The supine apprehension test helps predict the risk of recurrent instability after a first-time anterior shoulder dislocation.
We previously identified the positive result of the supine apprehension test after completion of rehabilitation following a first dislocation as a possible predictor of high risk for redislocation. We extend the follow-up of a previous cohort of patients with first-time shoulder dislocations to better assess this test. Fifty-three men aged 17 to 27 years who sustained a first traumatic shoulder dislocation were treated by shoulder immobilization for 4 weeks and then rehabilitated with a standard physical therapy protocol. At 6-week follow-up, a supine anterior apprehension test was performed to assess the risk of redislocation. The patients were observed prospectively for a minimum of 75 months. Of the 53 participants, 52 (mean age, 20.2 years) completed the study follow-up. Of the 52 subjects, 41 (79%) were combat soldiers. Follow-up was between 75 and 112 months. Of the 52 subjects, 31 (60%) redislocated at a range of 3 to 70 months after the initial dislocation. Eleven of 14 subjects (79%; confidence interval, 52%-92%) with a positive anterior apprehension test result redislocated, compared with 20 of 38 patients (53%; confidence interval, 37%-68%) with a negative test result. Patients with a positive test result redislocated more and earlier (P = .02, PROC LIFETEST, SAS). The results of the supine apprehension test after a first shoulder dislocation and rehabilitation can help predict risk for recurrent instability. It potentially may be included as a variable in decision analysis models.


Achieving the Lowest Effective Antipsychotic Dose for Patients with Remitted Psychosis: A Proposed Guided Dose-Reduction Algorithm.
Continuing antipsychotic treatment in patients with schizophrenia under clinical remission remains controversial. Even though the mainstream opinion declares an outweighed balance against medication discontinuation, recent reviews and critiques suggest that some patients may remain symptom free and well functioning after stopping antipsychotics, but few predictors can identify who can try medication discontinuation, whilst no guidelines exist for reducing medication to reach the lowest effective dose safely. Analyzing the findings from studies employing different methodologies, adopting evidence from pharmacodynamic research, and observing dose reduction in stable patients, as well as taking inspiration from the metaphor of the Cantor set in natural philosophy, we introduce an alternative solution and propose a guided dose-reduction algorithm that follows a set of clear precautions and instructions. The algorithm recommends only a fraction (no more than 25%) of the dosage to be reduced at a time, with at least a 6-month stabilization period required before reducing another 25% of the dose. Patients are empowered to actively participate in decision making when they are ready for further dose tapering, or should they retreat to a previous dosage if warning signs of a relapse re-emerge. An intermittent or irregular dosing schedule can be used to adapt this algorithm to real-world practice. Our preliminary findings suggest that patients with remitted psychosis can do well along this path. We anticipate that this approach can help optimize the risk-benefit ratio and instill a hope in patients with schizophrenia that they can maintain in stable remission under a lower antipsychotic dose without an increased risk of relapse.


Automated structural comparisons clarify the phylogeny of the right-hand-shaped polymerases.
Polymerases are essential for life, being responsible for replication, transcription, and the repair of nucleic acid molecules. Those that share a right-hand-shaped fold and catalytic site structurally similar to the DNA polymerase I of Escherichia coli may catalyze RNA- or DNA-dependent RNA polymerization, reverse transcription, or DNA replication in eukarya, archaea, bacteria, and their viruses. We have applied novel computational methods for structure-based clustering and phylogenetic analyses of this functionally diverse polymerase superfamily, which currently comprises six families. We identified a structural core common to all right-handed polymerases, composed of 57 amino acid residues, harboring two positionally and chemically conserved residues, the catalytic aspartates. The structural conservation within each of the six families is considerable, for example, the structural core shared by family Y DNA polymerases covers over 90% of the polymerase domain of the Sulfolobus solfataricus Dpo4. Our phylogenetic analyses propose an early separation of RNA-dependent polymerases that use primers from those that are primer-independent. Furthermore, the exchange of polymerase genes between viruses and their hosts is evident. Because of this horizontal gene transfer, the phylogeny of polymerases does not always reflect the evolutionary history of the corresponding organisms.


Three-year longitudinal clinical trial of arterial function assessed by a oscillometric non-invasive method in comparison with carotid sclerosis and transferrin kidney-transplanted patients.
Chronic kidney disease remains one of the main risk factors of cardiovascular disease. However, patients with kidney transplantation have better life expectancy and better quality of life compared with patients on dialysis. In patients with a well-functioning graft, the main cause of death is cardiovascular in origin. Metabolic pathways have complex effects on arterial function that can be monitored by conventional ultrasonography and with the assessment of arterial stiffness by oscillometric non-invasive technique. Forty-one primer cadaver kidney-transplanted patient were involved in a 3-year longitudinal clinical trial (21 female, 20 male; average age, 40.16 ± 12.56 years). Arterial stiffness parameters referring to rigidity of the arterial wall (pulse wave velocity [PWV], augmentation index, and pulse pressure) were investigated. Correlation between stiffness, and laboratory parameters (serum creatinine, urea, hemoglobin, albumin, cholesterine, triglycerides, transferrin, uric acid, glomerular filtration rate, and C-reactive protein) were analyzed. A non-invasive oscillometric method--Tensiomed Arteriograph--was applied to assess the arterial stiffness parameters. Statistical analysis was performed with the use of Statistica for Windows, version 8.0. A value of P < .05 was considered statistically significant for all statistical tests. We found a positive correlation between PWV and left ventricular wall thickness and a negative correlation between PWV and ejection fraction. We also found a positive significant correlation between serum level of transferrin and PWV. There was simultaneous significant progression concerning PWV and carotid artery sclerosis in a 3-year follow-up. There was no fatal cardiovascular event during the study period among our patients. All of our patients involved in this study are still alive. Our findings suggest that arterial stiffness monitoring is a reliable method to assess global cardiovascular risk among kidney-transplanted patients. The oscillometric method is convenient, fast, painless technique to monitor arterial function, which, in the case of pathological findings, proposes more frequent cardiovascular control.


Reactive oxygen species (ROS) mediate the effects of leucine on translation regulation and type I collagen production in hepatic stellate cells.
The amino acid leucine causes an increase of collagen alpha1(I) synthesis in hepatic stellate cells through the activation of translational regulatory mechanisms and PI3K/Akt/mTOR and ERK signaling pathways. The aim of the present study was to evaluate the role played by reactive oxygen species on these effects. Intracellular reactive oxygen species levels were increased in hepatic stellate cells incubated with leucine 5 mM at early time points, and this effect was abolished by pretreatment with the antioxidant glutathione. Preincubation with glutathione also prevented 4E-BP1, eIF4E and Mnk-1 phosphorylation induced by leucine, as well as enhancement of procollagen alpha1(I) protein levels. Inhibitors for MEK-1 (PD98059), PI3K (wortmannin) or mTOR (rapamycin) did not affect leucine-induced reactive oxygen species production. However, preincubation with glutathione prevented ERK, Akt and mTOR phosphorylation caused by treatment with leucine. The mitochondrial electron chain inhibitor rotenone and the NADPH oxidase inhibitor apocynin prevented reactive oxygen species production caused by leucine. Leucine also induced an increased phosphorylation of IR/IGF-R that was abolished by pretreatment with either rotenone or apocynin. Therefore, leucine exerts on hepatic stellate cells a prooxidant action through NADPH oxidase and mitochondrial Reactive oxygen species production and these effects mediate the activation of IR/IGF-IR and signaling pathways, finally leading to changes in translational regulation of collagen synthesis.


A chronological review of experimental infection studies of the role of wild animals and livestock in the maintenance and transmission of Crimean-Congo hemorrhagic fever virus.
This article provides a definitive review of experimental studies of the role of wild animals and livestock in the maintenance and transmission of Crimean-Congo hemorrhagic fever virus (CCHFV), the etiologic agent of Crimean-Congo hemorrhagic fever (CCHF), beginning with the first recognized outbreak of the human disease in Crimea in 1944. Published reports by researchers in the former Soviet Union, Bulgaria, South Africa, and other countries where CCHF has been observed show that CCHFV is maintained in nature in a tick-vertebrate-tick enzootic cycle. Human disease most commonly results from the bite of an infected tick, but may also follow crushing of infected ticks or exposure to the blood and tissues of infected animals during slaughter. Wild and domestic animals are susceptible to infection with CCHFV, but do not develop clinical illness. Vertebrates are important in CCHF epidemiology, as they provide blood meals to support tick populations, transport ticks across wide geographic areas, and transmit CCHFV to ticks and humans during the period of viremia. Many aspects of vertebrate involvement in the maintenance and spread of CCHFV are still poorly understood. Experimental investigations in wild animals and livestock provide important data to aid our understanding of CCHFV ecology. This article is the second in a series of reviews of more than 70 years of research on CCHF, summarizing important findings, identifying gaps in knowledge, and suggesting directions for future research.


DNA origami-based single-molecule force spectroscopy elucidates RNA Polymerase III pre-initiation complex stability.
The TATA-binding protein (TBP) and a transcription factor (TF) IIB-like factor are important constituents of all eukaryotic initiation complexes. The reason for the emergence and strict requirement of the additional initiation factor Bdp1 in the RNA polymerase (RNAP) III system, however, remained elusive. A poorly studied aspect in this context is the effect of DNA strain arising from DNA compaction and transcriptional activity on initiation complex formation. We made use of a DNA origami-based force clamp to follow the assembly of human initiation complexes in the RNAP II and RNAP III systems at the single-molecule level under piconewton forces. We demonstrate that TBP-DNA complexes are force-sensitive and TFIIB is sufficient to stabilise TBP on a strained promoter. In contrast, Bdp1 is the pivotal component that ensures stable anchoring of initiation factors, and thus the polymerase itself, in the RNAP III system. Thereby, we offer an explanation for the crucial role of Bdp1 for the high transcriptional output of RNAP III.


Skin complications of Bacillus Calmette-Guérin immunization.
Bacillus Calmette-Guerin (BCG) vaccination has been performed since 1921, and remains the best method of preventing severe infections caused by Mycobacterium tuberculosis. Tuberculosis, in its various forms, remains a public health problem, and more than 100 countries continue BCG vaccination in an effort to control the disease. Since the initiation of BCG vaccination, numerous complications have been reported. In this review we will focus on the cutaneous complications of BCG vaccination. Recent case reports detail the development of large keloids, and also of juvenile sarcoidosis after BCG vaccination. Adverse outcomes from inadvertent intradermal injection of the forearm and from revaccination with BCG have also been reported. Other recently described skin complications subsequent to BCG vaccination include lupus vulgaris, delayed granuloma formation, cutaneous BCG infection in immune disorders, anterior chest wall mass, acute erythroderma with multiple skin abscesses, ulceration at the BCG site during Kawasaki disease, fixed drug eruption, and cutaneous abscesses following mesotherapy. BCG vaccination will continue to be a key method of preventing severe tuberculosis infections for the foreseeable future. The World Health Organization currently recommends BCG vaccination for all infants living in tuberculosis endemic areas. As such, it is important for health care providers to recognize the routinely anticipated cutaneous findings of the vaccination, in addition to complications relating to the injection. Subsequent care of these skin complications is of paramount importance to the health of these patients.


Location-specific responses to thermal stress in larvae of the reef-building coral Montastraea faveolata.
The potential to adapt to a changing climate depends in part upon the standing genetic variation present in wild populations. In corals, the dispersive larval phase is particularly vulnerable to the effects of environmental stress. Larval survival and response to stress during dispersal and settlement will play a key role in the persistence of coral populations. To test the hypothesis that larval transcription profiles reflect location-specific responses to thermal stress, symbiont-free gametes from three to four colonies of the scleractinian coral Montastraea faveolata were collected from Florida and Mexico, fertilized, and raised under mean and elevated (up 1 to 2 degrees C above summer mean) temperatures. These locations have been shown to exchange larvae frequently enough to prevent significant differentiation of neutral loci. Differences among 1,310 unigenes were simultaneously characterized using custom cDNA microarrays, allowing investigation of gene expression patterns among larvae generated from wild populations under stress. Results show both conserved and location-specific variation in key processes including apoptosis, cell structuring, adhesion and development, energy and protein metabolism, and response to stress, in embryos of a reef-building coral. These results provide first insights into location-specific variation in gene expression in the face of gene flow, and support the hypothesis that coral host genomes may house adaptive potential needed to deal with changing environmental conditions.


The effect of excess weight gain with intensive diabetes mellitus treatment on cardiovascular disease risk factors and atherosclerosis in type 1 diabetes mellitus: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) study.
Intensive diabetes mellitus therapy of type 1 diabetes mellitus reduces diabetes mellitus complications but can be associated with excess weight gain, central obesity, and dyslipidemia. The purpose of this study was to determine whether excessive weight gain with diabetes mellitus therapy of type 1 diabetes mellitus is prospectively associated with atherosclerotic disease. Subjects with type 1 diabetes mellitus (97% white, 45% female, mean age 35 years) randomly assigned to intensive or conventional diabetes mellitus treatment during the Diabetes Control and Complications Trial (DCCT) underwent intima-media thickness (n = 1015) and coronary artery calcium score (n = 925) measurements during follow-up in the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Intensive treatment subjects were classified by quartile of body mass index change during the DCCT. Excess gainers (4th quartile, including conventional treatment subjects meeting this threshold) maintained greater body mass index and waist circumference, needed more insulin, had greater intima-media thickness (+5%, P < 0.001 EDIC year 1, P = 0.003 EDIC year 6), and trended toward greater coronary artery calcium scores (odds ratio, 1.55; confidence interval, 0.97 to 2.49; P = 0.07) than minimal gainers. DCCT subjects meeting metabolic syndrome criteria for waist circumference and blood pressure had greater intima-media thickness in both EDIC years (P = 0.02 to < 0.001); those meeting high-density lipoprotein criteria had greater coronary artery calcium scores (odds ratio, 1.6; confidence interval, 1.1 to 2.4; P = 0.01) during follow-up. Increasing frequency of a family history of diabetes mellitus, hypertension, and hyperlipidemia was associated with greater intima-media thickness with intensive but not conventional treatment. Excess weight gain in DCCT is associated with sustained increases in central obesity, insulin resistance, dyslipidemia and blood pressure, as well as more extensive atherosclerosis during EDIC. URL for DCCT: http://clinicaltrials.gov; Unique identifier: NCT00360815. URL for EDIC: http://clinicaltrials.gov; Unique identifier: NCT00360893.


Formae speciales of cereal powdery mildew: close or distant relatives?
Powdery mildew is an important disease of cereals, affecting both grain yield and end-use quality. The causal agent of powdery mildew on cereals, Blumeria graminis, has been classified into eight formae speciales (ff.spp.), infecting crops and wild grasses. Advances in research on host specificity and resistance, and on pathogen phylogeny and origins, have brought aspects of the subspecific classification system of B. graminis into ff.spp. into question, because it is based on adaptation to certain hosts rather than strict host specialization. Cereals therefore cannot be considered as typical non-hosts to non-adapted ff.spp. We introduce the term 'non-adapted resistance' of cereals to inappropriate ff.spp. of B. graminis, which involves both pathogen-associated molecular pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). There is no clear distinction between the mechanisms of resistance to adapted and non-adapted ff.spp. Molecular evolutionary data suggest that the taxonomic grouping of B. graminis into different ff.spp. is not consistent with the phylogeny of the fungus. Imprecise estimates of mutation rates and the lack of genetic variation in introduced populations may explain the uncertainty with regard to divergence times, in the Miocene or Holocene epochs, of ff.spp. of B. graminis which infect cereal crop species. We propose that most evidence favours divergence in the Holocene, during the course of early agriculture. We also propose that the forma specialis concept should be retained for B. graminis pathogenic on cultivated cereals to include clades of the fungus which are strongly specialized to these hosts, i.e. ff.spp. hordei, secalis and tritici, as well as avenae from cultivated A. sativa, and that the forma specialis concept should no longer be applied to B. graminis from most wild grasses.


[Seroepidemiology of Toxoplasma gondii infection among Atayal aborigines and local animals in Nan-ao district, Ilan county and Jen-ai district, Nan-tou county, Taiwan].
In this study, latex agglutination test (LAT) was used to detect sera anti-toxoplasma antibodies of Atayal aborigines and local animals in Nan-ao district, Ilan county and Jen-ai district, Nan-tou county as a measure of exposure to the Toxoplasma gondii. Out of 422 Atayal aborigines and 64 different animals were tested in Nan-ao district and 82 Atayal children in Jen-ai district were also screened, the positive rates for sera anti-toxoplasma antibodies were 21.8%, 17.2% and 15.9%, respectively. In Nan-ao district, neither were the positive rates significantly different in males (22.1%) and females (21.4%), nor in humans (21.8%) and dogs (19.6%) (P > 0.05). The seroprevalence in adults (28.3%) was significantly higher than that in children (18.7%) (P < 0.05), and the highest seropositive rate (38.1%) was in the age group 50-59 years and the lowest (7.7%) was in the age group 1-9 years. In general, the age pattern of prevalence is consistent with increasing duration of exposure to Toxoplasma gondii with age. For animals, the seropositive rate in dogs (19.6%) was also significantly higher than that in wild rats (7.7%) (P < 0.05). No significant difference in seropositive rate of Atayal children was observed between Nan-ao and Jen-ai districts (P > 0.05).


Long-term quality of life after surgery for adenocarcinoma of the esophagogastric junction: extended gastrectomy or transthoracic esophagectomy?
Esophagectomy with gastric tube reconstruction and extended transhiatal gastrectomy with Roux-en-Y reconstruction are alternative procedures in current therapeutic concepts for adenocarcinoma of the esophagogastric junction (AEG). The impact of these operations on long-term health-related quality of life (HRQL) is incompletely understood. Patients with cancer-free survival of at least 24 months after esophagectomy (ESO) or extended gastrectomy (GAST) for AEG were identified from a prospectively maintained database. EORTC questionnaires were sent out to assess health-related general (QLQ-C30) and cancer-specific (OG-25) quality of life. Numeric scores were calculated for each conceptual area and compared with those of healthy reference populations. 123 patients (ESO n = 71; GAST n = 52) completed the self-rated questionnaires. HRQL was consistently lower in surgical patients (GAST and ESO) compared with healthy reference populations. Also, there was a general trend for a better HRQL in GAST compared with ESO patients. This trend was statistically significant for physical function (p = 0.04), dyspnea (p = 0.02), and reflux (p = 0.03). Subgroup analysis revealed no significant differences between patients with or without prior neoadjuvant therapy. After mid- and long-term follow-up, HRQL after extended gastrectomy with Roux-en-Y reconstruction is superior to that after esophagectomy and gastric tube reconstruction. Improved HRQL after gastrectomy is mainly due to less pulmonary and reflux-related symptoms. Our findings may influence the choice of the surgical strategy for patients with AEG.


The molecular circuit of steroid signalling in plants.
Steroid hormones are key regulators of growth and physiology in both plants and animals. The plant steroid hormones known as brassinosteroids (BRs) are essential for a wide range of developmental processes throughout the life cycle. In contrast with animal steroid hormones, which act mostly through nuclear receptors, BRs act through a cell-surface receptor kinase. The BR signal transduction pathway from the cell-surface receptor to nuclear gene expression has been elucidated in great molecular detail, and thus serves as a paradigm for receptor kinase signalling in plants. Furthermore, several mechanisms of signal integration have been identified that explain how BRs and other hormonal and environmental signals co-regulate specific developmental outputs in a synergistic or antagonistic manner.


"Prescribing sunshine": a national, cross-sectional survey of 1,089 New Zealand general practitioners regarding their sun exposure and vitamin D perceptions, and advice provided to patients.
The health effects of ultraviolet radiation vary according to wavelength, timing and pattern of exposure, personal characteristics and practices. Negative effects include skin cancers, eye diseases and immune suppression; positive effects primarily relate to endogenous vitamin D production which protects against bone disease. Drafting comprehensive guidelines regarding appropriate sun protective behaviours and vitamin D sufficiency is challenging. Advice given by general practitioners is potentially influential because they are widely respected. A survey instrument was developed, pre-tested and provided to practising GP's, either by on-line link or mailed, reply paid hard-copy. Odds ratios, differences in means, or ratios of geometric means from regression models are reported for potential predictor variables with 95% confidence intervals. Data (demographic, training, practicing, information accessing, confidence in vitamin D knowledge) suitable for analysis were obtained from 1,089 GPs (32% participation). Many (43%) were 'not at all confident' about their vitamin D knowledge. Recent information led 29% to recommend less sun protection during winter months and 10% less all year. Confidence was positively associated with non-'Western' medical training, information sources read and practising in a metropolitan centre with a medical school. Reading the Melanoma Clinical Practice Guidelines was associated with lower estimates of the amount of summer sun exposure required to obtain adequate vitamin D. Increasing years in practice was negatively associated with provision of recommended advice about summer and winter sun protection. Greater concern about vitamin D than skin cancer was expressed by females and those in practice longer. Concern about the potentially negative impact of skin cancer prevention on vitamin D status may undermine appropriate sun protective recommendations. Reading some educational resources was associated with confidence about vitamin D knowledge and a perception that significantly less summer sun exposure was required for those with high sun sensitivity to achieve adequate vitamin D, suggesting a potentially positive impact of such resources. Education could be targeted towards groups least likely to promote existing recommendations. Authoritative guidelines about vitamin D and sun protection would be a valued resource among GPs. Study findings are potentially valuable to help guide public policy and target interventions.


Evaluation of activity limitation and social participation, and the effects of reconstructive surgery in people with disability due to leprosy: a prospective cohort study.
To assess how activity limitation and social participation of individuals with leprosy-related disability change over time, and to quantify the effect of reconstructive surgery. Individuals with disability due to leprosy who accepted invitations for assessment at a leprosy clinic between March and July 2007 were interviewed using the SALSA Scale (measuring activity limitation) and the Participation Scale (assessing social participation). All participants were offered reconstructive surgery. Follow-up interviews were done 1 year after the first interview or 1 year after surgery. The main outcomes were changes in SALSA score and Participation score. We used analysis of variance to identify the effects of independent factors on mean SALSA and Participation scores. We interviewed 222 participants, 15 of whom took up the offer of surgery and 207 who did not. Comparison of SALSA Scale scores at baseline and 1 year revealed that activity limitation did not significantly change over time in individuals who declined surgery; however, participants who had surgery showed a significant improvement at 1 year (p < 0.001). Social participation improved over time in both groups, but the difference was significant only in the non-surgery group (p < 0.001). The findings suggest that reconstructive surgery has beneficial effects on functioning. Evaluation of the need for, and effect of, surgery in larger studies is recommended.


Excessive daytime sleepiness and adherence to antihypertensive medications among Blacks: analysis of the counseling African Americans to control hypertension (CAATCH) trial.
Excessive daytime sleepiness (EDS) often occurs as a result of insufficient sleep, sleep apnea, illicit substance use, and other medical and psychiatric conditions. This study tested the hypothesis that blacks exhibiting EDS would have poorer self-reported adherence to hypertensive medication using cross-sectional data from the Counseling African-Americans to Control Hypertension (CAATCH) trial. A total of 1,058 hypertensive blacks (average age 57±12 years) participated in CAATCH, a randomized controlled trial evaluating the effectiveness of a multilevel intervention for participants who receive care from community health centers in New York City. Data analyzed in this study included baseline sociodemographics, medical history, EDS, and medication adherence. We used the Epworth Sleepiness Scale, with a cutoff score of ≥10, to define EDS. Medication adherence was measured using an abbreviated Morisky Medication Adherence scale, with a score >0 indicating nonadherence. Of the sample, 71% were female, 72% received at least a high school education, 51% reported a history of smoking, and 33% had a history of alcohol consumption. Overall, 27% of the participants exhibited EDS, and 44% of those who exhibited EDS were classified as adherent to prescribed antihypertensive medications. Multivariable logistic regression analysis, adjusting for effects of age, body mass index, sex, education, and smoking and drinking history indicated that participants who exhibited EDS were more than twice as likely to be nonadherent (odds ratio 2.28, 95% confidence interval 1.42-3.67, P<0.001). Analysis of the CAATCH data showed a high prevalence of EDS among hypertensive blacks. EDS is a significant predictor of nonadherence to prescribed medications for hypertension. These findings point to a modifiable variable that can be targeted in future interventions focusing on medication adherence.


Revealing silent vibration modes of nanomaterials by detecting anti-Stokes hyper-Raman scattering with femtosecond laser pulses.
We proposed a scheme in which normal Raman scattering is coupled with hyper-Raman scattering for generating a strong anti-Stokes hyper-Raman scattering in nanomaterials by using femtosecond laser pulses. The proposal was experimentally demonstrated by using a single-layer MoS2 on a SiO2/Si substrate, a 17 nm-thick MoS2 on an Au/SiO2 substrate and a 9 nm-thick MoS2 on a SiO2-SnO2/Ag/SiO2 substrate which were confirmed to be highly efficient for second harmonic generation. A strong anti-Stokes hyper-Raman scattering was also observed in other nanomaterials possessing large second-order susceptibilities, such as silicon quantum dots self-assembled into "coffee" rings and tubular Cu-doped ZnO nanorods. In all the cases, many Raman inactive vibration modes were clearly revealed in the anti-Stokes hyper-Raman scattering. Apart from the strong anti-Stokes hyper-Raman scattering, Stokes hyper-Raman scattering with small Raman shifts was detected during the ablation process of thick MoS2 layers. It was also observed by slightly defocusing the excitation light. The detection of anti-Stokes hyper-Raman scattering may serve as a new technique for studying the Raman inactive vibration modes in nanomaterials.


Amide proton transfer CEST of the cervical spinal cord in multiple sclerosis patients at 3T.
The ability to evaluate pathological changes in the spinal cord in multiple sclerosis (MS) is limited because T1 - and T2 -w MRI imaging are not sensitive to biochemical changes in vivo. Amide proton transfer (APT) chemical exchange saturation transfer (CEST) can indirectly detect amide protons associated with proteins and peptides, potentially providing more pathological specificity. Here, we implement APT CEST in the cervical spinal cord of healthy and MS cohorts at 3T. APT CEST of the cervical spinal cord was obtained in a cohort of 10 controls and 10 MS patients using a novel respiratory correction methodology. APT was quantified using two methods: 1) APTw , based off the conventional magnetization transfer ratio asymmetry, and 2) ΔAPT, a spatial characterization of APT changes in MS patients relative to the controls. Respiratory correction yielded highly reproducible z-spectra in white matter (intraclass correlation coefficient = 0.82). APTw signals in normal-appearing white matter (NAWM) of MS patients were significantly different from healthy controls (P = 0.04), whereas ΔAPT of MS patients highlighted large APT differences in NAWM. Respiration correction in the spinal cord is necessary to accurately quantify APT CEST, which can provide unique biochemical information regarding disease processes within the spinal cord. Magn Reson Med 79:806-814, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Pharmacists and immunizations: a national survey.
To obtain information about pharmacists' current involvement in and willingness to provide immunization services, and to assess perceived barriers to providing immunization services. Cross-sectional mail survey. National. Random sample of 5,342 pharmacists from chain, independent, mass merchandiser/grocery, primary care clinic, and health maintenance organization settings. None. Responses to survey on pharmacy-based immunization services--current involvement, willingness to get involved, perceived obstacles, and patients' interest. Three mailings yielded a response rate of 25.3% (1,348 responses). Only 53.1% of respondents knew correctly whether their state allowed pharmacists to administer immunizations. Although a significant number of pharmacists were involved in immunization activities, such as counseling and promotion, only 2.2% and 0.9% of respondents were involved in actual administration of adult and childhood immunizations, respectively. In general, men, independents, owners/partners, and pharmacists who had attended immunization-related educational programs were more willing to provide immunization services than were women, chain and staff pharmacists, and educational program nonattendees. Pharmacists who had attended immunization-related educational programs also perceived pharmacist- and patient-related factors as less problematic for pharmacy-based immunization services than did nonattendees. This survey provides a baseline measure of the nature and extent of pharmacist involvement in immunizations that can be used now and in future years. The profession can use the findings on pharmacists' willingness to provide immunization services and their perception of obstacles to such services as a basis for targeted educational and promotional programs and materials.


Determination of superoxide dismutase mimetic activity in common culinary herbs.
Under conditions of oxidative stress, the removal of superoxide, a free radical associated with chronic inflammation, is catalysed by superoxide dismutase (SOD). Thus in addition to acting as an antioxidant, SOD may also be utilized as an anti-inflammatory agent. Some plant derived foods have been shown to have SOD mimetic (SODm) activity however it is not known if this activity is possessed by culinary herbs which have previously been shown to possess both antioxidant and anti-inflammatory properties. The aim of the study was to ascertain if the culinary herbs rosemary, sage and thyme possess SODm activity, and to investigate the influence of cooking and digestion on this activity. Transition metal ion content was also determined to establish if it could likely contribute to any SODm activity detected. All extracts of uncooked (U), cooked (C) and cooked and digested (C&D) herbs were shown to possess SODm activity, which was significantly correlated with previously determined antioxidant and anti-inflammatory activities of these herbs. SODm activity was significantly increased following (C) and (C&D) for rosemary and sage only. The impact of (C) and (C&D) on the SODm for thyme may have been influenced by its transition metal ion content. SODm activity may contribute to the herbs' antioxidant and anti-inflammatory activities however the source and significance of this activity need to be established.


Reduced intestinal tumorigenesis in APCmin mice lacking melanin-concentrating hormone.
Melanin-concentrating hormone (MCH) is an evolutionary conserved hypothalamic neuropeptide that in mammals primarily regulates appetite and energy balance. We have recently identified a novel role for MCH in intestinal inflammation by demonstrating attenuated experimental colitis in MCH deficient mice or wild type mice treated with an anti-MCH antibody. Therefore, targeting MCH has been proposed for the treatment of inflammatory bowel disease. Given the link between chronic intestinal inflammation and colorectal cancer, in the present study we sought to investigate whether blocking MCH might have effects on intestinal tumorigenesis that are independent of inflammation. Tumor development was evaluated in MCH-deficient mice crossed to the APCmin mice which develop spontaneously intestinal adenomas. A different cohort of MCH-/- and MCH+/+ mice in the APCmin background was treated with dextran sodium sulphate (DSS) to induce inflammation-dependent colorectal tumors. In Caco2 human colorectal adenocarcinoma cells, the role of MCH on cell survival, proliferation and apoptosis was investigated. APCmin mice lacking MCH developed fewer, smaller and less dysplastic tumors in the intestine and colon which at the molecular level are characterized by attenuated activation of the wnt/beta-catenin signaling pathway and increased apoptotic indices. Form a mechanistic point of view, MCH increased the survival of colonic adenocarcinoma Caco2 cells via inhibiting apoptosis, consistent with the mouse studies. In addition to modulating inflammation, MCH was found to promote intestinal tumorigenesis at least in part by inhibiting epithelial cell apoptosis. Thereby, blocking MCH as a therapeutic approach is expected to decrease the risk for colorectal cancer.


A Simple and Novel Fecal Biomarker for Colorectal Cancer: Ratio of Fusobacterium Nucleatum to Probiotics Populations, Based on Their Antagonistic Effect.
Gut microbial dysbiosis contributes to the development of colorectal cancer (CRC). We evaluated the utility of fecal bacterial biomarker candidates identified by our 16S rDNA sequencing analysis for CRC diagnosis. We measured the relative abundance of Fusobacterium nucleatum (Fn), Faecalibacterium prausnitzii (Fp), Bifidobacterium (Bb), and Lactobacillus (Lb) by quantitative PCR in fecal samples from 2 cohorts of 903 individuals. We evaluated and validated the diagnostic performance of these microbial ratios and investigated the antagonistic effect of Fn against 3 different indicator stains. The microbial ratio of Fn to Bb (Fn/Bb) had a superior sensitivity of 84.6% and specificity of 92.3% in detecting CRC (area under the curve, AUC = 0.911). The combination of Fn/Bb and Fn/Fp improved the diagnostic value (AUC = 0.943). Moreover, the combination of Fn/Bb and Fn/Fp offered 60.0% specificity and 90.0% sensitivity in detecting stage I of CRC (AUC = 0.804). In particular, Fn was negatively correlated with Fp in the CRC group. The performance for CRC diagnosis was confirmed in the validation cohort II. The culture supernatant from Fn exhibited strong bactericidal activity against probiotics Fp and Bb strains. This study found that Fn could play a role in microbiota dysbiosis via the secreted antagonistic substances against probiotics. Moreover, the ratio of Fn to the important probiotics Fp and Bb was identified as a valuable biomarker for screening early CRC.


Intravenous Ketamine Infusion for Complex Regional Pain Syndrome: Survey, Consensus, and a Reference Protocol.
To find and reach a consensus on the usage of ketamine in the treatment of complex regional pain syndrome and to determine a reference protocol for future studies. Three hundred fifty-one medical professionals participated in our survey on practice procedures, with 104 respondents providing information on their usage of ketamine for treating the pain associated with complex regional pain syndrome. Respondents answered questions about inpatient treatment, outpatient treatment, children vs adults, safety, and basic demographic information. An expert group then met to reach a consensus for a reference protocol. There is a difference in how inpatients are treated compared with outpatients, making it necessary to have two different reference protocols. The duration of pain relief varied from one to 10 days to one to six months, with a correlation between the duration of pain relief and total infusion hours per round. The consensus reference protocols are made up of nine recommended topics. Reference protocols need to be validated by extensive research before guidelines can be created.


Extracellular proteolysis alters tooth development in transgenic mice expressing urokinase-type plasminogen activator in the enamel organ.
By catalyzing plasmin formation, the urokinase-type plasminogen activator (uPA) can generate widespread extracellular proteolysis and thereby play an important role in physiological and pathological processes. Dysregulated expression of uPA during organogenesis may be a cause of developmental defects. Targeted epithelial expression of a uPA-encoding transgene under the control of the keratin type-5 promoter resulted in enzyme production by the enamel epithelium, which does not normally express uPA, and altered tooth development. The incisors of transgenic mice were fragile, chalky-white and, by scanning electron microscopy, their labial surface appeared granular. This phenotype was attributed to a defect in enamel formation during incisor development, resulting from structural and functional alterations of the ameloblasts that differentiate from the labial enamel epithelium. Immunofluorescence revealed that disorganization of the ameloblast layer was associated with a loss of laminin-5, an extracellular matrix molecule mediating epithelial anchorage. Amelogenin, a key protein in enamel formation, was markedly decreased at the enamel-dentin junction in transgenics, presumably because of an apparent alteration in the polarity of its secretion. In addition, increased levels of active transforming growth factor-beta could be demonstrated in mandibles of transgenic mice. Since the alterations detected could be attributed to uPA catalytic activity, this model provides evidence as to how dysregulated proteolysis, involving uPA or other extracellular proteases, may have developmental consequences such as those leading to enamel defects.


Using hierarchical cluster models to systematically identify groups of jobs with similar occupational questionnaire response patterns to assist rule-based expert exposure assessment in population-based studies.
Rule-based expert exposure assessment based on questionnaire response patterns in population-based studies improves the transparency of the decisions. The number of unique response patterns, however, can be nearly equal to the number of jobs. An expert may reduce the number of patterns that need assessment using expert opinion, but each expert may identify different patterns of responses that identify an exposure scenario. Here, hierarchical clustering methods are proposed as a systematic data reduction step to reproducibly identify similar questionnaire response patterns prior to obtaining expert estimates. As a proof-of-concept, we used hierarchical clustering methods to identify groups of jobs (clusters) with similar responses to diesel exhaust-related questions and then evaluated whether the jobs within a cluster had similar (previously assessed) estimates of occupational diesel exhaust exposure. Using the New England Bladder Cancer Study as a case study, we applied hierarchical cluster models to the diesel-related variables extracted from the occupational history and job- and industry-specific questionnaires (modules). Cluster models were separately developed for two subsets: (i) 5395 jobs with ≥1 variable extracted from the occupational history indicating a potential diesel exposure scenario, but without a module with diesel-related questions; and (ii) 5929 jobs with both occupational history and module responses to diesel-relevant questions. For each subset, we varied the numbers of clusters extracted from the cluster tree developed for each model from 100 to 1000 groups of jobs. Using previously made estimates of the probability (ordinal), intensity (µg m(-3) respirable elemental carbon), and frequency (hours per week) of occupational exposure to diesel exhaust, we examined the similarity of the exposure estimates for jobs within the same cluster in two ways. First, the clusters' homogeneity (defined as >75% with the same estimate) was examined compared to a dichotomized probability estimate (<5 versus ≥5%; <50 versus ≥50%). Second, for the ordinal probability metric and continuous intensity and frequency metrics, we calculated the intraclass correlation coefficients (ICCs) between each job's estimate and the mean estimate for all jobs within the cluster. Within-cluster homogeneity increased when more clusters were used. For example, ≥80% of the clusters were homogeneous when 500 clusters were used. Similarly, ICCs were generally above 0.7 when ≥200 clusters were used, indicating minimal within-cluster variability. The most within-cluster variability was observed for the frequency metric (ICCs from 0.4 to 0.8). We estimated that using an expert to assign exposure at the cluster-level assignment and then to review each job in non-homogeneous clusters would require ~2000 decisions per expert, in contrast to evaluating 4255 unique questionnaire patterns or 14983 individual jobs. This proof-of-concept shows that using cluster models as a data reduction step to identify jobs with similar response patterns prior to obtaining expert ratings has the potential to aid rule-based assessment by systematically reducing the number of exposure decisions needed. While promising, additional research is needed to quantify the actual reduction in exposure decisions and the resulting homogeneity of exposure estimates within clusters for an exposure assessment effort that obtains cluster-level expert assessments as part of the assessment process.


Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis.
Prostaglandins derived from the cyclooxygenase (COX) pathway and epoxyeicosatrienoic acids (EETs) from the cytochrome P450/soluble epoxide hydrolase (sEH) pathway are important eicosanoids that regulate angiogenesis and tumorigenesis. COX-2 inhibitors, which block the formation of prostaglandins, suppress tumor growth, whereas sEH inhibitors, which increase endogenous EETs, stimulate primary tumor growth and metastasis. However, the functional interactions of these two pathways in cancer are unknown. Using pharmacological inhibitors as probes, we show here that dual inhibition of COX-2 and sEH synergistically inhibits primary tumor growth and metastasis by suppressing tumor angiogenesis. COX-2/sEH dual pharmacological inhibitors also potently suppress primary tumor growth and metastasis by inhibiting tumor angiogenesis via selective inhibition of endothelial cell proliferation. These results demonstrate a critical interaction of these two lipid metabolism pathways on tumorigenesis and suggest dual inhibition of COX-2 and sEH as a potential therapeutic strategy for cancer therapy.


The eukaryotic translation initiation factor eIF4E elevates steady-state m7G capping of coding and noncoding transcripts.
Methyl-7-guanosine (m7G) "capping" of coding and some noncoding RNAs is critical for their maturation and subsequent activity. Here, we discovered that eukaryotic translation initiation factor 4E (eIF4E), itself a cap-binding protein, drives the expression of the capping machinery and increased capping efficiency of ∼100 coding and noncoding RNAs. To quantify this, we developed enzymatic (cap quantification; CapQ) and quantitative cap immunoprecipitation (CapIP) methods. The CapQ method has the further advantage that it captures information about capping status independent of the type of 5' cap, i.e., it is not restricted to informing on m7G caps. These methodological advances led to unanticipated revelations: 1) Many RNA populations are inefficiently capped at steady state (∼30 to 50%), and eIF4E overexpression increased this to ∼60 to 100%, depending on the RNA; 2) eIF4E physically associates with noncoding RNAs in the nucleus; and 3) approximately half of eIF4E-capping targets identified are noncoding RNAs. eIF4E's association with noncoding RNAs strongly positions it to act beyond translation. Coding and noncoding capping targets have activities that influence survival, cell morphology, and cell-to-cell interaction. Given that RNA export and translation machineries typically utilize capped RNA substrates, capping regulation provides means to titrate the protein-coding capacity of the transcriptome and, for noncoding RNAs, to regulate their activities. We also discovered a cap sensitivity element (CapSE) which conferred eIF4E-dependent capping sensitivity. Finally, we observed elevated capping for specific RNAs in high-eIF4E leukemia specimens, supporting a role for cap dysregulation in malignancy. In all, levels of capping RNAs can be regulated by eIF4E.


Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study.
To characterise whether some selective serotonin reuptake inhibitor (SSRI) antidepressants reduce tamoxifen's effectiveness by inhibiting its bioactivation by cytochrome P450 2D6 (CYP2D6). Population based cohort study. Women living in Ontario aged 66 years or older treated with tamoxifen for breast cancer between 1993 and 2005 who had overlapping treatment with a single SSRI. Risk of death from breast cancer after completion of tamoxifen treatment, as a function of the proportion of time on tamoxifen during which each SSRI had been co-prescribed. Of 2430 women treated with tamoxifen and a single SSRI, 374 (15.4%) died of breast cancer during follow-up (mean follow-up 2.38 years, SD 2.59). After adjustment for age, duration of tamoxifen treatment, and other potential confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine (an irreversible inhibitor of CYP2D6) were associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (P<0.05 for each comparison). By contrast, no such risk was seen with other antidepressants. We estimate that use of paroxetine for 41% of tamoxifen treatment (the median overlap in our sample) would result in one additional breast cancer death within five years of cessation of tamoxifen for every 19.7 (95% confidence interval 12.5 to 46.3) patients so treated; the risk with more extensive overlap would be greater. Paroxetine use during tamoxifen treatment is associated with an increased risk of death from breast cancer, supporting the hypothesis that paroxetine can reduce or abolish the benefit of tamoxifen in women with breast cancer.


Low-dose human chorionic gonadotropin during the proliferative phase may adversely affect endometrial receptivity in oocyte recipients.
The effect of low-dose human chorionic gonadotropin (hCG) administration in the proliferative phase of oocyte recipients was investigated in a prospective randomized trial. Sibling oocytes from the same donor were shared at random among two different recipients. In group I oocyte recipients received 750 IU of hCG every three days concomitant to endometrial preparation with estradiol until hCG injection to the donor, whereas in group II recipients received no hCG during endometrial priming with estradiol. Endometrial thickness was significantly lower in group I compared with group II, although similar endometrial thickness was detected during the mock cycle. Pregnancy rates were significantly lower in group I than in group II (13.6% vs. 45.4%, p<0.05). Implantation rates were also significantly lower in group I (1.7% vs. 22.4%, p<0.01). The study was discontinued prematurely for ethical reasons when 22 cycles were completed, as pregnancy rates were very low in group I. In conclusion, hCG administration in the proliferative phase might directly affect endometrial proliferation and receptivity.


Formation of Carbon Monoxide during Seed Germination and Seedling Growth.
Carbon monoxide was formed during the growth of cucumber seedlings in the dark in atmospheres containing 5 percent oxygen or less, but not by aerobic seedlings. The highest level recorded was 6000 ppm. Carbon monoxide was also formed by Euphorbia. Germinating seeds of rye, cucumber, and other species also produced carbon monoxide at levels of 10 to 25 ppm.


Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial.
To compare the safety and efficacy of two once-daily antiretroviral regimens containing lamivudine (3TC) or tenofovir disoproxil fumarate (TDF), each administered with didanosine (ddI) and efavirenz (EFV) as initial therapy to HIV-1-infected subjects. Single centre, randomized (1: 1), open-label study in antiretroviral-naive, HIV-infected adults. Subjects commenced either 3TC/ddI/EFV (3TC group) or TDF/ddI/EFV (TDF group). Safety, Medication Event Monitoring System (MEMScap) and plasma EFV concentration monitoring was performed over the study period. Comparisons between groups were assessed using chi test and linear regression analysis was used to assess the relationship between EFV concentrations and virological response. Seventy-seven subjects were enrolled prior to recruitment being suspended, 36 to the 3TC group and 41 to the TDF group. Intention-to-treat analysis in which last observation carried forward (LOCF) found the mean viral log10 load [95% confidence interval (CI)] at weeks 4 and 12 to be 2.67 (2.47-2.87) and 1.83 (1.74-1.92) for the 3TC group and 2.75 (2.45-3.05) and 2.28 (1.96-2.6) for the TDF group (P = 0.013). Emergence of resistance occurred in five of 41 (12.2%) subjects in the TDF group up to week 12 compared with none of 36 in the 3TC group, (P < 0.05); these five subjects shared similar baseline characteristics (CD4+ cell counts < 200 x 10 cells/l and HIV-1 RNA > 100,000 copies/ml). Despite MEMScap monitoring showing > 99% adherence in all subjects, among the five failures, three had low EFV concentrations. TDF/ddI/EFV as initial therapy appears to have diminished efficacy in subjects with CD4 < 200 x 10 cells/l and viral load > 100,000 copies/ml. Treatment failure with resistance was not attributable to baseline resistance, efavirenz exposure or poor adherence.


Melanocortin 1-receptor (MC1R) mutations are associated with plumage colour in chicken.
The co-segregation of plumage colour and sequence polymorphism in the melanocortin 1-receptor gene (MC1R) was investigated using an intercross between the red junglefowl and White Leghorn chickens. The results provided compelling evidence that the Extended black (E) locus controlling plumage colour is equivalent to MC1R. E/MC1R was assigned to chromosome 11 with overwhelming statistical support. Sequence analysis indicated that the E92K substitution, causing a constitutively active receptor in the sombre mouse, is the most likely causative mutation for the Extended black allele carried by the White Leghorn founders in this intercross. The MC1R sequence associated with the recessive buttercup (ebc) allele indicated that this allele evolved from a dominant Extended black allele as it shared the E92K and M71T substitutions with some E alleles. It also carried a third missense mutation H215P which thus may interfere with the constitutive activation of the receptor caused by E92K (and possibly M71T).


Structure, function and dynamics in the mur family of bacterial cell wall ligases.
For bacteria, the structural integrity of its cell wall is of utmost importance for survival, and to this end, a rigid scaffold called peptidoglycan, comprised of sugar molecules and peptides, is synthesized and located outside the cytoplasmic membrane of the cell. Disruption of this peptidoglycan layer has for many years been a prime target for effective antibiotics, namely the penicillins and cephalosporins. Because this rigid layer is synthesized by a multi-step pathway numerous additional targets also exist that have no counterpart in the animal cell. Central to this pathway are four similar ligase enzymes, which add peptide groups to the sugar molecules, and interrupting these steps would ultimately prove fatal to the bacterial cell. The mechanisms of these ligases are well understood and the structures of all four of these ligases are now known. A detailed comparison of these four enzymes shows that considerable conformational changes are possible and that these changes, along with the recruitment of two different N-terminal binding domains, allows these enzymes to bind a substrate which at one end is identical and at the other has the growing polypeptide tail. Some insights into the structure-function relationships in these enzymes is presented.


Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type.
The lifelong accumulation of somatic mutations underlies age-related phenotypes and cancer. Mutagenic forces are thought to shape the genome of aging cells in a tissue-specific way. Whole genome analyses of somatic mutation patterns, based on both types and genomic distribution of variants, can shed light on specific processes active in different human tissues and their effect on the transition to cancer. To analyze somatic mutation patterns, we compile a comprehensive genetic atlas of somatic mutations in healthy human cells. High-confidence variants are obtained from newly generated and publicly available whole genome DNA sequencing data from single non-cancer cells, clonally expanded in vitro. To enable a well-controlled comparison of different cell types, we obtain single genome data (92% mean coverage) from multi-organ biopsies from the same donors. These data show multiple cell types that are protected from mutagens and display a stereotyped mutation profile, despite their origin from different tissues. Conversely, the same tissue harbors cells with distinct mutation profiles associated to different differentiation states. Analyses of mutation rate in the coding and non-coding portions of the genome identify a cell type bearing a unique mutation pattern characterized by mutation enrichment in active chromatin, regulatory, and transcribed regions. Our analysis of normal cells from healthy donors identifies a somatic mutation landscape that enhances the risk of tumor transformation in a specific cell population from the kidney proximal tubule. This unique pattern is characterized by high rate of mutation accumulation during adult life and specific targeting of expressed genes and regulatory regions.


Association of Genetic Risk of Obesity with Postoperative Complications Using Mendelian Randomization.
The extent to which obesity and genetics determine postoperative complications is incompletely understood. We performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990 and 2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome-wide genotyping data to the Electronic Medical Records and Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease-9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score was constructed from 97 obesity-risk single-nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk of obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components. Individuals with overweight or obese BMI (≥25 kg/m2) had increased risk of incisional hernia (odds ratio [OR] 1.7-5.5, p < 3.1 × 10-20), and people with obesity (BMI ≥ 30 kg/m2) had increased risk of postoperative infection (OR 1.2-2.3, p < 2.5 × 10-5). In the eMERGE cohort, genetically predicted BMI was associated with incisional hernia (OR 2.1 [95% CI 1.8-2.5], p = 1.4 × 10-6) and postoperative infection (OR 1.6 [95% CI 1.4-1.9], p = 3.1 × 10-6). Association findings were similar after limitation of the cohorts to those who underwent abdominal procedures. Clinical and Mendelian randomization studies suggest that obesity, as measured by BMI, is associated with the development of postoperative incisional hernia and infection.


The 3D Genome Shapes the Regulatory Code of Developmental Genes.
We revisit the notion of gene regulatory code in embryonic development in the light of recent findings about genome spatial organization. By analogy with the genetic code, we posit that the concept of code can only be used if the corresponding adaptor can clearly be identified. An adaptor is here defined as an intermediary physical entity mediating the correspondence between codewords and objects in a gratuitous and evolvable way. In the context of the gene regulatory code, the encoded objects are the gene expression levels, while the concentrations of specific transcription factors in the cell nucleus provide the codewords. The notion of code is meaningful in the absence of direct physicochemical relationships between the objects and the codewords, when the mediation by an adaptor is required. We propose that a plausible adaptor for this code is the gene domain, that is, the genome segment delimited by topological insulators and comprising the gene and its enhancer regulatory sequences. We review recent evidences, based on genome-wide chromosome conformation capture experiments, showing that preferential contact domains found in metazoan genomes are the physical traces of gene domains. Accordingly, genome 3D folding plays a direct role in shaping the developmental gene regulatory code.


Atomic-resolution electrochemistry with the atomic force microscope: copper deposition on gold.
The atomic force microscope (AFM) was used to image an electrode surface at atomic resolution while the electrode was under potential control in a fluid electrolyte. A new level of subtlety was observed for each step of a complete electrochemical cycle that started with an Au(111) surface onto which bulk Cu was electrodeposited. The Cu was stripped down to an underpotential-deposited monolayer and finally returned to a bare Au(111) surface. The images revealed that the underpotential-deposited monolayer has different structures in different electrolytes. Specifically, for a perchloric acid electrolyte the Cu atoms are in a close-packed lattice with a spacing of 0.29 +/- 0.02 nanometer (nm). For a sulfate electrolyte they are in a more open lattice with a spacing of 0.49 +/- 0.02 nm. As the deposited Cu layer grew thicker, the Cu atoms converged to a (111)-oriented layer with a lattice spacing of 0.26 +/- 0.02 nm for both electrolytes. A terrace pattern was observed during dissolution of bulk Cu. Images were obtained of an atomically resolved Cu monolayer in one region and an atomically resolved Au substrate in another in which a 30 degrees rotation of the Cu monolayer lattice from the Au lattice is clearly visible.


A meta-analysis of sensory modulation symptoms in individuals with autism spectrum disorders.
Sensory modulation symptoms are common in persons with autism spectrum disorders (ASD); however have a heterogeneous presentation. Results from 14 studies indicated a significant high difference between ASD and typical groups in the presence/frequency of sensory symptoms, with the greatest difference in under-responsivity, followed by over-responsivity and sensation seeking. Three moderators that reduced the variability in findings among studies were: chronological age, severity of autism, and type of control group. Sensory differences were highest for studies of children ages 6-9 years, samples with more than 80% with an autism diagnosis, and compared to a CA matched versus a MA or DD matched group. It is important to consider these moderators in the design of studies and interventions addressing sensory symptoms.


Hypothermia Inhibits the Expression of Receptor Interacting Protein Kinases 1 and 3 After Transient Spinal Cord Ischaemia in Rabbits.
Necroptosis, a form of regulated necrosis, might be a potential mechanism of delayed paraplegia; therefore, its role in transient spinal cord ischaemia was investigated by immunohistochemical analysis of necroptosis related protein receptor interacting protein kinase (RIP) 1, RIP3, and cellular inhibitor of apoptosis protein (cIAP) 1/2. This study used rabbit normothermic (n = 24) and hypothermic (n = 24) transient spinal cord ischaemia models and sham controls (n = 6). Neurological function was assessed according to a modified Tarlov score at 8 h, 1, 2, and 7 days after reperfusion (n = 6 each). Morphological changes in the spinal cord were examined using haematoxylin and eosin staining in the sham, 2, and 7 day groups. Western blot and histochemical analyses of RIP1, RIP3, and cIAP1/2, and double label fluorescent immunocytochemical studies of RIP3 and cIAP1/2 were performed at 8 h, 1, and 2 days after reperfusion (n = 6 each). There were significant differences in neurological function between the normothermic and hypothermic groups (median scores 0 and 5 at 7 days, p = .023). In the normothermic group, most motor neurons were lost seven days after reperfusion (p = .046 compared with sham), but they were preserved in the hypothermic group. Western blot analysis revealed the upregulation of RIP1, RIP3, and cIAP1/2 at 8 h in the normothermic group (RIP1, p = .032; RIP3, p < .001; cIAP1/2, p = .041 compared with sham), and the overexpression of RIP3 was prolonged for two days. In the hypothermic group, the expression of these proteins was not observed. The double label fluorescent immunocytochemical study revealed the induction of RIP3 and cIAP1/2 in the same motor neurons. These data suggest that transient normothermic ischaemia induces necroptosis, a potential factor in delayed motor neuron death, and that hypothermia may inhibit necroptosis.


The "July Effect": A Look at July Medical Admissions in Teaching Hospitals.
We examined the effect of admission for myocardial infarction, heart failure, or pneumonia during the first academic quarter compared with all other quarters in teaching versus nonteaching hospitals on length of stay, cost, and mortality. Using data 2011 Nationwide Inpatient Sample, multivariable modeling with an interaction term was used to test teaching hospital effect by academic quarter. Logistic regression was used for mortality and log-transformed linear models for cost and length of stay. Charlson Index scores were similar in teaching and nonteaching hospitals. Patients admitted to teaching hospitals for myocardial infarction in the first quarter had a higher risk-adjusted mortality (1.217; confidence interval, 1.147-1.290) than those admitted to a nonteaching hospital during the same quarter (0.849; confidence interval, 0.815-0.885). Mean cost heart failure admissions averaged $584 more, and the mean length of stay was longer (0.10; P = .0127), during the first academic quarter. These effects were not present for quarters 2 through 4. This study suggests small increases in mortality among patients admitted with myocardial infarction in the first academic quarter compared with all other quarters in teaching versus nonteaching hospitals. Increased cost and longer stay were seen for those admitted with heart failure.


Telomere length in Parkinson's disease: A meta-analysis.
Parkinson's disease (PD) is a common and severe movement disorder. Differences in telomere length (TL) have been reported as possible risk factors for several neuropsychiatric disorders, including PD. Results from published studies for TL in PD are inconsistent, highlighting the need for a meta-analysis. In the current work, a meta-analysis of published studies for TL in PD was carried out. PubMed, Web of Science and Google Scholar databases were used to identify relevant articles that reported TL in groups of PD patients and controls. A random-effects model was used for meta-analytical procedures. The meta-analysis included eight primary studies, derived from populations of European and Asian descent, and did not show a significant difference in TL between 956 PD patients and 1284 controls (p value: 0.246). Our results show that there is no consistent evidence of shorter telomeres in PD patients and suggest the importance of future studies on TL and PD that analyze other populations and also include assessment of TL from different brain regions.


Amplification of genes for chorion proteins during oogenesis in Drosophila melanogaster.
The endochorion and exochorion of Drosophila eggs are synthesized by the ovarian follicle cells during a brief period of about 5 hr. In this terminal phase of egg chamber development, the structural genes for several abundant chorion proteins are expressed at high levels according to a temporally regulated program. The female-sterile mutation ocelliless maps at the site of the genes for two of these proteins, the 36,000- and 38,000-dalton chorion proteins (c36 and c38), which are closely linked. The mutation results in a cis-acting reduction in the amounts of c36 and c38 that accumulate in late-stage egg chambers. We have investigated the mechanism that underlies this decreased production by using cDNA clones complementary to these gene sequences. Unexpectedly, it was found that, in normal females, the genes for c36, c38, and at least one other chorion protein are specifically amplified more than 10-fold in the DNA of late-stage egg chambers. The extra replication involves at least some adjacent chromosomal sequences and begins prior to the onset of mRNA and protein synthesis. The additional DNA remains stable after gene expression has ceased. The behavior of these genes is thus reminiscent of the properties of the DNA puffs that have been described in several groups of Diptera. The extent of amplification of c36 and c38, but not of the 18,000-dalton chorion protein c18 (which is unlinked), was decreased in the egg chambers of flies homozygous for ocelliless, suggesting that altered gene dosage may be responsible for the decreased synthesis of chorion proteins in the mutant.


A Novel Glycolipid Biosurfactant Confers Grazing Resistance upon Pantoea ananatis BRT175 against the Social Amoeba Dictyostelium discoideum.
Pantoea is a versatile genus of bacteria with both plant- and animal-pathogenic strains, some of which have been suggested to cause human infections. There is, however, limited knowledge on the potential determinants used for host association and pathogenesis in animal systems. In this study, we used the model host Dictyostelium discoideum to show that isolates of Pantoea ananatis exhibit differential grazing susceptibility, with some being resistant to grazing by the amoebae. We carried out a high-throughput genetic screen of one grazing-resistant isolate, P. ananatis BRT175, using the D. discoideum pathosystem to identify genes responsible for the resistance phenotype. Among the 26 candidate genes involved in grazing resistance, we identified rhlA and rhlB, which we show are involved in the biosynthesis of a biosurfactant that enables swarming motility in P. ananatis BRT175. Using liquid chromatography-mass spectrometry (LC-MS), the biosurfactant was shown to be a glycolipid with monohexose-C10-C10 as the primary congener. We show that this novel glycolipid biosurfactant is cytotoxic to the amoebae and is capable of compromising cellular integrity, leading to cell lysis. The production of this biosurfactant may be important for bacterial survival in the environment and could contribute to the establishment of opportunistic infections. IMPORTANCE The genetic factors used for host interaction by the opportunistic human pathogen Pantoea ananatis are largely unknown. We identified two genes that are important for the production of a biosurfactant that confers grazing resistance against the social amoeba Dictyostelium discoideum. We show that the biosurfactant, which exhibits cytotoxicity toward the amoebae, is a glycolipid that incorporates a hexose rather than rhamnose. The production of this biosurfactant may confer a competitive advantage in the environment and could potentially contribute to the establishment of opportunistic infections.


Prolonged swimming exercise training induce hypophosphatemic osteopenia in stroke-prone spontaneously hypertensive rats (SHRSP).
Stroke-prone spontaneously hypertensive rats (SHRSP) induce spontaneous osteoporosis. To elucidate the specific characteristics of bone metabolism, the SHRSP was compared with age matched Wistar-Kyoto (WKY) rats. We investigated the effects of prolonged swimming exercise training on bone mineral density (BMD) and metabolism in the SHRSP. Seven-week-old male SHRSP and WKY were divided into three groups; the sedentary control WKY group (n = 6, WKY), the sedentary control SHRSP group (n = 6, SP) and the swimming exercise training SHRSP group (n = 6, SWIM) (in pool with 60 min./day, 5 days/week for 12 weeks). The femoral BMD, bone mineral content (BMC), strength, Ca and P contents (%) of SHRSP were approximately 17, 27, 25, 20 and 9%, respectively, lower than that of WKY (p < 0.001). Serum alkaline phosphatase (AlP) had not changed between both of SP and WKY, but tartrate-resistant acid phosphatase (TrAcP) of SP approximately 3-fold higher than that of WKY (p < 0.05). Both serum calcium (Ca) and intact parathyroid hormone (i-PTH) were similar between SP and WKY. However, serum phosphate (P) of SP was approximately 18% lower than that of WKY (N.S.). These results suggested that SHRSP induces osteopenia by the bone turnover of the promoted osteoclast activity with disturbed phosphate homeostasis. On the other hand, the femoral BMD and strength were approximately 7% and 20%, respectively, decreased in the SWIM (p < 0.001), and femoral bone Ca and P contents (%) were also approximately 11% and 14%, respectively, lower than that of SP (p < 0.001). There were no significant difference between SWIM and SP on serum Ca, but serum P of SWIM was significantly lower than that of SP (p < 0.05). These results suggested that the prolonged swimming exercise training in the SHRSP induces more cruelly hypophosphatemia, and leading to osteopenia eventually. We conclude that SHRSP induces osteopenia with disturbance of phosphate homeostasis, and the prolonged swimming exercise in the SHRSP might deteriorate hypophosphatemia and osteopenia.


All-atom 3D structure prediction of transmembrane β-barrel proteins from sequences.
Transmembrane β-barrels (TMBs) carry out major functions in substrate transport and protein biogenesis but experimental determination of their 3D structure is challenging. Encouraged by successful de novo 3D structure prediction of globular and α-helical membrane proteins from sequence alignments alone, we developed an approach to predict the 3D structure of TMBs. The approach combines the maximum-entropy evolutionary coupling method for predicting residue contacts (EVfold) with a machine-learning approach (boctopus2) for predicting β-strands in the barrel. In a blinded test for 19 TMB proteins of known structure that have a sufficient number of diverse homologous sequences available, this combined method (EVfold_bb) predicts hydrogen-bonded residue pairs between adjacent β-strands at an accuracy of ∼70%. This accuracy is sufficient for the generation of all-atom 3D models. In the transmembrane barrel region, the average 3D structure accuracy [template-modeling (TM) score] of top-ranked models is 0.54 (ranging from 0.36 to 0.85), with a higher (44%) number of residue pairs in correct strand-strand registration than in earlier methods (18%). Although the nonbarrel regions are predicted less accurately overall, the evolutionary couplings identify some highly constrained loop residues and, for FecA protein, the barrel including the structure of a plug domain can be accurately modeled (TM score = 0.68). Lower prediction accuracy tends to be associated with insufficient sequence information and we therefore expect increasing numbers of β-barrel families to become accessible to accurate 3D structure prediction as the number of available sequences increases.


A Review of Glass-Ionomer Cements for Clinical Dentistry.
This article is an updated review of the published literature on glass-ionomer cements and covers their structure, properties and clinical uses within dentistry, with an emphasis on findings from the last five years or so. Glass-ionomers are shown to set by an acid-base reaction within 2-3 min and to form hard, reasonably strong materials with acceptable appearance. They release fluoride and are bioactive, so that they gradually develop a strong, durable interfacial ion-exchange layer at the interface with the tooth, which is responsible for their adhesion. Modified forms of glass-ionomers, namely resin-modified glass-ionomers and glass carbomer, are also described and their properties and applications covered. Physical properties of the resin-modified glass-ionomers are shown to be good, and comparable with those of conventional glass-ionomers, but biocompatibility is somewhat compromised by the presence of the resin component, 2 hydroxyethyl methacrylate. Properties of glass carbomer appear to be slightly inferior to those of the best modern conventional glass-ionomers, and there is not yet sufficient information to determine how their bioactivity compares, although they have been formulated to enhance this particular feature.


Compliance with walking aid use in children with cerebral palsy in India.
A 3-mo prospective descriptive study of 50 Indian ambulant children with cerebral palsy using different types of walkers or elbow crutches was done to determine compliance with use of the prescribed device. Children were between 6 and 16 yrs of age and of either sex. Data were collected by means of proxy log entries made by the child's caregivers throughout the day. The data collected consisted of the number of times and the distance the child walked each time with or without the prescribed walking aid. Compliance was taken as the number of times the child used the walking aid during ambulation. Overall mean compliance was 49.1%. Children using the reciprocal walker showed the greatest compliance (60.2%), whereas those using elbow crutches (34.9%) and walkers with gutter attachments (14.8%) showed the least. Compliance was greatest for distances of 50-100 m (57.5%), whereas it was the least for distances of >150 m (25.9%).


MoS2 nano flakes with self-adaptive contacts for efficient thermoelectric energy harvesting.
We examine the potential of the low-dimensional material MoS2 for the efficient conversion of waste heat to electricity via the Seebeck effect. Recently monolayer MoS2 nano flakes with self-adaptive Mo6S6 contacts were formed, which take advantage of mechanical stability and chemical covalent bonding to the MoS2. Here, we study the thermoelectric properties of these junctions by calculating their conductance, thermopower and thermal conductance due to both electrons and phonons. We show that thermoelectric figures of merit ZT as high as ∼2.8 are accessible in these junctions, independent of the flake size and shape, provided the Fermi energy is close to a band edge. We show that Nb dopants as substituents for Mo atoms can be used to tune the Fermi energy, and despite the associated inhomogeneous broadening, room temperature values as high as ZT ∼ 0.6 are accessible, increasing to 0.8 at 500 K.


Combination treatment of intravenous immunoglobulin and cultivated oral mucosal epithelial transplantation for ocular cicatricial pemphigoid.
Ocular cicatricial pemphigoid (OCP) is a progressive cicatrising autoimmune disease affecting the skin and mucous membranes, including ocular surface epithelia. Although systemic immunosuppression is advocated, both progression of ocular surface inflammation and systemic side effects remain a problem. For the treatment of an active OCP, both control of autoimmune reaction and ocular surface reconstruction are necessary. We believe that the combination of intravenous immunoglobulin (IVIg) and cultivated oral mucosal epithelial transplantation (COMET) is a powerful treatment modality while minimising the risk of postoperative consequences inevitably associated with immunosuppression. A patient with OCP successfully treated by a combination of IVIg and COMET is described here.


Serious infections in a population-based cohort of 86,039 seniors with rheumatoid arthritis.
To assess risk and risk factors for serious infections in seniors with rheumatoid arthritis (RA) using a case-control study nested within an RA cohort. We assembled a retrospective RA cohort age ≥66 years from Ontario health administrative data across 1992-2010. Nested case-control analyses were done, comparing RA patients with a primary diagnosis of infection (based on hospital or emergency department records) to matched RA controls. We assessed independent effects of drugs, adjusting for demographics, comorbidity, and markers of RA severity. A total of 86,039 seniors with RA experienced 20,575 infections, for a rate of 46.4 events/1,000 person-years. The most frequently occurring events included respiratory infections, herpes zoster, and skin/soft tissue infections. Factors associated with infection included higher comorbidity, rural residence, markers of disease severity, and history of previous infection. In addition, anti-tumor necrosis factor agents and disease-modifying antirheumatic drugs were associated with a several-fold increase in infections, with an adjusted odds ratio (OR) ranging from 1.2-3.5. The drug category with the greatest effect estimate was glucocorticoids, which exhibited a clear dose response with an OR ranging from 4.0 at low doses to 7.6 at high doses. Seniors with RA have significant morbidity related to serious infections, which exceeds previous reports among younger RA populations. Rural residence, higher comorbidity, markers of disease severity, and previous infection were associated with serious infections in seniors with RA. Our results emphasize that many RA drugs may increase the risk of infection, but glucocorticoids appear to confer a particular risk.


Ovulatory responses and plasma luteinizing hormone concentrations in dairy heifers after treatment with exogenous progesterone and estradiol benzoate.
The objectives of this experiment were to determine the effects of 0.5 mg estradiol benzoate, administered intramuscularly 24 h after removal of CIDR-B progesterone containing intravaginal devices, on the time to estrus, ovulation and peak LH concentration in dairy heifers. Ovulatory responses and plasma LH concentrations were examined using 14 Friesian dairy heifers in 2 separate treatment periods. All heifers received a CIDR-B progesterone-containing intravaginal device with an attached 10-mg estradiol benzoate capsule for 12 d. Within each period, 24 h after CIDR-B removal, 7 heifers received an intramuscular injection of 0.5 mg estradiol benzoate while the remaining 7 heifers received an intramuscular injection of a placebo. Blood samples for LH assay were collected at 0, 6 and 12 h, and then every 4 h for 60 h after estradiol injection. Detection of estrus was conducted at 4-h intervals, and ultrasonographical examination to detect ovulation was conducted every 8 h for 88 h after removal of the CIDR-B device. Treatment with estradiol benzoate tended to reduce the time from device removal to the LH peak in Period 1 (median time to LH peak 40.1 vs 63.9 h; P = 6.07). In Period 2, treatment with estradiol had no significant effect on the time to the LH peak, standing estrus or ovulation. We hypothesize that the period effect was due to the stage of cycle at the time of treatment. For heifers treated in Period 1, the stage of cycle was random. However, because of the prior synchronization of estrus, which was implicit in the experimental design, heifers in Period 2 tended to be in late diestrus. The administration of estradiol benzoate after treatment with exogenous progesterone appears to overcome the variability in timing of LH peaks typically occurring in a herd of synchronized heifers due to different stages of follicular development.


Altered social and non-social decision-making in recreational and dependent cocaine users.
Maladaptive decision-making is assumed to be a core feature of cocaine addiction. Indeed, numerous studies have reported deficits in non-social decision-making tasks and reward-related impulsivity in dependent cocaine users. However, social decision-making has not been examined in cocaine users yet. Moreover, it is unknown if even recreational and non-dependent cocaine use is linked to decision-making deficits. Therefore, we investigated whether recreational and dependent cocaine users exhibit alterations in social and non-social decision-making. The performance of healthy controls (n = 68), recreational cocaine users (n = 68) and dependent cocaine users (n = 30) in classical decision-making paradigms (Iowa Gambling Task, Delay Discounting) and in social interaction paradigms (Distribution Game, Dictator Game) was assessed. Decisions in the social interaction tasks of both cocaine user groups were more self-serving compared with controls as cocaine users preferred higher monetary payoffs for themselves. In the Iowa Gambling Task, only dependent cocaine users were more likely to choose disadvantageous card decks, reflecting worse decision-making. They were also more likely to choose immediate smaller rewards over larger delayed rewards in the Delay Discounting task. Our results imply that both recreational and dependent cocaine users are more concerned with their own monetary gain when interacting with another person. Furthermore, primarily dependent cocaine users are less foresighted and more impulsive regarding immediate reward. Overall, social interaction deficits are already present in recreational users, while non-social decision-making deficits occur predominantly in dependent cocaine users. Thus, social interaction training and cognitive remediation strategies may improve treatment success and quality of life in cocaine dependence.


Opportunities and challenges for modelling epidemiological and evolutionary dynamics in a multihost, multiparasite system: Zoonotic hybrid schistosomiasis in West Africa.
Multihost multiparasite systems are evolutionarily and ecologically dynamic, which presents substantial trans-disciplinary challenges for elucidating their epidemiology and designing appropriate control. Evidence for hybridizations and introgressions between parasite species is gathering, in part in line with improvements in molecular diagnostics and genome sequencing. One major system where this is becoming apparent is within the Genus Schistosoma, where schistosomiasis represents a disease of considerable medical and veterinary importance, the greatest burden of which occurs in sub-Saharan Africa. Interspecific hybridizations and introgressions bring an increased level of complexity over and above that already inherent within multihost, multiparasite systems, also representing an additional source of genetic variation that can drive evolution. This has the potential for profound implications for the control of parasitic diseases, including, but not exclusive to, widening host range, increased transmission potential and altered responses to drug therapy. Here, we present the challenging case example of haematobium group Schistosoma spp. hybrids in West Africa, a system involving multiple interacting parasites and multiple definitive hosts, in a region where zoonotic reservoirs of schistosomiasis were not previously considered to be of importance. We consider how existing mathematical model frameworks for schistosome transmission could be expanded and adapted to zoonotic hybrid systems, exploring how such model frameworks can utilize molecular and epidemiological data, as well as the complexities and challenges this presents. We also highlight the opportunities and value such mathematical models could bring to this and a range of similar multihost, multi and cross-hybridizing parasites systems in our changing world.


Noise-resilient estimation of optical flow by use of overlapped basis functions.
Conventional techniques for the computation of optical flow from image gradients are used to formulate the problem as a nonlinear optimization that comprises a gradient constraint term and a field smoothness factor. The results of these techniques are often erroneous, highly sensitive to noise and numerical precision, determined sparsely, and computationally expensive. We regularize the gradient constraint equation by modeling optical flow as a linear combination of a set of overlapped basis functions. We develop a theory for estimating model parameters robustly and reliably. We prove that the extended-least-squares solution proposed here is unbiased and robust to small perturbations in the gradient estimates and to mild deviations from the gradient constraint. Our solution is obtained with a numerically stable sparse matrix inversion, which gives a reliable flow-field estimate over the entire frame. To validate our claims, we perform a series of experiments on standard benchmark data sets at a range of noise levels. Overall, our algorithm outperforms by a wide margin the others considered in the comparison. We demonstrate the applicability of our algorithm to image mosaicking and to motion superresolution through experiments on noisy compressed sequences. We conclude that our flow-field model offers greater accuracy and robustness than conventional optical flow techniques in a variety of situations and permits real-time operation.


Estimating Functional Connectivity Networks via Low-Rank Tensor Approximation With Applications to MCI Identification.
Functional connectivity network (FCN) has become an increasingly important approach to gain a better understanding of the brain, as well as discover informative biomarkers for diagnosis of neurodegenerative diseases. Due to its importance, many FCN estimation methods have been developed in the past decades, including methods based on the classical Pearson's correlation, (regularized) partial correlation, and some higher-order variants. However, most of the existing methods estimate one FCN at a time, thus ignoring the possibly shared structure among FCNs from different subjects. Recently, researchers introduce group constraints (or population priors) into FCN estimation by assuming that FCNs are topologically identical across subjects. Obviously, such a constraint/prior is too strong to be satisfied in practice, especially when both patients and healthy subjects are involved simultaneously in the group. To address this problem, we propose a novel FCN estimation approach based on an assumption that the involved FCNs have similar but not necessarily identical topology. More specifically, we implement this idea under a two-step learning framework. First, we independently estimate FCNs based on traditional methods, such as Pearson's correltion and sparse representation, making sure that each FCN captures the specific properties of the corresponding subject. Then, we stack the estimated FCNs (in fact, their adjacency matrices) into a tensor, and refine the stacked FCNs via low-rank tensor approximation. Finally, we apply the improved FCNs to identify subjects with mild cognitive impairment (MCI) from healthy controls, and achieve a higher classification accuracy.


Isolation and primary characterization of an amidase from Rhodococcus rhodochrous.
Amidase (EC 18.104.22.168) was purified to homogeneity from Rhodococcus rhodochrous M8 using isopropanol fractionation and exchange chromatography on Mono Q. The isolated amidase consists of four identical subunits with molecular weight 42+/-2 kD. The activity of the enzyme is maximal at 55-60 degrees C and within the pH range 5-8. The amidase from R. rhodochrous M8 is highly sensitive to such sulfhydryl reagents as Hg2+ and Cu2+. Chelators (EDTA and o-phenanthroline) and serine proteinase inhibitors (PMSF and DIFP) did not inhibit the activity of the enzyme. The enzyme exhibits hydrolytic and acyl transferase activity and does not possess urease activity. Aliphatic amides (acetamide and propionamide) were the best substrates for the amidase from R. rhodochrous M8, whereas bulky aromatic amides were poor substrates of this enzyme. The properties of the isolated enzyme are similar to those found in the corresponding amidase from Arthrobacter sp. J-1 and an amidase with wide substrate specificity from Brevibacterium sp. R312.


The effect of diet and time after bacterial infection on fecundity, resistance, and tolerance in Drosophila melanogaster.
Mounting and maintaining an effective immune response in the face of infection can be costly. The outcome of infection depends on two host immune strategies: resistance and tolerance. Resistance limits pathogen load, while tolerance reduces the fitness impact of an infection. While resistance strategies are well studied, tolerance has received less attention, but is now considered to play a vital role in host-pathogen interactions in animals. A major challenge in ecoimmunology is to understand how some hosts maintain their fitness when infected while others succumb to infection, as well as how extrinsic, environmental factors, such as diet, affect defense. We tested whether dietary restriction through yeast (protein) limitation affects resistance, tolerance, and fecundity in Drosophila melanogaster. We predicted that protein restriction would reveal costs of infection. Because infectious diseases are not always lethal, we tested resistance and tolerance using two bacteria with low lethality: Escherichia coli and Lactococcus lactis. We then assayed fecundity and characterized bacterial infection pathology in individual flies at two acute phase time points after infection. As expected, our four fecundity measures all showed a negative effect of a low-protein diet, but contrary to predictions, diet did not affect resistance to either bacteria species. We found evidence for diet-induced and time-dependent variation in host tolerance to E. coli, but not to L. lactis. Furthermore, the two bacteria species exhibited remarkably different infection profiles, and persisted within the flies for at least 7 days postinfection. Our results show that acute phase infections do not necessarily lead to fecundity costs despite high bacterial loads. The influence of intrinsic variables such as genotype are the prevailing factors that have been studied in relation to variation in host tolerance, but here we show that extrinsic factors should also be considered for their role in influencing tolerance strategies.


Stability and digestibility of one- or bi-layered medium-chain triglyceride emulsions with gum Arabic and whey protein isolates by pancreatic lipase in vitro.
Interfacial engineering approaches have been used to design functional foods so as to control lipase-induced digestion of emulsified lipids and release of bioactive lipophilic components in the gastrointestinal tract. In this study, emulsion droplets with the interface stabilized with gum Arabic (GA) and whey protein isolate (WPI) were prepared by mixing or sequential adsorption. WPI/GA intramolecular soluble complexes (ISCs) have superior emulsifying properties in stabilizing oil-in-water emulsions. The impact of the interfaces for WPI/GA ISC-layered (one-layered) and double-layered emulsions formed by sequential deposition of WPI or GA on the lipolysis of emulsions was investigated using an in vitro simulated gastrointestinal model. Transglutaminase and dithiothreitol were introduced to crosslink the interfacial proteins and improve the interfacial stability. The ISC-layered emulsion was less stable to aggregation than the double-layered ones in simulated gastric fluid due to dissociation of ISCs caused by the electrostatic screening of ions and proteolysis of interfacial proteins driven by pepsin. The ISC-layered emulsion conferred a significant slower rate and extent of lipid digestion compared to the double-layered emulsions post gastric proteolysis (P < 0.05). It is presumed for the ISC-layered emulsion that the destabilization to aggregation and coalescence within the simulated gastrointestinal fluids and the steric hindrance of the robust and thick interfacial layer might contribute to delaying free fatty acids release. It suggests that both the initial interfacial properties and the stability of the emulsified lipid droplets within the simulated gastrointestinal fluids play an important role in determining the rate and extent of lipid digestion. It is predicted that direct destabilization of emulsified lipids using interfacial engineering approaches has the potential of modifying lipid digestibility or bioactive release at specific sites within the gastrointestinal tract.


Advanced monitoring of systemic hemodynamics in critically ill patients with acute brain injury.
Hemodynamic monitoring is widely used in critical care; however, the impact of such intervention in patients with acute brain injury (ABI) remains unclear. Using PubMed, a systematic review was performed (1966-August 2013), and 118 studies were included. Data were extracted using the PICO approach. The evidence was classified, and recommendations were developed according to the GRADE system. Electrocardiography and invasive monitoring of arterial blood pressure should be the minimal hemodynamic monitoring required in unstable or at-risk patients in the intensive care unit. Advanced hemodynamic monitoring (i.e., assessment of preload, afterload, cardiac output, and global systemic perfusion) could help establish goals that take into account cerebral blood flow and oxygenation, which vary depending on diagnosis and disease stage. Choice of techniques for assessing preload, afterload, cardiac output, and global systemic perfusion should be guided by specific evidence and local expertise. Hemodynamic monitoring is important and has specific indications among ABI patients. Further data are necessary to understand its potential for therapeutic interventions and prognostication.