A dual-spectrometer approach to reflectance measurements under sub-optimal sky conditions.
This paper presents a practical method for the development of spectral reflectance libraries under sub-optimal sky conditions. Although there are commercially available spectrometers which simultaneously measure both downwelling and upwelling radiance to mitigate the impact of sub-optimal sky conditions, these spectrometers only record in the visible and near infra-red. There are presently no commercially available spectrometers with this capability that can record the visible through short-wave infra-red. This paper presents a practical method of recording and processing data using coordinated measurements from two full-range spectrometers and discusses potential pitfalls and solutions required to achieve accurate reflectance spectra. Results demonstrate that high-quality spectral reflectance libraries can be developed with this approach.


Iron-catalyzed protodehalogenation of alkyl and aryl halides using hydrosilanes.
A simple and efficient iron-catalyzed protodehalogenation of alkyl and aryl halides using phenylhydrosilane is disclosed. The reaction utilizes FeCl3 without the requirement of ligands. Unactivated alkyl and aryl halides were successfully reduced in good yields; sterically hindered tertiary halides were also reduced including the less reactive chlorides. The scalability of this methodology was demonstrated by a gram-scale synthesis with a catalyst loading as low as 0.5 mol%. Notably, disproportionation of phenylsilane leads to diphenylsilane that further reduces the halides. Preliminary mechanistic studies revealed a non-radical pathway and the source of hydrogen is PhSiH3via deuterium labeling studies. Our methodology represents simplicity and provides a good alternative to typical tin, aluminum and boron hydride reagents.


Cannulation practices at haemodialysis initiation via an arteriovenous fistula or arteriovenous graft.
A functioning long-term vascular access is required for haemodialysis therapy; however, establishing this can be challenging in the setting of advanced age and vessels damaged by diabetes. Complications include the inability to insert two needles for the treatment resulting in miscannulation trauma and in some cases insertion of a temporary central venous access device. The broad objective of this review is to define the evidence base regarding cannulation practices in the initiation of haemodialysis via an arteriovenous fistula or an arteriovenous graft. This review uses the framework recommended by the Joanna Briggs Institute and the process by which papers were included or excluded followed the standard Preferred Reporting Items for Systematic Reviews and Meta-Analyses group approach. A total of 20 primary research studies met the inclusion criteria. Cannulation in the 10- to 15-week period rather than delaying past this time frame is associated with the best outcomes. New vascular access given time to mature through single-needle haemodialysis treatments may improve long-term patency. Duplex ultrasound mapping prior to initiation of cannulation supports the clinical decision-making process on timing of and selection of cannulation sites. Cannulation trauma at the initiation of haemodialysis could potentially be reduced with a strategy of incremental haemodialysis using single-needle treatment supported with duplex ultrasonography assessment to 'map' the vascular access as a guide for clinicians prior to cannulation initiation.


[Long-term survival of patients with acute myocardial infarction in Iceland].
Despite the decreasing incidence rate of acute coronary syndromes worldwide, the incidence of NSTEMI (Non- ST elevation myocardial infarction) has increased relative to STEMI (ST elevation myocardial infarction). The aim of this study was to compare long-term survival rates of NSTEMI and STEMI patients and to explore the effects of risk factors on survival. All patients hospitaized for acute myocardial infarction at Landspitali University Hospital during the calendar year of 2006 were included in the study. Information about risk factors was obtained using electronic medical records. The primary endpoint was all cause mortality, the secondary endpoint was defined as death or myocardial infartion. Patients were followed up to January 1st 2015. Among 447 patients diagnosed with acute myocardial infarction in Iceland in 2006, 280 patients were diagnosed with NSTEMI (I21.4) and 167 with STEMI (I21, I21.9). NSTEMI and STEMI incidence rates per 100.000 inhabitants in Iceland were 91.3 and 55.9, respectively. The mean age of NSTEMI patients was 73.0 years, women were on average 8.4 years older than men. The mean age of STEMI patients was 65.3 years, women were on average 7.3 years older than men. The five-year survival rate for NSTEMI patients was 51%, 42% among women and 57% among men. The five-year survival rate for STEMI patients was 77%, 68% among women and 80% among men. Five year age-adjusted survival rates were higher for STEMI than NSTEMI (logrank: p <0.01). The incidence of NSTEMI was higher than that of STEMI in Iceland in 2006. The worse prognosis of women as compared to men was due to the higher mean age of women. Overall, long-term survival of NSTEMI patients was worse than that of STEMI patients even after adjustment for difference in age.


An efficient synergistic cancer therapy by integrating cell cycle inhibitor and photosensitizer into polydopamine nanoparticles.
Multifunctional nanomedicines are highly demanded in the development of new cancer theranostic approaches to achieve more effective and safer treatment. Herein, we designed a polydopamine (PDA) nanoparticle by loading with cell cycle inhibitor nocodazole (NOC) and photosensitizer ZnPc(TAP)4 12+ (ZnPc12+) for simultaneous tumor imaging and efficient synergistic therapy. It was found that the loaded NOC can facilitate enhanced nuclear uptake of ZnPc12+ in MCF-7 cells, resulting in PDA-NOC-ZnPc12+ nanoparticles not only inhibiting cell proliferation and inducing cell cycle G2/M arrest, but also improving photodynamic therapy (PDT) efficacy. Compared with the respective single anticancer action, PDA-NOC-ZnPc12+ nanoparticles exhibited better anticancer efficacy in tumor-bearing mice, demonstrating the synergistic effect of combination therapy with a cell cycle inhibitor and photosensitizer. Particularly, PDA-NOC-ZnPc12+ resulted in a high accumulation of ZnPc12+ in tumors but low retention in livers, without rendering distinct toxicity to the treated animals. Such PDA-based nanocarriers functionalized with dual-drug loading and bioimaging may have great potential for diagnosis and combination therapy of cancer.


Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics.
Quantitative morphometric determinations of neuronal and glial density, neuron-glia ratios, and neuronal size were performed in the prefrontal, anterior cingulate, and primary motor cortex of ten controls and ten schizophrenics diagnosed by Feighner criteria under blind conditions to assess whether neuronal degeneration had occurred. Stepwise multiple regression and multiple classification analyses were used to evaluate the effect of potential confounding variables such as age, postmortem interval, fixation, hypoxia, and neuroleptic exposure on the measures studied. The neuronal density was significantly lower in layer VI of the prefrontal, layer V of the cingulate, and layer III of motor cortex. There was also a trend toward fewer neurons in most layers of both prefrontal and motor cortex, although by discriminant analysis this generalized pattern was significant only for the prefrontal area. The glial density also tended to be lower throughout most layers of all three cortical regions. There were no differences in the neuron-glia ratios or neuronal size between the two groups. The data do not support the presence of neuronal degeneration in schizophrenic cortex as it is conventionally described by neuropathologists, but do suggest the possibility that cytoarchitectural variations in cortical structure might exist in this group of schizophrenics.


Analysis of the upstream activating sequence and site of carbon and nitrogen source repression in the promoter of an early-induced sporulation gene of Bacillus subtilis.
The transcription from the spoVG promoter of Bacillus subtilis is induced at the start of the stationary phase of growth and is dependent on the expression of the spoOA, spoOB, and spoOH genes. It is repressed in cells grown in the presence of excess glucose and glutamine and is under the negative control of the abrB gene. The spoOA and spoOB gene products function to suppress the negative control exerted by abrB. Transcription initiation requires the form of RNA polymerase holoenzyme that contains the spoOH gene product, sigma H. Optimal transcription also requires an upstream A-T-rich region termed the upstream activating sequence (UAS). The mechanism of UAS function was examined through mutational analysis of the spoVG promoter region. Deletion of the UAS or positioning the UAS one half turn or one full turn of the DNA helix upstream of its location in wild-type spoVG resulted in a severe reduction in promoter activity. Deletion of most of the UAS abolished the abrB-dependent repression of spoVG transcription. Higher activity was observed when the UAS was inserted 10 bp (one turn of the helix) upstream than when the sequence was repositioned either 5 or 13 bp upstream. Sequences upstream of the UAS were found not to be involved with the position-dependent function of the UAS. Positioning the UAS 42 or 116 bp upstream eliminated the stimulatory effect of the sequence on spoVG transcription. These data indicate that the UAS functions effectively when it is in close proximity to the -35 region. In vitro transcription analysis indicated that the deletion and insertion mutation affecting the UAS impair RNA polymerase-spoVG promoter interaction. Deletion of the UAS showed that the negative effect of exogenous glucose and glutamine is not dependent on the UAS but is exerted at a site within or near the -35 and -10 regions.


Metatranscriptomics reveals the molecular mechanism of large granule formation in granular anammox reactor.
Granules enriched with anammox bacteria are essential in enhancing the treatment of ammonia-rich wastewater, but little is known about how anammox bacteria grow and multiply inside granules. Here, we combined metatranscriptomics, quantitative PCR and 16S rRNA gene sequencing to study the changes in community composition, metabolic gene content and gene expression in a granular anammox reactor with the objective of understanding the molecular mechanism of anammox growth and multiplication that led to formation of large granules. Size distribution analysis revealed the spatial distribution of granules in which large granules having higher abundance of anammox bacteria (genus Brocadia) dominated the bottom biomass. Metatranscriptomics analysis detected all the essential transcripts for anammox metabolism. During the later stage of reactor operation, higher expression of ammonia and nitrite transport proteins and key metabolic enzymes mainly in the bottom large granules facilitated anammox bacteria activity. The high activity resulted in higher growth and multiplication of anammox bacteria and expanded the size of the granules. This conceptual model for large granule formation proposed here may assist in the future design of anammox processes for mainstream wastewater treatment.


Mechanistic studies comparing the incorporation of (+) and (-) isomers of 3TCTP by HIV-1 reverse transcriptase.
Among the nucleoside inhibitors used clinically as anti-HIV drugs which target HIV-1 reverse transcriptase (RT), (-)-2', 3'-dideoxy-3'-thiacytidine [(-)SddC or 3TC] is the only analogue with the unnatural L(-) nucleoside configuration. 3TC has been shown to be more potent and less toxic than the D(+) isomer, (+)SddC, which has the natural nucleoside configuration. The mechanistic basis for the stereochemical selectivity and differential toxicity of the isomeric SddC compounds is not completely understood although a number of factors may clearly come into play including differences in uptake, metabolic activation, degradation, and transport. We used a pre-steady-state kinetic analysis to determine the maximum rate of incorporation, kpol, nucleotide-binding affinity, Kd, and efficiency of incorporation, kpol/Kd, for the (-) and (+) isomeric SddCTP compounds as well as the corresponding dideoxy and natural nucleoside triphosphates into a primer-template complex using HIV-1 reverse transcriptase. The affinity (Kd) of the dNTP was much tighter and the efficiency (kpol/Kd) of incorporation by enzyme into the primer-template complex was much higher for the DNA/RNA primer-template compared to DNA/DNA. The maximum rate of incorporation, kpol, followed the trend of dCTP > ddCTP > (+)SddCTP > (-)SddCTP while the Kd values determined for the DNA/RNA primer-template followed the order (-)SddCTP congruent with (+)SddCTP congruent with ddCTP > dCTP. The corresponding efficiency of incorporation followed the trend dCTP > ddCTP > (+)SddCTP > (-)SddCTP. These data suggest that perturbations on the ribose ring of cytidine analogues (C --> S) decrease the rate and efficiency of incorporation but enhance the binding affinity. These results are discussed in the context of a computer modeled structure of the ternary complexes of RT, DNA/RNA primer-template, and SddCTP analogues as well as implications for structure-activity relationships and further drug design. This information provides a mechanistic basis for understanding the inhibition of HIV-1 reverse transcriptase by 3TC.


Social signals and algorithmic trading of Bitcoin.
The availability of data on digital traces is growing to unprecedented sizes, but inferring actionable knowledge from large-scale data is far from being trivial. This is especially important for computational finance, where digital traces of human behaviour offer a great potential to drive trading strategies. We contribute to this by providing a consistent approach that integrates various datasources in the design of algorithmic traders. This allows us to derive insights into the principles behind the profitability of our trading strategies. We illustrate our approach through the analysis of Bitcoin, a cryptocurrency known for its large price fluctuations. In our analysis, we include economic signals of volume and price of exchange for USD, adoption of the Bitcoin technology and transaction volume of Bitcoin. We add social signals related to information search, word of mouth volume, emotional valence and opinion polarization as expressed in tweets related to Bitcoin for more than 3 years. Our analysis reveals that increases in opinion polarization and exchange volume precede rising Bitcoin prices, and that emotional valence precedes opinion polarization and rising exchange volumes. We apply these insights to design algorithmic trading strategies for Bitcoin, reaching very high profits in less than a year. We verify this high profitability with robust statistical methods that take into account risk and trading costs, confirming the long-standing hypothesis that trading-based social media sentiment has the potential to yield positive returns on investment.


Feasibility of quantitative pain assessment in outpatient oncology practice.
Although physicians view failure to assess pain systematically as the most important barrier to outpatient cancer pain management, little is known about pain assessment in this setting. We sought to determine whether pain is routinely assessed and whether routine quantitative pain assessment is feasible in a busy outpatient oncology practice. We conducted a pre- and postintervention chart review of 520 randomly selected medical and radiation oncology patient visits at a community hospital-based private outpatient practice. The intervention consisted of training health assistants (HAs) to measure and document patient pain scores by using a visual analog scale. The main outcome measures included HA documentation of patient pain scores, quantitative and qualitative mention of pain in the physician note, and analgesic treatment before and after the intervention. After the intervention, HA documentation of pain scores increased from 1% to 75.6% (P < .0001). Physician documentation increased from 0% to 4.8% for quantitative documentation (P < .01), and from 60.0% to 68.3% for qualitative documentation (not significant). Of all the patients, 23.1% reported significant pain. Subgroups with greater pain included patients actively receiving radiation treatments and patients with lung cancer. Of patients with significant pain, 28.2% had no mention of pain in the physician note and 47.9% had no documented analgesic treatment. Quantitative pain assessment was virtually absent before our intervention but easily implemented and sustained in a busy outpatient oncology practice. Pain score collection identified a high prevalence of pain, patient subgroups at risk for pain, and a significant proportion of patients with pain that was neither evaluated nor treated by their oncologists.


Deuterated Polyunsaturated Fatty Acids Reduce Oxidative Stress and Extend the Lifespan of C. elegans.
Chemically reinforced essential fatty acids (FAs) promise to fight numerous age-related diseases including Alzheimer's, Friedreich's ataxia and other neurological conditions. The reinforcement is achieved by substituting the atoms of hydrogen at the bis-allylic methylene of these essential FAs with the isotope deuterium. This substitution leads to a significantly slower oxidation due to the kinetic isotope effect, inhibiting membrane damage. The approach has the advantage of preventing the harmful accumulation of reactive oxygen species (ROS) by inhibiting the propagation of lipid peroxidation while antioxidants potentially neutralize beneficial oxidative species. Here, we developed a model system to mimic the human dietary requirement of omega-3 in Caenorhabditis elegans to study the role of deuterated polyunsaturated fatty acids (D-PUFAs). Deuterated trilinolenin [D-TG(54:9)] was sufficient to prevent the accumulation of lipid peroxides and to reduce the accumulation or ROS. Moreover, D-TG(54:9) significantly extended the lifespan of worms under normal and oxidative stress conditions. These findings demonstrate that D-PUFAs can be used as a food supplement to decelerate the aging process, resulting in extended lifespan.


Facial affect recognition and exit examination performance in medical students: a prospective exploratory study.
Facial affect recognition (FAR) abilities underpin emotional intelligence (EI). The latter is suggested to predict academic success and to be important for clinician-patient interaction. It is therefore of interest to investigate the possible association between FAR and academic performance in undergraduate medical students. We assessed the association between the ability to recognize emotions through facial expression and exit examination performance, a measure of clinical proficiency, in undergraduate medical students stratified by gender at a South African tertiary institution using a prospective descriptive design. Data on the perception of facial expressions and exit examination marks were obtained from 144 (61%) females and 93 (39%) males with a mean age of 24.1 ± 1.6 years. Facial affect recognition measures on the Hexagon and Animation tasks were individually correlated with academic performance indicators using Pearson correlation. The perceptual discrimination of anger was associated with improved performance in anaesthetics (r = .24; p = .004) and urology (r = .24; p = .001), while the recognition of happiness was associated with decreased performance in obstetrics (r = -.21, p = .002). Gender was an effect modifier in the relationship between perceptual discrimination of anger and urology performance (p = .03), with a strong positive relationship for males, but a non-significant relationship for females. There was no overall correlation between FAR and overall academic performance or with gender. However, subject (specialty) specific findings with recognition of specific emotions and with gender as effect modifier poses interesting questions about EI and FAR and prompts further research into FAR as a useful tool. Being an objective test and offering a more focused assessment makes FAR worthy of further application.


Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma.
Adenosine potentiates mast cell activation, but the receptor type and molecular mechanisms involved have not been defined. We, therefore, investigated the effects of adenosine on the human mast cell line HMC-1. Both the A2a selective agonist CGS21680 and the A2a/A2b nonselective agonist 5'-N-ethylcarboxamidoadenosine (NECA) increased cAMP, but NECA was fourfold more efficacious and had a Hill coefficient of 0.55, suggesting the presence of both A2a and A2b receptors. NECA 10 microM evoked IL-8 release from HMC-1, but CGS21680 10 microM had no effect. In separate studies we found that enprofylline, an antiasthmatic previously thought to lack adenosine antagonistic properties, is as effective as theophylline as an antagonist of A2b receptors at concentrations achieved clinically. Both theophylline and enprofylline 300 micro completely blocked the release of IL-8 by NECA. NECA, but not CGS21680, increases inositol phosphate formation and intracellular calcium mobilization through a cholera and pertussis toxin-insensitive mechanism. In conclusion, both A2a and A2b receptors are present in HMC-1 cells and are coupled to adenylate cyclase. In addition, A2b receptors are coupled to phospholipase C and evoke IL-8 release. This effect is blocked by theophylline and enprofylline, raising the possibility that this mechanism contributes to their antiasthmatic effects.


Metabolic consequences of long-term rapamycin exposure on common marmoset monkeys (Callithrix jacchus).
Rapamycin has been shown to extend lifespan in rodent models, but the effects on metabolic health and function have been widely debated in both clinical and translational trials. Prior to rapamycin being used as a treatment to extend both lifespan and healthspan in the human population, it is vital to assess the side effects of the treatment on metabolic pathways in animal model systems, including a closely related non-human primate model. In this study, we found that long-term treatment of marmoset monkeys with orally-administered encapsulated rapamycin resulted in no overall effects on body weight and only a small decrease in fat mass over the first few months of treatment. Rapamycin treated subjects showed no overall changes in daily activity counts, blood lipids, or significant changes in glucose metabolism including oral glucose tolerance. Adipose tissue displayed no differences in gene expression of metabolic markers following treatment, while liver tissue exhibited suppressed G6Pase activity with increased PCK and GPI activity. Overall, the marmosets revealed only minor metabolic consequences of chronic treatment with rapamycin and this adds to the growing body of literature that suggests that chronic and/or intermittent rapamycin treatment results in improved health span and metabolic functioning. The marmosets offer an interesting alternative animal model for future intervention testing and translational modeling.


The prevalence and determinants of undiagnosed and diagnosed type 2 diabetes in middle-aged irish adults.
The prevalence of type 2 diabetes within the Republic of Ireland is poorly defined, although a recent report suggested 135,000 cases in adults aged 45+, with approximately one-third of these undiagnosed. This study aims to assess the prevalence of undiagnosed and diagnosed diabetes in middle-aged adults, and compare features related to either condition, in order to investigate why certain individuals remain undetected. This was a cross-sectional study involving a sample of 2,047 men and women, aged between 50-69 years, randomly selected from a large primary care centre. Univariate logistic regression was used to explore socio-economic, metabolic and other health related variable associations with undiagnosed or diagnosed diabetes. A final multivariate analysis was used to determine odds ratios and 95% confidence intervals for having undiagnosed compared to diagnosed diabetes, adjusted for gender, age and significant covariates determined from univariate models. The total prevalence of diabetes was 8.5% (95% CI: 7.4%-8.8%); 72 subjects (3.5%) had undiagnosed diabetes (95% CI: 2.8%-4.4%) and 102 subjects (5.0%) had diagnosed diabetes (95% CI: 4.1%-6.0%). Obesity, dyslipidaemia, and family history of diabetes were positively associated with both undiagnosed and diagnosed type 2 diabetes. Compared with diagnosed subjects, study participants with undiagnosed diabetes were significantly more likely to have low levels of physical activity and were less likely to be on treatment for diabetes-related conditions or to have private medical insurance. The prevalence of diabetes within the Cork and Kerry Diabetes and Heart Disease Study is comparable to recent estimates from the Slán National Health and Lifestyle Survey, a study which was nationally representative of the general population. A considerable proportion of diabetes cases were undiagnosed (41%), emphasising the need for more effective detection strategies and equitable access to primary healthcare.


Transforming Retinal Photographs to Entropy Images in Deep Learning to Improve Automated Detection for Diabetic Retinopathy.
Entropy images, representing the complexity of original fundus photographs, may strengthen the contrast between diabetic retinopathy (DR) lesions and unaffected areas. The aim of this study is to compare the detection performance for severe DR between original fundus photographs and entropy images by deep learning. A sample of 21,123 interpretable fundus photographs obtained from a publicly available data set was expanded to 33,000 images by rotating and flipping. All photographs were transformed into entropy images using block size 9 and downsized to a standard resolution of 100 × 100 pixels. The stages of DR are classified into 5 grades based on the International Clinical Diabetic Retinopathy Disease Severity Scale: Grade 0 (no DR), Grade 1 (mild nonproliferative DR), Grade 2 (moderate nonproliferative DR), Grade 3 (severe nonproliferative DR), and Grade 4 (proliferative DR). Of these 33,000 photographs, 30,000 images were randomly selected as the training set, and the remaining 3,000 images were used as the testing set. Both the original fundus photographs and the entropy images were used as the inputs of convolutional neural network (CNN), and the results of detecting referable DR (Grades 2-4) as the outputs from the two data sets were compared. The detection accuracy, sensitivity, and specificity of using the original fundus photographs data set were 81.80%, 68.36%, 89.87%, respectively, for the entropy images data set, and the figures significantly increased to 86.10%, 73.24%, and 93.81%, respectively (all p values <0.001). The entropy image quantifies the amount of information in the fundus photograph and efficiently accelerates the generating of feature maps in the CNN. The research results draw the conclusion that transformed entropy imaging of fundus photographs can increase the machinery detection accuracy, sensitivity, and specificity of referable DR for the deep learning-based system.


Measuring potential predictors of burnout and engagement among young veterinary professionals; construction of a customised questionnaire (the Vet-DRQ).
The Job Demands-Resources model (JD-R model) was used as the theoretical basis of a tailormade questionnaire to measure the psychosocial work environment and personal resources of recently graduated veterinary professionals. According to the JD-R model, two broad categories of work characteristics that determine employee wellbeing can be distinguished: job demands and job resources. Recently, the JD-R model has been expanded by integrating personal resource measures into the model. Three semistructured group interviews with veterinarians active in different work domains were conducted to identify relevant job demands, job resources and personal resources. These demands and resources were organised in themes (constructs). For measurement purposes, a set of questions ('a priori scale') was selected from the literature for each theme. The full set of a priori scales was included in a questionnaire that was administered to 1760 veterinary professionals. Exploratory factor analysis and reliability analysis were conducted to arrive at the final set of validated scales (final scales). 860 veterinarians (73 per cent females) participated. The final set of scales consisted of seven job demands scales (32 items), nine job resources scales (41 items), and six personal resources scales (26 items) which were considered to represent the most relevant potential predictors of work-related wellbeing in this occupational group. The procedure resulted in a tailormade questionnaire: the Veterinary Job Demands and Resources Questionnaire (Vet-DRQ). The use of valid theory and validated scales enhances opportunities for comparative national and international research.


Pre-clinical evaluation of a 213Bi-labeled 2556 antibody to HIV-1 gp41 glycoprotein in HIV-1 mouse models as a reagent for HIV eradication.
Any strategy for curing HIV infection must include a method to eliminate viral-infected cells. Based on our earlier proof-of-principle results targeting HIV-1 infected cells with radiolabeled antibody (mAb) to gp41 viral antigen, we embarked on identifying a suitable candidate mAb for preclinical development. Among the several human mAbs to gp41 tested, mAb 2556 was found to have high affinity, reactivity with multimeric forms of gp41 present on both the surface of virus particles and cells expressing HIV-1 Env, and recognition of a highly conserved epitope of gp41 shared by all HIV-1 subtypes. Also, mAb 2556 was the best in competition with HIV-1+ serum antibodies, which is an extremely important consideration for efficacy in the treatment of HIV patients. When radiolabeled with alpha-emitting radionuclide 213-Bismuth ((213)Bi) - (213)Bi-2556 efficiently and specifically killed ACH-2 human lymphocytes chronically infected with HIV-1, and HIV-1 infected human peripheral blood mononuclear cells (hPBMCs). The number of binding sites for (213)Bi-2556 on the surface of the infected cells was >10(6). The in vivo experiments were performed in two HIV-1 mouse models--splenic and intraperitoneal. In both models, the decrease in HIV-1 infected hPBMCs from the spleens and peritoneum, respectively, was dose-dependent with the most pronounced killing of hPBMCs observed in the 100 µCi (213)Bi-2556 group (P = 0.01). Measurement of the blood platelet counts and gross pathology of the treated mice demonstrated the lack of toxicity for (213)Bi-2556. We describe the preclinical development of a novel radiolabeled mAb reagent that could potentially be part of an HIV eradication strategy that is ready for translation into the clinic as the next step in its development. As viral antigens are very different from "self" human antigens - this approach promises high selectivity, increased efficacy and low toxicity, especially in comparison to immunotoxins.


Assessment of the characterization of nonabsorbing nanoparticles in suspension from effective optical properties.
We analyze a method recently proposed to retrieve the size, refractive index, and concentration of particles in nonabsorbing nanofluids from measurements of the complex effective refractive index of two dilutions of the nanofluid [Opt. Lett.39, 559 (2014)]. The method uses simple formulas to retrieve the particles' parameters. First, we discuss precautions needed with the new method when inferring the refractive index of the particles from measurements of the imaginary part of the effective refractive index of two dilutions of the original nanofluid. Then we analyze the use of this methodology to obtain some average radius in the size of polydisperse suspensions and in the case of suspensions of weakly absorbing particles. We also perform an error analysis considering fixed errors in measurements and calculating the errors in the retrieved size, refractive index, and concentration of particles. Finally, we characterize experimentally nanofluids of polymeric particles fabricated of poly(methyl-methacrylate) (PMMA) and polystyrene (PS) for which we achieved an uncertainty of 5×10(-3) and 1×10(-2) in the determination of the particle refractive index, respectively, and a precision better than 3% in the determination of their radii.


Phase I evaluation of therapy with four schedules of 5-fluorouracil by continuous infusion combined with recombinant interferon alpha.
The purpose of this study was to determine the maximum tolerated dose and dose-limiting toxicities of 5-fluorouracil (5-FU) when administered concurrently with recombinant IFN-alpha using four continuous infusion (CI) dosing schedules of 5-FU. Forty-five patients with advanced or refractory cancers were treated with 5-FU by CI, plus IFN during the infusion only, by one of four schedules: schedule A: 24-h 5-FU infusion repeated weekly, 9 x 10(6) units IFN x 2 doses weekly; schedule B: 48-h 5-FU infusion repeated weekly, 9 x 10(6) units IFN x 4 doses weekly; schedule C: 5-day 5-FU infusion repeated every 3 weeks, 9 x 10(6) units IFN three times weekly; and schedule D: 21-day 5-FU infusion, repeated after 7 days off therapy, 9 x 10(6) units IFN three times weekly. At least three patients were treated at all dose levels. Doses of 5-FU were escalated to the next level if less than one half of the patients at a given level developed grades 2-4 toxicity. The maximum tolerated dose for 5-FU was 2150 mg/m2/week for schedule A (24-h CI), 2350 mg/m2/week for schedule B (48-h CI), 750 mg/m2/day for schedule C (5-day CI), and 175 mg/m2/day for schedule D (21-day CI). Median delivered dose intensities at these levels were 1788 mg/m2/week for schedule A, 2192 mg/m2/week for schedule B, 1250 mg/m2/week for schedule C, and 593 mg/m2/week for schedule D. The dose-limiting toxicities were hematological and gastrointestinal (stomatitis, diarrhea, nausea, anorexia) for schedules A and B and gastrointestinal (mostly stomatitis) for schedules C and D. Severe fatigue due to IFN was rare. Responses correlated with toxicity >/= grade 2, but not with increased dose intensity. Responses were noted in several tumor types on schedules A, B, and D. 5-FU can be combined with IFN using 24- and 48-h high-dose and long-term low-dose CI schedules, with large differences in dose intensity at maximum tolerated dose. Shorter infusions produce less mucosal and more hematological toxicity. Tumor responses were seen on both short- and long-term CI schedules. Future studies can establish the efficacies of these new schedules of 5-FU/IFN administration in specific tumor types.


Thalassaemia in Sri Lanka: implications for the future health burden of Asian populations. Sri Lanka Thalassaemia Study Group.
Thalassaemias pose an increasing problem for the Indian subcontinent and many Asian countries. We analysed the different types of thalassaemia in the Sri Lankan population, surveyed gene frequencies in schoolchildren, and estimated the burden of disease and requirements for its control. We analysed blood samples from patients attending clinics in nine hospitals and defined the different types of beta thalassaemia by high-performance liquid chromatography (HPLC) and DNA analysis. The range of mutations was obtained by analysis of beta-globin genes. Capillary blood was obtained from schoolchildren from different parts of the island and analysed by HPLC to provide an approximate assessment of the carrier frequency of beta thalassaemia and haemoglobin E (HbE). To estimate the frequency of alpha thalassaemia the alpha-globin genotypes were also analysed when it was possible. Blood samples were obtained from 703 patients with beta thalassaemia and from 1600 schoolchildren. The thalassaemia mutations were unevenly spread. Although 23 different beta-thalassaemia mutations were found, three accounted for the thalassaemia phenotype in about 70% of the patients, most whom are homozygotes or compound heterozygotes for IVS1-5 (G-->C) or IVS1-1 (G-->A). The third common mutation, codon 26 (G-->A), which produces HbE, interacts with one or other of these mutations to produce HbE/beta thalassaemia; this comprises 13.0-30.9% of cases in the main centres. Samples from 472 patients were analysed to determine the alpha-globin genotype. Overall, 15.5% patients were carriers for deletion forms of alpha+ thalassaemia. Average gene frequencies showed that there will be more than 2000 patients requiring treatment at any one time, in the future, of whom those with HbE/beta thalassaemia will account for about 40%. In Sri Lanka, interactions of the two common beta-thalassaemia alleles will nearly always result in a transfusion-dependent disorder. However, about 40% of patients will have HbE/beta thalassaemia, which has a variable course. The management of these disorders could require about 5% of the total health budget. We need to learn more about the natural history and appropriate management of HbE/beta thalassaemia if resources are to be used effectively.


The unconditional release of mentally ill offenders from indefinite commitment: a study of Missouri insanity acquittees.
Using a database of all Missouri insanity acquittees committed on July 1, 1997 (N = 873) and all insanity acquittees unconditionally released from 1986 through 1997 (N = 193), this study calculated the lengths of commitment and identified variables associated with the unconditional release of insanity acquittees from indefinite commitment by the mental health and criminal justice systems. The study found that 85 percent of insanity acquittees were still under commitment 5 years after acquittal and 76 percent 10 years after acquittal. Factors that decreased the odds of being unconditionally released included never having been married; having a psychotic disorder, a mood disorder, a substance abuse disorder, or mental retardation/borderline intellectual functioning; and having committed a serious crime. These results support achievement of the intended goal of Missouri's insanity acquittee statute, which is to maximize public safety considerations, but have had the unintended effect of increasing the inpatient insanity acquittee population, resulting in fewer resources for voluntary patients.


Young People's Perceptions of Sexual Assault in Residential Care: "It Does Happen a Lot".
The Australian Royal Commission into Institutional Responses to Child Sexual Abuse (the Royal Commission) examined child sexual abuse within a wide range of institutions that provide services to children, this included residential facilities. The current study (funded by the Royal Commission) considers young people's perception of safety in residential care; specifically, the current study attended to the voices of young people who spoke about sexual harassment and assault in qualitative interviews. Interviews were conducted with young people aged between 13 and 21 years who were or had recently been in residential care. Participants were asked for their perceptions of situations in a series of vignettes describing various levels and types of sexual assault and harassment. During these interviews, the young people in this study voluntarily reported known incidences of sexual assault and harassment in varying levels, perpetrated by workers, individuals outside of residential care, and peers within residential care. Sexual assault and harassment was discussed in heteronormative and gendered ways with young men seen as perpetrators and protectors, and young women seen as being vulnerable. Further, it was evident from this study, that there were varying responses to these situations from workers within the residential care facilities.


Rapid diagnostic imaging of acute, nonclassic appendicitis by leukoscintigraphy with sulesomab, a technetium 99m-labeled antigranulocyte antibody Fab' fragment. LeukoScan Appendicitis Clinical Trial Group.
The purpose of this study was to evaluate the safety and efficacy of a technetium 99m-labeled antigranulocyte antibody Fab' fragment (sulesomab) as a diagnostic imaging agent in patients with suspected acute, nonclassic appendicitis. This prospective multicenter trial involved 141 children and adults with suspected acute, nonclassic appendicitis. The investigators interpreted planar images acquired 15 to 30 minutes and 1, 2, and 4 hours after injection and also by single-photon emission computed tomography (SPECT). The imaging results were confirmed surgically, whereas nonsurgical patients were considered as not having appendicitis (intent to treat). Sulesomab had a sensitivity of 91% (29/32 patients) and a negative predictive rate of 97% for acute appendicitis. It detected additional abnormalities in 7 of 9 patients with other inflammatory abdominal disease and had a specificity of 92% (91/99 patients) and a positive predictive value of 80% for surgically confirmed right-lower-quadrant disease. In positive studies, 26% were identified by planar imaging at 15 to 30 minutes, 46% by 1 hour, 63% by 2 hours, and 71% by 4 hours; 29% required SPECT to detect the abnormality. Scanning time was 5 to 10 minutes per planar image and about 45 minutes for a SPECT study. Investigators found that sulesomab would have changed clinical management or reduced additional diagnostic studies in 64% of the patients. Adverse events were infrequent, minor, and self-limiting (9/141 patients, 6%). No human antimurine antibody response occurred in 48 evaluable patients. Sulesomab is safe, well-tolerated, and with no apparent immunogenicity. Focal inflammation or infection in the setting of suspected atypical appendicitis is rapidly and accurately detected. Management decisions incorporating sulesomab imaging potentially provide clear patient benefits, especially by correctly predicting surgery to be unnecessary in 97% of patients without acute appendicitis.


General pharmacology of Vitex leucoxylon Linn leaves.
Ethanol extract (ETE) and cold aqueous infusion (CAI) of Vitex leucoxylon leaf were evaluated in a battery of tests to define the activity profile of the plant. CAI depressed SMA, antagonised d-amphetamine stereotypy and oxotremorine tremors, shortened the duration of mice immobility in behavioural 'despair' test and lowered serum total cholesterol level. ETE showed significant inhibition of carrageenin paw oedema and granulation tissue formation in rats. Suppression of acetic acid writhing was observed with both ETE and CAI. LD50 value of ETE was > 3000 mg kg-1 (ip) and that of CAI 1050 (800-1200) mgkg-1.


Interactions between dietary vitamin E intake and SIRT1 genetic variation influence body mass index.
Genetic variation in SIRT1 has been associated with body mass index (BMI) and risk of obesity. SIRT1 may be influenced by diet. We studied the gene-diet interaction on BMI at the SIRT1 locus. In 4575 elderly men and women in the population-based Rotterdam Study, the effect on BMI of 3 SIRT1 genetic variants (rs7895833, rs1467568, and haplotype 1) was studied in relation to dietary intakes of energy, fat, calcium, milk, antioxidant vitamins, and niacin. There was no difference in energy or fat intakes by SIRT1 genotype. Significant interactions for BMI were shown between SIRT1 genetic variants and intakes of fat, vitamin E, calcium, and milk. Only the interactions between vitamin E intake and rs1467568 and haplotype 1 remained significant (P < 0.001) after Bonferroni correction for multiple testing. Further analyses across vitamin E-intake tertiles showed highly significant associations of SIRT1 genetic variants with BMI in the lowest tertile [effect sizes (in kg/m(2)): 0.5-0.7 per allele copy; P = 1.9 x 10(-4)-5.7 x 10(-7)] with no associations in the higher tertiles. Dietary vitamin E intake may modulate the relation of SIRT1 genetic variants with BMI. Associations of SIRT1 variants with BMI in the lowest tertile of vitamin E intake may be explained by low intake of this antioxidant vitamin or by other associated dietary or lifestyle habits. These data provide support that gene-diet interactions influence BMI. Replication of our findings and further in-depth studies of dietary patterns that modify SIRT1 may lead to clinical studies of dietary modification of SIRT1 to influence obesity.


The effects of black garlic (Allium satvium) extracts on lipid metabolism in rats fed a high fat diet.
The mechanism of how black garlic effects lipid metabolism remains unsolved. Therefore, the objectives of this study were to determine the effects of black garlic on lipid profiles and the expression of related genes in rats fed a high fat diet. Thirty-two male Sqrague-Dawley rats aged 4 weeks were randomly divided into four groups (n=8) and fed the following diets for 5 weeks: normal food diet, (NF); a high-fat diet (HF); and a high-fat diet + 0.5% or 1.5% black garlic extract (HFBG0.5 or HFBG1.5). Body weights and blood biochemical parameters, including lipid profiles, and expressions of genes related to lipid metabolism were determined. Significant differences were observed in the final weights between the HFBG1.5 and HF groups. All blood biochemical parameters measured in the HFBG1.5 group showed significantly lower values than those in the HF group. Significant improvements of the plasama lipid profiles as well as fecal excretions of total lipids and triglyceride (TG) were also observed in the HFBG1.5 group, when compared to the HF diet group. There were significant differences in the levels of mRNA of sterol regulatory element binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and glucose-6-phosphate dehydrogenase (G6PDH) in the HFBG1.5 group compared to the HF group. In addition, the hepatic expression of (HMG-CoA) reductase and Acyl-CoA cholesterol acyltransferase (ACAT) mRNA was also significantly lower than the HF group. Consumption of black garlic extract lowers SREBP-1C mRNA expression, which causes downregulation of lipid and cholestrol metahbolism. As a result, the blood levels of total lipids, TG, and cholesterol were decreased.


Molecular Control of Triplet-Pair Spin Polarization and Its Optoelectronic Magnetic Resonance Probes.
ConspectusPreparing and manipulating pure magnetic states in molecular systems are the key initial requirements for harnessing the power of synthetic chemistry to drive practical quantum sensing and computing technologies. One route for achieving the requisite higher spin states in organic systems exploits the phenomenon of singlet fission, which produces pairs of triplet excited states from initially photoexcited singlets in molecular assemblies with multiple chromophores. The resulting spin states are characterized by total spin (quintet, triplet, or singlet) and its projection onto a specified molecular or magnetic field axis. These excited states are typically highly polarized but exhibit an impure spin population pattern. Herein, we report the prediction and experimental verification of molecular design rules that drive the population of a single pure magnetic state and describe the progress toward its experimental realization.A vital feature of this work is the close partnership among theory, chemical synthesis, and spectroscopy. We begin by presenting our theoretical framework for understanding spin manifold interconversion in singlet fission systems. This theory makes specific testable predictions about the intermolecular structure and orientation relative to an external magnetic field that should lead to pure magnetic state preparation and provides a powerful tool for interpreting magnetic spectra. We then test these predictions through detailed magnetic spectroscopy experiments on a series of new molecular architectures that meet one or more of the identified structural criteria. Many of these architectures rely on the synthesis of molecules with features unique to this effort: rigid bridges between chromophores in dimers, heteroacenes with tailored singlet/triplet-pair energy level matching, or side-group engineering to produce specific crystal structures. The spin evolution of these systems is revealed through our application and development of several magnetic resonance methods, each of which has different sensitivities and relevance in environments relevant to quantum applications.Our theoretical predictions prove to be remarkably consistent with our experimental results, though experimentally meeting all the structural prescriptions demanded by theory for true pure-state preparation remains a challenge. Our magnetic spectra agree with our model of triplet-pair behavior, including funneling of the population to the ms = 0 magnetic sublevel of the quintet under specified conditions in dimers and crystals, showing that this phenomenon is subject to control through molecular design. Moreover, our demonstration of novel and/or highly sensitive detection mechanisms of spin states in singlet fission systems, including photoluminescence (PL), photoinduced absorption (PA), and magnetoconductance (MC), points the way toward both a deeper understanding of how these systems evolve and technologically feasible routes toward experiments at the single-molecule quantum limit that are desirable for computational applications.


Linear Supramolecular Polymers Driven by Anion-Anion Dimerization of Difunctional Phosphonate Monomers Inside Cyanostar Macrocycles.
Supramolecular polymers have enabled far-reaching fundamental science and the development of diverse macromolecular technologies owing to the reversible and noncovalent chemical connectivities that define their properties. Despite the unabated development of these materials using highly tailorable recognition elements, anion-based polymers remain rare as a result of the weak interactions they mediate. Here, we use design rules inspired by cation-driven polymers to demonstrate a new noncovalent link based on receptor-stabilized anion-anion interactions that enables the efficient linear polymerization of simple difunctional phosphonates. The linear main chain connectivity and molecular topology were confirmed by single crystal X-ray diffraction, which demonstrates the rare 2:2 stoichiometry between the anionic phosphonate end groups and a pair of π-stacked cyanostar macrocycles. The stability of these links enables rapid polymerization of difunctional phosphonates employing different aliphatic linkers (C6H12, C8H16, C10H20, C12H24). Diphosphonates with greater chain flexibility (C12H24) enable greater polymerization with an average degree of polymerization of nine emerging at 10 mM. Viscosity measurements show a transition from oligomers to polymers at the critical polymerization concentration of 5 mM. In a rare correlation, NMR spectroscopy shows a coincident molecular signature of the polymerization at 5 mM. These polymers are highly concentration dependent, reversibly polymerize with acid and base, and respond to competitive anions. They display the design simplicity of metallo-supramolecular polymers with transfer of the strong 2:2 recognition chemistry to macromolecules. The simplicity and understanding of this new class of supramolecular polymer is anticipated to open opportunities in tailoring anion-based functional materials.


Combating counterfeit medicines and illicit trade in tobacco products: minefields in global health governance.
This article examines two spheres of global governance in which the World Health Organization (WHO) has sought to exercise international leadership - combating "counterfeit" medicines and illicit trade in tobacco products. Medicines and tobacco products lie at polar opposite ends of the health spectrum, and are regulated for vastly different reasons and through different tools and approaches. Nevertheless, attempts to govern counterfeit trade in each of these products raise a host of somewhat similar challenges, involving normative and operational conflicts that cut across the crowded intersection of health protection and promotion, intellectual property protection, and activity to combat transnational organized crime. As negotiations of an illicit trade protocol to the WHO Framework Convention on Tobacco Control enter their final stages, lessons learned from counterfeit medicines governance need to be applied to ensure that the most appropriate governance arrangements are adopted.


Aestivation of the African malaria mosquito, Anopheles gambiae in the Sahel.
The African malaria mosquito, Anopheles gambiae, inhabits diverse environments including dry savannas, where surface waters required for larval development are absent for 4-8 months per year. Under such conditions, An. gambiae virtually disappears. Whether populations survive the long dry season by aestivation (a dormant state promoting extended longevity during the summer) or are reestablished by migrants from distant locations where larval sites persist has remained an enigma for over 60 years. Resolving this question is important, because fragile dry season populations may be more susceptible to control. Here, we show unequivocally that An. gambiae aestivates based on a demographic study and a mark release-recapture experiment spanning the period from the end of one wet season to the beginning of the next. During the dry season, An. gambiae was barely detectable in Sahelian villages of Mali. Five days after the first rain, before a new generation of adults could be produced, mosquito abundance surged 10-fold, implying that most mosquitoes were concealed locally until the rain. Four days after the first rain, a marked female An. gambiae s.s. was recaptured. Initially captured, marked, and released at the end of the previous wet season, she has survived the 7-month-long dry season. These results provide evidence that An. gambiae persists throughout the dry season by aestivation and open new questions for mosquito and parasite research. Improved malaria control by targeting aestivating mosquitoes using existing or novel strategies may be possible.


Simplifying numerical ray tracing for characterization of optical systems.
Ray tracing, a computational method for tracing the trajectories of rays of light through matter, is often used to characterize mechanical or biological visual systems with aberrations that are larger than the effect of diffraction inherent in the system. For example, ray tracing may be used to calculate geometric point spread functions (PSFs), which describe the image of a point source after it passes through an optical system. Calculating a geometric PSF is useful because it gives an estimate of the detail and quality of the image formed by a given optical system. However, when using ray tracing to calculate a PSF, the accuracy of the estimated PSF directly depends on the number of discrete rays used in the calculation; higher accuracies may require more computational power. Furthermore, adding optical components to a modeled system will increase its complexity and require critical modifications so that the model will describe the system correctly, sometimes necessitating a completely new model. Here, we address these challenges by developing a method that represents rays of light as a continuous function that depends on the light's initial direction. By utilizing Chebyshev approximations (via the chebfun toolbox in MATLAB) for the implementation of this method, we greatly simplified the calculations for the location and direction of the rays. This method provides high precision and fast calculation speeds that allow the characterization of any symmetrical optical system (with a centered point source) in an analytical-like manner. Next, we demonstrate our methods by showing how they can easily calculate PSFs for complicated optical systems that contain multiple refractive and/or reflective interfaces.


PERISCOPE: road towards effective control of pertussis.
The resurgence and changing epidemiology of pertussis in high-income countries, the high infant mortality caused by pertussis in low-income countries, and the increasing morbidity in all age groups worldwide call for a concerted effort to both improve the current vaccines and develop new vaccines and vaccination strategies against pertussis. In this Personal View, we identify several key obstacles on the path to developing a durable solution for global control of pertussis. To systematically address these obstacles, the PERtussIS Correlates Of Protection Europe (PERISCOPE) Consortium was established in March, 2016. The objectives of this consortium are to increase scientific understanding of immunity to pertussis in humans induced by vaccines and infections, to identify biomarkers of protective immunity, and to generate technologies and infrastructure for the future development of improved pertussis vaccines. By working towards the accelerated licensure and implementation of novel, well tolerated, and effective pertussis vaccines, we hope to strengthen and stimulate further collaboration and transparency between the key stakeholders, including the public, the scientific community, public health institutes, regulatory authorities, and vaccine manufacturers.


Contribution of Organic Nitrates to Organic Aerosol over South Korea during KORUS-AQ.
The role of anthropogenic NOx emissions in secondary organic aerosol (SOA) production is not fully understood but is important for understanding the contribution of emissions to air quality. Here, we examine the role of organic nitrates (RONO2) in SOA formation over the Korean Peninsula during the Korea-United States Air Quality field study in Spring 2016 as a model for RONO2 aerosol in cities worldwide. We use aircraft-based measurements of the particle phase and total (gas + particle) RONO2 to explore RONO2 phase partitioning. These measurements show that, on average, one-fourth of RONO2 are in the condensed phase, and we estimate that ≈15% of the organic aerosol (OA) mass can be attributed to RONO2. Furthermore, we observe that the fraction of RONO2 in the condensed phase increases with OA concentration, evidencing that equilibrium absorptive partitioning controls the RONO2 phase distribution. Lastly, we model RONO2 chemistry and phase partitioning in the Community Multiscale Air Quality modeling system. We find that known chemistry can account for one-third of the observed RONO2, but there is a large missing source of semivolatile, anthropogenically derived RONO2. We propose that this missing source may result from the oxidation of semi- and intermediate-volatility organic compounds and/or from anthropogenic molecules that undergo autoxidation or multiple generations of OH-initiated oxidation.


Designing the Crops for the Future; The CropBooster Program.
The realization of the full objectives of international policies targeting global food security and climate change mitigation, including the United Nation's Sustainable Development Goals, the Paris Climate Agreement COP21 and the European Green Deal, requires that we (i) sustainably increase the yield, nutritional quality and biodiversity of major crop species, (ii) select climate-ready crops that are adapted to future weather dynamic and (iii) increase the resource use efficiency of crops for sustainably preserving natural resources. Ultimately, the grand challenge to be met by agriculture is to sustainably provide access to sufficient, nutritious and diverse food to a worldwide growing population, and to support the circular bio-based economy. Future-proofing our crops is an urgent issue and a challenging goal, involving a diversity of crop species in differing agricultural regimes and under multiple environmental drivers, providing versatile crop-breeding solutions within wider socio-economic-ecological systems. This goal can only be realized by a large-scale, international research cooperation. We call for international action and propose a pan-European research initiative, the CropBooster Program, to mobilize the European plant research community and interconnect it with the interdisciplinary expertise necessary to face the challenge.


Body size and predatory performance in wolves: is bigger better?
1. Large body size hinders locomotor performance in ways that may lead to trade-offs in predator foraging ability that limit the net predatory benefit of larger size. For example, size-related improvements in handling prey may come at the expense of pursuing prey and thus negate any enhancement in overall predatory performance due to increasing size. 2. This hypothesis was tested with longitudinal data from repeated observations of 94 individually known wolves (Canis lupus) hunting elk (Cervus elaphus) in Yellowstone National Park, USA. Wolf size was estimated from an individually based sex-specific growth model derived from body mass measurements of 304 wolves. 3. Larger size granted individual wolves a net predatory advantage despite substantial variation in its effect on the performance of different predatory tasks; larger size improved performance of a strength-related task (grappling and subduing elk) but failed to improve performance of a locomotor-related task (selecting an elk from a group) for wolves > 39 kg. 4. Sexual dimorphism in wolf size also explained why males outperformed females in each of the three tasks considered (attacking, selecting, and killing). 5. These findings support the generalization that bigger predators are overall better hunters, but they also indicate that increasing size ultimately limits elements of predatory behaviour that require superior locomotor performance. We argue that this could potentially narrow the dietary niche of larger carnivores as well as limit the evolution of larger size if prey are substantially more difficult to pursue than to handle.


The role of bicarbonate and fluid loading in improving resuscitation from prolonged cardiac arrest with rapid manual chest compression CPR.
Rapid manual chest compression (120 compressions/min) CPR has been shown to improve hemodynamics and survival when compared with standard CPR (60 compressions/min) in a canine model of prolonged cardiac arrest. The study showing improved survival with rapid manual CPR empirically included treatment with bicarbonate and initial fluid loading. To determine the role of bicarbonate and fluid loading in the success of rapid manual chest compression CPR, 31 mongrel dogs were studied. After instrumentation with micromanometer-tipped catheters to measure aortic and right atrial pressures, the animals were assigned sequentially to three treatment groups. Group A underwent rapid manual chest compressions at 120 compressions/min, bicarbonate treatment, and initial fluid loading. Group B underwent rapid manual compressions at 120 compressions/min without bicarbonate or fluid loading. Group C underwent standard CPR at 80 compressions/min with bicarbonate and fluid loading. After 30 minutes of ventricular fibrillation, defibrillation was attempted. Seven of 11 dogs in group A survived 24 hours. None of the animals in group B resuscitated or survived. Three of the ten dogs in group C survived 24 hours. Survival with rapid manual CPR without bicarbonate and initial fluid loading was significantly less than when these interventions were used (P less than .01). To examine the separate contribution of bicarbonate and fluid therapy, two additional groups of animals were studied. Fourteen animals (group D) received rapid manual CPR with bicarbonate therapy, and 12 (group E) received rapid manual CPR with fluid loading only.(ABSTRACT TRUNCATED AT 250 WORDS)


[Oral health and perceptions regarding dental care in patients with mental disorders living in therapeutic residences].
Patients with mental disorders have considerable difficulty in access to dental care, including the refusal of oral health professionals to offer care to this clientele and the inadequate professional training of oral health professionals regarding this issue. The present study was carried out in therapeutic residences in order to assess the oral health conditions of the residents as well as their perceptions regarding the dental care they have received. Thirty-eight individuals participated in the study. Data were collected through clinical examinations and a semi-structured interview. Data analysis revealed a high number of caries and the need for dentures, with 42.5% of the individuals needing complete dentures and 30.3% needing partial dentures. Regarding periodontal conditions, 28.5% of the dental elements exhibited losses of over 4 mm of periodontal insertion. Data from the interviews were submitted to content analysis, which enabled the establishment of two categories: the association of pain with the presence of teeth and mutilating dental care. Oral health was associated to dental extraction, which was considered the only solution to oral health disturbances, indicating that, for this population, oral health signifies not having teeth.


The iMpact on practice, oUtcomes and costs of New roles for health pROfeSsionals: a study protocol for MUNROS.
The size and composition of the European Union healthcare workforce are key drivers of expenditure and performance; it now includes new health professions and enhanced roles for established professions. This project will systematically analyse how this has contributed to health service redesign, integration and performance in 9 European countries (Scotland, England, Netherlands, Germany, Italy, Czech Republic, Poland, Norway, and Turkey(i)). This paper describes the protocol for collection of survey data in 3 distinct care pathways, and sets it in the context of the wider programme. Questionnaires will be distributed to healthcare professionals (n=14,580), managers (n=3564) and patients (n=19,440) in 3 care pathways (breast cancer; type 2 diabetes; and coronary heart disease) within 12 hospitals and associated primary care settings in each country. Questionnaire topics will include demography, the different professionals working on the care pathway, the tasks they do and the time taken, their decision-making abilities when considering skill mix, specialisation and integration of care. Patient satisfaction, healthcare utilisation and preferences will be explored. In later work, register data and data from patient records will be used to record clinical outcomes. Data will also be collected on workforce and procedure costs. Descriptive analysis will identify the different models of care and multivariate analysis will establish the most clinically and cost-effective models. This protocol was approved by ethical committees in each country. Findings will be disseminated through national/international clinical, health services research and health workforce conferences, and publications in national/international peer-reviewed journals.


TSSC3 overexpression reduces stemness and induces apoptosis of osteosarcoma tumor-initiating cells.
Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents, typically presenting with poor prognosis. Recent studies suggested that tumor initiating cells (T-ICs) drive tumor formation and relapse or metastasis and are relatively resistant to cell death induced by conventional chemo- and radiotherapies. Therefore, the poor prognosis of OS appears to be associated with T-ICs. Here, we enriched T-ICs in OS cell lines and evaluated whether the imprinted gene TSSC3 (tumor-suppressing STF cDNA 3) associated with apoptosis could affect T-ICs in OS. Sarcosphere selection and serial clone-forming unit assays were successfully used to enrich T-ICs from OS cell lines. Enrichment of T-ICs from a malignantly transformed hFOB1.19 osteoblast cell line (MThFOB1.19) indicated that OS T-ICs could originate from differentiated cells, and most of these MThFOB1.19 cells showed stem-like features. TSSC3 was expressed at a low level in T-ICs, while overexpression of TSSC3 could efficiently downregulate the expression of stem cell markers Nanog, Oct4 and Sox2 in T-ICs and decrease the clone formation rate, as well as downregulate tumorigenesis in MThFOB1.19 cells, supporting a suppressive role for TSSC3 in OS T-ICs. Furthermore, overexpression of TSSC3 was found to induce apoptosis of OS T-ICs through increasing cleaved caspase-3 (active form), increasing the release of Cyt c and decreasing pro-caspase-9 (pro-enzyme form), as well as disruption of the mitochondrial membrane potential (ΔΨ). Taken together, our findings provide preliminary evidence that TSSC3 inhibits OS tumorigenicity through reducing stemness and promoting apoptosis of T-ICs. Thus, targeting TSSC3 may be a promising approach to suppressing tumorigenicity in OS.


Smokers with airway obstruction are more likely to quit smoking.
Chronic obstructive pulmonary disease (COPD), usually caused by tobacco smoking, is one of the leading causes of morbidity and mortality. Smoking cessation at an early stage of the disease usually stops further progression. A study was undertaken to determine if diagnosis of airway obstruction was associated with subsequent success in smoking cessation, as advised by a physician. 4494 current smokers (57.4% men) with a history of at least 10 pack-years of smoking were recruited from 100 000 subjects screened by spirometric testing for signs of airway obstruction. At the time of screening all received simple smoking cessation advice. 1177 (26.2%) subjects had airway obstruction and were told that they had COPD and that smoking cessation would halt rapid progression of their lung disease. No pharmacological treatment was proposed. After 1 year all subjects were invited for a follow up visit. Smoking status was assessed by history and validated by exhaled carbon monoxide level. Nearly 70% attended a follow up visit (n = 3077): 61% were men, mean (SD) age was 52 (10) years, mean (SD) tobacco exposure 30 (17) pack-years, and 33.3% had airway obstruction during the baseline examination. The validated smoking cessation rate in those with airway obstruction was 16.3% compared with 12.0% in those with normal spirometric parameters (p = 0.0003). After correction for age, sex, nicotine dependence, number of cigarettes smoked daily, and lung function, success in smoking cessation was predicted by lower lung function, lower nicotine dependence, and lower tobacco exposure. Simple smoking cessation advice combined with spirometric testing resulted in good 1 year cessation rates, especially in subjects with airway obstruction.


Propagation and attenuation of mechanical signals in ultrasoft 2D solids.
The propagation of elastic waves in soft materials plays a crucial role in the spatiotemporal transmission of mechanical signals, e.g., in biological mechanotransduction or in the failure of marginal solids. At high Reynolds numbers Re ≫ 1, inertia dominates and wave propagation is readily observed. However, mechanical cues in soft and biological materials often occur at low Re, where waves are overdamped. Overdamped waves are not only difficult to observe experimentally, also theoretically their description remains incomplete. Here, we present direct measurements of the propagation and attenuation of mechanical signals in colloidal soft solids, induced by an optical trap. We derive an analytical theory for low Re wave propagation and damping, which is in excellent agreement with the experiments. Our results present both a previously unexplored method to characterize damped waves in soft solids and a theoretical framework showing how localized mechanical signals can provoke a remote and delayed response.


The moderating role of rational beliefs in the relationship between irrational beliefs and posttraumatic stress symptomology.
Rational Emotive Behaviour Therapy (REBT) assumes that rational beliefs act as cognitive protective factors against the development of psychopathology; however little empirical evidence exists regarding the nature of the possible protective effects that they offer. The current study investigates whether rational beliefs moderate the impact of irrational beliefs on posttraumatic stress symptomology (PTS). Three hundred and thirteen active law enforcement, military, and related emergency service personnel took part in the current study. Sequential moderated multiple regression analysis was employed to investigate: (i) the direct impact of irrational beliefs on PTS; (ii) the direct impact of rational beliefs on PTS; (iii) the moderating effects of rational beliefs in the relationship between irrational beliefs and PTS. The irrational beliefs predicted by REBT theory emerged as critical predictors of PTS symptomology, in particular Depreciation beliefs. Rational beliefs (Preferences, and Acceptance beliefs) had a direct, negative impact on levels of PTS, and Acceptance beliefs moderated the impact of Catastrophizing beliefs on PTS. Irrational beliefs are important cognitive vulnerability factors in symptoms of PTS, while rational beliefs (Acceptance) appear to have a protective role in the emergence of PTS symptoms, both directly and by moderating the impact of Catastrophizing beliefs.


Interaction between the Stress Phase Angle (SPA) and the Oscillatory Shear Index (OSI) Affects Endothelial Cell Gene Expression.
Hemodynamic forces play an important role in the non-uniform distribution of atherosclerotic lesions. Endothelial cells are exposed simultaneously to fluid wall shear stress (WSS) and solid circumferential stress (CS). Due to variations in impedance (global factors) and geometric complexities (local factors) in the arterial circulation a time lag arises between these two forces that can be characterized by the temporal phase angle between CS and WSS (stress phase angle-SPA). Asynchronous flows (SPA close to -180°) that are most prominent in coronary arteries have been associated with localization of atherosclerosis. Reversing oscillatory flows characterized by an oscillatory shear index (OSI) that is great than zero are also associated with atherosclerosis localization. In this study we examined the relationship between asynchronous flows and reversing flows in altering the expression of 37 genes relevant to atherosclerosis development. In the case of reversing oscillatory flow, we observed that the asynchronous condition upregulated 8 genes compared to synchronous hemodynamics, most of them proatherogenic. Upregulation of the pro-inflammatory transcription factor NFκB p65 was confirmed by western blot, and nuclear translocation of NFκB p65 was confirmed by immunofluorescence staining. A comparative study between non-reversing flow and reversing flow found that in the case of synchronous hemodynamics, reversing flow altered the expression of 11 genes, while in the case of asynchronous hemodynamics, reversing flow altered the expression of 17 genes. Reversing flow significantly upregulated protein expression of NFκB p65 for both synchronous and asynchronous conditions. Nuclear translocation of NFκB p65 was confirmed for synchronous and asynchronous conditions in the presence of flow reversal. These data suggest that asynchronous hemodynamics and reversing flow can elicit proatherogenic responses in endothelial cells compared to synchronous hemodynamics without shear stress reversal, indicating that SPA as well as reversal flow (OSI) are important parameters characterizing arterial susceptibility to disease.


Red yeast rice ameliorates high-fat diet-induced atherosclerosis in Apoe-/- mice in association with improved inflammation and altered gut microbiota composition.
Gut microbiota plays an important role in many metabolic diseases and has been linked to cardiovascular disease, including atherosclerosis. Clinical studies suggest that red yeast rice (RYR) has the potential to reduce blood lipid levels. However, the mechanisms under which RYR regulates atherosclerosis by affecting the composition of the gut microbiome have not been elucidated. In the current study, results showed that treatment with RYR significantly decreased the plaque formation and levels of cholesterol and low-density lipoprotein (LDL) compared with the atherosclerotic model group which were fed with a high-fat diet. In addition, the height of enteral villus in the red Monascus group was increased, indicating that RYR can improve the intestinal barrier function. Further analysis revealed that RYR might attenuate atherosclerosis through inhibiting hydroxy methylglutaryl-CoA reductase and the consequent inflammatory signaling pathways mediated by TLR2 and TLR4. Moreover, the RYR treatment led to significant structural changes on the intestinal microbiota of high-fat diet-fed mice and reduced the relative abundance of Alistipes and Flavonifractor that exhibited positive relationships with the plasma levels of cholesterol and LDL. Collectively, these findings illustrated that RYR could significantly protect against atherosclerosis, which was possibly associated with the alterations in the gut microbiota composition.


[Social dysfunction in schizotypy].
Schizotypy is a personality organisation that is closely related to schizotypal personality disorder and schizophrenia and is characterised by deficits in social functioning. Although the dimensions of social dysfunction have not yet been fully explored certain aspects of social dysfunction are promising predictive markers for schizophrenia. To describe schizotypy and its influence on social functioning. We reviewed the literature systematically using the online databases PubMed and PsycINFO. The disorder known as schizotypy lies at the basis of schizotypal personality disorder. Both disorders are characterised by an increased risk for schizophrenia. The social dysfunctioning seen in schizotypy corresponds to the social dysfunction seen in schizophrenia. Impairments in social cognition are causal factors of this social dysfunction. Both the negative and the positive dimension of schizotypy influence social cognition. More focused, objective and interactive research to the various aspects of social functioning in schizotypy is needed in order to discover potential premorbid markers for schizophrenia.


Specific chemotherapeutic agents induce metastatic behaviour through stromal- and tumour-derived cytokine and angiogenic factor signalling.
Recent studies reveal that chemotherapy can enhance metastasis due to host responses, such as augmented expression of adhesion molecules in endothelial cells and increased populations of myeloid cells. However, it is still unclear how tumour cells contribute to this process. Here, we observed that paclitaxel and carboplatin accelerated lung metastasis in tumour-bearing mice, while doxorubicin and fluorouracil did not. Mechanistically, paclitaxel and carboplatin induced similar changes in cytokine and angiogenic factors. Increased levels of CXCR2, CXCR4, S1P/S1PR1, PlGF and PDGF-BB were identified in the serum or primary tumour tissues of tumour-bearing mice treated by paclitaxel. The serum levels of CXCL1 and PDGF-BB and the tissue level of CXCR4 were also elevated by carboplatin. On the other hand, doxorubicin and fluorouracil did not induce such changes. The chemotherapy-induced cytokine and angiogenic factor changes were also confirmed in gene expression datasets from human patients following chemotherapy treatment. These chemotherapy-enhanced cytokines and angiogenic factors further induced angiogenesis, destabilized vascular integrity, recruited BMDCs to metastatic organs and mediated the proliferation, migration and epithelial-to-mesenchymal transition of tumour cells. Interestingly, inhibitors of these factors counteracted chemotherapy-enhanced metastasis in both tumour-bearing mice and normal mice injected intravenously with B16F10-GFP cells. In particular, blockade of the SDF-1α-CXCR4 or S1P-S1PR1 axes not only compromised chemotherapy-induced metastasis but also prolonged the median survival time by 33.9% and 40.3%, respectively. The current study delineates the mechanism of chemotherapy-induced metastasis and provides novel therapeutic strategies to counterbalance pro-metastatic effects of chemo-drugs via combination treatment with anti-cytokine/anti-angiogenic therapy.


Quantum chemical modeling of enzymatic reactions: the case of histone lysine methyltransferase.
Quantum chemical cluster models of enzyme active sites are today an important and powerful tool in the study of various aspects of enzymatic reactivity. This methodology has been applied to a wide spectrum of reactions and many important mechanistic problems have been solved. Herein, we report a systematic study of the reaction mechanism of the histone lysine methyltransferase (HKMT) SET7/9 enzyme, which catalyzes the methylation of the N-terminal histone tail of the chromatin structure. In this study, HKMT SET7/9 serves as a representative case to examine the modeling approach for the important class of methyl transfer enzymes. Active site models of different sizes are used to evaluate the methodology. In particular, the dependence of the calculated energies on the model size, the influence of the dielectric medium, and the particular choice of the dielectric constant are discussed. In addition, we examine the validity of some technical aspects, such as geometry optimization in solvent or with a large basis set, and the use of different density functional methods.


Major histocompatibility complex class II-restricted antigen presentation across a species barrier: conservation of restriction determinants in evolution.
The existence of at least three alleles of the HLA-DRB3 gene within the human population is evident. These alleles express DRw52 determinants and react with monoclonal antibody (mAb) 22.214.171.124. The polymorphic epitope recognized by 220.127.116.11 is not only present on human cells but is also expressed on chimpanzee (Pan troglodytes) class II-positive cells. The 18.104.22.168 determinant already existed before speciation of man and chimpanzee, and is at least 5,000,000 yr old. Two-dimensional gel electrophoresis demonstrated that the various HLA- and Patr-DRw52 molecules that are reactive with 22.214.171.124 exhibit isoelectric point differences due to primary amino acid heterogeneity, as was confirmed by sequencing data. Sequence comparison allowed us to map the binding site of mAb 220.127.116.11 to the alpha helix of the major histocompatibility complex (MHC) class II DRB1 domain surrounding the antigen-binding cleft. Despite MHC sequence variation, chimpanzee antigen-presenting cells can present antigen (purified protein derivative) to human T cell lines and vice versa. Only the HLA- and Patr-DRw52 molecules were shown to function as restriction elements for antigen presentation across this species barrier. It is concluded that these particular restriction determinants probably have been conserved in evolution. The HLA- and Patr-DRw52 molecules represent alleles displaying polymorphism that has been selected for in evolution. Such "biomutants" may thus be more useful to study the biological significance of MHC molecules than MHC variants that have been generated by in vitro mutagenesis experiments.


Automated characterization and parameter-free classification of cell tracks based on local migration behavior.
Cell migration is the driving force behind the dynamics of many diverse biological processes. Even though microscopy experiments are routinely performed today by which populations of cells are visualized in space and time, valuable information contained in image data is often disregarded because statistical analyses are performed at the level of cell populations rather than at the single-cell level. Image-based systems biology is a modern approach that aims at quantitatively analyzing and modeling biological processes by developing novel strategies and tools for the interpretation of image data. In this study, we take first steps towards a fully automated characterization and parameter-free classification of cell track data that can be generally applied to tracked objects as obtained from image data. The requirements to achieve this aim include: (i) combination of different measures for single cell tracks, such as the confinement ratio and the asphericity of the track volume, and (ii) computation of these measures in a staggered fashion to retrieve local information from all possible combinations of track segments. We demonstrate for a population of synthetic cell tracks as well as for in vitro neutrophil tracks obtained from microscopy experiment that the information contained in the track data is fully exploited in this way and does not require any prior knowledge, which keeps the analysis unbiased and general. The identification of cells that show the same type of migration behavior within the population of all cells is achieved via agglomerative hierarchical clustering of cell tracks in the parameter space of the staggered measures. The recognition of characteristic patterns is highly desired to advance our knowledge about the dynamics of biological processes.


Incidence and distribution of experimental metastases in mutant mice with defective organ microenvironments (genotypes Sl/Sld and W/Wv).
Mice carrying mutations at the Sl (steel) and W (dominant white spotting) loci develop abnormalities on 3 migratory embryonic stem cell populations: hematopoietic stem cells, neural crest-derived melanocytes, and primordial germ cells. Transplantation experiments have indicated that the Sl locus affects the microenvironment where stem cells migrate, proliferate, and differentiate, while the W locus affects the migratory cells themselves. The Sl locus encodes for a multipotent growth factor known as stem cell factor. The W locus encodes the c-kit protein tyrosine kinase receptor whose ligand is the stem cell factor. We have investigated the incidence and organ distribution of experimental metastases after systemic intra-arterial injection of B16-G3.26 melanoma cells into mutant Sl/Sld and W/Wv mice. Both mutant mouse strains had a markedly lower incidence of ovarian metastases when compared with their congenic +/+ mice. In contrast to the rare colonization of the ovaries, Sl/Sld and W/Wv mice developed metastases in the myocardium, kidney, and stomach--anatomic sites that were infrequently or never affected in their congenic nonmutant mice. The only organs in which the average number of metastatic colonies differed between Sl/Sld and W/Wv mice were the bone marrow and kidneys. The average number of colonized bones per mouse in the Sl/Sld group was 5.0 +/- 3.1 (SD), compared with 12.7 +/- 5.3 in the W/Wv group. The average number of metastatic nodules in the kidneys of Sl/Sld mice was 24.6 +/- 9, while W/Wv mice had 15.5 +/- 2.5. Mutant mice with multiple metastatic nodules in the kidneys, heart, and stomach were also found to have forestomach papillomas, an enlarged duodenum, kidney abnormalities, and small body size. The results of this study provide useful information on potential mechanisms of interaction of metastatic cells with their target organs, and suggest that there are additional organ defects associated with the mutations in the Sl and W loci. They also document the importance of mutant mice in metastasis research.


miR-27b represses migration of mouse MSCs to burned margins and prolongs wound repair through silencing SDF-1a.
Interactions between stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXCR4 are crucial for the recruitment of mesenchymal stem cells (MSCs) from bone marrow (BM) reservoirs to damaged tissues for repair during alarm situations. MicroRNAs are differentially expressed in stem cell niches, suggesting a specialized role in stem cell regulation. Here, we gain insight into the molecular mechanisms involved in regulating SDF-1α. MSCs from green fluorescent protein transgenic male mice were transfused to irradiated recipient female C57BL/6 mice, and skin burn model of bone marrow-chimeric mice were constructed. Six miRNAs with differential expression in burned murine skin tissue compared to normal skin tissue were identified using microarrays and bioinformatics. The expression of miR-27b and SDF-1α was examined in burned murine skin tissue using quantitative real-time PCR (qPCR) and immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA). The Correlation of miR-27b and SDF-1α expression was analyzed by Pearson analysis Correlation. miRNAs suppressed SDF-1α protein expression by binding directly to its 3'UTR using western blot and luciferase reporter assay. The importance of miRNAs in MSCs chemotaxis was further estimated by decreasing SDF-1α in vivo and in vitro. miR-23a, miR-27a and miR-27b expression was significantly lower in the burned skin than in the normal skin (p<0.05). We also found that several miRNAs suppressed SDF-1α protein expression, while just miR-27a and miR-27b directly bound to the SDF-1α 3'UTR. Moreover, the forced over-expression of miR-27a and miR-27b significantly reduced the directional migration of mMSCs in vitro. However, only miR-27b in burn wound margins significantly inhibited the mobilization of MSCs to the epidermis. miR-27b may be a unique signature of the stem cell niche in burned mouse skin and can suppress the directional migration of mMSCs by targeting SDF-1α by binding directly to its 3'UTR.


'Nipped in the Budd': hepatic venous outflow obstruction in evolution.
Hepatic venous thrombosis (Budd-Chiari) in evolution is a rare phenomenon and carries a high morbidity and mortality. We describe the case of a 39-year-old Bangladeshi lady who presented with severe abdominal pain secondary to a perforated duodenal ulcer and during her hospital admission developed an asymptomatic Budd-Chiari syndrome (BCS). Our report highlights the important role of an inflammatory focus, and how this process with an associated reactive thrombocytosis may act as a trigger for the development of BCS in an individual with predisposing risk factors. Our patient had been on the contraceptive pill, and was homozygous for the C677T mutation of 5,10-methylenetetrahydrofolate reductase, which results in hyperhomocysteinaemia. These pro-thrombotic risk factors were compounded by the thrombogenic potential of subsequent laparoscopic surgery, and resulted in an evolving thrombus that progressed into the inferior vena cava causing hepatic infarction. A particular feature of this case was the radiological demonstration of complete regression of the thrombus and the hepatic parenchymal changes, upon resolution of the inflammation and normalization of the platelet count. These changes occurred with oral anticoagulation as the only treatment modality, since our patient declined systemic thrombolysis. The demonstration of complete radiological resolution raises the question of how long one should continue oral anticoagulants and, indeed, whether in some instances a conservative approach may be the best management strategy for evolving BCS.


Multiple intraductal papillomas of breast clinically masquerading as malignancy.
Intraductal papilloma is characterized by proliferation of epithelial and myoepithelial cells overlying fibro-vascular stalks creating an arborescent structure within the lumen of duct. Some times multiple papillomas with florid proliferation of epithelium may be confused with malignancy. A case of multiple intraductal papillomas of breast with ulceration of overlying skin and large lump leading to clinical diagnosis of malignancy is documented here. A 45-year-old female presented with ulcerated mass of six months duration in the left breast. On examination, a firm, immobile lump of 8x 10 cm in size involving nipple with excoriation of surrounding skin and serosanguinous discharge from nipple was present. There was no axillary lymphadenopathy. No family history of carcinoma breast was present. Fine needle aspiration smears showed benign cellular changes with apocrine metaplasia. Biopsy from an area adjacent to nipple showed intraductal papilloma. Simple mastectomy showed lobulated dirty white mass with well circumscribed nodules below the nipple and areola. On histology with immunohistochemistry a diagnosis of multiple intraductal papillomas was made. Patient is on regular follow-up and doing well. The case highlights the problem in differentiating marked papillomatosis from a malignant lesion of breast and importance of biopsy with immunohistochemistry in such cases for proper management.


Associations between Activity Pacing, Fatigue, and Physical Activity in Adults with Multiple Sclerosis: A Cross Sectional Study.
Fatigue is common in people with multiple sclerosis (MS). Activity pacing is a behavioral way to cope with fatigue and limited energy resources. However, little is known about how people with MS naturally pace activities to manage their fatigue and optimize daily activities. This study explored how activity pacing relates to fatigue and physical activity in people with MS. Participants were 80 individuals (60 females, 20 males) with a diagnosis of MS. The participants filled in questionnaires on their activity pacing, fatigue, physical activity, and health-related quality of life, 3-6 weeks before discharge from rehabilitation. The relationships between the variables were examined using hierarchical regression. After controlling for demographics, health-related quality of life, and perceived risk of overactivity, no associations were found between activity pacing and fatigue (β = 0.20; t = 1.43, p = 0.16) or between activity pacing and physical activity (β = -0.24; t = -1.61, p = 0.12). The lack of significant associations between activity pacing and fatigue or physical activity suggests that without interventions, there appears to be no clear strategy amongst people with MS to manage fatigue and improve physical activity. People with MS may benefit from interventions to manage fatigue and optimize engagement in physical activity.


Impact of Staphylococcus aureus on pathogenesis in polymicrobial infections.
Polymicrobial infections involving Staphylococcus aureus exhibit enhanced disease severity and morbidity. We reviewed the nature of polymicrobial interactions between S. aureus and other bacterial, fungal, and viral cocolonizers. Microbes that were frequently recovered from the infection site with S. aureus are Haemophilus influenzae, Enterococcus faecalis, Pseudomonas aeruginosa, Streptococcus pneumoniae, Corynebacterium sp., Lactobacillus sp., Candida albicans, and influenza virus. Detailed analyses of several in vitro and in vivo observations demonstrate that S. aureus exhibits cooperative relations with C. albicans, E. faecalis, H. influenzae, and influenza virus and competitive relations with P. aeruginosa, Streptococcus pneumoniae, Lactobacillus sp., and Corynebacterium sp. Interactions of both types influence changes in S. aureus that alter its characteristics in terms of colony formation, protein expression, pathogenicity, and antibiotic susceptibility.


Three-dimensional printed multiphase scaffolds for regeneration of periodontium complex.
Tooth-supporting periodontium forms a complex with multiple tissues, including cementum, periodontal ligament (PDL), and alveolar bone. In this study, we developed multiphase region-specific microscaffolds with spatiotemporal delivery of bioactive cues for integrated periodontium regeneration. Polycarprolactione-hydroxylapatite (90:10 wt%) scaffolds were fabricated using three-dimensional printing seamlessly in three phases: 100-μm microchannels in Phase A designed for cementum/dentin interface, 600-μm microchannels in Phase B designed for the PDL, and 300-μm microchannels in Phase C designed for alveolar bone. Recombinant human amelogenin, connective tissue growth factor, and bone morphogenetic protein-2 were spatially delivered and time-released in Phases A, B, and C, respectively. Upon 4-week in vitro incubation separately with dental pulp stem/progenitor cells (DPSCs), PDL stem/progenitor cells (PDLSCs), or alveolar bone stem/progenitor cells (ABSCs), distinctive tissue phenotypes were formed with collagen I-rich fibers especially by PDLSCs and mineralized tissues by DPSCs, PDLSCs, and ABSCs. DPSC-seeded multiphase scaffolds upon in vivo implantation yielded aligned PDL-like collagen fibers that inserted into bone sialoprotein-positive bone-like tissue and putative cementum matrix protein 1-positive/dentin sialophosphoprotein-positive dentin/cementum tissues. These findings illustrate a strategy for the regeneration of multiphase periodontal tissues by spatiotemporal delivery of multiple proteins. A single stem/progenitor cell population appears to differentiate into putative dentin/cementum, PDL, and alveolar bone complex by scaffold's biophysical properties and spatially released bioactive cues.


Effectiveness of weekend physical rehabilitation for functional recovery in geriatric patients with hip fracture.
To test the hypothesis that the functional outcome of hip fracture patients who receive weekend rehabilitation is better than that of similar patients who undergo non-weekend rehabilitation. The present retrospective observational study used data from the Japan Rehabilitation Database spanning 2005-2015. We identified in-hospital hip fracture patients admitted to acute hospitals. After applying exclusion criteria, 469 patients were eligible. The primary outcome was motor Functional Independence Measure (FIM) efficiency. Of the patients with hip fracture, 68.0% received weekend rehabilitation. The patients who received weekend rehabilitation had significantly higher scores in motor FIM efficiency (mean 1.08 vs 0.73, P < 0.001), FIM efficiency (mean 1.12 vs 0.79, P = 0.001) and shorter length of stay (mean 32 vs 54, P < 0.001) than the patients without weekend rehabilitation. Multivariate linear regression analysis identified the weekend rehabilitation as a significant factor in motor FIM efficiency (coefficient 0.237, 95% confidence interval 0.074-0.400, P = 0.004), FIM efficiency (coefficient 0.235, 95% confidence interval 0.079-0.391, P = 0.003) and length of stay (coefficient -9.649, 95% confidence interval -18.194 to -1.104, P = 0.027). The present cohort analysis showed that weekend rehabilitation for hip fracture patients can lead to functional recovery and reduce the length of stay. Geriatr Gerontol Int 2018; 18: 1143-1146.