Inhibition by oral N-acetylcysteine of cigarette smoke-induced "bronchitis" in the rat.
Specific pathogen-free rats were exposed to the cigarette smoke (CS) of 25 cigarettes daily for 14 days and concurrently given N-acetylcysteine (Nac) as 1% of their drinking water (average daily dose 973 mg/kg). The thickness of the epithelium was measured at four airway levels and the numbers of mucus-containing secretory cells, stained for neutral or acidic glycoprotein (NGP or AGP respectively), were counted in surface epithelium at eight airway levels. Cigarette smoke increased the thickness of the epithelium at three of the airway levels studied by between 37 and 72%. The number of secretory cells was increased at all airway levels distal to the upper trachea by between 102 and 421%. Secretory cells containing NGP were reduced in number but this was more than offset by a large increase in the number of secretory cells containing AGP at all airway levels. N-acetylcysteine inhibited CS-induced epithelial thickening. Nac also inhibited the CS-induced increase in the number of secretory cells with AGP, but had little effect on the CS-induced reduction in the number of cells with NGP. Thus, prophylactic oral N-acetylcysteine led to an overall inhibition of CS-induced mucous cell hyperplasia and epithelial hypertrophy. The results suggest a novel anti-inflammatory action for a drug with known mucolytic effects.


Daily activity and light exposure levels for five species of lemurs at the Duke Lemur Center.
Light is the primary synchronizer of all biological rhythms, yet little is known about the role of the 24-hour luminous environment on nonhuman primate circadian patterns, making it difficult to understand the photic niche of the ancestral primate. Here we present the first data on proximate light-dark exposure and activity-rest patterns in free-ranging nonhuman primates. Four individuals each of five species of lemurs at the Duke Lemur Center (Eulemur mongoz, Lemur catta, Propithecus coquereli, Varecia rubra, and Varecia variegata variegata) were fitted with a Daysimeter-D pendant that contained light and accelerometer sensors. Our results reveal common as well as species-specific light exposure and behavior patterns. As expected, all five species were more active between sunrise and sunset. All five species demonstrated an anticipatory increase in their pre-sunrise activity that peaked at sunrise with all but V. rubra showing a reduction within an hour. All five species reduced activity during mid-day. Four of the five stayed active after sunset, but P. coquereli began reducing their activity about 2 hours before sunset. Other subtle differences in the recorded light exposure and activity patterns suggest species-specific photic niches and behaviors. The eventual application of the Daysimeter-D in the wild may help to better understand the adaptive evolution of ancestral primates.


Increase in bone protein components with healing rat fractures: enhancement by zinc treatment.
The alteration in bone components in the femoral-diaphyseal tissues with fracture healing was investigated. Rats were sacrificed 7 and 14 days after the femoral fracture. Protein content in the femoral-diaphyseal tissues was markedly elevated by fracture healing. Analysis with sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that many protein molecules were induced in the diaphyseal tissues with fracture healing. Moreover, when the femoral-diaphyseal tissues with fracture healing were cultured for 24 and 48 h in a serum-free medium, many proteins in the bone tissues were released into the medium. Also, the culture of the diaphyseal tissues with fracture healing caused a significant increase in bone alkaline phosphatase activity and deoxyribonucleic acid (DNA) content. Meanwhile, the presence of zinc acexamate (10-5 and 10-4 M), a stimulator of bone formation, in a culture medium induced a significant elevation of protein content and alkaline phosphatase activity in the diaphyseal tissues with fracture healing. Such an effect was completely abolished by the presence of cycloheximide (10-6 M), an inhibitor of protein synthesis. The present study suggests that fracture healing induces a newly synthesized bone protein component including stimulatory factor(s) for bone formation. Zinc supplementation may stimulate the healing of femoral fracture.


[Medico economic analysis in first line chemotherapy in advanced lung cancer].
Our objective was to analyse economic consequences modifying first line chemotherapy in treatment non small cell lung cancer IIIB-IV. Therefore a cost minimisation has been performed. Resources consumption were collected in a Pneumology department for 21 patients receiving previously mitomycine-ifosfamide-platin and for the 21 first patients receiving vinorelbine-platin, new patients diagnosed during year 2001. Costs were derived from hospital accounting system, economic analysis performed from the hospital and from the health French system points of view. Activity Synthetic Index point decrease of 2.9% per patient in vinorelbine-platin versus mitomycine-ifosfamide-platin, as an increase of 64.6% of hospital drug spending is registered (1,893 Euro versus 1,150 Euro) and an over cost of 15.7% for health French system (14179 Euro versus 12,257 Euro). Whatever the perspective of economic analysis, vinorelbine-platin arm is dominated by the mitomycine-ifosfamide-platin arm.


In vitro inhibition of human cGMP-specific phosphodiesterase-5 by polyphenols from red grapes.
A moderate consumption of red wine may reduce the risk of cardiovascular diseases via wine-derived phenolic compounds. A variety of biological mechanisms have been proposed for wine-derived phenolic compounds including nitric oxide-mediated vasorelaxation. This study examined whether the vasodilating effect of wine-derived phenolic compounds was associated with the inhibition of phosphodiesterases (PDEs) and, in particular, PDE5. For this purpose, human recombinant PDE5A1 isoform was prepared by expression of the full-length cDNA of PDE5A1 into COS-7 cells. Red wine and the extracts from grape skin inhibited PDE5A1 activity, whereas the seed extracts had a negligible effect. The mixture of anthocyanins inhibited the enzyme activity (IC50 = 11.6 microM), with malvidin-3-O-beta-glucoside (IC50 = 35.4 microM) and malvidin (IC50 = 24.9 microM) the most potent among the monoglucosides and aglycons, respectively. trans-Resveratrol and trans-piceid exhibited negligible effects, whereas hydroxycinnamates were completely inactive. These results indicate that polyphenols-induced vasorelaxation may also be sustained by smooth muscle PDE inhibition by anthocyanins present in red wines and grapes.


Clinical outcome after a reactive hypothermic EEG following cardiac arrest.
Reactive electroencephalography (EEG) background during therapeutic hypothermia (TH) is related to favorable prognosis after cardiac arrest (CA), but its predictive value is not 100 %. The aim of this study was to investigate outcome predictors after a first reactive EEG recorded during TH after CA. We studied a cohort of consecutive comatose adults admitted between February 2008 and November 2012, after successful resuscitation from CA, selecting patients with reactive EEG during TH. Outcome was assessed at three months, and categorized as survivors and non-survivors (no patient was in vegetative state). Demographics, clinical variables, EEG features, serum neuron-specific enolase (NSE) and procalcitonin, were compared using uni- and multivariable analyses. A total of 290 patients were treated with TH after cardiac arrest; 146 had an EEG during TH, which proved reactive in 90 of them; 77 (86 %) survived and 13 (14 %) died (without recovery from coma). The group of non-survivors had a higher occurrence of discontinuous EEG (p = 0.006; multivariate analysis p = 0.026), and a higher serum NSE peak (p = 0.021; multivariate analysis p = 0.014); conversely, demographics, and other clinical variables including serum procalcitonin did not differ. A discontinuous EEG and high serum NSE are associated with mortality after CA in patients with poor outcome despite a reactive hypothermic EEG. This suggests more severe cerebral damage, but not to higher extent of systemic disease.


Analysis of essential oils from Voacanga africana seeds at different hydrodistillation extraction stages: chemical composition, antioxidant activity and antimicrobial activity.
In this study, essential oils from Voacanga africana seeds at different extraction stages were investigated. In the chemical composition analysis, 27 compounds representing 86.69-95.03% of the total essential oils were identified and quantified. The main constituents in essential oils were terpenoids, alcohols and fatty acids accounting for 15.03-24.36%, 21.57-34.43% and 33.06-57.37%, respectively. Moreover, the analysis also revealed that essential oils from different extraction stages possessed different chemical compositions. In the antioxidant evaluation, all analysed oils showed similar antioxidant behaviours, and the concentrations of essential oils providing 50% inhibition of DPPH-scavenging activity (IC50) were about 25 mg/mL. In the antimicrobial experiments, essential oils from different extraction stages exhibited different antimicrobial activities. The antimicrobial activity of oils was affected by extraction stages. By controlling extraction stages, it is promising to obtain essential oils with desired antimicrobial activities.


Effects of ADHD, conduct disorder, and gender on substance use and abuse in adolescence.
The relationships of attention deficit hyperactivity disorder (ADHD), conduct disorder, and gender to substance abuse were studied in a large population-based sample of adolescent twins. Structured interviews were administered to 626 pairs of 17-year-old twins (674 girls and 578 boys) and their mothers to generate lifetime psychiatric diagnoses, and computerized measures of current substance use were obtained. Hierarchical logit analyses were performed to assess the independent effects of ADHD, conduct disorder, and gender on current substance use, frequency of substance use, and DSM-III-R diagnoses of substance use disorders. Conduct disorder was found to increase the risk of substance use and abuse in adolescents regardless of gender. In contrast, independent of its association with conduct disorder, an ADHD diagnosis did not significantly increase the risk of substance use problems. This study found no significant gender differences in the effects of ADHD and conduct disorder on substance use and abuse, although there was some suggestion that girls with ADHD might be at slightly higher risk than boys for substance abuse. In addition, increased risk of substance abuse among adolescents with conduct disorder may be primarily confined to those with persistent conduct disorder.


Quality of life in prostatic cancer patients.
As a first effort to introduce quality-of-life assessment in prostatic cancer clinical trials, the European Organization for Research and Treatment of Cancer Genitourinary Group, in cooperation with European Organization for Research and Treatment Quality of Life Group, initiated protocol 30853, coordinated by Louis Denis. This protocol compared the efficacy of treatment with orchiectomy alone to that with Zoladex (Zeneca Pharmaceuticals, Alderley Macclesfield, Cheshire, UK) plus flutamide in previously untreated patients with metastatic cancer. The use of patient-administered quality-of-life questionnaires was optional, and of 327 patients, only 22% had pretreatment assessments. This trial revealed many clinician's considerable reluctance to perform quality of life research, partly because of feasibility problems and partly because of doctors' doubts about the value of such efforts. Psychologic distress, fatigue, issues of social and family life, and pain were found to be the most important concerns on a subjective basis, and this finding was confirmed by objective parameters. There was a discrepancy between doctors' evaluations and patients' opinions about subjective morbidity, namely sexual status and pain. Quality of life assessment should become a mandatory part of clinical trials in prostate cancer.


Expression of a recombinant apolipoprotein(a) in HepG2 cells. Evidence for intracellular assembly of lipoprotein(a).
Apolipoprotein(a) (apo(a)), a large glycoprotein with extensive homology to plasminogen, forms a complex with apolipoprotein B100 (apoB100), which circulates in human plasma in the form of lipoprotein(a) (Lp(a)). Evidence indicates that the association of apo(a) with apoB100 occurs in the extracellular environment. We have reevaluated the possibility that apo(a)-B100 association can also occur as an intracellular event through studies with HepG2 cells stably transfected with an apo(a) minigene. Several lines of evidence support this possibility. First, continued Lp(a) production was demonstrated following incubation of transfected HepG2 cells with anti-apo(a) antisera, conditions that effectively block the fluid-phase association of apo(a) and apoB100 in vitro. Second, an apo(a)-B100 complex was detectable in Western blot analyses of transfected HepG2 lysates following immunoprecipitation with anti-apo(a) antisera. These studies incorporated precautions to eliminate cell-surface attachment of preformed apo(a)-B100 complexes to the low density lipoprotein receptor and were conducted in the presence of the lysine analog epsilon-aminocaproic acid, which precludes apo(a)-B100 association occurring during the isolation and analyses. Third, the presence of an intracellular apo(a)-B100 complex was demonstrated in lipoproteins isolated from microsomal contents. Of particular significance was the observation that this complex contained the precursor form of apo(a), which is not secreted, in addition to the mature, recombinant form. Finally, direct evidence was provided for the synthesis of a precursor form of apo(a) in a nascent intracellular complex with apoB100 following treatment of transfected HepG2 cells with brefeldin A plus N-acetyl-leucyl-leucyl-norleucinal. Taken together, these data suggest that apo(a)-B100 association can occur as an intracellular event in a human hepatoma-derived cell line, raising important implications for the regulation of Lp(a) secretion from human liver.


The efficacy of balance training with video game-based therapy in subacute stroke patients: a randomized controlled trial.
The video game-based therapy emerged as a potential valid tool in improving balance in several neurological conditions with controversial results, whereas little information is available regarding the use of this therapy in subacute stroke patients. The aim of this study was to investigate the efficacy of balance training using video game-based intervention on functional balance and disability in individuals with hemiparesis due to stroke in subacute phase. Fifty adult stroke patients participated to the study: 25 subjects were randomly assigned to balance training with Wii Fit, and the other 25 subjects were assigned to usual balance therapy. Both groups were also treated with conventional physical therapy (40 min 2 times/day). The main outcome was functional balance (Berg Balance Scale-BBS), and secondary outcomes were disability (Barthel Index-BI), walking ability (Functional Ambulation Category), and walking speed (10-meters walking test). Wii Fit training was more effective than usual balance therapy in improving balance (BBS: 53 versus 48, P = 0.004) and independency in activity of daily living (BI: 98 versus 93, P = 0.021). A balance training performed with a Wii Fit as an add on to the conventional therapy was found to be more effective than conventional therapy alone in improving balance and reducing disability in patients with subacute stroke.


Removal of potassium negative resistance in perfused squid giant axons.
Squid giant axons, internally and externally perfused with solutions having potassium as the only cation, exhibit an approximately linear steady-state current-voltage relation. When small amounts of calcium and magnesium are present in the external potassium solution, the current-voltage curve is markedly nonlinear, exhibiting the rectification and negative resistance which have been observed for intact axons in isosmotic potassium solutions. The effects of perfusion and removal of external divalent cations are interpreted in terms of two components of current, a linear component and a nonlinear time-varying component. The former is increased and the latter diminished by the removal of the external divalent cations.


Modulation of apoptosis with cytokines in B-cell chronic lymphocytic leukaemia.
In B chronic lymphocytic leukaemia (B-CLL) non-proliferating peripheral blood (PB) B cells have a long life span in vivo. In cultures, these cells die spontaneously by apoptosis. Interleukin (IL) 4 inhibits spontaneous apoptosis (SA) and promotes survival of B-CLL B cells in vitro. No such effect is observed in PB B cells from normal healthy donors. The anti-apoptotic effect of IL4 is independent of mitogen-induced cell activation but depends on the concentration of IL4. The protective effect of IL4 is specific and it is significantly reduced or abolished with anti-IL4 antibody. Interferon (IFN)-gamma and alpha- IFN also protect B-CLL B cells from apoptosis in vitro. Sera from B-CLL patients have increased levels of IFN-gamma when compared with sera from healthy donors. In addition, B-cells in B-CLL express detectable levels of IFN-gamma mRNA. Other cytokines, namely ILl, IL2, IL6 and IL7 do not affect SA of B-CLL B cells. By contrast, IL5 and antibody to apolipoprotein-1 (APO- 1) receptor increase SA significantly and in a dose-dependent manner. Interleukin 4 protects B-CLL B cells from IL5-, anti(alpha) APO-1- and steroid-induced apoptosis. The mode of action of the cytokines inducing apoptosis or protecting B-CLL B cells from dying is largely unknown. Recently the bcl-2 proto-oncogene has been associated with prolonged cell survival. However, the involvement of bel-2 in spontaneous, cytokine-induced or steroid-induced apoptosis in B-CLL has been controversial. Some authors have reported down-regulation of bcl-2 protein expression in B-CLL B-cells undergoing SA or in steroid-treated cells with IL4 preventing this down-regulation. By contrast, others observed no significant loss of bcl-2 protein expression in steroid-, alpha-APO-1 - and IL5-treated cells when compared with untreated or fresh cells. Also, no correlation between bcl-2 protein expression and protection with IL4 has been reported. In conclusion, in B-CLL IL4, IFN-gamma and alpha-IFN promote the survival of the leukaemic cells. These cytokines may therefore be involved in the pathogenesis of the B-CLL.


FORMIDABEL: The Belgian Ants Database.
FORMIDABEL is a database of Belgian Ants containing more than 27.000 occurrence records. These records originate from collections, field sampling and literature. The database gives information on 76 native and 9 introduced ant species found in Belgium. The collection records originated mainly from the ants collection in Royal Belgian Institute of Natural Sciences (RBINS), the 'Gaspar' Ants collection in Gembloux and the zoological collection of the University of Liège (ULG). The oldest occurrences date back from May 1866, the most recent refer to August 2012. FORMIDABEL is a work in progress and the database is updated twice a year. THE LATEST VERSION OF THE DATASET IS PUBLICLY AND FREELY ACCESSIBLE THROUGH THIS URL: http://ipt.biodiversity.be/resource.do?r=formidabel. The dataset is also retrievable via the GBIF data portal through this link: http://data.gbif.org/datasets/resource/14697 A dedicated geo-portal, developed by the Belgian Biodiversity Platform is accessible at: http://www.formicidae-atlas.be FORMIDABEL is a joint cooperation of the Flemish ants working group "Polyergus" (http://formicidae.be) and the Wallonian ants working group "FourmisWalBru" (http://fourmiswalbru.be). The original database was created in 2002 in the context of the preliminary red data book of Flemish Ants (Dekoninck et al. 2003). Later, in 2005, data from the Southern part of Belgium; Wallonia and Brussels were added. In 2012 this dataset was again updated for the creation of the first Belgian Ants Atlas (Figure 1) (Dekoninck et al. 2012). The main purpose of this atlas was to generate maps for all outdoor-living ant species in Belgium using an overlay of the standard Belgian ecoregions. By using this overlay for most species, we can discern a clear and often restricted distribution pattern in Belgium, mainly based on vegetation and soil types.


Long-term mortality after transcatheter aortic valve implantation for aortic stenosis in immunosuppression-treated patients: a propensity-matched multicentre retrospective registry-based analysis.
Data regarding patients with a previous medical record of immunosuppression treatment who have undergone transcatheter aortic valve implantation (TAVI) are limited and extremely inconclusive. Available studies are mostly short term observations; thus there is a lack of evidence on efficacy and safety of TAVI in this specific group of patients. To compare the in-hospital and long-term outcomes between patients with or without a medical history of immunosuppressive treatment undergoing TAVI for aortic valve stenosis (AS). We conducted a retrospective registry-based analysis including patients undergoing TAVI for AS at 5 centres between January 2009 and August 2017. The primary endpoint was long-term all-cause mortality. Secondary endpoints comprised major vascular complications, life-threatening or disabling bleeding, stroke and new pacemaker implantation. Of 1451 consecutive patients who underwent TAVI, two propensity-matched groups including 25 patients with a history of immunosuppression and 75 patients without it were analysed. No differences between groups in all-cause mortality were found in a median follow-up time of 2.7 years following TAVI (p = 0.465; HR = 0.73; 95% CI: 0.30-1.77). The rate of major vascular complications (4.0% vs. 5.3%) was similar in the two groups (p = 1.000). There were no statistically significant differences in the composite endpoint combining life-threatening or disabling bleeding, major vascular complications, stroke and new pacemaker implantation (40.0% vs. 20.0%, p = 0.218). Patients who had undergone TAVI for AS had similar long-term mortality regardless of whether they had a previous medical record of immunosuppression. Procedural complication rates were comparable between the groups.


How Graphene Islands Are Unidirectionally Aligned on the Ge(110) Surface.
The unidirectional alignment of graphene islands is essential to the synthesis of wafer-scale single-crystal graphene on Ge(110) surface, but the underlying mechanism is not well-understood. Here we report that the necessary coalignment of the nucleating graphene islands on Ge(110) surface is caused by the presence of step-pattern; we show that on the preannealed Ge(110) textureless surface the graphene islands appear nonpreferentially orientated, while on the Ge(110) surfaces with natural step pattern, all graphene islands emerge coaligned. First-principles calculations and theoretical analysis reveal this different alignment behaviors originate from the strong chemical binding formed between the graphene island edges and the atomic steps on the Ge(110) surface, and the lattice matching at edge-step interface dictates the alignment of graphene islands with the armchair direction of graphene along the [-110] direction of the Ge(110) substrate.


pH-Switched Near-Infrared Fluorescent Strategy for Ratiometric Detection of ONOO- in Lysosomes and Precise Imaging of Oxidative Stress in Rheumatoid Arthritis.
Rheumatoid arthritis (RA) is well-known as a kind of autoimmune disease, which brings unbearable pain to the patients by multiple organ complications besides arthritis. To date, RA can be hardly cured, but early diagnosis and standard treatment can relieve symptoms and pain. Therefore, an effective tool to assist the early diagnosis of RA deserves considerable attention. On account of the overexpressed ONOO- during the early stage of RA, a near-infrared (NIR) receptor, Lyso-Cy, is proposed in this work by linker chemistry to expand the conjugated rhodamine framework by cyanine groups. Contributed by the pH-sensitive spiral ring in rhodamine, receptor Lyso-Cy has been found to be workable in lysosomes specifically, which was confirmed by the pH-dependent spectra with a narrow responding region and a well-calculated pKa value of 5.81. We presented an excellent ratiometric sensing protocol for ONOO- in an acidic environment, which was also available for targeting ONOO- in lysosomes selectively. This innovative dual-targeting responsive design is expected to be promising for assisting RA diagnosis at an early stage with respect to the joint inflammatory model established in this work at the organism level.


The primary localization of free radical generation after anoxia/reoxygenation in isolated endothelial cells.
While free radical-mediated reperfusion injury is clearly important in a variety of disparate organs, the particular cellular source of these radicals is unclear. To address this question, we subjected relatively pure (92% +/- 3% by factor VIII immunoassay) cultures of rat pulmonary artery endothelial cells to 0 to 45 minutes of anoxia (95% N2, 5% CO2), followed by reoxygenation (95% air, 5% CO2), to simulate ischemia/reperfusion. Cell injury was assayed after reoxygenation by the release of previously incorporated 51chromium and/or lactate dehydrogenase, and viability was determined by means of trypan blue exclusion. These three end points correlated closely. Without anoxia, the cells remained viable, with minimal evidence of injury for the entire experimental period, while 45 minutes of hypoxia followed by 30 minutes of reoxygenation produced substantial evidence of cell injury in 71% +/- 6% of the cells. This injury was reduced to 21% +/- 2% by treatment with the highly specific free radical scavengers superoxide dismutase and catalase together, either before anoxia or after anoxia, but just before reoxygenation. Similar protection was provided by xanthine oxidase inhibition with allopurinol. The injury was mimicked (without anoxia) by the exogenous generation of superoxide radicals with xanthine and xanthine oxidase. These experiments establish the essential components of free radical generation at reperfusion to be localized within the isolated endothelial cell in the absence of neutrophils or parenchymal cells.


Lr67/Yr46 confers adult plant resistance to stem rust and powdery mildew in wheat.
We demonstrate that Lr67/Yr46 has pleiotropic effect on stem rust and powdery mildew resistance and is associated with leaf tip necrosis. Genes are designated as Sr55, Pm46 and Ltn3 , respectively. Wheat (Triticum aestivum) accession RL6077, known to carry the pleiotropic slow rusting leaf and yellow rust resistance genes Lr67/Yr46 in Thatcher background, displayed significantly lower stem rust (P. graminis tritici; Pgt) and powdery mildew (Blumeria graminis tritici; Bgt) severities in Kenya and in Norway, respectively, compared to its recurrent parent Thatcher. We investigated the resistance of RL6077 to stem rust and powdery mildew using Avocet × RL6077 F6 recombinant inbred lines (RILs) derived from two photoperiod-insensitive F3 families segregating for Lr67/Yr46. Greenhouse seedling tests were conducted with Mexican Pgt race RTR. Field evaluations were conducted under artificially initiated stem rust epidemics with Pgt races RTR and TTKST (Ug99 + Sr24) at Ciudad Obregon (Mexico) and Njoro (Kenya) during 2010-2011; and under natural powdery mildew epiphytotic in Norway at Ås and Hamar during 2011 and 2012. In Mexico, a mean reduction of 41 % on stem rust severity was obtained for RILs carrying Lr67/Yr46, compared to RILs that lacked the gene, whereas in Kenya the difference was smaller (16 %) but significant. In Norway, leaf tip necrosis was associated with Lr67/Yr46 and RILs carrying Lr67/Yr46 showed a 20 % reduction in mean powdery mildew severity at both sites across the 2 years of evaluation. Our study demonstrates that Lr67/Yr46 confers partial resistance to stem rust and powdery mildew and is associated with leaf tip necrosis. The corresponding pleiotropic, or tightly linked, genes, designated as Sr55, Pm46, and Ltn3, can be utilized to provide broad-spectrum durable disease resistance in wheat.


Antisense technologies. Improvement through novel chemical modifications.
Antisense agents are valuable tools to inhibit the expression of a target gene in a sequence-specific manner, and may be used for functional genomics, target validation and therapeutic purposes. Three types of anti-mRNA strategies can be distinguished. Firstly, the use of single stranded antisense-oligonucleotides; secondly, the triggering of RNA cleavage through catalytically active oligonucleotides referred to as ribozymes; and thirdly, RNA interference induced by small interfering RNA molecules. Despite the seemingly simple idea to reduce translation by oligonucleotides complementary to an mRNA, several problems have to be overcome for successful application. Accessible sites of the target RNA for oligonucleotide binding have to be identified, antisense agents have to be protected against nucleolytic attack, and their cellular uptake and correct intracellular localization have to be achieved. Major disadvantages of commonly used phosphorothioate DNA oligonucleotides are their low affinity towards target RNA molecules and their toxic side-effects. Some of these problems have been solved in 'second generation' nucleotides with alkyl modifications at the 2' position of the ribose. In recent years valuable progress has been achieved through the development of novel chemically modified nucleotides with improved properties such as enhanced serum stability, higher target affinity and low toxicity. In addition, RNA-cleaving ribozymes and deoxyribozymes, and the use of 21-mer double-stranded RNA molecules for RNA interference applications in mammalian cells offer highly efficient strategies to suppress the expression of a specific gene.


Fine-tuning vitamin E-containing telodendrimers for efficient delivery of gambogic acid in colon cancer treatment.
Certain natural products such as gambogic acid (GA) exhibit potent antitumor effects. Unfortunately, administration of these natural products is limited by their poor solubility in conventional pharmaceutical solvents. In this study, a series of telodendrimers, composed of linear polyethylene glycol (PEG)-blocking-dendritic oligomer of cholic acid (CA) and vitamin E (VE), have been designed with architectures optimized for efficient delivery of GA and other natural anticancer compounds. Two of the telodendrimers with segregated CA and VE domains self-assembled into stable cylindrical and/or spherical nanoparticles (NPs) after being loaded with GA as observed under transmission electron microscopy (TEM), which correlated with the dynamic light scattering (DLS) analysis of sub-30 nm particle sizes. A very high GA loading capacity (3:10 drug/polymer w/w) and sustained drug release were achieved with the optimized telodendrimers. These novel nanoformulations of GA were found to exhibit similar in vitro cytotoxic activity against colon cancer cells as the free drug. Near-infrared fluorescence small animal imaging revealed preferential accumulation of GA-loaded NPs into tumor tissue. The optimized nanoformulation of GA achieved superior antitumor efficacy compared to GA-Cremophor EL formulation at equivalent doses in HT-29 human colon cancer xenograft mouse models. Given the mild adverse effects associated with this natural compound and the enhanced anticancer effects via tumor targeted telodendrimer delivery, the optimized GA nanoformulation is a promising alternative to the traditional chemotherapy in colon cancer treatment.


Major Depressive Disorder (MDD) and Schizophrenia- Addressing Unmet Needs With Partial Agonists at the D2 Receptor: A Review.
Second-generation antipsychotics are common candidates for the adjunctive treatment of major depressive disorder and for the treatment of schizophrenia. However, unmet needs remain in the treatment of both disorders. Considering schizophrenia, antipsychotics are the most common treatment and have demonstrated good efficacy. Still, side effects of these treatments are commonly reported and may impact adherence to the medication and functioning in patients with schizophrenia. Regarding major depressive disorder, despite the availability of several classes of antidepressants, many patients do not achieve remission. Adjunctive treatment with antipsychotics may improve clinical and functional outcomes. Compared with dopamine D2 receptor antagonism that is exhibited by most antipsychotics, partial agonism may result in improved outcomes in major depressive disorder and in schizophrenia. Aripiprazole, cariprazine, and brexpiprazole have partial agonism at the dopamine D2 receptor and could potentially overcome limitations associated with D2 antagonism. The objectives of this review were (1) to discuss the goal of treatment with second-generation antipsychotics in major depressive disorder and schizophrenia, and the clinical factors that should be considered, and (2) to examine the short- and long-term existing data on the efficacy and safety of D2 receptor partial agonists (aripiprazole, cariprazine, and brexpiprazole) in the adjunctive treatment of major depressive disorder and in the treatment of schizophrenia.


Re-examining the 16S rDNA sequence of Halomonas salina.
Previous reports of 16S rDNA sequencing of members of the family Halomonadaceae Franzmann et al. 1989 include two different sequences that were both attributed to the type strain of Halomonas salina (Valderrama et al. 1991) Dobson and Franzmann 1996 (basonym Deleya salina Valderrama et al. 1991). The two sequences are sufficiently different for them to belong to two different species within the genus Halomonas. In order to determine which of the two sequences corresponded to that of the type strain of Halomonas salina, the designated type strains of this species were obtained from the ATCC and the DSMZ. It was possible to show that only one of the previous sequences corresponded to the sequences obtained from DSMZ 5928T and ATCC 49509T.


Short-course combination treatment for experimental chronic Chagas disease.
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects millions of people in the Americas and across the world, leading to considerable morbidity and mortality. Current treatment options, benznidazole (BNZ) and nifurtimox, offer limited efficacy and often lead to adverse side effects because of long treatment durations. Better treatment options are therefore urgently required. Here, we describe a pyrrolopyrimidine series, identified through phenotypic screening, that offers an opportunity to improve on current treatments. In vitro cell-based washout assays demonstrate that compounds in the series are incapable of killing all parasites; however, combining these pyrrolopyrimidines with a subefficacious dose of BNZ can clear all parasites in vitro after 5 days. These findings were replicated in a clinically predictive in vivo model of chronic Chagas disease, where 5 days of treatment with the combination was sufficient to prevent parasite relapse. Comprehensive mechanism of action studies, supported by ligand-structure modeling, show that compounds from this pyrrolopyrimidine series inhibit the Qi active site of T. cruzi cytochrome b, part of the cytochrome bc1 complex of the electron transport chain. Knowledge of the molecular target enabled a cascade of assays to be assembled to evaluate selectivity over the human cytochrome b homolog. As a result, a highly selective and efficacious lead compound was identified. The combination of our lead compound with BNZ rapidly clears T. cruzi parasites, both in vitro and in vivo, and shows great potential to overcome key issues associated with currently available treatments.


Flexible sigmoidoscopy as a screening procedure for asymptomatic colorectal carcinoma in patients with inguinal hernia.
In patients about to have hernia repair, preoperative screening studies for early colorectal cancer using the rigid proctosigmoidoscope and barium enema have previously shown minimal cost effectiveness and poor patient acceptance. Flexible sigmoidoscopy may be more acceptable to patients and of greater diagnostic value. Between October 1980 and December 1983, 100 consecutive asymptomatic male surgical patients were examined using the Olympus 60 flexible proctosigmoidoscope. All patients were admitted for elective hernia repair. Age ranged from 21 to 88 years (mean 59.7). All patients with stool positive for occult blood on admission were excluded from this study. In addition, patients with any gastrointestinal symptoms, history of colorectal disease, or family history of colorectal polyps or carcinoma were excluded. Examinations were done under direct supervision of an attending surgeon (W.W. or C.S.C.). Of the 22 patients who had one or more benign polyps, three had villous adenomas. Two additional patients had carcinoma. Results of examination were completely normal in 63, while 13 patients were found to have hemorrhoids or diverticular disease. There were no complications and the procedure was well tolerated by all patients.


Interaction between capacitative Ca2+ influx and Ca2+-dependent Cl- currents in Xenopus oocytes.
The relationship between capacitative Ca2+ influx and activation of Ca2+-dependent Cl- channels was monitored in intact Xenopus oocytes following stimulation of 5-hydroxytryptamine (5-HT) receptors, through the activity of Ca2+-dependent Cl- channels using the double-electrode voltage-clamp technique. Under voltage-clamp conditions, 5-HT evoked a rapid transient inward current followed by a slowly developing secondary inward current. The secondary current reflected depletion-activated Ca2+ entry. Hyperpolarising pulses evoked sustained Ca2+-dependent Cl- currents when applied during the transient inward current, but evoked hump-like currents which inactivated rapidly when applied during the secondary inward current. Hump currents arose from Ca2+ entering through the depletion-activated pathway. The hump currents inactivated with hyperpolarising pulses at < 5-s intervals, and recovered monoexponentially with a time constant of around 8 s. Currents in response to hyperpolarising pulses during the transient current did not inactivate, suggesting that inactivation was associated with Ca2+ entry. When ca2+ release evoked by inositol 1,4,5-triphosphate [ins(1,4,5)p3] was prevented by heparin injection, hyperpolarising pulses during ca2+ ionophore application also generated hump currents that were dependent on external ca2+, inactivated and recovered from inactivation with a similar time course as the humps following 5-ht treatment. Pretreatment with the Ca2+ adenosine 5'-triphosphatase (Ca2+ATPase) inhibitor thapsigargin reduced the rate of rise of the hump current, increased the time-to-peak of the current and slowed the rate of decay. Pharmacological interventions to disrupt the cytoskeleton reduced the amplitude of the hump current. It is suggested that, following hyperpolarisation in the presence of Ca2+ entry, the ensuing Ca2+ influx interacts with Cl- channels in a way that might reflect both Ca2+ inhibition of Ca2+ entry and clustering of Cl- channels in the plasma membrane.


A critical review of clinical applications of topographic mapping of brain potentials.
A brief review of several aspects of topographic mapping of brain potentials is presented. Some general factors of importance for the construction of brain maps are considered, namely, how to sample in space and how to deal with the influence of the reference electrode. The issue of what is a representative map is examined for the cases of both steady and dynamic states. Special attention is paid to the methodology of assessing whether a brain map may be considered "normal" or "abnormal" on the basis of multivariate statistical considerations. Besides being used to visualize statistical comparisons between sets of EEG data, brain maps may be used as a first step for a model-based analysis in order to estimate the localization of equivalent dipolar sources of the electrical activity within the brain. The question of whether brain maps may yield added value to multivariate quantitative EEG analysis is examined for the following clinical cases: (1) developmental disorders; (2) space-occupying lesions; (3) epilepsy; (4) cerebrovascular diseases; (5) dementia; and (6) psychiatric diseases. It is concluded that brain mapping may be valuable as a comprehensive and attractive form of data reduction to represent a complex set of multichannel (optimally at least 64) EEG signals, but only if the user is well aware of the pitfalls involved. Brain mapping might supplement quantitative topographic analysis if it can be used as the basis for solving the inverse problem in EEG. More extensive and well-controlled studies are necessary in order to establish the clinical value of complementing a routine EEG examination with brain mapping.


Who can we reach and who can we keep? Predictors of intervention engagement and adherence in a cluster randomized controlled trial in South Africa.
Engaging and retaining young men in community-based interventions is highly challenging. The purpose of this study was to investigate the individual factors that predict intervention engagement and adherence in a sample of at-risk South African men. Baseline data were collected as a part of a cluster randomised control trial (RCT) situated in Khayelitsha and Mfuleni, two peri-urban settlements situated on the outskirts of Cape Town, South Africa. Neighbourhoods were randomised to one of three intervention conditions. We performed univariate descriptive statistics to report neighbourhood and individual socio-demographic factors, and ran multivariate models, adjusting for entry of study, to determine if high adherence and consistency of engagement with the intervention were associated with socio-behavioural demographics and risk behaviours, such as hazardous substance use, gangsterism, and criminal activity. Total of 729 men were on average 22.5 years old (SD 2.8), with a mean of 10 years of education. More than half of the sample were single (94%), lived with their parents (66%) and had an income below ~$30 (52%). The overall mean of adherence is 0.41 (SD 0.24) and mean of consistency of engagement is 0.61 (SD 0.30). Our data indicated that completing more years of education, living with parents, and having higher socioeconomic status were significantly associated with higher rates of engagement and adherence. Men with a history of gang membership demonstrated higher levels of adherence and consistent engagement with the intervention, compared with other men who were recruited to the intervention. Crucially, our data show that young men with a history of substance use, and young men who report symptoms of depression and high levels of perceived stress are equally likely as other young men to adhere to the intervention and attend intervention sessions consistently. Our results may contribute to a better understanding of young men's patterns of engagement and adherence to public health interventions. The results may have important implications for policy and practice, as they may be useful in planning more effective interventions and could potentially be used to predict which young men can be reached through community-based interventions. ClinicalTrials.gov registration, NCT02358226. Prospectively registered 24 November 2014.


Nanostructured gold microelectrodes for extracellular recording from electrogenic cells.
We present a new biocompatible nanostructured microelectrode array for extracellular signal recording from electrogenic cells. Microfabrication techniques were combined with a template-assisted approach using nanoporous aluminum oxide to develop gold nanopillar electrodes. The nanopillars were approximately 300-400 nm high and had a diameter of 60 nm. Thus, they yielded a higher surface area of the electrodes resulting in a decreased impedance compared to planar electrodes. The interaction between the large-scale gold nanopillar arrays and cardiac muscle cells (HL-1) was investigated via focused ion beam milling. In the resulting cross-sections we observed a tight coupling between the HL-1 cells and the gold nanostructures. However, the cell membranes did not bend into the cleft between adjacent nanopillars due to the high pillar density. We performed extracellular potential recordings from HL-1 cells with the nanostructured microelectrode arrays. The maximal amplitudes recorded with the nanopillar electrodes were up to 100% higher than those recorded with planar gold electrodes. Increasing the aspect ratio of the gold nanopillars and changing the geometrical layout can further enhance the signal quality in the future.


A method for collecting detailed data on direct and indirect medical expenses of cancer patients.
A complex data collection system involving seven community based practices and a university affiliated hospital has been developed. Four types of data are being collected: 1) medical status, 2) billings for a six month period, 3) patient reports of direct and indirect costs for a six month period and how they affected family finances and 4) diaries of direct and indirect costs for a week in which treatment was received and a week in which treatment was not received. Three groups are involved in collecting these data: physicians, their office staff and a central project telephone interviewer. Office staff are paid overtime rates for their work which is in addition to their regular responsibilities. Telephone follow-up interviews have contributed to compliance and have helped insure consistency in the data. Two hundred and fifteen patients have provided complete information to date. Refusal rate has been approximately 26% and drop out rate among persons enrolled in the study has been 21%. Patients most difficult to recruit and hold in the study have been very sick, elderly or on welfare. Total direct costs of data collection are estimated to be $48.00 per patient.


Association of natural killer cell depletion with induction of mixed chimerism and allograft tolerance in non-human primates.
Nonmyeloablative T cell depletion followed by donor bone marrow infusion has proved to be an effective approach to induction of mixed chimerism and tolerance of organ allografts in non-human primates. To help define the mechanisms involved we have compared T cell depletion with ATG versus anti-CD2 monoclonal antibody with respect to establishment of mixed chimerism and induction of tolerance. Both nonmyeloablative regimens included low dose total body irradiation (1.5 Gy x 2), thymic irradiation (7 Gy), splenectomy and kidney plus donor bone marrow transplantation, followed by a 4-week posttransplant course of cyclosporine. In addition, the ATG group (13 recipients) received antithymocyte globulin, although the LOCD2b group (10 recipients) were treated with an anti-CD2 monoclonal antibody (LOCD2b). In the ATG group, 11 of 13 monkeys developed multilineage chimerism and 9 survived for more than 100 days without kidney allograft rejection. In contrast, 0/10 monkeys in the LOCD2b group developed chimerism, 5 died of infection and 5 suffered progressive rejection; only 1 recipient survived beyond 100 days. Sequential monitoring of peripheral blood mononuclear cells revealed greater T cell (CD3+) depletion in the LOCD2b-treated animals compared to those receiving ATG. However, NK cells (CD16+CD8+) were significantly more depleted in the ATG group and NK function remained abrogated longer after ATG than LOCD2b treatment (3 weeks vs. <5 days). Despite excellent T cell depletion by LoCD2b, ATG was more effective in inducing chimerism and tolerance. This difference correlated with anti-NK activity of the two reagents. These data suggest that NK cells may also resist engraftment of allogeneic bone marrow cells in this model.


Influence of CO2 and low concentrations of O2 on fermentative metabolism of the rumen ciliate Dasytricha ruminantium.
The effects of ruminal concentrations of CO2 and O2 on glucose-stimulated and endogenous fermentation of the rumen isotrichid ciliate Dasytricha ruminantium were investigated. Principal metabolic products were lactic, butyric and acetic acids, H2 and CO2. Traces of propionic acid were also detected; formic acid present in the incubation supernatants was found to be a fermentation product of the bacteria closely associated with this rumen ciliate. 13C NMR spectroscopy revealed alanine as a minor product of glucose fermentation by D. ruminantium. Glucose uptake and metabolite formation rates were influenced by the headspace gas composition during the protozoal incubations. The uptake of exogenously supplied D-glucose was most rapid in the presence of O2 concentrations typical of those detected in situ (i.e. 1-3 microM). A typical ruminal gas composition (high CO2, low O2) led to increased butyrate and acetate formation compared to results obtained using O2-free N2. At a partial pressure of 66 kPa CO2 in N2, increased cytosolic flux to butyrate was observed. At low O2 concentrations (1-3 microM dissolved in the protozoal suspension) in the absence of CO2, increased acetate and CO2 formation were observed and D. ruminantium utilized lactate in the absence of extracellular glucose. The presence of both O2 and CO2 in the incubation headspaces resulted in partial inhibition of H2 production by D. ruminantium. Results suggest that at the O2 and CO2 concentrations that prevail in situ, the contribution made by D. ruminantium to the formation of ruminal volatile fatty acids is greater than previously reported, as earlier measurements were made under anaerobic conditions.


Design of the Subpopulations and Intermediate Outcome Measures in COPD (SPIROMICS) AIR Study.
Population-based epidemiological evidence suggests that exposure to ambient air pollutants increases hospitalisations and mortality from chronic obstructive pulmonary disease (COPD), but less is known about the impact of exposure to air pollutants on patient-reported outcomes, morbidity and progression of COPD. The Subpopulations and Intermediate Outcome Measures in COPD (SPIROMICS) Air Pollution Study (SPIROMICS AIR) was initiated in 2013 to investigate the relation between individual-level estimates of short-term and long-term air pollution exposures, day-to-day symptom variability and disease progression in individuals with COPD. SPIROMICS AIR builds on a multicentre study of smokers with COPD, supplementing it with state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, ozone, sulfur dioxide and black carbon. In the parent study, approximately 3000 smokers with and without airflow obstruction are being followed for up to 3 years for the identification of intermediate biomarkers which predict disease progression. Subcohorts undergo daily symptom monitoring using comprehensive daily diaries. The air monitoring and modelling methods employed in SPIROMICS AIR will provide estimates of individual exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand the health effects of short-term and long-term exposures to air pollution on COPD morbidity, including exacerbation risk, patient-reported outcomes and disease progression. The institutional review boards of all the participating institutions approved the study protocols. The results of the trial will be presented at national and international meetings and published in peer-reviewed journals.


Low-Grade Myofibroblastic Sarcoma on Back with Repeated Localized Recurrence and Regional Metastasis.
Low-grade myofibroblastic sarcoma (LGMS) is a rare spindle cell tumor with indolent course. Due to rarity and low-grade histologic features of LGMS, accurate diagnosis is challenging. We report a 63-year-old female patient with a three-month history of a 3.1 cm×2.5 cm sized, firm, skin-colored, painless, protruding left back mass. Initial excisional biopsy was performed and the mass was diagnosed as nodular fasciitis. After 18 months after excision, the mass recurred with pain and grew larger. Considering the clinical manifestations, diagnostic impression was changed as dermatofibrosarcoma protuberans not nodular fasciitis. Second wide excision was performed and the histopathology revealed proliferative atypical spindle cells with moderate nuclear atypia and a distinctive whorling pattern, which is suggestive of low-grade sarcoma. Additional computed tomography and positron emission tomography revealed no metastasis and suspicious residual viable malignant tissue. To remove suspicious residual tumor, third wide excision were performed and the diagnosis confirmed as LGMS. A microscopically clear resection was achieved with deep and lateral safety margin 0.6 cm each. Despite of postoperative radiotherapy with 35 times, recurrence of the tumor and lung metastasis was found after 7 months later. LGMS rarely metastasizes and occurs most commonly in the head and neck region. Thus, we report a rare case of LGMS on back which repeated localized recurrence and regional lung metastasis occurred despite wide excision and adjuvant radiotherapy.


Effects of an Acute Physical Activity Break on Test Anxiety and Math Test Performance.
(1) Background: Test anxiety has been found to negatively affect students' mental health and academic performance. A primary explanation for this is that anxiety-related thoughts occupy working memory resources during testing that cannot be used for test-related processes (such as information retrieval and problem-solving). The present intervention study investigated whether physical activity could decrease anxiety levels and improve maths test performance in sixth-grade children. (2) Methods: Sixty-eight children of 11-12 years from two primary schools in New South Wales, Australia were categorised as low or high anxious from their scores on a trait-anxiety questionnaire. After this assessment, they were randomly assigned to the activity break condition, in which they had to do several physical activities of moderate intensity (i.e., star jumps) for 10 min, or the control condition, in which they played a vocabulary game for 10 min. The outcome measures were children's anxiety levels at the beginning, during, and at the end of the test, invested mental effort, perceived task difficulty and maths test performance. (3) Results: Results showed that regardless of the condition, low anxious students performed better on the maths test than high anxious children. No differences were found for any of the variables between the activity break condition and the control condition. (4) Conclusions: Although test anxiety was not reduced as expected, this study showed that short physical activity breaks can be used before examinations without impeding academic performance.


Monomeric 16-Electron π-Diborene Complexes of Zn(II) and Cd(II).
Despite the prevalence of stable π-complexes of most d10 metals, such as Cu(I) and Ni(0), with ethylene and other olefins, complexation of d10 Zn(II) to simple olefins is too weak to form isolable complexes due to the metal ion's limited capacity for π-backdonation. By employing more strongly donating π-ligands, namely neutral diborenes with a high-lying π(B═B) orbital, monomeric 16-electron M(II)-diborene (M = Zn, Cd) π-complexes were synthesized in good yields. Metal-B2 π-interactions in both the solid and solution state were confirmed by single-crystal X-ray analyses and their solution NMR and UV-vis absorption spectroscopy, respectively. The M(II) centers adopt a trigonal planar geometry and interact almost symmetrically with both boron atoms. The MB2 planes significantly twist out of the MX2 planes about the M-centroid(B-B) vector, with angles ranging from 47.0° to 85.5°, depending on the steric interactions between the diborene ligand and the MX2 fragment.


First results from a Swiss level I trauma centre participating in the UK Trauma Audit and Research Network (TARN): prospective cohort study.
Patient characteristics and risk factors for death of Swiss trauma patients in the Trauma Audit and Research Network (TARN). Descriptive analysis of trauma patients (≥16 years) admitted to a level I trauma centre in Switzerland (September 1, 2009 to August 31, 2010) and entered into TARN. Multivariable logistic regression analysis was used to identify predictors of 30-day mortality. Of 458 patients 71% were male. The median age was 50.5 years (inter-quartile range [IQR] 32.2-67.7), median Injury Severity Score (ISS) was 14 (IQR 9-20) and median Glasgow Coma Score (GCS) was 15 (IQR 14-15). The ISS was >15 for 47%, and 14% had an ISS >25. A total of 17 patients (3.7%) died within 30 days of trauma. All deaths were in patients with ISS >15. Most injuries were due to falls <2 m (35%) or road traffic accidents (29%). Injuries to the head (39%) were followed by injuries to the lower limbs (33%), spine (28%) and chest (27%). The time of admission peaked between 12:00 and 22:00, with a second peak between 00:00 and 02:00. A total of 64% of patients were admitted directly to our trauma centre. The median time to CT was 30 min (IQR 18-54 min). Using multivariable regression analysis, the predictors of mortality were older age, higher ISS and lower GCS. Characteristics of Swiss trauma patients derived from TARN were described for the first time, providing a detailed overview of the institutional trauma population. Based on these results, patient management and hospital resources (e.g. triage of patients, time to CT, staffing during night shifts) could be evaluated as a further step.


The development of socio-sexual behavior in belugas (Delphinapterus leucas) under human care.
Although a catalog of beluga socio-sexual behavior has been established, to date, little is known about the development of beluga (Delphinapterus leucas) socio-sexual behavior. The present study explored how socio-sexual behavior developed in belugas under human care by recording the behavior of 5 belugas between years 4 and 10 of life. Overall, the presence of young male conspecifics was the most influential predictor of whether or not the subjects engaged in socio-sexual behavior, and social networks particularly emphasized the relationships between males in the social group. The subjects of the present study were also more likely to be involved in socio-sexual behavior as they matured and were more likely to be involved if they were male. Additionally, specific socio-sexual behaviors of the repertoire, including horizontal s-postures and pelvic thrusts, increased in prevalence throughout development. These findings have implications for conservation efforts as social group composition may contribute to the development of socio-sexual behavior, which in turn may influence the reproductive success of beluga populations. Furthermore, because socio-sexual behavior composes a substantial portion of a beluga's activity budget and the majority of the time spent socializing, it is likely crucial for social bonding and well-being in belugas, especially males.


CT in adult supraglottitis.
We describe the CT appearance of supraglottitis and its complications in three adults. The most common CT findings were thickening of the epiglottis, aryepiglottic folds, false and true vocal cords, obliteration of the preepiglottic fa, thickening of the platysma muscle, and reticulation of the subcutaneous fat. Multiple loculated fluid-density collections consistent with abscesses were seen in one patient. Although the diagnosis of supraglottitis is generally made on the basis of the patient's history and by direct endoscopy, CT may be used to confirm the diagnosis when an adequate laryngoscopic examination cannot be performed. CT is also useful in evaluating the complications of this disorder.


Hypovitaminosis D in internal medicine inpatients.
Some studies have suggested that hypovitaminosis D may be a consequence of protein-calorie malnutrition. This study assessed both the relationship between vitamin D status, malnutrition, calcium and phosphorus metabolism indices and the importance attached by internists to these alterations. There were 239 patients admitted to an internal medicine division who underwent examinations to assess nutritional state, liver and renal function, and bone metabolism. At the end of the study, the clinical data included in the discharge letter, the treatment prescribed, and the diagnosis assigned to patients on their hospital discharge form were collected. Hypovitaminosis D was found in 72% and hypoalbuminemia in 34.3% of patients. Subjects with hypovitaminosis were generally older and had lower albumin levels than those with mild or no hypovitaminosis. 25-Hydroxyvitamin D was inversely related with parathyroid hormone and directly related with albumin. Alterations of calcium and phosphorus metabolism were present in 55.6% and recorded by the division's physicians for only 13.53% of patients, of whom 72.37% were not specifically treated. There is a direct correlation between 25-hydroxyvitamin D and albumin levels. The high incidence and the metabolic consequence of hypovitaminosis D and of protein-calorie malnutrition is significantly underestimated and undertreated by physicians.


Time course of word production in fast and slow speakers: a high density ERP topographic study.
The transformation of an abstract concept into an articulated word is achieved through a series of encoding processes, which time course has been repeatedly investigated in the psycholinguistic and neuroimaging literature on single word production. The estimates of the time course issued from previous investigations represent the timing of process duration for mean processing speed: as production speed varies significantly across speakers, a crucial question is how the timing of encoding processing varies with speed. Here we investigated whether between-subjects variability in the speed of speech production is distributed along all encoding processes or if it is accounted for by a specific processing stage. We analysed event-related electroencephalographical (ERP) correlates during overt picture naming in 45 subjects divided into three speed subgroups according to their production latencies. Production speed modulated waveform amplitudes in the time window ranging from about 200 to 350 ms after picture presentation and the duration of a stable electrophysiological spatial configuration in the same time period. The remaining time windows from picture onset to 200 ms before articulation were unaffected by speed. By contrast, the manipulation of a psycholinguistic variable, word age-of-acquisition, modulated ERPs in all speed subgroups in a different and later time period, starting at around 400 ms after picture presentation, associated with phonological encoding processes. These results indicate that the between-subject variability in the speed of single word production is principally accounted for by the timing of a stable electrophysiological activity in the 200-350 ms time period, presumably associated with lexical selection.


Further insight into the reaction FeO(+) + H2 → Fe(+) + H2O: temperature dependent kinetics, isotope effects, and statistical modeling.
The reactions of FeO(+) with H2, D2, and HD were studied in detail from 170 to 670 K by employing a variable temperature selected ion flow tube apparatus. High level electronic structure calculations were performed and compared to previous theoretical treatments. Statistical modeling of the temperature and isotope dependent rate constants was found to reproduce all data, suggesting the reaction could be well explained by efficient crossing from the sextet to quartet surface, with a rigid near thermoneutral barrier accounting for both the inefficiency and strong negative temperature dependence of the reactions over the measured range of thermal energies. The modeling equally well reproduced earlier guided ion beam results up to translational temperatures of about 4000 K.


Hypoxia-induced switch in SNAT2/SLC38A2 regulation generates endocrine resistance in breast cancer.
Tumor hypoxia is associated with poor patient outcomes in estrogen receptor-α-positive (ERα+) breast cancer. Hypoxia is known to affect tumor growth by reprogramming metabolism and regulating amino acid (AA) uptake. Here, we show that the glutamine transporter, SNAT2, is the AA transporter most frequently induced by hypoxia in breast cancer, and is regulated by hypoxia both in vitro and in vivo in xenografts. SNAT2 induction in MCF7 cells was also regulated by ERα, but it became predominantly a hypoxia-inducible factor 1α (HIF-1α)-dependent gene under hypoxia. Relevant to this, binding sites for both HIF-1α and ERα overlap in SNAT2's cis-regulatory elements. In addition, the down-regulation of SNAT2 by the ER antagonist fulvestrant was reverted in hypoxia. Overexpression of SNAT2 in vitro to recapitulate the levels induced by hypoxia caused enhanced growth, particularly after ERα inhibition, in hypoxia, or when glutamine levels were low. SNAT2 up-regulation in vivo caused complete resistance to antiestrogen and, partially, anti-VEGF therapies. Finally, high SNAT2 expression levels correlated with hypoxia profiles and worse outcome in patients given antiestrogen therapies. Our findings show a switch in the regulation of SNAT2 between ERα and HIF-1α, leading to endocrine resistance in hypoxia. Development of drugs targeting SNAT2 may be of value for a subset of hormone-resistant breast cancer.


The obesity-induced transcriptional regulator TRIP-Br2 mediates visceral fat endoplasmic reticulum stress-induced inflammation.
The intimate link between location of fat accumulation and metabolic disease risk and depot-specific differences is well established, but how these differences between depots are regulated at the molecular level remains largely unclear. Here we show that TRIP-Br2 mediates endoplasmic reticulum (ER) stress-induced inflammatory responses in visceral fat. Using in vitro, ex vivo and in vivo approaches, we demonstrate that obesity-induced circulating factors upregulate TRIP-Br2 specifically in visceral fat via the ER stress pathway. We find that ablation of TRIP-Br2 ameliorates both chemical and physiological ER stress-induced inflammatory and acute phase response in adipocytes, leading to lower circulating levels of inflammatory cytokines. Using promoter assays, as well as molecular and pharmacological experiments, we show that the transcription factor GATA3 is responsible for the ER stress-induced TRIP-Br2 expression in visceral fat. Taken together, our study identifies molecular regulators of inflammatory response in visceral fat that-given that these pathways are conserved in humans-might serve as potential therapeutic targets in obesity.


Searching for an environmental effect of parental alcoholism on offspring alcohol use disorder: a genetically informed study of children of alcoholics.
The children-of-twins design was used to isolate a potentially causal environmental impact of having an alcoholic parent on offspring alcohol use disorder, by an examination of whether the children of alcoholics were at a higher risk for alcohol use disorders than were the children of nonalcoholic parents, even after correlated familial factors were controlled. Participants were 1,224 male and female twins from 836 twin pairs selected from the Australian Twin Registry, 2,334 of the twins' 18-39-year-old offspring, and 983 spouses of the twins. Lifetime histories of Diagnostic and Statistical Manual of Mental Disorders (4th ed.) alcohol use disorders were obtained by structured, psychiatric, telephone interviews conducted individually with each of the family members. Comparisons of the offspring of twins who were discordant for alcoholism indicated that there was no longer a statistically significant difference between the children of alcoholics and the children of nonalcoholics after genetic and family environmental factors correlated with having an alcoholic parent were controlled. The results of this study suggest that the direct causal effect of being exposed to an alcoholic parent on offspring alcohol use disorder is modest at best.


Evidence for genetic heterogeneity in Dent's disease.
Dent's disease (X-linked nephrolithiasis) is a proximal tubulopathy that has been consistently associated with inactivating mutations in the CLCN5 gene encoding the ClC-5 chloride channel expressed in tubular epithelial cells. We performed mutation analysis of the coding region of CLCN5 by DNA sequencing in 32 unrelated males, all of whom met the following three clinical criteria for the diagnosis of Dent's disease: (1) low-molecular-weight (LMW) proteinuria; (2) hypercalciuria; and (3) at least one of the following: nephrocalcinosis, kidney stones, renal insufficiency, hypophosphatemia, or hematuria. Sixteen mutations (ten missense, four nonsense, two frameshift) were found in 19 patients. Mutations were confirmed by restriction analysis or allele-specific polymerase chain reaction (PCR), segregated with disease in the families, and were not polymorphisms. In the other 13 patients with Dent's disease, the coding sequence of CLCN5 was normal. In these 13 patients, we also sequenced two regions of the CLCN5 promoter (626 and 586 bp, respectively, 2.1 and 1 kb upstream of exon 2) containing regulatory sites [activating protein-1 (AP-1)-like, AP-4, and cyclic adenosine monophosphate (cAMP)-receptor element binding protein (CREB)] and primary and secondary transcription start sites. We found no mutations in these promoter sequences in any of the 13 patients. In one three-generation family, the absence of mutation was confirmed by sequencing in two additional affected family members, and in this family haplotype analysis excluded linkage to the region of the CLCN5 gene. There were no differences between the 19 patients with CLCN5 mutations and the 13 without mutations with regard to any clinical features of Dent's disease. These findings suggest that mutation in other gene(s) may be responsible for the phenotype of Dent's disease in some patients.


Cordyceps sinensis attenuates HBx‑induced cell apoptosis in HK‑2 cells through suppressing the PI3K/Akt pathway.
The authors' previous studies demonstrated that the major renal damage from hepatitis B virus infection is HBx‑induced apoptosis of renal tubular epithelial cells. Cordyceps sinensis is one of the most valuable of traditional Chinese medicines and is extensively used to treat chronic renal diseases. However, there is no research on the potential renal protective effect of C. sinensis on HBx‑induced apoptosis of renal tubular cells. The protective effect and underlying mechanism of C. sinensis were examined using a renal tubular epithelial cell line stably overexpressing HBx. HK‑2 cells were stably transfected with pCMV‑HBx to establish HBx‑overexpression in an in vitro cell model and HK‑2 cells transfected with an empty vector were generated as a control. The effect of C. sinensis on cell proliferation and apoptosis, the phosphatidylinositol‑3‑kinase (PI3K)/protein kinase B (Akt) signaling pathway, and the enzyme activity of caspase‑3 and caspase‑9 was measured. The present study demonstrated that HBx transfection inhibited cell proliferation; increased apoptosis, caspase‑3 and caspase‑9 activity; and increased the activity of the PI3K/Akt pathway. Treatment with C. sinensis attenuated all of these HBx‑induced responses. HBx triggered apoptosis and activated the PI3K/Akt signaling pathway in HK‑2 cells. C. sinensis treatment significantly attenuated the effect of HBx, at least in part by suppressing the PI3K/Akt signaling pathway.


Life support for trauma and transport: a mobile ICU for safe in-hospital transport of critically injured patients.
In-hospital transport of newly injured patients is complicated by inadequate monitoring and adverse events. LSTAT (Life Support for Trauma and Transport, Integrated Medical Systems Inc) is a platform with multiple integrated systems (ventilator, defibrillator, suction, hemodynamic monitors, infusion and invasive monitoring channels, capnography, blood analysis, and electrocardiography) that allow seamless monitoring and effective life-saving interventions during transport. The platform functions as a mobile ICU and has preliminarily been tested with success in combat settings. This is the first evaluation of LSTAT in the civilian transport arena. Major trauma patients requiring trauma team activation, who were transported from the Emergency Department through different hospital departments (usually CT or angiography) to the ICU or operating room were included prospectively (December 2002 through April 2003). Patients were monitored and transported either by conventional means (conventional group) or by LSTAT (LSTAT group). Primary outcomes related to resource consumption and process of care; secondary outcomes related to clinical events. A questionnaire was completed by the surgeons participating in transports to document perceptions and preferences about means of in-hospital transport. Of 178 patients enrolled, 85 (48%) were in the LSTAT and 93 (52%) in the conventional groups. The two groups were similar except for age and mechanism of injury. Time of hand-bagging, preparation for transport, and return of blood results was significantly shorter in the LSTAT than in the conventional group (p < 0.001 for all). Significantly fewer LSTAT than conventional transports required more than one escorting physician (p < 0.001). Significantly more surveyed surgeons preferred LSTAT to conventional methods to transfer patients. There were no differences in adverse events, hospital stay, or mortality between the two groups. LSTAT emerges as a safe and convenient method of in-hospital transport. It allows uninterrupted monitoring, immediate response to physiologic changes, and reduction in human resource consumption. Process of care is improved. LSTAT's potential to improve clinical outcomes needs to be tested in different environments, including the prehospital setting.


Early postoperative anticoagulation after mechanical valve replacement: a Canadian survey.
The optimal approach to anticoagulation during the early postoperative period after mechanical valve replacement, by which early thromboembolism is prevented without bleeding complications, is not yet known. The study aim was to examine the practice patterns of Canadian cardiac surgeons with regard to early postoperative anticoagulation after mechanical valve implantation. A questionnaire was sent to 100 Canadian cardiac surgeons in July 2004, and 57 responses were received. Data were collected regarding the approaches to early postoperative anticoagulation following uncomplicated isolated mechanical aortic valve replacement (AVR) and mitral valve replacement (MVR). Heparin was administered routinely after AVR and MVR by 63% and 68% of surgeons, respectively. This was most commonly initiated on postoperative day (POD) 1, and given either subcutaneously (AVR, 28%; MVR, 25%) or intravenously (AVR, 33%; MVR, 42%). Alternatively, low-molecular-weight heparin was used by 21% and 23% of surgeons after AVR and MVR, respectively. Oral warfarin was usually started on POD 1 (72% and 68%, respectively), with 40% prescribing an initial dose between 2.5 and 5.0 mg, and 51% administering between 5.1 and 7.5 mg. When heparin was not used, oral anticoagulation was more often administered earlier (AVR, p = 0.003; MVR, p = 0.006), but not at higher doses (AVR, p = 0.07; MVR, p = 0.2). Following surgery, aspirin was prescribed by 61% and 65% of surgeons after AVR and MVR, respectively. The study results highlighted a significant variability in the management of early postoperative anticoagulation after mechanical valve implantation. The clinical impact of these findings is unknown, and can only be assessed through a prospective trial.


Are change of direction speed and agility different abilities from time and coordinative perspectives?
This study aimed to test whether agility and change of direction speed (COD) are independent capacities using the same movement pattern (1) in terms of the completion time and (2) the entropy. Seventeen semi-professional female football players participated in the study. The agility task consisted of a Y-shaped (45° COD) task with three possible exit options (center, right and left) performed pre-planned or in reaction to the movement of two testers (i.e., blocking exit gates). Players' acceleration was measured using an inertial measurement unit. Entropy was calculated from the acceleration signal and completion time was extracted using a magnet-based timing system. Significantly greater times and lower entropy (p<0.001) were found during agility runs to pre-planned COD runs. Furthermore, weak to moderate correlations were found between COD and agility for both completion time (r = 0.29, p<0.001) and entropy (r = 0.53, p<0.001, r2 = 28.1%). These results highlight that COD speed and agility are independent capacities and skills, and as such, should be tested and trained as distinct, separate qualities. Modifying task constraints including a reactive stimulus (i.e., cognitive factors), is essential for increasing task complexity by altering the biomechanical and coordinative aspects of the action.


An independent evaluation of a new method for automated interpretation of lung scintigrams using artificial neural networks.
The purpose of this study was to evaluate a new automated method for the interpretation of lung perfusion scintigrams using patients from a hospital other than that where the method was developed, and then to compare the performance of the technique against that of experienced physicians. A total of 1,087 scintigrams from patients with suspected pulmonary embolism comprised the training group. The test group consisted of scintigrams from 140 patients collected in a hospital different to that from which the training group had been drawn. An artificial neural network was trained using 18 automatically obtained features from each set of perfusion scintigrams. The image processing techniques included alignment to templates, construction of quotient images based on the perfusion/template images, and finally calculation of features describing segmental perfusion defects in the quotient images. The templates represented lungs of normal size and shape without any pathological changes. The performance of the neural network was compared with that of three experienced physicians who read the same test scintigrams according to the modified PIOPED criteria using, in addition to perfusion images, ventilation images when available and chest radiographs for all patients. Performances were measured as area under the receiver operating characteristic curve. The performance of the neural network evaluated in the test group was 0.88 (95% confidence limits 0.81-0.94). The performance of the three experienced experts was in the range 0.87-0.93 when using the perfusion images, chest radiographs and ventilation images when available. Perfusion scintigrams can be interpreted regarding the diagnosis of pulmonary embolism by the use of an automated method also in a hospital other than that where it was developed. The performance of this method is similar to that of experienced physicians even though the physicians, in addition to perfusion images, also had access to ventilation images for most patients and chest radiographs for all patients. These results show the high potential for the method as a clinical decision support system.


Auxin distribution is differentially affected by nitrate in roots of two rice cultivars differing in responsiveness to nitrogen.
Although ammonium (NH4(+)) is the preferred form of nitrogen over nitrate (NO3(-)) for rice (Oryza sativa), lateral root (LR) growth in roots is enhanced by partial NO3(-) nutrition (PNN). The roles of auxin distribution and polar transport in LR formation in response to localized NO3(-) availability are not known. Time-course studies in a split-root experimental system were used to investigate LR development patterns, auxin distribution, polar auxin transport and expression of auxin transporter genes in LR zones in response to localized PNN in 'Nanguang' and 'Elio' rice cultivars, which show high and low responsiveness to NO3(-), respectively. Patterns of auxin distribution and the effects of polar auxin transport inhibitors were also examined in DR5::GUS transgenic plants. Initiation of LRs was enhanced by PNN after 7 d cultivation in 'Nanguang' but not in 'Elio'. Auxin concentration in the roots of 'Nanguang' increased by approx. 24 % after 5 d cultivation with PNN compared with NH4(+) as the sole nitrogen source, but no difference was observed in 'Elio'. More auxin flux into the LR zone in 'Nanguang' roots was observed in response to NO3(-) compared with NH4(+) treatment. A greater number of auxin influx and efflux transporter genes showed increased expression in the LR zone in response to PNN in 'Nanguang' than in 'Elio'. The results indicate that higher NO3(-) responsiveness is associated with greater auxin accumulation in the LR zone and is strongly related to a higher rate of LR initiation in the cultivar 'Nanguang'.


Duodenal nutrient exclusion improves metabolic syndrome and stimulates villus hyperplasia.
Surgical interventions that prevent nutrient exposure to the duodenum are among the most successful treatments for obesity and diabetes. However, these interventions are highly invasive, irreversible and often carry significant risk. The duodenal-endoluminal sleeve (DES) is a flexible tube that acts as a barrier to nutrient-tissue interaction along the duodenum. We implanted this device in Zucker Diabetic Fatty (ZDF) rats to gain greater understanding of duodenal nutrient exclusion on glucose homeostasis. ZDF rats were randomised to four groups: Naive, sham ad libitum, sham pair-fed, and DES implanted. Food intake, body weight (BW) and body composition were measured for 28 days postoperatively. Glucose, lipid and bile acid metabolism were evaluated, as well as histological assessment of the upper intestine. DES implantation induced a sustained decrease in BW throughout the study that was matched by pair-fed sham animals. Decreased BW resulted from loss of fat, but not lean mass. DES rats were also found to be more glucose tolerant than either ad libitum-fed or pair-fed sham controls, suggesting fat mass independent metabolic benefits. DES also reduced circulating triglyceride and glycerol levels while increasing circulating bile acids. Interestingly, DES stimulated a considerable increase in villus length throughout the upper intestine, which may contribute to metabolic improvements. Our preclinical results validate DES as a promising therapeutic approach to diabetes and obesity, which offers reversibility, low risk, low invasiveness and triple benefits including fat mass loss, glucose and lipid metabolism improvement which mechanistically may involve increased villus growth in the upper gut.


Cooperativity of self-organized Brownian motors pulling on soft cargoes.
We study the cooperative dynamics of Brownian motors moving along a one-dimensional track when an external load is applied to the leading motor, mimicking molecular motors pulling on membrane-bound cargoes in intracellular traffic. Due to the asymmetric loading, self-organized motor clusters form spontaneously. We model the motors with a two-state noise-driven ratchet formulation and study analytically and numerically the collective velocity-force and efficiency-force curves resulting from mutual interactions, mostly hard-core repulsion and weak (nonbinding) attraction. We analyze different parameter regimes including the limits of weak noise, mean-field behavior, rigid coupling, and large numbers of motors, for the different interactions. We present a general framework to classify and quantify cooperativity. We show that asymmetric loading leads generically to enhanced cooperativity beyond the simple superposition of the effects of individual motors. For weakly attracting interactions, the cooperativity is mostly enhanced, including highly coordinated motion of motors and complex nonmonotonic velocity-force curves, leading to self-regulated clusters. The dynamical scenario is enriched by resonances associated to commensurability of different length scales. Large clusters exhibit synchronized dynamics and bidirectional motion. Biological implications are discussed.


A longitudinal study on lung disease in dental technicians: what has changed after seven years?
The aim of this 7-year follow-up study was to determine respiratory changes in dental technicians. In our region, in the year 2005, 36 dental technicians were evaluated with a cross-sectional study on respiratory occupational diseases, and in 2012 we evaluated them again. Inclusion of information on respiratory symptoms and demographic features questionnaires was applied. Pulmonary function tests (PFT) were performed. Chest X-rays (CXR) were evaluated according to the ILO-2000 classification. For the comparisons of the technicians' findings in 2005 and 2012, data analyses were performed with the Wilcoxon test in addition to descriptive statistical procedures. In 2012, 19 out of the 36 technicians continued to work in the same place, so we were able to evaluate their findings. The prevalence of respiratory symptoms in dental technician was as follows: dyspnea 7 (37%), cough 6 (32%), and phlegm 5 (26%). According to ILO classifications in 2005, among the 36 technicians, 5 (13.8%) had pneumoconiosis. At the end of 7 years, there were 9 pneumoconiosis cases among the 19 remaining technicians (47%). Thus, there was a statistically significant progression on the profusion of the radiologic findings (p < 0.005). Also there was a significant worsening on spirometric findings (p < 0.05). In dental technicians, a determination of both radiologic and functional progressions at the end of 7 years demonstrate that the primary and secondary preventive measures are necessary for these workplaces. Workplaces must be regularly controlled for worker health and hygiene.


A novel laparoscopic near-infrared fluorescence spectrum system with indocyanine green fluorescence overcomes limitations of near-infrared fluorescence image-guided surgery.
Near-infrared (NIR) fluorescence image-guided surgery (FIGS) introduces a revolutionary new approach to address this basic challenge in minimally invasive surgery. However, current FIGS systems have some limitations - the infrared rays cannot detect and visualise thick tissues with low concentrations of the fluorescent agent. We established a novel laparoscopic fluorescence spectrum (LFS) system using indocyanine green (ICG) fluorescence to overcome these limitations. Bovine serum albumin (BSA) was conjugated to ICG, and the mixtures were serially diluted at 5 × 10-8-5 × 10-1 mg/mL. We used the LFS system and a NIR camera system (NLS; SHINKO OPTICAL CO., LTD Tokyo, Japan) to determine the optical dilution for the fluorescence detection. BSA was conjugated to ICG (5.0 × 10-2 mg/mL) and used to coat the clips. We attempted to identify the fluorescence-coated clip from the serosal side of the cadaveric porcine stomach tissues using the LFS system and the NIR camera system. We measured the depth of the cadaveric porcine stomach wall at the thickest part that could be confirmed. We could not visualise fluorescence concentrations <2.5 × 10-3 mg/mL using the NIR camera system. The spectrum was detected at a concentration <2.5 × 10-3 mg/mL. We were able to identify the spectrum of ICG (829 nm) to a 13-mm depth of cadaveric porcine stomach wall by using the LFS system but could not identify the same with the NIR camera system regardless of wall thickness. The novel LFS system with NIR fluorescence imaging in this ex vivo and cadaveric porcine model was confirmed useful at deeper depths and lower concentrations. Based on these findings, we anticipate that the LFS system can be integrated and routinely used in minimally invasive surgery.


Examining the context of microbicide acceptability among married women and men in India.
Married women in India are increasingly at risk of HIV, often due to their husbands' extramarital sexual behaviour. Topical microbicides may provide protection to women who are unable to negotiate condom use. During the formative phase of a study to develop measures related to microbicide acceptability, we conducted in-depth interviews with 14 'high-risk' and 16 'low-risk' married women and 15 husbands. Some participants had recently completed a 2-week microbicide safety trial. A sequence of in-depth interviews with each participant explored the context of microbicide acceptability, including perceptions of couple harmony, vulnerability to HIV, sexual power, and ability to control life events. Women's perceptions of control and sexual power influenced attitudes towards microbicide use. HIV risk was most commonly associated with partner infidelity and easily detected, according to both men and women, by a lack of marital harmony. Despite this, high-risk women denied perceiving HIV risk until confronted with specific evidence of a husband's positive HIV or STI diagnosis. This study provides an in-depth examination of HIV risk for Indian married women, identifying potential determinants of microbicide use, and providing guidance for the development of psychometric scales to measure couple harmony, HIV risk perception, and sexual power and control.


A physiologically based model of interaural time difference discrimination.
Interaural time difference (ITD) is a cue to the location of sounds containing low frequencies and is represented in the inferior colliculus (IC) by cells that respond maximally at a particular best delay (BD). Previous studies have demonstrated that single ITD-sensitive cells contain sufficient information in their discharge patterns to account for ITD acuity on the midline (ITD = 0). If ITD discrimination were based on the activity of the most sensitive cell available ("lower envelope hypothesis"), then ITD acuity should be relatively constant as a function of ITD. In response to broadband noise, however, the ITD acuity of human listeners degrades as ITD increases. To account for these results, we hypothesize that pooling of information across neurons is an essential component of ITD discrimination. This report describes a neural pooling model of ITD discrimination based on the response properties of ITD-sensitive cells in the IC of anesthetized cats. Rate versus ITD curves were fit with a cross-correlation model of ITD sensitivity, and the parameters were used to constrain a population model of ITD discrimination. The model accurately predicts ITD acuity as a function of ITD for broadband noise stimuli when responses are pooled across best frequency (BF). Furthermore, ITD tuning based solely on a system of internal delays is not sufficient to predict ITD acuity in response to 500 Hz tones, suggesting that acuity is likely refined by additional mechanisms. The physiological data confirms evidence from the guinea pig that BD varies systematically with BF, generalizing the observation across species.


Comprehensive Assessment of the Antigenic Impact of Human Papillomavirus Lineage Variation on Recognition by Neutralizing Monoclonal Antibodies Raised against Lineage A Major Capsid Proteins of Vaccine-Related Genotypes.
Human papillomavirus (HPV) is the causative agent of cervical and other epithelial cancers. Naturally occurring variants of HPV have been classified into lineages and sublineages based on their whole-genome sequences, but little is known about the impact of this diversity on the structure and function of viral gene products. The HPV capsid is an icosahedral lattice comprising 72 pentamers of the major capsid protein (L1) and the associated minor capsid protein (L2). We investigated the potential impact of this genome variation on the capsid antigenicity of lineage and sublineage variants of seven vaccine-relevant, oncogenic HPV genotypes by using a large panel of monoclonal antibodies (MAbs) raised against the L1 proteins of lineage A antigens. Each genotype had at least one variant that displayed a ≥4-fold reduced neutralizing antibody sensitivity against at least one MAb, demonstrating that naturally occurring variation can affect one or more functional antigenic determinants on the HPV capsid. For HPV16, HPV18, HPV31, and HPV45, the overall impact was of a low magnitude. For HPV33 (sublineages A2 and A3 and lineages B and C), HPV52 (lineage D), and HPV58 (lineage C), however, variant residues in the indicated lineages and sublineages reduced their sensitivity to neutralization by all MAbs by up to 1,000-fold, suggesting the presence of key antigenic determinants on the surface of these capsids. These determinants were resolved further by site-directed mutagenesis. These data improve our understanding of the impact of naturally occurring variation on the antigenicity of the HPV capsid of vaccine-relevant oncogenic HPV genotypes.IMPORTANCE Human papillomavirus (HPV) is the causative agent of cervical and some other epithelial cancers. HPV vaccines generate functional (neutralizing) antibodies that target the virus particles (or capsids) of the most common HPV cancer-causing genotypes. Each genotype comprises variant forms that have arisen over millennia and which include changes within the capsid proteins. In this study, we explored the potential for these naturally occurring variant capsids to impact recognition by neutralizing monoclonal antibodies. All genotypes included at least one variant form that exhibited reduced recognition by at least one antibody, with some genotypes affected more than others. These data highlight the impact of naturally occurring variation on the structure of the HPV capsid proteins of vaccine-relevant oncogenic HPV genotypes.


Healthcare Utilization Patterns for Acute Febrile Illness in Bangladesh, Nepal, and Pakistan: Results from the Surveillance for Enteric Fever in Asia Project.
Characterizing healthcare-seeking patterns for acute febrile illness is critical for generating population-based enteric fever incidence estimates from facility-based surveillance data. We used a hybrid model in the Surveillance for Enteric Fever in Asia Project (SEAP) to assess incidence of enteric fever at 6 study hospitals in 3 countries. We recruited individuals presenting to the hospitals and obtained blood cultures to evaluate for enteric fever. For this analysis, we undertook cluster random household surveys in Dhaka, Bangladesh (2 sites); Karachi, Pakistan; Kathmandu, Nepal; and Kavrepalanchok, Nepal between January 2017 and February 2019, to ascertain care-seeking behavior for individuals with 1) fever for ≥3 consecutive days within the past 8 weeks; or 2) fever resulting in hospitalization within the past year. We also collected data about disease severity and household demographics and assets. We used mixed-effect multivariable logistic regression models to identify determinants of healthcare seeking at study hospitals and determinants of culture-confirmed enteric fever. We enrolled 31 841 households (53 926 children) in Bangladesh, 25 510 households (84 196 children and adults) in Nepal, and 21 310 households (108 031 children and adults) in Pakistan. Children <5 years were most likely to be taken to the study hospitals for febrile illness at all sites. Household wealth was positively correlated with healthcare seeking in 4 of 5 study sites, and at least one marker of disease severity was positively associated with healthcare seeking in 3 of 5 catchment areas. Wealth and disease severity were variably predictive of blood culture-confirmed enteric fever. Age, household wealth, and disease severity are important determinants of healthcare seeking for acute febrile illness and enteric fever risk in these communities, and should be incorporated into estimation models for enteric fever incidence.


Sustainability of the effect of optical intervention on the reading performance of children with dyslexia.
Dyslexia is a learning disability associated with reading difficulties in children. Due to the potential of poor school outcomes interventions have been employed to help students with dyslexia read. This study was aimed at identifying the sustainability of the effect of combined Visual Tracking Magnifier (VTM) and Ministry of Education (MOE) interventions and MOE intervention alone on the reading performance of school children with dyslexia after discontinuation of intervention. This prospective, interventional study was conducted on primary school children with dyslexia aged 8 - 11 years. The participants underwent comprehensive ophthalmic and optometric examinations and were categorized into groups A, B, and C, comprising primary school children at level 1 or 2. Groups A and B received combined VTM and MOE interventions for 12 and 24 weeks, respectively, and group C received MOE intervention alone. The reading performance was assessed at baseline and 12, 24, and 36 weeks post-intervention. Both components of the reading performance improved significantly for school children at both levels in all study groups (all P < 0.05). However, the reading performance improvement was only approximately 28% in group C and 38% - 50% in groups A and B. In group A, students at level 1 showed significantly improved reading speed from baseline to 12 weeks post-VTM intervention and reading rate from baseline to 24 weeks post-VTM intervention (both P < 0.05). Students at level 2 showed significantly improved reading speed and rate from baseline to 12 and 24 weeks post-VTM intervention (all P < 0.05). In group B, students at both levels showed significantly improved reading speed and rate from baseline to 24 and 36 weeks post-VTM intervention (all P < 0.05). Students at level 2 showed significantly improved reading speed 12 weeks after cessation of intervention (at 36 weeks post-VTM intervention) compared to 24 weeks post-VTM intervention (P < 0.05). The improvement remaining stable 12 weeks after discontinuation of intervention indicated a sustained effect. Combined or individual intervention improved the reading performance of school children with dyslexia at levels 1 and 2. However, combined intervention showed a better reading improvement effect. Improvement in the reading performance was maintained after discontinuation of the VTM intervention. Further interventional studies with a longer study period after discontinuation of this optical intervention are required to confirm the long-term sustainability of its positive effects on the reading performance of school children with dyslexia.