Is embellishing UCAS personal statements accepted practice in applications to medicine and dentistry?
The assessment of non-academic achievements through the personal statement remains part of the selection process at most UK medical and dental schools. Such statement offers applicants an opportunity to highlight their non-academic achievements, but the highly competitive nature of the process may tempt them to exaggerate their accomplishments. The challenge is that selectors cannot discern applicants' exaggerated claims from genuine accounts and the system risks preferentially selecting dishonest applicants. To explore the level and perception of deception on UCAS personal statements among applicants to medical and dental schools. To investigate the association between attitudes towards deception and various other demographic variables and cognitive ability via the UKCAT. An online survey was completed with first year students from six UK medical schools and one dental school. Questionnaire items were classified into three categories involving individual acts, how they suspect their peers behave, and overall perceptions of personal statements to influence the selection process. Descriptive statistics were used to investigate responses to questionnaire items. t-Tests were used to investigate the relationship between items, demographic variables and cognitive ability. Candidates recognized that putting fraudulent information or exaggerating one's experience on UCAS personal statement was dishonest; however there is a widespread belief that their peers do it. Female respondents and those with a higher UKCAT score were more likely to condemn deceptive practices. The existing selection process is open to abuse and may benefit dishonest applicants. Admission systems should consider investing in systems that can pursue traceable information that applicants provide, and nullify the application should it contain fraudulent information.


Mercury accumulation in sea lamprey (Petromyzon marinus) from Lake Huron.
We determined whole-fish total mercury (Hg) concentrations of 40 male and 40 female adult sea lampreys (Petromyzon marinus) captured in the Cheboygan River, a tributary to Lake Huron, during May 2011. In addition, bioenergetics modeling was used to explore the effects of sex-related differences in activity and resting (standard) metabolic rate (SMR) on mercury accumulation. The grand mean for Hg concentrations was 519 ng/g (standard error of the mean=46 ng/g). On average, males were 16% higher in Hg concentration than females. Bioenergetics modeling results indicated that 14% higher activity and SMR in males would account for this observed sex difference in Hg concentrations. We concluded that the higher Hg concentration in males was most likely due to higher rate of energy expenditure in males, stemming from greater activity and SMR. Our findings have implications for estimating the effects of sea lamprey populations on mercury cycling within ecosystems, as well as for the proposed opening of sea lamprey fisheries. Eventually, our results may prove useful in improving control of sea lamprey, a pest responsible for substantial damage to fisheries in lakes where it is not native.


Molecular evolutionary analysis of the influenza A(H1N1)pdm, May-September, 2009: temporal and spatial spreading profile of the viruses in Japan.
In March 2009, pandemic influenza A(H1N1) (A(H1N1)pdm) emerged in Mexico and the United States. In Japan, since the first outbreak of A(H1N1)pdm in Osaka and Hyogo Prefectures occurred in the middle of May 2009, the virus had spread over 16 of 47 prefectures as of June 4, 2009. We analyzed all-segment concatenated genome sequences of 75 isolates of A(H1N1)pdm viruses in Japan, and compared them with 163 full-genome sequences in the world. Two analyzing methods, distance-based and Bayesian coalescent MCMC inferences were adopted to elucidate an evolutionary relationship of the viruses in the world and Japan. Regardless of the method, the viruses in the world were classified into four distinct clusters with a few exceptions. Cluster 1 was originated earlier than cluster 2, while cluster 2 was more widely spread around the world. The other two clusters (clusters 1.2 and 1.3) were suggested to be distinct reassortants with different types of segment assortments. The viruses in Japan seemed to be a multiple origin, which were derived from approximately 28 transported cases. Twelve cases were associated with monophyletic groups consisting of Japanese viruses, which were referred to as micro-clade. While most of the micro-clades belonged to the cluster 2, the clade of the first cases of infection in Japan originated from cluster 1.2. Micro-clades of Osaka/Kobe and the Fukuoka cases, both of which were school-wide outbreaks, were eradicated. Time of most recent common ancestor (tMRCA) for each micro-clade demonstrated that some distinct viruses were transmitted in Japan between late May and early June, 2009, and appeared to spread nation-wide throughout summer. Our results suggest that many viruses were transmitted from abroad in late May 2009 irrespective of preventive actions against the pandemic influenza, and that the influenza A(H1N1)pdm had become a pandemic stage in June 2009 in Japan.


σ-Aromaticity in an unsaturated ring: osmapentalene derivatives containing a metallacyclopropene unit.
In general, aromaticity can be clarified as π- and σ-aromaticity according to the type of electrons with major contributions. The traditional π-aromaticity generally describes the π-conjugation in fully unsaturated rings whereas σ-aromaticity may stabilize fully saturated rings with delocalization caused by σ-electron conjugation. Reported herein is an example of σ-aromaticity in an unsaturated three-membered ring (3 MR), which is supported by experimental observations and theoretical calculations. Specifically, when the 3 MR in cyclopropaosmapentalene is cleaved by ethane through two isodesmic reactions, both of them are highly endothermic (+29.7 and +35.0 kcal mol(-1)). These positive values are in sharp contrast to the expected exothermicity, thus indicating aromaticity in the 3 MR. Further nucleus-independent chemical shift and anisotropy of the current-induced density calculations reveal the nature of σ-aromaticity in the unsaturated 3 MR.


Video: intrahepatic Glissonian approach for pure laparoscopic right hemihepatectomy.
To present a video of laparoscopic right hepatectomy using Glissonian technique. A new strategy for liver transection is presented. Liver is divided in three parts. The posterior part, containing short hepatic veins, is divided with stapler before liver transection. Anterior part is fully divided with harmonic scalpel, and the middle part, containing hepatic veins from segments 5 and 8, is the last part to be transected. A 41-year-old woman with right-sided hepatolithiasis and choledocholithiasis was referred for surgical treatment. Patient was positioned in left lateral position. Four trocars were used. Operation began with division of liver ligaments, right liver mobilization, and exposure of the retrohepatic vena cava. Cholecystectomy was performed, followed by intrahepatic access to the right Glissonian pedicle (containing arterial, portal, and bile duct branches of segments 5-8). Two small incisions were performed around hilar plate according to specific anatomic landmarks. A vascular clamp was introduced into those incisions, resulting in ischemic delineation of right liver. Clamp was replaced by a vascular stapler, and stapler was fired. Liver parenchyma was divided by harmonic scalpel combined with vascular stapler. The specimen was extracted through suprapubic incision. Intraoperative cholangiography confirmed a 2-cm common bile duct stone which was immediately removed by endoscopy (endoscopic retrograde cholangiopancreatography, ERCP). Falciform ligament was sutured to maintain the liver in its original anatomical position, avoiding hepatic vein kinking, and abdominal cavity was drained. Operative time was 180 min, with blood loss estimated at 50 ml, without need for transfusion. Postoperative recovery was uneventfully, and patient was discharged on the fourth postoperative day. Laparoscopic intrahepatic Glissonian approach is feasible and is a useful technique for rapid and safe control of the right liver pedicle, facilitating laparoscopic right hemihepatectomy. The special strategy described may help laparoscopic surgeons to safely perform this challenging procedure.


Relationship between rate of posterior uveal melanoma flattening following plaque radiotherapy and gene expression profile class of tumor cells.
To evaluate the relationship between rate of flattening of posterior uveal melanomas (PUMs) over the first 6 months following I-125 plaque radiotherapy and gene expression profile (GEP) class of tumor cells obtained by fine needle aspiration biopsy (FNAB) prior to treatment. Retrospective analysis of relationship between GEP of PUM cells obtained by FNAB at or prior to treatment and rate of tumor flattening following I-125 plaque radiotherapy. Impact of initial tumor thickness was minimized by pairing cases so baseline tumor thickness in subgroups was matched to within ± 0.5 mm. Paired t-testing compared mean tumor thickness in GEP subgroups at 3- and 6-months post treatment assessments. Our initial group consisted of 269 patients. Seventy-seven tumors (28.6%) were GEP class 2. Twenty-seven of these were treated by I-125 plaque radiotherapy post-FNAB and returned for post treatment evaluations at 3 and 6 months. A matched GEP class 1 tumor was identified for 25 class 2 cases. Matched tumor pairs ranged in thickness from 2.5 to 11.5 mm at baseline. Mean tumor thickness at baseline in the GEP 1 subgroup was 5.8 and 5.9 mm in the GEP 2 subgroup. Three-months post plaque, mean tumor thickness was 4.5 mm in class 1 cases and 4.6 mm in class 2 cases (paired t = 0.31, P = 0.76). The 6-month post-plaque, mean tumor thickness was 4.0 mm in each subgroup (paired t = 0.25, P = 0.81). Our study showed a lack of association between the GEP class and the rate of flattening of posterior uveal melanomas following I-125 plaque radiotherapy of PUMs.


Virologic response and haematologic toxicity of boceprevir- and telaprevir-containing regimens in actual clinical settings.
Effectiveness, safety and tolerability of boceprevir (BOC) and telaprevir (TPV) in actual clinical settings remain unknown. We determined rates of sustained virologic response (SVR) and haematologic adverse effects among persons treated with BOC- or TPV-containing regimens, compared with pegylated interferon/ribavirin (PEG/RBV). Using an established cohort of hepatitis C virus (HCV)-infected persons, Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), we identified those treated with a BOC- or TPV-containing regimen and HCV genotype 1-infected controls treated with PEG/RBV. We excluded those with HIV coinfection and missing HCV RNA values to determine SVR. Primary endpoints were SVR (undetectable HCV RNA ≥12 weeks after treatment completion) and haematologic toxicity (grade 3/4 anaemia, neutropenia and thrombocytopenia). We evaluated 2288 persons on BOC-, 409 on TPV-containing regimen and 6308 on PEG/RBV. Among these groups, respectively, 31%, 43% and 9% were treatment-experienced; 17%, 37% and 14% had baseline cirrhosis; 63%, 54% and 48% were genotype 1a. SVR rates among noncirrhotics were as follows: treatment naïve: 65% (BOC), 67% (TPV) and 31% (PEG/RBV); treatment experienced: 57% (BOC), 54% (TPV) and 13% (PEG/RBV); (P-value not significant for BOC vs TPV; P < 0.0001 for BOC or TPV vs PEG/RBV). Haematologic toxicities among BOC-, TPV- and PEG/RBV-treated groups were as follows: grade 3/4 anaemia 7%, 11% and 3%; grade 4 thrombocytopenia 2.2%, 5.4% and 1.7%; grade 4 neutropenia 8.2%, 5.6% and 3.4%. SVR rates are higher and closer to those reported in pivotal clinical trials among BOC- and TPV-treated persons compared with PEG/RBV-treated persons. Haematologic adverse events are frequent, but severe toxicity is uncommon.


Western Australian Food Security Project.
The aim of the Western Australian (WA) Food Security Project was to conduct a preliminary investigation into issues relating to food security in one region within the Perth metropolitan area in Western Australia. The first phase of the project involved a food audit in one lower income area that was typical of the region, to identify the range, variety and availability of foods in the region. A comprehensive food audit survey was provided to all food outlet owners/operators in one lower socio-economic region within the City of Mandurah (n = 132 outlets). The purpose of the survey was to investigate the range, variety and availability of foods in the Mandurah region as well as examining specific in-store characteristics such as the types of clientele and in-store promotions offered. Surveys were competed for 99 outlets (response rate = 75%). The range of foods available were predominantly pre-prepared with more than half of the outlets pre-preparing the majority of their food. Sandwiches and rolls were the most popular items sold in the outlets surveyed (n = 51 outlets) followed by pastries such as pies, sausage rolls and pasties (n = 33 outlets). Outlets considered their healthiest food options were sandwiches or rolls (n = 51 outlets), salads (n- = 50 outlets), fruit and vegetables (n = 40 outlets), seafood (n = 27 outlets), meats such as chicken (n = 26 outlets and hot foods such as curries, soups or quiches (n = 23 outlets). The majority of outlets surveyed considered pre-prepared food including sandwiches, rolls and salads, as healthy food options regardless of the content of the filling or dressings used. Few outlets (n = 28%) offered a choice of bread type other than white or wholemeal. High fat pastries and dressings were popular client choices (n = 77%) as were carbonated drinks (n = 88%) and flavoured milks (n = 46%). These findings clearly indicate the need for further investigation of the impact of access to quality, healthy foods at reasonable cost (food security) on public health, particularly in lower socio-economic areas.


Phosphatidylinositol 3,5-bisphosphate defines a novel PI 3-kinase pathway in resting mouse fibroblasts.
PtdIns(3,5)P2 is identified as the product of an agonist-independent, wortmannin-sensitive pathway in resting mouse cells. Results are presented here to indicate that PtdIns(3,5)P2 is formed by phosphorylation of PtdIns3P at the D-5 position, and they suggest that relatively constant cellular levels of PtdIns3P and PtdIns(3, 5)P2 are maintained by the concerted action of PtdIns3P 5-kinase and PtdIns(3,5)P2 5-phosphatase. These studies imply a novel mechanism for the action of PtdIns-specific phosphoinositide 3-hydroxykinases in mammalian cells.


Antimodified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying antirheumatic drugs.
To perform a detailed analysis of the autoantibody response against post-translationally modified proteins in patients with rheumatoid arthritis (RA) in sustained remission and to explore whether its composition influences the risk for disease relapse when tapering disease modifying antirheumatic drug (DMARD) therapy. Immune responses against 10 citrullinated, homocitrullinated/carbamylated and acetylated peptides, as well as unmodified vimentin (control) and cyclic citrullinated peptide 2 (CCP2) were tested in baseline serum samples from 94 patients of the RETRO study. Patients were classified according to the number of autoantibody reactivities (0-1/10, 2-5/10 and >5/10) or specificity groups (citrullination, carbamylation and acetylation; 0-3) and tested for their risk to develop relapses after DMARD tapering. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining the role of autoantibodies in predicting relapse. Patients varied in their antimodified protein antibody response with the extremes from recognition of no (0/10) to all antigens (10/10). Antibodies against citrullinated vimentin (51%), acetylated ornithine (46%) and acetylated lysine (37%) were the most frequently observed subspecificities. Relapse risk significantly (p=0.011) increased from 18% (0-1/10 reactivities) to 34% (2-5/10) and 55% (>5/10). With respect to specificity groups (0-3), relapse risk significantly (p=0.021) increased from 18% (no reactivity) to 28%, 36% and finally to 52% with one, two or three antibody specificity groups, respectively. The data suggest that the pattern of antimodified protein antibody response determines the risk of disease relapse in patients with RA tapering DMARD therapy. 2009-015740-42; Results.


Predicted global distribution of Burkholderia pseudomallei and burden of melioidosis.
Burkholderia pseudomallei, a highly pathogenic bacterium that causes melioidosis, is commonly found in soil in Southeast Asia and Northern Australia1,2. Melioidosis can be difficult to diagnose due to its diverse clinical manifestations and the inadequacy of conventional bacterial identification methods3. The bacterium is intrinsically resistant to a wide range of antimicrobials, and treatment with ineffective antimicrobials may result in case fatality rates (CFRs) exceeding 70%4,5. The importation of infected animals has, in the past, spread melioidosis to non-endemic areas6,7. The global distribution of B. pseudomallei and burden of melioidosis, however, remain poorly understood. Here, we map documented human and animal cases, and the presence of environmental B. pseudomallei, and combine this in a formal modelling framework8-10 to estimate the global burden of melioidosis. We estimate there to be 165,000 (95% credible interval 68,000-412,000) human melioidosis cases per year worldwide, of which 89,000 (36,000-227,000) die. Our estimates suggest that melioidosis is severely underreported in the 45 countries in which it is known to be endemic and that melioidosis is likely endemic in a further 34 countries which have never reported the disease. The large numbers of estimated cases and fatalities emphasise that the disease warrants renewed attention from public health officials and policy makers.


Towards graphene iodide: iodination of graphite oxide.
Halogenated graphene derivatives are interesting owing to their outstanding physical and chemical properties. In this paper, we present various methods for the synthesis of iodinated graphene derivatives by the iodination of graphite oxides prepared according to either the Hummers or Hofmann method. Both graphite oxides were iodinated by iodine or hydroiodic acid under reflux or in an autoclave at elevated temperatures (240 °C) and pressures (over 100 bar). The influence of both graphite oxide precursors on the properties of resulting iodinated graphenes was investigated by various techniques, including SEM, SEM-EDS, high-resolution XPS, FTIR, STA, and Raman spectroscopy. Electrical resistivity was measured by a standard four point technique. In addition, the electrochemical properties were investigated by cyclic voltammetry. Although the iodinated graphenes were structurally similar, they had remarkably different concentrations of iodine. The most highly iodinated graphenes (iodine concentration above 30 wt%) exhibited relatively high C/O ratios, confirming high degrees of reduction. Iodine is incorporated in the form of covalent bonds to carbon atoms or as polyiodide anions non-covalently bonded through the charge transfer reaction with the graphene framework. Iodinated graphenes with such properties could be used as the starting material for further chemical modifications or as flame-retardant additives.


Atrazine chlorohydrolase from Pseudomonas sp. strain ADP: gene sequence, enzyme purification, and protein characterization.
Pseudomonas sp. strain ADP metabolizes atrazine to carbon dioxide and ammonia via the intermediate hydroxyatrazine. The genetic potential to produce hydroxyatrazine was previously attributed to a 1.9-kb AvaI DNA fragment from strain ADP (M. L. de Souza, L. P. Wackett, K. L. Boundy-Mills, R. T. Mandelbaum, and M. J. Sadowsky, Appl. Environ. Microbiol. 61:3373-3378, 1995). In this study, sequence analysis of the 1.9-kb AvaI fragment indicated that a single open reading frame, atzA, encoded an activity transforming atrazine to hydroxyatrazine. The open reading frame for the chlorohydrolase was determined by sequencing to be 1,419 nucleotides and encodes a 473-amino-acid protein with a predicted subunit molecular weight of 52,421. The deduced amino acid sequence matched the first 10 amino acids determined by protein microsequencing. The protein AtzA was purified to homogeneity by ammonium sulfate precipitation and anion-exchange chromatography. The subunit and holoenzyme molecular weights were 60,000 and 245,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and gel filtration chromatography, respectively. The purified enzyme in H2(18)O yielded [18O]hydroxyatrazine, indicating that AtzA is a chlorohydrolase and not an oxygenase. The most related protein sequence in GenBank was that of TrzA, 41% identity, from Rhodococcus corallinus NRRL B-15444R. TrzA catalyzes the deamination of melamine and the dechlorination of deethylatrazine and desisopropylatrazine but is not active with atrazine. AtzA catalyzes the dechlorination of atrazine, simazine, and desethylatrazine but is not active with melamine, terbutylazine, or desethyldesisopropylatrazine. Our results indicate that AtzA is a novel atrazine-dechlorinating enzyme with fairly restricted substrate specificity and contributes to the microbial hydrolysis of atrazine to hydroxyatrazine in soils and groundwater.


Electrolyzed-reduced water scavenges active oxygen species and protects DNA from oxidative damage.
Active oxygen species or free radicals are considered to cause extensive oxidative damage to biological macromolecules, which brings about a variety of diseases as well as aging. The ideal scavenger for active oxygen should be 'active hydrogen'. 'Active hydrogen' can be produced in reduced water near the cathode during electrolysis of water. Reduced water exhibits high pH, low dissolved oxygen (DO), extremely high dissolved molecular hydrogen (DH), and extremely negative redox potential (RP) values. Strongly electrolyzed-reduced water, as well as ascorbic acid, (+)-catechin and tannic acid, completely scavenged O.-2 produced by the hypoxanthine-xanthine oxidase (HX-XOD) system in sodium phosphate buffer (pH 7.0). The superoxide dismutase (SOD)-like activity of reduced water is stable at 4 degrees C for over a month and was not lost even after neutralization, repeated freezing and melting, deflation with sonication, vigorous mixing, boiling, repeated filtration, or closed autoclaving, but was lost by opened autoclaving or by closed autoclaving in the presence of tungsten trioxide which efficiently adsorbs active atomic hydrogen. Water bubbled with hydrogen gas exhibited low DO, extremely high DH and extremely low RP values, as does reduced water, but it has no SOD-like activity. These results suggest that the SOD-like activity of reduced water is not due to the dissolved molecular hydrogen but due to the dissolved atomic hydrogen (active hydrogen). Although SOD accumulated H2O2 when added to the HX-XOD system, reduced water decreased the amount of H2O2 produced by XOD. Reduced water, as well as catalase and ascorbic acid, could directly scavenge H2O2. Reduce water suppresses single-strand breakage of DNA b active oxygen species produced by the Cu(II)-catalyzed oxidation of ascorbic acid in a dose-dependent manner, suggesting that reduced water can scavenge not only O2.- and H2O2, but also 1O2 and .OH.


Use of elastin fibre detection in the diagnosis of ventilator associated pneumonia.
Elastin fibre detection could be a simple and reliable marker of ventilator associated pneumonia. To confirm this, a prospective study was undertaken to evaluate the diagnostic yield of elastin fibre detection in the diagnosis of ventilator associated pneumonia. Seventy eight mechanically ventilated patients were evaluated by examining endotracheal aspirates for the presence of elastin fibres. All patients were previously treated with antibiotics. Quantitative bacterial cultures of endotracheal aspirates and protected specimen brush samples were also performed. Patients were classified into three diagnostic categories: group 1, definite pneumonia (n = 25); group 2, probable pneumonia (n = 35); and group 3, controls (n = 18). Patients with definite and probable pneumonia were grouped together. The presence of elastin fibres in endotracheal aspirate samples was more frequent in groups 1 and 2, being found in 19 of the 60 patients compared with five of the control group. Although the presence of elastin fibres had a low sensitivity (32%), it was a reasonably specific marker (72%) of pneumonia. This specificity increased to 86% and 81% respectively when only Gram negative bacilli and Pseudomonas aeruginosa pneumonia were considered. Again, calculated sensitivity was 43% and 44% when analysing cases infected by Gram negative bacilli and Ps aeruginosa, respectively. The negative predictive value of the detection of elastin fibres in pneumonia caused by Ps aeruginosa was 81%. Detection was more frequent with infection by Gram negative bacilli (14/19), particularly with Ps aeruginosa (8/14). By contrast, pneumonia due to Gram positive cocci or non-bacterial agents uncommonly resulted in positive elastin fibre preparations (4/19, 21%). When analysing patients with and without chronic obstructive pulmonary disease, the diagnostic value of elastin fibre detection did not change. Potassium hydroxide preparation of elastin fibres is a rapid and simple specific marker of ventilator associated pneumonia and may be a useful technique to help diagnose pulmonary infections in mechanically ventilated patients, although this assessment is at present limited to patients without adult respiratory distress syndrome.


A fluorescent probe strategy for the detection and discrimination of hydrogen peroxide and peroxynitrite in cells.
Aryl boronate fluorescent probes allow the non-invasive study of dynamic cellular processes involving the reactive species, hydrogen peroxide (H2O2) and peroxynitrite (ONOO-). However, the ability of these probes to differentiate between these two species remains unclear. Here, we report a boronate-functionalised hemicyanine dye (HD-BPin) as a potential strategy to distinguish between H2O2 at 704 nm (red channel) and ONOO- at 460 nm (blue channel) in solution and in cells. This work also highlights the choice of fluorophore before boronate functionalization can dictate the observed selectivity between these two species.


β-Klotho deficiency shifts the gut-liver bile acid axis and induces hepatic alterations in mice.
β-Klotho (encoded by Klb) is an obligate coreceptor, mediating both fibroblast growth factor (FGF)15 and FGF21 signaling. Klb-/- mice are refractory to metabolic FGF15 and FGF21 action and exhibit derepressed (increased) bile acid (BA) synthesis. Here, we deeply phenotyped male Klb-/- mice on a pure C57BL/6J genetic background, fed a chow diet focusing on metabolic aspects. This aims to better understand the physiological consequences of concomitant FGF15 and FGF21 signaling deficiency, in particular on the gut-liver axis. Klb-/- mice present permanent growth restriction independent of adiposity and energy balance. Klb-/- mice also exhibit few changes in carbohydrate metabolism, combining normal gluco-tolerance, insulin sensitivity, and fasting response with increased gluconeogenic capacity and decreased glycogen mobilization. Livers of Klb-/- mice reveal pathologic features, including a proinflammatory status and initiation of fibrosis. These defects are associated to a massive shift in BA composition in the enterohepatic system and blood circulation featured by a large excess of microbiota-derived deoxycholic acid, classically known for its genotoxicity in the gastrointestinal tract. In conclusion, β-Klotho is a gatekeeper of hepatic integrity through direct action (mediating FGF21 anti-inflammatory signaling) and indirect mechanisms (mediating FGF15 signaling that maintains BA level and composition).


Use of the Leksell Gamma Knife for localized small field lens irradiation in rodents.
For most basic radiobiological research applications involving irradiation of small animals, it is difficult to achieve the same high precision dose distribution realized with human radiotherapy. The precision for irradiations performed with standard radiotherapy equipment is +/-2 mm in each dimension, and is adequate for most human treatment applications. For small animals such as rodents, whose organs and tissue structures may be an order of magnitude smaller than those of humans, the corresponding precision required is closer to +/-0.2 mm, if comparisons or extrapolations are to be made to human data. The Leksell Gamma Knife is a high precision radiosurgery irradiator, with precision in each dimension not exceeding 0.5 mm, and overall precision of 0.7 mm. It has recently been utilized to treat ocular melanoma and induce targeted lesions in the brains of small animals. This paper describes the dosimetry and a technique for performing irradiation of a single rat eye and lens with the Gamma Knife while allowing the contralateral eye and lens of the same rat to serve as the "control". The dosimetry was performed with a phantom in vitro utilizing a pinpoint ion chamber and thermoluminescent dosimeters, and verified by Monte Carlo simulations. We found that the contralateral eye received less than 5% of the administered dose for a 15 Gy exposure to the targeted eye. In addition, after 15 Gy irradiation 15 out of 16 animals developed cataracts in the irradiated target eyes, while 0 out of 16 contralateral eyes developed cataracts over a 6-month period of observation. Experiments at 5 and 10 Gy also confirmed the lack of cataractogenesis in the contralateral eye. Our results validate the use of the Gamma Knife for cataract studies in rodents, and confirmed the precision and utility of the instrument as a small animal irradiator for translational radiobiology experiments.


A model for HIV disclosure of a parent's and/or a child's illness.
HIV prevalence in Kenya remains steady at 5.6% for adults 15 years and older, and 0.9% among children aged below 14 years. Parents and children are known to practice unprotected sex, which has implications for continued HIV spread within the country. Additionally, due to increased accessibility of antiretroviral therapy, more HIV-positive persons are living longer. Therefore, the need for HIV disclosure of a parent's and/or a child's HIV status within the country will continue for years to come. We conducted a qualitative phenomenological study to understand the entire process of disclosure from the time of initial HIV diagnosis of an index person within an HIV-affected family, to the time of full disclosure of a parent's and/or a child's HIV status to one or more HIV-positive, negative, or untested children within these households. Participants were purposively selected and included 16 HIV-positive parents, seven HIV-positive children, six healthcare professionals (physician, clinical officer, psychologist, registered nurse, social worker, and a peer educator), and five HIV-negative children. All participants underwent an in-depth individualized semistructured interview that was digitally recorded. Interviews were transcribed and analyzed in NVivo 8 using the modified Van Kaam method. Six themes emerged from the data indicating that factors such as HIV testing, living with HIV, evolution of disclosure, questions, emotions, benefits, and consequences of disclosure interact with each other and either impede or facilitate the HIV disclosure process. Kenya currently does not have guidelines for HIV disclosure of a parent's and/or a child's HIV status. HIV disclosure is a process that may result in poor outcomes in both parents and children. Therefore, understanding how these factors affect the disclosure process is key to achieving optimal disclosure outcomes in both parents and children. To this end, we propose an HIV disclosure model incorporating these six themes that is geared at helping healthcare professionals provide routine, clinic-based, targeted, disclosure-related counseling/advice and services to HIV-positive parents and their HIV-positive, HIV-negative, and untested children during the HIV disclosure process. The model should help improve HIV disclosure levels within HIV-affected households. Future researchers should test the utility and viability of our HIV disclosure model in different settings and cultures.


Hypoxia inducible factor (HIF-1a and HIF-2a) expression in early esophageal cancer and response to photodynamic therapy and radiotherapy.
Hypoxia inducible factor 1a and 2a (HIF-1a and HIF-2a) are key proteins regulating cellular response to hypoxia. Because the efficacy of photodynamic therapy (PDT) is dependent on the presence of oxygen, the assessment of HIF-1a and HIF-2a expression may be of value in predicting clinical response to PDT. Using recently produced MoAbs, we examined the expression of HIF1a and HIF2a in a series of 37 early-stage esophageal cancers treated with PDT and with additional radiotherapy in case of incomplete response after PDT. Strong expression of the HIF1a and of HIF2a proteins in all optical fields examined was noted in 51% and in 13% of cases, respectively. High expression was associated with a low complete response (CR) rate and with the absence of bcl-2 protein expression. On the contrary, bcl-2 expression was associated with a high CR rate. Combined analysis of HIF1a and bcl-2 protein expression revealed that of 16 cases with high HIF1a expression and the absence of bcl-2 reactivity, only 1 (7%) responded completely to PDT (P = 0.007). Bivariate analysis showed that HIF1a expression was independently related to response to PDT (P = 0.04; t ratio = 2.8), whereas bcl-2 approached significance (P = 0.07; t-ratio = 1.8). The final response to radiotherapy was high (70%) and independent of the HIF and bcl-2 status, which may be a result of reoxygenation after cellular depletion mediated by PDT. The present study suggests that assessment of HIF and of bcl-2 expression are important predictors of in vivo sensitivity to PDT. Modulation of PDT response with bioreductive drugs and/or drugs targeting bcl-2 (i.e., taxanes) may prove of significant therapeutic importance in a subgroup of patients with high HIF expression.


A method for quantifying cellular uptake of fluorescently labeled siRNA.
Efficient intracellular delivery of siRNA is a significant hurdle to its therapeutic success. For biological studies on the efficiency of carrier-mediated uptake of siRNA, quantitative determination of the amount of internalized siRNA is required. In this study, when the apparent uptake of fluorescently labeled siRNA, formulated in different lipo- and polyplexes, was examined using different techniques, major differences were observed. Additional experiments showed that these differences could be explained by quenching phenomena that were dependent on interactions between siRNA and carrier and their intracellular environment. Differences in fluorescent signal of complexed siRNA due to quenching could be overcome by measuring the fluorescent signal after lysing the transfected cells in lysis buffer that contained 2% SDS to dissociate siRNA from the complexes. This method offers a simple approach for quantifying cellular uptake of siRNA, which might help in the development of more efficient delivery systems.


Development of hospital-based guidelines for skeletal survey in young children with bruises.
To develop guidelines for performing an initial skeletal survey (SS) for children <24 months of age presenting with bruising in the hospital setting, combining available evidence with expert opinion. Applying the Rand/UCLA Appropriateness Method, a multispecialty panel of 10 experts relied on evidence from the literature and their own clinical expertise in rating the appropriateness of performing SS for 198 clinical scenarios characterizing children <24 months old with bruising. After a moderated discussion of initial ratings, the scenarios were revised. Panelists re-rated SS appropriateness for 219 revised scenarios. For the 136 clinical scenarios in which SS was deemed appropriate, the panel finally assessed the necessity of SS. Panelists agreed that SS is "appropriate" for 62% (136/219) of scenarios, and "inappropriate" for children ≥ 12 months old with nonpatterned bruising on bony prominences. Panelists agreed that SS is "necessary" for 95% (129/136) of the appropriate scenarios. SS was deemed necessary for infants <6 months old regardless of bruise location, with rare exceptions, but the necessity of SS in older children depends on bruise location. According to the panelists, bruising on the cheek, eye area, ear, neck, upper arm, upper leg, hand, foot, torso, buttock, or genital area necessitates SS in children <12 months. The appropriateness and necessity of SS in children presenting for care to the hospital setting with bruising, as determined by a diverse panel of experts, depends on age of the child and location of bruising.


Individual and contextual factors related to family practice residents' assessment and counseling for tobacco cessation.
Tobacco use is the chief avoidable cause of death in the United States. Physicians, however, are not routinely assessing this risk and providing counseling for risk reduction. This study examines tobacco cessation counseling practices among family practice residents and explores the determinants of residents' smoking-counseling behaviors and counseling duration. One hundred ten family practice residents (response rate = 93.2%) from four Texas residency training programs completed a survey designed to assess tobacco cessation counseling practices. A high proportion of residents reported that they usually or always assessed tobacco use (59.3%) and advised their patients to quit smoking (80.9%), with a lower proportion reporting specific counseling behaviors (7.3% - 21.9%), referrals (1.8%), or follow-up visits (1.8%). Year of residency, perceived effectiveness, and the interaction between perceived effectiveness and residency year were significantly associated with number of counseling behaviors, and year of residency and perceived effectiveness were significantly associated with counseling duration. Faculty physicians should assist residents to implement the Public Health Service-sponsored clinical practice guideline for tobacco control. There is a need to increase behavioral skills and perceived effectiveness for assessing and counseling smokers among first-year residents.


The effects of heat shock on the morphology and protein synthesis of the epidermis of Xenopus laevis larvae.
By scanning electron microscopy, we have observed that a 20-min heat shock at 37 degrees C, although not lethal, causes extensive damage to the epidermis of 30-h and 2-d (post-fertilization) Xenopus laevis larvae. The primary effects of heat shock are the apical swelling of the epidermal cells, giving the epidermis a "cobblestone" appearance, and the selective shedding of the ciliated cells. The shed cells may be cell fragments, however, because some of them are anucleate. Shed cells also exhibit the enriched synthesis of a group of heat shock proteins of 62,000 D molecular weight, suggesting that these proteins are specific to the shed cells. Prolonged heat shock of these larvae (i.e., 30 min at 37 degrees C) results in the complete disintegration of the epidermis, followed by larval death. At later stages of development (3-d and 4-d post-fertilization), the epidermis becomes more resistant to heat-induced damage inflicted by a 20-min heat shock. This increase in resistance coincides with the development of large secretory cells and the loss of ciliated cells in the epidermis and thus parallels a change in the state of histological differentiation.


Iridium(iii) hydrido complexes for the catalytic dehydrogenation of hydrazine borane.
The synthesis of 3,5-disubstituted cyclometalated iridium(iii) hydrido complexes of the type [3,5-R2(POCOP)IrHX] (3,5-R2(POCOP) = κ3-C5HR2-2,6-(OPtBu2)2 with R = t-Bu, COOMe; X = Cl, H) is described. All complexes were investigated in the catalytic dehydrogenation of hydrazine borane and compared with the unsubstituted compounds [(POCOP)IrHX] (X = Cl, H). All catalysts are highly active and recyclable, clearly maintaining hydrogen production activity. The dehydrogenation products were structurally characterised by solid state NMR and FTIR spectroscopy. Experimental observations were complemented by a dispersion-corrected DFT study to rationalise the mechanism of hydrazine borane dehydrogenation.


Optical superheterodyne receiver.
Optical communications experiments at 6328 A, comparing the fading characteristics of coherent and noncoherent optical detection, have been performed over a 1-km real atmospheric path in different weather conditions. The results show that fading is less severe for noncoherent detection and that the fading characteristic for both types vary significantly with weather conditions. In addition, the similarity of optical FM to rf FM is demonstrated. The measurements were performed using a remote laser transmitter and an optical superheterodyne receiver operating simultaneously in both a coherent and noncoherent detection mode. The receiver, tunable over a frequency range of 1 GHz at the IF difference frequency of 30 MHz, has automatic frequency control and also uses a precision angle tracking servo to maintain receiver spatial alignment with a remote transmitter. The angle and frequency tracking capability permit operation between moving transmitter and receiver terminals.


Progenetix.net: an online repository for molecular cytogenetic aberration data.
Through sequencing projects and, more recently, array-based expression analysis experiments, a wealth of genetic data has become accessible via online resources. In contrast, few of the (molecular-) cytogenetic aberration data collected in the last decades are available in a format suitable for data mining procedures. www.progenetix.net is a new online repository for previously published chromosomal aberration data, allowing the addition of band-specific information about chromosomal imbalances to oncologic data analysis efforts. http://www.progenetix.net firstname.lastname@example.com


Human serum albumin adsorption study on 62-MHz miniaturized quartz gravimetric sensors.
We have designed and fabricated 25-microm-thick quartz resonators operating at a fundamental resonance frequency of approximately 62 MHz. The results show a substantial increase in the mass sensitivity compared to single monolithic commercial resonators operating at lower frequencies in the approximately 5-10-MHz range. The overall performance of the micromachined resonators is demonstrated for the example of human serum albumin protein adsorption from aqueous buffer solutions onto gold electrodes functionalized with self-assembled monolayers. The results show a saturation adsorption frequency change of 6.8 kHz as opposed to 40 Hz for a commercial approximately 5-MHz sensor under identical loading conditions. From the analysis of the adsorption isotherm, the equilibrium adsorption constant of the adsorption of the protein layer was found to be K = 8.03 x 10(6) M(-1), which is in agreement with the values reported in the literature. The high sensitivity of the miniaturized QCM devices can be a significant advantage in both vapor and solution adsorption analyses.


Time-frequency analysis of the ECG in the diagnosis of vasovagal syndrome in older people.
The Smoothed Pseudo Wigner-Ville Distribution (SPWVD) is used for the time-frequency analysis of variations in RR interval. A novel technique to determine the smoothing window lengths is implemented, and a new heart rate variability (HRV) metric is developed, instantaneous center frequency variability (ICFV), which uses the time-frequency map generated by the SPWVD. The technique is then applied to 50 patients with unexplained falls and age > 60, undergoing head-upright tilt table testing (HUT). Eighteen of the patients were diagnosed with vasovagal syndrome. Attempts at syncope prediction using the new metric is an improvement on traditional techniques: an ICFV less than 0.07 Hz from 90 s to 180 s after tilt is predictive of a negative test (negative predictive value: 0.77). The comorbidity and autonomic degeneration present in elderly patients are thought to be responsible for lowering the negative predictive value.


Signal decomposition for X-ray dark-field imaging.
Grating-based X-ray dark-field imaging is a new imaging modality. It allows the visualization of structures at micrometer scale due to small-angle scattering of the X-ray beam. However, reading darkfield images is challenging as absorption and edge-diffraction effects also contribute to the dark-field signal, without adding diagnostic value. In this paper, we present a novel--and to our knowledge the first--algorithm for isolating small-angle scattering in dark-field images, which greatly improves their interpretability. To this end, our algorithm utilizes the information available from the absorption and differential phase images to identify clinically irrelevant contributions to the dark-field image. Experimental results on phantom and ex-vivo breast data promise a greatly enhanced diagnostic value of dark-field images.


A gamma34.5 mutant of herpes simplex 1 causes severe inflammation in the brain.
A number of viral vectors are currently being evaluated as potential gene therapy vectors for gene delivery to the brain. As well as evaluating their ability to express a transgene for extended periods of time it is also essential to examine any cytotoxic immune response to such vectors as this may not only limit transgene expression but also cause irreparable harm. This work describes the effect of inoculating a gamma34.5 mutant of herpes simplex type 1 (1716lacZ) into the brain of different strains of rats and mice. Animals were monitored for weight loss and signs of illness, and their brains were evaluated for inflammation, beta-galactosidase expression and recoverable infectious virus. We report that there is (i) a powerful immune response consisting of an early non-specific phase and a later presumably T-cell-mediated phase; (ii) significant weight loss in some animals strains accompanied by severe signs of clinical illness and (iii) transient reporter gene expression in all animal strains examined. To be useful for gene therapy we suggest this virus requires further modification, it should be tested in several animal strains and the dose of virus used may be critical in order to limit damage.


The DRD2 TaqI-B polymorphism and its relationship to smoking abstinence and withdrawal symptoms.
The dopamine receptor D2 (DRD2) gene has polymorphisms that have been linked to regulation of the dopamine system and to an increased prevalence of smoking. The present study examined the relationship of the DRD2 TaqI-A and -B polymorphisms with short-term clinical outcome (abstinence and withdrawal symptoms), collected from daily (14 pre-quit and 42 post-quit) diary data among smokers (n=116) treated with the nicotine patch plus either venlafaxine or placebo. The results showed that B1/B1 or B1/B2 smokers were slightly less likely to be abstinent on a given day than those homozygous for the TaqI-B2 allele. Significant DRD2 TaqI-B x time interactions were found for several of the withdrawal scales, indicating that those smokers with the B1/B1 or B1/B2 genotypes tended to report more symptoms over time compared to those with the B2/B2 genotype. No interactions or main effects were found for the DRD2 TaqI-A polymorphism. The findings demonstrate that smokers homozygous for the TaqI-B2 allele experience progressive improvement in self-reported withdrawal symptoms while smokers with the TaqI-B1 allele showing little change.


Parents' Perceived Satisfaction of Care, Communication and Environment of the Pediatric Intensive Care Units at a Tertiary Children's Hospital.
This study aims to identify parental perceptions on pediatric intensive care-related satisfaction within three domains: environment, child's care provided and communication. In addition, it aims to identify whether parent's socio-demographics and child's clinical variables predict parents' perceived satisfaction. In this study, a total of 123 parents whose child received care in the PICU of a tertiary children's hospital in Amman completed the Arabic version of the parents satisfaction survey (PSS). A cross-sectional, descriptive-correlational design was used to collect data. All data were collected between June and October of 2013. Central tendency measures and percentages of replies for each domain revealed that at least 7 items were rated poorly satisfied. More than half of the parents were not satisfied with the noise level of the PICU, the time nurses spent at the child's bedside, as well as the way the healthcare team prepare them for the child's admission. Almost 90% of the parents believed that the nurses ignored their child's needs by not listening to parents and by responding slowly to child's needs. Stepwise regression analysis showed that that the number of hospital admissions, health insurance and the severity of illness was the main predictor of parents' satisfaction. In conclusion, the availability of health care professionals, the support and the information they share with the child's parents are all significant to parent's satisfaction and hence to better quality of care. Targeting the domains of low satisfaction reported by the parents could increase parent's satisfaction and achieve quality improvement required for this population.


Methicillin-resistant Staphylococcus aureus in extended-care facilities: experiences in a Veterans' Affairs nursing home and a review of the literature.
To delineate the spread of methicillin-resistant Staphylococcus aureus (MRSA) in a nursing home care unit (NHCU), determine its consequences, and discuss this experience in the context of reports from other nursing homes. Observational and descriptive; routine and special surveillance for MRSA, including a facility-wide prevalence survey; characterization of MRSA isolates by disk diffusion and agar dilution susceptibility studies and restriction enzyme analysis of plasmid (REAP) DNA. A 120-bed skilled nursing facility that is an integral part of the Veterans' Affairs Medical Center (VAMC), Portland, Oregon. The patients are predominantly elderly men with severe underlying diseases and functional impairments. An asymptomatic carrier brought MRSA into the NHCU in December 1987. During the next 15 months, 24 additional MRSA cases were detected. A prevalence survey conducted in March 1989 indicated that 39 (34%) of the 114 patients and 8 (7%) of the 117 employees were colonized or infected with MRSA. All strains were resistant to ciprofloxacin. REAP DNA indicated that 37 of 41 strains recovered in the March survey had identical patterns. Although 16 episodes of MRSA infection occurred in NHCU residents during 1988 through 1989, the outbreak had little effect on overall patterns of infectious morbidity and mortality in the facility. The outbreak, however, did result in an increased MRSA caseload at the medical center's acute-care division. During the last three years, MRSA colonization and infection have become common in the NHCU at the Portland VAMC; this experience parallels that reported by several nursing homes in other parts of the country.


Pattern of inbreeding depression, condition dependence, and additive genetic variance in Trinidadian guppy ejaculate traits.
In polyandrous species, a male's reproductive success depends on his fertilization capability and traits enhancing competitive fertilization success will be under strong, directional selection. This leads to the prediction that these traits should show stronger condition dependence and larger genetic variance than other traits subject to weaker or stabilizing selection. While empirical evidence of condition dependence in postcopulatory traits is increasing, the comparison between sexually selected and 'control' traits is often based on untested assumption concerning the different strength of selection acting on these traits. Furthermore, information on selection in the past is essential, as both condition dependence and genetic variance of a trait are likely to be influenced by the pattern of selection acting historically on it. Using the guppy (Poecilia reticulata), a livebearing fish with high levels of multiple paternity, we performed three independent experiments on three ejaculate quality traits, sperm number, velocity, and size, which have been previously shown to be subject to strong, intermediate, and weak directional postcopulatory selection, respectively. First, we conducted an inbreeding experiment to determine the pattern of selection in the past. Second, we used a diet restriction experiment to estimate their level of condition dependence. Third, we used a half-sib/full-sib mating design to estimate the coefficients of additive genetic variance (CVA) underlying these traits. Additionally, using a simulated predator evasion test, we showed that both inbreeding and diet restriction significantly reduced condition. According to predictions, sperm number showed higher inbreeding depression, stronger condition dependence, and larger CVA than sperm velocity and sperm size. The lack of significant genetic correlation between sperm number and velocity suggests that the former may respond to selection independently one from other ejaculate quality traits. Finally, the association between sperm number and condition suggests that this trait may mediate the genetic benefits of polyandry which have been shown in this species.


The role of spatial interactions in perceptual synchrony.
To understand how the visual system processes synchronies between visual patterns, we investigated the temporal acuity for detecting a Gabor pattern whose orientation was alternated (vertical-horizontal) in a different temporal phase from three other Gabor patterns. Thresholds of both advanced and lagged temporal-phase offsets were measured for various temporal frequencies of orientation alternation and for various spatial distances between Gabor patterns. The thresholds for advanced phase offsets were lower than those for lagged phase offsets; the target pattern whose orientation changed earlier than the others was easier to detect than the target whose orientation changed later by the same amount. It was found that the amount of this temporal asymmetry increased proportionally with the distance between patterns. The upper temporal-frequency limit of orientation alternation for detecting the target pattern also systematically decreased with the distance between patterns. These results were interpreted as reflecting the temporal dynamics of mutual interactions between local orientation detectors, which necessarily involve a greater degree of temporal blur and longer delays of interacting signals as the spatial distance between detectors increases. This explanation leads to the notion that perceptual synchrony between visual patterns is determined in a space-time relative manner.


In vivo effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in rodents: Drug discrimination and thermoregulation.
Recent clinical studies support the use of 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct treatment for posttraumatic stress disorder (PTSD). Despite these promising findings, MDMA administration in controlled settings can increase blood pressure, heart rate, and body temperature. Previous studies indicate thatO-demethylated metabolites of MDMA contribute to its adverse effects. As such, limiting the conversion of MDMA to reactive metabolites may mitigate some of its adverse effects and potentially improve its safety profile for therapeutic use. We compared the interoceptive and hyperthermic effects of a deuterium-substituted form of MDMA (d2-MDMA) to MDMA using rodent drug discrimination and biotelemetry procedures, respectively. Compared to MDMA, d2-MDMA produced full substitution for a 1.5 mg/kg MDMA training stimulus with equal potency and effectiveness in the drug discrimination experiment. In addition, d2-MDMA produced increases in body temperature that were shorter-lasting and of lower magnitude compared to equivalent doses of MDMA. Last, d2-MDMA and MDMA were equally effective in reversing the hypothermic effects of the selective 5-HT2A/2C antagonist ketanserin. These findings indicate that deuterium substitution of hydrogen at the methylenedioxy ring moiety does not impact MDMA's interoceptive effects, and compared to MDMA, d2-MDMA has less potential for producing hyperthermic effects and likely has similar pharmacodynamic properties. Given that d2-MDMA produces less adverse effects than MDMA, but retains similar desirable effects that are thought to relate to the effective treatment of PTSD, additional investigations into its effects on cardiovascular functioning and pharmacokinetic properties are warranted.


Severe acute exacerbation of chronic hepatitis B during pegylated interferon treatment and early intervention with corticosteroid.
Severe acute exacerbation or liver failure induced by standard interferon-α(IFN-α) therapy had been reported to occur in few patients with chronic hepatitis B. However, no report showed that pegylated interferon-α therapy was able to induce severe acute exacerbation of chronic hepatitis B. Here, we describe three patients with severe acute exacerbation of chronic hepatitis B during pegylated interferon-α2a (Pegasys) treatment. One patient progressed into acute-on-chronic liver failure (ACLF) at the second week of Pegasys treatment. Two patients progressed into acute-on-chronic pre-liver failure (pre-ACLF) at the second and eighth week of Pegasys treatment, respectively. Three patients recovered after early combined intervention with corticosteroid and lamivudine. Our data indicated that there was a risk of severe acute exacerbation among patients with chronic hepatitis B during receiving Pegasys treatment. Importantly, early combined intervention with corticosteroid and lamivudine should be introduced to prevent the disease progression and improve their prognosis once severe acute exacerbation was diagnosed.


Differences in heart rate reserve of similar physical activities during work and in leisure time - A study among Danish blue-collar workers.
Recent studies suggest that while leisure-time physical activity (LTPA) promotes general health, engaging in occupational physical activity (OPA) may have negative health consequences. It has been hypothesized that the different health effects from OPA and LTPA can be explained by differences in physical activity (PA) intensity in these two domains. To assess the intensity of OPA and LTPA, we aimed to study the percentage heart rate reserve (%HRR) during similar types of OPA and LTPA during workdays. Data from the NOMAD study on Danish blue-collar workers (n=124) with objective measurements of PA (using accelerometers) and heart rate (using heart rate monitors) for 4 workdays were analysed. Activities of sitting, standing, moving, walking, and stair climbing were identified and %HRR in each of these activities was determined for work and leisure. %HRR was significantly higher during OPA than LTPA. These differences were more pronounced in men than in women. Although not statistically significant in the fully adjusted model, we found indications that these differences were more pronounced in those with low compared to high fitness. To our knowledge, this is the first study with objective measurements showing that %HRR is higher during the same gross-body postural activities when performed at work compared to leisure-time during workdays. This elevated intensity may help explaining the negative health consequences of engagement in high levels of OPA. Future guidelines should distinguish OPA from LTPA, possibly by advising workers to remain active during their leisure time, in particular when they are highly active at work.


Cu²⁺ accentuates distinct misfolding of Aβ₁₋₄₀ and Aβ₁₋₄₂ peptides, and potentiates membrane disruption.
Central to Alzheimer's disease is the misfolding of amyloid-beta (Aβ) peptide, which generates an assorted population of amorphous aggregates, oligomers and fibres. Metal ion homoeostasis is disrupted in the brains of sufferers of Alzheimer's disease and causes heightened Alzheimer's disease phenotype in animal models. In the present study, we demonstrate that substochiometric Cu²⁺ affects the misfolding pathway of Aβ₁₋₄₀, and the more toxic Aβ₁₋₄₂, in markedly different ways. Cu²⁺ accelerates Aβ₁₋₄₀ fibre formation. In contrast, for Aβ₁₋₄₂, substoichiometric levels of Cu²⁺ almost exclusively promote the formation of oligomeric and protofibrillar assemblies. Indeed, mature Aβ₁₋₄₂ fibres are disassembled into oligomers when Cu²⁺ is added. These Cu²⁺ stabilized oligomers of Aβ₁₋₄₂ interact with the lipid bilayer, disrupting the membrane and increasing permeability. Our investigation of Aβ₁₋₄₀/Aβ₁₋₄₂ mixtures with Cu²⁺ revealed that Aβ₁₋₄₀ neither contributed to nor perturbed formation of Aβ₁₋₄₂ oligomers, although Cu²⁺-Aβ₁₋₄₂ does frustrate Cu²⁺-Aβ₁₋₄₀ fibre growth. Small amounts of Cu²⁺ accentuate differences in the propensity of Aβ₁₋₄₀ and Aβ₁₋₄₂ to form synaptotoxic oligomers, providing an explanation for the connection between disrupted Cu²⁺ homoeostasis and elevated Aβ₁₋₄₂ neurotoxicity in Alzheimer's disease.


On my own terms: Motivations for self-treating opioid-use disorder with non-prescribed buprenorphine.
The opioid overdose crisis in the United States has prompted an expansion of treatment services, including pharmacotherapy with buprenorphine. However, many people who use illicit opioids (PWUIO) self-treat their opioid-use disorder (OUD) with non-prescribed buprenorphine (NPB) in lieu of attending formal treatment. The present study aims to qualitatively understand motivations of people who are self-treating their OUD with NPB. Qualitative study designed to supplement and contextualize quantitative findings from natural history study of buprenorphine diversion, self-treatment, and use of substance use disorder treatment services. Interviews were audio-recorded, transcribed, systematically coded and analyzed via Iterative Categorization. The Dayton, Ohio metropolitan area in the midwestern United States; a site previously characterized as high impact in the national opioid overdose crisis. Sixty-five individuals (35 men and 30 women) who met the DSM-5 criteria for OUD (moderate or severe) and had used NPB at least one time in the six months prior to their intake interview. Participants described four key motivators for self-treating with NPB: perceived demands of formal treatment, the desire to utilize non-prescribed buprenorphine in combination with a geographic relocation, to self-initiate treatment while preparing for formal services, and to bolster a sense of self-determination and agency in their recovery trajectory. Use of NPB is a recognized self-treatment modality among PWUIO, with some PWUIO transitioning into sustained recovery episodes or enrollment in formal treatment. Understanding the motivations for opting out of treatment is crucial for improving forms of care for people with OUD.


Copy-when-uncertain: bumblebees rely on social information when rewards are highly variable.
To understand the relative benefits of social and personal information use in foraging decisions, we developed an agent-based model of social learning that predicts social information should be more adaptive where resources are highly variable and personal information where resources vary little. We tested our predictions with bumblebees and found that foragers relied more on social information when resources were variable than when they were not. We then investigated whether socially salient cues are used preferentially over non-social ones in variable environments. Although bees clearly used social cues in highly variable environments, under the same conditions they did not use non-social cues. These results suggest that bumblebees use a 'copy-when-uncertain' strategy.


Gain-of-function mutation of microRNA-140 in human skeletal dysplasia.
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders1-5, but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia. Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice6. This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects. In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects. Furthermore, the mutant miR-140-5p seed competes with the conserved RNA-binding protein Ybx1 for overlapping binding sites. This finding may explain the potent target repression and robust in vivo effect by this mutant miRNA even in the absence of evolutionary selection of miRNA-target RNA interactions, which contributes to the strong regulatory effects of conserved miRNAs7,8. Our study presents the first case of a pathogenic gain-of-function miRNA mutation and provides molecular insight into neomorphic actions of emerging and/or mutant miRNAs.


Regulation and flexibility of genomic imprinting during seed development.
Genomic imprinting results in monoallelic gene expression in a parent-of-origin-dependent manner. It is achieved by the differential epigenetic marking of parental alleles. Over the past decade, studies in the model systems Arabidopsis thaliana and maize (Zea mays) have shown a strong correlation between silent or active states with epigenetic marks, such as DNA methylation and histone modifications, but the nature of the primary imprint has not been clearly established for all imprinted genes. Phenotypes and expression patterns of imprinted genes have fueled the perception that genomic imprinting is specific to the endosperm, a seed tissue that does not contribute to the next generation. However, several lines of evidence suggest a potential role for imprinting in the embryo, raising questions as to how imprints are erased and reset from one generation to the next. Imprinting regulation in flowering plants shows striking similarities, but also some important differences, compared with the mechanisms of imprinting described in mammals. For example, some imprinted genes are involved in seed growth and viability in plants, which is similar in mammals, where imprinted gene regulation is essential for embryonic development. However, it seems to be more flexible in plants, as imprinting requirements can be bypassed to allow the development of clonal offspring in apomicts.


Workshop 6 (synthesis): linking between flood risks and land use changes.
Land use changes, such as deforestation, are increasing the world's vulnerability to flooding. Detailed knowledge of the local situation is essential for risk assessment and design of effective flood prevention measures and governs the infrastructure and engineering measures implemented. However extreme floods in large catchments can overwhelm both natural capacity and constructed flood management measures.


Changes in uncoupling protein and GLUT4 glucose transporter expressions in interscapular brown adipose tissue of diabetic rats: relative roles of hyperglycaemia and hypoinsulinaemia.
We have studied the time course and relative effects of hypoinsulinaemia and hyperglycaemia on concentrations of uncoupling protein (UCP) and glucose transporter (GLUT4) and their mRNAs in brown adipose tissue (BAT) during the early phase of diabetes induced by streptozotocin. Two days after intravenous injection of streptozotocin, plasma insulin concentration was at its lowest and glycaemia was higher than 22 mmol/l. After 3 days, a 60% decrease in BAT UCP mRNA concentration and a 36% decrease in UCP was observed. Concomitantly, there was an 80% decrease in GLUT4 mRNA and a 44% decrease in GLUT4 levels. When hyperglycaemia was prevented by infusing phlorizin into diabetic rats, BAT UCP mRNA and protein levels were further decreased (respectively 90% and 60% lower than in control rats). In contrast, the marked decreases in GLUT4 mRNA and protein concentrations in BAT were similar in hyperglycaemic and normoglycaemic diabetic rats. Infusion of physiological amounts of insulin restored normoglycaemia in diabetic rats, and BAT UCP and GLUT4 mRNA and protein concentrations were maintained at the level of control rats. When insulin infusion was stopped, a 75% decrease in BAT UCP mRNA level and a 75% decrease in GLUT4 mRNA level were observed after 24 h, but UCP and GLUT4 concentrations did not decrease. This study shows that insulin plays an important role in the regulation of UCP and GLUT4 mRNA and protein concentrations in BAT. Hyperglycaemia partially prevents the rapid decrease in concentration of UCP and its mRNA observed in insulinopenic diabetes whereas it did not affect the decrease in GLUT4 mRNA and protein concentration. It is suggested that UCP is produced by a glucose-dependent gene.


Characterization of a silicon transporter gene family in Cylindrotheca fusiformis: sequences, expression analysis, and identification of homologs in other diatoms.
The transport of silicon is an integral part of the synthesis of the silicified cell wall of diatoms, yet knowledge of the number, features, and regulation of silicon transporters is lacking. We report the isolation and sequence determination of five silicon transporter (SIT) genes from Cylindrotheca fusiformis, and examine their expression patterns during cell wall synthesis. The encoded SIT amino acid sequences are highly conserved in their putative transmembrane domains. Nine conserved cysteines in this domain may account for the sensitivity of silicon uptake to sulfhydryl blocking agents. A less conserved C-terminal domain is predicted to form coiled-coil structures, suggesting that the SITs interact with other proteins. We show that SIT gene expression is induced just prior to, and during, cell wall synthesis. The genes are expressed at very different levels, and SIT1 is expressed in a different pattern from SIT 2-5. Hybridization experiments show that multiple SIT gene copies are present in all diatom species tested. From the data we infer that individual transporters play specific roles in silicon uptake, and propose that the cell regulates uptake by controlling the amount or location of each. The identification of all SIT genes in C. fusiformis will enhance our understanding of the mechanism and control of silicon transport in diatoms.


Host-Derived Sialic Acids Are an Important Nutrient Source Required for Optimal Bacterial Fitness In Vivo.
A major challenge facing bacterial intestinal pathogens is competition for nutrient sources with the host microbiota.Vibrio cholerae is an intestinal pathogen that causes cholera, which affects millions each year; however, our knowledge of its nutritional requirements in the intestinal milieu is limited. In this study, we demonstrated that V. cholerae can grow efficiently on intestinal mucus and its component sialic acids and that a tripartite ATP-independent periplasmic SiaPQM strain, transporter-deficient mutant NC1777, was attenuated for colonization using a streptomycin-pretreated adult mouse model. In in vivo competition assays, NC1777 was significantly outcompeted for up to 3 days postinfection. NC1777 was also significantly outcompeted in in vitro competition assays in M9 minimal medium supplemented with intestinal mucus, indicating that sialic acid uptake is essential for fitness. Phylogenetic analyses demonstrated that the ability to utilize sialic acid was distributed among 452 bacterial species from eight phyla. The majority of species belonged to four phyla, Actinobacteria (members of Actinobacillus, Corynebacterium, Mycoplasma, and Streptomyces), Bacteroidetes (mainly Bacteroides, Capnocytophaga, and Prevotella), Firmicutes (members of Streptococcus, Staphylococcus, Clostridium, and Lactobacillus), and Proteobacteria (including Escherichia, Shigella, Salmonella, Citrobacter, Haemophilus, Klebsiella, Pasteurella, Photobacterium, Vibrio, and Yersinia species), mostly commensals and/or pathogens. Overall, our data demonstrate that the ability to take up host-derived sugars and sialic acid specifically allows V. cholerae a competitive advantage in intestinal colonization and that this is a trait that is sporadic in its occurrence and phylogenetic distribution and ancestral in some genera but horizontally acquired in others. Sialic acids are nine carbon amino sugars that are abundant on all mucous surfaces. The deadly human pathogen Vibrio cholerae contains the genes required for scavenging, transport, and catabolism of sialic acid. We determined that the V. cholerae SiaPQM transporter is essential for sialic acid transport and that this trait allows the bacterium to outcompete noncatabolizers in vivo. We also showed that the ability to take up and catabolize sialic acid is prevalent among both commensals and pathogens that colonize the oral cavity and the respiratory, intestinal, and urogenital tracts. Phylogenetic analysis determined that the sialic acid catabolism phenotype is ancestral in some genera such as Yersinia, Streptococcus, and Staphylococcus and is acquired by horizontal gene transfer in others such as Vibrio, Aeromonas, and Klebsiella. The data demonstrate that this trait has evolved multiple times in different lineages, indicating the importance of specialized metabolism to niche expansion.


Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System: Pressing Needs and Best Research Practices.
The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19-severe acute respiratory syndrome coronavirus 2-gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1-7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1-7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.


Patient characteristics, treatment patterns, and mortality in elderly patients newly diagnosed with ALL.
To describe patient characteristics and treatment patterns among elderly patients (≥66 years) newly diagnosed with acute lymphoblastic leukemia (ALL), we analyzed 100% Medicare ALL data from 2007 to 2015. Only 764 out of 1428 (53.5%) elderly patients received treatment within 90 d of diagnosis with ≥30-d follow-up; 32.4% received chemotherapy without tyrosine kinase inhibitors (TKIs), 8.8% received both chemotherapy and TKIs, 9.8% received steroids only and 2.6% received TKIs only. Among 717 patients receiving chemotherapy any time during follow-up, 65.8% received only one course of treatment. Patients treated with chemotherapy or TKIs compared to untreated patients were younger (<75 years: 51.5 vs. 21.7%) and had a lower comorbidity burden (Charlson Comorbidity index ≤ 2: 90.9 vs. 71.4%). Overall, 67.5% of patients died within 3 years of diagnosis. Our findings demonstrate that many elderly ALL patients are not treated in the real-world setting and highlight the need for tolerable therapies for these patients.


Using computational fluid dynamics to describe H2S mass transfer across the water-air interface in sewers.
For the past 70 years, researchers have dealt with the investigation of odour in sewer systems caused by hydrogen sulphide formations and the development of approaches to describe it. The state-of-the-art models are one-dimensional. At the same time, flow and transport phenomena in sewers can be three-dimensional, for example the air flow velocities in circular pipes or flow velocities of water and air in the reach of drop structures. Within the past years, increasing computational capabilities enabled the development of more complex models. This paper uses a three-dimensional two-phase computational fluid dynamics model to describe mass transfer phenomena between the two phases: water and air. The solver has been extended to be capable of accounting account for temperature dependency, the influence of pH value and a conversion to describe simulated air phase concentrations as partial pressure. Its capabilities are being explored in different application examples and its advantages compared to existing models are demonstrated in a highly complex three-dimensional test case. The resulting interH2SFoam solver is a significant step in the direction of describing and analysing H2S emissions in sewers.


Communication and common interest.
Explaining the maintenance of communicative behavior in the face of incentives to deceive, conceal information, or exaggerate is an important problem in behavioral biology. When the interests of agents diverge, some form of signal cost is often seen as essential to maintaining honesty. Here, novel computational methods are used to investigate the role of common interest between the sender and receiver of messages in maintaining cost-free informative signaling in a signaling game. Two measures of common interest are defined. These quantify the divergence between sender and receiver in their preference orderings over acts the receiver might perform in each state of the world. Sampling from a large space of signaling games finds that informative signaling is possible at equilibrium with zero common interest in both senses. Games of this kind are rare, however, and the proportion of games that include at least one equilibrium in which informative signals are used increases monotonically with common interest. Common interest as a predictor of informative signaling also interacts with the extent to which agents' preferences vary with the state of the world. Our findings provide a quantitative description of the relation between common interest and informative signaling, employing exact measures of common interest, information use, and contingency of payoff under environmental variation that may be applied to a wide range of models and empirical systems.


Clinical and Genetic Correlates of Bipolar Disorder With Childhood-Onset Attention Deficit Disorder.
Bipolar disorder (BD) with co-occurring attention deficit-hyperactivity disorder (ADHD) is associated with an unfavorable course of illness. We aimed to identify potential clinical and genetic correlates of BD with and without ADHD. Among patients with BD (N = 2,198) enrolled in the Mayo Clinic Bipolar Biobank we identified those with ADHD diagnosed in childhood (BD+cADHD; N = 350), those with adult-onset attention deficit symptoms (BD+aAD; N = 254), and those without ADHD (N = 1,594). We compared the groups using linear or logistic regression adjusting for age, sex, and recruitment site. For genotyped patients (N = 1,443), logistic regression was used to compare ADHD and BD polygenic risk scores (PRSs) between the BD groups, as well as to non-BD controls (N = 777). Compared to the non-ADHD BD group, BD+cADHD patients were younger, more often men and had a greater number of co-occurring anxiety and substance use disorders (all p < 0.001). Additionally, BD+cADHD patients had poorer responses to lithium and lamotrigine (p = 0.005 and p = 0.007, respectively). In PRS analyses, all BD patient subsets had greater genetic risk for BD and ADHD when compared to non-BD controls (p < 0.001 in all comparisons). BD+cADHD patients had a higher ADHD-PRS than non-ADHD BD patients (p = 0.012). However, BD+aAD patients showed no evidence of higher ADHD-PRS than non-ADHD BD patients (p = 0.38). BD+cADHD was associated with a greater number of comorbidities and reduced response to mood stabilizing treatments. The higher ADHD PRS for the BD+cADHD group may reflect a greater influence of genetic factors on early presentation of ADHD symptoms.


Sexual Networks of Racially Diverse Young MSM Differ in Racial Homophily But Not Concurrency.
Substantial racial disparities exist in HIV infection among young men who have sex with men (YMSM). However, evidence suggests black YMSM do not engage in greater levels of risk behavior. Sexual networks may help explain this paradox. This study used egocentric exponential random graph models to examine variation in concurrency (ie, 2 or more simultaneous partners) and homophily (ie, same race/ethnicity partners) across race/ethnicity groups in a diverse sample of YMSM. Data for this study come from a longitudinal cohort study of YMSM. Participants (n = 1012) provided data regarding their sexual contacts during the 6 months before their first study visit. A series of egocentric exponential random graph models examined how providing separate estimates for homophily and concurrency parameters across race/ethnicity improved the fit of these models. Networks were simulated using these parameters to examine how local network characteristics impact risk at the whole network level. Results indicated that homophily, but not concurrency, varied across race/ethnicity. Black participants witnessed significantly higher race/ethnicity homophily compared with white and Latino peers. Extrapolating from these models, black individuals were more likely to be in a connected component with an HIV-positive individual and closer to HIV-positive individuals. However, white individuals were more likely to be in large connected components. These findings suggest that high racial homophily combined with existing disparities in HIV help perpetuate the spread of HIV among black YMSM. Nonetheless, additional work is required to understand these disparities given that homophily alone cannot sustain them indefinitely.


Modelling the treated course of schizophrenia: development of a discrete event simulation model.
In schizophrenia, modelling techniques may be needed to estimate the long-term costs and effects of new interventions. However, it seems that a simple direct link between symptoms and costs does not exist. Decisions about whether a patient will be hospitalized or admitted to a different healthcare setting are based not only on symptoms but also on social and environmental factors. This paper describes the development of a model to assess the dependencies between a broad range of parameters in the treatment of schizophrenia. In particular, the model attempts to incorporate social and environmental factors into the decision-making process for the prescription of new drugs to patients. The model was used to analyse the potential benefits of improving compliance with medication by 20% in patients in the UK. A discrete event simulation (DES) model was developed, to describe a cohort of schizophrenia patients with multiple psychotic episodes. The model takes into account the patient's sex, disease severity, potential risk of harm to self and society, and social and environmental factors. Other variables that change over time include the number of psychiatric consultations, the presence of psychotic episodes, symptoms, treatments, compliance, side-effects, the lack of ability to take care of him/herself, care setting and risk of harm. Outcomes are costs, psychotic episodes and symptoms. Univariate and multivariate sensitivity analyses were performed. Direct medical costs were considered (year of costing 2002), applying a 6.0% discount rate for costs and a 1.5% discount rate for outcome. The timeframe of the model is 5 years. When 50% of the decisions about the patient care setting are based on symptoms, a 20% increase in compliance was estimated to save 16,147 pounds and to avoid 0.55 psychotic episodes per patient over 5 years. Sensitivity analysis showed that the costs savings associated with increased compliance are robust over a range of variations in parameters. DES offers a flexible structure for modelling a disease, taking into account how a patient's history affects the course of the disease over time. This approach is particularly pertinent to schizophrenia, in which treatment decisions are complex. The model shows that better compliance increases the time between relapses, decreases the symptom score, and reduces the requirement for treatment in an intensive patient care setting, leading to cost savings. The extent of the cost savings depends on the relative importance of symptoms and of social and environmental factors in these decisions.


An NGF mimetic, MIM-D3, stimulates conjunctival cell glycoconjugate secretion and demonstrates therapeutic efficacy in a rat model of dry eye.
The aim of this study was to evaluate the efficacy of MIM-D3, a small molecule nerve growth factor (NGF) peptidomimetic, as a therapeutic agent in rats with scopolamine induced dry eye. NGF plays an important role in ocular surface maintenance and corneal wound healing and was recently shown to have mucin secretagogue activity in conjunctival cells. We investigated whether MIM-D3 increased glycoconjugate secretion in conjunctival cells in vitro and in rat tear fluids in vivo. Primary rat conjunctival cell cultures were treated with increasing concentrations of MIM-D3 and evaluated for glycoconjugate secretion, proliferation and MAPK1/2 activation. Glycoconjugates were quantitated in tear fluids from normal rats treated topically with increasing doses of MIM-D3 (0.4%, 1% and 2.5%). Dry eye was induced in rats by subcutaneous scopolamine treatment, administered by surgically implanted osmotic pumps for 14 or 28 days. Aqueous tear production, tear clearance, fluorescein corneal staining and tear break-up time (tBUT) were evaluated. Glycoconjugates and NGF were quantitated in the tear fluids by enzyme-linked lectin assay (ELLA) and enzyme-linked immunosorbant assay (ELISA), respectively. We found that 50 μM MIM-D3 statistically significantly induced a 1.3-fold increase in glycoconjugate secretion and a 2.3-fold increase in MAPK1/2 activation without increasing proliferation from conjunctival cell cultures. Application of 2.5% MIM-D3 in normal rat eyes statistically significantly increased tear glycoconjugate concentration by 2.3-fold. In the experimental dry eye model, application of 1% MIM-D3 to rat eyes for either 1 or 17 consecutive days, followed by 1 week of no dosing produced a statistically significant decrease in corneal staining (p < 0.001), a slight increase in tBUT, and increases in tear glycoconjugates (p < 0.05) compared to vehicle. Scopolamine treatment also caused a statistically significant increase of endogenous NGF in tears (p < 0.005). We concluded that the increase in glycoconjugate concentration by the 1% MIM-D3 dose may have improved the quality and stability of the tear film, and thereby improved healing on the ocular surface in dry eye. Therefore, MIM-D3 may have therapeutic potential as a topical agent for the treatment of dry eye.


Morphology of epithelial cells lining the digestive tract of the giant keyhole limpet, Megathura crenulata (Mollusca; Vetigastropoda).
To understand the digestive functions in the giant keyhole limpet, it is important to know the types of cells present in each region of the gut and their roles in the secretion of digestive enzymes and absorption of nutrients. This study describes the morphology of cells lining the entire gut and identifies sites that may be secreting materials to aid digestion. Previous studies involving electron microscopy and enzyme analysis have focused on the salivary and digestive glands of several gastropods. Studies on the rest of the gut tract typically include only histological descriptions of the epithelia and although several types of cells have been described, they appear very similar. The purpose of this study is to determine if electron microscopy can provide better insights into the functions of cells in these poorly studied regions of the gut. Our ultrastructural observations suggest that only two types of cells, mucus secreting cells and apocrine secretory cells make up the epithelium in the esophagus, style sac, and intestine. These regions account for 85% of the length of the entire digestive tract. Apocrine secretory cells contain pigment granules, bear cilia, and/or microvilli at their apices, and release product into the gut lumen via apocrine secretion. This suggests that the secretory processes involved with digestion are occurring in most regions of the gut and that apocrine secretion is the primary mode by which materials are introduced into the gut lumen. The lips, salivary glands, stomach, and digestive gland lack apocrine secretory cells and the epithelial cells are similar to those described in other gastropods. J. Morphol. 271:1134-1151, 2010. (c) 2010 Wiley-Liss, Inc.


Mucoadhesive, triclosan-loaded polymer microspheres for application to the oral cavity: preparation and controlled release characteristics.
The aim of this study was to develop mucoadhesive microspheres that can be utilised for the controlled release of triclosan in oral-care formulations, specifically dental pastes. Using a double-emulsion solvent evaporation technique, triclosan was incorporated into microspheres that were prepared from Gantreztrade mark MS-955, Carbopol 974P, polycarbophil or chitosan and the profiles for its release were established under simulated 'in use' conditions. Triclosan was rapidly released into a sodium lauryl sulphate containing buffer from all but the chitosan microspheres. The release of triclosan from microspheres suspended in a non-aqueous paste, was found to be sustained over considerable time-periods, which were influenced strongly by the nature of the polymeric carrier. For microspheres that were fabricated from Gantrez, Carbopol or polycarbophil, the release appeared to obey zero-order kinetics whereas in the case of chitosan-derived vehicles, the release profile fitted the Baker and Lonsdale model. The work has demonstrated that these polymeric microspheres, particularly those of chitosan, are promising candidates for the sustained release of triclosan in the oral cavity.


Non-Visual Photopigments Effects of Constant Light-Emitting Diode Light Exposure on the Inner Retina of Wistar Rats.
The retina is part of the central nervous system specially adapted to capture light photons and transmit this information to the brain through photosensitive retinal cells involved in visual and non-visual activities. However, excessive light exposure may accelerate genetic retinal diseases or induce photoreceptor cell (PRC) death, finally leading to retinal degeneration (RD). Light pollution (LP) caused by the characteristic use of artificial light in modern day life may accelerate degenerative diseases or promote RD and circadian desynchrony. We have developed a working model to study RD mechanisms in a low light environment using light-emitting diode (LED) sources, at constant or long exposure times under LP conditions. The mechanism of PRC death is still not fully understood. Our main goal is to study the biochemical mechanisms of RD. We have previously demonstrated that constant light (LL) exposure to white LED produces a significant reduction in the outer nuclear layer (ONL) by classical PRC death after 7 days of LL exposure. The PRCs showed TUNEL-positive labeling and a caspase-3-independent mechanism of cell death. Here, we investigate whether constant LED exposure affects the inner-retinal organization and structure, cell survival and the expression of photopigments; in particular we look into whether constant LED exposure causes the death of retinal ganglion cells (RGCs), of intrinsically photosensitive RGCs (ipRGCs), or of other inner-retinal cells. Wistar rats exposed to 200 lx of LED for 2 to 8 days (LL 2 and LL 8) were processed for histological and protein. The results show no differences in the number of nucleus or TUNEL positive RGCs nor inner structural damage in any of LL groups studied, indicating that LL exposure affects ONL but does not produce RGC death. However, the photopigments melanopsin (OPN4) and neuropsin (OPN5) expressed in the inner retina were seen to modify their localization and expression during LL exposure. Our findings suggest that constant light during several days produces retinal remodeling and ONL cell death as well as significant changes in opsin expression in the inner nuclear layer.


Variation in the proportions of individual pepsins secreted by the cat in response to vagal stimulation and hypoglycaemia.
1. Gastric juice was collected at regular intervals during electrical stimulation of the vagus in anaesthetized cats and during insulin hypoglycaemia in both anaesthetized and conscious cats. The total amounts of acid and pepsin secreted were similar in the three groups. 2. Pepsins were examined by agar-gel electrophoresis. Resting juice contained two pepsins, and up to nine pepsins could be detected after stimulation. Three patterns of pepsin secretion were found. 3. The most noticeable feature was the variation in the proportion of total pepsin attributable to the pepsin which migrated most rapidly during electrophoresis (pepsin 1). In response to insulin hypoglycaemia, anaesthetized cats secreted only a small proportion of total pepsin 1 and conscious cats secreted a large proportion as pepsin 1. During direct electrical stimulation of the vagus, the proportion of pepsin 1 rose. 4. The possibility of a dependence of pepsin 1 secretion on vagal stimulation is discussed and the relevance of this to peptic ulcer and to vagotomy is considered.


Challenges and controversies in diagnosis and management of gonadotropin dependent precocious puberty: An Indian perspective.
Managing precocious puberty (PP) has been a challenge due to lack of standardized definition, gonadotrophins assay, gonadotrophin stimulation, timings for blood sampling, and parameters for assessing outcomes. This review evaluated available literature to simplify the algorithm for managing gonadotrophin dependent/central PP (CPP), with an Indian perspective. CPP is one of the commonest forms of PP and mimics the normal course of puberty, at an age <8 and 9 years for girls and boys respectively. Basal and post gonadotrophin hormone releasing hormone analog (GnRHa) luteinizing hormone (LH) ≥0.3-0.6 IU/L and ≥4-5 IU/L (30-60 min after GnRH/GnRHa administration) respectively, using modern ultrasensitive automated chemiluminescence assays, can be considered positive for central puberty initiation. Uterine length of >3.5 cm and uterine volume of >1.8 ml are two most specific indicators for true CPP. Therapy is indicated in children with CPP with accelerated bone age, height advancement, or psychosocial stress. Treatment goal is to halt puberty progression to a socially acceptable age, allowing the child to attain optimal height potential. GnRHa is the treatment of choice, with best height outcomes when initiated <6 years age. Treatment is recommended till 11 years age. LH suppression to <3 U/L may be a reasonable target in patients on GnRHa therapy. Medroxyprogesterone acetate holds an important place in managing PP in India, cause of high costs associated with GnRHa therapy. There is an urgent need for clinical trials from India, for establishing Indian cut-off for diagnosis, treatment and follow-up of children with PP.