Clinical course of accommodative esotropia.
To report the clinical course of patients having accommodative esotropia and to determine whether the strabismus resolves during the adolescent years. Patients diagnosed with accommodative esotropia from 1983 to 1991 were recalled to the clinic for re-examination. For all patients, the clinical records indicated that the esotropia had begun in early childhood and was controllable at some time during the follow-up period with plus power single vision glasses and/or bifocals. Re-examination included assessment of patient history, visual acuity, ocular alignment, versions, sensory fusion, and refractive error. The ocular alignment status with and without any current plus single vision and/or bifocal correction, and the refractive error at recall, were compared to the same findings taken at the patient's initial clinic visit. These findings were compared to determine whether the accommodative esotropia had resolved, improved, remained the same, or increased in amount. Thirty-nine patients participated in the study. At the time of recall their average age and follow-up period were 16.8 and 9.5 years, respectively. Before treatment, the mean eso deviation was 14.5 delta at distance and 21.6 delta at near. At recall, 15 patients used single vision glasses, 9 used glasses with bifocals, 11 used contact lenses, and 4 patients used no optical correction. Five patients (12.8%) had best corrected acuity in one eye of 20/30 or poorer. Twenty patients (57.1%) were not strabismic with their current refractive correction, whereas 15 patients (42.8%) continued to be esotropic (intermittent or constant) at distance and/or near. When assessing ocular alignment without the current plus power correction, 26 patients (82%) were esotropic and 4 patients (15.6%) were heterophoric. The mean deviation without the optical correction was 18.6 delta at distance and 19 delta at near. Of the 4 patients presenting without an optical correction, 3 were esotropic at distance and/or near and 1 patient was heterophoric. Six patients (15.3%) also had inferior oblique overaction, 2 which occurred with superior oblique palsy. Thirty-three patients (86.8%) fused the Worth dot test at distance and/or near, and 35 patients (89.7%) had stereopsis (mean, 84 sec arc). The mean spherical equivalent refractive error changed for the group from 2.77 D hyperopia at the initial evaluation to 1.95 D hyperopia at recall (mean refractive shift = -0.08 D/year). Accommodative esotropia persists for most patients into adolescence and early adulthood. These patients need to be carefully monitored during this period because most do not outgrow their hyperopia and some can again become esotropic.


Sustaining large-scale infrastructure to promote pre-competitive biomedical research: lessons from mouse genomics.
Bio-repositories and databases for biomedical research enable the efficient community-wide sharing of reagents and data. These archives play an increasingly prominent role in the generation and dissemination of bioresources and data essential for fundamental and translational research. Evidence suggests, however, that current funding and governance models, generally short-term and nationally focused, do not adequately support the role of archives in long-term, transnational endeavours to make and share high-impact resources. Our qualitative case study of the International Knockout Mouse Consortium and the International Mouse Phenotyping Consortium examines new governance mechanisms for archive sustainability. Funders and archive managers highlight in interviews that archives need stable public funding and new revenue-generation models to be sustainable. Sustainability also requires archives, journal publishers, and funders to implement appropriate incentives, associated metrics, and enforcement mechanisms to ensure that researchers use archives to deposit reagents and data to make them publicly accessible for academia and industry alike.


Cyclic stretch regulates autocrine IGF-I in vascular smooth muscle cells: implications in vascular hyperplasia.
Vascular smooth muscle cells (VSMC) subjected to acute or chronic stretch display enhanced growth rates in vitro and in vivo. Clinical examples of vascular hyperplasia (e.g., systolic hypertension and postinjury restenosis) suggest that local insulin-like growth factor I (IGF-I) expression is enhanced. Therefore, we investigated the role of in vitro cyclic stretch on rat VSMC IGF-I secretion and cellular growth. In serum-free medium, cyclic stretch (1 Hz at 120% resting length for 48 h) stimulated thymidine incorporation approximately 40% above that seen in nonstretched cells. Graded stretch magnitude (100-125% resting length) yielded graded increases in VSMC growth. Exogenous IGF-I increased growth of serum-starved, nonstretched VSMC in a dose-dependent manner, with maximal growth seen with 10(-7) M. IGF-I secretion from stretched cells was 20- to 30-fold greater than from those cells cultured in a static environment. Stretch-induced increases in growth were completely blocked on addition of anti-IGF-I and partially blocked with platelet-derived growth factor (PDGF) antibodies and with a tyrosine kinase inhibitor (tyrphostin-1). Finally, blockade of stretch-activated cation channels with GdCl3 profoundly inhibited stretch-induced growth. We conclude that stretch increases VSMC IGF-I secretion and that such autocrine IGF-I is required for stretch-induced growth. PDGF and stretch-sensitive cation channels are likely additional components of a complex pathway that regulates stretch-induced VSMC seen in systolic hypertension and postinjury restenosis.


The impact of the Oncotype DX Recurrence Score on treatment decisions and clinical outcomes in patients with early breast cancer: the Maccabi Healthcare Services experience with a unified testing policy.
The Oncotype DX Recurrence Score is a validated prognosticator in oestrogen receptor positive (ER+) breast cancer. Our retrospective analysis of a prospectively defined cohort summarises the clinical implications associated with Oncotype DX testing according to the Maccabi Healthcare Services (MHS) policy. The MHS eligibility criteria for testing included ER+ N0/pN1mic invasive tumours, discussion of test implications with an oncologist, ductal carcinoma 0.6-1 cm Grade 2-3, HER2 negative ductal carcinomas with 1.1-4.0 cm Grade 1-2, or lobular carcinoma. Large (> 1 cm) Grade 3 tumours could have grade reassessed. We linked Recurrence Score results with patients' information and used chi-squared tests to assess the associations thereof. Between January 2008 and December 2011, tests were performed on 751 patients (MHS-eligible, 713); 54%, 38%, and 8% of patients had low, intermediate, and high Recurrence Score results, respectively. Recurrence Score distribution varied significantly with age (P = 0.002), with increasing Recurrence Score values with decreasing age. The proportion of patients with high Recurrence Score results varied by grade/size combination and histology, occurring in 32% of small (≤ 1 cm) Grade 3 and 3% of larger (1.1-4 cm) Grade 1 ductal tumours and only in 2% of lobular carcinomas. Chemotherapy was administered to 1%, 13%, and 61% of patients with low, intermediate, and high Recurrence Score results, respectively (P < 0.0001), but only to 2% of intermediate score patients ≥ 65 years. Luteinising-hormone-releasing hormone agonists with tamoxifen were used in 27% of low Recurrence Score patients ≤ 50 years. With a median follow-up of 26 months, no systemic recurrences were documented, whereas four patients exhibited locoregional recurrences. In summary, in this low-to-moderate risk patient population, testing identified 46% of patients as intermediate/high risk. Treatment decisions were influenced by Recurrence Score results and patients' age. The current MHS policy seems to achieve the goal of promoting chemotherapy use according to the test results in a prespecified patient population.


Electromagnetic scattering by spheroidal volumes of discrete random medium.
We use the superposition T-matrix method to compare the far-field scattering matrices generated by spheroidal and spherical volumes of discrete random medium having the same volume and populated by identical spherical particles. Our results fully confirm the robustness of the previously identified coherent and diffuse scattering regimes and associated optical phenomena exhibited by spherical particulate volumes and support their explanation in terms of the interference phenomenon coupled with the order-of-scattering expansion of the far-field Foldy equations. We also show that increasing nonsphericity of particulate volumes causes discernible (albeit less pronounced) optical effects in forward and backscattering directions and explain them in terms of the same interference/multiple-scattering phenomenon.


Stereotactic Radiosurgery for Patients with 10 or More Brain Metastases.
The JLGK0901 study showed the non-inferiority of stereotactic radiosurgery (SRS) alone as the initial treatment for 5-10 as compared to 2-4 brain metastases (BM) in terms of overall survival and most secondary endpoints [Lancet Oncol 2014;15:387-395]. A trend for patients with 5-10 tumors to undergo SRS alone has since become apparent. The next step is to reappraise whether results of SRS treatment alone for tumor numbers ≥10 differ from those for 2-9 tumors. During the past 2 decades, several retrospective studies have demonstrated the SRS alone treatment strategy to have certain benefits for carefully selected patients with ≥10 BM, i.e., a sufficiently long survival period with lower incidences of neurological death, neurological deterioration, local recurrence, and SRS-related complications. Herein, we introduce our Mito experiences with SRS for ≥10 BM, employing a case-matched study on 934 patients, 467 each in groups with 2-9 BM and ≥10 BM. Post-SRS treatment results, i.e., median survival time, neurological death-free survival time and cumulative incidences of local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-related complications, were not inferior for patients with ≥10 BM as compared to those with 2-9 BM. We conclude that patients with ≥10 tumors are not unfavorable candidates for SRS alone.


Reporter bacteriophage T7NLC utilizes a novel NanoLuc::CBM fusion for the ultrasensitive detection of Escherichia coli in water.
Rapid detection of bacteria responsible for foodborne diseases is a growing necessity for public health. Reporter bacteriophages (phages) are robust biorecognition elements uniquely suited for the rapid and sensitive detection of bacterial species. The advantages of phages include their host specificity, ability to distinguish viable and non-viable cells, low cost, and ease of genetic engineering. Upon infection with reporter phages, target bacteria express reporter enzymes encoded within the phage genome. In this study, the T7 coliphage was genetically engineered to express the newly developed luceriferase, NanoLuc (NLuc), as an indicator of bacterial contamination. While several genetic approaches were employed to optimize reporter enzyme expression, the novel achievement of this work was the successful fusion of the NanoLuc reporter to a carbohydrate binding module (CBM) with specificity to crystalline cellulose. This novel chimeric reporter (nluc::cbm) bestows the specific and irreversible immobilization of NanoLuc onto a low-cost, widely available crystalline cellulosic substrate. We have shown the possibility of detecting the immobilized fusion protein in a filter plate which resulted from a single CFU of E. coli. We then demonstrated that microcrystalline cellulose can be used to concentrate the fusion reporter from 100 mL water samples allowing a limit of detection of <10 CFU mL-1E. coli in 3 hours. Therefore, we conclude that our phage-based detection assay displays significant aptitude as a proof-of-concept drinking water diagnostic assay for the low-cost, rapid and sensitive detection of E. coli. Additional improvements in the capture efficiency of the phage-based fusion reporter should allow a limit of detection of <10 CFU per 100 mL.


Small high-density lipoprotein is associated with monocyte subsets in stable coronary artery disease.
High-density lipoprotein (HDL) particles are heterogeneous in structure and function and the role of HDL subfractions in atherogenesis is not well understood. It has been suggested that small HDL may be dysfunctional in patients with coronary artery disease (CAD). Monocytes are considered to play a key role in atherosclerotic diseases. Circulating monocytes can be divided into three subtypes according to their surface expression of CD14 and CD16. Our aim was to examine whether monocyte subsets are associated with HDL subfractions in patients with atherosclerosis. We included 90 patients with angiographically stable CAD. Monocyte subsets were defined as classical monocytes (CD14++CD16-; CM), intermediate monocytes (CD14++CD16+; IM) and non-classical monocytes (CD14+CD16++; NCM). HDL subfractions were measured by electrophoresis on polyacrylamide gel. Serum levels of small HDL correlated with circulating pro-inflammatory NCM and showed an inverse relationship to circulating CM independently from other lipid parameters, risk factors, inflammatory parameters or statin treatment regime, respectively. IM were not associated with small HDL. In particular, patients with small HDL levels in the highest tertile showed dramatically increased levels of NCM (14.7 ± 7% vs. 10.7 ± 5% and 10.8 ± 5%; p = 0.006) and a decreased proportion of CM (79.3 ± 7% vs. 83.7 ± 6% and 83.9 ± 6%; p = 0.004) compared to patients in the two lower tertiles. In contrast, intermediate HDL, large HDL and total HDL were not associated with monocyte subset distribution. Small HDL levels are associated with pro-inflammatory NCM and inversely correlated with CM. This may suggest that small HDL could have dysfunctional anti-inflammatory properties in patients with established CAD.


Construction and immunogenicity in a prime-boost regimen of a Semliki Forest virus-vectored experimental HIV clade A vaccine.
A novel, experimental subunit human immunodeficiency virus (HIV) vaccine, SFV.HIVA, was constructed. This consists of Semliki Forest virus (SFV), which is a suitable vaccine vector for use in humans, and a passenger gene encoding HIVA, which is an immunogen derived from HIV-1 clade A that is being currently tested in clinical trials of combined DNA- and modified vaccinia virus Ankara (MVA)-vectored vaccines in Oxford (UK) and Nairobi (Kenya). In the mouse, the SFV.HIVA vaccine was highly immunogenic for T cell-mediated immune responses and induced T cell memory that lasted for at least 6 months. SFV.HIVA was also compared to the vaccines currently used in the clinical trials and was shown to be as effective in T cell induction as pTHr.HIVA DNA but less immunogenic than MVA.HIVA. When tested in a prime-boost regimen, SFV.HIVA-induced responses could be boosted by MVA.HIVA. This work is a part of a long-term effort to build a panel of subunit vaccines expressing a common immunogen, which will allow both a direct comparison of various vaccine vectors and combined vaccination regimens in humans and provide more flexibility and/or a potential optimization of vaccinations for individuals based on their pre-existing anti-vector immunity.


Patient adherence: a blind spot in cost-effectiveness analyses?
Despite evidence that medication adherence can influence cost-effectiveness analysis (CEA) results, the extent to which published CEAs include adherence has not been fully characterized. To characterize inclusion of patient adherence in CEAs of self-administered medications and to examine whether industry sponsorship affects adherence inclusion, because adherence exclusion might overstate the interventions' cost-effectiveness. Systematic review of the English-language medical literature published between 1998 and 2003 identified 177 original CEAs of self-administered medications. Two trained readers independently abstracted data. Adherence inclusion was estimated overall and by study characteristics. Predictors of inclusion were assessed with chi2 tests and logistic regression. Among 177 CEAs, 30.5% explicitly modeled adherence; of these, only half modeled adherence in both base-case and sensitivity analyses. Only 21% of studies performed sensitivity analysis on adherence; fewer than half of these provided sufficient information to determine the impact on results. Of the remaining 20 studies, 9 were sensitive to adherence. Adherence inclusion varied across clinical areas (P = .022). Only 30% of chronic anticoagulation studies, 52% of cardiovascular risk reduction studies, 38% of neuropsychiatric studies, and 32% of HIV antiretroviral studies considered suboptimal adherence. Among 128 CEAs that disclosed study sponsorship, adherence was included in 25.4% of industry-sponsored and 35.1% of non-industrysponsored studies (P = .17). Few CEAs modeled suboptimal medication adherence. As CEAs are meant to model "real world" costs and effects of interventions, investigators would do well to explicitly consider medication adherence in the future.


Beta-actin deficiency with oxidative posttranslational modifications in Rett syndrome erythrocytes: insights into an altered cytoskeletal organization.
Beta-actin, a critical player in cellular functions ranging from cell motility and the maintenance of cell shape to transcription regulation, was evaluated in the erythrocyte membranes from patients with typical Rett syndrome (RTT) and methyl CpG binding protein 2 (MECP2) gene mutations. RTT, affecting almost exclusively females with an average frequency of 1∶10,000 female live births, is considered the second commonest cause of severe cognitive impairment in the female gender. Evaluation of beta-actin was carried out in a comparative cohort study on red blood cells (RBCs), drawn from healthy control subjects and RTT patients using mass spectrometry-based quantitative analysis. We observed a decreased expression of the beta-actin isoforms (relative fold changes for spots 1, 2 and 3: -1.82±0.15, -2.15±0.06, and -2.59±0.48, respectively) in pathological RBCs. The results were validated by western blotting and immunofluorescence microscopy. In addition, beta-actin from RTT patients also showed a dramatic increase in oxidative posttranslational modifications (PTMs) as the result of its binding with the lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE). Our findings demonstrate, for the first time, a beta-actin down-regulation and oxidative PTMs for RBCs of RTT patients, thus indicating an altered cytoskeletal organization.


Imaging recommendations for acute stroke and transient ischemic attack patients: A joint statement by the American Society of Neuroradiology, the American College of Radiology, and the Society of NeuroInterventional Surgery.
Stroke is a leading cause of death and disability worldwide. Imaging plays a critical role in evaluating patients suspected of acute stroke and transient ischemic attack, especially before initiating treatment. Over the past few decades, major advances have occurred in stroke imaging and treatment, including Food and Drug Administration approval of recanalization therapies for the treatment of acute ischemic stroke. A wide variety of imaging techniques has become available to assess vascular lesions and brain tissue status in acute stroke patients. However, the practical challenge for physicians is to understand the multiple facets of these imaging techniques, including which imaging techniques to implement and how to optimally use them, given available resources at their local institution. Important considerations include constraints of time, cost, access to imaging modalities, preferences of treating physicians, availability of expertise, and availability of endovascular therapy. The choice of which imaging techniques to employ is impacted by both the time urgency for evaluation of patients and the complexity of the literature on acute stroke imaging. Ideally, imaging algorithms should incorporate techniques that provide optimal benefit for improved patient outcomes without delaying treatment.


Unusual responses of nocturnal pineal melatonin synthesis and secretion to swimming: attempts to define mechanisms.
The effect of swimming at night on rat pineal melatonin synthesis was compared with that of light exposure at night. Rats were forced to swim at 0030 hr (lights out at 2000 hr) and sacrificed by decapitation 15 and 30 min later, immediately after swimming. Other groups of animals were exposed to white light (650 muW/cm2) for 15 and 30 min at same time. Swimming caused a rapid and highly significant drop in the melatonin content in the pineal gland; however, the activity of N-acetyltransferase (NAT), the supposed rate limiting enzyme in the melatonin production, was not changed. Despite the drop in pineal melatonin levels, serum concentrations of the indole remained elevated in the rats that swam. In contrast, melatonin levels in the pineal and serum of light exposed rats fell precipitously, accompanied by a significant suppression of NAT activity. Since we anticipated that the strenuous exercise associated with swimming may induce release of artrial natriuretic peptide (ANP) from the heart, which in turn could cause the release of pineal melatonin, in a second study we injected physiological saline intravenously to stretch the cardiac muscle and release ANP. Three milliliters of normal saline was injected during the day into the jugular vein of anesthetized rats that were pretreated with isoproterenol to stimulate pineal melatonin production. Animals were killed 15 min after the saline injection, and pineal NAT activity and pineal melatonin levels were measured. The saline injections caused no alteration in the elevated levels of either NAT or melatonin.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of two asymmetric headgear force systems: A finite element analysis.
The aim of this study was to evaluate the effect of displacement patterns of the molar teeth in response to different asymmetric headgear loading using 3D finite element method. A series of twenty-five facebow with different left vs. right outer bow length and different expansion of left vs. right were designed. The non-favored side (right side) was shortened at intervals of 10 mm, and favored side (left side) was expanded 10 degree greater than right side and 5 degree expansion were successively added. At the first phase, each side received 200-g load, implying the neck strap to displace toward shorter arm. At the second phase, a total of 400-g load was applied to the ends of the outer bow. Because of the neck strap displacement, the shorter arm received greater load than the left side, the magnitude of the applied force to each side depended on difference of left vs. right outer bow length and expansion. All systems were effective in promoting asymmetric distal movement of the molars. However, the asymmetrical facebow with the 40 mm shortening and 25 degree expansion outer bow when unequal force applied could be used in asymmetric mechanics. Medial and occlusal displacing forces were observed in all systems. Both equal and unequal force application is effective for molar distalization. Expansion of the outer bow in the affected side and shortening of the outer bow in the normal side were effective to produced differential distal molar movement.


Quantifying structure dependent responses in Li-ion cells with excess Li spinel cathodes: matching voltage and entropy profiles through mean field models.
Measurements of the open circuit voltage of Li-ion cells have been extensively used as a non-destructive characterisation tool. Another technique based on entropy change measurements has also been applied for this purpose. More recently, both techniques have been used to make qualitative statements about aging in Li-ion cells. One proposed cause of cell failure is point defect formation in the electrode materials. The steps in voltage profiles, and the peaks in entropy profiles are sensitive to order/disorder transitions arising from Li/vacancy configurations, which are affected by the host lattice structures. We compare the entropy change results, voltage profiles and incremental capacity (dQ/dV) obtained from coin cells with spinel lithium manganese oxide (LMO) cathodes, Li1+yMn2-yO4, where excess Li y was added in the range 0 ≤ y ≤ 0.2. A clear trend of entropy and dQ/dV peak amplitude decrease with excess Li amount was determined. The effect arises, in part, from the presence of pinned Li sites, which disturb the formation of the ordered phase. We modelled the voltage, dQ/dV and entropy results as a function of the interaction parameters and the excess Li amount, using a mean field approach. For a given pinning population, we demonstrated that the asymmetries observed in the dQ/dV peaks can be modelled by a single linear correction term. To replicate the observed peak separations, widths and magnitudes, we had to account for variation in the energy interaction parameters as a function of the excess Li amount, y. All Li-Li repulsion parameters in the model increased in value as the defect fraction, y, increased. Our paper shows how far a computational mean field approximation can replicate experimentally observed voltage, incremental capacity and entropy profiles in the presence of phase transitions.


Low specificity of HIV-testing on sputum specimens kept at ambient temperatures for 4 to 7 days: a blinded comparison.
HIV testing on sputum using the QraQuick HIV1/2(R) assay has high sensitivity and specificity, and holds promise for application in tuberculosis surveys. Its performance under conditions that may occur during surveys in resource-poor countries is however, unknown. We assessed, in a blinded comparison with HIV serum testing, the sensitivity and specificity of the OraQuick(R) assay for detecting HIV antibody in sputum specimens kept at ambient temperature for up to 7 days, with and without decontaminant. Paired sputum and blood specimens from consecutively diagnosed smear-positive tuberculosis patients were tested with OraQuick(R) and 2 HIV-1/2 ELISA's. Sputum was tested within 24 hours of collection, split into 2 aliquots with and without addition of cetylpyridium chloride, and tested again after 4 and 7 days. Complete data was available for 377/435 (87%) enrolled patients; 132 (35%) tested HIV positive on serum. The sensitivity of the sputum test was 94.7% (95% CI 89.4-97.8) on day 1, 93.2% on day 4 and 92.9% on day 7. The specificity was 92.9% (95% CI 88.9-95.8) on day 1, and declined to 76.7% on day 4 (p < 0.001) and to 62.7% on day 7 (p < 0.001). Adding cetylpyridium chloride further decreased the specificity to 67.8% on day 4 (p = 0.04) and to 49.6% on day 7 (p = 0.004). Transportation of sputum specimens at ambient temperatures for 4 days or more, and addition of decontaminant, strongly affect the specificity of the OraQuick(R) assay. Unless applied within one day, this assay is not suitable for estimation of HIV-prevalence among tuberculosis patients in survey settings.


Loading of MHC class I and II presentation pathways by exogenous antigens: a quantitative in vivo comparison.
The MHC class I pathway is usually fueled by endogenous Ags, while exogenous Ags reach the MHC class II pathway. Although exogenous epitopes may also enter the MHC class I pathway, quantification of the efficiency of the process has remained a difficult task. In an attempt of such a quantification, we directly compared the amount of exogenous virus-like particles required for induction of cytotoxic T cell responses by cross-priming with the amount of virus-like particles required for induction of Th cell responses by the conventional route of MHC class II loading as an internal standard. Surprisingly, we found that cross-presentation of peptides derived from exogenous Ags on MHC class I molecules is of only marginally lower efficiency ( approximately 1- to 10-fold) than the classical MHC class II pathway in vitro and in vivo. Thus, Ag quantities required for cross-presentation and cross-priming are similar to those required for fueling the MHC class II pathway.


Phylogeography and population genetic structure of the great leaf-nosed bat (Hipposideros armiger) in China.
The geographical patterns of the genetic structure of Hipposideros armiger in China were assessed by analyzing sequence variation in the mitochondrial DNA control region. Analysis of molecular variance revealed a very strong genetic structure among 5 regions in H. armiger. A neighbor-joining tree, haplotype network construction by TCS and multidimensional scaling plots all showed significant geographic differentiation among 5 regions. The high genetic structure detected in H. armiger could be a consequence of poor dispersal ability, local adaptation, or marked female philopatry. The lack of genetic structure among 3 regions separated by the Gaoligong Range and the Qiongzhou Strait could be due to incomplete lineage sorting. Our estimated times of divergence for H. armiger populations suggested a relatively recent split. The S Yunnan population with the highest genetic diversity and the Hainan population with the lowest genetic diversity should be equally given priority for conservation. Although H. armiger has been shown to carry viruses implicated in human disease, we find little evidence for population mixing. We thus suggest minimizing disturbance to bats' roosting caves for minimizing the potential risk of virus transmission.


The effects of the stem cell on ciliary regeneration of injured rabbit sinonasal epithelium.
Defects in mucosal healing after sinonasal surgery cause infection, scar formation causing obstruction, relapse of the disease within a shorter period and revision surgery. The present study aimed to create a functional ciliated epithelium using a stem cell and stem cell sheet of adipose tissue origin and to show such regeneration ultra-structurally on experimentally injured rabbit nasal epithelium. This was an experimental animal study and basic research. A total of 18 white New Zealand rabbits were divided into three groups. The medial wall of the maxillary sinus of the subjects was peeled off bilaterally. No additional procedure was applied to the subjects in Group 1. In Group 2, adipose tissue-derived mesenchymal stem cell was implanted on the wound edges of the subjects. In Group 3, a stem cell sheet of three layers was laid onto the defect area. All subjects were killed after 3 weeks. The presence of the stem cell stained with bromo-deoxyuridine was assessed with a light microscope, whereas cilia density, ciliated orientation and cilia structure were evaluated with a scanning electron microscope. Ciliary densities in Group 2 and Group 3 were statistically superior compared to the control group (p < 0.001, p = 0.007). Cilia morphology in Group 2 and Group 3 was also better than the control group (p < 0.01, p = 0.048). Ciliary orientation in Group 2 was scored highest (p < 0.01). The ratio of BrDu-stained cells was observed to be 27% in Group 3 and 8% in Group 2. Sub-epithelial recovery was observed to be better in Group 3. Adipose tissue-derived mesenchymal stem cell increased the healing of the injured maxillary sinus mucosa of the rabbits in terms of cilia presence, density and morphology regardless of the implementation technique. Level of evidence NA.


Optimization of protocols for human ovarian tissue cryopreservation with sucrose, 1,2-propanediol and human serum.
Chemotherapy and/or radiotherapy protocols have improved the long-term survival of cancer patients. Frequent consequences of antiblastic treatments, used to eradicate malignancies, are the partial loss of ovarian function, which in children and young women can result in permanent sterility. Ovarian tissue cryopreservation implemented before the beginning of treatment may potentially restore fertility. However, the physical effects of cryopreservation can damage oocyte survival and decrease follicular cell integrity and stromal preservation. The aim of this study was to examine the effects of different concentrations of 1,2-propanediol (PROH) and sucrose as cryoprotectants and human serum as protein support. Particular concentrations tested were 1.26, 1.5 and 1.08 mol/l PROH, 0.175, 0.2, 0.224 and 0.3 mol/l of sucrose and 20%, 30% and 40% human serum in the freezing solutions and normal or raised sucrose concentrations in the dilution solutions. Ovarian cortical slices from 13 patients, aged 5-38 years, were cryopreserved using slow freezing-rapid thawing. Tests were conducted using light and transmission electron microscopy. Cryo-damage occurred predominantly in the stromal and follicular cells. The best preservation of morphological characteristics was obtained using the freeze-thaw protocol in which concentrations of cryoprotectants were among the lowest (1.26 mol/l PROH+0.175 mol/l sucrose) with 30% human serum.


Randomized trial of inhaled fluticasone propionate in chronic stable pulmonary sarcoidosis: a pilot study.
Pulmonary sarcoidosis is a disease in which the pathological processes are distributed along lymphatic pathways, particularly those around the bronchovascular bundles. Delivery of disease-modulating drugs by the inhaled route is therefore an attractive option. The aim of this study was to determine the efficacy of inhaled fluticasone propionate 2 mg x day(-1) in adults with stable pulmonary sarcoidosis. Forty-four adult patients (22 from each centre) were enrolled from outpatient clinics in two London teaching hospitals in a two centre, double-blind, randomized, placebo-controlled trial. Primary end points were home recordings of peak expiratory flow rate (PEFR), forced expiratory volume in one second (FEV1), and forced vital capacity (FVC). Secondary end points were symptom scores, use of rescue bronchodilator medication, and clinic values for PEFR, FEV1, FVC, forced mid-expiratory flow (FEF25-75%), diffusion capacity of the lung for carbon monoxide (DL,CO), and total lung capacity (TLC). Symptom scores of cough, breathlessness and wheeze were lower in the active treatment group, but this did not reach statistical significance, and a general health perception assessment (Short Form (SF)-36) showed a difference between active and placebo treatment. No significant differences were found between the two groups in any physiological outcome measure. No new adverse reactions were detected. The results of this pilot study do not show an objective benefit of inhaled fluticasone propionate in pulmonary sarcoidosis where the disease is stable and is controlled without the use of inhaled corticosteroids.


Separate effects of urinary chondroitin sulphate and heparan sulphate on the crystallization of urinary calcium oxalate: differences between stone formers and normal control subjects.
1. Urinary glycosaminoglycans were recovered from the papain digest of polyanions precipitated sequentially by cetylpyridinium chloride and sodium acetate-saturated ethanol. Those from the early morning urine of 48 stone formers and 43 normal control subjects measured 11 and 16 micrograms of uronic acid/ml of urine, respectively. 2. Preparative agarose gel electrophoresis of the recovered glycosaminoglycans in barium acetate buffer (pH 5.8) yielded fractions containing purely chondroitin sulphate, co-polymeric chondroitin/dermatan sulphates and heparan sulphate. Identification was based on the susceptibility of the fractions to chondroitinase or nitrous acid treatment. Similar compositions of glycosaminoglycan classes were observed in samples from stone formers and normal control subjects. 3. The fractionated glycosaminoglycans were dissolved in urine ultrafiltrate to assay for nucleation-promoting and growth-inhibiting activities towards crystallization of urinary calcium oxalate. When compared at the same uronic acid concentration, both the urinary chondroitin sulphate isomers and heparan sulphates of stone formers demonstrated the capacity to enhance crystal nucleation from calcium oxalate endogenous in urine ultrafiltrates, whereas only urinary heparan sulphates of normal control subjects demonstrated this capacity. 4. Tissue-derived reference chondroitin sulphate, dermatan sulphate and heparin, when similarly tested, showed negligible crystal nucleation-promoting activity. The tissue-derived heparan sulphate was similar to the urinary heparan sulphates in showing marked crystal nucleation-promoting activity. 5. Crystal-growth inhibitory activity was evident in all urinary glycosaminoglycan fractions studied. In particular, urinary heparan sulphate of normal control subjects showed higher activity than that of stone formers or the chondroitin sulphate isomers of both stone formers and normal control subjects (P < 0.005).


Prevention of allergic disease in childhood: clinical and epidemiological aspects of primary and secondary allergy prevention.
The development and phenotypic expression of atopic diseases depends on a complex interaction between genetic factors, environmental exposure to allergens,and non-specific adjuvant factors, such as tobacco smoke, air pollution and infections. Preventive measures may include both exposure to allergens and adjuvant risk/protective factors and pharmacological treatment. These measures may address the general population, children at risk for development of atopic disease (high-risk infants), children with early symptoms of allergic disease or children with chronic disease. The objective for this review was to evaluate possible preventive measures as regards prevention of development of allergic disease in childhood--primary prevention--and also some aspects of the effect of specific allergy treatment as regards secondary prevention in children with allergic asthma and allergic rhinoconjunctivitis. In one prospective observational study of a birth cohort of unselected infants we evaluated possible predictive/risk factors. In two prospective intervention studies including 1 yr birth cohorts of high-risk(HR) infants we investigated the effect of feeding HR infants exclusively breast milk (BM) and/or hydrolyzed cow's milk-based formula the first 4-6 months as regards: (i) the allergy preventive effect of BM/extensively hydrolysed formula (eHF) compared with ordinary cow's milk-based formula, (ii) the effect of two different eHFs, a whey (Profylac) and a casein-based (Nutramigen) formula, as regards development of cow's milk protein allergy (CMA), and (iii) a comparison of the preventive effect of eHF (Profylac/Nutramigen) with a partially hydrolyzed cow's milk-based formula (pHF) (NanHA) as regards development of CMA. None of the mothers had a restricted diet during pregnancy or lactation period. In two prospective randomized intervention studies we evaluated the preventive effect of specific allergen avoidance and specific immunotherapy (SIT) in children with allergic asthma and allergic rhinoconjunctivitis, respectively. The combination of atopic heredity and elevated cord blood IgE resulted in the best predictive discrimination as regards development of allergic disease. The optimal high-risk group was defined by either double parental atopic predisposition or single atopic predisposition, the latter combined with a cord blood IgE > or = 0.3 kU/1. 66% of unselected infants were daily exposed to tobacco smoke, which was a significant risk factor for recurrent wheezing until the age of 1.5 yr. HR infants were breastfed for a longer period and less exposed to tobacco smoke than unselected infants. Exclusively BM/eHF for at least 4 months was associated with a significantly reduced cumulative prevalence of CMA [3.6% (5/141) vs. 20%(15/75) in the control group] up to 5 yr. The effect of the two different eHFs was similar. Exclusively breastfed infants were significantly less exposed to tobacco smoke and pets, had solid foods introduced later and belonged to higher social classes. pHF was significantly (p = 0.05) less effective than eHF as regards prevention of development of CMA. A diet period of 4 months seems to be as efficient as 6 months or more as regards development of CMA. A few ongoing prospective, randomized intervention studies have produced the first indication that avoidance of indoor allergens such as house dust mite (HDM) in HR infants may reduce the incidence of severe wheeze and sensitization during the first 1-4 yr of age. Long-term follow-up is awaited. In a prospective, double-blind placebo-controlled study in children with doctors diagnosed asthma and documented HDM allergy, we found that semipermeable polyurethane mattress and pillow encasings (Allergy Control) when compared with placebo encasings resulted in a significant perennial reduction of HDM exposure and a significant reduction in the needed dose of inhaled steroids by approximately 50% (mean dose: 408 microg--227 microg/day) after 1-yr follow-up. In another randomized prospective study we investigated the possible preventive effect of SIT in children with allergic rhinoconjunctivitis and grass/birch pollen allergy as regards development of asthma. Among those without asthma significantly fewer in the SIT group developed asthma when compared with the control group (19/79 = 24% vs.32/72 = 44%) after the first 3 yr; and methacholinebronchial provocation test results improved significant in the SIT group. The results of our studies support the evidence that the risk for development of early allergic manifestations e.g. CMA and atopic dermatitis can be reduced significantly by simple dietary measures for the first4 months of life. In all infants breastfeeding should beencouraged for at least 4-6 months, and exposure to tobacco smoke should be avoided during pregnancy and early childhood. In HR infants a documented hypoallergenic formula (at present eHF) is recommended if exclusive breastfeeding is not possible for the first 4 months. In homes of HR-infants, current evidence supports measures to reduce the levels of indoor allergens. e.g. HDM and pets. In symptomatic children allergen-specific treatment may influence both the symptoms and the prognosis. Allergen avoidance can reduce the need for pharmacological treatment, SIT may have the potential for preventing the development of asthma in children with allergic rhinoconjunctivitis. and it may be possible to interfere with the natural course of allergic diseases.


A decision exercise to engage cancer patients and families in deliberation about Medicare coverage for advanced cancer care.
Concerns about unsustainable costs in the US Medicare program loom as the number of retirees increase and experiences serious and costly illnesses like cancer. Engagement of stakeholders, particularly cancer patients and their families, in prioritizing insured services offers a valuable strategy for informing Medicare coverage policy. We designed and evaluated a decision exercise that allowed cancer patients and family members to choose Medicare benefits for advanced cancer patients. The decision tool, Choosing Health plans All Together (CHAT) was modified to select services for advanced cancer patients. Patients with a cancer history (N = 246) and their family members (N = 194) from North Carolina participated in 70 CHAT sessions. Variables including participants' socio-demographic characteristics, health status, assessments of the exercise and results of group benefit selections were collected. Routine descriptive statistics summarized participant characteristics and Fisher's exact test compared group differences. Qualitative analysis of group discussions were used to ascertain reasons for or against selecting benefits. Patients and family members (N = 440) participated in 70 CHAT exercises. Many groups opted for such services as palliative care, nursing facilities, and services not currently covered by the Medicare program. In choosing among four levels of cancer treatment coverage, no groups chose basic coverage, 27 groups (39%) selected intermediate coverage, 39 groups (56%) selected high coverage, and 4 groups (6%) chose the most comprehensive cancer coverage. Reasons for or against benefit selection included fairness, necessity, need for prioritizing, personal experience, attention to family needs, holistic health outlook, preference for comfort, freedom of choice, and beliefs about the proper role of government. Participants found the exercise very easy (59%) or fairly easy (39%) to understand and very informative (66%) or fairly informative (31%). The majority agreed that the CHAT exercise led to fair decisions about priorities for coverage by which they could abide. It is possible to involve cancer patients and families in explicit discussions of their priorities for affordable advanced cancer care through the use of decision tools designed for this purpose. A key question is whether such a conversation is possible on a broader, national level.


Ecophysiology of xerophytic and halophytic vegetation of a coastal alluvial plain in northern Venezuela: IV. Tillandsia flexuosa Sw. and Schomburgkia humboldtiana Reichb., epiphytic CAM plants.
A comparison of the performance of two epiphytes with crassulacean acid metabolism (CAM) was made during the rainy season and dry season at the Ciénega el Ostional, Chichiriviche in northern Venezuela. The epiphytic bromeliad, Tillandsia flexuosa has water-retaining tanks and leaf trichomes, and propagates mainly vegetatively to produce large populations in the shrubby island vegetation. The epiphytic orchid, Schomburgkia humboldtiana formed smaller populations, and had large succulent leaves with uniform chlorenchyma and no distinct water-storage parenchyma, unlike T. flexuosa. Both epiphytes were myrmecophilous. Leaf succulence (kg m-2 ) declined by ∼ 10% in the dry season for both plants. Both epiphytes showed reduced CO2 uptake during Phase I (dark period) and (dawn-dusk) titratable acidity (ΔH+ ) in the dry season. Water-use efficiency (WUE) was higher for S. humboldtiana (16.0 × 10-3 mol CO2 per mol H2 O compared with 5.0 × 10 -3 for T. flexuosa) although WUE remained constant during rainy and dry season for each species. Sixty to seventy per cent of the dawn dusk titratable acidity was derived internally from respiratory CO2 (recycling) for both species, and in absolute terms, recycling decreased in the dry season, in contrast to the expected progression under drought stress. Recycling is an important facet of carbon balance for both species in both rainy and dry seasons. Leaf Na+ concentration was higher than values quoted for terrestrial salt stressed CAM plants. Fructose and glucose declined in leaf bases of T. flexuosa during the dark period, but not in the more distal regions of the leaf. S. humboldtiana showed a decrease in sucrose at night, and mannitol was also an important constituent of the leaves. Xylem sap tension maxima increased from 0.38 ± 0.09 MPa (rainy season) to only 0.55 ± 0.06 MPa (dry season) for T. flexuosa, these values being much lower than those found for terrestrial shrubs and herbs at the same site, the two epiphytes use CAM in conjunction with differing morphological adaptations to maintain growth throughout the year at the Ciénega el Ostional, but it would seem that T. flexuosa has better physiological characteristics for maintenance of carbon acquisition during the dry season.


Design of a multi-sensor sonar system for indoor range measurement as a navigational aid for the blind.
This paper reports the methodology for the design of a sonar-based ranging and guidance system. The intended application of the system is to help a blind person avoid obstacles as he/she navigates his/her environment. Six sonar transceivers are arranged radially on a headgear worn by the user. The transceivers detect discrete range data at discrete-time sampling instances. A panoramic map of the environment is generated from the discrete-space sensory data. The paper emphasizes the challenges faced during the measurement of omnidirectional ranging information in indoor environments. Situations have been identified where erroneous range readings are generated due to channel cross talk caused by echo bouncing off multiple surfaces. Several sonar control and measurement schemes were developed and tested to avoid these situations. The results and performance of these different control schemes are compared in this paper. A microcontroller-based system commands the sonar ping sequences, acquires the echo return times and computes the ranges. The set of range data is transmitted to a PC, which utilizes the information to build a spatialized audio map of the surrounding obstacles. The hardware and software layout for the system are described in this paper.


Comparative Study of Plasma Endotoxin with Procalcitonin Levels in Diagnosis of Bacteremia in Intensive Care Unit Patients.
Both procalcitonin (PCT) and plasma endotoxin levels cannot be solely used for a definite diagnosis of bacteremia or sepsis, and there has been few study comparing the values of the two biomarkers for the diagnosis of bacteremia. The aim of this study was to identify bacteria causing bacteremia and evaluate the role of the two biomarkers in the diagnosis of bacteremia in Intensive Care Unit (ICU). The medical records of 420 patients in ICU were retrospectively reviewed. Patients (n = 241) who met the inclusion criteria were subjected to blood culture (BC) for the analysis of the endotoxin or PCT levels. The exclusion criteria included the presence of infection with human immunodeficiency virus and/or AIDS, neutropenia without sepsis, pregnancy, treatment with immunosuppressive therapies, or blood diseases such as hematological tumors. Patients' BC episodes were divided into BC negative, Gram-negative (GN) bacteria, Gram-positive bacteria, and fungi groups. The PCT and plasma endotoxin levels were compared in the different groups. A total of 241 patients with 505 episodes of BC were analyzed. The GN bacteria group showed higher levels of PCT and endotoxin than the BC negative, Gram-positive bacteria, and fungi groups. GN bacteremia was more prevalent than Gram-positive bacteremia. The GN bacteremia caused by non-Enterobacteriaceae infection presented higher endotoxin level than that by Enterobacteriaceae, but no significant difference in PCT levels was observed between the two groups. The plasma endotoxin significantly differed among different groups and was bacterial species dependent. Plasma endotoxin was more related to GN than to Gram-positive bacteremia, and that endotoxin level was species dependent, but PCT level remained relatively more stable within the GN bacteria caused bacteremia. Both GN and positive bacteria caused bacteremia in the ICU patients in different regions of China. And PCT is a more valuable biomarker than endotoxin in the diagnosis of bacteremia.


Fatal and nonfatal poisoning by hydrogen sulfide at an industrial waste site.
An adult man (A) entered a pit to collect seepage at an industrial waste site in Japan. As he suddenly lost consciousness, three colleagues (B, C, D) entered the pit to rescue him. All of these men lost consciousness in the pit. Two workers (A and B) died soon after the accident, one worker (C) died 22 days after the accident, and one worker (D) survived. Since hydrogen sulfide gas was detected in the atmosphere of the pit, gas poisoning was suspected. Toxicological analyses of sulfide and thiosulfate, a metabolite of sulfide, in blood and urine of the victims were made using the extractive alkylation technique combined with gas chromatography/mass spectrometry (GC/MS). Sulfide was detected in the blood of A and B at levels of 0.13 and 0.11 mg/L, respectively, somewhat higher than in healthy persons. Thiosulfate was detected in whole blood of deceased victims A and B, in the plasma of deceased victim C, at concentrations of 10.53, 4.59, and 4.14 mg/L, respectively. These values were similar to those found in fatal cases of hydrogen sulfide poisoning. Thiosulfate was not detected in the plasma of survivor D. With respect to urine samples, thiosulfate was the highest in the non-acute death victim C (137.20 mg/L), followed by that in the survivor D (29.34 mg/L), and low (0.90 mg/L) and not detected in the acute death victims, A and B, respectively. Based on these results, all four patients were victims of hydrogen sulfide poisoning. The concentrations of thiosulfate in blood and urine were more useful than that for sulfide for determining hydrogen sulfide poisoning. Thiosulfate in urine was the only indicator of hydrogen sulfide poisoning in the non-fatal victim.


Tuning of Recombinant Protein Expression in Escherichia coli by Manipulating Transcription, Translation Initiation Rates, and Incorporation of Noncanonical Amino Acids.
Protein synthesis in cells has been thoroughly investigated and characterized over the past 60 years. However, some fundamental issues remain unresolved, including the reasons for genetic code redundancy and codon bias. In this study, we changed the kinetics of the Eschrichia coli transcription and translation processes by mutating the promoter and ribosome binding domains and by using genetic code expansion. The results expose a counterintuitive phenomenon, whereby an increase in the initiation rates of transcription and translation lead to a decrease in protein expression. This effect can be rescued by introducing slow translating codons into the beginning of the gene, by shortening gene length or by reducing initiation rates. On the basis of the results, we developed a biophysical model, which suggests that the density of co-transcriptional-translation plays a role in bacterial protein synthesis. These findings indicate how cells use codon bias to tune translation speed and protein synthesis.


Cochlear implant in the treatment of incapacitating unilateral tinnitus: case report.
Several studies have shown that cochlear implants may reduce or even eliminate tinnitus in patients with bilateral profound hearing loss. However, there are not consistent references regarding ipsilateral tinnitus compared to unilateral profound hearing loss. The aim of this paper is to describe audiological results of a patient with asymmetrical hearing loss with incapacitating ipsilateral tinnitus in the ear subjected to cochlear implant surgery. Audiological exams and responses to perception protocols for tinnitus before and after surgery were analyzed. The tests showed improvements in the hearing threshold on the side with the implant, improvements in speech perception and a significant reduction in tinnitus perception, which consequently led to an improvement in the patient's quality of life.


Attribution of climate forcing to economic sectors.
A much-cited bar chart provided by the Intergovernmental Panel on Climate Change displays the climate impact, as expressed by radiative forcing in watts per meter squared, of individual chemical species. The organization of the chart reflects the history of atmospheric chemistry, in which investigators typically focused on a single species of interest. However, changes in pollutant emissions and concentrations are a symptom, not a cause, of the primary driver of anthropogenic climate change: human activity. In this paper, we suggest organizing the bar chart according to drivers of change-that is, by economic sector. Climate impacts of tropospheric ozone, fine aerosols, aerosol-cloud interactions, methane, and long-lived greenhouse gases are considered. We quantify the future evolution of the total radiative forcing due to perpetual constant year 2000 emissions by sector, most relevant for the development of climate policy now, and focus on two specific time points, near-term at 2020 and long-term at 2100. Because sector profiles differ greatly, this approach fosters the development of smart climate policy and is useful to identify effective opportunities for rapid mitigation of anthropogenic radiative forcing.


Plant-Parasitic Nematodes and Food Security in Sub-Saharan Africa.
Sub-Saharan Africa (SSA) is a region beset with challenges, not least its ability to feed itself. Low agricultural productivity, exploding populations, and escalating urbanization have led to declining per capita food availability. In order to reverse this trend, crop production systems must intensify, which brings with it an elevated threat from pests and diseases, including plant-parasitic nematodes. A holistic systems approach to pest management recognizes disciplinary integration. However, a critical under-representation of nematology expertise is a pivotal shortcoming, especially given the magnitude of the threat nematodes pose under more intensified systems. With more volatile climates, efficient use of water by healthy root systems is especially crucial. Within SSA, smallholder farming systems dominate the agricultural landscape, where a limited understanding of nematode problems prevails. This review provides a synopsis of current nematode challenges facing SSA and presents the opportunities to overcome current shortcomings, including a means to increase nematology capacity.


Radiomics in radiooncology - Challenging the medical physicist.
Noticing the fast growing translation of artificial intelligence (AI) technologies to medical image analysis this paper emphasizes the future role of the medical physicist in this evolving field. Specific challenges are addressed when implementing big data concepts with high-throughput image data processing like radiomics and machine learning in a radiooncology environment to support clinical decisions. Based on the experience of our interdisciplinary radiomics working group, techniques for processing minable data, extracting radiomics features and associating this information with clinical, physical and biological data for the development of prediction models are described. A special emphasis was placed on the potential clinical significance of such an approach. Clinical studies demonstrate the role of radiomics analysis as an additional independent source of information with the potential to influence the radiooncology practice, i.e. to predict patient prognosis, treatment response and underlying genetic changes. Extending the radiomics approach to integrate imaging, clinical, genetic and dosimetric data ('panomics') challenges the medical physicist as member of the radiooncology team. The new field of big data processing in radiooncology offers opportunities to support clinical decisions, to improve predicting treatment outcome and to stimulate fundamental research on radiation response both of tumor and normal tissue. The integration of physical data (e.g. treatment planning, dosimetric, image guidance data) demands an involvement of the medical physicist in the radiomics approach of radiooncology. To cope with this challenge national and international organizations for medical physics should organize more training opportunities in artificial intelligence technologies in radiooncology.


DNA-based stable isotope probing: a link between community structure and function.
DNA-based molecular techniques permit the comprehensive determination of microbial diversity but generally do not reveal the relationship between the identity and the function of microorganisms. The first direct molecular technique to enable the linkage of phylogeny with function is DNA-based stable isotope probing (DNA-SIP). Applying this method first helped describe the utilization of simple compounds, such as methane, methanol or glucose and has since been used to detect microbial communities active in the utilization of a wide variety of compounds, including various xenobiotics. The principle of the method lies in providing (13)C-labeled substrate to a microbial community and subsequent analyses of the (13)C-DNA isolated from the community. Isopycnic centrifugation permits separating (13)C-labeled DNA of organisms that utilized the substrate from (12)C-DNA of the inactive majority. As the whole metagenome of active populations is isolated, its follow-up analysis provides successful taxonomic identification as well as the potential for functional gene analyses. Because of its power, DNA-SIP has become one of the leading techniques of microbial ecology research. But from other point of view, it is a labor-intensive method that requires careful attention to detail during each experimental step in order to avoid misinterpretation of results.


Spatiotemporal beam self-cleaning for high-resolution nonlinear fluorescence imaging with multimode fiber.
Beam self-cleaning (BSC) in graded-index (GRIN) multimode fibers (MMFs) has been recently reported by different research groups. Driven by the interplay between Kerr effect and beam self-imaging, BSC counteracts random mode coupling, and forces laser beams to recover a quasi-single mode profile at the output of GRIN fibers. Here we show that the associated self-induced spatiotemporal reshaping allows for improving the performances of nonlinear fluorescence (NF) microscopy and endoscopy using multimode optical fibers. We experimentally demonstrate that the beam brightness increase, induced by self-cleaning, enables two and three-photon imaging of biological samples with high spatial resolution. Temporal pulse shortening accompanying spatial beam clean-up enhances the output peak power, hence the efficiency of nonlinear imaging. We also show that spatiotemporal supercontinuum (SC) generation is well-suited for large-band NF imaging in visible and infrared domains. We substantiated our findings by multiphoton fluorescence imaging in both microscopy and endoscopy configurations.


Detergent-free extraction of a functional low-expressing GPCR from a human cell line.
Dopamine receptors (DRs) are class A G-Protein Coupled Receptors (GPCRs) prevalent in the central nervous system (CNS). These receptors mediate physiological functions ranging from voluntary movement and reward recognition to hormonal regulation and hypertension. Drugs targeting dopaminergic neurotransmission have been employed to treat several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, Huntington's disease, attention deficit hyperactivity disorder (ADHD), and Tourette's syndrome. In vivo, incorporation of GPCRs into lipid membranes is known to be key to their biological function and, by inference, maintenance of their tertiary structure. A further significant challenge in the structural and biochemical characterization of human DRs is their low levels of expression in mammalian cells. Thus, the purification and enrichment of DRs whilst retaining their structural integrity and function is highly desirable for biophysical studies. A promising new approach is the use of styrene-maleic acid (SMA) copolymer to solubilize GPCRs directly in their native environment, to produce polymer-assembled Lipodisqs (LQs). We have developed a novel methodology to yield detergent-free D1-containing Lipodisqs directly from HEK293f cells expressing wild-type human dopamine receptor 1 (D1). We demonstrate that D1 in the Lipodisq retains activity comparable to that in the native environment and report, for the first time, the affinity constant for the interaction of the peptide neurotransmitter neurotensin (NT) with D1, in the native state.


Antecedents and consequences of unawareness of memory impairment in dementia.
To assess the prevalence, antecedents, and consequences of unawareness of memory impairment in dementia. Persons (n = 1,862) from a geographically defined community without dementia at enrollment subsequently underwent clinical classification (248 with dementia, 611 with mild cognitive impairment, 1,003 with no cognitive impairment), memory testing, and self-appraisal of memory. Memory performance was regressed on self-appraised memory, and the residuals served as an index of memory awareness. After clinical classification, participants completed brief cognitive testing at 3-year intervals for up to 15 years. When unawareness was defined as a score at or below thresholds ranging from the 15th to 25th percentiles, it was more common in dementia (67%-83%) and mild cognitive impairment (15%-33%) than in no cognitive impairment (2%-6%; all p < .001). A continuous measure of awareness (M = 0.00, SD = 0.61) was reduced by 0.37-unit in mild cognitive impairment (SE = 0.04, p < .001) and 1.04-unit in dementia (SE = 0.06), p < .001) compared with those without cognitive impairment, and these associations were weaker in Black persons than White persons (estimate for dementia by race = 0.37, SE = 0.12, p = .003; estimate for mild cognitive impairment by race = 0.30, SE = 0.08, p < .001). Higher premorbid neuroticism was associated with better memory awareness in dementia. Higher memory awareness was not related to mortality in mild cognitive impairment or dementia but had a marginal association with slower cognitive decline in mild cognitive impairment. Unawareness of memory impairment is a common manifestation of dementia, particularly in White persons, but is not strongly related to adverse disease outcomes. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Electrical activity of the hypothalamus effects of intraventricular catecholamines.
The injection of epinephrine into the third ventricle of the rat brain causes a biphasic elevation and depression in the integrated multiple-unit electrical activity of the median eminence. Activity in the arcuate nucleus decreases after the injection of the catecholamines. These changes in the integrated multiple-unit electrical activity may be related to the secretion of hormones by the anterior pituitary gland.


Effects of hypoxia on gene and protein expression in the blue crab, Callinectes sapidus.
Increases in hypoxic conditions are one of the major factors responsible for declines in estuarine habitat quality, yet to date there are no indicators for recognizing populations of estuarine organisms that are suffering from chronic hypoxic stress. Here we test the hypothesis that alterations in gene and protein expression of antioxidant enzymes and other stress-specific proteins can be used as molecular indicators of hypoxic stress. Blue crabs, Callinectes sapidus, were exposed to 2-3 ppm DO for 5 days. Gene expression was measured using macroarrays constructed from cDNA of 10 partial gene transcripts cloned from blue crab hepatopancreas. Significant (p< or =0.05) down-regulation of gene expression was found for MnSOD, hemocyanin, ribosomal S15 and L23. Subtractive hybridization using RNA from control and hypoxic hepatopancreas tissues also indicated down-regulation of hemocyanin transcription. In contrast, Western blotting showed a significant (p< or =0.05) increase of hemocyanin protein in the hepatopancreas and cross-linking of MnSOD proteins in hypoxia-exposed crabs. Thus, hypoxia-responsive cDNA arrays and Westerns may be useful diagnostic tools for monitoring effects of hypoxia in estuarine crustacea.


Correlates of Untreated Hypercholesterolemia in Older Adults: A Community-Based Household Survey in China.
Hypercholesterolemia is common in older adults and less treated, but little is known about correlates of untreated hypercholesterolemia. Using a standard interview method we examined a random sample of 7,572 participants aged ≥60 years in a community-based household survey across 7 provinces of China during 2007-2012, and documented 328 cases of hypercholesterolemia from self-reported doctor diagnosis. Compared to participants with normal cholesterol, older adults with hypercholesterolemia had higher socioeconomic position and larger body mass index. In patients with hypercholesterolemia, 209 were not treated using lipid-lowering medications (63.7%, 95% confidence interval (CI) 58.5%-68.9%). Untreated hypercholesterolemia was significantly associated with female sex (adjusted odds ratio 2.13, 95%CI 1.17-3.89), current smoking (3.48, 1.44-8.44), heavy alcohol drinking (3.13,1.11-8.84), chronic bronchitis (2.37,1.14-4.90) and high level of meat consumptions (2.85,1.22-6.65). Although having coronary heart disease exposed participants for treatment, half of participants with coronary heart disease did not receive lipid-lowering medications. Among hypercholesterolemia participants with stroke, hypertension or diabetes, more than half of them did not receive lipid-lowering medications. The high proportion of untreated hypercholesterolemia in older, high-risk Chinese adults needs to be mitigated through multi-faceted primary and secondary prevention strategies to increase population opportunities of treating hypercholesterolemia.


Mutual exclusivity and phonological novelty constrain word learning at 16 months.
Studies report that infants as young as 1 ; 3 to 1 ; 5 will seek out a novel object in response to hearing a novel label (e.g. Halberda, 2003; Markman, Wasow & Hansen, 2003). This behaviour is commonly known as the 'mutual exclusivity' response (Markman, 1989; 1990). However, evidence for mutual exclusivity does not imply that the infant has associated a novel label with a novel object. We used an intermodal preferential looking task to investigate whether infants aged 1 ; 4 could use mutual exclusivity to guide their association of novel labels with novel objects. The results show that infants can successfully map a novel label onto a novel object, provided that the novel label has no familiar phonological neighbours. Therefore, as early as 1 ; 4, infants can use mutual exclusivity to form novel word-object associations, although this process is constrained by the phonological novelty of a label.


Intratissue lymphovenous communications in the mechanism of action of vascularized lymph node transfer.
Vascularized lymph node transfer (VLNT) as a surgical treatment for cancer-related lymphedema has shown beneficial effects. The mechanism of action of this procedure involves lymphangiogenesis and lymphovenous communications (LVC) within the lymph nodes. We propose intratissue LVC as an additional element responsible for drainage of lymph to blood in the flap and examine this hypothesis in the current study. This prospective study determined the passage of lymph to the venous system via intratissue LVC in 26 free flaps used for breast reconstruction. We evaluated whether fluorescence was positive in the pedicle vein after increasing time intervals following intradermal injection of indocyanine green (ICG) dye into the flaps using near infra-red fluorescence lymphography. We studied 26 free flaps, 22 deep inferior epigastric perforator (DIEP) flaps (84.6%), and 4 superior gluteal artery perforator (SGAP) flaps (15.4%). Fluorescence in the pedicle vein was positive in 22 of the 26 flaps (P = 0.000). The median time for fluorescence evaluation in the pedicle vein was 120 min. Fluorescence in the pedicle vein after ICG intradermal injection indicates functional intratissue LVC in free flaps. J. Surg. Oncol. 2017;115:27-31. © 2016 Wiley Periodicals, Inc.


Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}-induced interleukin 6 production and the myeloma proliferative component.
To conduct in vitro studies as well as a phase 2 clinical trial in patients with smoldering or indolent multiple myeloma to determine if interleukin 1 (IL-1) inhibitors can delay or prevent active myeloma. Stromal cells were cocultured with IL-1beta-expressing myeloma cells in the presence of dexamethasone, IL-1 receptor antagonist (IL-1Ra), or both. Levels of interleukin 6 (IL-6) and of apoptosis were also quantified. Between November 19, 2002, and May 24, 2007, 47 patients were enrolled in the study and subsequently treated with IL-1Ra. In 25 (53%) of the 47 study patients, low-dose dexamethasone (20 mg/wk) was added. The primary end point was progression-free survival (PFS). In vitro, IL-1Ra was superior to dexamethasone at inhibiting IL-6 production; maximal IL-6 inhibition and apoptosis induction were achieved by addition of both IL-1Ra and dexamethasone. In the clinical trial, 3 patients achieved a minor response to IL-1Ra alone; 5 patients achieved a partial response and 4 patients a minor response after addition of dexamethasone. Seven patients showed a decrease in the plasma cell labeling index that paralleled a decrease in high-sensitivity C-reactive protein (hs-CRP) levels. The median overall PFS was 37.5 months. The median PFS for patients without (n=12) or with (n=35) a greater than 15% decrease in 6-month vs baseline hs-CRP levels was 6 months and more than 3 years, respectively (P=.002). Disease stability was maintained in 8 patients who received therapy for more than 4 years. In patients with smoldering or indolent multiple myeloma who were at risk of progression to active myeloma, treatment with IL-1 inhibitors decreased the myeloma proliferative rate and hs-CRP levels in those who responded, leading to a chronic disease state and an improved PFS. clinicaltrials.gov identifier: NCT00635154.


Study on Ajuga reptans Extract: A Natural Antioxidant in Microencapsulated Powder Form as an Active Ingredient for Nutraceutical or Pharmaceutical Purposes.
The administration of natural antioxidants is considered to be a prevention strategy for chronic diseases and a useful tool for the healthcare system to reduce the administration of expensive and often not effective treatments. The chemical characterization of a methanolic extract (AJ) of Ajuga reptans L. was performed, and its antioxidant activity was evaluated. AJ and the major compounds, characterized by chromatographic techniques as phenylpropanoids and iridoids, were able to reduce the Reactive Oxygen Species levels in cancer cell lines (melanoma, A375, cervical cancer, HeLa, and alveolar adenocarcinoma, A549), stimulated by E. coli lipopolysaccharide. However, a clinical translation of these results encountered a significant limitation represented by the poor water solubility and bioavailability of the extract and compounds. Consequently, a hydro-soluble powder system (AJEP3) was developed by spray-drying encapsulating AJ into a multi-component solid matrix that is based on L-proline and hydroxyethylcellulose as loading and coating agents, and lecithin as solubility enhancer. The technological approach led to a satisfactory process yield (71.5%), encapsulation efficiency (99.9%), and stability. The in vitro water dissolution rate of the bioactive compounds appeared to be improved with respect to the extract, suggesting higher feasibility in the manufacturing and administration; even the in vitro biological activity of the produced multi-component AJEP3 was clearly enhanced.


Structural differences between the hormone and antihormone estrogen receptor complexes bound to the hormone response element.
To investigate the molecular mechanism(s) by which the estrogen receptor (ER) modulates transcription, we compared the structures of receptor complexes containing estradiol, the agonist diethylstilbestrol, and the antagonist ICI164,384. The binding of ICI164,384 to nontransformed 8-9S ER does not preclude the salt-induced dissociation of the 90-kDa heat shock protein and releases the transformed homodimeric 5S ER as classically observed in the presence of agonist. We report that calf ER binds to the estrogen response element of the Xenopus vitellogenin A2 gene in either the absence or presence of hormone, agonist, or antagonist. These binding interactions were highly sequence- and receptor-specific. These findings indicate that ligand binding in vitro is not absolutely required for dimerization or specific DNA binding of the ER. As demonstrated by gel retardation assays, the ICI164,384-ER complex bound to the response element displays a slower mobility than complexes formed in the presence of estradiol or agonist. This difference in electrophoretic mobility is suggestive of a conformational change in the complex induced by the ligand. An exchange experiment demonstrated that this alteration of the structure is reversible. We suggest that ICI164,384 induces conformational modifications within the ligand-binding domain of the receptor that do not prevent binding to the response element but could fail to promote subsequent events required for gene transcription.


Acute exercise increases resistance to oxidative stress in young but not older adults.
A single bout of acute exercise increases oxidative stress and stimulates a transient increase in antioxidant enzymes. We asked whether this response would induce protection from a subsequent oxidative challenge, different from that of exercise, and whether the effects were affected by aging. We compared young (20 ± 1 years, n = 8) and older (58 ± 6 years, n = 9) healthy men and women. Resistance to oxidative stress was measured by the F2-isoprostane response to forearm ischemia/reperfusion (I/R) trial. Each participant underwent the I/R trial twice, in random order; once after performing 45 min of cycling on the preceding day (IRX) and a control trial without any physical activity (IRC). Baseline F2-isoprostane levels were significantly lower at IRX compared to IRC (P < 0.05) and not different between groups. F2-isoprostane response to IRX was significantly lower compared to IRC in young (P < 0.05) but not different in the older group. Superoxide dismutase activity in response to acute exercise was significantly higher in young compared to older adults (P < 0.05). These data suggest that signal transduction of acute exercise may be impaired with aging. Repeated bouts of transient reactive oxygen species production as seen with regular exercise may be needed to increase resistance to oxidative stress in older individuals.


Dual-beam interference from a lensed multicore fiber and its application to optical trapping.
A multicore all-fiber probe is demonstrated that has been fabricated using an electric arc fusion splicer. Interference of the fiber output when coherent light is coupled into two cores is investigated. The properties of the fringes created when the fiber is probing different media were found to be in general agreement with a beam propagation method simulation. Optical manipulation of microspheres near to the end of the probe is examined and the potential for controlled trapping explored. Polymer microspheres with diameters of 2 microns were formed into regular patterns due to the presence of the interference fringes.


What must a psychological theory of reasoning explain? Comment on Barrouillet, Gauffroy, and Lecas (2008).
In this comment, it is argued that the modification of mental models theory of conditional inference proposed by P. Barrouillet, C. Gauffroy, and J.-F. Lecas to deal with truth value gaps merely patches up a problem in the theory, rather than accomplishing the fundamental and systematic revision that is necessary. It is argued that P. Barrouillet et al.'s modified mental model theory fails to meet the criteria of good theory of reasoning by invoking an algorithmic-level distinction to resolve a failing in the computational-level theory of the task.


Clinical potential of combined organic nitrate and phosphodiesterase type 5 inhibitor in treatment-resistant hypertension.
NO donor drugs (eg, isosorbide mononitrate; ISMN) and phosphodiesterase 5 inhibitors (eg, sildenafil) have antihypertensive properties, and the combination can markedly reduce blood pressure (BP). The objective of this "proof-of-concept" study was to investigate the effect on BP of a combination of single oral doses of sildenafil (50 mg) and ISMN (10 mg) in patients with treatment-resistant hypertension. Six subjects with treatment-resistant hypertension were included, and their usual antihypertensive medication was continued during the study. Sildenafil alone, ISMN alone, and the combination all reduced brachial and central aortic BPs compared with placebo. The combination of sildenafil and ISMN produced the largest fall in BP (maximum brachial BP reduction of 26/18 mm Hg compared with placebo), without producing significant adverse effects. ISMN, alone and in combination with sildenafil, also reduced arterial wave reflection and central BP. In summary, in patients with treatment-resistant hypertension maintained on their usual antihypertensive treatment, sildenafil given alone and ISMN given alone both acutely reduced BP. There was additional BP reduction when these drugs were given in combination. In this therapeutically challenging group of patients, the combination of an NO donor drug and a phosphodiesterase 5 inhibitor may represent an effective treatment. Longer studies in larger numbers of patients are now justified.


Platelet P2Y12 is involved in murine pulmonary metastasis.
The involvement of platelets in tumor progression is well recognized. The depletion of circulating platelets or pharmacologic inhibitors of platelet activation decreases the metastatic potential of circulating tumor cells in metastasis mouse models. The platelet ADP receptor P2Y12 amplifies the initial hemostatic responses activated by a variety of platelet agonists and stabilizes platelet aggregation, playing a crucial role in granule secretion, integrin activation and thrombus formation. However, the relationship between P2Y12 and tumor progression is not clear. In our study, the Lewis Lung Carcinoma (LLC) spontaneous metastatic mouse model was used to evaluate the role of P2Y12 in metastasis. The results demonstrated that P2Y12 deficiency significantly reduced pulmonary metastasis. Further studies indicated that P2Y12 deficiency diminished the ability of LLC cells to induce platelet shape change and release of active TGFβ1 by a non-contact dependent mechanism resulting in a diminished, platelet-induced EMT-like transformation of the LLC cells, and that transformation probably is a prerequisite of LLC cell metastasis. Immunohistochemical analyses indicated an obvious P2Y12 deficiency related attenuation of recruitment of VEGFR1+ bone marrow derived cell clusters, and extracellular matrix fibronectin deposition in lungs, which presumably are required for pre-metastatic niche formation. In contrast to the LLC cells, non-epithelial melanoma B16 cells induced platelet aggregation in a cell number and P2Y12-dependent manner. Also, a platelet induced EMT-like transformation of B16 cells is dependent on P2Y12. In agreement with the LLC cell model, platelet P2Y12 deficiency also results in significantly less lung metastasis in the B16 melanoma experimental metastasis model. These results demonstrate that P2Y12 is a safe drug target for anti-thrombotic therapy, and that P2Y12 may serve as a new target for inhibition of tumor metastasis.


Bridge experience with long-term implantable left ventricular assist devices. Are they an alternative to transplantation?
If long-term use of left ventricular assist devices (LVADs) as bridges to transplantation is successful, the issue of permanent device implantation in lieu of transplantation could be addressed through the creation of appropriately designed trials. Our medium-term experience with both pneumatically and electrically powered ThermoCardiosystems LVADs is presented to outline the benefits and limitations of device support in lieu of transplantation. Detailed records were kept prospectively for all patients undergoing LVAD insertion. Fifty-eight LVADs were inserted over 5 years, with a survival rate of 74%. Mean patient age was 50 years, and duration of support averaged 98 days. Although common, both preexisting infection and infection during LVAD support were not associated with increased mortality or decreased rate of successful transplantation. Thromboembolic complications were rare, occurring in only three patients (5%) despite the absence of anticoagulation. Ventricular arrhythmias were well tolerated in all patients except in cases of early perioperative right ventricular failure, with no deaths. Right ventricular failure occurred in one third of patients and was managed in a small percentage by right ventricular assist device (RVAD) support and/or inhaled nitric oxide therapy. There were no serious device malfunctions, but five graft-related hemorrhages resulted in two deaths. Finally, a variety of noncardiac surgical procedures were performed in LVAD recipients, with no major morbidity and mortality. Over all, our medium-term experience with implantable LVAD support is encouraging. Although additional areas of investigation exist, improvements in patients selection and management together with device alterations that have reduced the thromboembolic incidence and facilitated patient rehabilitation lead us to believe that a prospective, randomized trial is indicated to study the role that LVADs may have as an alternative to medical management.


Erlotinib in lung cancer - molecular and clinical predictors of outcome.
A clinical trial that compared erlotinib with a placebo for non-small-cell lung cancer demonstrated a survival benefit for erlotinib. We used tumor-biopsy samples from participants in this trial to investigate whether responsiveness to erlotinib and its impact on survival were associated with expression by the tumor of epidermal growth factor receptor (EGFR) and EGFR gene amplification and mutations. EGFR expression was evaluated immunohistochemically in non-small-cell lung cancer specimens from 325 of 731 patients in the trial; 197 samples were analyzed for EGFR mutations; and 221 samples were analyzed for the number of EGFR genes. In univariate analyses, survival was longer in the erlotinib group than in the placebo group when EGFR was expressed (hazard ratio for death, 0.68; P=0.02) or there was a high number of copies of EGFR (hazard ratio, 0.44; P=0.008). In multivariate analyses, adenocarcinoma (P=0.01), never having smoked (P<0.001), and expression of EGFR (P=0.03) were associated with an objective response. In multivariate analysis, survival after treatment with erlotinib was not influenced by the status of EGFR expression, the number of EGFR copies, or EGFR mutation. Among patients with non-small-cell lung cancer who receive erlotinib, the presence of an EGFR mutation may increase responsiveness to the agent, but it is not indicative of a survival benefit.


Shape distortions and Gestalt grouping in anorthoscopic perception.
When a figure moves behind a stationary narrow slit, observers often report seeing the figure as a whole, a phenomenon called slit viewing or anorthoscopic perception. Interestingly, in slit viewing, the figure is perceived compressed along the axis of motion. As with other perceptual distortions, it is unclear whether the perceptual space in the vicinity of the slit or the representation of the figure itself undergoes compression. In a psychophysical experiment, we tested these two hypotheses. We found that the percept of a stationary bar, presented within the slit, was not distorted even when at the same time a circle underwent compression by moving through the slit. This result suggests that the compression of form results from figural rather than from space compression. In support of this hypothesis, we found that when the bar was perceptually grouped with the circle, the bar appeared compressed. Our results show that, in slit viewing, the distortion occurs at a non-retinotopic level where grouped objects are jointly represented.


Interprofessional education: effects on professional practice and healthcare outcomes (update).
The delivery of effective, high-quality patient care is a complex activity. It demands health and social care professionals collaborate in an effective manner. Research continues to suggest that collaboration between these professionals can be problematic. Interprofessional education (IPE) offers a possible way to improve interprofessional collaboration and patient care. To assess the effectiveness of IPE interventions compared to separate, profession-specific education interventions; and to assess the effectiveness of IPE interventions compared to no education intervention. For this update we searched the Cochrane Effective Practice and Organisation of Care Group specialised register, MEDLINE and CINAHL, for the years 2006 to 2011. We also handsearched the Journal of Interprofessional Care (2006 to 2011), reference lists of all included studies, the proceedings of leading IPE conferences, and websites of IPE organisations. Randomised controlled trials (RCTs), controlled before and after (CBA) studies and interrupted time series (ITS) studies of IPE interventions that reported objectively measured or self reported (validated instrument) patient/client or healthcare process outcomes. At least two review authors independently assessed the eligibility of potentially relevant studies. For included studies, at least two review authors extracted data and assessed study quality. A meta-analysis of study outcomes was not possible due to heterogeneity in study designs and outcome measures. Consequently, the results are presented in a narrative format. This update located nine new studies, which were added to the six studies from our last update in 2008. This review now includes 15 studies (eight RCTs, five CBA and two ITS studies). All of these studies measured the effectiveness of IPE interventions compared to no educational intervention. Seven studies indicated that IPE produced positive outcomes in the following areas: diabetes care, emergency department culture and patient satisfaction; collaborative team behaviour and reduction of clinical error rates for emergency department teams; collaborative team behaviour in operating rooms; management of care delivered in cases of domestic violence; and mental health practitioner competencies related to the delivery of patient care. In addition, four of the studies reported mixed outcomes (positive and neutral) and four studies reported that the IPE interventions had no impact on either professional practice or patient care. This updated review reports on 15 studies that met the inclusion criteria (nine studies from this update and six studies from the 2008 update). Although these studies reported some positive outcomes, due to the small number of studies and the heterogeneity of interventions and outcome measures, it is not possible to draw generalisable inferences about the key elements of IPE and its effectiveness. To improve the quality of evidence relating to IPE and patient outcomes or healthcare process outcomes, the following three gaps will need to be filled: first, studies that assess the effectiveness of IPE interventions compared to separate, profession-specific interventions; second, RCT, CBA or ITS studies with qualitative strands examining processes relating to the IPE and practice changes; third, cost-benefit analyses.


Multi-test analysis and model-based estimation of the prevalence of Taenia saginata cysticercus infection in naturally infected dairy cows in the absence of a 'gold standard' reference test.
The diagnostic values of seven serological tests (ELISAs) and of the obligatory European Union-approved routine visual meat inspection for the detection of Taenia saginata cysticercosis were investigated. A total of 793 slaughtered dairy cows were selected in three European Union approved abattoirs in Switzerland, an endemic area (apparent prevalence by enhanced meat inspection up to 4.5%) with typically low parasite burdens. ELISAs based on a somatic larval antigen, isoelectric focused somatic larval antigen, larval excretory/secretory antigens, peptide HP6-2, peptide Ts45S-10, pooled peptide solution and a monoclonal antibody antigen capture assay were initially screened. As there is no perfect diagnostic 'gold standard' reference test, the obligatory meat inspection and four selected serological tests were further analysed using Bayesian inference to estimate the "true" prevalence and the diagnostic test sensitivities and specificities. The ELISA for specific antibody detection based on excretory/secretory antigens showed highest sensitivity and specificity with 81.6% (95% credible interval: 70-92) and 96.3% (95% credible interval: 94-99), respectively. The Bayesian model estimated the specificity of the ELISA, based on the synthetic peptide Ts45S-10 as 55.2% (95% credible interval: 46-65) and sensitivity as 84.7% (95% credible interval: 82-88). The sensitivity of the ELISA based on mAbs, detecting circulating antigen, was 14.3% (95% credible interval: 9-23) with a specificity of 93.7% (95% credible interval: 92-96). The diagnostic sensitivity of the obligatory standard European Union meat inspection procedure for the detection of T. saginata cysticercus infection at the abattoir was estimated to be 15.6% (95% credible interval: 10-23). Based on these data, the modelled prevalence of cysticercosis in dairy cows presented at abattoirs in Switzerland was estimated to be 16.5% (95% credible interval: 13-21). These cattle also had a high prevalence of infection with Dicrocoelium dendriticum (60.8%) and Fasciola hepatica (13.5%).


An integrated strategy based on UPLC-DAD-QTOF-MS for metabolism and pharmacokinetic studies of herbal medicines: Tibetan "Snow Lotus" herb (Saussurea laniceps), a case study.
Saussurea laniceps Hand.-Mazz. (SL) has long been used under the herbal name Tibetan "Snow Lotus" for the treatment of rheumatoid arthritis, stomachache and dysmenorrhea in Tibetan folk medicine. Since herbal medicine (HM) is a synergistical system with multiple components, both of the metabolism and pharmacokinetic studies of HM are interdependent. This study aimed to develop an integrated strategy based on the UPLC-DAD-QTOF-MS technique for metabolism and pharmacokinetic studies of HM. SL was used here as a test herb to verify the feasibility of the proposed strategy. SL was administered to rats, then, the blood plasma, urine and feces were analyzed to determine the metabolic profiles. Using our strategy, umbelliferone and scopoletin were evaluated to be the key bioactive components. Their pharmacokinetic parameters were measured and biotransformation pathways were elucidated. After oral administration of SL to rats, 17 components in blood, 10 components in urine and 2 components in feces were identified and characterized using our UPLC-DAD-QTOF-MS method. Umbelliferone, scopoletin and their metabolites were found to be the major components involved in the metabolism process. Literature reports also suggest that umbelliferone and scopoletin are responsible for the therapeutic effects of SL, thus these two components were selected as the active markers for pharmacokinetic study. In the test of validity, the established method presented good linearity with R(2)>0.99. The relative standard deviation value was below 13.9% for precision, and recovery studies for accuracy were found to be within the range 91.8-112.5%. The present strategy offers, simultaneously, precision in quantitative analysis (metabolism study) and accuracy in quantitative analysis (pharmacokinetic study) with greater efficiency and less costs, which is therefore reliably used for integrated metabolism and pharmacokinetic studies of HM.


Poor Response to Periodontal Treatment May Predict Future Cardiovascular Disease.
Periodontal disease has been associated with cardiovascular disease (CVD), but whether the response to the treatment of periodontal disease affects this association has not been investigated in any large prospective study. Periodontal data obtained at baseline and 1 y after treatment were available in 5,297 individuals with remaining teeth who were treated at a specialized clinic for periodontal disease. Poor response to treatment was defined as having >10% sites with probing pocket depth >4 mm deep and bleeding on probing at ≥20% of the sites 1 y after active treatment. Fatal/nonfatal incidence rate of CVD (composite end point of myocardial infarction, stroke, and heart failure) was obtained from the Swedish cause-of-death and hospital discharge registers. Poisson regression analysis was performed to analyze future risk of CVD. During a median follow-up of 16.8 y (89,719 person-years at risk), those individuals who did not respond well to treatment (13.8% of the sample) had an increased incidence of CVD ( n = 870) when compared with responders (23.6 vs. 15.3%, P < 0.001). When adjusting for calendar time, age, sex, educational level, smoking, and baseline values for bleeding on probing, probing pocket depth >4 mm, and number of teeth, the incidence rate ratio for CVD among poor responders was 1.28 (95% CI, 1.07 to 1.53; P = 0.007) as opposed to good responders. The incidence rate ratio among poor responders increased to 1.39 (95% CI, 1.13 to 1.73; P = 0.002) for those with the most remaining teeth. Individuals who did not respond well to periodontal treatment had an increased risk for future CVD, indicating that successful periodontal treatment might influence progression of subclinical CVD.


[Thrombophilic study in dialysis patients].
Chronic kidney disease is a complex phenotype that results from the association of underlying kidney disease and environmental and genetic factors. In addition to the traditional risk factors, genetic factors are involved in the etiology of renal disease, including single nucleotide polymorphisms which could account for the increased mortality from cardiovascular disease of our hemodialysis patients. The genes that influence the development and rate of progression of kidney disease deserve to be better defined. We have evaluated the alterations of thrombophilia genes in hemodialysis patients and in blood donors and we have compared the results obtained. The objective of the present study is to identify biomarkers of morbidity and mortality, which allow us to identify patients with chronic kidney disease at high risk, thanks to which it is possible to implement accurate therapeutic strategies and preventive strategies that have the objective of intensifying controls in these patients.


Rat Schwann cells in bioresorbable nerve guides to promote and accelerate axonal regeneration.
A micro-structured, biodegradable, semipermeable hollow nerve guide implant was developed to bridge nerve lesions. Quantitative comparison of cell migration and axonal growth using time lapse video recording in vitro revealed that axons grow eight times faster than neuritotrophic Schwann cells migrate. To accelerate regeneration, purified Schwann cells are best injected into nerve guides before implantation. Nerve guides made from resorbable poly-lactide-co-glycolide support Schwann cell attachment, cell survival, and axonal outgrowth in vitro. The therapeutic concept aims at the development of an 'intelligent neuroprosthesis' that first mediates regeneration and then disappears.