Druggable proteins required for B lymphocyte survival and immune responses are an emerging source of new treatments for autoimmunity and lymphoid malignancy. In this study, we show that mice with an ...inactivating mutation in the intramembrane protease signal peptide peptidase-like 2A (SPPL2A) unexpectedly exhibit profound humoral immunodeficiency and lack mature B cell subsets, mirroring deficiency of the cytokine B cell-activating factor (BAFF). Accumulation of Sppl2a-deficient B cells was rescued by overexpression of the BAFF-induced survival protein B cell lymphoma 2 (BCL2) but not BAFF and was distinguished by low surface BAFF receptor and IgM and IgD B cell receptors. CD8-negative dendritic cells were also greatly decreased. SPPL2A deficiency blocked the proteolytic processing of CD74 MHC II invariant chain in both cell types, causing dramatic build-up of the p8 product of Cathepsin S and interfering with earlier steps in CD74 endosomal retention and processing. The findings illuminate an important role for the final step in the CD74-MHC II pathway and a new target for protease inhibitor treatment of B cell diseases.
Background Debate continues over whether transhiatal esophagectomy (THE) offers decreased morbidity and mortality compared with transthoracic esophagectomy (TTE). To definitively answer this ...question, we used the Nationwide Inpatient Sample database to compare morbidity and mortality after THE and TTE. Study Design Using ICD-9 procedure codes, we queried the Nationwide Inpatient Sample database for patients undergoing THE and TTE. Multivariate statistical analysis was completed to compare morbidity, mortality, length of stay, and hospital volume analysis between the groups. Results Between 1999 and 2003, 17,395 patients included in the Nationwide Inpatient Sample underwent esophagectomy. Mean patient age was similar in those undergoing THE and TTE (61.9 versus 62.0 years, respectively). Overall morbidity and mortality after esophagectomy were 50.7% and 8.8%, respectively. In-hospital mortality after THE was 8.91% compared with 8.47% after TTE (p = 0.642). Multivariate regression analysis showed no difference in the incidence of mediastinitis, wound, infectious, pulmonary, gastrointestinal, cardiovascular, systemic, procedure-related, or overall complications or hospital length of stay between the two groups. Controlling additionally for hospital volume showed high-volume centers (more than 10 esophagectomies per year) had significantly lower mortality rates than low-volume centers (10 or fewer esophagectomies per year, p = 0.024). Additionally, low-volume centers have a higher incidence of gastrointestinal and systemic complications in the TTE group (p = 0.048 and p = 0.038, respectively). Conclusions This large-volume, multicenter study constitutes the largest cohort in the literature to compare outcomes after THE and TTE. These findings indicate the outcomes after THE and TTE for esophageal disease are equivalent, although higher-volume centers will have lower morbidity and mortality.
Plasmodium falciparum antigens expressed on the surface of infected erythrocytes are important targets of naturally acquired immunity against malaria, but their high number and variability provide ...the pathogen with a powerful means of escape from host antibodies. Although broadly reactive antibodies against these antigens could be useful as therapeutics and in vaccine design, their identification has proven elusive. Here we report the isolation of human monoclonal antibodies that recognize erythrocytes infected by different P. falciparum isolates and opsonize these cells by binding to members of the RIFIN family. These antibodies acquired broad reactivity through a novel mechanism of insertion of a large DNA fragment between the V and DJ segments. The insert, which is both necessary and sufficient for binding to RIFINs, encodes the entire 98 amino acid collagen-binding domain of LAIR1, an immunoglobulin superfamily inhibitory receptor encoded on chromosome 19. In each of the two donors studied, the antibodies are produced by a single expanded B-cell clone and carry distinct somatic mutations in the LAIR1 domain that abolish binding to collagen and increase binding to infected erythrocytes. These findings illustrate, with a biologically relevant example, a novel mechanism of antibody diversification by interchromosomal DNA transposition and demonstrate the existence of conserved epitopes that may be suitable candidates for the development of a malaria vaccine.
Conservation management requires knowledge of how a target species interacts with other species. Some relatively common species can modify the environment to the advantage of rarer, endangered ...species. Thus, local enhancement of those common species can positively influence remaining populations of the rarer species. The endangered pygmy bluetongue lizard Tiliqua adelaidensis inhabits burrows that are constructed by lycosid and mygalomorph spiders. We recorded 490 burrows in a 1 ha plot at the end of one season, and then observed at regular intervals the formation and loss of burrows, and the changes in occupancy status of each burrow over the next season. We found spiders in 94% of all newly constructed burrows and deduced that they had built the burrows. We found no evidence that lizards dug new burrows or deepened existing burrows. The numbers of both lizards and spiders in the burrows declined over the spring and summer, with lizards moving from their burrows more often early in the season than later. However, there was no strong trend for lizards to replace spiders in burrows. In fact, lizards tended to occupy deeper burrows than spiders, suggesting little negative impact of lizards on spiders. However, spiders had a positive impact on lizards by providing the refuge burrows central for lizard survival. Although lizards readily accept artificial burrows, long-term conservation for the lizards must include viable spider populations to maintain a supply of suitable burrow refuges.
Objective Resident work-hour regulations were instituted to improve patient care during resident training. Although initial data have not shown the intended benefit of limiting resident work hours, ...concern has developed as to whether resident operative experience has significantly decreased since instituting the work-hour restrictions. Methods Resident operative logs were reviewed for 3 training institutions in the western United States for residents graduating in the years 1999–2007. Residents were divided into pre–work-hour restriction (1999–2002) and post–work-hour restriction (2003–2007) groups. Thoracic, cardiac, and all combined cases were reviewed separately for all residents at yearly intervals. Statistical analysis was subsequently conducted. Results A total of 37 residents were identified from 3 different programs over the study period. Thoracic cases were lower during the first year of training but increased in the second and third years of training after work-hour restrictions (78 vs 42, 65 vs 72, and 102 vs 138; P = .17, P = .59, and P = .11, respectively). Cardiac cases were substantially lower during each year of training after work-hour restrictions (190 vs 153, 154 vs 108, and 116 vs 76; P = 0.15, P < .0001, and P = .001, respectively). Overall total cases were also lower over all years of residency after work-hour restrictions (251 vs 195, 219 vs 187, and 234 vs 214; P = .03, P = .049, and P = .59, respectively). Conclusions The overall volume of thoracic surgery cases was not significantly different after the implementation of the 80-hour work-week restriction. The total number of cardiac cases logged was substantially less during the same time period, and therefore as a result, the total number of cases performed after the implementation of the work-hour restrictions was also reduced. Although recent data have not shown an improvement in patient outcomes after restriction of resident work hours, we speculate that in a time of increasingly complex cases, reduction in resident case volumes caused by work-hour restrictions and decreasing cardiac cases might lead to inadequate operative experience.
Populations of the Australian sleepy lizard, Tiliqua rugosa, near Mt. Mary, South Australia carry natural infestations of two tick species Aponomma hydrosauri and Amblyomma limbatum. In field ...experiments at two sites, 18 km apart, lizards with experimentally increased tick loads had smaller home ranges, moved shorter distances in a day, and were found basking more but moving less often than lizards from which ticks were experimentally removed. The results were consistent for adult lizards in two years, and for sub-adults in a third year. Laboratory trials showed that juvenile lizards that had tick infestations had lower sprint speeds than uninfested siblings, and that adults with tick infestations had less endurance than those that were uninfested. The results contrast with those of a previous survey that showed that lizards with high tick loads had greater body size and remained longer at a site, but indicate that there may be a balance, for lizards, between the fitness advantages in occupying habitats with high-quality resources, and the costs from parasites that also prefer those habitats.
Broccoli sprouts (BS) are the richest source of sulforaphane (SFN), which is a potent inducer of phase II enzymes, which play a critical role in preventing oxidative stress (OS) and inflammation.
The ...objective of this study was to determine if ingestion of whole BS improves airway inflammatory and physiologic outcomes, and OS in adults with asthma and allergic sensitization to an indoor allergen.
The study is a double-blind, placebo-controlled, randomized trial to compare the effects of BS with placebo (alfalfa sprouts AS) on airway inflammation and markers of OS. Forty adults (aged 18-50 years) were randomized to eat either (a) 100 g of BS daily or (b) 100 g of AS daily for 3 days. Fractional exhaled nitric oxide (FENO), forced expiratory volume 1, nasal epithelial and PBMC gene expression, inflammatory and OS biomarkers, and symptoms were assessed both before and after ingestion of the sprouts. The primary outcome variable was the change in FENO. Secondary outcome measures included rhinitis and asthma symptoms, lung function, and OS and inflammatory biomarkers.
BS ingestion for 3 consecutive days did not reduce FENO, despite resulting in a marked increase in serum SFN concentrations (21 vs 22 parts per billion, P = .76). Furthermore, BS consumption did not induce cytoprotective antioxidant genes in either PBMCs or nasal epithelial cells, reduce OS and inflammatory markers, or improve lung function.
Ingestion of whole BS for 3 days does not appear to improve eosinophilic pulmonary inflammation, inflammatory and OS biomarkers, or clinical features of asthma among atopic adults with asthma despite resulting in a marked increase in serum SFN levels.
Monogamy is relatively rarely reported in taxa other than birds. The reproductive system of many lizard species appears to involve multiple mating partners for both the male and the female. However, ...short-term monogamous relationships have been reported in some lizard species, either where the male defends a territory that is only occupied by a single adult female, or where males stay with females for a period of time after mating, apparently to guard against rival males. There are a few reported cases of more prolonged monogamous relationships in lizards, with the Australian sleepy lizard,
Tiliqua rugosa, the best studied example. Adult males and females of this species form monogamous pairs for an extended period before mating each spring, and they select the same partner in successive years. The paper reviews possible functions of monogamy in this and other lizard species, and suggests that the additional perspective from studying lizards may enrich our overall understanding of monogamous behaviour.
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