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Simple Summary: We hypothesised that change in a magnetic resonance imaging (MRI) biomarker, the apparent diffusion coefficient (ADC) after 14 days of treatment could be a proxy for tumour regression grade (TRG) on pathology. Measurement of the imaging biomarker was standardised across centres. We restricted measurements to liver metastases from colorectal cancer and ensured a standardised chemotherapy approach. We identified and eliminated significant measurement error due to MRI scanner performance. We excluded studies that failed to conform to the imaging protocol or where images contained movement artefact. We ensured stability of the scanners by periodic quality control testing and used a standard, widely used data analysis technique to derive the ADC. Despite these measures, our results showed no significant correlation between ADC and TRG or between ADC and percentage of viable tumour, percentage necrosis, percentage fibrosis or a tumour proliferation index. This may reflect the complex cellular architecture of tumours after treatment. Background: Tumour apparent diffusion coefficient (ADC) from diffusion-weighted magnetic resonance imaging (MRI) is a putative pharmacodynamic/response biomarker but the relationship between drug-induced effects on the ADC and on the underlying pathology has not been adequately defined. Hypothesis: Changes in ADC during early chemotherapy reflect underlying histological markers of tumour response as measured by tumour regression grade (TRG). Methods: Twenty-six patients were enrolled in the study. Baseline, 14 days, and pre-surgery MRI were performed per study protocol. Surgical resection was performed in 23 of the enrolled patients; imaging-pathological correlation was obtained from 39 lesions from 21 patients. Results: There was no evidence of correlation between TRG and ADC changes at day 14 (study primary endpoint), and no significant correlation with other ADC metrics. In scans acquired one week prior to surgery, there was no significant correlation between ADC metrics and percentage of viable tumour, percentage necrosis, percentage fibrosis, or Ki67 index. Conclusions: Our hypothesis was not supported by the data. The lack of meaningful correlation between change in ADC and TRG is a robust finding which is not explained by variability or small sample size. Change in ADC is not a proxy for TRG in metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

The interstellar objects 1I/'Oumuamua and 2I/Borisov confirm the long-held expectation that bodies from one stellar system will be carried to another, allowing, in principle, interstellar panspermia. Life might be transferred between stellar systems, depending on the nature of the bodies and how they escaped their systems. 2I/Borisov appears to be a comet, with no more likelihood of carrying life than Solar System comets. In contrast, the nature of 1I/'Oumuamua has been difficult to determine. We review various hypotheses for its origin, including ejection of N2 ice from the surface of an exo-Pluto, formation in a molecular cloud by freezing of H2, and a derelict solar sail of alien construction. Of these, the N2 ice fragment hypothesis is uniquely falsifiable, plausible, and completely consistent with all observations. The possibility of interstellar panspermia would be made more probable if 'Oumuamua originated on a dwarf planet rather than a comet, although substantial challenges to transfer of life would remain. Of proposed mechanisms for interstellar panspermia, transfer of life via rocky meteoroids is perhaps less improbable. [ABSTRACT FROM AUTHOR]

Cancer represents a major cause of mortality globally and by 2050 will be the major cause of ill health and death across the world, most particularly in low- and middle-income countries (LMIC). For forty years, there has been increasing recognition of the need to better understand how the modifiable factors related to diet, nutrition and physical activity can influence the risk of cancer, responses to treatment, and survival. The International Collaboration on Nutrition in relation to Cancer (ICONIC) - a task force of the International Union of Nutritional Sciences (IUNS) - was established in 2018, as a development from the UK NIHR Cancer and Nutrition Collaboration and as a mechanism to bring together wider international expressions of interest in nutrition and cancer. ICONIC has engaged in a range of activities, with a current focus of effort in three main areas: 1) building wider capability and stronger capacity for excellence in research and practice in Africa, with the longer-term ambition to develop a high quality, context-specific research programme in this region, 2) facilitating international collaboration and developing activities in the area of childhood cancers, and 3) developing an agenda for prehabilitation (personalised management of exercise, nutrition and psychological support before the start of definitive treatment) for cancer. ICONIC's ambition is to build an international nutrition and cancer community - spanning research, education and training, in clinical and public health practice – to create coherence and common language across the two communities, and promote improved care and outcomes for those affected by cancer. • ICONIC is addressing lack of synergy between nutrition and cancer communities. • Most research on nutrition and cancer risk derived from high-income countries. • Need to build capability and capacity towards major prospective study for Africa. • Nutritional assessment should conform to an agreed Quality Assurance Framework. • Prehabilitation new concept for management and support of those living with cancer. [ABSTRACT FROM AUTHOR]

The International Malnutrition Task Force (IMTF) of the International Union of Nutritional Sciences was set up as an advocacy and capacity-building initiative in 2005 at a time when malnutrition contributed to 60% of deaths among children under-five, and when a reduction in under-five mortality by two-thirds had been set as Millennium Development Goal 4. By forging partnerships through regional networks of academics, and linking with international agencies and non-governmental organizations, IMTF was able to increase awareness of the urgent need to address the prevention and treatment of child malnutrition. With modest funding, but a common purpose, partners initiated capacity building efforts to reduce high inpatient mortality rates among children admitted with severe malnutrition. In all regions, these initiatives catalysed scaling-up of the WHO 10-step treatment guidelines, resulting in substantial improvements in child survival. Many lessons were learned during this process including the importance of operational research, supervision and teamwork, political commitment, and the potential of eLearning. By establishing alliances between academics, health professionals, policy makers, and national and international paediatric and nutrition societies through a Task Force, we suggest that similar benefits might accrue in other fields, including childhood cancer and school feeding. • The 10-step approach to treating severe malnutrition has become the 'reference standard'. • The social and environmental context of malnutrition must be acknowledged. • Quality assurance in delivering care and in data collection is vital. • WHO malnutrition guidelines are scalable to national level. [ABSTRACT FROM AUTHOR]

At least HT ht of C-type asteroids, possibly more, will be of the type CM or CR that match the Chicxulub impactor. The size of the Chicxulub crater leads to an estimated asteroid impactor diameter, HT ht [1],[4],[5]. Despite its central importance, the choice of HT ht appears unjustified. The mean timescale for an impact with a Chicxulub-scale comet is most likely HT ht Gyr, while the mean timescale with an asteroid remains HT ht Myr. [Extracted from the article]

The article presents the discussion on good nutrition being fundamental for good health and the prevention, treatment and management of disease. Topics include relationship between food, nutrition, physical activity and health however being complex, dynamic, and multi-faceted and highly affected by biological as well as environmental, socio-economic; and identifying the foundational nutrition competencies requiring to support all medical students.

The FAO of the UN convened an Expert Working Group meeting to provide recommendations related to protein quality evaluation of Follow-up Formula for Young Children (FUF-YC) and Ready-to-Use Therapeutic Foods (RUTFs). The protein and amino acid (AA) scoring patterns for the target age groups were defined and recommendations provided on the use of currently available protein and indispensable AA digestibility data. For FUF-YC, an age category of 1-2.9 y was identified, and a matching protein requirement of 0.86 g · kg-1 · d-1 with corresponding AA requirements were recommended. For RUTF, the protein requirement recommended was 2.82 g · kg-1 · d-1, to achieve a catch-up weight gain of 10 g · kg-1 · d-1 in children recovering from severe acute malnutrition. The AA requirements were factorially derived based on the adult protein requirement for maintenance and tissue AA composition. A flowchart was proposed for the best available methods to estimate digestibility coefficients (of either protein or AAs), in the following order: human, growing pig, and rat true ileal AA digestibility values. Where this is not possible, fecal protein digestibility values should be used. The Expert Working Group recommends the use of the Protein Digestibility Corrected Amino Acid Score (PDCAAS), with existing protein digestibility values, or the Digestible Indispensable Amino Acid Score provided that individual AA digestibility values are available for protein quality evaluation using the latter score. The Group also recommends the use of ileal digestibility of protein or of AAs for plant-based protein sources, recognizing the possible effects of antinutritional factors and impaired gut function. A PDCAAS score of ≥90% can be considered adequate for these formulations, whereas with a score <90%, the quantity of protein should be increased to meet the requirements. Regardless of the protein quality score, the ability of formulations to support growth in the target population should be evaluated. Future research recommendations are also proposed based on the knowledge gaps identified. [ABSTRACT FROM AUTHOR]

If the Solar system had a history of planet migration, the signature of that migration may be imprinted on the populations of asteroids and comets that were scattered in the planets' wake. Here, we consider the dynamical and collisional evolution of the inner Solar system asteroids that join the Oort cloud. We compare the Oort cloud asteroid populations produced by migration scenarios based on the 'Nice' and 'Grand Tack' scenarios, as well as a null hypothesis where the planets have not migrated, to the detection of one such object, C/2014 S3 (PANSTARRS). Our simulations find that the discovery of C/2014 S3 (PANSTARRS) only has a |$\gt 1{{\ \rm per\ cent}}$|  chance of occurring if the Oort cloud asteroids evolved on to Oort cloud orbits when the Solar system was |${\lesssim } 1\, \rm {Myr}$|  old, as this early transfer to the Oort cloud is necessary to keep the amount of collisional evolution low. We argue that this only occurs when a giant (≳30 m ⊕) planet orbits at |$1\sim 2\, \rm {au}$|⁠, and thus our results strongly favour a 'Grand Tack'-like migration having occurred early in the Solar system's history. [ABSTRACT FROM AUTHOR]

Louis Pasteur’s vaccine against rabies was introduced in France during 1885. A year later it became available within the United States. This article tells the story of the first use of the Pasteur vaccine in America and describes the early history of the vaccine’s production and distribution across the country by Pasteur Institutes established for this purpose. Highlights of Pasteur’s landmark studies on rabies are presented: research which pioneered the field of virology and the use of immunization to prevent infectious diseases. [ABSTRACT FROM AUTHOR]

We provide a fast method for computing constraints on impactor pre-impact orbits, applying this to the late giant impacts in the Solar system. These constraints can be used to make quick, broad comparisons of different collision scenarios, identifying some immediately as low-probability events, and narrowing the parameter space in which to target follow-up studies with expensive N-body simulations. We benchmark our parameter space predictions, finding good agreement with existing N-body studies for the Moon. We suggest that high-velocity impact scenarios in the inner Solar system, including all currently proposed single impact scenarios for the formation of Mercury, should be disfavoured. This leaves a multiple hit-andrun scenario as the most probable currently proposed for the formation of Mercury. [ABSTRACT FROM AUTHOR]

Objective: We aimed to assess outcomes [rates of recovery, default, case fatality; rate of weight gain and rate of Mean Upper Arm Circumference (MUAC) gain] of children aged 6-59 months with severe acute malnutrition (SAM) at the Outpatient Therapeutic Center at Gado Refugee Camp, Cameroon, in relation to international standards. We retrospectively analysed fles of 254 children with SAM aged 6-59 months admitted from April 2015 to August 2016. Results: 72.8% got discharged as recovered, 0.8% died and none defaulted. 26.8% got referred to stabilization center, mostly for poor weight gain (44.1%). Mean rate of weight gain was 4.4 g/kg/day and MUAC gain 0.3 mm/cm/day; median duration of treatment 44.5 days. Amongst those with marasmus, kwashiorkor and marasmic kwashiorkor, median duration of stay was 48, 24.5 and 36.3 days (p = 0.002); recovery rates were similar 73, 71.4, 71.4% respec- tively (p = 0.7); Median rates of weight gain, 4.4, 6.7 and 8.1 g/kg/day (p = 0.05). 49 children had been incorrectly diagnosed and treated as SAM. International Standards were met in terms of case fatality rate and default rate but not rates of recovery and weight gain. Separate gender charts must be used to calculate weight for height z scores as combined charts cause signifcant errors. [ABSTRACT FROM AUTHOR]

Giant impacts refer to collisions between two objects each of which is massive enough to be considered at least a planetary embryo. The putative collision suffered by the proto-Earth that created the Moon is a prime example, though most Solar System bodies bear signatures of such collisions. Current planet formation models predict that an epoch of giant impacts may be inevitable, and observations of debris around other stars are providing mounting evidence that giant impacts feature in the evolution of many planetary systems. This chapter reviews giant impacts, focussing on what we can learn about planet formation by studying debris around other stars. Giant impact debris evolves through mutual collisions and dynamical interactions with planets. General aspects of this evolution are outlined, noting the importance of the collision-point geometry. The detectability of the debris is discussed using the example of the Moon-forming impact. Such debris could be detectable around another star up to 10 Myr post-impact, but model uncertainties could reduce detectability to a few 100 yr window. Nevertheless the 3 % of young stars with debris at levels expected during terrestrial planet formation provide valuable constraints on formation models; implications for super-Earth formation are also discussed. Variability recently observed in some bright disks promises to illuminate the evolution during the earliest phases when vapour condensates may be optically thick and acutely affected by the collision-point geometry. The outer reaches of planetary systems may also exhibit signatures of giant impacts, such as the clumpy debris structures seen around some stars. [ABSTRACT FROM AUTHOR]

Many asteroids are likely rubble-piles that are a collection of smaller objects held together by gravity and possibly cohesion. These asteroids are seismically shaken by impacts, which leads to excitation of their constituent particles. As a result it has been suggested that their surfaces and sub-surface interiors may be governed by a size sorting mechanism known as the Brazil Nut Effect. We study the behavior of a model asteroid that is a spherical, self-gravitating aggregate with a binary size-distribution of particles under the action of applied seismic shaking. We find that above a seismic threshold, larger particles rise to the surface when friction is present, in agreement with previous studies that focussed on cylindrical and rectangular box configurations. Unlike previous works we also find that size sorting takes place even with zero friction, though the presence of friction does aid the sorting process above the seismic threshold. Additionally we find that while strong size sorting can take place near the surface, the innermost regions remain unsorted under even the most vigorous shaking. [ABSTRACT FROM AUTHOR]

Rabies is an acute encephalomyelitis in humans and animals caused by rabies virus (RABV) infection. Because the neuropathological changes are very mild in rabies, it has been assumed that neuronal dysfunction likely explains the severe clinical disease. Recently, degenerative changes have been observed in neuronal processes (dendrites and axons) in experimental rabies. In vitro studies have shown evidence of oxidative stress that is caused by mitochondrial dysfunction. Recent work has shown that the RABV phosphoprotein (P) interacts with mitochondrial Complex I leading to overproduction of reactive oxygen species, which results in injury to axons. Amino acids at positions 139 to 172 of the P are critical in this process. Rabies vectors frequently show behavioral changes. Aggressive behavior with biting is important for transmission of the virus to new hosts at a time when virus is secreted in the saliva. Aggression is associated with low serotonergic activity in the brain. Charlton and coworkers performed studies in experimentally infected striped skunks with skunk rabies virus and observed aggressive behavioral responses. Heavy accumulation of RABV antigen was found in the midbrain raphe nuclei, indicating that impaired serotonin neurotransmission from the brainstem may account for the aggressive behavior. We now have an improved understanding of how RABV causes neuronal injury and how the infection results in behavioral changes that promote viral transmission to new hosts. [ABSTRACT FROM AUTHOR]

In this article, the author focuses on a study conducted by paediatric nephrologist Malcolm Coulthard related to the infusion of albumin in treating nephrotic syndrome and oedematous malnutrition or kwashiorkor, which was published in a previous issue. Topics discussed include reanalysis of the study revealing changes in albumin concentration, arguing for clinical trials of intravenous albumin, adoption of WHO guidelines for the care of malnourished children and changes in protein kinetics.

The Oort cloud is usually thought of as a collection of icy comets inhabiting the outer reaches of the Solar system, but this picture is incomplete. We use simulations of the formation of the Oort cloud to show that ∼4 per cent of the small bodies in the Oort cloud should have formed within 2.5 au of the Sun, and hence be ice-free rock-iron bodies. If we assume that these Oort cloud asteroids have the same size distribution as their cometary counterparts, the Large Synoptic Survey Telescope should find roughly a dozen Oort cloud asteroids during 10 years of operations. Measurement of the asteroid fractionwithin the Oort cloud can serve as an excellent test of the Solar system's formation and dynamical history. Oort cloud asteroids could be of particular concern as impact hazards as their high mass density, high impact velocity, and low visibility make them both hard to detect and hard to divert or destroy. However, they should be a rare class of object, and we estimate globally catastrophic collisions should only occur about once per billion years. [ABSTRACT FROM AUTHOR]

We consider the observational signatures of giant impacts between planetary embryos. While the debris released in the impact remains in a clump for only a single orbit, there is a much longer lasting asymmetry caused by the fact that all debris must pass through the collision-point. The resulting asymmetry is stationary, it does not orbit the star. The debris is concentrated in a clump at the collision-point, with a more diffuse structure on the opposite side. The asymmetry lasts for typically around 1000 orbital periods of the progenitor, which can be several Myr at distances of ∼50 au. We describe how the appearance of the asymmetric disc depends on the mass and eccentricity of the progenitor, as well as viewing orientation. The wavelength of observation, which determines the grain sizes probed, is also important. Notably, the increased collision rate of the debris at the collision-point makes this the dominant production site for any secondary dust and gas created. For dust small enough to be removed by radiation pressure, and gas with a short lifetime, this causes their distribution to resemble a jet emanating from the (stationary) collision-point. We suggest that the asymmetries seen at large separations in some debris discs, like Beta Pictoris, could be the result of giant impacts. If so, this would indicate that planetary embryos are present and continuing to grow at several tens of au at ages of up to tens of Myr. [ABSTRACT FROM AUTHOR]

Purpose: To compare semi-quantitative (SQ) and pharmacokinetic (PK) parameters for analysis of dynamic contrast enhanced MR data (DCE-MRI) and investigate error-propagation in SQ parameters. Methods: Clinical data was collected from five patients with type 2-neurofibromatosis (NF2) receiving anti-angiogenic therapy for rapidly growing vestibular schwannoma (VS). There were 7 VS and 5 meningiomas. Patients were scanned prior to therapy and at days 3 and 90 of treatment. Data was collected using a dual injection technique to permit direct comparison of SQ and PK parameters. Monte Carlo modeling was performed to assess potential measurement errors in SQ parameters in persistent, washout, and weakly enhancing tissues. The simulation predictions for five semi-quantitative parameters were tested using the clinical DCE-MRI data. Results: In VS, SQ parameters and Ktrans showed close correlation and demonstrated similar therapy induced reductions. In meningioma, only the denoised Signal Enhancement Ratio (Rse1/se2(DN)) showed a significant therapy induced reduction (p<0.05). Simulation demonstrated: 1) Precision of SQ metrics normalized to the pre-contrast-baseline values (MSErel and ∑MSErel) is improved by use of an averaged value from multiple baseline scans; 2) signal enhancement ratio Rmse1/mse2 shows considerable susceptibility to noise; 3) removal of outlier values to produce a new parameter, Rmse1/mse2(DN), improves precision and sensitivity to therapy induced changes. Direct comparison of in-vivo analysis with Monte Carlo simulation supported the simulation predicted error distributions of semi-quantitative metrics. Conclusion: PK and SQ parameters showed similar sensitivity to anti-angiogenic therapy induced changes in VS. Modeling studies confirmed the benefits of averaging baseline signal from multiple images for normalized SQ metrics and demonstrated poor noise tolerance in the widely used signal enhancement ratio, which is corrected by removal of outlier values. [ABSTRACT FROM AUTHOR]

The article discusses the report "Measuring Up" published by the Academy of Medical Royal Colleges in 2013 concerning the prevalence of obesity in Great Britain. Topics discussed include obesity as the major factor for the development of non-communicable diseases such as type 2 diabetes, cardiovascular disease and respiratory ill-health, obesity as a risk factor for the development of social and mental problems in childhood, and measures taken by healthcare professionals to prevent obesity.

Abstract: Human rabies has traditionally been considered a uniformly fatal disease. However, recent decades have seen several instances in which individuals have developed clinical signs of rabies, but survived, usually with permanent neurologic sequelae. Most of these patients had received prophylactic rabies vaccine before the onset of illness. The best outcomes have been seen in patients infected with bat viruses, which appear to be less virulent for humans than strains associated with other rabies vectors. In 2003, an article by rabies experts suggested that survival might be improved through a combination of vaccine, anti-rabies immunoglobulin, antiviral drugs and the anesthetic ketamine, which had shown benefit in an animal model. One year later, a girl in Milwaukee who developed rabies after bat exposure was treated with some of these measures, plus a drug-induced (therapeutic) coma, and survived her illness with mild neurologic sequelae. Although the positive outcome in this case has been attributed to the treatment regimen, it more likely reflects the patient’s own brisk immune response, as anti-rabies virus antibodies were detected at the time of hospital admission, even though she had not been vaccinated. This conclusion is supported by the failure of the “Milwaukee Protocol” to prevent death in numerous subsequent cases. Use of this protocol should therefore be discontinued. Future research should focus on the use of animal models to improve understanding of the pathogenesis of rabies and for the development of new therapeutic approaches. [Copyright &y& Elsevier]

Since 1983 Richard Millet has published a considerable volume of fictional and critical writings, including short stories, récits, and twelve novels. This study concentrates on four key novels published between 1995 and 2003 that take place in the imaginary village of Siom in the Corrèze: La Gloire des Pythres, L'Amour des trois sœurs Piale, Lauve le pur, and Ma vie parmi les ombres. Names feature increasingly prominently in these novels, and the aim of this study is to describe the different ways in which they are present and to analyse the functions they perform. They are found to have extraordinarily powerful effects. Some names, predominantly those from France's literary heritage, act as tokens of a dreamed-of communion with the past. Others, names of fictional characters and places, are found to be so intensely meaningful that they determine destinies. Yet others, the names of the main families in the novels, provide fragile foundations. Their names, on the one hand, serve to root them in a village and a genealogy, but, on the other, embody forces that destroy all hope of enduring. In each case the proper noun expresses a dream of presence that remains unfulfilled. [ABSTRACT FROM PUBLISHER]

ABSTRACT We study the evolution of debris created in the giant impacts expected during the final stages of terrestrial planet formation. The starting point is the debris created in a simulation of the Moon-forming impact. The dynamical evolution is followed for 10 Myr including the effects of Earth, Venus, Mars and Jupiter. The spatial distribution evolves from a clump in the first few months to an asymmetric ring for the first 10 kyr and finally becoming an axisymmetric ring by about 1 Myr after the impact. By 10 Myr after the impact 20 per cent of the particles have been accreted on to Earth and 17 per cent on to Venus, with 8 per cent ejected by Jupiter and other bodies playing minor roles. However, the fate of the debris also depends strongly on how fast it is collisionally depleted, which depends on the poorly constrained size distribution of the impact debris. Assuming that the debris is made up of 30 per cent by mass mm-cm-sized vapour condensates and 70 per cent boulders up to 500 km, we find that the condensates deplete rapidly on ∼1000 yr time-scales, whereas the boulders deplete predominantly dynamically. By considering the luminosity of dust produced in collisions within the boulder-debris distribution we find that the Moon-forming impact would have been readily detectable around other stars in Spitzer 24 μm surveys for around 25 Myr after the impact, with levels of emission comparable to many known hot dust systems. The vapour condensates meanwhile produce a short-lived, optically thick, spike of emission. We use these surveys to make an estimate of the fraction of stars that form terrestrial planets, FTPF. Since current terrestrial planet formation models invoke multiple giant impacts, the low fraction of 10-100 Myr stars found to have warm (> rsim150 K) dust implies that [ABSTRACT FROM AUTHOR]

ABSTRACT We study the relationship between coronal X-ray emission and stellar age for late-type stars, and the variation of this relationship with spectral type. We select 717 stars from 13 open clusters and find that the ratio of X-ray to bolometric luminosity during the saturated phase of coronal emission decreases from 10−3.1 for late K dwarfs to 10−4.3 for early-F-type stars [across the range 0.29 ≤ ( B− V)0 < 1.41]. Our determined saturation time-scales vary between 107.8 and 108.3 yr, though with no clear trend across the whole FGK range. We apply our X-ray emission-age relations to the investigation of the evaporation history of 121 known transiting exoplanets using a simple energy-limited model of evaporation and taking into consideration Roche lobe effects and different heating/evaporation efficiencies. We confirm that a linear cut-off of the planet distribution in the M2/ R3 versus a−2 plane is an expected result of population modification by evaporation and show that the known transiting exoplanets display such a cut-off. We find that for an evaporation efficiency of 25 per cent we expect around one in ten of the known transiting exoplanets to have lost ≥5 per cent of their mass since formation. In addition we provide estimates of the minimum formation mass for which a planet could be expected to survive for 4 Gyr for a range of stellar and planetary parameters. We emphasize the importance of the earliest periods of a planet's life for its evaporation history with 75 per cent expected to occur within the first Gyr. This raises the possibility of using evaporation histories to distinguish between different migration mechanisms. For planets with spin-orbit angles available from measurements of the Rossiter-McLaughlin effect, no difference is found between the distributions of planets with misaligned orbits and those with aligned orbits. This suggests that dynamical effects accounting for misalignment occur early in the life of the planetary system, although additional data are required to test this. [ABSTRACT FROM AUTHOR]

In Richard Miller's 2003 rdcit Le Renard dans le nom, the fox in the name is the volpes etymo-logically present in the name of the principal character Pierre-Marie Lavolps. When a young girl is murdered, Lavolps is presumed to be the murderer on the evidence of his name. Examination of the evidence brings associations with animality and the archaism of rural France, but also the cultural symbolism of the fox, as represented by Le Roman de Renart. In the end, the name is seen to function as a fragile metaphor for an otherness that overflows, for example, the name as understood by literary onomastics. [ABSTRACT FROM AUTHOR]

The author reflects on the significance of impact factor to the radiology journals in Great Britain. The author mentions that impact factor is a tool that measures the significance of a particular journal in its field, assessing the size of readership, distribution and affiliation with professional organizations. Despite the criticisms made on the scheme, he adds that the tool is an important quality driver of academic publications.

It is generally accepted that there are not prominent features of neuronal cell death in rabies encephalitis. However, Hemachudha and coworkers recently reported widespread apoptosis in the central nervous system of several human rabies cases (BMC Infect Dis 5: 104, 2005). In this study we have evaluated morphological features and markers of neuronal apoptosis in postmortem brain tissue from 12 cases of human rabies who died in four different countries. Histopathological analysis, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling) staining, and immunostaining for cleaved (activated) caspase-3 were performed on paraffin-embedded tissues from the cerebral cortex, hippocampus, and brainstem, and additional regional areas from one of the cases. We did not find morphological evidence of neuronal apoptosis or TUNEL staining in any of the cases of rabies encephalitis. Similarly, immunostained cleaved caspase-3 was not seen in neurons, but prominent staining was observed in microglial processes. We conclude that neuronal apoptosis does not play an important pathogenetic role in human rabies encephalitis. [ABSTRACT FROM AUTHOR]

Summary: Targeted therapeutics have challenged how imaging techniques assess tumour response to treatment because many new agents are thought to cause cytostasis rather than cytotoxicity. Advanced tracer development, image acquisition, and image analysis have been used to produce quantitative biomarkers of pathophysiology, with particular focus on measurement of tumour vascular characteristics. Here, we critically appraise strategies available to generate imaging biomarkers for use in development of targeted therapeutics. We consider important practical and technical features of data acquisition and analysis because these factors determine the precise physiological meaning of every biomarker. We discuss the merits of volume-based and other size-based metrics for assessment of targeted therapeutics, and we examine the strengths and weaknesses of CT, MRI, and PET biomarkers derived from conventional clinical data. We review imaging biomarkers of tumour microvasculature and discuss imaging strategies that probe other physiological processes including cell proliferation, apoptosis, and tumour invasion. We conclude on the need to develop comprehensive compound-specific imaging biomarkers that are appropriate for every class of targeted therapeutics, and to investigate the complementary information given in multimodality imaging studies of targeted therapeutics. [Copyright &y& Elsevier]

There is recent in vitro evidence that human neurons express the innate immune response receptor, Toll-like receptor-3 (TLR-3), and that expression is enhanced in viral infections. The authors examined the immunohistochemical expression of TLR-3 in the cerebellar cortex of postmortem human brains. Purkinje cells were found to express TLR-3 in all cases of rabies (4 of 4) and herpes simplex encephalitis (2 of 2) as well as in cases of amyotrophic lateral sclerosis (1 of 2), stroke (1 of 2), and Alzheimer's disease (3 of 3). In cases of viral infection, direct viral infection was not necessary for enhanced neuronal TLR-3 expression, suggesting that soluble factors likely play an important role in inducing TLR-3 expression. In addition to neurons, occasional Bergmann glia expressed TLR-3 in some cases. This study has provided evidence that human brain neurons can express TLR-3 in vivo and suggests that neurons may play an important role in initiating an inflammatory reaction in a variety of neurological diseases. Journal of NeuroVirology (2006) 12 , 229–234. [ABSTRACT FROM AUTHOR]

Less neurovirulent strains of rabies virus have been recognized to be stronger inducers of neuronal apoptosis in vitro than more neurovirulent strains, but few studies have clarified whether this also applies in vivo. A comparative study was performed in two-day-old ICR mice inoculated in a hindlimb thigh muscle with recombinant rabies virus vaccine strain SAD-L16 (L16) or SAD-D29 (D29), which contains an attenuating substitution of Arg333 in the rabies virus glycoprotein. Histopathological and immunohistochemical analyses of brains were performed at early daily time points and in moribund animals. Both viruses caused progressive limb weakness; mortality with L16 was 100% at day 7 post-inoculation (p.i.) and 75% at 17 days p.i. for D29 and Kaplan–Meyer survival curves were significantly different. L16 spread to the brain more quickly than D29, and both viruses produced multifocal lesions in the brainstem and cerebellum associated with inflammatory changes and neuronal apoptosis. There was more disseminated involvement of the brain and many more infected neurons in L16 infection, particularly in the neostriatum, hippocampus, and cerebral cortex. Both viruses induced neuronal apoptosis, which was most marked in the brainstem tegmentum and internal granular layer of the cerebellum. In light of the lower burden of infection and smaller number of neurons infected with D29, this less virulent virus was a stronger inducer of neuronal apoptosis than the more virulent L16. These findings support previous in vitro studies indicating that there is an inverse relationship between pathogenicity and apoptosis. Induction of apoptosis, which is an innate mechanism in which the host restricts viral spread, may contribute to severe clinical neurological disease when there is viral invasion into the central nervous system. [ABSTRACT FROM AUTHOR]

Cells, individuals, and societies are complex systems in which the integrity of structure and function is protected through tight regulation and control. For each level of organization, health represents the ability to maintain integrity in response to the wider environment. Critical stages during growth and development act as checkpoints, where choice is exercised, and help determine future direction. Important among factors influencing the checkpoints include the availability of nutrients or foods within the immediate environment. At the cellular and whole-body levels, this information can be communicated to future generations. Recent work on the developmental origins of adult disease indicate specific factors that set limits on structure and function and potentially limit the capacity of the cell and individual to respond to environmental stressors that represent potential risk factors for neoplastic change. Epigenetic mechanisms modulate structure and function at the cellular and tissue levels, reflecting the potential for the growth and development of individuals, and reflect the food and nutrients available to the body as a whole and within the wider society. Understanding the nature and the interaction of the critical factors that determine and regulate variable stable and unstable gene expression will be increasingly important in characterizing abnormal cellular function and risk of disease for individuals and populations. This will require the ability to synthesize large data sets within and between different levels of organization to develop and refine a deeper understanding of how the systems are effectively integrated and regulated within and across generations and where this fails in the genesis of cancer. [ABSTRACT FROM AUTHOR]

Chronic bronchitis, a disease mainly of cigarette smokers, shares many clinical features with cystic fibrosis, a disease of altered ion transport, suggesting that the negative effects of cigarette smoke on mucociliary clearance may be mediated through alterations in ion transport. We tested the hypothesis that cigarette smoke extract would inhibit chloride secretion in human bronchial epithelial cells. In agreement with studies in canine trachea, cigarette smoke extract inhibited net chloride secretion without affecting sodium transport. We performed microelectrode impalements and impedance analysis studies to investigate the physiological mechanisms of this inhibition. These data demonstrated that cigarette smoke extract caused an acute increase in membrane resistances in conjunction with apical membrane hyperpolarization, an effect consistent with inhibition of an apical membrane anion conductance. After this acute phase, both membrane resistances decreased while membrane potentials continued to hyperpolarize, indicating that cigarette smoke extract also inhibited the basolateral entry of chloride into the cell. Furthermore, cigarette smoke extract caused an increase in mucin secretion. Therefore, the ion transport phenotype of human bronchial epithelial cells exposed to cigarette smoke extract is similar to that of cystic fibrosis epithelia in which there is sodium absorption out of proportion to chloride secretion in the setting of increased mucus secretion. [ABSTRACT FROM AUTHOR]

Because morphologic changes in natural rabies are usually relatively mild, it is thought that the severe clinical disease with a fatal outcome must be due to neuronal dysfunction of rabies virus-infected neurons. The precise bases of this functional impairment are unknown, and current knowledge on electrophysiological alterations, effects on ion channels and neurotransmission, and neurotoxicity are reviewed. Rabies virus may induce neuronal death, possibly through apoptotic mechanisms. Neuronal apoptosis has been observed in vitro and also in vivo under particular experimental conditions. The relevance of neuronal apoptosis in these situations to natural rabies has not yet been fully elucidated. [ABSTRACT FROM AUTHOR]

The challenge virus standard-11 strain (CVS) of fixed rabies virus produces neuronal apoptosis in widespread areas of the brain of mice after intracerebral inoculation. The role of the adaptive immune response in producing neuronal apoptosis in this model was evaluated by comparing the infections in adult C57BL/6J mice with nude mice (T cell deficient) and Rag1 mice (T and B cell deficient). Both stains of immunodeficient mice showed very similar clinical disease and neuropathological findings, including marked neuronal apoptosis. The adaptive immune response is unlikely of fundamental importance in producing neuronal apoptosis in the brains of mice in this model. [ABSTRACT FROM AUTHOR]

The metabolic fate of salvaged urea-nitrogen was explored in normal adults who had consumed a diet that provided 36 g protein/day for 7 days. We hypothesised that the colonic microflora utilise nitrogen derived from urea salvage to synthesise lysine in functionally significant amounts for the host. Oral lactose-[(15)N(15)N]ureide is resistant to digestion but is fermented by the colonic microflora to release (15)NH3, which can be used for amino acid synthesis. Prime and intermittent oral doses of lactose-[(15)N(15)N]ureide were ingested for 18 h, urine was collected every 3 h and stools were collected for a further 2 days. Amino acids were isolated from urine and from faecal bacterial protein and the enrichment measured. Compared with baseline values, there was significant enrichment (atoms per cent excess) in faecal bacterial glycine (0.0526), alanine (0.117), lysine (0.0875) and histidine (0.0487), and in urinary glycine (0.016), alanine (0.0144) and lysine (0.0098), but not hisitidine. These data show that the gastrointestinal bacteria can utilise urea-nitrogen in the formation of essential and non-essential amino acids that are available to the host. We estimate that on this low protein diet the amount of lysine from bacterial synthesis and available to the host may be 30 mg/kg/day. These data have important implications for our current perceptions for the dietary requirements for essential amino acids. [ABSTRACT FROM AUTHOR]

The neurogenic differentiation-1 (NEUROD1), neurogenin-3 (NEUROG3), and hepatic nuclear factor-1alpha (TCF1) genes are interacting transcription factors implicated in controlling islet cell development and insulin secretion. Polymorphisms of these genes (Ala45Thr [NEUROD1], Ser199Phe [NEUROG3], and Ala98Val [TCF1]) have been postulated to influence the development of type 2 diabetes. We have investigated the role and interaction between these variants using PCR/restriction fragment-length polymorphism assays in 454 subjects recruited as part of a population survey in South India. Additionally, 97 South Indian parent-offspring trios were studied. Polymorphisms of all three genes were associated with either fasting blood glucose (FBG) and/or 2-h blood glucose (BG) in either the total dataset or when restricted to a normoglycemic population. A monotonically increasing effect, dependent on the total number of risk-associated alleles carried, was observed across the whole population (P < 0.0001 for FBG and 2-h BG), raising FBG by a mean of 2.9 mmol/l and 2-h BG by a mean of 4.3 mmol/l. Similarly, an ascending number of the same risk alleles per subject increased the likelihood of type 2 diabetes (P = 0.002). In conclusion, we observed a combined effect of variations in NEUROD1, NEUROG3, and TCF1 in contributing to overall glucose intolerance in a South Indian population. [ABSTRACT FROM AUTHOR]

Mild traumatic brain injury (MTBI) is a common reason for hospital attendance and is associated with significant delayed morbidity. We studied a series of 80 persons with MTBI. Magnetic resonance imaging (MRI) and neuropsychological testing were used in the acute phase and a questionnaire for post-concussion syndrome (PCS) and return to work status at 6 months. In 26 subjects abnormalities were seen on MRI, of which 5 were definitely traumatic. There was weak correlation with abnormal neuropsychological tests for attention in the acute period. There was no significant correlation with a questionnaire for PCS and return to work status. Although non-specific abnormalities are frequently seen, standard MRI techniques are not helpful in identifying patients with MTBI who are likely to have delayed recovery. [ABSTRACT FROM AUTHOR]

There are still many unanswered questions in the pathogenesis of rabies, but recent progress has been made. During most of the long incubation period of rabies, the virus likely remains close the site of viral entry. Centripetal spread to the central nervous system and spread within the central nervous system occur by fast axonal transport. Neuronal dysfunction, rather than neuronal death, is responsible for the clinical features and fatal outcome in natural rabies. Recent work has changed our perspective on the ecology of rabies virus under particular circumstances in certain species. Hopefully, advances in our understanding of rabies pathogenesis will lead to advances in the treatment of this dreaded disease. [ABSTRACT FROM AUTHOR]

Rabies is a fatal disease in humans, and, to date, the only survivors of the disease have received rabies vaccine before the onset of illness. The approach to management of the rabies normally should be palliative. In unusual circumstances, a decision may be made to use an aggressive approach to therapy for patients who present at an early stage of clinical disease. No single therapeutic agent is likely to be effective, but a combination of specific therapies could be considered, including rabies vaccine, rabies immunoglobulin, monoclonal antibodies, ribavirin, interferon-a, and ketamine. Corticosteroids should not be used. As research advances, new agents may become available in the future for the treatment of human rabies. [ABSTRACT FROM AUTHOR]

Haplotype combination 112/121 and its intrinsic variants (UCSNP43, -19, and -63) identified within the calpain 10 gene are associated with increased risk of type 2 diabetes in Mexican-Americans. We evaluated whether this haplotype combination and its constituent haplotypes and variants contribute to increased susceptibility to impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) and type 2 diabetes in a South Indian population. Two study groups were used: 95 families ascertained through a proband with type 2 diabetes and 468 subjects recruited as part of an urban survey (69.1% with normal glucose tolerance, 12.8% with IFG/IGT, and 18.2% with type 2 diabetes). The four-locus haplotype combination 1112/1121 (UCSNP44, -43, -19, and -63) in South Indians conferred both a 10.7-fold increased risk for IFG/IGT (P = 0.001) and a 5.78- to 6.52-fold increased risk for type 2 diabetes in the two study groups (families P = 0.025, urban survey P = 0.015). A combination of the 1112 haplotype with the 1221 haplotype also appeared to increase risk for both IFG/IGT and type 2 diabetes. Contrary to what might be expected, quantitative trait analysis in the families found that transmission of the disease-related 1121 and 1112 haplotypes was associated with a reduced hip size and lower waist-to-hip ratio, respectively. This study supports the paradigm that specific haplotype combinations of calpain 10 variants increase risk of both IFG/IGT and type 2 diabetes. However, the relative infrequency of the "at-risk" combinations in the South Indian population suggests that calpain 10 is not a common determinant of susceptibility to type 2 diabetes. [ABSTRACT FROM AUTHOR]

An experimental model of rabies was established in the fruit-eating bat species Artibeus jamaicensis . The infections caused by CVS-N2c and CVS-B2c, which are both stable variants of CVS-24, were compared after inoculation of adult bats in the right masseter muscle. CVS-N2c produced neurologic signs of rabies with paresis, ataxia, and inability to fly, while CVS-B2c did not produce neurologic signs. Bats were sacrificed and the distribution of rabies virus antigen was assessed in tissue sections with immunoperoxidase staining. Both viruses spread to the brain stem and bilaterally to the trigeminal ganglia by days 2 to 3. CVS-N2c had disseminated widely in the central nervous system (CNS) by day 4 and had involved the spinal cord, thalamus, cerebellum, and cerebral cortex. CVS-B2c had infected neurons in the spinal cord on day 5 and in the cerebellum, thalamus, and cerebral cortex on day 6. Infected pyramidal neurons of the hippocampus were observed on day 5 in CVS-N2c infection, but infected neurons were never noted in the hippocampus in CVS-B2c infection. CVS-N2c infected many more neurons and more prominently involved neuronal processes than CVS-B2c. CVS-N2c spread more efficiently in the CNS than CVS-B2c. Morphologic changes of apoptosis or biochemical evidence of DNA fragmentation were not observed in neurons with either virus after this route of inoculation. The different neurovirulent properties of these CVS variants in this model were not related to their in vivo ability to induce apoptosis. [ABSTRACT FROM AUTHOR]

Examines the synthesis of hepatic secretory proteins in normal adults with adequate protein diet. Evaluation of the plasma concentration of albumin; Rates of hepatic lipoprotein synthesis; Increase of the formation of the acute-phase proteins in person with inflammation.

Focuses on a study which determined the synthesis of hepatic secretory proteins in normal adults consuming a diet marginally adequate in protein. Methods; Results; Interpretation of findings.

Examines the mechanisms involved in the development and regulation of mucus hypersecretory phenotype. Symptoms of mucus hypersecretion; Information on the major macromolecular component of respiratory mucus; Basis of mucus hypersecretion; Therapies for mucus hypersecretion.

Focuses on the influence of the structure and functioning of society on human nutrition. Discussion on the medical care for malnourished children; Role of media in information dissemination on nutrition and diet; Determination of the nature of the goodness of fit.

Steve Desch, Alan Jackson, Jessica Noviello and Ariel Anbar assess the evidence for what type of object caused the end–Cretaceous extinction and suggest best practices for writing and reviewing inter–disciplinary papers [ABSTRACT FROM AUTHOR]

The article focuses on the need to revise the case definitions for presumed infectious encephalitis and encephalopathy. It states that encephalitis requires three major criteria including brain inflammation to be consistent with encephalitis which needs pathological confirmation, defined pathological evidence of acute infection from clinical specimen, and laboratory evidence of an autoimmune condition is needed. It mentions the need of case definitions to be sensitive and specific.

Presents information on a study that examined whether erythrocyte glutathione deficiency in symptom-free HIV infection is associated with decreased synthesis rate. Physiologic effects of glutathione, a tripeptide present in high concentrations in all mammalian cells; Methodology; Results; Discussion.

Presents information on a study which determined the mechanism responsible for the altered glutathione homeostasis in HIV infection. Methodology; Results and discussion.