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Both trichloroethylene (TCE) and tetrachloroethylene (PCE) are high-priority chemicals subject to numerous human health risk evaluations by a range of agencies. Metabolism of TCE and PCE determines their ultimate toxicity; important uncertainties exist in quantitative characterization of metabolism to genotoxic moieties through glutathione (GSH) conjugation and species differences therein.This study aimed to address these uncertainties using novelLiverWe found that, although efficiency of metabolism varied among models, consistent with known differences in their metabolic capacity, formation rates of DCVG and TCVG generally followed the patternsFor TCE, the new data provided additional empirical support for inclusion of GSH conjugation-mediated kidney effects as critical for the derivation of noncancer toxicity values. For PCE, the data reduced previous uncertainties regarding the extent of TCVG formation in humans; this information was used to update several candidate kidney-specific noncancer toxicity values. Overall, MPCC-derived data provided physiologically relevant estimates of GSH-mediated metabolism of TCE and PCE to reduce uncertainties in interspecies extrapolation that constrained previous risk evaluations, thereby increasing the precision of risk characterizations of these high-priority toxicants. https://doi.org/10.1289/EHP12006.

Summary Background Malaria remains a key cause of mortality in low-income countries. RTS,S/AS01 is currently the most advanced malaria vaccine, demonstrating ∼50% efficacy in controlled human malaria infection (CHMI) studies in malaria-naive adults and ∼30%–40% efficacy in field trials in African infants and children. However, a higher vaccine efficacy is desirable. Methods Modification of the vaccine regimen in a CHMI trial in malaria-naive individuals resulted in significant increase in protection. While three equal monthly RTS,S/AS01 doses (RRR) were used originally, the administration of a delayed third dose with 20% of the original antigen dose (RRr) resulted in ∼87% protection, linked to enhanced antibody affinity maturation. Here, we sought to identify a novel molecular basis for this higher protective efficacy using Systems Serology. Findings We demonstrate that the delayed fractional dose maintains monocyte phagocytosis and NK activation mediated by NANP6-specific antibodies, key correlates of protection for the RRR regimen. However, it is also marked by a higher breadth of C-term Fc effector functions, including enhanced phagocytosis. The RRr regimen breaches immunodominance of the humoral immune response, inducing a balanced response across the C-terminal (Pf16) and NANP region of CSP, both of which were linked to protection. Conclusions Collectively, these data point to an unexpectedly concordant evolution in Fab avidity and expanded C-term Fc effector functions, providing novel insights into the basis for higher protection conferred by the delayed fractional dose in malaria-naive individuals. Funding This research was supported by PATH’s Malaria Vaccine Initiative and the MGH Research Scholars program.

SARS-CoV-2 infection causes more severe disease in pregnant women compared to age-matched non-pregnant women. Whether maternal infection causes changes in the transfer of immunity to infants remains unclear. Maternal infections have previously been associated with compromised placental antibody transfer, but the mechanism underlying this compromised transfer is not established. Here, we used systems serology to characterize the Fc-profile of influenza-, pertussis-, and SARS-CoV-2-specific antibodies transferred across the placenta. Influenza- and pertussis-specific antibodies were actively transferred. However, SARS-CoV-2-specific antibody transfer was significantly reduced compared to influenza- and pertussis-specific antibodies, and cord titers and functional activity were lower than in maternal plasma. This effect was only observed in third trimester infection. SARS-CoV-2-specific transfer was linked to altered SARS-CoV-2-antibody glycosylation profiles and was partially rescued by infection-induced increases in IgG and increased FCGR3A placental expression. These results point to unexpected compensatory mechanisms to boost immunity in neonates, providing insights for maternal vaccine design., Highlights • SARS-CoV-2-specific antibodies have a decreased placental transfer • SARS-CoV-2-spike antibodies have altered glycosylation profiles in pregnant women • Pregnant women with SARS-CoV-2 during the third trimester have elevated IgG levels • SARS-CoV-2-specific antibody transfer is efficient after second trimester infection, Atyeo et al. reveals a deficiency in SARS-CoV-2-antibody placental transfer among women infected during the third trimester. While bulk antibody transfer remains unaltered, SARS-CoV-2-antibodies show perturbed Fc glycosylation profiles and elevated IgG and FCGR3A placental expression that suggest compensation for poor transfer.

Summary Humoral responses in COVID-19 disease are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined postmortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers, a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific “disease-related” B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections and suggest that achieving herd immunity through natural infection may be difficult., Highlights 1. Acute phase SARS-CoV-2-specific T cells display an activated cytotoxic phenotype 2. Broad and polyfunctional SARS-CoV-2-specific T cell responses in convalescent phase 3. Detection of SARS-CoV-2-specific T cell responses also in seronegative individuals, Buggert and colleagues provide a phenotypic and functional map of SARS-CoV-2-specific T cells across the full spectrum of exposure, infection, and COVID-19 severity. They observe that SARS-CoV-2-specific T cells generate a broad, robust and functionally replete response in convalescent individuals, that may provide protection from recurrent episodes of severe COVID-19.

Vaccine development has the potential to be accelerated by coupling tools such as systems immunology analyses and controlled human infection models to define the protective efficacy of prospective immunogens without expensive and slow phase 2b/3 vaccine studies. Among human challenge models, controlled human malaria infection trials have long been used to evaluate candidate vaccines, and RTS,S/AS01 is the most advanced malaria vaccine candidate, reproducibly demonstrating 40 to 80% protection in human challenge studies in malaria-naïve individuals. Although antibodies are critical for protection after RTS,S/AS01 vaccination, antibody concentrations are inconsistently associated with protection across studies, and the precise mechanism(s) by which vaccine-induced antibodies provide protection remains enigmatic. Using a comprehensive systems serological profiling platform, the humoral correlates of protection against malaria were identified and validated across multiple challenge studies. Rather than antibody concentration, qualitative functional humoral features robustly predicted protection from infection across vaccine regimens. Despite the functional diversity of vaccine-induced immune responses across additional RTS,S/AS01 vaccine studies, the same antibody features, antibody-mediated phagocytosis and engagement of Fc gamma receptor 3A (FCGR3A), were able to predict protection across two additional human challenge studies. Functional validation using monoclonal antibodies confirmed the protective role of Fc-mediated antibody functions in restricting parasite infection both in vitro and in vivo, suggesting that these correlates may mechanistically contribute to parasite restriction and can be used to guide the rational design of an improved vaccine against malaria.

A successful Staphylococcus aureus vaccine remains elusive, and one controversy in the field is whether humans generate a protective adaptive immune response to infection. We developed a bacterial challenge murine assay that directly assesses the protective capacity of adoptively transferred human serum samples. We first validated the model by showing that postpneumococcal vaccine serum samples from humans induced effective clearance of Streptococcus pneumoniae in mice. We then found that human serum samples adoptively transferred from children with invasive S. aureus infections exhibited protection from disease in a murine model, with some samples conferring near complete protection. These findings demonstrate that human serum samples are capable of conferring a protective adaptive response generated by humans during invasive staphylococcal disease, allowing for the study of protective factors in a murine model. Identification of the protective factors present in the most efficacious serum samples would be of high interest as potential staphylococcal vaccine candidates or passive therapeutics.

Humoral responses in COVID-19 disease are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined postmortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers, a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+TFH cell differentiation together with an increase in T-bet+TH1 cells and aberrant extra-follicular TNF-a accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections and suggest that achieving herd immunity through natural infection may be difficult. Funding: This work was supported by NIH U19 AI110495 to SP, NIH R01 AI146779 to AGS, NIH R01AI137057 and DP2DA042422 to DL, BMH was supported by NIGMS T32 GM007753, TMC was supported by T32 AI007245. Funding for these studies from the Massachusetts Consortium of Pathogen Readiness, the Mark and Lisa Schwartz Foundation and Enid Schwartz is also acknowledged. Conflict of Interest: None. Ethical Approval: This study was performed with the approval of the Institutional Review Boards at the Massachusetts General Hospital and the Brigham and Women's Hospital.

Summary Background Development of an effective vaccine against the pathogenic blood-stage infection of human malaria has proved challenging, and no candidate vaccine has affected blood-stage parasitemia following controlled human malaria infection (CHMI) with blood-stage Plasmodium falciparum. Methods We undertook a phase I/IIa clinical trial in healthy adults in the United Kingdom of the RH5.1 recombinant protein vaccine, targeting the P. falciparum reticulocyte-binding protein homolog 5 (RH5), formulated in AS01B adjuvant. We assessed safety, immunogenicity, and efficacy against blood-stage CHMI. Trial registered at ClinicalTrials.gov, NCT02927145. Findings The RH5.1/AS01B formulation was administered using a range of RH5.1 protein vaccine doses (2, 10, and 50 μg) and was found to be safe and well tolerated. A regimen using a delayed and fractional third dose, in contrast to three doses given at monthly intervals, led to significantly improved antibody response longevity over ∼2 years of follow-up. Following primary and secondary CHMI of vaccinees with blood-stage P. falciparum, a significant reduction in parasite growth rate was observed, defining a milestone for the blood-stage malaria vaccine field. We show that growth inhibition activity measured in vitro using purified immunoglobulin G (IgG) antibody strongly correlates with in vivo reduction of the parasite growth rate and also identify other antibody feature sets by systems serology, including the plasma anti-RH5 IgA1 response, that are associated with challenge outcome. Conclusions Our data provide a new framework to guide rational design and delivery of next-generation vaccines to protect against malaria disease. Funding This study was supported by USAID, UK MRC, Wellcome Trust, NIAID, and the NIHR Oxford-BRC., Graphical abstract, Highlights The RH5.1/AS01B vaccine is safe, well tolerated, and immunogenic in healthy adults A delayed fractional third dose significantly improves antibody response longevity In vivo blood-stage P. falciparum growth rate is significantly lower in vaccinees In vitro IgG-mediated growth inhibition activity is associated with challenge outcome, Context and significance A highly effective vaccine against the human malaria parasite Plasmodium falciparum is urgently needed. One vaccine strategy aims to prevent parasite growth in the blood, protecting against clinical disease; however, this has proved exceptionally challenging. Here we show that a candidate vaccine (reticulocyte-binding protein homolog 5.1 [RH5.1]/AS01B) is safe in a phase I/IIa clinical trial and identify a vaccination regimen that improves the durability of the human antibody response, which is critical for long-term protection. Following experimental challenge of vaccinated adults with malaria, we observed that the vaccine could reduce parasite growth in the blood and identified immune responses that could predict how well the vaccine performs. These data will help guide the design of improved vaccines in the future., Minassian et al. report that the RH5.1/AS01B vaccine against blood-stage Plasmodium falciparum malaria is safe and immunogenic in a phase I/IIa clinical trial. They demonstrate a significantly reduced blood-stage parasite growth rate in vaccinees following controlled human malaria infection and identify that in vitro antibody-mediated growth inhibition activity is associated with challenge outcome.

The complement system plays a critical role in innate immune defense against pathogens, both via non-specific direct pathogen recognition and killing or via antigen-specific indirect recruitment by complement fixing antibodies. While various assays for measuring complement activation have been developed, few provide a high-throughput, sample-sparing approach to interrogate the qualitative differences in the ability of antibodies to drive complement activation. Here we present a high-throughput, sample-sparing, bead-based assay to evaluate antigen-specific antibody-dependent complement activation against nearly any antigen. Optimization of buffer composition, kinetics of immune complex formation, as well as complement source all contribute critically to the development of a robust, highly flexible and high-throughput approach to analyze antibody-dependent complement deposition (ADCD). Thus, the optimized bead-based, antigen-specific assay represents a simple, highly adaptable platform to profile antibody-dependent complement activation across pathogens and diseases., Highlights • Optimized flow-based assay for the detection of antibody-mediated complement deposition • Robust, rapid and reproducible high-throughput bead-based assay applicable to various diseases, including HIV and influenza • Lot controlled complement is a controlled source for exogenous complement that correlates with human complement activity

This prospective cohort study investigated the influence of an artificial playing surface on injury risk and perceptions of muscle soreness in elite English Premiership Rugby Union players. Time loss (from 39.5 matches) and abrasion (from 27 matches) injury risk was compared between matches played on artificial turf and natural grass. Muscle soreness was reported over the 4 days following one match played on each surface by 95 visiting players (i.e., normally play on natural grass surfaces). There was a likely trivial difference in the overall injury burden relating to time-loss injuries between playing surfaces [rate ratio = 1.01, 90% confidence interval (CI): 0.73-1.38]. Abrasions were substantially more common on artificial turf (rate ratio = 7.92, 90% CI: 4.39-14.28), although the majority of these were minor and only two resulted in any reported time loss. Muscle soreness was consistently higher over the 4 days following a match on artificial turf in comparison with natural grass, although the magnitude of this effect was small (effect sizes ranging from 0.26 to 0.40). These results suggest that overall injury risk is similar for the two playing surfaces, but further surveillance is required before inferences regarding specific injury diagnoses and smaller differences in overall injury risk can be made. Language: en

A radar meteor echo is the radar scattering signature from the free electrons generated by the entry of extraterrestrial particles into the atmosphere. Three categories of scattering mechanisms exist: specular, nonspecular trails, and head echoes. Generally, there are two types of radars utilized to detect meteors. Traditional VHF all-sky meteor radars primarily detect the specular trails, while high-power, large-aperture (HPLA) radars efficiently detect meteor head echoes and, in some cases, nonspecular trails. The fact that head echo measurements can be performed only with HPLA radars limits these studies in several ways. HPLA radars are sensitive instruments constraining the studies to the lower masses, and these observations cannot be performed continuously because they take place at national observatories with limited allocated observing time. These drawbacks can be addressed by developing head echo observing techniques with modified all-sky meteor radars. Such systems would also permit simultaneous detection of all different scattering mechanisms using the same instrument, rather than requiring assorted different classes of radars, which can help clarify observed differences between the different methodologies. In this study, we demonstrate that such concurrent observations are now possible, enabled by the enhanced design of the Southern Argentina Agile Meteor Radar (SAAMER). The results presented here are derived from observations performed over a period of 12 days in August 2011 and include meteoroid dynamical parameter distributions, radiants, and estimated masses. Overall, the SAAMER's head echo detections appear to be produced by larger particles than those which have been studied thus far using this technique., Facultad de Ciencias Astronómicas y Geofísicas

Observations of naturally enhanced ion acoustic lines (NEIALs) taken with the Poker Flat Incoherent Scatter Radar (PFISR) using a mode with very high time resolution are presented. The auroral event took place over Poker Flat, Alaska on 8 February 2007 at 09:35 UT (~22:00 MLT), and the radar data are complemented by common-volume high-resolution auroral imaging. The NEIALs occurred during only one of the standard 15-s integration periods. The raw data of this time show very intermittent NEIALs which occur only during a few very short time intervals (≤1 s) within the 15-s period. The time sampling of the raw data, ~19 ms on average, allows study of the time development of the NEIALs, though there are indications that even finer time resolution would be of interest. The analysis is based on the assumption that the NEIAL returns are the result of Bragg scattering from ion-acoustic waves that have been enhanced significantly above thermal levels. The spectra of the raw data indicate that although the up- and down-shifted shoulders can both become enhanced at the same time, (within 19 ms), they are most often enhanced individually. The overall power in the up-and down-shifted shoulders is approximately equal throughout the event, with the exception of one time, when very large up-shifted power was observed with no corresponding down-shifted power. This indicates that during the 480 μs pulse, the strongly enhanced ion-acoustic waves were only traveling downward and not upward. The exact time that the NEIALs occurred was when the radar beam was on the boundary of a fast-moving (~10 km/s), bright auroral structure, as seen in the high resolution auroral imaging of the magnetic zenith. When viewed with high time resolution, the occurrence of NEIALs is associated with rapid changes in auroral luminosity within the radar field of view due to fast-moving auroral fine structures.

We present results from a coordinated camera and radar study of the auroral ionosphere conducted during March of 2006 from Poker Flat, Alaska. The campaign was conducted to coincide with engineering tests of the first quarter installation of the Poker Flat Incoherent Scatter Radar (PFISR). On 31 March 2006, a moderately intense auroral arc, (~10 kR at 557.7 nm), was located in the local magnetic zenith at Poker Flat. During this event the radar observed 7 distinct periods of abnormally large backscattered power from the F-region. These were only observed in the field-aligned radar beam, and radar spectra from these seven times show naturally enhanced ion-acoustic lines (NEIALs), the first observed with PFISR. These times corresponded to (a) when the polar cap boundary of the auroral oval passed through the magnetic zenith, and (b) when small-scale filamentary dark structures were visible in the magnetic zenith. The presence of both (a) and (b) was necessary for their occurrence. Soft electron precipitation occurs near the magnetic zenith during these same times. The electron density in the vicinity where NEIALs have been observed by previous studies is roughly between 5 and 30×1010 m−3. Broad-band extremely low frequency (BBELF) wave activity is observed in situ by satellites and sounding rockets to occur with similar morphology, during active auroral conditions, associated with the poleward edge of the aurora and soft electron precipitation. The observations presented here suggest further investigation of the idea that NEIALs and BBELF wave activity are differently-observed aspects of the same wave phenomenon. If a connection between NEIALs and BBELF can be established with more data, this could provide a link between in situ measurements of downward current regions (DCRs) and dynamic aurora, and ground-based observations of dark auroral structures and NEIALs. Identification of in situ processes, namely wave activity, in ground-based signatures could have many implications. One specific example of interest is identifying and following the temporal and spatial evolution of regions of potential ion outflow over large spatial and temporal scales using ground-based optical observations.

Background The accuracy of estimating glomerular filtration rate from plasma creatinine (eGFR) has been questioned but it is unclear how much covert error in several reference methods that have been used has contributed to this perceived inaccuracy. The aim of the study was to evaluate eGFR in comparison with a second ‘gold standard’ to test the performance of the primary gold standard and to examine the influence of patient demographics (age, body mass index (BMI), extracellular fluid volume (ECV) and gender). Design Non-fasting multisample GFR and ECV were measured in 80 subjects simultaneously and independently with Cr-51-EDTA (GFREDTA) and iohexol (GFRiohexol). Percentage bias and imprecision in the prediction of, and disagreement with, GFREDTA were compared between eGFR and GFRiohexol. Another simplified method for measuring GFR, the slope-only method (SOGFR), was also evaluated against multisample GFR (measured with the opposing indicator). Accuracies were assessed in all subjects and across age, BMI and ECV boundaries of 65 y, 29 kg m−2 and 14 L. Results eGFR was less precise than GFRiohexol (imprecisions of 22·3% and 12·9%; P

The SIERRA nightside auroral sounding rocket made observations of the origins of ion upflow, at topside F-region altitudes (below 700 km), comparatively large topside plasma densities (above 20 000/cc), and low energies (10 eV). Upflowing ions with bulk velocities up to 2 km/s are seen in conjunction with the poleward edge of a nightside substorm arc. The upflow is limited within the poleward edge to a region (a) of northward convection, (b) where Alfvénic and Pedersen conductivities are well-matched, leading to good ionospheric transmission of Alfvénic power, and (c) of soft electron precipitation (below 100 eV). Models of the effect of the soft precipitation show strong increases in electron temperature, increasing the scale height and initiating ion upflow. Throughout the entire poleward edge, precipitation of moderate-energy (100s of eV) protons and oxygen is also observed. This ion precipitation is interpreted as reflection from a higher-altitude, time-varying field-aligned potential of upgoing transversely heated ion conics seeded by the low altitude upflow.

This prospective cohort study investigated the influence of an artificial playing surface on injury risk and perceptions of muscle soreness in elite English Premiership Rugby Union players. Time loss (from 39.5 matches) and abrasion (from 27 matches) injury risk was compared between matches played on artificial turf and natural grass. Muscle soreness was reported over the 4 days following one match played on each surface by 95 visiting players (i.e., normally play on natural grass surfaces). There was a likely trivial difference in the overall injury burden relating to time-loss injuries between playing surfaces [rate ratio = 1.01, 90% confidence interval (CI): 0.73-1.38]. Abrasions were substantially more common on artificial turf (rate ratio = 7.92, 90% CI: 4.39-14.28), although the majority of these were minor and only two resulted in any reported time loss. Muscle soreness was consistently higher over the 4 days following a match on artificial turf in comparison with natural grass, although the magnitude of this effect was small (effect sizes ranging from 0.26 to 0.40). These results suggest that overall injury risk is similar for the two playing surfaces, but further surveillance is required before inferences regarding specific injury diagnoses and smaller differences in overall injury risk can be made.

Shwachman-Diamond Syndrome (SDS) is an autosomal recessive disorder characterized by bone marrow failure with significant predisposition to the development of poor prognosis myelodysplasia and leukemia, exocrine pancreatic failure and metaphyseal chondrodysplasia. Although the SBDS gene mutated in this disorder is highly conserved in Archaea and all eukaryotes, the function is unknown. To interpret the molecular consequences of SDS-associated mutations, we have solved the crystal structure of the Archaeoglobus fulgidus SBDS protein orthologue at a resolution of 1.9 angstroms, revealing a three domain architecture. The N-terminal (FYSH) domain is the most frequent target for disease mutations and contains a novel mixed alpha/beta-fold identical to the single domain yeast protein Yhr087wp that is implicated in RNA metabolism. The central domain consists of a three-helical bundle, whereas the C-terminal domain has a ferredoxin-like fold. By genetic complementation analysis of the essential Saccharomyces cerevisiae SBDS orthologue YLR022C, we demonstrate an essential role in vivo for the FYSH domain and the central three-helical bundle. We further show that the common SDS-related K62X truncation is non-functional. Most SDS-related missense mutations that alter surface epitopes do not impair YLR022C function, but mutations affecting residues buried in the hydrophobic core of the FYSH domain severely impair or abrogate complementation. These data are consistent with absence of homozygosity for the common K62X truncation mutation in individuals with SDS, indicating that the SDS disease phenotype is a consequence of expression of hypomorphic SBDS alleles and that complete loss of SBDS function is likely to be lethal.

Since the 1980s the concept that chronic renal failure (CRF) progresses linearly and that the factors affecting progression may be separate from those initiating renal disease has dominated nephrology. In particular, the idea that hyperfiltration, rather than being a compensatory increase in the single nephron glomerular filtration rate (SNGFR) of surviving nephrons, was also the cause of their eventual demise, has thrown suspicion onto dietary protein as a factor sustaining progression. Much of the evidence rests on rats. This review concentrates on the evidence from humans and dogs and concludes that phosphate and glomerular hypertension, rather than protein are likely to accelerate progression. More important, self-sustaining progression is probably a terminal feature of CRF rather than the prevalent influence on its course. CRF is probably the result of a variety of cumulative renal insults and greater insight is therefore likely to come from the study of spontaneous renal diseases in animals, rather ...

Dogs have provided classic models of induced hypertension. This paper shows that despite being susceptible to hypertension, they are naturally resistant to its development even when renal function is severely compromised. The proportion of hypertensive dogs was almost as low among those with reduced glomerular filtration rate (GFR) (9%) as those with normal GFR (6%). Dogs with GFR less than 33% of the normal lower limit (with an average GFR equivalent to 10 mL min-1 in a 70-kg patient) had arterial pressures not significantly above normal. Only dogs with a GFR 33-75% of the lower limit of normal had significantly elevated systolic pressure, though none was actually hypertensive. Since there was no correlation between arterial pressure and GFR below 33% of lower limit, the dogs in the 33-75% range may be showing an effect of increased pressure, rather than a cause. In humans with GFR less than 33% of normal, the majority are hypertensive. Since various aspects of canine cardiovascular and renal function are comparable with humans, the question is why dogs, despite being capable of developing hypertension, are resistant to it, even when they have chronic renal insufficiency.

Sheep which were predominantly urinary excretors (U) or faecal excretors (F) of sodium were exposed to a 75% reduction of water intake for 72 h. The experiment was performed on moderate, low or high sodium intakes (0.4, 0.05 or 1.2 mmol kg-1 day-1) to test the hypothesis that dehydration natriuresis was not a cause of sodium depletion but a defence against hypernatraemia. Dehydration caused elevation of plasma sodium concentration, osmolality, antidiuretic hormone (ADH) and oxytocin but, as in other experiments, a fall in haematocrit. The two higher levels of sodium intake were associated with dehydration natriuresis but also a smaller increase in faecal sodium excretion in both U and F sheep. On low sodium intake, however, neither urinary nor faecal sodium excretion increased in either group of sheep although the rise in plasma sodium concentration caused by dehydration was similar. Thus, when there is a risk of sodium depletion, due to low sodium intake, dehydration natriuresis does not occur, consistent with the hypothesis. Active sodium transport inhibitor (ASTI) and atrial natriuretic peptide (ANP) fell rather than rose during dehydration. Since aldosterone is suppressed by the higher levels of sodium intake, none of these hormones is likely to mediate dehydration natriuresis in sheep. F sheep showed more effective renal and faecal water conservation when dehydrated. During water restriction, the urinary potassium excretion of U sheep was significantly reduced, unlike that of F sheep; moreover, the latter maintained an identical plasma potassium concentration between baseline and restriction period, whereas in U sheep it was 0.3 mmol l-1 higher during water restriction. Increased drinking rather than reduced urine output was the basis of rehydration when ad lib. water intake was restored.

This review outlines the importance of considering other aspects of treatment for underlying conditions, and other nursing measures, when fluid therapy is employed in small animal patients. The choice of fluid therapy should be based on rationally defined therapeutic targets and not following a strict set of procedures. Monitoring should also be a constant feature during fluid therapy so that adjustments can be made according to a patient's response to the treatment.

This review aims to provide information on the pathophysiological principles, most of them straightforward, which underpin the successful use of fluid therapy in the treatment of certain conditions. Attention is mainly focused on the concepts underlying parenteral fluid therapy, including some of the misconceptions inherent in this form of treatment. Finally, interesting trends in parenteral fluid therapy are identified.

The central focus of this review is the fact that the nutritional requirement for sodium in healthy adult mammals outside their reproductive period is unlikely to exceed 0.6 mmol/kg/ day; claims that it is greater in humans imply an unidentified defect in renal sodium conservation. Lack of awareness of nutritional requirement mars the design of many experiments, both on laboratory animals and clinical trials, with arbitrary attribution of groups to ‘low’ or ‘high’ intakes, the latter often absurdly high. Much of the problem arises from misplaced confidence that excess sodium is harmlessly excreted and that a generous excess is therefore salutary. Evidence for the link between dietary salt and hypertension is discussed. The focus of concern should be the fact that the age-related rise in human blood pressure is an accompaniment of excess salt intake rather than a natural phenomenon; even avoidance of this rise would exempt many from the need for treatment, later in life. Many of the putative risks of lower...

NEWS of the invention of the wheel seems to have escaped those busy reinventing or redefining it. The article by Paul Gibbs ( VR , January 25, 2014, vol 174, pp 85-91) is welcome for the wealth of encouraging detail that it provides, but its omissions are astonishing. No mention, for example, of two of the key protagonists, Calvin Schwabe, in the USA, and Lord Soulsby, in the UK, not least as chairman of the House of Lords report …

Progress in veterinary medicine is usually driven by advances originating from the much larger biomedical research community. However, the reverse can also be true, and this needs to be more widely acknowledged, argues Bob Michell , who discusses oral rehydration as an example

Sheep receiving a total of about 31 mmol day-1 (0.5 mmol kg-1) of sodium were classified according to the predominant route of sodium excretion; urinary (U) or faecal (F). U sheep had a greater water turnover than F sheep; their intake was 41% higher and they produced 133% more urine but there was little difference in faecal water loss. Most faecal sodium was readily exchangeable with water in both groups. When sodium intake was reduced by 80% (to 6 mmol day-1; 0.1 mmol kg-1), the reduction in total sodium excretion was equally effective in F sheep and U sheep after 48 h and after 2 weeks the overall losses of sodium were smaller in F sheep. On sodium intakes close to requirement (0.1 mmol kg-1 or less) the majority of the sheep excreted most of their sodium in faeces and did so on intakes up to 0.5 mmol kg-1 day-1. Excess dietary sodium is mainly excreted renally. When sodium intake is increased abruptly (by 20 mmol day-1, 0.3 mmol kg-1), total sodium excretion only increases gradually but after about 3 days it 'overshoots' as in humans.

Treatment of clinical cases of heart failure in dogs, using frusemide, was associated with statistically significant reductions in plasma concentrations of potassium, magnesium, sodium and chloride, compared with healthy controls and untreated dogs with dysrhythmias. The reductions in sodium and chloride seem too slight to be clinically significant but those in magnesium and potassium could potentially have harmful effects, including the induction of cardiac dysrhythmias. Indeed, diuretic-treated dogs with ventricular ectopic beats in their electrocardiograms had significantly lower plasma potassium concentrations than other dogs undergoing diuretic treatment. As potassium and magnesium are predominantly intracellular cations, the falls in plasma concentration may well be associated with substantial deficits within cells, including those of the myocardium.

In the period 1945–1965 the key features of the regulation of salt and water balance seemed to have emerged yet the next 20 years revealed an increasing disparity between physiological theory and clinical fact. During the 1980s it was recognised, belatedly, that the physiological defence against excess salt is almost as important as that against depletion and that two main types of hormone were vital in this defence. There was also increasing emphasis on the role of non-renal factors in the regulation of salt and water balance. Despite this rapid progress the paradox remains: all we know about the physiology of sodium balance still does not enable us to explain convincingly its three most obvious disturbances; cardiac, hepatic and nephrotic oedema. In this subject, clinical problems continue to provide the force behind the scientific advances.

The aim of the study was to determine the extent to which glomerular filtration rate (GFR) measured with one filtration marker is associated with extracellular fluid volume (ECV) measured independently with another. Cr-51-EDTA and iohexol were injected simultaneously into opposite arms in 20 normal volunteers and 60 patients. Cubital samples taken bilaterally at 20, 40, 60, 120, 180 and 240 min were assayed for marker injected contralaterally. GFR was scaled to body surface area of 1.73 m(2) (GFR/BSA). GFR was also expressed as marker transit time (GFR/ECV) and ECV as the product of marker transit time and GFR/BSA. In normal subjects, changes between fasting and non-fasting ECV/BSA correlated positively with changes in GFR/BSA, but not GFR/ECV. GFR/BSA and GFR/ECV correlated positively (regression slope approximately 4 ml.min(-1).litre(-1)) and negatively (-2.7 ml x min(-1) x litre(-1)), respectively, with ECV/BSA. The difference, 6.7 ml x min(-1) x litre(-1), expressed as a fraction of average scaled GFR ( approximately 90 ml x min(-1)) is close to the reciprocal of average ECV/BSA (13.5 litres.1.73 m(-2)), consistent with the expected slope of the regression on ECV/BSA of the difference-to-average ratio of GFR/BSA and GFR/ECV. In contrast, in 29 patients with impaired GFR (estimated from plasma creatinine), ECV/BSA correlated inversely with GFR/ECV (slope approximately -5 ml x min(-1) x litre(-1)) but showed no relation with GFR/BSA. We conclude that in normal subjects GFR/BSA increases in response to increasing ECV/BSA, but the increase is not proportionate, leading to a weak inverse association between GFR/ECV and ECV/BSA. When ECV is expanded in patients with renal impairment, however, there is no GFR response, leading to a reduction in GFR/ECV.

The concept of a regulatory link between the gastrointestinal tract and kidneys is not new. The idea that dietary intake and composition can affect renal function is perhaps self-evident, but defining this relationship, especially in terms of sensors and effectors, is proving more difficult. That the gastrointestinal tract can exert some control over renal function was strengthened by the early observation that oral ingestion of a sodium chloride load has a greater natriuretic effect than when the same amount is given intravenously. This effect was subsequently shown to be independent of changes in aldosterone and atrial natriuretic peptide, although not necessarily angiotensin-II. However, the nature of any intestinal natriuretic peptide remains uncertain, despite suggestions that various gut-derived hormones, including guanylin and uroguanylin, may be involved. There is also an emerging concept of gastrointestinal taste and taste-like receptor mechanisms present throughout the gastrointestinal tract, which may govern the excretion of other key electrolytes, including potassium and phosphate. The evidence for gut sensors of nutrients such as proteins, amino acids, glucose, and acid is now becoming more established. Thus, we can anticipate the existence and eventual characterization of several gut ion sensors.

Although the article by Reilly et al on physical activity to prevent obesity in young children emphasises that adherence to protocol was good,1 an interview with Reilly on the Today programme (7.20 am, 6 October 2006) cited the difficulty in getting children to increase their activity as much as required—that is, not a negative outcome, but a problem in achieving sufficient increase to make the intervention effective. Which was the case?

The reports from the Shipman inquiry will lead to changes in the way the medical profession is regulated. Bob Michell fears that the veterinary profession will be affected, too.

Shwachman-Diamond Syndrome (SDS) is an autosomal recessive disorder characterized by bone marrow failure with significant predisposition to the development of poor prognosis myelodysplasia and leukemia, exocrine pancreatic failure and metaphyseal chondrodysplasia. Although the SBDS gene mutated in this disorder is highly conserved in Archaea and all eukaryotes, the function is unknown. To interpret the molecular consequences of SDS-associated mutations, we have solved the crystal structure of the Archaeoglobus fulgidus SBDS protein orthologue at a resolution of 1.9 angstroms, revealing a three domain architecture. The N-terminal (FYSH) domain is the most frequent target for disease mutations and contains a novel mixed alpha/beta-fold identical to the single domain yeast protein Yhr087wp that is implicated in RNA metabolism. The central domain consists of a three-helical bundle, whereas the C-terminal domain has a ferredoxin-like fold. By genetic complementation analysis of the essential Saccharomyces cerevisiae SBDS orthologue YLR022C, we demonstrate an essential role in vivo for the FYSH domain and the central three-helical bundle. We further show that the common SDS-related K62X truncation is non-functional. Most SDS-related missense mutations that alter surface epitopes do not impair YLR022C function, but mutations affecting residues buried in the hydrophobic core of the FYSH domain severely impair or abrogate complementation. These data are consistent with absence of homozygosity for the common K62X truncation mutation in individuals with SDS, indicating that the SDS disease phenotype is a consequence of expression of hypomorphic SBDS alleles and that complete loss of SBDS function is likely to be lethal.

With medical general practitioners soon being able to buy themselves out of the requirement to provide overnight cover for their patients, for how much longer will the veterinary profession be able to sustain its 24-hour commitment? Here, Professor Bob Michell argues that it is time for the profession to rethink how it provides out-of-hours services--and, with the RCVS about to review the situation, concludes that something will have to change.

ON a busy day it would be easy to skim the contents of Veterinary Record and pass over an article on cadmium and feline hypertension. That would be a pity as the article by Finch and others (2011), summarised on p 125 in this week's Veterinary Record , is an introduction to an intriguing area of pathophysiology. It also reminds us of the very interesting biological molecules that are the metallothioneins and alerts us to a much larger body of excellent recent research on feline hypertension (Finch 2011). Metallothioneins are ubiquitous, small, cysteine-rich proteins that readily bind zinc, cadmium and copper; they occur in plants as well as animals (Hassinen and others 2011). They function as intracellular metal ‘buffers’ or ‘metallochaperones’, important in zinc and copper homeostasis and protecting against heavy metal toxicity and oxidative damage (Sutherland and Stillman 2011). There are four metallothioneins (MT1, 2, 3 and 4) of which MT1 and MT2 are inducible by a wide range of stimuli including metals, drugs and inflammatory mediators. Together with MT3 they may also have an important role in …

Acid-base balance and electrolyte concentrations, including ionised calcium, were monitored during intravenous fluid therapy of 1 1 collapsed diarrhoeic suckler calves aged five to 10 days. Six healthy calves of similar age and type were used to provide control data. All the diarrhoeic calves were severely acidotic (TCO 2