Implementing a fax referral program for quitline smoking cessation services in urban health centers: a qualitative study.
Fax referral services that connect smokers to state quitlines have been implemented in 49 U.S. states and territories and promoted as a simple solution to improving smoker assistance in medical practice. This study is an in-depth examination of the systems-level changes needed to implement and sustain a fax referral program in primary care. The study involved implementation of a fax referral system paired with a chart stamp prompting providers to identify smoking patients, provide advice to quit and refer interested smokers to a state-based fax quitline. Three focus groups (n = 26) and eight key informant interviews were conducted with staff and physicians at two clinics after the intervention. We used the Chronic Care Model as a framework to analyze the data, examining how well the systems changes were implemented and the impact of these changes on care processes, and to develop recommendations for improvement. Physicians and staff described numerous benefits of the fax referral program for providers and patients but pointed out significant barriers to full implementation, including the time-consuming process of referring patients to the Quitline, substantial patient resistance, and limitations in information and care delivery systems for referring and tracking smokers. Respondents identified several strategies for improving integration, including simplification of the referral form, enhanced teamwork, formal assignment of responsibility for referrals, ongoing staff training and patient education. Improvements in Quitline feedback were needed to compensate for clinics' limited internal information systems for tracking smokers. Establishing sustainable linkages to quitline services in clinical sites requires knowledge of existing patterns of care and tailored organizational changes to ensure new systems are prioritized, easily integrated into current office routines, formally assigned to specific staff members, and supported by internal systems that ensure adequate tracking and follow up of smokers. Ongoing staff training and patient self-management techniques are also needed to ease the introduction of new programs and increase their acceptability to smokers.


Sex differences in the association between amyloid and longitudinal brain volume change in cognitively normal older adults.
Amyloid positivity is a biomarker of AD pathology, yet the associations between amyloid positivity and brain volumetric changes, especially in the hippocampus, are inconsistent. We hypothesize that sex differences in associations may contribute to inconsistent findings among cognitively normal older adults. Using linear mixed effects models, we examined the association of amyloid positivity with prospective volumetric changes (mean = 3.3 visits) of parahippocampal gyrus (phg), hippocampus, entorhinal cortex (erc), precuneus, and fusiform gyrus among 171 Baltimore Longitudinal Study of Aging participants aged ≥55 years. Amyloid positivity was defined by a mean 11C-Pittsburgh Compound B (PiB) distribution volume ratio (DVR) cut-off of 1.062. All analyses included age, race, sex, education, APOE e4 carrier status, and two-way interactions of these covariates with time. Two-way interaction between sex and PiB+/- status and three-way interaction of sex and PiB+/- status with time were added to assess whether sex modified associations. PiB+ status was associated with greater volumetric declines in the phg (β = -0.036, SE = 0.011, p = 0.001) and erc (β = -0.019, SE = 0.009, p = 0.045). Sex modified the association of PiB+ status and rates of volumetric declines in fusiform (β = -0.117, SE = 0.049, p = 0.019). PiB+ males had steeper rates of volumetric declines in phg (β = -0.051, SE = 0.013, p < 0.001) and erc (β = -0.029, SE = 0.012, p = 0.014) than PiB- males, while there was no difference in rates of volumetric change between PiB+ and PiB- females. Amyloidosis is a marker of entorhinal and parahippocampal volume loss. Amyloid positivity is a predictor of volume loss in brain regions affected by early AD pathology in men, but not women.


eXframe: reusable framework for storage, analysis and visualization of genomics experiments.
Genome-wide experiments are routinely conducted to measure gene expression, DNA-protein interactions and epigenetic status. Structured metadata for these experiments is imperative for a complete understanding of experimental conditions, to enable consistent data processing and to allow retrieval, comparison, and integration of experimental results. Even though several repositories have been developed for genomics data, only a few provide annotation of samples and assays using controlled vocabularies. Moreover, many of them are tailored for a single type of technology or measurement and do not support the integration of multiple data types. We have developed eXframe - a reusable web-based framework for genomics experiments that provides 1) the ability to publish structured data compliant with accepted standards 2) support for multiple data types including microarrays and next generation sequencing 3) query, analysis and visualization integration tools (enabled by consistent processing of the raw data and annotation of samples) and is available as open-source software. We present two case studies where this software is currently being used to build repositories of genomics experiments - one contains data from hematopoietic stem cells and another from Parkinson's disease patients. The web-based framework eXframe offers structured annotation of experiments as well as uniform processing and storage of molecular data from microarray and next generation sequencing platforms. The framework allows users to query and integrate information across species, technologies, measurement types and experimental conditions. Our framework is reusable and freely modifiable - other groups or institutions can deploy their own custom web-based repositories based on this software. It is interoperable with the most important data formats in this domain. We hope that other groups will not only use eXframe, but also contribute their own useful modifications.


Searching for novel biomarkers using a mouse model of CLN3-Batten disease.
CLN3-Batten disease is a rare, autosomal recessive disorder involving seizures, visual, motor and cognitive decline, and premature death. The Cln3Δex7/8 mouse model recapitulates several phenotypic characteristics of the most common 1.02kb disease-associated deletion. Identification of reproducible biomarker(s) to facilitate longitudinal monitoring of disease progression and provide readouts for therapeutic response has remained elusive. One factor that has complicated the identification of suitable biomarkers in this mouse model has been that variations in animal husbandry appear to significantly influence readouts. In the current study, we cross-compared a number of biological parameters in blood from Cln3Δex7/8 mice and control, non-disease mice on the same genetic background from multiple animal facilities in an attempt to better define a surrogate marker of CLN3-Batten disease. Interestingly, we found that significant differences between Batten and non-disease mice found at one site were generally not maintained across different facilities. Our results suggest that colony variation in the Cln3Δex7/8 mouse model of CLN3-Batten disease can influence potential biomarkers of the disease.


The Incidence of Postoperative Seizures Following Treatment of Postinfectious Hydrocephalus in Ugandan Infants: A Post Hoc Comparison of Endoscopic Treatment vs Shunt Placement in a Randomized Controlled Trial.
There are currently no published data directly comparing postoperative seizure incidence following endoscopic third ventriculostomy (ETV), with/without choroid plexus cauterization (CPC), to that for ventriculoperitoneal shunt (VPS) placement. To compare postoperative epilepsy incidence for ETV/CPC and VPS in Ugandan infants treated for postinfectious hydrocephalus (PIH). We performed an exploratory post hoc analysis of a randomized trial comparing VPS and ETV/CPC in 100 infants (<6 mo old) presenting with PIH. Minimum follow-up was 2 yr. Variables associated with and the incidence of postoperative epilepsy were compared (intention-to-treat) using a bivariate analysis. Time to first seizure was compared using the Kaplan-Meier method, and the relative risk for the 2 treatments was determined using Mantel-Haenszel hazard ratios. Seizure incidence was not related to age (P = .075), weight (P = .768), sex (P = .151), head circumference (P = .281), time from illness to hydrocephalus onset (P = .973), or hydrocephalus onset to treatment (P = .074). Irritability (P = .027) and vision deficit (P = .04) were preoperative symptoms associated with postoperative seizures. Ten (10%) patients died, and 20 (20%) developed seizures over the follow-up period. Overall seizure incidence was 9.4 per 100 person-years (9.4 and 9.5 for ETV/CPC and VPS, respectively; P = .483), with no significant difference in seizure risk between groups (hazard ratio, 1.02; 95% CI: 0.42, 2.45; P = .966). Mean time to seizure onset was 8.5 mo for ETV/CPC and 11.2 mo for VPS (P = .464). As-treated, per-protocol, and attributable-intervention analyses yielded similar results. Postoperative seizure incidence following treatment of PIH was 20% within 2 yr, regardless of treatment modality.


Immersion, Absorption, and Spiritual Experience: Some Preliminary Findings.
Many traditions have utilized silent environments to induce altered states of consciousness and spiritual experiences. Neurocognitive explorations of spiritual experience can aid in understanding the underlying mechanism, but these are surprisingly rare. We present the verbal report and the electroencephalographic (EEG) alpha profile of a female participant scoring a maximal 34 on the Absorption Scale, recorded before and while she was immersed in a whole-body perceptual deprivation (WBPD) tank. We analyze her trancelike experience in terms of the imagery reported: a spaceship, corridors, doors, a man dressed in white, speaking to God, the sun, supernova, concentric images, and an out-of-body experience. Her report is indicative of a spiritual experience, given that she felt that she was "meeting God" in the laboratory. She exhibited both frontal and parietal left > right alpha power asymmetry at baseline, whereas in the WBPD condition, there was a global increase in alpha power and especially a sharp increase in right-frontal alpha power. Her verbal report and EEG alpha profile were compared to those of another female participant, also scoring high on absorption, whose verbal report was also indicative of a trancelike experience. For further comparison, we present the data for two participants scoring low on absorption. Spiritual experience that can be verbalized might be associated with a marked increase in right-frontal alpha power, as reported here. In contrast, a mystical experience characterized by ineffability would be indicated by a marked increase in left-frontal alpha power.


[Role of minimal invasive surgery for primary and secondary hyperparathyroidism].
The standard surgical approach to treat primary (pHPT) and secondary hyperparathyroidism (sHPT) used to be a cervicotomy with exploration of all four parathyroid glands. This access has been challenged recently by the introduction of minimally invasive techniques in order to achieve superior cosmesic results and to reduce theatre time. We analyzed the advantages and morbidities of these surgical aproaches. Between 1997 and 2006 a total of 123 patients (109 with pHPT and 14 with sHPT) underwent parathyroidectomy at the ENT Department in Luzern. Ultrasonographic scanning was performed on 74 patients (68%), szintigraphy in 8 patients (7%) and both scanning methods in 27 patients (25%). 103 patients were available for follow-up. The indications for each technique were reviewed and outcome measures included serum Calcium and parathyroid hormone levels. Sensitivity for preoperative ultrasonographic and scintigraphic scanning was 67% and 65% for identification of the correct quadrant and 74% and 71% for identification of the correct side. A bilateral exploration was performed until June 2001 for all patients. Thereafter, a minimally invasive approach was chosen for patients with pHPT, whereas patients with sHPT still require bilateral exploration. Adequate preoperative localization was a prerequisite for a minimally invasive technique. Mean postoperative serum Kalzium levels were within the normal range, independently of the surgical technique and disease. Two patients developed hypercalcemia after an initially successful operation. Review of the literature confirms the shift from bilateral exploration towards minimally invasive techniques. The incidence of persistent or recurrent disease as well as the rate of complications seems comparable. Operation time for minimally invasive techniques is reduced in the hands of an experienced surgeon. However, proper preoperative localization of the diseased parathyroid gland is not always possible and the expenses of intraoperative parathyroid hormone measures do not lower the overall costs. Considerable experience and a multidisiplinary approach (endocrinologist, surgeon, pathologist) is required to adopt efficient minimally invasive techniques. As for sHPT, bilateral exploration remains the treatment of choice.


Reconstructing Mayaro virus circulation in French Guiana shows frequent spillovers.
Characterizing the circulation of Mayaro virus (MAYV), an emerging arbovirus threat, is essential for risk assessment but challenging due to cross-reactivity with other alphaviruses such as chikungunya virus (CHIKV). Here, we develop an analytical framework to jointly assess MAYV epidemiology and the extent of cross-reactivity with CHIKV from serological data collected throughout French Guiana (N = 2697). We find strong evidence of an important sylvatic cycle for MAYV with most infections occurring near the natural reservoir in rural areas and in individuals more likely to go to the forest (i.e., adult males) and with seroprevalences of up to 18% in some areas. These findings highlight the need to strengthen MAYV surveillance in the region and showcase how modeling can improve interpretation of cross-reacting assays.


Inflammatory gene expression in monocytes of patients with schizophrenia: overlap and difference with bipolar disorder. A study in naturalistically treated patients.
Accumulating evidence indicates an activated inflammatory response system as a vulnerability factor for schizophrenia (SZ) and bipolar disorder (BD). We aimed to detect a specific inflammatory monocyte gene expression signature in SZ and compare such signature with our recently described inflammatory monocyte gene signature in BD. A quantitative-polymerase chain reaction (Q-PCR) case-control gene expression study was performed on monocytes of 27 SZ patients and compared to outcomes collected in 56 BD patients (all patients naturalistically treated). For Q-PCR we used nine 'SZ specific genes' (found in whole genome analysis), the 19 BD signature genes (previously found by us) and six recently described autoimmune diabetes inflammatory monocyte genes. Monocytes of SZ patients had (similar to those of BD patients) a high inflammatory set point composed of three subsets of strongly correlating genes characterized by different sets of transcription/MAPK regulating factors. Subset 1A, characterized by ATF3 and DUSP2, and subset 1B, characterized by EGR3 and MXD1, were shared between BD and SZ patients (up-regulated in 67% and 51%, and 34% and 41%, respectively). Subset 2, characterized by PTPN7 and NAB2 was up-regulated in the monocytes of 62% BD, but down-regulated in the monocytes of 48% of SZ patients. Our approach shows that monocytes of SZ and BD patients overlap, but also differ in inflammatory gene expression. Our approach opens new avenues for nosological classifications of psychoses based on the inflammatory state of patients, enabling selection of those patients who might benefit from an anti-inflammatory treatment.


Improving the cost-effectiveness of photographic screening for diabetic macular oedema: a prospective, multi-centre, UK study.
Retinal screening programmes in England and Scotland have similar photographic grading schemes for background (non-proliferative) and proliferative diabetic retinopathy, but diverge over maculopathy. We looked for the most cost-effective method of identifying diabetic macular oedema from retinal photographs including the role of automated grading and optical coherence tomography, a technology that directly visualises oedema. Patients from seven UK centres were recruited. The following features in at least one eye were required for enrolment: microaneurysms/dot haemorrhages or blot haemorrhages within one disc diameter, or exudates within one or two disc diameters of the centre of the macula. Subjects had optical coherence tomography and digital photography. Manual and automated grading schemes were evaluated. Costs and QALYs were modelled using microsimulation techniques. 3540 patients were recruited, 3170 were analysed. For diabetic macular oedema, England's scheme had a sensitivity of 72.6% and specificity of 66.8%; Scotland's had a sensitivity of 59.5% and specificity of 79.0%. When applying a ceiling ratio of £30,000 per quality adjusted life years (QALY) gained, Scotland's scheme was preferred. Assuming automated grading could be implemented without increasing grading costs, automation produced a greater number of QALYS for a lower cost than England's scheme, but was not cost effective, at the study's operating point, compared with Scotland's. The addition of optical coherence tomography, to each scheme, resulted in cost savings without reducing health benefits. Retinal screening programmes in the UK should reconsider the screening pathway to make best use of existing and new technologies.


When age matters: differences in facial mimicry and autonomic responses to peers' emotions in teenagers and adults.
Age-group membership effects on explicit emotional facial expressions recognition have been widely demonstrated. In this study we investigated whether Age-group membership could also affect implicit physiological responses, as facial mimicry and autonomic regulation, to observation of emotional facial expressions. To this aim, facial Electromyography (EMG) and Respiratory Sinus Arrhythmia (RSA) were recorded from teenager and adult participants during the observation of facial expressions performed by teenager and adult models. Results highlighted that teenagers exhibited greater facial EMG responses to peers' facial expressions, whereas adults showed higher RSA-responses to adult facial expressions. The different physiological modalities through which young and adults respond to peers' emotional expressions are likely to reflect two different ways to engage in social interactions with coetaneous. Findings confirmed that age is an important and powerful social feature that modulates interpersonal interactions by influencing low-level physiological responses.


The date of interbreeding between Neandertals and modern humans.
Comparisons of DNA sequences between Neandertals and present-day humans have shown that Neandertals share more genetic variants with non-Africans than with Africans. This could be due to interbreeding between Neandertals and modern humans when the two groups met subsequent to the emergence of modern humans outside Africa. However, it could also be due to population structure that antedates the origin of Neandertal ancestors in Africa. We measure the extent of linkage disequilibrium (LD) in the genomes of present-day Europeans and find that the last gene flow from Neandertals (or their relatives) into Europeans likely occurred 37,000-86,000 years before the present (BP), and most likely 47,000-65,000 years ago. This supports the recent interbreeding hypothesis and suggests that interbreeding may have occurred when modern humans carrying Upper Paleolithic technologies encountered Neandertals as they expanded out of Africa.


Design of peptides, proteins, and peptidomimetics in chi space.
Peptide and protein biological activities depend on their three dimensionals structures in the free state and when interacting with their receptors/acceptors. The backbone conformations such as alpha-helix, beta-sheet, beta-turn, and so forth provide critical templates for the three-dimensional structure, but the overall shape and intrinsic stereoelectronic properties of the peptide or protein important for molecular recognition, signal transduction, enzymatic specificity, immunomodulation, and other biological effects depend on arrangement of the side chain groups in three-dimensional chi space (their chi 1, chi 2, etc. torsional angles). In this paper we explore approaches to the de novo design of polypeptides and peptidomimetics with biased or specific conformational/topographical properties in chi space. We consider computational and experimental methods that can be used to examine the effects of specific structural modifications in constraining side chain groups of amino acid residues and their similarities in chi space to the natural amino acids to evaluate what sort of mimetics are likely to mimic normal amino acids. We then examine some of the asymmetric synthetic methods that are being developed to obtain the amino acid mimetics. Finally, we consider selected examples in the literature where these specialized amino acids have been incorporated in biologically active peptides and the specific insights they have provided regarding the topographical requirements for bioactive peptide potency, selectivity, and other biochemical and pharmacological properties. Constraints in chi space show great promise as useful tools in peptide, protein, and peptidomimetic de novo design of structures and pharmacophores with specific stereostructural, biochemical and biological properties.


Concurrent Training in Rugby Sevens: Effects of High-Intensity Interval Exercises.
To assess the impact of 2 high-intensity interval-training (HIT) programs (short interval vs sprint interval training) on muscle strength and aerobic performances in a concurrent training program in amateur rugby sevens players. Thirty-six amateur rugby sevens players were randomly assigned to strength and short interval training (INT), strength and sprint interval training (SIT), or a strength-only training group (CON) during an 8-wk period. Maximal strength and power tests, aerobic measurements (peak oxygen uptake [VO2peak] and maximal aerobic velocity), and a specific repeated-sprint ability (RSA) test were conducted before and immediately after the overall training period. From magnitude-based inference and effect size (ES ± 90% confidence limit) analyses, the current study revealed substantial gains in maximal strength and jump-height performance in all groups. The difference in change of slow concentric torque production was greater in CON than in SIT (0.65 ± 0.72, moderate). VO2peak and, consequently, mean performance in the RSA test were improved in the SIT group only (0.64 ± 0.29, moderate; -0.54 ± 0.35, moderate). The study did not emphasize interference on strength development after INT but showed a slight impairment of slow concentric torque production gains after SIT. Compared with INT, SIT would appear to be more effective to develop VO2peak and RSA but could induce lower muscle-strength gains, especially at low velocity.


Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells.
Pancreatic cancer is a devastating disease with a survival rate of <5%. Moreover, pancreatic cancer aggressiveness is closely related to high levels of prosurvival mediators, which can ultimately lead to rapid disease progression. One of the mechanisms that enables tumor cells to evade cellular stress and promote unhindered proliferation is the endoplasmic reticulum (ER) stress response. Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response (UPR). The UPR initially compensates for damage, but it eventually triggers cell death if ER dysfunction is severe or prolonged. Triptolide, a diterpene triepoxide, has been shown to be an effective compound against pancreatic cancer. Our results show that triptolide induces the UPR by activating the PKR-like ER kinase-eukaryotic initiation factor 2α axis and the inositol-requiring enzyme 1α-X-box-binding protein 1 axis of the UPR and leads to chronic ER stress in pancreatic cancer. Our results further show that glucose-regulated protein 78 (GRP78), one of the major regulators of ER stress, is downregulated by triptolide, leading to cell death by apoptosis in MIA PaCa-2 cells and autophagy in S2-VP10 cells.


Autoxidation and oxygen binding properties of recombinant hemoglobins with substitutions at the αVal-62 or βVal-67 position of the distal heme pocket.
The E11 valine in the distal heme pocket of either the α- or β-subunit of human adult hemoglobin (Hb A) was replaced by leucine, isoleucine, or phenylalanine. Recombinant proteins were expressed in Escherichia coli and purified for structural and functional studies. (1)H NMR spectra were obtained for the CO and deoxy forms of Hb A and the mutants. The mutations did not disturb the α1β2 interface in either form, whereas the H-bond between αHis-103 and βGln-131 in the α1β1 interfaces of the deoxy α-subunit mutants was weakened. Localized structural changes in the mutated heme pocket were detected for the CO form of recombinant Hb (rHb) (αV62F), rHb (βV67I), and rHb (βV67F) compared with Hb A. In the deoxy form the proximal histidyl residue in the β-subunit of rHb (βV67F) has been altered. Furthermore, the interactions between the porphyrin ring and heme pocket residues have been perturbed in rHb (αV62I), rHb (αV62F), and rHb (βV67F). Functionally, the oxygen binding affinity (P50), cooperativity (n50), and the alkaline Bohr Effect of the three α-subunit mutants and rHb (βV67L) are similar to those of Hb A. rHb (βV67I) and rHb (βV67F) exhibit low and high oxygen affinity, respectively. rHb (βV67F) has P50 values lower that those reported for rHb (αL29F), a B10 mutant studied previously in our laboratory (Wiltrout, M. E., Giovannelli, J. L., Simplaceanu, V., Lukin, J. A., Ho, N. T., and Ho, C. (2005) Biochemistry 44, 7207-7217). These E11 mutations do not slow down the autoxidation and azide-induced oxidation rates of the recombinant proteins. Results from this study provide new insights into the roles of E11 mutants in the structure-function relationship in hemoglobin.


Analysis of Melanin Structure and Biochemical Composition in Conjunctival Melanocytic Lesions Using Pump-Probe Microscopy.
We analyze melanin structure and biochemical composition in conjunctival melanocytic lesions using pump-probe microscopy to assess the potential for this method to assist in melanoma diagnosis. Pump-probe microscopy interrogates transient excited-state photodynamic properties of absorbing molecules, which yields highly specific molecular information with subcellular spatial resolution. This method is applied to analyze melanin in 39 unstained, thin biopsy specimens of melanocytic conjunctival lesions. Quantitative features of the biochemical composition and structure of melanin in histopathologic specimens are assessed using a geometric representation of principal component analysis (PCA) and principles of mathematical morphology. Diagnostic power is determined using a feature selection algorithm combined with cross validation. Conjunctival melanomas show higher biochemical heterogeneity and different overall biochemical composition than primary acquired melanosis of the conjunctiva (PAM) without severe atypia. The molecular signatures of PAMs with severe atypia more closely resemble melanomas than other types of PAMs. Pigment organization in the tissue becomes more disorganized as diagnosis of the lesions worsen, but nevi are more inconsistent biochemically and structurally than other lesions. Relatively high sensitivity (SE) and specificity (SP) is achieved for differentiating between various melanocytic lesions, particularly PAMs without severe atypia and melanomas (SE = 89%; SP = 87%). Pump-probe microscopy is a powerful tool that can identify quantitative, phenotypic differences between various types of conjunctival melanocytic lesions. This study further validates the use of pump-probe microscopy as a potential diagnostic aid for histopathologic evaluation of conjunctival melanocytic lesions.


Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease.
Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.


Robotic salvage retroperitoneal and pelvic lymph node dissection for 'node-only' recurrent prostate cancer: technique and initial series.
To describe the technique of robot-assisted high-extended salvage retroperitoneal and pelvic lymphadenectomy (sRPLND+PLND) for 'node-only' recurrent prostate cancer. In all, 10 patients underwent robot-assisted sRPLND+PLND (09/2015-03/2016) for 'node-only' recurrent prostate cancer, as identified by 11 C-acetate positron emission tomography/computed tomography imaging. Our anatomical template extends from bilateral renal artery/vein cranially up to Cloquet's node caudally, completely excising lymphatic-fatty tissue from aorto-caval and iliac vascular trees; RPLND precedes PLND. Meticulous node-mapping assessed nodes at four prospectively assigned anatomical zones. The median operative time was 4.8 h, estimated blood loss 100 mL and hospital stay 1 day. No patient had an intraoperative complication, open conversion or blood transfusion. Three patients had spontaneously resolving Clavien-Dindo grade II postoperative complications. The mean (range) number of nodes excised per patient was 83 (41-132) and mean (range) number of positive nodes per patient was 23 (0-109). Seven patients (70%) had positive nodes on final pathology. Node-positive rates per anatomical level I, II, III and IV were 28%, 32%, 33% and 33%, respectively. In patients with positive nodes, the median PSA level had decreased by 83% at the 2-month follow-up. The initial series of robot-assisted sRPLND+PLND is presented, wherein we duplicate open surgery with superior nodal counts and decreased morbidity. Robot-assisted technical details for an anatomical LND template up to the renal vessels are presented. Longer follow-up is necessary to assess oncological outcomes.


Can explicit suggestions about the harmfulness of EMF exposure exacerbate a nocebo response in healthy controls?
While there has been consistent evidence that symptoms reported by individuals who suffer from Idiopathic Environmental Intolerance attributed to Electromagnetic Fields (IEI-EMF) are not caused by EMF and are more closely associated with a nocebo effect, whether this response is specific to IEI-EMF sufferers and what triggers it, remains unclear. The present experiment tested whether perceived EMF exposure could elicit symptoms in healthy participants, and whether viewing an 'alarmist' video could exacerbate a nocebo response. Participants were randomly assigned to watch either an alarmist (N = 22) or control video (N = 22) before completing a series of sham and active radiofrequency (RF) EMF exposure provocation trials (2 open-label, followed by 12 randomized, double-blind, counterbalanced trials). Pre- and post-video state anxiety and risk perception, as well as belief of exposure and symptom ratings during the open-label and double-blind provocation trials, were assessed. Symptoms were higher in the open-label RF-ON than RF-OFF trial (p < .001). No difference in either symptoms (p = .183) or belief of exposure (p = .144) was observed in the double-blind trials. Participants who viewed the alarmist video had a significant increase in symptoms (p = .041), state anxiety (p < .01) and risk perception (p < .001) relative to the control group. These results reveal the crucial role of awareness and belief in the presentation of symptoms during perceived exposure to EMF, showing that healthy participants exhibit a nocebo response, and that alarmist media reports emphasizing adverse effects of EMF also contribute to a nocebo response.


In-house ELISA screening using a locally-isolated Leptospira in Malaysia: determination of its cut-off points.
Leptospirosis is a zoonotic disease caused by Leptospira species and is distributed globally. Microscopic agglutination test (MAT) is the serological 'gold standard' for diagnosis of leptospirosis but it is time-consuming and labour-intensive. An alternative serological method that is rapid, sensitive and specific is important for early treatment to reduce morbidity and mortality. The use of local Leptospira isolation may improve the sensitivity and specificity of the test because it may varies from one geographical region to another region. The objective of this study was to determine the sensitivity, specificity and cut-off points for an in-house Immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA) using a locally isolated Leptospiral strain IMR/175 as the antigen for the detection of anti-Leptospiral IgM. Serum samples from 270 patients with clinical symptoms of leptospirosis were subjected to the in-house IgM ELISA, MAT and Leptospirosis rapid test. The optimal cut-off values for positivity and negativity of the IgM ELISA were determined by Receiver Operating Characteristic curves and mean ± 2 standard deviation (SD) analyses of the ELISA values. The area under the curve (AUC) which indicates the diagnostic performance of the in-house IgM ELISA was 0.953 (95% Confidence Interval, CI: 0.928, 0.978). The sensitivity and specificity of 90.38% and 87.72% respectively were obtained with the cut-off point of 0.55. A higher sensitivity (96.15%) was obtained when the cut-off point was set at 0.45. The in-house IgM ELISA assay using local Leptospira isolation was shown to be sensitive and may be suitable to use for the serological diagnosis of leptospirosis for our local hospital setting.


The Assessment of Bone Regulatory Pathways, Bone Turnover, and Bone Mineral Density in Vegetarian and Omnivorous Children.
Vegetarian diets contain many beneficial properties as well as carry a risk of inadequate intakes of several nutrients important to bone health. The aim of the study was to evaluate serum levels of bone metabolism markers and to analyze the relationships between biochemical bone markers and anthropometric parameters in children on vegetarian and omnivorous diets. The study included 70 prepubertal children on a lacto-ovo-vegetarian diet and 60 omnivorous children. Body composition, bone mineral content (BMC), and bone mineral density (BMD) were assessed by dual-energy X-ray absorptiometry. Biochemical markers-bone alkaline phosphatase (BALP), C-terminal telopeptide of type I collagen (CTX-I), osteoprotegerin (OPG), nuclear factor κB ligand (RANKL), sclerostin, and Dickkopf-related protein 1 (Dkk-1)-were measured using immunoenzymatic assays. In vegetarians, we observed a significantly higher level of BALP (p = 0.002) and CTX-I (p = 0.027), and slightly lower spine BMC (p = 0.067) and BMD (p = 0.060) than in omnivores. Concentrations of OPG, RANKL, sclerostin, and Dkk-1 were comparable in both groups of children. We found that CTX-I was positively correlated with BMC, total BMD, and lumbar spine BMD in vegetarians, but not in omnivores. A well-planned vegetarian diet with proper dairy and egg intake does not lead to significantly lower bone mass; however, children following a lacto-ovo-vegetarian diet had a higher rate of bone turnover and subtle changes in bone regulatory markers. CTX-I might be an important marker for the protection of vegetarians from bone abnormalities.


Tailoring particle arrays by isotropic plasma etching: an approach towards percolated perpendicular media.
Plasma etching of densely packed arrays of polystyrene particles leads to arrays of spherical nanostructures with adjustable diameters while keeping the periodicity fixed. A linear dependence between diameter of the particles and etching time was observed for particles down to sizes of sub-50 nm. Subsequent deposition of Co/Pt multilayers with perpendicular magnetic anisotropy onto these patterns leads to an exchange-decoupled, single-domain magnetic nanostructure array surrounded by a continuous magnetic film. The magnetic reversal characteristic of the film-particle system is dominated by domain nucleation and domain wall pinning at the particle locations, creating a percolated perpendicular media system.


Fat and hydration monitoring by abdominal bioimpedance analysis: data interpretation by hierarchical electrical modeling.
In a previous publication, it was demonstrated that the abdominal subcutaneous fat layer thickness (SFL) is strongly correlated with the abdominal electrical impedance when measured with a transversal tetrapolar electrode arrangement. This article addresses the following questions: 1) To which extent do different abdominal compartments contribute to the impedance? 2) How does the hydration state of tissues affect the data? 3) Can hydration and fat content be assessed independently? For simulating the measured data a hierarchical electrical model was built. The abdomen was subdivided into three compartments (subcutaneous fat, muscle, mesentery). The true anatomical structure of the compartment boundaries was modeled using finite-element modeling (FEM). Each compartment is described by an electrical tissue model parameterized in physiological terms. Assuming the same percent change of the fat fraction in the mesentery and the SFL the model predicts a change of 1,24 omega/mm change of the SFL compared to 1,1 omega/mm measured. 42% of the change stem from the SFL, 56% from the mesentery and 2% from changes of fat within the muscle compartment. A 1% increase of the extracellular water in the muscle is not discernible from a 1% decrease of the SFL. The measured data reflect not only the SFL but also the visceral fat. The tetrapolar electrode arrangement allows the measurement of the abdominal fat content only if the hydration remains constant.


Comparison of diffusion charging and mobility-based methods for measurement of aerosol agglomerate surface area.
We compare different approaches to measure surface area of aerosol agglomerates. The objective was to compare field methods, such as mobility and diffusion charging based approaches, with laboratory approach, such as Brunauer, Emmett, Teller (BET) method used for bulk powder samples. To allow intercomparison of various surface area measurements, we defined 'geometric surface area' of agglomerates (assuming agglomerates are made up of ideal spheres), and compared various surface area measurements to the geometric surface area. Four different approaches for measuring surface area of agglomerate particles in the size range of 60-350 nm were compared using (i) diffusion charging-based sensors from three different manufacturers, (ii) mobility diameter of an agglomerate, (iii) mobility diameter of an agglomerate assuming a linear chain morphology with uniform primary particle size, and (iv) surface area estimation based on tandem mobility-mass measurement and microscopy. Our results indicate that the tandem mobility-mass measurement, which can be applied directly to airborne particles unlike the BET method, agrees well with the BET method. It was also shown that the three diffusion charging-based surface area measurements of silver agglomerates were similar within a factor of 2 and were lower than those obtained from the tandem mobility-mass and microscopy method by a factor of 3-10 in the size range studied. Surface area estimated using the mobility diameter depended on the structure or morphology of the agglomerate with significant underestimation at high fractal dimensions approaching 3.


Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling.
JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2). This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes. Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported. This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.


Brassinosteroid enhances resistance to fusarium diseases of barley.
Fusarium pathogens are among the most damaging pathogens of cereals. These pathogens have the ability to attack the roots, seedlings, and flowering heads of barley and wheat plants with disease, resulting in yield loss and head blight disease and also resulting in the contamination of grain with mycotoxins harmful to human and animal health. There is increasing evidence that brassinosteroid (BR) hormones play an important role in plant defense against both biotic and abiotic stress agents and this study set out to determine if and how BR might affect Fusarium diseases of barley. Application of the epibrassinolide (epiBL) to heads of 'Lux' barley reduced the severity of Fusarium head blight (FHB) caused by Fusarium culmorum by 86% and reduced the FHB-associated loss in grain weight by 33%. Growth of plants in soil amended with epiBL resulted in a 28 and 35% reduction in Fusarium seedling blight (FSB) symptoms on the Lux and 'Akashinriki' barley, respectively. Microarray analysis was used to determine whether growth in epiBL-amended soil changed the transcriptional profile in stem base tissue during the early stages of FSB development. At 24 and 48 h post F. culmorum inoculation, there were 146 epiBL-responsive transcripts, the majority being from the 48-h time point (n = 118). Real-time reverse-transcription polymerase chain reaction analysis validated the results for eight transcripts, including five defense genes. The results of gene expression studies show that chromatin remodeling, hormonal signaling, photosynthesis, and pathogenesis-related genes are activated in plants as a result of growth in epiBL.


A new look at painful diabetic neuropathy.
The prevalence of diabetes mellitus and its chronic complications continue to increase alarmingly. Consequently, the massive expenditure on diabetic distal symmetrical polyneuropathy (DSPN) and its sequelae, will also likely rise. Up to 50% of patients with diabetes develop DSPN, and about 20% develop neuropathic pain (painful-DSPN). Painful-DSPN can cast a huge burden on sufferers' lives with increased rates of unemployment, mental health disorders and physical co-morbidities. Unfortunately, due to limited understanding of the mechanisms leading to painful-DSPN, current treatments remain inadequate. Recent studies examining the pathophysiology of painful-DSPN have identified maladaptive alterations at the level of both the peripheral and central nervous systems. Additionally, genetic studies have suggested that patients with variants of voltage gated sodium channels may be more at risk of developing neuropathic pain in the presence of a disease trigger such as diabetes. We review the recent advances in genetics, skin biopsy immunohistochemistry and neuro-imaging, which have the potential to further our understanding of the condition, and identify targets for new mechanism based therapies.


Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions.
Long noncoding RNAs (lncRNAs) are key regulators of chromatin state, yet the nature and sites of RNA-chromatin interaction are mostly unknown. Here we introduce Chromatin Isolation by RNA Purification (ChIRP), where tiling oligonucleotides retrieve specific lncRNAs with bound protein and DNA sequences, which are enumerated by deep sequencing. ChIRP-seq of three lncRNAs reveal that RNA occupancy sites in the genome are focal, sequence-specific, and numerous. Drosophila roX2 RNA occupies male X-linked gene bodies with increasing tendency toward the 3' end, peaking at CES sites. Human telomerase RNA TERC occupies telomeres and Wnt pathway genes. HOTAIR lncRNA preferentially occupies a GA-rich DNA motif to nucleate broad domains of Polycomb occupancy and histone H3 lysine 27 trimethylation. HOTAIR occupancy occurs independently of EZH2, suggesting the order of RNA guidance of Polycomb occupancy. ChIRP-seq is generally applicable to illuminate the intersection of RNA and chromatin with newfound precision genome wide.


Feedback regulation by trypsin: evidence for intraluminal CCK-releasing peptide.
The mechanism by which intraluminal proteases inhibit pancreatic secretion and CCK release was investigated in conscious rats. We hypothesized that the stimulation of pancreatic secretion and CCK release that occurs in the absence of luminal trypsin is caused by a trypsin-sensitive, cholecystokinin (CCK)-releasing peptide that is tonically secreted intraluminally by the small intestine. We tested whether rapid saline perfusion of the lumen of the proximal intestine in rats with jejunostomies would wash out the putative peptide, thereby inhibiting the spontaneous pancreatic secretion caused by diverting bile and pancreatic juice from the intestine. Rats were prepared with cannulas draining bile and pancreatic juice, a duodenal cannula and a jejunostomy 10-12 cm from the ligament of Treitz. During diversion of bile and pancreatic juice to the exterior, the proximal intestine was perfused with phosphate-buffered saline at 3 ml/min via the duodenal cannula and the intestinal washes collected from the jejunostomy outlet. Rapid intestinal perfusion significantly inhibited pancreatic protein and fluid secretion stimulated by diversion of bile and pancreatic juice to the exterior. Reinfusion of the concentrated intestinal washes prevented the "washout" inhibition. The active factor in the intestinal washes was heat stable and trypsin sensitive. Rapid washout perfusion of isolated jejunal loops in Thiry-Vella fistula rats reduced plasma CCK from 20.4 +/- 3.6 to 10.4 +/- 1.8 pM, and reinfusion of the washes into the loop returned plasma CCK to 17.1 +/- 3.8 pM. The results support the hypothesis that a trypsin-sensitive, CCK-releasing peptide in intestinal secretions mediates feedback regulation of pancreatic secretion in rats.


Trifluoperazine, a Well-Known Antipsychotic, Inhibits Glioblastoma Invasion by Binding to Calmodulin and Disinhibiting Calcium Release Channel IP3R.
Calcium (Ca2+) signaling is an important signaling process, implicated in cancer cell proliferation and motility of the deadly glioblastomas that aggressively invade neighboring brain tissue. We have previously demonstrated that caffeine blocks glioblastoma invasion and extends survival by inhibiting Ca2+ release channel inositol 1,4,5-trisphosphate receptor (IP3R) subtype 3. Trifluoperazine (TFP) is an FDA-approved antipsychotic drug for schizophrenia. Interestingly, TFP has been recently reported to show a strong anticancer effect on lung cancer, hepatocellular carcinoma, and T-cell lymphoma. However, the possible anticancer effect of TFP on glioblastoma has not been tested. Here, we report that TFP potently suppresses proliferation, motility, and invasion of glioblastoma cells in vitro, and tumor growth in in vivo xenograft mouse model. Unlike caffeine, TFP triggers massive and irreversible release of Ca2+ from intracellular stores by IP3R subtype 1 and 2 by directly interacting at the TFP-binding site of a Ca2+-binding protein, calmodulin subtype 2 (CaM2). TFP binding to CaM2 causes a dissociation of CaM2 from IP3R and subsequent opening of IP3R. Compared with the control neural stem cells, various glioblastoma cell lines showed enhanced expression of CaM2 and thus enhanced sensitivity to TFP. On the basis of these findings, we propose TFP as a potential therapeutic drug for glioblastoma by aberrantly and irreversibly increasing Ca2+ in glioblastoma cells. Mol Cancer Ther; 16(1); 217-27. ©2016 AACR.


The role of mathematical modelling in guiding the science and economics of malaria elimination.
Unprecedented efforts are now underway to eliminate malaria from many regions. Despite the enormous financial resources committed, if malaria elimination is perceived as failing it is likely that this funding will not be sustained. It is imperative that methods are developed to use the limited data available to design site-specific, cost-effective elimination programmes. Mathematical modelling is a way of including mechanistic understanding to use available data to make predictions. Different strategies can be evaluated much more rapidly than is possible through trial and error in the field. Mathematical modelling has great potential as a tool to guide and inform current elimination efforts. Economic modelling weighs costs against characterised effects or predicted benefits in order to determine the most cost-efficient strategy but has traditionally used static models of disease not suitable for elimination. Dynamic mathematical modelling and economic modelling techniques need to be combined to contribute most effectively to ongoing policy discussions. We review the role of modelling in previous malaria control efforts as well as the unique nature of elimination and the consequent need for its explicit modelling, and emphasise the importance of good disease surveillance. The difficulties and complexities of economic evaluation of malaria control, particularly the end stages of elimination, are discussed.


Changes in inflammatory and coagulation biomarkers: a randomized comparison of immediate versus deferred antiretroviral therapy in patients with HIV infection.
Among a subgroup of participants in the Strategies for Management of Antiretroviral Therapy (SMART) Trial that were naïve to antiretroviral therapy (ART) or off ART (6 months or longer) at study entry, risk of AIDS and serious non-AIDS events were increased for participants who deferred ART compared with those randomized to (re)initiate ART immediately. Our objective was to determine whether ART initiation in this group reduced markers of inflammation and coagulation that have been associated with increased mortality risk in SMART. Changes in these biomarkers have been described after stopping ART, but not after starting ART in SMART. Stored specimens for 254 participants (126 drug conservation [DC] and 128 viral suppression [VS]) who were naïve to ART or off ART (6 months or longer) were analyzed for interleukin-6, high sensitivity C-reactive protein, and D-dimer at baseline and Months 2 and 6. At Month 6, 62% of the VS group had HIV RNA less than 400 copies/mL and median CD4 count was 190 cells/mm3 higher than for the DC group (590 versus 400 cells/mm3). Compared with DC, the VS group had 32% (95% confidence interval, 19%-43%) lower D-dimer levels at Month 6 (P < 0.001); differences were not significant for high sensitivity C-reactive protein or interleukin-6 levels. In this randomized comparison of immediate versus delayed ART initiation, D-dimer, but not interleukin-6 and high sensitivity C-reactive protein, declined significantly after starting ART. Further studies are needed to determine whether improvements in D-dimer are associated with reduced risk of clinical disease and whether adjunct treatments used in combination with ART can reduce inflammation among individuals with HIV infection.


Proceedings of the fourth international conference on central hypoventilation.
Central hypoventilation syndromes (CHS) are rare diseases of central autonomic respiratory control associated with autonomous nervous dysfunction. Severe central hypoventilation is the hallmark and the most life-threatening feature. CHS is a group of not-fully defined disorders. Congenital CHS (CCHS) (ORPHA661) is clinically and genetically well-characterized, with the disease-causing gene identified in 2003. CCHS presents at birth in most cases, and associated with Hirschsprung's disease (ORPHA99803) and neural crest tumours in 20% and 5% of cases, respectively. The incidence of CCHS is estimated to be 1 of 200,000 live births in France, yet remains unknown for the rest of the world. In contrast, late-onset CHS includes a group of not yet fully delineated diseases. Overlap with CCHS is likely, as a subset of patients harbours PHOX2B mutations. Another subset of patients present with associated hypothalamic dysfunction. The number of these patients is unknown (less than 60 cases reported worldwide). Treatment of CHS is palliative using advanced techniques of ventilation support during lifetime. Research is ongoing to better understand physiopathological mechanisms and identify potential treatment pathways.The Fourth International Conference on Central Hypoventilation was organised in Warsaw, Poland, April 13-15, 2012, under the patronage of the European Agency for Health and Consumers and Public Health European Agency of European Community. The conference provided a state-of-the-art update of knowledge on all the genetic, molecular, cellular, and clinical aspects of these rare diseases.


Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue.
Immune defence against pathogens entering the gut is accomplished by lymphocytes in the gut-associated lymphoid tissue (GALT), a major compartment of the immune system. The GALT, comprising Peyer's patches, lamina propria lymphocytes and intra-epithelial lymphocytes of the intestine, is populated by lymphocytes that migrate there from the vasculature. Here we report that, in mice deficient for the beta7 integrin subfamily of adhesion molecules, the formation of the GALT is severely impaired. This is probably due to a failure of beta7-/- lymphocytes to arrest and adhere to the vasculature at the site of transmigration into the GALT.


[Association between cardiometabolic risk factors, physical activity and sedentariness in Chilean university students].
There is a huge evidence in adults, that a high level of physical activity and a low level of sedentariness are associated independently with a reduction of cardiometabolic risk factors (CMRF). This association has been poor evaluated in young people and the results are not conclusive. To estimate the association between CMRF, physical activity and sedentariness in Chilean university students. Cross-sectional study. Sample of 326 students who enrolled at University of La Frontera, Temuco, Chile, in 2014. They were selected randomly and stratified according to faculty, career and gender. We measured anthropometry, blood pressure, lipidic profile, glycemia, insulin resistance, tobacco and alcohol consumption. These variables were associated with physical activity level (PAL) and sedentariness using the IPAQ questionnaire. The students with a low PAL had a higher probability of abdominal obesity (OR: 4.68; IC 95% 1.86-11.73), metabolic syndrome (OR: 3.80; IC 95% 1.23-11.73) and triglycerides elevated (OR: 2.61 IC 95%; 1.18-5.75), compared with students with moderate and vigorous PAL (p < 0.05). There were no association between CMRF and sedentariness, even after fit by physical activity. We found an association between CMRF and PAL which was independent of sedentatiness. We believe it is very important to implement effective physical activity programs at universities. It is necesary to encourage students in order to increase the physical activity level to a moderate and vigorous range with the purpose of decreasing their cardiovascular risk. We consider it is recommendable to keep studying the association between sedentariness and CMRF.


Phlebotominae sand flies in Paraguay: abundance distribution in the Southeastern region.
From September 1993 to August 2001, 7,190 phlebotomine were collected with CDC light trap in an endemic area for human leishmaniasis, in the departments of Misiones and Itap a, Paraguay. Eleven species were identified: Lutzomyia neivai (93.7%), L. whitmani (4.1%), and L. fischeri, L. shannoni, L. migonei, L. misionensis, L. cortelezzii, L. pessoai, L. alphabetica, Brumptomyia avellari and B. guimaraesi (less than 1%). The last three species are new records for the country. The biodiversity and phlebotomine abundance were associated with the proximity to primary forest or gallery forest, but L. neivai was also found in peridomestic periurban environment. L. neivai was found throughout the year, and showed a period of higher activity from September to April (spring to fall) with a unimodal or bimodal pattern in relation to the annual rainy peaks during the summer. Background literature about phlebotomine from Paraguay has been reviewed.


Anti-elite politics and emotional reactions to socio-economic problems: Experimental evidence on "pocketbook anger" from France, Germany, and the United States.
Many observers have noticed the importance of anger in contemporary politics, particularly with reference to populism. This article addresses the question under which conditions people become angry about a specific aspect of their lives: their personal financial situation. Specifically, it asks if populist anti-elite rhetoric has a causal influence on anger and if this influence differs across socio-economic groups. The theoretical expectation is that anti-elite rhetoric allows people to externalize responsibility for an unfavorable financial situation and thereby to turn negative self-conscious emotions into anger. The argument is tested with original survey data from France, Germany, and the United States. The empirical analysis yields three main insights. First, negative emotional reactions to respondents' personal finances (and anger in particular) are surprisingly widespread in all three countries. Second, there is a pronounced socio-economic gradient in the distribution of anger and other negative emotions. Third, and most importantly, randomly exposing participants to populist anti-elite rhetoric causes considerably higher expressed anger about one's financial situation in France and Germany, but less so in the United States. This suggests a causal role of anti-elite rhetoric in stirring "pocketbook anger." This is true in particular in the middle classes. The notion that populist rhetoric reduces negative self-conscious emotions, such as shame, is not supported by the data.


Real-time intravital imaging of cancer models.
High-resolution intravital imaging (IVM) has proven to be a powerful technique to visualise dynamic processes that are important for tumour progression, such as the interplay between tumour cells and cellular components of the tumour microenvironment. The development of IVM tools, including imaging windows and photo-marking of individual cells, has led to the visualisation of dynamic processes and tracking of individual cells over a time span of days. In order to visualise these dynamic processes, several strategies have been described to develop fluorescent IVM tumour models. Genetic tools to engineer fluorescent tumour cell lines have advanced the applications of cell line-based tumour models to study, for example, changes in behaviour or transcriptional and differentiation state of individual cells in a tumour. In order to study tumour progression, fluorescent genetic mouse models have been engineered that better recapitulate human tumours. These technically challenging tumour models are key in visualising dynamic processes during cancer progression and in the translational aspects of IVM experiments.


Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses.
Therapeutic vaccination with human papillomavirus type 16 synthetic long peptides (HPV16-SLPs) results in T cell-mediated regression of HPV16-induced premalignant lesions but fails to install clinically effective immunity in patients with HPV16-positive cervical cancer. We explored whether HPV16-SLP vaccination can be combined with standard carboplatin and paclitaxel chemotherapy to improve immunity and which time point would be optimal for vaccination. This was studied in the HPV16 E6/E7-positive TC-1 mouse tumor model and in patients with advanced cervical cancer. In mice and patients, the presence of a progressing tumor was associated with abnormal frequencies of circulating myeloid cells. Treatment of TC-1-bearing mice with chemotherapy and therapeutic vaccination resulted in superior survival and was directly related to a chemotherapy-mediated altered composition of the myeloid cell population in the blood and tumor. Chemotherapy had no effect on tumor-specific T cell responses. In advanced cervical cancer patients, carboplatin-paclitaxel also normalized the abnormal numbers of circulating myeloid cells, and this was associated with increased T cell reactivity to recall antigens. The effect was most pronounced starting 2 weeks after the second cycle of chemotherapy, providing an optimal immunological window for vaccination. This was validated with a single dose of HPV16-SLP vaccine given in this time window. The resulting proliferative HPV16-specific T cell responses were unusually strong and were retained after all cycles of chemotherapy. In conclusion, carboplatin-paclitaxel therapy fosters vigorous vaccine-induced T cell responses when vaccination is given after chemotherapy and has reset the tumor-induced abnormal myeloid cell composition to normal values.


Application of Europium-Doped Very Small Iron Oxide Nanoparticles to Visualize Neuroinflammation with MRI and Fluorescence Microscopy.
Our recent studies demonstrated that electrostatically stabilized very small superparamagnetic iron oxide particles (VSOPs) are promising MRI probes for detecting various pathological aspects of autoimmunity in the central nervous system (CNS). However, investigation of the precise tissue and cellular distribution of VSOP has been technically limited due to the need to use iron detection methods for VSOP visualization. Therefore, we assessed here the utility of europium (Eu)-doped VSOP as an MRI tool for in vivo investigations in the animal model experimental autoimmune encephalomyelitis (EAE), and as a tool to investigate histopathological processes in the CNS using fluorescence microscopy. We demonstrated that Eu-VSOP display the same properties as VSOP in terms of revealing inflammation-mediated changes by binding to brain endothelium in vitro, and in terms of visualizing brain lesions in EAE in vivo. MRI examinations with Eu-VSOP confirm that at peak disease particles accumulated inside the choroid plexus, and in cerebellar and meningeal lesions. Importantly, Eu-VSOP-based MRI showed for the first time in a longitudinal setup that particles were absent from the choroid plexus in mice during remission of EAE, but accumulated again during subsequent relapse. Within the choroid plexus, Eu-VSOP were associated both with monocytes/macrophages present in the plexus stroma, and associated with epithelial cells. Using Eu-VSOP, we demonstrated for the first time the involvement of the choroid plexus in relapses. Thus, Eu-VSOP have the potential to reveal various aspects of choroid plexus involvement in neuroinflammation, including monocyte recruitment from the blood and alterations of the choroid plexus epithelium.


A descending dopamine pathway conserved from basal vertebrates to mammals.
Dopamine neurons are classically known to modulate locomotion indirectly through ascending projections to the basal ganglia that project down to brainstem locomotor networks. Their loss in Parkinson's disease is devastating. In lampreys, we recently showed that brainstem networks also receive direct descending dopaminergic inputs that potentiate locomotor output. Here, we provide evidence that this descending dopaminergic pathway is conserved to higher vertebrates, including mammals. In salamanders, dopamine neurons projecting to the striatum or brainstem locomotor networks were partly intermingled. Stimulation of the dopaminergic region evoked dopamine release in brainstem locomotor networks and concurrent reticulospinal activity. In rats, some dopamine neurons projecting to the striatum also innervated the pedunculopontine nucleus, a known locomotor center, and stimulation of the dopaminergic region evoked pedunculopontine dopamine release in vivo. Finally, we found dopaminergic fibers in the human pedunculopontine nucleus. The conservation of a descending dopaminergic pathway across vertebrates warrants re-evaluating dopamine's role in locomotion.


Point mutation in kit receptor tyrosine kinase reveals essential roles for kit signaling in spermatogenesis and oogenesis without affecting other kit responses.
The Kit receptor tyrosine kinase functions in hemato- poiesis, melanogenesis and gametogenesis. Kit receptor-mediated cellular responses include proliferation, survival, adhesion, secretion and differentiation. In mast cells, Kit-mediated recruitment and activation of phosphatidylinositol 3'-kinase (PI 3-kinase) produces phosphatidylinositol 3'-phosphates, plays a critical role in mediating cell adhesion and secretion and has contributory roles in mediating cell survival and proliferation. To investigate the consequences in vivo of blocking Kit-mediated PI 3-kinase activation we have mutated the binding site for the p85 subunit of PI 3-kinase in the Kit gene, using a knock-in strategy. Mutant mice have no pigment deficiency or impairment of steady-state hematopoiesis. However, gametogenesis is affected in several ways and tissue mast cell numbers are affected differentially. While primordial germ cells during embryonic development are not affected, Kit(Y719F)/Kit(Y719F) males are sterile due to a block at the premeiotic stages in spermatogenesis. Furthermore, adult males develop Leydig cell hyperplasia. The Leydig cell hyperplasia implies a role for Kit in Leydig cell differentiation and/or steroidogenesis. In mutant females follicle development is impaired at the cuboidal stages resulting in reduced fertility. Also, adult mutant females develop ovarian cysts and ovarian tubular hyperplasia. Therefore, a block in Kit receptor-mediated PI 3-kinase signaling may be compensated for in hematopoiesis, melanogenesis and primordial germ cell development, but is critical in spermatogenesis and oogenesis.


Accuracy and Reliability of the Kinect Version 2 for Clinical Measurement of Motor Function.
The introduction of low cost optical 3D motion tracking sensors provides new options for effective quantification of motor dysfunction. The present study aimed to evaluate the Kinect V2 sensor against a gold standard motion capture system with respect to accuracy of tracked landmark movements and accuracy and repeatability of derived clinical parameters. Nineteen healthy subjects were concurrently recorded with a Kinect V2 sensor and an optical motion tracking system (Vicon). Six different movement tasks were recorded with 3D full-body kinematics from both systems. Tasks included walking in different conditions, balance and adaptive postural control. After temporal and spatial alignment, agreement of movements signals was described by Pearson's correlation coefficient and signal to noise ratios per dimension. From these movement signals, 45 clinical parameters were calculated, including ranges of motions, torso sway, movement velocities and cadence. Accuracy of parameters was described as absolute agreement, consistency agreement and limits of agreement. Intra-session reliability of 3 to 5 measurement repetitions was described as repeatability coefficient and standard error of measurement for each system. Accuracy of Kinect V2 landmark movements was moderate to excellent and depended on movement dimension, landmark location and performed task. Signal to noise ratio provided information about Kinect V2 landmark stability and indicated larger noise behaviour in feet and ankles. Most of the derived clinical parameters showed good to excellent absolute agreement (30 parameters showed ICC(3,1) > 0.7) and consistency (38 parameters showed r > 0.7) between both systems. Given that this system is low-cost, portable and does not require any sensors to be attached to the body, it could provide numerous advantages when compared to established marker- or wearable sensor based system. The Kinect V2 has the potential to be used as a reliable and valid clinical measurement tool.


Mechanistic investigations of confinement effects on the self-assembly of symmetric amphiphilic copolymers in thin films.
The self-assembly of a copolymer thin film, whose molecular structure is composed of one hydrophobic branch and two hydrophilic branches, gives a cylindrical structure consisting of a hydrophobic core and a hydrophilic outer surface. The confinement-induced loss of entropy leads the copolymer to self-assemble into a hexagonal arrangement of cylindrical structures. This hexagonal arrangement is of two induced self-assembly structures under one-dimensional confinement in thin films, i.e., micellar structures with uniform density of an individual core, as well as lamellar structures with two separated hydrophobic layers and one hydrophilic layer. When the repulsive force of the confinement is greater for the hydrophobic polymeric component than for the hydrophilic polymeric component, the self-assembled density of the cores is broad. A proportional change in the individual volume suggests interactions between the walls and the hydrophobic core, which plays a vital role in the formation of the self-assembled structure. A basic understanding of the one-dimensional confinement investigated in this study serves to elucidate the more complex two- and three-dimensional confinements and provides further insights for the design of nanomaterials with novel morphologies.


More than Mental Health: Parent Physical Health and Early Childhood Behavior Problems.
Caring for young children is a physically demanding task, and some evidence suggests parental physical limitations may impact the parent-child relationship and child behavioral development, but research examining this dynamic is nascent. This study aims to explicate the role of general parent physical health problems in child disruptive behavior outcomes. A model that included physical and mental health, parenting style and self-efficacy, and child behavior symptom ratings was derived. The tenability of the model was assessed using Pearson's correlations, followed by structural equation modeling using data from 375 parents with a child between 18 months and 5 years. After several modifications to the initial model, findings revealed that higher levels of parent self-reported physical and mental health concerns indirectly influence child behavior symptoms through different pathways. Impaired parent physical health was associated with poorer parental self-efficacy and more disruptive child behavior, whereas increased parent mental health concerns were associated with a more negative parenting style and lower self-efficacy, which was related to more child behavior symptoms. Findings elucidate the need for increased awareness and screening of parent physical health limitations in pediatric primary care. Furthermore, appropriate interventions among parents with physical health problems may target different aspects of parenting than routinely discussed.


Surgical treatment strategies and outcome in patients with breast cancer metastatic to the spine: a review of 87 patients.
Aggressive surgical management of spinal metastatic disease can provide improvement of neurological function and significant pain relief. However, there is limited literature analyzing such management as is pertains to individual histopathology of the primary tumor, which may be linked to overall prognosis for the patient. In this study, clinical outcomes were reviewed for patients undergoing spinal surgery for metastatic breast cancer. Respective review was done to identify all patients with breast cancer over an eight-year period at a major cancer center and then to select those with symptomatic spinal metastatic disease who underwent spinal surgery. Pre- and postoperative pain levels (visual analog scale [VAS]), analgesic medication usage, and modified Frankel grade scores were compared on all patients who underwent surgery. Univariate and multivariate analyses were used to assess risks for complications. A total of 16,977 patients were diagnosed with breast cancer, and 479 patients (2.8%) were diagnosed with spinal metastases from breast cancer. Of these patients, 87 patients (18%) underwent 125 spinal surgeries. Of the 76 patients (87%) who were ambulatory preoperatively, the majority (98%) were still ambulatory. Of the 11 patients (13%) who were nonambulatory preoperatively, four patients were alive at 3 months postoperatively, three of which (75%) regained ambulation. The preoperative median VAS of six was significantly reduced to a median score of two at the time of discharge and at 3, 6, and 12 months postoperatively (P < 0.001 for all time points). A total of 39% of patients experienced complications; 87% were early (within 30 days of surgery), and 13% were late. Early major surgical complications were significantly greater when five or more levels were instrumented. In patients with spinal metastases specifically from breast cancer, aggressive surgical management provides significant pain relief and preservation or improvement of neurological function with an acceptably low rate of complications.


The Immunomodulatory Activity of Jacaric Acid, a Conjugated Linolenic Acid Isomer, on Murine Peritoneal Macrophages.
This study aims at demonstrating the immunomodulatory property of jacaric acid, a conjugated linolenic acid (CLNA) isomer that is present in jacaranda seed oil, on murine peritoneal macrophages. Our results showed that jacaric acid exhibited no significant cytotoxicity on the thioglycollate-elicited murine peritoneal macrophages as revealed by the neutral red uptake assay, but markedly increased their cytostatic activity on the T-cell lymphoma MBL-2 cells as measured by the fluorometric CyQuant® NF Cell Proliferation Assay Kit. Flow cytometric analysis indicated that jacaric acid could enhance the endocytic activity of macrophages and elevated their intracellular production of superoxide anion. Moreover, jacaric acid-treated macrophages showed an increase in the production of nitric oxide which was accompanied by an increase in the expression level of inducible nitric oxide synthase protein. In addition, the secretion of several pro-inflammatory cytokines, including interferon-γ, interleukin-1β and tumor necrosis factor-α, was up-regulated. Collectively, our results indicated that the naturally-occurring CLNA isomer, jacaric acid, could exhibit immunomodulating activity on the murine peritoneal macrophages in vitro, suggesting that this CLNA isomer may act as an immunopotentiator which can be exploited for the treatment of some immunological disorders with minimal toxicity and fewer side effects.


Ancient mitochondrial DNA from the northern fringe of the Neolithic farming expansion in Europe sheds light on the dispersion process.
The European Neolithization process started around 12 000 years ago in the Near East. The introduction of agriculture spread north and west throughout Europe and a key question has been if this was brought about by migrating individuals, by an exchange of ideas or a by a mixture of these. The earliest farming evidence in Scandinavia is found within the Funnel Beaker Culture complex (Trichterbecherkultur, TRB) which represents the northernmost extension of Neolithic farmers in Europe. The TRB coexisted for almost a millennium with hunter-gatherers of the Pitted Ware Cultural complex (PWC). If migration was a substantial part of the Neolithization, even the northerly TRB community would display a closer genetic affinity to other farmer populations than to hunter-gatherer populations. We deep-sequenced the mitochondrial hypervariable region 1 from seven farmers (six TRB and one Battle Axe complex, BAC) and 13 hunter-gatherers (PWC) and authenticated the sequences using postmortem DNA damage patterns. A comparison with 124 previously published sequences from prehistoric Europe shows that the TRB individuals share a close affinity to Central European farmer populations, and that they are distinct from hunter-gatherer groups, including the geographically close and partially contemporary PWC that show a close affinity to the European Mesolithic hunter-gatherers.


Preliminary evidence of effectiveness of TECAR in lymphedema.
Lymphedema of the lower limbs often contributes to the mobility impairment of morbidly obese patients. Defining novel costeffective protocols is important for reducing treatment costs. The study aimed to assess if Capacitive and Resistive Energy Transfer (TECAR) can reduce edema and the minimum number of sessions needed to observe volume reduction. Forty-eight severely obese subjects (age range: 46-78 years; BMI >40 kg/m2) with bilateral lower limb lymphedema were divided into three groups undergoing either manual lymphatic drainage, pressure therapy, or TECAR, in addition to a multidisciplinary rehabilitation program. They were compared to a control group composed by 12 women (age: 67.4 ± 8.9 years, BMI: 44.6 ± 4.1 Kg/m2) undergoing only the rehabilitation program. A handheld laser scanner 3D system was used for volume measurements. In addition, patients were evaluated with a Timed Up and Go (TUG) test and pain/heaviness of the lower limbs with a Visual Analog Scale (VAS). A significant volume reduction was observed after 6 sessions of TECAR: specifically, in the whole limb (PRE: 9.7+2.8 dm3; POST: 9.4+2.8 dm3; p<0.05) and in the thigh (PRE: 3.5+1.3 dm3; POST: 3.3+1.2 dm3; p<0.05). The TUG and VAS for pain showed a significant improvement in all groups. Our preliminary results suggest that TECAR can provide a relatively early reduction of lower limb edema with improvement of patients' function and pain.


Climate change and the ash dieback crisis.
Beyond the direct influence of climate change on species distribution and phenology, indirect effects may also arise from perturbations in species interactions. Infectious diseases are strong biotic forces that can precipitate population declines and lead to biodiversity loss. It has been shown in forest ecosystems worldwide that at least 10% of trees are vulnerable to extinction and pathogens are increasingly implicated. In Europe, the emerging ash dieback disease caused by the fungus Hymenoscyphus fraxineus, commonly called Chalara fraxinea, is causing a severe mortality of common ash trees (Fraxinus excelsior); this is raising concerns for the persistence of this widespread tree, which is both a key component of forest ecosystems and economically important for timber production. Here, we show how the pathogen and climate change may interact to affect the future spatial distribution of the common ash. Using two presence-only models, seven General Circulation Models and four emission scenarios, we show that climate change, by affecting the host and the pathogen separately, may uncouple their spatial distribution to create a mismatch in species interaction and so a lowering of disease transmission. Consequently, as climate change expands the ranges of both species polewards it may alleviate the ash dieback crisis in southern and occidental regions at the same time.


Impact of oral capsule of Peganum harmala on alleviating urinary symptoms in men with benign prostatic hyperplasia; a randomized clinical trial.
Introduction: Benign prostatic hyperplasia (BPH) is considered as a major cause of lower urinary tract symptoms (LUTS) in older men and its most common sign is nocturia. Objectives: This study aimed to determine the effect of the seeds of Peganum harmala compared with tamsulosin on alleviating urinary symptoms in patients with BPH. Patients and Methods: In this single blind clinical trial study, 90 patients diagnosed with BPH and LUTS, based on international prostate standard survey (IPSS) were divided into three groups. The first group was received oral capsule of P. harmala, the second group was administered tamsulosin with oral P. harmala seed and the third group was received tamsulosin drug and they were evaluated after 4 weeks. Results: The results showed that the difference between mean scores of IPSS was significant after the intervention (P=0.001). Besides, the mean of IPSS in the three groups was significantly different (P=0.001) (the first group 41.9±5.3, the second group 21.0±4.4 ,the third group 16.5±3.7 respectively). However, after the intervention, patients in the second group had the lowest average on most indicators of IPSS but the difference was only significant about urinary frequency, nocturia and intermittency(P<0.05). Conclusion: Application of Peganum harmala seed can be useful in reducing urinary symptoms in patients with BPH.


Factors Affecting Staff Turnover of Young Academics: Job Embeddedness and Creative Work Performance in Higher Academic Institutions.
Young academics have been facing a problem of high turnover rate due to missing links between the institutions' policies and the performance. This study explores the effect of job embeddedness and community embeddedness on creative work performance and intentions to leave of young teaching staff in academic institutions in Pakistan. In this study, 300 qualified young academics from public and private universities were selected as subjects and asked to complete a questionnaire. Data were collected via mail-survey. A variance-based structural equation model is employed to measure the path model. The results show that the fit-dimension of organizational- and community-embeddedness, along with the moderating effect of organization size and the availability of nearby alternative jobs have a significant impact on improving perceived creative performance and reducing staff turnover intentions. This study suggests that organizations should focus on organizational-fit and community-fit constructs in their nurturing strategies to embed young teachers in their academic institutions. This study also suggests that monetary rewards only are relatively ineffective to improve retention. Hence, public and private sector universities should facilitate meaningful contributions from young teachers in creative work and provide opportunities for social interactions and personal development.


Living autologous heart valves engineered from human prenatally harvested progenitors.
Heart valve tissue engineering is a promising strategy to overcome the lack of autologous growing replacements, particularly for the repair of congenital malformations. Here, we present a novel concept using human prenatal progenitor cells as new and exclusive cell source to generate autologous implants ready for use at birth. Human fetal mesenchymal progenitors were isolated from routinely sampled prenatal chorionic villus specimens and expanded in vitro. A portion was cryopreserved. After phenotyping and genotyping, cells were seeded onto synthetic biodegradable leaflet scaffolds (n=12) and conditioned in a bioreactor. After 21 days, leaflets were endothelialized with umbilical cord blood-derived endothelial progenitor cells and conditioned for additional 7 days. Resulting tissues were analyzed by histology, immunohistochemistry, biochemistry (amounts of extracellular matrix, DNA), mechanical testing, and scanning electron microscopy (SEM) and were compared with native neonatal heart valve leaflets. Fresh and cryopreserved cells showed comparable myofibroblast-like phenotypes. Genotyping confirmed their fetal origin. Neo-tissues exhibited organization, cell phenotypes, extracellular matrix production, and DNA content comparable to their native counterparts. Leaflet surfaces were covered with functional endothelia. SEM showed cellular distribution throughout the polymer and smooth surfaces. Mechanical profiles approximated those of native heart valves. Prenatal fetal progenitors obtained from routine chorionic villus sampling were successfully used as an exclusive, new cell source for the engineering of living heart valve leaflets. This concept may enable autologous replacements with growth potential ready for use at birth. Combined with the use of cell banking technology, this approach may be applied also for postnatal applications.


Managing finances of shipping living donor kidneys for donor exchanges.
Kidney donor exchanges enable recipients with immunologically incompatible donors to receive compatible living donor grafts; however, the financial management of these exchanges, especially when an organ is shipped, is complex and thus has the potential to impede the broader implementation of donor exchange programs. Representatives from transplant centers that utilize the National Kidney Registry database to facilitate donor exchange transplants developed a financial model applicable to paired donor exchanges and donor chain transplants. The first tenet of the model is to eliminate financial liability to the donor. Thereafter, it accounts for the donor evaluation, donor nephrectomy hospital costs, donor nephrectomy physician fees, organ transport, donor complications and recipient inpatient services. Billing between hospitals is based on Medicare cost report defined costs rather than charges. We believe that this model complies with current federal regulations and effectively captures costs of the donor and recipient services. It could be considered as a financial paradigm for the United Network for Organ Sharing managed donor exchange program.


Transcriptional coregulators in the control of energy homeostasis.
Metabolic programs controlling energy homeostasis are governed at the transcriptional level by the integrated action of several transcription factors. Among these, nuclear receptors including peroxisome proliferator-activated receptors, estrogen-related receptors or thyroid hormone receptors play prominent roles by adapting gene expression programs to the endocrine and metabolic context that they sense via their ligand-binding domain. Coregulators assist nuclear receptors to positively or negatively influence the transcription of target genes, and thereby comprise an integral part of the transcriptional circuitry. This review focuses on how coregulators, including PGC-1 and p160 coactivators, Sirt-1, RIP140 and NCoR corepressors, control the balance between energy storage and expenditure, with a particular emphasis on how these proteins integrate physiological stimuli in vivo. The general picture that emerges indicates that these coregulators are metabolic switches, which convergently regulate metabolic pathways through their pleiotropic interactions with nuclear receptors and other transcription factors.


Sauropod dinosaur osteoderms from the Late Cretaceous of Madagascar.
Osteoderms are bones embedded within the dermis, and are common to select members of most major tetrapod lineages. The largest known animals that bear osteoderms are members of Titanosauria, a diverse clade of sauropod dinosaurs. Here we report on two titanosaur osteoderms recovered from the Upper Cretaceous Maevarano Formation of Madagascar. Each osteoderm was discovered in association with a partial skeleton representing a distinct ontogenetic stage of the titanosaur Rapetosaurus krausei. Combined, these specimens provide novel insights into the arrangement and function of titanosaur osteoderms. Taphonomic data confirm that Rapetosaurus developed only limited numbers of osteoderms in its integument. The adult-sized osteoderm is the most massive integumentary skeletal element yet discovered, with an estimated volume of 9.63 litres. Uniquely, this specimen possesses an internal cavity equivalent to more than half its total volume. Large, hollow osteoderms may have functioned as mineral stores in fecund, rapidly growing titanosaurs inhabiting stressed environments.


Intrathecal effects of daclizumab treatment of multiple sclerosis.
We previously reported that daclizumab, a humanized monoclonal antibody against CD25, reduced contrast-enhancing lesions (CEL) in patients with multiple sclerosis (MS) who were suboptimal responders to interferon-β and that this response correlated with expansion of CD56(bright) NK cells. These data have been reproduced in a placebo-controlled multicenter trial (CHOICE study). The current study investigates whether daclizumab monotherapy reduces CEL in untreated patients with relapsing-remitting MS (RRMS) and the effects of daclizumab on the intrathecal immune system. Sixteen patients with RRMS with high inflammatory activity were enrolled in an open-label, baseline-vs-treatment, phase II trial of daclizumab monotherapy for 54 weeks and followed by serial clinical and MRI examinations and immunologic biomarkers measured in the whole blood and CSF. The trial achieved predefined outcomes. There was an 87.7% reduction in brain CEL (primary) and improvements in Multiple Sclerosis Functional Composite (secondary), Scripps Neurologic Rating Scale, and Expanded Disability Status Scale (tertiary) outcomes. There was significant expansion of CD56(bright) NK cells in peripheral blood and CSF, with resultant decrease in T cells/NK cells and B cells/NK cells ratios and IL-12p40 in the CSF. Surprisingly, CD25 Tac epitope was equally blocked on the immune cells in the CSF and in peripheral blood. Daclizumab monotherapy inhibits formation of MS plaques in patients with RRMS and immunoregulatory NK cells may suppress activation of pathogenic immune responses directly in the CNS compartment. The study provides Class III evidence that daclizumab reduces the number of contrast-enhancing lesions in treatment-naive patients with RRMS over a 54-week period.


Anti-hyperglycemic activity of zinc plus cyclo (his-pro) in genetically diabetic Goto-Kakizaki and aged rats.
We previously reported that treatment of streptozotocin-induced diabetic rats with zinc plus cyclo (his-pro) (CHP) decreased fed blood glucose levels and water intake. The present study was conducted to examine the dose-dependent, acute, and chronic treatment effects of CHP on oral glucose tolerance (OGT), fed blood glucose levels, water intake, and plasma insulin levels in young and aged Sprague-Dawley (S-D) rats, nondiabetic Wistar rats, and genetically diabetic Goto-Kakizaki (G-K) rats. Acute gastric gavage of 10 mg zinc plus 1.0 mg CHP/kg body weight significantly improved OGT in 4- and 13-month-old nondiabetic S-D rats and in 2-month-old diabetic G-K rats. Young S-D and G-K rats returned to pretreatment OGT values 1 week after acute gavage of zinc plus CHP (ZC), but improved OGT values persisted for at least 1 week after gavage in aged S-D rats. OGT values and fed blood glucose decreased to the greatest extent among other treatments when G-K rats were given free access to drinking water containing 1.0 to 1.5 mg CHP/L plus 10 mg zinc/L for 2 weeks. Although food and water intake showed a tendency to decrease, no statistically significant differences were observed in young G-K rats. Plasma insulin levels and blood glucose levels in both normal and diabetic G-K rats decreased with 2-week treatment with ZC. To test the direct effects of ZC on muscle tissue, we observed the effect of various doses of ZC on normal and G-K rat muscle slices. The optimal level of CHP alone for maximal muscle glucose uptake in muscle slices from normal rats was 10 microg/mL and 5.0 microg/mL in G-K rats, and ZC stimulated glucose uptake. However, no statistically significant difference was demonstrated between normal and G-K rat tissues in this study. These results indicate that oral intake of an optimal dose of ZC stimulates blood glucose metabolism, probably by stimulating muscle glucose utilization.


Identification of Tat-SF1 cellular targets by exon array analysis reveals dual roles in transcription and splicing.
Tat specific factor 1 (Tat-SF1) interacts with components of both the transcription and splicing machineries and has been classified as a transcription-splicing factor. Although its function as an HIV-1 dependency factor has been investigated, relatively little is known about the cellular functions of Tat-SF1. To identify target genes of Tat-SF1, we utilized a combination of RNAi and exon-specific microarrays. These arrays, which survey genome-wide changes in transcript and individual exon levels, revealed 450 genes with transcript level changes upon Tat-SF1 depletion. Strikingly, 98% of these target genes were down-regulated upon depletion, indicating that Tat-SF1 generally activates gene expression. We also identified 89 genes that showed differential exon level changes after Tat-SF1 depletion. The 89 genes showed evidence of many different types of alternative exon use consistent with the regulation of transcription initiation sites and RNA processing. Minimal overlap between genes with transcript-level and exon-level changes suggests that Tat-SF1 does not functionally couple transcription and splicing. Biological processes significantly enriched with transcript- and exon-level targets include the cell cycle and nucleic acid metabolism; the insulin signaling pathway was enriched with Tat-SF1 transcript-level targets but not exon-level targets. Additionally, a hexamer, ATGCCG, was over-represented in the promoter region of genes showing changes in transcription initiation upon Tat-SF1 depletion. This may represent a novel motif that Tat-SF1 recognizes during transcription. Together, these findings suggest that Tat-SF1 functions independently in transcription and splicing of cellular genes.


Treatment of industrial wastewater produced by desulfurization process in a coal-fired power plant via FO-MD hybrid process.
In this study, the feasibility of forward osmosis (FO) hybridized with membrane distillation (MD) was systematically investigated for treating flue gas desulfurization (FGD) wastewater. FO experiments were conducted using raw FGD wastewater obtained from a coal-fired power plant in Korea. Severe membrane fouling in FO was observed since FGD wastewater contained various components (i.e., particles, colloids, organics, and ions). The combined fouling layer by particulates and scales was identified via scanning electron microscope (SEM), energy dispersive X-ray (EDX) and X-ray diffraction (XRD). Therefore, fouling control strategies were suggested and evaluated. Microfiltration (MF) pre-treatment was effective in removing particulates and mitigating the initial fouling. Antiscalant-blended draw solution (DS) could inhibit the formation of membrane scaling. With such fouling control schemes, FO achieved the highest recovery rate compared to other desalting processes (i.e., RO and MD), suggesting that FO is suitable for treating wastewater with high fouling potential and high TDS. Finally, the diluted DS was recovered by MD. MD could re-concentrate the diluted DS up to 50% recovery rate with no significant flux decline. Rapid flux decline was then observed due to membrane scaling. Thus, appropriate antiscalants in DS should be considered to inhibit scaling formation in FO and MD simultaneously.