Radiomics-Based Outcome Prediction for Pancreatic Cancer Following Stereotactic Body Radiotherapy.
(1) Background: Radiomics use high-throughput mining of medical imaging data to extract unique information and predict tumor behavior. Currently available clinical prediction models poorly predict treatment outcomes in pancreatic adenocarcinoma. Therefore, we used radiomic features of primary pancreatic tumors to develop outcome prediction models and compared them to traditional clinical models. (2) Methods: We extracted and analyzed radiomic data from pre-radiation contrast-enhanced CTs of 74 pancreatic cancer patients undergoing stereotactic body radiotherapy. A panel of over 800 radiomic features was screened to create overall survival and local-regional recurrence prediction models, which were compared to clinical prediction models and models combining radiomic and clinical information. (3) Results: A 6-feature radiomic signature was identified that achieved better overall survival prediction performance than the clinical model (mean concordance index: 0.66 vs. 0.54 on resampled cross-validation test sets), and the combined model improved the performance slightly further to 0.68. Similarly, a 7-feature radiomic signature better predicted recurrence than the clinical model (mean AUC of 0.78 vs. 0.66). (4) Conclusion: Overall survival and recurrence can be better predicted with models based on radiomic features than with those based on clinical features for pancreatic cancer.


Productive and persistent infection of human thymic epithelial cells in vitro with HIV-1.
Infection with HIV-1 results in a disruption of the thymic microenvironment and the presence of HIV-1 in thymic epithelial cells has been demonstrated in vivo. In the present study, we examined the susceptibility of a highly enriched culture of thymic epithelial cells (TEC) to infection in vitro by HIV-1 laboratory strains and primary isolates. Replication in TEC is shown to depend on the virus and on the expression of CD4 molecules that are found to be expressed at a low density on the plasma membrane. Our results are consistent with infection of TEC controlled by the efficiency of the interactions between the envelope glycoprotein of the virus and the cell surface molecules. As a consequence, certain HIV-1 viruses induce a productive and persistent infection in TEC without damaging the cells. Altogether these results support the idea that TEC may act as a reservoir for HIV-1 in the thymus but are probably destroyed by an indirect mechanism involving infection of thymocytes.


Transcriptional response in the peripheral blood of patients infected with Salmonella enterica serovar Typhi.
We used microarrays and transcriptional profiling of peripheral blood to investigate the host response of 29 individuals who contracted typhoid fever in the Mekong Delta region of Vietnam. Samples were taken over a nine month period encompassing acute disease, convalescence, and recovery. We found that typhoid fever induced a distinct and highly reproducible signature in the peripheral blood that changed during treatment and convalescence, returning in the majority of cases to the "normal" profile as measured in healthy uninfected controls. Unexpectedly, there was a strong, distinct signature of convalescence present at day 9 after infection that remained virtually unchanged one month after acute infection and in some cases persisted as long as nine months despite a complete clinical recovery in all patients. Patients who retain the convalescent signature may be genetically or temporarily incapable of developing an effective immune response and may be more susceptible to reinfection, relapse, or the establishment of a carrier state.


Evidence supporting the existence of a NUPR1-like family of helix-loop-helix chromatin proteins related to, yet distinct from, AT hook-containing HMG proteins.
NUPR1, a small chromatin protein, plays a critical role in cancer development, progression, and resistance to therapy. Here, using a combination of structural bioinformatics and molecular modeling methods, we report several novel findings that enhance our understanding of the biochemical function of this protein. We find that NUPR1 has been conserved throughout evolution, and over time it has undergone duplications and transpositions to form other transcriptional regulators. Using threading, homology-based molecular modeling, molecular mechanics calculations, and molecular dynamics simulations, we generated structural models for four of these proteins: NUPR1a, NUPR1b, NUPR2, and the NUPR-like domain of GTF2-I. Comparative analyses of these models combined with extensive linear motif identification reveal that these four proteins, though similar in their propensities for folding, differ in size, surface changes, and sites amenable for posttranslational modification. Lastly, taking NUPR1a as the paradigm for this family, we built models of a NUPR-DNA complex. Additional structural comparisons revealed that NUPR1 defines a new family of small-groove-binding proteins that share structural features with, yet are distinct from, helix-loop-helix AT-hook-containing HMG proteins. These models and inferences should lead to a better understanding of the function of this group of chromatin proteins, which play a critical role in the development of human malignant diseases.


Dentin permeability: effects of crown preparation.
Sequential crown reductions of extracted human teeth were made to evaluate both regional differences in dentin permeability and the effects of tooth reduction. Two different methods of tooth reduction were used. In group 1, tooth reduction was nonuniform but was done in a manner similar to conventional crown preparations. Maximum, total crown permeability was measured using a pressurized fluid filtration technique after removing the smear layer. Regional reductions in permeability were accomplished by creating smear layers on mesial, distal, buccal, lingual, and occlusal surfaces sequentially. Between each step, changes in dentin permeability were measured. In group 2, tooth reductions were uniform and regional permeability was reduced by localized application of potassium oxalate. Both methods demonstrated increased permeability of dentin as the prepared surfaces approached the pulp chamber. Generally, the mesial surfaces were more permeable than the distal surfaces. The occlusal and lingual surfaces were the least permeable regions.


Sensitivity of spinal neurons to GABA and glycine during voluntary movement in behaving monkeys.
GABAergic and glycinergic inhibition play key roles in the function of spinal motor pathways. However, there is little direct information on the extent to which inhibition controls the activity of spinal neurons during behavior or the relative effectiveness of GABA and glycine on cell activity under normal conditions. These issues were investigated in three macaque monkeys trained to perform voluntary ramp-and-hold wrist movements and grip. Pipettes with an extracellular recording electrode and iontophoresis barrels were used to eject GABA, glycine, and/or their respective antagonists, bicuculline and strychnine, as the activity of single neurons was recorded in the C6-T1 spinal segments during hand movements. The firing rate of the vast majority of neurons decreased when an inhibitory neurotransmitter was ejected from the electrode, suggesting that most movement-related spinal neurons are sensitive to both GABA and glycine. Most movement-related neurons exhibited increased activity during iontophoresis of an antagonist, suggesting that both GABAergic and glycinergic inhibition actively regulate the majority of spinal neurons during movement. These conclusions were supported by the responses of neurons tested with both agonists or both antagonists. Bicuculline and strychnine produced the largest increases in firing rate during dynamic movements (ramp phase), smaller increases during maintained torque/force (hold phase), and the smallest increase during the rest period. Since excitatory inputs also tend to increase progressively from rest to static to dynamic muscle contractions, this result is consistent with coupled excitatory and inhibitory inputs to spinal neurons during movement.


Genome-wide study on the polysomic genetic factors conferring plasticity of flower sexuality in hexaploid persimmon.
Sexuality is one of the fundamental mechanisms that work towards maintaining genetic diversity within a species. In diploid persimmons (Diospyros spp.), separated sexuality, the presence of separate male and female individuals (dioecy), is controlled by the Y chromosome-encoded small-RNA gene, OGI. On the other hand, sexuality in hexaploid Oriental persimmon (Diospyros kaki) is more plastic, with OGI-bearing genetically male individuals, able to produce both male and female flowers (monoecy). This is thought to be linked to the partial inactivation of OGI by a retrotransposon insertion, resulting in DNA methylation of the OGI promoter region. To identify the genetic factors regulating branch sexual conversion, genome-wide correlation/association analyses were conducted using ddRAD-Seq data from an F1 segregating population, and using both quantitative and diploidized genotypes, respectively. We found that allelic ratio at the Y-chromosomal region, including OGI, was correlated with male conversion based on quantitative genotypes, suggesting that OGI can be activated in cis in a dosage-dependent manner. Genome-wide association analysis based on diploidized genotypes, normalized for the effect of OGI allele dosage, detected three fundamental loci associated with male conversion. These loci underlie candidate genes, which could potentially act epigenetically for the activation of OGI expression.


Chromosome polysomy and histological characteristics in oral premalignant lesions.
Head and neck tumorigenesis has been postulated to represent a multistep process driven by the accumulation of carcinogen-induced genetic changes throughout the exposed tissue field. To better explore this genetic instability process at the tissue level, 59 regions within 26 biopsy tissue specimens from individuals with oral leukoplakia have been subjected to chromosome 9 in situ hybridization analysis, and the degree of chromosome instability was related to known clinical/pathological parameters associated with tumor risk. Whereas chromosome indices were similar between high-risk lesion sites and low-risk lesion sites, high-risk lesions showed higher levels of chromosome polysomy than did low-risk sites [median PIs (polysomy indices), 2.1 versus 1.4, respectively]. Similarly, dysplastic regions showed significantly higher chromosome polysomy levels than hyperplastic regions (median PIs, 2.4 versus 1.5, respectively). Interestingly, however, hyperplastic regions in the same biopsy as dysplastic regions showed two-times higher polysomy levels than those in biopsies without dysplasia (median PIs, 2.6 versus 1.3, respectively), suggesting that chromosome polysomy determinations provide a field measurement for the degree of ongoing genetic insult. Finally, chromosome polysomy tended to persist or increase in the superficial epithelial layers in regions showing koilocytosis, whereas their frequency decreased in nonkoilocytotic regions, suggesting that epigenetic factors may serve to perpetuate the levels of genetically unstable cells in the epithelium. These results provide direct support for the field cancerization process and suggest that measurements of genetic instability might provide additional biological information beyond histology and lesion site characteristics in the assessment of head and neck cancer risk.


Multicentre prospective observational study on professional wound care using honey (Medihoney™).
In recent years, the treatment of wounds with honey has received an increasing amount of attention from healthcare professionals in Germany and Austria. We conducted a prospective observational multicentre study using Medihoney™ dressings in 10 hospitals - nine in Germany and one in Austria. Wound-associated parameters were monitored systematically at least three times in all patients. Data derived from the treatment of 121 wounds of various aetiologies over a period of 2 years were analysed. Almost half of the patients were younger than 18 years old, and 32% of the study population was oncology patients. Overall, wound size decreased significantly during the study period and many wounds healed after relatively short time periods. Similarly, perceived pain levels decreased significantly, and the wounds showed noticeably less slough/necrosis. In general, our findings show honey to be an effective and feasible treatment option for professional wound care. In addition, our study showed a relationship between pain and slough/necrosis at the time of recruitment and during wound healing. Future comparative trials are still needed to evaluate the extent to which the positive observations made in this and other studies can definitely be attributed to the effects of honey in wound care.


Cocoa ameliorates renal injury in Zucker diabetic fatty rats by preventing oxidative stress, apoptosis and inactivation of autophagy.
Redox balance, autophagy and apoptosis are main processes involved in the development of diabetic nephropathy. Epidemiological and animal studies suggest that cocoa might reduce the risk of diabetic complications. However, the molecular mechanisms responsible for these potential preventive activities and whether cocoa exerts beneficial effects on dysregulated signalling pathways involved in cellular antioxidant defence, autophagy and apoptosis in the diabetic kidney remain largely unknown. Therefore, this work investigated the effect of a cocoa-rich diet on the mentioned processes in the renal cortex of Zucker Diabetic Fatty (ZDF) rats. Male ZDF rats were fed either a control or cocoa-rich diet (10%), and Zucker lean animals received the control diet (10-20 weeks-of-life). ZDF rats fed with cocoa decreased body weight and glucose and insulin levels, and improved renal function. Cocoa intake further prevented the enhanced renal cortical oxidative stress in diabetic rats by regulating the antioxidant defence system and close-related proteins to cytoprotection and cell response; thus, cocoa diminished oxidative markers (reactive oxygen species and carbonyl groups) and NADPH-oxidase-4 levels, and restored key enzymatic antioxidant activities (superoxide dismutase and catalase), nuclear-erythroid-2-related factor-2, and ERK-MAPK levels, as well as sirtuin-1/5'-AMP-activated-protein kinase signalling. Moreover, in ZDF rats cocoa-rich diet contributed to alleviation of the renal cortical injury through autophagy activation (p62 upregulation, and downregulation of beclin-1 and LC3), and inhibition of apoptosis (Bcl-xL stimulation and suppression of Bax and caspases-9 and -3). These findings provide the first in vivo evidence on the molecular mechanisms of cocoa to circumvent renal cortical damage that involve improvement of antioxidant competences, stimulation of autophagy and suppression of apoptosis in ZDF rats.


Protective effects of Brussels sprouts towards B[a]P-induced DNA damage: a model study with the single-cell gel electrophoresis (SCGE)/Hep G2 assay.
The aim of this study was to investigate the chemoprotective effects of Brussels sprouts juice towards benzo[a]pyrene (B(a)P)-induced DNA damage in the single-cell gel electrophoresis (SCGE)/Hep G2 test system. This assay combines the advantages of the SCGE assay with that of the use of human-derived cells possessing inducible phase I and phase II enzymes. Co-treatment of Hep G2 cells with small amounts of Brussels sprouts juice (0.25-2.0 microl/ml) and B(a)P reduced the genotoxic effect of the latter in a dose-dependent manner. Contrary to the results with the crude juice, unexpected synergistic effects were observed with allyl isothiocyanate (AITC, 1.0-6.0 microM), a breakdown product of sinigrin, which is the most abundant glucosinolate in Brussels sprouts. Although these concentrations of AITC did not cause DNA damage per se, at higher concentrations (> or =25 microM), the compound caused a pronounced dose-dependent DNA damage by itself. Mechanistic studies showed that Brussels sprouts juice causes induction of activities of ethoxyresorufin O-deethylase (EROD) and glutathione S-transferase (GST) at dose levels which were protective towards B(a)P. In combined treatment experiments with (+/-)-anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE, 5.0 microM), the main genotoxic metabolite of B(a)P, and Brussels sprouts juice, only weak protection was found indicating that the mechanism of chemoprotection of Brussels sprouts is not mediated through inactivation of this metabolite. In conclusion, our findings show that Brussels sprouts are highly protective against B(a)P-induced DNA damage in human-derived cells.


Sleepy driving on the real road and in the simulator--A comparison.
Sleepiness has been identified as one of the most important factors contributing to road crashes. However, almost all work on the detailed changes in behavior and physiology leading up to sleep related crashes has been carried out in driving simulators. It is not clear, however, to what extent simulator results can be generalized to real driving. This study compared real driving with driving in a high fidelity, moving base, driving simulator with respect to driving performance, sleep related physiology (using electroencephalography and electrooculography) and subjective sleepiness during night and day driving for 10 participants. The real road was emulated in the simulator. The results show that the simulator was associated with higher levels of subjective and physiological sleepiness than real driving. However, both for real and simulated driving, the response to night driving appears to be rather similar for subjective sleepiness and sleep physiology. Lateral variability was more responsive to night driving in the simulator, while real driving at night involved a movement to the left in the lane and a reduction of speed, both of which effects were absent in the simulator. It was concluded that the relative validity of simulators is acceptable for many variables, but that in absolute terms simulators cause higher sleepiness levels than real driving. Thus, generalizations from simulators to real driving must be made with great caution.


Course and prognosis of childhood epilepsy: 5-year follow-up of the Dutch study of epilepsy in childhood.
Knowing the prognosis of epilepsy will undoubtedly influence the treatment strategy. This study aimed to define the prospects of newly diagnosed childhood epilepsy, assess the dynamics of its course, identify relevant variables and develop models to assess the individual prognosis. Four hundred and fifty-three children with newly diagnosed epilepsy were followed for 5 years. Terminal remission at 5 years (TR5) was compared with terminal remission at 2 years (TR2) and with the longest remission during follow-up. Variables defined at intake and at 6 months of follow-up were analysed for their prognostic relevance. In multivariate analyses, combinations of variables were tested to develop reliable models for the calculation of the individual prognosis. Data on treatment, course during follow-up and epilepsy syndromes were also studied. Three hundred and forty-five children (76%) had a TR5 >1 year, 290 (64%) >2 years and 65 (14%) had not had any seizure during the entire follow-up. Out of 108 children (24%) with TR5 <1 year, 27 were actually intractable at 5 years. Medication was started in 388 children (86%). In 227 of these (59%), anti-epileptic drugs (AEDs) could be withdrawn. A TR5 >1 year was attained by 46% on one AED, on the second AED by 19%, and by 9% on all additional AED regimes. Almost 60% of the children treated with a second or additional AED regime had a TR5 >1 year. Variables predicting the outcome at intake were aetiology, history of febrile seizures and age. For intake and 6-month variables combined, sex, aetiology, postictal signs, history of febrile seizures and TR at 6 months were significant. The model derived from intake variables only predicted TR5 <1 year correctly in 36% and TR5 >1 year in 85% (sensitivity 0.65, specificity 0.64). The corresponding values for the model derived from intake and 6-month variables were 43 and 88% (sensitivity 0.69, specificity 0.71). The course of the epilepsy was constantly favourable in 51%, steadily poor in 17%, improving in 25% and deteriorating in 6%. Intractability was in part only a temporary phenomenon. The outcome at 5 years in this cohort of children with newly diagnosed epilepsy was favourable in 76%; 64% were off medication at that time. Almost a third of the children had a fluctuating course; improvement was clearly more common than deterioration. After failure of the first AED, treatment can still be successful. Models predicting the outcome have fewer misclassifications when predicting a long terminal remission than when predicting continuing seizures.


Matrix metalloproteinases -8 and -9 and tissue inhibitor of metalloproteinase-1 in burn patients. A prospective observational study.
Matrix metalloproteinases (MMPs) -8 and -9 are released from neutrophils in acute inflammation and may contribute to permeability changes in burn injury. In retrospective studies on sepsis, levels of MMP-8, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) differed from those of healthy controls, and TIMP-1 showed an association with outcome. Our objective was to investigate the relationship between these proteins and disease severity and outcome in burn patients. In this prospective, observational, two-center study, we collected plasma samples from admission to day 21 post-burn, and burn blister fluid samples on admission. We compared MMP-8, -9, and TIMP-1 levels between TBSA<20% (N = 19) and TBSA>20% (N = 30) injured patients and healthy controls, and between 90-day survivors and non-survivors. MMP-8, -9, and TIMP-1 levels at 24-48 hours from injury, their maximal levels, and their time-adjusted means were compared between groups. Correlations with clinical parameters and the extent of burn were analyzed. MMP-8, -9, and TIMP-1 levels in burn blister fluids were also studied. Plasma MMP-8 and -9 were higher in patients than in healthy controls (P<0.001 and P = 0.016), but only MMP-8 differed between the TBSA<20% and TBSA>20% groups. MMP-8 and -9 were not associated with clinical severity or outcome measures. TIMP-1 differed significantly between patients and controls (P<0.001) and between TBSA<20% and TBSA>20% groups (P<0.002). TIMP-1 was associated with 90-day mortality and correlated with the extent of injury and clinical measures of disease severity. TIMP-1 may serve as a new biomarker in outcome prognostication of burn patients.


Differences in the Epidemiology of Childhood Infections with Avian Influenza A H7N9 and H5N1 Viruses.
The difference between childhood infections with avian influenza viruses A(H5N1) and A(H7N9) remains an unresolved but critically important question. We compared the epidemiological characteristics of 244 H5N1 and 41 H7N9 childhood cases (<15 years old), as well as the childhood cluster cases of the two viruses. Our findings revealed a higher proportion of H5N1 than H7N9 childhood infections (31.1% vs. 6.4%, p = 0.000). However, the two groups did not differ significantly in age (median age: 5.0 vs. 5.5 y, p = 0.0651). The proportion of clustered cases was significantly greater among children infected with H5N1 than among children infected with H7N9 [46.7% (71/152) vs. 23.6% (13/55), p = 0.005], and most of the childhood cases were identified as secondary cases [46.4% (45/97) vs. 33.3% (10/30), p = 0.000]. Mild status accounted for 79.49% and 22.66%, severe status for 17.95% and 2.34%, and fatal cases for 2.56% and 75.00% of the H7N9 and H5N1 childhood infection cases (all p<0.05), respectively. The fatality rates for the total, index and secondary childhood cluster cases were 52.86% (37/70), 88.5% (23/26) and 33.33% (15/45), respectively, in the H5N1 group, whereas no fatal H7N9 childhood cluster cases were identified. In conclusion, lower severity and greater transmission were found in the H7N9 childhood cases than in the H5N1 childhood cases.


Ependymoma of the spinal cord in children and adolescents: a retrospective series from the HIT database.
Reports on spinal cord ependymoma in children are rare. The aim of this study was to evaluate the clinical spectrum, treatment, and outcome of children with primary ependymoma of the spinal cord who were registered in the database of the pediatric German brain tumor studies Hirntumor (HIT) '91 and HIT 2000. Between 1991 and 2007, 29 patients (12 male and 17 female, median age at diagnosis 13.6 years) with primary spinal cord ependymoma (myxopapillary ependymoma WHO Grade I, II, and III tumors in 6, 17, and 6 patients, respectively) were identified. Four patients had neurofibromatosis Type 2. With a median follow-up of 4.2 years (range 0.48-15 years), 28 patients (96.6%) were alive. Seven patients (24.1%) developed progressive disease or relapse, 2 after gross-total resection (GTR) and 5 after incomplete resection or biopsy. One patient with anaplastic ependymoma (WHO Grade III) died 65 months after diagnosis of disease progression. Primary adjuvant treatment (radiotherapy, chemotherapy, or both) was used in 8 (50%) of 16 patients following GTR and in 9 (82%) of 11 patients who underwent less than a GTR. Three additional patients were treated adjuvantly following progression. Estimated progression-free survival and overall survival rates at 5 years were 72.3% (95% CI 50%-86%) and 100%, respectively. Progression-free survival at 5 years is 84.4% (95% CI 50%-96%) for patients following GTR compared with 57.1% (95% CI 25%-69%) for patients who achieved a less than GTR (p = 0.088, log-rank test). A high relapse incidence (4 of 6) was observed among patients with myxopapillary ependymoma. Gross-total resection is the mainstay of treatment for patients with primary spinal cord ependymoma and may be achieved in about 50% of the patients using modern surgical techniques. Primary adjuvant treatment was commonly used in children with spinal cord ependymoma irrespective of the extent of resection or tumor grade. The impact of adjuvant treatment on progression-free and overall survival has to be investigated in a prospective trial.


A learning theory for reward-modulated spike-timing-dependent plasticity with application to biofeedback.
Reward-modulated spike-timing-dependent plasticity (STDP) has recently emerged as a candidate for a learning rule that could explain how behaviorally relevant adaptive changes in complex networks of spiking neurons could be achieved in a self-organizing manner through local synaptic plasticity. However, the capabilities and limitations of this learning rule could so far only be tested through computer simulations. This article provides tools for an analytic treatment of reward-modulated STDP, which allows us to predict under which conditions reward-modulated STDP will achieve a desired learning effect. These analytical results imply that neurons can learn through reward-modulated STDP to classify not only spatial but also temporal firing patterns of presynaptic neurons. They also can learn to respond to specific presynaptic firing patterns with particular spike patterns. Finally, the resulting learning theory predicts that even difficult credit-assignment problems, where it is very hard to tell which synaptic weights should be modified in order to increase the global reward for the system, can be solved in a self-organizing manner through reward-modulated STDP. This yields an explanation for a fundamental experimental result on biofeedback in monkeys by Fetz and Baker. In this experiment monkeys were rewarded for increasing the firing rate of a particular neuron in the cortex and were able to solve this extremely difficult credit assignment problem. Our model for this experiment relies on a combination of reward-modulated STDP with variable spontaneous firing activity. Hence it also provides a possible functional explanation for trial-to-trial variability, which is characteristic for cortical networks of neurons but has no analogue in currently existing artificial computing systems. In addition our model demonstrates that reward-modulated STDP can be applied to all synapses in a large recurrent neural network without endangering the stability of the network dynamics.


Effect of phosphate group addition on the properties of denture base resins.
Acrylic resins are prone to microbial adherence, especially by Candida albicans. Surface-charged resins alter the ionic interaction between the denture resin and Candida hyphae, and these resins are being developed as a means to reduce microbial colonization on the denture surface. The purpose of this study was to investigate the physical and mechanical properties of phosphate-containing polymethyl methacrylate resins for their suitability as a denture material. Using PMMA with cross-linker (Lucitone 199) as a control, 4 experimental groups containing various levels of phosphate with and without cross-linker were generated. The properties examined were impact strength, fracture toughness, wettability (contact angle), and resin bonding ability to denture teeth. Impact strength was tested in the Izod configuration (n=16), and fracture toughness (n=13) was measured using the single-edge notched bend test. Wettability was determined by calculating the contact angle of water on the material surface (n=12), while ISO 1567 was used for bonding ability (n=12). The data were analyzed by 1- and 2-way ANOVA (alpha=.05). A trend of increased hydrophilicity, as indicated by lower contact angle, was observed with increased concentrations of phosphate. With regard to the other properties, no significant differences were found when compared with the control acrylic resin. No adverse physical effect due to the addition of a phosphate-containing monomer was found in the acrylic denture resins. Additional mechanical and physical properties, biocompatibility, and clinical efficacy studies are needed to confirm the in vivo anti-Candida activity of these novel resins.


Effect of a Primary Care Walking Intervention with and without Nurse Support on Physical Activity Levels in 45- to 75-Year-Olds: The Pedometer And Consultation Evaluation (PACE-UP) Cluster Randomised Clinical Trial.
Pedometers can increase walking and moderate-to-vigorous physical activity (MVPA) levels, but their effectiveness with or without support has not been rigorously evaluated. We assessed the effectiveness of a pedometer-based walking intervention in predominantly inactive adults, delivered by post or through primary care nurse-supported physical activity (PA) consultations. A parallel three-arm cluster randomised trial was randomised by household, with 12-mo follow-up, in seven London, United Kingdom, primary care practices. Eleven thousand fifteen randomly selected patients aged 45-75 y without PA contraindications were invited. Five hundred forty-eight self-reporting achieving PA guidelines were excluded. One thousand twenty-three people from 922 households were randomised between 2012-2013 to one of the following groups: usual care (n = 338); postal pedometer intervention (n = 339); and nurse-supported pedometer intervention (n = 346). Of these, 956 participants (93%) provided outcome data (usual care n = 323, postal n = 312, nurse-supported n = 321). Both intervention groups received pedometers, 12-wk walking programmes, and PA diaries. The nurse group was offered three PA consultations. Primary and main secondary outcomes were changes from baseline to 12 mo in average daily step-counts and time in MVPA (in ≥10-min bouts), respectively, measured objectively by accelerometry. Only statisticians were masked to group. Analysis was by intention-to-treat. Average baseline daily step-count was 7,479 (standard deviation [s.d.] 2,671), and average time in MVPA bouts was 94 (s.d. 102) min/wk. At 12 mo, mean steps/d, with s.d. in parentheses, were as follows: control 7,246 (2,671); postal 8,010 (2,922); and nurse support 8,131 (3,228). PA increased in both intervention groups compared with the control group; additional steps/d were 642 for postal (95% CI 329-955) and 677 for nurse support (95% CI 365-989); additional MVPA in bouts (min/wk) were 33 for postal (95% CI 17-49) and 35 for nurse support (95% CI 19-51). There were no significant differences between the two interventions at 12 mo. The 10% (1,023/10,467) recruitment rate was a study limitation. A primary care pedometer-based walking intervention in predominantly inactive 45- to 75-y-olds increased step-counts by about one-tenth and time in MVPA in bouts by about one-third. Nurse and postal delivery achieved similar 12-mo PA outcomes. A primary care pedometer intervention delivered by post or with minimal support could help address the public health physical inactivity challenge. isrctn.com ISRCTN98538934.


Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34+ Cells.
Human cytomegalovirus (HCMV) latency is typically harmless but reactivation can be largely detrimental to immune compromised hosts. We modeled latency and reactivation using a traceable HCMV laboratory strain expressing the Gaussia luciferase reporter gene (HCMV/GLuc) in order to interrogate the viral modulatory effects on the human adaptive immunity. Humanized mice with long-term (more than 17 weeks) steady human T and B cell immune reconstitutions were infected with HCMV/GLuc and 7 weeks later were further treated with granulocyte-colony stimulating factor (G-CSF) to induce viral reactivations. Whole body bio-luminescence imaging analyses clearly differentiated mice with latent viral infections vs. reactivations. Foci of vigorous viral reactivations were detectable in liver, lymph nodes and salivary glands. The number of viral genome copies in various tissues increased upon reactivations and were detectable in sorted human CD14+, CD169+, and CD34+ cells. Compared with non-infected controls, mice after infections and reactivations showed higher thymopoiesis, systemic expansion of Th, CTL, Treg, and Tfh cells and functional antiviral T cell responses. Latent infections promoted vast development of memory CD4+ T cells while reactivations triggered a shift toward effector T cells expressing PD-1. Further, reactivations prompted a marked development of B cells, maturation of IgG+ plasma cells, and HCMV-specific antibody responses. Multivariate statistical methods were employed using T and B cell immune phenotypic profiles obtained with cells from several tissues of individual mice. The data was used to identify combinations of markers that could predict an HCMV infection vs. reactivation status. In spleen, but not in lymph nodes, higher frequencies of effector CD4+ T cells expressing PD-1 were among the factors most suited to distinguish HCMV reactivations from infections. These results suggest a shift from a T cell dominated immune response during latent infections toward an exhausted T cell phenotype and active humoral immune response upon reactivations. In sum, this novel in vivo humanized model combined with advanced analyses highlights a dynamic system clearly specifying the immunological spatial signatures of HCMV latency and reactivations. These signatures can be merged as predictive biomarker clusters that can be applied in the clinical translation of new therapies for the control of HCMV reactivation.


Estimating the value of non-use benefits from small changes in the provision of ecosystem services.
The unit of trade in ecosystem services is usually the use of a proportion of the parcels of land associated with a given service. Valuing small changes in the provision of an ecosystem service presents obstacles, particularly when the service provides non-use benefits, as is the case with conservation of most plants and animals. Quantifying non-use values requires stated-preference valuations. Stated-preference valuations can provide estimates of the public's willingness to pay for a broad conservation goal. Nevertheless, stated-preference valuations can be expensive and do not produce consistent measures for varying levels of provision of a service. Additionally, the unit of trade, land use, is not always linearly related to the level of ecosystem services the land might provide. To overcome these obstacles, we developed a method to estimate the value of a marginal change in the provision of a non-use ecosystem service--in this case conservation of plants or animals associated with a given land-cover type. Our method serves as a tool for calculating transferable valuations of small changes in the provision of ecosystem services relative to the existing provision. Valuation is achieved through stated-preference investigations, calculation of a unit value for a parcel of land, and the weighting of this parcel by its ability to provide the desired ecosystem service and its effect on the ability of the surrounding land parcels to provide the desired service. We used the water vole (Arvicola terrestris) as a case study to illustrate the method. The average present value of a meter of water vole habitat was estimated at UK £ 12, but the marginal value of a meter (based on our methods) could range between £ 0 and £ 40 or more.


MicroRNA profiling of human intermediate monocytes.
Among the three human monocyte subsets, intermediate CD14++CD16+ monocytes have been characterized as particularly proinflammatory cells in experimental studies and as potential biomarkers of cardiovascular risk in clinical cohorts. To further substantiate the distinct role of intermediate monocytes within human monocyte heterogeneity, we assessed subset-specific expression of miRNAs as central epigenetic regulators of gene expression. We hypothesized that intermediate monocytes have a distinct miRNA profile compared to classical and non-classical monocytes. By using small RNA-seq we analyzed 662 miRNAs in the three monocyte subsets. We identified 38 miRNAs that are differentially expressed in intermediate monocytes compared to both classical and non-classical monocytes with a p value of <10-10, of which two miRNAs - miR-6087 (upregulated) and miR-150-5p (downregulated) - differed in their expression more than ten-fold. Pathway analysis of the 38 differentially expressed miRNAs linked intermediate monocytes to distinct biological processes such as gene regulation, cell differentiation, toll-like receptor signaling as well as antigen processing and presentation. Moreover, differentially expressed miRNAs were connected to those genes that we previously identified as markers of intermediate monocytes. In aggregation, we provide first genome-wide miRNA data in the context of monocyte heterogeneity, which substantiate the concept of monocyte trichotomy in human immunity. The identification of miRNAs that are specific for intermediate monocytes may allow to develop strategies, which particularly target this cell population while sparing the other two subsets.


Truncating alpha-helix E' of p66 human immunodeficiency virus reverse transcriptase modulates RNase H function and impairs DNA strand transfer.
The properties of recombinant p66/p51 human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) containing C-terminal truncations in its p66 polypeptide were evaluated. Deletion end points partly or completely removed alpha-helix E' of the RNase H domain (p66 delta 8/p51 and p66 delta 16/p51, respectively), while mutant p66 delta 23/p51 lacked alpha E' and the beta 5'-alpha E' connecting loop. Although dimerization and DNA polymerase properties of all mutants were not significantly different from those of the parental enzyme, p66 delta 16/p51 and p66 delta 23/p51 RT lacked ribonuclease H (RNase H) activity. In contrast, RT mutant p66 delta 8/p51 retained endonuclease activity but lacked the directional processing feature of the parental enzyme. Despite retaining full endoribonuclease function, p66 delta 8/p51 RT barely supported transfer of nascent (-)-strand DNA between RNA templates representing the 5' and 3' ends of retroviral genome, shedding light on the requirement for the endonuclease and directional processing functions of the RNase H domain during replication.


Geographical information systems in the management of the 2009-2010 emergency oral anti-rabies vaccination of foxes in north-eastern Italy.
Emergency oral fox vaccination campaigns, targeting a recent rabies epidemic in wild foxes (Vulpes vulpes) in north-eastern Italy, were implemented twice, first in the winter of 2009 and then in the spring of 2010. Following on an unsuccessful manual bait distribution campaign, vaccine baits were aerially distributed by helicopters using a satellite-navigated, computer-supported, automatic bait drop system. The flight paths were traced with distance of 500-1,000 m from one another to optimise helicopter missions and guarantee homogeneous coverage of the vaccination area. The vaccine distribution was evaluated by superimposing a 1 km-step grid and weighing the number of baits per cell. The implementation of a geographical information system for the management of vaccine distribution proved to be useful, both for the planning and execution phases, of the campaigns. It supported effective management of the flights and allowed near real-time monitoring of the campaigns. In addition, it facilitated the identification of areas with suboptimal bait density that would require additional flights or supplementary, manual distribution.


Green tea flavonols inhibit glucosidase II.
Green tea is getting into the focus of scientific interest due to its beneficial health effects, most of which are attributed to its catechin content. Polyphenolic tea catechins have antioxidant, antiproliferative, antiangiogenic and proapoptotic effects, which makes them promising anticancer compounds. Other poly-hydroxy molecules have similar antitumor potentials through the inhibition of glucosidase II, which affects the glycoprotein maturation and quality control in the endoplasmic reticulum. We investigated the effect of tea catechins on glucosidase II activity in rat liver microsomes using 4-methylumbelliferyl glucoside and 4-nitrophenyl glucoside as substrates. A concentration-dependent inhibition with non-competitive kinetics was found. The IC50 and Ki values for certain tea catechins were comparable with those of N-butyldeoxynojirimycin, the widely used glucosidase inhibitor. The possible interference of tea catechins with the glycoprotein processing in the endoplasmic reticulum should be considered as a potential mechanism of their dietary or pharmacological effects.


Amplification of 11q13 in ovarian carcinoma.
Amplification at the 11q13 locus is commonly observed in breast, ovarian, head and neck, oral, and esophageal cancer. Studies of this region led to the identification of multiple amplicons containing several potential oncogenes including EMSY, PAK1, RSF1, and GAB2. Here, we investigate the amplification of the above four genes and their prognostic significance in histologically and clinically defined subsets of ovarian cancer. Amplification of all four genes was assessed by fluorescent in situ hybridization in tissue microarrays containing 538 clinically annotated ovarian carcinomas with 12 years of follow-up data. Overall, for the entire cohort, EMSY was amplified in 44 (16%) of 269 cases, PAK1 was amplified in 38 (15%) of 255 cases, RSF1 was amplified in 37 (12%) of 310 cases, and GAB2 was amplified in 41 (16%) of 255 cases. Amplification of EMSY, PAK1, RSF1, and GAB2 were all highly correlated with each other and with a serous histology. Univariate survival analysis showed that tumors with EMSY and RSF1 amplification were associated with a significantly worse outcome. A molecular inversion probe array was then used to study the 11q13 amplicon in 33 high grade serous carcinomas. The core of the amplicon mapped to a 6-Mb region encompassing EMSY, PAK1, RSF1, and GAB2. However, a second more telomeric amplicon was also observed for which no candidate genes have been identified. In summary, amplification of these four putative oncogenes from 11q13 in early ovarian cancer is associated with a serous histology and in the case of EMSY and RSF1 a poor outcome. These findings support the hypothesis that the11q13 amplicon in ovarian cancer is likely driven by a cassette of genes rather than by a single oncogene. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.


Direct depiction of bone microstructure using MRI with zero echo time.
This paper reports a proof of principle of direct depiction of trabecular bone microstructure in vitro by means of magnetic resonance imaging (MRI). Such depiction is achieved by (1)H imaging of water embedded in the bone matrix. The fast transverse relaxation of this compartment with T2(⁎) on the order of a few hundreds of microseconds is addressed by a three-dimensional MRI technique with zero echo time (ZTE). ZTE imaging at an isotropic spatial resolution of 56 μm is demonstrated in a trabecular bone specimen extracted from a bovine bone. In the MR images, the trabecular bone structure is clearly depicted and a high level of robustness against off-resonance artefacts is observed. The structural accuracy of the MR data is investigated by comparison with x-ray micro-computed tomography.


Validation of the Test Your Memory (F-TYM Test) in a French memory clinic population.
The Test Your Memory (TYM) test has been proposed for screening dementia. We present a French version and its validation in memory clinics. F-TYM was administered to 201 patients with memory complaints visiting five secondary referral hospital centers. Final diagnosis was dementia in 34%, amnestic mild cognitive impairment (MCI) in 32%, non-amnestic MCI in 11%, absence of cognitive disorder in 23% and F-TYM scores were respectively (M ± SD) 30.9 ± 7.6, 40.5 ± 6.3, 44.3 ± 4.5 and 43.5 ± 6.6 (p < .0001). F-TYM showed high correlation with MMSE (r = .78), excellent internal consistency, no effect of educational level, sex, or mood but a significant effect of age (p = .004). A F-TYM score ≤ 39 had 0.90 sensitivity and 0.70 specificity for diagnosis of dementia. F-TYM was unable to discriminate MCI and patients without cognitive disorders. F-TYM could be proposed for screening of dementia in patients with memory complaints.


Aggregation of amphiphilic polymers in the presence of adhesive small colloidal particles.
The interaction of amphiphilic polymers with small colloids, capable to reversibly stick onto the chains, is studied. Adhesive small colloids in solution are able to dynamically bind two polymer segments. This association leads to topological changes in the polymer network configurations, such as looping and cross-linking, although the reversible adhesion permits the colloid to slide along the chain backbone. Previous analyses only consider static topologies in the chain network. We show that the sliding degree of freedom ensures the dominance of small loops, over other structures, giving rise to a new perspective in the analysis of the problem. The results are applied to the analysis of the equilibrium between colloidal particles and star polymers, as well as to block copolymer micelles. The results are relevant for the reversible adsorption of silica particles onto hydrophilic polymers, used in the process of formation of mesoporous materials of the type SBA or MCM, cross-linked cyclodextrin molecules threading on the polymers and forming the structures known as polyrotaxanes. Adhesion of colloids on the corona of the latter induce micellization and growth of larger micelles as the number of colloids increase, in agreement with experimental data.


Simple, Efficient CRISPR-Cas9-Mediated Gene Editing in Mice: Strategies and Methods.
Genetic modification of almost any species is now possible using approaches based on targeted nucleases. These novel tools now bypass previous limited species windows, allowing precision nucleotide modification of the genome at high efficiency, rapidly and economically. Here we focus on the modification of the mouse genome; the mouse, with its short generation time and comparatively low maintenance/production costs is the perfect mammal with which to probe the genome to understand its functions and complexities. Further, using targeted nucleases combined with homologous recombination, it is now possible to precisely tailor the genome, creating models of human diseases and conditions directly and efficiently in zygotes derived from any mouse strain. Combined these approaches make it possible to sequentially and progressively refine mouse models to better reflect human disease, test and develop therapeutics. Here, we briefly review the strategies involved in designing targeted nucleases (sgRNAs) providing solutions and outlining in detail the practical processes involved in precision targeting and modification of the mouse genome and the establishing of new precision genetically modified mouse lines.


Genetics of parathyroid tumours.
Primary hyperparathyroidism (PHPT), due to parathyroid tumours, may occur as part of a complex syndrome or as an isolated (nonsyndromic) disorder, and both forms can occur as familial (i.e. hereditary) or nonfamilial (i.e. sporadic) disease. Syndromic PHPT includes multiple endocrine neoplasia (MEN) types 1 to 4 (MEN1 to MEN4) and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome. Syndromic and hereditary PHPT are often associated with multiple parathyroid tumours, in contrast to sporadic PHPT, in which single parathyroid adenomas are more common. In addition, parathyroid carcinomas may occur in ~15% of patients with the HPT-JT syndrome. MEN1 is caused by abnormalities of the MEN1 gene which encodes a tumour suppressor; MEN2 and MEN3 are due to mutations of the rearranged during transfection (RET) proto-oncogene, which encodes a tyrosine kinase receptor; MEN4 is due to mutations of a cyclin-dependent kinase inhibitor (CDNK1B); and HPT-JT is due to mutations of cell division cycle 73 (CDC73), which encodes parafibromin. Nonsyndromic PHPT, which may be hereditary and referred to as familial isolated hyperparathyroidism, may also be due to MEN1, CDC73 or calcium-sensing receptor (CASR) mutations. In addition, ~10% of patients presenting below the age of 45 years with nonsyndromic, sporadic PHPT may have MEN1, CDC73 or CASR mutations, and overall more than 10% of patients with PHPT will have a mutation in one of 11 genes. Genetic testing is available and of value in the clinical setting, as it helps in making the correct diagnosis and planning the management of these complex disorders associated with parathyroid tumours.


Dual role for pilus in adherence to epithelial cells and biofilm formation in Streptococcus agalactiae.
Streptococcus agalactiae is a common human commensal and a major life-threatening pathogen in neonates. Adherence to host epithelial cells is the first critical step of the infectious process. Pili have been observed on the surface of several gram-positive bacteria including S. agalactiae. We previously characterized the pilus-encoding operon gbs1479-1474 in strain NEM316. This pilus is composed of three structural subunit proteins: Gbs1478 (PilA), Gbs1477 (PilB), and Gbs1474 (PilC), and its assembly involves two class C sortases (SrtC3 and SrtC4). PilB, the bona fide pilin, is the major component; PilA, the pilus associated adhesin, and PilC, are both accessory proteins incorporated into the pilus backbone. We first addressed the role of the housekeeping sortase A in pilus biogenesis and showed that it is essential for the covalent anchoring of the pilus fiber to the peptidoglycan. We next aimed at understanding the role of the pilus fiber in bacterial adherence and at resolving the paradox of an adhesive but dispensable pilus. Combining immunoblotting and electron microscopy analyses, we showed that the PilB fiber is essential for efficient PilA display on the surface of the capsulated strain NEM316. We then demonstrated that pilus integrity becomes critical for adherence to respiratory epithelial cells under flow-conditions mimicking an in vivo situation and revealing the limitations of the commonly used static adherence model. Interestingly, PilA exhibits a von Willebrand adhesion domain (VWA) found in many extracellular eucaryotic proteins. We show here that the VWA domain of PilA is essential for its adhesive function, demonstrating for the first time the functionality of a prokaryotic VWA homolog. Furthermore, the auto aggregative phenotype of NEM316 observed in standing liquid culture was strongly reduced in all three individual pilus mutants. S. agalactiae strain NEM316 was able to form biofilm in microtiter plate and, strikingly, the PilA and PilB mutants were strongly impaired in biofilm formation. Surprisingly, the VWA domain involved in adherence to epithelial cells was not required for biofilm formation.


Cytosolic 5'-nucleotidase II interacts with the leucin rich repeat of NLR family member Ipaf.
IMP/GMP preferring cytosolic 5'-nucleotidase II (cN-II) is a bifunctional enzyme whose activities and expression play crucial roles in nucleotide pool maintenance, nucleotide-dependent pathways and programmed cell death. Alignment of primary amino acid sequences of cN-II from human and other organisms show a strong conservation throughout the entire vertebrata taxon suggesting a fundamental role in eukaryotic cells. With the aim to investigate the potential role of this homology in protein-protein interactions, a two hybrid system screening of cN-II interactors was performed in S. cerevisiae. Among the X positive hits, the Leucin Rich Repeat (LRR) domain of Ipaf was found to interact with cN-II. Recombinant Ipaf isoform B (lacking the Nucleotide Binding Domain) was used in an in vitro affinity chromatography assay confirming the interaction obtained in the screening. Moreover, co-immunoprecipitation with proteins from wild type Human Embryonic Kidney 293 T cells demonstrated that endogenous cN-II co-immunoprecipitated both with wild type Ipaf and its LRR domain after transfection with corresponding expression vectors, but not with Ipaf lacking the LRR domain. These results suggest that the interaction takes place through the LRR domain of Ipaf. In addition, a proximity ligation assay was performed in A549 lung carcinoma cells and in MDA-MB-231 breast cancer cells and showed a positive cytosolic signal, confirming that this interaction occurs in human cells. This is the first report of a protein-protein interaction involving cN-II, suggesting either novel functions or an additional level of regulation of this complex enzyme.


Synthesis and characterisation of thioether functionalised gallium and indium alkoxides.
This paper provides evidence of formerly unknown thioether coordination in metal alkoxides. The thioether functionalised alkanols serving as alcoholate ligands have been prepared by a generic route. The gallium and indium alkoxides provide the first evidence for sulphur coordination in the liquid and solid state in metal alkoxide derivatives. The presence of amines suppresses the coordination of thioether moieties leading to a well-known bonding mode in aminoalcoholates.


Disrupting vesicular trafficking at the endosome attenuates transcriptional activation by Gcn4.
The late endosome (MVB) plays a key role in coordinating vesicular transport of proteins between the Golgi complex, vacuole/lysosome, and plasma membrane. We found that deleting multiple genes involved in vesicle fusion at the MVB (class C/D vps mutations) impairs transcriptional activation by Gcn4, a global regulator of amino acid biosynthetic genes, by decreasing the ability of chromatin-bound Gcn4 to stimulate preinitiation complex assembly at the promoter. The functions of hybrid activators with Gal4 or VP16 activation domains are diminished in class D mutants as well, suggesting a broader defect in activation. Class E vps mutations, which impair protein sorting at the MVB, also decrease activation by Gcn4, provided they elicit rapid proteolysis of MVB cargo proteins in the aberrant late endosome. By contrast, specifically impairing endocytic trafficking from the plasma membrane, or vesicular transport to the vacuole, has a smaller effect on Gcn4 function. Thus, it appears that decreasing cargo proteins in the MVB through impaired delivery or enhanced degradation, and not merely the failure to transport cargo properly to the vacuole or downregulate plasma membrane proteins by endocytosis, is required to attenuate substantially transcriptional activation by Gcn4.


Three-year incidence and cumulative prevalence of retinopathy: the atherosclerosis risk in communities study.
To describe the three-year incidence and cumulative prevalence of retinopathy and its risk factors. Population-based, prospective cohort study in four US communities. In the Atherosclerosis Risk in Communities (ARIC) Study, 981 participants had retinal photography of one randomly selected eye at the third examination (1993 to 1995) and three years later at the fourth examination (1996). Photographs were graded on both occasions for retinopathy signs (for example, microaneurysm, retinal hemorrhage, and/or cotton-wool spots). Incidence was defined as participants without retinopathy at the third examination who developed retinopathy at the fourth examination, and cumulative prevalence was defined to include incident retinopathy as well as participants who had retinopathy at both the third and fourth examinations. The three-year incidence and cumulative prevalence of any retinopathy in the whole cohort was 3.8% and 7.7%, respectively. In multivariable analysis, incident retinopathy was related to higher mean arterial blood pressure (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.0 to 2.3, per standard deviation increase in risk factor levels), fasting serum glucose (OR 1.6, 95% CI 1.3 to 2.1), serum total cholesterol (OR 1.4, 95% CI 1.0, 2.0), and plasma fibrinogen (OR 1.4, 95% CI 1.1 to 1.9). Among persons without diabetes, the three-year incidence and cumulative prevalence of nondiabetic retinopathy was 2.9% and 4.3%, respectively. Incident nondiabetic retinopathy was related to higher mean arterial blood pressure (OR 1.4, 95% CI 0.9 to 2.3) and fasting serum glucose (OR 1.5, 95% CI 1.0 to 2.3). Among persons with diabetes, the three-year incidence and cumulative prevalence of diabetic retinopathy was 10.1% and 27.2%, respectively. Retinopathy signs occur frequently in middle-aged people, even in those without diabetes. Hypertension and hyperglycemia are risk factors for incident retinopathy.


Metabolic syndrome increases the risk for premature employment exit: A longitudinal study among 60 427 middle-aged and older workers from the Lifelines Cohort Study and Biobank.
This study aimed to examine whether (i) metabolic syndrome (MetS) increases the risk for premature employment exit and (ii) a dose-response relationship exists between an increasing number of MetS components and premature employment exit among middle-aged and older workers. A sample of N=60 427 Dutch workers (40-64 years old) from the Lifelines Cohort Study and Biobank were examined using data from five measurement waves during a total median follow-up time of 4.2 years. MetS components were based on physical measures, blood markers, and medication use. Premature employment exit types (ie, unemployment, work disability, and early retirement) were determined using questionnaires. MetS and number of MetS components were examined as risk factors for premature employment exit using competing risk regression analysis. MetS significantly increased the risk for work disability [adjusted sub distribution hazard ratio (SHR) 1.78, 95% confidence interval (CI) 1.54-2.05] and unemployment (adjusted SHR 1.16, 95% CI 1.06-1.26). A clear dose-response relationship was found for an increasing number of MetS components and work disability. No associations were found between MetS (components) and early retirement after adjusting for sociodemographic factors. MetS was identified as a modifiable early-stage cardio-metabolic risk factor especially for work disability and, to a lesser extent, for unemployment. Further, a clear dose-response relationship was found between an increasing number of MetS components and work disability. MetS interventions and prevention might help to prolong working lives. More awareness is needed among employers and occupational health professionals about the premature employment exit risk faced by middle-aged and older workers with MetS.


Successful pregnancy and cesarean delivery via noninvasive ventilation in mitochondrial myopathy.
We report a case study of a 22-year-old woman with mitochondrial thymidine kinase 2 deficiency and chronic respiratory failure due to severe neuromuscular weakness requiring noninvasive positive pressure ventilation (NIPPV) since 12 years of age. During pregnancy and cesarean delivery, she was successfully supported with NIPPV. A multidisciplinary team approach should be used in pregnant patients with these disorders with specific attention to management of pulmonary complications, selection of route of delivery, anesthesia, and analgesia.


Spontaneous metastasis in mouse models of testicular germ-cell tumours.
Testicular germ-cell tumours (TGCTs) are the most common cancer in young men; the incidence is increasing worldwide and they have an unusually high rate of metastasis. Despite significant work on TGCTs and their metastases in humans, absence of a mouse model of spontaneous metastasis has greatly limited our understanding of the mechanisms by which metastatic potential is acquired and on their modes of dissemination. We report a new model of spontaneous TGCT metastasis in the 129 family of mice and provide evidence that these are true metastases derived directly from primary testicular cancers rather than independently from ectopic stem cells. These putative metastases (pMETs) occur at similar frequencies among TGCT-affected males in six genetically distinct TGCT-susceptible strains and were largely found in anatomical sites that are consistent with patterns of TGCT metastasis in humans. Various lines of evidence support their pluripotency and germ-cell origin, including presence of multiple endodermal, mesodermal and ectodermal derivatives as well as cells showing OCT4 and SSEA-1 pluripotency markers. In addition, pMETs were never found in males that did not have a TGCT, suggesting that metastases are derived from primary tumours. Finally, pMETS and primary TGCTs shared several DNA copy number variants suggesting a common cellular and developmental origin. Together, these results provide the first evidence for spontaneous TGCT metastasis in mice and show that these metastases originate from primary TGCTs rather than independently from ectopic stem cells.


Identification of the cystic fibrosis gene: chromosome walking and jumping.
An understanding of the basic defect in the inherited disorder cystic fibrosis requires cloning of the cystic fibrosis gene and definition of its protein product. In the absence of direct functional information, chromosomal map position is a guide for locating the gene. Chromosome walking and jumping and complementary DNA hybridization were used to isolate DNA sequences, encompassing more than 500,000 base pairs, from the cystic fibrosis region on the long arm of human chromosome 7. Several transcribed sequences and conserved segments were identified in this cloned region. One of these corresponds to the cystic fibrosis gene and spans approximately 250,000 base pairs of genomic DNA.


S3 detection as a diagnostic and prognostic aid in emergency department patients with acute dyspnea.
Dyspneic emergency department (ED) patients present a diagnostic dilemma. Recent technologic advances have made it possible to capture information about pathologic heart sounds at ECG recording. This study evaluates the effect of an S3 captured by acoustic cardiography on emergency physician diagnostic accuracy and confidence in their diagnosis of acute decompensated heart failure, as well as the patient's prognosis. Dyspneic ED patients older than 40 years who were not dialysis dependent were prospectively enrolled in this multinational study. Treating emergency physicians, initially blinded to all laboratory and acoustic cardiography results, estimated acute decompensated heart failure probability from 0% to 100% on a visual analog scale. The emergency physician repeated the visual analog scale after acoustic cardiography results were provided. Physician diagnostic accuracy for and confidence in acute decompensated heart failure were evaluated against a reference standard diagnosis, as determined by 2 independent cardiologists blinded to acoustic cardiography. Patients were followed through 90 days to determine the relationship of the S3 to adverse events. Nine hundred ninety-five patients with acoustic cardiography results were enrolled from March to October 2006 at 7 US and 2 international sites. Median age was 63 years, 55% were men, and 44% were white. The reference diagnosis was acute decompensated heart failure in 41.5%. After initial history and physical examination, the treating physician's initial sensitivity, specificity, and accuracy for acute decompensated heart failure as a possible diagnosis were 89.0% (95% confidence interval [CI] 85.5% to 91.8%), 58.2% (95% CI 54.0% to 62.2%), and 71.0% (95% CI 68.4% to 73.8%), respectively. Acoustic cardiography had an accuracy of 68% (95% CI 65.4% to 71.3%), sensitivity of 40.2% (95% CI 35.5% to 45.1%), and specificity of 88.5% (95% CI 85.5% to 90.9%). Emergency physician confidence and diagnostic accuracy were influenced by adding information about the presence or absence of S3. In a multivariable model, the S3 added no independent prognostic information for 30-day (odds ratio 1.20; 95% CI 0.67 to 2.14) or 90-day events (odds ratio 1.22; 95% CI 0.78 to 1.90). In patients presenting with acute dyspnea, the acoustic cardiography S3 was specific for acute decompensated heart failure and affected physician confidence but did not improve diagnostic accuracy for acute decompensated heart failure, largely because of its low sensitivity. Further, the acoustic cardiography S3 provided no significant independent prognostic information.


Host-targeting agents for treatment of hepatitis B virus infection.
Hepatitis B virus (HBV) infection is a major cause of chronic liver disease, including liver cirrhosis, liver failure and hepatocellular carcinoma (HCC)-the second leading and fastest rising cause of cancer death world-wide. While de novo infection can be efficiently prevented by vaccination and chronic infection can be controlled using antivirals targeting the viral polymerase, the development of efficient antiviral strategies to eliminate the virus and thus to cure infection remains a key unmet medical need. The recent progress in the development of robust infectious HBV cell culture models now enables the investigation of the full viral life cycle, including a more detailed study of the molecular mechanisms of virus-host interactions responsible for viral persistence. The understanding of these virus-host interactions will be instrumental for the development of curative treatments. Host-dependency factors have recently emerged as promising candidates to treat and prevent infection by various pathogens. This review focuses on the potential of host-targeting agents (HTAs) as novel antivirals to treat and cure HBV infection. These include HTAs that inhibit de novo and re-infection, synthesis and spread of cccDNA as well as development of immune-based approaches eliminating or curing infected hepatocytes, including the eradication of viral cccDNA.


Non-DLVO silica interaction forces in NMP-water mixtures. I. A symmetric system.
Despite the success of DLVO theory, there exist numerous examples of interactions that do not follow its predictions. One prominent example is the interaction between hydrophilic surfaces in mixtures of water with another polar, associating solvent. Interactions of such surfaces are still poorly understood yet play a key role in a wide variety of processes in nature, biology, and industry. The interaction forces between a silica sphere and a glass plate in N-methyl-2-pyrrolidone (NMP)-water binary mixtures were measured using the AFM technique. The interactions in pure NMP and pure water agreed qualitatively with DLVO theory. In contrast, the addition of NMP to water drastically altered the interactions, which no longer followed DLVO predictions. An unusually strong, long-range (50-80 nm), multistepped attractive force was observed on the approach of hydrophilic surfaces in the NMP concentration range of 30-50 vol %, where the adhesive pull-off force was also maximized. The maximum attractive force was observed at an NMP concentration near 30 vol %, consistent with the formation of a strong hydrogen-bonded complex between NMP and water near the solid surface. The analysis of force profiles, zeta potentials, solution viscosity, and contact angles suggests that attraction arises from the bridging of surface-adsorbed macrocluster layers known to form on hydrophilic surfaces in mixtures of associating liquids.


Time-course and regional analyses of the physiopathological changes induced after cerebral injection of an amyloid β fragment in rats.
Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid β protein (Aβ) formed by pathological processing of the Aβ precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated Aβ fragment 25-35 (Aβ(25-35)) in rats. Using a combined biochemical, behavioral, and morphological approach, we analyzed the peptide effects after 1, 2, and 3 weeks in the hippocampus, cortex, amygdala, and hypothalamus. The scrambled Aβ(25-35) peptide was used as negative control. The aggregated forms of Aβ peptides were first characterized using electron microscopy, infrared spectroscopy, and Congo Red staining. Intracerebroventricular injection of Aβ(25-35) decreased body weight, induced short- and long-term memory impairments, increased endocrine stress, cerebral oxidative and cellular stress, neuroinflammation, and neuroprotective reactions, and modified endogenous amyloid processing, with specific time-course and regional responses. Moreover, Aβ(25-35), the presence of which was shown in the different brain structures and over 3 weeks, provoked a rapid glial activation, acetylcholine homeostasis perturbation, and hippocampal morphological alterations. In conclusion, the acute intracerebroventricular Aβ(25-35) injection induced substantial central modifications in rats, highly reminiscent of the human physiopathology, that could contribute to physiological and cognitive deficits observed in AD.


Direct fabrication of seamless roller molds with gapless and shaped-controlled concave microlens arrays.
This Letter demonstrates the direct fabrication of gapless concave microlenses on glass cylinders, which can be used as seamless roller molds for the continuous imprinting of large-area microlens arrays. The method involves femtosecond laser exposures followed by a chemical wet-etching process. A honeycomb-like concave microlens array was fabricated on a glass cylinder with a diameter of 3 mm. We demonstrated the flexibility of the method in tuning the shape and depth of the concave structures by the arrangements of the laser exposure spots and laser powers, and examined the replicating ability of the roller mold by the polymer castling method.


Evolutionary potential of marine phytoplankton under ocean acidification.
Marine phytoplankton have many obvious characters, such as rapid cell division rates and large population sizes, that give them the capacity to evolve in response to global change on timescales of weeks, months or decades. However, few studies directly investigate if this adaptive potential is likely to be realized. Because of this, evidence of to whether and how marine phytoplankton may evolve in response to global change is sparse. Here, we review studies that help predict evolutionary responses to global change in marine phytoplankton. We find limited support from experimental evolution that some taxa of marine phytoplankton may adapt to ocean acidification, and strong indications from studies of variation and structure in natural populations that selection on standing genetic variation is likely. Furthermore, we highlight the large body of literature on plastic responses to ocean acidification available, and evolutionary theory that may be used to link plastic and evolutionary responses. Because of the taxonomic breadth spanned by marine phytoplankton, and the diversity of roles they fill in ocean ecosystems and biogeochemical cycles, we stress the necessity of treating taxa or functional groups individually.


Antigen signal strength during priming determines effector CD4 T cell function and antigen sensitivity during influenza virus challenge.
TCR signal strength during priming is a key determinant of CD4 T cell activation, but its impact on effector CD4 T functions in vivo remains unclear. In this study, we compare the functionality of CD4 T cell responses induced by peptides displaying varying binding half-lives with MHC class II before and after influenza virus infection. Although significant quantitative and qualitative differences in CD4 T cell responses were observed before infection between mice vaccinated with low- or high-stability peptides, both mice mounted robust early Th1 effector cytokine responses upon influenza challenge. However, only effector CD4 T cells induced by low-stability peptides proliferated and produced IL-17A after influenza challenge. In contrast, effector T cells elicited by higher-stability peptides displayed a terminally differentiated phenotype and divided poorly. This defective proliferation was T cell intrinsic but could not be attributed to a reduced expression of lymph node homing receptors. Instead, we found that CD4 T cells stimulated with higher-stability peptides exhibited decreased responsiveness to low levels of Ag presentation. Our study reveals the critical role of TCR signal strength during priming for the function and Ag sensitivity of effector CD4 T cells during viral challenge.


What makes family caregivers happy during the first 2 years post stroke?
This study aimed to identify aspects of the caregiving situation contributing to family caregivers' psychological well-being. Longitudinal cohort study with structured quantitative interviews 1, 3, 6, and 12 months post stroke. A subset of participants also completed surveys 18 and 24 months post stroke. Participants included individuals hospitalized for their first stroke and their family caregivers. Psychological well-being was assessed by the Positive Affect Scale. A total of 399 stroke survivor, caregiver dyads completed the 1-year follow-up and 80 dyads completed the second year of follow-up. Using mixed effects modeling for longitudinal data, caregivers reported more psychological well-being when they provided more assistance to stroke survivors who had fewer symptoms of depression, better cognitive functioning, and who had more severe strokes. In addition, caregivers who maintained participation in valued activities had more mastery, gained personally providing care, were in better physical health, were older, and were from Quebec reported more psychological well-being. Caregivers followed for a second year post stroke reported better psychological well-being when caring for stroke survivors with fewer symptoms of depression and more severe strokes and when the caregivers had a greater sense of mastery and gained more personally providing care. Our findings contribute to the caregiver intervention development literature by identifying aspects of the caregiving situation that are associated with positive outcomes. Incorporating specific aspects, for example, strategies to enhance caregiver mastery into programs and services offered to caregivers may enhance their positive experiences with providing care and ultimately enhance the sustainability of the caregiving situation.


Anticoagulant-related hemorrhage in acute cerebral embolism.
Five patients with nonseptic cerebral embolism of cardiac origin are reported in whom early anticoagulant therapy resulted in clinical deterioration or death from frank hemorrhage into the acute infarct. In each patient an initial CT scan excluded the presence of intracerebral hemorrhage and a second CT scan, after clinical deterioration had occurred, documented frank hemorrhage into the infarcted zone. All five patients had large infarctions in the right middle cerebral artery territory and three patients were mildly hypertensive. Four patients received heparin within 36 hours of their stroke and one was on warfarin at time of the embolism. Clinical deterioration occurred after intervals of several hours (2 cases), 5-6 days (2 cases) and 30 days (1 case). In only 2 patients was anticoagulant activity excessive at time of clinical deterioration. This report illustrates the danger of early anticoagulant therapy of acute nonseptic cerebral embolism, particularly in the setting of large infarction.


Expression of a surface-associated antigen on Y-cells in the cat lateral geniculate nucleus is regulated by visual experience.
The monoclonal antibody Cat-301, generated against cat spinal cord (McKay and Hockfield, 1982), recognizes a surface-associated antigen that, in the cat lateral geniculate nucleus (LGN), is selectively expressed on Y-cells (Hockfield et al., 1983; Hendry et al., 1984; Sur et al., 1984). We now report that the antigen recognized by Cat-301 appears late in development, along a time course similar to that described for the maturation of the physiological properties of Y-cells in the LGN, and that its expression is sharply reduced by monocular lid suture or dark-rearing from birth, 2 visual deprivation procedures that lead to a reduction in the proportion of Y-cells recorded physiologically in the LGN (Sherman et al., 1972; Kratz et al., 1979; reviewed in Sherman and Spear, 1982). Monocular lid suture in the adult has no effect on Cat-301 antigen levels or, as previously reported (Sherman et al., 1972), on the proportion of physiologically recorded Y-cells. In addition, reversing the monocular deprivation in adulthood by opening the neonatally sutured eye and suturing closed the previously normal eye for 6 months restores neither normal levels of Cat-301 labeling nor, as previously reported (Geisert et al., 1982), the proportion of recordable Y-cells. The development of Cat-301 immunoreactivity thus parallels the development of LGN Y-cell physiology. The relative reduction in levels of immunoreactivity consequent to neonatal, but not adult, visual deprivation shows that Cat-301 antigen expression does not simply reflect the level of visually evoked electrical activity in the LGN, but rather reflects a process that depends on the nature of visual experience early in life.(ABSTRACT TRUNCATED AT 250 WORDS)


S-RNase-based self-incompatibility in Petunia inflata.
For the Solanaceae-type self-incompatibility, also possessed by Rosaceae and Plantaginaceae, the specificity of self/non-self interactions between pollen and pistil is controlled by two polymorphic genes at the S-locus: the S-locus F-box gene (SLF or SFB) controls pollen specificity and the S-RNase gene controls pistil specificity. This review focuses on the work from the authors' laboratory using Petunia inflata (Solanaceae) as a model. Here, recent results on the identification and functional studies of S-RNase and SLF are summarized and a protein-degradation model is proposed to explain the biochemical mechanism for specific rejection of self-pollen tubes by the pistil. The protein-degradation model invokes specific degradation of non-self S-RNases in the pollen tube mediated by an SLF, and can explain compatible versus incompatible pollination and the phenomenon of competitive interaction, where SI breaks down in pollen carrying two different S-alleles. In Solanaceae, Plantaginaceae and subfamily Maloideae of Rosaceae, there also exist multiple S-locus-linked SLF/SFB-like genes that potentially function as the pollen S-gene. To date, only three such genes, all in P. inflata, have been examined, and they do not function as the pollen S-gene in the S-genotype backgrounds tested. Interestingly, subfamily Prunoideae of Rosaceae appears to possess only a single SLF/SFB gene, and competitive interaction, observed in Solanaceae, Plantaginaceae and subfamily Maloideae, has not been observed. Thus, although the cytotoxic function of S-RNase is an integral part of SI in Solanaceae, Plantaginaceae and Rosaceae, the function of SLF/SFB may have diverged. This highlights the complexity of the S-RNase-based SI mechanism. The review concludes by discussing some key experiments that will further advance our understanding of this self/non-self discrimination mechanism.


Time-course of "off-line" prefrontal rTMS effects--a PET study.
Low-frequency "off-line" repetitive transcranial magnetic stimulation (rTMS) over the course of several minutes has attained considerable attention as a research tool in cognitive neuroscience due to its ability to induce functional disruptions of brain areas. This disruptive rTMS effect is highly valuable for revealing a causal relationship between brain and behavior. However, its influence on remote interconnected areas and, more importantly, the duration of the induced neurophysiological effects, remain unknown. These aspects are critical for a study design in the context of cognitive neuroscience. In order to investigate these issues, 12 healthy male subjects underwent 8 H(2)(15)O positron emission tomography (PET) scans after application of long-train low-frequency rTMS to the right dorsolateral prefrontal cortex (DLPFC). Immediately after the stimulation train, regional cerebral blood flow (rCBF) increases were present under the stimulation site as well as in other prefrontal cortical areas, including the ventrolateral prefrontal cortex (VLPFC) ipsilateral to the stimulation site. The mean increases in rCBF returned to baseline within 9 min. The duration of this unilateral prefrontal rTMS effect on rCBF is of particular interest to those who aim to influence behavior in cognitive paradigms that use an "off-line" approach.


Erythropoietin therapy in the perioperative setting.
Recombinant human erythropoietin has been approved for use in patients undergoing autologous donation in Japan, Europe, and Canada since 1993, 1994, and 1996, respectively, and for perisurgical adjuvant therapy without autologous donation in Canada and the United States since 1996. Early clinical trials of erythropoietin therapy in the setting of autologous donation have provided important information regarding clinical safety, erythropoietin dose, and erythropoietic response. Later trials of perisurgical erythropoietin therapy without autologous donation provided data on efficacy (reduced allogeneic blood exposure) that led to approval of erythropoietin in patients undergoing surgery. However, the erythropoietin doses (300 U/kg subcutaneous x14 days) used in these trials, and their subsequent inclusion in labeling for the use of this product, are costly and tedious to administer. A recent study reported that a weekly regimen of erythropoietin (600 U/kg) for 4 weeks is less costly but just as effective at reducing allogeneic blood exposure in elective orthopaedic surgery. The most cost effective regimen that has been shown to minimize allogeneic exposure is preoperative erythropoietin therapy (600 U/kg subcutaneous weekly x2 and 300 U/kg subcutaneous on day of surgery) coupled with acute normovolemic hemodilution in patients undergoing radical retropubic prostatectomy. A similar regimen of erythropoietin therapy in patients undergoing coronary artery bypass grafting (2500 U/kg subcutaneous in divided doses for 2 weeks preoperatively) coupled with hemodilution also was effective. Low dose erythropoietin therapy coupled with acute normovolemic hemodilution ultimately may be shown to be cost equivalent to the predonation of three autologous blood units before elective surgery.


When does risk become residual? A systematic review of research on flood risk management in West Africa.
Flood events in West Africa have devastating impacts on the lives of people. Additionally, developments such as climate change, settlement expansion into flood-prone areas, and modification of rivers are expected to increase flood risk in the future. Policy documents have issued calls for conducting local risk assessments and understanding disaster risk in diverse aspects, leading to an increase in such research. Similarly, in a shift from flood protection to flood risk management, the consideration of various dimensions of flood risk, the necessity of addressing flood risk through an integrated strategy containing structural and non-structural measures, and the presence of residual risk are critical perspectives raised. However, the notion of "residual risk" remains yet to be taken up in flood risk management-related academic literature. This systematic review seeks to approach the notion of residual risk by reviewing information on flood impacts, common measures, and recommendations in academic literature. The review reveals various dimensions of impacts from residual flood risk aside from material damage, in particular, health impacts and economic losses. Infrastructural measures were a dominant category of measures before and after flood events and in recommendations, despite their shortcomings. Also, spatial planning interventions, a more participatory and inclusive governance approach, including local knowledge, sensitisation, and early warning systems, were deemed critical. In the absence of widespread access to insurance schemes, support from social networks after flood events emerged as the most frequent measure. This finding calls for in-depth assessments of those networks and research on potential complementary formal risk transfer mechanisms. The online version contains supplementary material available at 10.1007/s10113-021-01826-7.


Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis.
To investigate the relationship between angiogenesis and hepatic tumorigenesis, we examined the expression of vascular endothelial growth factor (VEGF) in 8 human colon carcinoma cell lines and in 30 human colorectal cancer liver metastases. Abundant message for VEGF was found in all tumors, localized to the malignant cells within each neoplasm. Two receptors for VEGF, KDR and flt1, were also demonstrated in most of the tumors examined. KDR and flt1 mRNA were limited to tumor endothelial cells and were more strongly expressed in the hepatic metastases than in the sinusoidal endothelium of the surrounding liver parenchyma. VEGF monoclonal antibody administration in tumor-bearing athymic mice led to a dose- and time-dependent inhibition of growth of subcutaneous xenografts and to a marked reduction in the number and size of experimental liver metastases. In hepatic metastases of VEGF antibody-treated mice, neither blood vessels nor expression of the mouse KDR homologue flk-1 could be demonstrated. These data indicate that VEGF is a commonly expressed angiogenic factor in human colorectal cancer metastases, that VEGF receptors are up-regulated as a concomitant of hepatic tumorigenesis, and that modulation of VEGF gene expression or activity may represent a potentially effective antineoplastic therapy in colorectal cancer.


Slow PIII component of the carp electroretinogram.
The slow PIII component of the electroretinogram (ERG) was studied in the isolated, aspartate-treated carp retina. Although the latter is richly populated with cones, slow PIII appeared to reflect almost exclusively the activity of rods; e.g. the spectral sensitivity of the potential paralleled closely the rod pigment curve, its operating range (i.e. the V-log I curve) was limited to 3 log units above absolute threshold, and raising background intensities to photopic levels produced saturation of the increment threshold function without evidence of a cone-mediated segment. Only after bleaching away a significant fraction of the porphyropsin was it possible to unmask a small photopic contribution to slow PIII, as evidenced by a displacement in the action spectrum to longer wavelengths. The spatial distribution of the slow PIII voltage within the retina (Faber, D.S. 1969. Ph.D. Thesis. State University of New York. Buffalo, N.Y.; Witkovsky, P.J. Nelson, and H. Ripps. 1973. J. Gen Physiol. 61:401) and its ability to survive aspartate treatment indicate that this potential arises in the Müller (glial) fiber. Additional support for this conclusion is provided by the slow rise time (several seconds) and long temporal integration (up to 40s) of the response. In many respects the properties of slow PIII resemble those of the c-wave, a pigment epithelial response also subserved by rod activity. On the other hand, the receptoral (fast PIII) and the b-wave components of the ERG behave quite differently. Unlike slow PIII, response saturation could not be induced, since both potentials are subserved by cones when the stimulus conditions exceed the limits of the scotopic range. Receptors appear to govern light adaptation at photopic background levels; both fast PIII and b-wave manifest identical incremental threshold values over this range of intensities. However, under scotopic conditions, the sensitivity of the b-wave is affected by luminous backgrounds too weak to alter fast PIII threshold, indicating a postreceptoral stage of adaptation.


TEMPORAL PATTERN OF KINESIOLOGY TAPE EFFICACY ON HAMSTRING EXTENSIBILITY.
Kinesiology tape has been advocated as a means of improving muscle flexibility, a potential modifiable risk factor for injury, over time. The epidemiology and etiology of hamstring injuries in sport have been well documented. To compare the temporal pattern of efficacy of kinesiology tape and traditional stretching techniques on hamstring extensibility over a five day period. Controlled laboratory study. Thirty recreationally active male participants (Mean ± SD: age 20.0 ± 1.55 years; height 179.3 ± 4.94 cm; mass 76.9 ± 7.57 kg) completed an active knee extension assessment (of the dominant leg) as a measure of hamstring extensibility. Three experimental interventions were applied in randomized order: Kinesiology tape (KT), static stretch (SS), proprioceptive neuromuscular facilitation (PNF). Measures were taken at baseline, +1min, + 30mins, + 3days and +5days days after each intervention. The temporal pattern of change in active knee extension was modelled as a range of regression polynomials for each intervention, quantified as the regression coefficient. Hamstring ROM with KT application at +3days was significantly greater than baseline (129.18 ± 15.46%, p = 0.01), SS (106.99 ± 9.84%, p = 0.03) and PNF (107.42 ± 136.13%, p = 0.03) interventions. The temporal pattern of changes in ROM for SS and PNF were best modelled by a negative linear function, although the strength of the correlation was weak in each case. In contrast, the KT data was optimised using a quadratic polynomial function (r(2) = 0.60), which yielded an optimum time of 2.76 days, eliciting a predicted ROM of 129.6% relative to baseline. Each intervention displayed a unique temporal pattern of changes in active knee extension. SS was best suited to immediate improvements, and PNF to +30 minutes in hamstring extensibility, whereas kinesiology tape offered advantages over a longer duration, peaking at 2.76 days. These findings have implications for the choice of intervention, timing and duration to assist clinicians in both a sporting and clinical context. 2c.


Modeling passive millimeter wave imaging sensor performance for discriminating small watercraft.
Passive millimeter wave (pmmW) imagers are quickly becoming practical sensor candidates for military and nonmilitary tasks. Our focus was to adapt the Night Vision [U.S. Army Research Development and Engineering Command, Communications and Electronics Research Development and Engineering Center, Night Vision and Electronics Sensors Directorate (NVESD)] passive thermal infrared imager performance models and apply them to pmmW imaging systems for prediction of field performance for the task of small watercraft and boat identification. The Night Vision Lab's infrared sensor model has been evolving since the 1950s, with the most current model being NVThermIP [Night Vision Thermal and Image Processing (NVThermIP) Model Users Manual, Rev. 9 (U.S. Army RDECON, CERDEC, NVESD, 2006)]. It has wide recognition as an engineering tool for sensor evaluation. This effort included collecting pmmW signatures for a representative set of targets, conducting an observer perception experiment, and deriving the task difficulty criteria that can be used in NVThermIP for identification of boats. The task difficulty criteria are used by designers and managers to create systems capable of meeting specific performance criteria in the field.


Inhibitory guidance in visual search: the case of movement-form conjunctions.
We used a probe-dot procedure to examine the roles of excitatory attentional guidance and distractor suppression in search for movement-form conjunctions. Participants in Experiment 1 completed a conjunction (moving X amongst moving Os and static Xs) and two single-feature (moving X amongst moving Os, and static X amongst static Os) conditions. "Active" participants searched for the target, whereas "passive" participants viewed the displays without responding. Subsequently, both groups located (left or right) a probe dot appearing in either an occupied or an unoccupied location. In the conjunction condition, the active group located probes presented on static distractors more slowly than probes presented on moving distractors, reversing the direction of the difference found within the passive group. This disadvantage for probes on static items was much stronger in conjunction than in single-feature search. The same pattern of results was replicated in Experiment 2, which used a go/no-go procedure. Experiment 3 extended the go/no-go procedure to the case of search for a static target and revealed increased probe localisation times as a consequence of active search, primarily for probes on moving distractor items. The results demonstrated attentional guidance by inhibition of distractors in conjunction search.


Generation of antigen receptor-specific suppressor T cell clones in man.
We have shown previously that CD8+ T cells proliferate upon exposure to autologous, antigen primed CD4+ T cells, and suppress the response of fresh T cells to the priming antigen but not irrelevant antigens. The stimulus and target of suppression in this system appears to be the antigen receptor on the surface of CD4+ cells, rather than the nominal antigen. In the current study, alloantigen primed CD4+ inducer cells and IL-2-containing medium were used to generate clones of suppressor cells from several individuals. The clones inhibited the response of fresh autologous T cells only to the original allogeneic stimulator cell and to stimulator cells that shared HLA-DR antigens with the priming cell. The clones were also genetically restricted, since they inhibited the response of HLA-A,B-compatible but not HLA-A,B-incompatible individuals. The availability of a method for reproducibly generating antigen receptor-specific suppressor T cell clones in vitro should make it possible to clarify the mechanism, whereby such cells are activated and exert their suppressive effect.


Source attribution of human salmonellosis: an overview of methods and estimates.
Reducing the burden of foodborne salmonellosis is challenging. It requires identification of the most important food sources causing disease and prioritization of effective intervention strategies. For this purpose, a variety of methods to estimate the relative contribution of different sources of Salmonella infections have been applied worldwide. Each has strengths and limitations, and the usefulness of each depends on the public health questions being addressed. In this study, we reviewed the source attribution methods and outcomes of several studies developed in different countries and settings, comparing approaches and regional differences in attribution estimates. Reviewed results suggest that illnesses and outbreaks are most commonly attributed to exposure to contaminated food, and that eggs, broiler chickens, and pigs are among the top sources. Although most source attribution studies do not attribute salmonellosis to produce, outbreak data in several countries suggest that exposure to raw vegetables is also an important source. International travel was also a consistently important exposure in several studies. Still, the relative contribution of specific sources to human salmonellosis varied substantially between studies. Although differences in data inputs, methods, and the point in the food system where attribution was estimated contribute to variability between studies, observed differences also suggest regional differences in the epidemiology of salmonellosis.