The use of omalizumab in allergen immunotherapy.

Although omalizumab (anti-IgE) is currently only approved for the treatment of asthma and chronic idiopathic urticaria, it has also been studied as an off-label treatment for numerous allergic conditions, including use as an adjunct to allergen immunotherapy in the treatment of allergic rhinitis, asthma, venom hypersensitivity and food allergy. We conducted a review of publications involving the use of omalizumab with allergen immunotherapy, by searching PubMed with key search terms of "omalizumab" and "immunotherapy." Omalizumab has been used in combination with inhalant allergen immunotherapy for the treatment of seasonal allergic rhinitis and comorbid asthma. While there have been no randomized controlled trials evaluating the addition of omalizumab to venom IT, several case reports and small patient series have been published on the use of omalizumab with venom IT. Omalizumab has been used in conjunction with oral immunotherapy for the treatment of milk, peanut and egg, as well as other foods in multi-allergen protocols. In conclusion, omalizumab used in conjunction with immunotherapy has shown promising results, especially in the reduction of adverse reactions. At this stage, larger, randomized, placebo-controlled trials are needed to better identify those patients who would benefit the most from the addition of omalizumab to immunotherapy, as well as optimal dosing strategies and duration of treatment.

Early-life gut microbiome and egg allergy.

BACKGROUND: Gut microbiota may play a role in egg allergy. We sought to examine the association between early-life gut microbiota and egg allergy. METHODS: We studied 141 children with egg allergy and controls from the multicenter Consortium of Food Allergy Research study. At enrollment (age 3 to 16 months), fecal samples were collected, and clinical evaluation, egg-specific IgE measurement, and egg skin prick test were performed. Gut microbiome was profiled by 16S rRNA sequencing. Analyses for the primary outcome of egg allergy at enrollment, and the secondary outcomes of egg sensitization at enrollment and resolution of egg allergy by age 8 years, were performed using Quantitative Insights into Microbial Ecology, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States, and Statistical Analysis of Metagenomic Profiles. RESULTS: Compared to controls, increased alpha diversity and distinct taxa (PERMANOVA P = 5.0 × 10-4 ) characterized the early-life gut microbiome of children with egg allergy. Genera from the Lachnospiraceae, Streptococcaceae, and Leuconostocaceae families were differentially abundant in children with egg allergy. Predicted metagenome functional analyses showed differential purine metabolism by the gut microbiota of egg-allergic subjects (Kruskal-Wallis Padj  = 0.021). Greater gut microbiome diversity and genera from Lachnospiraceae and Ruminococcaceae were associated with egg sensitization (PERMANOVA P = 5.0 × 10-4 ). Among those with egg allergy, there was no association between early-life gut microbiota and egg allergy resolution by age 8 years. CONCLUSION: The distinct early-life gut microbiota in egg-allergic and egg-sensitized children identified by our study may point to targets for preventive or therapeutic intervention.

Oral Immunotherapy for Food Allergy.

Food allergy is a potentially life-threatening condition with no approved therapies apart from avoidance and injectable epinephrine for treatment of acute allergic reactions. Oral immunotherapy (OIT) is an experimental treatment in which patients consume gradually increasing quantities of the food to which they are allergic in an attempt to induce some level of desensitization. While desensitization is possible in most patients, OIT carries significant risks for allergic reactions, and the ability to induce longer-term tolerance has not yet been established. This review focuses on selected studies of OIT for the treatment of common food allergies such as cow's milk, hen's egg, and peanut.

Component-resolved analysis of IgA, IgE, and IgG4 during egg OIT identifies markers associated with sustained unresponsiveness.

BACKGROUND: In a previously reported CoFAR study, 55 subjects with egg allergy underwent randomized, placebo-controlled egg oral immunotherapy (eOIT). Active treatment induced desensitization in most and sustained unresponsiveness (SU) in a smaller subset. We hypothesized that component-resolved analysis of IgE, IgG4, IgA, IgA1, and IgA2 may identify potential biomarkers of SU in OIT subjects. METHODS: Longitudinal samples for 51 egg-allergic subjects (37 active and 14 placebo) were available. Egg white (EW)-, ovalbumin (OVA)-, and ovomucoid (OVM)-specific levels of IgA, IgA1, and IgA2 were quantified by ELISA. IgE and IgG4 to these antigens were quantified using ImmunoCAP® . Clinical responders achieved SU to egg; all others were considered nonresponders. Between-group comparisons were made among active and placebo, as well as responders and nonresponders. RESULTS: No placebo subjects achieved responder status. Through month 48, among the 37 active subjects, baseline IgE-OVM was lower in responders (median 3.97 kU/l, n = 19) than in nonresponders (10.9 kU/l, n = 18, P = 0.010). Logistic regression analysis revealed that lower baseline IgE-EW (P = 0.038), IgE-OVM (P = 0.032), and a higher IgG4/IgE-OVM ratio (P = 0.013) were associated with clinical response. Relative increases in IgG4-EW, IgA-EW, and IgA2-EW were observed in responders (P = 0.024, 0.024, and 0.029, respectively). IgG4/IgE, IgA/IgE, and IgA2/IgE ratios for EW and IgA/IgE ratio for OVA were found to be significantly elevated among responders (P = 0.004, 0.009, 0.028, and 0.008, respectively). CONCLUSIONS: Increased IgG4-EW, IgA-EW, and IgA2-EW during eOIT are associated with clinical response to eOIT. Lower pretreatment IgE-EW and IgE-OVM are also associated with SU. Future studies are needed to evaluate and validate these potential biomarkers.

Ediacaran skeletal metazoan interpreted as a lophophorate.

While many skeletal biomineralized genera are described from Ediacaran (635-541 million years ago, Ma) strata, none have been suggested to have an affinity above the Porifera-Cnidaria metazoan grade. Here, we reinterpret the widespread terminal Ediacaran (approx. 550-541 Ma) sessile goblet-shaped Namacalathus as a triploblastic eumetazoan. Namacalathus has a stalked cup with radially symmetrical cross section, multiple lateral lumens and a central opening. We show that the skeleton of Namacalathus is composed of a calcareous foliated ultrastructure displaying regular concordant columnar inflections, with a possible inner organic-rich layer. These features point to an accretionary growth style of the skeleton and an affinity with the Lophotrochozoa, more specifically within the Lophophorata (Brachiopoda and Bryozoa). Additionally, we present evidence for asexual reproduction as expressed by regular budding in a bilateral pattern. The interpretation of Namacalathus as an Ediacaran total group lophophorate is consistent with an early radiation of the Lophophorata, as known early Cambrian representatives were sessile, mostly stalked forms, and in addition, the oldest known calcareous Brachiopoda (early Cambrian Obolellida) and Bryozoa (Ordovician Stenolaemata) possessed foliated ultrastructures.

Circulating TSLP associates with decreased wheezing in non-atopic preschool children: data from the URECA birth cohort.

BACKGROUND: Mouse models of atopic march suggest that systemic, skin-derived thymic stromal lymphopoietin (TSLP) mediates progression from eczema to asthma. OBJECTIVE: We investigated whether circulating TSLP is associated with eczema, allergic sensitization, or recurrent wheezing in young children. METHODS: A prospective analysis of the relationship between plasma levels of TSLP to allergic sensitization and recurrent wheezing was conducted in the birth cohort from the Urban Environment and Childhood Asthma (URECA) study. Plasma TSLP levels were measured at 1, 2, and 3 years of age and analysed for correlation with clinical parameters in each of the three years. Only those children with consecutive samples for all three years were included in this analysis. RESULTS: We detected TSLP in 33% of 236 children for whom plasma samples were available for all three years. Overall, a consistently significant association was not found between TSLP and eczema or allergic sensitization. With regard to recurrent wheezing, children with detectable TSLP at one year of age were significantly less likely to experience recurrent wheezing by 3 years compared with those children without detectable TSLP, but this was only seen in children without aeroallergen sensitization at 3 years (P < 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Contrary to our expectations, circulating TSLP was not significantly associated with eczema, allergen sensitization, or recurrent wheezing during the first three years of life. Early presence of circulating TSLP was significantly associated with reduced incidence of recurrent wheeze in those children not sensitized to aeroallergen. These findings suggest a possible underlying distinction between pathogenesis of developing atopic vs. non-atopic recurrent wheeze.

A phase 1 study of heat/phenol-killed, E. coli-encapsulated, recombinant modified peanut proteins Ara h 1, Ara h 2, and Ara h 3 (EMP-123) for the treatment of peanut allergy.

BACKGROUND: Immunotherapy for peanut allergy may be limited by the risk of adverse reactions. OBJECTIVE: To investigate the safety and immunologic effects of a vaccine containing modified peanut proteins. METHODS: This was a phase 1 trial of EMP-123, a rectally administered suspension of recombinant Ara h 1, Ara h 2, and Ara h 3, modified by amino acid substitutions at major IgE-binding epitopes, encapsulated in heat/phenol-killed E. coli. Five healthy adults were treated with 4 weekly escalating doses after which 10 peanut-allergic adults received weekly dose escalations over 10 weeks from 10 mcg to 3063 mcg, followed by three biweekly doses of 3063 mcg. RESULTS: There were no significant adverse effects in the healthy volunteers. Of the 10 peanut-allergic subjects [4 with intermittent asthma, median peanut IgE 33.3 kUA /l (7.2-120.2), and median peanut skin prick test wheal 11.3 mm (6.5-18)]; four experienced no symptoms; one had mild rectal symptoms; and the remaining five experienced adverse reactions preventing completion of dosing. Two were categorized as mild, but the remaining three were more severe, including one moderate reaction and two anaphylactic reactions. Baseline peanut IgE was significantly higher in the five reactive subjects (median 82.4 vs 17.2 kUA /l, P = 0.032), as was baseline anti-Ara h 2 IgE (43.3 versus 8.3, P = 0.036). Peanut skin test titration and basophil activation (at a single dilution) were significantly reduced after treatment, but no significant changes were detected for total IgE, peanut IgE, or peanut IgG4. CONCLUSIONS: Rectal administration of EMP-123 resulted in frequent adverse reactions, including severe allergic reactions in 20%.

Potential mechanisms for the association between fall birth and food allergy.

BACKGROUND: Season of birth has been reported as a risk factor for food allergy, but the mechanisms by which it acts are unknown. METHODS: Two populations were studied: 5862 children from the National Health and Nutrition Examination Survey (NHANES) III and 1514 well-characterized food allergic children from the Johns Hopkins Pediatric Allergy Clinic (JHPAC). Food allergy was defined as self-report of an acute reaction to a food (NHANES), or as milk, egg, and peanut allergy. Logistic regression compared fall or nonfall birth between (i) food allergic and nonallergic subjects in NHANES, adjusted for ethnicity, age, income, and sex, and (ii) JHPAC subjects and the general Maryland population. For NHANES, stratification by ethnicity and for JHPAC, eczema were examined. RESULTS: Fall birth was more common among food allergic subjects in both NHANES (OR, 1.91; 95% CI, 1.31-2.77) and JHPAC/Maryland (OR, 1.31; 95% CI, 1.18-1.47). Ethnicity interacted with season (OR, 2.34; 95% CI, 1.43-3.82 for Caucasians; OR, 1.19; 95% CI, 0.77-1.86 for non-Caucasians; P = 0.04 for interaction), as did eczema (OR, 1.47; 95% CI, 1.29-1.67 with eczema; OR, 1.00; 95% CI, 0.80-1.23 without eczema; P = 0.002 for interaction). CONCLUSIONS: Fall birth is associated with increased risk of food allergy, and this risk is greatest among those most likely to have seasonal variation in vitamin D during infancy (Caucasians) and those at risk for skin barrier dysfunction (subjects with a history of eczema), suggesting that vitamin D and the skin barrier may be implicated in seasonal associations with food allergy.

Dendritic cell and T cell responses in children with food allergy.

BACKGROUND: Food allergy (FA) and eosinophilic oesophagitis (EE) are increasingly common clinical problems. Dendritic cells (DCs) are key regulators of the sensitization and effector phases of allergic immune responses, but their role in these diseases is largely unknown. OBJECTIVE: To evaluate for alterations in the phenotype and function of DCs in children with IgE-mediated milk allergy or EE compared with their non-affected siblings. METHODS: Plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) were prepared from peripheral blood of children with milk allergy (FA), EE, and non-affected siblings (CON). Purified pDCs and mDCs were cultured alone or with autologous CD4(+) lymphocytes. Cytokine levels in plasma, or culture supernatants following stimulation, were measured using multiplex array immunoassay. Cell-surface molecule expression was determined by flow cytometry. RESULTS: DCs from FA subjects produced greater levels of pro-inflammatory cytokines (IL-6, TNF-α), granulocyte macrophage-colony forming factor, and mDC-derived IL-10 compared with controls following allergen exposure. T(H) 2 but not T(H) 1 cytokines were spontaneously produced in DC-CD4(+) T cell co-cultures from children with FA and were not significantly increased after stimulation with milk extract, suggesting an ongoing activation in vivo. This hypothesis was further supported by evidence for elevated IL-5 and IL-13 protein in the plasma of children with both FA and EE. The only significant DC phenotypic differences were: (1) reduced levels of CD80 in EE subjects and (2) FcɛRI expression that correlated with serum IgE levels in both groups of subjects. CONCLUSION: This study suggests that DCs from children with FA and EE produce more pro-inflammatory cytokines, and that their CD4(+) T cells are spontaneously activated to produce T(H) 2 cytokines in the presence of FcɛRI-bearing DCs.

Umbilical cord plasma 25-hydroxyvitamin D concentration and immune function at birth: the Urban Environment and Childhood Asthma study.

BACKGROUND: Recent studies have reported conflicting data on the association between maternal intake of vitamin D during pregnancy and asthma. OBJECTIVE: To assess the influence of prenatal vitamin D status on immune function at birth. METHODS: In an inner-city birth cohort of 568 newborns, 520 of whom had at least one atopic parent, we measured the umbilical cord (UC) plasma concentration of 25-hydroxyvitamin D (25(OH)D) and the cytokine responses of UC blood mononuclear cells (UCMCs) to stimuli including phytohaemagglutinin (PHA), lipopolysaccharide (LPS), and peptidoglycan. In a subset, the UCMC expression of regulatory T cell markers and the suppressive activity of CD4(+) CD25(+) UCMCs were measured. Results The 25th, 50th, and 75th percentiles of UC plasma 25(OH)D level were 15.0, 20.2, and 25.6 ng/mL, respectively. Most cytokine responses of UCMC were not correlated with UC 25(OH)D concentration; however, IFN-γ release after LPS stimulation was weakly positively correlated with UC 25(OH)D concentration (r=0.11, P=0.01). PHA responses were not significantly correlated with 25(OH)D concentration. The UC plasma 25(OH)D concentration was inversely related to the number of CD25(+) (r=-0.20, P=0.06), CD25(Bright) (r=-0.21, P=0.05), and CD25(+) FoxP3 (r=-0.29, P=0.06) cells as a proportion of CD4(+) T cells in UC blood (r=-0.26, P=0.04) but not to the suppressive activity of CD4(+) CD25(+) cells (r=0.17, P=0.22). CONCLUSION AND CLINICAL RELEVANCE: UC 25(OH)D concentration was not correlated with most UCMC cytokine responses to multiple stimuli. There was a suggestion of a weakly positive correlation with IFN-γ release after LPS stimulation. The proportions of CD25(+) , CD25(Bright) , and CD25(+) FoxP3 cells to total CD4(+) T cells were inversely correlated with UC 25(OH)D concentration. Our findings suggest that higher vitamin D levels at birth may be associated with a lower number of T-regulatory cells. Vitamin D status in utero may influence immune regulation in early life.

Ediacaran metazoan reveals lophotrochozoan affinity and deepens root of Cambrian Explosion.

Through exceptional preservation, we establish a phylogenetic connection between Ediacaran and Cambrian metazoans. We describe the first three-dimensional, pyritized soft tissue in Namacalathus from the Ediacaran Nama Group, Namibia, which follows the underlying form of a stalked, cup-shaped, calcitic skeleton, with six radially arranged lobes projecting into an apical opening and lateral lumens. A thick body wall and probable J-shaped gut are present within the cup, and the middle layer of the often-spinose skeleton and skeletal pores are selectively pyritized, supporting an organic-rich composition and tripartite construction with possible sensory punctae. These features suggest a total group lophotrochozoan affinity. These morphological data support molecular phylogenies and demonstrates that the origin of modern lophotrochozoan phyla, and their ability to biomineralize, had deep roots in the Ediacaran.

Regional nutrient decrease drove redox stabilisation and metazoan diversification in the late Ediacaran Nama Group, Namibia.

The late Ediacaran witnessed an increase in metazoan diversity and ecological complexity, marking the inception of the Cambrian Explosion. To constrain the drivers of this diversification, we combine redox and nutrient data for two shelf transects, with an inventory of biotic diversity and distribution from the Nama Group, Namibia (~550 to ~538 Million years ago; Ma). Unstable marine redox conditions characterised all water depths in inner to outer ramp settings from ~550 to 547 Ma, when the first skeletal metazoans appeared. However, a marked deepening of the redoxcline and a reduced frequency of anoxic incursions onto the inner to mid-ramp is recorded from ~547 Ma onwards, with full ventilation of the outer ramp by ~542 Ma. Phosphorus speciation data show that, whilst anoxic ferruginous conditions were initially conducive to the drawdown of bioavailable phosphorus, they also permitted a limited degree of phosphorus recycling back to the water column. A long-term decrease in nutrient delivery from continental weathering, coupled with a possible decrease in upwelling, led to the gradual ventilation of the Nama Group basins. This, in turn, further decreased anoxic recycling of bioavailable phosphorus to the water column, promoting the development of stable oxic conditions and the radiation of new mobile taxa.

Sodium taurocholate modifies the bile acid-independent fraction of canalicular bile flow in the rhesus monkey.

Bile acid-independent secretion and the choleretic response to taurocholate were determined in rhesus monkeys fitted with indwelling silastic cannulas in the common bile ducts. Bile acids were infused intravenously in random order at 3.5, 7.0, or 10.5 mumol/min for 1.5 h each. When data were analyzed with a single regression line, bile flow increased in proportion to the level of bile acid secretion, although the y-intercepts (the conventional measurement of bile acid-independent secretion) varied widely (77.9+/-40.9 ml/24 h). The variation in y-intercepts was observed between animals and with repeated studies in the same animal and could not be explained by sex differences or the effects of the indwelling silastic cannulas, but seemed to be related to the order of bile acid infusion. With only two taurocholic acid infusion rates (7.0 and 3.5 mumol/min), [(14)C]erythritol clearance was greater per mole of secreted bile acid when the initial bile acid infusion was at the high level, but approached zero at low bile acid secretion rates, which suggests that so-called bile acid-independent canalicular flow is closely related to bile acid secretion or is small in size. The augmentation in [(14)C]erythritol clearance when the high infusion rate was given first was also associated with an increase in biliary clearance of [(3)H]inulin, which indicates that the premeability to inulin was also enhanced. Identical experiments which substituted equimolar infusions of a nonmicelle-forming bile acid (taurodehydrocholate) for taurocholate failed to demonstrate any difference in choleretic response or biliary clearance of [(3)H]inulin with the order of bile acid infusion. These experiments demonstrate that a micelleforming bile acid, taurocholate, can increase the permeability of the biliary system to large molecular weight solutes and simultaneously modify the y-intercept and the volume of bile secreted in response to the transported bile acid. Taurocholate may, therefore, modify its own choleretic response, perhaps by altering the structure or function of bile secretory membranes, and appears to be a major determinant of so-called bile acid-independent flow in rhesus monkeys.

Controls on the evolution of Ediacaran metazoan ecosystems: A redox perspective.

A growing number of detailed geochemical studies of Ediacaran (635-541 Ma) marine successions have provided snapshots into the redox environments that played host to the earliest known metazoans. Whilst previous compilations have focused on the global evolution of Ediacaran water column redox chemistry, the inherent heterogeneity evident in palaeogeographically distinct environments demands a more dissected approach to better understand the nature, interactions and evolution of extrinsic controls on the development of early macrobenthic ecosystems. Here, we review available data of local-scale redox conditions within a palaeogeographic and sequence stratigraphic framework, to explore the mechanisms controlling water column redox conditions and their potential impact on the record of metazoans. The openly connected Laurentian margin, North America (632-540 Ma) and Nama basin, Namibia (550-538 Ma), and the variably restricted Yangtze Block, South China (635-520 Ma), show continued redox instability after the first fossil evidence for metazoans. This may support opportunistic benthic colonisation during periods of transient oxygenation amidst episodic upwelling of anoxic waters beneath a very shallow, fluctuating chemocline. The first skeletal metazoans appeared under conditions of continued redox stratification, such as those which characterise the Dengying Formation of the Yangtze Block and the Kuibis Subgroup of the Nama basin. Current data, however, suggests that successful metazoan reef-building demanded more persistent oxia. We propose that cratonic positioning and migration throughout the Ediacaran Period, in combination with gradually increasing dissolved oxygen loading, may have provided a first-order control on redox evolution through regulating circulation mechanisms in the Mirovian Ocean. Some unrestricted lower slope environments from mid-high latitudes benefited from sustained oxygenation via downwelling, whilst transit of isolated cratons towards more equatorial positions stifled pervasive ventilation either through ineffective surface ocean mixing, Ekman-induced upwelling, elevated surface ocean productivity or a combination of these processes.

Intraspecific variation in an Ediacaran skeletal metazoan: Namacalathus from the Nama Group, Namibia.

Namacalathus hermanastes is one of the oldest known skeletal metazoans, found in carbonate settings of the terminal Ediacaran (~550-541 million years ago [Ma]). The palaeoecology of this widespread, goblet-shaped, benthic organism is poorly constrained yet critical for understanding the dynamics of the earliest metazoan communities. Analysis of in situ assemblages from the Nama Group, Namibia (~548-541 Ma), shows that Namacalathus exhibited size variation in response to differing water depths, hydrodynamic conditions and substrate types. In low-energy, inner ramp environments, Namacalathus attains the largest average sizes but grew in transient, loosely aggregating, monospecific aggregations attached to microbial mats. In high-energy mid-ramp reefs, Namacalathus spatially segregated into different palaeoecological habitats with distinct size distributions. In outer ramp environments, individuals were small and formed patchy, dense, monospecific aggregations attached to thin microbial mats. Asexual budding is common in all settings. We infer that variations in size distribution in Namacalathus reflect differences in habitat heterogeneity and stability, including the longevity of mechanically stable substrates and oxic conditions. In the Nama Group, long-lived skeletal metazoan communities developed within topographically heterogeneous mid-ramp reefs, which provided diverse mechanically stable microbial substrates in persistently oxic waters, while inner and outer ramp communities were often ephemeral, developing during fleeting episodes of either oxia and/or substrate stability. We conclude that Namacalathus, which forms a component of these communities in the Nama Group, was a generalist that adapted to various palaeoecological habitats within a heterogeneous ecosystem landscape where favourable conditions persisted, and was also able to opportunistically colonise transiently hospitable environments. These early skeletal metazoans colonised previously unoccupied substrates in thrombolitic reefs and other microbial carbonate settings, and while they experienced relatively low levels of interspecific competition, they were nonetheless adapted to the diverse environments and highly dynamic redox conditions present in the terminal Ediacaran.

Dynamic anoxic ferruginous conditions during the end-Permian mass extinction and recovery.

The end-Permian mass extinction, ∼252 million years ago, is notable for a complex recovery period of ∼5 Myr. Widespread euxinic (anoxic and sulfidic) oceanic conditions have been proposed as both extinction mechanism and explanation for the protracted recovery period, yet the vertical distribution of anoxia in the water column and its temporal dynamics through this time period are poorly constrained. Here we utilize Fe-S-C systematics integrated with palaeontological observations to reconstruct a complete ocean redox history for the Late Permian to Early Triassic, using multiple sections across a shelf-to-basin transect on the Arabian Margin (Neo-Tethyan Ocean). In contrast to elsewhere, we show that anoxic non-sulfidic (ferruginous), rather than euxinic, conditions were prevalent in the Neo-Tethys. The Arabian Margin record demonstrates the repeated expansion of ferruginous conditions with the distal slope being the focus of anoxia at these times, as well as short-lived episodes of oxia that supported diverse biota.

Low-oxygen waters limited habitable space for early animals.

The oceans at the start of the Neoproterozoic Era (1,000-541 million years ago, Ma) were dominantly anoxic, but may have become progressively oxygenated, coincident with the rise of animal life. However, the control that oxygen exerted on the development of early animal ecosystems remains unclear, as previous research has focussed on the identification of fully anoxic or oxic conditions, rather than intermediate redox levels. Here we report anomalous cerium enrichments preserved in carbonate rocks across bathymetric basin transects from nine localities of the Nama Group, Namibia (∼550-541 Ma). In combination with Fe-based redox proxies, these data suggest that low-oxygen conditions occurred in a narrow zone between well-oxygenated surface waters and fully anoxic deep waters. Although abundant in well-oxygenated environments, early skeletal animals did not occupy oxygen impoverished regions of the shelf, demonstrating that oxygen availability (probably >10 µM) was a key requirement for the development of early animal-based ecosystems.

Ocean acidification and the Permo-Triassic mass extinction.

Ocean acidification triggered by Siberian Trap volcanism was a possible kill mechanism for the Permo-Triassic Boundary mass extinction, but direct evidence for an acidification event is lacking. We present a high-resolution seawater pH record across this interval, using boron isotope data combined with a quantitative modeling approach. In the latest Permian, increased ocean alkalinity primed the Earth system with a low level of atmospheric CO2 and a high ocean buffering capacity. The first phase of extinction was coincident with a slow injection of carbon into the atmosphere, and ocean pH remained stable. During the second extinction pulse, however, a rapid and large injection of carbon caused an abrupt acidification event that drove the preferential loss of heavily calcified marine biota.

Sarcoidosis and common variable immunodeficiency. Report of 8 cases and review of the literature.

The true incidence of sarcoidosis in common variable immunodeficiency (CVID) is unknown. We report here 8 cases of sarcoidosis among 80 patients with CVID followed in our clinics, along with 22 well-documented cases reported in the literature. Sarcoidosis, therefore, represents an important entity to consider among patients with CVID who exhibit clinical, radiographic, laboratory, and biopsy findings compatible with sarcoidosis. Conversely, the diagnosis of CVID should be considered in patients with sarcoidosis who do not exhibit the characteristic hypergammaglobulinemia and who have a history of recurrent infections. Although many features of sarcoidosis are similar in patients with CVID to those in patients with sarcoidosis alone, there are many important differences. Patients with CVID in whom sarcoidosis develops present with hypogammaglobulinemia rather than hypergammaglobulinemia and have a higher prevalence of recurrent infections, thrombocytopenia, and splenic involvement. Steroids, in most cases, appeared helpful in reducing adenopathy and splenomegaly, improving uveitis, lowering serum alkaline phosphatase, and reversing hematologic abnormalities. The underlying pathophysiology responsible for the association of these 2 disorders in the same patient remains obscure. However, as more patients are identified, it may be possible to gain a better understanding of the immunologic defect responsible for the dual presentation of these 2 relatively uncommon diseases.