Perceptions regarding tobacco control strategies amongst female youth in Delhi, India - a qualitative study.
Tobacco-related cancer is one of the commonest causes of cancer-related mortality in low- and middle-income countries. As per Global Youth Tobacco Survey-4, India; nearly one-fifth of students aged 13-15 used any form of the tobacco product. Tobacco related challenges have been countered through various tobacco control strategies; however, ignorance and non-compliance to tobacco control strategies to combat the tobacco epidemic shield the tobacco industry in India as well. There is limited literature on perception of tobacco use and tobacco control strategies amongst female youth. Hence, the present study aimed to assess tobacco control perception and perceived challenges through a qualitative approach amongst the youth of Delhi, India. Thematic analysis design of qualitative research was used amongst students of the Senior Secondary (Class XII) at a Government School of Delhi. One-to-one in-depth interviews were carried out for 6-7 individual participants in a day depending upon their availability. A summative content analysis was conducted of all the responses obtained by a data coder who was blinded to the identity of the respondent. A total of 82 school children participated in the study. The majority (82.9%, N = 68) of the participants felt that 'Tobacco is dangerous to health' and 41.5% (N = 34) of the participants were aware of some of the existing tobacco control laws in the country. Around 53.7% (N = 44) of the study respondents considered existing tobacco related laws to be ineffective. Regarding the perceived challenges; 31.7% (N = 26) of the respondents considered the lack of strict tobacco control laws and punishment strategies as the main factors. The findings from this study substantiated the focus on school based tobacco control strategies. The participants were well appraised regarding the impending danger of tobacco use and dynamic involvement of youth in tobacco control policies is the need of the hour.


Predictors of infection with Trichomonas vaginalis: a prospective study of low income African-American adolescent females.
To identify psychosocial predictors of Trichomonas vaginalis infection among low income African-American adolescent females living in a high risk urban area of the United States. Baseline plus 6 and 12 month follow up data collected as part of an HIV prevention intervention trial were utilised. The baseline sample consisted of 522 African-American females, 14-18 years of age. Recruitment sites were located in low income neighbourhoods of Birmingham, Alabama, characterised by high rates of unemployment, substance abuse, violence, teenage pregnancy, and sexually transmitted infections. Self administered vaginal swab specimens were cultured for T vaginalis. Baseline measures collected as part of a self administered survey and face to face interviews were used to predict subsequent infection with T vaginalis at any of the three assessment periods conducted over the span of 1 year. At baseline, 12.9% were diagnosed with T vaginalis. At the 6 and 12 month follow ups, T vaginalis was diagnosed in 8.9% and 10.2%, respectively. The strongest multivariate predictor of T vaginalis infection was biologically confirmed marijuana use; those using marijuana were more than six times as likely to test positive for T vaginalis (adjusted odds ratio (AOR) = 6.2, p = 0.0003). Other multivariate predictors were reporting that typical sex partners were at least 5 years older (AOR = 2.6; p = 0.005), reporting sex with non-steady partners (AOR = 1.9; p = 0.02), and history of delinquency (AOR = 1.3; p = 0.02). The odds of testing positive increased by 31% for every one unit increase on a six item scale measure of delinquency. Infection with T vaginalis was common and significant multivariate predictors comprised a constellation of problem behaviours, each of which are potentially amenable to behavioural intervention.


Maternal care and birth outcomes among ethnic minority women in Finland.
Care during pregnancy and labour is of great importance in every culture. Studies show that people of migrant origin have barriers to obtaining accessible and good quality care compared to people in the host society. The aim of this study is to compare the access to and use of maternity services, and their outcomes among ethnic minority women having a singleton birth in Finland. The study is based on data from the Finnish Medical Birth Register in 1999-2001 linked with the information of Statistics Finland on woman's country of birth, citizenship and mother tongue. Our study data included 6,532 women of foreign origin (3.9% of all singletons) giving singleton birth in Finland during 1999-2001 (compared to 158,469 Finnish origin singletons). Most women have migrated during the last fifteen years, mainly from Russia, Baltic countries, Somalia and East Europe. Migrant origin women participated substantially in prenatal care. Interventions performed or needed during pregnancy and childbirth varied between ethnic groups. Women of African and Somali origin had most health problems resulted in the highest perinatal mortality rates. Women from East Europe, the Middle East, North Africa and Somalia had a significant risk of low birth weight and small for gestational age newborns. Most premature newborns were found among women from the Middle East, North Africa and South Asia. Primiparous women from Africa, Somalia and Latin America and Caribbean had most caesarean sections while newborns of Latin American origin had more interventions after birth. Despite good general coverage of maternal care among migrant origin women, there were clear variations in the type of treatment given to them or needed by them. African origin women had the most health problems during pregnancy and childbirth and the worst perinatal outcomes indicating the urgent need of targeted preventive and special care. These study results do not confirm either healthy migrant effect or epidemiological paradox according to which migrant origin women have considerable good birth outcomes.


Structural determinants of lipid specificity within Ups/PRELI lipid transfer proteins.
Conserved lipid transfer proteins of the Ups/PRELI family regulate lipid accumulation in mitochondria by shuttling phospholipids in a lipid-specific manner across the intermembrane space. Here, we combine structural analysis, unbiased genetic approaches in yeast and molecular dynamics simulations to unravel determinants of lipid specificity within the conserved Ups/PRELI family. We present structures of human PRELID1-TRIAP1 and PRELID3b-TRIAP1 complexes, which exert lipid transfer activity for phosphatidic acid and phosphatidylserine, respectively. Reverse yeast genetic screens identify critical amino acid exchanges that broaden and swap their lipid specificities. We find that amino acids involved in head group recognition and the hydrophobicity of flexible loops regulate lipid entry into the binding cavity. Molecular dynamics simulations reveal different membrane orientations of PRELID1 and PRELID3b during the stepwise release of lipids. Our experiments thus define the structural determinants of lipid specificity and the dynamics of lipid interactions by Ups/PRELI proteins.


Acute badminton injuries.
During 1990-1994, 1.2% of all sports injuries that required emergency care at the University Hospital of Umeå were caused by badminton. In 90.7% of the cases the patients described themselves as recreational players or beginners. There were 51.3% minor injuries (AIS 1) and 48.7% moderate injuries (AIS 2). The lower extremities were affected in 92.3% of the cases. Achilles tendon ruptures (34.6%) and ankle sprains and fractures (29.5%) were the most frequent. By the time of the follow-up (10-69 months), 52.6% of the players still had symptoms from the injuries and 39.5% had not been able to return to playing badminton. Our data indicate the importance of adequate treatment and rehabilitation after acute badminton injuries.


Upgrading Existing Buildings to Universal Design. What Cost-Benefit Analyses Can Tell Us.
This article is based on a project aimed at finding the benefits of different measures to upgrade existing public buildings and outdoor areas to be accessible for all. The study was initiated by The Ministry of Children and Equality. The ministry asked for a study of benefits based on a stated preferences (SP) method and an easy-to-complete calculation tool for CBA. In the project 18 commonly used measures and their typical costs were identified. The benefits of each measure were analysed in a stated preference study. The SP analyses included 9 multiple choices in 4 different sequences in an Internet based survey with 800 respondents. The project concluded that it is possible to use stated preferences survey to identify the respondent's valuation of measures to improve accessibility in existing buildings. Some of the measures have a high cost-/benefit ratio. The project report including the calculation manual is based on the average valuation for each measure. But in the background analyses (not referred in the report) there are also some analyses of valuations for target groups for the various measures. The target groups were defined for each measure based on information about the respondents' abilities and use of technical aids. The analyses presented in this paper indicate how valuation varies between the target groups and the average population. This is named the measures profile. Some measures have benefits for the target group that are only twice as high as for the average citizen while another type of measures has high benefits only the target group. The first type which has a wide profile often has high overall socioeconomic benefits, while the last group with a narrow profile more often has low overall socioeconomic benefits, but may be very important for certain user groups and therefore essential for the elimination of discrimination and exclusion of those groups.


A New Computational Model of High-Order Stochastic Simulation Based on Spatial Legendre Moments.
Multiple-point simulations have been introduced over the past decade to overcome the limitations of second-order stochastic simulations in dealing with geologic complexity, curvilinear patterns, and non-Gaussianity. However, a limitation is that they sometimes fail to generate results that comply with the statistics of the available data while maintaining the consistency of high-order spatial statistics. As an alternative, high-order stochastic simulations based on spatial cumulants or spatial moments have been proposed; however, they are also computationally demanding, which limits their applicability. The present work derives a new computational model to numerically approximate the conditional probability density function (cpdf) as a multivariate Legendre polynomial series based on the concept of spatial Legendre moments. The advantage of this method is that no explicit computations of moments (or cumulants) are needed in the model. The approximation of the cpdf is simplified to the computation of a unified empirical function. Moreover, the new computational model computes the cpdfs within a local neighborhood without storing the high-order spatial statistics through a predefined template. With this computational model, the algorithm for the estimation of the cpdf is developed in such a way that the conditional cumulative distribution function (ccdf) can be computed conveniently through another recursive algorithm. In addition to the significant reduction of computational cost, the new algorithm maintains higher numerical precision compared to the original version of the high-order simulation. A new method is also proposed to deal with the replicates in the simulation algorithm, reducing the impacts of conflicting statistics between the sample data and the training image (TI). A brief description of implementation is provided and, for comparison and verification, a set of case studies is conducted and compared with the results of the well-established multi-point simulation algorithm, filtersim. This comparison demonstrates that the proposed high-order simulation algorithm can generate spatially complex geological patterns while also reproducing the high-order spatial statistics from the sample data.


Chronic continuous and intermittent L-3,4-dihydroxyphenylalanine treatments differentially affect basal ganglia function in 6-hydroxydopamine lesioned rats--an autoradiographic study using [3H]flunitrazepam.
The effects of chronic 'continuous' and 'intermittent' L-3,4-dihydroxyphenylalanine treatments on GABA receptor function in the basal ganglia of rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle was investigated, by autoradiography with [3H]flunitrazepam. The 6-hydroxydopamine lesion itself, increased [3H]flunitrazepam binding in the substantia nigra pars reticulata (+17%, with respect to intact side) and entopeduncular nucleus (+44%), but decreased binding in the globus pallidus of the denervated hemisphere (-20%). 'Intermittent' L-3,4-dihydroxyphenylalanine treatment reduced the [3H]flunitrazepam binding changes observed in the substantia nigra pars reticulata (-13%) and entopeduncular nucleus (-4%), whereas 'continuous' infusion of the same daily dose of L-3,4-dihydroxyphenylalanine had less effect (+14%, substantia nigra pars reticulata; +26%, entopeduncular nucleus). In contrast, the [3H]flunitrazepam binding decrease in the globus pallidus of the 6-hydroxydopamine lesioned animals was unaffected by either regime of chronic L-3,4-dihydroxyphenylalanine treatment. The changes in GABA receptor function implied by these results provide further insight into the pathophysiological effects of L-3,4-dihydroxyphenylalanine treatment on basal ganglia function, following dopamine denervation. In accordance with existing electrophysiological and biochemical evidence on this subject, the main implications of these results include reduced GABA sensitivity of neurons in the entopeduncular nucleus and substantia nigra pars reticulata, following chronic 'intermittent', but not chronic 'continuous' L-3,4-dihydroxyphenylalanine treatment; this may be due to a reversal of the 6-hydroxydopamine induced decrease in the GABA-mediated neurotransmission in the striatoentopeduncular and striatonigral pathways. In contrast, the regulation of GABA receptors in the globus pallidus does not appear to be subject to modulation by chronic L-3,4-dihydroxyphenylalanine administration, suggesting that dopamine replacement in this manner does not modify the 6-hydroxydopamine induced increase in GABA-mediated neurotransmission in the stratopallidal pathway.


ZIPCO, a putative metal ion transporter, is crucial for Plasmodium liver-stage development.
The malaria parasite, Plasmodium, requires iron for growth, but how it imports iron remains unknown. We characterize here a protein that belongs to the ZIP (Zrt-, Irt-like Protein) family of metal ion transport proteins and have named ZIP domain-containing protein (ZIPCO). Inactivation of the ZIPCO-encoding gene in Plasmodium berghei, while not affecting the parasite's ability to multiply in mouse blood and to infect mosquitoes, greatly impairs its capacity to develop inside hepatocytes. Iron/zinc supplementation and depletion experiments suggest that ZIPCO is required for parasite utilization of iron and possibly zinc, consistent with its predicted function as a metal transporter. This is the first report of a ZIP protein having a crucial role in Plasmodium liver-stage development, as well as the first metal ion transporter identified in Plasmodium pre-erythrocytic stages. Because of the drastic dependence on iron of Plasmodium growth, ZIPCO and related proteins might constitute attractive drug targets to fight against malaria.


Antitumor Mechanism of the Essential Oils from Two Succulent Plants in Multidrug Resistance Leukemia Cell.
Drug resistance remains a major challenge in the treatment of cancer. The multiplicity of the drug resistance determinants raises the question about the optimal strategies to deal with them. Essential oils showed to inhibit the growth of different tumor cell types. Essential oils contain several chemical classes of compounds whose heterogeneity of active moieties can help prevent the development of drug resistance. In the present paper, we analyzed, by gas chromatography-mass spectrometry the chemical composition of the essential oil of the leaves of Kalanchoe beharensis obtained by hydrodistillation and compared the chemical composition of its essential oil with that of Cyphostemma juttae. Our results demonstrated the anticancer and proapoptotic activities of both species against acute myeloid leukemia on an in vitro model and its multidrug resistant variant involving NF-κB pathway. The essential oils of both species produced a significant decrease in many targets of NF-κB both at mRNA and protein levels. The results corroborate the idea that essential oils may be a good alternative to traditional drugs in the treatment of cancer, especially in drug resistant cancer.


Patient expectations regarding total knee arthroplasty: differences among the United States, United Kingdom, and Australia.
Total knee arthroplasty is an effective treatment for severe osteoarthritis of the knee. Our aim was to determine whether patients from the United Kingdom, United States, and Australia have different preoperative expectations regarding total knee arthroplasty and whether these expectations have an impact on outcomes and patient satisfaction. Patients from the United Kingdom, the United States, and Australia were recruited into a prospective observational study of primary total knee arthroplasty for the treatment of osteoarthritis. Preoperative expectations, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Short Form-36 (SF-36) scores, and demographic, socioeconomic, and follow-up data, including satisfaction with outcome, were obtained from self-administered patient questionnaires. A total of 598 patients with a mean age of sixty-nine years at the time of the index arthroplasty were recruited; 58% were women. The majority of patients expected to have no pain at twelve months after the surgery, and with the numbers available there was no significant difference among the countries with regard to pain expectations. Australian patients were more likely than patients in the United Kingdom or the United States to expect better function at twelve months after the surgery. With the numbers available, satisfaction scores at twelve months did not differ significantly among the countries and were not influenced by preoperative expectations. Australian patients were more likely than patients in the United Kingdom or the United States to be unwilling to undergo total knee arthroplasty again at twelve months under similar circumstances. Patients from different countries have different expectations regarding total knee arthroplasty, which are not fully explained by differences in sociodemographic factors, clinical characteristics, and pain and functional status. Australian patients had the highest expectations but, despite reporting similar outcomes and satisfaction following total knee arthroplasty, they were more likely not to want to have the surgery again under similar circumstances.


Loss of selective endothelial cell vasoactive functions caused by hypercholesterolemia in pig coronary arteries.
The influence of hypercholesterolemia on the reactivity of coronary arteries was investigated after feeding a high-cholesterol diet to pigs for 9 weeks. After this duration of hypercholesterolemia, the fatty or intimal proliferative changes of atherosclerosis were not yet evident in the coronary arteries by light or electron microscopy. Changes in isometric tension were compared in isolated ring segments of coronary arteries from normal and hypercholesterolemic animals. The endothelium failed to inhibit contractions caused by 5-hydroxytryptamine in coronary arteries from hypercholesterolemic animals, but it did so in normal vessels. In contracted arteries, endothelium-dependent relaxations caused by 5-hydroxytryptamine and substance P were reduced by hypercholesterolemia. In contrast, endothelium-dependent relaxations mediated by norepinephrine acting at alpha 2-adrenoceptors and those caused by the calcium ionophore A23187 were unaffected. Endothelium-independent beta-adrenergic relaxations caused by norepinephrine, as well as those caused by nitroprusside, and papaverine also were unaffected by hypercholesterolemia. The loss of selective endothelial cell receptor-mediated relaxation suggests that it is not the ability of the coronary artery endothelium to elaborate vasodilators, but the initiation of the coronary artery endothelial cell response to 5-hydroxytryptamine and substance P that is affected by hypercholesterolemia. Thus, during hypercholesterolemia, selective endothelial cell dysfunction giving rise to abnormal coronary artery reactivity precedes the onset of coronary artery atherosclerosis.


Close relationships and adjustment to a life crisis: the case of breast cancer.
When life crises occur, significant others are thought to help alleviate distress and resolve practical problems. Yet life crises may overwhelm significant others, eroding their ability to provide effective support. The accuracy of these contrasting accounts of relationship functioning was evaluated in a study of 102 breast cancer patients and their significant others, interviewed at 4 and 10 months after diagnosis. Results largely confirmed the negative account of relationship functioning. Although significant others provided support in response to patients' physical impairment, they withdrew support in response to patients' emotional distress. Moreover, support from significant others did not alleviate patients' distress or promote physical recovery. These results reveal limits to the effectiveness of close relationships in times of severe stress.


The emergence of mupirocin resistance among clinical isolates of methicillin-resistant Staphylococcus aureus in Trinidad: a first report.
The objective of the study was to investigate the trend of mupirocin resistance among methicillin-resistant Staphylococcus aureus (MRSA) in Trinidad. No premarketing susceptibility surveillance was ever done following the introduction of mupirocin in 1986. A total of 188 MRSA strains recovered over a 2-year period from various body sites were tested for mupirocin resistance via the disc diffusion method. The major sources of MRSA were surgical site infections (74.0%) and bloodstream infections (8.0%). High-level and low-level mupirocin resistance were detected in 26.1 and 44.1% of MRSA stains, respectively. Resistances to other non-beta-lactam antibiotics were also high. Ninety-eight percent of all MRSA were resistant to erythromycin. This was followed by resistance rates of 96.8, 95.2, 94.1, 93.6, and 93.1%, for gentamicin, ciprofloxacin, amikacin and tobramycin, co-trimoxazole, and tetracycline, respectively. No MRSA strains were found to be resistant to vancomycin, linezolid, and quinupristin-dalfopristin. The study showed that mupirocin resistance among Trinidadian MRSA strains was relatively high compared to that seen in other countries. Because of the increasing prevalence of MRSA at the San Fernando General Hospital (SFGH) and the apparently increasing resistance to mupirocin, frequent monitoring of MRSA susceptibility patterns and infection control initiatives may be helpful in reducing the incidence of MRSA with a concomitant decrease in mupirocin resistance. This report is the first after 20 years of continuous use of the drug at the SFGH.


Reproductive healthcare utilization in urban poor settlements of Delhi: Baseline survey of ANCHUL (Ante Natal and Child Health care in Urban Slums) project.
Disparity in utilization of reproductive healthcare services between the urban poor and the urban non-poor households in the developing nations is well known. However, disparity may also exist within urban poor households. Our objective was to document the extent of disparity in reproductive healthcare utilization among the urban poor and to identify the socio-demographic determinants of underutilization with a view to characterizing this vulnerable subpopulation. A survey of 16,221 households was conducted in 39 clusters from two large urban poor settlements in Delhi. From 13,451 consenting households, socio-demographic data and information on births, maternal and child deaths within the previous year was collected. Details of antenatal care (ANC) was collected from 597 pregnant women. Information on ANC and postnatal care was also obtained from 596 recently delivered (within six months) mothers. All data were captured electronically using a customized and validated smart phone application. Households were categorized into quintiles of socio-economic position (SEP) based on dwelling characteristics and possession of durable assets using principal component analysis. Potential socio-demographic determinants of reproductive healthcare utilization were examined using random effects logistic regression. The prevalence of facility based birthing was 77% (n = 596 mothers). Of the 596 recently delivered mothers only 70% had an ANC registration card, 46.3% had ANC in their first trimester, 46% had visited a facility within 4 weeks post-delivery and 27% were using modern contraceptive methods. Low socio-economic position was the most important predictor of underutilization with a clear gradient across SEP quintiles. Compared to the poorest, the least poor women were more likely to be registered for ANC (OR 1.96, 95%CI 0.95-4.15) and more likely to have made ≥ 4 ANC visits (OR 5.86, 95%CI 2.82-12.19). They were more likely to have given birth in a facility (OR 4.87, 95%CI 2.12-11.16), to have visited a hospital within one month of childbirth (OR 3.18, 95%CI 1.62-6.26). In general, government funded health insurance and conditional cash transfers schemes were underutilized in this community. The poorest segment of the urban poor population utilizes reproductive healthcare facilities the least. Strategies to improve access and utilization of healthcare services among the poorest of the poor may be necessary to achieve universal health coverage.


Sequence-Specific Detection of Aristolochia DNA - A Simple Test for Contamination of Herbal Products.
Herbal medicines are used globally for their health benefits as an alternative therapy method to modern medicines. The market for herbal products has increased rapidly over the last few decades, but this has in turn increased the opportunities for malpractices such as contamination or substitution of products with alternative plant species. In the 1990s, a series of severe renal disease cases were reported in Belgium associated with weight loss treatment, in which the active species Stephania tetrandra was found to be substituted with Aristolochia fangchi. A. fangchi contains toxic aristolochic acids, which have been linked to kidney failure, as well as cancers of the urinary tract. Because of these known toxicities, herbal medicines containing these compounds, or potentially contaminated by these plants, have been restricted or banned in some countries, but they are still available via the internet and in alternate formulations. In this study, a DNA based method based on quantitative real-time PCR (qPCR) was tested to detect and distinguish Aristolochia subg. Siphisia (Duch.) O.C.Schmidt species from a range of medicinal plants that could potentially be contaminated with Aristolochia material. Specific primers were designed to confirm that Aristolochia subg. Siphisia can be detected, even in small amounts, if it is present in the products, fulfilling the aim of offering a simple, cheaper and faster solution than the chemical methods. A synthetic gBlock template containing the primer sequences was used as a reference standard to calibrate the qPCR assay and to estimate the copy number of a target gene per sample. Generic primers covering the conserved 5.8S rRNA coding region were used as internal control to verify DNA quality and also as a reference gene for relative quantitation. To cope with potentially degraded DNA, all qPCR primer sets were designed to generate PCR products of under 100 bp allowing detection and quantification of A. fangchi gBlock even when mixed with S. tetrandra gBlock in different ratios. All proportions of Aristolochia, from 100 to 2%, were detected. Using standards, associating the copy number to each start quantity, the detection limit was calculated and set to about 50 copies.


Stimulation through the T cell receptor induces Cbl association with Crk proteins and the guanine nucleotide exchange protein C3G.
We and others have recently identified Cbl, the protein product of the c-cbl protooncogene, as an early tyrosine kinase substrate upon T cell activation and have shown that Cbl forms in vivo complexes with Src family tyrosine kinases, Grb2 adaptor protein, and the p85 subunit of PI-3 kinase. Here we show that Cbl associates with all three forms of the human Crk protein, predominantly CrkL, following T cell receptor activation of Jurkat T cells. Association between Cbl and Crk proteins was confirmed in normal human peripheral blood-derived T cells. In vitro, Cbl was able to interact with the Crk SH2 domain but not the SH3 domain. A phosphopeptide corresponding to a potential Crk SH2 domain-binding motif in Cbl (pYDVP) specifically inhibited binding between Cbl and Crk SH2 domain. Anti-Cbl antibody completely immunodepleted the CrkL-associated 120kDa phosphotyrosyl polypeptide, suggesting that the recently described p130cas-related Crk-associated p116 of T cells may be Cbl. Consistent with this possibility, the 4F4 antibody used to characterize the p116 polypeptide cross-reacted with Cbl protein when it was resolved on one- or two-dimensional gels. CrkL was constitutively associated with a substantial amount of the guanine nucleotide exchange protein C3G, and a fraction of the C3G protein was coimmunoprecipitated with Cbl in activated Jurkat T cells. These results suggest the possibility that Cbl may participate in a signaling pathway that regulates guanine nucleotide exchange on small G-proteins in T cells.


Comparative analysis of microsatellite loci in four fruit fly species of the genus Ceratitis (Diptera: Tephritidae).
The possibility to cross-species amplify microsatellites in fruit flies of the genus Ceratitis was tested with the polymerase chain reaction (PCR) by analysing 23 Ceratitis capitata (Wiedemann) microsatellite markers on the genomic DNA of three other economically important, congeneric species: C. rosa (Karsch), C. fasciventris (Bezzi) and C. cosyra (Walker). Twenty-two primer pairs produced amplification products in at least one of the three species tested. The majority of the products were similar, if not identical in size to those expected in C. capitata. The structures of the repeat motifs and their flanking sequences were examined for a total of 79 alleles from the three species. Sequence analysis revealed the same repeat type as the homologous C. capitata microsatellites in the majority of the loci, suggesting their utility for population analysis across the species range. A total of seven loci were differentially present/absent in C. capitata, C. rosa, C. fasciventris and C. cosyra, suggesting that it may be possible to differentiate these four species using a simple sequence repeat-based PCR assay. It is proposed that medfly-based microsatellite markers could be utilized in the identification and tracing of the geographical origins of colonist pest populations of the four tested species and in the assessment of their risk and invasive potentials; thereby assisting regulatory authorities in implementing quarantine restrictions and other pest control measures.


Brain abscess in children.
Brain abscess is a serious life-threatening complication of several diseases. The objective of this study was to look at the clinical profile of patients, predisposing conditions, microbiology and outcome of children suffering from brain abscess. Thirty children aged less than 15 years were reviewed. There were 15 males and 15 females. The mean age of presentation was 5.6+/-4.4 years. The duration of illness at the time of admission was 17.6+/-24.6 days. Typically patients presented with fever, vomiting, headache and seizures. The predisposing conditions found were cyanotic congenital heart disease in 11 (37%) of children, meningitis in 6 (20%), septicemia in 7 (23%) and no underlying cause was found in 5 (17%) children. The most common microbe in children with cyanotic congenital heart disease was of the Streptococcus milleri group (52%). Computerized tomography confirmed the diagnosis and the most common location of the abscess was the parietal lobe of the cerebral hemisphere. All abscesses were large, more than 2 cm in diameter and were aspirated surgically. Excision was performed in 6 children. Five children expired, one due to a intracranial bleeding and the others due to severe cerebral edema and tentorial herniation. Complications were seen in 20 children and 16 had sequelae, hemiparesis in 11 and seizure disorder in 5. Brain abscess is a serious infection with poor outcome if diagnosed late. Delayed surgical drainage has high morbidity and mortality. The threshold for diagnosis should be low, particularly in children with a predisposing condition like cyanotic congenital heart disease.


Efficient charge transfer and utilization of near-infrared solar spectrum by ytterbium and thulium codoped gadolinium molybdate (Gd2(MoO4)3:Yb/Tm) nanophosphor in hybrid solar cells.
In this work, thulium and ytterbium codoped gadolinium molybdate (Gd2(MoO4)3:Yb/Tm) nanophosphors (NPs) have been synthesized, followed by being incorporated into a photo-catalytic titania (TiO2) nanoparticle layer. In detail, morphology and phase identification of the prepared NPs are first characterized and then the up-conversion of the Gd2(MoO4)3:Yb/Tm NPs is studied. Electron transfer dynamics after interfacing with bare or NP-doped electron donor TiO2 and the corresponding photovoltaic performance of solar cells are explored. The results show that Gd2(MoO4)3:Yb/Tm NPs excited at 976 nm exhibit intense blue (460-498 nm) and weak red (627-669 nm) emissions. The lifetime of electron transfer is shortened from 817 to 316 ps after incorporating NPs and correspondingly the electron transfer rate outstrips by 3 times that of the bare TiO2. Consequently, a notable power conversion efficiency of 4.15% is achieved as compared to 3.17% of pure TiO2/PTB7. This work demonstrates that the co-doping of robust rare earth ions with different unique functions can widen the harvesting range of the solar spectrum, boost electron transfer rate and eventually strengthen device performance, without complicated interfacial and structural engineering.


Exposure to microorganisms, febrile and airway-obstructive symptoms, immune status and lung function of Swedish farmers.
A questionnaire was sent to 512 farmers, members of a local farmer's health association. Eighty were interviewed, and their serum precipitins and total serum immunoglobulin E (IgE) values were determined. Forty-five underwent extensive pulmonary function tests. On the basis of the clinical evaluation it was estimated that 19% of the farmers had experienced febrile reactions (fever and/or shivering) following exposure to organic dust, 50% of the 19% having been exposed within the last 2.5 years. Common causes were moldy grain, hay, and woodchips. The pulmonary function, gas exchange, and chest radiographs of those who had previously had febrile reactions were normal. Only 13% showed positive precipitin reactions in Ouchterlony double-diffusion tests. With more sensitive tests, positive precipitins were found in 59%, but they were negatively correlated with febrile episodes. Air samples collected during work with hay and grain on 21 farms contained between 10(7) to 2 X 10(9) microorganisms/m3. The highest values were associated with symptoms of alveolitis. Eleven percent of the farmers reported obstructive chest symptoms following exposure to organic dust. This group showed decreased pulmonary function and elevated serum IgE levels and included a high proportion of smokers and exsmokers. No correlation was found between febrile and obstructive reactions.


The incidence of symptomatic lower-extremity lymphedema following treatment of uterine corpus malignancies: a 12-year experience at Memorial Sloan-Kettering Cancer Center.
To describe the incidence of symptomatic postoperative lower-extremity lymphedema in women treated for uterine corpus cancer, and to evaluate its relationship to regional lymph node removal and postoperative therapy. A retrospective chart review of all patients with uterine corpus cancer managed over a 12-year period (1/93-12/04). All patients had a hysterectomy as part of their therapy. We identified patients with leg lymphedema - as described by the physician or reported by the patient - through medical records. We excluded cases of leg edema that developed secondary to medical conditions such as cardiovascular and renal disease, venous thrombosis, and end-stage recurrent malignancy. Lymphedema dermal changes and related fibrosis were graded using the common terminology criteria for adverse events. In all, 1,289 patients with uterine corpus malignancy were evaluated. We excluded other chronic lower-extremity edema that was related to a variety of medical conditions in 74 patients (5.7%). With a median follow-up of 3 years (interquartile range, 1.1-5.4 years), new symptomatic post-treatment lower-extremity lymphedema was noted in 16 patients. Patients who had lymph nodes removed at initial surgery had a higher rate of developing lymphedema (16/670, 2.4%) than those who did not (0/619, 0%) (P = 0.0001). Furthermore, symptomatic lymphedema was limited to patients who had 10 or more regional lymph nodes removed 16/469 (3.4%). Lymphedema was noted at a median of 5.3 months after surgery (range, 1-32 months). Lymphedema was unilateral in 11 patients (69%) and bilateral in 5 (31%); moreover, it was considered grade 1 in 12 patients (75%) and grade 2 in 4 (25%). Age, weight, stage, type of hysterectomy, and type of postoperative adjuvant therapy were not associated with lymphedema. To date, this is the largest series evaluating symptomatic lower-extremity lymphedema in women with uterine corpus cancer. Patients who had 10 or more regional lymph nodes removed at initial surgery appeared to be at higher risk for developing new symptomatic leg lymphedema. Patients undergoing surgery with lymphadenectomy for uterine corpus malignancy should be informed about the possibility of postoperative new symptomatic leg lymphedema. A prospective evaluation of leg lymphedema is needed to accurately determine the incidence, severity, and risk factors of this complication.


Causal Discovery from Discrete Data using Hidden Compact Representation.
Causal discovery from a set of observations is one of the fundamental problems across several disciplines. For continuous variables, recently a number of causal discovery methods have demonstrated their effectiveness in distinguishing the cause from effect by exploring certain properties of the conditional distribution, but causal discovery on categorical data still remains to be a challenging problem, because it is generally not easy to find a compact description of the causal mechanism for the true causal direction. In this paper we make an attempt to find a way to solve this problem by assuming a two-stage causal process: the first stage maps the cause to a hidden variable of a lower cardinality, and the second stage generates the effect from the hidden representation. In this way, the causal mechanism admits a simple yet compact representation. We show that under this model, the causal direction is identifiable under some weak conditions on the true causal mechanism. We also provide an effective solution to recover the above hidden compact representation within the likelihood framework. Empirical studies verify the effectiveness of the proposed approach on both synthetic and real-world data.


Comparison of ureteroscopic pneumatic lithotripsy and extracorporeal shock wave lithotripsy for the management of proximal ureteral stones: A single center experience.
To evaluate and compare the effectiveness of ureteroscopic (URS) pneumatic lithotripsy versus extracorporeal shock wave lithotripsy (ESWL) in the management of the proximal ureteral stones in terms of stone- free rates, complications and costs involved. We included 200 patients in Group 1 who underwent ESWL and 200 patients in Group 2 who underwent URS intervention. We used Modulith SL X lithotripter 3rd generation Storz medical for ESWL group while Swiss pneumatic lithoclast was used to break the stone in the URS group. Stone-free status was defined as stone fragment of less than 4 mm on follow- up kidney ureter and bladder X-ray after 3 months of procedure. SPSS version 16 was used for statistical analysis. The mean age in ESWL and URS groups were 39.21±13.36, and 43.13±13.65 years respectively. Mean stone size was 10.47±3.7 mm (ESWL) and 13.6±6.6 mm (URS). Stone- free rate after single procedure was (125/200 patients) 62.5% for ESWL and (168/200 patients) 84% for URS group (p=0.001). Complications included post procedure sepsis in 3 (1.5%) patient of ESWL, while 7 (3.5%) patients of URS groups. Steinstrasse was seen in 4 (2%) patients of ESWL group. No mortality was seen in both groups. Mean costs for ESWL were US $320±50 while US $1100±150 for URS group (p=0.001). The stone-free rates after single procedure were significantly higher for the URS group while the complication rates were comparable in both groups. Treatment costs were significantly lower for the ESWL group.


The Relationship between Dark Triad Personality Traits and Sexting Behaviors among Adolescents and Young Adults across 11 Countries.
Sexting is an increasingly common phenomenon among adolescents and young adults. Some studies have investigated the role of personality traits in different sexting behaviors within mainstream personality taxonomies like Big Five and HEXACO. However, very few studies have investigated the role of maladaptive personality factors in sexting. Therefore, the present study investigated the relationship between Dark Triad Personality Traits and experimental (i.e., sharing own sexts), risky (i.e., sexting under substance use and with strangers), and aggravated sexting (i.e., non-consensual sexting and sexting under pressure) across 11 countries. An online survey was completed by 6093 participants (Mage = 20.35; SDage = 3.63) from 11 different countries which covered four continents (Europe, Asia, Africa, and America). Participants completed the Sexting Behaviors Questionnaire and the 12-item Dark Triad Dirty Dozen scale. Hierarchical regression analyses showed that sharing own sexts was positively predicted by Machiavellianism and Narcissism. Both risky and aggravated sexting were positively predicted by Machiavellianism and Psychopathy. The present study provided empirical evidence that different sexting behaviors were predicted by Dark Triad Personality Traits, showing a relevant role of Machiavellianism in all kinds of investigated sexting behaviors. Research, clinical, and education implications for prevention programs are discussed.


Autophagy Is Required for Maturation of Surfactant-Containing Lamellar Bodies in the Lung and Swim Bladder.
Autophagy is an intracellular degradation system, but its physiological functions in vertebrates are not yet fully understood. Here, we show that autophagy is required for inflation of air-filled organs: zebrafish swim bladder and mouse lung. In wild-type zebrafish swim bladder and mouse lung type II pulmonary epithelial cells, autophagosomes are formed and frequently fuse with lamellar bodies. The lamellar body is a lysosome-related organelle that stores a phospholipid-containing surfactant complex that lines the air-liquid interface and reduces surface tension. We find that autophagy is critical for maturation of the lamellar body. Accordingly, atg-deficient zebrafish fail to maintain their position in the water, and type-II-pneumocyte-specific Fip200-deficient mice show neonatal lethality with respiratory failure. Autophagy suppression does not affect synthesis of the surfactant phospholipid, suggesting that autophagy supplies lipids and membranes to lamellar bodies. These results demonstrate an evolutionarily conserved role of autophagy in lamellar body maturation.


Intake of long-chain ω-3 fatty acids from diet and supplements in relation to mortality.
Evidence from experimental studies suggests that the long-chain ω-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid have beneficial effects that may lead to reduced mortality from chronic diseases, but epidemiologic evidence is mixed. Our objective was to evaluate whether intake of long-chain ω-3 fatty acids from diet and supplements is associated with cause-specific and total mortality. Study participants (n = 70,495) were members of a cohort study (the Vitamins and Lifestyle Study) who were residents of Washington State aged 50-76 years at the start of the study (2000-2002). Participants were followed for mortality through 2006 (n = 3,051 deaths). Higher combined intake of eicosapentaenoic acid and docosahexaenoic acid from diet and supplements was associated with a decreased risk of total mortality (hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.73, 0.93) and mortality from cancer (HR = 0.77, 95% CI: 0.64, 0.92) but only a small reduction in risk of death from cardiovascular disease (HR = 0.87, 95% CI: 0.68, 1.10). These results suggest that intake of long-chain ω-3 fatty acids may reduce risk of total and cancer-specific mortality.


Potential contribution of maternal zinc supplementation during pregnancy to maternal and child survival.
Mild-to-moderate zinc deficiency may be relatively common worldwide, but the public health importance of this degree of zinc deficiency is not well defined. The purpose of this review was to provide a conceptual framework for evaluating the public health importance of maternal zinc deficiency as it relates to fetal growth and development, complications of pregnancy, labor and delivery, and maternal and infant health. The mechanisms through which zinc deficiency could influence health outcomes are well described. The results of experimental studies conducted in animal models have motivated concern about the potential health effects of mild-to-moderate maternal zinc deficiency. Observational studies in human populations have produced strong associations between poor maternal zinc status and various indicators of poor pregnancy outcome, but supplementation trials have not produced strong, or even consistent results. Supplementation trials are needed to define the public health importance of maternal zinc deficiency worldwide.


Rapid tea catechins and caffeine determination by HPLC using microwave-assisted extraction and silica monolithic column.
A rapid reversed-phase high performance liquid chromatographic method using a monolithic column for the determination of eight catechin monomers and caffeine was developed. Using a mobile phase of water:acetonitrile:methanol (83:6:11) at a flow rate of 1.4 mL min(-1), the catechins and caffeine were isocratically separated in about 7 min. The limits of detection and quantification were in the range of 0.11-0.29 and 0.33-0.87 mg L(-1), respectively. Satisfactory recoveries were obtained (94.2-105.2 ± 1.8%) for all samples when spiked at three concentrations (5, 40 and 70 mg L(-1)). In combination with microwave-assisted extraction (MAE), the method was applied to the determination of the catechins and caffeine in eleven tea samples (6 green, 3 black and 2 oolong teas). Relatively high levels of caffeine were found in black tea, but higher levels of the catechins, especially epigallocatechin gallate (EGCG) were found in green teas.


Localization of TFPI-2 in the nucleus modulates MMP-2 gene expression in breast cancer cells.
TFPI-2 has recently been recognized as a tumor suppressor, which not only plays a fundamental role in modulation of ECM integrity, but also involves the regulation of many oncogenes. In this study, we investigated the potential mechanism of TFPI-2 in the suppression of breast cancer growth and invasion. We showed that, with either over-expression of TFPI-2 or after treatment with exogenous rTFPI-2, breast cancer cells exhibited reduced proliferation and invasion. We demonstrated that in addition to being secreted, TFPI-2 was also distributed throughout the cytoplasm and nucleus. Nuclear localization of TFPI-2 contributed to inhibition of MMP-2 mRNA expression, which could be reversed after the nuclear localization signal was deleted. In the nucleus, interaction of TFPI-2 with Ap-2α attenuated the binding of AP-2α to the MMP-2 promoter, therefore reducing the transcriptional activity of the gene. Our results suggest that one of the mechanisms by which TFPI-2 inhibits breast cancer cell invasion could be via the regulation of MMP-2 gene transcription.


Living Well with a Disability, a Self-Management Program.
Approximately 56.7 million persons in the United States have functional impairments that can lead to disability. As a group, persons with disabilities show disparities in measures of overall health when compared with the general population. Much of this can be attributed to secondary conditions rather than to the impairment itself. Persons with disabilities can prevent and manage many of the conditions that contribute to these disparities. The Living Well with a Disability program was developed to support persons with disabilities to manage their health. The curriculum helps participants achieve early success in self-management of quality-of-life goals to build confidence for making health behavior changes; it includes 11 chapters that facilitators use to conduct an orientation session and 10 weekly, 2-hour sessions. The program has been implemented by 279 community-based agencies in 46 states. On the basis of the data from the field trial, these community applications have served approximately 8,900 persons since 1995, resulting in an estimated savings of $6.4-$28.8 million for health care payers. Persons with disabilities have unique needs that can be addressed through multiple levels of intervention to reduce health disparities. The Living Well with a Disability program is a promising intervention that has demonstrated improvements in health-related quality of life and health care use.


The anticoagulant treatment for sepsis induced disseminated intravascular coagulation; network meta-analysis.
The benefits and harm caused by anticoagulant treatments for sepsis induced disseminated intravascular coagulation (DIC) remain unclear. Therefore, we performed a network meta-analysis to assess the effect of available anticoagulant treatments on patient mortality, DIC resolution and the incidence of bleeding complication in patients with septic DIC. We considered all studies from four recent systematic reviews and searched the PubMed, MEDLINE, and Cochrane databases for other studies that investigated anticoagulant treatment for septic DIC using antithrombin, thrombomodulin, heparin, or protease inhibitors in adult critically ill patients. These four anticoagulants and placebo were compared. The primary outcome in this study was patient mortality, and the secondary outcomes were the DIC resolution rate and incidence of bleeding complications. The network meta-analysis included 1340 patients from nine studies. There were no significant differences in the risks of mortality and bleeding complications among all direct comparisons and the network meta-analysis. Using a placebo was associated with a significantly lower rate of DIC resolution, compared to antithrombin in the direct comparison (odds ratio [OR]: 0.20, 95% credible interval [95% CrI]: 0.046-0.81) and in the network meta-analysis (OR: 0.20, 95% CrI: 0.043-0.84). Our study revealed no significant differences in the risks for mortality and bleeding complications when a placebo and all four anticoagulants were compared in septic DIC patients. The results also indicated that antithrombin was associated with a five-fold higher likelihood of DIC resolution, compared to placebo.


Revealing the appetite of the marine aquarium fish trade: the volume and biodiversity of fish imported into the United States.
The aquarium trade and other wildlife consumers are at a crossroads forced by threats from global climate change and other anthropogenic stressors that have weakened coastal ecosystems. While the wildlife trade may put additional stress on coral reefs, it brings income into impoverished parts of the world and may stimulate interest in marine conservation. To better understand the influence of the trade, we must first be able to quantify coral reef fauna moving through it. Herein, we discuss the lack of a data system for monitoring the wildlife aquarium trade and analyze problems that arise when trying to monitor the trade using a system not specifically designed for this purpose. To do this, we examined an entire year of import records of marine tropical fish entering the United States in detail, and discuss the relationship between trade volume, biodiversity and introduction of non-native marine fishes. Our analyses showed that biodiversity levels are higher than previous estimates. Additionally, more than half of government importation forms have numerical or other reporting discrepancies resulting in the overestimation of trade volumes by 27%. While some commonly imported species have been introduced into the coastal waters of the USA (as expected), we also found that some uncommon species in the trade have also been introduced. This is the first study of aquarium trade imports to compare commercial invoices to government forms and provides a means to, routinely and in real time, examine the biodiversity of the trade in coral reef wildlife species.


Local-global processing bias is not a unitary individual difference in visual processing.
A large body of research reports individual differences in local and global visual processing in relation to expertise, culture and psychopathology. However, recent research has suggested that various different measures of local-global processing are not strongly associated with one another, calling its construct validity into question. The current study sought to further explore the validity of local-global processing biases in perception by developing three tasks based on two existing paradigms: the Embedded Figures Test (EFT) and the Navon hierarchical letters task. The newly developed tasks aimed to control for stimulus and response factors that may have impacted upon the reliability of previous research. They were administered to a large sample of undergraduate students (N>100). The results of two new versions of the EFT indicated that disembedding performance is influenced by the structure of the embedding context. In addition, global precedence and interference in the Navon task remained present even when local attentional approaches to global hierarchical stimuli were restricted. Inter-task correlations within the EFT were high but low between the EFT and the Navon task, lending support to the notion that local-global processing is not a monolithic construct, but representative of a number of distinct perceptual abilities and biases. Future research may use these task distinctions to pinpoint more precisely which aspects of perceptual processing characterise specific (clinical) participant populations.


Qualitative interviews vs standardized self-report questionnaires in assessing quality of life in heart transplant recipients.
Quality of life (QoL) studies in heart transplant recipients (HTRs) using validated, quantitative, self-report questionnaires have reported poor QoL in approximately 20% of patients. This consecutive mixed methods study compared self-report questionnaires, the Medical Outcomes Study 36-item Short Form Health Survey (MOS SF-36) and the Atkinson Life Satisfaction Scale, with phenomenologically informed audiovisual (AV) qualitative interview data in 27 medically stable HTRs (70% male; age 53 ± 13.77 years; time since transplant 4.06 ± 2.42 years). Self-report questionnaire data reported poor QoL and more distress compared with previous studies and normative population samples; in contrast, 52% of HTRs displayed pervasive distress according to visual methodology. Using qualitative methods to assess QoL yields information that would otherwise remain unobserved by the exclusive use of quantitative QOL questionnaires.


Regulation of Mitochondrial Function and Biogenesis in Cucumber (Cucumis sativus L.) Cotyledons during Early Seedling Growth.
The aim of this work was to characterize the respiratory metabolism of the greening cotyledons of cucumber (Cucumis sativus L.) during early seedling growth and to investigate how this is integrated with changes in mitochondrial biogenesis and function. In light-grown cotyledons, lipid mobilization extended from germination to 6 days postimbibition, reaching a maximum at 3 to 4 days postimbibition. The rate of dark oxygen uptake reached a maximum at 2 days postimbibition in dark-grown and 3 days postimbibition in light-grown cotyledons. Development of photosynthetic capacity occurred from 4 to 7 days postimbibition. In dark-grown cotyledons, lipid mobilization extended beyond 7 days postimbibition, and there was no greening or acquisition of photosynthetic competence. Measurements of mitochondrial function indicated that the respiratory capacity of the tissue changed such that during lipid mobilization there was a much greater capacity for the operation of the nondecarboxylating portion of the citric acid cycle (succinate to oxaloacetate), whereas during the development of photosynthetic function the activity of the remainder of the cycle (oxaloacetate to succinate) was induced. Comparison of the maximum capacities for mitochondrial substrate oxidations in vitro with the rates of in vivo substrate oxidations, predicted from the rate of lipid breakdown, indicated that mitochondria in this tissue operate at or below state 4 rates, suggesting limitation by both availability of ADP and substrate.


Breast cancer diagnosis using a microfluidic multiplexed immunohistochemistry platform.
Biomarkers play a key role in risk assessment, assessing treatment response, and detecting recurrence and the investigation of multiple biomarkers may also prove useful in accurate prediction and prognosis of cancers. Immunohistochemistry (IHC) has been a major diagnostic tool to identify therapeutic biomarkers and to subclassify breast cancer patients. However, there is no suitable IHC platform for multiplex assay toward personalized cancer therapy. Here, we report a microfluidics-based multiplexed IHC (MMIHC) platform that significantly improves IHC performance in reduction of time and tissue consumption, quantification, consistency, sensitivity, specificity and cost-effectiveness. By creating a simple and robust interface between the device and human breast tissue samples, we not only applied conventional thin-section tissues into on-chip without any additional modification process, but also attained perfect fluid control for various solutions, without any leakage, bubble formation, or cross-contamination. Four biomarkers, estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR) and Ki-67, were examined simultaneously on breast cancer cells and human breast cancer tissues. The MMIHC method improved immunoreaction, reducing time and reagent consumption. Moreover, it showed the availability of semi-quantitative analysis by comparing Western blot. Concordance study proved strong consensus between conventional whole-section analysis and MMIHC (n = 105, lowest Kendall's coefficient of concordance, 0.90). To demonstrate the suitability of MMIHC for scarce samples, it was also applied successfully to tissues from needle biopsies. The microfluidic system, for the first time, was successfully applied to human clinical tissue samples and histopathological diagnosis was realized for breast cancers. Our results showing substantial agreement indicate that several cancer-related proteins can be simultaneously investigated on a single tumor section, giving clear advantages and technical advances over standard immunohistochemical method. This novel concept will enable histopathological diagnosis using numerous specific biomarkers at a time even for small-sized specimens, thus facilitating the individualization of cancer therapy.


Fluorescence of a tryptophan bearing peptide from smooth muscle myosin light chain kinase upon binding to two closely related calmodulins.
We have investigated the fluorescence of a calmodulin binding peptide (AS19) based on the sequence of the calmodulin binding domain of smooth muscle myosin light chain kinase and bearing a tryptophan residue at position 5 upon binding to two closely related calmodulins. The emission maximum of peptide AS19 bound to the engineered SYNCAM calmodulin was 318 nm and a vibrational structure was clearly apparent. The emission maximum of peptide AS19 bound to chicken gizzard calmodulin (ChG CaM) was 327 nm and its spectrum was featureless. Red edge excitation effect supports the assumption that the polarity of Trp-5 environment is larger in the complex with ChG CaM than with SYNCAM, in agreement with fluorescence spectra. Time-resolved fluorescence and anisotropy measurements showed that, in both complexes, the tryptophan emitting state was 1La. The X-ray structure of the calmodulin-peptide complex has been resolved (W. E. Meador, A. R. Means, and F. A. Quiocho, 1992, Science 257, 1251-1255). The Trp binding site has been characterized. It differs by a single-point mutation between the two calmodulins: Met-144 of ChG CaM has been replaced by Val in SYNCAM. This suggests that the spectral relaxation of Trp-5 in the complex with ChG CaM as compared to SYNCAM is due to the polarizability of the sulfur atom containing Met side chain that is higher than that of Val. This provides an ideal system to investigate the origin of the Stokes shift of the indole moiety in proteins.


Plantar Warts: Epidemiology, Pathophysiology, and Clinical Management.
Verrucae plantaris (plantar warts) are common cutaneous lesions of the plantar aspect of the foot that are caused by the human papillomavirus (HPV). Ubiquitous in our environment, asymptomatic infection with HPV occurs frequently, with most infections controlled or cleared by cellular and humoral immune responses. However, certain populations have been observed to manifest plantar warts at higher rates compared with the general population, placing them at increased risk for wart-induced pain and complications. Plantar warts shed HPV, which can then infect other sites in the plantar region or spread to other people. Although controlling risk factors is useful in preventing infection, the pervasive nature of HPV makes these preventive measures frequently impractical. This literature review outlines the current knowledge regarding the relationship between plantar wart pathophysiology, HPV transmission, and epidemiologic characteristics. Given the high propensity for treatment resistance of plantar warts and no established, practical, and reliable method of prevention, HPV prophylaxis for populations that demonstrate high rates of plantar warts may be of benefit in controlling the spread of lesions.


Immunohistochemical localization of short chain cartilage collagen (type X) in avian tissues.
Monoclonal antibodies were produced against the recently described short chain cartilage collagen (type X collagen), and one (AC9) was extensively characterized and used for immunohistochemical localization studies on chick tissues. By competition enzyme-linked immunosorbent assay, antibody AC9 was observed to bind to an epitope within the helical domain of type X collagen and did not react with the other collagen types tested, including the minor cartilage collagens 1 alpha, 2 alpha, 3 alpha, and HMW-LMW. Indirect immunofluorescence analyses with this antibody were performed on unfixed cryostat sections from various skeletal and nonskeletal tissues. Only those of skeletal origin showed detectable reactivity. Within the cartilage portion of the 13-d-old embryonic tibiotarsus (a developing long bone) fluorescence was observed only in that region of the diaphysis containing hypertrophic chondrocytes. None was detectable in adjacent regions or in the epiphysis. Slight fluorescence was also present within the surrounding sleeve of periosteal bone. Consistent with these results, the antibody did not react with the cartilages of the trachea and sclera, which do not undergo hypertrophy during the stages examined. It did, however, lightly react with the parietal bones of the head, which form by intramembranous ossification. These results are consistent with our earlier biochemical analyses, which showed type X collagen to be a product of that subpopulation of chondrocytes that have undergone hypertrophy. In addition, either it or an immunologically cross-reactive molecule is also present in bone, and exhibits a diminished fluorescent intensity as compared with hypertrophic cartilage.


Sexual signalling in bladder grasshoppers: tactical design for maximizing calling range.
Pair formation in the bladder grasshopper (Bullacris membracioides) is by duetting and male phonotaxis. Low-frequency stridulatory signals are emitted by an abdominal resonator in the male and are answered by females using a species-specific time delay. Acoustic transmission in the natural environment was studied using playback of sexual signals over distances of 450m under two atmospheric conditions (day and night). Upward-refracting sound conditions and a sound shadow zone beyond approximately 50m prevailed during the day. Acoustic enhancement was demonstrated at night when downward-refracting temperature inversions created a tunnel effect with sound caught between the ground and zones of different temperatures. Transmission conditions are almost ideal at night when the species actually calls; calling distances of 150m for the male signal in the afternoon increased to 1.5-1.9km at night, arguably the largest calling distance yet reported for insects. In contrast, female calls transmit over a maximum of 50m, signifying a marked discrepancy in the active space of sex-specific signals. Transmission distance may, however, be profoundly affected by levels of masking noise. Adaptations to increase the signal range may variously be found in the signal itself, in behaviour patterns or in the sensory system. Here we demonstrate aspects of the first two types of adaptation in the sexual signalling system of a grasshopper in which maximizing the calling range appears to be the major selection pressure, with lesser effects imposed by inter- and intraspecific pressures and by the transmission channel.


The efficiency of two-photon photolysis of a "caged" fluorophore, o-1-(2-nitrophenyl)ethylpyranine, in relation to photodamage of synaptic terminals.
Localized photolysis of caged neurotransmitters with the two-photon effect for investigations at synaptic preparations was evaluated by determining the toxicity to synaptic transmission of pulsed near-IR laser light focused into the terminals of the snake neuromuscular junction, and measuring the extent of photolysis of a conventional caging group with similar irradiation in microcuvette experiments. Photodamage was seen in synaptic terminals as a large, irreversible increase of spontaneous synaptic activity with laser flashes of 5 ms at 1 Hz at average powers > 5 mW and was due to multiphoton absorption. Localized photolysis due to two-photon absorption was investigated for a representative caged fluorophore, the 1-(2-nitrophenyl)ethyl ether of pyranine (NPE-HPTS). Irradiation of NPE-HPTS at 5 mW with the same optical arrangement produced very low rates of photolysis. NPE-HPTS photolysis mechanisms were investigated at high laser powers by measuring (1) the kinetics of two-photon fluorescence generated by two-photon photolysis in the focal volume and (2) the rates of HPTS accumulation inside closed 2-10 microm radius vesicles, measured with one-photon excitation during two-photon photolysis by repetitive 10 micros laser exposures. The two-photon crosssection of NPE-HPTS photolysis calculated from the rates is 0.02-0.04 GM (10(-50) cm4 x s/photon) and limits the efficiency of photolysis at 5 mW. With free diffusional exchange, 50% steady-state cage depletion in the focal volume was estimated to occur only at high laser powers of ca. 72 mW, masked in experiments by multiphoton bleaching. Based on these results, the two-photon photolysis cross-section needed for 50% steady-state photolysis of a caged neurotransmitter at 5 mW is calculated as 31 GM, much higher than in existing caged compounds.


Work-based resources as moderators of the relationship between work hours and satisfaction with work-family balance.
This study reports an investigation of the relationships of work hours, job complexity, and control over work time to satisfaction with work-family balance. Based on data from a sample of 570 telephone call center representatives, a moderated hierarchical regression analysis revealed that work hours were negatively related to satisfaction with work-family balance, consistent with the resource drain perspective. Job complexity and control over work time were positively associated with satisfaction with work-family balance. Control over work time moderated the relationship such that as work hours rose, workers with low control experienced a decline in work-family balance satisfaction, while workers with high control did not. Results encourage greater research attention to work characteristics, such as job complexity and control over work time, and skills that represent resources useful to the successful integration of work and family demands.


Localization of the gene for familial adenomatous polyposis on chromosome 5.
Colorectal cancer is the second most common cancer in the United Kingdom and other developed countries in the West. Although it is usually not familial, there is a rare dominantly inherited susceptibility to colon cancer, familial adenomatous polyposis (FAP; also often previously called familial polyposis coli). During adolescence affected individuals develop from a few hundred to over a thousand adenomatous polyps in their large bowel. These are sufficiently likely to give rise to adenocarcinomas to make prophylactic removal of the colon usual in diagnosed FAP individuals. Adenomas may occur elsewhere in the gastrointestinal tract and the condition is often associated with other extracolonic lesions, such as epidermoid cysts, jaw osteomata and fibrous desmoid tumours. Adenomata have been suggested to be precancerous states for most colorectal tumours. Knudson has suggested that the mutation for a dominantly inherited cancer susceptibility may be the first step in a recessive change in the tumour cells, and that the same gene may be involved in both familial and non-familial cases of a given tumour. Following up a case report of an interstitial deletion of chromosome 5 in a mentally retarded individual with multiple developmental abnormalities and FAP, we have now shown that the FAP gene is on chromosome 5, most probably near bands 5q21-q22.


Elimination of mouse splenic macrophages correlates with increased susceptibility to experimental disseminated candidiasis.
To evaluate the role of macrophages in experimental disseminated candidiasis, mouse splenic macrophages were eliminated by i.v. delivery of liposome-entrapped dichloromethylene diphosphonate (L-Cl2MDP). Splenic tissue sections that were immunoperoxidase-stained with mAbs against marginal zone macrophages (MONTS-4), red pulp macrophages (SK39), and neutrophils (SK208) showed that 3 days after L-Cl2MDP treatment, macrophages but not neutrophils were depleted, and circulating neutrophils responded normally to an irritated peritoneum and showed normal phagocytic ability. That is, in response to thioglycollate in the peritoneum, neutrophils migrated in normal numbers to the peritoneal cavity and expressed the normal activation phenotype of high Mac-1 and low Mel-14 Ag levels. These neutrophils also showed normal ability to ingest Candida albicans yeast cells in both in vitro and in vivo assays. However, the spleens from L-Cl2MDP-treated mice lost their ability to bind yeast, which agrees with our previous findings that yeast cells bind specifically to marginal zone macrophages. When macrophage-depleted were systemically challenged with C. albicans, clearance of viable fungal elements from blood was slower, their kidneys had higher recoverable CFU, and both BALB/cByJ and congenitally thymic-deficient (nude) mouse strains did not survive as long as control mice. Mice given L-Cl2MDP recovered most of their macrophage function by 56 days and became normal in their resistance to C. albicans. These results indicate that macrophages play an important role in host resistance to experimental disseminated candidiasis, but the mechanism does not appear to involve T cell functions.


TLR9 agonist protects mice from radiation-induced gastrointestinal syndrome.
Radiation-induced gastrointestinal syndrome (RIGS) is due to the clonogenic loss of crypt cells and villi depopulation, resulting in disruption of mucosal barrier, bacterial invasion, inflammation and sepsis. Intestinal macrophages could recognize invading bacterial DNA via TLR9 receptors and transmit regenerative signals to the neighboring crypt. We therefore investigated whether systemic administration of designer TLR9 agonist could ameliorate RIGS by activating TLR9. Male C57Bl6 mice were distributed in four experimental cohorts, whole body irradiation (WBI) (8.4-10.4 Gy), TLR9 agonist (1 mg/kg s.c.), 1 h pre- or post-WBI and TLR9 agonist+WBI+iMyd88 (pretreatment with inhibitory peptide against Myd88). Animals were observed for survival and intestine was harvested for histological analysis. BALB/c mice with CT26 colon tumors in abdominal wall were irradiated with 14 Gy single dose of whole abdominal irradiation (AIR) for tumor growth study. Mice receiving pre-WBI TLR9 agonist demonstrated improvement of survival after 10.4 Gy (p<0.03), 9.4 Gy (p<0.008) and 8.4 Gy (p<0.002) of WBI, compared to untreated or iMyd88-treated controls. Post-WBI TLR9 agonist mitigates up to 8.4 Gy WBI (p<0.01). Histological analysis and xylose absorption test demonstrated significant structural and functional restitution of the intestine in WBI+TLR9 agonist cohorts. Although, AIR reduced tumor growth, all animals died within 12 days from RIGS. TLR9 agonist improved the survival of mice beyond 28 days post-AIR (p<0.008) with significant reduction of tumor growth (p<0.0001). TLR9 agonist treatment could serve both as a prophylactic or mitigating agent against acute radiation syndrome and also as an adjuvant therapy to increase the therapeutic ratio of abdominal Radiation Therapy for Gastro Intestinal malignancies.


The majority of the type III effector inventory of Pseudomonas syringae pv. tomato DC3000 can suppress plant immunity.
The Pseudomonas syringae type III protein secretion system (T3SS) and the type III effectors it injects into plant cells are required for plant pathogenicity and the ability to elicit a hypersensitive response (HR). The HR is a programmed cell death that is associated with effector-triggered immunity (ETI). A primary function of P. syringae type III effectors appears to be the suppression of ETI and pathogen-associated molecular pattern-triggered immunity (PTI), which is induced by conserved molecules on microorganisms. We reported that seven type III effectors from P. syringae pv. tomato DC3000 were capable of suppressing an HR induced by P. fluorescens(pHIR11) and have now tested 35 DC3000 type III effectors in this assay, finding that the majority of them can suppress the HR induced by HopA1. One newly identified type III effector with particularly strong HR suppression activity was HopS2. We used the pHIR11 derivative pLN1965, which lacks hopA1, in related assays and found that a subset of the type III effectors that suppressed HopA1-induced ETI also suppressed an ETI response induced by AvrRpm1 in Arabidopsis thaliana. A. thaliana plants expressing either HopAO1 or HopF2, two type III effectors that suppressed the HopA1-induced HR, were reduced in the flagellin-induced PTI response as well as PTI induced by other PAMPs and allowed enhanced in planta growth of P. syringae. Collectively, our results suggest that the majority of DC3000 type III effectors can suppress plant immunity. Additionally, the construct pLN1965 will likely be a useful tool in determining whether other type III effectors or effectors from other types of pathogens can suppress either ETI, PTI, or both.


Use of faropenem as an indicator of carbapenemase activity in the Enterobacteriaceae.
The aim of this study was to determine the ability of a disc susceptibility test using faropenem (10 μg) to predict carbapenemase activity in Enterobacteriaceae. A collection of 166 isolates of carbapenemase-producing Enterobacteriaceae (CPE) and 82 isolates of Enterobacteriaceae that produced other β-lactamases was compiled from diverse sources. Disc susceptibility testing was performed using the CLSI/EUCAST methodology with discs of faropenem (10 μg), temocillin (30 μg), and four carbapenems (each 10 μg). A further prospective evaluation of the faropenem disc susceptibility test was performed using 205 consecutive isolates referred to a United Kingdom reference laboratory in parallel with molecular methods for carbapenemase detection. Of 166 isolates of CPE, 99% showed growth up to the edge of a 10-μg faropenem disc compared with only 6% of other β-lactamase producers (sensitivity, 99%; specificity, 94%). A "double zone" around 10-μg faropenem discs was frequently associated with OXA-48 producers. Of the carbapenems, the most useful agent was imipenem, where a zone diameter of ≤ 23 mm as a predictor of carbapenemase activity had a sensitivity of 99% and a specificity of 85%. The presence of no zone of inhibition around a 30-μg temocillin disc was a consistent feature of strains producing OXA-48 carbapenemase. For 205 isolates of Enterobacteriaceae referred to a United Kingdom reference laboratory, growth up to a 10-μg faropenem disc correctly identified 84 of 86 carbapenemase producers (98% sensitivity), with a specificity of 87%. Disc susceptibility testing using faropenem (10 μg) is a simple, convenient, and highly predictive screening test for carbapenemase-producing Enterobacteriaceae.


Cocaine in hair, saliva, skin swabs, and urine of cocaine users' children.
The concentrations of cocaine and benzoylecgonine (BE) in the hair, saliva, skin secretions, and urine samples of cocaine-using mothers, their children, and other adults living in the same environment were compared. Subjects were screened from urban cocaine dependence treatment patients. Drug using adults had mean hair concentrations of 2.4 ng cocaine/mg hair (range = 0-12.2, sigma = 3.1, 15/16 positive) and 0.39 ng BE/mg hair (range = 0-1.9, sigma = 0.62), compared with children's mean hair concentrations of 2.4 ng cocaine/mg of hair (range = 0-14.4, sigma = 3.8, 22/24 positive) and 0.74 ng benzoylecgonine/mg hair (range = 0-5.4 sigma = 1.3). None of the children's urine specimens (0/22) were positive above 300 ng BE/ml. In contrast, 3/16 adult urine specimens were positive, even though they were enrolled in drug treatment. Saliva had detectable levels of BE for only one child (1/17) and one adult (1/17). Forehead swabs contained measurable quantities of cocaine for most children (19/26) and adults (15/17) and BE for children (7/26) and adults (7/17). Unlike urine results, overall hair cocaine concentrations for adults paralleled those of children and a clear cut-off concentration could not be established to differentiate these two groups.


Hyphomicrobium nitrativorans sp. nov., isolated from the biofilm of a methanol-fed denitrification system treating seawater at the Montreal Biodome.
A budding prosthecate bacterial strain, designated NL23(T), was isolated from a methanol-fed denitrification system treating seawater at the Montreal Biodome, Canada. Phylogenetic analysis based on 16S rRNA (rRNA) gene sequences showed that the strain was affiliated with the genus Hyphomicrobium of the Alphaproteobacteria and was most closely related to Hyphomicrobium zavarzinii with 99.4 % sequence similarity. Despite this high level of 16S rRNA gene sequence similarity, DNA-DNA hybridization assays showed that strain NL23(T) was only distantly related to H. zavarzinii ZV-622(T) (12 %). Strain NL23(T) grew aerobically, but also had the capacity to grow under denitrifying conditions in the presence of nitrate without nitrite accumulation. Growth occurred at pH 7.0-9.5, with 0-1 % NaCl and at temperatures of 15-35 °C. Major fatty acids were C18 : 1ω7c or ω6c (84.6 %) and C18 : 0 (8.5 %), and major quinones were Q8 (5 %) and Q9 (95 %). The complete genome of the strain was sequenced and showed a DNA G+C content of 63.8 mol%. Genome analysis predicted open reading frames (ORF) encoding the key enzymes of the serine pathway as well as enzymes involved in methylotrophy. Also, ORF encoding a periplasmic nitrate reductase (Nap), a nitrite reductase (Nir), a nitric oxide reductase (Nor) and a nitrous oxide reductase (Nos) were identified. Our results support that strain NL23(T) represents a novel species within the genus Hyphomicrobium, for which the name Hyphomicrobium nitrativorans sp. nov. is proposed. The type strain is NL23(T) ( = ATCC BAA-2476(T) = LMG 27277(T)).


Sodium bicarbonate treatment during transient or sustained lactic acidemia in normoxic and normotensive rats.
Lactic acidosis is a frequent cause of poor outcome in the intensive care settings. We set up an experimental model of lactic acid infusion in normoxic and normotensive rats to investigate the systemic effects of lactic acidemia per se without the confounding factor of an underlying organic cause of acidosis. Sprague Dawley rats underwent a primed endovenous infusion of L(+) lactic acid during general anesthesia. Normoxic and normotensive animals were then randomized to the following study groups (n = 8 per group): S) sustained infusion of lactic acid, S+B) sustained infusion+sodium bicarbonate, T) transient infusion, T+B transient infusion+sodium bicarbonate. Hemodynamic, respiratory and acid-base parameters were measured over time. Lactate pharmacokinetics and muscle phosphofructokinase enzyme's activity were also measured. Following lactic acid infusion blood lactate rose (P<0.05), pH (P<0.05) and strong ion difference (P<0.05) drop. Some rats developed hemodynamic instability during the primed infusion of lactic acid. In the normoxic and normotensive animals bicarbonate treatment normalized pH during sustained infusion of lactic acid (from 7.22 ± 0.02 to 7.36 ± 0.04, P<0.05) while overshoot to alkalemic values when the infusion was transient (from 7.24 ± 0.01 to 7.53 ± 0.03, P<0.05). When acid load was interrupted bicarbonate infusion affected lactate wash-out kinetics (P<0.05) so that blood lactate was higher (2.9 ± 1 mmol/l vs. 1.0 ± 0.2, P<0.05, group T vs. T+B respectively). The activity of phosphofructokinase enzyme was correlated with blood pH (R2 = 0.475, P<0.05). pH decreased with acid infusion and rose with bicarbonate administration but the effects of bicarbonate infusion on pH differed under a persistent or transient acid load. Alkalization affected the rate of lactate disposal during the transient acid load.


FDG-PET and CSF biomarker accuracy in prediction of conversion to different dementias in a large multicentre MCI cohort.
In this multicentre study in clinical settings, we assessed the accuracy of optimized procedures for FDG-PET brain metabolism and CSF classifications in predicting or excluding the conversion to Alzheimer's disease (AD) dementia and non-AD dementias. We included 80 MCI subjects with neurological and neuropsychological assessments, FDG-PET scan and CSF measures at entry, all with clinical follow-up. FDG-PET data were analysed with a validated voxel-based SPM method. Resulting single-subject SPM maps were classified by five imaging experts according to the disease-specific patterns, as "typical-AD", "atypical-AD" (i.e. posterior cortical atrophy, asymmetric logopenic AD variant, frontal-AD variant), "non-AD" (i.e. behavioural variant FTD, corticobasal degeneration, semantic variant FTD; dementia with Lewy bodies) or "negative" patterns. To perform the statistical analyses, the individual patterns were grouped either as "AD dementia vs. non-AD dementia (all diseases)" or as "FTD vs. non-FTD (all diseases)". Aβ42, total and phosphorylated Tau CSF-levels were classified dichotomously, and using the Erlangen Score algorithm. Multivariate logistic models tested the prognostic accuracy of FDG-PET-SPM and CSF dichotomous classifications. Accuracy of Erlangen score and Erlangen Score aided by FDG-PET SPM classification was evaluated. The multivariate logistic model identified FDG-PET "AD" SPM classification (Expβ = 19.35, 95% C.I. 4.8-77.8, p < 0.001) and CSF Aβ42 (Expβ = 6.5, 95% C.I. 1.64-25.43, p < 0.05) as the best predictors of conversion from MCI to AD dementia. The "FTD" SPM pattern significantly predicted conversion to FTD dementias at follow-up (Expβ = 14, 95% C.I. 3.1-63, p < 0.001). Overall, FDG-PET-SPM classification was the most accurate biomarker, able to correctly differentiate either the MCI subjects who converted to AD or FTD dementias, and those who remained stable or reverted to normal cognition (Expβ = 17.9, 95% C.I. 4.55-70.46, p < 0.001). Our results support the relevant role of FDG-PET-SPM classification in predicting progression to different dementia conditions in prodromal MCI phase, and in the exclusion of progression, outperforming CSF biomarkers.


Diagnosis and clinical management of long-QT syndrome.
To give an overview over the substantial advances in the diagnosis and management of Long-QT syndrome since its first description 60 years ago. LQT syndrome remains the most common inherited arrhythmia and is a leading cause for sudden unexplained death accounting for up to 20-25% of cases. Rapid progress of genetic technology over the past 2 decades has significantly improved our understanding of molecular and genetic mechanisms of LQT. Despite all those novel insights, phenotype assessment and appropriate risk stratification in LQT remains challenging - even for the expert. This review outlines our current understanding and approach to the clinical diagnosis and management of LQT as well as recent insights into genotype-phenotype correlations. Genetic testing has evolved beyond a pure diagnostic tool and is in addition increasingly integrated as complementary prognostic marker. With regard to the management of LQT, there is now evidence that the protective effect of beta-blockers is rather substance-specific than a class effect. Novel approaches - in conjunction with standard beta-blockers - are emerging including gene-specific treatment for certain subtypes of LQT. A specialized inherited arrhythmia clinic is the preferred resource for the complex risk stratification and individualized management of individuals with LQT.


Ru(ii) polypyridyl complexes as photocages for bioactive compounds containing nitriles and aromatic heterocycles.
Photocaging allows for precise spatiotemporal control over the release of biologically active compounds with light. Most photocaged molecules employ organic photolabile protecting groups; however, biologically active compounds often contain functionalities such as nitriles and aromatic heterocycles that cannot be caged with organic groups. Despite their prevalence, only a few studies have reported successful caging of nitriles and aromatic heterocycles. Recently, Ru(ii)-based photocaging has emerged as a powerful method for the release of bioactive molecules containing these functional groups, in many cases providing high levels of spatial and temporal control over biological activity. This Feature Article discusses recent developments in applying Ru(ii)-based photocaging towards biological problems. Our groups designed and synthesized Ru(ii)-based platforms for the photoinduced delivery of cysteine protease and cytochrome P450 inhibitors in order to achieve selective control over enzyme inhibition. We also reported Ru(ii) photocaging groups derived from higher-denticity ancillary ligands that possess photophysical and photochemical properties distinct from more traditional Ru(ii)-based caging groups. In addition, for the first time, we are able to rapidly synthesize and screen Ru(ii) polypyridyl complexes that elicit desired properties by solid-phase synthesis. Finally, our work also defined steric and orbital mixing effects that are important factors in controlling photoinduced ligand exchange.


Munc18c phosphorylation by the insulin receptor links cell signaling directly to SNARE exocytosis.
How the Sec1/Munc18-syntaxin complex might transition to form the SNARE core complex remains unclear. Toward this, Munc18c tyrosine phosphorylation has been correlated with its dissociation from syntaxin 4. Using 3T3-L1 adipocytes subjected to small interfering ribonucleic acid reduction of Munc18c as a model of impaired insulin-stimulated GLUT4 vesicle exocytosis, we found that coordinate expression of Munc18c-wild type or select phosphomimetic Munc18c mutants, but not phosphodefective mutants, restored GLUT4 vesicle exocytosis, suggesting a requirement for Munc18c tyrosine phosphorylation at Tyr219 and Tyr521. Surprisingly, the insulin receptor (IR) tyrosine kinase was found to target Munc18c at Tyr521 in vitro, rapidly binding and phosphorylating endogenous Munc18c within adipocytes and skeletal muscle. IR, but not phosphatidylinositol 3-kinase, activation was required. Altogether, we identify IR as the first known tyrosine kinase for Munc18c as part of a new insulin-signaling step in GLUT4 vesicle exocytosis, exemplifying a new model for the coordination of SNARE assembly and vesicle mobilization events in response to a single extracellular stimulus.


Burden of oral disease among older adults and implications for public health priorities.
Dental disease is largely preventable. Many older adults, however, experience poor oral health. National data for older adults show racial/ethnic and income disparities in untreated dental disease and oral health-related quality of life. Persons reporting poor versus good health also report lower oral health-related quality of life. On the basis of these findings, suggested public health priorities include better integrating oral health into medical care, implementing community programs to promote healthy behaviors and improve access to preventive services, developing a comprehensive strategy to address the oral health needs of the homebound and long-term-care residents, and assessing the feasibility of ensuring a safety net that covers preventive and basic restorative services to eliminate pain and infection.


Statin use and knee osteoarthritis progression: Results from a post-hoc analysis of the SEKOIA trial.
Epidemiological and experimental studies have suggested that lipid disorders might be involved in the pathophysiology of knee osteoarthritis (OA). Studies assessing the effect of statins on knee OA progression have shown conflicting results. We investigated the impact of statin use on radiological progression in patients with radiological and symptomatic knee OA. In total, 336 patients from the placebo arm of SEKOIA trial completed the 3-year follow-up and were included in this post-hoc analysis. Statin use was recorded at baseline interview. Minimal medial tibiofemoral joint space was measured on plain radiographs by an automated method at baseline and then annually. Radiologic progression was defined as joint space narrowing≥0.5mm over 3 years. Overall, 71 patients were statin users (21.1%). They had a higher BMI (31.1±5.3 vs. 29.3±5.2kg/m2, P=0.008), a higher sum of metabolic factors (≥3 factors: 43.7% vs 7.2%; P for trend<0.001) and a higher rate of radiological progression (49.3% vs. 32.1%, P=0.007) as compared to statin non-users. The significant association between radiological progression and statin use was independent of age, gender, WOMAC global score, disease duration, baseline joint space width, hypertension, type 2 diabetes, obesity (BMI>30kg/m2) and cardiovascular diseases [relative risk 1.49 (95% CI: 1.10-2.02), P=0.010]. Among patients with knee OA, statin use was associated with radiological worsening over 3 years, regardless of other potential confounding factors (obesity, type 2 diabetes, hypertension, disease duration, symptom intensity and radiological severity).


DNA-MVA vaccine protection after X4 SHIV challenge in macaques correlates with day-of-challenge antiviral CD4+ cell-mediated immunity levels and postchallenge preservation of CD4+ T cell memory.
The ability of vaccines to induce immunity both in mucosal and systemic compartments may be required for prevention of HIV infection and AIDS. We compared DNA-MVA vaccination regimens adjuvanted by IL-12 DNA, administered intramuscularly and nasally or only nasally. Most of the vaccinated Rhesus macaques developed mucosal and systemic humoral and cell-mediated SHIV-specific immune responses. Stimulation of mucosal anti-Env IgA responses was limited. After rectal challenge with SHIV 89.6P, all vaccinated and naive animals became infected. However, most of the vaccinated animals showed significant control of viremia and protection from CD4(+) T cell loss and AIDS progression compared to the control animals. The levels of CD4(+) and CD8(+) T cell virus-specific responses measured on the day of challenge correlated with the level of viremia control observed later during the chronic infection. Postchallenge viremia levels inversely correlated with the preservation of SHIV-specific CD4(+)/IL-2(+) and CD8(+)/TNF-alpha(+) T cells but not with CD4(+)/IFN-gamma(+) T cells measured over time after challenge. We also found that during the early chronic infection SHIV vaccination permitted a more significant preservation of both naive and memory CD4(+) T cells compared to controls. In addition, we observed a more significant and prolonged preservation of memory CD4(+) T cells after SHIV vaccination and challenge than that observed after SIV vaccination and challenge. As the antiviral immunity stimulated by vaccination is present in the memory CD4(+) T cell subpopulations, its more limited targeting by SHIV compared to SIV may explain the better control of X4 tropic SHIV than R5 tropic SIVs by vaccination.


A systematic review of the incidence and prevalence of autoimmune disease in multiple sclerosis.
As new therapies emerge which increase the risk of autoimmune disease it is increasingly important to understand the incidence of autoimmune disease in multiple sclerosis (MS). The purpose of this review is to estimate the incidence and prevalence of comorbid autoimmune disease in MS. The PUBMED, EMBASE, SCOPUS and Web of Knowledge databases, conference proceedings, and reference lists of retrieved articles were searched, and abstracts were independently screened by two reviewers. The data were abstracted by one reviewer using a standardized data collection form, and the findings were verified by a second reviewer. We assessed quality of the included studies using a standardized approach and conducted meta-analyses of population-based studies. Sixty-one articles met the inclusion criteria. We observed substantial heterogeneity with respect to the populations studied, methods of ascertaining comorbidity, and reporting of findings. Based solely on population-based studies, the most prevalent autoimmune comorbidities were psoriasis (7.74%) and thyroid disease (6.44%). Our findings also suggest an increased risk of inflammatory bowel disease, likely uveitis and possibly pemphigoid. Fewer than half of the studies identified were of high quality. Population-based studies that report age, sex and ethnicity-specific estimates of incidence and prevalence are needed in jurisdictions worldwide.


In vivo transfection of lamprey brain neurons by gene gun delivery of DNA.
The lamprey has been used extensively in studies of CNS axon regeneration. Progress in determining molecular mechanisms involved in regeneration will require the ability to manipulate expression of target genes or to introduce new genes, but in vivo neuronal transfection has posed difficulties in the mature intact nervous system of vertebrates, including the lamprey. In this paper we report successful transfection of neurons in the brain of living lampreys by means of a hand-held Helios Gene Gun. Particle-mediated ("gene gun") gene transfer has been applied to a variety of cell and tissue types but although it has been used in brain slices and dissociated cultured neurons, to our knowledge it has not been reported as a method for transfection of brain cells in a living animal. Gold particles coated with plasmids containing the gene for the reporter beta-galactosidase were propelled by helium at 150--200 psi toward the exposed floor of the 4th ventricle. Transfected animals were examined by X-gal histochemistry at various recovery times. beta-glactosidase activity was detected as early as 2 days after gene transfer and lasted for at least 6 weeks, the longest time studied. Transgene expression lasted longer in neurons than in glia. The expression product was transported anterogradely into reticulospinal axons and by 6 weeks could be traced into the spinal cord for 8--10 mm caudal to the obex. This raises the possibility of identifying the growth cones of developing or regenerating axons belonging to transfected neurons in functional studies of manipulated genes.