Vocal tract area functions and formant frequencies in opera tenors' modal and falsetto registers.
According to recent model investigations, vocal tract resonance is relevant to vocal registers. However, no experimental corroboration of this claim has been published so far. In the present investigation, ten professional tenors' vocal tract configurations were analyzed using MRI volumetry. All subjects produced a sustained tone on the pitch F4 (349 Hz) on the vowel /a/ (1) in modal and (2) in falsetto register. The area functions were estimated from the MRI data and their associated formant frequencies were calculated. In a second condition the same subjects repeated the same tasks in a sound treated room and their formant frequencies were estimated by means of inverse filtering. In both recordings similar formant frequencies were observed. Vocal tract shapes differed between modal and falsetto register. In modal as compared to falsetto the lip opening and the oral cavity were wider and the first formant frequency was higher. In this sense the presented results are in agreement with the claim that the formant frequencies differ between registers.


Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative.
Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI's Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.


Burnout risk in medical students in Spain using the Maslach Burnout Inventory-Student Survey.
It is questionable whether the Maslach Burnout is suitable for studying burnout prevalence in preclinical medical students because many questions are patient-centered and the students have little or no contact with patients. Among factors associated with burnout in medical students, the gender shows conflicting results. The first aim of this study was to investigate the prevalence of the risk of burnout in medical students in preclinical and clinical years of training, using the Maslach Burnout Inventory-Student Survey, specifically designed and validated to assess the burnout in university students, and secondly, to investigate the association between gender and burnout subscales. A cross-sectional study was carried out in a sample of 270 Spanish medical students-176 (65%) in the third year and 94 (35%) in the sixth year of training-using the Maslach Burnout Inventory-Student Survey questionnaire. Internal consistencies (Cronbach's alpha) for the three subscales on the whole sample were as follows: for exhaustion 0.78, cynicism 0.78, and efficacy 0.71. Moreover, the prevalence of burnout risk was significantly higher in sixth-year students 35 (37.5%) compared with students in third year of training 26 (14.8%) (χ(2) test, p < 0.0001). No significant association was found between gender and burnout subscales. The Maslach Burnout Inventory-Student Survey overcame difficulties encountered when students have little or no contact with patients. Our findings show that the risk of burnout prevalence doubled from the third year to sixth year of training and that gender was not significantly associated with any of the subscales of burnout.


Cannabidiol in medical marijuana: Research vistas and potential opportunities.
The high and increasing prevalence of medical marijuana consumption in the general population invites the need for quality evidence regarding its safety and efficacy. Herein, we synthesize extant literature pertaining to the phytocannabinoid cannabidiol (CBD) and its brain effects. The principle phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) and CBD are the major pharmacologically active cannabinoids. The effect of CBD on brain systems as well as on phenomenological measures (e.g. cognitive function) are distinct and in many cases opposite to that of Δ9-THC. Cannabidiol is without euphoriant properties, and exerts antipsychotic, anxiolytic, anti-seizure, as well as anti-inflammatory properties. It is essential to parcellate phytocannabinoids into their constituent moieties as the most abundant cannabinoid have differential effects on physiologic systems in psychopathology measures. Disparate findings and reports related to effects of cannabis consumption reflect differential relative concentration of Δ9-THC and CBD. Existing literature, notwithstanding its deficiencies, provides empirical support for the hypothesis that CBD may exert beneficial effects on brain effector systems/substrates subserving domain-based phenomenology. Interventional studies with purified CBD are warranted with a call to target-engagement proof-of-principle studies using the research domain criteria (RDoC) framework.


Display of Moving Parts of a Scene.
Methods for emphasizing the moving parts of a scene. By photographic or electronic means, a past image can be subtracted from the present one to emphasize the moving parts of a motion picture scene. Rhythms and patterns of motion become more noticeable, and changes in velocity can give an impression of accelerations and the force pattern.


The fragile X protein binds mRNAs involved in cancer progression and modulates metastasis formation.
The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression.


Panic disorder with agoraphobia associated with dizziness: characteristic symptoms and psychosocial sequelae.
The aim of this study was to assess the prevalence of symptoms of panic disorder in a representative community sample of people with dizziness and to compare the profile of those whose panic was consistently linked to attacks of dizziness with those in whom dizziness was just one of many, variable somatic symptoms of panic. Validated questionnaires assessing physical and psychological symptoms, occupational disability, and handicap were administered to 128 people reporting dizziness in an epidemiological survey. Nearly two thirds of the sample reported having panic attacks, and one in four met key criteria for panic disorder. People whose panic symptoms were consistently associated with dizziness reported higher rates of vertigo than those with panic unrelated to dizziness, and higher rates of fainting, agoraphobic behavior, and occupational disability than either comparison group. Explanation of perceptual-motor triggers for disorientation may increase the predictability of attacks, thus reducing vulnerability to dizziness-provoked panic.


Is There an Islamist Political Advantage?
There is a widespread presumption that Islamists have an advantage over their opponents when it comes to generating mass appeal and winning elections. The question remains, however, as to whether these advantages-or, what we refer to collectively as an Islamist political advantage-actually exist. We argue that-to the extent that Islamists have a political advantage-the primary source of this advantage is reputation rather than the provision of social services, organizational capacity, or ideological hegemony. Our purpose is not to dismiss the main sources of the Islamist governance advantage identified in scholarly literature and media accounts, but to suggest a different causal path whereby each of these factors individually and sometimes jointly promotes a reputation for Islamists as competent, trustworthy, and pure. It is this reputation for good governance that enables Islamists to distinguish themselves in the streets and at the ballot box.


Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.
We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.


Mapping stress in polycrystals with sub-10 nm spatial resolution.
From aircraft to electronic devices, and even in Formula One cars, stress is the main cause of degraded material performance and mechanical failure in applications incorporating thin films and coatings. Over the last two decades, the scientific community has searched for the mechanisms responsible for stress generation in films, with no consensus in sight. The main difficulty is that most current models of stress generation, while atomistic in nature, are based on macroscopic measurements. Here, we demonstrate a novel method for mapping the stress at the surface of polycrystals with sub-10 nm spatial resolution. This method consists of transforming elastic modulus maps measured by atomic force microscopy techniques into stress maps via the local stress-stiffening effect. The validity of this approach is supported by finite element modeling simulations. Our study reveals a strongly heterogeneous distribution of intrinsic stress in polycrystalline Au films, with gradients as high as 100 MPa nm-1 near the grain boundaries. Consequently, our study discloses the limited capacity of macroscopic stress assessments and standard tests to discriminate among models, and the great potential of nanometer-scale stress mapping.


Both early and late control sequences of SV40 and polyoma promote transcription of Escherichia coli gpt gene in transfected cells.
Eucaryotic expression vectors containing two selective markers, the herpes simplex 1 thymidine kinase gene (tk) and the Escherichia coli gpt gene (Eco gpt) coding for a xanthine-guanine phosphoribosyl-transferase ( XGPRT ) were constructed. These plasmids were used to transfect mouse Ltk- cells followed by selection of either tk+ or XGPRT + colonies. The transcription and maturation of the Eco gpt mRNA is dependent on the presence of a eucaryotic promoter sequence at its 5' end and on the presence of a viral intron and a poly(A) addition site at its 3' end ( Mulligan and Berg, 1980). Here, we report that both simian virus 40 (SV40) and polyoma early and late promoters permit the transcription of this gene integrated into the cellular genome. Polyoma DNA fragments lacking the TATA box, or both the TATA and CAAT boxes directing early transcription, efficiently promote Eco gpt expression. Furthermore, a fragment terminating approximately 300 nucleotides upstream of the initiation site of early RNA permits Eco gpt synthesis when the early strand is joined to the Eco gpt-coding strand. The SV40 early promoter is 2- to 3-fold more efficient than the controlling sequence of late transcription. These results strongly suggest that the switch from a predominance of early RNA to that of late RNA occurring after the onset of DNA replication is caused by the increase in the abundance of template and by the concomitant repression of early transcription by the T antigen. The presence of the tk gene in all the plasmids constructed permits the analysis of Eco gpt expression as a non-selected marker in tk+ clones selected for growth in HAT medium.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical significance of elevated alpha-fetoprotein in adults and children.
The aim of the current study is to identify underlying pathology associated with elevated serum alpha-fetoprotein (AFP; >20 ng/ml) among patients referred to a tertiary-care academic medical center with emphasis in liver diseases, hepatobiliary surgery, and liver transplantation. From May 1992 to April 1997, 386 patients (320 adults and 66 children) with elevated AFP (>20 ng/ml) were identified from the Medical Archival System (MARS) database at the University of Pittsburgh Medical Center. The medical records from all these patients were retrospectively reviewed. Radiological, pathological, and biochemical profiles were obtained at the time of documented elevated AFP. These patients included: 218 adults with malignancies, 102 adults without malignancies, 18 children and infants with malignancies, and 48 children and infants without malignancies. Thirty-two percent of adults were found to have raised AFP with liver disease and without hepatocellular carcinoma and 78% had some type of malignancy, predominantly hepatocellular carcinoma. Seventy-three percent of infants and children had elevated AFP without malignancy. Based on our findings, we recommend that all patients (adults, infants and children) with raised AFP of >20 ng/ml should undergo thorough evaluation to rule out malignant disease.


Ammonia and bicarbonate transport by rat cortical collecting ducts perfused in vitro.
We measured bicarbonate and ammonia transport by isolated perfused cortical collecting ducts from deoxycorticosterone-treated rats. With no ammonia in the perfusate and bath solutions, the collecting ducts secreted bicarbonate. The bicarbonate secretion was prevented when the rats were given 40 mM NH4Cl to drink. When 4 mM total ammonia was added to the perfusate and bath, the collecting ducts secreted ammonia and the direction of bicarbonate transport reversed toward absorption. Under those conditions the collected total ammonia concentration exceeded the value predicted by the diffusion-trapping model, assuming pH equilibrium. However, when carbonic anhydrase was added to the perfusate (to assure pH equilibrium), the collected total ammonia concentration decreased to the level predicted by the diffusion-trapping model. We conclude that rat cortical collecting ducts can secrete bicarbonate at substantial rates; the rate of bicarbonate secretion is modified by changes in the acid-base intake of the rats; ammonia secretion occurs by simple nonionic diffusion in this segment; the ammonia secretion is enhanced by the presence of acidic pH disequilibrium in the lumen; and ammonia in the perfusion and bath solutions inhibits bicarbonate secretion by rat cortical collecting ducts, a response that may be important for the regulation of renal bicarbonate excretion.


Priority Setting for Occupational Cancer Prevention.
Selecting priority occupational carcinogens is important for cancer prevention efforts; however, standardized selection methods are not available. The objective of this paper was to describe the methods used by CAREX Canada in 2015 to establish priorities for preventing occupational cancer, with a focus on exposure estimation and descriptive profiles. Four criteria were used in an expert assessment process to guide carcinogen prioritization: (1) the likelihood of presence and/or use in Canadian workplaces; (2) toxicity of the substance (strength of evidence for carcinogenicity and other health effects); (3) feasibility of producing a carcinogen profile and/or an occupational estimate; and (4) special interest from the public/scientific community. Carcinogens were ranked as high, medium or low priority based on specific conditions regarding these criteria, and stakeholder input was incorporated. Priorities were set separately for the creation of new carcinogen profiles and for new occupational exposure estimates. Overall, 246 agents were reviewed for inclusion in the occupational priorities list. For carcinogen profile generation, 103 were prioritized (11 high, 33 medium, and 59 low priority), and 36 carcinogens were deemed priorities for occupational exposure estimation (13 high, 17 medium, and 6 low priority). Prioritizing and ranking occupational carcinogens is required for a variety of purposes, including research, resource allocation at different jurisdictional levels, calculations of occupational cancer burden, and planning of CAREX-type projects in different countries. This paper outlines how this process was achieved in Canada; this may provide a model for other countries and jurisdictions as a part of occupational cancer prevention efforts.


A comparison of blue light and caffeine effects on cognitive function and alertness in humans.
The alerting effects of both caffeine and short wavelength (blue) light have been consistently reported. The ability of blue light to enhance alertness and cognitive function via non-image forming neuropathways have been suggested as a non-pharmacological countermeasure for drowsiness across a range of occupational settings. Here we compare and contrast the alerting and psychomotor effects of 240 mg of caffeine and a 1-h dose of ~40 lx blue light in a non-athletic population. Twenty-one healthy subjects performed a computer-based psychomotor vigilance test before and after each of four randomly assigned trial conditions performed on different days: white light/placebo; white light/240 mg caffeine; blue light/placebo; blue light/240 mg caffeine. The Karolinska Sleepiness Scale was used to assess subjective measures of alertness. Both the caffeine only and blue light only conditions enhanced accuracy in a visual reaction test requiring a decision and an additive effect was observed with respect to the fastest reaction times. However, in a test of executive function, where a distraction was included, caffeine exerted a negative effect on accuracy. Furthermore, the blue light only condition consistently outperformed caffeine when both congruent and incongruent distractions were presented. The visual reactions in the absence of a decision or distraction were also enhanced in the blue light only condition and this effect was most prominent in the blue-eyed participants. Overall, blue light and caffeine demonstrated distinct effects on aspects of psychomotor function and have the potential to positively influence a range of settings where cognitive function and alertness are important. Specifically, despite the widespread use of caffeine in competitive sporting environments, the possible impact of blue light has received no research attention.


Pattern of mutations that results in loss of reduced folate carrier function under antifolate selective pressure augmented by chemical mutagenesis.
Chemical mutagenesis with N-methyl-N-nitrosourea was employed to study the pattern of mutations in the reduced folate carrier (RFC1) that results in transport-related methotrexate resistance and to identify amino acid residues that are critical to carrier structure and/or function. Thirty-four methotrexate transport-defective L1210 leukemia cell lines were isolated with folic acid as the sole folate source under antifolate selective pressure. The RFC1 mRNA levels were comparable with, or not substantially decreased, in most of these cell lines relative to wild-type L1210 cells. The molecular basis for the transport defects was investigated by sequencing multiple RFC1 cDNA clones isolated from these mutants by reverse transcription-polymerase chain reaction, which encompassed the entire coding region. The mutations identified were further confirmed either by direct sequencing or, when applicable, by restriction analysis of total reverse transcription-polymerase chain reaction products. The majority of mutations (21) led to single amino acid substitutions that were in, or near, 9 of 12 predicted transmembrane domains, with the highest frequencies in the first, fifth, and eighth. There were no mutations in the sixth, ninth, and twelfth transmembrane domains. Glycine, serine, and arginine were the most frequently mutated residues. These data suggest that several transmembrane domains, rather than the amino- and carboxyl-termini, and the large intracellular loop between the sixth and seventh transmembrane domains play key roles as sites for RFC1 inactivation because of single point mutations. This panel of mutated cell lines offers an important resource for studies on RFC1 structure-function and for the evaluation of transport-related cross-resistance patterns with new-generation antifolate inhibitors of tetrahydrofolate cofactor-dependent enzymes.


Molecular and particulate depositions for regional myocardial flows in sheep.
The deposition of microspheres in small tissue regions is not strictly flow dependent. In comparison with the soluble flow marker 2-iododesmethylimipramine (IDMI), deposition of 16.5-microns microspheres was mildly but systematically biased into high flow regions of rabbit hearts (Bassingthwaighte JB, Malone MA, Moffett T-C, King RB, Little SE, Link JM, Krohn KA. Am J Physiol 1987;253 (Heart Circ Physiol 22):H184-H193). To examine the possibility of bias in larger hearts, a similar study was undertaken in sheep. 141Ce- and 103Ru-labeled 16.5-microns microspheres in one syringe and 125I- and 131I-DMI in another syringe were injected simultaneously into the left atrium of five open-chest sheep while obtaining reference blood samples from the femoral artery. In six other sheep, one microsphere type and one IDMI were used. Hearts were removed 1 minute after injection, cut into approximately 254 pieces averaging 217 mg, and regional deposition densities calculated for each tracer from the isotopic counts. Correlations in the five animals between the two differently labeled IDMIs and between the two microspheres were both greater than or equal to 0.98. In all 11 sheep, scatter plots of microsphere deposition densities versus IDMI densities showed that differences between microspheres and IDMI had substantially more scatter (0.84 less than r less than 0.98) but were not random. Microsphere depositions tended to be lower than IDMI depositions in low flow regions and higher in high flow regions, in accord with the expected bias that at a bifurcation a microsphere is most likely to enter the branch with higher flow. There was less bias ascribable to endomyocardial/epicardial maldistribution. Thus, while microsphere depositions appear to err systematically with respect to flow when the regions of interest are small enough that the diameters of their arterioles are only a few times those of the microspheres, microspheres are, in sheep as in rabbits, adequate for estimating regional flows.


Induction of tolerance by monoclonal antibody therapy.
A major goal in immunology has been to find a means of selectively abolishing an individual's potential to mount an immune response to certain antigens, while preserving responsiveness to others. The facility to induce such specific immunological unresponsiveness in an adult would have major implications for tissue-grafting, the control of allergy and for treatment of autoimmune disease. Classical work has shown that immunosuppressive regimes, such as irradiation, anti-lymphocyte globulin or thoracic duct drainage, may facilitate tolerance induction. We describe here a technique by which the immune system of mice can be manipulated to be tolerant to certain protein antigens by administering these during a brief pulse of treatment with a monoclonal antibody directed to the L3T4 molecule on helper T lymphocytes. This technique has the potential to form the basis of a novel generalized means of tolerance induction.


Histamine H3 receptor activation reduces the impairment in prepulse inhibition (PPI) of the acoustic startle response and Akt phosphorylation induced by MK-801 (dizocilpine), antagonist at N-Methyl-d-Aspartate (NMDA) receptors.
We have investigated the effect of the local activation of histamine H3 receptors (H3Rs) in the rat prefrontal cortex (PFCx) on the impairment of pre-pulse inhibition (PPI) of the startle response induced by the systemic administration of MK-801, antagonist at glutamate N-Methyl-d-Aspartate (NMDA) receptors, and the possible functional interaction between H3Rs and MK-801 on PFCx dopaminergic transmission. Infusion of the H3R agonist RAMH (19.8 ng/1 μl) into the PFCx reduced or prevented the inhibition by MK-801 (0.15 mg/kg, ip) of PPI evoked by different auditory stimulus intensities (5, 10 and 15 dB), and the RAMH effect was blocked by the H3R antagonist/inverse agonist ciproxifan (30.6 ng/1 μl). MK-801 inhibited [3H]-dopamine uptake (-45.4 ± 2.1%) and release (-32.8 ± 2.6%) in PFCx synaptosomes or slices, respectively, and molecular modeling indicated that MK-801 binds to and blocks the rat and human dopamine transporters. However, H3R activation had no effect on the inhibitory action of MK-801 on dopamine uptake and release. In PFCx slices, MK-801 and the activation of H3Rs or dopamine D1 receptors (D1Rs) stimulated ERK-1/2 and Akt phosphorylation. The co-activation of D1Rs and H3Rs prevented ERK-1/2 and Akt phosphorylation, and H3R activation or D1R blockade prevented the effect of MK-801. In ex vivo experiments, the intracortical infusion of the D1R agonist SKF-81297 (37 ng/1 μl) or the H3R agonist RAMH increased Akt phosphorylation, prevented by D1R/H3R co-activation. These results indicate that MK-801 enhances dopaminergic transmission in the PFCx, and that H3R activation counteracts the post-synaptic actions of dopamine.


Sex-dependent effects of letrozole on anxiety in middle-aged rats.
Aromatase catalyzes the conversion of testosterone to estradiol and is involved in the physiological effects of sex hormones on brain function. Animal experiments have shown that the aromatase inhibitor, letrozole, can induce anxiety in young ovariectomized females that are used as a model of aging. Whether or not these effects would be similar in intact middle-aged animals is unknown. The aim of our study was to analyze the effects of letrozole on anxiety in middle-aged rats of both sexes. Fifteen month old male and female rats were treated daily with either letrozole or vehicle for 2 weeks. The elevated plus maze was used to test anxiety-like behaviour. Sex differences were found not only in plasma concentrations of testosterone but also in the effects of letrozole treatment on plasma testosterone (P<.05). The interaction between sex and treatment was also proven in locomotor activity (P<.05) and time spent in the open arms of the elevated plus maze (P<.05). Letrozole-treated male rats spent 95% less time in the open arms of the elevated plus maze than the control rats did (P<.05) suggesting an anxiogenic effect of aromatase inhibition. This difference was not found between letrozole-treated and vehicle-treated females. In contrast to previous experiments on young animals, letrozole seems to induce anxiety in male but not in female middle-aged rats. This sex-specific effect might be related to sex differences of oestrogen and androgen signalling in aging brains. These results should be taken into account in clinical applications of letrozole, especially in men.


Complementary and alternative therapies for back pain II.
Back and neck pain are important health problems with serious societal and economic implications. Conventional treatments have been shown to have limited benefit in improving patient outcomes. Complementary and Alternative Medicine (CAM) therapies offer additional options in the management of low back and neck pain. Many trials evaluating CAM therapies have poor quality and inconsistent results. To systematically review the efficacy, effectiveness, cost-effectiveness, and harms of acupuncture, spinal manipulation, mobilization, and massage techniques in management of back, neck, and/or thoracic pain. MEDLINE, Cochrane Central, Cochrane Database of Systematic Reviews, CINAHL, and EMBASE were searched up to 2010; unpublished literature and reference lists of relevant articles were also searched. study selection: All records were screened by two independent reviewers. Primary reports of comparative efficacy, effectiveness, harms, and/or economic evaluations from randomized controlled trials (RCTs) of the CAM therapies in adults (age ≥ 18 years) with back, neck, or thoracic pain were eligible. Non-randomized controlled trials and observational studies (case-control, cohort, cross-sectional) comparing harms were also included. Reviews, case reports, editorials, commentaries or letters were excluded. Two independent reviewers using a predefined form extracted data on study, participants, treatments, and outcome characteristics. 265 RCTs and 5 non-RCTs were included. Acupuncture for chronic nonspecific low back pain was associated with significantly lower pain intensity than placebo but only immediately post-treatment (VAS: -0.59, 95 percent CI: -0.93, -0.25). However, acupuncture was not different from placebo in post-treatment disability, pain medication intake, or global improvement in chronic nonspecific low back pain. Acupuncture did not differ from sham-acupuncture in reducing chronic non-specific neck pain immediately after treatment (VAS: 0.24, 95 percent CI: -1.20, 0.73). Acupuncture was superior to no treatment in improving pain intensity (VAS: -1.19, 95 percent CI: 95 percent CI: -2.17, -0.21), disability (PDI), functioning (HFAQ), well-being (SF-36), and range of mobility (extension, flexion), immediately after the treatment. In general, trials that applied sham-acupuncture tended to produce negative results (i.e., statistically non-significant) compared to trials that applied other types of placebo (e.g., TENS, medication, laser). Results regarding comparisons with other active treatments (pain medication, mobilization, laser therapy) were less consistent Acupuncture was more cost-effective compared to usual care or no treatment for patients with chronic back pain. For both low back and neck pain, manipulation was significantly better than placebo or no treatment in reducing pain immediately or short-term after the end of treatment. Manipulation was also better than acupuncture in improving pain and function in chronic nonspecific low back pain. Results from studies comparing manipulation to massage, medication, or physiotherapy were inconsistent, either in favor of manipulation or indicating no significant difference between the two treatments. Findings of studies regarding costs of manipulation relative to other therapies were inconsistent. Mobilization was superior to no treatment but not different from placebo in reducing low back pain or spinal flexibility after the treatment. Mobilization was better than physiotherapy in reducing low back pain (VAS: -0.50, 95 percent CI: -0.70, -0.30) and disability (Oswestry: -4.93, 95 percent CI: -5.91, -3.96). In subjects with acute or subacute neck pain, mobilization compared to placebo significantly reduced neck pain. Mobilization and placebo did not differ in subjects with chronic neck pain. Massage was superior to placebo or no treatment in reducing pain and disability only amongst subjects with acute/sub-acute low back pain. Massage was also significantly better than physical therapy in improving back pain (VAS: -2.11, 95 percent CI: -3.15, -1.07) or disability. For subjects with neck pain, massage was better than no treatment, placebo, or exercise in improving pain or disability, but not neck flexibility. Some evidence indicated higher costs for massage use compared to general practitioner care for low back pain. Reporting of harms in RCTs was poor and inconsistent. Subjects receiving CAM therapies reported soreness or bleeding on the site of application after acupuncture and worsening of pain after manipulation or massage. In two case-control studies cervical manipulation was shown to be significantly associated with vertebral artery dissection or vertebrobasilar vascular accident. Evidence was of poor to moderate grade and most of it pertained to chronic nonspecific pain, making it difficult to draw more definitive conclusions regarding benefits and harms of CAM therapies in subjects with acute/subacute, mixed, or unknown duration of pain. The benefit of CAM treatments was mostly evident immediately or shortly after the end of the treatment and then faded with time. Very few studies reported long-term outcomes. There was insufficient data to explore subgroup effects. The trial results were inconsistent due probably to methodological and clinical diversity, thereby limiting the extent of quantitative synthesis and complicating interpretation of trial results. Strong efforts are warranted to improve the conduct methodology and reporting quality of primary studies of CAM therapies. Future well powered head to head comparisons of CAM treatments and trials comparing CAM to widely used active treatments that report on all clinically relevant outcomes are needed to draw better conclusions.


The efficiency of a new automated mosquito larval counter and its impact on larval survival.
To achieve consistent and standardized rearing for mosquito immature stages, it is crucial to control the initial number of larvae present in each larval tray. In addition, maintaining an optimal and synchronized development rate of larvae is essential to maximize the pupal production and optimize male sorting in a mass-rearing setting. Manual counting is labor intensive, time consuming and error prone. Therefore, this study aimed to investigate the use of a customized automated counter for the quantification of mosquito larvae. The present prototype of the mosquito larval counter uses a single counting channel consisting of three parts: a larvae dispenser, an electronic counting unit and computer control software. After the separation of the larvae from eggs and debris, batches of different numbers of Aedes aegypti first instar larvae were manually counted and introduced into the counter through the upper loading funnel and channeled out from the bottom of the counter by gravitational flow. The accuracy and repeatability of the mosquito larval counter were determined in relation to larval density and water quality. We also investigated its impact on larval survival. Results showed an impact of larval density and water quality on the accuracy of the device. A -6% error and a repeatability of +/- 2.56% average value were achieved with larval densities up to 10 larvae/mL of clean water. Moreover, the use of the mosquito larval counter did not have any effect on larval survival or development. Under recommended conditions, the mosquito larval counter can be used to enumerate the number of mosquito larvae at a given density. However, future developments involving the use of multiple channels or larger input larvae container would help to expand its use in large-scale facilities.


ESR analyses of picket fence MnII and 6th ligand coordinated FeIII porphyrins (S = 5/2) and a CoII(hfac) complex (S = 3/2) with sizable ZFS parameters revisited: a full spin Hamiltonian approach and quantum chemical calculations.
The fictitious spin-1/2 (effective spin-1/2) Hamiltonian approach has been the putative method to analyze the conventional fine-structure/hyperfine ESR spectra of high spin metallocomplexes with sizable zero-field splitting (ZFS) tensors since the early 1950s, and the approach gives salient principal geff-values far from g = 2 without explicitly affording their ZFS values in most cases. The experimental geff-values thus determined, however, never agree with those (gtrue-values) of the true principal g-tensors, which are obtainable from reliable quantum chemical calculations. We have recently derived exact or extremely accurate analytical expressions for the geff/gtrue relationships for the spin quantum number S's up to S = 7/2 (T. Yamane et al., Phys. Chem. Chem. Phys., 2017, 19, 24769-24791). In this work, we have removed the limitation of the collinearity between g- and ZFS tensors and derived the generalized geff/gtrue relationships. To illustrate the usefulness of the present approach, we have revisited important typical high spin systems with large ZFS values such as picket fence metalloporphyrins with MnII (S = 5/2) (Q. Yu et al., Dalton Trans., 2015, 44, 9382-9390), a 6th ligand coordinated porphyrin with FeIII (S = 5/2) (Y. Ide et al., Dalton Trans., 2017, 46, 242-249) and a pseudo-octahedral CoII (S = 3/2)(hfac)2 complex (D. V. Korchagin et al., Dalton Trans., 2017, 46, 7540-7548), completing the ESR spectral and magnetic susceptibility analyses and gaining significant physical insights into their electronic structures. The off-principal axis extra peaks overlooked in the documented spectra of the picket fence MnII porphyrins have fully been assigned, affording their accurate true g-, hyperfine and ZFS tensors, for the first time. For the CoII complex, the occurrence of the non-collinearity between the g- and ZFS tensors has been discussed by using the generalized geff/gtrue relationships. We have attempted to carry out reliable DFT-based and ab initio quantum chemical calculations of their magnetic tensors, in which spin-orbit couplings are incorporated, reproducing the experimental true tensors. We emphasize that the incorporation of multi-reference nature in the electron configuration is important to interpret the magnetic tensors for the CoII complex.


Effect of Tribulus terrestris in mercuric chloride-induced renal accumulation of mercury and nephrotoxicity in rat.
Mercury generates free radicals and subsequently increases oxidative stress, which leads to renal injury. Tribulus terrestris (TT) has good anti-inflammatory and antioxidant properties. Hydroalcoholic extract of different dose of TT was evaluated against mercuric chloride-induced nephrotoxicity. Rats (n = 6) were treated with TT at doses of 100, 200, and 300 mg/kg. Drugs were administered orally for 7 days. Single dose of mercuric chloride (5 mg/kg, intraperitoneal) on the 5th day caused significant elevation of blood urea nitrogen, serum creatinine, malondialdehyde, liver fatty acid binding protein, kidney injury molecule-1, and kidney mercury level and fall in glutathione, superoxide dismutase, glutathione peroxidase, and histopathological changes in disease control as compared to normal control group (P < 0.001). Dose of TT 200 and 300 mg/kg significantly (P < 0.001) prevented the renal injury, and mercury accumulation in kidney tissues significantly decreases in higher dose, i.e., 300 mg/kg as compared to control group. Our result indicates that the treatment of TT exerted significant protection against renal damage induced by mercuric chloride possibly due to its antioxidant and anti-inflammatory properties and by decreasing the renal accumulation of mercury.


Sequence of excitation as a factor in sympathetic-parasympathetic interactions in the heart.
We determined the influence of differences in the time of initiation of sympathetic and vagal stimulation (both at 10 Hz) on the cardiac autonomic interactions in 16 open-chest anesthetized dogs. We always ended the concurrent sympathetic and vagal stimulations simultaneously. Sympathetic stimulation alone for 1 minute increased heart rate by 90 +/- 7 (mean +/- SEM) beats per minute, and vagal stimulation alone for 1 minute decreased heart rate by 67 +/- 5 beats per minute; i.e., the algebraic sum of these responses was an increase of 23 beats per minute. However, combined sympathetic and vagal stimulation for 1 minute actually decreased heart rate by 35 beats per minute; i.e., the vagal effects predominated. When vagal stimulation was initiated first, the chronotropic responses to combined stimulation were not significantly affected by the duration of antecedent vagal stimulation. However, when sympathetic stimulation was initiated first, the vagal predominance (disparity between the summated individual responses and the combined response) progressively diminished as we increased the duration of antecedent sympathetic stimulation. The vagal predominance diminished from a value of 67 +/- 21 beats per minute when the stimulations were initiated simultaneously to a value of 37 +/- 21 beats per minute when the duration of antecedent sympathetic stimulation was 10 minutes. Sympathetic stimulation releases not only norepinephrine but also neuropeptide Y, and this neuropeptide inhibits vagal neurotransmission. Our data suggest, therefore, that the longer the antecedent sympathetic stimulation, the greater the inhibition of vagal neurotransmission (presumably by the neuropeptide Y) and, therefore, the less pronounced the vagal predominance.


Improved Simulation of Electrodiffusion in the Node of Ranvier by Mesh Adaptation.
In neural structures with complex geometries, numerical resolution of the Poisson-Nernst-Planck (PNP) equations is necessary to accurately model electrodiffusion. This formalism allows one to describe ionic concentrations and the electric field (even away from the membrane) with arbitrary spatial and temporal resolution which is impossible to achieve with models relying on cable theory. However, solving the PNP equations on complex geometries involves handling intricate numerical difficulties related either to the spatial discretization, temporal discretization or the resolution of the linearized systems, often requiring large computational resources which have limited the use of this approach. In the present paper, we investigate the best ways to use the finite elements method (FEM) to solve the PNP equations on domains with discontinuous properties (such as occur at the membrane-cytoplasm interface). 1) Using a simple 2D geometry to allow comparison with analytical solution, we show that mesh adaptation is a very (if not the most) efficient way to obtain accurate solutions while limiting the computational efforts, 2) We use mesh adaptation in a 3D model of a node of Ranvier to reveal details of the solution which are nearly impossible to resolve with other modelling techniques. For instance, we exhibit a non linear distribution of the electric potential within the membrane due to the non uniform width of the myelin and investigate its impact on the spatial profile of the electric field in the Debye layer.


Hemodynamic basis for the acute cardiac effects of troglitazone in isolated perfused rat hearts.
Troglitazone is a thiazolidinedione used for the treatment of NIDDM and potentially for other insulin-resistant disease states. Troglitazone has recently been shown to increase cardiac output and stroke volume in human subjects. These actions are thought to be mediated by the reduction of peripheral resistance, but a potential direct effect on cardiac function has not been studied. Therefore, we investigated the direct cardiac hemodynamic effects of troglitazone in isolated perfused rat hearts. Five groups of hearts were studied. Hearts were tested under isovolumetric contraction with a constant coronary flow, and troglitazone (0.2, 0.5, and 1.0 micromol) was administered by bolus injection. Peak isovolumetric left ventricular pressure (LVPmax), peak rate of rise of LVP (dP/dt(max)), and peak rate of fall of LVP (dP/dt(min)) were significantly increased 1 min after troglitazone administration in a dose-dependent manner, while the heart rate (HR) and coronary perfusion pressure (CPP) were significantly decreased (P < 0.05). HR was then fixed by pacing and/or CPP was fixed with nitroprusside to eliminate any effect of the two variables on the action of troglitazone. With constant HR and/or constant CPP, the effect of troglitazone on LVPmax, dP/dt(max), and dP/dt(min) was still unchanged. In addition, the positive inotropic, positive lusitropic, and negative chronotropic actions of troglitazone were not influenced even when hearts were pretreated with prazosin, propranolol, or nifedipine. In conclusion, troglitazone has direct positive inotropic, positive lusitropic, negative chronotropic, and coronary artery dilating effects. The inotropic and chronotropic actions of troglitazone are not mediated via adrenergic receptors or calcium channels. These findings have important clinical implications for diabetic patients with congestive heart failure.


Use estimates of in-feed antimicrobials in swine production in the United States.
When considering the development of antimicrobial resistance in food animals, comparing gross use estimates of different antimicrobials is of little value due to differences in potencies, duration of activity, relative effect on target and commensal bacteria, and mechanisms of resistance. However, it may be valuable to understand quantities of different antimicrobials used in different ages of swine and for what applications. Therefore, the objective of this project was to construct an estimate of antimicrobial use through the feed in swine production in the United States. Estimates were based on data from the National Animal Health Monitoring System (NAHMS) Swine 2006 Study and from a 2009 survey of swine-exclusive practitioners. Inputs consisted of number of pigs in a production phase, feed intake per day, dose of the antimicrobial in the feed, and duration of administration. Calculations were performed for a total of 102 combinations of antimicrobials (n=17), production phases (n=2), and reasons for use (n=3). Calculations were first conducted on farm-level data, and then extrapolated to the U.S. swine population. Among the nursery phase estimates, chlortetracycline had the largest estimate of use, followed by oxytetracycline and tilmicosin. In the grower/finisher phase, chlortetracycline also had the largest use estimate, followed by tylosin and oxytetracycline. As an annual industry estimate for all phases, chlortetracycline had the highest estimated use at 533,973 kg. The second and third highest estimates were tylosin and oxytetracycline with estimated annual uses of 165,803 kg and 154,956 kg, respectively. The estimates presented here were constructed to accurately reflect available data related to production practices, and to provide an example of a scientific approach to estimating use of compounds in production animals.


Seeing and ballistic pointing at perisaccadic targets.
We studied the effects of visual references and the level of illumination on the localization of stimuli flashed briefly near the start of saccades. A translucent shutter made it possible to remove visual references, but admit light, at different times after saccadic onset. The results show that post-saccadic visual references are not necessary for compression: a consistent compression of verbally reported relative stimulus distances is found at all shutter latencies and at all post-shutter levels of illumination. They also show that positions indicated by blind pointing show no compression except when visual references remain in view for a substantial time after saccades. These results confirm that the visual system uses multiple representations of space and suggest that it weights them differently for different tasks and different viewing conditions. No single map is used exclusively for conscious perception or for motor action, and conscious perception is always subject to compression at the time of saccades.


Childhood, adolescent and early adult body mass index in relation to adult mortality: results from the British 1946 birth cohort.
Adult body mass index (BMI) has been consistently related to mortality, but little is known about the impact of earlier life BMI on adult mortality. The aim is to investigate the impact of childhood, adolescent and early adult BMI on premature adult all-cause mortality. The British 1946 cohort study was used to assess the association of BMI in childhood, adolescence and adulthood with mortality 26-60 years (332 deaths). 4462 (83%) respondents were available for analysis at age 26 years. Splines were used in Cox regression to model the associations between BMI and mortality. In both genders, adult BMI from 20 years onwards showed a consistent U-shaped relationship with adult mortality (overall p value <0.05 for BMI at ages 20, 26 and 36 years). In women, a similar relationship was observed for adolescent BMI at 15 years (p=0.02); the HR comparing women with low BMI (2 SDs below mean) versus mean BMI was 2.96 (95% CI 1.26 to 6.97). The corresponding HR for women with BMI 2 SDs above the mean was 1.97 (0.95 to 4.10). BMI in childhood was generally not associated with adult mortality except female BMI at 4 years where a U-shaped relationship was observed (p=0.02); HR for BMI 2 SDs below mean versus mean was 2.13 (0.97 to 4.70) and the corresponding HR for 2 SDs above the mean was 1.67 (0.85 to 3.28). This association was not attenuated by subsequent BMI change or mediators. High and low BMI from early adulthood were related to adult premature mortality suggesting that promoting a normal weight in early adulthood could prevent premature mortality.


Acquired immunodeficiency syndrome-associated malignancies.
Acquired immunodeficiency syndrome (AIDS)-associated malignancies are a concern to all physicians. Because patients usually are seen initially by nonspecialists, primary care physicians, especially, may find useful information about AIDS-related malignancy. Cancers remain a part of the clinical definition of AIDS. Kaposi's sarcoma (KS) and non-Hodgkin's lymphomas are the malignancies most frequently seen in AIDS. Acquired immunodeficiency syndrome KS occurs in young men between 20 and 40 years of age, and involves the skin in more than 90% of patients. Visceral dissemination is common. The prognosis is related to immune functional status and the extent of disease involvement. Acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma is generally a B-cell malignancy. Advanced disease at presentation and proclivity for central nervous system involvement are characteristic. Knowledge of the common manifestations of these cancers, methods of diagnosis, and potential treatment options is important for physicians.


Hydrophobicity Varying with Temperature, Pressure, and Salt Concentration.
Temperature-, pressure-, and salt-concentration-induced variations in the solubility of small nonpolar solutes in aqueous solution and the corresponding variations in the solvent-induced pair attraction between such solute molecules are investigated. The variations in the solvation free energy of a solute and those in the solvent-induced pair attraction are well reproduced by a mean-field approximation in which the repulsive cores of solute molecules are treated as hard spheres and the mean-field energy of a solute molecule is taken to be the average potential energy that the solute molecule feels in solution. The mechanisms of variation in the solvation free energy and those of variation in the solvent-induced pair potential, with increasing temperature, pressure, and salt concentration, are clarified. Correlations between the solvation free energy and the solvent-induced pair potential at a contact distance in temperature, pressure, and salt concentration variations are near linear in any mode of variation, but the slope of the linear relation is dependent on the mode of variation and is determined by a ratio of the solvation thermodynamic quantities characteristic of each mode of variation.


Interrelations between translation and general mRNA degradation in yeast.
Messenger RNA (mRNA) degradation is an important element of gene expression that can be modulated by alterations in translation, such as reductions in initiation or elongation rates. Reducing translation initiation strongly affects mRNA degradation by driving mRNA toward the assembly of a decapping complex, leading to decapping. While mRNA stability decreases as a consequence of translational inhibition, in apparent contradiction several external stresses both inhibit translation initiation and stabilize mRNA. A key difference in these processes is that stresses induce multiple responses, one of which stabilizes mRNAs at the initial and rate-limiting step of general mRNA decay. Because this increase in mRNA stability is directly induced by stress, it is independent of the translational effects of stress, which provide the cell with an opportunity to assess its response to changing environmental conditions. After assessment, the cell can store mRNAs, reinitiate their translation or, alternatively, embark on a program of enhanced mRNA decay en masse. Finally, recent results suggest that mRNA decay is not limited to non-translating messages and can occur when ribosomes are not initiating but are still elongating on mRNA. This review will discuss the models for the mechanisms of these processes and recent developments in understanding the relationship between translation and general mRNA degradation, with a focus on yeast as a model system.


Internalizing disorders and leukocyte telomere erosion: a prospective study of depression, generalized anxiety disorder and post-traumatic stress disorder.
There is evidence that persistent psychiatric disorders lead to age-related disease and premature mortality. Telomere length has emerged as a promising biomarker in studies that test the hypothesis that internalizing psychiatric disorders are associated with accumulating cellular damage. We tested the association between the persistence of internalizing disorders (depression, generalized anxiety disorder and post-traumatic stress disorder) and leukocyte telomere length (LTL) in the prospective longitudinal Dunedin Study (n=1037). Analyses showed that the persistence of internalizing disorders across repeated assessments from ages 11 to 38 years predicted shorter LTL at age 38 years in a dose-response manner, specifically in men (β=-0.137, 95% confidence interval (CI): -0.232, -0.042, P=0.005). This association was not accounted for by alternative explanatory factors, including childhood maltreatment, tobacco smoking, substance dependence, psychiatric medication use, poor physical health or low socioeconomic status. Additional analyses using DNA from blood collected at two time points (ages 26 and 38 years) showed that LTL erosion was accelerated among men who were diagnosed with internalizing disorder in the interim (β=-0.111, 95% CI: -0.184, -0.037, P=0.003). No significant associations were found among women in any analysis, highlighting potential sex differences in internalizing-related telomere biology. These findings point to a potential mechanism linking internalizing disorders to accelerated biological aging in the first half of the life course, particularly in men. Because internalizing disorders are treatable, the findings suggest the hypothesis that treating psychiatric disorders in the first half of the life course may reduce the population burden of age-related disease and extend health expectancy.


Morphology of human Fallopian tubes after infection with Mycoplasma genitalium and Mycoplasma hominis--in vitro organ culture study.
Female infertility can be caused by scarring and occlusion of the Fallopian tubes. Sexually transmitted bacteria can damage the delicate epithelial layer of human Fallopian tubes (HFT). Genital mycoplasmas are associated with human reproductive failure. Yet, there is not enough evidence that mycoplasmas can cause tubal factor infertility. We analysed the effects of infections with Mycoplasma hominis and Mycoplasma genitalium on the HFT epithelium and compared them with the effects of infections with genital pathogens: Chlamydia trachomatis and Neisseria gonorrhoeae. We used an in vitro model in which pieces of normal HFT were infected with different bacteria, and the outcome of the infections was analysed by scanning electron microscopy (SEM) and confocal microscopy. The presence of M. hominis did not cause any morphological changes of the epithelium of HFT. Noticeable changes in the morphology of the ciliated cells were observed in M. genitalium-infected tissue. Five days post-infection, the cilia were abnormally swollen and some of the ciliated cells fell off the epithelium. These effects could be inhibited by pre-incubation of M. genitalium with antibody directed against the C-terminal part of the adhesion protein MgPa before infection of HFT organ culture. We have shown that the presence of M. genitalium, but not M. hominis, in the HFT organ culture affected the epithelium and resulted in cilia damage. The effect of infection with M. genitalium on the HFT was, however, very moderate when compared with the extensive damage of the epithelium caused by N. gonorrhoeae or C. trachomatis.


Conjugation of an scFab domain to the oligomeric HIV envelope protein for use in immune targeting.
A promising strategy for the enhancement of vaccine-mediated immune responses is by directly targeting protein antigens to immune cells. Targeting of antigens to the dendritic cell (DC) molecule Clec9A has been shown to enhance antibody affinity and titers for model antigens, and influenza and enterovirus antigens, and may be advantageous for immunogens that otherwise fail to elicit antibodies with sufficient titers and breadth for broad protection, such as the envelope protein (Env) of HIV. Previously employed targeting strategies often utilize receptor-specific antibodies, however it is impractical to conjugate a bivalent IgG antibody to oligomeric antigens, including HIV Env trimers. Here we designed single chain variable fragment (scFv) and single chain Fab (scFab) constructs of a Clec9A-targeting antibody, expressed as genetically fused conjugates with the soluble ectodomain of Env, gp140. This conjugation did not affect the presentation of Env neutralising antibody epitopes. The scFab moiety was shown to be more stable than scFv, and in the context of gp140 fusions, was able to mediate better binding to recombinant and cell surface-expressed Clec9A, although the level of binding to cell-surface Clec9A was lower than that of the anti-Clec9A IgG. However, binding to Clec9A on the surface of DCs was not detected. Mouse immunization experiments suggested that the Clec9A-binding activity of the scFab-gp140 conjugate was insufficient to enhance Env-specific antibody responses. This is an important first proof of principle study demonstrating the conjugation of a scFab to an oligomeric protein antigen, and that an scFab displays better antigen binding than the corresponding scFv. Future developments of this technique that increase the scFab affinity will provide a valuable means to target oligomeric proteins to cell surface antigens of interest, improving vaccine-generated immune responses.


Sleep environment risks for younger and older infants.
Sudden infant death syndrome and other sleep-related causes of infant mortality have several known risk factors. Less is known about the association of those risk factors at different times during infancy. Our objective was to determine any associations between risk factors for sleep-related deaths at different ages. A cross-sectional study of sleep-related infant deaths from 24 states during 2004-2012 contained in the National Center for the Review and Prevention of Child Deaths Case Reporting System, a database of death reports from state child death review teams. The main exposure was age, divided into younger (0-3 months) and older (4 months to 364 days) infants. The primary outcomes were bed-sharing, objects in the sleep environment, location (eg, adult bed), and position (eg, prone). A total of 8207 deaths were analyzed. Younger victims were more likely bed-sharing (73.8% vs. 58.9%, P < .001) and sleeping in an adult bed/on a person (51.6% vs. 43.8%, P < .001). A higher percentage of older victims had an object in the sleep environment (39.4% vs. 33.5%, P < .001) and changed position from side/back to prone (18.4% vs. 13.8%, P < .001). Multivariable regression confirmed these associations. Risk factors for sleep-related infant deaths may be different for different age groups. The predominant risk factor for younger infants is bed-sharing, whereas rolling into objects in the sleep area is the predominant risk factor for older infants. Parents should be warned about the dangers of these specific risk factors appropriate to their infant's age.


Beyond the Cell Cycle: Enhancing the Immune Surveillance of Tumors Via CDK4/6 Inhibition.
Inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6) were originally designed to block proliferation and cell cycle progression of cancer cells in which the activity of these kinases is dysregulated. CDK4/6 inhibitors have already been FDA approved for the treatment of estrogen receptor (ER)-positive breast cancer and are being tested in numerous other cancer types. However, several recent studies have identified novel effects of CDK4/6 inhibitors on tumor growth, most notably an indirect effect resulting from the activation of immune surveillance. This Perspective discusses these recent observations, including the effects that CDK4/6 inhibitors may have on immune cells themselves. It is likely that CDK4/6 inhibitors will have a broader impact than their expected induction of cell cycle arrest in the treatment of human cancers. Mol Cancer Res; 16(10); 1454-7. ©2018 AACR.


Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis.
We have examined the hypothesis that neuronal programmed cell death requires a genetic program; we used a model wherein rat sympathetic neurons maintained in vitro are deprived of NGF and subsequently undergo apoptosis. To evaluate gene expression potentially necessary for this process, we used a PCR-based technique and in situ hybridization; patterns of general gene repression and selective gene induction were identified in NGF-deprived neurons. A temporal cascade of induced genes included "immediate early genes," which were remarkable in that their induction occurred hours after the initial stimulus of NGF removal and the synthesis of some required ongoing protein synthesis. The cascade also included the cell cycle gene c-myb and the genes encoding the extracellular matrix proteases transin and collagenase. Concurrent in situ hybridization and nuclear staining revealed that while c-jun was induced in most neurons, c-fos induction was restricted to neurons undergoing chromatin condensation, a hallmark of apoptosis. To evaluate the functional role of the proteins encoded by these genes, neutralizing antibodies were injected into neurons. Antibodies specific for either c-Jun or the Fos family (c-Fos, Fos B, Fra-1, and Fra-2) protected NGF-deprived neurons from apoptosis, whereas antibodies specific for Jun B, Jun D, or three nonimmune antibody preparations had no protective effect. Because these induced genes encode proteins ranging from a transcription factor necessary for death to proteases likely involved in tissue remodeling concurrent with death, these data may outline a genetic program responsible for neuronal programmed cell death.


Beta-aminoisobutyric acid is released by contracting human skeletal muscle and lowers insulin release from INS-1 832/3 cells by mediating mitochondrial energy metabolism.
This study aimed to examine if beta-aminoisobutyric acid (BAIBA) is (i) secreted by skeletal muscle in humans during exercise, (ii) associated with insulin secretory function in vivo, and (iii) directly linked with acute glucose-mediated insulin release by pancreatic beta cells in vitro. Following 2-weeks of single-leg immobilization, plasma BAIBA concentrations were measured in the brachial artery and the femoral veins of each leg in healthy male subjects, at rest and during two-legged dynamic knee-extensor exercise. During a 2-h hyperglycamic clamp, insulin secretory function and levels of plasma BAIBA were assessed in non-diabetic individuals, non-diabetic individuals following 24-h hyperglycemia and patients with type 2 diabetes. Direct effects of BAIBA on acute glucose-mediated insulin release were probed in INS-1832/3 cells under normal and 'diabetes-like' conditions. Finally, the effect of BAIBA on mitochondrial function was assessed in INS-1832/3 cells using extracellular flux analysis. (i) BAIBA is released from skeletal muscle at rest and during exercise under healthy conditions but is suppressed during exercise following leg immobilization, (ii) plasma BAIBA concentrations inversely associate with insulin secretory function in humans, (iii) BAIBA lowers mitochondrial energy metabolism in INS-1 832/3 cells in parallel with decreased insulin secretionConclusion/interpretation: BAIBA is a myokine released by skeletal muscle during exercise and indepedantly alters the triggering pathway of insulin secretion in cultured INS-1832/3 cells.


Health behaviors, service utilization, and access to care among older mothers of color who have children with developmental disabilities.
This study examined health behaviors, utilization, and access to care among older Latina and Black American mothers who co-reside with a child with developmental disabilities. Using data from the National Health Interview Survey National Center for Health Statistics (2005a), we compared Latina and Black American caregivers to similar women who did not have caregiving responsibilities. Findings showed that Latina caregivers were more likely to smoke and have insurance; Black American caregivers were less likely to be able to afford medication and mental health care; and both groups were less likely to have seen a doctor in the past year than their noncaregiving counterparts. Findings suggest that service providers should consider developing programs that focus on health for caregivers of color. Furthermore, results suggest that providers should take into account differing trends across ethnicities when designing programs.


Giving Your Last Gift: A Study of the Knowledge, Attitude and Information of Greek Students Regarding Organ Donation.
Organ donation rates in Greece are the lowest in the European Union. Studying and improving young students' awareness may increase organ donation rates. This study aimed to investigate young students' knowledge, attitude and information regarding organ donation and whether they are modified by putative predictors. A 62-item electronic questionnaire was sent to 1451 eligible students aged 18-30 years in 16 Greek public technical schools. Two composite scales (knowledge and attitude) were created. The multivariate statistical analysis included ordinal logistic and linear regression, as appropriate. Only 37.9% of the students knew the correct definition of organ donation, 40.3% knew which organs can be donated, 27.4% were informed about the new Greek legislation, and 83.1% acknowledged the need for better information. Although 60.5% would donate an organ after death, only 16.1% would become living donors. Although 83.1% of the students declared knowing what brain death means, 18.6% believe that a brain-dead person could fully recover and 32.3% are unsure about it. Being a health professional or a blood donor, the parent's educational level, the wish to donate all organs after death, the information from announcements or posters, the fear of organ removal after death without prior consent, the consent for autopsy, the wish for better information, and the misbelief that a brain-dead person could fully recover emerged as important predictors of the knowledge and attitude, regarding organ donation. An important lack of knowledge and misperceptions were noted regarding organ donation. Significant predictors were identified.


Ibrutinib Monotherapy in Symptomatic, Treatment-Naïve Patients With Waldenström Macroglobulinemia.
Purpose Ibrutinib is active in previously treated Waldenström macroglobulinemia (WM). MYD88 mutations ( MYD88MUT) and CXCR4 mutations ( CXCR4MUT) affect ibrutinib response. We report on a prospective study of ibrutinib monotherapy in symptomatic, untreated patients with WM, and the effect of CXCR4MUT status on outcome. Patients and Methods Symptomatic, treatment-naïve patients with WM were eligible. Ibrutinib (420 mg) was administered daily until progression or unacceptable toxicity. All tumors were genotyped for MYD88MUT and CXCR4MUT. Results A total of 30 patients with WM received ibrutinib. All carried MYD88MUT, and 14 (47%) carried a CXCR4MUT. After ibrutinib treatment, median serum IgM levels declined from 4,370 to 1,513 mg/dL, bone marrow involvement declined from 65% to 20%, and hemoglobin level rose from 10.3 to 13.9 g/dL ( P < .001 for all comparisons). Overall (minor or more than minor) and major (partial or greater than partial) responses for all patients were 100% and 83%, respectively. Rates of major (94% v 71%) and very good partial (31 v 7%) responses were higher and time to major responses more rapid (1.8 v 7.3 months; P = 0.01) in patients with wild-type CXCR4 versus those with CXCR4MUT, respectively. With a median follow-up of 14.6 months, disease in two patients (both with CXCR4MUT) progressed. The 18-month, estimated progression-free survival is 92% (95% CI, 73% to 98%). All patients are alive. Grade 2/3 treatment-related toxicities in > 5% of patients included arthralgia (7%), bruising (7%), neutropenia (7%), upper respiratory tract infection (7%), urinary tract infection (7%), atrial fibrillation (10%), and hypertension (13%). There were no grade 4 or unexpected toxicities. Conclusion Ibrutinib is highly active, produces durable responses, and is safe as primary therapy in patients with symptomatic WM. CXCR4MUT status affects responses to ibrutinib.


Orbital volume augmentation for late enophthalmos using the deep lateral wall.
Orbital volume augmentation to address enophthalmos and hollowing of the superior sulcus has been described with a variety of materials and from a variety of approaches.(1-4) A common location for volume augmentation is the inferomedial orbital wall; this surface is often the one that was expanded related to orbital trauma, and it is easily accessed through hidden conjunctival or caruncular incisions.


Organic farming enhances soil microbial abundance and activity-A meta-analysis and meta-regression.
Population growth and climate change challenge our food and farming systems and provide arguments for an increased intensification of agriculture. A promising option is eco-functional intensification through organic farming, an approach based on using and enhancing internal natural resources and processes to secure and improve agricultural productivity, while minimizing negative environmental impacts. In this concept an active soil microbiota plays an important role for various soil based ecosystem services such as nutrient cycling, erosion control and pest and disease regulation. Several studies have reported a positive effect of organic farming on soil health and quality including microbial community traits. However, so far no systematic quantification of whether organic farming systems comprise larger and more active soil microbial communities compared to conventional farming systems was performed on a global scale. Therefore, we conducted a meta-analysis on current literature to quantify possible differences in key indicators for soil microbial abundance and activity in organic and conventional cropping systems. All together we integrated data from 56 mainly peer-reviewed papers into our analysis, including 149 pairwise comparisons originating from different climatic zones and experimental duration ranging from 3 to more than 100 years. Overall, we found that organic systems had 32% to 84% greater microbial biomass carbon, microbial biomass nitrogen, total phospholipid fatty-acids, and dehydrogenase, urease and protease activities than conventional systems. Exclusively the metabolic quotient as an indicator for stresses on microbial communities remained unaffected by the farming systems. Categorical subgroup analysis revealed that crop rotation, the inclusion of legumes in the crop rotation and organic inputs are important farming practices affecting soil microbial community size and activity. Furthermore, we show that differences in microbial size and activity between organic and conventional farming systems vary as a function of land use (arable, orchards, and grassland), plant life cycle (annual and perennial) and climatic zone. In summary, this study shows that overall organic farming enhances total microbial abundance and activity in agricultural soils on a global scale.


Phenol sulfotransferases: hormonal regulation, polymorphism, and age of onset of breast cancer.
In recent years, significant effort has been made to identify genes that influence breast cancer risk. Because the high-penetrance breast cancer susceptibility genes BRCA1 and 2 play a role only in a small fraction of breast cancer cases, understanding the genetic risk of the majority of breast cancers will require the identification and analysis of several lower penetrance genes. The estrogen-signaling pathway plays a crucial role in the pathophysiology of breast cancer; therefore, polymorphism in genes involved in this pathway is likely to influence breast cancer risk. Our detailed analysis of gene expression profiles of estrogen- and 4-OH-tamoxifen-treated ZR75-1 breast cancer cells identified members of the sulfotransferase 1A (SULT1A) phenol sulfotransferase family as downstream targets of tamoxifen. On the basis of the induction of SULT1A by 4-OH-tamoxifen and the known inherited variability in SULT1A enzymatic activity, we hypothesized that polymorphism in sulfotransferase genes might influence the risk of breast cancer. Using an RFLP that distinguishes an arginine to histidine change in exon 7 of the SULT1A1 gene, we characterized SULT1A1 genotypes in relation to breast cancer risk. An analysis of 444 breast cancer patients and 227 controls revealed no effect of SULT1A1 genotype on the risk of breast cancer (P = 0.69); however, it did appear to influence the age of onset among early-onset affected patients (P = 0.04). Moreover, individuals with the higher activity SULT1A1*1 allele were more likely to have other tumors in addition to breast cancer (P = 0.004; odds ratio, 3.02; 95% confidence interval, 1.32, 8.09). The large number of environmental mutagens and carcinogens activated by sulfotransferases and the high frequency of the SULT1A1*1 allele in human populations warrants additional studies to address the role of SULT genes in human cancer.


Renal involvement in a patient with cobalamin A type (cblA) methylmalonic aciduria: a 42-year follow-up.
Chronic renal failure is a well-known long-term complication of methylmalonic aciduria (MMA-uria), occurring even under apparently optimal metabolic management. The onset of renal dysfunction seems to be dependent on the type of defect and vitamin B12-responsiveness. We report on a patient with a vitamin B12-responsive cobalamin A type (cblA) MMA-uria caused by a homozygous stop mutation (p.R145X) in the cobalamin A gene (MMAA). She was diagnosed with chronic kidney disease (CKD) stage III at the age of 12 years. Following re-evaluation, the patient received vitamin B12 (hydroxocobalamin) treatment, resulting in a significant decrease in the concentration of methylmalonic acid (MMA) in urine and plasma. Until age 29 years glomerular filtration rate remained stable probably due to hydroxocobalamin treatment slowing down progression to end-stage renal failure. Kidney biopsies showed non-specific manifestations of chronic interstitial inflammation. The patient received a renal transplant at age 35 years. Under continuous treatment with hydroxocobalamin there is no evidence of kidney damage due to MMA-uria until the last follow-up 6 years after transplantation. This case report illustrates (i) a long-term follow-up of a patient with MMA-uria due to cblA deficiency, (ii) the involvement of the kidney as a target organ and (iii) the importance of early and adequate vitamin B12 substitution in responsive patients. Further investigation will be necessary to prove the protective effect of hydroxocobalamin in the kidney in vitamin B12-responsive patients.


Co-regulation map of the human proteome enables identification of protein functions.
Assigning functions to the vast array of proteins present in eukaryotic cells remains challenging. To identify relationships between proteins, and thereby enable functional annotation of proteins, we determined changes in abundance of 10,323 human proteins in response to 294 biological perturbations using isotope-labeling mass spectrometry. We applied the machine learning algorithm treeClust to reveal functional associations between co-regulated human proteins from ProteomeHD, a compilation of our own data and datasets from the Proteomics Identifications database. This produced a co-regulation map of the human proteome. Co-regulation was able to capture relationships between proteins that do not physically interact or colocalize. For example, co-regulation of the peroxisomal membrane protein PEX11β with mitochondrial respiration factors led us to discover an organelle interface between peroxisomes and mitochondria in mammalian cells. We also predicted the functions of microproteins that are difficult to study with traditional methods. The co-regulation map can be explored at www.proteomeHD.net .


Cross-reactive CD8+ T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses.
Preexisting T-cell immunity directed at conserved viral regions promotes enhanced recovery from influenza virus infections, with there being some evidence of cross-protection directed at variable peptides. Strikingly, many of the immunogenic peptides derived from the current pandemic A(H1N1)-2009 influenza virus are representative of the catastrophic 1918 "Spanish flu" rather than more recent "seasonal" strains. We present immunological and structural analyses of cross-reactive CD8(+) T-cell-mediated immunity directed at a variable (although highly cross-reactive) immunodominant NP(418-426) peptide that binds to a large B7 family (HLA-B*3501/03/0702) found throughout human populations. Memory CD8(+) T-cell specificity was probed for 12 different NP(418) mutants that emerged over the 9 decades between the 1918 and 2009 pandemics. Although there is evidence of substantial cross-reactivity among seasonal NP(418) mutants, current memory T-cell profiles show no preexisting immunity to the 2009-NP(418) variant or the 1918-NP(418) variant. Natural infection with the A(H1N1)-2009 virus, however, elicits CD8(+) T cells specific for the 2009-NP(418) and 1918-NP(418) epitopes. This analysis points to the potential importance of cross-reactive T-cell populations that cover the possible spectrum of T-cell variants and suggests that the identification of key residues/motifs that elicit cross-reactive T-cell sets could facilitate the evolution of immunization protocols that provide a measure of protection against unpredicted pandemic influenza viruses. Thus, it is worth exploring the potential of vaccines that incorporate peptide variants with a proven potential for broader immunogenicity, especially to those that are not recognized by the current memory T-cell pool generated by exposure to influenza variants that cause successive seasonal epidemics.


Comparison of weight-for-height and mid-upper arm circumference (MUAC) in a therapeutic feeding programme in South Sudan: is MUAC alone a sufficient criterion for admission of children at high risk of mortality?
The present study was performed to describe the operational implications of using mid-upper arm circumference (MUAC) as a single admission criterion for treatment of severe acute malnutrition in South Sudan. We performed a retrospective analysis of routine programme data of children with severe acute malnutrition aged 6-59 months admitted to a therapeutic feeding programme using weight-for-height Z-score (WHZ) and/or MUAC. To understand the implications of using MUAC as a single admission criterion, we compared patient characteristics and treatment outcomes for children admitted with MUAC<115 mm (irrespective of WHZ) v. children admitted with WHZ<-3 and MUAC≥115 mm. Of 2205 children included for analysis, 719 (32·6 %) were admitted to the programme with MUAC<115 mm and 1486 (67·4 %) with WHZ<-3 and MUAC≥115 mm. Children who would have been admitted using a single MUAC<115 mm criterion were more severely malnourished and more likely to be female and younger. Compared with children admitted with WHZ<-3 and MUAC≥115 mm, children who would have been admitted using MUAC<115 mm were less likely to recover (54 % v. 69 %) and had higher risk of death (4 % v. 1 %), but responded to treatment with greater weight and MUAC gains. MUAC<115 mm would have failed to identify 33 % of deaths, while 98 % were identified by WHZ<-3 alone and 100 % by MUAC<130 mm. The study shows that MUAC<115 mm identified more severely malnourished children with a higher risk of mortality but failed to identify a third of the children who died. Admission criteria for therapeutic feeding should be adapted to the programmatic context with consideration for both operational and public health implications.


Cationic antimicrobial peptides do not change recombination frequency in Escherichia coli.
Cationic antimicrobial peptides are ubiquitous immune effectors of multicellular organisms. We previously reported, that in contrast to most of the classic antibiotics, cationic antimicrobial peptides (AMPs) do not increase mutation rates in E. coli Here, we provide new evidence showing that AMPs do not stimulate or enhance bacterial DNA recombination in the surviving fractions. Recombination accelerates evolution of antibiotic resistance. Our findings have implications for our understanding of host-microbe interactions, the evolution of innate immune defences, and shed new light on the dynamic of antimicrobial-resistance evolution.


Urine VCAM-1 as a marker of renal pathology activity index in lupus nephritis.
Although renal pathology is highly predictive of the disease course in lupus nephritis, it cannot be performed serially because of its invasive nature and associated morbidity. The goal of this study is to investigate whether urinary levels of CXC ligand 16 (CXCL16), monocyte chemotactic protein-1 (MCP-1) or vascular cell adhesion molecule-1 (VCAM-1) in patients with lupus nephritis are predictive of particular features of renal pathology in renal biopsies obtained on the day of urine procurement. CXCL16, MCP-1, and VCAM-1 levels were measured in urine samples from 74 lupus nephritis patients and 13 healthy volunteers. Of the patients enrolled, 24 patients had a concomitant kidney biopsy performed at the time of urine collection. In addition, patients with other renal diatheses were also included as controls. All three molecules were elevated in the urine of systemic lupus erythematosus patients, although VCAM-1 (area under curve = 0.92) and MCP-1 (area under curve = 0.87) were best at distinguishing the systemic lupus erythematosus samples from the healthy controls, and were also most strongly associated with clinical disease severity and active renal disease. For patients in whom concurrent renal biopsies had also been performed, urine VCAM-1 exhibited the strongest association with the renal pathology activity index and glomerulonephritis class IV, although it correlated negatively with the chronicity index. Interestingly, urinary VCAM-1 was also elevated in anti-neutrophil cytoplasmic antibodies-associated glomerulonephritis, focal segmental glomerulosclerosis and membranous nephropathy but not in minimal-change disease. Urinary VCAM-1 emerges as a reliable indicator of the activity:chronicity ratios that mark the underlying renal pathology in lupus nephritis. Since VCAM-1 is involved in the acute phase of inflammation when leukocytic infiltration is ongoing, longitudinal studies are warranted to establish whether tracking urine VCAM-1 levels may help monitor clinical and pathological disease activity over time.


The forum as a friend: parental mental illness and communication on open Internet forums.
The aim of this study was to identify how daughters or sons to parents suffering from mental illness perceive their situation. The objective was to provide new knowledge based on what they communicate on open Internet forums. The sample consisted of forum posts written by individuals who reported that they had mentally ill parents. Data collection comprised 301 comments from 35 forum threads on 5 different Swedish Internet forums, and predetermined inclusion criteria were used. Data were analyzed qualitatively using thematic analysis. The analysis generated four themes: "Caregiver burden," "Knowledge seeking," "Support from the forum," and "Frustration and powerlessness over health care." The results showed that parents' mental illness affected the forum writers on several levels, and they often felt stigmatized. The writers often lacked knowledge of their parents' mental illness and sought out Internet forums for information and support from peers in similar situations. The psychiatric care given to the parents was a source of dissatisfaction among the forum writers, who often felt that their parents did not receive adequate care. This study shows that fear of stigmatization and perceived lack of care and support caused forum writers to anonymously seek out Internet forums for information and support from others with similar experiences. The role of social support and the attractiveness of anonymity and availability typical for open Internet forums ought to be considered by health care professionals and researchers when developing new ways for providing support for children or adolescents with a mentally ill parent.


Primary Care Research Team Assessment (PCRTA): development and evaluation.
Since the early 1990s the United Kingdom (UK) Department of Health has explicitly promoted a research and development (R&D) strategy for the National Health Service (NHS). General practitioners (GPs) and other members of the primary care team are in a unique position to undertake research activity that will complement and inform the research undertaken by basic scientists and hospital-based colleagues and lead directly to a better evidence base for decision making by primary care professionals. Opportunities to engage in R&D in primary care are growing and the scope for those wishing to become involved is finally widening. Infrastructure funding for research-active practices and the establishment of a range of support networks have helped to improve the research capacity and blur some of the boundaries between academic departments and clinical practice. This is leading to a supportive environment for primary care research. There is thus a need to develop and validate nationally accepted quality standards and accreditation of performance to ensure that funders, collaborators and primary care professionals can deliver high quality primary care research. Several strategies have been described in national policy documents in order to achieve an improvement in teaching and clinical care, as well as enhancing research capacity in primary care. The development of both research practices and primary care research networks has been recognised as having an important contribution to make in enabling health professionals to devote more protected time to undertake research methods training and to undertake research in a service setting. The recognition and development of primary care research has also brought with it an emphasis on quality and standards, including an approach to the new research governance framework. In 1998, the NHS Executive South and West, and later the London Research and Development Directorate, provided funding for a pilot project based at the Royal College of General Practitioners (RCGP) to develop a scheme to accredit UK general practices undertaking primary care R&D. The pilot began with initial consultation on the development of the process, as well as the standards and criteria for assessment. The resulting assessment schedule allowed for assessment at one of two levels: Collaborative Research Practice (Level I), with little direct experience of gaining project or infrastructure funding Established Research Practice (Level II), with more experience of research funding and activity and a sound infrastructure to allow for growth in capacity. The process for assessment of practices involved the assessment of written documentation, followed by a half-day assessment visit by a multidisciplinary team of three assessors. IMPLEMENTATION--THE PILOT PROJECT: Pilot practices were sampled in two regions. Firstly, in the NHS Executive South West Region, where over 150 practices expressed an interest in participating. From these a purposive sample of 21 practices was selected, providing a range of research and service activity. A further seven practices were identified and included within the project through the East London and Essex Network of Researchers (ELENoR). Many in this latter group received funding and administrative support and advice from ELENoR in order to prepare written submissions for assessment. Some sample loss was encountered within the pilot project, which was attributable largely to conflicting demands on participants' time. Indeed, the preparation of written submissions within the South West coincided with the introduction of primary care groups (PCGs) in April 1999, which several practices cited as having a major impact on their participation in the pilot project. A final sample of 15 practices (nine in the South West and six through ELENoR) underwent assessment through the pilot project. A formal evaluation of the Primary Care Research Team Assessment (PCRTA) pilot was undertaken by an independent researcher (FM). This was supplemented with feedback from the assessment team members. The qualitative aspect of the evaluation, which included face-to-face and telephone interviews with assessors, lead researchers and other practice staff within the pilot research practices, as well as members of the project management group, demonstrated a positive view of the pilot scheme. Several key areas were identified in relation to particular strengths of research practices and areas for development including: Strengths Level II practices were found to have a strong primary care team ethos in research. Level II practices tended to have a greater degree of strategic thinking in relation to research. Development areas Level I practices were found to lack a clear and explicit research strategy. Practices at both levels had scope to develop their communication processes for dissemination of research and also for patient involvement. Practices at both levels needed mechanisms for supporting professional development in research methodology. The evaluation demonstrated that practices felt that they had gained from their participation and assessors felt that the scheme had worked well. Some specific issues were raised by different respondents within the qualitative evaluation relating to consistency of interpretation of standards and also the possible overlap of the assessment scheme with other RCGP quality initiatives. The pilot project has been very successful and recommendations have been made to progress to a UK scheme. Management and review of the scheme will remain largely the same, with a few changes focusing on the assessment process and support for practices entering the scheme. Specific changes include: development of the support and mentoring role of the primary care research networks increased peer and external support and mentoring for research practices undergoing assessment development of assessor training in line with other schemes within the RCGP Assessment Network work to ensure consistency across RCGP accreditation schemes in relation to key criteria, thereby facilitating comparable assessment processes refinement of the definition of the two groups, with Level I practices referred to as Collaborators and Level II practices as Investigator-Led. The project has continued to generate much enthusiasm and support and continues to reflect current policy. Indeed, recent developments include the proposed new funding arrangements for primary care R&D, which refer to the RCGP assessment scheme and recognise it as a key component in the future R&D agenda. The assessment scheme will help primary care trusts (PCTs) and individual practices to prepare and demonstrate their approach to research governance in a systematic way. It will also provide a more explicit avenue for primary care trusts to explore local service and development priorities identified within health improvement programmes and the research priorities set nationally for the NHS.


Of Atkins and men: deviations from clinical definitions of mental retardation in death penalty cases.
Under Atkins v. Virginia, the Eighth Amendment exempts from execution individuals who meet the clinical definitions of mental retardation set forth by the American Association on Intellectual and Developmental Disabilities and the American Psychiatric Association. Both define mental retardation as significantly subaverage intellectual functioning accompanied by significant limitations in adaptive functioning, originating before the age of 18. Since Atkins, most jurisdictions have adopted definitions of mental retardation that conform to those definitions. But some states, looking often to stereotypes of persons with mental retardation, apply exclusion criteria that deviate from and are more restrictive than the accepted scientific and clinical definitions. These state deviations have the effect of excluding from Atkins's reach some individuals who plainly fall within the class it protects. This article focuses on the cases of Roger Cherry, Jeffrey Williams, Michael Stallings, and others, who represent an ever-growing number of individuals inappropriately excluded from Atkins. Left unaddressed, the state deviations discussed herein permit what Atkins does not: the death-sentencing and execution of some capital defendants who have mental retardation.


Multiple approaches to microbial source tracking in tropical northern Australia.
Microbial source tracking is an area of research in which multiple approaches are used to identify the sources of elevated bacterial concentrations in recreational lakes and beaches. At our study location in Darwin, northern Australia, water quality in the harbor is generally good, however dry-season beach closures due to elevated Escherichia coli and enterococci counts are a cause for concern. The sources of these high bacteria counts are currently unknown. To address this, we sampled sewage outfalls, other potential inputs, such as urban rivers and drains, and surrounding beaches, and used genetic fingerprints from E. coli and enterococci communities, fecal markers and 454 pyrosequencing to track contamination sources. A sewage effluent outfall (Larrakeyah discharge) was a source of bacteria, including fecal bacteria that impacted nearby beaches. Two other treated effluent discharges did not appear to influence sites other than those directly adjacent. Several beaches contained fecal indicator bacteria that likely originated from urban rivers and creeks within the catchment. Generally, connectivity between the sites was observed within distinct geographical locations and it appeared that most of the bacterial contamination on Darwin beaches was confined to local sources.