Molecular systematics of the bubblegum coral genera (Paragorgiidae, Octocorallia) and description of a new deep-sea species.
Bubblegum octocorals (Paragorgia and Sibogagorgia) play an important ecological role in many deep-sea ecosystems. However, these organisms are currently threatened by destructive fishing methods such as bottom trawling. Taxonomic knowledge of conservation targets is necessary for the creation and implementation of efficient conservation strategies. However, for most deep-sea coral groups this knowledge remains incomplete. For instance, despite its similarities with Paragorgia, Sibogagorgia is particular in lacking polyp sclerites, which are present in groups like Paragorgia and the Coralliidae. Although two kinds of sclerites are very similar between Paragorgia and Sibogagorgia, other characters challenge the monophyly of these genera. Here we help to clarify the taxonomy and evolutionary relationships of the bubblegum octocorals and related taxa by examining molecular data. We employed nucleotide sequences of mitochondrial (ND6, ND6-ND3 intergenic spacer, ND3, ND2, COI, msh1 and 16S) and nuclear (28S and ITS2) genomic regions from several taxa to infer molecular phylogenetics and to examine the correspondence of morphological features with the underlying genetic information. Our data strongly supported the monophyly of the genus Paragorgia, the family Coralliidae (precious corals), and a group of undescribed specimens resembling Sibogagorgia. Further morphological observations were congruent regarding the uniqueness of the undescribed specimens, here defined as a new species, Sibogagorgia cauliflora sp. nov., which occurs in both sides of the North American landmass at depths below 1700 m. This new species resembles S. dennisgordoni with branching in one plane but has fairly different radiate sclerites and significantly divergent DNA sequences. The existence of several diagnostic characters of Sibogagorgia in S. cauliflora indicates that they indeed belong to this genus. It is however remarkable that a small number of medullar canals are also found in this species; medullar canals have been considered as the main diagnostic character of Paragorgia. Thus, the evidence generated here indicates that the presence or absence of these canals per se is not a conclusively diagnostic character for either genus. The lack of internal-node resolution in the inferred phylogenetic hypotheses of these genera does not allow us to propose a clear scenario regarding the evolution of these traits.


A scanning electron microscopic observation of inner carious dentin after cleansing and of the dentin-resin interface.
Inner carious dentin after cleansing and the dentin-resin interface were observed with scanning electron microscopy. Results suggested that, similar to 10% citric acid-3% ferric chloride solution, 10% ethylenediaminetetraacetic acid may thoroughly remove the smear layer on the surface of inner carious dentin and make it possible for the dentinal bonding agent to penetrate the cleansed dentin to form an acid-proof layer and dense resin tags. These changes may improve the bond strength as well as tubule aperture seal. Ethylenediaminetetraacetic acid is not destructive to collagen, and may be of negligible toxicity to the pulp of intact dentin.


CD4 T cells can reject major histocompatibility complex class I-incompatible skin grafts.
We have re-investigated the roles of CD4 and CD8 T cell subsets in skin graft rejection across a single class I MHC disparity. Recipient mice were transplanted with skin from donors transgenic for the class I MHC molecule Kb. As expected, CD8 T cells were sufficient for rapid injection; but surprisingly, CD4 T cells were also competent to do the same. Rejection was dependent on one or the other subset, since elimination of both resulted in indefinite graft survival. The possibility that alloantibody was the downstream effector of CD4 mediated rejection was excluded because CD8-depleted mice rendered B cell deficient still rejected rapidly, but T cell-depleted recipients with pre-existing high titers of alloantibody were unable to do so. In addition, if CD4 cells act to reject by recruiting and/or activating macrophages then this was not dependent on CR3, IFN-gamma or TNF-alpha. Transplantation of skin grafts where the MHC class I disparity was at the level of passenger leukocytes only, demonstrated that transient bystander damage could occur, but that this was insufficient to result in full rejection. We surmise that for CD4 T cells to reject an MHC class I-incompatible graft it is necessary that an appropriate allogeneic peptide is processed and presented in the context of recipient MHC class II. CD4 T cells from B6 mice may fail to reject skin from MHC class I mutants because of the lack of such MHC class II-restricted presentation.


The National COVID-19 Epi Model (NCEM): Estimating cases, admissions and deaths for the first wave of COVID-19 in South Africa.
In March 2020 the South African COVID-19 Modelling Consortium was formed to support government planning for COVID-19 cases and related healthcare. Models were developed jointly by local disease modelling groups to estimate cases, resource needs and deaths due to COVID-19. The National COVID-19 Epi Model (NCEM) while initially developed as a deterministic compartmental model of SARS-Cov-2 transmission in the nine provinces of South Africa, was adapted several times over the course of the first wave of infection in response to emerging local data and changing needs of government. By the end of the first wave, the NCEM had developed into a stochastic, spatially-explicit compartmental transmission model to estimate the total and reported incidence of COVID-19 across the 52 districts of South Africa. The model adopted a generalised Susceptible-Exposed-Infectious-Removed structure that accounted for the clinical profile of SARS-COV-2 (asymptomatic, mild, severe and critical cases) and avenues of treatment access (outpatient, and hospitalisation in non-ICU and ICU wards). Between end-March and early September 2020, the model was updated 11 times with four key releases to generate new sets of projections and scenario analyses to be shared with planners in the national and provincial Departments of Health, the National Treasury and other partners. Updates to model structure included finer spatial granularity, limited access to treatment, and the inclusion of behavioural heterogeneity in relation to the adoption of Public Health and Social Measures. These updates were made in response to local data and knowledge and the changing needs of the planners. The NCEM attempted to incorporate a high level of local data to contextualise the model appropriately to address South Africa's population and health system characteristics that played a vital role in producing and updating estimates of resource needs, demonstrating the importance of harnessing and developing local modelling capacity.


Childhood aggression and the co-occurrence of behavioural and emotional problems: results across ages 3-16 years from multiple raters in six cohorts in the EU-ACTION project.
Childhood aggression and its resulting consequences inflict a huge burden on affected children, their relatives, teachers, peers and society as a whole. Aggression during childhood rarely occurs in isolation and is correlated with other symptoms of childhood psychopathology. In this paper, we aim to describe and improve the understanding of the co-occurrence of aggression with other forms of childhood psychopathology. We focus on the co-occurrence of aggression and other childhood behavioural and emotional problems, including other externalising problems, attention problems and anxiety-depression. The data were brought together within the EU-ACTION (Aggression in Children: unravelling gene-environment interplay to inform Treatment and InterventiON strategies) project. We analysed the co-occurrence of aggression and other childhood behavioural and emotional problems as a function of the child's age (ages 3 through 16 years), gender, the person rating the behaviour (father, mother or self) and assessment instrument. The data came from six large population-based European cohort studies from the Netherlands (2x), the UK, Finland and Sweden (2x). Multiple assessment instruments, including the Child Behaviour Checklist (CBCL), the Strengths and Difficulties Questionnaire (SDQ) and Multidimensional Peer Nomination Inventory (MPNI), were used. There was a good representation of boys and girls in each age category, with data for 30,523 3- to 4-year-olds (49.5% boys), 20,958 5- to 6-year-olds (49.6% boys), 18,291 7- to 8-year-olds (49.0% boys), 27,218 9- to 10-year-olds (49.4% boys), 18,543 12- to 13-year-olds (48.9% boys) and 10,088 15- to 16-year-olds (46.6% boys). We replicated the well-established gender differences in average aggression scores at most ages for parental ratings. The gender differences decreased with age and were not present for self-reports. Aggression co-occurred with the majority of other behavioural and social problems, from both externalising and internalising domains. At each age, the co-occurrence was particularly prevalent for aggression and oppositional and ADHD-related problems, with correlations of around 0.5 in general. Aggression also showed substantial associations with anxiety-depression and other internalizing symptoms (correlations around 0.4). Co-occurrence for self-reported problems was somewhat higher than for parental reports, but we found neither rater differences, nor differences across assessment instruments in co-occurrence patterns. There were large similarities in co-occurrence patterns across the different European countries. Finally, co-occurrence was generally stable across age and sex, and if any change was observed, it indicated stronger correlations when children grew older. We present an online tool to visualise these associations as a function of rater, gender, instrument and cohort. In addition, we present a description of the full EU-ACTION projects, its first results and the future perspectives.


Can a precast pit latrine concrete floor withstand emptying operations? An investigation from Malawi.
For fecal sludge from households in low- and middle-income countries to be treated offsite it needs to be removed, which can be greatly affected by the pit latrine floor design. However, it is unclear whether precast pit latrine concrete floors (latrine slabs) can withstand emptiers and their equipment. To investigate this issue, 28 prefabricated latrine slabs were purchased in two cities of Malawi. They were first visually evaluated, and then their compression strength was tested. Additionally, each seller was asked a series of questions to better understand their business, training, and construction practices. Results showed that households should perform due diligence to ensure that they are purchasing a safe precast latrine slab. Commonly reported problems included nonstandard reinforcement material and spacing, in addition to slabs that were not thick enough or were not large enough in diameter. The results of this research illustrate the inherent complexity in ensuring high-quality decentralized sanitation solutionsand how one component, the user interface, if implemented poorly, can affect the rest of the value chain. The findings from this work can help inform training and initiatives that engage artisans and suppliers who play a role in the provision of onsite sanitation service delivery.


Nosocomial infection with gentamicin-carbenicillin-resistant Pseudomonas aeruginosa.
Pseudomonas aeruginosa resistant to both gentamicin and carbenicillin was isolated with increasing frequency at the Cincinnati Veterans Administration Hospital during the period 1971 to 1974. A comparison of patients from whom P. aeruginosa was isolated during this period failed to reveal any significant clinical differences between the patients colonized or infected with resistant organisms and those colonized or infected with susceptible organisms. Overt clinical infection attributable to either organism was rare. The antibiotic-resistant organisms were isolated most frequently from urine. Isolation of the antibiotic-resistant organisms was more frequent from patients who had previously received gentamicin.


Improvement in word recognition score with level is associated with hearing aid ownership among patients with hearing loss.
Market surveys consistently show that only 22% of those with hearing loss own hearing aids. This is often ascribed to cosmetics, but is it possible that patients apply a different auditory criterion than do audiologists and manufacturers? We tabulated hearing aid ownership in a survey of 1000 consecutive patients. We separated hearing loss cases, with one cohort in which word recognition in quiet could improve with gain (vs. 40 dB HL) and another without such improvement but nonetheless with audiometric thresholds within the manufacturer's fitting ranges. Overall, we found that exactly 22% of hearing loss patients in this sample owned hearing aids; the same finding has been reported in many previous, well-accepted surveys. However, while all patients in the two cohorts experienced difficulty in noise, patients in the cohort without word recognition improvement were found to own hearing aids at a rate of 0.3%, while those patients whose word recognition could increase with level were found to own hearing aids at a rate of 50%. Results also coherently fit a logistic model where shift of the word recognition performance curve by level corresponded to the likelihood of ownership. In addition to the common attribution of low hearing aid usage to patient denial, cosmetic issues, price, or social stigma, these results provide one alternative explanation based on measurable improvement in word recognition performance.


Fourier analysis of light scattered by elongated scatterers.
Biological stimulation of living cells is sometimes associated with morphological changes. A practical method is developed to monitor cell stimulation by means of their conformational changes through interpretation of the pattern of light scattered from a cell population. For this purpose a mathematical model is suggested that predicts the power spectrum from a population of elliptic objects with a given eccentricity. A computer simulation of that model is presented together with supporting experimental results of the simulation. The predicted and the measured spectra are in good agreement. This technique was applied to elongated cells that become circular on exposure to a human hormone, indicating the potential applicability of the method in biology and medicine. The method and the apparatus presented in this study could be applied to bioassays of cell systems that respond to a variety of stimulants and to trace quantitatively the structural changes that occur during biological processes.


Rickettsial infections in the tropics and in the traveler.
The purpose of this review is to describe recent advances in our understanding of the pathogenesis, epidemiology, and clinical features of rickettsial diseases with emphasis placed on those relating to travel and tropical medicine. Rickettsioses are becoming increasingly recognized as causes of febrile illness in travelers and in those residing in the tropics. In South and Central America, infection with Rickettsia rickettsii continues to have severe consequences. Resurgence of Mediterranean spotted fever in Bulgaria highlights the threat of rickettsial infections when there is a lapse in vector and reservoir control. Similar to African tick-bite fever, Rickettsia parkeri is an emerging cause of eschar-associated infection in Brazil, Argentina, and Uruguay. Several reports of murine typhus requiring hospitalization demonstrate the risk of this infection to the traveler. The use of fluoroquinolones for milder spotted fevers may fall out of favor with evidence of deleterious effects in those treated with ciprofloxacin. With globalization and increased access to travel, clinical awareness of rickettsial diseases is of increasing importance. Although the growing number of rickettsial species may be daunting to the clinician, recognition of the patterns of rickettsial disease will ensure prompt and effective therapy.


Processing of changes in visual speech in the human auditory cortex.
Seeing a talker's articulatory gestures may affect the observer's auditory speech percept. Observing congruent articulatory gestures may enhance the recognition of speech sounds [J. Acoust. Soc. Am. 26 (1954) 212], whereas observing incongruent gestures may change the auditory percept phonetically as occurs in the McGurk effect [Nature 264 (1976) 746]. For example, simultaneous acoustic /ba/ and visual /ga/ are usually heard as /da/. We studied cortical processing of occasional changes in audiovisual and visual speech stimuli with magnetoencephalography. In the audiovisual experiment congruent (acoustic /iti/, visual /iti/) and incongruent (acoustic /ipi/, visual /iti/) audiovisual stimuli, which were both perceived as /iti/, were presented among congruent /ipi/ (acoustic /ipi/, visual /ipi/) stimuli. In the visual experiment only the visual components of these stimuli were presented. A visual change both in audiovisual and visual experiments activated supratemporal auditory cortices bilaterally. The auditory cortex activation to a visual change occurred later in the visual than in the audiovisual experiment, suggesting that interaction between modalities accelerates the detection of visual change in speech.


Differential patterns of microRNA expression in neuroblastoma are correlated with prognosis, differentiation, and apoptosis.
Neuroblastoma accounts for 15% of pediatric cancer deaths, and although a few protein-coding genes, such as MYCN, are involved with aggressive pathogenicity, the identification of novel biological targets for therapeutic intervention is still a necessary prerequisite for improving patient survival. Expression profiling of 157 microRNA (miRNA) loci in 35 primary neuroblastoma tumors indicates that 32 loci are differentially expressed in favorable and unfavorable tumor subtypes, indicating a potential role of miRNAs in neuroblastoma pathogenesis. Many of these loci are significantly underexpressed in tumors with MYCN amplification, which have particularly poor prognoses. Interestingly, we found that miRNA expression levels substantially change in a MYCN-amplified cell line following exposure to retinoic acid, a compound which is well known for causing reductions in MYCN expression and for inducing neuroblastoma cell lines to undergo neuronal differentiation. We also show that small interfering RNA inhibition of MYCN by itself causes similar alterations in the expression of miRNA loci. In vitro functional studies of one locus, miR-184, indicate that it plays a significant role in apoptosis. The association of experimentally induced alterations of miRNA expression in neuroblastoma cell lines with differentiation or apoptosis leads us to conclude that these loci play important roles in neuroblastoma pathogenesis. We further suggest that MYCN may mediate a tumorigenic effect, in part, through directly or indirectly regulating the expression of miRNAs that are involved with neural cell differentiation and/or apoptosis, warranting substantial further studies of miRNAs as potential therapeutic targets.


Analysis of nursing home capital reimbursement systems.
An increasing number of States are using a fair-rental approach for reimbursement of nursing home capital costs. In this study, two variants of the fair-rental capital-reimbursement approach are compared with the traditional cost-based approach in terms of after-tax cash flow to the investor, cost to the State, and rate of return to investor. Simulation models were developed to examine the effects of each capital-reimbursement approach both at specific points in time and over various periods of time. Results indicate that although long-term costs were similar for the three systems, both fair-rental approaches may be superior to the traditional cost-based approach in promoting and controlling industry stability and, at the same time, in providing an adequate return to investors.


Feedback-dependent generalization.
Generalization provides a window into the representational changes that occur during motor learning. Neural network models have been integral in revealing how the neural representation constrains the extent of generalization. Specifically, two key features are thought to define the pattern of generalization. First, generalization is constrained by the properties of the underlying neural units; with directionally tuned units, the extent of generalization is limited by the width of the tuning functions. Second, error signals are used to update a sensorimotor map to align the desired and actual output, with a gradient-descent learning rule ensuring that the error produces changes in those units responsible for the error. In prior studies, task-specific effects in generalization have been attributed to differences in neural tuning functions. Here we ask whether differences in generalization functions may arise from task-specific error signals. We systematically varied visual error information in a visuomotor adaptation task and found that this manipulation led to qualitative differences in generalization. A neural network model suggests that these differences are the result of error feedback processing operating on a homogeneous and invariant set of tuning functions. Consistent with novel predictions derived from the model, increasing the number of training directions led to specific distortions of the generalization function. Taken together, the behavioral and modeling results offer a parsimonious account of generalization that is based on the utilization of feedback information to update a sensorimotor map with stable tuning functions.


Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study.
Similar to most chronic diseases, Alzheimer's disease (AD) develops slowly from a preclinical phase into a fully expressed clinical syndrome. We aimed to use longitudinal data to calculate the rates of amyloid β (Aβ) deposition, cerebral atrophy, and cognitive decline. In this prospective cohort study, healthy controls, patients with mild cognitive impairment (MCI), and patients with AD were assessed at enrolment and every 18 months. At every visit, participants underwent neuropsychological examination, MRI, and a carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET scan. We included participants with three or more (11)C-PiB PET follow-up assessments. Aβ burden was expressed as (11)C-PiB standardised uptake value ratio (SUVR) with the cerebellar cortex as reference region. An SUVR of 1·5 was used to discriminate high from low Aβ burdens. The slope of the regression plots over 3-5 years was used to estimate rates of change for Aβ deposition, MRI volumetrics, and cognition. We included those participants with a positive rate of Aβ deposition to calculate the trajectory of each variable over time. 200 participants (145 healthy controls, 36 participants with MCI, and 19 participants with AD) were assessed at enrolment and every 18 months for a mean follow-up of 3·8 (95% CI CI 3·6-3·9) years. At baseline, significantly higher Aβ burdens were noted in patients with AD (2·27, SD 0·43) and those with MCI (1·94, 0·64) than in healthy controls (1·38, 0·39). At follow-up, 163 (82%) of the 200 participants showed positive rates of Aβ accumulation. Aβ deposition was estimated to take 19·2 (95% CI 16·8-22·5) years in an almost linear fashion-with a mean increase of 0·043 (95% CI 0·037-0·049) SUVR per year-to go from the threshold of (11)C-PiB positivity (1·5 SUVR) to the levels observed in AD. It was estimated to take 12·0 (95% CI 10·1-14·9) years from the levels observed in healthy controls with low Aβ deposition (1·2 [SD 0·1] SUVR) to the threshold of (11)C-PiB positivity. As AD progressed, the rate of Aβ deposition slowed towards a plateau. Our projections suggest a prolonged preclinical phase of AD in which Aβ deposition reaches our threshold of positivity at 17·0 (95% CI 14·9-19·9) years, hippocampal atrophy at 4·2 (3·6-5·1) years, and memory impairment at 3·3 (2·5-4·5) years before the onset of dementia (clinical dementia rating score 1). Aβ deposition is slow and protracted, likely to extend for more than two decades. Such predictions of the rate of preclinical changes and the onset of the clinical phase of AD will facilitate the design and timing of therapeutic interventions aimed at modifying the course of this illness. Science and Industry Endowment Fund (Australia), The Commonwealth Scientific and Industrial Research Organisation (Australia), The National Health and Medical Research Council of Australia Program and Project Grants, the Austin Hospital Medical Research Foundation, Victorian State Government, The Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association.


Therapeutic recreation camps: an effective intervention for children and young people with chronic illness?
Since the 1930s, therapeutic recreation (TR) has been used in the UK to help young people cope with severe illness. This article surveys four systematic reviews and poses five questions that a paediatrician might ask: (1) How to select a TR experience and for which patient?; (2) Does TR augment brain injury rehabilitation?; (3) How do TR camps benefit children?; (4) Is TR cost-effective?; (5) What additional research is needed? Methodological weaknesses in research impair the strength of conclusions. There is little research about matching of TR experiences to individuals, disease groups or age groups, or about the effect of TR camps in brain injury rehabilitation. TR interventions enhance self-esteem, disease knowledge, emotional well-being, adaptation to illness and symptom control. Educationalists suggest that self-esteem is helped most in mid to late adolescence. Where studied, TR camps are safe, which reassures parents. There have been few studies on cost-effectiveness. We conclude that young people benefit from TR. However, better-quality research would help select and further develop these experiences for young people with ill health.


Significance of the difference in the estimates of glomerular filtration rate obtained using different models.
Chronic kidney disease (CKD) prevalence is rising in Nigeria. Most cases are diagnosed as end stage disease despite availability of formulae to estimate glomerular filtration rate (GFR). Existing formulae, none of which is modelled on Nigerian variables, give different estimates. This study tests the significance of the difference in the estimates obtained using Modified Diet in Renal Disease (MDRD) Study and Chronic Kidney Disease-Epidemiology (CKD-Epi) formulae. This is a cross-sectional study. Data on age, gender, and serum creatinine were used to estimate GFR. Paired sample t test was used to check for difference in means, Pearson correlation test for correlation and Bland and Altman plot for systematic bias. Simple linear regression was used to check for presence and significance of proportional bias. Of the 166 patients studied, 62 were males and 104 were females. Mean age was 49.06 years ± 15.26. Youngest was 18 years and the oldest 81 years. Mean eGFR of 69.4 and 72.77 ml/min/1.73m2 for MDRD and CKD-Epi models respectively differed significantly, P < 0.001. Bland and Altman plot showed lack of agreement of eGFR estimates from the two models with significant bias of -3.37ml/min/1.73m2 despite good correlation, r = 0.984. There was significant proportional bias, P < 0.001. MDRD significantly underestimated GFR compared to CKD-Epi in a Nigerian population. This bias was proportional and increased as mean eGFR increased. MDRD and CKD-Epi models do not agree in their measurements of eGFR and should not be used interchangeably. There is urgent need for further studies to develop GFR estimating model on Nigerian variables.


The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity.
Genotoxic chemotherapy is the most common cancer treatment strategy. However, its untargeted generic DNA-damaging nature and associated systemic cytotoxicity greatly limit its therapeutic applications. Here, we used a haploid genetic screen in human cells to discover an absolute dependency of the clinically evaluated anticancer compound YM155 on solute carrier family member 35 F2 (SLC35F2), an uncharacterized member of the solute carrier protein family that is highly expressed in a variety of human cancers. YM155 generated DNA damage through intercalation, which was contingent on the expression of SLC35F2 and its drug-importing activity. SLC35F2 expression and YM155 sensitivity correlated across a panel of cancer cell lines, and targeted genome editing verified SLC35F2 as the main determinant of YM155-mediated DNA damage toxicity in vitro and in vivo. These findings suggest a new route to targeted DNA damage by exploiting tumor and patient-specific import of YM155.


Disorders of the calcium-sensing receptor.
The human calcium-sensing receptor (CaSR) is a 1078-amino-acid cell surface protein which is expressed in the parathyroids, thyroid cells and the kidney, and is a member of the family of G protein-coupled receptors. The CaSR allows regulation of parathyroid hormone (PTH) secretion and renal tubular calcium reabsorption in response to alterations in extracellular calcium concentrations. The human CaSR gene is located on chromosome 3q13.3-q21, and loss of function CaSR mutations have been reported in the hypercalcaemic disorders of familial benign (hypocalciuric) hypercalcaemia (FBH or FHH) and neonatal severe primary hyperparathyroidism (NSHPT). In addition, gain of function CaSR mutations have been observed in a novel familial syndrome of hypocalcaemia with hypercalciuria. The human CaSR gene on chromosome 3q13.3-q21 is likely to be one of several, as two other loci for FBH have been located on chromosome 19p and 19q13. Cloning and characterisation of these genes will help to further elucidate the mechanisms regulating extracellular calcium.


Purification of Enterocytozoon bieneusi spores from stool specimens by gradient and cell sorting techniques.
A three-step method for the purification of Enterocytozoon bieneusi spores from stool specimens was developed. The primary process of purification of the spores from bacterial contaminants involved Percoll gradient centrifugation followed by additional separation using cesium chloride density gradient centrifugation. The cesium chloride-isolated spores were further purified using a flow cytometer with cell sorting capabilities. Sorting was performed without the use of antibodies, fluorochromes, or dyes, leaving the sorted spores in their native state, which appears to be less destructive for spores. When quantified by flow cytometry using tubes with known numbers of highly fluorescent polystyrene beads, the sorted material showed a slight decrease in light scatter characteristics compared with the slightly larger Encephalitozoon species spores. Although the overall recovery of the E. bieneusi spores was low, calcofluor and Gram chromotrope staining, indirect immunofluorescence assay, and transmission electron microscopy revealed that the sorted material was highly purified and contained large numbers of E. bieneusi spores and relatively few bacteria and other debris. The sorted material appeared to be sufficiently pure and could be used for in vitro culture and for the development of a variety of diagnostic reagents as well as in studying the genome of E. bieneusi and host-parasite interactions.


[Gait analysis associated with anterior cruciate ligament reconstruction].
To determine how selected gait parameters, measured by three-dimensional To determine how selected gait parameters, measured by three-dimensional motion capture system, may change as a result of anterior cruciate ligament (ACL) deficiency and following ACL reconstruction. The study was performed on 29 ACL-deficient subjects prior to and at 3, 6, 9 and 12 months after ACL reconstructive surgery by the four stranded hamstring tendon technique. The group was examined at an average of 2.6 months after injury (range: 2 weeks-16 months). But at presurgery, gait analysis was performed using the DorealSoft DVMC-8801 three-dimensional motion capture system. Kinematic data were recorded for the lower extremities. The results obtained from the injured subjects were compared with those of 58 individuals without ACL damage. Each subject was asked to walk on a motorized treadmill (ECON USA) with different slopes and perform-after a 6 minute familiarization time-at least 2 minutes of walking at a constant speed of 1.9 km/h. The ACL-deficient patients exhibited a quadriceps avoidance pattern prior to and at 3 months post-surgery. In the operated individuals, the spatial-temporal parameters and the knee angle had already regained a normal pattern for the ACL-deficient extremity during gait at 6 months post-surgery. However, the relative ACL movement parameter-which describes the tibial translation into the direction of ACL-and the angular acceleration showed no significant statistical difference as compared with the values of healthy control group at just 9 months post-surgery. The ACL surgical repair significantly alters lower-extremity gait patterns, and that the establishment of pre-injury gait patterns takes at least 9 months to occur. 3D gait analysis for assessment of patients undergoing anterior cruciate ligament reconstruction surgery can precisely reflect knee biomechanical changes, and assist to explore optimal treatment approach and postoperative rehabilitation methods.


Dynamic Plasmonic Pixels.
Information display utilizing plasmonic color generation has recently emerged as an alternative paradigm to traditional printing and display technologies. However, many implementations so far have either presented static pixels with a single display state or rely on relatively slow switching mechanisms such as chemical transformations or liquid crystal transitions. Here, we demonstrate spatial, spectral, and temporal control of light using dynamic plasmonic pixels that function through the electric-field-induced alignment of plasmonic nanorods in organic suspensions. By tailoring the geometry and composition (Au and Au@Ag) of the nanorods, we illustrate light modulation across a significant portion of the visible and infrared spectrum (600-2400 nm). The fast (∼30 μs), reversible nanorod alignment is manifested as distinct color changes, characterized by shifts of observed chromaticity and luminance. Integration into larger device architectures is showcased by the fabrication of a seven-segment numerical indicator. The control of light on demand achieved in these dynamic plasmonic pixels establishes a favorable platform for engineering high-performance optical devices.


Effects of pulsed electric field on secondary metabolism of Vitis vinifera L. cv. Gamay Fréaux suspension culture and exudates.
Plant cell cultures provide a large potential for the production of secondary metabolites. Through the application of different physical and chemical cell stress factors, we investigated the production of the secondary metabolites in plant cell cultures. The effects of pulsed electric field (PEF) and ethephon on growth and secondary metabolism, particularly anthocyanins and phenolic acids synthesis, were investigated by using suspension culture of Vitis vinifera L. cv. Gamay Fréaux as a model system. Anthocyanins were measured by spectrophotometer and extracellular phenolic acids were determined by high-performance liquid chromatography. The compounds were identified by liquid chromatography-mass spectrometry and nuclear magnetic resonance. After the treatments with PEF and ethephon, the concentrations of anthocyanins and phenolic acids in cell culture were higher than in the control, without loss of biomass. The combination of PEF treatment and ethephon improved secondary metabolites formation. Production levels of extracellular phenolic acids, 3-O-glucosyl-resveratrol were increased by PEF and ethephon treatments. The results show that PEF induced a defense response of plant cells and may have altered the cell/membrane's dielectric properties. PEF, an external stimulus or stress, is proposed as a promising new abiotic elicitor for stimulating secondary metabolites biosynthesis in plant cell cultures.


Counter-Punishment, Communication, and Cooperation among Partners.
We study how communication affects cooperation in an experimental public goods environment with punishment and counter-punishment opportunities. Participants interacted over 30 rounds in fixed groups with fixed identifiers that allowed them to trace other group members' behavior over time. The two dimensions of communication we study are asking for a specific contribution level and having to express oneself when choosing to counter-punish. We conduct four experimental treatments, all involving a contribution stage, a punishment stage, and a counter-punishment stage in each round. In the first treatment communication is not possible at any of the stages. The second treatment allows participants to ask for a contribution level at the punishment stage and in the third treatment participants are required to send a message if they decide to counter-punish. The fourth combines the two communication channels of the second and third treatments. We find that the three treatments involving communication at any of the two relevant stages lead to significantly higher contributions than the baseline treatment. We find no difference between the three treatments with communication. We also relate our results to previous results from treatments without counter-punishment opportunities and do not find that the presence of counter-punishment leads to lower cooperation level. The overall pattern of results shows that given fixed identifiers the key factor is the presence of communication. Whenever communication is possible contributions and earnings are higher than when it is not, regardless of counter-punishment opportunities.


Retinopathy associated with enterococcus enteropathy in the neonatal rat.
Preretinal neovascularization has been previously observed in neonatal rats with spontaneously occurring diarrhea. This neovascularization appears analogous to retinopathy of prematurity (ROP), which occurs in human neonates. A new enterococcus species, designated Enterococcus rattus, has been isolated from the duodenum of these rats. In the present controlled study, the effect of the enteropathy induced by this organism on the retinal vasculature in the neonatal rat was further investigated. One hundred fifty newborn Sprague-Dawley rats were randomly assigned to 6 expanded litters (n = 25). On the second day of life, animals were gavaged with either 100 microl of E. rattus suspension (1.0 X 10(7) colony forming units, inoculated group, n = 100 rats) or 100 microl saline (control group, n = 50 rats). All rats were raised in room air and were killed on day 13 of life. Duodenal and blood samples were cultured. The retinal vasculature was assessed using fluorescent microscopy and ADPase staining in a masked manner. Two additional inoculated litters and one control litter were studied for evaluation of arterial blood gases and validation of the grading method for preretinal neovascularization. One hundred percent of rats in the inoculated group developed severe diarrhea and had duodenal cultures positive for E. rattus compared with 0% in the control group. Preretinal neovascularization similar to ROP occurred in 55% of rats in the inoculated group compared with 2% in the control group (P = 0.001). Retinal vascular areas were reduced in the inoculated group (mean +/- SD, 89% +/- 5% versus 96% +/- 2%; P < 0.001). Rats in the inoculated group demonstrated severe growth retardation (final weight, 9.7 +/- 2.2 versus 16.7 +/- 2.7 g, P < 0.001). Inoculated animals also experienced acidosis (pH 7.31 +/- 0.06 versus 7.39 +/- 0.06 control, P = 0.04). A previously undescribed enterococcal enteropathy was associated with preretinal neovascularization similar to ROP in the neonatal rat. This supports an independent role for factors other than inspired oxygen in the development of ROP.


COVID-19, Inter-household Contact and Mental Well-Being Among Older Adults in the US and the UK.
Interacting with family members and friends from other households is a key part of everyday life and is crucial to people's mental well-being. The COVID-19 pandemic severely curtailed face-to-face contact between households, particularly for older adults (aged 60 and above), due to their high risk of developing severe illness if infected by COVID-19. In-person contact, where possible, was largely replaced by virtual interaction during the pandemic. This article examines how inter-household contact in face-to-face and virtual forms, as well as combinations of the two forms of contact, related to older adults' mental well-being during the pandemic. Data from two national longitudinal surveys, collected from the same respondents before (2018-2019) and during (June 2020) the pandemic, were comparatively analysed: the Health and Retirement Study in the US and Understanding Society in the UK. The findings showed a notable increase in loneliness in the US and a decline in general mental well-being in the UK following the outbreak of COVID-19. In both countries, more frequent inter-household face-to-face contact during the pandemic was associated with better general mental well-being, but inter-household virtual contact, via means such as telephone and digital media, was not associated with general mental well-being in either the US or the UK. In the US, older adults who engaged more frequently in virtual contact were more likely to feel lonely during the pandemic, particularly if their face-to-face contact was limited. In both countries, the increase in loneliness following the outbreak of the pandemic was greater for older adults who reported more virtual contact. The findings suggest that household-centred crisis management during the COVID-19 pandemic had unintended mental health implications in both the US and the UK, despite contextual differences between the two countries. Although face-to-face contact between households helped to sustain older adults' mental well-being, virtual contact was not a qualitatively equivalent alternative. The findings also provide an important evidence base for informing policy developments and for supporting the mental health of older people during the COVID-19 pandemic and in the longer term.


Stimulation of the α7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice.
Surgery and critical illness often associate with cognitive decline. Surgical trauma or infection can lead independently to learning and memory impairments via similar, but not identical, cellular signaling of the innate immune system that promotes neuroinflammation. In this study we explored the putative synergism between aseptic orthopedic surgery and infection, the latter reproduced by postoperative lipopolysaccharide (LPS) administration. We observed that surgery and LPS augmented systemic inflammation up to postoperative d 3 and this was associated with further neuroinflammation (CD11b and CD68 immunoreactivity) in the hippocampus in mice compared with those receiving surgery or LPS alone. Administration of a selective α7 subtype nicotinic acetylcholine receptor (α7 nAChR) agonist 2 h after LPS significantly improved neuroinflammation and hippocampal-dependent memory dysfunction. Modulation of nuclear factor-kappa B (NF-κB) activation in monocytes and regulation of the oxidative stress response through nicotinamide adenine dinucleotide phosphate (NADPH) signaling appear to be key targets in modulating this response. Overall, these results suggest that it may be conceivable to limit and possibly prevent postoperative complications, including cognitive decline and/or infections, through stimulation of the cholinergic antiinflammatory pathway.


Beyond infection - Maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders.
Immune molecules such as cytokines and chemokines and the cells that produce them within the brain, notably microglia, are critical for normal brain development. This recognition has in recent years led to the working hypothesis that inflammatory events during pregnancy, e.g. in response to infection, may disrupt the normal expression of immune molecules during critical stages of neural development and thereby contribute to the risk for neurodevelopmental disorders such as autism spectrum disorder (ASD). This hypothesis has in large part been shepherded by the work of Dr. Paul Patterson and colleagues, which has elegantly demonstrated that a single viral infection or injection of a viral mimetic to pregnant mice significantly and persistently impacts offspring immune and nervous system function, changes that underlie ASD-like behavioral dysfunction including social and communication deficits. Subsequent studies by many labs - in humans and in non-human animal models - have supported the hypothesis that ongoing disrupted immune molecule expression and/or neuroinflammation contributes to at least a significant subset of ASD. The heterogeneous clinical and biological phenotypes observed in ASD strongly suggest that in genetically susceptible individuals, environmental risk factors combine or synergize to create a tipping or threshold point for dysfunction. Importantly, animal studies showing a link between maternal immune activation (MIA) and ASD-like outcomes in offspring involve different species and diverse environmental factors associated with ASD in humans, beyond infection, including toxin exposures, maternal stress, and maternal obesity, all of which impact inflammatory or immune pathways. The goal of this review is to highlight the broader implications of Dr. Patterson's work for the field of autism, with a focus on the impact that MIA by diverse environmental factors has on fetal brain development, immune system development, and the pathophysiology of ASD.


Do GOLD stages of COPD severity really correspond to differences in health status?
The purpose of this study was to assess whether different stages of chronic obstructive pulmonary disease (COPD) severity defined according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria correlate with meaningful differences in health status. A total of 381 COPD patients, aged 73+/-6 yrs, were classified in the five GOLD stages. Disease-specific (St George Respiratory Questionnaire (SGRQ)) and generic indexes of health status were measured in all patients. Multivariate analysis of covariance or Kruskal Wallis tests were used to compare health status indexes across the spectrum of GOLD stages of COPD severity. GOLD stages of COPD severity significantly differed in SGRQ components and Barthel's index, but not in the indexes assessing cognitive and affective status and quality of sleep. The largest variation in health status was observed at the transition from stage IIa to stage IIb, while there were no other significant differences between consecutive stages. Both female sex and comorbidity were associated with a greater impact of COPD on the health status. In conclusion, the upper limit of stage IIb (forced expiratory volume in one second of 49%) marks a threshold for dramatic worsening of health status. Progression of chronic obstructive pulmonary disease severity from stage 0 to stage IIa does not correspond to any meaningful difference in health status.


An Update of the International Society of Sexual Medicine's Guidelines for the Diagnosis and Treatment of Premature Ejaculation (PE).
In 2009, the International Society for Sexual Medicine (ISSM) convened a select panel of experts to develop an evidence-based set of guidelines for patients suffering from lifelong premature ejaculation (PE). That document reviewed definitions, etiology, impact on the patient and partner, assessment, and pharmacological, psychological, and combined treatments. It concluded by recognizing the continually evolving nature of clinical research and recommended a subsequent guideline review and revision every fourth year. Consistent with that recommendation, the ISSM organized a second multidisciplinary panel of experts in April 2013, which met for 2 days in Bangalore, India. This manuscript updates the previous guidelines and reports on the recommendations of the panel of experts. The aim of this study was to develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of PE for family practice clinicians as well as sexual medicine experts. A comprehensive literature review was performed. This article contains the report of the second ISSM PE Guidelines Committee. It offers a new unified definition of PE and updates the previous treatment recommendations. Brief assessment procedures are delineated, and validated diagnostic and treatment questionnaires are reviewed. Finally, the best practices treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with PE, in facilitating treatment of their patients. Development of guidelines is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to a more complete understanding of the pathophysiology as well as new efficacious and safe treatments for this sexual dysfunction. We again recommend that these guidelines be reevaluated and updated by the ISSM in 4 years. Althof SE, McMahon CG, Waldinger MD, Serefoglu EC, Shindel AW, Adaikan PG, Becher E, Dean J, Giuliano F, Hellstrom WJG, Giraldi A, Glina S, Incrocci L, Jannini E, McCabe M, Parish S, Rowland D, Segraves RT, Sharlip I, and Torres LO. An update of the International Society of Sexual Medicine's guidelines for the diagnosis and treatment of premature ejaculation (PE). Sex Med 2014;2:60-90.


Natural compounds that regulate lymph node sinus macrophages: Inducing an anti-tumor effect by regulating macrophage activation.
Recent progress in anti-tumor therapy has revealed the significance of anti-tumor immune responses in tumor progression and clinical course in several kinds of malignant tumors. The draining lymph node is an important immune system component that contains a number of antigen-presenting cells, which induce rapid immune responses to foreign antigens. Current studies have shown that higher expression of CD169 on lymph node sinus macrophages is associated with the induction of anti-tumor immunity. In the present study, we searched for natural compounds that regulate the CD169-positive phenotype in macrophages to identify potential new anti-cancer agents targeting macrophage activation. Among 50 natural compounds, aculeatiside A, naringin, and onionin A significantly induced the CD169-positive phenotype in human monocyte-derived macrophages. These compounds also induced CD169 overexpression and secretion of inflammatory cytokines, including interleukin (IL)-1β and IL-12, in murine macrophages. Subcutaneous injection of aculeatiside A and naringin enhanced mRNA expression of IL-1β, IL12, and CD169 in regional lymph nodes in mice. These findings suggest aculeatiside A and naringin may enhance anti-tumor immune responses by inducing CD169-positive macrophages in lymph nodes.


Heterogeneity of the Head and Neck Squamous Cell Carcinoma Immune Landscape and Its Impact on Immunotherapy.
Head and neck squamous cell carcinomas (HNSCCs) are highly aggressive, multi-factorial tumors in the upper aerodigestive tract affecting more than half a million patients worldwide each year. Alcohol, tobacco, and human papillomavirus (HPV) infection are well known causative factors for HNSCCs. Current treatment options for HNSCCs are surgery, radiotherapy, chemotherapy, or combinatorial remedies. Over the past decade, despite the marked improvement in clinical outcome of many tumor types, the overall 5-year survival rate of HNSCCs remained ∼40-50% largely due to poor availability of effective therapeutic options for HNSCC patients with recurrent disease. Therefore, there is an urgent and unmet need for the identification of specific molecular signatures that better predict the clinical outcomes and markers that serve as better therapeutic targets. With recent technological advances in genomic and epigenetic analyses, our knowledge of HNSCC molecular characteristics and classification has been greatly enriched. Clinical and genomic meta-analysis of multicohort HNSCC gene expression profile has clearly demonstrated that HPV+ and HPV- HNSCCs are not only derived from tissues of different anatomical regions, but also present with different mutation profiles, molecular characteristics, immune landscapes, and clinical prognosis. Here, we briefly review our current understanding of the biology, molecular profile, and immunological landscape of the HPV+ and HPV- HNSCCs with an emphasis on the diversity and heterogeneity of HNSCC clinicopathology and therapeutic responses. After a review of recent advances and specific challenges for effective immunotherapy of HNSCCs, we then conclude with a discussion on the need to further enhance our understanding of the unique characteristics of HNSCC heterogeneity and the plasticity of immune landscape. Increased knowledge regarding the immunological characteristics of HPV+ and HPV- HNSCCs would improve therapeutic targeting and immunotherapy strategies for different subtypes of HNSCCs.


Somatic-cell mutation induced by short exposures to cigarette smoke in urate-null, oxidative stress-sensitive Drosophila.
We previously reported that a urate-null strain of Drosophila is hypersensitive to cigarette smoke (CS), and we suggested that CS induces oxidative stress in Drosophila because uric acid is a potent antioxidant. Although the carcinogenic risk of CS exposure is widely recognized; documentation of in vivo genotoxic activity of environmental CS, especially gaseous-phase CS, remains inconclusive. To date, somatic-cell mutations in Drosophila resulting from exposure to CS have not been detected via the somatic mutation and recombination test (wing spot test) with wild-type flies, a widely used Drosophila assay for the detection of somatic-cell mutation; moreover, genotoxicity has not been documented via a DNA repair test that involves DNA repair-deficient Drosophila. In this study, we used a new Drosophila strain (y v ma-l; mwh) to examine the mutagenicity induced by gaseous-phase CS; these flies are urate-null due to a mutation in ma-l, and they are heterozygous for multiple wing hair (mwh), a mutation that functions as a marker for somatic-cell mutation. In an assay with this newly developed strain, a superoxide anion-producing weed-killer, paraquat, exhibited significant mutagenicity; in contrast, paraquat was hardly mutagenic with a wild-type strain. Drosophila larvae were exposed to CS for 2, 4 or 6h, and then kept at 25°C on instant medium until adulthood. After eclosion, mutant spots, which consisted of mutant hairs on wings, were scored. The number of mutant spots increased significantly in an exposure time-dependent manner in the urate-null females (ma-l (-/-)), but not in the urate-positive females (ma-l (+/-)). In this study, we showed that short-term exposure to CS was mutagenic in this in vivo system. In addition, we obtained suggestive data regarding reactive oxygen species production in larva after CS exposure using the fluorescence probe H2DCFDA. These results suggest that oxidative damage, which might be countered by uric acid, was partly responsible for induction of somatic cell mutations in Drosophila larvae exposed to CS.


Validation of a protocol for the assessment of skin temperature and blood flow in childhood localised scleroderma.
Localised scleroderma (LS) is the most common form of scleroderma seen in children, and usually presents unilaterally. Infrared thermography (IRT) and laser Doppler (LD) have both been reported to be useful in assessing the active, inflammatory stage of LS. We developed and validated a protocol using these techniques for the assessment of unilateral LS activity in children. We investigated the spatial variability and repeatability of LD measurements from adult control forearm skin, and the inter- and intra-operator reproducibility of both LD blood flow trace analysis and IRT skin temperature analysis. Software was developed to produce overlay images of thermograms onto digital photographs of skin sites. In a group of seven adult control subjects, we established the normal range for skin temperature and LD blood flow at six standardised sites (forehead, cheek, abdomen, back, arm and leg), and measured contralateral differences in readings. In a group of 34 children with LS, we investigated the skin temperature and LD blood flow in unaffected skin at the same six sites. In adults, physiological variability in LD blood flow and skin temperature between the two sides of the body was found to be greater than the uncertainty introduced into the measurements by (inter alia) limited intra- or inter-operator reproducibility. The cheek displayed the highest mean asymmetry in both skin temperature (0.5 degrees C) and LD blood flow (40%). Our protocol combines IRT, LD and photography for LS assessment in children, and establishes a normal range of readings in line with other authors.


Effectiveness of Chinese herbal medicine for cancer palliative care: overview of systematic reviews with meta-analyses.
Chinese herbal medicines (CHM) are often used in managing cancer related symptoms but their effectiveness and safety is controversial. We conducted this overview of meta-analyses to summarize evidence on CHM for cancer palliative care. We included systematic reviews (SRs) with meta-analyses of CHM clinical trials on patients diagnosed with any type of cancer. Methodological quality of included meta-analyses was assessed with the Methodological Quality of Systematic Reviews (AMSTAR) Instrument. Fifty-one SRs with meta-analyses were included. They covered patients with lung (20 SRs), gastric (8 SRs), colorectal (6 SRs), liver (6 SRs), breast (2 SRs), cervical (1 SR), esophageal (1 SR), and nasopharyngeal (1 SR) cancers. Six SRs summarized evidence on various types of cancer. Methodological quality of included meta-analyses was not satisfactory. Overall, favorable therapeutic effects in improving quality of life among cancer patients have been reported. Conflicting evidence exists for the effectiveness of CHM in prolonging survival and in reducing chemotherapy and/or radiotherapy related toxicities. No serious adverse effects were reported in all included studies. Evidence indicated that CHM could be considered as an option for improving quality of life among patients receiving palliative care. It is unclear if CHM may increase survival, or reduce therapy related toxicities.


KIF4A and PP2A-B56 form a spatially restricted feedback loop opposing Aurora B at the anaphase central spindle.
The mitotic kinase Aurora B is concentrated at the anaphase central spindle by the kinesin MKlp2 during mitotic exit and cytokinesis. This pool of Aurora B phosphorylates substrates including the kinesin KIF4A to regulate central spindle length. In this paper, we identify a counteracting system in which PP2A-B56γ and -ε, but not PP2A-B56α, -β, and -δ, are maintained at the central spindle by KIF4A. Biochemical assays show that PP2A-B56γ can dephosphorylate the T799 Aurora B site on KIF4A and thereby counteract the Aurora B- and microtubule-stimulated ATPase activity of KIF4A. In agreement with these observations, combined silencing of PP2A-B56γ and -ε resulted in increased phosphorylation of KIF4A T799 and decreased central spindle growth in anaphase B. Furthermore, reduced turnover of regulatory phosphorylation on another Aurora B substrate MKlp1 was observed, suggesting that PP2A-B56γ and -ε play a general role opposing Aurora B at the central spindle. KIF4A and PP2A-B56γ and -ε therefore create a spatially restricted negative feedback loop counteracting Aurora B in anaphase.


Are people willing to buy natural disaster insurance in China? Risk awareness, insurance acceptance, and willingness to pay.
After the Wenchuan earthquake (magnitude 7.9, May 12, 2008), intensive debates on how China should establish a natural disaster insurance system were initiated among researchers, policymakers, and insurance professionals. Our focus was the social aspects of disaster insurance, explored in China through a nationwide survey. Our questionnaires investigated people's risk awareness, insurance acceptance, their opinions on governmental measures for disaster management, and their willingness to pay for disaster house insurance. We analyzed the results at both regional and individual scales. We found that the integrated hazard index and respondents' experience of insurance (considered objective factors), and their opinions on the importance of insurance and government responsibility (considered subjective factors) showed strong correlation with the regional overall acceptance of disaster insurance. An individual's decision to participate highly depended on his/her experience of both insurance and disaster and his/her opinion on the importance of insurance as a coping mechanism. Respondents from poverty-stricken or less-developed counties were not necessarily more reluctant to accept natural disaster insurance, though they exhibited relatively lower ability to afford insurance. In general, respondents had correct perceptions of natural disasters in their areas; however, people from regions with a greater multihazard threat showed less willingness to accept disaster insurance because they tended to expect the government to undertake to cover losses and considered insurance to be less important. People's willingness to pay for an assumed disaster house insurance was also investigated and analyzed. We consequently discuss the policy implications for developing a disaster insurance system in China.


Family communication about sex: what are parents saying and are their adolescents listening?
Communication between parents and adolescents about sex, particularly in minority families, has been understudied; more information is needed both on which sex-related topics are discussed and on how their content is transmitted. Parent-adolescent communication about 10 sex-related topics was examined in a sample of 907 Hispanic and black 14-16-year-olds. Chi-square analyses were performed to test for significant differences across the 10 topics in discussions reported by the adolescents (with either parent) and by the mothers. The openness of communication, parent-adolescent agreement about communication of topics and differences by gender and ethnicity were also examined. Significantly higher proportions of mothers and adolescents reported discussions of HIV or AIDS (92% by mothers and 71% by adolescents, respectively) and STDs (85% and 70%, respectively) than of issues surrounding sexual behavior, contraceptive use and physical development (27-74% for these other eight topics as reported by mothers vs. 15-66% as reported by adolescents). The gender of the adolescent and of the parent holding the discussion, but not the family's ethnicity, significantly influenced findings, with adolescents of both sexes more likely to report discussions with mothers than with fathers, and with parents more likely to discuss any of the 10 topics with an adolescent of the same gender than of the opposite gender. The likelihood of a topic being discussed and of mother-adolescent agreement that a topic was discussed both increased with an increasing degree of openness in the communication process. Consistent with research among white samples, mothers of black and Hispanic adolescents are the primary parental communicators about sexual topics. To facilitate communication, educational programs for parents should cover not only what is discussed, but how the information is conveyed.


In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
Expressed prostatic secretions (EPS) are proximal fluids of the prostate that are increasingly being utilized as a clinical source for diagnostic and prognostic assays for prostate cancer (PCa). These fluids contain an abundant amount of microvesicles reflecting the secretory function of the prostate gland, and their protein composition remains poorly defined in relation to PCa. Using expressed prostatic secretions in urine (EPS-urine), exosome preparations were characterized by a shotgun proteomics procedure. In pooled EPS-urine exosome samples, ~900 proteins were detected. Many of these have not been previously observed in the soluble proteome of EPS generated by our labs or other related exosome proteomes. We performed systematic comparisons of our data against previously published, prostate-related proteomes, and global annotation analyses to highlight functional processes within the proteome of EPS-urine derived exosomes. The acquired proteomic data have been deposited to the Tranche repository and will lay the foundation for more extensive investigations of PCa derived exosomes in the context of biomarker discovery and cancer biology.


Reliability and validity of the Older Americans Resources and Services (OARS) social resources scale in six European countries.
The purpose of this article is to examine data quality, reliability, and construct validity of the Older Americans Resources and Services social resources scale in six European countries (The Netherlands, Luxembourg, Italy, Austria, the United Kingdom, and Sweden). A questionnaire was administered through face-to-face interviews in five countries, and postal interview in the sixth, to representative populations of adults aged 50 to 90 living independently (N = 12,478). This article examines missing values and distribution of items in the social resources scale, and consistency of skew and kurtosis across countries. We performed item-total correlations and ran confirmatory factor analyses to test a three-factor model obtained in previous U.S. and Spanish analyses. Cronbach's alpha determined the reliability of the factors. We observed a relatively large proportion of missing data for one item (have someone who would help you). All items correlated with a score equal to or greater than 0.20. Although the confirmatory factor analyses generally supported the acceptability of the three-factor structure in the European data, the reliability of two dimensions (dependability and affective) was unacceptably low. Differences across countries make it unlikely that researchers can develop a single social resources scale that would have item equivalence in multiple countries.


Investigation of familial segregation of hyperreactive malarial splenomegaly in Kumasi, Ghana.
Hyperreactive malarial splenomegaly (HMS), a common cause of massive splenomegaly in malaria-endemic regions, is defined as persistent splenomegaly without demonstrable underlying disease. Previous studies have found HMS more frequently in certain tribes in Papua New Guinea, Uganda and Nigeria, with strong familial associations in Uganda and Papua New Guinea. This case-control study aimed to determine the extent of familial association of splenomegaly and the pattern of segregation of the condition in families in Ghana. It involved 22 HMS cases with 99 relatives, and 15 population controls of similar socio-economic background with 51 relatives. The pedigree of each family was recorded. Clinical and laboratory data were collected on all participants, including the presence and degree of splenomegaly. Relatives with splenomegaly were identified for 27% of HMS cases and for 6.7% of population controls (P=0.04). There were significant differences in the IgM levels, which were higher (P=0.005), and the haemoglobin levels, which were lower (P=0.009), in cases compared with controls. In Ghana, relatives of HMS cases are more likely to have splenomegaly than population controls, but with no obvious pattern of Mendelian segregation. HMS aetiology in Ghana is likely to be complex, involving multiple genetic and environmental factors.


Deletion of L4 domains reveals insights into the importance of ribosomal protein extensions in eukaryotic ribosome assembly.
Numerous ribosomal proteins have a striking bipartite architecture: a globular body positioned on the ribosomal exterior and an internal loop buried deep into the rRNA core. In eukaryotes, a significant number of conserved r-proteins have evolved extra amino- or carboxy-terminal tail sequences, which thread across the solvent-exposed surface. The biological importance of these extended domains remains to be established. In this study, we have investigated the universally conserved internal loop and the eukaryote-specific extensions of yeast L4. We show that in contrast to findings with bacterial L4, deleting the internal loop of yeast L4 causes severely impaired growth and reduced levels of large ribosomal subunits. We further report that while depleting the entire L4 protein blocks early assembly steps in yeast, deletion of only its extended internal loop affects later steps in assembly, revealing a second role for L4 during ribosome biogenesis. Surprisingly, deletion of the entire eukaryote-specific carboxy-terminal tail of L4 has no effect on viability, production of 60S subunits, or translation. These unexpected observations provide impetus to further investigate the functions of ribosomal protein extensions, especially eukaryote-specific examples, in ribosome assembly and function.


Chance long-distance or human-mediated dispersal? How Acacia s.l. farnesiana attained its pan-tropical distribution.
Acacia s.l. farnesiana, which originates from Mesoamerica, is the most widely distributed Acacia s.l. species across the tropics. It is assumed that the plant was transferred across the Atlantic to southern Europe by Spanish explorers, and then spread across the Old World tropics through a combination of chance long-distance and human-mediated dispersal. Our study uses genetic analysis and information from historical sources to test the relative roles of chance and human-mediated dispersal in its distribution. The results confirm the Mesoamerican origins of the plant and show three patterns of human-mediated dispersal. Samples from Spain showed greater genetic diversity than those from other Old World tropics, suggesting more instances of transatlantic introductions from the Americas to that country than to other parts of Africa and Asia. Individuals from the Philippines matched a population from South Central Mexico and were likely to have been direct, trans-Pacific introductions. Australian samples were genetically unique, indicating that the arrival of the species in the continent was independent of these European colonial activities. This suggests the possibility of pre-European human-mediated dispersal across the Pacific Ocean. These significant findings raise new questions for biogeographic studies that assume chance or transoceanic dispersal for disjunct plant distributions.


Infant sex predicts breast milk energy content.
During human evolutionary history, and for many around the world, breast milk is the primary source of nutritional energy for infants. Variation in breast milk quality might logically have important effects on infant health, growth, and development, yet the sources of this variation remain largely unelucidated. We quantified nutrient and energy content of breast milk from 25 healthy, well-nourished Massachusetts mothers with infants aged 2-5 months. We examined several potential sources of variation in milk quality, particularly feeding patterns, infant sex, and maternal breast growth during pregnancy. After controlling for time since last feeding, a known correlate of milk composition, we found that mothers of male infants produced milk that had 25% greater energy content than mothers of female infants (P < 0.001). Change in maternal bra cup size during pregnancy was associated with 16.17 kcal/100 ml greater energy content of milk (P = 0.009), but was not significant after taking infant sex into account. Greater nutritional investment in sons may account for the greater observed growth rates in male compared to female infants.


A systematic review of behavioral and treatment outcome studies among HIV-infected men who have sex with men who abuse crystal methamphetamine.
Men who have sex with men (MSM) have the highest incidence of HIV infection in the United States. One of the contributing factors to HIV spread among this group is the use of crystal methamphetamine ("meth"). The objective was to review the behavioral impact of crystal meth use in HIV-infected MSM and potential treatment options. A systematic review of MEDLINE identified studies that evaluated the clinical effects of crystal meth on the HIV-infected MSM population. Search terms included HIV, methamphetamine, MSM, antiretroviral therapy, adherence, resistance, and treatment. U.S. citations in the English language in peer-reviewed journals until December 2010 were included. The primary author reviewed eligible articles, and relevant data including study design, sample, and outcomes were entered into an electronic data table. The 61 included studies highlight that HIV-infected MSM who use crystal meth are more likely to report high-risk sexual behaviors, incident sexually transmitted infections, and serodiscordant unprotected anal intercourse, compared to HIV-infected MSM who do not use crystal meth. Medication adherence in this population is notably low, which may contribute to transmission of resistant virus. No medications have proven effective in the treatment of crystal meth addiction, and the role of behavioral therapies, such as contingency management are still in question. HIV-infected MSM who abuse crystal meth have worse HIV-related health outcomes. Behavioral interventions have shown variable results in treating crystal meth addiction, and more investigation into rehabilitation options are needed. The results presented support efforts to develop and implement novel interventions to reduce crystal meth use in HIV-infected MSM.


Comparison of the vaccine efficacy of gamma-irradiated Schistosoma japonicum cercariae with the defined antigen Sj62(IrV-5) in pigs.
Development of a vaccine against Schistosoma japonicum which can protect both man and the domestic animal zoonotic reservoirs of infection would be an invaluable tool in attempts to control this infection in those areas in which conventional control methods have failed to break transmission. The pig is a natural host of S. japonicum and because of its anatomical and immunological similarities to humans, it is a potentially valuable host for studies on S. japonicum in particular and schistosomes in general. Radiation-attenuated cercariae are highly effective in inducing immunity in experimental schistosomosis and there are promising reports of partial protection against schistosomes with recombinant-derived individual antigens. In the present study we have set out to establish a protocol for inducing protection with gamma-irradiated cercariae in pigs and to assess the protective capacity of recombinant and naked DNA formulations of Sj62, a 62kDa region of S. japonicum myosin. The corresponding S. mansoni version or Sj62, recombinant IrV-5, has previously been implicated in irradiated vaccine immunity in S. mansoni infections and has been shown to induce high levels of immunity in a variety of hosts. Groups of pigs were immunised three times at 2-week intervals with 2000 cercariae irradiated at 20krad, with Sj62 as a recombinant (rSj62) incorporated in Freund's adjuvant, a micellar preparation, or as a naked DNA construct. Vaccination with irradiated cercariae did not induce significant anti-Sj62 antibody but following intramuscular challenge with 2000 cercariae, the vaccinated pigs showed >95% resistance as assessed by reduced faecal egg output, worm tissue egg burdens and also reduced septal fibrosis. Immunisation with each of the Sj62 formulations induced significant anti-Sj62 antibody responses, the highest titre (>12,800) being with the Freund's preparation but none of the Sj62-immunised groups showed significant resistance to challenge. The data suggest that Sj62 shows little promise as a vaccine candidate for schistosomosis.


Evaluation of the removal of point-of-sale tobacco displays in Ireland.
To evaluate the short-term impacts of removing point-of-sale tobacco displays in Ireland, implemented in July 2009. Retailer compliance was assessed using audit surveys in 2007, 2008 and 2009. Using a monthly survey of 1000 adults carried out since 2002, changes in smoking prevalence were assessed; attitudes were measured using extra questions added for a 10-month period before and after the law. Youth responses were assessed using a cohort of 180 13-15 year olds, interviewed in June and August 2009. Immediately following implementation, compliance was 97%. Support for the law increased among adults after implementation (58% Apr-Jun vs 66% Jul-Dec, p<0.001). Recall of displays decreased significantly for adults (49% to 22%; p<0.001), more so among teenagers (81% to 22%; p<0.001). There were no significant short-term changes in prevalence among youths or adults. The proportion of youths believing more than a fifth of children their age smoked decreased from 62% to 46%, p<0.001). Post-legislation, 14% of adult smokers thought the law had made it easier to quit smoking and 38% of teenagers thought it would make it easier for children not to smoke. Compliance was very high and the law was well supported. Recall of displays dropped significantly among adults and teenagers post-legislation and there were encouraging signs that the law helped de-normalise smoking.


Synchronized, concurrent optical coherence tomography and videostroboscopy for monitoring vocal fold morphology and kinematics.
Voice disorders affect a large number of adults in the United States, and their clinical evaluation heavily relies on laryngeal videostroboscopy, which captures the medial-lateral and anterior-posterior motion of the vocal folds using stroboscopic sampling. However, videostroboscopy does not provide direct visualization of the superior-inferior movement of the vocal folds, which yields important clinical insight. In this paper, we present a novel technology that complements videostroboscopic findings by adding the ability to image the coronal plane and visualize the superior-inferior movement of the vocal folds. The technology is based on optical coherence tomography, which is combined with videostroboscopy within the same endoscopic probe to provide spatially and temporally co-registered images of the mucosal wave motion, as well as vocal folds subsurface morphology. We demonstrate the capability of the rigid endoscopic probe, in a benchtop setting, to characterize the complex movement and subsurface structure of the aerodynamically driven excised larynx models within the 50 to 200 Hz phonation range. Our preliminary results encourage future development of this technology with the goal of its use for in vivo laryngeal imaging.


[Work and health: the activity of burning toxic waste in cement kilns in Cantagalo, Rio de Janeiro State].
This study analyzes the work and health conditions through the discourse of the employees involved in the activity of toxic waste co-processing in cement kilns in Cantagalo, RJ. A qualitative approach was adopted using a semi-structured interview with 13 individuals. After analyzing the discourse, it was possible to observe relevant failures in the work process planning, in the identification of risks, in preventing diseases, in monitoring health impacts and to the environment, even their identification and notification to the competent authorities. The assimilation of the uncertainties of the process, favoring the interests of the entrepreneurs, has passed on the workers the burden of illness, rendered acceptable in that they deny clinical evidences. It is imperative to establish a broad debate involving public and private entities, the society in all its representations, confronting ethical, environmental and health issues to the interests of capital in order to set new guidelines for the process.


Efficacy of Interpersonal Psychotherapy plus pharmacotherapy in chronically depressed inpatients.
Clinical guidelines recommend the combination of pharmaco- and psychotherapy for the treatment of chronic depression, although there are only a few studies supporting an additive effect of psychotherapy. Forty-five inpatients with a chronic Major Depressive Disorder were randomized to 5 weeks of either Interpersonal Psychotherapy (IPT) modified for an inpatient setting (15 individual and 8 group sessions) plus pharmacotherapy or to medication plus Clinical Management (CM). The 17-item Hamilton Rating Scale for Depression was the primary outcome measure. The study included a prospective naturalistic follow-up, 3- and 12-months after discharge. Intent-to-treat analyses revealed a significantly greater reduction of depressive symptoms as well as better global functioning of patients treated with IPT compared to the CM group at week 5. Response and sustained response rates differed significantly between the two treatment conditions, favouring the IPT group. Remission rates were considerably higher for IPT patients who completed the treatment (67% vs. 32%). Patients who initially responded to IPT exhibited greater treatment gains at 12 months since only 7% of these subjects relapsed compared with 25% of the CM subjects. In the long-term, additional IPT led to a lower symptom level and higher global functioning. The study uses data of a subset of patients from a larger trial. Both treatment groups did not receive comparable amounts of therapeutic attention. Extrapolating the data from this inpatient study to chronically depressed outpatients may not be possible. Intensive combined treatment provides superior acute and long-term effects over standard treatment in chronically depressed inpatients.


Dimming-discrete-multi-tone (DMT) for simultaneous color control and high speed visible light communication.
Visible light communication (VLC) using LEDs has attracted significant attention recently for the future secure, license-free and electromagnetic-interference (EMI)-free optical wireless communication. Dimming technique in LED lamp is advantageous for energy efficiency. Color control can be performed in the red-green-blue (RGB) LEDs by using dimming technique. It is highly desirable to employ dimming technique to provide simultaneous color and dimming control and high speed VLC. Here, we proposed and demonstrated a LED dimming control using dimming-discrete-multi-tone (DMT) modulation. High speed DMT-based VLC with simultaneous color and dimming control is demonstrated for the first time to the best of our knowledge. Demonstration and analyses for several modulation conditions and transmission distances are performed, for instance, demonstrating the data rate of 103.5 Mb/s (using RGB LED) with fast Fourier transform (FFT) size of 512.


Ol4E-T, a eukaryotic translation initiation factor 4E-binding protein of medaka fish (Oryzias latipes), can interact with nanos3 and vasa in vitro.
Maternal factors have essential roles in the specification and development of germ cells in metazoans. In Drosophila, a number of genes such as oskar, vasa, nanos, and tudor are required for specific steps in pole cell formation and further germline development. Drosophila cup, another maternal factor, is confirmed as a main factor in normal oogenesis, maintenance, and survival of female germ-line stem cells by interaction with Nanos. Through searching for the homolog of Drosophila cup in the medaka, the homolog of eukaryotic translation initiation factor 4E (eIF4E)-transporter, named Ol4E-T, was identified. Reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization revealed that Ol4E-T is maternally deposited in the embryo and Ol4E-T expression is maintained throughout embryogenesis. Ol4E-T is predominantly expressed in the adult gonads. In the testes, Ol4E-T is expressed in the same regions where medaka vasa, named olvas is expressed. In the ovary, expression of Ol4E-T conforms to that of nanos3 and olvas. Ol4E-T harbors a well-conserved eIF4E-binding motif, YTKEELL, by which Ol4E-T interacts with eIF4E in medaka. Additionally, Ol4E-T can interact with medaka Nanos3 and Olvas, as shown by yeast two hybridization. The spatial expression and interactions between Ol4E-T with germ cell markers Olvas and Nanos3 suggest a role for Ol4E-T in germ-line development in medaka.


Adaptive resistance of Pseudomonas aeruginosa induced by aminoglycosides and killing kinetics in a rabbit endocarditis model.
Adaptive resistance following the first exposure to aminoglycosides is a recently described in vitro phenomenon in Pseudomonas aeruginosa and other aerobic gram-negative bacilli. We investigated the in vivo relevance of adaptive resistance in P. aeruginosa following a single dose of amikacin in the experimental rabbit endocarditis model. Rabbits with P. aeruginosa endocarditis received either no therapy (control) or a single intravenous (i.v.) dose of amikacin (80 mg/kg of body weight) at 24 h postinfection, after which they were sacrificed at 5, 8, 12, 16, or 24 h postdose. Excised aortic vegetations were subsequently exposed ex vivo to amikacin at 2.5, 5, 10 or 20 times the MIC for 90 min. In vivo adaptive resistance was identified when amikacin-induced pseudomonal killing within excised aortic vegetations was less in animals receiving single-dose amikacin in vivo than in vegetations from control animals not receiving amikacin in vivo. Maximal adaptive resistance occurred between 8 and 16 h after the in vivo amikacin dose, with complete refractoriness to ex vivo killing by amikacin seen at 12 h postdose. By 24 h postdose, bacteria within excised vegetations had partially recovered their initial amikacin susceptibility. In a parallel treatment study, we demonstrated that amikacin given once daily (but not twice daily) at a total dose of 80 mg/kg i.v. for 1-day treatment significantly reduced pseudomonal densities within aortic vegetations versus those in untreated controls. When therapy was continued for 3 days with the same total daily dose (80 mg/kg/day), amikacin given once or twice daily significantly reduced intravegetation pseudomonal densities versus those in controls. However, amikacin given once daily was still more effective than the twice-daily regimen. These data confirm the induction of aminoglycoside adaptive resistance in vivo and further support the advantages of once-daily aminoglycoside dosing regimens in the treatment of serious pseudomonal infections.


Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis.
Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging-Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex. On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β -4·0, 95% CI -5·5 to -2·6; p<0·0001; R2 0·22, p<0·0001) and with survival (-2·0, -3·2 to -0·8; 0·003; 0·15, <0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral α-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology. US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).


CONVERGENCE BEHAVIOR OF THE ACTIVE MASK SEGMENTATION ALGORITHM.
We study the convergence behavior of the Active Mask (AM) framework, originally designed for segmenting punctate image patterns. AM combines the flexibility of traditional active contours, the statistical modeling power of region-growing methods, and the computational efficiency of multiscale and multiresolution methods. Additionally, it achieves experimental convergence to zero-change (fixed-point) configurations, a desirable property for segmentation algorithms. At its a core lies a voting-based distributing function which behaves as a majority cellular automaton. This paper proposes an empirical measure correlated to the convergence behavior of AM, and provides sufficient theoretical conditions on the smoothing filter operator to enforce convergence.


Cartilage T1ρ and T2 relaxation times: longitudinal reproducibility and variations using different coils, MR systems and sites.
To evaluate the longitudinal reproducibility and variations of cartilage T1ρ and T2 measurements using different coils, MR systems and sites. Single-Site study: Phantom data were collected monthly for up to 29 months on four GE 3T MR systems. Data from phantoms and human subjects were collected on two MR systems using the same model of coil; and were collected on one MR system using two models of coils. Multi-site study: Three participating sites used the same model of MR systems and coils, and identical imaging protocols. Phantom data were collected monthly. Human subjects were scanned and rescanned on the same day at each site. Two traveling human subjects were scanned at all three sites. Single-Site Study: The phantom longitudinal RMS-CVs ranged from 1.8% to 2.7% for T1ρ and 1.8-2.8% for T2. Significant differences were found in T1ρ and T2 values using different MR systems and coils. Multi-Site Study: The phantom longitudinal RMS-CVs ranged from 1.3% to 2.6% for T1ρ and 1.2-2.7% for T2. Across three sites (n = 16), the in vivo scan-rescan RMS-CV was 3.1% and 4.0% for T1ρ and T2, respectively. Phantom T1ρ and T2 values were significantly different between three sites but highly correlated (R > 0.99). No significant difference was found in T1ρ and T2 values of traveling controls, with cross-site RMS-CV as 4.9% and 4.4% for T1ρ and T2, respectively. With careful quality control and cross-calibration, quantitative MRI can be readily applied in multi-site studies and clinical trials for evaluating cartilage degeneration.


The p12 subunit of human polymerase delta modulates the rate and fidelity of DNA synthesis.
This study examines the role of the p12 subunit in the function of the human DNA polymerase delta (Pol delta) holoenzyme by comparing the kinetics of DNA synthesis and degradation catalyzed by the four-subunit complex, the three-subunit complex lacking p12, and site-directed mutants of each lacking proofreading exonuclease activity. Results show that p12 modulates the rate and fidelity of DNA synthesis by Pol delta. All four complexes synthesize DNA in a rapid burst phase and a slower, more linear phase. In the presence of p12, the burst rates of DNA synthesis are approximately 5 times faster, while the affinity of the enzyme for its DNA and dNTP substrates appears unchanged. The p12 subunit alters Pol delta fidelity by modulating the proofreading 3' to 5' exonuclease activity. In the absence of p12, Pol delta is more likely to proofread DNA synthesis because it cleaves single-stranded DNA twice as fast and transfers mismatched DNA from the polymerase to the exonuclease sites 9 times faster. Pol delta also extends mismatched primers 3 times more slowly in the absence of p12. Taken together, the changes that p12 exerts on Pol delta are ones that can modulate its fidelity of DNA synthesis. The loss of p12, which occurs in cells upon exposure to DNA-damaging agents, converts Pol delta to a form that has an increased capacity for proofreading.


First-in-human study of CH5132799, an oral class I PI3K inhibitor, studying toxicity, pharmacokinetics, and pharmacodynamics, in patients with metastatic cancer.
This phase I dose-escalation study investigated the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of CH5132799. Patients with metastatic solid tumors were eligible for the study. CH5132799 was administered orally once daily or twice daily in 28-day cycles. Thirty-eight patients with solid tumors received CH5132799 at 2 to 96 mg once daily or 48 to 72 mg twice daily. The MTD was 48 mg on the twice-daily schedule but was not reached on the once daily schedule. DLTs were grade 3 elevated liver function tests (LFT), grade 3 fatigue, grade 3 encephalopathy, grade 3 diarrhea, and grade 3 diarrhea with grade 3 stomatitis; all DLTs were reversible. Most drug-related adverse events were grade 1/2. Diarrhea (34%) and nausea (32%) were the most common events. Mean Cmax and AUC0-24 in steady state at MTD were 175 ng/mL and 1,550 ng·h/mL, respectively, consistent with efficacious exposure based on preclinical modeling. Reduction in SUVmax with [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) was observed in 5 of 7 patients at MTD. A patient with PIK3CA-mutated clear cell carcinoma of the ovary achieved a partial response by GCIG CA125 criteria and further, a heavily pretreated patient with triple-negative breast cancer had marked improvement in her cutaneous skin lesions lasting six cycles. CH5132799 is well tolerated at the MTD dose of 48 mg twice daily. At this dose, the drug had a favorable PK and PD profile and preliminary evidence of clinical activity.


CRF19_cpx is an Evolutionary fit HIV-1 Variant Strongly Associated With Rapid Progression to AIDS in Cuba.
Clinicians reported an increasing trend of rapid progression (RP) (AIDS within 3 years of infection) in Cuba. Recently infected patients were prospectively sampled, 52 RP at AIDS diagnosis (AIDS-RP) and 21 without AIDS in the same time frame (non-AIDS). 22 patients were sampled at AIDS diagnosis (chronic-AIDS) retrospectively assessed as > 3 years infected. Clinical, demographic, virological, epidemiological and immunological data were collected. Pol and env sequences were used for subtyping, transmission cluster analysis, and prediction of resistance, co-receptor use and evolutionary fitness. Host, immunological and viral predictors of RP were explored through data mining. Subtyping revealed 26 subtype B strains, 6 C, 6 CRF18_cpx, 9 CRF19_cpx, 29 BG-recombinants and other subtypes/URFs. All patients infected with CRF19 belonged to the AIDS-RP group. Data mining identified CRF19, oral candidiasis and RANTES levels as the strongest predictors of AIDS-RP. CRF19 was more frequently predicted to use the CXCR4 co-receptor, had higher fitness scores in the protease region, and patients had higher viral load at diagnosis. CRF19 is a recombinant of subtype D (C-part of Gag, PR, RT and nef), subtype A (N-part of Gag, Integrase, Env) and subtype G (Vif, Vpr, Vpu and C-part of Env). Since subtypes D and A have been associated with respectively faster and slower disease progression, our findings might indicate a fit PR driving high viral load, which in combination with co-infections may boost RANTES levels and thus CXCR4 use, potentially explaining the fast progression. We propose that CRF19 is evolutionary very fit and causing rapid progression to AIDS in many newly infected patients in Cuba.


Gender differences in response to HIV infection.
There is strong epidemiologic evidence from studies of i.v. drug users in New York City for the existence of one or more gender-related cofactors in response to HIV infection. The strength of the evidence comes from the variety of data sets that indicate a gender-related cofactor and from the consistency of the pattern found: in all of the data sets, females appear to have a more "favorable" response than do males. The extent of underrepresentation of females in the cases of AIDS in i.v. drug users--a possible 35% reduction in the development of clinical AIDS-suggests that such a cofactor should be considered of practical importance. Identifying the mechanism(s) for a gender difference may lead to ways of deliberately affecting the course of the infection. Further research on the gender difference may also contribute to our understanding of interactions among the various components of the immune system and the interaction of the immune system with other behavioral and physiologic systems.