Increased Respiratory Disease Mortality at a Microwave Popcorn Production Facility with Worker Risk of Bronchiolitis Obliterans

Background

Bronchiolitis obliterans, an irreversible lung disease, was first associated with inhalation of butter flavorings (diacetyl) in workers at a microwave popcorn company. Excess rates of lung-function abnormalities were related to cumulative diacetyl exposure. Because information on potential excess mortality would support development of permissible exposure limits for diacetyl, we investigated respiratory-associated mortality during 2000–2011 among current and former workers at this company who had exposure to flavorings and participated in cross-sectional surveys conducted between 2000–2003.

Methods

We ascertained workers'' vital status through a Social Security Administration search. Causes of death were abstracted from death certificates. Because bronchiolitis obliterans is not coded in the International Classification of Disease 10^th revision (ICD-10), we identified respiratory mortality decedents with ICD-10 codes J40–J44 which encompass bronchitis (J40), simple and mucopurulent chronic bronchitis (J41), unspecified chronic bronchitis (J42), emphysema (J43), and other chronic obstructive pulmonary disease (COPD) (J44). We calculated expected number of deaths and standardized mortality ratios (SMRs) with 95% confidence intervals (CI) to determine if workers exposed to diacetyl experienced greater respiratory mortality than expected.

Results

We identified 15 deaths among 511 workers. Based on U.S. population estimates, 17.39 deaths were expected among these workers (SMR = 0.86; CI:0.48-1.42). Causes of death were available for 14 decedents. Four deaths among production and flavor mixing workers were documented to have a multiple cause of ‘other COPD’ (J44), while 0.98 ‘other COPD’-associated deaths were expected (SMR = 4.10; CI:1.12–10.49). Three of the 4 ‘other COPD’-associated deaths occurred among former workers and workers employed before the company implemented interventions reducing diacetyl exposure in 2001.

Conclusion

Workers at the microwave popcorn company experienced normal rates of all-cause mortality but higher rates of COPD-associated mortality, especially workers employed before the company reduced diacetyl exposure. The demonstrated excess in COPD-associated mortality suggests continued efforts to lower flavoring exposure are prudent.     

The Loss of Gnai2 and Gnai3 in B Cells Eliminates B Lymphocyte Compartments and Leads to a Hyper-IgM Like Syndrome

B lymphocytes are compartmentalized within lymphoid organs. The organization of these compartments depends upon signaling initiated by G-protein linked chemoattractant receptors. To address the importance of the G-proteins Gα_i2 and Gα_i3 in chemoattractant signaling we created mice lacking both proteins in their B lymphocytes. While bone marrow B cell development and egress is grossly intact; mucosal sites, splenic marginal zones, and lymph nodes essentially lack B cells. There is a partial block in splenic follicular B cell development and a 50-60% reduction in splenic B cells, yet normal numbers of splenic T cells. The absence of Gα_i2 and Gα_i3 in B cells profoundly disturbs the architecture of lymphoid organs with loss of B cell compartments in the spleen, thymus, lymph nodes, and gastrointestinal tract. This results in a severe disruption of B cell function and a hyper-IgM like syndrome. Beyond the pro-B cell stage, B cells are refractory to chemokine stimulation, and splenic B cells are poorly responsive to antigen receptor engagement. Gα_i2 and Gα_i3 are therefore critical for B cell chemoattractant receptor signaling and for normal B cell function. These mice provide a worst case scenario of the consequences of losing chemoattractant receptor signaling in B cells.     

Genotypic variation in the persistence of transgenerational responses to seasonal cues*

Phenotypes respond to environments experienced directly by an individual, via phenotypic plasticity, or to the environment experienced by ancestors, via transgenerational environmental effects. The adaptive value of environmental effects depends not only on the strength and direction of the induced response but also on how long the response persists within and across generations, and how stably it is expressed across environments that are encountered subsequently. Little is known about the genetic basis of those distinct components, or even whether they exhibit genetic variation. We tested for genetic differences in the inducibility, temporal persistence, and environmental stability of transgenerational environmental effects in Arabidopsis thaliana. Genetic variation existed in the inducibility of transgenerational effects on traits expressed across the life cycle. Surprisingly, the persistence of transgenerational effects into the third generation was uncorrelated with their induction in the second generation. Although environmental effects for some traits in some genotypes weakened over successive generations, others were stronger or even in the opposite direction in more distant generations. Therefore, transgenerational effects in more distant generations are not merely caused by the retention or dissipation of those expressed in prior generations, but they may be genetically independent traits with the potential to evolve independently.     

Transforming Growth Factor-β3 (TGF-β3) Knock-in Ameliorates Inflammation Due to TGF-β1 Deficiency While Promoting Glucose Tolerance

Three homologues of TGF-β exist in mammals as follows: TGF-β1, TGF-β2, and TGF-β3. All three proteins share high homology in their amino acid sequence, yet each TGF-β isoform has unique heterologous motifs that are highly conserved during evolution. Although these TGF-β proteins share similar properties in vitro, isoform-specific properties have been suggested through in vivo studies and by the unique phenotypes for each TGF-β knock-out mouse. To test our hypothesis that each of these homologues has nonredundant functions, and to identify such isoform-specific roles, we genetically exchanged the coding sequence of the mature TGF-β1 ligand with a sequence from TGF-β3 using targeted recombination to create chimeric TGF-β1/3 knock-in mice (TGF-β1^Lβ3/Lβ3). In the TGF-β1^Lβ3/Lβ3 mouse, localization and activation still occur through the TGF-β1 latent associated peptide, but cell signaling is triggered through the TGF-β3 ligand that binds to TGF-β receptors. Unlike TGF-β1^−/− mice, the TGF-β1^Lβ3/Lβ3 mice show neither embryonic lethality nor signs of multifocal inflammation, demonstrating that knock-in of the TGF-β3 ligand can prevent the vasculogenesis defects and autoimmunity associated with TGF-β1 deficiency. However, the TGF-β1^Lβ3/Lβ3 mice have a shortened life span and display tooth and bone defects, indicating that the TGF-β homologues are not completely interchangeable. Remarkably, the TGF-β1^Lβ3/Lβ3 mice display an improved metabolic phenotype with reduced body weight gain and enhanced glucose tolerance by induction of beneficial changes to the white adipose tissue compartment. These findings reveal both redundant and unique nonoverlapping functional diversity in TGF-β isoform signaling that has relevance to the design of therapeutics aimed at targeting the TGF-β pathway in human disease.     

Molecular Characterization and Evolution of Self-Incompatibility Genes in Arabidopsis thaliana: The Case of the Sc Haplotype

The switch from an outcrossing mode of mating enforced by self-incompatibility to self-fertility in the Arabidopsis thaliana lineage was associated with mutations that inactivated one or both of the two genes that comprise the self-incompatibility (SI) specificity-determining S-locus haplotype, the S-locus receptor kinase (SRK) and the S-locus cysteine-rich (SCR) genes, as well as unlinked modifier loci required for SI. All analyzed A. thaliana S-locus haplotypes belong to the SA, SB, or SC haplotypic groups. Of these three, the SC haplotype is the least well characterized. Its SRKC gene can encode a complete open-reading frame, although no functional data are available, while its SCRC sequences have not been isolated. As a result, it is not known what mutations were associated with inactivation of this haplotype. Here, we report on our analysis of the Lz-0 accession and the characterization of its highly rearranged SC haplotype. We describe the isolation of its SCRC gene as well as the subsequent isolation of SCRC sequences from other SC-containing accessions and from the A. lyrata S36 haplotype, which is the functional equivalent of the A. thaliana SC haplotype. By performing transformation experiments using chimeric SRK and SCR genes constructed with SC- and S36-derived sequences, we show that the SRKC and SCRC genes of Lz-0 and at least a few other SC-containing accessions are nonfunctional, despite SCRC encoding a functional full-length protein. We identify the probable mutations that caused the inactivation of these genes and discuss our results in the context of mechanisms of S-locus inactivation in A. thaliana.     

Restricted gene flow within and between rapidly diverging Neotropical plant species

Speciation involves the evolution of traits and genetic differences that contribute to reproductive isolation and the cessation of gene flow, and studying closely related species and divergent populations gives insight into how these phenomena proceed. Here, we document patterns of gene flow within and between two members of a rapid Neotropical species radiation, Costus pulverulentus and Costus scaber (Costaceae). These species co‐occur in the tropical rainforest and share pollinators, but are reproductively isolated by a series of prezygotic barriers, some of which show evidence of reinforcement at sympatric sites. Here, we genotype microsatellite markers in plants from eight sites that span the geographical range of both species, including four sympatric sites. We also genotype putative hybrids found at two sympatric sites. We find high levels of genetic isolation among populations within each species and low but detectable levels of introgression between species at sympatric sites. Putative hybrids identified by morphology are consistent with F1 or more advanced hybrids. Our results highlight the effectiveness of prezygotic isolating mechanisms at maintaining species boundaries in young radiations and provide empirical data on levels of gene flow consistent with reinforcement.     

Plant-derived pharmaceuticals for the developing world

Plant-produced vaccines and therapeutic agents offer enormous potential for providing relief to developing countries by reducing the incidence of infant mortality caused by infectious diseases. Vaccines derived from plants have been demonstrated to effectively elicit an immune response. Biopharmaceuticals produced in plants are inexpensive to produce, require fewer expensive purification steps, and can be stored at ambient temperatures for prolonged periods of time. As a result, plant-produced biopharmaceuticals have the potential to be more accessible to the rural poor. This review describes current progress with respect to plant-produced biopharmaceuticals, with a particular emphasis on those that target developing countries. Specific emphasis is given to recent research on the production of plant-produced vaccines toward human immunodeficiency virus, malaria, tuberculosis, hepatitis B virus, Ebola virus, human papillomavirus, rabies virus and common diarrheal diseases. Production platforms used to express vaccines in plants, including nuclear and chloroplast transformation, and the use of viral expression vectors, are described in this review. The review concludes by outlining the next steps for plant-produced vaccines to achieve their goal of providing safe, efficacious and inexpensive vaccines to the developing world.