Mice Deficient in T-bet Form Inducible NO Synthase-Positive Granulomas That Fail to Constrain Salmonella.

Clearance of intracellular infections caused by Salmonella Typhimurium (STm) requires IFN-γ and the Th1-associated transcription factor T-bet. Nevertheless, whereas IFN-γ-/- mice succumb rapidly to STm infections, T-bet-/- mice do not. In this study, we assess the anatomy of immune responses and the relationship with bacterial localization in the spleens and livers of STm-infected IFN-γ-/- and T-bet-/- mice. In IFN-γ-/- mice, there is deficient granuloma formation and inducible NO synthase (iNOS) induction, increased dissemination of bacteria throughout the organs, and rapid death. The provision of a source of IFN-γ reverses this, coincident with subsequent granuloma formation and substantially extends survival when compared with mice deficient in all sources of IFN-γ. T-bet-/- mice induce significant levels of IFN-γ- after challenge. Moreover, T-bet-/- mice have augmented IL-17 and neutrophil numbers, and neutralizing IL-17 reduces the neutrophilia but does not affect numbers of bacteria detected. Surprisingly, T-bet-/- mice exhibit surprisingly wild-type-like immune cell organization postinfection, including extensive iNOS+ granuloma formation. In wild-type mice, most bacteria are within iNOS+ granulomas, but in T-bet-/- mice, most bacteria are outside these sites. Therefore, Th1 cells act to restrict bacteria within IFN-γ-dependent iNOS+ granulomas and prevent dissemination

Clinical symptoms, signs and tests for identification of impending and current water-loss dehydration in older people (Review)

BackgroundThere is evidence that water-loss dehydration is common in older people and associated with many causes of morbidity and mortality.However, it is unclear what clinical symptoms, signs and tests may be used to identify early dehydration in older people, so that support can be mobilised to improve hydration before health and well-being are compromised.ObjectivesTo determine the diagnostic accuracy of state (one time), minimally invasive clinical symptoms, signs and tests to be used as screeningtests for detecting water-loss dehydration in older people by systematically reviewing studies that have measured a reference standard and at least one index test in people aged 65 years and over. Water-loss dehydration was defined primarily as including everyone with either impending or current water-loss dehydration (including all those with serum osmolality ≥ 295 mOsm/kg as being dehydrated).Search methodsStructured search strategies were developed for MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL, LILACS, DARE and HTAdatabases (The Cochrane Library), and the International Clinical Trials Registry Platform (ICTRP). Reference lists of included studiesand identified relevant reviews were checked. Authors of included studies were contacted for details of further studies.Selection criteriaTitles and abstracts were scanned and all potentially relevant studies obtained in full text. Inclusion of full text studies was assessed independently in duplicate, and disagreements resolved by a third author. We wrote to authors of all studies that appeared to have collected data on at least one reference standard and at least one index test, and in at least 10 people aged ≥ 65 years, even where no comparative analysis has been published, requesting original dataset so we could create 2 x 2 tables.Data collection and analysis.Diagnostic accuracy of each test was assessed against the best available reference standard for water-loss dehydration (serum or plasma osmolality cut-off≥295mOsm/kg, serumosmolarity or weight change) within each study. For each index test study data were presented in forest plots of sensitivity and specificity. The primary target condition was water-loss dehydration (including either impending or current water-loss dehydration). Secondary target conditions were intended as current (> 300 mOsm/kg) and impending (295 to 300 mOsm/kg) water-loss dehydration, but restricted to current dehydration in the final review.We conducted bivariate random-effects meta-analyses (Stata/IC, StataCorp) for index tests where there were at least four studies and study datasets could be pooled to construct sensitivity and specificity summary estimates. We assigned the same approach for index tests with continuous outcome data for each of three pre-specified cut-off points investigated.Pre-set minimum sensitivity of a useful test was 60%, minimum specificity 75%. As pre-specifying three cut-offs for each continuoustest may have led to missing a cut-off with useful sensitivity and specificity, we conducted post-hoc exploratory analyses to createreceiver operating characteristic (ROC) curves where there appeared some possibility of a useful cut-off missed by the original three.These analyses enabled assessment of which tests may be worth assessing in further research. A further exploratory analysis assessed the value of combining the best two index tests where each had some individual predictive ability.Main resultsThere were few published studies of the diagnostic accuracy of state (one time), minimally invasive clinical symptoms, signs or tests tobe used as screening tests for detecting water-loss dehydration in older people. Therefore, to complete this review we sought, analysed and included raw datasets that included a reference standard and an index test in people aged ≥ 65 years.We included three studies with published diagnostic accuracy data and a further 21 studies provided datasets that we analysed. Weassessed 67 tests (at three cut-offs for each continuous outcome) for diagnostic accuracy of water-loss dehydration (primary targetcondition) and of current dehydration (secondary target condition).Only three tests showed any ability to diagnose water-loss dehydration (including both impending and current water-loss dehydration) as stand-alone tests: expressing fatigue (sensitivity 0.71 (95% CI 0.29 to 0.96), specificity 0.75 (95% CI 0.63 to 0.85), in one study with 71 participants, but two additional studies had lower sensitivity); missing drinks between meals (sensitivity 1.00 (95% CI 0.59 to 1.00), specificity 0.77 (95% CI 0.64 to 0.86), in one study with 71 participants) and BIA resistance at 50 kHz (sensitivities 1.00 (95% CI 0.48 to 1.00) and 0.71 (95% CI 0.44 to 0.90) and specificities of 1.00 (95% CI 0.69 to 1.00) and 0.80 (95% CI 0.28 to 0.99) in 15 and 22 people respectively for two studies, but with sensitivities of 0.54 (95% CI 0.25 to 0.81) and 0.69 (95% CI 0.56 to 0.79) and specificities of 0.50 (95% CI 0.16 to 0.84) and 0.19 (95% CI 0.17 to 0.21) in 21 and 1947 people respectively in two other studies). In post-hoc ROC plots drinks intake, urine osmolality and axillial moisture also showed limited diagnostic accuracy. No test was consistently useful in more than one study.Combining two tests so that an individual both missed some drinks between meals and expressed fatigue was sensitive at 0.71 (95%CI 0.29 to 0.96) and specific at 0.92 (95% CI 0.83 to 0.97).There was sufficient evidence to suggest that several stand-alone tests often used to assess dehydration in older people (including fluid intake, urine specific gravity, urine colour, urine volume, heart rate, dry mouth, feeling thirsty and BIA assessment of intracellular water or extracellular water) are not useful, and should not be relied on individually as ways of assessing presence or absence of dehydration in older people.No tests were found consistently useful in diagnosing current water-loss dehydration.Authors’ conclusionsThere is limited evidence of the diagnostic utility of any individual clinical symptom, sign or test or combination of tests to indicatewater-loss dehydration in older people. Individual tests should not be used in this population to indicate dehydration; they miss a highproportion of people with dehydration, and wrongly label those who are adequately hydrated.Promising tests identified by this review need to be further assessed, as do new methods in development. Combining several tests may improve diagnostic accuracy

Phase relationships of North Atlantic ice-rafted debris and surface-deep climate proxies during the last glacial period

We report stable isotope, core scanning XRF, and ice-rafted detritus (IRD) data in glacial-aged sediments from piston Core KN166-14-JPC-13 (hereafter referred to as JPC-13) retrieved at 53.1°N 33.5°W on the southern Gardar Drift, North Atlantic. A chronology was established by correlating millennial-scale features in the benthic [delta]18O record to Portuguese Margin Core MD95-2042. Once the alignment of benthic [delta]18O of JPC-13 to MD95-2042 is fixed, the relative timing of proxy variables is used to determine the phasing of changes in IRD and surface-deep hydrography. Each peak in North Atlantic IRD coincided with a decrease in benthic [delta]18O that, in turn, has been linked to warming in Antarctica (Events A1-A7). The IRD pulses are followed shortly thereafter by abrupt decreases in planktonic [delta]18O, indicating warming and increased heat transport to the subpolar North Atlantic associated with Greenland interstadials (GIS) 8, 12,14, and 16-17. Grain-size and elemental (K/Ti) variations indicate that Iceland-Scotland Overflow Water (ISOW) was stronger during these long, warm interstadial periods of Marine Isotope Stage (MIS) 3. The results are consistent with interhemispheric phase relationships inferred from Iberian Margin sediment cores and with methane synchronization of Greenland and Antarctic ice cores

Multichannel Seismic Investigations of Sediment Drifts on the west Antarctic Peninsula Pacific Margin: Preliminary Results from Research Cruise JR298

Observations across both the West Antarctic and Antarctic Peninsula ice sheets over recent decades have confirmed that the region is warming and undergoing major and potentially rapid changes as a result. These changes have manifest in the form of significant ice-sheet thinning and retreat, and in dramatic short-lived events such as ice-shelf collapses. The longer-term backdrop to this recent change is vital information for our understanding of future ice and climate evolution, and for wider knowledge of ice-sheet function and sensitivity. Providing context on geological timescales, such records can be obtained from two main sources: (1) from ice cores extracted from the ice sheet interiors and (2) from continuous marine sedimentary sequences recovered from the sea floor surrounding the Antarctic continent. Whilst ice cores provide a very high-resolution archive of palaeo-climate, they offer data over only a relatively short window of time (<1 million years) and provide little information on how the ice and oceans were changing at the ice sheet periphery. By contrast, sediments derived from the Antarctic continent have discharged continuously to the continental slope and deeper ocean over millions of years, and are sensitive recorders of both ice sheet an oceanographic variability. Repeated continental margin-derived turbidity currents, in combination with the activity of along-slope currents, have led to the accumulation of large hemi-pelagic depositional bodies, termed sediment drifts that are, today, oriented orthogonal to the continental margin and record continuous sedimentation on the continental rise since at least the Miocene. Along the Antarctic Peninsula Pacific margin, a chain of twelve large sediment drifts separated out by channels eroded by turbidity currents provide unique archives of environmental changes in Antarctica‘s ice sheets and the Southern Ocean. IODP proposal 732FULL2 aims to recover drill cores extending back into the Pliocene from the crests of a number of the drifts, as well as from the top of the Belgica trough mouth fan, during a future leg to the region. Two further sites will recover older strata that can be accessed at relatively shallow depth by drilling through eroded drift flanks where the overburden is particularly thin. However, before recovering sequences from these bodies, a full understanding of their geometry, internal architecture, age and stratigraphic evolution is required. We present preliminary results from recent Natural Environment Research Council (UKIODP Programme) funded site survey cruise JR298 that obtained high-resolution multichannel seismic (MCS) reflection data over the proposed drill sites and adjacent working areas. A first look at the seismic data from several of the drilling targets will be presented, and some initial interpretations regarding the (i) sedimentary processes that operated during the formation and evolution of the drifts and fan, and (ii) links between depositional systems on the continental rise, palaeo-ice-sheet dynamics and past oceanographic processes within the datasets will be discussed. Further geophysical analyses, in combination with marine sediment cores retrieved from the proposed sites, will aim to shed light upon continental margin sediment delivery, Antarctic ice-sheet history and stability, and Antarctic margin palae-oceanography that form the key scientific objectives of the planned drilling campaign

Searching for the most detailed, continuous, late Miocene to Quaternary records of Antarctic Peninsula and West Antarctic Ice Sheet dynamics

Changes observed in the West Antarctic Ice Sheet (WAIS) and Antarctic Peninsula Ice Sheet (APIS) over recent decades include thinning and break up of ice shelves, glacier flow acceleration and grounding line retreat. How rapidly and how far these ice sheets will retreat in a warmer climate, however, remains uncertain. For example, it remains unclear whether or not the marine-based WAIS “collapsed” during Quaternary interglacial periods, including the last one, contributing more than 3 m to global sea-level rise. Continuous long-term records of ice sheet change with precise chronology are needed in order to answer these questions. On the Antarctic continental shelf, sedimentary records are interrupted by numerous unconformities resulting from glacial erosion, good core recovery has only been achieved from platforms sited on sea ice or ice shelves, and establishing reliable chronologies has proved challenging. In contrast, sediment drifts on the upper continental rise around Antarctica contain expanded, continuous successions dominated by muddy lithologies from which good recovery can be achieved using standard scientific ocean drilling methods. Ocean Drilling Program (ODP) Leg 178 demonstrated that sediment drifts west of the Antarctic Peninsula contain a rich high-resolution archive of Southern Ocean paleoceanography and APIS history that extends back to at least the late Miocene. The potential of existing ODP cores from the drifts is, however, compromised by incomplete composite sections and lack of precise chronological control. An International Ocean Discovery Program proposal (732-Full2) for future drilling on these drifts has been scientifically approved and is with the JOIDES Resolution Facilities Board for scheduling. The main aims of the proposal are to obtain continuous, high-resolution records from sites on sediment drifts off both the Antarctic Peninsula and West Antarctica (southern Bellingshausen Sea). The challenges will then be achieving good chronological control using a range of established and novel techniques and interpreting what facies variations indicate in terms of changes in the ice sheets. During a 2015 research cruise on RRS James Clark Ross (JR298) we obtained additional site survey data around the proposed sites including high-resolution multichannel seismic reflection data, piston cores and box cores. We will present results from this cruise and interpret them in terms of sedimentary processes that operated during the development of the drifts, and links between depositional systems on the continental rise, paleoice-sheet dynamics and paleoceanographic processes

Mice deficient in T-bet form inducible NO synthase-positive granulomas that fail to constrain Salmonella

Clearance of intracellular infections caused by Salmonella Typhimurium (STm) requires IFN-γ and the Th1-associated transcription factor T-bet. Nevertheless, whereas IFN-γ-/- mice succumb rapidly to STm infections, T-bet-/- mice do not. In this study, we assess the anatomy of immune responses and the relationship with bacterial localization in the spleens and livers of STm-infected IFN-γ-/- and T-bet-/- mice. In IFN-γ-/- mice, there is deficient granuloma formation and inducible NO synthase (iNOS) induction, increased dissemination of bacteria throughout the organs, and rapid death. The provision of a source of IFN-γ reverses this, coincident with subsequent granuloma formation and substantially extends survival when compared with mice deficient in all sources of IFN-γ. T-bet-/- mice induce significant levels of IFN-γ- after challenge. Moreover, T-bet-/- mice have augmented IL-17 and neutrophil numbers, and neutralizing IL-17 reduces the neutrophilia but does not affect numbers of bacteria detected. Surprisingly, T-bet-/- mice exhibit surprisingly wild-type-like immune cell organization postinfection, including extensive iNOS+ granuloma formation. In wild-type mice, most bacteria are within iNOS+ granulomas, but in T-bet-/- mice, most bacteria are outside these sites. Therefore, Th1 cells act to restrict bacteria within IFN-γ-dependent iNOS+ granulomas and prevent dissemination