Combined Deletion of Slc30a7 and Slc30a8 Unmasks a Critical Role for ZnT8 in Glucose-Stimulated Insulin Secretion.
Polymorphisms in the SLC30A8 gene, which encodes the ZnT8 zinc transporter, are associated with altered susceptibility to type 2 diabetes (T2D), and SLC30A8 haploinsufficiency is protective against the development of T2D in obese humans. SLC30A8 is predominantly expressed in pancreatic islet β-cells, but surprisingly, multiple knockout mouse studies have shown little effect of Slc30a8 deletion on glucose tolerance or glucose-stimulated insulin secretion (GSIS). Multiple other Slc30a isoforms are expressed at low levels in pancreatic islets. We hypothesized that functional compensation by the Slc30a7 isoform, which encodes ZnT7, limits the impact of Slc30a8 deletion on islet function. We therefore analyzed the effect of Slc30a7 deletion alone or in combination with Slc30a8 on in vivo glucose metabolism and GSIS in isolated islets. Deletion of Slc30a7 alone had complex effects in vivo, impairing glucose tolerance and reducing the glucose-stimulated increase in plasma insulin levels, hepatic glycogen levels, and pancreatic insulin content. Slc30a7 deletion also affected islet morphology and increased the ratio of islet α- to β-cells. However, deletion of Slc30a7 alone had no effect on GSIS in isolated islets, whereas combined deletion of Slc30a7 and Slc30a8 abolished GSIS. These data demonstrate that the function of ZnT8 in islets can be unmasked by removal of ZnT7 and imply that ZnT8 may affect T2D susceptibility through actions in other tissues where it is expressed at low levels rather than through effects on pancreatic islet function.


Prevalence of risk factors for statin-induced myopathy in rheumatoid arthritis patients.
Statins are widely prescribed in patients with rheumatoid arthritis (RA). Although statins offer overwhelming cardiovascular benefits, their use can be associated with the development of a statin-induced myopathy. Several factors increase the risk of developing statin-induced myopathy, including the single nucleotide polymorphism (SNP) rs4149056, located within the gene encoding solute carrier organic anion transporter (SLCO1B1). We aimed to identify the frequency of risk factors for statin-induced myopathy and establish whether the rs4149056 genotype is more prevalent in RA. A total of 396 RA patients and 438 non-RA controls were studied. DNA samples were obtained from all patients. The SNP rs4149056 was identified using real-time polymerase chain reaction and melting curve analysis. Genotypic and allelic frequencies were calculated using the chi-squared test. Almost 80% of RA patients had one or more risk factor (range 1-5) for the development of statin-induced myopathy. Of the 74 RA patients treated with statins, 90% had one or more (range 1-4) risk factors. No differences in genotype or allelic frequencies were observed between RA patients and controls. RA patients harbour multiple risk factors for statin-induced myopathy. However, the frequency of the rs4149056 genotypes does not differ according to the presence of RA. Despite this, no cases of statin-induced myopathy were observed in this cohort over a period of four years of follow-up. Thus, we conclude that statin use among RA patients is probably safe, but large-scale prospective studies are needed to confirm this. In the meantime, it may be good practice systematically to consider and record myopathy risk factors in these patients.


SU-E-T-207: Flatness and Symmetry Threshold Detection Using Statistical Process Control.
AAPM TG-142 guidelines state that beam uniformity (flatness and symmetry) should maintain a constancy of 1 % relative to baseline. The focus of this study is to determine if statistical process control (SPC) methodology using process control charts (PCC) of steering coil currents (SCC) can detect changes in beam uniformity prior to exceeding the 1% constancy criteria. SCCs for the transverse and radial planes are adjusted such that a reproducibly useful photon or electron beam is available. Transverse and radial - positioning and angle SCC are routinely documented in the Morning Check file during daily warm-up. The 6 MV beam values for our linac were analyzed using average and range (Xbar/R) PCC. Using this data as a baseline, an experiment was performed in which each SCC was changed from its mean value (steps of 0.01 or 0.02 Ampere) while holding the other SCC constant. The effect on beam uniformity was measured using a beam scanning system. These experimental SCC values were plotted in the PCC to determine if they would exceed the predetermined limits. The change in SCC required to exceed the 1% constancy criteria was detected by the PCC for 3 out of the 4 steering coils. The reliability of the result in the one coil not detected (transverse position coil) is questionable because the SCC slowly drifted during the experiment (0.05 A) regardless of the servo control setting. X-bar/R charts of SCC can detect exceptional variation prior to exceeding the beam uniformity criteria set forth in AAPM TG-142. The high level of PCC sensitivity to change may result in an alarm when in fact minimal change in beam uniformity has occurred. Further study is needed to determine if a combination of individual SCC alarms would reduce the false positive rate for beam uniformity intervention. This project was supoorted by a grant from Varian Medical Systems, Inc.


Influence of growth environment on tolerance to UV-B radiation, germination speed, and morphology of Metarhizium anisopliae var. acridum conidia.
We previously reported wide variability in UV-B tolerance among different Metarhizium anisopliae isolates [Braga, G.U.L., Flint, S.D., Miller, C.D., Anderson, A.J., Roberts, D.W., 2001a. Variability in response to UV-B among species and strains of Metarhizium isolated from sites at latitudes from 61 degrees N to 54 degrees S. J. Invertebr. Pathol. 78, 98-108] as well as wide phenotypic variability in some of these isolates in response to alterations in their growth environments [Rangel, D.E.N., Braga, G.U.L., Flint, S.D., Anderson, A.J., Roberts, D.W., 2004. Variations in UV-B tolerance and germination speed of M. anisopliae conidia produced on artificial and natural substrates. J. Invertebr. Pathol. 87, 77-83]. Studies on other biological systems have demonstrated that strong selective pressure for tolerance to a stress factor may reduce the phenotypic variability of this trait. In the present study, conidia of the isolate most tolerant to radiation and heat, ARSEF 324, presented very little phenotypic variability in UV-B tolerance in response to production on either artificial culture medium or infected insects. The phenotypic plasticities in two other traits (conidial morphology and germination speed), however, were considerably higher.


Randomized trial of IV valproate vs metoclopramide vs ketorolac for acute migraine.
We compared the efficacy of IV valproate with metoclopramide and with ketorolac in patients presenting to an emergency department (ED) with acute migraine. This was a double-blind comparative efficacy trial. Patients were randomized to 1,000 mg sodium valproate, 10 mg metoclopramide, or 30 mg ketorolac, each administered as an IV drip over 15 minutes. The primary outcome was improvement in headache by 1 hour, measured on a verbal 0 to 10 scale, at baseline and 60 minutes later. Important secondary outcomes included (1) need for rescue medication in the ED, and (2) sustained headache freedom. Three hundred thirty patients were enrolled over 30 months beginning in October 2010. Baseline characteristics were comparable among the 3 arms. On the primary outcome, patients receiving IV valproate improved by a mean of 2.8 (95% confidence interval [CI]: 2.3, 3.3) on the 0 to 10 scale; those receiving IV metoclopramide improved by 4.7 (95% CI: 4.2, 5.2); and those receiving IV ketorolac improved by 3.9 (95% CI: 3.3, 4.5). On the secondary endpoints, 69% (95% CI: 60%, 78%) of patients receiving valproate required rescue medication, compared with 33% (95% CI: 24%, 42%) of metoclopramide patients and 52% (95% CI: 42%, 63%) of those assigned to ketorolac. Sustained headache freedom was achieved in 4% (95% CI: 0%, 7%) of those randomized to valproate, 11% (95% CI: 5%, 17%) of metoclopramide patients, and 16% (95% CI: 9%, 23%) receiving ketorolac. In the metoclopramide arm, 6% (95% CI: 3%, 12%) of patients reported feeling "very restless" after investigational medication administration. Valproate was less efficacious than either metoclopramide or ketorolac. Metoclopramide demonstrated superiority to ketorolac on several endpoints. This study provides Class I evidence that in ED patients with acute migraine, IV valproate is inferior to metoclopramide or ketorolac in improving headache outcomes.


Neuroprotective effects of Ellagic acid against acrylamide-induced neurotoxicity in rats.
Acrylamide (ACR) is an environmental contaminant and a well-known neurotoxin. Ellagic acid (EA), a natural plant polyphenol, has shown a variety of beneficial effects. The present study was designed to explore whether EA could attenuate ACR-induced neurotoxicity in rats and to explore the underlying mechanisms. Animals were divided into five groups. Group 1 was treated with normal saline (2 mL/kg) for 30 days. Group 2 was treated with ACR (20 mg/kg, orally) for 30 days. Groups 3 and 4 were treated with ACR and EA (10 and 30 mg/kg, orally) for 30 days. Group 5 was treated with EA (30 mg/kg, orally) for 30 days. Open field, rotarod and passive avoidance test were conducted to evaluate behavioral changes, respectively. The brain cortex was used for histological examination. Different oxidative parameters and inflammatory biomarkers were assessed in the brain cortex. ACR-administered rats showed a considerable impairment in exploratory behavior, motor performance as well as cognition. Our data also showed that ACR administration significantly increases malondialdehyde, nitric oxide, interleukin-1β and tumor necrosis factor-α levels. Moreover, it decreases brain glutathione level, superoxide dismutase, glutathione peroxidase, catalase activity. Co-administration of EA (especially 30 mg/kg, p.o.) prevented these changes; however, it did not affect the glutathione peroxidase activity. These results were supported by histopathological observations of the brain. Our results suggest that EA can be useful for protecting brain tissue against ACR-induced neurotoxicity through ameliorative effects on inflammatory indices and oxidative stress parameters.


Developing a Korean communication skills attitude scale: comparing attitudes between Korea and the West.
We aimed to develop a Korean version of the Communication Skills Attitude Scale (CSAS) created by Rees et al. in order to elucidate the positive and negative aspects of Korean pre-medical and medical students' attitudes towards communication skills (CS) learning. We performed two surveys. In the first of these, 325 pre-medical and medical students completed a translated version of the CSAS. In the second survey, 257 medical students and doctors-in-training answered five open-ended questions to obtain more qualitative data about their attitudes. Results Principal component analysis with direct oblimin rotation performed with the data from the first survey produced the following five factors: facilitation of interpersonal skills; doubts about the importance of CS learning in medicine; motivation; negative attitudes towards assessment, and overconfidence. from the second survey indicated that facilitation and importance within a medical context were two core attitudinal factors and suggested some modification to the CSAS to improve its fit for Korean pre-medical and medical students. Using a Korean version of the CSAS (CSAS-K), we determined five factors that revealed a somewhat complex attitude structure among students towards CS learning. The CSAS required some modification, possibly because CS teaching and learning in Korea are in the development stage. Finally, the educational implications of the results are discussed.


Airway wall thickness is increased in COPD patients with bronchodilator responsiveness.
Bronchodilator responsiveness (BDR) is a common but variable phenomenon in COPD. The CT characteristics of airway dimensions that differentiate COPD subjects with BDR from those without BDR have not been well described. We aimed to assess airway dimensions in COPD subjects with and without BDR. We analyzed subjects with GOLD 1-4 disease in the COPDGene® study who had CT airway analysis. We divided patients into two groups: BDR + (post bronchodilator ΔFEV1 ≥ 10%) and BDR-(post bronchodilator ΔFEV1 < 10%). The mean wall area percent (WA%) of six segmental bronchi in each subject was quantified using VIDA. Using 3D SLICER, airway wall thickness was also expressed as the square root wall area of an airway of 10 mm (Pi10) and 15 mm (Pi15) diameter. %Emphysema and %gas trapping were also calculated. 2355 subjects in the BDR-group and 1306 in the BDR + group formed our analysis. The BDR + group had a greater Pi10, Pi15, and mean segmental WA% compared to the BDR-group. In multivariate logistic regression using gender, race, current smoking, history of asthma, %emphysema, %gas trapping, %predicted FEV1, and %predicted FVC, airway wall measures remained independent predictors of BDR. Using a threshold change in FEV1 ≥ 15% and FEV1 ≥ 12% and 200 mL to divide patients into groups, the results were similar. BDR in COPD is independently associated with CT evidence of airway pathology. This study provides us with greater evidence of changes in lung structure that correlate with physiologic manifestations of airflow obstruction in COPD.


The role of fathers in child feeding: perceived responsibility and predictors of participation.
The role of fathers in shaping their child's eating behaviour and weight status through their involvement in child feeding has rarely been studied. This study aims to describe fathers' perceived responsibility for child feeding, and to identify predictors of how frequently fathers eat meals with their child. Four hundred and thirty-six Australian fathers (M age = 37 years, SD = 6 years; 34% university educated) of a 2-5-year-old child (M age = 3.5 years, SD = 0.9 years; 53% boys) were recruited via contact with mothers enrolled in existing research projects or a university staff and student email list. Data were collected from fathers via a self-report questionnaire. Descriptive and hierarchical linear regression analyses were conducted. The majority of fathers reported that the family often/mostly ate meals together (79%). Many fathers perceived that they were responsible at least half of the time for feeding their child in terms of organizing meals (42%); amount offered (50%) and deciding if their child eats the 'right kind of foods' (60%). Time spent in paid employment was inversely associated with how frequently fathers ate meals with their child (β = -0.23, P < 0.001); however, both higher perceived responsibility for child feeding (β = 0.16, P < 0.004) and a more involved and positive attitude toward their role as a father (β = 0.20, P < 0.001) were positively related to how often they ate meals with their child, adjusting for a range of paternal and child covariates, including time spent in paid employment. Fathers from a broad range of educational backgrounds appear willing to participate in research studies on child feeding. Most fathers were engaged and involved in family meals and child feeding. This suggests that fathers, like mothers, should be viewed as potential agents for the implementation of positive feeding practices within the family.


Comparison of statistical significance criteria.
We study and compare two classes of statistical criteria to assess the significance of exceptional words. Indeed, the Z-score-like criteria, or the normal approximation that is a strict equivalent, suffer from several drawbacks in terms of sensitivity and specificity. Thanks to the combinatorial structure of words, a computation of the exact P-value has been made possible by recent mathematical results. We study here the drawbacks of the Z-score, the choice of the threshold and the tightness to the P-value. A major conclusion is that the normal approximation is always very poor and overestimates statistical significance.


Adolescence: a transient period of proprioceptive neglect in sensory integration of postural control.
In the current study, we adopted the hypothesis that the body scheme disturbances occurring during adolescence might lead subjects to transiently neglect proprioceptive information and that adolescents might rely more strongly on vision to control their orientation and stabilize their body. To check this point, we asked adolescents 14-15 years to maintain vertical stance while very slow sinusoidal oscillations in the frontal plane were applied to the supporting platform at 0.01 Hz (below the detection threshold of the semicircular canal system) and at 0.06 Hz (above) with the eyes open and closed. Two postural components, orientation and segmental stabilization, were analyzed at the head, shoulder, trunk, and pelvis levels. At the lowest frequency without vision, the performances of adolescents were much less efficient than those of adults. Moreover, this study showed that vision plays a predominant role in adolescents' control of orientation and body stabilization. At 0.06 Hz without vision, a clearcut difference was observed between the strategies used by girls and boys; specifically, the maturation of the segmental stabilization processes was found to be more advanced in girls than in boys. However, no such difference was observed at 0.01 Hz. Lastly, comparisons between the data obtained in adolescents and those previously obtained in young adults (Vaugoyeau, Viel, Amblard, Azulay, & Assaiante, 2008) clearly show that adolescents use different postural strategies and that they are not yet capable of reaching comparable postural performance levels to those observed in adults. Because adolescents were not able to use the proprioceptive information available to improve their postural control, we concluded that they showed a maturational lag in comparison with adults. This suggests that the mechanisms underlying postural control are still maturing during adolescence, which might constitute a transient period of proprioceptive neglect in sensory integration of postural control.


Transcriptional analysis of genes involved in nodulation in soybean roots inoculated with Bradyrhizobium japonicum strain CPAC 15.
Biological nitrogen fixation in root nodules is a process of great importance to crops of soybean [Glycine max (L.) Merr.], as it may provide the bulk of the plant's needs for nitrogen. Legume nodulation involves several complex steps and, although studied for many decades, much remains to be understood. This research aimed at analyzing the global expression of genes in soybean roots of a Brazilian cultivar (Conquista) inoculated with Bradyrhizobium japonicum CPAC 15, a strain broadly used in commercial inoculants in Brazil. To achieve this, we used the suppressive subtractive hybridization (SSH) technique combined with Illumina sequencing. The subtractive library (non-inoculated x inoculated) of soybean roots resulted in 3,210 differentially expressed transcripts at 10 days after inoculation were studied. The data were grouped according to the ontologies of the molecular functions and biological processes. Several classes of genes were confirmed as related to N2 fixation and others were reported for the first time. During nodule formation, a higher percentage of genes were related to primary metabolism, cell-wall modifications and the antioxidant defense system. Putative symbiotic functions were attributed to some of these genes for the first time.


Evidence for functional state transitions in intensively-managed soil ecosystems.
Soils are fundamental to terrestrial ecosystem functioning and food security, thus their resilience to disturbances is critical. Furthermore, they provide effective models of complex natural systems to explore resilience concepts over experimentally-tractable short timescales. We studied soils derived from experimental plots with different land-use histories of long-term grass, arable and fallow to determine whether regimes of extreme drying and re-wetting would tip the systems into alternative stable states, contingent on their historical management. Prior to disturbance, grass and arable soils produced similar respiration responses when processing an introduced complex carbon substrate. A distinct respiration response from fallow soil here indicated a different prior functional state. Initial dry:wet disturbances reduced the respiration in all soils, suggesting that the microbial community was perturbed such that its function was impaired. After 12 drying and rewetting cycles, despite the extreme disturbance regime, soil from the grass plots, and those that had recently been grass, adapted and returned to their prior functional state. Arable soils were less resilient and shifted towards a functional state more similar to that of the fallow soil. Hence repeated stresses can apparently induce persistent shifts in functional states in soils, which are influenced by management history.


Antigen-induced changes on high endothelial venules in rat cervical lymph nodes.
The effect of antigenic stimulation (paratyphoid vaccine) on high endothelial venules (HEVs) of rat cervical lymph nodes was studied using conventional histological and histometrical techniques. The sequential changes of some morphometric parameters (lymph node weight, HEV diameters) after the antigenic stimulation were studied in rat cervical lymph nodes over a period of five days with daily measurements. Measurements were made on the HEVs in the paracortex especially near the corticomedullary junction. HEVs diameters began to increase two days after the antigenic stimulation (p<0.001) and erythrocytes were increased in the lumen of the HEVs. On day four, most of the lymphocytes were detected between the endothelial cells of the HEVs (p<0.001). On day five, not only HEVs were increased in number but also endothelial cells were increased in height (p<0.001). The weight of the lymph nodes was also highest on this day. The changes of HEVs determined after antigenic stimulation suggest that these specialized vessels have an important regulatory role in the primary immune response.


Screening mammography in older women. Effect of wealth and prognosis.
Wealthy women have higher rates of screening mammography than poor women do. Screening mammography is beneficial for women with substantial life expectancies, but women with limited life expectancies are unlikely to benefit. It is unknown whether higher screening rates in wealthy women are due to increased screening in women with substantial life expectancies, limited life expectancies, or both. This study examines the relationship between wealth and screening mammography use in older women according to life expectancy. A cohort study was performed of 4222 women 65 years or older with Medicare participating in the 2002 and 2004 Health and Retirement Survey. Women were categorized according to wealth and life expectancy (based on 5-year prognosis from a validated prognostic index). The outcome was self-reported receipt of screening mammography within 2 years. Overall, within 2 years, 68% of women (2871 of 4222) received a screening mammogram. Screening was associated with wealth (net worth, > $100 000) and good prognosis (< or = 10% probability of dying in 5 years). Screening mammography was more common among wealthy women than among poor women (net worth, < $10 000) both for women with good prognosis (82% vs 68%; P < .001) and for women with limited prognoses (> or = 50% probability of dying in 5 years) (48% vs 32%; P = .02). These associations remained after multivariate analysis accounting for age, race, education, proxy report, and rural residence. Poorer older women with favorable prognoses are at risk of not receiving screening mammography when they are likely to benefit. Wealthier older women with limited prognoses are often screened when they are unlikely to benefit.


Fluoride-Ion Batteries: On the Electrochemical Stability of Nanocrystalline La0.9Ba0.1F2.9 against Metal Electrodes.
Over the past years, ceramic fluorine ion conductors with high ionic conductivity have stepped into the limelight of materials research, as they may act as solid-state electrolytes in fluorine-ion batteries (FIBs). A factor of utmost importance, which has been left aside so far, is the electrochemical stability of these conductors with respect to both the voltage window and the active materials used. The compatibility with different current collector materials is important as well. In the course of this study, tysonite-type La 0.9 Ba 0.1 F 2.9 , which is one of the most important electrolyte in first-generation FIBs, was chosen as model substance to study its electrochemical stability against a series of metal electrodes viz. Pt, Au, Ni, Cu and Ag. To test anodic or cathodic degradation processes we carried out cyclic voltammetry (CV) measurements using a two-electrode set-up. We covered a voltage window ranging from -1 to 4 V, which is typical for FIBs, and investigated the change of the response of the CVs as a function of scan rate (2 mV/s to 0.1 V/s). It turned out that Cu is unstable in combination with La 0.9 Ba 0.1 F 2.9 , even before voltage was applied. The cells with Au and Pt electrodes show reactions during the CV scans; in the case of Au the irreversible changes seen in CV are accompanied by a change in color of the electrode as investigated by light microscopy. Ag and Ni electrodes seem to suffer from contact issues which, most likely, also originate from side reactions with the electrode material. The experiments show that the choice of current collectors in future FIBs will become an important topic if we are to develop long-lasting FIBs. Most likely, protecting layers between the composite electrode material and the metal current collector have to be developed to prevent any interdiffusion or electrochemical degradation processes.


Reagentless and calibrationless silicate measurement in oceanic waters.
Determination of silicate concentration in seawater without addition of liquid reagents was the key prerequisite for developing an autonomous in situ electrochemical silicate sensor (Lacombe et al., 2007) [11]. The present challenge is to address the issue of calibrationless determination. To achieve such an objective, we chose chronoamperometry performed successively on planar microelectrode (ME) and ultramicroelectrode (UME) among the various possibilities. This analytical method allows estimating simultaneously the diffusion coefficient and the concentration of the studied species. Results obtained with ferrocyanide are in excellent agreement with values of the imposed concentration and diffusion coefficient found in the literature. For the silicate reagentless method, successive chronoamperometric measurements have been performed using a pair of gold disk electrodes for both UME and ME. Our calibrationless method was tested with different concentrations of silicate in artificial seawater from 55 to 140×10(-6) mol L(-1). The average value obtained for the diffusion coefficient of the silicomolybdic complex is 2.2±0.4×10(-6) cm(2) s(-1), consistent with diffusion coefficient values of molecules in liquid media. Good results were observed when comparing known concentration of silicate with experimentally derived ones. Further work is underway to explore silicate determination within the lower range of oceanic silicate concentration, down to 0.1×10(-6) mol L(-1).


An empirically-derived taxonomy of moral concepts.
We propose that methods from the study of category-based induction can be used to test the descriptive accuracy of theories of moral judgment. We had participants rate the likelihood that a person would engage in a variety of actions, given information about a previous behavior. From these likelihood ratings, we extracted a hierarchical, taxonomic model of how moral violations relate to each other (Study 1). We then tested the descriptive adequacy of this model against an alternative model inspired by Moral Foundations Theory, using classic tasks from induction research (Studies 2a and 2b), and using a measure of confirmation, which accounts for the baseline frequency of these violations (Study 3). Lastly, we conducted focused tests of combinations of violations where the models make differing predictions (Study 4). This research provides new insight into how people represent moral concepts, connecting classic methods from cognitive science with contemporary themes in moral psychology. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Single-access laparoscopic sigmoidectomy as definitive surgical management of prior diverticulitis in a human patient.
Single-access laparoscopic surgery should offer minimal scarring without compromising surgical outcome. It is enhanced by both innovative port technology and technical expertise learned by developing natural orifice transluminal endoscopic surgery (NOTES). Sigmoidectomy in a human via a single laparoscopic port. University hospital. Patient A 40-year-old woman with previously documented diverticular abscess. The multichannel single port (Triport; Advanced Surgical Concepts, Wicklow, Ireland) was placed at the umbilicus. The sigmoid was retracted by both intraluminal sigmoidoscopy and magnetic anchoring. Mesenteric dissection between the mid-descending colon and the colorectal junction was carried out close to the colon using a Ligasure Advance (Covidien, Valley lab, Norwalk Connecticut). The stapler anvil was passed retrogradely per ano to lie within the descending colon. A linear stapler effected proximal and distal sigmoidal transection. Magnetic attraction then delivered the in situ anvil pike into a colotomy placed adjacent to the proximal staple line. After its position was secured with an endoloop, the pike was mated with its stapler head positioned in the rectal stump. This allowed creation of a double-stapled colorectal anastomosis 10 cm from the anal verge. Specimen retrieval was performed via the umbilical port site. Extent of scarring, occurrence of surgical complications, technical adequacy, and clinical outcome. No intraoperative complications occurred during the 90-minute procedure. A total of 40 cm of sigmoid was resected. The patient convalesced without complication and went home 4 days after surgery. At the 1-month review, she was fully recovered and her single umbilical scar was well healed. With advancing surgical technology and technique, truly minimally invasive surgical procedures are feasible. Understanding of NOTES can therefore extend beyond its experimental application into contemporary surgical practice.


Anabolic androgenic steroid abuse in the United Kingdom: An update.
Anabolic androgenic steroids (AASs) are prescribed for medical conditions related to low testosterone. Abuse of AASs has surged as they become recognised as potent image enhancement drugs. The primary goal of most abusers is to obtain a more attractive outward appearance. Abuse is complex. There are a vast range of AAS substances illegally available, the nature of their true composition is difficult to evaluate. Users follow dosing patterns which incorporate a number of different AASs, in addition to other pharmaceutical substances believed to complement the desired physical effects or manage unwanted effects. Animal work and medical case reports suggest potential to cause serious hepatotoxicity, plus possible neurotoxicity, nephrotoxicity and damage to the cardiovascular and reproductive systems. As the long-term AASs users reach maturity, further controlled experimentation, with larger sample sizes, is required. Data gathering should be directed towards the most vulnerable group of AAS users, females and adolescent boys.


Surface dark screening solitons.
We report on the existence of surface dark screening solitons at the interface between a dielectric medium (air) and a self-defocusing nonlinear material, taking advantage of photorefractive diffusion and drift nonlinearities. It is very interesting that a surface dark soliton is just like half of a dark soliton in bulk, but not a whole dark soliton propagating along surface. The excitation, propagation, and stability of this type of soliton are studied by using the beam-propagation method. Another interesting thing is that this type of dark soliton can be excited by a planar light beam without a necessary dark notch.


C2 domain protein MIN1 promotes eyespot organization in Chlamydomonas reinhardtii.
Assembly and asymmetric localization of the photosensory eyespot in the biflagellate, unicellular green alga Chlamydomonas reinhardtii requires coordinated organization of photoreceptors in the plasma membrane and pigment granule/thylakoid membrane layers in the chloroplast. min1 (mini-eyed) mutant cells contain abnormally small, disorganized eyespots in which the chloroplast envelope and plasma membrane are no longer apposed. The MIN1 gene, identified here by phenotypic rescue, encodes a protein with an N-terminal C2 domain and a C-terminal LysM domain separated by a transmembrane sequence. This novel domain architecture led to the hypothesis that MIN1 is in the plasma membrane or the chloroplast envelope, where membrane association of the C2 domain promotes proper eyespot organization. Mutation of conserved C2 domain loop residues disrupted association of the MIN1 C2 domain with the chloroplast envelope in moss cells but did not abolish eyespot assembly in Chlamydomonas. In min1 null cells, channelrhodopsin-1 (ChR1) photoreceptor levels were reduced, indicating a role for MIN1 in ChR1 expression and/or stability. However, ChR1 localization was only minimally disturbed during photoautotrophic growth of min1 cells, conditions under which the pigment granule layers are disorganized. The data are consistent with the hypothesis that neither MIN1 nor proper organization of the plastidic components of the eyespot is essential for localization of ChR1.


Pneumomediastinum after retching.
A 25-year-old woman with hirsutism presented to the Emergency Department of the medicine faculty in Gaziantep University with a 4-h History of dyspnoea, dysphagia, coughing, continuous and progressive chest pain radiating to the back and palpation of her neck. The physical examination was significant for diffuse neck and chest subcutaneous emphysema. The x-ray study and CT scan of the chest revealed pneumomediastinum. The patient reported that 6 h before presentation she took spironolactone due to hirsutism and she retched. Retching caused the symptoms. The patient was followed conservatively and fully recovered over the next 7 days. Spontaneous pneumomediastinum developed in this patient with no underlying lung disease, presumably from air leakage secondary to the excessive elevation of intrathoracic pressure due to retching. Pneumomediastinum is an uncommon disease arising most frequently and remains largely underdiagnosed clinically, especially in young, healthy patients.


Fresh Fruit Juice of Opuntia dillenii Haw. Attenuates Acetic Acid-Induced Ulcerative Colitis in Rats.
The present study aimed to evaluate the protective effect of fresh fruit juice of Opuntia dillenii Haw. (FJOD) on acetic acid-induced ulcerative colitis in rats. Fresh FJOD (2.5 and 5 ml/kg) and sulfasalazine (100 mg/kg) were given orally for seven consecutive days prior to colitis induction on the eighth day by intrarectal acetic acid (4% v/v) administration. Macroscopic, clinical activity scoring, biochemical, and histopathological examinations of colon were used to assess colonic damage. FJOD and sulfasalazine treatment significantly attenuated the macroscopic damage, clinical activity score, and wet weight of the colon when compared to disease control and further showed significantly reduced levels of myeloperoxidase, malondialdehyde, and serum lactate dehydrogenase and enhanced colonic levels of reduced glutathione. The protective effect of FJOD may be attributed to its antioxidant and anti-inflammatory activities in ulcerative colitis. The observed effects may be due to the presence of phenolics, flavonoids, and betalains in the fruit juice of Opuntia dillenii.


High-dose acetylsalicylic acid after cerebral infarction. A Swedish Cooperative Study.
Within 3 weeks of the event, 505 patients with cerebral infarction, minor or major stroke, were randomly assigned to treatment with acetylsalicylic acid (ASA) 1.5 g/day or placebo in a double-blind clinical trial with a follow-up of 2 years in all patients. Primary events were considered to be recurrent stroke or death; secondary events, myocardial infarction and transient ischemic attack. There was no difference in stroke recurrence rate in the ASA and placebo groups (12 and 13%, respectively), nor was there any significant difference in the rate of recurrent stroke or death, first event counted (23% in the ASA and 22% in the placebo group). The risk of transient ischemic attack and myocardial infarction was not reduced in the ASA group. In the present study there was no prophylactic effect of high-dose ASA after cerebral infarction. A compilation of the major trials of ASA after transient ischemic attack and cerebral infarction is presented.


Intact skin and not stripped skin is crucial for the safety and efficacy of peanut epicutaneous immunotherapy (EPIT) in mice.
Epicutaneous immunotherapy (EPIT) on intact skin with an epicutaneous delivery system has already been used in preclinical and clinical studies. In epicutaneous vaccination and immunotherapy, the stripping of skin before application of the allergen is suggested to facilitate the passage of allergen through immune cells. The aim of this study was to compare the immunological response induced by EPIT performed on intact and stripped skin in a mouse model of peanut allergy. After oral sensitization with peanut and cholera toxin, BALB/c mice were epicutaneously treated using an epicutaneous delivery system (Viaskin® (DBV Technologies, Paris) applied either on intact skin or on stripped skin. Following EPIT, mice received an exclusive oral peanut regimen, aimed at triggering esophageal and jejunal lesions. We assessed eosinophil infiltration by histology, mRNA expression in the esophagus, antibody levels and peripheral T-cell response. EPIT on intact skin significantly reduced Th2 immunological response (IgE response and splenocyte secretion of Th2 cytokines) as well as esophageal eosinophilia (2.7 ± 0.9, compared to Sham 19.9 ± 1.5, p < 0.01), mRNA expression of Th2 cytokines in tissue and intestinal villus sub-atrophia (2.9 ± 0.2 vs Sham, 2.1 ± 0.2, p < 0.05). By contrast, EPIT on stripped skin reinforced Th2 systemic immunological response as well as eosinophil infiltration (26.8 ± 15.1), mRNA expression of Th2 cytokines and duodenal villus/crypt-ratio (2.4 ± 0.3). Epicutaneous allergen-specific immunotherapy needs the integrity of superficial layers of the stratum corneum to warranty safety of treatment and to induce a tolerogenic profile of the immune response.


Causal mechanisms of soil organic matter decomposition: deconstructing salinity and flooding impacts in coastal wetlands.
Coastal wetlands significantly contribute to global carbon storage potential. Sea-level rise and other climate-change-induced disturbances threaten coastal wetland sustainability and carbon storage capacity. It is critical that we understand the mechanisms controlling wetland carbon loss so that we can predict and manage these resources in anticipation of climate change. However, our current understanding of the mechanisms that control soil organic matter decomposition, in particular the impacts of elevated salinity, are limited, and literature reports are contradictory. In an attempt to improve our understanding of these complex processes, we measured root and rhizome decomposition and developed a causal model to identify and quantify the mechanisms that influence soil organic matter decomposition in coastal wetlands that are impacted by sea-level rise. We identified three causal pathways: (1) a direct pathway representing the effects of flooding on soil moisture, (2) a direct pathway representing the effects of salinity on decomposer microbial communities and soil biogeochemistry, and (3) an indirect pathway representing the effects of salinity on litter quality through changes in plant community composition over time. We used this model to test the effects of alternate scenarios on the response of tidal freshwater forested wetlands and oligohaline marshes to short- and long-term climate-induced disturbances of flooding and salinity. In tidal freshwater forested wetlands, the model predicted less decomposition in response to drought, hurricane salinity pulsing, and long-term sea-level rise. In contrast, in the oligohaline marsh, the model predicted no change in response to drought and sea-level rise, and increased decomposition following a hurricane salinity pulse. Our results show that it is critical to consider the temporal scale of disturbance and the magnitude of exposure when assessing the effects of salinity intrusion on carbon mineralization in coastal wetlands. Here, we identify three causal mechanisms that can reconcile disparities between long-term and short-term salinity impacts on organic matter decomposition.


Sugammadex affects emergence agitation in children undergoing strabismus surgery.
Objective Emergence agitation (EA) has a multifactorial origin, and the effect of sugammadex on EA has not been established. We investigated the effect of sugammadex on EA incidence and severity. Methods We performed a retrospective study of children aged 1 to 13 years who underwent strabismus surgery. Patients received sugammadex or conventional neuromuscular reversal agents. The primary outcome variables were EA incidence and severity. Secondary outcome variables were postoperative fentanyl use, postoperative nausea and vomiting, time from reversal agent administration to extubation, time from the end of surgery to arrival in the post-anesthesia care unit (PACU) and time spent in the PACU. We used propensity score matching to eliminate baseline imbalances. Results Age, sex, use of desflurane, and intraoperative fentanyl were significant predictors of agitation severity using a multivariable analysis. Sugammadex did not significantly affect EA in logistic regression and multiple regression analyses. In the propensity-matched analysis, patients in the sugammadex group showed rapid recovery, but there was no difference in the EA incidence or severity. Conclusion Sugammadex did not affect EA incidence or severity compared with conventional cholinesterase inhibitors, although it showed a favorable recovery profile in children undergoing strabismus surgery.


HCV-Related Mortality Among HIV/HCV Co-infected Patients: The Importance of Behaviors in the HCV Cure Era (ANRS CO13 HEPAVIH Cohort).
Mortality among individuals co-infected with HIV and hepatitis C virus (HCV) is relatively high. We evaluated the association between psychoactive substance use and both HCV and non-HCV mortality in HIV/HCV co-infected patients in France, using Fine and Gray's competing-risk model adjusted for socio-demographic, clinical predictors and confounding factors, while accounting for competing causes of death. Over a 5-year median follow-up period, 77 deaths occurred among 1028 patients. Regular/daily cannabis use, elevated coffee intake, and not currently smoking were independently associated with reduced HCV-mortality (adjusted sub-hazard ratio [95% CI] 0.28 [0.10-0.83], 0.38 [0.15-0.95], and 0.28 [0.10-0.79], respectively). Obesity and severe thinness were associated with increased HCV-mortality (2.44 [1.00-5.93] and 7.25 [2.22-23.6] versus normal weight, respectively). Regular binge drinking was associated with increased non-HCV-mortality (2.19 [1.10-4.37]). Further research is needed to understand the causal mechanisms involved. People living with HIV/HCV co-infection should be referred for tobacco, alcohol and weight control interventions and potential benefits of cannabis-based therapies investigated.


Phenotypic and Genotypic Characterization of Uromyces appendiculatus from Phaseolus vulgaris in the Americas.
Populations of 90 Uromyces appendiculatus isolates were collected from throughout the Americas and evaluated for virulence on 19 standard bean rust differentials, and also on 12 landraces of Phaseolus vulgaris from South and Central America. The landrace differentials represented geographical centers of bean domestication. Three groups were observed. Two groups were isolates from centers of bean domestication and a third heterogeneous group comprised isolates from countries in South and Central America. Molecular analysis using random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR) was also conducted on these isolates. Cluster analysis of the molecular profiles showed three groups that corresponded to those obtained by virulence tests. These results show a clear differentiation of the pathogen population along similar lines as its host and suggest parallel evolution in the bean rust pathosystem.


SERS nanosensors and nanoreporters: golden opportunities in biomedical applications.
This article provides an overview of recent developments and applications of surface-enhanced Raman scattering (SERS) nanosensors and nanoreporters in our laboratory for use in biochemical monitoring, medical diagnostics, and therapy. The design and fabrication of different types of plasmonics-active nanostructures are discussed. The SERS nanosensors can be used in various applications including pH sensing, protein detection, and gene diagnostics. For DNA detection the 'Molecular Sentinel' nanoprobe can be used as a homogenous bioassay in solution or on a chip platform. Gold nanostars provide an excellent multi-modality theranostic platform, combining Raman and SERS with two-photon luminescence (TPL) imaging as well as photodynamic therapy (PDT), and photothermal therapy (PTT). Plasmonics-enhanced and optically modulated delivery of nanostars into brain tumor in live animals was demonstrated; photothermal treatment of tumor vasculature may induce inflammasome activation, thus increasing the permeability of the blood brain-tumor barrier. The imaging method using TPL of gold nanostars provides an unprecedented spatial selectivity for enhanced targeted nanostar delivery to cortical tumor tissue. A quintuple-modality nanoreporter based on gold nanostars for SERS, TPL, magnetic resonance imaging (MRI), computed tomography (CT), and PTT has recently been developed. The possibility of combining spectral selectivity and high sensitivity of the SERS process with the inherent molecular specificity of bioreceptor-based nanoprobes provides a unique multiplex and selective diagnostic modality. Several examples of optical detection using SERS in combination with other detection and treatment modalities are discussed to illustrate the usefulness and potential of SERS nanosensors and nanoreporters for medical applications.


Validation of two multiplex real-time PCR assays based on single nucleotide polymorphisms of the HA1 gene of equine influenza A virus in order to differentiate between clade 1 and clade 2 Florida sublineage isolates.
We validated 2 multiplex real-time PCR (rtPCR) assays based on single nucleotide polymorphisms (SNPs) of the hemagglutinin-1 ( HA1) gene of H3N8 equine influenza A virus (EIV) to determine clade affiliation of prototype and field isolates. Initial validation of the 2 multiplex rtPCR assays (SNP1 and SNP2) was performed using nucleic acid from 14 EIV Florida sublineage clade 1 and 2 prototype strains. We included in our study previously banked EIV rtPCR-positive nasal secretions from 341 horses collected across the United States in 2012-2017 to determine their clade affiliation. All 14 EIV prototype strains were identified correctly as either Florida sublineage clade 1 or clade 2 using the 2 SNP target positions. Of 341 EIV rtPCR-positive samples, 337 (98.8%) and 4 (1.2%) isolates were classified as belonging to clade 1 and 2 Florida sublineage EIV, respectively. All clade 1 Florida sublineage EIV strains were detected in domestic horses, three clade 2 Florida sublineage EIV strains originated from horses recently imported into the United States, and one clade 2 Florida sublineage EIV strain originated from a healthy horse recently vaccinated with a modified-live intranasal EIV vaccine containing the American lineage strain A/eq/Kentucky/1991. EIV Florida sublineage clade differentiation using a fast and reliable multiplex rtPCR platform will help monitor the introduction of clade 2 Florida sublineage EIV strains into North America via international transportation.


Effect of La doping on CO adsorption at ceria surfaces.
In this paper we use density functional theory corrected for on-site Coulomb interactions (DFT+U) to study the adsorption of CO at La-doped ceria (111) and (110) surfaces. Doping of ceria with La is known to enhance oxidation of CO to CO(2) and this study investigates the atomic level details of this reaction. With La(3+) doping, an [La(3+)-O(-)] defect state with an oxygen hole is formed at both surfaces. The formation energy of an oxygen vacancy is reduced and vacancy formation results in the appearance of Ce(3+), instead of hole compensation. On the doped surfaces weak and strong adsorption of CO is found. In the former, the molecule remains intact. In the latter, the final adsorption species depends strongly on the surface and whether oxygen vacancies are present or not. On (111) a CO(2)-like species forms, while on the (110) surface, mono- or bidentate carbonates are present. La-doping of ceria surfaces shows enhanced reactivity over the undoped surfaces and we discuss the origin of the enhanced reactivity and the nature of the surface species upon CO adsorption.


Effects of a Workplace Intervention Targeting Psychosocial Risk Factors on Safety and Health Outcomes.
The goal of this study was to test the effectiveness of a workplace intervention targeting work-life stress and safety-related psychosocial risk factors on health and safety outcomes. Data were collected over time using a randomized control trial design with 264 construction workers employed in an urban municipal department. The intervention involved family- and safety-supportive supervisor behavior training (computer-based), followed by two weeks of behavior tracking and a four-hour, facilitated team effectiveness session including supervisors and employees. A significant positive intervention effect was found for an objective measure of blood pressure at the 12-month follow-up. However, no significant intervention results were found for self-reported general health, safety participation, or safety compliance. These findings suggest that an intervention focused on supervisor support training and a team effectiveness process for planning and problem solving should be further refined and utilized in order to improve employee health with additional research on the beneficial effects on worker safety.


Density functional theory in transition-metal chemistry: a self-consistent Hubbard U approach.
Transition-metal centers are the active sites for a broad variety of biological and inorganic chemical reactions. Notwithstanding this central importance, density-functional theory calculations based on generalized-gradient approximations often fail to describe energetics, multiplet structures, reaction barriers, and geometries around the active sites. We suggest here an alternative approach, derived from the Hubbard U correction to solid-state problems, that provides an excellent agreement with correlated-electron quantum chemistry calculations in test cases that range from the ground state of Fe2 and Fe2- to the addition elimination of molecular hydrogen on FeO+. The Hubbard U is determined with a novel self-consistent procedure based on a linear-response approach.


Neural mechanisms of top-down control during spatial and feature attention.
Theories of visual selective attention posit that both spatial location and nonspatial stimulus features (e.g., color) are elementary dimensions on which top-down attentional control mechanisms can selectively influence visual processing. Neuropsychological and neuroimaging studies have demonstrated that regions of superior frontal and parietal cortex are critically involved in the control of visual-spatial attention. This frontoparietal control network has also been found to be activated when attention is oriented to nonspatial stimulus features (e.g., motion). To test the generality of the frontoparietal network in attentional control, we directly compared spatial and nonspatial attention in a cuing paradigm. Event-related fMRI methods permitted the isolation of attentional control activity during orienting to a location or to a nonspatial stimulus feature (color). Portions of the frontoparietal network were commonly activated to the spatial and nonspatial cues. However, direct statistical comparisons of cue-related activity revealed subregions of the frontoparietal network that were significantly more active during spatial than nonspatial orienting when all other stimulus, task, and attentional factors were equated. No regions of the frontal-parietal network were more active for nonspatial cues in comparison to spatial cues. These findings support models suggesting that subregions of the frontal-parietal network are highly specific for controlling spatial selective attention.


Administration of intrapulmonary sodium polyacrylate to induce lung injury for the development of a porcine model of early acute respiratory distress syndrome.
The loss of alveolar epithelial and endothelial integrity is a central component in acute respiratory distress syndrome (ARDS); however, experimental models investigating the mechanisms of epithelial injury are lacking. The purpose of the present study was to design and develop an experimental porcine model of ARDS by inducing lung injury with intrapulmonary administration of sodium polyacrylate (SPA). The present study was performed at the Centre for Comparative Medicine, University of British Columbia, Vancouver, British Columbia. Human alveolar epithelial cells were cultured with several different concentrations of SPA; a bioluminescence technique was used to assess cell death associated with each concentration. In the anesthetized pig model (female Yorkshire X pigs (n = 14)), lung injury was caused in 11 animals (SPA group) by injecting sequential aliquots (5 mL) of 1% SPA gel in aqueous solution into the distal airway via a rubber catheter through an endotracheal tube. The SPA was dispersed throughout the lungs by manual bag ventilation. Three control animals (CON group) underwent all experimental procedures and measurements with the exception of SPA administration. The mean (± SD) ATP concentration after incubation of human alveolar epithelial cells with 0.1% SPA (0.92 ± 0.27 μM/well) was approximately 15% of the value found for the background control (6.30 ± 0.37 μM/well; p < 0.001). Elastance of the respiratory system (E RS) and the lung (E L) increased in SPA-treated animals after injury (p = 0.003 and p < 0.001, respectively). Chest wall elastance (E CW) did not change in SPA-treated animals. There were no differences in E RS, E L, or E CW in the CON group when pre- and post-injury values were compared. Analysis of bronchoalveolar lavage fluid showed a significant shift toward neutrophil predominance from before to after injury in SPA-treated animals (p < 0.001) but not in the CON group (p = 0.38). Necropsy revealed marked consolidation and congestion of the dorsal lung lobes in SPA-treated animals, with light-microscopy evidence of bronchiolar and alveolar spaces filled with neutrophilic infiltrate, proteinaceous debris, and fibrin deposition. These findings were absent in animals in the CON group. Electron microscopy of lung tissue from SPA-treated animals revealed injury to the alveolar epithelium and basement membranes, including intra-alveolar neutrophils and fibrin on the alveolar surface and intravascular fibrin (microthrombosis). In this particular porcine model, the nonimmunogenic polymer SPA caused a rapid exudative lung injury. This model may be useful to study ARDS caused by epithelial injury and inflammation.


Serum Folate of Less than 7.0 ng/mL is a Marker of Malnutrition.
To identify clinical/laboratory factors associated with folate deficiency in tertiary care patients. We reviewed the medical records of 1019 patients with serum folate <7.0 ng/mL, 301 patients with serum folate of 15 ng/mL, and 300 patients with serum folate > 23 ng/mL. Serum prealbumin levels were subnormal in 54.8% of patients with serum folate <7.0 ng/mL. Vitamin B12, hemoglobin, and serum albumin levels were significantly lower in the <7.0 ng/mL folate group. In 62.4% of patients with serum folate <7.0 ng/mL, 1 or more markers of malnutrition were present. The low-folate group had a significantly higher prevalence of gastrointestinal (GI) disorders, sepsis, and abnormal serum creatinine level. There were no significant differences in the 2 groups regarding diabetes; behavioral/neurological disorders, including drug and alcohol abuse; bariatric surgery; or a diagnosis of malnutrition. The average body mass index (BMI) for the <7.0 ng/mL and 15 ng/mL folate groups was significantly different (28.89 and 28.31, respectively), although the difference does not appear to be clinically meaningful. The prevalence of folate deficiency depends on what is considered a normal serum folate level. Approximately 10% of tertiary-care patients have levels <7.0 ng/mL and exhibit other markers of malnutrition. It is recommended that patients with GI disorders, chronic kidney disease, and sepsis be routinely tested for serum folate levels, before administration of vitamin supplements. Patients with serum folate levels <7.0 ng/mL should be evaluated for malnutrition, despite BMI > 25. Folate supplementation should be administered only after excluding coexisting vitamin B12 deficiency.


Automatic grouping of regular structures.
To cope with the continuously incoming stream of input, the visual system has to group information across space and time. Usually, spatial and temporal grouping are investigated separately. However, recent findings revealed that these two grouping mechanisms strongly interact and should therefore be studied together rather than in isolation. Here, we show that spatio-temporal grouping is very sensitive to the spatial layout of the stimuli and that the grouping processes do not require the observer's awareness. The experimental observations are compared with outcomes of simulations with a neural network model applying low-level inhibitory and excitatory interactions. The modeling results suggest that the observed interactions between spatial and temporal grouping may take place at a relatively early stage of visual processing.


Physical and chemical tuning of two-dimensional transition metal dichalcogenides.
The development of two-dimensional (2D) materials has been experiencing a renaissance since the adventure of graphene. Layered transition metal dichalcogenides (TMDs) are now playing increasingly important roles in both fundamental studies and technological applications due to their wide range of material properties from semiconductors, metals to superconductors. However, a material with fixed properties may not exhibit versatile applications. Due to the unique crystal structures, the physical and chemical properties of 2D TMDs can be effectively tuned through different strategies such as reducing dimensions, intercalation, heterostructure, alloying, and gating. With the flexible tuning of properties 2D TMDs become attractive candidates for a variety of applications including electronics, optoelectronics, catalysis, and energy.


SU-E-T-189: Arc Splitting for VMAT Patient QA.
To determine the need for arc splitting for VMAT prostate patient quality assurance. Prior to Eclipse version 10.0, a verification plan for VMAT treatment could only be created which mirrored the clinical plan; if the plan called for a full arc, then the verification plan also contained a full arc. In this case, for a center that uses the Sun Nuclear MapCheck device with its Isocentric Mounting Fixture, the full fluence of an arc is delivered en face to the device. The question arose as to whether partial arcs, if they could be created, would fail a center's criteria, while the full arc passed them, in effect, whether there are cancellations occurring and not being observed. With Eclipse version 10.0, it is now possible to split a clinical arc into many subdivisions for verification, the software recommends no more than 40 partial arcs, for computing speed limitations. Twelve VMAT plans for prostate patients were investigated, in order to search for the aforementioned cancellations. Two full arcs were used clinically in all cases. Verification plans were created consisting of (1) the two full arcs; (2) 8 partial arcs of 90 degrees each; and (3) 16 partial arcs of 45 degrees each. These were all analyzed against our criteria of 3%/3mm with a threshold of 10%, and 95% of points passing. Of 288 partial arcs and 49,670 points analyzed, there were a total of 100 points (0.2%) that failed the 3%/3mm criteria. No arcs, however, failed the 95% passing criteria. Moreover, there was no evidence of cancellation; if a point failed low, there was no corresponding high failure in another partial arc. In this study, splitting a full arc into partial arcs revealed no unseen failures.


Increased levels of diadenosine polyphosphates in dry eye.
To analyze the levels of the diadenosine polyphosphates Ap4A and Ap5A in tears, in a set of control subjects and in groups of symptomatic and nonsymptomatic persons with dry eye. Ninety-seven subjects participated in the study. The subjects were divided into five experimental groups: control subjects; symptomatic patients with normal tear secretion; symptomatic patients with low tear secretion; forced blink; and corneal mechanical stimulation provided by a gas esthesiometer. The Schirmer I test was used to measure and collect tear secretions from each subject. All samples were processed by high pressure liquid chromatography (HPLC) and their Ap4A and Ap5A levels determined. The levels of Ap4A and Ap5A in tears were greater in all symptomatic patients than in control subjects, especially in symptomatic subjects with low tear secretion. Within the symptomatic subjects with normal tear secretion, significant differences in concentrations of Ap4A and Ap5A were found between men and women. In the forced blink experiments, concentrations of the Ap4A and Ap5A rose with increasing blink frequency. When the cornea was mechanically stimulated, the levels of Ap4A and Ap5A rose significantly during both moderate and high-flow rate tests. The increased levels of Ap4A and Ap5A in tears of patients with dry eye allow these dinucleotides to be used as objective biomarkers in dry eye conditions.


Interleukin 7 enhances cytolytic T lymphocyte generation and induces lymphokine-activated killer cells from human peripheral blood.
The effects of purified recombinant interleukin 7 (IL-7) on the generation of cytolytic T lymphocytes (CTL) in mixed lymphocyte culture (MLC) and on the induction of lymphokine-activated killer (LAK) cells in autologous cultures of human peripheral blood mononuclear cells were investigated. IL-7 was found to induce the generation of both CTL and LAK cells in bulk cultures. The appearance of peak CTL activity in MLC established with exogenous IL-7 was delayed in comparison with replicate cultures containing exogenous IL-2, but both cytokines stimulated quantitatively similar levels of antigen-specific lytic activity. An IL-2-neutralizing antiserum inhibited substantially, but not completely, the effect of IL-7 on CTL generation, implying the existence of both an indirect component of IL-7 activity via IL-2 utilization, as well as an IL-2-independent component. Cell surface phenotypic analysis of IL-2- or IL-7-generated CTL effector cells revealed that CD8+ cells were responsible for the vast majority of lytic activity. Limiting dilution analysis (LDA) revealed that essentially identical frequencies of CTL precursors (CTL-P) were capable of clonal expansion and/or differentiation in the presence of exogenous IL-2, IL-4, or IL-7, supporting the concept that all three of these cytokines are capable of exerting a major influence on T cell growth and differentiation. Approximately half of the CTL-P that responded in IL-7-supplemented LDA cultures did so in an IL-2-independent manner. IL-7 stimulated the development of LAK cells in autologous bulk cultures, but only weakly in comparison with IL-2. In contrast to its effects on CTL generation, the induction of LAK cells by IL-7 was virtually independent of IL-2. LAK cells induced by IL-7, like those induced by IL-2, were phenotypically heterogeneous and included CD8+, CD56+, and gamma/delta+ cells. Limiting dilution analysis indicated that IL-2 stimulated fivefold more LAK-P than IL-7 and 220-fold more than IL-4. Collectively, these data suggest that IL-7 has potent regulatory effects on human cytolytic cell populations and, either alone or in combination with other cytokines, could be important for the in vitro expansion of cells for adoptive immunotherapy.


Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin.
NMDA receptors are linked to intracellular cytoskeletal and signaling molecules via the PSD-95 protein complex. We report a novel family of postsynaptic density (PSD) proteins, termed Shank, that binds via its PDZ domain to the C terminus of PSD-95-associated protein GKAP. A ternary complex of Shank/GKAP/PSD-95 assembles in heterologous cells and can be coimmunoprecipitated from rat brain. Synaptic localization of Shank in neurons is inhibited by a GKAP splice variant that lacks the Shank-binding C terminus. In addition to its PDZ domain, Shank contains a proline-rich region that binds to cortactin and a SAM domain that mediates multimerization. Shank may function as a scaffold protein in the PSD, potentially cross-linking NMDA receptor/PSD-95 complexes and coupling them to regulators of the actin cytoskeleton.


Implementing a strategic plan for child health: a Sydney case study.
The aim of this paper is to describe the implementation of a strategic plan, Health Gain for Children and Youth of Central Sydney, over a 10-year period to December 2005. Descriptive information was obtained from the records and minutes of all relevant committees, interviews with key workers who were involved with the committees, managers and senior health professionals, and from the involvement of the authors throughout the process of the implementation. An implementation steering committee was established to oversee the implementation of the plan. Rather than adopting a uniform approach to assigning responsibility for the implementation of each strategy in the plan or developing specific costs and time frames for each strategy, a more pragmatic, flexible and opportunistic approach was taken. Most of the plan's strategies were implemented over a 7-year time frame using a combination of service reorientation and implementation of new programmes, some of which were funded from sources not anticipated during the development of the plan. Implementation required a dedicated driver, commitment at senior level and participation by many staff at many levels. Outcomes, monitored through data collected at 5-year intervals, revealed positive trends in a number of child and youth health indicators. The successful implementation of the strategic plan required pragmatism, flexibility, opportunism and the commitment and involvement of staff at all organisational levels. It is envisaged that this approach provides a firm base for future evidence-based developments to benefit the health and well-being of children, youth and their families and reduce health inequities.


Mapping implied body actions in the human motor system.
The human visual system is highly tuned to perceive actual motion as well as to extrapolate dynamic information from static pictures of objects or creatures captured in the middle of motion. Processing of implied motion activates higher-order visual areas that are also involved in processing biological motion. Imagery and observation of actual movements performed by others engenders selective activation of motor and premotor areas that are part of a mirror-neuron system matching action observation and execution. By using single-pulse transcranial magnetic stimulation, we found that the mere observation of static snapshots of hands suggesting a pincer grip action induced an increase in corticospinal excitability as compared with observation of resting, relaxed hands, or hands suggesting a completed action. This facilitatory effect was specific for the muscle that would be activated during actual execution of the observed action. We found no changes in responsiveness of the tested muscles during observation of nonbiological entities with (e.g., waterfalls) or without (e.g., icefalls) implied motion. Thus, extrapolation of motion information concerning human actions induced a selective activation of the motor system. This indicates that overlapping motor regions are engaged in the visual analysis of physical and implied body actions. The absence of motor evoked potential modulation during observation of end posture stimuli may indicate that the observation-execution matching system is preferentially activated by implied, ongoing but not yet completed actions.


Efficacy and safety of sitagliptin added to insulin in Japanese patients with type 2 diabetes: the EDIT randomized trial.
To clarify the efficacy and safety of adding sitagliptin to insulin therapy in Japanese patients with suboptimally controlled type 2 diabetes (T2DM). This was a 24-week, prospective, randomized, open-labeled, controlled trial. Patients with T2DM who were suboptimally controlled despite receiving at least twice daily injection of insulin were enrolled in the study. The patients were randomized to continuation of insulin treatment (Insulin group) or addition of sitagliptin 50 to 100 mg daily to insulin treatment (Ins+Sita group). The primary outcome was change in HbA1c at week 24. Adding sitagliptin to insulin significantly reduced HbA1c from 7.9 ± 1.0% at baseline to 7.0 ± 0.8% at week 24 (P <0.0001), while there was no significant change in HbA1c in the Insulin group (7.8 ± 0.7% vs. 7.8 ± 1.1%, P = 0.32). The difference in HbA1c reduction between the groups was 0.9% (95% confidence interval, 0.4 to 1.5, P = 0.01). There was no significant weight gain in either group. Incidence of hypoglycemia was significantly reduced in the Ins+Sita group compared with the Insulin group. Treatment satisfaction was improved in the Ins+Sita group. Baseline HbA1c level and beta cell function were associated with the magnitude of reduction in HbA1c in the Ins+Sita group. Adding sitagliptin to insulin reduced HbA1c without weight gain or increase in hypoglycemia, and improved treatment satisfaction in Japanese patients with T2DM who were suboptimally controlled despite at least twice daily injection of insulin. The University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000004678.


Building capacity in health research in the developing world.
Strong national health research systems are needed to improve health systems and attain better health. For developing countries to indigenize health research systems, it is essential to build research capacity. We review the positive features and weaknesses of various approaches to capacity building, emphasizing that complementary approaches to human resource development work best in the context of a systems and long-term perspective. As a key element of capacity building, countries must also address issues related to the enabling environment, in particular: leadership, career structure, critical mass, infrastructure, information access and interfaces between research producers and users. The success of efforts to build capacity in developing countries will ultimately depend on political will and credibility, adequate financing, and a responsive capacity-building plan that is based on a thorough situational analysis of the resources needed for health research and the inequities and gaps in health care. Greater national and international investment in capacity building in developing countries has the greatest potential for securing dynamic and agile knowledge systems that can deliver better health and equity, now and in the future.


Geometry-invariant GRIN lens: iso-dispersive contours.
A dispersive model of a gradient refractive index (GRIN) lens is introduced based on the idea of iso-dispersive contours. These contours have constant Abbe number and their shape is related to iso-indicial contours of the monochromatic geometry-invariant GRIN lens (GIGL) model. The chromatic GIGL model predicts the dispersion throughout the GRIN structure by using the dispersion curves of the surface and the center of the lens. The analytical approach for paraxial ray tracing and the monochromatic aberration calculations used in the GIGL model is employed here to derive closed-form expressions for the axial and lateral color coefficients of the lens. Expressions for equivalent refractive index and the equivalent Abbe number of the homogeneous equivalent lens are also presented and new aspects of the chromatic aberration change due to aging are discussed. The key derivations and explanations of the GRIN lens optical properties are accompanied with numerical examples for the human and animal eye GRIN lenses.


Geographic variation in adult survival and reproductive tactics of the mosquito Aedes albopictus.
Climate differences across latitude can result in seasonal constraints and selection on life history characters. Since Aedes albopictus (Skuse) invaded North America in the mid-1980s, it has spread across a range of approximately 14 degrees latitude and populations in the north experience complete adult mortality due to cold winter temperatures that are absent in the south. Life table experiments were conducted to test for differences in the adult survival and reproductive schedules of Ae. albopictus females from two populations from the northern (Bloomington, IN [BL] and Manassas, VA [VA]; approximately 39 degrees N) and southern (Tampa, FL and Fort Myers, FL; approximately 27-28 degrees N) extremes of the species distribution in North America Regardless of population origin, age-specific hazard rate increased with reproductive output and decreased with number of bloodmeals. Larger females took fewer bloodmeals, and they had greater hazard rates than did smaller females. There were no consistent differences between northern versus southern populations in resource allocation between reproduction and maintenance, reproduction over time, and reproductive investment among offspring, suggesting that latitudinal variation in climate is probably not a main selective factor impinging on adult mortality and reproductive schedules. One possible effect of climate on geographic differences in life history was detected. BL had lower survivorship, lower lifetime reproductive output, and lower adult reproductive rate than did all other populations. This result may be an indirect result of lower egg survivorship due to the severity of winter in BL compared with other populations, including VA at approximately the same latitude. Such a scenario may make the BL population more prone to extinction, irregularly recolonized from more favorable sites, and thus more susceptible to founder effects, genetic drift, and inbreeding, resulting in lower mean values of fitness-related traits.


FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression.
FoxO transcription factors are important targets of insulin action. To better understand the role of FoxO proteins in the liver, we created transgenic mice expressing constitutively active FoxO1 in the liver using the alpha1-antitrypsin promoter. Fasting glucose levels are increased, and glucose tolerance is impaired in transgenic (TGN) versus wild type (WT) mice. Interestingly, fasting triglyceride and cholesterol levels are reduced despite hyperinsulinemia, and post-prandial changes in triglyceride levels are markedly suppressed in TGN versus WT mice. Activation of pro-lipogenic signaling pathways (atypical protein kinase C and protein kinase B) and the ability to suppress beta-hydroxybutyrate levels are not impaired in TGN. In contrast, de novo lipogenesis measured with (3)H(2)O is suppressed by approximately 70% in the liver of TGN versus WT mice after refeeding. Gene-array studies reveal that the expression of genes involved in gluconeogenesis, glycerol transport, and amino acid catabolism is increased, whereas genes involved in glucose utilization by glycolysis, the pentose phosphate shunt, lipogenesis, and sterol synthesis pathways are suppressed in TGN versus WT. Studies with adenoviral vectors in isolated hepatocytes confirm that FoxO1 stimulates expression of gluconeogenic genes and suppresses expression of genes involved in glycolysis, the shunt pathway, and lipogenesis, including glucokinase and SREBP-1c. Together, these results indicate that FoxO proteins promote hepatic glucose production through multiple mechanisms and contribute to the regulation of other metabolic pathways important in the adaptation to fasting and feeding in the liver, including glycolysis, the pentose phosphate shunt, and lipogenic and sterol synthetic pathways.


Transverse testicular ectopia, a case report and review of literature.
Crossed testicular ectopia (CTE)/transverse testicular ectopia (TTE) is a rare but well known congenital anomaly, in which both gonads migrate toward the same hemiscrotum. It is usually associated with other abnormalities such as persistent Mullerian duct syndrome, true hermaphroditism, inguinal hernia, hypospadias, pseudohermaphroditism, and scrotal anomalies. About 100 cases of transverse testicular ectopia have been reported in published studies. We report a case of transverse testicular ectopia in an 8-month-old boy who presented with right inguinal hernia and nonpalpable left testis. On exploration, both testes were present in the right inguinal region. Bilateral orchiopexy was performed by crossing the left testis in the extra-peritoneal space and ipsilateral scrotal orchiopexy. The diagnosis could not be made preoperatively in most of reported cases.


Chromatin mediation of a transcriptional memory effect in yeast.
Previous studies have described a transcriptional "memory effect," whereby transcript levels of many Abf1-regulated genes in the budding yeast Saccharomyces cerevisiae are undiminished even after Abf1 has dissociated from its regulatory sites. Here we provide additional support for this effect and investigate its molecular basis. We show that the effect is observed in a distinct abf1 ts mutant from that used in earlier studies, demonstrating that it is robust, and use chromatin immunoprecipitation to show that Abf1 association is decreased similarly from memory effect and transcriptionally responsive genes at the restrictive temperature. We also demonstrate that the association of TATA-binding protein and Pol II decreases after the loss of Abf1 binding for transcriptionally responsive genes but not for memory effect genes. Examination of genome-wide nucleosome occupancy data reveals that although transcriptionally responsive genes exhibit increased nucleosome occupancy in abf1 ts yeast, the promoter regions of memory effect targets show no change in abf1 ts mutants, maintaining an open chromatin conformation even after Abf1 eviction. This contrasting behavior reflects different inherent propensity for nucleosome formation between the two classes, driven by the presence of A/T-rich sequences upstream of the Abf1 site in memory effect gene promoters. These sequence-based differences show conservation in closely related fungi and also correlate with different gene expression noise, suggesting a physiological basis for greater access to "memory effect" promoter regions. Thus, our results establish a conserved mechanism underlying a transcriptional memory effect whereby sequences surrounding Abf1 binding sequences affect local nucleosome occupancy following loss of Abf1 binding. Furthermore, these findings demonstrate that sequence-based differences in the propensity for nucleosome occupancy can influence the transcriptional response of genes to an altered regulatory signal.


CIGARETTE TAXES AND TEEN MARIJUANA USE.
The spillover effect of cigarette taxes on youth marijuana use has been the subject of intense public debate. Opponents of cigarette taxes warn that tax hikes will cause youths to substitute toward marijuana. On the other hand, public health experts often claim that because tobacco is a "gateway" drug, higher cigarette taxes will deter youth marijuana use. Using data from the National and State Youth Risk Behavior Surveys (YRBS) for the period 1991-2017, we explore the relationship between state excise taxes on cigarettes and teen marijuana use. In general, our results fail to support either of the above hypotheses. Rather, we find little evidence to suggest that teen marijuana use is sensitive to changes in the state cigarette tax. This null result holds for the sample period where cigarette taxes are observed to have the largest effect on teen cigarette use and across a number of demographic groups in the data. Finally, we find preliminary evidence that the recent adoption of state e-cigarette taxes is associated with a reduction in youth marijuana use.


Hematin-derived anticoagulant. Generation in vitro and in vivo.
Prolongation of clotting times produced by hematin was investigated both in vitro and in vivo. Hematin-derived anticoagulant (HDA) was found to be due to a degradative product or derivative of hematin, and was generated in vitro in standing (aging) aqueous solutions of the parent compound. Generation of HDA in vitro was inhibited by antioxidants. The anticoagulant effect of HDA was inhibited by freshly prepared hematin, fresh Sn-protoporphyrin, imidazole, or the iron chelator desferrioxamine. Ferrioxamine did not inhibit HDA, and inhibition by imidazole was reversed with ferric citrate, suggesting a role for iron in the mechanism of HDA activity. HDA activity was dissociated from hematin in plasma by clotting with thrombin. HDA segregated into the clot fraction, whereas hematin remained largely in the serum fraction, suggesting that HDA may preferentially bind to fibrinogen. TLC and HPLC showed a single peak of HDA activity that was not associated with the parent compound. Evidence for HDA generation in vivo was found when rats were injected with fresh (no HDA) hematin. Prolongation of clotting times appeared after hematin appeared in the plasma, and anticoagulant activity persisted after a fall in plasma hematin concentration. Thus, there was a temporal dissociation between hematin and HDA, suggesting that a modification of hematin must occur in vivo before an anticoagulant effect is produced. Generation of HDA in vitro has implications for hematin preparation and administration. Generation of HDA in vivo suggests that similar modifications of endogenous heme or other porphyrins may occur to produce HDA under physiologic or pathophysiologic conditions.


The Escherichia coli polB locus is identical to dinA, the structural gene for DNA polymerase II. Characterization of Pol II purified from a polB mutant.
Escherichia coli DNA polymerase II (Pol II) is a member of the group B, "alpha-like" family of DNA polymerases. Pol II is encoded by the damage-inducible dinA gene and exhibits SOS induction under the control of Lex A repressor. The polB gene was originally designated as the structural gene for Pol II based on the absence of detectable Pol II activity in cell lysates prepared from a strain containing the mutant polB100 allele. Because polB and dinA mapped at different chromosomal locations, it remained an open question whether polB, in addition to lexA, might be involved in regulating the expression of Pol II. We have cloned and sequenced the polB100 mutant allele, including adjacent surrounding sequences, and have expressed the mutant dinA gene from Pol B100 on a high copy number plasmid. Our sequence data reveal that polB and dinA represent the same gene and that the original transduction mapping of polB was inaccurate. We purified the mutant Pol B100 polymerase and show that it retains 5 to 10% of the wild-type level of polymerase activity. The Pol B100 mutation, Gly401 --> Asp401, is not located within any of the five conserved domains that define group B polymerases. Pol B100 retains a wild-type level of 3' --> 5' exonuclease activity. We suggest that the normal level of exonucleolytic proofreading associated with the mutant Pol B100 enzyme may explain the repeated failures, over the past two decades, to detect phenotypes in polB mutant strains.


MUC4-expressing pancreatic adenocarcinomas show elevated levels of both T1 and T2 cytokines: potential pathobiologic implications.
The human MUC4 mucin plays an important role in the pathogenesis of pancreatic cancer. Recently, we have demonstrated that MUC4 expression in pancreatic tumor cells is regulated by interferon-gamma (IFNgamma) and by retinoic acid via transforming growth factor beta 2 (TGFbeta-2). In the present study, we established the pathobiological association of various cytokines and MUC4 in pancreatic tumor tissues and tumor cell lines. Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and/or immunohistochemical analyses, we examined the expression of MUC4, IFNgamma, TGFbetas, and several immunologically relevant cytokines in a panel of 11 pancreatic adenocarcinomas (PA), three normal pancreatic (NP) tissue specimens, and 11 pancreatic tumor cell lines. Our data revealed that both MUC4 and IFNgamma were expressed at moderate to high levels in the majority of PA, while being undetectable in NP. Moreover, transcript for interleukin 2 (IL-2), a known marker of activated T helper 1 (TH1) lymphocytes, exhibited an expression profile similar to IFNgamma, suggesting a role of these immune effector cells as a potential source of IFNgamma in PA. Of note, IFNgamma protein was detected in the inflamed tissues neighboring tumor areas. Furthermore, TGFbetas were expressed by most cell lines and frequently upregulated in PA compared with NP. Interestingly, both IL-12 and IL-10, two key cytokines of the TH1 and TH2 pathways, respectively, were expressed at higher levels in PA relative to NP. These observations support the potential implication of IFNgamma and TGFbetas in MUC4 regulation in vivo and suggest a complex interaction of TH1 and TH2 signaling in the pancreatic tumor microenvironment. These findings may provide useful insights into the pathobiology of pancreatic cancer.


Adolescent growth: genes, hormones and the peer group. Proceedings of the 20th Aschauer Soiree, held at Glücksburg castle, Germany, 15th to 17th November 2013.
The association between poverty, malnutrition, illness and poor socioeconomic conditions on the one side, and poor growth and short adult stature on the other side, is well recognized. Yet, the simple assumption by implication that poor growth and short stature result from poor living conditions, should be questioned. Recent evidence on the impact of the social network on adolescent growth and adult height further challenges the traditional concept of growth being a mirror of health. Twenty-nine scientists met at Glücksburg castle, Northern Germany, November 15th - 17th 2013, to discuss genetic, endocrine, mathematical and psychological aspects and related issues, of child and adolescent growth and final height.


Enhanced antitumor effect of oncolytic adenovirus expressing interleukin-12 and B7-1 in an immunocompetent murine model.
We investigated whether an armed viral platform, where lytic property of a viral infection is coupled to viral-mediated delivery of therapeutic genes, could increase the therapeutic potential of a viral-based therapy. We generated interleukin (IL)-12-expressing oncolytic adenovirus (YKL-IL-12) and IL-12- and B7-1-expressing (YKL-IL12/B7) oncolytic adenovirus. Therapeutic efficacy of these newly engineered adenoviruses was then evaluated in vivo using an immunocompetent mouse bearing murine melanoma B16-F10 tumors. Overall survival was assessed with the Kaplan-Meier method. The induction of immune cell cytotoxicity was assessed by CTL assay, IFN-gamma enzyme-linked immunospot assay, and immunohistochemical studies. YKL-IL12/B7 oncolytic adenovirus, expressing both IL-12 and B7-1, showed a higher incidence of complete tumor regression compared with the analogous oncolytic adenovirus, YKL-1, or IL-12-expressing, YKL-IL12. Significant survival advantage was also seen in response to YKL-IL12/B7. Moreover, IL-12 and IFN-gamma levels produced in tumors treated with YKL-IL12/B7 was significantly greater than those treated with YKL-IL12. The enhanced survival advantage was mediated by the induction of immune cell cytotoxicity. In agreement with these results, massive infiltration of CD4(+) and CD8(+) T cells into tissues surrounding the necrotic area of the tumor was observed following in situ delivery of YKL-IL12/B7. Combination of oncolysis and the enhancement of antitumor immune response by oncolytic adenovirus expressing both IL-12 and B7-1 elicits potent antitumor effect and survival advantage.


Impact of migration and fitness on the stability of lethal t-haplotype polymorphism in Mus musculus: a computer study.
The t-haplotype is a chromosomal region in Mus musculus characterized by meiotic drive such that heterozygous males transmit t-bearing chromosomes to roughly 90% of their offspring. Most naturally occurring t-haplotypes express a recessive embryonic lethality, preventing fixation of the t-haplotype. Surprisingly, the t-haplotype occurs in nature as a persistent, low-frequency polymorphism. Early modeling studies led LEWONTIN to hypothesize that this low level polymorphism results from a balance between genetic drift in small demes and interdemic migration. Here, we show that while combination of deme size and migration rate that predict natural t-haplotype frequencies exist, the range of such values is too narrow to be biologically plausible, suggesting that small deme size and interdemic migration alone do not explain the observed t-haplotype frequencies. In response, we tested other factors that might explain the observed t-polymorphism. Two led to biologically plausible models: substantially reduced heterozygous fitness and reduced meiotic drive. This raises the question whether these phenomena occur in nature. Our data suggest an alternative explanation: there is no stable, low-level t-polymorphism. Rather wild populations are in one of two stable states characterized by extinction of the t-haplotype and a high t-haplotype frequency, respectively, or in transition between the two.


Involvement of CD8(+) T Cells in Multiple Sclerosis.
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by focal demyelination patches associated with inflammatory infiltrates containing T lymphocytes. For decades, CD4(+) T cells have been recognized as playing a major role in the disease, especially in animal models, which has led to the development of several therapies. However, interest has recently developed in the involvement of CD8(+) T cells in MS following the analysis of infiltrating T cells in human brain lesions. A broad range of evidence now suggests that the pathological role of this T cell subset in MS may have been underestimated. In this review, we summarize the literature implicating CD8(+) T cells in the pathophysiology of MS. We present data from studies in the fields of genetics, anatomopathology and immunology, mainly in humans but also in animal models of MS. Altogether, this strongly suggests that CD8(+) T cells may be major effectors in the disease process, and that the development of treatments specifically targeting this subset would be germane.


A structured learning programme for venepuncture and cannulation.
This article discusses a structured learning programme that offers a standardised assessment for all healthcare staff to learn venepuncture and/or cannulation. Nurses from four NHS trusts in London and the south east, with a special interest and expertise in cannulation and venepuncture, devised the programme to reduce the need for repeated training and assessment when staff take up new posts within these trusts. The authors in their respective trusts have used the tool over a four-year period and findings from a study in Chelsea and Westminster Healthcare NHS Trust are presented to demonstrate its use by staff. The tool has recently been reviewed by its authors and is being disseminated to organisations across the United Kingdom (UK). These organisations will evaluate it, with a long-term objective to standardise the training and assessment of venepuncture and cannulation across the UK.


Opercular syndrome: A case report and review.
We present a 9-year-old boy with history of perinatal asphyxia and neonatal seizures; who presented with delayed development of speech, with predominant dysarthria, dysphagia, and drooling of saliva and unable to protrude tongue along with delayed motor and mental milestones. He had complex partial seizures since last 3 years requiring multiple anti-epileptic drugs. He had dysarthria, nasal twang, and drooling of saliva with difficulty in chewing and swallowing. Hearing and understanding were normal. Bilateral trigemino-facio-linguo-pharyngeal palsy was noticed on voluntary movements with normal jaw jerk with preserved automatic and emotional motor movements. Electroencephalography revealed focal left fronto-temporal epileptiform discharges and brain imaging was suggestive of bilateral cortical and subcortical region encephalomalacia, predominantly involving bilateral opercular region. The clinical and neuroimaging features correspond to bilateral opercular syndrome which could have resulted from the perinatal insult in this case.


The carboxyl terminus of B class ephrins constitutes a PDZ domain binding motif.
Ephrin B proteins function as ligands for B class Eph receptor tyrosine kinases and are postulated to possess an intrinsic signaling function. The sequence at the carboxyl terminus of B-type ephrins contains a putative PDZ binding site, providing a possible mechanism through which transmembrane ephrins might interact with cytoplasmic proteins. To test this notion, a day 10.5 mouse embryonic expression library was screened with a biotinylated peptide corresponding to the carboxyl terminus of ephrin B3. Three of the positive cDNAs encoded polypeptides with multiple PDZ domains, representing fragments of the molecule GRIP, the protein syntenin, and PHIP, a novel PDZ domain-containing protein related to Caenorhabditis elegans PAR-3. In addition, the binding specificities of PDZ domains previously predicted by an oriented library approach (Songyang, Z., Fanning, A. S., Fu, C., Xu, J., Marfatia, S. M., Chishti, A. H., Crompton, A., Chan, A. C., Anderson, J. M., and Cantley, L. C. (1997) Science 275, 73-77) identified the tyrosine phosphatase FAP-1 as a potential binding partner for B ephrins. In vitro studies demonstrated that the fifth PDZ domain of FAP-1 and full-length syntenin bound ephrin B1 via the carboxyl-terminal motif. Lastly, syntenin and ephrin B1 could be co-immunoprecipitated from transfected COS-1 cells, suggesting that PDZ domain binding of B ephrins can occur in cells. These results indicate that the carboxyl-terminal motif of B ephrins provides a binding site for specific PDZ domain-containing proteins, which might localize the transmembrane ligands for interactions with Eph receptors or participate in signaling within ephrin B-expressing cells.


Recovery of trace evidence in forensic archaeology and the use of alternate light sources (ALS).
The effectiveness of alternate light source (ALS) to fluoresce bone and other materials is well-attested to in a laboratory setting but rarely, if ever, has it been used in field excavation. This study examined the recovery rates of fragmentary bone, fabric, and metal, both with and without the use of an ALS, through practical and controlled excavation experiments with multiple users. All archaeology, including forensic archaeology and crime scene investigation more generally, should account for trace evidence. Currently, there is limited empirical data for the recovery of evidence from excavation, and those studies that do exist, highlight the short-comings in current methods. Six comparable test pits were created, representing empty graves in which only trace evidence remained. Each contained 20 fragments of bone (≤10mm), 16 hair fibres, two pieces of fabric and two lead pieces, which were back-filled and left for over 15 weeks. Three excavators were each tasked with excavating two test pits: one using ALS, one in daylight conditions. The results of the experiment identified some critical aspects of using blue 455nm wavelength ALS in the field, and the importance of experienced practitioners. Sample evidence was small in size and recovery rates were low. In daylight conditions, an average of 46% of trace evidence was identified, while just 40% was recovered using ALS. This excludes hair fibres which were almost undetectable in all conditions. When using ALS, smaller bone fragments were more than twice as likely to be recovered, but less non-fluorescent materials were found. The experience of each excavator had a positive correlation with excavation results. Excavation error rates were calculated, demonstrating that excavation is comparable using either technique, but daylight conditions lead to greater accuracy. The findings suggest that ALS can be used to increase recovery of some evidence types. Test pits provided none of the usual primary evidence associated with graves and excavators had no prior experience of ALS. While retrieval rates were low, almost all recovered items were found in situ and an accurate records maintained. Error rates in forensic archaeology are essential and it is hoped that the method outlined here can be developed towards the establishment of acceptable error rates. While ALS use in forensic archaeology should not be considered a panacea to issues of trace evidence recovery, a combination of well-tested archaeological excavation methods, alongside the implementation of such proven forensic techniques, would likely lead to improved recovery of evidence.