A long-term subacute sclerosing panencephalitis survivor treated with intraventricular interferon-alpha for 13 years.
Subacute sclerosing panencephalitis (SSPE) is a rare, progressive, and fatal central nervous system disorder resulting from persistent measles virus infection. Long-term data are scarce, with a maximum follow-up period of 10 years. Interferon-alpha (IFN-α) is a protein that exerts its antiviral activity via enhancement of cellular immune response and is reported to be an effective drug for the treatment of SSPE. However, there is currently no consensus regarding the optimal duration of IFN-α therapy. Here, we present a case report of a patient with SSPE treated with long-term intraventricular IFN-α therapy, which facilitated clinical improvement and neurological stabilization without causing serious adverse effects. To the best of our knowledge, this is one of the longest follow-up studies investigating a patient with SSPE receiving intraventricular INF-α treatment. Further studies are necessary to validate the benefits and safety of long-term intraventricular IFN-α treatment in patients with SSPE.


Potential Effects of Adropin in Subarachnoid Hemorrhage.
Subarachnoid Hemorrhage (SAH) typically, occurs in patients over 55 years of age and can cause a significant loss of productivity. SAH also has a high mortality rate and those who survive often suffer from early and secondary brain injuries that can result from the condition. By gaining a better understanding of the pathophysiology of SAH, it may be possible to identify therapeutic agents to improve outcomes. Adropin is a novel peptide that is primarily secreted in the liver and brain. Research has shown that adropin can activate endothelial NO synthase through post-transcriptional mechanisms. Studies in animal models have demonstrated that therapies using synthetic adropin peptide or adropin overexpression can have positive effects on reducing infarct dimensions and enhancing neurological functioning. In this review, we aim to discuss the potential effect of Adropin on SAH and its potential as a therapeutic agent.


The synthesis of interface-modulated ultrathin Ni(ii) MOF/g-C3N4 heterojunctions as efficient photocatalysts for CO2 reduction.
It is highly desirable to improve charge separation and to provide catalytic functions for the efficient photocatalytic CO2 reduction reaction (CO2RR) on g-C3N4 (CN). Here, dimension-matched ultrathin NiMOF/CN heterojunctions have been successfully constructed by the in situ growth of NiMOF nanosheets on hydroxylated and 1,4-aminobenzoic acid (AA) functionalized CN nanosheets, respectively, with ultrasonic assistance. The resultant NiMOF/CN heterojunctions exhibited excellent photocatalytic activities for the CO2RR to produce CO and CH4, especially NiMOF/CN-AA, which had photoactivity 18 times higher than that of bare CN. Based on the surface photovoltage responses, wavelength-dependent photocurrent action spectra, electrochemical impedance spectra, and CO2 electrochemical reduction data, it is clearly confirmed that the exceptional photoactivity mainly resulted from the favorable charge transport properties of ultrathin CN and coupled NiMOF, and from the greatly enhanced charge separation via excited high-level electron transfer from CN to NiMOF in the resultant intimately contacted heterojunction caused by the induction effect of AA, and also from the provided catalytic functionality of the central Ni(ii) for CO2 activation. This work provides a feasible synthetic protocol to fabricate MOF-containing dimension-matched heterojunctions with good charge separation for efficient photocatalysis.


[Development of Molecular Transformation Reactions Using Visible Light and Main Group Elements].
Owing to their ability to induce excitation of specific molecular orbitals or initiate chemical reactions, photochemical reactions have the potential to be more effective at selectively activating target molecules than thermal reactions. The thermal reactions transfer thermal energy to activate molecules, which often leads to the activation of multiple molecular species, including undesired ones, resulting in non-selectivity. This nonselectivity may result in undesirable side reactions or decrease reaction efficiency. Additionally, photochemical reactions can induce selective activation by absorbing specific wavelengths of light. However, visible light-driven photocatalytic reactions typically require expensive transition metal catalysts or organic dyes, leaving plenty of room for improvement. To address the aforementioned issues, the photochemical properties of the main group elements, such as halogens, were optimized and methodologies for visible light-induced reactions were developed. Activation of molecular halogen, halogen-carbon bonds, and halogen bonding interactions were independently investigated and various methodologies were reported. These developed reactions are excellent methodologies that use inexpensive raw materials and are thus predicted to contribute significantly toward sustainability.


MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment.
3,4-Methylenedioxymethamphetamine (MDMA, designated as "Ecstasy" if illicitly marketed in tablet form) induces significant decrements in neuronal serotonin (5-HT) markers in humans, nonhuman primates, and rats as a function of dosing and dosing regimen. In rats, MDMA-mediated effects are attributed, in part, to selective high-affinity transport of MDMA into 5-HT neurons by the 5-HT transporter (SERT), followed by extensive 5-HT release. To clarify whether SERT-selective effects of MDMA at human monoamine transporters can account for the reported MDMA-induced selective toxicity of serotonin neurons in primate brain. We investigated the interaction of [(3)H](+/-, RS)- (+, S)- and (-, R)-MDMA with the human SERT, dopamine (DA) transporter (DAT), and norepinephrine (NE) transporter (NET) in stably transfected human embryo kidney (HEK)-293 cells. The human DAT, NET, and SERT actively transported [(3)H]RS(+/-)-MDMA saturably, stereoselectively, and in a temperature-, concentration-, and transporter-dependent manner. MDMA exhibited the highest affinity for the NET>>SERT>or=DAT, the same rank order for MDMA inhibition of [(3)H]DA, [(3)H]NE, and [(3)H]5-HT transport and stimulated release of the [(3)H]monoamines, which differed from reports derived from rodent monoamine transporters. The extent of MDMA-induced release of 5-HT was higher compared with release of DA or NE. The affinity of MDMA for the human SERT in transfected cells does not clarify the apparent selective toxicity of MDMA for serotonin neurons, although conceivably, its higher efficacy for stimulating 5-HT release may be a distinguishing factor. The findings highlight the need to investigate MDMA effects in DAT-, SERT-, and NET-expressing neurons in the primate brain and the therapeutic potential of NET or DAT inhibitors, in addition to SERT-selective inhibitors, for alleviating the pharmacological effects of MDMA.


Emerging drugs for the acute treatment of relapses in adult neuromyelitis optica spectrum disorder patients.
Neuromyelitis optica spectrum disorders (NMOSD) are rare but often devastating neuroinflammatory autoimmune diseases of the central nervous system. Acute treatment is critically important and it should be initiated early and aggressively, as relapses result in severe residual disability. Acute treatments are still based on clinical experience and observational studies. The most commonly used treatments are steroids and plasmapheresis. Several new treatments to improve management and recovery after relapses in NMOSD are currently under investigation. This review discusses current and the most recent advances in active development of phase II/III clinical trials for acute treatment options and therapeutic strategies that can help management improvement of NMOSD during a relapse. These treatments include bevacizumab, ublituximab and HBM9161. NMOSD relapses require prompt evaluation and timely treatment to restore function and mitigate disability. Timing is critical. Plasmapheresis showed better outcomes in terms of recovery when compared to high-dose intravenous methylprednisolone alone. Some groups suggest that plasmapheresis could be considered as an initial treatment approach in different clinical scenarios due to its higher effectiveness. Future research and/or real-world data will establish the advantages and disadvantages of these new treatments and define the appropriate patient profile.


Characterization of proteomic changes in cardiac mitochondria in streptozotocin-diabetic rats using iTRAQ™ isobaric tags.
Diabetes now affects more than 5% of the world's population and heart failure is the most common cause of death amongst diabetic patients. Accumulating evidence supports a view that myocardial mitochondrial structural and functional changes are central to the onset of diabetic heart failure, but the exact nature of these changes at the proteomic level remains unclear.Here we report on proteomic changes in diabetic rat heart mitochondria following 120 days of streptozotocin-diabetes using the recently developed iTRAQ™ labeling method, which permits quantification of proteins directly from complex mixtures, bypassing the limitations associated with gel-based methods such as 2-DE. Of 252 unique proteins identified, 144 were represented in at least three of six individual paired experiments. Relative amounts of 65 proteins differed significantly between the groups, confirming that the cardiac mitochondrial proteome is indeed impacted by diabetes. The most significant changes were increased protein levels of enzymes involved in mitochondrial oxidation of long-chain fatty acids, which was also confirmed by enzyme assays, and decreased levels of multiple enzymes involved in oxidative phosphorylation and catabolism of short-chain fatty acids and branched-chain amino acids. We also found significant changes in levels of several enzymes linked to oxidative stress.


Citrullinated fibrinogen inhibits thrombin-catalysed fibrin polymerization.
Citrullination is the post-translational modification of arginine residues by peptidylarginine deiminases (PADIs). Fibrinogen is one substrate of PADIs under physiological conditions. Fibrinogen is an important factor for blood coagulation and inducing inflammation. The citrullinated form of fibrinogen appears in rheumatoid arthritis synovial tissue together with the production of autoantibodies that target self-peptides containing citrulline. However, whether the function of fibrinogen changes after citrullination remains unclear. We found that citrullinated fibrinogen markedly impairs the function of thrombin-catalysed fibrin polymerization and also inhibits fibrin formation. Increased citrullinated fibrinogen might thus affect the balance between coagulation and fibrinolysis and alter antigenicity under physiological conditions. These data suggest that citrullination of proteins could physiologically change functions and subsequently generate pro-inflammatory conditions and autoimmune reactions.


How the Community Shapes Unmet Need for Modern Contraception: An Analysis of 44 Demographic and Health Surveys.
Unmet need for modern contraception is a major public health concern in resource-constrained countries. Recent research supports the application of social-ecological theories to explain how characteristics of a woman's community shape modern contraception use. However, this research focuses largely on individual countries and uses a limited number of community-level effects. We fitted three random-effects logistic regression models to examine associations between 13 community-level variables and the odds of reporting unmet need, unmet need for spacing, and unmet need for limiting for all parous, female respondents in 44 DHS surveys collected in 2010-2015 (n=528,101). Community variables explain significant variance in unmet need between communities. Associations between community variables and unmet need differ by urban and rural residence. The results highlight several commonalities in how the community shapes unmet need across resource-constrained settings and may help in designing structural-level interventions.


[Intrauterine Device Totally Embedded in the Bladder Wall:Report of One Case].
Intrauterine device(IUD)migrating to the bladder is rare,especially the migration far away from the uterus into the bladder wall.Due to no obvious clinical symptom in the early stage and being far away from the uterus,the IUD totally embedded in the bladder wall is prone to misdiagnosis and delay in treatment.We reported one case of such migration,aiming to improve the clinical management of the IUD totally embedded in the bladder wall.


On the mechanism of Mallory's phosphotungstic acid-haematoxylin stain.
The mechanism of Mallory's (1900) phosphotungstic acid-haematoxylin (PTAH) stain is not yet fully understood; staining properties vary with the age of the dye solution. In this study, a 1 year-old solution was employed as described previously. Paper chromatograms revealed blue, red and yellow components of phosphotungstic acid-haematoxylin. Modification of reactive groups as well as consecutive treatment of sections with haematoxylin and phosphotungstic acid indicated hydrogen bond formation by the blue component. Substitution of brazilin for haematoxylin proved that two free phenolic --OH groups per dye residue are essential for binding of the blue phosphotungstic acid-haematoxylin chelate. Uptake of the red fraction was determined by the polyacid moiety of the dye. Van der Waals forces presumably contributed to dye binding, but did not govern the selectivity of the red and blue components of PTAH for various tissue structures.


Deaths due to childhood asthma. Are they preventable?
Seven cases of death in patients with severe asthma are presented. The cause of death in asthmatic children is discussed under the following headings: mucus plugs, insufficient treatment, infection, aspiration, concomitant disease, oversedation, theophylline toxicity, overuse of metered dose pressurized aerosols, inadequate steroid therapy, and sudden cardiopulmonary arrest. The authors conclude that asthmatic deaths are preventable.


Influence of salinity and sedimentation on Vibrio infection of the Hawaiian coral Montipora capitata.
Environmental cofactors alter host-pathogen interactions and influence disease dynamics by impairing host resistance and/or increasing pathogen virulence. Terrestrial runoff is recognized as a major threat to coral reef health. However, the direct links between runoff and coral disease are not clear. Montipora white syndrome (MWS) is a coral disease that occurs in the Hawaiian archipelago, can be caused by various bacterial pathogens, including Vibrio species, and is linked to conditions associated with heavy rainfall and runoff. The objective of this study was to determine whether a short-term hyposalinity stress (20 ppt for 24 h) or sedimentation stress (1000 g m-2 d-1) would influence bacterial infection of the coral Montipora capitata. Hyposalinity increased M. capitata susceptibility to infection by 2 MWS pathogens, Vibrio coralliilyticus strain OCN008 and Vibrio owensii strain OCN002. Specifically, hyposalinity allowed OCN008 to infect at lower doses (106 CFU ml-1 compared with 108 CFU ml-1) and reduced the amount of time before onset of OCN002 infection at high doses (108 CFU ml-1). In contrast, short-term sedimentation stress did not affect M. capitata infection by either of these 2 pathogens. Although several studies have found a correlation between runoff and increased coral disease prevalence in field studies, this is the first study to show that one aspect of runoff (reduced salinity) enhances bacterial infection of coral using manipulative experiments.


Regulation of Cbl-associated protein/Cbl pathway in muscle and adipose tissues of two animal models of insulin resistance.
The phosphatidylinositol 3-kinase-independent pathway to induce glucose transport may involve the tyrosine phosphorylation of the protooncogene c-Cbl. In the present study, we examined whether acute exposure to insulin stimulates the tyrosine phosphorylation of Cbl and its association with Cbl-associated protein (CAP) in muscle and adipose tissue of rats in vivo. We report herein that insulin induces Cbl tyrosine phosphorylation and association with CAP in adipose tissue but not in muscle. We also examined the expression and tyrosyl-phosphorylation state of Cbl and CAP/Cbl association in adipose tissue of rats submitted to prolonged fasting and in monosodium glutamate (MSG)-insulin-resistant rats. An increase in Cbl phosphorylation is observed in the fat of MSG rats, parallel with an increase in association of CAP-Cbl as well as an augment in CAP and Cbl protein expression in the adipose tissue of these animals. These events are accompanied by a decrease in insulin-stimulated insulin receptor/ insulin receptor substrate (IRS)-1 tyrosine phosphorylation and an increase in the IRS-2/phosphatidylinositol 3-kinase/Akt/Foxo1 pathway. In adipocytes of fasted rats, there is a decrease in CAP and Cbl protein expression, insulin-induced Cbl phosphorylation, and the association with CAP. In parallel, there is also a decrease in the insulin receptor/IRSs/Akt/Foxo1 pathway. Thus, insulin is able to induce Cbl tyrosine phosphorylation and its association with CAP in the adipose tissue of normal rats. In addition, our data provide evidence that the CAP-Cbl pathway may have a role in the modulation of adiposity in fasting and in MSG-treated rats.


Ag Nanoparticles (Ag NM300K) in the Terrestrial Environment: Effects at Population and Cellular Level in Folsomia candida (Collembola).
The effects of nanomaterials have been primarily assessed based on standard ecotoxicity guidelines. However, by adapting alternative measures the information gained could be enhanced considerably, e.g., studies should focus on more mechanistic approaches. Here, the environmental risk posed by the presence of silver nanoparticles (Ag NM300K) in soil was investigated, anchoring population and cellular level effects, i.e., survival, reproduction (28 days) and oxidative stress markers (0, 2, 4, 6, 10 days). The standard species Folsomia candida was used. Measured markers included catalase (CAT), glutathione reductase (GR), glutathione S-transferase (GST), total glutathione (TG), metallothionein (MT) and lipid peroxidation (LPO). Results showed that AgNO₃ was more toxic than AgNPs at the population level: reproduction EC₂₀ and EC₅₀ was ca. 2 and 4 times lower, respectively. At the cellular level Correspondence Analysis showed a clear separation between AgNO₃ and AgNP throughout time. Results showed differences in the mechanisms, indicating a combined effect of released Ag⁺ (MT and GST) and of AgNPs (CAT, GR, TG, LPO). Hence, clear advantages from mechanistic approaches are shown, but also that time is of importance when measuring such responses.


"Giant" hollow multilayer capsules by microfluidic templating.
Monodisperse microgels were synthesized by a microfluidic setup and used as a sacrificial template for the fabrication of "giant" hollow polyelectrolyte capsules with rigid walls consisting of covalently cross-linked polyelectrolytes and metal nanoparticles. First, a simple tubing-needle-based microfluidic system is utilized to produce size-monodisperse, degradable "giant" microgels consisting of dextran chains linked via carbonate esters. Second, these monodisperse microgels are subjected to a layer-by-layer coating of negatively charged platinum nanoparticles (Pt(NP)'s) and a positively charged diazoresin (DAR). Three bilayers of Pt(NP)'s and DAR are used to obtain a stable membrane on the microgels. Finally, the sacrificial dextran-based microgel cores are smoothly hydrolyzed and removed without rupture of the polyelectrolyte membrane due to the covalently linked hybrid polyelectrolyte/nanoparticle nature of the membrane. Scanning electron and confocal microscopy are used to characterize the capsules. The capability of encapsulating materials of interest is also shown by the addition of fluorescent polystyrene particles to the monomer mixture and subsequent visualization of embedded polystyrene particles in coated microgels after microfluidic polymerization and layer-by-layer coating. The obtained "giant" microcapsules are envisaged to be used as microreactors or drug-delivery systems.


Inhibition of fatty acid synthesis by expression of an acetyl-CoA carboxylase-specific ribozyme gene.
We describe the construction of ribozyme genes that are specific to acetyl-CoA carboxylase [ACC; acetyl-CoA: carbon-dioxide ligase (ADP-forming), EC 184.108.40.206] mRNAs and the effects of their expression on long-chain fatty acid synthesis. In a cell-free system, these ribozymes precisely cleave ACC mRNA at the expected sites. 30A5 preadipocyte cells stably transfected with the ribozyme gene show a substantial reduction in the amount of ACC mRNA as compared to non-ribozyme-expressing cells. The decrease in ACC mRNA was associated with a significant decrease in ACC enzyme activity, and the rate of fatty acid synthesis fell to about 30-70% of the control. When these cells are induced to differentiate into adipocytes, lipid accumulation is very slow in comparison with control cells. The activity of fatty acid synthase and the mRNA level of beta-actin were not affected. These data indicate that ribozymes designed to specifically target ACC mRNA under in vivo conditions act by decreasing the ACC mRNA level, which, in turn, decreases fatty acid synthesis.


Prevalence of hormone therapy, factors associated with its use, and knowledge about menopause: a population-based household survey.
The aim of the study was to assess the prevalence of hormone therapy (HT), the factors associated with its use, and the importance of knowledge about menopause and HT. A cross-sectional population-based study with 749 Brazilian women aged 45 to 60 years living in the Campinas Metropolitan Region was carried out between September 2012 and June 2013. The dependent variable was current or previous HT use. The independent variables were sociodemographic data, health-related problems, and knowledge about menopause assessed using a score that was obtained with a questionnaire on various aspects of menopause. The mean age of the women was 52.5 (±4.4) years. With regard to the menopause status, 16% were premenopausal, 16% were perimenopausal, and 68% were postmenopausal. Among all the women included, 19.5% reported current or previous HT use. In multiple regression analysis, being postmenopausal (prevalence ratio [PR] 2.76; 95% CI, 1.74-4.38), receiving information about menopause from physicians and health service workers (PR 2.73; 95% CI, 1.91-3.89), having bilateral oophorectomy (PR 2.18; 95% CI, 1.49-3.17), experiencing work interruption due to hot flashes (PR 1.44; 95% CI, 1.03-2.01), and having extensive knowledge about menopause (PR 1.12; 95% CI, 1.05-1.19) were associated with a higher prevalence of HT use. The prevalence of HT use was 19.5%. Menopause status, information source, surgical menopause, work interruption due to hot flashes, and knowledge about menopause were associated with HT use. Education promoted by healthcare systems can increase HT use in women who have indications for treatment.


Direct repeat unit (dru) typing and antimicrobial resistance of methicillin-resistant Staphylococcus pseudintermedius isolated from dogs in Atlantic Canada.
There are few reports investigating the characterization of methicillin-resistant Staphylococcus pseudintermedius (MRSP) in dogs in Canada and none from Atlantic Canada. The objectives of this study were to strain type MRSP isolates cultured at a regional diagnostic laboratory using direct repeat unit (dru) typing and to describe their antimicrobial resistance profiles. Ninety-four isolates recovered from dogs between 2010 and 2012 had dru typing, cluster analysis, and antimicrobial susceptibility testing done. The majority of isolates belonged to type dt11a (30.9%), dt10h (24.5%), dt9a (18.1%), and dt11af (10.6%) with the remaining 15.9% of isolates distributed among 13 dru types. The predominant dru types identified were similar in Ontario; however, cluster 9a appears to be less common in Atlantic Canada. A significant difference in the distribution of clusters among Atlantic provinces was detected (P = 0.01). Resistance to ≥ 2 non-β-lactam antimicrobials was observed in 71.4% of the isolates. The MRSP isolates from this study were notably less resistant than those reported in the literature. A more comprehensive study of the MRSP dru types could help further elucidate the distribution of this pathogen in Canada.


Comparison of Chemical Compositions and Antioxidant Activity of Essential Oils from Litsea Cubeba, Cinnamon, Anise, and Eucalyptus.
The purpose of this study was to compare the antioxidant activity of litsea cubeba oil (LCO), cinnamon oil (CO), anise oil (AO), and eucalyptus oil (EUC) in vitro. The chemical compositions of the essential oils (EOs) were analyzed using gas chromatography-mass spectrometry (GC-MS). The antioxidant activity of the four EOs was evaluated through scavenging DPPH free radicals, chelating Fe2+, scavenging hydroxyl free radicals, and inhibiting yolk lipid peroxidation. The results showed that the major compounds found in LCO, CO, AO, and EUC are citral (64.29%), cinnamaldehyde (84.25%), anethole (78.51%), and 1,8-cineole (81.78%), respectively. The four EOs all had certain antioxidant activity. The ability to scavenge DPPH radical was ranked in the order of LCO > CO > AO > EUC. The hydroxyl radical scavenging ability was ranked in the order of EUC > CO > LCO > AO. The chelating Fe2+ capacity was ranked in the order of EUC > AO > CO > LCO. The yolk lipid peroxidation inhibition ability was ranked in the order of CO > AO > EUC > LCO. In different antioxidant activity assays, the antioxidant activity of the EOs was different. It was speculated that the total antioxidant activity of an EO may be the result of the joint action of different antioxidant capacities.


Glycoprotein 2 of zymogen granule membranes shares immunological cross-reactivity and sequence similarity with phospholipase A2.
Glycoprotein 2 (GP2), the major protein of rat pancreatic zymogen granule membranes (ZGMs), cross-reacted with an antiserum against porcine secretory phospholipase A2 (sPLA2). Amino acid sequence comparison showed 45% similarity and 23% identity between porcine PLA2 and the C-terminal portion of GP2. An antiserum to intestinal brush border Ca(2+)-independent PLA2 (bbPLA2) also recognized GP2. The antigenic and sequence similarities between GP2, sPLA2, and bbPLA2 imply that the role of GP2 in cellular function is associated with phospholipid binding and/or hydrolysis.


Acupuncture therapy for experimental stomach ulcer and c-Fos expression in rats.
To determine the role of acupuncture therapy in treating experimental gastric ulcer in rats. Twenty-eight adult male Sprague-Dawley rats were randomly divided into four groups (pre-acupuncture group; acupuncture group; paradistance-acupuncture group; and control group), and pre-acupuncture, paradistance-acupuncture, and control groups received 5 muL acetic acid (200 mL/L HAc) injection after a same course of electroacupuncture (EA) treatment (4 Hz, 0.6 mA, 0.45 ms, 45 min for 4 d). The rats in these three groups recovered within 4 d. The acupuncture group received EA therapy for 4 d, after HAc injection. The stomach was dissected to compare the pathological structures of ulcer. Also c-Fos activation in the nuclei of solitary tract (NTS) was observed under microscope after regular immunohistochemistry staining of brain stem sections. The number of ulcers was different among the four groups, especially between control group and paradistance-acupuncture group or pre-acupuncture group. In the latter group, the number of ulcers was much less. The gastric ulcer area was consistent with the histopathological results, indicating that pre-acupuncture had an obvious therapeutic effect on gastric ulcers. Acupuncture had a very modest effect and paradistance-acupuncture had no effect on gastric ulcers. No therapeutic effect was found in the control group. Fos-Li neurons in NTS induced by noxious gastric ulcer showed a significant difference between pre-acupuncture and control groups. Acupuncture before ulceration can obviously alleviate ulcer. The production of c-Fos proves that the vagus nerve mediates the induction of c-Fos in nuclei of solitary tract following experimental ulceration, suggesting that parasympathetic afferents promote the process of noxious visceral stimulation.


The pharmacokinetic and pharmacodynamic properties of different formulations of biphasic insulin aspart: a randomized, glucose clamp, crossover study.
Type 2 diabetes patients on premixed insulin are commonly prescribed biphasic insulin with low prandial insulin content, such as biphasic insulin aspart (BIAsp) 30, comprising 30% insulin aspart (IAsp). The new formulations BIAsp 50 and BIAsp 70 contain 50% and 70% soluble IAsp, respectively. We compared the pharmacodynamics (PD) and pharmacokinetics (PK) of BIAsp 30, 50, and 70 and IAsp in a glucose clamp trial. In this randomized, double-blind, crossover study at a clinical research institute, 32 type 1 diabetes patients on basal-bolus therapy each underwent four glucose clamps (clamp level 5 mmol/L, duration 28 h post-dosing [12 h for IAsp]) and received a single dose of 0.4 U/kg BIAsp 30, 50, or 70 and IAsp. Main PD/PK outcome parameters measured were early- and late-phase glucose disposal (area under the curve of glucose infusion rate [AUC(GIR)]), nonesterified fatty acid concentrations, and IAsp concentrations. With increasing proportions of soluble IAsp, the insulin formulations showed significantly higher early metabolic activity (ratio of AUC(GIR) 0-6 h: BIAsp 50/BIAsp 30 = 1.28 [P < 0.001], BIAsp 70/BIAsp 50 = 1.18 [P < 0.001), IAsp/BIAsp 70 = 1.15 [P < 0.01]) and lower late metabolic activity (ratio of AUC(GIR) 12-28 h: BIAsp 50/BIAsp 30 = 0.17 [P < 0.01], BIAsp 70/BIAsp 50 = 0.21 [P < 0.05]). Likewise, early IAsp levels were significantly greater and late PK concentrations were significantly lower with increasing proportion of soluble IAsp. There are significant differences between the early and late PD and PK effects among BIAsp 30, 50, and 70 and IAsp that should allow tailored treatment with the convenience of prandial and basal insulin in each injection.


Generation of quinoneimine intermediates in the bioactivation of 3-(N-phenylamino)alanine (PAA) by human liver microsomes: a potential link between eosinophilia-myalgia syndrome and toxic oil syndrome.
Eosinophilia-myalgia syndrome (EMS) was an intoxication episode that occurred in the US in 1989 and affected 1,500 people. EMS was associated with the ingestion of manufactured L-tryptophan, and 3-(N-phenylamino)alanine (PAA) was identified as one of the contaminants present in the L-tryptophan batches responsible for intoxication. In previous studies (Martínez-Cabot et al., Chem Res. Toxicol., in press), we have shown that the incubation of 3-(N-phenylamino)propane-1,2-diol (PAP), a toxic biomarker of the oil batches that caused Toxic Oil Syndrome in Spain, with human liver microsomes generates a reactive quinoneimine intermediate. The structural similarity between PAA and PAP led Mayeno and co-workers (Mayeno et al. (1995) Chem. Res. Toxicol. 8, 911-916) to hypothesize that both xenobiotics could be linked to a common etiologic agent. We thus set about to study the bioactivation of PAA by human liver microsomes. Under these conditions, PAA is converted to its 4'-hydroxy derivative, an unstable intermediate that is rapidly transformed into the final metabolites 4-aminophenol and formylglycine, which were identified in the incubations by GC/MS using the H2(18)O-labeled medium. We also provide evidence that 4-aminophenol and formylglycine are formed from a quinoneimine intermediate via a pathway similar to that demonstrated for PAP bioactivation. This quinoneimine, in the absence of nucleophiles in the incubation medium, could isomerize to give the corresponding imine, which could undergo hydrolysis to yield the aforementioned final products. These findings establish that EMS and TOS are linked by a common toxic metabolite (4-aminophenol) and that they may be further linked by the concomitant release of potentially hazardous carbonyl species.


First-pass determination of the right ventricular ejection fraction using two regions of interest and the right anterior oblique view.
The right ventricular ejection fraction (RVEF) was determined on the right anterior oblique view in 9 patients during the first pass of a bolus of technetium-99m employing a gamma camera with high count-rate capability. The RVEF was calculated by using: (i) a fixed end-diastolic region of interest (ROI); and (ii) an end-diastolic and end-systolic ROI. Because of the movement of the tricuspid plane the first of these methods often gave low values, and agreement between the first two peaks was not as good as that when the second method was used. The mean for the second method was in agreement with that in a previous study using a gated first-pass technique and two ROIs but was somewhat higher than those reported by workers using either one ROI or the anterior view.


Red-emission oligofluorene electrophosphorescent diodes based on bis[2-(9,9-dihexyl-9H-fluoren-2-yl)quinolineC3,N]acetylacetonatoiridium(III) and solvent treatment for interface modification.
Efficient solution-processed organic light emitting diodes based on oligofluorene doped with bis[2-(9,9-dihexyl-9H-fluoren-2-yl)quinoline-C3,N]- acetylacetonatoiridium(III) [Ir(C6flq)2(acac)] have been demonstrated. The oligofluorene and [Ir(C6flq)2(acac)] show excellent solubility and processibility, with a device performance of 7.83+/-0.52 cd A(-1) and 3.30+/-0.10 lm W(1-) at 2479+/-45 cd m(-2) brightness with Commission International de L'Eclairage coordinates (0.66, 0.33). It was discovered that the efficiency can be further enhanced by exposing the finished organic thin film to a polar solvent or solvent vapor before deposition of the cathode contact. As a result, a peak efficiency of 12.20+/-0.16 cd A(-1) and 6.35+/-0.03 lm W(1-) at 1821+/-238 cd m(-2) brightness is achieved. This efficiency enhancement can be attributed to the presence of interface dipoles between the light-emitting layer and cathode contact.


Low level arsenite exposures suppress the development of bone marrow erythroid progenitors and result in anemia in adult male mice.
Epidemiological studies report an association between chronic arsenic (As) exposure and anemia in men, and women who are predisposed to anemia. The purpose of these studies was to determine whether a 60 d drinking water exposure of adult male C57BL/6J mice to 0, 100, and 500ppb arsenite (As+3) results in anemia due to alterations in erythroid progenitor cell development in the bone marrow. Exposure to 500ppb As+3 for 60 d resulted in a reduction of mean corpuscular hemoglobin (MCH) levels, but did not significantly alter red blood cell (RBC) counts, hemoglobin (Hgb) levels, mean corpuscular Hgb concentrations (MCHC), or mean corpuscular volumes (MCV). Attenuation of burst-forming unit-erythroid (BFU-E) colony formation was observed in bone marrow cells of mice exposed to 500ppb As+3. The differentiation of late-stage bone marrow erythroblasts as defined by CD71 and Ter119 surface marker expression was reduced with the 500ppb As+3 exposure. Mice exposed to 500ppb As+3 also had elevated serum levels of erythropoietin (EPO). Collectively, these results show that exposure to low levels of As+3 attenuate the development of early BFU-E cells and reduce the differentiation of late-stage erythroblasts. This suppression of bone marrow erythropoiesis may be a contributing factor to the mild hypochromic anemia observed in 500ppb As+3 exposed mice.


Allergic fungal sinusitis with massive intracranial extension presenting with tearing.
A 24-year-old male presented with tearing, and subsequent workup and imaging showed a mass with fluid involving the nasopharynx, the paranasal sinuses, and the posterior dehiscence of the left frontal sinus intracranially compressing the frontal lobe significantly. Microscopic examination confirmed the diagnosis of allergic fungal sinusitis. Endoscopic drainage and sinostomy was performed by the otolaryngology (ear-nose-throat) service. The patient was followed 9 months postoperatively and did well with resolution of the epiphora. Although epiphora alone is an unusual presentation of allergic fungal sinusitis, ophthalmologists need to be aware of this entity, as it may invade the orbit through the sinus cavities or compress on the nasolacrimal duct before it causes other mass-related symptoms. Radiology and the characteristic histopathologic findings are the most useful in establishing the correct diagnosis.


Anterior calcaneal osteotomy for symptomatic juvenile pes planus.
Five patients with symptomatic flexible pes planus unresponsive to conservative therapy underwent nine open wedge anterior calcaneal osteotomies and advancement of the posterior tibial tendon. The average follow-up was 6 years, 8 months. Three patients exhibited medial and plantar talonavicular subluxation and naviculocuneiform sag. There were three excellent results, three very good, two good, and one poor. The patient with a poor rating was asymptomatic, had normal foot motion, and was satisfied with the procedure.


Synthesis and biological activity of PTEN-resistant analogues of phosphatidylinositol 3,4,5-trisphosphate.
The activation of phosphatidylinositol 3-kinase (PI 3-K) and subsequent production of PtdIns(3,4,5)P3 launches a signal transduction cascade that impinges on a plethora of downstream effects on cell physiology. Control of PI 3-K and PtdIns(3,4,5)P3 levels is an important therapeutic target in treatments for allergy, inflammation, cardiovascular, and malignant human diseases. We designed metabolically stabilized, that is, phosphatase resistant, analogues of PtdIns(3,4,5)P3 as probes for long-lived potential agonists or potential antagonists for cellular events mediated by PtdIns(3,4,5)P3. In particular, two types of analogues were prepared containing phosphomimetics that would be selectively resistant to the lipid 3-phosphatase PTEN. The total asymmetric synthesis of the 3-phosphorothioate-PtdIns(3,4,5)P3 and 3-methylenephosphonate-PtdIns(3,4,5)P3 analogues is described. These two analogues showed differential binding to PtdIns(3,4,5)P3 binding modules, and both were potential long-lived activators that mimicked insulin action in sodium transport in A6 cells.


Response of the bacterial metagenome in port environments to changing environmental conditions.
Port environments are highly dynamic and hotspots for marine bioinvasion. This study investigated the bacterial diversity at two geographically distant ports (Mangalore-marine port; and Haldia-riverine port) using next-generation sequencing during southwest monsoon and non-monsoon (Pre-monsoon) seasons. During southwest monsoon, at both marine and riverine ports, operational taxonomic units (OTUs) affiliated to bacteria reported to have hydrocarbon degrading ability were observed. Whereas during pre-monsoon, a significant increase in benthic bacterial OTUs was evident at the marine port, and the riverine port was characterized by oceanic species OTUs. Results suggest that the dynamics of prevalent environmental conditions, driven by seasons, led to emergence of ecologically relevant bacteria, many of which have been observed for the first time in Indian coastal waters. Their presence could be used as indicators of prevailing environmental conditions and nature of anthropogenic influence in port ecosystems. Unravelling functional roles of such ecologically relevant species is a way forward.


Educators' perceptions of e-cigarettes in Australian secondary schools.
Secondary schools are a setting in which e-cigarette use among students has increased significantly, resulting in an urgent need for educators to develop and implement strategies to curb youth vaping. Research assessing school-based vaping prevention efforts is limited and largely confined to the US. This study assessed Australian secondary school staff members' experiences with e-cigarettes and explored (i) the presence of e-cigarette policies and educational programs, (ii) barriers to policy development and implementation, and (iii) desired support. Public, Catholic, and Independent secondary schools across Australia were sent an invitation to participate in this study, which involved completion of an online survey. A total of 218 school staff members (55% women) participated. Respondents included school principals, teachers, and other staff members. Data collection occurred May to September 2022. Both quantitative and qualitative data were collected. Nearly half (46%) of all school staff members surveyed reported finding a student with an e-cigarette on campus at least monthly, and one-third (36%) of principals reported suspending or expelling students at least monthly for e-cigarette possession or use. The vast majority of those surveyed agreed that e-cigarette use is increasingly becoming a problem in secondary schools (93%) and reported being concerned about e-cigarette use by students (94%). Only half (51%) reported that their school had an e-cigarette policy in place. The discreet appearance of e-cigarettes (83%) and difficulties pinpointing from where the vapor/scent is coming (73%) were the most frequently reported barriers to policy enforcement. The results of this study suggest that e-cigarettes present a threat to secondary school environments. There is an urgent need to develop, implement, and enforce both school- and government-level e-cigarette policies to prevent and reduce youth vaping in Australian secondary schools.


Gender and history of suicidality: are these factors related to U.S. college students' current suicidal thoughts, feelings, and actions?
Gender and history of suicidality (HS vs. NoHS) were related to current symptoms of depression, reasons for living, and reports of self-destructive and life-threatening behavior in a college student sample. Overall, college men reported engaging in more life-threatening and potentially suicidal behavior than college women on the Life Attitudes Schedule (LAS). No gender effects were obtained on the symptoms of depression and reasons for living measures. Results suggest that the LAS may be a particularly effective way to identify college students at risk for self-destructive and suicidal behavior. As expected, HS individuals were more depressed, had fewer reasons for living, and reported engaging in more current suicidal and life-threatening behavior than NoHS participants. However, gender and history of suicidality were found to interact. NoHS women reported avoiding a variety of injury-producing and health-diminishing behaviors that were common for all other groups of college students. Meanwhile, HS women endorsed fewer current reasons for living than did NoHS women, NoHS men, and NoHS men. These findings were interpreted both with regard to cultural and gender-specific expectations for the expression of self-destructive, suicidal, and life-threatening behavior. Implications for the prevention of college women's and men's suicidal behavior were also noted.


[Palliative care management of patients in a dermatology department].
The number of patients referred to French University dermatology departments for skin cancers has increased continuously for many years. The aim of this study was to assess the management and number of patients who died in our dermatology department over a 10-year period. All cases of patients who died in our dermatology department from 1992 to 2002 were retrospectively assessed. Demographic data, past history, main diagnosis, duration of hospitalisation and main treatment given were recorded. The number of patients who died increased from 9 per year at the beginning of the study period to 25 per year at the end of this study. The mean age of patients remained unchanged at 66.5 years old. Forty-nine percent of patients in this study had metastatic melanoma, with no significant modification during the study period. Morphine-based drugs were used (mainly orally) in 41 percent of patients at the beginning of the study and in 56 percent (mainly via subcutaneous infusions) at the end of the study. Forty-five percent of patients were managed in close collaboration with the palliative care unit. This study showed a three-fold increase in the number of patients referred for end-of-life care in a dermatology department during a 10-year period. Most of these patients had disseminated malignant melanoma. Major changes in patient management occurred during this period.


Development of an immediate release excipient composition for 3D printing via direct powder extrusion in a hospital.
3D printing offers the possibility to prepare personalized tablets on demand, making it an intriguing technology for hospital pharmacies. For the implementation of 3D-printed tablets into the digital Closed Loop Medication Management system, the required tablet formulation and development of the manufacturing process as well as the pharmaceutical validation were conducted. The goal of the formulation development was to enable an optimal printing process and rapid dissolution of the printed tablets for the selected model drugs Levodopa/Carbidopa. The 3D printed tablets were prepared by direct powder extrusion. Printability, thermal properties, disintegration, dissolution, physical properties and storage stability were investigated by employing analytical methods such as HPLC-UV, DSC and TGA. The developed formulation shows a high dose accuracy and an immediate drug release for Levodopa. In addition, the tablets exhibit high crushing strength and very low friability. Unfortunately, Carbidopa did not tolerate the printing process. This is the first study to develop an immediate release excipient composition via direct powder extrusion in a hospital pharmacy setting. The developed process is suitable for the implementation in Closed-Loop Medication Management systems in hospital pharmacies and could therefore contribute to medication safety.


Mesenchymal stromal cell-derived exosomes improve mitochondrial health in pulmonary arterial hypertension.
Secreted exosomes are bioactive particles that elicit profound responses in target cells. Using targeted metabolomics and global microarray analysis, we identified a role of exosomes in promoting mitochondrial function in the context of pulmonary arterial hypertension (PAH). Whereas chronic hypoxia results in a glycolytic shift in pulmonary artery smooth muscle cells (PASMCs), exosomes restore energy balance and improve O2 consumption. These results were confirmed in a hypoxia-induced mouse model and a semaxanib/hypoxia rat model of PAH wherein exosomes improved the mitochondrial dysfunction associated with disease. Importantly, exosome exposure increased PASMC expression of pyruvate dehydrogenase (PDH) and glutamate dehydrogenase 1 (GLUD1), linking exosome treatment to the TCA cycle. Furthermore, we show that although prolonged hypoxia induced sirtuin 4 expression, an upstream inhibitor of both GLUD1 and PDH, exosomes reduced its expression. These data provide direct evidence of an exosome-mediated improvement in mitochondrial function and contribute new insights into the therapeutic potential of exosomes in PAH.


[Effects on the pharmacokinetics of furosemide after acute exposure to high altitude at 4010 meters in rats].
The paper is to report the pharmacokinetics of furosemide in rats living at plain area and high altitude. After intragastric administration of furosemide (2.87 mg x kg(-1)), serial blood samples (0.5 mL) were collected by retro-orbital puncture at 0, 20 min, 40 min, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h, samples were determined by LC-MS/MS, and plasma concentration-time data were analyzed by DAS 2.0 software to get the related pharmacokinetic parameters. The main pharmacokinetic parameters: area under curve (AUC), mean residence time (MRT), the biological half-life (t1/2) and the peak concentration (C(max)) of furosemide, were significantly increased at high altitude, the time to reach peak concentration (t(max)) and clearance (CL) was significantly decreased. This study found significant changes on the pharmacokinetics of furosemide under the special environment of high altitude. This finding may provide some references for clinical rational application of furosemide at high altitude.


Identification of the Drosophila eIF4A gene as a target of the DREF transcription factor.
The DNA replication-related element-binding factor (DREF) regulates cell proliferation-related gene expression in Drosophila. We have carried out a genetic screening, taking advantage of the rough eye phenotype of transgenic flies that express full-length DREF in the eye imaginal discs and identified the eukaryotic initiation factor 4A (eIF4A) gene as a dominant suppressor of the DREF-induced rough eye phenotype. The eIF4A gene was here found to carry three DRE sequences, DRE1 (-40 to -47), DRE2 (-48 to -55), and DRE3 (-267 to -274) in its promoter region, these all being important for the eIF4A gene promoter activity in cultured Drosophila Kc cells and in living flies. Knockdown of DREF in Drosophila S2 cells decreased the eIF4A mRNA level and the eIF4A gene promoter activity. Furthermore, specific binding of DREF to genomic regions containing DRE sequences was demonstrated by chromatin immunoprecipitation assays using anti-DREF antibodies. Band mobility shift assays using Kc cell nuclear extracts revealed that DREF could bind to DRE1 and DRE3 sequences in the eIF4A gene promoter in vitro, but not to the DRE2 sequence. The results suggest that the eIF4A gene is under the control of the DREF pathway and DREF is therefore involved in the regulation of protein synthesis.


A general method to synthesize and sinter bulk ceramics in seconds.
Ceramics are an important class of materials with widespread applications because of their high thermal, mechanical, and chemical stability. Computational predictions based on first principles methods can be a valuable tool in accelerating materials discovery to develop improved ceramics. It is essential to experimentally confirm the material properties of such predictions. However, materials screening rates are limited by the long processing times and the poor compositional control from volatile element loss in conventional ceramic sintering techniques. To overcome these limitations, we developed an ultrafast high-temperature sintering (UHS) process for the fabrication of ceramic materials by radiative heating under an inert atmosphere. We provide several examples of the UHS process to demonstrate its potential utility and applications, including advancements in solid-state electrolytes, multicomponent structures, and high-throughput materials screening.


Priority setting in health care as portrayed in South Korean and Israeli newspapers.
Studies have reported differences in the public's understanding of, trust in, and satisfaction with its priority-setting processes and outcomes across countries. How the media frames and reports decision making processes and outcomes may both reflect and affect the public's knowledge of and attitudes toward them. Nevertheless, no studies have analyzed how priority-setting decision making processes are portrayed in the media. We analyzed 202 newspaper articles published over a decade, from January 2000 through December 2009, in leading newspapers of Israel and South Korea. The findings reveal intriguing differences between the countries in both the number and content of the reports. The issue of priority setting is much less salient in Korean than in Israeli society. While the complexity of the task was the most prevalent theme in the Israeli reports sampled, benefits package expansion decisions were most common in the Korean reports. Similarly, the Israeli reports emphasized the qualifications and backgrounds of individual members of the decision making committee, but the equivalent Korean committee was not portrayed as a major actor, and so received less attention. The least reported theme in both countries was priority-setting procedures and principles. These findings, along with results from previous studies which indicate that public satisfaction with the two systems differs between the countries, provoke several interesting future research questions.


[Focal infectious lesions of the renal parenchyma. Comparative contribution of echography and x-ray computed tomography].
Nineteen cases of focal infectious lesions of renal parenchyma studied included 10 cases of acute focal bacterial nephritis (AFBN) and 9 of abscess, cases of pyelonephritis without radiological signs being excluded from this report. Each patient had been investigated by intravenous urography (IVU), ultrasound and CT scan imaging. Comparison of value of the different radiological explorations showed that urographic signs were inconstant and only weakly specific, the most valuable examination being CT scan imaging. The latter images show hypodense zones, clearer with contrast, of a rather triangular form and either single or multiple in AFBN, and mainly nodular images in abscess cases. Ultrasound is of intermediate value, being of high performance in cases of abscess but failing to demonstrate AFBN in about half the cases. However, it should not be totally neglected because of its case of access.


Use of carprofen for the treatment of pain and inflammation in dogs.
Most studies of nonsteroidal anti-inflammatory drugs (NSAID) do not demonstrate appreciable differences in efficacy. As awareness of the adverse effects associated with NSAID use increases, safety is becoming the primary concern among physicians when selecting NSAID for use by their human patients. However, veterinarians may be less aware of the safety concerns associated with NSAID use. A wide range of NSAID is used to treat human beings with osteoarthrits; however, it is imperative to remember that dogs are especially sensitive to these drugs, and reports of serious, and occasionally fatal, complications are numerous. Carprofen is a propionic acid-derived NSAID that has anti-inflammatory, analgesic, and antipyretic activity. In animals, carprofen is as potent as indomethacina and more potent than aspirin or phenlbutazone, but carprofen appears to be safer than most other NSAID.


Affected family members' experience of, and coping with, aggression and violence within the context of problematic substance use: a qualitative study.
Families have an important role supporting a family member with problematic substance use (PSU), although this can often be challenging and confronting. Previous research has identified high rates of family aggression and violence within the context of PSU, although few studies have examined this issue from the perspective of affected family members (AFMs) supporting a member with PSU. The aims of the current study were to understand AFMs' experience of aggression and violence while supporting a member with PSU, and to explicate the strategies they used to prevent and cope with this behaviour. Semi-structured, audio-recorded qualitative interviews were conducted with 31 AFMs from the state of Victoria in Australia. Interpretative Phenomenological Analysis was used to guide data collection and analysis. Almost 70% of participants experienced PSU-related family aggression and/or violence. Two main themes and related sub-themes were abstracted from the data capturing their experiences of this behaviour and the strategies they used to try to prevent and cope in this situation. Aggression and/or violence were variable, changeable and unpredictable; and aggression and/or violence altering social interactions and family dynamics. As a consequence, it was upsetting, stressful and emotionally exhausting to AFMs. In response to this experience, and largely through trial and error, they used several direct strategies to try to prevent and cope with the behaviour; however, most continued to struggle in these circumstances. They also highlighted additional indirect measures, which, if adopted, would enhance their existing direct strategies. More effective primary, secondary and tertiary preventive measures are needed to address family aggression and violence within the context of PSU. More support is needed for family members affected by PSU to enable them to 'stand up to,' to prevent and cope effectively with this behaviour, and to increase their help-seeking and access to specialist services and support groups. More appropriate policies and social services are needed to meet the needs of AFMs.


Renoprotective effects of Vitamin D and renin-angiotensin system.
Vitamin D has many physiological functions. First it is a primary regulator of calcium homeostasis. Beyond that, vitamin D and its receptors (VDR) play important role in the immune system, cardiovascular system, reproductive system and insulin resistance. An important aspect of vitamin D pleiotropic effects is the interaction with components of the renin-angiotensin system (RAS). It was demonstrated that vitamin D-null mice have a sustained elevation of renin expression. The combination of both the AT1 blockers and the vitamin D analogues, leads to a marked amelioration of the molecular and clinical markers of diabetic nephropathy. This combination may protect the kidney through the effects on both the glomerular and the tubulointerstitial compartments. There are different studies that corroborate the renoprotective action of vitamin D in CKD. In fact the renoprotective mechanisms in humans remain to be assessed, but these are realized through reduction of proteinuria, high blood pressure, inflammation as well as hemodynamic effects. An important mechanism is the role of vitamin D as a potent negative endocrine regulator of renin expression. It was shown that low levels of vitamin D represent a novel risk factor for the progression of renal disease but it is not demonstrated yet that vitamin D can prolong the time to end-stage renal disease. This question remains to be answered in other future controlled clinical trials.


Multiple Sclerosis Presenting with Sixth Nerve Palsy in a Child.
We report a child with multiple sclerosis who presented with sixth nerve palsy. She is a twelve-year-old Bahraini female presented to the ophthalmology department complaining of double vision. She also had imbalance and paraesthesia. Extraocular muscle examination showed restriction of abduction in the right eye. There was no change in vision. MRI showed right eye optic neuritis (ON) and demyelination which was indicative of multiple sclerosis (MS). Ocular coherence tomography (OCT) showed thinning of nerve fibres of both eyes which was consistent with subclinical optic neuritis. Neurological examination showed brisk knee jerk on the left side and incoordination of movement on the same side. Disability Status Scale (EDSS) showed a score of 3.0. She was given Solu-medrol 500 mg intravenously (IV) in addition to omeprazole 40 mg IV and Vitamin D3 (cholecalciferol) 50,000 IU cap weekly for 8 weeks and Neurorubine forte tablets (vitamin B1, 6, 12) once a day for 2 months. She became asymptomatic in her follow-up visits. Children with MS can present as sixth cranial nerve palsy. Clinicians should have a high index of suspicion for early diagnosis and treatment. In addition to MRI, OCT is a useful diagnostic tool for optic neuritis and MS especially in children.


Shear stress and VEGF activate IKK via the Flk-1/Cbl/Akt signaling pathway.
Vascular endothelial cells are continuously exposed to mechanical (e.g., shear stress) and chemical (e.g., growth factors) stimuli. It is important to elucidate the mechanisms by which cells perceive and integrate these different stimuli to regulate the downstream signaling pathways. We (50) have previously reported the shear-induced interplay between two membrane receptors, integrins and Flk-1. In the present study, we investigated the molecular mechanisms regulating the downstream IkappaB kinase (IKK) pathway in response to shear stress and VEGF. Both shear stress and VEGF induced a transient increase of IKK activity. These effects were inhibited by SU-1498, a specific Flk-1 inhibitor, and by a negative mutant of Casitas B-lineage lymphoma (Cbl) with tyrosine-to-phenylalanine mutations at sites 700, 731, and 774 (Cbl(nm)). Because Flk-1 and Cbl form a complex upon shearing or VEGF applications (50), these results suggest that shear stress and VEGF activate IKK via the receptor Flk-1 and its recruitment of the adapter protein Cbl. The inhibition of the shear- and VEGF-induced IKK activities by a negative mutant of Akt indicates that Akt acts upstream to IKK in response to shear stress and VEGF. Furthermore, SU-1498 and Cbl(-nm) abolished the shear- and VEGF-induced Akt activity, indicating that Akt acts at a level downstream to Flk-1 and Cbl. Therefore, our results indicate that the signaling events induced by shear stress and VEGF converge at the membrane receptor Flk-1 and that these stimuli share the Flk-1/Cbl/Akt pathway in activating IKK activation.


Fouling potentials of polysaccharides in membrane bioreactors (MBRs) assessed by lectin affinity chromatography.
In this study, the fouling potentials of polysaccharides contained in mixed liquor suspension in a membrane bioreactor (MBR) treating municipal wastewater were investigated using lectin affinity chromatography. This investigation was carried out with different membranes to assess the effects of membrane materials on fouling potentials of polysaccharides. In lectin affinity chromatography, some polysaccharides with high affinity to the lectin in the column can be retained in the column. The fouling potentials of the retained polysaccharides were evaluated by dead-end filtration test. Degree of reduction in fouling potential differed considerably when different lectins were used in affinity chromatography indicating that fouling potentials of polysaccharide differed depending on types of polysaccharide. Trends in the reduction of fouling potential were different depending on membrane materials. Characteristics of the organic matter associated with polysaccharides removed by lectins were investigated by means of excitation-emission matrices (EEM). The results of EEM analysis indicate that the characteristics of the organic matter eluted from different lectins were different as long as elution reagents for the lectin were different. Characteristics of the organic matter eluted from the lectins which have the same elution reagent were similar in terms of shapes of EEM fluorescence spectra. However, the trends in reduction of fouling potentials could not be explained by the characteristics of organic matter assessed by EEM analysis. On the basis of the results obtained in this study, it can be concluded that characteristics of membrane and structures or properties of sugar chain would play an important role in determining fouling potentials.


Copper-carbene complexes as catalysts in the synthesis of functionalized styrenes and aliphatic alkenes.
(NHC)-Cu (NHC = N-heterocyclic carbene) complexes efficiently catalyzed the methylenation of a variety of aliphatic and aromatic aldehydes and ketones in the presence of trimethylsilyldiazomethane, triphenylphosphine, and 2-propanol. The copper catalysts are not only inexpensive compared to rhodium complexes, but they also exhibit better functional group compatibility with aromatic aldehydes and ketones. Indeed very high yields were obtained for the formation of styrenes containing nitro, trifluoromethyl, amino, and ester groups, as well as for pyridine-, pyrrole-, and indole-substituted alkenes.


Toxicity of inorganic nanomaterials in biomedical imaging.
Inorganic nanoparticles have shown promising potentials as novel biomedical imaging agents with high sensitivity, high spatial and temporal resolution. To translate the laboratory innovations into clinical applications, their potential toxicities are highly concerned and have to be evaluated comprehensively both in vitro and in vivo before their clinical applications. In this review, we first summarized the in vivo and in vitro toxicities of the representative inorganic nanoparticles used in biomedical imagings. Then we further discuss the origin of nanotoxicity of inorganic nanomaterials, including ROS generation and oxidative stress, chemical instability, chemical composition, the surface modification, dissolution of nanoparticles to release excess free ions of metals, metal redox state, and left-over chemicals from synthesis, etc. We intend to provide the readers a better understanding of the toxicology aspects of inorganic nanomaterials and knowledge for achieving optimized designs of safer inorganic nanomaterials for clinical applications.


Zhuangzi and collaboration in animals: a critical conceptual analysis of shared intentionality.
Shared intentionality is a specific form of shared agency where a group can be understood to have an intention. It has been conjectured that humans are better equipped for collaboration than other animals because humans but not other great apes share intentions. However, exporting shared intentionality from a debate about the ontology of mental state attributions like intentions to groups does not seamlessly lend itself to evolutionary science. To explore and de-center the implicit assumptions of Western conceptions of cooperation, I look at Zhuangzi's philosophy of (in)action. This philosophy treats the actions of individuals as always a form of co-action alongside other agencies to whom one must adapt. Thinking of collaboration as a product of skillful co-action, not shared intention, sidesteps asking about cooperation in "kinds" or levels. Instead, it directs attention to the know-how and behavioral flexibility needed to make our constant coordination adaptive.


Neuropsychological function in mild sleep-disordered breathing.
Although a broad range of neuropsychological deficits has been reported in patients with severe sleep disordered breathing (SDB), little is known about the impact of mild SDB on neuropsychological performance. In this study, we compared neuropsychological test performance in two groups of carefully screened volunteers who differed clearly according to the respiratory disturbance index (RDI). Controls (n = 20) were identified on the basis of an RDI < 5; cases (n = 32) had an RDI in the range of 10-30. Cases and controls were well matched with regard to IQ, age, and sex. Cases had significantly more self-reported snorting and apneas and a higher body mass index than controls but did not differ according to sleepiness as measured by either the multiple sleep latency test or the Epworth sleepiness scale. An extensive battery of neuropsychological and performance tests was administered after an overnight sleep study. Cases performed significantly more poorly on a visual vigilance task (perceptual sensitivity, d': 2.24 +/- 0.64 vs. 2.70 +/- 0.53, p = 0.01, for cases and controls, respectively) and a test of working memory, the Wechsler adult intelligence scale-revised digits backwards test (6.12 +/- 2.20 vs. 7.55 +/- 2.22, p = 0.02), than controls. The groups did not differ in their performance on other tests of memory, information processing, and executive functioning. In summary, subjects with mild SDB may manifest a vigilance deficit in the absence of substantial sleepiness. Subjects with a mildly elevated RDI (10-30) without sleepiness do not appear to suffer appreciable deficits in more complex neuropsychological processes (e.g. executive functions).


Sticky Trap Design Considerations for Entrapping Bed Bugs.
Little evidence has been presented on the usefulness of sticky traps for monitoring bed bugs, Cimex lectularius. We examined how the surface roughness around the adhesive of a sticky trap affects both bed bug behavior and adhesive entrapment. In the first assay, bed bugs were placed onto acetate paper discs with different roughness averages (Ra). Each disc was surrounded by sticky trap adhesive and number of captured bed bugs were recorded. The second assay was set up similarly to the first assay except that the outer portion of the acetate disc had a different Ra than the center. In the third assay, bed bugs were placed into circular acetate arenas where they were surrounded by different Ra treatments. The number of times the bed bugs contacted the Ra treatment but did not cross onto the treatment was recorded. Results of these assays showed that as the acetate surfaces got smoother (lower Ra), bed bugs were more likely to get trapped in sticky trap adhesives but also less likely to travel across the smoother surfaces they encountered. A sticky trap design with a smooth plastic film around the adhesive was tested in the field to see if it could capture bed bugs in apartments with known bed bug activity. This trap was not only able to capture bed bugs but was also able to detect unknown German cockroach, Blattela germanica, infestations. Sticky trap designs with smooth surfaces around an adhesive could be used to monitor not only bed bugs but also German cockroaches.


Age-Related Unstructured Spike Patterns and Molecular Localization in Drosophila Circadian Neurons.
Aging decreases sleep quality by disrupting the molecular machinery that regulates the circadian rhythm. However, we do not fully understand the mechanism that underlies this process. In Drosophila, sleep quality is regulated by precisely timed patterns of spontaneous firing activity in posterior DN1 (DN1p) circadian clock neurons. How aging affects the physiological function of DN1p neurons is unknown. In this study, we found that aging altered functional parameters related to neural excitability and disrupted patterned spike sequences in DN1p neurons during nighttime. We also characterized age-associated changes in intrinsic membrane properties related to spike frequency adaptations and synaptic properties, which may account for the unstructured spike patterns in aged DN1p neurons. Because Slowpoke binding protein (SLOB) and the Na+/K+ ATPase β subunit (NaKβ) regulate clock-dependent spiking patterns in circadian networks, we compared the subcellular organization of these factors between young and aged DN1p neurons. Young DN1p neurons showed circadian cycling of HA-tagged SLOB and myc-tagged NaKβ targeting the plasma membrane, whereas aged DN1p neurons showed significantly disrupted subcellular localization patterns of both factors. The distribution of SLOB and NaKβ signals also showed greater variability in young vs. aged DN1p neurons, suggesting aging leads to a loss of actively formed heterogeneity for these factors. These findings showed that aging disrupts precisely structured molecular patterns that regulate structured neural activity in the circadian network, leading to age-associated declines in sleep quality. Thus, it is possible to speculate that a recovery of unstructured neural activity in aging clock neurons could help to rescue age-related poor sleep quality.


Does a regional accent perturb speech processing?
The processing costs involved in regional accent normalization were evaluated by measuring differences in lexical decision latencies for targets placed at the end of sentences with different French regional accents. Over a series of 6 experiments, the authors examined the time course of comprehension disruption by manipulating the duration and presentation conditions of accented speech. Taken together, the findings of these experiments indicate that regional accent normalization involves a short-term adjustment mechanism that develops as a certain amount of accented signal is available, resulting in a temporary perturbation in speech processing.


Integrated analysis of mRNA and miRNA expression profiles in livers of Yimeng black pigs with extreme phenotypes for backfat thickness.
Fat deposition is an important economic trait in farm animals as well as obesity related diseases in humans, and the liver is a central organ involved in regulating lipid synthesis and metabolism in mammals. In this study, the pig liver transcriptome of two groups (H and L) showing differences in backfat thickness were profiled using RNA-Seq and miRNA-Seq to further explore the molecular mechanism of fat deposition. A total of 238 differentially expressed genes (DEGs) and 58 differentially expressed miRNAs were identified between the H and L group. These genes and miRNAs were functionally related to lipid metabolism, including CYP1A1/2, HMGCS2, ACSS2, UBE2L6, miR-27a, and miR-31. Functional enrichment analysis revealed that genes associated with oxidative stress might be responsible for fat deposition in pigs. Two miRNA-mRNA interaction networks involved in lipid metabolism were identified, and these provided new insights into the molecular regulation that determines fat content in these pigs. Overall, our study furthers our understanding of the molecular mechanisms involved in fat deposition, and these results may help in the design of selection strategies to improve the quality of pork meat and to combat obesity in humans.


Synergistic bifunctional catalyst design based on perovskite oxide nanoparticles and intertwined carbon nanotubes for rechargeable zinc-air battery applications.
Advanced morphology of intertwined core-corona structured bifunctional catalyst (IT-CCBC) is introduced where perovskite lanthanum nickel oxide nanoparticles (LaNiO3 NP) are encapsulated by high surface area network of nitrogen-doped carbon nanotubes (NCNT) to produce highly active and durable bifunctional catalyst for rechargeable metal-air battery applications. The unique composite morphology of IT-CCBC not only enhances the charge transport property by providing rapid electron-conduction pathway but also facilitates in diffusion of hydroxyl and oxygen reactants through the highly porous framework. Confirmed by electrochemical half-cell testing, IT-CCBC in fact exhibits very strong synergy between LaNiO3 NP and NCNT demonstrating bifunctionality with significantly improved catalytic activities of oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). Furthermore, when compared to the state-of-art catalysts, IT-CCBC outperforms Pt/C and Ir/C in terms of ORR and OER, respectively, and shows improved electrochemical stability compared to them after cycle degradation testing. The practicality of the catalyst is corroborated by testing in a realistic rechargeable zinc-air battery utilizing atmospheric air in ambient conditions, where IT-CCBC demonstrates superior charge and discharge voltages and long-term cycle stability with virtually no battery voltage fading. These improved electrochemical properties of the catalyst are attributed to the nanosized dimensions of LaNiO3 NP controlled by simple hydrothermal technique, which enables prolific growth of and encapsulation by highly porous NCNT network. The excellent electrochemical results presented in this study highlight IT-CCBC as highly efficient and commercially viable bifunctional catalyst for rechargeable metal-air battery applications.


Heme oxygenase-1 in macrophages controls prostate cancer progression.
Innate immune cells strongly influence cancer growth and progression via multiple mechanisms including regulation of epithelial to mesenchymal transition (EMT). In this study, we investigated whether expression of the metabolic gene, heme oxygenase-1 (HO-1) in tumor microenvironment imparts significant effects on prostate cancer progression.We showed that HO-1 is expressed in MARCO-positive macrophages in prostate cancer (PCa) xenografts and human prostate cancers. We demonstrated that macrophage specific (LyzM-Cre) conditional deletion of HO-1 suppressed growth of PC3 xenografts in vivo and delayed progression of prostate intraepithelial neoplasia (PIN) in TRAMP mice. However, initiation and progression of cancer xenografts in the presence of macrophages lacking HO-1 resulted in loss of E-cadherin, a known marker of poor prognosis as well as EMT. Application of CO, a product of HO-1 catalysis, increased levels of E-cadherin in the adherens junctions between cancer cells. We further showed that HO-1-driven expression of E-cadherin in cancer cells cultured in the presence of macrophages is dependent on mitochondrial activity of cancer cells.In summary, these data suggest that HO-1-derived CO from tumor-associated macrophages influences, in part, E-cadherin expression and thus tumor initiation and progression.


T. marneffei infection complications in an HIV-negative patient with pre-existing pulmonary sarcoidosis: a rare case report.
Talaromyces marneffei (T. marneffei) is a thermal dimorphic pathogenic fungus that often causes fatal opportunistic infections in human immunodeficiency virus (HIV)-infected patients. Although T. marneffei-infected cases have been increasingly reported among non-HIV-infected patients in recent years, no cases of T. marneffei infection have been reported in pulmonary sarcoidosis patients. In this case, we describe a T. marneffei infection in an HIV-negative patient diagnosed with pulmonary sarcoidosis. A 41-year-old Chinese man who had pre-existing pulmonary sarcoidosis presented with daily hyperpyrexia and cough. Following a fungal culture from bronchoalveolar lavage (BAL), the patient was diagnosed with T. marneffei infection. A high-resolution computed tomography (HRCT) chest scan revealed bilateral lung diffuse miliary nodules, multiple patchy exudative shadows in the bilateral superior lobes and right inferior lobes, air bronchogram in the consolidation of the right superior lobe, multiple hilar and mediastinal lymphadenopathies and local pleural thickening. After 3 mos of antifungal therapy, the patient's pulmonary symptoms rapidly disappeared, and the physical condition improved markedly. A subsequent CT re-examination demonstrated that foci were absorbed remarkably after treatment. The patient is receiving follow-up therapy and assessment for a cure. This case suggested that clinicians should pay more attention to non-HIV-related lung infections in patients with pulmonary sarcoidosis. Early diagnosis and treatment with antifungal therapy can improve the prognosis of T. marneffei infection.


Evaluation of laboratory parameters reflecting activity of lupus nephritis in children: indicators of severe renal lesions.
Assessment of activity of lupus nephritis is critical in the management and ultimate prognosis of patients. Clinical and laboratory data of 18 children with lupus nephritis were examined to determine what factors reflect activity of renal lesions. Using a histologic scoring system with an activity index (AI) and a chronicity index (CI), correlations between histologic scores and laboratory parameters were analyzed. Serum total protein, albumin and complement at the time of renal biopsy inversely correlated with the AI, but not parameters correlated with the CI. Serum complement levels correlated inversely with the amount of glomerular immune deposits, while the AI and CI correlated with the amount of immune deposits. These results suggest that hypoalbuminemia and hypocomplementemia are indicators of severe, active lupus nephritis, pointing to the need for early renal biopsy and intensive therapy.


Accelerated appearance of an ascitic tumour after long-term application of interferon to NZB/W mice.
In two similarly designed experiments female NZB/W mice treated with mouse L-cell interferon developed an ascitic tumour when the treatment was begun at 3.5 months of age. But no tumour appeared within a 6 months' observation period when 6 months old mice were used. A transient rise of anti-DNA antibodies preceded the tumour appearance in mice. The ascitic tumour was sensitive to antimetabolites and insensitive, or marginally sensitive, to alkylating agents or interferon. The tumour cells were adapted to growth in suspension in vitro. They caused tumour growth in various inbred and random-bred mouse lines. Attempts to transfer the tumour to Swiss mice with cell free preparations were unsuccessful.


Mesh and layered electrospun fiber architectures as vehicles for Lactobacillus acidophilus and Lactobacillus crispatus intended for vaginal delivery.
Bacterial vaginosis (BV) is a recurrent condition that affects millions of women worldwide. The use of probiotics is a promising alternative or an adjunct to traditional antibiotics for BV prevention and treatment. However, current administration regimens often require daily administration, thus contributing to low user adherence and recurrence. Here, electrospun fibers were designed to separately incorporate and sustain two lactic acid producing model organisms, Lactobacillus crispatus (L. crispatus) and Lactobacillus acidophilus (L. acidophilus). Fibers were made of polyethylene oxide and polylactic-co-glycolic acid in two different architectures, one with distinct layers and the other with co-spun components. Degradation of mesh and layered fibers was evaluated via mass loss and scanning electron microscopy. The results show that after 48 h and 6 days, cultures of mesh and layered fibers yielded as much as 108 and 109 CFU probiotic/mg fiber in total, respectively, with corresponding daily recovery on the order of 108 CFU/(mg·day). In addition, cultures of the fibers yielded lactic acid and caused a significant reduction in pH, indicating a high level of metabolic activity. The formulations did not affect vaginal keratinocyte viability or cell membrane integrity in vitro. Finally, mesh and layered probiotic fiber dosage forms demonstrated inhibition of Gardnerella, one of the most prevalent and abundant bacteria associated with BV, respectively resulting in 8- and 6.5-log decreases in Gardnerella viability in vitro after 24 h. This study provides initial proof of concept that mesh and layered electrospun fiber architectures developed as dissolving films may offer a viable alternative to daily probiotic administration.


In vivo selection of phage for the optical imaging of PC-3 human prostate carcinoma in mice.
There is an increasing medical need to detect and spatially localize early and aggressive forms of prostate cancer. Affinity ligands derived from bacteriophage (phage) library screens can be developed to molecularly target prostate cancer with fluorochromes for optical imaging. Toward this goal, we used in vivo phage display and a newly described micropanning assay to select for phage that extravasate and bind human PC-3 prostate carcinoma xenografts in severe combined immune deficiency mice. One resulting phage clone (G1) displaying the peptide sequence IAGLATPGWSHWLAL was fluorescently labeled with the near-infrared fluorophore AlexaFluor 680 and was evaluated both in vitro and in vivo for its ability to bind and target PC-3 prostate carcinomas. The fluorescently labeled phage clone (G1) had a tumor-to-muscle ratio of approximately 30 in experiments. In addition, prostate tumors (PC-3) were readily detectable by optical-imaging methods. These results show proof of principle that disease-specific library-derived fluorescent probes can be rapidly developed for use in the early detection of cancers by optical means.


Hybridization effects on wave packet dynamics in topological insulator thin films.
Theoretical study of electron wave packet dynamics in topological insulator (TI) thin films is presented. We have investigated real space trajectories and spin dynamics of electron wave packets in TI thin films. Our focus is on the role of hybridization between the electronic states of the two surfaces. This allows us to access the crossover regime of a thick film with no hybridization to a thin film with finite hybridization. We show that the electron wave packet undergoes side-jump motion in addition to zitterbewegung. The oscillation frequency of zitterbewegung can be tuned by the strength of hybridization, which in turn can be tuned by the thickness of the film. We find that the spin expectations also exhibit zitterbewegung tunable by hybridization. We also show that it is possible to obtain persistent zitterbewegung, oscillations which do not decay, in both the real space trajectories as well as spin dynamics. The zitterbewegung oscillation frequency in TI thin films falls in a parameter regime where it might be possible to observe these effects using present day experimental techniques.


Pharmacokinetic and bioequivalence study of a telmisartan/S-amlodipine fixed-dose combination (CKD-828) formulation and coadministered telmisartan and S-amlodipine in healthy subjects.
A new fixed-dose combination (FDC) formulation of telmisartan 80 mg and S-amlodipine 5 mg (CKD-828) has been developed to increase convenience (as only one tablet is required per day) and improve treatment compliance. The pharmacokinetic characteristics and tolerability of an FDC of telmisartan and S-amlodipine were compared to those after coadministration of the individual agents in this randomized, open-label, single-dose, two-way, four-period, crossover study. To analyze the telmisartan and S-amlodipine plasma concentrations using a validated liquid chromatography-tandem mass spectrometry method, serial blood samples were collected up to 48 hours post-dose for telmisartan and 144 hours post-dose for S-amlodipine, in each period. Forty-eight healthy subjects were enrolled, and 43 completed the study. The mean peak plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the last measurement (AUC0-t) values of telmisartan were 522.29 ng/mL and 2,475.16 ng·h/mL for the FDC, and 540.45 ng/mL and 2,559.57 ng·h/mL for the individual agents concomitantly administered, respectively. The mean Cmax and AUC0-t values of S-amlodipine were 2.71 ng/mL and 130.69 ng·h/mL for the FDC, and 2.74 ng/mL and 129.81 ng·h/mL for the individual agents concomitantly administered, respectively. The geometric mean ratio (GMR) and 90% confidence interval (CI) for the telmisartan Cmax and AUC0-t (FDC of telmisartan and S-amlodipine/concomitant administration) were 0.8509 (0.7353-0.9846) and 0.9431 (0.8698-1.0226), respectively. The GMR and 90% CI for the S-amlodipine Cmax and AUC0-t (FDC/concomitant administration) were 0.9829 (0.9143-1.0567) and 0.9632 (0.8798-1.0546), respectively. As the intrasubject variability of the Cmax for telmisartan administered individually was 42.94%, all 90% CIs of the GMRs fell within the predetermined acceptance range. Both treatments were well tolerated in this study. CKD-828 FDC tablets were shown to be bioequivalent to coadministration of the individual agents with the respective strength, in healthy subjects under fasting conditions. There was no significant difference in safety profile between the two treatments.


Potential of risk-based population guidelines to reduce cardiovascular risk in a large integrated health system.
We evaluated an alternative way to implement guidelines using an automated risk calculator and risk-based decision tool to calculate patients' risk of cardiovascular disease (CVD) and recommend therapies. We compared such an approach with traditional guidelines. A retrospective cohort study of 1,506,109 Kaiser Permanente Southern California members 35 years or older. We estimated 3-year risks of fatal and nonfatal myocardial infarction and stroke using an independently developed risk calculator, then graphically compared risks with observed outcomes. We used the area under the receiver operating characteristics curve to assess discrimination, and the Hosmer-Lemeshow statistic to test fit. We compared the characteristics and outcomes of populations identified for medication therapy by the risk-based decision tool and traditional guidelines using bivariate statistics. A risk score was obtained in 72% (1,082,158) of members. The risk calculator was fairly good in discrimination: the area under the curve was 0.774 (95% CI, 0.770-0.779) for myocardial infarction and 0.805 (95% CI, 0.801-0.808) for stroke. Predictiveness and fit was good based on graphical analysis and Hosmer-Lemeshow P < .0001. The risk-based decision tool identified high-risk patients for treatment who were not identified by traditional guidelines (3.80% of all those identified for statins, 3.04% for antihypertensives), as well as low-risk patients who were identified by guidelines (3.80% for statins, 2.51% for antihypertensives). The risk calculator provided risk estimates in most patients and demonstrated fairly good discrimination and predictiveness. The risk-based decision tool identified high-risk patients for treatment not identified by traditional guidelines, as well as low-risk patients for whom treatment may be unnecessary.


Physician frontline treatment preferences for stage III/IV classic Hodgkin lymphoma: the real-world US CONNECT study.
Aim: To understand US physicians' frontline (1L) treatment preferences/decision-making for stage III/IV classic Hodgkin lymphoma (cHL). Materials & methods: Medical oncologists and/or hematologists (≥2 years' practice experience) who treat adults with stage III/IV cHL were surveyed online (October-November 2020). Results: Participants (n = 301) most commonly considered trial efficacy/safety data and national guidelines when selecting 1L cHL treatments. Most physicians (91%) rated overall survival (OS) as the most essential attribute when selecting 1L treatment. Variability was seen among regimen selection for hypothetical newly diagnosed patients, with OS cited as the most common reason for regimen selection. Conclusion: While treatment selection varied based on patient characteristics, US physicians consistently cited OS as the top factor considered when selecting a 1L treatment for cHL.


Meta-analysis of gene expression profiles related to relapse-free survival in 1,079 breast cancer patients.
The transcriptome of breast cancers have been extensively screened with microarrays and large sets of genes associated with clinical features have been established. The aim of this study was to validate original gene sets on a large cohort of raw breast cancer microarray data with known clinical follow-up. We recovered 20 publications and matched them to Affymetrix HGU133A annotations. Raw Affymetrix HGU133A microarray data were extracted from GEO and MAS5 normalized. For classifying patients using the selected gene sets, we applied prediction analysis of microarrays and constructed Kaplan-Meier plots. A new classification including all patients was generated using supervised principal components analysis. Seven studies including 1,470 patients were downloaded from GEO. Notably, we uncovered 641 microarrays representing 251 individual tumor specimens among them, which were repeatedly described under independent GEO identifiers. We excluded all redundant data and used the remaining 1,079 samples. Eight of the 20 gene sets were able to predict response at a significance of P < 0.05. The discrimination of good and poor prognosis groups exclusively relying on gene expression data resulted in high significance (P = 1.8E-12). A model including genes fitted by both gene expression and clinical covariates (lymph node status and grade) contains 44 genes and can predict response at P = 9.5E-7. The outcome provides a ranking of the gene lists regarding applicability on an independent dataset. We established a consensus predictor combining the available clinical and gene expression data. The database comprising expression profiles of 1,079 breast cancers can be used to classify individual patients.


Combined popliteal and saphenous nerve blocks at the knee: an underused alternative to general or spinal anesthesia for foot and ankle surgery.
Peripheral nerve blocks at the ankle have long been used for foot surgery. However, when local foot and ankle blocks are inappropriate or contraindicated, general and spinal anesthesia are the common alternatives. Both have disadvantages and require added equipment and monitors. Combined popliteal and saphenous nerve blocks at the knee can offer a desirable alternative to general and spinal anesthesia for foot and ankle surgery. In addition, popliteal and saphenous nerve blocks provide anesthesia of the entire lower leg, thus permitting a greater variety of procedures to be performed. This article reviews the anatomical considerations, various block techniques, and surgical applications of this useful approach to lower-leg anesthesia.


Protective effect of ginsenoside Rg1 on 661W cells exposed to oxygen-glucose deprivation/reperfusion via keap1/nrf2 pathway.
To construct an in vitro model of oxygen-glucose deprivation/reperfusion (OGD/R) induced injury to the optic nerve and to study the oxidative damage mechanism of ischemia-reperfusion (I/R) injury in 661W cells and the protective effect of ginsenoside Rg1. The 661W cells were treated with different concentrations of Na2S2O4 to establish OGD/R model in vitro. Apoptosis, intracellular reactive oxygen species (ROS) levels and superoxide dismutase (SOD) levels were measured at different time points during the reperfusion injury process. The injury model was pretreated with graded concentrations of ginsenoside Rg1. Real-time polymerase chain reaction (PCR) was used to measure the expression levels of cytochrome C (cyt C)/B-cell lymphoma-2 (Bcl2)/Bcl2 associated protein X (Bax), heme oxygenase-1 (HO-1), caspase9, nuclear factor erythroid 2-related factor 2 (nrf2), kelch-like ECH-associated protein 1 (keap1) and other genes. Western blot was used to detect the expression of nrf2, phosphorylated nrf2 (pnrf2) and keap1 protein levels. Compared to the untreated group, the cell activity of 661W cells treated with Na2S2O4 for 6 and 8h decreased (P<0.01). Additionally, the ROS content increased and SOD levels decreased significantly (P<0.01). In contrast, treatment with ginsenoside Rg1 reversed the cell viability and SOD levels in comparison to the Na2S2O4 treated group (P<0.01). Moreover, Rg1 reduced the levels of caspase3, caspase9, and cytC, while increasing the Bcl2/Bax level. These differences were all statistically significant (P<0.05). Western blot analysis showed no significant difference in the protein expression levels of keap1 and nrf2 with Rg1 treatment, however, Rg1 significantly increased the ratio of pnrf2/nrf2 protein expression compared to the Na2S2O4 treated group (P<0.001). The OGD/R process is induced in 661W cells using Na2S2O4. Rg1 inhibits OGD/R-induced oxidative damage and alleviates the extent of apoptosis in 661W cells through the keap1/nrf2 pathway. These results suggest a potential protective effect of Rg1 against retinal I/R injury.


Epileptic seizure detection based on the kernel extreme learning machine.
This paper presents a pattern recognition model using multiple features and the kernel extreme learning machine (ELM), improving the accuracy of automatic epilepsy diagnosis. After simple preprocessing, temporal- and wavelet-based features are extracted from epileptic EEG signals. A combined kernel-function-based ELM approach is then proposed for feature classification. To further reduce the computation, Cholesky decomposition is introduced during the process of calculating the output weights. The experimental results show that the proposed method can achieve satisfactory accuracy with less computation time.


BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1.
BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-γ) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD-1/PD-L1 axis by combining anti-PD-1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncover an interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provide mechanistic insight into the transcriptional regulation of CD274.


Recent developments in cyclodextrin functionalized monolithic columns for the enantioseparation of chiral drugs.
The use of monolithic supports containing cyclodextrins (CDs) or their derivatives as chiral stationary phases (CSPs) has drawn much attention in the field of enantioseparations. The present review summarized the recent developments in CD functionalized monolithic columns. After introducing their classification in Section 1, various strategies applied to the preparation of the three types of CD functionalized monoliths, i.e. silica based monoliths, organic polymer based monoliths and organic-silica based hybrid monoliths, are thoroughly summarized in Section 2. Particularly, three different preparation strategies for covalently immobilizing CDs onto monoliths, including multi-step strategy, single-step strategy and one-pot strategy, are discussed. In the last section, the applications of CD functionalized monoliths in chiral separation of pharmaceuticals are highlighted.