Unprecedented advances in human genome science are underway with potential to benefit public health. For example, it is estimated that within a decade, geneticists and epidemiologists will complete a catalog of the majority of genes associated with common chronic diseases. Such rapid advances create possibilities, if not the mandate, for translational research in how best to apply these and other anticipated discoveries for both individual and population health benefit. Driving these discoveries are rapid advances in infrastructure (e.g., the International HapMap Project to catalog human genetic variation; http://www.hapmap.org), analytical methods, and technology. This expansion in capabilities quickly has taken us from a genetics paradigm—where the influence of individual genes on health outcomes is paramount, to a genomics paradigm—where the complex influence of individual genes is considered in concert with each other and with environmental exposures on health outcomes. We discuss these and similar groundbreaking discoveries with an eye toward understanding their importance to child health and human development, and the role of behavioral science research conducted at the interface of pediatrics and genomic discovery.
Theories of learning have historically taken, as their starting point, the assumption that learning processes have universal applicability. This position has been argued on grounds of parsimony, but has received two significant challenges: first, from the observation that some kinds of learning, such as spatial learning, seem to obey different rules from others, and second, that some kinds of learning take place in processing modules that are separate from each other. These challenges arose in the behavioural literature but have since received considerable support from neurobiological studies, particularly single neuron studies of spatial learning, confirming that there are indeed separable (albeit highly intercommunicating) processing modules in the brain which may not always interact (within or between themselves) according to classic associative principles. On the basis of these neurobiological data, reviewed here, it is argued that rather than assuming universality of associative rules, it is more parsimonious to assume sets of locally operating rules, each specialised for a particular domain. By this view, although almost all learning is associative in one way or another, the behavioural-level characterization of the rules governing learning may vary depending on which neural modules are involved in a given behavior. Neurobiological studies, in tandem with behavioural studies, can help reveal the nature of these modules and the local rules by which they interact.
associative learning; spatial learning; geometric module; place cells; grid cells
From December 1966 through December 1984, there were 561 pancreas transplants reported to the American College of Surgeons/National Institutes of Health Organ Transplant Registry, including 60 from 1966 through June 1977, 206 from July 1977 through December 1982 and 295 from January 1983 through December 1984. One-year graft function-survival rates (insulin-independent) in each of the three periods were 3%, 20% and 40%, and the corresponding patient survival rates were 40%, 72% and 77%. Currently 140 patients have functioning grafts, 76 for more than one year. Of the transplants since July 1977, one-year graft survival rates according to technique are 41% for enteric drainage (N = 155), 30% for polymer injection (N = 260) and 29% for urinary drainage (N = 47). Pancreas graft survival rates at one year according to whether or not the recipients have had a kidney transplant were 35% for recipients of simultaneous grafts (N = 281), 28% in recipients of a pancreas after a kidney (N = 112) and 26% in recipients of a pancreas only who did not have uremia (N = 106); corresponding patient survival rates were 69%, 83% and 83%. Overall, one-year pancreas graft survival rates according to whether the patients did or did not have end-stage diabetic nephropathy were 33% versus 25% and the corresponding patient survival rates were 73% versus 84% (P < .01). Patient survival rates were significantly higher in those without than in those with end-stage diabetic nephropathy. An analysis of technically successful grafts according to principal immunosuppressant showed one-year function rates of 46% in 258 cyclosporine-treated recipients and 26% in 143 azathioprine-treated recipients.
Pancreas graft survival rates have progressively improved and the procedure has become safer with advances in surgical technique and immunosuppression. Pancreas transplantation is currently applicable to patients with diabetes mellitus whose complications are, or predictably will be, more serious than the possible side effects of long-term immunosuppression.
In 2008, the KiKK study in Germany reported a 1.6-fold increase in solid cancers and a 2.2-fold increase in leukemias among children living within 5 km of all German nuclear power stations. The study has triggered debates as to the cause(s) of these increased cancers. This article reports on the findings of the KiKK study; discusses past and more recent epidemiological studies of leukemias near nuclear installations around the world, and outlines a possible biological mechanism to explain the increased cancers. This suggests that the observed high rates of infant leukemias may be a teratogenic effect from incorporated radionuclides. Doses from environmental emissions from nuclear reactors to embryos and fetuses in pregnant women near nuclear power stations may be larger than suspected. Hematopoietic tissues appear to be considerably more radiosensitive in embryos/fetuses than in newborn babies. Recommendations for advice to local residents and for further research are made.
Objective: To describe the history and methods of the National Collegiate Athletic Association (NCAA) Injury Surveillance System (ISS) as a complement to the sport-specific chapters that follow.
Background: The NCAA has maintained the ISS for intercollegiate athletics since 1982. The primary goal of the ISS is to collect injury and exposure data from a representative sample of NCAA institutions in a variety of sports. Relevant data are then shared with the appropriate NCAA sport and policy committees to provide a foundation for evidence-based decision making with regard to health and safety issues.
Description: The ISS monitors formal team activities, numbers of participants, and associated time-loss athletic injuries from the first day of formal preseason practice to the final postseason contest for 16 collegiate sports. In this special issue of the
Journal of Athletic Training, injury information in 15 collegiate sports from the period covering 1988–1989 to 2003–2004 is evaluated.
Conclusions: Athletic trainers and the NCAA have collaborated for 25 years through the NCAA ISS to create the largest ongoing collegiate sports injury database in the world. Data collection through the ISS, followed by annual review via the NCAA sport rules and sports medicine committee structure, is a unique mechanism that has led to significant advances in health and safety policy within and beyond college athletics. The publication of this special issue and the evolution of an expanded Web-based ISS enhance the opportunity to apply the health and safety decision-making process at the level of the individual athletic trainer and institution.
athletics; sports; exposures; athletic injuries; injury mechanisms; injury rates; injury surveillance; practices; games
Recent data suggest that globally, between 5% and 10% of all new HIV cases are the result of unsafe injecting practices, and experts agree that reducing these practices is key to tackling the spread of HIV. And yet, despite the overwhelming evidence that providing sterile syringes to injection drug users (IDU) through syringe exchange programs (SEPs) or other means is an effective way of reducing HIV transmission among high-risk subpopulations, IDU in most settings still do not have access to sterile injecting equipment or if they do, access remains too restricted to effectively reduce the risk of HIV transmission. Vorobjov and colleagues have presented in this journal an interesting and timely study from Estonia comparing individuals who obtain syringes from SEPs and those who obtain syringes from pharmacies. As the authors point out, Estonia faces an unacceptably high HIV incidence rate of 50 new HIV cases per 100,000, this rate driven primarily by injection drug use. As such, the authors argue that Estonia's SEP network does not have the capacity to serve a growing IDU population at risk of transmitting HIV and pharmacy dispensation of clean syringes may be one potential approach to decreasing syringe sharing among high-risk injectors. It may be overly optimistic to consider the impact of higher threshold interventions such as pharmacy-based SEPs, given that IDU populations that engage in HIV risk behaviours such as syringe sharing are often hidden or hard to reach. Despite the need for a cautious approach, however, the findings presented by Vorobjov et al. may chart one potential course towards a more comprehensive societal response to reducing the health harms associated with injection drug use.
The Actinopterygii or ray-finned fishes comprise, in addition to the large superorder of teleosts, four other superorders, namely the cladistians, the chondrosteans, the ginglymodes, and the halecomorphs, each with a limited number of species. The telencephalon of actinopterygian fishes differs from that in all other vertebrates in that it consists of a pair of solid lobes. Lateral ventricles surrounded by nervous tissue are entirely lacking. At the end of the nineteenth century, the theory was advanced that the unusual configuration of the forebrain in actinopterygians results from an outward bending or eversion of its lateral walls. This theory was accepted by some authors, rejected or neglected by others, and modified by some other authors. The present paper is based on the data derived from the literature, complemented by new observations on a large collection of histological material comprising specimens of all five actinopterygian superorders. The paper consists of three parts. In the first, a survey of the development of the telencephalon in actinopterygian fishes is presented. The data collected show clearly that an outward bending or eversion of the pallial parts of the solid hemispheres is the principal morphogenetic event in all five actinopterygian superorders. In all of these superorders, except for the cladistians, eversion is coupled with a marked thickening of the pallial walls. In the second part, some aspects of the general morphology of the telencephalon in mature actinopterygians are highlighted. It is pointed out that (1) the degree of eversion varies considerably among the various actinopterygian groups; (2) eversion leads to the transformation of the telencephalic roof plate into a wide membrane or tela choroidea, which is bilaterally attached to the lateral or ventrolateral aspect of the solid hemispheres; (3) the lines of attachment or taeniae of the tela choroidea form the most important landmarks in the telencephalon of actinopterygians, indicating the sites where the greatly enlarged ventricular surface of the hemispheres ends and its reduced meningeal surface begins; (4) the meningeal surface of the telencephalon shows in most actinopterygians bilaterally a longitudinally oriented sulcus externus, the depth of which is generally positively correlated with the degree of eversion; (5) a distinct lateral olfactory tract, occupying a constant topological position close to the taenia, is present in all actinopterygians studied; and (6) this tract is not homologous to the tract of the same name in the evaginated and inverted forebrains of other groups of vertebrates. In the third and final section, the concept that the structural organization of the pallium in actinopterygians can be fully explained by a simple eversion of its walls, and the various theories, according to which the eversion is complicated by extensive shifts of its constituent cell groups, are discussed and evaluated. It is concluded that there are no reasons to doubt that the pallium of actinopterygian fishes is the product of a simple and complete eversion.
Evagination; Eversion; Lateral olfactory tract; Membranous roof; Sulcus externus; Taenia
This commentary presents the view of an Expert Group of Indian nephrologists on adaptation and implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for evaluation and management of mineral and bone disorder in chronic kidney disease (CKD-MBD) for practice in India. Zonal meetings of nephrologists drawn from the cross-section were convened to discuss the KDIGO guidelines. Recommendations were presented in a central meeting of zonal representatives. The finalized recommendations were reviewed by all the participants. There was a broad agreement on most of the recommendations made by the KDIGO workgroup. Significant departures in the current guidelines from the previous Kidney Disease Outcome Quality Initiative (KDOQI) guidelines were also noted. The participants agreed that the available evidence did not allow more precise recommendations, and the recommended best practice suggestions were often based on relatively weak evidence. There is a remarkable lack of data from Indian patients. We comment on specific areas and amplify certain concepts where we feel that further guidance that goes beyond what is stated in the document might help Indian nephrologists in appropriate implementation of the KDIGO guidelines. This commentary is intended to help define practically implementable best practices based on current disease concepts and available research evidence, thereby positively affecting the quality of management of CKD-MBD in India, and eventually improving patient outcomes.
Chronic kidney disease; guideline; hyperparathyroidism; KDIGO; mineral and bone disorder
In a recent publication (K. Ishikawa et al., 2008, Science
320, 661–664), the authors described how replacing the endogenous mitochondrial DNA (mtDNA) in a weakly metastatic mouse tumor cell line with mtDNA from a highly metastatic cell line enhanced tumor progression through enhanced production of reactive oxygen species (ROS). The authors attributed the transformation from a low-metastatic cell line to a high-metastatic phenotype to overproduction of ROS (hydrogen peroxide and superoxide) caused by a dysfunction in mitochondrial complex I protein encoded by mtDNA transferred from the highly metastatic tumor cell line. In this critical evaluation, using the paper by Ishikawa et al. as an example, we bring to the attention of researchers in the free radical field how the failure to appreciate the complexities of dye chemistry could potentially lead to pitfalls, misinterpretations, and erroneous conclusions concerning ROS involvement. Herein we make a case that the authors have failed to show evidence for formation of superoxide and hydrogen peroxide, presumed to be generated from complex I deficiency associated with mtDNA mutations in metastatic cells.
Reactive oxygen species; Fluorescent probes; Metastasis; Mitochondria; Dichlorodihydrofluorescein; Hydroethidine; Hydrogen peroxide; Superoxide; Free radicals
The moral arguments and the decision-making processes arising from them in the context of the dilemmas that arise in considering the appropriateness and implementation of withholding or withdrawing treatment in certain neonates form the basis of this commentary. It is concluded that the differing opinions on management of these babies by individual paediatricians results from their differing moral outlooks rather than from any incoherence in the moral arguments set out in the Dutch report.
This paper addresses Colin Holmes's suggestion that the psychopathic disorder is best regarded not as a psychiatric concept, but as an ethical one. The paper argues that the concept of psychopathy, like many other concepts, can span both psychiatry and ethics, and that it is not clear what removing if from the realm of psychiatry would entail. Also, the question of whether the concept of psychopathy is useful for psychiatrists must be separated from the question of whether psychopaths should be exonerated from the moral and legal responsibility for their actions.
OBJECTIVES--To provide a commentary on the economic evaluations of the Oxcheck and British family heart studies: direct comparison of their relative effectiveness and cost effectiveness; comparisons with other interventions; and consideration of problems encountered. DESIGN--Modelling from cost and effectiveness data to estimate of cost per life year gained. SUBJECTS--Middle aged men and women. INTERVENTIONS--Screening for cardiovascular risk factors followed by appropriate lifestyle advice and drug intervention in general practice, and other primary coronary risk management strategies. MAIN OUTCOME MEASURES--Life years gained; cost per life year gained. RESULTS--Depending on the assumed duration of risk reduction, the programme cost per discounted life year gained ranged from 34,800 pounds for a 1 year duration to 1500 pounds for 20 years for the British family heart study and from 29,300 pounds to 900 pounds for Oxcheck. These figures exclude broader net clinical and cost effects and longer term clinical and cost effects other than coronary mortality. CONCLUSIONS--Despite differences in underlying methods, the estimates in the two economic analyses of the studies can be directly compared. Neither study was large enough to provide precise estimates of the overall net cost. Modelling to cost per life year gained provides more readily interpretable measures. These estimates emphasise the importance of the relatively weak evidence on duration effect. Only if the effect lasts at least five years is the Oxcheck programme likely to be cost effective. The effect must last for about 10 years to justify the extra cost associated with the British family heart study.
Two forms of the equation for expression of the rate constant for electron transfer through a Marcus-type treatment are discussed. In the first (exergonic) form, the Arrhenius exponential term was replaced by its classical Marcus term; in the second (endergonic) form, the forward rate constant was replaced by the reverse rate constant (the forward rate constant in the exergonic direction), which was expanded to an equivalent Marcus term and multiplied by the equilibrium constant. When the classical Marcus treatment was used, these two forms of the rate equation give identical curves relating the logarithm of the rate constant to the driving force. The Marcus term for the relation between activation free-energy, ΔG#, reorganization energy, λ, and driving force, ΔGo, derived from parabolas for the reactant and product states, was identical when starting from exergonic or endergonic parabolas. Moser and colleagues introduced a quantum mechanical correction factor to the Marcus term in order to fit experimental data. When the same correction factor was applied in the treatment for the endergonic direction by Page and colleagues, a different curve was obtained from that found than with the exergonic form. We show that the difference resulted from an algebraic error in development of the endergonic equation.
Marcus theory; Moser-Dutton treatment; endergonic reaction; rate constant
den Dunnen et al. [den Dunnen, W.F.A., Brouwer, W.H., Bijlard, E., Kamphuis, J., van Linschoten, K., Eggens-Meijer, E., Holstege, G., 2008. No disease in the brain of a 115-year-old woman. Neurobiol. Aging] had the opportunity to follow up the cognitive functioning of one of the world’s oldest woman during the last 3 years of her life. They performed two neuropsychological evaluations at age 112 and 115 that revealed a striking preservation of immediate recall abilities and orientation. In contrast, working memory, retrieval from semantic memory and mental arithmetic performances declined after age 112. Overall, only a one-point decrease of MMSE score occurred (from 27 to 26) reflecting the remarkable preservation of cognitive abilities. The neuropathological assessment showed few neurofibrillary tangles (NFT) in the hippocampal formation compatible with Braak staging II, absence of amyloid deposits and other types of neurodegenerative lesions as well as preservation of neuron numbers in locus coeruleus. This finding was related to a striking paucity of Alzheimer disease (AD)-related lesions in the hippocampal formation. The present report parallels the early descriptions of rare “supernormal” centenarians supporting the dissociation between brain aging and AD processes. In conjunction with recent stereological analyses in cases aged from 90 to 102 years, it also points to the marked resistance of the hippocampal formation to the degenerative process in this age group and possible dissociation between the occurrence of slight cognitive deficits and development of AD-related pathologic changes in neocortical areas. This work is discussed in the context of current efforts to identify the biological and genetic parameters of human longevity.
Disease; Brain aging; Centenarians; Longevity; Neuronal vulnerability
Lemogne and colleagues offer an interesting extension to their previous work on visual perspective and depression: Individuals at-risk for depression (defined as higher scores on Harm Avoidance), without a history of mood disorders, report retrieval of positive memories from the 3rd person perspective. Their findings suggest that the retrieval of positive experiences from the 3rd person perspective may be a risk-factor for depression, not just a lingering consequence of it. Their study, however, also reports a genetic association in a severely underpowered sample. Rather than focusing on gene × environment interactions, which large, well-powered studies on related phenotypes have failed to detect, a greater understanding of the phenomenology of visual perspective may be a more fruitful avenue for future research.
Visual perspective; genetics; Neuroticism; Depression; Autobiographical Memory; 5-HTT
Causal inferences about the effect of an exposure on an outcome may be biased by errors in the measurement of either the exposure or the outcome. Measurement errors of exposure and outcome can be classified into 4 types: independent nondifferential, dependent nondifferential, independent differential, and dependent differential. Here the authors describe how causal diagrams can be used to represent these 4 types of measurement bias and discuss some problems that arise when using measured exposure variables (e.g., body mass index) to make inferences about the causal effects of unmeasured constructs (e.g., “adiposity”). The authors conclude that causal diagrams need to be used to represent biases arising not only from confounding and selection but also from measurement.
bias (epidemiology); body mass index; causality; confounding factors (epidemiology)
A significant fraction of patients with cervical spinal cord injury suffer from respiratory muscle paralysis and dependence on chronic mechanical ventilation. In selected patients, diaphragm pacing (DP) through electrical stimulation of the phrenic nerves provides an alternative to mechanical ventilation with significant advantages in life quality.
A case report of an individual who successfully underwent DP using intramuscular diaphragm electrodes. A brief review of the state of the art of DP including the clinical benefits of DP, patient selection and evaluation, description of equipment, methods of transition from mechanical ventilation to DP, potential complications and side effects, long-term outcome, and potential future developments in this field is included.
Several available DP systems are available, including conventional ones in which electrodes are positioned directly on the phrenic nerves through thoracotomy and less invasive systems in which electrodes are placed within the diaphragm through laparoscopy. For patients with only unilateral phrenic nerve function, a combined intercostal and unilateral diaphragm pacing system is under development.
In patients with ventilator-dependent tetraplegia, there are alternative methods of ventilatory support, which offer substantial benefits compared to mechanical ventilation.
Spinal cord injuries; Tetraplegia; Mechanical respiratory ventilation; Diaphragm pacing; Phrenic nerve pacing; Respiratory insufficiency; Electric stimulation; Respiration, artificial