Parasite biodiversity faces extinction and redistribution in a changing climate.
Climate change is a well-documented driver of both wildlife extinction and disease emergence, but the negative impacts of climate change on parasite diversity are undocumented. We compiled the most comprehensive spatially explicit data set available for parasites, projected range shifts in a changing climate, and estimated extinction rates for eight major parasite clades. On the basis of 53,133 occurrences capturing the geographic ranges of 457 parasite species, conservative model projections suggest that 5 to 10% of these species are committed to extinction by 2070 from climate-driven habitat loss alone. We find no evidence that parasites with zoonotic potential have a significantly higher potential to gain range in a changing climate, but we do find that ectoparasites (especially ticks) fare disproportionately worse than endoparasites. Accounting for host-driven coextinctions, models predict that up to 30% of parasitic worms are committed to extinction, driven by a combination of direct and indirect pressures. Despite high local extinction rates, parasite richness could still increase by an order of magnitude in some places, because species successfully tracking climate change invade temperate ecosystems and replace native species with unpredictable ecological consequences.


Red Meat and Colorectal Cancer: A Quantitative Update on the State of the Epidemiologic Science.
The potential relationship between red meat consumption and colorectal cancer (CRC) has been the subject of scientific debate. Given the high degree of resulting uncertainty, our objective was to update the state of the science by conducting a systematic quantitative assessment of the epidemiologic literature. Specifically, we updated and expanded our previous meta-analysis by integrating data from new prospective cohort studies and conducting a broader evaluation of the relative risk estimates by specific intake categories. Data from 27 independent prospective cohort studies were meta-analyzed using random-effects models, and sources of potential heterogeneity were examined through subgroup and sensitivity analyses. In addition, a comprehensive evaluation of potential dose-response patterns was conducted. In the meta-analysis of all cohorts, a weakly elevated summary relative risk was observed (1.11, 95% CI: 1.03-1.19); however, statistically significant heterogeneity was present. In general, summary associations were attenuated (closer to the null and less heterogeneous) in models that isolated fresh red meat (from processed meat), adjusted for more relevant factors, analyzed women only, and were conducted in countries outside of the United States. Furthermore, no clear patterns of dose-response were apparent. In conclusion, the state of the epidemiologic science on red meat consumption and CRC is best described in terms of weak associations, heterogeneity, an inability to disentangle effects from other dietary and lifestyle factors, lack of a clear dose-response effect, and weakening evidence over time. KEY TEACHING POINTS: •The role of red meat consumption in colorectal cancer risk has been widely contested among the scientific community.•In the current meta-analysis of red meat intake and colorectal cancer, we comprehensively examined associations by creating numerous sub-group stratifications, conducting extensive sensitivity analyses, and evaluating dose-response using several different methods.•Overall, all summary associations were weak in magnitude with no clear dose-response patterns.•Interpretation of findings from epidemiologic studies investigating diet and health outcomes involves numerous methodological considerations, such as accurately measuring food intake, dietary pattern differences across populations, food definitions, outcome classifications, bias and confounding, multicollinearity, biological mechanisms, genetic variation in metabolizing enzymes, and differences in analytical metrics and statistical testing parameters.


Cone beam CT dosimetry: a unified and self-consistent approach including all scan modalities--with or without phantom motion.
This article describes a common methodology and measurement technique, encompassing both conventional (helical and axial) CT scanning using phantom translation and cone beam (or narrow fan beam) CT scans about a stationary phantom. Cone beam CT systems having beam widths along the z-axis wide enough to cover a significant anatomical length (50-160 mm) in a single axial rotation (e.g., in cardiac CT) are rapidly proliferating in the clinic, referred to herein as stationary cone beam CT (SCBCT). The integral format of the CTDI paradigm is not appropriate for a stationary phantom, and is not useful for predicting the dose in SCBCT, nor for perfusion studies or CT fluoroscopy. Likewise, the pencil chamber has limited utility in this domain (even one of extended length). By demonstrating, both experimentally and theoretically, the match between the dose distribution f(z) for a wide cone beam and that due to an axial scan series D(z), it is shown that the dose on the central ray of the cone beam f(0) is both spatially colocated and numerically equal to the dose predicted by CTDI for the axial series; and thus f(0) is the logical (and unique) choice for a SCBCT dose-descriptor consistent with the CTDI-based dose of conventional CT. This dose f(0) can be readily measured using a conventional (short) ionization chamber. Additionally, Monte Carlo simulations of Boone [J. M. Boone, "Dose spread functions in computed tomography: A Monte Carlo study," Med. Phys. 36, 4547-4554 (2009)], expressed as a scatter LSF (or DSF), allow the application of a convolution-based model [R. L. Dixon, M. T. Munley, and E. Bayram, "An improved analytical model for CT dose simulation with a new look at the theory of CT dose," Med. Phys. 32, 3712-3728 (2005)] of the axial dose profile f(z) for any primary beam width a (any n x T), fan beam and cone beam alike, from a single LSF kernel; its simple form allows the results to be expressed as simple analytical equations. The experimental data of Mori et al. [S. Mori, M. Endo, K. Nishizawa, T. Tsunoo, T. Aoyama, H. Fujiwara, and K. Murase, "Enlarged longitudinal dose profiles in cone-beam CT and the need for modified dosimetry," Med. Phys. 32, 1061-1069 (2005)] from a 256 channel cone beam scanner for a variety of beam widths (28-138 mm) are used to corroborate the theory. Useful commonalities between SCBCT and conventional CT dose are revealed, including a common equilibrium dose parameter A(eq), which is independent of z-collimator aperture a (or n x T), and a common analytical (exponential growth) function H(lambda) describing the relative approach to scatter equilibrium at z = 0 for both modalities (with lambda = a or lambda = scan length L). This function exhibits good agreement with the above-mentioned cone beam data of Mori et al. for H(a) as well as with data H(L) obtained from conventional CT scanning [R. L. Dixon and A. C. Ballard, "Experimental validation of a versatile system of CT dosimetry using a conventional ion chamber: Beyond CTDI100," Med. Phys. 34(8), 3399-3413 (2007)] for the same directly irradiated, phantom length L = a. This methodology and associated mathematical theory provide a physically self-consistent description of dose between stationary phantom CT and conventional CT, and has predictive capabilities which can be used to effect a substantial reduction in data collection; provide a bridge between modalities; and predict the relevant peak doses f(0) for perfusion studies.


Early legume responses to inoculation with Rhizobium sp. NGR234.
Interactions between legumes and rhizobia are controlled by the sequential exchange of symbiotic signals. Two different techniques, 2D-PAGE electrophoresis and differential display were used to study the effects of rhizobial signals on legume development. Application of variously substituted lipo-oligo-saccharidic Nod-factors to roots of Vigna unguiculata resulted in changes in the phosphorylation patterns of microsomal proteins. Reliable amino-acid sequences were obtained for one Nod-factor enhanced protein which was highly homologous to the 57-kDa subunit from Arabidopsis thaliana vacuolar membrane H(+)-ATPase. Immuno-blotting techniques demonstrated that Nod-factors cause rapid and massive increases of this enzyme in treated roots, suggesting that H(+)-ATPases play symbiotic roles. Concomitantly, we used differential display (DD) techniques on mRNA isolated from root-hairs to analyse early root responses to NGR234. Significant matches of several DD clones to known sequences were found. Clone D2.62 was homologous to a multitude of receptor kinases including S receptor-like kinases of A. thaliana and clone D4.1 showed similarities to Lotus japonicus phosphatidylinositol transfer-like protein III and late nodulin 16. Independent confirmatory analyses of these differentially expressed clones indicated expression at very low levels.


Phytochemical phenolics in organically grown vegetables.
Fruit and vegetable intake is inversely correlated with risks for several chronic diseases in humans. Phytochemicals, and in particular, phenolic compounds, present in plant foods may be partly responsible for these health benefits through a variety of mechanisms. Since environmental factors play a role in a plant's production of secondary metabolites, it was hypothesized that an organic agricultural production system would increase phenolic levels. Cultivars of leaf lettuce, collards, and pac choi were grown either on organically certified plots or on adjacent conventional plots. Nine prominent phenolic agents were quantified by HPLC, including phenolic acids (e. g. caffeic acid and gallic acid) and aglycone or glycoside flavonoids (e. g. apigenin, kaempferol, luteolin, and quercetin). Statistically, we did not find significant higher levels of phenolic agents in lettuce and collard samples grown organically. The total phenolic content of organic pac choi samples as measured by the Folin-Ciocalteu assay, however, was significantly higher than conventional samples (p < 0.01), and seemed to be associated with a greater attack the plants in organic plots by flea beetles. These results indicated that although organic production method alone did not enhance biosynthesis of phytochemicals in lettuce and collards, the organic system provided an increased opportunity for insect attack, resulting in a higher level of total phenolic agents in pac choi.


Improving mammographic decision accuracy by incorporating observer ratings with interpretation time.
Mammography is currently the most established technique for the early detection of breast cancer. However, mammography would benefit from further improvements as it does produce some errors, such as not finding all early-stage cancers. The objectives of this study were first, to measure the timing of correct and incorrect reading decisions in mammography and second, to exploit those dependencies to improve accuracy in mammographic interpretation. To address these objectives, an experiment was conducted where experienced breast imaging radiologists reviewed 400 mammographic regions equally divided among images that contained simulated benign masses, malignant masses, malignant microcalcifications and no lesions. The experiment recorded the radiologists' decision as well as the length of time the mammogram was interpreted in. The experiment results showed that incorrect detection as well as incorrect classification decisions were associated with longer interpretation times (p<0.0001). The timing results were used to create a model that would flag cases for review that had a higher probability of error. The flagged cases had a median accuracy drop of 13% for detection decisions and 16% for classification decisions compared with unflagged cases. This suggests that interpretation time can be incorporated into mammographic decision-making in order to identify cases with higher probabilities of perceptual error that require further review.


Insights about Screen-Use Conflict from Discussions between Mothers and Pre-Adolescents: A Thematic Analysis.
Digital screens have become an integral part of everyday life. In the wake of the digital swell, pre-adolescents and their parents are learning to navigate seemingly new terrain regarding digital media use. The present study aimed to investigate parent and pre-adolescent perceptions of screen use and the source of conflict surrounding digital media. We employed a qualitative thematic analysis of 200 parent and pre-adolescent dyads discussing screen use. Our analysis showed five overarching themes for screen use perceptions and conflict: screen time, effects of screen use, balance, rules, and reasons for screen use. In contrast to previous studies that mainly focused on parental perceptions, we were also able to shed light on pre-adolescent perceptions of screen use and the difference in opinions with their parents. Furthermore, we found that patterns of the source of screen use conflict were oftentimes rooted in the age-old developmental tug of war between autonomy-seeking pre-adolescents and authority-seeking parents. Though navigating autonomy-granting and seeking behavior is familiar to developmental scientists, negotiating these challenges in a new digital world is unfamiliar. Autonomy support, open dialogue, and playful interaction between parents and children are needed to understand and resolve conflict of digital media use in family contexts.


A single-shot approach for measuring two-photon action cross-section of fluorescent markers.
We report on a novel method designed for measuring two-photon action cross sections spectra in a single shot without tuning the excitation wavelength. Our technique is based on (i) using a nonlinear photonic crystal fiber to broaden the spectrum of the femtosecond excitation pulses and (ii) exploiting angular dispersion to focus different wavelengths to different lateral positions. As a result, two-photon fluorescence signal at different excitation wavelengths can be obtained simultaneously. As a proof of principle, the relative two-photon action cross sections of rhodamine green and DiI-C(18) are measured over 740 - 860 nm range using fluorescein as a reference. Our results are in good agreement with that obtained using conventional tunable mode-locked laser.


A new hyperapolytic species, Trilocularia eberti sp. n. (Cestoda: Tetraphyllidea), from Squalus cf. mitsukurii (Squaliformes: Squalidae) off South Africa with comments on its development and fecundity.
A new species of tetraphyllidean cestode in the genus Trilocularia is described from an undescribed shark species, Squalus cf. mitsukurii, off the coast of South Africa. Trilocularia eberti sp. n. is the second known member of its genus, and like its congener, T. gracilis (Olsson, 1866-1867) Olsson, 1869, is extremely hyperapolytic, dropping proglottids from its strobila while they are still very immature. Characteristic of the genus, it possesses a distinctive scolex with triloculated bothridia, but differs conspicuously from its congener in its possession of an anterior loculus that is much larger in width relative to the paired posterior loculi, and also in its possession of an anterior, enlarged region of its free proglottids that is triangular with a slit-like ventral aperture, rather than rounded and cup-like. This anterior region of the free proglottid is used in attachment, and its development is described. For assessment of fecundity, an attempt was made to record all free proglottids of all ages found in both host individuals, and yielded an average estimate of 362 free proglottids being produced per individual worm of T. eberti sp. n. Both Trilocularia species parasitize sharks of the genus Squalus, and given the host specificity typically exhibited by tetraphyllideans and preliminary examinations of other members of this shark genus, it is likely that other Squalus species will be found to host additional new Trilocularia species.


Organic Polyradicals as Redox Mediators: Effect of Intramolecular Radical Interactions on Their Efficiency.
The spin-spin interactions between unpaired electrons in organic (poly)radicals, especially nitroxides, are largely investigated and are of crucial importance for their applications in areas such as organic magnetism, molecular charge transfer, or multiple spin labeling in structural biology. Recently, 2,2,6,6-tetramethylpiperidinyloxyl and polymers functionalized with nitroxides have been described as successful redox mediators in several electrochemical applications; however, the study of spin-spin interaction effect in such an area is absent. This communication reports the preparation of a novel family of discrete polynitroxide molecules, with the same number of radical units but different arrangements to study the effect of intramolecular spin-spin interactions on their electrochemical potential and their use as oxidation redox mediators in a Li-oxygen battery. We find that the intensity of interactions, as measured by the d1/d electron paramagnetic resonance parameter, progressively lowers the reduction potential. This allows us to tune the charging potential of the battery, optimizing its energy efficiency.


Temperature-dependent absorption and emission of potassium double tungstates with high ytterbium content.
We study the spectroscopic properties of thin films of potassium ytterbium gadolinium double tungstates, KYb0.57Gd0.43(WO4)2, and potassium ytterbium lutetium double tungstates, KYb0.76Lu0.24(WO4)2, specifically at the central absorption line near 981 nm wavelength, which is important for amplifiers and lasers. The absorption cross-section of both thin films is found to be similar to those of bulk potassium rare-earth double tungstates, suggesting that the crystalline layers retain their spectroscopic properties albeit having >50 at.% Yb3+ concentration. The influence of sample temperature is investigated and found to substantially affect the measured absorption cross-section. Since amplifiers and lasers typically operate above room temperature due to pump-induced heating, the temperature dependence of the peak-absorption cross-section of the KYb0.57Gd0.43(WO4)2 is evaluated for the sample being heated from 20 °C to 170 °C, resulting in a measured reduction of peak-absorption cross-section at the transitions near 933 nm and 981 nm by ~40% and ~52%, respectively. It is shown that two effects, the change of Stark-level population and linewidth broadening due to intra-manifold relaxation induced by temperature-dependent electron-phonon interaction, contribute to the observed behavior. The effective emission cross-sections versus temperature have been calculated. Luminescence-decay measurements show no significant dependence of the luminescence lifetime on temperature.


Neuropsychiatric outcomes of stroke.
The most common neuropsychiatric outcomes of stroke are depression, anxiety, fatigue, and apathy, which each occur in at least 30% of patients and have substantial overlap of prevalence and symptoms. Emotional lability, personality changes, psychosis, and mania are less common but equally distressing symptoms that are also challenging to manage. The cause of these syndromes is not known, and there is no clear relation to location of brain lesion. There are important gaps in knowledge about how to manage these disorders, even for depression, which is the most studied syndrome. Further research is needed to identify causes and interventions to prevent and treat these disorders.


[Turkish Adult Risk Factor survey 2014: Overall mortality and coronary disease incidence in Turkey's geographic regions].
This study aimed to examine the overall and coronary mortality in the 2014 Turkish Adult Risk Factor Study survey, and the distribution of cumulative mortality and incident coronary heart disease (CHD) across 7 geographic regions. Information on mode of death was appropriately obtained. Information collected from survivors was based on history, examination of the cardiovascular system and the Minnesota coding of electrocardiograms. Cox regression analyses were performed. Of the 1.323 participants to be surveyed, 87 were lost to follow-up, 753 examined, and 35 ascertained as deceased. In 448 subjects, verbal information alone was obtained regarding health status. Nineteen deaths were of coronary and cerebrovascular origin. Cumulative 24-year assessment of the entire cohort in the age bracket 45-74 years disclosed high coronary mortality, at 7.3 per 1000 person-years in men and 3.8 in women, and recorded a limited decline of 18% since the year 2000. Age-adjusted Cox regression analysis, comprising 614 deaths and 482 incident CHD over a follow-up of 9.6 years, revealed higher mortality rates in the Mediterranean region and in men in the Black Sea and Marmara regions. The age-adjusted CHD incidence was significantly higher in males of the Mediterranean and females of the Southeast regions. An estimated 400-420.000 incident CHD cases develop currently each year in Turkey. The generally high age-adjusted overall mortality in Turkey displays significant differences across geographic regions. Age-adjusted CHD incidence is not regressing sufficiently, and is especially high among men of the Mediterranean and women of the Southeast regions.


Transvaginal repair of Neobladder Vaginal Fistula with Martius Flap.
Neobladder vaginal fistula (NVF) is a known complication after cystectomy and orthotopic diversion in women, occurring in 3-5% of women. Possible risk factors for fistula formation include compromised tissue vascularity due to surgical dissection and/or radiotherapy, suture line proximity, local tissue recurrence, and injury to the vaginal wall during dissection. The surgical repair of a NVF can be challenging secondary to vaginal shortening, atrophy, local inflammation from chronic exposure to urinary leakage, and the proximity of the neobladder to the anterior vaginal wall. In this video, we present transvaginal repair of a NVF with Martius flap interposition. This is the case of a 47 year old woman with a history of radical cystectomy and creation of a Studer pouch secondary to bladder cancer two years prior who subsequently developed a NVF. Evaluation included an office cystoscopy which demonstrated a 3-4mm left-sided neobladder vaginal fistula at the level of the ileal-urethral anastomosis. No pelvic organ prolapse or evidence of bladder cancer recurrence was appreciated. A vaginal approach for the NVF repair was performed with a Martius flap interposition. A water-tight closure was achieved without any intraoperative or immediate postoperative complications. The urethral Foley was removed at 2 weeks and by 4 weeks the patient did not report any urinary leakage. Neobladder vaginal fistula is a rare complication following cystectomy and orthotopic urinary diversion that can be repaired using a transvaginal approach. A Martius flap interposition is important to augment success of the repair. If a transvaginal approach fails a transabdominal approach or conversion to cutaneous diversion may be necessary.


Grating interferometer based scanning setup for hard X-ray phase contrast imaging.
In x-ray radiography, particularly for technical and industrial applications, a scanning setup is very often favorable when compared to a direct two-dimensional image acquisition. Here, we report on an efficient scanning method for grating based x-ray phase contrast imaging with tube based sources. It uses multiple line detectors for staggered acquisition of the individual phase-stepping images. We find that the total exposure time does not exceed the time needed in an equivalent scanning setup for absorption radiography. Therefore, we conclude that it should be possible to implement the method into a scanning system without affecting the scanning speed or significant increase in cost but with the advantage of providing both the phase contrast and the absorption information at once.


Fast measurement of the quadriceps femoris muscle transverse relaxation time at high magnetic field using segmented echo-planar imaging.
To assess and validate a technique for transverse relaxation time (T2 ) measurements of resting and recovering skeletal muscle following exercise with a high temporal resolution and large volume coverage using segmented spin-echo echo-planar imaging (sSE-EPI). Experiments were performed on a 3T magnetic resonance imaging (MRI) scanner using a multislice sSE-EPI technique applied at different echo times (TEs). T2 measurements were first validated in vitro in calibrated T2 phantoms (range: 25-152 ms) by comparing sSE-EPI, standard spin-echo (SE), and multislice multiecho (MSME) techniques (using a fitting procedure or a 2-TEs calculation). In vivo measurements of resting T2 quadriceps femoris (QF) muscle were performed with both sSE-EPI and MSME sequences. Finally, sSE-EPI was used to quantify T2 changes in recovering muscle after an exercise. T2 values measured in vitro with sSE-EPI were similar to those assessed with SE (P > 0.05). In vitro and in vivo T2 measurements obtained with sSE-EPI were independent of the T2 determination procedure (P > 0.05). In contrast, both in vitro and in vivo T2 values derived from MSME were significantly different when using 2-TEs calculation as compared to the fitting procedure (P < 0.05). sSE-EPI allowed the detection of increased T2 values in the QF muscle immediately after exercise (+14 ± 9%), while lower T2 values were recorded less than 2 min afterwards (P < 0.05). sSE-EPI sequence is a relevant method to monitor exercise-induced T2 changes of skeletal muscles over large volume coverage and to detect abnormal patterns of muscle activation. 1 J. Magn. Reson. Imaging 2017;45:356-368.


Immunology and homeopathy. 3. Experimental studies on animal models.
A search of the literature and the experiments carried out by the authors of this review show that there are a number of animal models where the effect of homeopathic dilutions or the principles of homeopathic medicine have been tested. The results relate to the immunostimulation by ultralow doses of antigens, the immunological models of the 'simile', the regulation of acute or chronic inflammatory processes and the use of homeopathic medicines in farming. The models utilized by different research groups are extremely etherogeneous and differ as the test medicines, the dilutions and the outcomes are concerned. Some experimental lines, particularly those utilizing mice models of immunomodulation and anti-inflammatory effects of homeopathic complex formulations, give support to a real effect of homeopathic high dilutions in animals, but often these data are of preliminary nature and have not been independently replicated. The evidence emerging from animal models is supporting the traditional 'simile' rule, according to which ultralow doses of compounds, that in high doses are pathogenic, may have paradoxically a protective or curative effect. Despite a few encouraging observational studies, the effectiveness of the homeopathic prevention or therapy of infections in veterinary medicine is not sufficiently supported by randomized and controlled trials.


Hacking 9-1-1: Infrastructure Vulnerabilities and Attack Vectors.
9-1-1 call centers are a critical component of prehospital care: they accept emergency calls, dispatch field responders such as emergency medical services, and provide callers with emergency medical instructions before their arrival. The aim of this study was to describe the technical structure of the 9-1-1 call-taking system and to describe its vulnerabilities that could lead to compromised patient care. 9-1-1 calls answered from mobile phones and landlines use a variety of technologies to provide information about caller location and other information. These interconnected technologies create potential cyber vulnerabilities. A variety of attacks could be carried out on 9-1-1 infrastructure to various ends. Attackers could target individuals, groups, or entire municipalities. These attacks could result in anything from a nuisance to increased loss of life in a physical attack to worse overall outcomes owing to delays in care for time-sensitive conditions. Evolving 9-1-1 systems are increasingly connected and dependent on network technology. As implications of cybersecurity vulnerabilities loom large, future research should examine methods of hardening the 9-1-1 system against attack.


An Improved Patient-Derived Xenograft Humanized Mouse Model for Evaluation of Lung Cancer Immune Responses.
Human tumor xenograft models do not replicate the human immune system and tumor microenvironment. We developed an improved humanized mouse model, derived from fresh cord blood CD34+ stem cells (CD34+ HSC), and combined it with lung cancer cell line-derived human xenografts or patient-derived xenografts (Hu-PDX). Fresh CD34+ HSCs could reconstitute detectable mature human leukocytes (hCD45+) in mice at four weeks without the onset of graft-versus-host disease (GVHD). Repopulated human T cells, B cells, natural killer (NK) cells, dendritic cells (DC), and myeloid-derived suppressor cells (MDSC) increased in peripheral blood, spleen, and bone marrow over time. Although cultured CD34+ HSCs labeled with luciferase could be detected in mice, the cultured HSCs did not develop into mature human immune cells by four weeks, unlike fresh CD34+ HSCs. Ex vivo, reconstituted T cells, obtained from the tumor-bearing humanized mice, secreted IFNγ upon treatment with phorbol myristate acetate (PMA) or exposure to human A549 lung tumor cells and mediated antigen-specific CTL responses, indicating functional activity. Growth of engrafted PDXs and tumor xenografts was not dependent on the human leukocyte antigen status of the donor. Treatment with the anti-PD-1 checkpoint inhibitors pembrolizumab or nivolumab inhibited tumor growth in humanized mice significantly, and correlated with an increased number of CTLs and decreased MDSCs, regardless of the donor HLA type. In conclusion, fresh CD34+HSCs are more effective than their expanded counterparts in humanizing mice, and do so in a shorter time. The Hu-PDX model provides an improved platform for evaluation of immunotherapy.


Managing pain in prison: staff perspectives.
The purpose of this paper is to present the findings of one part of a larger study, funded by the National Institute for Health Research, which explored the management of pain in adult male prisoners in one large category B prison in England. In this paper, the authors focus on the attitudes and perceptions of prison staff towards pain management in prison. A qualitative design was utilised to explore the staff perceptions of pain and pain management in one adult male prison. Questionnaires were provided for all staff with prisoner contact, and a follow up focus group was undertaken to further explore questionnaire data. The questionnaire and focus group findings demonstrated that staff had a good awareness of pain and pain management in prison, with both physical and emotional pain identified. The frequency of approaches by prisoners to staff for pain relief was noted to be high, whilst awareness of how the prison environment could potentially exacerbate pain was discussed. The acquisition of analgesia by prisoners for secondary gain was identified as a challenge to both assessing levels of pain and providing pain relief in prison, illustrating the complexity of providing care within a custodial culture. The effect on staff of caring for prisoners found to be confrontational and deceitful was significant for participants, with feelings of anger and frustration reported. Research LIMITATIONS/IMPLICATIONS: This study was undertaken in one adult male category B prison with a very high turnover of prisoners. Staff working in other types of prison, for example, higher security or those more stable with longer sentenced prisoners could provide alternative views, as may staff caring for younger offenders and women. The challenges to undertaking research in prison with staff who can understandably be reluctant to engage in reflection on their practice cannot be underestimated and impact significantly on available methodologies. This qualitative research is the first of its kind to offer the perspectives of both health care professionals and prison staff working with prisoners complaining of pain in an English prison. It provides the groundwork for further research and development.


Could hyperthermia with proton therapy mimic carbon ion therapy? Exploring a thermo-radiobiological rationale.
Hyperthermia has been conventionally used in conjunction with photon beam irradiation. With a gradual increase in particle therapy facilities worldwide, this paper explores the physical, thermal and radiobiological implications of using a combination of hyperthermia with proton beam therapy. Hyperthermia is known to exhibit radiobiological features similar to those of high linear energy transfer radiation. Protons have many of the physical dose distribution properties of (12)C ion therapy. Thus, the thermo-radiobiological advantages of hyperthermia coupled with the physical dose distribution advantages of proton beams could possibly mimic (12)C ion therapy.


Dynamic nuclear polarization NMR spectroscopy of microcrystalline solids.
Dynamic nuclear polarization (DNP) solid-state NMR has been applied to powdered microcrystalline solids to obtain sensitivity enhancements on the order of 100. Glucose, sulfathiazole, and paracetamol were impregnated with bis-nitroxide biradical (bis-cyclohexyl-TEMPO-bisketal, bCTbK) solutions of organic solvents. The organic solvents were carefully chosen to be nonsolvents for the compounds, so that DNP-enhanced solid-state NMR spectra of the unaltered solids could be acquired. A theoretical model is presented that illustrates that for externally doped organic solids characterized by long spin-lattice relaxation times (T(1)((1)H) > 200 s), (1)H-(1)H spin diffusion can relay enhanced polarization over micrometer length scales yielding substantial DNP enhancements (ε). ε on the order of 60 are obtained for microcrystalline glucose and sulfathiazole at 9.4 T and with temperatures of ca. 105 K. The large gain in sensitivity enables the rapid acquisition of (13)C-(13)C correlation spectra at natural isotopic abundance. It is anticipated that this will be a general method for enhancing the sensitivity of solid-state NMR experiments of organic solids.


Surface acoustic wave diffraction driven mechanisms in microfluidic systems.
Acoustic forces arising from high-frequency surface acoustic waves (SAW) underpin an exciting range of promising techniques for non-contact manipulation of fluid and objects at micron scale. Despite increasing significance of SAW-driven technologies in microfluidics, the understanding of a broad range of phenomena occurring within an individual SAW system is limited. Acoustic effects including streaming and radiation force fields are often assumed to result from wave propagation in a simple planar fashion. The propagation patterns of a single SAW emanating from a finite-width source, however, cause a far richer range of physical effects. In this work, we seek a better understanding of the various effects arising from the incidence of a finite-width SAW beam propagating into a quiescent fluid. Through numerical and experimental verification, we present five distinct mechanisms within an individual system. These cause fluid swirling in two orthogonal planes, and particle trapping in two directions, as well as migration of particles in the direction of wave propagation. For a range of IDT aperture and channel dimensions, the relative importance of these mechanisms is evaluated.


Finite element modeling of impulsive excitation and shear wave propagation in an incompressible, transversely isotropic medium.
Elastic properties of materials can be measured by observing shear wave propagation following localized, impulsive excitations and relating the propagation velocity to a model of the material. However, characterization of anisotropic materials is difficult because of the number of elasticity constants in the material model and the complex dependence of propagation velocity relative to the excitation axis, material symmetries, and propagation directions. In this study, we develop a model of wave propagation following impulsive excitation in an incompressible, transversely isotropic (TI) material such as muscle. Wave motion is described in terms of three propagation modes identified by their polarization relative to the material symmetry axis and propagation direction. Phase velocities for these propagation modes are expressed in terms of five elasticity constants needed to describe a general TI material, and also in terms of three constants after the application of two constraints that hold in the limit of an incompressible material. Group propagation velocities are derived from the phase velocities to describe the propagation of wave packets away from the excitation region following localized excitation. The theoretical model is compared to the results of finite element (FE) simulations performed using a nearly incompressible material model with the five elasticity constants chosen to preserve the essential properties of the material in the incompressible limit. Propagation velocities calculated from the FE displacement data show complex structure that agrees quantitatively with the theoretical model and demonstrates the possibility of measuring all three elasticity constants needed to characterize an incompressible, TI material.


Limit Cases: How and Why We Can and Should Decriminalise HIV Transmission, Exposure, And Non-Disclosure.
Across the world, people living with HIV and AIDS (PLHA) face investigation, prosecution, conviction, and punishment if they transmit HIV to another person, expose others to the risk of HIV acquisition, or fail to disclose in advance their HIV positive status. This article seeks to explain why limiting the criminalisation of HIV is important and necessary; identifies some of the ways in which it has been, and might be, limited; and, finally, offers some reflections on whether there exists a principled limit to decriminalisation arguments (ie whether there are cases which, even if the general principles underpinning decriminalisation is accepted, justify state punishment). Drawing on recent international policy guidance, current scientific knowledge about HIV prevention and treatment, and research on the impact of criminalisation of PLHA, the article argues that decriminalisation is critical to eradicating HIV and should be a public health priority, that biomedical advances in prevention and treatment will assist the decriminalisation project but are insufficient in the absence of legal and criminal justice practice reform.


Distinction of seropositive NMO spectrum disorder and MS brain lesion distribution.
Neuromyelitis optica and its spectrum disorder (NMOSD) can present similarly to relapsing-remitting multiple sclerosis (RRMS). Using a quantitative lesion mapping approach, this research aimed to identify differences in MRI brain lesion distribution between aquaporin-4 antibody-positive NMOSD and RRMS, and to test their diagnostic potential. Clinical brain MRI sequences for 44 patients with aquaporin-4 antibody-positive NMOSD and 50 patients with RRMS were examined for the distribution and morphology of brain lesions. T2 lesion maps were created for each subject allowing the quantitative comparison of the 2 conditions with lesion probability and voxel-wise analysis. Sixty-three percent of patients with NMOSD had brain lesions and of these 27% were diagnostic of multiple sclerosis. Patients with RRMS were significantly more likely to have lesions adjacent to the body of the lateral ventricle than patients with NMOSD. Direct comparison of the probability distributions and the morphologic attributes of the lesions in each group identified criteria of "at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or the presence of a subcortical U-fiber lesion; or a Dawson's finger-type lesion," which could distinguish patients with multiple sclerosis from those with NMOSD with 92% sensitivity, 96% specificity, 98% positive predictive value, and 86% negative predictive value. Careful inspection of the distribution and morphology of MRI brain lesions can distinguish RRMS and NMOSD.


Sexually dimorphic expression of KCC2 and GABA function.
GABA(A) receptors have an age-adapted function in the brain. During early development, they mediate depolarizing effects, which result in activation of calcium-sensitive signaling processes that are important for the differentiation of the brain. In more mature stages of development and in adults, GABA(A) receptors acquire their classical hyperpolarizing signaling. The switch from depolarizing to hyperpolarizing GABA(A)-ergic signaling is triggered through the developmental shift in the balance of chloride cotransporters that either increase (i.e. NKCC1) or decrease (i.e. KCC2) intracellular chloride. The maturation of GABA(A) signaling follows sex-specific patterns, which correlate with the developmental expression profiles of chloride cotransporters. This has first been demonstrated in the substantia nigra, where the switch occurs earlier in females than in males. As a result, there are sensitive periods during development when drugs or conditions that activate GABA(A) receptors mediate different transcriptional effects in males and females. Furthermore, neurons with depolarizing or hyperpolarizing GABA(A)-ergic signaling respond differently to neurotrophic factors like estrogens. Consequently, during sensitive developmental periods, GABA(A) receptors may act as broadcasters of sexually differentiating signals, promoting gender-appropriate brain development. This has particular implications in epilepsy, where both the pathophysiology and treatment of epileptic seizures involve GABA(A) receptor activation. It is important therefore to study separately the effects of these factors not only on the course of epilepsy but also design new treatments that may not necessarily disturb the gender-appropriate brain development.


A signal sequence domain essential for processing, but not import, of mitochondrial pre-ornithine carbamyl transferase.
Studies using deletion mutagenesis indicate that a processing recognition site lies proximal to the normal cleavage position between gln32 and ser33 of pre-ornithine carbamyl transferase (pOCT). pOCT cDNA was manipulated to delete codons specifying amino acids 22-30 of the signal sequence. The mutant precursor, designated pOCT delta 22-30, was imported to the matrix compartment by purified mitochondria, but remained largely unprocessed; the low level of processing that was observed did not involve the normal cleavage site. Several manipulations performed downstream of the normal pOCT processing site (deletion, substitution, and hybrid protein constructions) affected neither import nor correct processing. Our data suggest that domains specifying import and processing site recognition may be functionally segregated within the signal peptide; that processing is not requisite for import of pOCT; and that a proximal region, not involving the normal signal peptide cleavage site, is required for processing site recognition.


Deep profiling and custom databases improve detection of proteoforms generated by alternative splicing.
Alternative pre-mRNA splicing has long been proposed to contribute greatly to proteome complexity. However, the extent to which mature mRNA isoforms are successfully translated into protein remains controversial. Here, we used high-throughput RNA sequencing and mass spectrometry (MS)-based proteomics to better evaluate the translation of alternatively spliced mRNAs. To increase proteome coverage and improve protein quantitation, we optimized cell fractionation and sample processing steps at both the protein and peptide level. Furthermore, we generated a custom peptide database trained on analysis of RNA-seq data with MAJIQ, an algorithm optimized to detect and quantify differential and unannotated splice junction usage. We matched tandem mass spectra acquired by data-dependent acquisition (DDA) against our custom RNA-seq based database, as well as SWISS-PROT and RefSeq databases to improve identification of splicing-derived proteoforms by 28% compared with use of the SWISS-PROT database alone. Altogether, we identified peptide evidence for 554 alternate proteoforms corresponding to 274 genes. Our increased depth and detection of proteins also allowed us to track changes in the transcriptome and proteome induced by T-cell stimulation, as well as fluctuations in protein subcellular localization. In sum, our data here confirm that use of generic databases in proteomic studies underestimates the number of spliced mRNA isoforms that are translated into protein and provides a workflow that improves isoform detection in large-scale proteomic experiments.


Performance of visual inspection, electrical conductance and laser fluorescence in detecting occlusal caries in vitro.
The aim of this study was to compare visual inspection (VI) and electrical conductance (EC) and laser fluorescence (LF) measurements in detecting occlusal caries. VI was based on fissure discoloration and performed with the naked eye. EC was measured with the ECM device (Lode Diagnostic, Groningen, The Netherlands), and LF was assessed with the DIAGNOdent apparatus (KaVo, Biberach, Germany). In extracted human premolars and molars, clinically sound sites (D0-/D1-lesions), enamel caries (D2-lesions), and dentinal caries (D3-/D4-lesions) were identified using recommended cut-off values. Thereafter, the teeth were cut longitudinally and analyzed by scanning electron microscopy for verification of caries depth. Reproducibility of VI was good, that of EC and LF excellent. In identifying caries at both the enamel and dentin level, the sensitivities of VI and LF were significantly (p < 0.05) higher than that of EC, while EC was significantly (p < 0.05) more specific. The positive predictive values, however, did not exceed 43%. Improved diagnoses at the dentinal level were obtained, when EC and LF were used as an adjunct to VI and when cut-off values were raised. Thus, visual inspection relying exclusively on fissure discoloration seems to allow only proper identification of sound occlusal surfaces. In cases of discolored fissures, the appliance-based methods help to avoid false positive identification of dentinal caries. However, attainable reliabilities of diagnoses do not seem to exceed about 50% to 60%.


Effect of minocycline on lumbar radicular neuropathic pain: a randomized, placebo-controlled, double-blind clinical trial with amitriptyline as a comparator.
Less than 50% of patients experience sufficient pain relief with current drug therapy for neuropathic pain. Minocycline shows promising results in rodent models of neuropathic pain but was not studied in humans with regard to the treatment of neuropathic pain. In this randomized, double-blind, placebo-controlled clinical trial, patients with subacute lumbar radicular pain received placebo, amitriptyline 25 mg, or minocycline 100 mg once a day (n = 20 per group) for 14 days. Primary outcome measure was the pain intensity in the leg as measured by a numeric rating scale ranging from 0 to 10 on days 7 and 14. Secondary outcome measures were the reduction of neuropathic pain symptoms in the leg as determined with a neuropathic pain questionnaire, consumption of rescue medication, and adverse events on days 7 and 14. Sixty patients were randomized and included in an intention-to-treat analysis. After 14 days, patients in the minocycline and amitriptyline groups reported a reduction of 1.47 (95% confidence interval, 0.16-2.83; P = 0.035) and 1.41 (95% confidence interval, 0.05-2.78; P = 0.043), respectively, in the numeric rating scale compared to the placebo group. No differences were seen in the neuropathic pain questionnaire values at any time point during treatment between the three groups. The rate of adverse events in the amitriptyline group was 10% versus none in the minocycline and placebo groups. No differences were noted in the consumption of rescue medication. Although both groups differed from placebo, their effect size was small and therefore not likely to be clinically meaningful.


Cannabidiol: a promising drug for neurodegenerative disorders?
Neurodegenerative diseases represent, nowadays, one of the main causes of death in the industrialized country. They are characterized by a loss of neurons in particular regions of the nervous system. It is believed that this nerve cell loss underlies the subsequent decline in cognitive and motor function that patients experience in these diseases. A range of mutant genes and environmental toxins have been implicated in the cause of neurodegenerative disorders but the mechanism remains largely unknown. At present, inflammation, a common denominator among the diverse list of neurodegenerative diseases, has been implicated as a critical mechanism that is responsible for the progressive nature of neurodegeneration. Since, at present, there are few therapies for the wide range of neurodegenerative diseases, scientists are still in search of new therapeutic approaches to the problem. An early contribution of neuroprotective and antiinflammatory strategies for these disorders seems particularly desirable because isolated treatments cannot be effective. In this contest, marijuana derivatives have attracted special interest, although these compounds have always raised several practical and ethical problems for their potential abuse. Nevertheless, among Cannabis compounds, cannabidiol (CBD), which lacks any unwanted psychotropic effect, may represent a very promising agent with the highest prospect for therapeutic use.


Hybridization and reproductive isolation among syntopic populations of the topminnows Fundulus notatus and F. olivaceus.
Fundulus notatus and Fundulus olivaceus are two closely related topminnow species that exhibit similar ecological niches and broad, largely overlapping, North American ranges extending throughout much of the Mississippi River drainage as well as the coastal drainages of the Gulf of Mexico. Previous studies have suggested that these two species are reproductively compatible despite cytogenetic differences and will hybridize when syntopic. We used nuclear and mtDNA loci to assess levels of hybridization and test for introgression in syntopic populations of these two species in four drainages in southern Illinois. Although hybridization was detected in all syntopic populations, an assessment of the proportion of hybrid individuals indicated a deficiency of hybrids relative to expectations under random mating. We determined that, although mtDNA introgression was prevalent and extended beyond the zones of contact, evidence of nuclear introgression was limited to the zone of sympatry.


Specific regulation of mechanical nociception by Gβ5 involves GABA-B receptors.
Mechanical, thermal, and chemical pain sensation is conveyed by primary nociceptors, a subset of sensory afferent neurons. The intracellular regulation of the primary nociceptive signal is an area of active study. We report here the discovery of a Gβ5-dependent regulatory pathway within mechanical nociceptors that restrains antinociceptive input from metabotropic GABA-B receptors. In mice with conditional knockout (cKO) of the gene that encodes Gβ5 (Gnb5) targeted to peripheral sensory neurons, we demonstrate the impairment of mechanical, thermal, and chemical nociception. We further report the specific loss of mechanical nociception in Rgs7-Cre+/- Gnb5fl/fl mice but not in Rgs9-Cre+/- Gnb5fl/fl mice, suggesting that Gβ5 might specifically regulate mechanical pain in regulator of G protein signaling 7-positive (Rgs7+) cells. Additionally, Gβ5-dependent and Rgs7-associated mechanical nociception is dependent upon GABA-B receptor signaling since both were abolished by treatment with a GABA-B receptor antagonist and since cKO of Gβ5 from sensory cells or from Rgs7+ cells potentiated the analgesic effects of GABA-B agonists. Following activation by the G protein-coupled receptor Mrgprd agonist β-alanine, enhanced sensitivity to inhibition by baclofen was observed in primary cultures of Rgs7+ sensory neurons harvested from Rgs7-Cre+/- Gnb5fl/fl mice. Taken together, these results suggest that the targeted inhibition of Gβ5 function in Rgs7+ sensory neurons might provide specific relief for mechanical allodynia, including that contributing to chronic neuropathic pain, without reliance on exogenous opioids.


Distribution and Incidence of Iris yellow spot virus in Colorado and Its Relation to Onion Plant Population and Yield.
Iris yellow spot virus (IYSV) is an emerging and potentially devastating disease of onion that was recently detected in Colorado and other onion producing regions in the western United States. In annual surveys, IYSV was confirmed in one of 18 fields (5.6%) in 2001, four of 24 (16.7%) in 2002, and 41 of 56 (73.2%) in 2003. IYSV was confirmed on volunteer onions in 2003 at all four locations where IYSV was observed in the onion crop the previous year. The disease was detected in six of seven western Colorado onion fields surveyed in 2003, but was not observed any year in southern or northeastern Colorado. The spatial variability of disease incidence, yield, and plant population also was mapped in two fields in 2003 using the global positioning system and a geographic information system. Disease incidence varied among cultivars, plant population, fields, and location in the field. Distinct disease gradients were observed in both fields with susceptible cultivars Teton and Granero, but not in the moderately resistant cultivar Sterling. In fields planted to the susceptible cultivars, disease incidence was highest on the field edges and lowest near the field centers. Plant population was negatively correlated with IYSV incidence in cultivar Sterling (R2 = 0.56, P = 0.003), but not with the susceptible cultivars. Yield of jumbo market class onions, but not total yield, was negatively correlated with increasing IYSV incidence (R2 = 0.37, P = 0.012) in cultivar Teton. Colossal market class yield, but not other yield components, was negatively correlated with IYSV incidence in cultivar Sterling (R2 = 0.28, P = 0.061). The results of these studies indicate the distribution of IYSV is rapidly expanding in Colorado and is associated with a general reduction in bulb size.


Differences Over Time in the Prognostic Effect of Return to Work Self-Efficacy on a Sustained Return to Work.
Purpose This study investigated the association between return to work self-efficacy (RTW-SE) and sustained return to work (RTW) at two different time points, over a 12-month period. The primary objective of the study was to examine if the relationship between RTW-SE and a sustained RTW changed over the RTW timeline. Methods This study used survey responses from a longitudinal cohort of n = 410 workers' compensation claimants with either an upper-body musculoskeletal injury or a psychological injury. A path analysis tested the associations between RTW-SE and a sustained RTW at two time-points. A Wald χ2 test compared nested models to determine if the association changed over time. Results RTW-SE measured at time- point 1 (T1) was associated with a sustained RTW at time-point two (T2) (β = 0.24, P < 0.05) but no association was found between RTW-SE at T2 and a sustained RTW at time-point three (T3) (β = 0.017, n.s.). Model comparisons revealed significant differences in the associations between RTW-SE and a sustained RTW, with the relationship being stronger in the early phase of RTW compared to the latter phase (χ2 = 5.002, p = 0.03). Conclusions The results indicate that RTW-SE at 4-6 months post-injury is important for a sustained RTW 6-months later although RTW-SE at 10-12 months post-injury had a negligible association over the same duration. Further research should investigate whether these findings generalize to other populations and what factors other than RTW-SE are associated with RTW in the later stages of the RTW process.


Directional cloning of DNA fragments using deoxyinosine-containing oligonucleotides and endonuclease V.
DNA fragments carrying internal recognition sites for the restriction endonucleases intended for cloning into a target plasmid pose a challenge for conventional cloning. A method for directional insertion of DNA fragments into plasmid vectors has been developed. The target sequence is amplified from a template DNA sample by PCR using two oligonucleotides each containing a single deoxyinosine base at the third position from the 5' end. Treatment of such PCR products with endonuclease V generates 3' protruding ends suitable for ligation with vector fragments created by conventional restriction endonuclease reactions. The developed approach generates terminal cohesive ends without the use of Type II restriction endonucleases, and is thus independent from the DNA sequence. Due to PCR amplification, minimal amounts of template DNA are required. Using the robust Taq enzyme or a proofreading Pfu DNA polymerase mutant, the method is applicable to a broad range of insert sequences. Appropriate primer design enables direct incorporation of terminal DNA sequence modifications such as tag addition, insertions, deletions and mutations into the cloning strategy. Further, the restriction sites of the target plasmid can be either retained or removed.


Interleukin-6 regulates pancreatic alpha-cell mass expansion.
Interleukin-6 (IL-6) is systemically elevated in obesity and is a predictive factor to develop type 2 diabetes. Pancreatic islet pathology in type 2 diabetes is characterized by reduced beta-cell function and mass, an increased proportion of alpha-cells relative to beta-cells, and alpha-cell dysfunction. Here we show that the alpha cell is a primary target of IL-6 actions. Beginning with investigating the tissue-specific expression pattern of the IL-6 receptor (IL-6R) in both mice and rats, we find the highest expression of the IL-6R in the endocrine pancreas, with highest expression on the alpha-cell. The islet IL-6R is functional, and IL-6 acutely regulates both pro-glucagon mRNA and glucagon secretion in mouse and human islets, with no acute effect on insulin secretion. Furthermore, IL-6 stimulates alpha-cell proliferation, prevents apoptosis due to metabolic stress, and regulates alpha-cell mass in vivo. Using IL-6 KO mice fed a high-fat diet, we find that IL-6 is necessary for high-fat diet-induced increased alpha-cell mass, an effect that occurs early in response to diet change. Further, after high-fat diet feeding, IL-6 KO mice without expansion of alpha-cell mass display decreased fasting glucagon levels. However, despite these alpha-cell effects, high-fat feeding of IL-6 KO mice results in increased fed glycemia due to impaired insulin secretion, with unchanged insulin sensitivity and similar body weights. Thus, we conclude that IL-6 is necessary for the expansion of pancreatic alpha-cell mass in response to high-fat diet feeding, and we suggest that this expansion may be needed for functional beta-cell compensation to increased metabolic demand.


Incidence of atherosclerotic cardiovascular disease among HIV patients receiving dialysis.
Atherosclerotic cardiovascular disease (ASCVD) is increasing in incidence in persons with human immunodeficiency virus (HIV). It is not known whether the morbidity and mortality rate of ASCVD is similarly increasing among patients with HIV end-stage renal disease (ESRD), who are living longer since the initiation of newer therapeutic regimens in 1997. We conducted a population-based study of 8,312 HIV ESRD patients enrolled in the US Renal Data System from 1987 to 2001. We determined the incidence of fatal and nonfatal ASCVD events stratified by date of dialysis therapy initiation. There were 3,112 HIV ESRD patients (77.9% men; mean age, 39.6 +/- 9.6 years) who initiated dialysis therapy before 1997 and 2,371 patients (71.5% men; mean age, 41.3 +/- 9.7 years) who initiated dialysis therapy after 1997. Cumulative incidences of ASCVD for those initiating dialysis therapy before 1997 compared with after 1997 were 10.6% versus 13.5% at 12 months, 18.8% versus 27.6% at 24 months, 26.2% versus 42.4% at 36 months, and 33.7% versus 65.9% at 48 months (P < 0.0001 by log rank). Those who initiated dialysis therapy after 1997 had a greater risk for developing ASCVD (adjusted hazard ratio, 1.57; 95% confidence interval, 1.29 to 1.92) than those who initiated dialysis therapy before 1997 after adjusting for demographics and ASCVD risk factors. There is an increased risk for ASCVD in patients with HIV who initiated dialysis therapy after 1997. This may reflect the long-term complications of multidrug regimens, as well as improved survival from these regimens leading to prolonged exposure to ASCVD risk factors.


Corticotropin-releasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus.
The present series of experiments tested the hypothesis that the behavioral activating and anxiogenic effects produced by intraventricular administration of corticotropin-releasing factor (CRF) may be mediated by noradrenergic neurons in the brain-stem locus coeruleus (LC). Results showed that infusion of CRF into the LC (100 ng) significantly increased nonambulatory spontaneous motor activity measured in photocell cages; ambulatory (i.e., locomotor) activity was not altered. In the modified Porsolt swim test, which examines arousal and agitation in a stressful situation, significant behavioral activation (i.e., decreased floating) was seen following infusion of CRF (10 ng) into the LC; a 500 ng dose of CRF was necessary to produce similar effects following infusion into the lateral ventricle. The results of these 2 tests suggest that the behavioral activating effects of CRF in the LC may be related to arousing or stress-related effects, rather than to increased locomotor activity per se. Anxiogenic activity was assessed in animals placed in an open field containing a small, darkened compartment. Infusion or CRF into the LC (1-100 ng) significantly increased the time spent in the compartment and decreased the amount of time spent exploring the outside of the compartment or venturing into the inner squares of the open field, all indices of anxiogenic behavior. Biochemical studies showed that bilateral infusion of CRF into the LC produced significant increases in the concentration of the norepinephrine metabolite 3,4-dihydroxyphenylglycol in such forebrain projection areas of the LC as the amygdala and posterior hypothalamus. These data, taken together, suggest that CRF produces its behavioral activating and anxiogenic effects, at least in part, by increasing the activity of LC noradrenergic neurons.


Amyloid and tau imaging biomarkers explain cognitive decline from late middle-age.
This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I-VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease.


High-dose 17beta-estradiol treatment prevents development of heart failure post-myocardial infarction in the rat.
Prognosis of heart failure remains poor despite therapeutic advances, such as angiotensin converting enzyme inhibition or beta-receptor blockade. Thus, more effective forms of treatment are urgently needed. Since estrogens have been shown to modulate migration and proliferation of cardiac fibroblasts and to modulate the expression of estrogen receptors of cardiomyocytes we examined whether high-dose estrogen treatment can affect post-myocardial infarction left ventricular remodeling. Female rats were treated with 17beta-estradiol (7.5 mg/90 d) or placebo for ten weeks, starting two weeks prior to experimental myocardial infarction. Eight weeks after infarction, in vivo echocardiographic and hemodynamic measurements as well as isolated heart perfusion were performed. In vivo, chronic estrogen treatment almost completely prevented the development of all signs of heart failure that occur in untreated infarcted hearts, such as increased left ventricular diameters (dilatation), reduced fractional shortening (systolic dysfunction) or increased left ventricular end-diastolic pressure (diastolic dysfunction). In vitro, the right- (indicating structural dilatation) and downward (indicating left ventricular dysfunction) shift of left ventricular pressure-volume curves occurring in untreated infarcted hearts was completely prevented by estrogen. High dose estradiol treatment prevented development of post-MI remodeling, as assessed by in vivo and in vitro parameters of LV dysfunction. Estrogen may hold the potential of becoming a new form of heart failure treatment.However, the mechanisms responsible for this striking and unexpected beneficial action of estrogen in heart failure remain to be elucidated.


Case-crossover studies of therapeutics: design approaches to addressing time-varying prognosis in elderly populations.
Self-controlled analysis methods implicitly adjust for time-invariant confounding within individuals. A person's prognosis often varies over time and affects both therapy choice and subsequent health outcomes. Current approaches may not be able to fully address this within-person confounding. We evaluated the potential impact of time-varying prognosis in self-controlled studies of treatment effects and the extent to which alternative adjustment strategies could mitigate these biases. We used Medicare data linked to prescription drug data from a pharmaceutical assistance program to conduct case-crossover studies of the relationship between intermittent use of five classes of preventive medications (statins, oral hypoglycemics, antihypertensives, osteoporosis, and glaucoma medications) and death-relationships that are strongly biased because of healthy-user and sick-stopper effects. We used the case-case time-control design to adjust for confounding from exposure trends related to prognosis. Each class of medications was evaluated separately, with the remaining four used as reference drugs to estimate prognosis-related exposure trends. The case-crossover odds ratios were 0.39, 0.38, 0.40, 0.39, and 0.45 for statin, antihypertensive, glaucoma, hypoglycemic, and osteoporosis drugs, respectively. After adjusting for the estimated noncausal prognosis-related trends in drug exposure among all eligible cases, odds ratios were clustered closer to null (0.99, 0.95, 1.02, 0.99, and 1.16, respectively). Consideration of the sociology of medication use leading to health outcomes is essential in designing and analyzing self-controlled studies of treatment effects. Although the case-case time-control design was able to reduce bias from prognosis-related exposure trends in our examples, the difficulty in identifying appropriate reference exposures could be prohibitive.


Steroid control of muscle remodeling during metamorphosis in Manduca sexta.
During metamorphosis in the tobacco hornworm, Manduca sexta, the abdominal body-wall muscle DEO1 is remodeled to form the adult muscle DE5. The degeneration of muscle DEO1 involves the dismantling of its contractile apparatus followed by the degeneration of muscle nuclei. As some nuclei are degenerating, others begin to incorporate 5-bromodeoxyuridine (BrdU), indicating the onset of nuclear proliferation. This proliferation is initially most evident at the site where the motoneuron contacts the muscle remnant. The developmental events involved in muscle remodeling are under the control of the steroid hormones, the ecdysteroids. The loss of the contractile elements of the larval muscle requires the rise and fall of the prepupal peak of ecdysteroids, whereas the subsequent loss of muscle nuclei is influenced by the slight rise in ecdysteroids seen after pupal ecdysis. Incorporation of BrdU by muscle nuclei depends on both the adult peak of the ecdysteroids and contact with the motoneuron. Unilateral axotomy blocks proliferation within the rudiment, but it does not block its subsequent differentiation into a very thin muscle in the adult.


MicroRNA-155 controls affinity-based selection by protecting c-MYC+ B cells from apoptosis.
The production of high-affinity antibodies by B cells is essential for pathogen clearance. Antibody affinity for antigen is increased through the affinity maturation in germinal centers (GCs). This is an iterative process in which B cells cycle between proliferation coupled with the acquisition of mutations and antigen-based positive selection, resulting in retention of the highest-affinity B cell clones. The posttranscriptional regulator microRNA-155 (miR-155) is critical for efficient affinity maturation and the maintenance of the GCs; however, the cellular and molecular mechanism by which miR-155 regulates GC responses is not well understood. Here, we utilized a miR-155 reporter mouse strain and showed that miR-155 is coexpressed with the proto-oncogene encoding c-MYC in positively selected B cells. Functionally, miR-155 protected positively selected c-MYC+ B cells from apoptosis, allowing clonal expansion of this population, providing an explanation as to why Mir155 deletion impairs affinity maturation and promotes the premature collapse of GCs. We determined that miR-155 directly inhibits the Jumonji family member JARID2, which enhances B cell apoptosis when overexpressed, and thereby promotes GC B cell survival. Our findings also suggest that there is cooperation between c-MYC and miR-155 during the normal GC response, a cooperation that may explain how c-MYC and miR-155 can collaboratively function as oncogenes.


A framework for mesencephalic dopamine systems based on predictive Hebbian learning.
We develop a theoretical framework that shows how mesencephalic dopamine systems could distribute to their targets a signal that represents information about future expectations. In particular, we show how activity in the cerebral cortex can make predictions about future receipt of reward and how fluctuations in the activity levels of neurons in diffuse dopamine systems above and below baseline levels would represent errors in these predictions that are delivered to cortical and subcortical targets. We present a model for how such errors could be constructed in a real brain that is consistent with physiological results for a subset of dopaminergic neurons located in the ventral tegmental area and surrounding dopaminergic neurons. The theory also makes testable predictions about human choice behavior on a simple decision-making task. Furthermore, we show that, through a simple influence on synaptic plasticity, fluctuations in dopamine release can act to change the predictions in an appropriate manner.


Polyphenols as food bioactive compounds in the context of Autism Spectrum Disorders: A critical mini-review.
Dietary polyphenols are bioactive compounds with potential in preventing and treating several chronic disorders, mainly due to their ability to modulate key pro-inflammatory and pro-oxidant signalling pathways. Although some studies have expressed concern about their efficacy in vivo, accumulating evidence has suggested that these compounds may achieve large concentrations in the gastrointestinal tract, which may be important in the context of intestinal and of neurological disorders, via modulation of the "gut-brain axis". Autism Spectrum disorders (ASD) are a group of lifelong neurodevelopmental disorders in which many patients suffer from gastrointestinal impairments. Thus, in the scope of these disorders, a growing number of studies have been focused on the microbiota-gut-brain axis. In this mini-review, we present gathered data on gut-to-brain communication in the scope of ASD and we address the advantages of polyphenols in the treatment of these disorders, presenting the more recent preclinical and clinical data on this issue. According to most studies, dietary polyphenols can be a promising strategy for the alleviation of ASD symptoms.


Probing the causes of thermal hysteresis using tunable Nagg micelles with linear and brush-like thermoresponsive coronas.
Self-assembled thermoresponsive polymers in aqueous solution have great potential as smart, switchable materials for use in biomedical applications. In recent years, attention has turned to the reversibility of these polymers' thermal transitions, which has led to debate over what factors influence discrepancies in the transition temperature when heating the system compared to the temperature obtained when cooling the system, known as the thermal hysteresis. Herein, we synthesize micelles with tunable aggregation numbers (Nagg) whose cores contain poly(n-butyl acrylate-co-N,N-dimethylacrylamide) (p(nBA-co-DMA)) and four different thermoresponsive corona blocks, namely poly(N-isopropylacrylamide) (pNIPAM), poly(N,N-diethylacrylamide) (pDEAm), poly(diethylene glycol monomethyl ether methacrylate) (pDEGMA) and poly(oligo(ethylene glycol) monomethyl ether methacrylate) (pOEGMA). By studying their thermoresponsive behavior, we elucidate the effects of changing numerous important characteristics both in the thermoresponsive chain chemistry and architecture, and in the structure of their self-assemblies. Our findings demonstrate large deviations in the reversibility between the self-assemblies and the corresponding thermoresponsive homopolymers; specifically we find that micelles whose corona consist of polymers with a brush-like architecture (pDEGMA and pOEGMA) exhibit irreversible phase transitions at a critical chain density. These results lead to a deeper understanding of stimuli-responsive self-assemblies and demonstrate the potential of tunable Nagg micelles for uncovering structure-property relationships in responsive polymer systems.


Determining the impact of flavored e-liquids on aldehyde production during Vaping.
1,2-Propylene glycol and glycerin, principal components of e-liquids, can thermally degrade to form acetaldehyde, acrolein, and formaldehyde when heated in electronic nicotine delivery systems (ENDS). Recently the flavors in e-liquids were suggested to be the major source of these aldehydes. We used the same 10 ENDS devices to test 5 e-liquid formulations (four flavored & one corresponding non-flavored) and measured device mass loss and levels of acetaldehyde, acrolein, and formaldehyde (30 replicate measurements per formulation). Despite finding reasonable variability in measurements of device mass loss, two out of 10 ENDS devices tested produced outlier values for aerosol levels acetaldehyde, acrolein, and formaldehyde. After removing these devices from further analysis, acceptable variability (≤20% RSD) in aerosol levels of acetaldehyde, and formaldehyde were found. The flavored formulations tested resulted in a consistent and selective increase of 150%-200% in acetaldehyde, no increase or decrease in acrolein and depending on the flavor formulation, an increase, a decrease or no change in formaldehyde levels. Comparison of our results to the literature illustrates the need for development of a standardized ENDS testing protocol. Our results further support that device variability must be fully characterized and considered before assessing the impact of e-liquid formulations.


Disabling Cas9 by an anti-CRISPR DNA mimic.
CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 gene editing technology is derived from a microbial adaptive immune system, where bacteriophages are often the intended target. Natural inhibitors of CRISPR-Cas9 enable phages to evade immunity and show promise in controlling Cas9-mediated gene editing in human cells. However, the mechanism of CRISPR-Cas9 inhibition is not known, and the potential applications for Cas9 inhibitor proteins in mammalian cells have not been fully established. We show that the anti-CRISPR protein AcrIIA4 binds only to assembled Cas9-single-guide RNA (sgRNA) complexes and not to Cas9 protein alone. A 3.9 Å resolution cryo-electron microscopy structure of the Cas9-sgRNA-AcrIIA4 complex revealed that the surface of AcrIIA4 is highly acidic and binds with a 1:1 stoichiometry to a region of Cas9 that normally engages the DNA protospacer adjacent motif. Consistent with this binding mode, order-of-addition experiments showed that AcrIIA4 interferes with DNA recognition but has no effect on preformed Cas9-sgRNA-DNA complexes. Timed delivery of AcrIIA4 into human cells as either protein or expression plasmid allows on-target Cas9-mediated gene editing while reducing off-target edits. These results provide a mechanistic understanding of AcrIIA4 function and demonstrate that inhibitors can modulate the extent and outcomes of Cas9-mediated gene editing.


Natural killer cell signaling pathways.
Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in the early defenses against foreign cells, as well as autologous cells undergoing various forms of stress, such as microbial infection or tumor transformation. NK cell activation is controlled by a dynamic balance between complementary and antagonistic pathways that are initiated upon interaction with potential target cells. NK cells express an array of activating cell surface receptors that can trigger cytolytic programs, as well as cytokine or chemokine secretion. Some of these activating cell surface receptors initiate protein tyrosine kinase (PTK)-dependent pathways through noncovalent associations with transmembrane signaling adaptors that harbor intracytoplasmic ITAMs (immunoreceptor tyrosine-based activation motifs). Additional cell surface receptors that are not directly coupled to ITAMs also participate in NK cell activation. These include NKG2D, which is noncovalently associated to the DAP10 transmembrane signaling adaptor, as well as integrins and cytokine receptors. NK cells also express cell surface inhibitory receptors that antagonize activating pathways through protein tyrosine phosphatases (PTPs). These inhibitory cell surface receptors are characterized by intracytoplasmic ITIMs (immunoreceptor tyrosine-based inhibition motifs). The tyrosine-phosphorylation status of several signaling components that are substrates for both PTKs and PTPs is thus key to the propagation of the NK cell effector pathways. Understanding the integration of these multiple signals is central to the understanding and manipulation of NK cell effector signaling pathways.


The Association of Panic Disorder, Posttraumatic Stress Disorder, and Major Depression With Smoking in American Indians.
Rates of cigarette smoking are disproportionately high among American Indian populations, although regional differences exist in smoking prevalence. Previous research has noted that anxiety and depression are associated with higher rates of cigarette use. We asked whether lifetime panic disorder, posttraumatic stress disorder, and major depression were related to lifetime cigarette smoking in two geographically distinct American Indian tribes. Data were collected in 1997-1999 from 1506 Northern Plains and 1268 Southwest tribal members; data were analyzed in 2009. Regression analyses examined the association between lifetime anxiety and depressive disorders and odds of lifetime smoking status after controlling for sociodemographic variables and alcohol use disorders. Institutional and tribal approvals were obtained for all study procedures, and all participants provided informed consent. Odds of smoking were two times higher in Southwest participants with panic disorder and major depression, and 1.7 times higher in those with posttraumatic stress disorder, after controlling for sociodemographic variables. After accounting for alcohol use disorders, only major depression remained significantly associated with smoking. In the Northern Plains, psychiatric disorders were not associated with smoking. Increasing psychiatric comorbidity was significantly linked to increased smoking odds in both tribes, especially in the Southwest. This study is the first to examine the association between psychiatric conditions and lifetime smoking in two large, geographically diverse community samples of American Indians. While the direction of the relationship between nicotine use and psychiatric disorders cannot be determined, understanding unique social, environmental, and cultural differences that contribute to the tobacco-psychiatric disorder relationship may help guide tribe-specific commercial tobacco control strategies.


Effects of dopamine on postural control in parkinsonian subjects: scaling, set, and tone.
1. This study investigates the effects of parkinsonism and of dopamine replacement therapy (levodopa) on scaling the magnitude of automatic postural responses based on sensory feedback and on predictive central set. Surface reactive torques and electromyographic (EMG) activity in response to backward surface translations were compared in patients with parkinsonism ON and OFF levodopa and in elderly control subjects. Correlations between the earliest postural responses [initial rate of change of torque and integrated EMG (IEMG)] and translation velocity provided a measure of postural magnitude scaling using somatosensory feedback. Correlations of responses with expected translation amplitude provided a measure of scaling dependent on predictive central set because the responses preceded amplitude completion. 2. Parkinsonian EMG responses in six leg and trunk muscles were not later than in elderly control subjects. In fact, quadriceps antagonist latencies were earlier than normal, resulting in coactivation at the knee not present in control subjects. EMG activation was fragmented, with short burst durations and high tonic levels that often returned to baseline with multiple bursts. In addition, parkinsonian responses showed smaller-than-normal agonist extensor bursts and larger-than-normal activation in tibialis and rectus femorus antagonist flexors. 3. Although parkinsonian subjects scaled postural responses to both displacement velocities and amplitudes, their torque response were smaller than those of elderly controls, especially in response to the largest displacement amplitudes. The gain (slope) of postural response magnitude scaling to displacement velocity was similar for parkinsonian and control subjects, although parkinsonian subjects had smaller torques. Parkinsonian subjects were also able to use prediction to scale responses to small expected displacement amplitudes, but many patients did not generate the larger plantarflexion torques required at larger displacement amplitudes. Reduced torque at large amplitudes was associated with less agonist gastrocnemius IEMG, increased tibialis antagonist burst responses, and increased tibialis tonic background activity. 4. Levodopa further reduced the already low magnitude of initial torque and IEMG responses to displacement velocities and amplitudes in parkinsonian patients. The ability to scale postural responses to velocity feedback was not affected by levodopa, but the ability to scale responses to large displacement amplitudes based on central set was worsened by levodopa. Levodopa also significantly reduced the tonic, background levels of EMG, particularly the distal gastrocnemius and tibialis activity. 5. High baseline muscle tone was apparent in parkinsonian subjects from their high background EMG activity in quiet stance, especially in tibialis and quadriceps, and the slow initial velocity of center of mass falling in response to displacements. By reducing tone, levodopa reduced passive stiffness to perturbations without increasing EMG burst magnitudes, resulting in less resistance to external displacements and thus faster center of body mass (COM) displacements. 6. The biggest postural deficit in parkinsonian subjects was not in response latency, pattern, or reactive or predictive scaling of response magnitude, but in quickly generating an adequate level of postural force. Dopamine improved tonic background postural tone but further weakened automatic postural responses to external displacements. Thus the basal ganglia may participate in postural control by regulating appropriate levels of background postural tone and by enabling adequate force generation for resisting external displacements.


Cancer revoked: oncogenes as therapeutic targets.
Recent findings show that even the brief inactivation of a single oncogene might be sufficient to result in the sustained loss of a neoplastic phenotype. It is therefore possible that the targeted inactivation of oncogenes could be a specific and effective treatment for cancer. So why does oncogene inactivation cause tumour regression and will this be a generally successful approach for the treatment of human neoplasia?


The Intricate Interplay between Mechanisms Underlying Aging and Cancer.
Age is the major risk factor in the incidence of cancer, a hyperplastic disease associated with aging. Here, we discuss the complex interplay between mechanisms underlying aging and cancer as a reciprocal relationship. This relationship progresses with organismal age, follows the history of cell proliferation and senescence, is driven by common or antagonistic causes underlying aging and cancer in an age-dependent fashion, and is maintained via age-related convergent and divergent mechanisms. We summarize our knowledge of these mechanisms, outline the most important unanswered questions and suggest directions for future research.


Sortal anaphora resolution to enhance relation extraction from biomedical literature.
Entity coreference is common in biomedical literature and it can affect text understanding systems that rely on accurate identification of named entities, such as relation extraction and automatic summarization. Coreference resolution is a foundational yet challenging natural language processing task which, if performed successfully, is likely to enhance such systems significantly. In this paper, we propose a semantically oriented, rule-based method to resolve sortal anaphora, a specific type of coreference that forms the majority of coreference instances in biomedical literature. The method addresses all entity types and relies on linguistic components of SemRep, a broad-coverage biomedical relation extraction system. It has been incorporated into SemRep, extending its core semantic interpretation capability from sentence level to discourse level. We evaluated our sortal anaphora resolution method in several ways. The first evaluation specifically focused on sortal anaphora relations. Our methodology achieved a F1 score of 59.6 on the test portion of a manually annotated corpus of 320 Medline abstracts, a 4-fold improvement over the baseline method. Investigating the impact of sortal anaphora resolution on relation extraction, we found that the overall effect was positive, with 50 % of the changes involving uninformative relations being replaced by more specific and informative ones, while 35 % of the changes had no effect, and only 15 % were negative. We estimate that anaphora resolution results in changes in about 1.5 % of approximately 82 million semantic relations extracted from the entire PubMed. Our results demonstrate that a heavily semantic approach to sortal anaphora resolution is largely effective for biomedical literature. Our evaluation and error analysis highlight some areas for further improvements, such as coordination processing and intra-sentential antecedent selection.


Preoperative evaluation of peripheral nerve injuries: What is the place for ultrasound?
OBJECTIVE The purpose of this study was to evaluate the usefulness of ultrasound in the preoperative workup of peripheral nerve lesions and illustrate how nerve ultrasonography can be integrated in routine clinical and neurophysiological evaluation and in the management of focal peripheral nerve injuries. The diagnostic role and therapeutic implications of ultrasonography for different neuropathies are described. METHODS The authors analyzed the use of ultrasound in 119 entrapment, tumoral, posttraumatic, or postsurgical nerve injuries of limbs evaluated in 108 patients during 2013 and 2014. All patients were candidates for surgery, and in all cases the evaluation included clinical examination, electrodiagnostic studies (nerve conduction study and electromyography), and ultrasound nerve study. Ultrasound was used to explore the nerve fascicular echotexture, continuity, and surrounding tissues. The maximum cross-sectional area (CSA) and the presence of epineurial hyperechogenicity or intraneural hyper- or hypoechogenicity, of anatomical anomalies, dynamic nerve dislocations, or compressions were recorded. The concordance rate of neurophysiological and ultrasonographic data was analyzed, classifying ultrasound findings as confirming, contributive, or nonconfirming with respect to electrodiagnostic data. The correlation between maximum nerve CSA and neurophysiological severity degree in entrapment syndromes was statistically analyzed. RESULTS Ultrasonography confirmed electrodiagnostic findings in 36.1% of cases and showed a contributive role in the diagnosis and surgical planning in 53.8% of all cases; the findings were negative ("nonconfirming") in only 10.1% of the patients. In 16% of cases, ultrasound was not only contributive, but had a key diagnostic role in the presence of doubtful electrodiagnostic findings. The contributive role differed according to etiology, being higher for tumors (100%) and for posttraumatic or postsurgical neuropathies (72.2%) than for entrapment neuropathies (43.8%). CONCLUSIONS Ultrasound is a powerful, noninvasive tool for the examination of peripheral nerve injuries, and can guide diagnosis of and surgical strategy for focal peripheral nerve injuries. It allows direct visualization of the cause and extent of nerve lesions and finds its place between electrodiagnostic tests and exploratory surgery. It can provide invaluable information, such as the presence and extent of a mass, scar compression, or neuromas. The authors recommend it as a complement to routine clinical and neurophysiological evaluation and as the first-line imaging modality for masses of suspected nerve origin.


Human TCR alpha/beta+ CD4-CD8- double-negative T cells in patients with autoimmune lymphoproliferative syndrome express restricted Vbeta TCR diversity and are clonally related to CD8+ T cells.
The peripheral expansion of alpha/beta+-CD4-CD8- double negative (DN) T cells in patients with autoimmune lymphoproliferative syndrome (ALPS) is a consistent feature of this disease, and part of the diagnostic criteria of ALPS. The origin of these cells remains undetermined. They could derive from mature T cells that have lost coreceptor expression, or represent a special minor cell lineage. To investigate relationship of DN and single positive (SP) T cells in ALPS, we used Immunoscope technology to analyze the TCRVbeta repertoire diversity of sorted DN and SP T cells, and we performed CDR3 sequence analyses of matching clonotypes. We show that DN T cells express all the Vbeta gene families that are used by their SP counterparts, though they dominantly use some Vbeta genes. Analysis of CDR3 length distribution revealed a diverse polyclonal TCR repertoire for sorted CD4+ T cells, whereas both DN and CD8+ T cells showed a skewed TCR repertoire with oligoclonal expansions throughout most of the Vbeta families. CDR3 sequencing of matching clonotypes revealed a significant sharing of CDR3 sequences from selected Vbeta-Jbeta transcripts between DN and CD8+ T cells. Altogether, these data strongly argue for a CD8 origin of DN T cells in ALPS.


Design, Fabrication, and Testing of a Hybrid CMOS/PDMS Microsystem for Cell Culture and Incubation.
We discuss the design, fabrication, and testing of a hybrid microsystem for stand-alone cell culture and incubation. The micro-incubator is engineered through the integration of a silicon CMOS die for the heater and temperature sensor, with multilayer silicone (PDMS) structures namely, fluidic channels and a 1.5-mm diameter 12-muL culture well. A 90-mum-thick PDMS membrane covers the top of the culture well, acting as barrier to contaminants while at the same time allowing the cells to breath and exchange gases with the ambient environment. The packaging for the microsystem includes a flexible polyimide electronic ribbon cable and four fluidic ports that provide external interfaces to electrical energy, closed-loop sensing and electronic control as well as solid and liquid supplies. The complete structure has a size of (2.5times2.5times0.6) cm(3). We have employed the device to successfully culture BHK-21 cells autonomously over a three day period in ambient environment.


Protein contribution to plant salinity response and tolerance acquisition.
The review is focused on plant proteome response to salinity with respect to physiological aspects of plant salt stress response. The attention is paid to both osmotic and ionic effects of salinity stress on plants with respect to several protein functional groups. Therefore, the role of individual proteins involved in signalling, changes in gene expression, protein biosynthesis and degradation and the resulting changes in protein relative abundance in proteins involved in energy metabolism, redox metabolism, stress- and defence-related proteins, osmolyte metabolism, phytohormone, lipid and secondary metabolism, mechanical stress-related proteins as well as protein posttranslational modifications are discussed. Differences between salt-sensitive (glycophytes) and salt-tolerant (halophytes) plants are analysed with respect to differential salinity tolerance. In conclusion, contribution of proteomic studies to understanding plant salinity tolerance is summarised and discussed.


Impaired cerebellar synaptic plasticity and motor performance in mice lacking the mGluR4 subtype of metabotropic glutamate receptor.
The application of the glutamate analog L-2-amino-4-phosphonobutyric acid (L-AP4) to neurons produces a suppression of synaptic transmission. Although L-AP4 is a selective ligand at a subset of metabotropic glutamate receptors (mGluRs), the precise physiological role of the L-AP4-activated mGluRs remains primarily unknown. To provide a better understanding of the function of L-AP4 receptors, we have generated and studied knockout (KO) mice lacking the mGluR4 subtype of mGluR that displays high affinity for L-AP4. The mGluR4 mutant mice displayed normal spontaneous motor activity and were unimpaired on the bar cross test, indicating that disruption of the mGluR4 gene did not cause gross motor abnormalities, impairments of novelty-induced exploratory behaviors, or alterations in fine motor coordination. However, the mutant mice were deficient on the rotating rod motor-learning test, suggesting that mGluR4 KO mice may have an impaired ability to learn complex motor tasks. Patch-clamp and extracellular field recordings from Purkinje cells in cerebellar slices demonstrated that L-AP4 had no effect on synaptic responses in the mutant mice, whereas in the wild-type mice 100 microM L-AP4 produced a 23% depression of synaptic responses with an EC50 of 2.5 microM. An analysis of presynaptic short-term synaptic plasticity at the parallel fiber-->Purkinje cell synapse demonstrated that paired-pulse facilitation and post-tetanic potentiation were impaired in the mutant mice. In contrast, long-term depression (LTD) was not impaired. These results indicate that an important function of mGluR4 is to provide a presynaptic mechanism for maintaining synaptic efficacy during repetitive activation. The data also suggest that the presence of mGluR4 at the parallel fiber-->Purkinje cell synapse is required for maintaining normal motor function.