However, despite their importance to the global climate history they have never been recorded in shallow marine carbonate successions. The Decontra section on the Maiella Platform , however, allows to resolve them for the first time in such a setting during the early to middle Miocene. The present study improves the stratigraphic resolution of parts of the Decontra section via orbital tuning of high‐resolution gamma ray (GR) and magnetic susceptibility data to the 405 kyr eccentricity metronome. The tuning allows, within the established biostratigraphic, sequence stratigraphic, and isotope stratigraphic frameworks, a precise correlation of the Decontra section with pelagic records of the Mediterranean region, as well as the global paleoclimatic record and the global sea level curve. Spectral series analyses of GR data further indicate that the 405 kyr orbital cycle is particularly well preserved during the Monterey Event. Since GR is a direct proxy for authigenic uranium precipitation during increased burial of organic carbon in the Decontra section, it follows the same long‐term orbital pacing as observed in the carbon isotope records. The 405 kyr GR beat is thus correlated with the carbon isotope maxima observed during the Monterey Event. Finally, the Mi‐events can now be recognized in the δ Orbitally tuned shallow marine carbonate succession in the Mediterranean regionCorrelation of Mi‐ and CM‐events within Miocene shallow marine carbonatesGamma ray and magnetic susceptibility as proxies on isolated carbonate ramps All of which are well recorded in pelagic successions, especially by stable carbon and oxygen isotope records and the resulting global δMiller et al., Woodruff and Savin, Woodruff and Savin, Miller et al., Westerhold et al., Holbourn et al., John et al., Mourik et al., Mutti et al., Mutti et al., Mutti and Bernoulli, Brandano et al., Reuter et al., Extensive records of both the Miocene oxygen isotope excursions (Mi‐events) [Mutti et al., Mutti et al., Reuter et al., For the correlation of shallow marine carbonate records with pelagic reference sections different methods have been developed and applied more or less successfully. Biostratigraphy is still the preferred method to place shallow marine sections into the global chronostratigraphy. Since planktonic marker species are mostly rare in these settings, biostratigraphy is often of only limited use for correlation with the global chronostratigraphy [e.g., Mutti et al., John et al., Brandano et al., Iryu et al., Reuter et al., 13C stratigraphy is still comparably low, limiting environmental interpretation as well as the accuracy of the correlation of shallow marine sections to higher resolution global records. One possible way to achieve an increase in stratigraphic resolution would be the application of astrochronology and orbital tuning in order to refine stratigraphic models established with conventional methods.Carbon isotope stratigraphy is a widely used method for stratigraphic correlations and the paleoclimatic interpretation and timing of environmental changes [Hilgen et al., Westerhold et al., Lirer et al., Mourik et al., Hinnov and Hilgen, Zeeden et al., Hilgen et al., Abels et al., Westerhold et al., Raffi et al., Lirer et al., Mourik et al., Zeeden et al., Zachos et al., Wade and Pälike, Pälike et al., Holbourn et al., Astrochronology became a standard method for the temporal refinement of the geological record [In this study we apply astrochronological principles to two geophysical proxy records (gamma ray and magnetic susceptibility) of an already biostratigraphically and chemostratigraphically dated succession of shallow water carbonates of the Maiella Platform , in order to investigate a possible expression of Mi‐ and CM‐events in the section. Furthermore, the use of orbital tuning of the section using the 405 kyr eccentricity “metronome” improved the already established age model.2The studied section is located in the northwest of the Maiella mountain range in eastern Central Italy. The 120 m thick Decontra section is exposed along a trail near the village Decontra leading into the Orfento river‐valley. The base of the lithostratigraphic section is located at the GPS coordinates 42°09′43.5″N, 014°02′21.6″E at the far end of the trail from the village . Results are reported in total counts (GR) and dimensionless SI units (MS). Measuring distances were 10 cm for GR and 5 cm for MS, based on size restriction of the used devices. Results of the measurements are summarized in Table Reuter et al. [During the logging of the section high‐resolution geophysical measurements, including total gamma radiation (GR) and magnetic susceptibility (MS), were carried out on site [r et al. .18O and δ13C) were measured on 89 bulk samples. TOC and carbonate were measured using a LECO CS300 analyzer at the University of Graz. For TOC 0.1–0.15 g of powdered bulk sample was decalcified using 2N HCl  prior to the LECO analysis. To calculate the carbonate content of the samples the total carbon (TC) was first measured for each bulk sample. Afterward total inorganic carbon (TIC) was calculated by subtracting the TOC from the TC content in each sample. Carbonate content was then calculated as calcite equivalent percentages using TIC with the stoichiometric formula (TIC × 8.34) [Reuter et al., Total organic carbon (TOC), carbonate content, and stable isotopes . The REDFIT settings used for each data set are shown in Figure Schulz and Mudelsee, Since different sedimentation rates within lithological units are likely, all subsequent analyses were conducted separately on each unit. Spectral analyses for both GR and MS were performed using REDFIT and Wavelet spectra . Linear interpolation was performed with double the original sample points in order to reduce aliasing of the data series. Interpolated data sets were used for both wavelet analysis as well as the used Gaussian band‐pass filters.The data sets were reinterpolated using Analyseries  and magnetic susceptibility (MS) values are relatively low throughout the section, they show clear patterns Figure . MS showReuter et al., Stonecipher, Nähr et al., Calcium carbonate content of the section typically varies between 90% and 95% in the Bryozoan Limestone as well as the lower part of the Cerratina cherty Limestone. Marked decreases (down to ~70%) occur in the upper part of the Cerratina cherty Limestone, which coincide with recorded occurrences of “marl layers” described in the literature [Reuter et al., Conversely, total organic carbon (TOC) is quite low throughout the section. Overall, the recorded trends of TOC seem to be directly related to lithology within the section. Average values for the Cerratina cherty Limestone are reported above ~0.2%, while the Bryozoan Limestone consistently shows values ranging from ~0.1 to ~0.15% TOC Figure . The pos4.2Reuter et al., REDFIT analysis of both GR and MS measurements resulted in significant peaks for both studied units, which are summarized in Table Laskar et al. [Calculating the sedimentation rates for both the Bryozoan and Cerratina cherty Limestones in this manner results in a good fit of the selected periodicities with the long (~405 kyr) and short (~100 kyr) eccentricity, as well as obliquity (~41 kyr). Sedimentation rates were then adjusted to improve the fit with the reported periodicities of known orbital cycles, resulting in the present age model Table . Supportr et al.  performeSignificant spectral peaks that fit orbital cyclicities using the estimated sedimentation rates for the Cerratina cherty Limestone are recorded at periodicities of 0.22 m, 0.54 m, and 2.28 m, respectively, with significances well above, or close to, the 95% AR1 Monte Carlo tested confidence interval  are not well reflected in the GR record. The absence of higher‐frequency peaks can be explained by the lower resolution of the GR measurements compared to that of the MS record.Wavelet spectra calculated using the reinterpolated data sets support the detected periodicities in GR and MS in both Cerratina cherty Limestone and Bryozoan Limestone. Additionally, the resolution of the wavelet spectra appears to be better for higher (shorter) frequencies (periodicities) for the GR signal, which in turn allows a better identification of the 100 kyr and 41 kyr peak in the Bryozoan Limestone Figure . NotableFilters of the assumed 405 kyr periodicity were examined for shifts in amplitude in GR and MS for both studied units, respectively. Amplitudes for the MS in the Cerratina cherty Limestone are strong in the lower part of the unit. The middle part is characterized by a slow decrease in amplitude, before an increase can be observed right at the boundary to the Bryozoan Limestone. Amplitudes for GR broadly reflect the trends of MS but are generally lower and less pronounced, reflecting the low‐significance 405 kyr peak recorded in the REDFIT power spectrum of GR.Within the Bryozoan Limestone the 405 kyr filter of MS shows constantly strong amplitudes, except for a single peak, that records a marked amplitude minimum in the middle part of the section. This amplitude minimum correlates directly with a planktonic foraminifera‐dominated Limestone that occurs in the middle part of the Bryozoan Limestone Figures  and 7. T55.1Reuter et al. [McManus et al., Reuter et al., r et al.  interpreMcManus et al., McManus et al., Chase et al., Anderson et al., McManus et al., McManus et al., McManus et al., Recent studies underscored the strong relationship between uranium precipitation, organic carbon rain, and prevailing redox conditions [e.g., Klinkhammer and Palmer, Russell et al., Föllmi, Mutti and Bernoulli, Reuter et al., Veizer, ten Kuile and Erez, Russell et al., Dunk et al., Russell et al., Accepting these hypotheses, it can be assumed that higher‐order variations observed in the natural gamma radiation of the Decontra section are likely a direct proxy for burial rates of organic matter. While it is currently unknown in which mineral phase uranium is preserved in the Decontra section, only calcium fluorapatite or calcium carbonate seems likely options considering the known lithology of the section [Veeh et al., Ku et al., Anderson, Zheng et al., Furthermore, dissolved uranium concentrations in the water column are rather unresponsive to changes caused by varying terrigenous input, since uranium is known to have a long residence time in the ocean (200–400 kyr) [5.2Ellwood et al., da Silva et al., Hladil et al., Karlin et al., Sparks et al., Hladil et al., Simmons et al., Kopp and Kirschvink, Magnetic susceptibility in carbonates deposited on isolated carbonate platforms can result from two different processes: (1) Deposition of detrital paramagnetic and ferromagnetic particles by means of aeolian transport processes [e.g., Bar‐Or et al., Reuter et al. [For aeolian transport of magnetic particles, variations in glaciation are suspected as major controlling factor. This is based on the assumption that higher surface area glaciation increased dust flux in the atmosphere through stronger surface winds, lowered surface humidity, and soil moisture, as well as increased desertification as a result of falling sea levels and decreases in vegetation [r et al.  as the mAissaoui et al., McNeill, Maloof et al., Kopp and Kirschvink, Kopp and Kirschvink, Kopp and Kirschvink, Hesse, Lean and McCave, Yamazaki and Kawahata, Kopp and Kirschvink, However, studies on the magnetic properties of platform carbonates in recent and ancient sediments suggest that magnetic susceptibility in carbonates with low‐terrigenous input is predominantly caused by the activity of magnetotactic bacteria [Kopp and Kirschvink, However, this relationship is only true when a significant amount of organic carbon is present in the first place to create an extended OATZ. In areas exhibiting habitually low organic carbon concentrations (≤0.4 wt %) the OATZ will never develop strong enough to facilitate an extensive population of magnetotactic bacteria [Applying these assumptions to the Decontra section where TOC levels are generally low (ranging from 0.06 to 0.31 wt %), variations in magnetic susceptibility are most likely related to an increase in organic carbon burial during times of higher primary productivity that caused the formation of an OATZ conductive to the growth of magnetotactic bacteria. Conversely, during times of lower productivity the generally rather high water energy at the Maiella carbonate ramp—especially in the Bryozoan Limestone—inhibited the establishment of anoxic conditions in the sediment largely preventing the growth of magnetotactic bacteria.5.3Cramer et al., Wade and Pälike, Holbourn et al., Mourik et al., Diester‐Haass et al., The available evidence can now be used to propose a positive feedback of primary productivity on both GR and MS data within the Decontra section. It can thus be assumed that the phase relationship of the two records with orbital eccentricity should be the same as other primary productivity proxies. It is further well established that increases in primary productivity are generally associated with eccentricity minima during the Oligocene/Miocene [see The correlation of long‐term GR maxima and with pronounced amplitude minima of the eccentricity curve, as well as larger trends in the MS record with the eccentricity amplitude modulation, offer additional support for the assumed phase relationship Figures .5.4Mutti et al., Reuter et al., Reuter et al., Praeorbulina, (2) the occurrences of Nephrolepidina praemarginata and N. morgani [Reuter et al., Lithothamnium Limestone [Carnevale et al., Until recently the poor biostratigraphic resolution of the Decontra section was a well‐known problem, which was resolved by applying chemostratigraphy as a main correlation tool [e.g., Praeorbulina is of particular importance as it constrains the age of the upper part of the Cerratina cherty Limestone. The currently accepted global first appearance datum (FAD) of Praeorbulina scianus occurs at 16.38 Ma [Wade et al., Iaccarino et al., Turco et al., Praeorbulina lineage is still highly debated. Nevertheless, the appearance of Globigerinoides sicanus with a morphotype showing a near‐spherical outline can be dated to 16.177 Ma in the Mediterranean, which significantly postdates the FO of Globigerinoides sicanus (in a broad sense) in the northern Atlantic, which occurs at 16.844 Ma [Iaccarino et al., Praeorbulina lineage in the northern Atlantic significantly predates the global datum, an occurrence of older specimen cannot be excluded in the Mediterranean. However, all currently available data support a maximum age of 16.177 Ma for the first occurrence of Praeorbulina in the Mediterranean. Based on the currently available data, this datum also needs to be assumed as correct for the Decontra section  of Praeorbulina, the FO of the taxon only offers a broadly constrained tie point by itself. Combining this loose tie point with constraints provided by chemostratigraphy allows an independent confirmation. Particularly, the correlation of the marked carbon isotope excursion correlated with the Monterey event, which lasted from ~16.9 to 13.5 Ma, would be shifted to an age of ~17.7 to ~14.3 Ma, if the maximum reported age (16.844 Ma) of the FO of Praeorbulina is used for the Decontra section. Using the onset of the Monterey event, defined by chemostratigraphic data, as an additional tie point, thus furthermore constrains the FO of Praeorbulina in the section roughly between the currently accepted local Mediterranean FO (16.177 Ma) and the proposed global FAD of Praeorbulina sicana (16.38 Ma)  [Reuter et al., 18O and δ13C records to the respective global records of Zachos et al. [Reuter et al. [Similarly, the occurrence of s et al.  by Reuter et al. .Reuter et al., Reuter et al., Praeorbulina cannot be older than 16.38 Ma. (4) The FO of Praeorbulina in the Decontra section is likely not the FAD, making this horizon likely younger than the maximum 16.177 Ma (16.38 Ma?) datum. (5) Cyclic variations in both the GR and MS record reflect variations in primary productivity that can be directly linked to changes in the orbital parameters. (6) Primary productivity maxima are correlated with minima in the long eccentricity cycle. (7) Sedimentation rates stayed reasonably constant within the lithological units of the section and no significant (recognizable) hiatuses occurred within the considered interval.Based on this biostratigraphic and chemostratigraphic frameworks, we are now able to use the cyclic variations detected in the MS and GR record to further tune the section to the long (405 kyr) eccentricity parameter. For this approach we used assumptions resulting from the preceding discussion: (1) The total age range of the Cerratina cherty Limestone is known to be from middle Aquitanian to late Burdigalian/early Langhian Figure  [Reuter Praeorbulina in the upper part of the Cerratina cherty Limestone with the first 405 kyr eccentricity minimum following the 16.177 Ma Mediterranean FO of Praeorbulina . This aFollowing this initial tuning to the 405 kyr filter, it was subsequently possible to correlate the eccentricity minima to smaller peaks in the MS and, to a smaller degree, in the lower resolution GR record. The current tuning thus results from the well‐constrained correlation with the 405 kyr eccentricity cycles, especially during the Monterey event, while offering a tentative tuning to the orbital eccentricity on a 100 kyr scale Figure . The tunWade and Pälike [Woodruff and Savin, Miller et al., Flower and Kennett, Zachos et al., Since no significant hiatus occurs between the transition from the Cerratina cherty Limestone to the Bryozoan Limestone, we correlated the minima in both filtered MS and GR with the 405 kyr eccentricity maxima of Cycle 37 (37 MI‐C5Bnr after the scheme of d Pälike ) at 15.25.5Vincent and Berger, Jacobs et al., John et al., Sprovieri et al., Brandano et al., Mourik et al., Reuter et al., Reuter et al. [The Monterey Excursion [r et al.  were abl13C record of the Monterey Excursion were first recognized by Woodruff and Savin [Jacobs et al., John et al., Abels et al., Mourik et al., Internal periodic variations in the δnd Savin , who defHolbourn et al., Mourik et al., More recently, improvements in orbital theory and orbital tuning of Integrated Ocean Drilling Program sites allowed a detailed interpretation of the CMs and to link their occurrences to the 405 kyr eccentricity cycle [Accepting the hypothesis that natural gamma radiation is a proxy for estimating organic carbon burial rates in isolated carbonate settings implies that maxima in GR and the carbon isotope maxima during the Monterey Excursion were caused by changes of the same ecological parameters. This, in turn, would indicate that GR maxima in the Decontra section should align well with the reported CMs of the Monterey Excursion.Weedon, 13C maxima.Unfortunately, the 405 kyr eccentricity signal is not well expressed in the GR signal of the Cerratina cherty Limestone, as result of increased aliasing caused by lower measurement rates [see Testing this hypothesis clearly shows that the observed GR maxima in the Bryozoan Limestone coincide closely with the occurrences of CMs during the time from 15 to 13.5 Ma Figures  and 7. F5.6Woodruff and Savin [Miller et al., Wright and Miller, Miller et al., Westerhold et al., John et al., Westerhold et al. [John et al. [Gradstein et al., Analogous to the carbon isotope maxima recorded by nd Savin , similard et al. , John etn et al. , and theUsing the new tuning of the Decontra section, all known oxygen isotope shifts (except Mi4) can now be directly correlated with significant sedimentological features observed in the Decontra section that can be interpreted to reflect changes in local paleoenvironmental conditions during the Mi‐events:Gattacceca et al., Brandano et al., Reuter et al., 2 and other nutrients causing higher primary productivity are a well‐known effect of volcanic events in the modern ocean [e.g., Uematsu et al., Mi1b can be correlated with the first occurrence of cherty limestone in the Cerratina cherty Limestone, expressed by a marked decrease in carbonate content (<70%) of the section. The generally high content of siliceous fossils in the Cerratina cherty Limestone is a result of extensive marine volcanism during the rotation of the Sardinia‐Corsica block between ~22 and 15 Ma [Mutti et al., Reuter et al., The coincidence of a cherty layer containing silica and clinoptilolite with the Mi1b event points toward an increased input of siliceous skeletal material during that time. The silica is derived from siliceous sponges and radiolarians [Similarly, Mi2a seems to be expressed by the occurrence of a second cherty layer in the Cerratina cherty Limestone, followed by a layer containing spiculitic chert nodules. Thus, production of siliceous plankton and sponges again increased during Mi2a at the Maiella Platform. The layer containing spiculitic chert nodules possibly points toward increased upwelling‐derived primary productivity causing extensive growth of siliceous sponges during the later stage of Mi2a.John et al., Föllmi, Mutti and Bernoulli, Mi2b [after Thiede, Sautter and Thunell, Curry et al., Little et al., Vecsei and Sanders, Eguchi et al., Flower and Kennett, Mutti and Bernoulli, The onset of Mi3a can be correlated to the first occurrence of a bed of planktonic foraminiferan limestone in the lower quarter of the Bryozoan Limestone  are either expressed as plankton‐rich , siliceous (Mi1b and Mi2), or phosphatic (Mi2b) horizons in the Decontra section. Siliceous horizons only occur in die Cerratina cherty Limestone deposited during the time of the Sardinia‐Corsica block rotation (~22–15 Ma.) [Reuter et al., 18O record precluded a more detailed correlation with the global oxygen isotope records.Although the oxygen isotope record of the Decontra section is at least partly altered by diagenesis, general patterns related to changes in local paleoceanographic conditions are still recognizable [18O record of the Decontra section and the global oxygen isotope stack of Zachos et al. [18O excursions (Mi1b to Mi5a) with positive excursions of the Decontra oxygen isotope record. Especially Mi4, which is not expressed in the lithological record, can be correlated with an excursion in the Decontra δ18O record . We applied a new integrated stratigraphy using cyclostratigraphy and eventstratigraphy in combination with an already established chemostratigraphic and biostratigraphic framework in order to significantly improve the stratigraphic resolution. Average accuracy of the new stratigraphic framework is estimated to be well below 200 kyr.Reuter et al. [Praeorbulina), carbon isotope stratigraphy, and also the processes involved in the formation of the GR and MS signals allowed the tuning of the section to filtered long (405 kyr) eccentricity using the orbital solution La2004 [Laskar et al., The results of the performed spectral analyses were used to orbitally tune a part of the section in order to significantly improve on the resolution of the biostratigraphy and chemostratigraphy established by r et al. . SedimenThe results of this first tuning were confirmed using event‐based (Mi‐ and CM‐events) stratigraphy. This integrated approach resulted in an age of 21.58 to 15.24 Ma for the Cerratina cherty Limestone. The Bryozoan Limestone can be constrained to a total age of 15.24 to 11.92 Ma. Further fine‐tuning allowed a final tentative correlation of the record to the unfiltered La2004 eccentricity solution, resulting in the first tuned shallow marine section spanning the early to middle Miocene (from 21.58 to 11.92 Ma)Woodruff and Savin, Holbourn et al., Prominent maxima in the GR‐log and the CM‐events [after 18O record of the Decontra section. Trends observed in the Decontra oxygen isotope curve can now be closely correlated to the global isotope record of Zachos et al. [Reuter et al. [The new age model also allowed a reevaluation of the δs et al. . Even cor et al. , was conHardenbol et al. [Haq et al. [Finally, in addition to the well‐preserved orbital cycles in the MS record long‐term trends further show a close correlation with third‐order sequences of l et al.  and the q et al. .ReadmeClick here for additional data file.Table S1Click here for additional data file.Figure S1Click here for additional data file.Figure S2Click here for additional data file.Figure S3Click here for additional data file.


Fish is a source of several nutrients that are important for healthy foetal development. Guidelines from Australia, Europe and the USA encourage fish consumption during pregnancy. The potential for contamination by heavy metals, as well as risk of listeriosis requires careful consideration of the shaping of dietary messages related to fish intake during pregnancy. This review critically evaluates literature on fish intake in pregnant women, with a focus on the association between neurodevelopmental outcomes in the offspring and maternal fish intake during pregnancy. Peer-reviewed journal articles published between January 2000 and March 2014 were included. Eligible studies included those of healthy pregnant women who had experienced full term births and those that had measured fish or seafood intake and assessed neurodevelopmental outcomes in offspring. Medline, Scopus, Web of Science, ScienceDirect and the Cochrane Library were searched using the search terms: pregnant, neurodevelopment, cognition, fish and seafood. Of 279 papers sourced, eight were included in the final review. Due to heterogeneity in methodology and measured outcomes, a qualitative comparison of study findings was conducted. This review indicates that the benefits of diets providing moderate amounts of fish during pregnancy outweigh potential detrimental effects in regards to offspring neurodevelopment. It is important that the type of fish consumed is low in mercury. This study reported an improved verbal Intelligence Quotient (IQ) in offspring aged nine years in children born to mothers who consumed up to two servings of fish per week compared with children born to mothers who had not consumed any fish during late pregnancy (32 weeks gestation). This association was not significant for fish consumption in early pregnancy (15 weeks gestation) suggesting that fish consumption may be of more benefit during the third trimester [A study by Oken regnancy . Mendez regnancy . Authorsregnancy . Gale etrimester .A report from the Avon Longitudinal Study of Parents and Children (ALSPAC) found that fish consumption during pregnancy of one to three servings per week was shown to provide a modest but significant improvement in developmental scores of the offspring for language and social activity at fifteen to eighteen months of age . A longen = 498) Japanese study did not demonstrate a positive or negative association between maternal fish intake during pregnancy and neurodevelopment as measured by the Neonatal Behavioural Assessment tool in infants at three days of age [n = 25,446) indicated a significant improvement in motor, cognitive and total developmental scores for eighteen month old children who were born to women within the highest three quintiles of fish intake during pregnancy. At six months, this improvement was only significant for children of women in the highest quintile of fish consumption, suggesting that age of testing may be relevant [A smaller . More research in this area is required to draw sound conclusions.Mendez et al.  found th [et al.  may have [et al.  reportedIt is important to note the number methodological limitations in research on diet and infant neurodevelopment that are present in these studies. This prevents the conclusion of a definitive relationship without further research, preferably clinical randomised controlled trials, and a proper meta-analysis.et al. 2011 [Measuring dietary intake in cohort studies is problematic due to the difficulty in obtaining detailed information without causing significant subject burden. All identified observational cohort studies in the current review used food frequency questionnaires (FFQs) to assess fish intake. No studies reported adjusting results from the FFQ for energy intake, a recommendation made by Freedman al. 2011  to preveal. 2011 ,21,24 reAssessing cognitive development differences in infancy and childhood is fraught with difficulties due to the nature of childhood development and the accurate measurement of such. Firstly, children develop in ‘spurts’ rather than in a continuous fashion, which means they may slip in and out of the ‘normal’ reference ranges, particularly in the earlier years ,28. To cet al. [et al. [et al. adjusted for paternal IQ but not the home environment [et al. considered maternal diet by classifying women as following a “prudent” or “western” dietary pattern [et al. [et al. [et al. [et al. [et al. [et al. [et al. [Secondly, there are multiple interrelated factors which impact on neurodevelopment, and not all confounders were accounted for in all analyses. Maternal intelligence, alcohol consumption, smoking and breastfeeding practices were included as covariates in all studies. However, factors including ethnicity, paternal intelligence, the home environment, drug use, dietary patterns, supplement use and maternal responsiveness were not always measured. The ALSPAC study reports by Daniels et al.  and Hibb [et al.  includedironment ,23. The ironment . An inta [et al.  also adj [et al.  adjusted [et al. , Mendez  [et al.  and Hibb [et al.  measured [et al.  reported [et al.  includedet al. [et al. [et al. [There is no universal standard for which neurodevelopmental tests are most appropriate for use in children of varying ages and at what age meaningful differences in neurocognitive development can be detected . Performet al. , Hibbeln [et al.  and Oken [et al.  used devn-3PUFA supplementation during pregnancy found no clear association between supplement use and infant cognitive outcomes [n-3PUFA [Due to the risks associated with consuming fish and seafood during pregnancy related to food safety and heavy metal contamination, pregnant women may question the necessity of including these foods in their diets, when nutrition supplements are readily accessible in Western countries . A systeoutcomes . This maoutcomes  and assooutcomes . Recent [n-3PUFA . BecauseThis review assessed the hypothesis that fish intake during pregnancy improves offspring neurodevelopmental outcomes. A review of the available evidence indicates that intake of fish during pregnancy is associated with positive foetal neurodevelopmental outcomes, as supported by seven of eight articles reviewed, which showed a beneficial impact on foetal neurodevelopment with one or more servings of fish per week compared with no fish intake. Based on the results from these observational studies the current recommendation of two to three servings per week appears appropriate. Randomised clinical trials have been conducted using fish oil supplementation in pregnancy, but not with fish considered as a whole food. Existing evidence is currently insufficient to inform advice regarding fish intake during pregnancy. Further well designed studies are required to strengthen the evidence base regarding the type and quantity of maternal fish consumption during pregnancy and associated neurodevelopmental outcomes in the offspring, while considering the contribution of mercury from fish-containing diets.


Thomas BerletI read with interest the recent meta-analysis by Chavez and colleagues that was published in Respiratory Research, addressing the diagnostic performance characteristics of thoracic ultrasonography (TUS) in the diagnosis of pneumonia in adults. Favourable results for the diagnostic accuracy were reported, with calculated pooled sensitivities and specificities of 94 % and 96 %, respectively .et al. enrolled 80 patients; 23 of these were diagnosed with interstitial pneumonia that could not be visualised with TUS [When I reviewed the original data that the meta-analysis by Chavez and colleagues was based upon, I detected a number of issues that I wish to comment on. The authors analysed ten studies –11. Six with TUS . Howeverwith TUS . These aChavez and colleagues included four studies that were performed in critically ill patients in intensive care units who suffered from a variety of respiratory conditions –5, 8. I Lichtenstein and colleagues studied 32 acute respiratory distress syndrome patients; 22 of these were diagnosed with pneumonia . The incA re-run of the meta-analysis by Chavez and colleagues , followiet al. [et al. [Since Chavez and colleagues performed their meta-analysis, another two clinical studies of the diagnostic accuracy of TUS for pneumonia have been published by Bourcier et al. , and Ber [et al. . One-hun [et al. , and 32  [et al.  patientsRe-analysis of the results of studies of the use of diagnostic ultrasonography for pneumonia confirms that TUS is a useful tool for the diagnosis of the inflammatory consolidation of pneumonia. However, further research is required to improve the diagnostic accuracy of TUS in the diagnosis of pneumonia in adults.Miguel A Chavez, Laura E Ellington, Robert H Gilman, William Checkleyet al. [et al. did not include interstitial findings by lung ultrasound within their methods [Over the last decade, there have been a growing number of research studies that evaluated the role of lung ultrasound for the diagnosis of pneumonia in adults . Many ofet al. . However methods , we deci methods .et al. could be revised [et al. found that 7 out of 17 participants who did not have pneumonia had an abnormal ultrasound. Of those, Parlamento et al. were able to rule out infectious causes of consolidation in two participants by examining the air bronchogram characteristics or by the absence of air bronchograms. Although Parlamento et al. did not explicitly discuss specific songraphic findings for the remaining five participants with alveolar-interstitial syndrome, and were implicitly considered as a negative ultrasound for pneumonia [Second, we agree with Berlet that the numbers contributed by the study of Parlamento  revised . Specifineumonia . Assuminet al. [et al. [et al. had expert sonographers who performed the ultrasound, and in our own discussion we further emphasize that sonographer expertise is a critical element in assessing diagnostic accuracy.Third, we agree with Berlet that equivocal ultrasound results (1.7 %) may affect estimates reported by Reissig et al.  and we c [et al.  had alreet al. [Fourth, Berlet raises important concerns regarding studies performed in critically ill patients in intensive care units –5, 8 thaet al. , 4, 8 haet al. , 7, 9–11Finally, since the publication of our meta-analysis, at least four new studies have been published , 15, 16.


Hyponatremia is especially common in older people. Recent evidence highlights that even mild, chronic hyponatremia can lead to cognitive impairment, falls and fractures, the latter being in part due to bone demineralization and reduced bone quality. Hyponatremia is therefore of special significance in frail older people. Management of hyponatremia in elderly individuals is particularly challenging. The underlying cause is often multi-factorial, a clear history may be difficult to obtain and clinical examination is unreliable. Established treatment modalities are often ineffective and carry considerable risks, especially if the diagnosis of underlying causes is incorrect. Nevertheless, there is some evidence that correction of hyponatremia can improve cognitive performance and postural balance, potentially minimizing the risk of falls and fractures. Oral vasopressin receptor antagonists (vaptans) are a promising innovation, but evidence of their safety and effect on important clinical outcomes in frail elderly individuals is limited. Hyponatremia is the commonest electrolyte imbalance encountered in clinical practice . It is aPrevalence of hyponatremia is known to increase in frail patient groups, particularly elderly patients where hyponatremia is observed in almost half of acute geriatric admissions ,10. Oldei.e., serum sodium 130–134 mmol/L developing over >48 h)  of the hyponatremic and normonatremic groups were 110 ± 2 mmol/L and 141 ± 1 mmol/L respectively. Following three months in a hyponatremic state, the rats had a 30% reduction in femoral bone mineral density (BMD) in comparison to the normonatremic rats (p < 0.001). Barsony et al. [et al. [+] of 112.7 ± 1.3 mmol/L and 10 rats were used as controls with a mean [sNa+] of 142.7 ± 1.1 mmol/L. A 16% reduction in BMD was seen in the hyponatremic group (p < 0.05). Thus, rodent studies by both Verbalis et al.  in the hyponatremic subjects (p < 0.01) whereas no relationship was seen in the normonatremic individuals (p = 0.99). This correlation was further established as the ORs for hyponatremia and osteoporosis at the femoral neck and total hip (defined by BMD with T-score < −2.5) were 2.87 and 2.85 (95% CI: 1.41–5.81 and 1.03–7.86). These results substantiate an association between hyponatremia and osteoporosis. An association between hyponatremia and osteoporosis was also demonstrated in the study by Kinsella et al. [T-scores of −2.6 and −2.3 (p = 0.03) respectively. Hyponatremic individuals also had a significantly higher prevalence of osteoporosis of 57.6% compared with 44.3% in controls (p = 0.04). Hoorn et al. [p = 0.105 and p = 0.473). Kinsella et al. [T-score, this shows that the increased risk of bone fractures caused by hyponatremia occurs independently of BMD.Verbalis et al.  demonstra et al. . They ren et al.  did not a et al.  establiset al. [Hoorn et al.  establiset al. [The work of Renneboog et al.  indicateet al. [et al. [et al. [et al. [In summary, human studies have consistently established a relationship between chronic hyponatremia and an increased risk of bone fractures. Chronic hyponatremia leads to decreased BMD in young and old rats but the effects of chronic hyponatremia on BMD in humans is less clear as studies have reported conflicting results. Verbalis et al.  and Kins [et al.  establis [et al.  reported [et al.  found noClinical management of hyponatremia is based on treating the underlying causes see  but accui.e., documentation of volemic status, appropriate investigations). The reported commonest cause of hyponatremia is SIADH [Accurate appreciation of the etiology of hyponatremia is essential, not only for appropriate clinical management but also to prevent development of hyponatremia. At present, there are few quality studies reporting etiology of hyponatremia in older people. Most reports are from retrospective studies that rely on diagnosis made by non-expert clinicians retrospectively reviewing case notes, which frequently lack sufficient detail to allow accurate diagnosis , co-morbidities , fluid overload and volume depletion ,32,33,34et al.  report tet al. ,33. HypoFurther research is required to accurately delineate the cause(s) of hyponatremia in older people. Future studies should be prospective and include expert panel review, with completion and full data availability of appropriate investigations. In the meantime establishing a reliable biomarker of hydration for older people is necessary in order to increase accuracy of the diagnostic process. Accurate understanding of etiology of hyponatremia in older people may help prevent and improve clinical management of hyponatremia which could potentially deliver significant health and economic benefits in the form of reduced complications of hyponatremia.Treatment will depend on the underlying cause, although a recent review article highlighted significant differences in expert panel consensus recommendations for treatment of hyponatremia . InvestiJudicious use of medications and optimal drug prescribing is one of the cornerstones of comprehensive geriatric assessment . Almost Since hyponatremia is usually a disorder of fluid balance rather than pure salt depletion, correction of volemic status is a mainstay of treatment. Fluid restriction, typically to about 800 mLs in 24 h, has long been the first line treatment of SIADH. It may be more acceptable in older people than younger patients but is often ineffective or poorly tolerated nevertheless. It can take a long time to be effective and is prone to failure due to hidden liquids in foods and discomfort from thirst. Moreover, in SIADH, there is a downward re-setting of the “thirst osmostat” and a lower plasma osmolality than normal will trigger thirst and increased fluid intake .Intravenous fluid resuscitation is indicated in all forms of hypovolemic hyponatremia. In hypovolemic hyponatremia, isotonic saline suffices and will often lead to very rapid sodium increase, as non-osmotic vasopressin secretion is rapidly suppressed. Most experts recommend using only isotonic saline (0.9% solution of sodium chloride), but boluses of hypertonic solutions are often used in acute and/or severe hyponatremia. No more than 100 mLs of 3% saline are recommended, though these can be repeated as needed . The latThe development of oral vasopressin receptor antagonists (vaptans) represents a major breakthrough in the treatment of SIADH and, potentially, other forms of euvolemic or hypervolemic hyponatremia. Unlike other treatments used for SIADH see , the vapA major concern in treatment of older people with any new agent is the safety profile. Preclinical data give some cause for concern as these are such powerful aquaretic agents, e.g., the diuresis observed in early studies of tolvaptan averaged over 5 liters per day . NeverthOverall, the vaptans currently have a role where simple and less expensive measures have failed. Yet, the potential for their use in very elderly people might be under-estimated , becauseHyponatremia is especially common in frail older patient groups. Even mild, chronic hyponatremia is associated with increased cognitive impairment, falls and fractures, possibly via a decrease in bone mineral density and/or bone quality. There is some evidence to show treatment of hyponatremia improves cognitive performance and postural stability. Therefore, correction of hyponatremia seems sensible in groups at high risk of falls, immobility or loss of independence from cognitive impairment. However, accurately diagnosing the causes of hyponatremia in this group is especially challenging, as hyponatremia may be multi-factorial, history hard to obtain due to cognitive or sensory impairment, and examination to determine volemic status is unreliable. Successful treatment also comes with its own challenges, both due to the potential for mis-diagnosis of underlying cause(s) and because all current therapies carry their own risks. Oral vasopressin receptor antagonists may be very helpful in this patient group, but the evidence base for their safety and efficacy on important outcomes in frail elderly groups is limited.


Oxidative stress is implicated in the pathophysiology of a wide variety of neurodegenerative disorders and its role in neurogenesis is becoming increasingly acknowledged. This special issue includes 8 articles that emphasize the implications of oxidative stress in neurodegeneration, neurotoxicity, and neurogenesis.β plaques and tau neurofibrillary tangles. In addition, the authors examine evidence of epigenetic regulation of Aβ plaque formation in AD neurons and discuss different potential therapeutic approaches. J. S. Cristovão et al. concentrate on the role of metal ions in AD and overview different proteins implicated in AD whose metal binding properties may underlie important biochemical and regulatory processes occurring in the brain during the pathophysiological process. Hyperphosphorylation and aggregation of tau in neurons not only are a central feature in AD but are present in other neurodegenerative diseases, termed tauopathies. S. M. A. Naini and N. Soussi-Yanicostas review the relationship between tau pathology and oxidative stress and present arguments in favor of the hypothesis that these are key components of a pathologic vicious circle in tauopathies. In a different direction, X. Hu et al. summarize recent literature describing the contribution of oxidative stress to brain damage after intracerebral hemorrhage. H. J. Olguín et al. describe dopamine dysfunction as a consequence of oxidative stress and discuss its implication in disease conditions, such as in Parkinson's disease. In an original article, A. Seguin et al. present interesting data on a drug screen performed using two different models of Friedreich's ataxia, yeast and Drosophila. In the original article by B. P. Carreira et al., the authors examine the role of nitric oxide in neurogenesis in adult hippocampus following seizures. They show that although nitric oxide is beneficial in the early stages of production of newborn neural cells, it is detrimental to the survival of newly differentiated neurons due to inflammation.Several original and review articles discuss the role of oxidative stress in neurodegenerative disorders and upon brain injury. S. K. Singh et al. open the issue by presenting a comprehensive review on the pathology of Alzheimer's disease (AD). Two other review articles focus on specific aspects implicated in AD. L. Zuo et al. discuss how oxidative stress is related to AD progression and to the formation of A


Nature Communications6: Article number:5862 10.1038/ncomms6862 (2015); Published: 01092015; Updated: 03292016et al. reporting the generation and use of Kaede transgenic mice was inadvertently omitted from the reference list of this article and should have been cited at instances where these mice are referred to. For example, in the Results section, Tomura et al. should have been cited as follows: ‘Since ILC3s are concentrated within the gut, we sought to test whether an ILC3 bias in the mLN reflected direct trafficking of ILC3s from the intestine to the mLN using transgenic Kaede mice '. The Methods section should have included the following: ‘The Kaede mice used in this study were kindly provided and transferred by Dr Miwa in Tsukuba University and Dr Tomura and Dr Kanagawa in RCAI, RIKEN, Japan.'Previous work by Tomura et al. Monitoring cellular movement in vivo with photoconvertible fluorescence protein ‘Kaede' transgenic mice. Proc. Natl Acad. Sci. USA. 105, 10871–10876 (2008).Tomura, M.,


Further, each control diet was fortified with either synthetic lysine or LPM to meet BIS (1992) specified lysine requirement resulting in the set of 12 test diets. Each of the eighteen diets was offered to quadruplets groups of 4 post-peak (52 weeks) commercial laying hens in each. The trial lasted for 119 days.The results revealed that the feed consumption and body weight changes and Roche yolk color and yolk index were significantly (p ≤ 0.05) different among different treatments. However, egg production, feed efficiency, egg weight, egg shape index, Haugh unit score, albumen index and shell thickness, and net returns remained non-significant (p ≤ 0.05) among different treatments. Among main factors, protein level (16% and 15% CP) made a significant (p ≤ 0.05) difference in egg production (79.6 and 75.1%) and feed efficiency . Among protein source GNE- and SFE-based diet fed groups showed significantly (p < 0.0%) higher feed consumption and body weight gain than SBM based diets fed birds. Yolk color  and yolk index  were significantly (p ≤ 0.05) different from the protein sources. CP level and Protein source interaction effects showed significant differences in albumen index and Haugh unit score.Optimum level of protein (16% CP) and GNE as a source of protein tended to be superior in increasing the performance and egg characteristics of post-peak layers and supplementation of lysine in either synthetic or LPM form found to be beneficial in optimizing their performance. Several commercial guidelines for laying hens ,2 were ret al., obtainedet al.,.Lactobacillus species [Lactobacillus species in layer diets did positively influence hen day egg production, feed efficiency, and egg weight [Supplementation of the low protein diets with crystalline amino acid is becoming relevant in feed formulation to minimize the nitrogen excretion and cost of production . Lysine  species  in layer species  reportedg weight .Keeping in view the aforesaid facts, a comparative study was designed to put on record the effect of lysine producing microbes, a mixed culture of about ten microbes which can produce lysine in the gut of the birds compared with that of synthetic lysine in post-peak commercial layers using soya or groundnut extraction or sunflower extraction protein source based diets at two levels of dietary protein.This research work was carried out as per the guidelines in force at the time of carrying out the experiment as well as in accordance with the International Ethics Committee guidelines to minimize pain or discomfort of the birds. The study was approved by the Institutional Ethics Committee.Bacillus subtilis, Trichoderma reessi, Corynebacterium glutamicum, Cellulomonas uda, Alcaligenes faecalis, Conidiobolus coronatus, Penicilium roquefortii, Aspergillus oryzae, Aspergillus niger, Sachharomyces cereviseae with a total viable count of 9000 million/g producing 1.238 g/day of L-Lysine in situ in bird in a 24 h period when fed at the rate of 1g LPM/bird. Such formulated diets with synthetic lysine or LPM irrespective of protein source provided 726 mg (16% CP) and 626 mg of lysine/kg (15% CP) while SBM, GNE, and SFE based diets without added lysine provided 706, 591, 593 (16% CP) and 646, 553 and 546 mg lysine/kg (15% CP), respectively. The ingredient and nutrient composition of the experimental diets are depicted in A set of 18 experimental diets  were ford 726 mg % CP and ® spherometer and by Vernier Caliper, respectively. Yolk index score, the ratio of height to diameter of yolk calculated in similar way. Egg shape index expressed as a relationship of length and breadth of the egg (in cm) obtained using Vernier Calipers. The height of albumin was recorded at two consistent places using Ames Haugh unit meter to obtain the Haugh unit score.The daily required quantity of specified diet was collectively offered to each replicate of four birds in divided dose of about 50% in morning and remaining 50% in the afternoon hours. All the birds were weighed individually at the beginning of the experiment as well as at every 28 days interval to monitor the pattern of body weight changes if any due to dietary regimen. The average body weight in the replicate group was then calculated. Egg produced from each replicate were recorded and weighed twice (Tuesday and Friday) in a week of the experimental period. The feed efficiency was calculated based on the amount of feed consumed to produce one kg egg mass as per replicate. On the terminal day of every 28-day interval, all the eggs produced from different replicate groups were collected and were weighed individually during the experimental period of 84 days. Further, on the immediate next day, each egg was broken and the entire contents were carefully placed on a glass slab for egg quality study. Albumen index score was calculated as the ratio height and diameter of thick albumen (in mm) which were measured by AmesH: is the height of albumen (mm)G: Gravitational force The shell pieces devoid of shell membranes at a broad end, narrow end, and middle band were selected and their thickness was measured using a digital calipers. The average of all the three pieces was represented as shell thickness. The color of the yolk of every broken open egg was scored by matching (contrast) technique using Roche yolk color fan .The data generated during the experiment were statistical analyzed by completely randomized design as well as by factorial design according to the methods described by Snedecor and Cochran .The performance of layers under different treatment is presented in viz., protein level × protein source, protein levels × supplemented lysine source and protein source × lysine source interaction also remained statistically non-significant (p > 0.05) in influencing the feed consumption, body weight gain, egg production, and net returns.Among protein sources, the SBM based diet group of layers recorded significantly (p < 0.05) lower daily feed consumption (118.9 g) as against those of GNE (125.8 g) and SFE (124.1 g) groups. Weight gain was significantly higher in SFE (51.8) with lowest being SBM group (31.1). Egg production was 78.2 per cent in GNE groups while that of SBM (77.7%) and SFE (76.1%) groups which were statistically similar (p ≤ 0.05). Sources of lysine did not show any significant difference in production parameters. Various interaction effects  viz., prLevel of protein, source of protein and lysine sources were non-significant in influencing egg weight, shape index, albumen index, Haugh unit score and shell thickness . Howeveret al. [et al. [et al.[et al. [et al. [et al. [et al. [et al. [et al. [et al. [et al. [et al. [et al. [Among different treatment, the feed consumption ranged significantly with, GNE-based diet fed group had highest feed consumption followed by that of SFE and SBM groups. Cumulative average egg production, feed efficiency, body weight gain, and net returns remained non-significant among different treatments. However, SFE-based groups showed numerically higher body weight gains (72 g) when compared to SBM based diet fed groups (17.4 g) which may be due to, relatively lower production (due to lower availability of lysine) in SFE group compared to soya groups leading to more body fat accumulation. Level of protein in the diet significantly affected the egg production and feed efficiency this is in contrary to Chaiyapoom et al.  were he  [et al.  also rep [et al.  and Parl. [et al. reported.[et al.  who in t.[et al. , yet in .[et al. . The egg.[et al.  and Proc [et al. . Kurtogl [et al. , Panda e [et al. , and Bon [et al.  observed [et al.  or the m [et al.  and in L [et al. . Yalcin  [et al.  reported [et al.  and Parl [et al.  noted be [et al.  also rep [et al.  and Soha [et al.  also repviz. protein level (16 and 15% CP), protein source  and lysine source  showed non-significant difference on egg weight, shape index, albumen index, Haugh unit score, and shell thickness this was also reported by Figueiredo et al. [Numerically, the data indicated better shape index with supplementation of LPM in low protein groups. The main factors o et al. , who reget al. [et al. [et al. [et al. [et al. [et al. [et al [et al. [Numerically, LPM supplementation was found to increase shape index, yolk color and yolk index. These results are similar to those of Sohail et al.  who repo [et al.  also rep [et al. ,32. Low  [et al.  findings [et al.  also rep [et al.  showed s [et al.  and Trin. [et al . GNE-bas [et al. , also foIt was concluded that the supplementation of lysine in the form of LPM was as good as synthetic lysine in optimizing the production performance of the birds; however, further studies are required in this direction to justify the above claim. Protein level was of greater significant in influencing the egg production and feed efficiency, indeed level of lysine to a some extent showed its importance but statistically it was not significant.This study was part of MVSc research program of GUM. BSVR designed the research program as mentor and GUM conducted the research work. GG and TMP worked as co – mentors for the MVSc program, provided technical guidance and also helped in preparing this manuscript. NS and KSG helped in carrying out research trial, laboratory analysis and in manuscript preparation All authors read and approved the final manuscript.


Recent phase II and III studies with intravenous immunoglobulin (IVIG) in patients with Alzheimer’s disease (AD) did not find evidence for the slowing of AD progression compared to placebo-treated patients, in contrast to encouraging results in pilot studies. An additional phase III trial is ongoing. If negative results are found, then further AD studies with IVIG are unlikely unless a manufacturer opts for a trial with high-dose IVIG, which would increase its anti-inflammatory effects but also the risk for adverse events. An alternative approach could be an AD-specific IVIG, supplementing IVIG with higher concentrations of selected antibodies purified from it or produced via recombinant polyclonal antibody technology. These antibodies could include those to amyloid-beta  fragments containing terminal sialic acid could be added to increase anti-inflammatory effects. While this product might be more effective in slowing AD clinical progression than current IVIG, there are difficulties with this approach. Preclinical studies would be required to determine which of the antibodies of interest for supplementing current IVIG  are actually present  in IVIG, and the effects of the product in mouse models of AD. An Investigational New Drug application for an AD-specific IVIG would require United States Food and Drug Administration approval. If the drug would be found to benefit AD patients, meeting the increased demand for IVIG would be challenging. Approximately 5.2 million Americans are currently diagnosed with Alzheimer’s disease (AD). The prevalence of this disorder in the United States is 4% for individuals under 65 years of age, 15% for those between 65 and 74 years of age, 44% for those between 75 and 84 years of age, and 38% for individuals 85 years of age and older [The five drugs approved by the United States Food and Drug Administration for treating AD provide short-term symptomatic benefits to approximately half of the patients who receive them, but are not believed to influence neuropathological progression of the disease. Since the amyloid cascade hypothesis was published in 1991 , AD ther9 [et al. [et al. [Intravenous immunoglobulin (IVIG) is another approach that has been examined for the treatment of AD. IVIG products contain purified plasma immunoglobulins (primarily IgG) from large numbers of healthy donors. These drugs are used to treat many autoimmune, immunodeficiency, and inflammatory disorders. The full range of antibodies in the human immune repertoire, estimated at 109 , is thou [et al.  and Schw [et al. ). Natura [et al. ,19, are  [et al. . Some of [et al. ). IVIG’s [et al. ,22.et al. in 2002 to contain anti-Aβ antibodies [+ AD patients and in patients with mild AD, but the trial was not powered to detect differences between subgroups. A phase III trial with Grifols’ IVIG Flebogamma™ is underway in which AD patients will undergo plasmapheresis and be treated with albumin and Flebogamma [Many natural antibodies are polyreactive, meaning they can bind to more than one antigen . Octaphatibodies , and thetibodies ,26. On ttibodies ,28 whichtibodies  which intibodies , there wtibodies , no signebogamma . The effebogamma , thoughtebogamma .et al. [Svetlicky et al.  reviewedet al. , anti-phet al. , myastheet al. , pemphiget al. , and smaet al. . In eachet al. . Anotheret al. . It was et al. .et al. [The doses of IVIG employed in the AD trials were those used for antibody replacement in immunodeficiency syndromes, so whether the higher doses which are required for IVIG’s anti-inflammatory effects (1 g/kg ) might bet al.  concludeet al. [+ (hyperphosphorylated tau-containing) hippocampal CA1 neurons [A second option could be an AD-specific IVIG. The effects of this product could initially be compared to those of current IVIG products in a mouse model of AD which develops both plaques and NFTs, such as the 3xTg-AD mouse . Most IVet al. , using aet al. . A secon neurons . Evidencin vitro and in some mouse models of AD [An AD-specific IVIG product could be generated by simply supplementing a current IVIG product with higher levels of its anti-Aβ antibodies, which have been shown to exert neuroprotective effects ls of AD ,54,57-59The few studies that have compared the levels of AD-related antibodies between IVIG products found differences between the products ,26,60. TA potential advantage of IVIG over monoclonal antibodies for AD therapy is that it contains antibodies against multiple proteins that are thought to contribute to AD’s development and progression. However, IVIG’s polyvalent antibodies have a range of antigen-binding affinities . An AD-sSome studies have reported that IVIG’s anti-Aβ antibodies are limited to those that are ‘conformation-specific’ (they do not recognize linear Aβ) , while oTau is an intraneuronal protein located primarily in axons, where it plays an important role in microtubule formation and stabilization through its binding to tubulin . The extet al. [et al. [IVIG products contain anti-tau antibodies , includiet al.  showed t [et al.  reportedet al., [et al. [There is an extensive literature about increased inflammatory processes in the AD brain . Centraet al., . Anti-cyet al., , interfeet al., , interfeet al., , granuloet al., , BAFF . Onet al.,  proposed [et al. , in whic [et al.  and IL-1 [et al. , both of [et al. .IVIG inhibits cell surface deposition of early complement activation fragments, the opsonins C4b and C3b . It bindAdvanced glycation end products (AGE) form when reducing sugars react with amino groups in proteins, lipids, and amino acids . The recIVIG has additional neuroprotective actions, including antioxidant  and antiTreatment with IVIG can raise serum viscosity, increasing the risk for thromboembolic events . Howeveret al. [Even if an AD-specific IVIG would be found to exert beneficial effects in AD patients, its relatively short duration of action would require continued treatment, which would consume a great deal of IVIG. The subjects in the IVIG AD trials received IVIG every two or four weeks ,28,30 anet al. ). Furtheet al. .With the exception of IVIG’s anti-Aβ antibodies , the effet al. [et al. subsequently reported the development of paralytic disease in wild-type mice and ‘tauopathy’ mice that were repeatedly immunized with a mixture of three phosphorylated tau fragments emulsified in CFA and pertussis toxin [The anti-tau antibodies which were reported in IVIG  bound toet al.  found thet al. , was givis toxin . Howeveris toxin . The ratis toxin -77 foundRegulatory issues would be of concern with regard to United States Food and Drug Administration approval of an AD-specific IVIG. There is a precedent for United States Food and Drug Administration approval of a multi-component plasma product: Factor Eight Inhibitor Bypassing Activity  is an activated prothrombin complex concentrate which, similar to IVIG, is produced from pooled human plasma. It contains four coagulation factors, namely factors II, VII, IX, and X ,152. FEIIf studies in mouse AD models suggest increased benefits of AD-specific IVIG compared to standard IVIG, then consideration could be given to producing the antibodies required to supplement current IVIG through recombinant technology, rather than purifying them from IVIG. The technology is available for production of recombinant human polyclonal antibodies on an industrial scale ,155. ThiA final obstacle would be the economic one. The question of how adequate supplies of IVIG could be maintained if there is an increased demand for it in AD patients was discussed previously  and willAlthough the multiple antibodies in IVIG should give it an advantage over monoclonal antibody for treatment of AD, its encouraging results in pilot studies have not been replicated in larger trials. Administration of high-dose IVIG would increase its anti-inflammatory effects but would likely be associated with increased adverse events, and many AD patients have risk factors which could preclude their receiving high-dose IVIG. An alternative approach could be to develop an AD-specific IVIG. This would require additional time and expense, but it might be the last and best chance for IVIG treatment of AD to succeed.


Curiosity found host rocks of basaltic composition and alteration assemblages containing clay minerals at Yellowknife Bay, Gale Crater. On the basis of the observed host rock and alteration minerals, we present results of equilibrium thermochemical modeling of the Sheepbed mudstones of Yellowknife Bay in order to constrain the formation conditions of its secondary mineral assemblage. Building on conclusions from sedimentary observations by the Mars Science Laboratory team, we assume diagenetic, in situ alteration. The modeling shows that the mineral assemblage formed by the reaction of a CO2-poor and oxidizing, dilute aqueous solution  in an open system with the Fe-rich basaltic-composition sedimentary rocks at 10–50°C and water/rock ratio (mass of rock reacted with the starting fluid) of 100–1000, pH of ∽7.5–12. Model alteration assemblages predominantly contain phyllosilicates , the bulk composition of a mixture of which is close to that of saponite inferred from Chemistry and Mineralogy data and to that of saponite observed in the nakhlite Martian meteorites and terrestrial analogues. To match the observed clay mineral chemistry, inhomogeneous dissolution dominated by the amorphous phase and olivine is required. We therefore deduce a dissolving composition of approximately 70% amorphous material, with 20% olivine, and 10% whole rock component.The Mars Science Laboratory rover  Thomson et al., Farley et al., Gale Crater is thought to have formed near the Noachian-Hesperian boundary with an age of about 3.7 Gyr, and although the exact age of the Gale sediments is not certain, crater counting suggests an ancient age [Mars Science Laboratory (MSL) rover Curiosity has identified and analyzed, for the first time on Mars, a set of mudstones. The mudstones record a history of deposition within a fluvio-lacustrine environment followed by low temperature, in situ diagenesis [Grotzinger et al., McLennan et al., Vaniman et al., Vaniman et al., Grotzinger et al. [At the Yellowknife Bay locality of Gale Crater, the Grotzinger et al., Grotzinger et al., Grotzinger et al., McLennan et al., Leveille et al. 2014[. Key textural observations are that the raised ridges postdate the sedimentary layering and sulfate veins postdate the raised ridges. The notably pure Ca-sulfate composition of the late veins was initially established by ChemCam (Laser Induced Breakdown Spectroscopy) and was confirmed by Alpha Proton X-ray Spectrometer (APXS) [McLennan et al., Vaniman et al., The 4.5 m thick Yellowknife Bay formation is subdivided into different members with the lowest one, Sheepbed, being an at least 1.5 m thick mudstone, but its lower contact is not visible; its upper contact to the overlying Gillespie member is sharp. The Sheepbed member is a mudstone of overall basaltic chemical composition with ∽15% smectite, ∽50% igneous minerals, and ∽35% X-ray amorphous material [Grotzinger et al., Williams et al., Bish et al., Morris et al., The Sheepbed mudstone has a sharp contact with the overlying 3 m thick succession of the Gillespie and Glenelg members, which contain fluvial sediments [e.g., Vaniman et al., Ming et al., McLennan et al., Grotzinger et al., McLennan et al. [Nesbitt [Two drilled samples of the mudstone, at locations named John_Klein and Cumberland, took place between Martian solar days (sols) 180 and 292 of the mission and allowed analysis of material beneath the uppermost, reddish oxidized dust coating. The samples were analyzed in the CheMin instrument by X-ray diffraction [Bish et al., Bish et al., Bish et al., CheMin and APXS analyses of the Portage soil were carried out between sols 55 and 102 at the Rocknest locality. This provides a mineralogical control on the country rock in the Gale Crater region [Schmidt et al., McLennan et al., Stolper et al., Schmidt et al., Schmidt et al., Chemically, the APXS analyses of other Gale Crater rocks have established the presence of a range of compositions. These include Fe-rich basaltic sediment as shown by the in situ analyses at Yellowknife Bay and the Portage soil analysis [Bishop et al., Curiosity team. Starting with unaltered rocks and soils found in the area, we aim to calculate a realistic mixture of dissolving minerals within those rocks and soils that reacted to form the secondary, clay-bearing assemblage during diagenesis. This will also help to decide whether some of the phases are detrital or authigenic or a mixture of both.By using the sedimentological constraints together with ChemCam and APXS major element analyses of representative basaltic and alkaline compositions of the Gale Crater rocks and soil, and the CheMin and SAM results during the first 300 sols, we establish an equilibrium thermochemical model for the subsurface mineral reactions in the Yellowknife Bay sediments of Gale Crater. This model envisages reaction of a pore water , see Methods) with the enclosing detrital sediment. In our model, we primarily study the production of clay through the inhomogeneous alteration of a Rocknest-type host rock, within which olivine and amorphous material are the predominant alteration phases, because both of which are relatively reactive compared to other phases. We also consider other host rock end-members (see Methods). There is clear evidence from terrestrial analogue environments such as altered Icelandic basalts and tuffs that olivine and glassy material are the most reactive phases [e.g., Reed and Spycher, Reed et al., Reed et al., Kühn [2004, chapter 3[ and for a discussion on databases and the mathematical-theoretical background [see, e.g., Ganguly, Oelkers and Schott, Reed, Reed, DeBraal et al., De Caritat et al., Schwenzer and Kring, Bridges and Schwenzer, Schwenzer et al., Schwenzer and Kring, Filiberto and Schwenzer, For the thermochemical modeling, we use the program CHIM-XPT (previously CHILLER) [Vaniman et al., Grotzinger et al., For host rock compositions in our modeling, we used a variety of rocks observed by Curiosity Table  and modereacted with the starting fluid). The plotted W/R ratio is thus a progress variable with very limited rock dissolution at the high W/R end and increased rock dissolution at the low W/R end. Note that W/R end represents the amount of rock reacted with the fluid not the total amount of rock present in a given volume of rock on Mars. Original magmatic minerals are observed in the mudstones [Vaniman et al., McLennan et al., 2. The amount of precipitation increases from a few milligram at high W/R to about 1 g at W/R of 1000 and on the order of 10 g at W/R of 100. We model between W/R of 1 and 100000 but only show 10 to 10000 for most of the runs. Higher W/R is unlikely within a sediment, but the lowest W/R would also produce phases with less H2O than phyllosilicates. W/R therefore describes the environment (freshwater inflow at high W/R in contrast to stagnant fluids with no fresh inflow at the low W/R), but at the same time reaction progress, because in a stagnant situation, more host rock will react over time, especially at low temperatures, where reactions are slow.Results of calculated equilibrium mineral assemblages are presented in diagrams of mineral abundance versus W/R ratio . CHIM-XPT can be controlled either by the set of O2-H2O-SO4-H+ or expressed in terms of HS-SO4-H2O-H+. During the reactions, the SO42−/HS− pair controls redox in the fluid [Reed et al., 2+/Fe3+ ratio of the host rock or soil (see section 2.3.2). Sulfur concentration of the fluid was taken as found in the Deccan Trap fluids [Minissale et al., In order to model a realistic starting fluid representative of water associated with diagenesis in the Yellowknife Bay sediments, we start with adapted water (AW). This is the fluid used in our previous Mars studies [see 2, depending on kinetics) dominated precipitate  were excluded from forming during the runs.For other calculations, we used the varying proportions of individual components, e.g., olivine and amorphous component. In total, over 100 runs with varying composition, temperature, and redox conditions were performed. APXS analyses were used for rock and soil compositions [3+ Table , thus giZolotov and Mironenko, Hausrath et al., McAdam et al., Gudbrandsson et al., Bridges and Schwenzer, Vaniman et al., Vaniman et al., Bish et al., The bulk rock models provide insights into the expected alteration mineralogy associated with the general chemistry of the rocks encountered at Yellowknife Bay. However, mineral dissolution is inhomogeneous and highly dependent on temperature and fluid chemistry [e.g., 3+ clay and the daphnite end-members of chlorite as the Fe2+ clay. In our plots of mineral abundance versus W/R, we plot the combined end-members of chlorite. Phases that are not known to form at low temperatures were excluded from the runs, these include garnet, amphiboles, and pyroxenes, as well as high-T mica.We use the following sheet silicates in our CHIM-XPT database: talc ; pyrophyllite; from the chlorite group clinochlore, daphnite, Mn-chlorite, Al-free chlorite; from the kaolinite group kaolinite, illite; from the smectite group montmorillonite ; beidellite , nontronite ; and serpentine . We note that there is no other kaolinite group mineral other than kaolinite, e.g., vermiculite, saponite, and hectorite are not in our database. In the interpretation of our models, nontronite serves as the Fe2+/Fe3+ in those assumptions, and the fact that the thermochemical database is necessarily limited relative to the full large range of possible natural mineral assemblages, we have modeled a best chemical match for the observed clays. Thus, in our runs, we take a nontronite + chlorite assemblage as a chemical analogue to the clay identified by Vaniman et al. [de Caritat et al., Ryan and Reynolds, Changela and Bridges, Hicks et al., Treiman et al., 2014[.As outlined above, we use a set of assumptions about the redox conditions of the starting fluid and the redox conditions in the dissolving rock. Bearing in mind the uncertainty of the FeVaniman et al., Ming et al., Bridges et al. [2 partial pressure of 185 mbar and thus a possible atmospheric pressure associated with ancient Mars. Therefore, to test the influence of CO2 dissolved in the incoming fluid, Portage soil was exposed to GPW fluid equilibrated with 185 mbar CO2  over almost all of the modeled W/R range; there is over 40% between W/R of 10,000 and ∽20 .In contrast to Jake_M, Ekwir_brushed Figure b, precip2 contents of the host rock , and at W/R mass of rock reacted with the incoming fluid of 100–1000, produce calculated mineral assemblages that most closely match the saponite-, sulfide-, and Fe oxide-bearing assemblages identified in the Sheepbed mudstone by CheMin [Morris et al., Vaniman et al., Bish et al., 2O. In contrast, in the nakhlite meteorites, the amorphous component is the last product of alteration and has a similar composition to the crystalline saponite phase, and crystallization of the amorphous gel is assumed to have been inhibited by kinetic effects [Changela and Bridges, Hicks et al., The CheMin analysis on Rocknest soil and Cumberland and John Klein drill fines returned three different amorphous compositions in the samples [3+ in the Portage amorphous component [see also Morris et al., Figure 1.24Fe0.76SiO4), pure forsterite (Mg2SiO4), olivine + host rock, olivine + amorphous, forsterite or fayalite + amorphous, and mixtures of all three components. We show (a) 50% forsterite and 50% Portage amorphous, Fe3+/Fetot = 45%; (b) 50% forsterite and 50% Portage amorphous, Fe3+/Fetot = 45%; (c) 70% olivine, 15% augite, 15% plagioclase, and Fe3+/Fetot = 0%; and (d) 70% Portage amorphous, 20% olivine, and 10% whole rock Fe3+/Fetot = 40% in Figure T. The bulk W/R of the rock unit is lower than the W/R of the models because of the presence of unreacted minerals in the mudstone, see also section 2 for more details. Pure forsterite runs produce an Al-free brucite dominated assemblage, which does not match the Al-bearing nature of the observed phyllosilicates. In contrast, other olivine-rich runs produce the expected serpentine-Fe oxide-SiO2 assemblage. A mixture of forsterite and amorphous component produces precipitates dominated by serpentine and ∽10% of nontronite, chlorite, and Fe oxide each  into account, we have modeled the reaction of a variety of mixtures leading from that observation: the minerals and mineral mixtures are ranging from pure olivine as observed in Gale . In contrast to the CO2-poor case . Nontronite formation, too, is not possible during the peak siderite formation . This observation alone would not rule out comprehensive alteration, but the minerals accompanying the clays, e.g., SiO2 (at larger quantities) and zeolite, in the model 0.08Ca0.38 Mg1.10Fe1.544O10(OH)2 at W/R of 100 and 0.17Ca0.38 Mg1.08Fe1.334O10(OH)2 at W/R of 10.It is not possible to exactly match the clay mineralogy in our models to the reported CheMin results, so we average the composition of all sheet silicates in the system at W/R 1000, 100, and 10 Figure  and compHowever, if the olivine preferentially reacts before the other phases and thus dominates the alteration assemblage at an early stage then this is a possible explanation for the Mg-rich ridges described by Leveille et al. [2014[. On Figure The presence of ∽20% clay in the Sheepbed mudstone is consistent with our model. The rock mixture dissolves, so 100% of the silica in the alteration assemblage stems from the rock dissolving in situ. For instance, at W/R of 1000 , we have 0.64E-02 mol of Si in the system, of which 0.11E-02 mole are in the resultant fluid. This means that a maximum of 20% of the silica is in the fluid after the reaction and could potentially have left the system. Silica from the “fluid in” component is negligible; it is in the 10E–5 range, 3 orders of magnitude smaller. If we look at silica at W/R of 100, then we predict 0.65E-01 mol in the system  and 0.37E-02 mol in the fluid. So there is now 6% remaining in the fluid. This means that for silica, between 80 and 94% of the silica from the rock can be deposited as clay. In other words, at W/R of 1000, the redeposition is almost complete and 20% clay alteration product would stem from dissolving the preexisting rock. Therefore a W/R ratio of 100–1000 is consistent with the magnitude of clay abundances in the Sheepbed mudstone.3+ or conditions to oxidize iron. We note that in the models shown in this study, the fluid at the start of the alteration is oxidizing (see section 2.1). This is in accordance with the observed presence of oxychlorine species in the sediment [Ming et al., The amount and nature of the Fe oxide precipitated at low to intermediate W/R is dependent on a complex interplay of the overall redox conditions of the system, the assemblage of Fe-bearing phases and their redox states. For nontronite (or ferric saponite) formation, the fluid and the host rock need to provide FeBristow et al. [T runs (not shown)—the amount of magnetite precipitated increases at higher temperatures. At this point, it is important to bear in mind that post formational processes can change the oxidation state of Fe [Cornell and Schwertmann, Leveille et al., Bristow et al. [Vaniman et al., 3+-oxide formation) appears to correlate with the absence or decrease in ferric relative to ferrous clay  forms alongside ∽10% Fe oxide/hydroxide. The assemblage is slightly dependent on W/R but overall similar at all W/R as shown by our Portage, 50% fayalite or forsterite and 50% amorphous runs plotted on Figure In accordance with the observations in Icelandic low-temperature surface fluids [The second stage is the main clay forming event—as discussed above—and occurs by the reaction of the local pore fluid (GPW) and selective dissolution of the basaltic sediments, in detail, a mixture of 70% amorphous material with 20% olivine and 10% host rock . This stage is pervasive, and olivine dissolution is congruent. This calculation results in a good match of the modeled clays to the CheMin observations—and in fact the nakhlite clays, too. We assume the W/R of the reaction is higher than 10, because at very low W/R talc formation exceeds 10%, but talc is not observed in the CheMin data. However, the bulk W/R, given the preservation of olivine in the rocks, is likely not high. The pH at W/R of 1000 to 10 changes from around 7.5 to 12 as the alteration progresses from that associated with the Mg-rich ridges and initial olivine dissolution to the main diagenetic assemblage of saponite and magnetite.Grotzinger et al., Nachon et al., Schwenzer et al., After this main clay-forming event, the sulfate veins formed [Cabrol et al., Pelkey and Jakorsky, Pelkey et al., Thomson et al., Schwenzer et al., Fairén et al., Williams et al., Grotzinger et al., Vaniman et al., 2-rich Martian atmosphere during precipitation of the minerals, because the availability of CO2 in the system would cause not only significant carbonate precipitation but also the formation of zeolites, quartz/SiO2, and kaolinite ) is a dilute aqueous solution derived from the mediation of a brine with the cation and anion contents in equilibrium with rocks of the Gale area.An early stage of diagenesis associated with Mg-rich ridges suggest some initial, localized alteration reactions associated with the early preferential alteration of olivine with GPW.3+/Fetot ratio of 0.3–0.5. The resultant relatively ferrous phyllosilicate produced is consistent with the dominance of magnetite rather than ferric oxide at a W/R of 100 and below. However, only a minor change in the redox state of the fluid might trigger magnetite formation at higher W/R.Inhomogeneous host rock dissolution of predominantly amorphous phase identified by CheMin, with lesser olivine and minor overall host rock contribution, occurred via reaction with GPW at 10–50°C, with a W/R of 100–1000, and pH of 7.5–12. This occurred in an open system with fluid flow and led to a clay-Fe oxide assemblage. The bulk compositions of the modeled phyllosilicate assemblages are similar to saponite clays observed at Yellowknife Bay and in the Lafayette Martian meteorite, though more ferrous with Fe2-rich atmosphere was possible. This is predicted by the absence of a significant carbonate abundance and the absence of phases including zeolites that our models predict are likely to be associated with such a CO2-charged fluid.The reactions associated with the clay and magnetite formation did not occur in a setting where exchange with an overlying CO