Betulinic acid derivatives as human immunodeficiency virus type 2 (HIV-2) inhibitors.
We previously reported that [[N-[3beta-hydroxyllup-20(29)-en-28-oyl]-7-aminoheptyl]carbamoyl]methane (A43D, 4) was a potent HIV-1 entry inhibitor. However, 4 was inactive against HIV-2 virus, suggesting the structural requirements for targeting these two retroviruses are different. In this study, a series of new betulinic acid derivatives were synthesized, and some of them displayed selective anti-HIV-2 activity at nanomolar concentrations. In comparison to compounds with anti-HIV-1 activity, a shorter C-28 side chain is required for optimal anti-HIV-2 activity.


High-dose rifampin improves bactericidal activity without increased intracerebral inflammation in animal models of tuberculous meningitis.
Tuberculous meningitis (TB meningitis) is the most severe form of tuberculosis (TB), requiring 12 months of multidrug treatment for cure, and is associated with high morbidity and mortality. High-dose rifampin (35 mg/kg/d) is safe and improves the bactericidal activity of the standard-dose (10 mg/kg/d) rifampin-containing TB regimen in pulmonary TB. However, there are conflicting clinical data regarding its benefit for TB meningitis, where outcomes may also be associated with intracerebral inflammation. We conducted cross-species studies in mice and rabbits, demonstrating that an intensified high-dose rifampin-containing regimen has significantly improved bactericidal activity for TB meningitis over the first-line, standard-dose rifampin regimen, without an increase in intracerebral inflammation. Positron emission tomography in live animals demonstrated spatially compartmentalized, lesion-specific pathology, with postmortem analyses showing discordant brain tissue and cerebrospinal fluid rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the same cohort of animals during TB treatment as well as imaging studies in two cohorts of TB patients demonstrated that spatiotemporal changes in localized blood-brain barrier disruption in TB meningitis are an important driver of rifampin brain exposure. These data provide unique insights into the mechanisms underlying high-dose rifampin in TB meningitis with important implications for developing new antibiotic treatments for infections.


Genetic modification of a chicken expression system for the galactosylation of therapeutic proteins produced in egg white.
As a tool for large scale production of recombinant proteins, chickens have advantages such as high productivity and low breeding costs compared to other animals. We previously reported the production of erythropoietin, the tumor necrosis factor receptor fused to an Fc fragment, and an Fc-fused single-chain Fv antibody in eggs laid by genetically manipulated chickens. In egg white, however, the incomplete addition of terminal sugars such as sialic acid and galactose was found on N-linked glycans of exogenously expressed proteins. This could be a draw back to the use of transgenic chickens since the loss of these terminal sugars may affect the functions and stability of recombinant proteins purified from chicken egg white for pharmaceutical usage. To overcome this problem, we studied galactosyltransferase (GalT) activity in the magnum where the majority of egg-white proteins are secreted. In the magnum, lower β1,4-GalT1 expression and poor galactose-transfer activity were observed. Thus, we supposed that the lack of GalT1 activity may partly cause the incomplete glycosylation of egg-white proteins, and generated genetically manipulated chickens expressing GalT1 by retrovirus-mediated gene transfer. In a Golgi fraction prepared from magnum cells of the genetically manipulated chickens, significant GalT activity was detected. The series of analyses revealed a considerable improvement in the galactosylation of native egg-white proteins as well as an exogenously expressed single-chain Fv antibody fused to an Fc fragment. We conclude that chickens with genetically modified GalT activity in the magnum could be an attractive platform for producing galactosylated therapeutics.


Fabrication of ROS-responsive nanoparticles by modifying the interior pore-wall of mesoporous silica for smart delivery of azoxystrobin.
The suboptimal efficiency in pesticide utilization may elevate residues, posing safety risks to human food and non-target organisms. To address this challenge, delivery systems, such as pathogen infection stimuli-responsive carriers, can be employed to augment the efficiency of fungicide utilization. The bursting of reactive oxygen species (ROS) is a common defense response of host plants to pathogenic infections. In this study, ROS-responsive mesoporous silica nanoparticles (MSN) modified with phenyl sulfide (PHS) as azoxystrobin (AZOX) carrier (MSN-PHS-AZOX) were fabricated. Results demonstrated that MSN-PHS-AZOX exhibited fungicide release kinetics dependent on ROS. In vitro inhibition experiments confirmed the fungicidal effect of MSN-PHS-AZOX on Botrytis cinerea, relying on external ROS. In vivo leaf experiments showcased the superior persistence of MSN-PHS-AZOX in compared to AZOX SC. Furthermore, MSN-PHS-AZOX exhibits favorable biosafety and lower toxicity to aquatic zebrafish compared to AZOX SC, with no adverse impact on cucumber leaf growth. These findings suggest the potential application of this ROS-responsive nano fungicide in managing plant disease in agricultural fields.


Household economic instability: Constructs, measurement, and implications.
A growing body of research demonstrates the multiple dimensions and dynamism of family income and employment. The metrics of household economic instability and their associations with household characteristics and hardship require further examination in order to compare across studies, subgroups, and historical periods. This paper empirically examines and compares commonly used measures of income and employment instability, how these measures inter-relate, vary by household characteristics, and how they predict household hardship. Using longitudinal data from the 2008 panel of the Survey of Income and Program Participation (SIPP), and focusing on households with children, this study examined a range of descriptive measures of economic instability, including in income, earnings, public assistance benefits, and employment status, and how these measures related to each other. Results indicate that overall rates of income and employment instability were high, particularly among less-educated families, those with young children, and those who did not own a home. Economic instability, particularly decreases in employment, was associated with increased household hardship three months later. Findings also show that the source of income included in the instability measure affects the patterns identified and conclusions drawn, whereas the specific type of measure used matters less. Results highlight the instability of public assistance benefits and suggest that safety net programs must take economic instability into account when designing programs and benefits.


Transmethylation inhibitors decrease chemotactic sensitivity and delay cell aggregation in Dictyostelium discoideum.
In Dictyostelium discoideum, extracellular cyclic AMP (cAMP) induces chemotaxis and cell aggregation. Suspensions of cAMP-sensitive cells respond to a cAMP pulse with a rapid, transient increase of protein carboxyl methylation. The transmethylation inhibitors cycloleucine, L-homocysteine thiolactone, and coformycin decrease chemotactic sensitivity and delay cell aggregation when administered in concentrations which do not influence cAMP binding to cell surface receptors or the activity of total phosphodiesterase. The ability of the drugs to inhibit chemotaxis could be correlated with their capacity to convert the initial transient positive response of carboxyl methylation to cAMP into a negative one. This suggests that both protein O-methyltransferase and protein methylesterase are activated after stimulation of aggregative cells with cAMP, the net effect being a transient, positive response of methylation. In the presence of a sufficiently large dose of inhibitor, methyltransferase is inhibited, whereas methylesterase activity is much less affected, so that a transient negative response of methylation to cAMP is observed. The slow, positive response of carboxyl methylation to cAMP which occurs ca. 2.5 to 5 min after stimulus administration is not affected by inhibitors of transmethylation. These results suggest that methylation reactions are involved in the chemotactic response of D. discoideum cells to cAMP.


Sysrev: A FAIR Platform for Data Curation and Systematic Evidence Review.
Well-curated datasets are essential to evidence based decision making and to the integration of artificial intelligence with human reasoning across disciplines. However, many sources of data remain siloed, unstructured, and/or unavailable for complementary and secondary research. Sysrev was developed to address these issues. First, Sysrev was built to aid in systematic evidence reviews (SER), where digital documents are evaluated according to a well defined process, and where Sysrev provides an easy to access, publicly available and free platform for collaborating in SER projects. Secondly, Sysrev addresses the issue of unstructured, siloed, and inaccessible data in the context of generalized data extraction, where human and machine learning algorithms are combined to extract insights and evidence for better decision making across disciplines. Sysrev uses FAIR - Findability, Accessibility, Interoperability, and Reuse of digital assets - as primary principles in design. Sysrev was developed primarily because of an observed need to reduce redundancy, reduce inefficient use of human time and increase the impact of evidence based decision making. This publication is an introduction to Sysrev as a novel technology, with an overview of the features, motivations and use cases of the tool. Methods: Sysrev. com is a FAIR motivated web platform for data curation and SER. Sysrev allows users to create data curation projects called "sysrevs" wherein users upload documents, define review tasks, recruit reviewers, perform review tasks, and automate review tasks. Conclusion: Sysrev is a web application designed to facilitate data curation and SERs. Thousands of publicly accessible Sysrev projects have been created, accommodating research in a wide variety of disciplines. Described use cases include data curation, managed reviews, and SERs.


Purification of a low molecular weight form of rat liver arginyl-tRNA synthetase.
Mammalian aminoacyl-tRNA synthetases are often found in several different molecular weight forms in the same extract, although the structural basis for this diversity is not clear. In this report, we describe the separation of high and low molecular weight forms of rat liver arginyl-tRNA synthetase, and the extensive purification to near homogeneity of the low molecular weight form of the enzyme, free of other aminoacyl-tRNA synthetases. The purified enzyme catalyses the incorporation into tRNA of 9,500 nmol of arginine/min/mg of protein under optimal assay conditions, corresponding to a turnover number of approximately 550 min-1. The molecular weight of the native enzyme was calculated to be approximately 59,000 based on a sedimentation coefficient of about 3.6 S and a Stokes radius of 39 A. The subunit molecular weight based on sodium dodecyl sulfate-acrylamide gel electrophoresis was also about 60,000, indicating that the enzyme is a monomer. The relation of this form of arginyl-tRNA synthetase to the high molecular weight form and its possible origin are discussed.


No decrease in myonuclear number after long-term denervation in mature mice.
Age-related but not artificially induced muscle fiber atrophy has been shown to occur without any decrease in myonuclear number, although these results remain controversial. The present study was carried out to clarify whether age difference affects the degree of decrease in myonuclear number occurring with denervation-induced fiber atrophy. After denervation of 3-wk-old (young) and 4-mo-old (mature) mice, single myofibers were isolated from the plantaris muscles by alkali maceration, and their fiber cross-sectional area (CSA), myonuclear number, and cytoplasm-to-myonucleus (C/N) ratios were analyzed. Fiber CSA in both young and mature mice decreased with denervation. Myonuclear number decreased in young mice 5 and 10 days after denervation but was unchanged in mature mice 10 and 120 days after denervation. C/N ratio decreased in mature mice but was unchanged in denervated young mice. These results suggest that age differences affect the degree of decrease of myonuclear number with denervation and that fiber cytoplasmic atrophy may occur without decrease in myonuclear number.


128 × 128 long-wavelength/mid-wavelength two-color HgCdTe infrared focal plane array detector with ultralow spectral cross talk.
High temporal and spatial coherent simultaneous long-wavelength/mid-wavelength (LW/MW) two-color focal plane array (FPA) infrared detection is the cutting-edge technique for third-generation infrared remote sensing. In this Letter, HgCdTe LW/MW two-color infrared detectors were designed and fabricated. The top long-wavelength and bottom mid-wavelength infrared planar photodiodes were processed by selective B(+)-implantation after etching the long-wavelength epilayer into a curvature and exposing the mid-wavelength layers for the implantation of the n region of the MW photodiode by a micro-mesa array technique. A 128×128 MW/LW HgCdTe infrared FPA detector is fabricated photo-lithographically by simultaneous nonplanar B(+)-implantation of the LW and MW photodiodes, passivation and metallization of the sidewalls, mesa isolation, and flip-chip hybridization with a read-out integrated circuit. The inner mechanisms for suppressing the cross talk and improving photoresponse have been carried out by combining experimental work with numerical simulations.


Fluorescence resonance energy transfer between polyphenolic compounds and riboflavin indicates a possible accessory photoreceptor function for some polyphenolic compounds.
The photoreceptive extreme tip of the wheat coleoptile exhibits intense green-yellow fluorescence under UV light, suggesting the presence of UV-absorbing materials. Fluorescence spectra of the intact coleoptile tip and tip homogenate showed the presence of the known photoreceptor pigments flavin and carotene, and a preponderance of phenolic compounds. Absorption spectra and fluorescence spectra of various phenolic compounds showed close overlap with the absorption and fluorescence spectra of the wheat coleoptile tip homogenate. Fluorescence spectra of several phenolic compounds showed close overlap with the absorption bands of flavin, carotene and pterine, suggesting possible energy transduction from phenols to these photoreceptors. Excitation of gentisic acid and ferulic acid with 340 nm light in the presence of flavin showed enhancement of flavin fluorescence in a concentration- and viscosity-dependent fashion, indicating fluorescence resonance energy transfer between them and riboflavin. Furthermore, several phenolic compounds tested generated superoxide anion on excitation at 340 nm, suggesting that superoxide-dependent signal cascades could operate in a polyphenol-mediated pathway. Phenolic compounds thus may act as accessory photoreceptors bringing about excitation energy transfer to the reactive photoreceptor molecules, or they may take over the function of the normal photoreceptor in genetic mutations lacking the system, or both processes may occur. The responses of plants to UV-B and UV-A light in mutants may be explained in terms of various phenolics acting as energy transducers in photoreceptor functioning.


The effectiveness and cost-effectiveness of behavioural interventions for the prevention of sexually transmitted infections in young people aged 13-19: a systematic review and economic evaluation.
To assess the effectiveness and cost-effectiveness of schools-based skills-building behavioural interventions to encourage young people to adopt and maintain safer sexual behaviour and to prevent them from acquiring sexually transmitted infections (STIs). Electronic bibliographic databases (e.g. MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, CINAHL, PsycINFO, CCRCT, NHS EED and DARE) were searched for the period 1985 to March 2008. Bibliographies of systematic reviews and related papers were screened and experts contacted to identify additional published and unpublished references. A systematic review of effectiveness and economic evaluation of cost-effectiveness were carried out. A descriptive map of studies that met inclusion criteria was produced, and keywords were developed and systematically applied to these studies to identify a policy-relevant subset of studies for the systematic review. Outcome data for variables including sexual behaviour were extracted. An economic model was developed to compare the costs and consequences of the behavioural interventions. A Bernoulli statistical model was constructed to describe the probability of STI infection. There were few significant differences between the interventions and comparators in terms of changes in sexual behaviour outcomes, although there were some significant differences for knowledge and some measures of self-efficacy. The studies included in this review conducted relatively short follow-up assessments at a time when many young people were becoming sexually active. It is therefore possible that favourable behaviour change may have occurred, and become more cost-effective, with time, as sexual activity becomes more routine in young people's lives. The quality of the intervention provider influenced whether or not young people found the interventions to be acceptable and engaging; enthusiasm and considerable expertise were important for effective class management and delivery of skills-building activities, and a supportive school culture was also helpful. Recognition of young people's individual needs in relation to sexual health was another important factor. No conclusions could be drawn on the impact of the interventions on sexual health inequalities due to a lack of relevant data on socioeconomic status, gender and ethnicity. The results of the economic evaluation were considered to be illustrative, mainly due to the uncertainty of the effect of intervention on behavioural outcomes. The results were most sensitive to changes in parameter values for the intervention effect, the transmission probability of STIs and the number of sexual partners. The costs of teacher-led and peer-led behavioural interventions, based on the resources estimated from the relevant randomised controlled trials in our systematic review, were 4.30 pounds and 15 pounds per pupil, respectively. Teacher-led interventions were more cost-effective than peer-led interventions due to the less frequent need for training. The incremental cost-effectiveness of the teacher-led and peer-led interventions was 20,223 pounds and 80,782 pounds per quality-adjusted life-year gained, respectively. An analysis of individual parameters revealed that future research funding should focus on assessing the intervention effect for condom use from a school-based intervention. School-based behavioural interventions for the prevention of STIs in young people can bring about improvements in knowledge and increased self-efficacy, but the interventions did not significantly influence sexual risk-taking behaviour or infection rates. Future investigation should include long-term follow-up to assess the extent to which safer sexual behaviour is adopted and maintained into adulthood, and prospective cohort studies are needed to look at the parameters that describe the transmission of STIs between partners. Funding should focus on the effectiveness of the interventions on influencing behaviour.


Cardiac beta-adrenoceptor blockade: the quest for selectivity.
In the search for improved drugs much attention has been focussed on the need for greater selectivity of action. Knowing that all drugs are poisons, the pharmacologist must attempt to define the required effect more narrowly but remain aware of potential unwanted effects. These may come as a result of the primary pharmacological effect or be due to other properties of the drug molecule manifesting themselves in clinical use. This paper illustrates the process of drug discovery and development with special reference to beta-adrenoceptor antagonists. Starting from the role of noradrenaline in sympathetic transmission, many compounds have been synthesized with therapeutic aims in mind. From a series of bronchodilators, dichloro-isoprenaline emerged which unexpectedly blocked stimulation of beta-receptors. This compound proved unsatisfactory leading to the introduction of the first clinically successful beta-blocker, pronethalol. Concern about potential carcinogenic effects led to its being replaced by propanolol. Failure to recognise the full range of clinical contra-indications resulted in propranolol causing severe cardio-vascular and bronchial adverse reactions. Soon it was recognized that propranolol was a powerful local anaesthetic potentially acting as a myocardial depressant. More serious was the recognition that in certain circumstances high levels of sympathetic tone were an adaptive response to pathophysiological change and that interruption by beta-blockade was inevitably serious for the patient. Attempts to identify the properties responsible for unwanted effects directed attention to comparison with non-local anaesthetic water soluble compounds still retaining beta-blocking activity. One such compound, practolol, also proved to exhibit a higher affinity for beta-receptors in the heart than elsewhere leading to the concept of cardioselective beta-blockade. The pharmacology of this agent is reviewed but it proved to have unacceptable side effects in clinical use. The importance of practolol was to demonstrate that anginal relief was due to beta-blockade and not local anaesthetic activity. It also showed that cardiovascular adverse reactions and bronchospasm were significantly less common than with propranolol. However, in addition to being cardioselective, practolol also showed intrinsic sympathomimetic activity. This resulted in a smaller bradycardia at rest. Contrary to predictions this property did not prevent practolol becoming well accepted by both doctors and patients as an effective anti-anginal drug. It was the unrelated skin, eye and mucous membrane reactions which led to the compound being withdrawn.(ABSTRACT TRUNCATED AT 400 WORDS)


S1 nuclease mapping of viral RNAs from a temperature-sensitive transformation mutant of murine sarcoma virus.
The structures of murine sarcoma virus (MuSV) ts110 viral RNA and intracellular RNA present in MuSV ts110-infected cells (6m2 cells) have been examined by S1 nuclease analysis. A previous study involving heteroduplex analysis of MuSV ts110 viral RNAs hybridized to wild-type DNA revealed the presence of two MuSV ts110 RNAs, 4.0 and 3.5 kilobases (kb) in length, containing overlapping central deletions relative to wild-type MuSV 124 viral RNA (Junghans et al., J. Mol. Biol. 161:229-255, 1982). Here we show that the deletion (termed delta 1) in the 4.0-kb RNA has a 5' border located at about nucleotide 2409 (using the numbering system of Van Beveren et al., Cell 27:97-108, 1981), a position 63 bases upstream of the junction of the p30 and p10 coding sequences. The 3' border of the delta 1 deletion is found 1,473 bases downstream at approximately nucleotide 3883, 10 nucleotides downstream of the first mos gene initiation codon. In the 3.5-kb MuSV ts110 RNA, the 5' border of the deleted central region (termed delta 2) is located in a splice consensus donor site at approximately nucleotide 2017, 330 bases downstream from the junction of the p12 and p30 coding sequences, and extends about 1,915 bases in the downstream direction to nucleotide 3935, found in a splice consensus acceptor site about 55 nucleotides downstream of the first mos gene initiation codon and 30 bases upstream of the second initiation codon. No alteration of polyadenylate addition sites was observed in either MuSV ts110 RNA species, as compared with MuSV 349 RNA. The observation that the 5' and 3' borders of the deletion in the 3.5-kb RNA are within in-frame splice donor and acceptor sites suggests strongly that the 3.5-kb RNA is derived from the 4.0-kb RNA by a temperature-sensitive splice mechanism. Data presented here show unequivocally that formation of the 3.5-kb MuSV ts110 RNA from which the P85gag-mos polypeptide is translated is temperature sensitive. At 33 degrees C, with S1 analysis, the 3.5-kb RNA is found readily in 6m2 cells. Within 4 h of a shift to 39 degrees C, however, only trace amounts of this RNA can be found. Moreover, reshifting 6m2 cells to 33 degrees C permits the reappearance of the 3.5-kb RNA at its original level.


Metric analysis of basal sphenoid angle in adult human skulls.
To analyze the variations in the angle basal sphenoid skulls of adult humans and their relationship to sex, age, ethnicity and cranial index. The angles were measured in 160 skulls belonging to the Museum of the Universidade Federal de São Paulo Department of Morphology. We use two flexible rules and a goniometer, having as reference points for the first rule the posterior end of the ethmoidal crest and dorsum of the sella turcica, and for the second rule the anterior margin of the foramen magnum and clivus, measuring the angle at the intersection of two. The average angle was 115.41°, with no statistical correlation between the value of the angle and sex or age. A statistical correlation was noted between the value of the angle and ethnicity, and between the angle and the horizontal cranial index. The distribution of the angle basal sphenoid was the same in sex, and there was correlation between the angle and ethnicity, being the proportion of non-white individuals with an angle >125° significantly higher than that of whites with an angle >125°. There was correlation between the angle and the cranial index, because skulls with higher cranial index tend to have higher basiesfenoidal angle too.


[The T mu- and T gamma-lymphocyte count and their ratio in patients with brucellosis of various focal natures].
The content of T mu- and T gamma-lymphocytes and their ratio in patients having subacute and chronic brucellosis with different foci of infection have been studied. The relationship between the decrease in the levels of T mu- and T gamma-cells and the clinical form of the disease and its clinical manifestations, such as polyarthritis, has been established. Manifestations of disturbances in the T mu-cell/T gamma-cell ratio were more pronounced in patients with subacute brucellosis in whom the lesions of the osteoarticular system prevailed. The detected changes in the counts of immunoregulatory cells in brucellosis are assumed to be of pathogenetic importance.


Preliminary results of a phase III trial of spontaneous animal tumors to heat and/or radiation: early normal tissue response and tumor volume influence on initial response.
A Phase III randomized trial was initiated to test the relative efficacies of heat alone, radiation alone and heat plus radiation using spontaneous malignancies in pet animals. Heat alone was inferior to the other two treatment arms as demonstrated by a significantly higher non-response rate and shorter response duration. The ratio of complete response rates (CR) for heat plus radiation to radiation alone or the thermal relative risk (TRR) was greater for tumors greater than 10 cm3 as compared to those less than 10 cm3 (TRR = 4.8 and 1.4, respectively). The overall TRR for complete responses was 2.3. The CR data for the combined therapy arm indicate at least an additive effect between heat and radiation for small tumors but most likely a synergistic effect in the larger tumor group. Based on the data currently available, no significant difference in response duration is observed between the two radiation arms, although a nonsignificant advantage to the combination therapy exists. Normal tissue effects were evaluated by incidence of full moist desquamation within the irradiated volume, late fibrosis and bone necrosis. Since the radiation skin dose depended upon the technique being used it was possible to estimate the dose to achieve moist desquamation in 50% of the animals (DD50) by a logistic regression model as being 3728 +/- 344 rad for radiation alone. Significant lowering of the DD50 was not observed for the addition of heat to radiation. Low patient numbers where intact skin was heated prevented an accurate analysis of the effect, however.


Cortical circuit alterations precede motor impairments in Huntington's disease mice.
Huntington's disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronic in vivo two-photon calcium imaging to longitudinally monitor the activity of identified single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in cortical network function, with an increase in activity that affects a large fraction of cells and occurs rather abruptly within one week, preceeding the onset of motor defects. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and human HD autopsy cases reveal a reduction in perisomatic inhibitory synaptic contacts on layer 2/3 pyramidal cells. Taken together, our study provides a time-resolved description of cortical network dysfunction in behaving HD mice and points to disturbed excitation/inhibition balance as an important pathomechanism in HD.


Estimated HIV incidence among high-risk heterosexuals in New York City, 2007.
Estimates of HIV incidence rates among high-risk heterosexuals (HRH) in the United States have been limited to heterosexual subgroups like prison inmates and commercial sex workers. In this analysis, we estimate incidence with detuned assay testing among a group of HRH defined through a multidimensional sampling strategy and recruited through respondent-driven sampling. Incidence was 3.31% per year (95% confidence interval = 1.43 to 6.47) overall and 2.59% per year (95% confidence interval = 0.84 to 6.06) among participants with no lifetime history of drug injection or male-to-male sex. This study design is suggested as an efficient method for recruiting HRH for cohort studies and behavioral interventions.


An mHealth Workplace-Based "Sit Less, Move More" Program: Impact on Employees' Sedentary and Physical Activity Patterns at Work and Away from Work.
Most workplace interventions that aim to reduce sedentary behaviour have 38 focused on employees' sedentary patterns at-work but less have focused on understanding the 39 impact beyond working time. The aim of this study was to evaluate the impact of a 13-week m-40 health workplace-based 'sit less, move more' intervention (Walk@WorkApp; W@W-App) on 41 physical activity (PA) and sitting in desk-based employees at-work and away from work. Participants (n = 141) were assigned by hospital to an intervention group (IG; used the W@W-App; n = 90) or an active comparison group (A-CG; monitored occupational activity; n = 51). The W@W-App, installed on the participants´ own smartphones, provided real-time feedback for occupational sitting, standing, and stepping, and gave access to automated strategies to sit less and move more at work. Changes between groups were assessed for total sitting time, sedentary bouts and breaks, and light and moderate-to-vigorous PA (activPAL3TM; min/day) between the baseline and after program completion. Compared to the A-CG, employees that used the W@W-App program increased their number of daily breaks and the time spent on short sedentary bouts (<20 min, p = 0.047) during weekends. Changes in shortest sedentary bouts (5-10 min) during weekends were also statistically significant (p < 0.05). No changes in workday PA or sitting were observed. Desk-based employees seemed to transfer the W@W-App program knowledge outside of work. Evaluating the impact of workplace (mHealth-based or not) interventions at work but also away from work would provide a better understating of the impact of such interventions.


How much for a star? Elements for a rational choice of sample size in preclinical trials.
In the preclinical field, preliminary estimation of the number of experimental units to be included in a study is an important step in the setting up of the study. This estimation must be based on a dialogue between the experimenter and the statistician. This article, intended for both experimenters and statisticians, is designed to facilitate their dialogue by describing certain elements that are involved in the calculation of the optimal sample size in addition to the factors that influence their quantification. The proposed approach will result in better analysis of each experiment and, therefore, more globally, in rationalization of the use of experimental units.


Intergovernmental policy opportunities for childhood obesity prevention in Australia: Perspectives from senior officials.
Early childhood (from conception to five years) is a key life stage for interventions to prevent obesity. In the Australian Federation, policy responsibility for obesity prevention sits across all levels of government and several intergovernmental institutions, rendering a complicated policy space. There is a gap in our understanding of the role of intergovernmentalism in developing obesity prevention policy in Australia. Given the complexity of intergovernmental structures and initiatives influencing childhood obesity prevention policy, it is important to understand the perspectives of senior health officials within the bureaucracy of government who through their roles may be able to influence processes or new strategies. Document analysis relating to obesity prevention in the intergovernmental context provided material support to the study. This analysis informed the interview guides for nine interviews with ten senior health department officials (one interview per jurisdiction). Several opportunities exist to support nutrition and obesity prevention in early childhood including marketing regulation (discretionary choices, breastmilk substitutes, commercial complementary foods and 'toddler milks') and supporting the early childhood education and care sector. This study found a widening structural gap to support national obesity policy in Australia. New public management strategies limit the ability of intergovernmental institutions to support coordination within and between governments to address complex issues such as obesity. Subnational informants perceived a gap in national leadership for obesity prevention, while a Commonwealth informant noted the commitment of the national government to partner with industry under a self-regulation model. In this gap, subnational leaders have pursued nationally consistent action to address obesity, including the development of a national obesity strategy as a bipartisan endeavour across jurisdictions. Public officials calculate the strategic possibilities of pursuing opportunities within state agendas but note the limited chances of structural change in the absence of national leadership and funding.


Novel PHEX nonsense mutation in a patient with X-linked hypophosphatemic rickets and review of current therapeutic regimens.
The most common form of familial hypophosphatemic rickets is X-linked. PHEX has been identified as the gene defective in this phosphate wasting disorder leading to decreased renal phosphate reabsorption, hypophosphatemia and inappropriate concentrations of 1,25-dihydroxyvitamin D in regard to hypophosphatemia. Clinical manifestation are skeletal deformities, short stature, osteomalacia, dental abscesses, bone pain, and loss of hearing. We report 3 cases of hypophosphatemic rickets with genetic mutational analysis of the PHEX gene. In 1 male patient an unknown nonsense mutation was found in exon 7, codon 245 (c.735T>G, Tyr245Term, Y245X). In both female patients known mutations were found: c.682delTC (exon 6, codon 228) and c.1952G>C (exon 19, codon 651, R651P). Age at diagnosis ranged from early childhood to the age of 35 years. Clinical complications were hip replacement in 1 patient, mild nephrocalcinosis in 2 patients and loss of hearing in 1 patient. All 3 patients have been treated with phosphate supplements and receive 1,25-dihydroxyvitamin D. Under this regimen all patients show stable biochemical markers with slight hyperparathyreoidism. In all patients at least one family member is affected by rickets, as well. We report a novel nonsense mutation of PHEX that has not been identified so far. The recent discovery of FGF23 and MEPE has changed our understanding of the kidney-bone metabolism, but also raises concerns about the efficacy of current therapeutic regimens that are reviewed in this context.


Osteopontin--a fibrosis-related marker--in dilated cardiomyopathy in patients with Emery-Dreifuss muscular dystrophy.
As osteopontin (OPN) may be assumed to have diagnostic/prognostic value in heart diseases, it is worth assessing whether it is also involved in the pathogenesis and can be applied in the diagnosis of the dilated cardiomyopathy (DCM) in Emery-Dreifuss muscular dystrophy (EDMD). Serum levels of osteopontin were quantified by means of sandwich immunoassay in 25 EDMD patients (10 laminopathies AD-EDMD and 15 emerinopathies--X-EDMD), eight carriers of X-EDMD, nine disease controls (patients with dystrophinopathy) and 20 age-matched healthy controls. The levels of circulating OPN were elevated in all AD-EDMD and X-linked EDMD patients, as well as in X-EDMD carriers and patients suffering progressive muscular dystrophy. There was no correlation between the osteopontin level and different cardiac parameters, including left-ventricular end-diastolic diameter, left atrial diameter, the left ventricular ejection fraction and the CK-MB level. There was a slight negative correlation with the ages of the patients. The presented results indicate that assessments of circulating OPN levels may help to identify EDMD patients at risk of dilated cardiomyopathy and might be therefore included among the set of biomarkers referred to with a view to appropriate early cardiologic diagnosis and therapy being commenced with in time.


Changing culture: An intervention to improve blood culture quality in the emergency department.
Blood cultures (BCs) remain a key investigation in ED patients at risk of bacteraemia. The aim of this study was to assess the effect of a multi-modal, nursing-led intervention to improve the quality of BCs in the ED, in terms of single culture, underfilling and contamination rates. The present study was conducted in the ED of a large urban tertiary referral hospital. The study included four phases: pre-intervention, intervention, post-intervention and sustainability periods. A multi-modal intervention to improve BC quality consisting small group education, posters, brief educational videos, social media presence, quality feedback, small group/individual mentoring and availability of BC collection kits was designed and delivered by two senior ED nurses over 7 weeks. Study data comprised rates of single, underfilled and contaminated cultures in each of three 18-week periods: pre-intervention (baseline), post-intervention and sustainability. Over the study period 4908 BC sets were collected during 2347 episodes of care in the ED. Single culture sets reduced from 56.2% in the pre-intervention period to 22.8% post-intervention (P < 0.01) and 18.8% in the sustainability period (P < 0.01). Underfilled bottle rates were also significantly reduced (aerobic 52.8% pre-intervention to 19.2% post-intervention, 18.8% sustainability, anaerobic 46.8% pre-intervention to 23.3% post-intervention, 23.8% sustainability). Skin contaminants were grown from 3.7% of BC sets in the pre-intervention period, improving to 1.5% in the post-intervention period (P < 0.001) and 2.1% in the sustainability period (P = 0.03). Total volume of blood cultured was significantly associated with diagnosis of bacteraemia. Significant improvements in BC quality are possible with nursing-based interventions in the ED.


Excited-state relaxation in PbSe quantum dots.
In solids the phonon-assisted, nonradiative decay from high-energy electronic excited states to low-energy electronic excited states is picosecond fast. It was hoped that electron and hole relaxation could be slowed down in quantum dots, due to the unavailability of phonons energy matched to the large energy-level spacings ("phonon-bottleneck"). However, excited-state relaxation was observed to be rather fast (< or =1 ps) in InP, CdSe, and ZnO dots, and explained by an efficient Auger mechanism, whereby the excess energy of electrons is nonradiatively transferred to holes, which can then rapidly decay by phonon emission, by virtue of the densely spaced valence-band levels. The recent emergence of PbSe as a novel quantum-dot material has rekindled the hope for a slow down of excited-state relaxation because hole relaxation was deemed to be ineffective on account of the widely spaced hole levels. The assumption of sparse hole energy levels in PbSe was based on an effective-mass argument based on the light effective mass of the hole. Surprisingly, fast intraband relaxation times of 1-7 ps were observed in PbSe quantum dots and have been considered contradictory with the Auger cooling mechanism because of the assumed sparsity of the hole energy levels. Our pseudopotential calculations, however, do not support the scenario of sparse hole levels in PbSe: Because of the existence of three valence-band maxima in the bulk PbSe band structure, hole energy levels are densely spaced, in contradiction with simple effective-mass models. The remaining question is whether the Auger decay channel is sufficiently fast to account for the fast intraband relaxation. Using the atomistic pseudopotential wave functions of Pb(2046)Se(2117) and Pb(260)Se(249) quantum dots, we explicitly calculated the electron-hole Coulomb integrals and the P-->S electron Auger relaxation rate. We find that the Auger mechanism can explain the experimentally observed P-->S intraband decay time scale without the need to invoke any exotic relaxation mechanisms.


Solar urticaria: a report on 57 cases.
Solar urticaria (SU) represents an uncommon skin disorder, characterized by pruritic erythema and wheals after sun exposure, that sometimes restricts normal daily life. To evaluate data concerning sex, age, natural history, associated diseases, and eliciting wavebands of 57 SU cases. Questionnaire for anamnestic data, laboratory examinations, phototesting. Sex: 25 (44%) males, 32 (56%) females. Age: The peak age was between 20 and 30 years. Skin type (ST): 12 (21%) ST II, 39 (68%) ST III, and 6 (11%) ST IV. Time between onset and complete disappearance of SU was from 2 to more than 6 years; the main peak (37 patients) between 4 and 6 years. There were histories of atopic dermatitis 12 (21%) and asthma or rhinitis 15 (26%). Association with other urticarias (U): 13 (21%) dermographic U, 2 food U, 3 heat U. Increased immunoglobin E (IgE): 19 (33%). Eliciting wavebands: 38 (67%) visible light (VIS), 16 (28%) long ultraviolet (UVA), 3 natural sunlight. Minimal urticarial dose (MUD): 20-37.5 J/cm2 for VIS-sensitive patients, 5-10 J/cm2 for UVA. In our series: 1. SU affects both sexes usually when they are under 30 years of age; 2. nearly half the patients are free of disease within 5 years; 3. in about one fourth of cases SU is associated with dermographic urticaria or displays a history of atopic dermatitis; 4. the wheals are elicited mainly by VIS or UVA; 5. SU can be prevented, at least in part, by antihistamines or by PUVA therapy.


The epidermal growth factor receptor (EGF-R) is present on the basolateral, but not the apical, surface of enterocytes in the human gastrointestinal tract.
While it is clear that luminal epidermal growth factor (EGF) stimulates repair of the damaged bowel, its significance in maintaining normal gut growth remains uncertain. If EGF is important in maintaining normal gut growth, the EGF receptor (EGF-R) should be present on the apical (luminal) surface in addition to the basolateral surface. AIMS/SUBJECTS/METHODS: This study examined the distribution of the EGF-R in the epithelium throughout the human gastro-intestinal tract using immunohistochemistry, electron microscopy, and western blotting of brush border preparations. Immunostaining of the oesophagus showed circumferential EGF-R positivity in the cells of the basal portions of the stratified squamous epithelium but surface cells were EGF-R negative. In the normal stomach, small intestine, and colon, immunostaining localised the receptor to the basolateral surface with the apical membranes being consistently negative. EGF-R positivity within the small intestine appeared to be almost entirely restricted to the proliferative (crypt) region. Western blotting demonstrated a 170 kDa protein in whole tissue homogenates but not in the brush border vesicle preparations. As the EGF-R is located only on the basolateral surfaces in the normal adult gastrointestinal tract, the major role of luminal EGF is probably to stimulate repair rather than to maintain normal gut growth.


Bacterial flora of the hemolymph of the blue crab, Callinectes sapidus: numerical taxonomy.
Bacteria isolated from the hemolymph of normal blue crabs were found to be predominantly Vibrio sp., Pseudomonas sp., Acinetobacter sp., Bacillus sp., Flavobacterium sp., and coliforms. Vibrio parahaemolyticus, a cosmopolitan facultative pathogen widely implicated in outbreaks of gastroenteritis related to the consumption of improperly processed seafood, was present in crabs collected between the months of May to November and was identified in up to 21% of the hemolymphs sampled.


Effect of hepatic glucose infusion on glucose intake and licking microstructure in deprived and nondeprived rats.
The effects of hepatic-portal glucose or saline infusions on intake and the temporal distribution of licking (lick microstructure) were evaluated in nondeprived and in 20.5-h food-deprived rats. Rats received portal infusions of isotonic glucose or saline (0.1 ml/min) for 2 h before and then throughout a 90-min period of access to a spout that delivered 12.5% glucose. Overall, a significant treatment-related intake suppression was obtained in nondeprived but not in deprived groups. For both groups, however, there was a significant positive linear relationship between the amount individual rats consumed under the saline (baseline) infusion condition and the extent to which portal glucose infusion suppressed intake. The linear fit for the deprived group was similar in slope, but right shifted, relative to the best fit for the nondeprived group. The individual-subject and group differences in response to portal glucose infusion are discussed in relation to the inconsistent literature on this treatment's short-term intake effects. We focused analysis of the licking pattern on those rats for which a prominent portal glucose infusion effect was obtained (i.e., nondeprived rats with higher than average baseline intakes). Features of the lick pattern associated with taste evaluation (1st min lick rate; lick burst duration) were not significantly affected by portal glucose infusion. Rather, the minute-by-minute rate of ingestion under glucose infusion declined more rapidly than under baseline tests, indicating that portal glucose infusion enhanced the inhibitory influence of the accumulating postingestive load.


Physiological roles of K+ channels in vascular smooth muscle cells.
In this review, we present the basic properties, physiological functions, regulation, and pathological alterations of four major classes of K+ channels that have been detected in vascular smooth muscle cells. Voltage-dependent K+ (Kv) channels open upon depolarization of the plasma membrane in vascular smooth muscle cells. The subsequent efflux of K+ through the channels induces repolarization to the resting membrane potential. Changes in the intracellular Ca2+ concentration and membrane depolarization stimulate large-conductance Ca2+-activated K+ (BKCa) channels, which are thought to play an important role in maintaining the membrane potential. ATP-sensitive K+ (K(ATP)) channels underscore the functional bond between cellular metabolism and membrane excitability. The blockade of KATP channel function results in vasoconstriction and depolarization in various types of vascular smooth muscle. Inward rectifier K+ (Kir) channels, which are expressed in smooth muscle of the small-diameter arteries, contribute to the resting membrane potential and basal tone. Kir channel activation has been shown to raise the extracellular K+ concentration to 10-15 mM, resulting in vasodilation. Each of K+ channels listed above is responsive to a number of vasoconstrictors and vasodilators, which act through protein kinase C (PKC) and protein kinase A (PKA), respectively. Impaired Kv, KATP, and Kir channel functions has been linked to a number of pathological conditions, which may lead to vasoconstriction.


[The effect of proton therapy on the protein-amino acid metabolism in Itsenko-Cushing disease].
The composition and blood concentration of free aminoacids and other aminocompounds were investigated using automatic aminoacid analysis by a physiological program in 12 patients with diagnosed corticotropin secreting hypophyseal disease (Itsenko-Cushing disease) before and 1-3 years after proton "hypophysectomy". Imbalance of components of the glucose-alanine cycle, expressed in hypoalaninemia and raised concentration of aminoacids with a bifurcated lateral chain, was detected against a background of marked hypercorticotropinemia and hypercorticolism. Single irradiation of the pituitary gland with a proton beam at absorbed doses of 100-120 Gy in the maximum of a deep field resulted in remission and normalization of aminograms of blood plasma (suggesting pathogenicity of proton-beam therapy) for 6-12 mos. The authors discussed probable mechanisms of the interrelationship of protein-amino-acid and carbohydrate metabolic derangements and their correlation with a type of changes in the hormonal balance.


As we were and as we Should Be, Combined Exercise Training in Adults with Schizophrenia: CORTEX-SP Study Part I.
Given the health benefits and the role of exercise as an anti-inflammatory adjuvant program, this study aimed to determine the effectiveness of a combined exercise program on cardiorespiratory fitness (CRF), body composition, and biochemical levels in adults with schizophrenia (SZ) characterized at baseline as metabolically unhealthy overweight with low CRF. Participants diagnosed with SZ (n = 112, 41.3 ± 10.4 yr, 28.7% women) were randomly assigned into a Treatment-As-Usual (TAU) control group (n = 53) or a supervised exercise group (n = 59, 3 days/week). Each combined exercise session consisted of both a low-volume high-intensity interval training (less than 10 min of high-intensity time per session) and a resistance circuit-training program. All variables were assessed pre-and post-intervention (20 weeks). For the assessment of CRF, a peak cardiopulmonary exercise test on a cycle ergometer was used. Following the intervention, participants from the exercise group (n = 51) showed increases in CRF (P < 0.001) through peak oxygen uptake (L·min-1; Δ = 17.6%; mL·kg.1·min-1, Δ = 19.6%) and the metabolic equivalent of task (Δ = 19%), with no significant changes (P > 0.05) in body composition and biochemical variables. However, the TAU group (n = 38) did not show any significant change in the study variables (P > 0.05). Between-group significant differences (P ≤ 0.05) were observed in CRF, first ventilatory threshold, and heart rate peak after the intervention period favoring the exercise group. This study demonstrated that a supervised combined exercise program in people with SZ helps to maintain body composition values and improve CRF levels. This could lead to an important clinical change in the characterization from metabolically unhealthy overweight to a metabolically healthy overweight population. Hence, exercise should be considered a co-adjuvant program in the treatment of the SZ population.


Evidence for the expression of Ia (H-2-associated) antigens on thymus-derived lymphocytes.
We have demonstrated in an anti-Ia serum the presence of specific antibodies reacting with T cells, as well as with B cells, using a highly sensitive dye exclusion test. This antiserum reacts with both spleen and lymph node in a characteristic biphasic titration curve killing up to 70% of these cells. It also reacts with cortisone-resistant thymocytes. The A.TH-alpha-A.TL serum can be absorbed with spleen, lymph node, cortisone-resistant thymus, or normal thymus cells. Further in vivo absorptions in BALB/c nude cannot remove all of the cytotoxic activity for normal BALB lymph node lymphocytes, while completely removing the activity for nude cells. A Thy-1 positive cell line derived from a C57Br leukemia is reactive with this anti-Ia serum.


Fish Oil Protects Wild Type and Uncoupling Protein 1-Deficient Mice from Obesity and Glucose Intolerance by Increasing Energy Expenditure.
The mechanisms and involvement of uncoupling protein 1 (UCP1) in the protection from obesity and insulin resistance induced by intake of a high-fat diet rich in omega-3 (n-3) fatty acids are investigated. C57BL/6J mice are fed either a low-fat (control group) or one of two isocaloric high-fat diets containing either lard (HFD) or fish oil (HFN3) as fat source and evaluated for body weight, adiposity, energy expenditure, glucose homeostasis, and inguinal white and interscapular brown adipose tissue (iWAT and iBAT, respectively) gene expression, lipidome, and mitochondrial bioenergetics. HFN3 intake protected from obesity, glucose and insulin intolerances, and hyperinsulinemia. This is associated with increased energy expenditure, iWAT UCP1 expression, and incorporation of n-3 eicosapentaenoic and docosahexaenoic fatty acids in iWAT and iBAT triacylglycerol. Importantly, HFN3 is equally effective in reducing body weight gain, adiposity, and glucose intolerance and increasing energy expenditure in wild-type and UCP1-deficient mice without recruiting other thermogenic processes in iWAT and iBAT, such as mitochondrial uncoupling and SERCA-mediated calcium and creatine-driven substrate cyclings. Intake of a high-fat diet rich in omega-3 fatty acids protects both wild-type and UCP1-deficient mice from obesity and insulin resistance by increasing energy expenditure through unknown mechanisms.


Effects of fluorine-containing usnic acid and fungus Beauveria bassiana on the survival and immune-physiological reactions of Colorado potato beetle larvae.
The search for compounds that interact synergistically with entomopathogenic fungi is aimed at enhancing the efficacy and stability of biological products against pest insects, for example, against the Colorado potato beetle (CPB). We hypothesized that fluorine-containing derivatives of usnic acid (FUA) might be candidates for the development of multicomponent bio-insecticides. The aim of this study was to analyze the co-influence of FUA and Beauveria bassiana on the survival and immune-physiological reactions of CPB larvae. Synergy between FUA and B. bassiana was observed after treatment of second, third and fourth larvae instars under laboratory conditions. Furthermore, synergy was observed in field trials in continental climate conditions in southeastern Kazakhstan. In a field experiment, the median lethal time was shortened three-fold, and cumulative mortality for 15 days increased by 36% in the combined treatment compared with a fungal infection alone. FUA treatment delayed larval development, decreased the total hemocyte count, and increased both the phenoloxidase activity in integuments and the detoxification enzyme rate in hemolymph. A combined treatment with fungus and FUA led to increases in the aforementioned changes. Toxicosis caused by FUA provides a stable synergistic effect between FUA and B. bassiana. The combination can be promising for the development of highly efficient products against CPB. © 2017 Society of Chemical Industry.


γ-Aminobutyric acid-, glycine-, and glutamate-immunopositive boutons on mesencephalic trigeminal neurons that innervate jaw-closing muscle spindles in the rat: ultrastructure and development.
Unlike other primary sensory neurons, the neurons in the mesencephalic trigeminal nucleus (Vmes) receive most of their synaptic input onto their somata. Detailed description of the synaptic boutons onto Vmes neurons is crucial for understanding the synaptic input onto these neurons and their role in the motor control of masticatory muscles. For this, we investigated the distribution of γ-aminobutyric acid (GABA)-, glycine-, and glutamate-immunopositive (+) boutons on Vmes neurons and their ultrastructural parameters that relate to transmitter release: Vmes neurons that innervate masseteric muscle spindles were identified by labeling with horseradish peroxidase injected into the muscle, and immunogold staining and quantitative ultrastructural analysis of synapses onto these neurons were performed in adult rats and during postnatal development. The bouton volume, mitochondrial volume, and active zone area of the boutons contacting labeled somata (axosomatic synapses) were similar to those of boutons forming axoaxonic synapses with Vmes neurons but smaller than those of boutons forming axodendritic or axosomatic synapses with most other neurons. GABA+ , glycine+ , and glutamate+ boutons constituted a large majority (83%) of all boutons on labeled somata. A considerable fraction of boutons (28%) was glycine(+) , and all glycine+ boutons were also GABA+ . Bouton size remained unchanged during postnatal development. These findings suggest that the excitability of Vmes neurons is determined to a great extent by GABA, glycine, and glutamate and that the relatively lower synaptic strength of axosomatic synapses may reflect the role of the Vmes neurons in modulating orofacial motor function.


Cutaneous Dengue Virus Inoculation Triggers Strong B Cell Reactions but Contrastingly Poor T Cell Responses.
Dengue is a global health problem without current specific treatment nor safe vaccines available. While severe dengue is related to pre-existing non-neutralizing dengue virus (DENV) antibodies, the role of T cells in protection or pathology is unclear. Using cutaneous DENV infection in immunocompetent mice we previously showed the generation of PNA+ germinal centers (GCs), now we assessed the activation and proliferation of B and T cells in draining lymph nodes (DLNs). We found a drastic remodelling of DLN compartments from 7 to 14 days post-infection (dpi) with greatly enlarged B cell follicles, occupying almost half of the DLN area compared to ~24% in naïve conditions. Enormous clusters of proliferating (Ki-67+) cells inside B follicles were found 14 dpi, representing ~33% of B cells in DLNs but only ~2% in non-infected mice. Inside GCs, we noticed an important recruitment of tingle body macrophages removing apoptotic cells. In contrast, the percentage of paracortex area and total T cells decreased by 14-16 dpi, compared to controls. Scattered randomly distributed Ki-67+ T cells were found, similar to non-infected mice. CD69 expression by CD4+ and CD8+ T cells was minor, while it was remarkable in B cells, representing 1764.7% of change from basal levels 3 dpi. The apparent lack of T cell responses cannot be attributed to apoptosis since no significant differences were observed compared to non-infected mice. This study shows massive B cell activation and proliferation in DLNs upon DENV infection. In contrast, we found very poor, almost absent CD4+ and CD8+ T cell responses.


Junction formation between cultured normal rat hepatocytes. An ultrastructural study on the presence of cholesterol and the structure of developing tight-junction strands.
In cultures of normal rat hepatocytes, isolated by collagenase perfusion, formation of junctions started 4-7 h after seeding. The junctional complexes were localized at two preferential sites of the contiguous membrane: apically and on both sides of open spaces with microvilli at some distance from the upper surface. The domains of early contact formation are characterized by a flattening of the membranes, a decrease in intercellular space, a depletion of intramembrane particles (IMPs) and a concentration of electron-dense and of fine fibrillar material in the cytoplasm immediately adjacent to the membrane. We were able to demonstrate the presence of cholesterol in these domains by formation of cholesterol-filipin complexes that deformed the membrane. However, membrane-deformation in these domains was often inhibited. This inhibition appeared to be due to the presence of pepsin-sensitive material, since full deformation was induced after mild proteolysis. The arrangement of IMPs into small gap junctions and short tight-junction strands is synchronous in the membranes of the neighbouring cells. The tight junctions are composed of two strands arranged in a slightly offset configuration. The possibility that the strands are lipidic in nature is not excluded.


Severe hypoglycemia from Helicobacter pylori triple-drug therapy and insulin detemir drug interaction.
Two drugs commonly used in triple-drug therapy for treatment of a Helicobacter pylori infection, clarithromycin and omeprazole, have rarely been associated with hypoglycemia when given alone. No documented interactions between H. pylori treatment with clarithromycin, amoxicillin, and omeprazole and insulin detemir have been previously reported. This case report describes an 82-year-old man with drug-controlled type 2 diabetes who experienced severe hypoglycemia during treatment for a H. pylori infection in an outpatient setting. His diabetes treatment included 32 units of insulin detemir once/day at bedtime and insulin aspart, determined by carbohydrate intake, 3 times/day with meals. After 5 days of clarithromycin 500 mg twice/day, amoxicillin 500 mg twice/day, and omeprazole 20 mg twice/day for treatment of the H. pylori infection, the patient experienced hypoglycemia and self-discontinued clarithromycin. Insulin detemir was decreased to 15 units and hypoglycemia reoccurred. Insulin detemir was further decreased to 10 units without further symptoms of hypoglycemia for the remainder of the H. pylori treatment. Once treatment was completed, the patient was instructed to resume taking 32 units of insulin detemir once/day. His blood glucose concentration returned to a baseline value, and he denied experiencing further hypoglycemic episodes. Health care practitioners should be aware of this possible drug interaction and anticipate that insulin detemir dosage adjustments may be required during treatment of H. pylori infection to avoid significant adverse events.


[Bloodstream Candida infections].
Nosocomial Candida infection is an everincreasing cause of morbidity, mortality and prolonged hospitalization of the patients in intensive care units. The increase of the candidiasis cases is due to growing population of immunocompromised patients and the use of new, aggressive, and invasive therapeutic strategies. Some manifestations of Candida albicans infections are associated with formation of biofilms on the surface of biomaterials. The incidence, epidemiology, clinical characteristics and treatment of Candida bloodstream infections are surveyed.


Enzyme-linked immunosorbent assay with polyvalent gonococcal antigen.
An indirect enzyme-linked immunosorbent assay (ELISA) with a mixture of eight different gonococcal outer-membrane proteins (OMP) as coating antigen was evaluated for detection of gonococcal antibody in 507 sera obtained from patients selected from high-risk and low-risk populations. The indirect ELISA method was more specific and sensitive when the polyvalent antigen was used than when OMP from only one serotype was used. Past episodes of the gonorrhoea had a significant influence on the seropositivity of the test. In a selected low-risk population the specificity of the assay was 94% and in a selected high-risk population the sensitivity was 78%. When sera from 24 asymptomatic individuals were tested the sensitivity was 83%. The ELISA polyvalent-antigen test should be useful as an aid for the detection of gonorrhoea in populations with a low prevalence.


Oblique radial glial divisions in the developing mouse neocortex induce self-renewing progenitors outside the germinal zone that resemble primate outer subventricular zone progenitors.
Radial glia cells function as neural stem cells in the developing brain and generate self-renewing and differentiating daughter cells by asymmetric cell divisions. During these divisions, the apical process or basal process of the elongated epithelial structure is asymmetrically partitioned into daughter cells, depending on developmental contexts. However, in mammalian neurogenesis, the relationship between these subcellular structures and self-renewability is largely unknown. We induced oblique cleavages of radial glia cells to split the apical and basal processes into two daughters, and investigated the fate and morphology of the daughters in slice cultures. We observed that the more basal daughter cell that inherits the basal process self-renews outside of the ventricular zone (VZ), while the more apical daughter cell differentiates. These self-renewing progenitors, termed "outer VZ progenitors," retain the basal but not the apical process, as recently reported for the outer subventricular zone (OSVZ) progenitors in primates (Fietz et al., 2010; Hansen et al., 2010); to self-renew, they require clonal Notch signaling between sibling cells. We also found a small endogenous population of outer VZ progenitors in the mouse embryonic neocortex, consistent with a low frequency of oblique radial glia divisions. Our results describe the general role of the basal process in the self-renewal of neural progenitors and implicate the loss of the apical junctions during oblique divisions as a possible mechanism for generating OSVZ progenitors. We propose that mouse outer VZ progenitors, induced by oblique cleavages, provide a model to study both progenitor self-renewal and OSVZ progenitors.


Forty years of control of the oestrous cycle in ruminants: progress made, unresolved problems and the potential impact of sperm encapsulation technology.
Pharmacological control of the oestrous cycle may, with or without sperm encapsulation, remain an indispensable part of any attempt to make artificial insemination available to the ranch-cattle industry. Of the current methods, those most likely to remain acceptable with regulatory agencies and to gain acceptance with industry are those involving the short-term use (7-10 days) of minimal effective doses of progestins (preferably progesterone) and the subsequent use of an analogue of prostaglandin F2 alpha. The use of microencapsulated sperm with a long lifespan would allow artificial insemination to be achieved without reference to the time when heat and ovulation may occur.


Validating the Repetitive Behavior Scale-revised in young children with autism spectrum disorder.
This study examined the factor structure of the Repetitive Behavior Scale-Revised (RBS-R) in a sample of 287 preschool-aged children with autism spectrum disorder (ASD). A confirmatory factor analysis was used to examine six competing structural models. Spearman's rank order correlations were calculated to examine the associations between factor scores and variables of interest. The 3- and 5-factor models were selected as preferable on the basis of fit statistics and parsimony. For both models, the strongest correlations were with problem behavior scores on the Child Behavior Checklist and repetitive behavior scores on the ADI-R. Developmental index standard scores were not correlated with factors in either model. The results confirm the utility of the RBS-R as a measure of repetitive behaviors in young children with ASD.


Surgical microanatomy of the müller muscle-conjunctival resection ptosis procedure.
To assess for alterations in the microscopic anatomy that occur as a result of the Müller muscle-conjunctival resection (MMCR) ptosis procedure and to better understand the mechanisms by which MMCR elevates the eyelid. Sixteen orbits from 8 fresh frozen Caucasian cadaver heads, ranging from 38 to 100 years of age were used. For each head, MMCR was performed on one side. The contralateral, unoperated orbit served as an anatomic control. Each exenterated orbital contents and excised MMCR specimen was evaluated. The histopathology of the eyelids and MMCR specimens were studied microscopically by staining with hematoxylin-eosin, elastic, and Verhoeff-Masson trichrome. Müller muscle and conjunctiva were present in all 8 of the excised MMCR specimens. Elastic fibers consistent with Müller muscle tendon or among the smooth muscle fibers were seen within all excised MMCR specimens. The levator aponeurosis was intact in 8 of 8 operated eyelids; however, the aponeurosis was plicated in all. The accessory lacrimal gland tissues were intact in all of the operated and unoperated eyelids. MMCR works by shortening the posterior lamella, which results in advancement of the levator palpebrae superioris muscle and plication of the levator aponeurosis. Plication of the levator aponeurosis likely contributes to the increased volumetric effect seen clinically after MMCR. Phenylephrine testing can help in fine-tuning the amount of resection, but given the mechanism of action of MMCR, adequate levator muscle function remains a critical factor in the success of the surgery. Moreover, MMCR preserves accessory lacrimal gland tissues.


Reflexology treatment relieves symptoms of multiple sclerosis: a randomized controlled study.
To evaluate the effect of reflexology on symptoms of multiple sclerosis (MS) in a randomized, sham-controlled clinical trial. Seventy-one MS patients were randomized to either study or control group, to receive an 11-week treatment. Reflexology treatment included manual pressure on specific points in the feet and massage of the calf area. The control group received nonspecific massage of the calf area. The intensity of paresthesias, urinary symptoms, muscle strength and spasticity was assessed in a masked fashion at the beginning of the study, after 1.5 months of treatment, end of study and at three months of follow-up. Fifty-three patients completed this study. Significant improvement in the differences in mean scores of paresthesias (P = 0.01), urinary symptoms (P = 0.03) and spasticity (P = 0.03) was detected in the reflexology group. Improvement with borderline significance was observed in the differences in mean scores of muscle strength between the reflexology group and the controls (P = 0.06). The improvement in the intensity of paresthesias remained significant at three months of follow-up (P = 0.04). Specific reflexology treatment was of benefit in alleviating motor; sensory and urinary symptoms in MS patients.


Systemic nf-kappaB activation in a transgenic mouse model of acute pancreatitis.
Transcription factor NF-kappaB has been implicated in numerous human inflammatory diseases. Acute pancreatitis can result in remote tissue injury, but the involved mechanisms are unknown. This study evaluates the role of systemic NF-kappaB activation in the pathogenesis of lung inflammation in a transgenic pancreatitis model. Using transgenic mice expressing photinus luciferase controlled by an NF-kappaB-dependent promoter, luciferase activity was measured in pancreas, liver, and lung tissues as a surrogate marker of NF-kappaB activity. Luciferase activity was measured by in vivo bioluminescence and correlated to an in vitro luciferase assay of organ homogenates. Following measurement of luciferase activity in uninjured animals, these animals were fed a choline-deficient, ethionine supplemented diet for 48 h to induce pancreatitis, and luciferase activity was then measured at 48, 60, 72, and 96 h. Lung inflammation was determined by total nucleated cell counts in bronchoalveolar lavage (BAL) fluid. Bioluminescence detected increased luciferase activity over the upper abdominal region at 48 and 60 h (P < 0.05), and over the thorax at 60 and 72 h (P < 0.05). Luciferase assays showed significantly increased luciferase activity in both liver and lung tissue at 48 (liver = P < 0.005, lung = P < 0.05) and 60 h (liver = P < 0.05, lung = P < 0.05) compared to activity in uninjured controls. Total nucleated cell counts in BAL fluid were significantly increased at 72 h (P < 0.05) compared with controls. In this model, NF-kappaB binding activity is increased in the liver and lung. These data suggest that the liver modulates pancreatitis-induced systemic inflammatory response syndrome (SIRS) and suggest strategies to reduce multisystem injury.


Multiple atypical recurrent meningiomas 13 years after radiotherapy for unilateral retinoblastoma: case report and review of the literature.
Radiotherapy is an important treatment modality for intracranial malignancies. Improved survival rates were achieved via a combination of surgery, chemotherapy and radiotherapy. On the other hand, improved survival rates made long-term complications of radiotherapy more apparent. Secondary neoplasms due to cranial irradiation are encountered more commonly in neurosurgical practice. Radiation-induced meningiomas are recognized as a common late complication of radiotherapy. However, radiation-induced meningiomas after radiotherapy for retinoblastoma have been reported rarely. Herein we report a patient who harboured multiple meningiomas 13 years after radiotherapy for unilateral retinoblastoma, which were recurrent despite surgical removal and chemotherapy.


Vitamin D Is Associated with Severity and Mortality of Non-alcoholic Fatty Liver Disease: A US Population-based Study.
Background and Aims: There has been increasing evidence that vitamin D deficiency may increase the risk of metabolic syndrome. Since metabolic syndrome is a major risk factor for non-alcoholic fatty liver disease (NAFLD), we aimed to investigate the association between vitamin D and the severity and mortality of NAFLD. Methods: Data was obtained from the United States Third National Health and Nutrition Examination Survey conducted in 1988-1994, with follow-up mortality data through 2011. NAFLD was defined by ultrasonographic detection of hepatic steatosis in the absence of other liver diseases and categorized as normal, mild, moderate or severe. The severity of hepatic fibrosis was determined by NAFLD fibrosis score (NFS). ANOVA (F-test) was used to evaluate the association between vitamin D level and degree of NAFLD, and Cox proportional hazards regression analysis was used for survival analyses. Results: Vitamin D levels for normal, mild, moderate and severe steatosis were 25.1 ± 0.29 ng/mL, 24.7 ± 0.42 ng/mL, 23.7 ± 0.37 ng/mL and 23.6 ± 0.60 ng/mL, respectively (trend p < 0.001). Likewise, vitamin D levels for low, intermediate and high NFS categories were 24.7 ± 0.38 ng/mL, 23.4 ± 0.42 ng/mL and 21.5 ± 0.57 ng/mL, respectively (trend p < 0.001). After median-follow up over 19 years, vitamin D deficiency was significantly associated with diabetes- and Alzheimer's disease-related mortality (hazard ratio (HR): 3.64, 95%CI: 1.51-8.82 and HR: 4.80, 95%CI: 1.53-15.1, respectively), with a borderline significance in overall mortality (HR: 1.16, 95%CI: 0.99-1.36, p = 0.06). Conclusions: Vitamin D level was inversely related to the degree of liver steatosis and fibrosis. Moreover, vitamin D deficiency was associated with diabetes- and Alzheimer's disease-related mortality in NAFLD patients.


Does pain in individuals with multiple sclerosis affect employment? A systematic review and meta-analysis.
Individuals with multiple sclerosis (MS) experience some of the highest unemployment rates among all groups of chronic illnesses. Pain has been found to be a common reason for sick leave or early retirement in healthy populations or other groups with chronic illness; however, there is little awareness regarding the effect of pain on the work status of individuals with MS. To estimate the extent to which individuals with pain differ in employment status compared with those without pain among MS patients. An extensive systematic review of the scientific literature was performed within the framework of the Cochrane Collaboration to identify studies focusing on the effect of pain on employment in individuals with MS. The following databases were searched: PubMed, EMBASE, PsychInfo, Web of Science, MD Consult and Elsevier, and Science Direct. The methodological quality of studies was assessed using the McMaster Critical Review Form. Ten articles met the inclusion criteria and were included in the systematic review. Of these studies, five that exhibited clinical, methodological and statistical homogeneity were included in the meta-analysis. The between-groups (pain + versus pain -) pooled random OR of being employed was 0.7 (strong), and was significantly different from unity (95% CI 0.5 to 0.9; P=0.001). The results of the present study indicated that individuals with MS who experience pain were significantly more likely to report a decreased employment rate than individuals with MS who were pain free.


Serum bone-turnover biomarkers are associated with the occurrence of peripheral and axial arthritis in psoriatic disease: a prospective cross-sectional comparative study.
A recent systematic review identified four candidate serum-soluble bone-turnover biomarkers (dickkopf-1, Dkk-1; macrophage-colony stimulating factor, M-CSF; matrix metalloproteinase-3, MMP-3; osteoprotegerin, OPG) showing possible association with psoriatic arthritis (PsA). We aimed to: (i) confirm and determine if these four biomarkers are associated with PsA; (ii) differentiate psoriasis cases with and without arthritis; and (iii) differentiate PsA cases with and without axial arthritis. A prospective cross-sectional comparative two-centre study recruited 200 patients with psoriasis without arthritis (PsC), 127 with PsA without axial arthritis (pPsA), 117 with PsA with axial arthritis (psoriatic spondyloarthritis, PsSpA), 157 with ankylosing spondylitis (AS) without psoriasis, and 50 matched healthy controls (HC). Serum biomarker concentrations were measured using ELISA. Multivariable regression and receiver operating characteristic analyses were performed. MMP-3 concentrations were significantly higher and M-CSF significantly lower in each arthritis disease group compared with HC (p ≤ 0.02). MMP-3 concentrations were significantly higher (adjusted odds ratio, ORadj 1.02 per ng/ml increase in concentration; p = 0.0004) and M-CSF significantly lower (ORadj 0.44 per ng/ml increase; p = 0.01) in PsA (pPsA and PsSpA combined) compared with PsC. Dkk-1 concentrations were significantly higher (ORadj 1.22 per ng/mL increase; p = 0.01), and OPG concentrations significantly lower (ORadj 0.20 per ng/mL increase; p = 0.02) in patients with axial arthritis (PsSpA and AS combined) than in those without (pPsA). Furthermore, Dkk-1 concentrations were significantly higher along a spectrum of increasing axial arthritis; Dkk-1 concentrations were higher in AS compared with PsSpA (ORadj 1.18 per ng/mL increase; p = 0.02). Receiver operating characteristic analysis showed MMP-3 to be the best single biomarker for differentiating PsA from PsC (AUC 0.70 for a cut-off of 14.51 ng/mL; sensitivity 0.76, specificity 0.60). MMP-3 and M-CSF are biomarkers for the presence of arthritis in psoriatic disease, and could therefore be used to screen for PsA in psoriasis cohorts. Dkk-1 and OPG are biomarkers of axial arthritis; they could therefore be used to screen for the presence of axial disease in PsA cases, and help differentiate PsSpA from AS. High concentrations of Dkk-1 in AS and PsSpA compared with HC, support previous reports that Dkk-1 is dysfunctional in the spondyloarthritides.


Plasma FGF21 Levels Are Not Associated with Weight Loss or Improvements in Metabolic Health Markers upon 12 Weeks of Energy Restriction: Secondary Analysis of an RCT.
Recent studies suggest that circulating fibroblast growth factor 21 (FGF21) may be a marker of metabolic health status. We performed a secondary analysis of a 12-week randomized controlled trial to investigate the effects of two energy restriction (ER) diets on fasting and postprandial plasma FGF21 levels, as well as to explore correlations of plasma FGF21 with metabolic health markers, (macro)nutrient intake and sweet-taste preference. Abdominally obese subjects aged 40-70 years (n = 110) were randomized to one of two 25% ER diets (high-nutrient-quality diet or low-nutrient-quality diet) or a control group. Plasma FGF21 was measured in the fasting state and 120 min after a mixed meal. Both ER diets did not affect fasting or postprandial plasma FGF21 levels despite weight loss and accompanying health improvements. At baseline, the postprandial FGF21 response was inversely correlated to fasting plasma glucose (ρ = -0.24, p = 0.020) and insulin (ρ = -0.32, p = 0.001), HOMA-IR (ρ = -0.34, p = 0.001), visceral adipose tissue (ρ = -0.24, p = 0.046), and the liver enzyme aspartate aminotransferase (ρ = -0.23, p = 0.021). Diet-induced changes in these markers did not correlate to changes in plasma FGF21 levels upon intervention. Baseline higher habitual polysaccharide intake, but not mono- and disaccharide intake or sweet-taste preference, was related to lower fasting plasma FGF21 (p = 0.022). In conclusion, we found no clear evidence that fasting plasma FGF21 is a marker for metabolic health status. Circulating FGF21 dynamics in response to an acute nutritional challenge may reflect metabolic health status better than fasting levels.


A system to generate simultaneous forced oscillation and continuous positive airway pressure.
Assessment of airway obstruction in patients with obstructive sleep apnoea (OSA) subjected to continuous positive airway pressure (CPAP) may be carried out using the forced oscillation technique (FOT). To facilitate routine application of forced oscillation (FO) in sleep studies, our aim was to design a system capable of generating CPAP and applying FOT simultaneously. We constructed a prototype CPAP + FO generator by connecting a specially designed electromagnetic valve in parallel with a conventional blower. The capacity of the prototype to generate forced oscillation (5 Hz +/- 1 hPa) was tested by connecting it to a model simulating spontaneous breathing. The response of the prototype for target CPAPs of 5, 10 and 15 hPa and imposed sinusoidal breathing with peak flow up to 0.75 L x s(-1) was excellent when compared with that reported for commercially available CPAP generators. The applicability of the prototype was tested by applying it to assess airway obstruction in four patients with OSA during sleep. We conclude that the generator designed is able to apply continuous positive airway pressure and forced oscillation simultaneously. The system could be useful for automatic and noninvasive assessment of airway obstruction in patients with obstructive sleep apnoea subjected to continuous positive airway pressure. Future development of the generator may be helpful in implementing a set-up for automatic titration of continuous positive airway pressure.


Dimerization of α-Conotoxins as a Strategy to Enhance the Inhibition of the Human α7 and α9α10 Nicotinic Acetylcholine Receptors.
The affinity of α-conotoxins, a class of nicotinic acetylcholine receptor (nAChR) peptide inhibitors, can be enhanced by dendrimerization. It has been hypothesized that this improvement arose from simultaneous binding of the α-conotoxins to several spatially adjacent sites. We here engineered several α-conotoxin dimers using a linker length compatible between neighboring binding sites on the same receptor. Remarkably, the dimer of α-conotoxin PeIA compared to the monomer displayed an increase in potency by 11-fold (IC50 = 1.9 nM) for the human α9α10 nAChR. The dimerization of α-conotoxin RgIA# resulted in a dual inhibitor that targets both α9α10 and α7 nAChR subtypes with an IC50 = ∼50 nM. The RgIA# dimer is therapeutically interesting because it is the first dual inhibitor that potently and selectively inhibits these two nAChR subtypes, which are both involved in the etiology of several cancers. We propose that the dimerization of α-conotoxins is a simpler and efficient alternative strategy to dendrimers for enhancing the activity of α-conotoxins.


Rapid eye movement sleep deprivation as a probe in elderly subjects.
The effects of a 2-night rapid eye movement (REM) sleep deprivation (RSD) procedure on electroencephalographic sleep and mood were examined in 15 healthy elderly control subjects, 14 elderly patients with endogenous depression, and 15 patients with primary degenerative dementia. Compared with control subjects, both patient groups maintained a higher amount of REM sleep time and REM activity during RSD. Unexpectedly, depressed patients showed little rebound in visually scored or automated REM sleep measures following RSD, and they showed stability of REM activity temporal distribution from baseline to recovery conditions. This contrasted with the rebound in REM sleep activity seen in control subjects, and the more modest increase in demented patients. The RSD was fairly specific, with some impact on delta sleep during the procedure but not during recovery sleep. Mood ratings were unaffected by RSD. These findings demonstrated a greater plasticity of REM sleep regulation in the healthy elderly control subjects and suggested a higher REM "pressure" with a "ceiling effect" in depressed patients. Patients with dementia appeared to have an impaired capacity to respond to the challenge of RSD.


Quasi Class-DE Driving of HIFU Transducer Arrays.
Recently, a method was proposed to determine the parameters for each Class DE driver in high-intensity focused ultrasound arrays for efficient operation and to compensate for variations in the impedance of each array element. This work extends that method to consider the effect of switch resistance and to provide limited control on the power delivered to the transducers with a constant supply voltage while keeping a good efficiency. The method is experimentally validated using an integrated driver developed by the authors. This paper also shows that the frequency range for efficient electrical operation is close to the frequency where the transducer array presents a peak in the conversion efficiency.


Cancer and ageing.
Tissue culture and transplantation techniques can be used to analyse the relationship between ageing and cancer. In vitro transformation experiments show that the transformation frequency in mesenchymal cells and salivary gland epithelium does not seem to be age-associated but in the bladder old epithelium can be transformed much more frequently than young. Preliminary transplantation experiments confirm this relationship. These experiments suggest that the increased age susceptibility is tissue dependent.


Diagnosing Polypoidal Choroidal Vasculopathy Using Color Fundus Photography, Optical Coherence Tomography, and Optical Coherence Tomography Angiography.
To compare the diagnostic accuracy of differentiating polypoidal choroidal vasculopathy (PCV) from exudative age-related macular degeneration (AMD), using color fundus photography (CFP), optical coherence tomography (OCT), and swept-source OCT angiography (SS-OCTA) without using indocyanine green angiography (ICGA). Treatment-naive eyes with exudative AMD that underwent CFP, OCT, SS-OCTA, and ICGA imaging before treatment were identified. Images of each patient were categorized into two sets (set A, CFP + OCT; set B, CFP + SS-OCTA). In set B, both the en face and cross-sectional B scans were analyzed. Each set was reviewed by two graders, and it was determined whether the presumed diagnosis was PCV. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) for the diagnosis of PCV were assessed for each set by comparing diagnoses that included ICGA. The number of polypoidal lesions in each set was calculated and compared to ICGA. A total of 94 eyes from 94 patients with AMD were included in the study, of which 66.0% were male, and the mean age was 71.8 ± 9.0 years. The PCV diagnosis rate using ICGA was 45.7%. The sensitivity was 0.88 for set A and 0.93 for set B, while the specificity was 0.94 for set A and 0.96 for set B. The AUC was 0.90 (95% confidence interval [CI], 0.83-0.97) for set A and 0.96 (95% CI, 0.90-1.00) for set B. Set A detected 1.28 ± 0.91 polypoidal lesions, while set B detected 1.47 ± 1.01; ICGA showed 1.51 ± 0.86. This study highlights that, without using ICGA, both CFP combined with OCT and CFP combined with SS-OCTA demonstrate high sensitivity, specificity, and AUC in diagnosing PCV. It is evident that SS-OCTA contributes to enhancing sensitivity, specificity, and AUC for PCV diagnosis.


Immunoglobulin allotypes in several North American Eskimo populations.
Genetic data consisting of immunoglobulin testing (GM and KM) from 631 Eskimos from 5 populations are reported. These populations are Savoonga, Gambell (St. Lawrence Island), Wales, King Island, and Mckenzie Delta, Baffin Island. The GM and KM haplotypes are analyzed and compared to those occurring in Greenland, Canadian, Alaskan, and Siberian Eskimos and to other Siberian indigenous populations. These analyses suggest that during the peopling of the New World, four separate migrant groups crossed Beringia at various times.


Bidirectional modulation of goal-directed actions by prefrontal cortical dopamine.
Instrumental actions are a vital cognitive asset that endows an organism with sensitivity to the consequences of its behavior. Response-outcome feedback allows responding to be shaped in order to maximize beneficial, and minimize detrimental, outcomes. Lesions of the medial prefrontal cortex (mPFC) result in behavior that is insensitive to changes in outcome value in animals and compulsive behavior in several human psychopathologies. Such insensitivity to changes in outcome value is a defining characteristic of instrumental habits: responses that are controlled by antecedent stimuli rather than goal expectancy. Little is known regarding the neurochemical substrates mediating this sensitivity. The present experiments used sensitivity to posttraining outcome devaluation to index the action-habit status of instrumental responding. Infusions of dopamine into the ventral mPFC (vmPFC), but not dorsal mPFC, restored outcome sensitivity bidirectionally-decreasing responding following outcome devaluation and increasing responding when the outcome was not devalued. This bidirectionality makes the possibility that these infusions nonspecifically dysregulated vmPFC dopamine transmission unlikely. VmPFC dopamine promoted instrumental responding appropriate to outcome value. Reinforcer consumption data indicated that this was not a consequence of altered sensitivity to the reinforcer itself. We suggest that vmPFC dopamine reengages attentional processes underlying goal-directed behavior.


Low Oral Bioavailability and Partial Gut Microbiotic and Phase II Metabolism of Brussels/Witloof Chicory Sesquiterpene Lactones in Healthy Humans.
Free and glycosylated sesquiterpene lactones (SLs), which are abundant in leafy vegetables including Brussels/witloof chicory, possess health-promoting effects in vivo. However, the pharmacokinetics of dietary source of SLs remain largely unknown. In this open-label and single-dose trial, sixteen healthy volunteers consumed 150 g of Brussels/witloof chicory juice containing 48.77 μmol SLs in 5 min. Blood, urine, and fecal samples were collected before and after chicory consumption in 24 h. No SLs were detected in the serum, urine, and fecal samples before chicory consumption in all of the participants. Chicory consumption increased lactucin, 11β,13-dihydrolactucin, and their glucuronide/sulfate conjugates, rather than lactucopicrin and 11β,13-dihydrolactucopicrin, as well as glycosylated SLs in biological samples. The peak concentration of total SLs in serum reached 284.46 nmol/L at 1 h, while, in urine, this peak was 220.3 nmol between 2 and 6 h. The recovery of total SLs in blood, urine, and feces was 7.03%, 1.13%, and 43.76% of the ingested dose, respectively. Human fecal suspensions with intestinal microbiota degraded glycosylated SLs in chicory, and converted lactucopicrin and 11β,13-dihydrolactucopicrin to lactucin and 11β,13-dihydrolactucin, respectively. Collectively, Brussels/witloof chicory SLs are poorly bioavailable and they undergo partial gut microbial and phase II metabolism in humans.


Purification of exfoliatin produced by Staphylococcus aureus of bacteriophage group 2 and its physicochemical properties.
An effective method for the isolation and purification of exfoliatin which has been recently reported by Melish and others as the staphylococcal toxin responsible for the scalded skin syndrome and the physicochemical properties of the purified toxin were described. From an active crude toxin produced by one of the clinical isolates of phage group 2, four types of toxic proteins which were all capable of causing the typical Nikolsky sign in neonatal mice were obtained and designated A, B, C, and D toxins. They had a molecular weight of about 24,000 and showed the same serological features in neutralization and precipitation tests, but were different from each other in showing a different single band with their respective mobilities in polyacrylamide disk electrophoresis. They were precipitated between pH 4.0 and 4.5 and lost their exfoliative capabilities. The resulting precipitates, however, could be solubilized in acetate buffer containing 0.5% sodium dodecyl sulfate, restoring their toxicities to almost the same extent as before. They were all stable when heated at 60 C for 60 min and at 100 C for 20 min, but lost their toxicities when heated at 100 C for 40 min. Additionally, the present authors observed that some staphylococcal strains not belonging to the typical phage group 2, isolated from patients with the scalded skin syndrome, were also capable of producing a similar but serologically unrelated exfoliative toxin.


Prostate cancer characterization by optical contrast enhanced photoacoustics.
During the past decades, prostate cancer (PCa), with an annual incident rate much higher than any other cancer, is the most commonly diagnosed cancer in American men. PCa has a relatively low progression rate yet the survival percentage decreases dramatically once the cancer has metastasized. Identifying aggressive from indolent PCa to prevent metastasis and death is critical to improve outcomes for patients with PCa. Standard procedure for assessing the aggressiveness of PCa involves the removal of tumor tissues by transrectal (TR) ultrasound (US) guided needle biopsy. The microscopic architecture of the biopsied tissue is visualized by histological or immunohistochemical staining procedures. The heterogeneity of the microscopic architecture is characterized by a Gleason score, a quantitative description of the aggressiveness of PCa. Due to the inability to identify the cancer cells, most noninvasive imaging modalities can only provide diagnosis of PCa at limited accuracy. This study investigates the feasibility of identifying PCa tumors and characterizing the aggressiveness of PCa by photoacoustic imaging assisted by cancer targeting polyacrylamide (PAA) nanoparticles (NPs). PAA is a biocompatible material used in clinics for the past 20 years. PAA NPs can protect capsulated optical contrast agents from interference by enzymes and enable prolonged systematic circulation in the living biological environment. The cancer targeting mechanism is achieved by conjugating the NPs to F3 peptides, which trace nucleolin overexpressed on the surface of cancer cells. Preliminary studies have shown that the NPs are capable of staining the PCa cells in vivo.


Exploring the Short-Term Memory of Heart Rate Variability through Model-Free Information Measures.
In this work, we perform a comparative analysis of discrete- and continuous-time estimators of information-theoretic measures quantifying the concept of memory utilization in short-term heart rate variability (HRV). Specifically, considering heartbeat intervals in discrete time we compute the measure of information storage (IS) and decompose it into immediate memory utilization (IMU) and longer memory utilization (MU) terms; considering the timings of heartbeats in continuous time we compute the measure of MU rate (MUR). All measures are computed through model-free approaches based on nearest neighbor entropy estimators applied to the HRV series of a group of 15 healthy subjects measured at rest and during postural stress. We find, moving from rest to stress, statistically significant increases of the IS and the IMU, as well as of the MUR. Our results suggest that both discrete-time and continuous-time approaches can detect the higher predictive capacity of HRV occurring with postural stress, and that such increased memory utilization is due to fast mechanisms likely related to sympathetic activation.