploids between diploid species of Aegilops and tetraploid wheat can act as bridges to overcome obstacles from direct hybridization and can be developed by the union of unreduced gametes. In this study, we developed seven Triticum turgidum - Ae. comosa and two T. turgidum - Ae. markgrafii amphidiploids. The unreduced gametes mechanisms, including first-division restitution (FDR) and single-division meiosis (SDM), were observed in triploid F1 hybrids of T. turgidum - Ae. comosa (STM) and T. turgidum - Ae. markgrafii (STC). Only FDR was observed in STC hybrids, whereas FDR or both FDR and SDM were detected in the STM hybrids. All seven pairs of M chromosomes of Ae. comosa and C chromosomes of Ae. markgrafii were distinguished by fluorescent in situ hybridization (FISH) probes pSc119.2 and pTa71 combinations with pTa-535 and (CTT)12/(ACT)7, respectively. Meanwhile, the chromosomes of tetraploid wheat and diploid Aegilops parents were distinguished by the same FISH probes. The amphidiploids possessed specific valuable traits such as multiple tillers, large seed size related traits, and stripe rust resistance that could be utilized in the genetic improvement of wheat.


Violence, abuse, alcohol and drug use, and sexual behaviors in street children of Greater Cairo and Alexandria, Egypt.
To measure the prevalence of HIV/AIDS risk behaviors and related factors in a large, probability-based sample of boys and girls aged 12-17 years living on the streets of Egypt's largest urban centers of Greater Cairo and Alexandria. Time-location sampling (TLS) was used to recruit a cross-sectional sample of street children. Procedures entailed using key informants and field observation to create a sampling frame of locations at predetermined time intervals of the day, where street children congregate in the two cities, selecting a random sample of time-locations from the complete list, and intercepting children in the selected time-locations to assess eligibility and conduct interviews. Interviews gathered basic demographic information, life events on the street (including violence, abuse, forced sex), sexual and drug use behaviors, and HIV/AIDS knowledge. A total of 857 street children were enrolled in the two cities, with an age, sex, and time-location composition matching the sampling frame. The majority of these children had faced harassment or abuse (93%) typically by police and other street children, had used drugs (62%), and, among the older adolescents, were sexually active (67%). Among the sexually active 15-17-year-olds, most reported multiple partners (54%) and never using condoms (52%). Most girls (53% in Greater Cairo and 90% in Alexandria) had experienced sexual abuse. The majority of street children experienced more than one of these risks. Overlaps with populations at highest risk for HIV were substantial, namely men who have sex with men, commercial sex workers, and injection drug users. Our study using a randomized TLS approach produced a rigorous, diverse, probability-based sample of street children and documented very high levels of multiple concurrent risks. Our findings strongly advocate for multiple services including those addressing HIV and STI prevention and care, substance use, shelters, and sensitization of authorities to the plight of street children in Egypt.


Development of a novel hyaluronic acid membrane for the treatment of ocular surface diseases.
Ocular surface diseases (OSD) can cause serious visual deterioration and discomfort. Commercial artificial tear solution containing hyaluronic acid (HA) show excellent biocompatibility and unique viscoelastic characteristics. Here, we developed a novel HA membrane (HAM) by chemical crosslinking using 1,4-butanediol diglycidyl ether for the effective treatment of OSDs. The main purpose of HAMs is to provide sustained release of HA to modulate the wound healing response in OSDs. The safety and efficacy of HAMs were investigated using primary cultured human corneal epithelial cells and various OSD rabbit models. In the dry state, the HAM is firm, transparent, and easy to manipulate. When hydrated, it swells rapidly with high water retention and over 90% transmission of visible light. Human corneal epithelial cells and rabbit eyes showed no toxic response to HAM. Addition of HAMs to the culture medium enhanced human corneal epithelial cell viability and expression of cell proliferation markers. Investigation of HAM wound healing efficacy using mechanical or chemical corneal trauma and conjunctival surgery in rabbits revealed that application of HAMs to the ocular surface enhanced healing of corneal epithelium and reduced corneal limbal vascularization, opacity and conjunctival fibrosis. The therapeutic potential of HAMs in various OSDs was successfully demonstrated.


Dickkopf-1: a suitable target for the management of myeloma bone disease.
Bone disease remains a major problem in the management of patients with multiple myeloma (MM) and is characterized by the presence of lytic lesions due to increased osteoclastic activity and reduced osteoblast function. Wingless-type and integrase 1 (Wnt)/beta-catenin signaling is a central pathway for bone development and homeostasis. Dickkopf-1 (Dkk-1) is a soluble inhibitor of Wnt, which disrupts osteoblast differentiation and action. Dkk-1 is produced by myeloma cells and overexpressed in myeloma microenvironment of patients with extensive bone disease. In addition to its direct inhibitory effect of Dkk-1 on osteoblasts, Dkk-1 disrupts the Wnt3a-regulated osteoprotegerin and receptor activator of NF-kappaB ligand (RANKL) expression in osteoblasts and thus it indirectly enhances osteoclast function in MM. Dkk-1 serum and bone marrow plasma levels are increased in MM patients and correlated with advanced International Staging System stage and presence of osteolytic lesions. Preclinical studies in mouse myeloma models showed that targeting Dkk-1 with neutralizing anti-Dkk-1 antibodies resulted in increased numbers of osteoblasts, reduced numbers of multinucleated osteoclasts and increased bone volume. The bone anabolic effect of anti-Dkk-1 may also be associated with reduced myeloma burden. These data show that Dkk-1 has a pivotal role in bone health and disease and is a novel target for the management of myeloma patients with lytic bone disease.


Lesions of area postrema attenuate but do not prevent anorectic action of peripheral serotonin in rats.
These studies assessed the effect of selectively ablating the area postrema (AP) on the action of peripheral serotonin [5-hydroxytryptamine (5-HT)] to reduce food intake in rats. Intraperitoneal 5-HT (0, 2.0, 4.0, and 8.0 mumol/kg) reduced the intakes of sweetened mash during a 30-min test in controls (APC) and in AP-lesioned rats (APX). The anorexia was dose dependent in controls but the dose-response function was flat after AP lesions. In another study, 2.0 mumol/kg 5-HT reduced intakes of both groups by approximately 25%, but AP lesions blunted the effect at 8.0 mumol/kg 5-HT (APX, -30% vs. APC, -85%). Behavioral analysis revealed that, compared with controls, AP lesions eliminated the decrease in frequency of feeding and reduced the incidence of resting and of an aberrant posture observed after 8.0 mumol/kg. Thus peripheral 5-HT decreases food intake in rats with AP lesions. Multiple mechanisms appear to be involved in the ability of peripheral 5-HT to reduce feeding. A high dose of 5-HT promotes responses associated with satiation but also produces behavioral toxicity; these effects involve the AP. Lower doses appear to engage processes that do not rely on the function of this circumventricular organ.


A guide to finite element analysis models of the spine for clinicians.
Finite element analysis (FEA) is a computer-based mathematical method commonly used in spine and orthopedic biomechanical research. Advances in computational power and engineering modeling and analysis software have enabled many recent technical applications of FEA. Through the use of FEA, a wide range of scenarios can be simulated, such as physiological processes, mechanisms of disease and injury, and the efficacy of surgical procedures. Such models have the potential to enhance clinical studies by allowing comparisons of surgical treatments that would be impractical to perform in human or animal studies, and by linking model results to treatment outcomes. While traditional ex vivo experiments are limited by variabilities in tissue, the complexity of test setup, cost, measurable biomechanical parameters, and the repeatability of experiments, FEA models can be used to measure a wide range of clinically relevant biomechanical parameters. Generic or patient-specific anatomical models can be modified to simulate different clinical and surgical conditions under simulated physiological conditions. Despite these capabilities, there is limited understanding of the clinical applicability and translational potential of FEA models. For spine surgeons, a comprehensive understanding of the key features, strengths, and limitations of FEA models of the spine and their ability to personalize treatment options and assist in clinical decision-making would significantly enhance the impact of FEA research. Furthermore, fostering collaborations between surgeons and engineers could augment the clinical use of these models. The purpose of this review was to highlight key features of FEA model building for clinicians. To illustrate these features, the authors present an example of the use of FEA models in comparing FDA-approved disc arthroplasty implants.


Unusual manifestations of infections due to Mycoplasma pneumoniae in children.
Mycoplasma pneumoniae (Mp) is an important cause of pneumonia in paediatric age, but also other organs or systems can be affected even without pulmonary involvement. The purpose of this study is to stress the unusual clinical features of Mp infection in children. A review of children affected with Mp infection with peculiar pulmonary and/or extra-pulmonary forms is reported. Diagnosis of Mp infection was always confirmed by serum anti-Mp antibody assay. Two patients with infection of the lower airways showed severe respiratory distress; nine cases with only extra-pulmonary manifestations presented urticaria and arthralgia; three patients had severe neuromuscular impairment, one of these resulting in flaccid tetraparesis; one 2-year-old child had anicteric hepatitis, without any sequelae; one case of a 6-year-old child presented severe haemolytic anaemia, and a 5-year-old child with Schonlein-Henoch purpura. In conclusion, Mp infection, a frequent cause of pneumonia at all paediatric ages, may also give rise to extrapulmonary manifestations. Frequently, muscular-articular or neurological systems, skin or other organs are involved. Clinical suspicion of Mp infection is essential in severe cases and the outcome of all pulmonary and/or extra-pulmonary manifestations depends on early diagnosis and specific therapy.


Overview of alopecia areata.
Alopecia areata is a complex genetic, immune-mediated disease that targets anagen hair follicles. The disease affects children and adults and is characterized by round or oval patches of hair loss, loss of all scalp hair (alopecia totalis), body hair (alopecia universalis), or ophiasis pattern hair loss. Patients may also present with patchy loss in multiple hair-bearing areas. Commonly associated diseases include asthma, allergic rhinitis, atopic dermatitis, thyroid disease, and automimmune diseases, such as thyroiditis and vitiligo. Nail abnormalities may precede, follow, or occur concurrently with hair loss activity. Alopecia areata has no known age, race, or ethnic preponderance and in contrast to other autoimmune diseases such as thyroiditis or lupus, the hair follicle does not usually sustain permanent injury and maintains its potential to regrow hair. It is estimated that alopecia areata affects between six and seven million individuals in the United States. Genes, the immune and nervous systems have all been implicated in the pathogenesis of alopecia areata. Although many treatments are available, there is still no cure. Bolstered by new scientific and translational opportunities from recently published genome-wide association studies, an ambitious treatment development program has recently been initiated by the National Alopecia Areata Foundation.


Association of depression and obesity with C-reactive protein in Germany: A large nationally representative study.
Depression and obesity often occur comorbidly, and once both are present, they further increase the risk of developing other medical comorbidities, likely due to the underlying chronic low-grade inflammation. We investigated to what extent depression and obesity are associated with levels of high-sensitivity C-reactive protein (hsCRP) in a nationally representative sample of the German adult population. We analyzed data from the German Health Interview and Examination Survey for Adults (DEGS1, N = 7115), and its mental health module (DEGS1-MH; N = 4483). Two different depression measures were used: current depressive symptoms assessed by the self-administered German version of the Patient Health Questionnaire-9 and major depressive disorder (MDD) in the last 12 months assessed by a modified German version of the Composite International Diagnostic Interview. Obesity was defined by body mass index calculated from measured data. Associations with log(x + 1)-transformed hsCRP levels were analyzed using multivariable linear regression models. Obese participants with depressive symptoms had significantly higher hsCRP compared to non-obese participants with depressive symptoms adjusted for sociodemographic and behavioral variables and medication use. In non-obese individuals, depressive symptoms were inversely associated with hsCRP, whereas MDD was not associated with hsCRP after adjustment for covariates. Additional analyses suggested symptom-specific associations of hsCRP as higher levels were linked to fatigue (β = 0.10, p <.001) while lower levels were linked to cognitive problems (β = -0.09, p <.001). Low SES, current smoking, lower levels of physical exercise, and the use of anti-inflammatory/anti-rheumatic medication and antidepressants were additional determinants of hsCRP in the fully adjusted models. Our data suggest that obesity status is more strongly associated with increased inflammation than depressive symptoms or MDD. The relationship between depression and hsCRP in our population-based sample is substantially influenced by obesity status as well as other medical factors, lifestyle, and socioeconomic status. Furthermore, our findings suggest that the association between hsCRP and depression is symptom-specific rather than generalized.


Fludeoxyglucose positron emission tomography in the diagnosis of giant cell arteritis.
We describe a case in which fludeoxyglucose F 18 positron emission tomography (PET) led directly to the diagnosis of giant cell arteritis in an elderly woman with a fever of unknown origin. The patient presented with a 3-month history of fatigue, fever, headache, visual disturbance, jaw claudication, and anemia. A computed tomographic scan showed an anterior mediastinal mass that was suspected of being malignant. A fludeoxyglucose F 18 PET scan performed for preoperative evaluation identified striking uptake of fludeoxyglucose F 18 in the walls of the entire aorta, left main coronary artery, and subclavian, carotid, and common iliac arteries bilaterally, suggestive of an arteritis, a diagnosis subsequently confirmed by the findings of an arterial biopsy. Her erythrocyte sedimentation rate was 129 mm/h. There was normalizaton of the PET scan 2 weeks following treatment with prednisolone. This case suggests that fludeoxyglucose F 18 PET contributes to the noninvasive diagnosis of giant cell arteritis, as well as to the evaluation of the extent of disease, response to therapy, and disease recurrence.


Caspase-Mediated Anti-Apoptotic Effect of Ginsenoside Rg5, a Main Rare Ginsenoside, on Acetaminophen-Induced Hepatotoxicity in Mice.
Frequent overdose of acetaminophen (APAP) is one of the most common and important incentives of acute hepatotoxicity. Prior to this work, our research group confirmed that black ginseng (Panax ginseng, BG) showed powerful protective effects on APAP-induced ALI. However, it is not clear which kind of individual ginsenoside from BG plays such a liver protection effect. The objective of the current investigation was to evaluate whether ginsenoside Rg5 (G-Rg5) protected against APAP-induced hepatotoxicity and the involved action mechanisms. Mice were administrated with G-Rg5 at two dosages of 10 or 20 mg/kg for 7 consecutive days. After the last treatment, all of the animals that received a single intraperitoneal injection of APAP (250 mg/kg) showed severe liver toxicity after 24 h, and the liver protection effects of G-Rg5 were examined. The results clearly indicated that pretreatment with G-Rg5 remarkably inhibited the production of serum tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) compared with the APAP group. Meanwhile, G-Rg5 decreased the hepatic malondialdehyde (MDA) content, the protein expression levels of 4-hydroxynonenal (4-HNE) and cytochrome P450 2E1 (CYP2E1) in the liver tissues. G-Rg5 decreased APAP caused the hepatic overexpression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Furthermore, analysis of immunohistochemistry and Western blotting also indicated that G-Rg5 pretreatment inhibited activation of apoptotic pathways mainly via increasing the expression of Bcl-2 protein, decreasing the expression of Bax protein, proliferating cell nuclear antigen (PCNA), cytochrome c, caspase-3, caspase-8, and caspase-9. Liver histopathological observation provided further evidence that pretreatment with G-Rg5 could significantly inhibit hepatocyte necrosis, inflammatory cell infiltration, and apoptosis caused by APAP. In conclusion, the present study clearly demonstrates that G-Rg5 exerts a liver protection effect against APAP-induced acute hepatotoxicity mainly via a caspase-mediated anti-apoptotic effect.


Maintaining mitochondrial ribosome function: The role of ribosome rescue and recycling factors.
The universally conserved process of protein biosynthesis is crucial for maintaining cellular homoeostasis and in eukaryotes, mitochondrial translation is essential for aerobic energy production. Mitochondrial ribosomes (mitoribosomes) are highly specialized to synthesize 13 core subunits of the oxidative phosphorylation (OXPHOS) complexes. Although the mitochondrial translation machinery traces its origin from a bacterial ancestor, it has acquired substantial differences within this endosymbiotic environment. The cycle of mitoribosome function proceeds through the conserved canonical steps of initiation, elongation, termination and mitoribosome recycling. However, when mitoribosomes operate in the context of limited translation factors or on aberrant mRNAs, they can become stalled and activation of rescue mechanisms is required. This review summarizes recent advances in the understanding of protein biosynthesis in mitochondria, focusing especially on the mechanistic and physiological details of translation termination, and mitoribosome recycling and rescue.


A functional leuABCD operon is required for leucine synthesis by the tyrosine-repressible transaminase in Escherichia coli K-12.
In Escherichia coli K-12, two enzymes, encoded by ilvE and tyrB, catalyze the amination of 2-ketoisocaproate (2-KIC) to form leucine. Although leucine-requiring derivatives of an ilvE strain that are unable to grow on 2-KIC were expected to have mutations only in tyrB, mapping studies showed that one such mutation was tightly linked to the leu operon (at 1.5 min), not to tyrB (at 92 min). Chromosomal fragments cloned because they complemented this mutation were found to complement leu mutations, and vice versa, but none of these fragments complemented a tyrB mutation. The Tn5 insertion and flanking host DNA from this anomalous mutant was cloned in vivo, using Mu dII4042, and an in vivo procedure was developed to isolate deletion derivatives of Tn5-containing plasmids. These deletion plasmids were used to determine the DNA sequences flanking the transposon. The data showed that Tn5 was inserted between bp 122 and 132 in the leu leader. In addition, other ilvE leu double mutants were found to be unable to grow on 2-KIC in place of leucine. The accumulation of 2-ketoisovalerate in ilvE leu double mutants was shown to interfere with 2-KIC amination by the tyrB-encoded transaminase and also by the aspC- and avtA-encoded transaminases (which are able to catalyze this reaction in vivo when the corresponding genes are present on multicopy plasmids).


Protein fraction of Calotropis procera latex protects against 5-fluorouracil-induced oral mucositis associated with downregulation of pivotal pro-inflammatory mediators.
Oral mucositis is an important dose-limiting and costly side effect of cancer chemotherapy. Soluble proteins obtained of the latex of Calotropis procera have been extensively characterized as anti-inflammatory in different experimentally induced inflammatory conditions, including arthritis and sepsis. In this study, the phytomodulatory laticifer proteins (LP) were challenged to regress the inflammatory events associated with 5-fluorouracil-induced oral mucositis. We also evaluated the expression of pro-inflammatory cytokines and inducible enzymes, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Oral mucositis was induced in hamsters by two injections of 5-fluorouracil (5-FU; 60 and 40 mg/kg, i.p., on experimental days 1 and 2, respectively). LP (5 mg/kg, i.p.) was injected 24 h before and 24 h after mechanical trauma of the cheek pouches. A normal control group received only saline. On day 10, the animals were sacrificed, and the cheek pouches were excised for macroscopic and histopathological analysis, myeloperoxidase activity measurement, and immunohistochemical assessment of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), iNOS, and COX-2. LP significantly inhibited macroscopic histopathological scores and myeloperoxidase activity compared with the 5-FU control group. 5-Fluorouracil also induced marked immunostaining of TNF-α, IL-1β, iNOS, and COX-2 on inflamed conjunctive and epithelial tissue compared with the normal control group. Such damage was significantly inhibited (p < 0.05) by LP treatment compared with the 5-FU group. These findings demonstrate an anti-inflammatory effect of LP on 5-FU-induced oral mucositis. The protective mechanism appears to involve inhibition of the expression of iNOS, COX-2, TNF-α, and IL-1β.


Observations on the host specificity of Hymenolepis straminea (Goeze).
The experimental infection of rodents as potential, definitive hosts with Hymenolepis straminea indicated that hamsters and field mice were susceptible to infection. By comparison, laboratory mice exhibited a significantly lowered susceptibility. Artificially induced depression of the immune response enabled the parasite to be cultured in several strains of laboratory mice, and suggested that the thymus played a major role in rejection of the parasite.


Porcine brain microvessel endothelial cells as an in vitro model to predict in vivo blood-brain barrier permeability.
The objective of the study was to establish primary cultured porcine brain microvessel endothelial cells (PBMECs) as an in vitro model to predict the blood-brain barrier (BBB) permeability in vivo. The intercellular tight junction formation of PBMECs was examined by electron microscopy and measured by transendothelial electrical resistance (TEER). The mRNA expression of several BBB transporters in PBMECs was determined by reverse transcriptionpolymerase chain reaction analysis. The in vitro permeability of 16 structurally diverse compounds, representing a range of passive diffusion and transporter-mediated mechanisms of brain penetration, was determined in PBMECs. Except for the perfusion flow rate marker diazepam, the BBB permeability of these compounds was determined either in our laboratory or as reported in literature using in situ brain perfusion technique in rats. Results in the present study showed that PBMECs had a high endothelium homogeneity, an mRNA expression of several BBB transporters, and high TEER values. Culturing with rat astrocyte-conditioned medium increased the TEER of PBMECs, but had no effect on the permeability of sucrose, a paracellular diffusion marker. The PBMEC permeability of lipophilic compounds measured under stirred conditions was greatly increased compared with that measured under unstirred conditions. The PBMEC permeability of the 15 test compounds, determined under the optimized study conditions, correlated with the in situ BBB permeability with an r2 of 0.60. Removal of the three system L substrates increased the r2 to 0.89. In conclusion, the present PBMEC model may be used to predict or rank the in vivo BBB permeability of new chemical entities in a drug discovery setting.


Use of the piggyBac transposon to create stable packaging cell lines for the production of clinical-grade self-inactivating γ-retroviral vectors.
Efforts to improve the biosafety of γ-retroviral-mediated gene therapy have resulted in a shift toward the use of self-inactivating (SIN) γ-retroviral vectors. However, scale-up and manufacturing of such vectors requires significant optimization of transient transfection-based processes or development of novel platforms for the generation of stable producer cell clones. To that end, we describe the use of the piggybac transposon to generate stable producer cell clones for the production of SIN γ-retroviral vectors. The piggybac transposon is a universal tool allowing for the stable integration of SIN γ-retroviral constructs into murine (PG13) and human 293-based Phoenix (GALV and RD114, respectively) packaging cell lines without reverse transcription. Following transposition, a high-titer clone is selected for manufacture of a master cell bank and subsequent γ-retroviral vector supernatant production. Packaging cell clones created using the piggybac transposon have comparable titers to non-SIN vectors generated via conventional methods. We describe herein the use of the piggybac transposon for the production of stable packaging cell clones for the manufacture of clinical-grade SIN γ-retroviral vectors for ex vivo gene therapy clinical trials.


The effect of treatment position, prone or supine, on dose-volume histograms for pelvic radiotherapy in patients with rectal cancer.
Patients undergoing radiotherapy for rectal cancer are generally treated in a prone position, with a full bladder, to reduce the volume of normal bowel in the high-dose volume. This position is difficult to maintain, and is not consistently reproducible. This study evaluates the volume of bowel and dose received in the prone and supine positions in patients undergoing pre-operative rectal cancer chemoradiation. Using CT planning, 19 consecutive patients with rectal cancer with a full bladder underwent CT scanning first in the prone position and then immediately afterwards in the supine position. The planning target volume was outlined for the prone position and transcribed to the supine scan using pre-set criteria. The bladder and small bowel were outlined in both positions. Radiotherapy was planned using three-dimensional conformal planning, and treatment was delivered using three fields with multileaf collimators in two phases: phase I, pelvis 45 Gy/25 fractions; and phase II, tumour 9 Gy/five fractions. For both positions, the volume of bowel receiving doses in 5 Gy increments from 5-45 Gy was calculated using dose-volume histograms. At 5 Gy and 10 Gy dose levels, a significantly higher volume of bowel was irradiated in the supine position (p<0.001). At 15 Gy, it was marginally significant (p = 0.018). From 20-45 Gy, there was no significant difference in the volume of bowel irradiated with each 5 Gy increment. This study demonstrates that the volume of bowel irradiated at doses associated with bowel toxicity in concurrent chemoradiation is not significantly higher in the supine position. This position could be adopted for patients undergoing pre-operative rectal cancer chemoradiation.


C-kit overexpression in neuroendocrine small cell carcinoma of the uterine cervix.
Neuroendocrine small cell carcinoma of the uterine cervix (NESCC) grows aggressively, and is resistant to anticancer agents and radiation, having an extremely poor prognosis. The incidence of c-kit proto-oncogene overexpression is high in gastrointestinal stromal tumors (GISTs) and small cell lung cancer, and tyrosine kinase inhibitors have been used effectively to treat GISTs. Few studies have investigated whether c-kit is overexpressed in NESCC. To investigate whether NESCC can be a target for molecular targeted therapy with tyrosine kinase inhibitors, we examined the expression of c-kit in this tumor. Twenty-one NESCCs were examined for c-kit expression by immunohistochemical staining using the labeled streptavidin-biotin complex (LSAB) method. The expression of c-kit was regarded as positive (overexpression) and negative when the membrane and cytoplasm of more or less than 25%, respectively, of tumor cells were stained. Nine NESCCs (43%) were c-kit-positive (overexpression). No difference in age or clinical stage was noted. No difference in prognosis was observed between the c-kit-positive and -negative patients. The incidence of c-kit overexpression was high in NESCC; therefore, the patients with this tumor may become a future target for molecular-targeted therapy with tyrosine kinase inhibitors.


Feline aelurostrongylosis and canine angiostrongylosis: a challenging diagnosis for two emerging verminous pneumonia infections.
Aelurostrongylus abstrusus and Angiostrongylus vasorum (Nematoda, Metastrongyloidea) are causative agents of verminous feline and canine pneumonia. Both are presently emerging in several geographical areas and are of major clinical importance. Given the range of parasitic and non-parasitic pathogens which may cause cardio-respiratory distress in dogs and cats, the unequivocal specific diagnosis of both diseases is pivotal for unravelling their epidemiology and central to therapy and control. Several conventional clinico-pathologic, diagnostic imaging and parasitological approaches are currently used in practice, but all have major limitations in the specific diagnosis of these diseases. Serological methods have shown promise in the diagnosis of A. abstrusus and A. vasorum infections, but no clinically useful tests are currently available. Additionally, there have been major advances in the development of novel molecular diagnostic tools for feline aelurostrongylosis, but efforts to develop molecular diagnostic tests are still preliminary for angiostrongylosis. This article provides a review of A. abstrusus and A. vasorum infections in cats and dogs, focusing on the advantages and shortcomings of classical diagnostic methodologies and on present diagnostic advances as well as future perspectives instrumental to epidemiological and clinical studies.


Pseudohexagonal 2D DNA crystals from double crossover cohesion.
Two-dimensional pseudohexagonal trigonal arrays have been constructed by self-assembly from DNA. The motif used is a bulged-junction DNA triangle whose edges and extensions are DNA double crossover (DX) molecules, rather than conventional DNA double helices. Experiments were performed to establish whether the success of this system results from the added stiffness of DX molecules or the presence of two sticky ends at the terminus of each edge. Removal of one sticky end precludes lattice formation, suggesting that it is the double sticky end that is the primary factor enabling lattice formation.


Responding to Sexual Objectification: The Role of Emotions in Influencing Willingness to Undertake Different Types of Action.
Women may respond to being sexual objectified in different ways, such as confronting the perpetrator, ignoring the action, blaming oneself or considering the action as flattering. However, there has been little research looking at what predicts each of these different responses. The present research assessed the role of emotions in promoting and deterring different anticipated responses to sexual objectification. In both Studies 1 (n = 189) and 2 (n = 187), female participants were asked to imagine themselves in a situation where they received an inappropriate sexual comment. Participants then rated the emotions they believed they would feel and how they thought they would act in the situation. I found that expecting feelings of anger resulted in women thinking they would confront the perpetrator (i.e., undertake an active response) and that expecting disgust negatively predicted the belief that they would view the action as flattering (i.e., anticipate a benign response). By contrast, expecting shame resulted in women believing they would blame themselves (i.e., undertake a self-blame response). Study 2 also found that expecting pride was positively associated with anticipating a benign response. These findings suggest that the emotions that women expect to feel influence their anticipated responses to sexual objectification. It is, therefore, important to consider the emotional reactions that women have to instances of sexual objectification.


Nationwide acute care physical therapist practice analysis identifies knowledge, skills, and behaviors that reflect acute care practice.
Acute care physical therapy is a rapidly evolving practice area, but little is known about the skills, knowledge, and behaviors necessary for a clinician to be most effective in this area. The objective of this study was to perform the first nationwide survey of acute care physical therapists to validate the knowledge, skill, and behavior sets that reflect practice parameters specific for acute care physical therapy. A survey format was used. The Acute Care Physical Therapy Practice Analysis Survey was created on the basis of current literature and consensus of a 9-member Subject Matter Expert (SME) Group. The survey sections addressed knowledge areas, professional behaviors, and patient/client management approaches reflecting practice parameters specific for acute care physical therapy. Additionally, respondent demographic information was collected. Pilot testing necessitated minor changes in the survey. After revision, the survey questionnaire was sent to a sample of experienced acute care physical therapists throughout the United States. A convenience sample of 522 physical therapists who identified themselves as having extensive experience in acute care practice was used. Of these, 254 completed the survey, for a response rate of 48.7%. Through the use of predetermined decision rules, 34 items were eliminated on the basis of a descriptive analysis of survey results as well as a failure of the items to meet the threshold of specificity for acute care practice, as determined through SME Group consensus. The potential for self-selection bias, a sample weighted heavily with American Physical Therapy Association members and Acute Care Section members, and a small proportion of clinicians (<3%) with less than 1 year of acute care experience may limit generalizability of these results. The results of this practice analysis describe distinct knowledge, skills, and behaviors specific for acute care physical therapy. The outcomes of the survey might assist in the development of professional (entry-level) acute care competencies, a petition for the recognition of specialization in acute care physical therapy, or both. In addition, the findings of this practice analysis could serve as the foundation for the development of residencies or fellowships in acute care practice.


Metabolite/phytohormone-gene regulatory networks in soybean organs under dehydration conditions revealed by integration analysis.
Metabolites, phytohormones, and genes involved in dehydration responses/tolerance have been predicted in several plants. However, metabolite/phytohormone-gene regulatory networks in soybean organs under dehydration conditions remain unclear. Here, we analyzed the organ specificity of metabolites, phytohormones, and gene transcripts and revealed the characteristics of their regulatory networks in dehydration-treated soybeans. Our metabolite/phytohormone analysis revealed the accumulation of raffinose, trehalose, and cis-zeatin (cZ) specifically in dehydration-treated roots. In dehydration-treated soybeans, raffinose, and trehalose might have additional roles not directly involved in protecting the photosynthetic apparatus; cZ might contribute to root elongation for water uptake from the moisture region in soil. Our integration analysis of metabolites-genes indicated that galactinol, raffinose, and trehalose levels were correlated with transcript levels for key enzymes (galactinol synthase, raffinose synthase, trehalose 6-phosphate synthase, trehalose 6-phosphate phosphatase) at the level of individual plants but not at the organ level under dehydration. Genes encoding these key enzymes were expressed in mainly the aerial parts of dehydration-treated soybeans. These results suggested that raffinose and trehalose are transported from aerial plant parts to the roots in dehydration-treated soybeans. Our integration analysis of phytohormones-genes indicated that cZ and abscisic acid (ABA) levels were correlated with transcript levels for key enzymes (cytokinin nucleoside 5'-monophosphate phosphoribohydrolase, cytokinin oxidases/dehydrogenases, 9-cis-epoxycarotenoid dioxygenase) at the level of individual plants but not at the organ level under dehydration conditions. Therefore, processes such as ABA and cZ transport, among others, are important for the organ specificity of ABA and cZ production under dehydration conditions.


Central retinal findings in Bothnia dystrophy caused by RLBP1 sequence variation.
To describe the central retinal findings early in the course of Bothnia dystrophy caused by the homozygous missense R234W sequence variation in the RLBP1 gene. In 8 young patients with Bothnia dystrophy (aged 9-34 years), high- and low-contrast distance visual acuity and visual fields were measured with Humphrey central (24-2) threshold testing and Goldmann perimetry. Central retinal thickness was measured with optical coherence tomography. Cross-sectional images were analyzed and a linear scanning protocol was applied to examine retinitis punctata albescence in the posterior pole. Affected visual acuity (4 of 8 cases) and poor low-contrast visual acuity (8 of 8 cases) were found. Significant foveal depression and visual field loss were evident with Humphrey threshold testing at all ages, and paracentral and central scotomata in the second decade of life advanced in adulthood as verified with Goldmann perimetry. Optical coherence tomography showed generalized retinal thinning in the central foveal, foveal (innermost ring diameter [Ø], 1 mm), and inner ring (Ø, 3 mm) areas in all ages, and early retinal thinning was found in the inferior areas of the outer macula (Ø, 6 mm). Foveal and extrafoveal thinning of the retinal layers and outer nuclear layer were found. Homogeneous retinitis punctata albescence changes were visualized in and/or adjacent to the retinal pigment epithelium-choriocapillaris complex with high reflectance. In the RLBP1-Bothnia dystrophy phenotype, a loss of function and thinning of the central macula are found, indicating early damage of the cone photoreceptors in this disease of the visual cycle. Retinitis punctata albescence spots in the posterior pole are situated close to or in the retinal pigment epithelium-choriocapillaris complex.


Food intakes by preschool children in Flanders compared with dietary guidelines.
The objective of this study was to compare food group intakes among preschool children with food-based dietary guidelines (FBDG) and to determine the proportion of children meeting these guidelines. Food consumption of preschool children (2.5-6.5 years) living in Flanders (Belgium) were assessed in a cross-sectional study, using proxy reported 3d estimated dietary records (EDR) (n 696). Statistical modelling was used to account for within-individual variation in the 3d EDR. Mean daily intakes of most food groups (beverages, vegetables, fruit and milk) were below the minimum recommendations. Only 'grains and potatoes' and 'meat products' were in line with the recommendations and 'bread and cereals' showed borderline intakes. Mean intakes of energy-dense and low-nutritious foods, which are discouraged within a healthy diet (like snacks and sugared drinks), were high. Furthermore, the percentage of children complying with the different food-based dietary guidelines was for most food groups extremely low (ranging from approximately 4% for fluid and vegetable intakes up to 99% for potato intakes). Boys had in general higher mean intakes of the recommended food groups. In conclusion, preschool children in Flanders follow eating patterns that do not meet Flemish FBDG. Although the impact of these eating habits on preschooler's current and future health should be further investigated, it is clear that nutrition education and intervention are needed among preschool children and their parents in Flanders.


Sperm extract injection into ascidian eggs signals Ca(2+) release by the same pathway as fertilization.
Injection of eggs of various species with an extract of sperm cytoplasm stimulates intracellular Ca(2+) release that is spatially and temporally like that occurring at fertilization, suggesting that Ca(2+) release at fertilization may be initiated by a soluble factor from the sperm. Here we investigate whether the signalling pathway that leads to Ca(2+) release in response to sperm extract injection requires the same signal transduction molecules as are required at fertilization. Eggs of the ascidian Ciona intestinalis were injected with the Src-homology 2 domains of phospholipase C gamma or of the Src family kinase Fyn (which act as specific dominant negative inhibitors of the activation of these enzymes), and the effects on Ca(2+) release at fertilization or in response to injection of a sperm extract were compared. Our findings indicate that both fertilization and sperm extract injection initiate Ca(2+) release by a pathway requiring phospholipase C gamma and a Src family kinase. These results support the hypothesis that, in ascidians, a soluble factor from the sperm cytoplasm initiates Ca(2+) release at fertilization, and indicate that the activating factor from the sperm may be a regulator, directly or indirectly, of a Src family kinase in the egg.


[Differential sonographic diagnosis of scrotal diseases].
High-resolution scrotal sonography proves valuable in addition to clinical investigation. On the basis of a retrospective analysis of 282 sonographic examinations this method's contributions to the differential diagnosis of diseases of the scrotum are shown. It is usually possible to distinguish testicular from extratesticular tumours; certain signs of inflammation allow the distinction between orchitis and tumour. Sonography is very important for the study of acute painful lesions of the scrotum, which are not palpable, such as rupture following a trauma, severe inflammation and even tumours.


The extracellular matrix in myocardial injury, repair, and remodeling.
The cardiac extracellular matrix (ECM) not only provides mechanical support, but also transduces essential molecular signals in health and disease. Following myocardial infarction, dynamic ECM changes drive inflammation and repair. Early generation of bioactive matrix fragments activates proinflammatory signaling. The formation of a highly plastic provisional matrix facilitates leukocyte infiltration and activates infarct myofibroblasts. Deposition of matricellular proteins modulates growth factor signaling and contributes to the spatial and temporal regulation of the reparative response. Mechanical stress due to pressure and volume overload and metabolic dysfunction also induce profound changes in ECM composition that contribute to the pathogenesis of heart failure. This manuscript reviews the role of the ECM in cardiac repair and remodeling and discusses matrix-based therapies that may attenuate remodeling while promoting repair and regeneration.


Linear predictive coding representation of correlated mutation for protein sequence alignment.
Although both conservation and correlated mutation (CM) are important information reflecting the different sorts of context in multiple sequence alignment, most of alignment methods use sequence profiles that only represent conservation. There is no general way to represent correlated mutation and incorporate it with sequence alignment yet. We develop a novel method, CM profile, to represent correlated mutation as the spectral feature derived by using linear predictive coding where correlated mutations among different positions are represented by a fixed number of values. We combine CM profile with conventional sequence profile to improve alignment quality. For distantly related protein pairs, using CM profile improves the profile-profile alignment with or without predicted secondary structure. Especially, at superfamily level, combining CM profile with sequence profile improves profile-profile alignment by 9.5% while predicted secondary structure does by 6.0%. More significantly, using both of them improves profile-profile alignment by 13.9%. We also exemplify the effectiveness of CM profile by demonstrating that the resulting alignment preserves share coevolution and contacts. In this work, we introduce a novel method, CM profile, which represents correlated mutation information as paralleled form, and apply it to the protein sequence alignment problem. When combined with conventional sequence profile, CM profile improves alignment quality significantly better than predicted secondary structure information, which should be beneficial for target-template alignment in protein structure prediction. Because of the generality of CM profile, it can be used for other bioinformatics applications in the same way of using sequence profile.


Development of a Fried Frailty Phenotype Questionnaire for Use in Screening Community-Dwelling Older Adults.
The aim of this study was to develop a Fried Frailty Phenotype Questionnaire (FFPQ) and a Japanese FRAIL (fatigue, resistance, ambulation, illnesses, and loss of weight) scale (FRAIL-J) and to evaluate the reliability and validity of both questionnaires in Japanese community-dwelling older adults. Cross-sectional analysis of Itoshima Frail Study (IFS). The IFS is an ongoing community-based prospective study in Itoshima (Japan). A total of 858 older adults age 65-75 years. The FRAIL-J comprises 5 existing items comparable to those in original FRAIL scale but with broader utilization in the Japanese healthcare system. In FFPQ, resistance, ambulation, and loss of weight were the same as those in FRAIL-J. Fatigue was the same with exhaustion in FFP and inactivity was assessed using a yes or no question. Data including demographics, and physical and cognitive functions, and objective physical activity was collected and analyzed in relation to both questionnaires. The FFPQ and FRAIL-J showed low internal consistency (Kuder-Richardson formula 20 coefficients = 0.32 and 0.29) and good test-retest reliability (intraclass correlation coefficients = 0.79 and 0.72). The correlations ranged from -0.22 to 0.49 when correlating each item with cross-sectional outcomes. Using FFP as a criterion, the ares under the curve for FRAIL-J and FFPQ were 0.86 and 0.88, respectively. The optimal cut-off for FRAIL-J was 2, with a higher Youden index (66.7% vs 20.3% for 3) and a high negative predictive value (99.5%) but low positive predictive value (13.1%). As for FFPQ, either 2 or 3 was evaluated as cut-off because the Youden index (62.2% vs 58.5%) and negative predictive value (99.7% vs 99.2%) were similar although the positive predictive value was low (9.7% vs 33.3%). Using a 2-point cut-off, both questionnaires had slight agreement with FFP. The highest agreement (kappa = 0.42) was found between FFP and FFPQ using a 3-point cut-off. The FFPQ and FRAIL-J can be used for frailty screening in Japanese community-dwelling older adults.


Regulation by SREBP-2 defines a potential link between isoprenoid and adenosylcobalamin metabolism.
Mevalonate kinase (MVK) catalyses an early step in cholesterol biosynthesis converting mevalonate to phosphomevalonate. Cob(I)alamin adenosyltransferase (MMAB) converts cob(I)alamin to adenosylcobalamin, functionally required for mitochondrial methylmalonyl-CoA mutase activity and succinyl-CoA formation. These two synthenic genes are found in a head-to-head formation on chromosome 12 in man and chromosome 5 in mouse. The 330bp intergenic region showed several conserved NF-Y sites indicative of potential bidirectional regulatory SREBP synergism. Both MVK and MMAB appear to be regulated in a similar manner, to a large extent by SREBP-2, since their tissue expression pattern was similar and both genes were suppressed by an excess of cholesterol as well as SREBP-2 knockdown. Statin treatment in mice upregulated both Mvk and Mmab mRNA levels indicating that this treatment may be useful in inborn errors of cblB complementation associated with methylmalonic aciduria as well as hyper IgD and periodic fever syndrome (HIDS).


Melatonin reduces the neuronal loss, downregulation of dopamine transporter, and upregulation of D2 receptor in rotenone-induced parkinsonian rats.
Parkinson's disease (PD) is a movement disorder resulting from nigrostriatal dopaminergic neurodegeneration. The impairment of mitochondrial function and dopamine synaptic transmission are involved in the pathogenesis of PD. Two mitochondrial inhibitors, 1-methyl-4-phenylpyridine (MPP(+)) and rotenone, have been used to induce dopaminergic neuronal death both in in vitro and in vivo models of PD. Because the uptake of MPP(+) is mediated by the dopamine transporter (DAT), we used a cell-permeable rotenone-induced PD model to investigate the role of DAT and dopamine D2 receptor (D2R) on dopaminergic neuronal loss. Rotenone subcutaneously infused for 14 days induced PD symptoms in rats, as indicated by reduced spontaneous locomotor activity (hypokinesis), loss of tyrosine hydroxylase (TH, a marker enzyme for dopamine neurons) immunoreactivity in the substantia nigra and striatum, obvious alpha-synuclein accumulation, downregulated DAT protein expression, and upregulated D2R expression. Interestingly, rotenone also caused significant noradrenergic neuronal loss in the locus coeruleus. Melatonin, an antioxidant, prevented nigrostriatal neurodegeneration and alpha-synuclein aggregation without affecting the rotenone-induced weight loss and hypokinesis. However, rotenone-induced hypokinesis was markedly reversed by the DAT antagonist nomifensine and body weight loss was attenuated by the D2R antagonist sulpiride. In addition, both antagonists significantly prevented the reduction of striatal TH or DAT immunoreactivity but not the loss of nigral TH- and DAT-immunopositive neurons. These results suggested that oxidative stress and DAT downregulation are involved in the rotenone-induced pathogenesis of nigrostriatal dopaminergic neurodegeneration, whereas D2R upregulation may simply represent a compensatory response.


Bone Mineral Density Increases in Trans Persons After 1 Year of Hormonal Treatment: A Multicenter Prospective Observational Study.
Sex steroids are important determinants of bone acquisition and bone homeostasis. Cross-sex hormonal treatment (CHT) in transgender persons can affect bone mineral density (BMD). The aim of this study was to investigate in a prospective observational multicenter study the first-year effects of CHT on BMD in transgender persons. A total of 231 transwomen and 199 transmen were included who completed the first year of CHT. Transwomen were treated with cyproterone acetate and oral or transdermal estradiol; transmen received transdermal or intramuscular testosterone. A dual-energy X-ray absorptiometry (DXA) was performed to measure lumbar spine (LS), total hip (TH), and femoral neck (FN) BMD before and after 1 year of CHT. In transwomen, an increase in LS (+3.67%, 95% confidence interval [CI] 3.20 to 4.13%, p < 0.001), TH (+0.97%, 95% CI 0.62 to 1.31%, p < 0.001), and FN (+1.86%, 95% CI 1.41 to 2.31%, p < 0.001) BMD was found. In transmen, TH BMD increased after 1 year of CHT (+1.04%, 95% CI 0.64 to 1.44%, p < 0.001). No changes were observed in FN BMD (-0.46%, 95% CI -1.07 to 0.16%, p = 0.144). The increase in LS BMD was larger in transmen aged ≥50 years (+4.32%, 95% CI 2.28 to 6.36%, p = 0.001) compared with transmen aged <50 years (+0.68%, 95% CI 0.19 to 1.17%, p = 0.007). In conclusion, BMD increased in transgender persons after 1 year of CHT. In transmen of postmenopausal age, the LS BMD increased more than in younger transmen, which may lead to the hypothesis that the increase in BMD in transmen is the result of the aromatization of testosterone to estradiol. © 2017 American Society for Bone and Mineral Research.


The role of adjuvant therapy in pemphigus: A systematic review and meta-analysis.
The assumption that adjuvant modalities have added value to oral glucocorticoids in the treatment of pemphigus is intuitively sound but has not been conclusively proven. We sought to compare the efficacy and safety of oral glucocorticoid treatment with or without adjuvants for pemphigus vulgaris and pemphigus foliaceus. We performed a systematic review and meta-analysis of randomized controlled trials. The primary outcome was remission. Secondary outcomes were disease control, time to disease control, relapse, time to relapse, cumulative glucocorticoid dose, withdrawal because of adverse events, and all-cause death. Trials were pooled irrespective of adjuvant type evaluated. Ten trials (559 participants) were included. Adjuvants evaluated were azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine, intravenous immunoglobulin, plasma exchange, and infliximab; not all were included in every analysis. Although adjuvants were not beneficial for achieving remission, they were found to collectively decrease the risk of relapse by 29% (relative risk 0.71, 95% confidence interval 0.53-0.95). Different adjuvants were pooled together. Adjuvants have a role in pemphigus treatment, at least in reducing the risk of relapse. Further randomized controlled trials of other promising modalities are warranted.


Polyphenols as Possible Markers of Botanical Origin of Honey.
In recent years, the botanical and geographical origin of food has become an important topic in the context of food quality and safety, as well as consumer protection, in accordance with international standards. Finding chemical markers, especially phytochemicals, characteristic for some kind of food is the subject of interest of a significant number of researchers in the world. This paper is focused on the use of polyphenols as potential markers for the determination of botanical origin of honey. It includes a review of the polyphenols present in various honey samples and the methods for their separation and identification. Special emphasis in this paper is placed on the identification of honey polyphenols using advanced LC-MS techniques in order to find specific markers of botanical origin of honey. In this regard, this study gives an overview of the literature that describes the use of LC-MS techniques for the isolation and determination of honey polyphenols. This review focuses on the research performed in the past two decades.


Storytelling in community intervention research: lessons learned from the walk your heart to health intervention.
Contextually and culturally congruent interventions are urgently needed to reduce racial, ethnic, and socioeconomic inequities in physical activity and cardiovascular disease. To examine a community-based participatory research (CBPR) process that incorporated storytelling into a physical activity intervention, and consider implications for reducing health inequities. We used a CBPR process to incorporate storytelling in an existing walking group intervention. Stories conveyed social support and problem-solving intervention themes designed to maintain increases in physical activity over time, and were adapted to the walking group context, group dynamics, challenges, and traditions. After describing of the CBPR process used to adapt stories to walking group sites, we discuss challenges and lessons learned regarding the adaptation and implementation of stories to convey key intervention themes. A CBPR approach to incorporating storytelling to convey intervention themes offers an innovative and flexible strategy to promote health toward the elimination of health inequities.