Problem formulation for risk assessment of combined exposures to chemicals and other stressors in humans

When the human health risk assessment/risk management paradigm was developed, it did not explicitly include a "problem formulation" phase. The concept of problem formulation was first introduced in the context of ecological risk assessment (ERA) for the pragmatic reason to constrain and focus ERAs on the key questions. However, this need also exists for human health risk assessment, particularly for cumulative risk assessment (CRA), because of its complexity. CRA encompasses the combined threats to health from exposure via all relevant routes to multiple stressors, including biological, chemical, physical and psychosocial stressors. As part of the HESI Risk Assessment in the 21st Century (RISK21) Project, a framework for CRA was developed in which problem formulation plays a critical role. The focus of this effort is primarily on a chemical CRA (i.e., two or more chemicals) with subsequent consideration of non-chemical stressors, defined as "modulating factors" (ModFs). Problem formulation is a systematic approach that identifies all factors critical to a specific risk assessment and considers the purpose of the assessment, scope and depth of the necessary analysis, analytical approach, available resources and outcomes, and overall risk management goal. There are numerous considerations that are specific to multiple stressors, and proper problem formulation can help to focus a CRA to the key factors in order to optimize resources. As part of the problem formulation, conceptual models for exposures and responses can be developed that address these factors, such as temporal relationships between stressors and consideration of the appropriate ModFs

Incidence of non-traumatic anterior knee pain among 11 - 17-years-olds

Objective. To investigate the incidence of anterior knee pain, as well as the effect of sport participation, age of onset and gender differences on the condition. Design. Questionnaires (N = 2 414), each containing 20 questions, were distributed to 10 - 17-year-old learners at 8 primary and 5 high schools in the Empangeni/Richards Bay area. The return rate was 76%. Results. Twenty-seven per cent of the respondents reported anterior knee pain. Of these, 21% experienced pain in the left knee only, 34% in the right knee only, and 45% in both knees. Furthermore, 31% had visited a medical doctor because of the knee pain, 82% reported that the pain interfered with their sport participation, and 37% had visited a physiotherapist or biokineticist, of whom 43% reported that the intervention they received was successful. Previously 37% of the subjects had taken medication for the condition. The highest incidence of anterior knee pain was reported for 12 and 13-year-old girls and 14 - 15-year-old boys, which correlates with the period of the adolescent growth spurt. The incidence of anterior knee pain was higher amongst those who participated in sport more than 3 days per week and lower amongst those who participated less than 3 days per week or not at all. Conclusions. Anterior knee pain is common amongst children between the ages of 10 and 17 years, with a peak during adolescence, especially among girls. Participation in physical activity increases the likelihood of anterior knee pain. South African Journal of Sports Medicine Vol. 19 (2) 2007: pp. 60-6

ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer

PMCID: PMC3446380This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations.

Oxygen, haemoglobin and cardiac output are integrated components of oxygen transport: each gram of haemoglobin transports 1.34 mls of oxygen in the blood. Low arterial partial pressure of oxygen (PaO2), and haemoglobin saturation (SaO2), are the indices used in clinical assessments, and usually result from low inspired oxygen concentrations, or alveolar/airways disease. Our objective was to examine low blood oxygen/haemoglobin relationships in chronically compensated states without concurrent hypoxic pulmonary vasoreactivity.165 consecutive unselected patients with pulmonary arteriovenous malformations were studied, in 98 cases, pre/post embolisation treatment. 159 (96%) had hereditary haemorrhagic telangiectasia. Arterial oxygen content was calculated by SaO2 x haemoglobin x 1.34/100.There was wide variation in SaO2 on air (78.5-99, median 95)% but due to secondary erythrocytosis and resultant polycythaemia, SaO2 explained only 0.1% of the variance in arterial oxygen content per unit blood volume. Secondary erythrocytosis was achievable with low iron stores, but only if serum iron was high-normal: Low serum iron levels were associated with reduced haemoglobin per erythrocyte, and overall arterial oxygen content was lower in iron deficient patients (median 16.0 [IQR 14.9, 17.4]mls/dL compared to 18.8 [IQR 17.4, 20.1]mls/dL, p<0.0001). Exercise tolerance appeared unrelated to SaO2 but was significantly worse in patients with lower oxygen content (p<0.0001). A pre-defined athletic group had higher Hb:SaO2 and serum iron:ferritin ratios than non-athletes with normal exercise capacity. PAVM embolisation increased SaO2, but arterial oxygen content was precisely restored by a subsequent fall in haemoglobin: 86 (87.8%) patients reported no change in exercise tolerance at post-embolisation follow-up.Haemoglobin and oxygen measurements in isolation do not indicate the more physiologically relevant oxygen content per unit blood volume. This can be maintained for SaO2 ≥78.5%, and resets to the same arterial oxygen content after correction of hypoxaemia. Serum iron concentrations, not ferritin, seem to predict more successful polycythaemic responses

Cross - national comparisons of attitudes towards suicide and suicidal persons in university students from 12 countries

This paper reports the results of a comparative investigation of attitudes to suicide and suicidal persons in 5,572 university students from 12 countries. Participants filled out two scales measuring attitudes towards suicide and suicidal persons, a measure of psychological distress together with the questions about suicidal behavior. Results showed that the highest suicide acceptance scores were observed in Austrian, UK, Japanese and Saudi Arabian samples and the lowest scores were noted in Tunisian, Turkish, Iranian and Palestinian samples. While the highest social acceptance scores for a suicidal friend were noted in Turkish, US, Italian and Tunisian samples, the lowest scores were seen in Japanese, Saudi Arabian, Palestinian and Jordanian samples. Compared to participants with a suicidal past, those who were never suicidal displayed more internal barriers against suicidal behavior. Men were more accepting of suicide than women but women were more willing to help an imagined suicidal peer. Participants with accepting attitudes towards suicide but rejecting attitudes towards suicidal persons reported more suicidal behavior and psychological distress, and were more often from high suicide rate countries and samples than their counterparts. They are considered to be caught in a fatal trap in which most predominant feelings of suicidality such as hopelessness or helplessness are likely to occur. We conclude that in some societies such as Japan and Saudi Arabia it might be difficult for suicidal individuals to activate and make use of social support systems

Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.Fil: Hutchison, M. A.. National Institutes of Health; Estados UnidosFil: Gu, X.. National Institutes of Health; Estados UnidosFil: Adrover, Martín Federico. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Lee, M. R.. National Institutes of Health; Estados UnidosFil: Hnasko, T. S.. University of California at San Diego; Estados UnidosFil: Alvarez, V. A.. National Institutes of Health; Estados UnidosFil: Lu, W.. National Institutes of Health; Estados Unido

Magnetism, FeS colloids, and Origins of Life

A number of features of living systems: reversible interactions and weak bonds underlying motor-dynamics; gel-sol transitions; cellular connected fractal organization; asymmetry in interactions and organization; quantum coherent phenomena; to name some, can have a natural accounting via $physical$ interactions, which we therefore seek to incorporate by expanding the horizons of `chemistry-only' approaches to the origins of life. It is suggested that the magnetic 'face' of the minerals from the inorganic world, recognized to have played a pivotal role in initiating Life, may throw light on some of these issues. A magnetic environment in the form of rocks in the Hadean Ocean could have enabled the accretion and therefore an ordered confinement of super-paramagnetic colloids within a structured phase. A moderate H-field can help magnetic nano-particles to not only overcome thermal fluctuations but also harness them. Such controlled dynamics brings in the possibility of accessing quantum effects, which together with frustrations in magnetic ordering and hysteresis (a natural mechanism for a primitive memory) could throw light on the birth of biological information which, as Abel argues, requires a combination of order and complexity. This scenario gains strength from observations of scale-free framboidal forms of the greigite mineral, with a magnetic basis of assembly. And greigite's metabolic potential plays a key role in the mound scenario of Russell and coworkers-an expansion of which is suggested for including magnetism.Comment: 42 pages, 5 figures, to be published in A.R. Memorial volume, Ed Krishnaswami Alladi, Springer 201

The systematic guideline review: method, rationale, and test on chronic heart failure

Background: Evidence-based guidelines have the potential to improve healthcare. However, their de-novo-development requires substantial resources-especially for complex conditions, and adaptation may be biased by contextually influenced recommendations in source guidelines. In this paper we describe a new approach to guideline development-the systematic guideline review method (SGR), and its application in the development of an evidence-based guideline for family physicians on chronic heart failure (CHF). Methods: A systematic search for guidelines was carried out. Evidence-based guidelines on CHF management in adults in ambulatory care published in English or German between the years 2000 and 2004 were included. Guidelines on acute or right heart failure were excluded. Eligibility was assessed by two reviewers, methodological quality of selected guidelines was appraised using the AGREE instrument, and a framework of relevant clinical questions for diagnostics and treatment was derived. Data were extracted into evidence tables, systematically compared by means of a consistency analysis and synthesized in a preliminary draft. Most relevant primary sources were re-assessed to verify the cited evidence. Evidence and recommendations were summarized in a draft guideline. Results: Of 16 included guidelines five were of good quality. A total of 35 recommendations were systematically compared: 25/35 were consistent, 9/35 inconsistent, and 1/35 un-rateable (derived from a single guideline). Of the 25 consistencies, 14 were based on consensus, seven on evidence and four differed in grading. Major inconsistencies were found in 3/9 of the inconsistent recommendations. We re-evaluated the evidence for 17 recommendations (evidence-based, differing evidence levels and minor inconsistencies) - the majority was congruent. Incongruity was found where the stated evidence could not be verified in the cited primary sources, or where the evaluation in the source guidelines focused on treatment benefits and underestimated the risks. The draft guideline was completed in 8.5 man-months. The main limitation to this study was the lack of a second reviewer. Conclusion: The systematic guideline review including framework development, consistency analysis and validation is an effective, valid, and resource saving-approach to the development of evidence-based guidelines

Red wine polyphenols prevent metabolic and cardiovascular alterations associated with obesity in Zucker fatty rats (Fa/Fa)

Peer reviewedPublisher PD

Electromagnetically Induced Transparency and Slow Light with Optomechanics

Controlling the interaction between localized optical and mechanical excitations has recently become possible following advances in micro- and nano-fabrication techniques. To date, most experimental studies of optomechanics have focused on measurement and control of the mechanical subsystem through its interaction with optics, and have led to the experimental demonstration of dynamical back-action cooling and optical rigidity of the mechanical system. Conversely, the optical response of these systems is also modified in the presence of mechanical interactions, leading to strong nonlinear effects such as Electromagnetically Induced Transparency (EIT) and parametric normal-mode splitting. In atomic systems, seminal experiments and proposals to slow and stop the propagation of light, and their applicability to modern optical networks, and future quantum networks, have thrust EIT to the forefront of experimental study during the last two decades. In a similar fashion, here we use the optomechanical nonlinearity to control the velocity of light via engineered photon-phonon interactions. Our results demonstrate EIT and tunable optical delays in a nanoscale optomechanical crystal device, fabricated by simply etching holes into a thin film of silicon (Si). At low temperature (8.7 K), we show an optically-tunable delay of 50 ns with near-unity optical transparency, and superluminal light with a 1.4 microseconds signal advance. These results, while indicating significant progress towards an integrated quantum optomechanical memory, are also relevant to classical signal processing applications. Measurements at room temperature and in the analogous regime of Electromagnetically Induced Absorption (EIA) show the utility of these chip-scale optomechanical systems for optical buffering, amplification, and filtering of microwave-over-optical signals.Comment: 15 pages, 9 figure