Acute inflammatory response to contrast agent aspiration and its mechanisms in the rat lung.

Objectives/hypothesisContrast agent (CA) aspiration is an established complication of upper gastrointestinal and videofluoroscopic swallow studies. The underlying molecular biological mechanisms of acute response to CA aspiration in the respiratory organs remain unclear. The aims of this study were to elucidate the histological and biological influences of three kinds of CAs on the lung and to clarify the differences in acute responses.Study designAnimal model.MethodsEight-week-old male Sprague Dawley rats were divided into five groups (n = 6 in each group). Three groups underwent tracheal instillation of one of three different CAs: barium (Ba) sulfate, nonionic contrast agents (NICAs), and ionic contrast agents (ICAs). A control group was instilled with saline and a sham group was instilled with air. All animals were euthanized on day 2 after treatment and histological and gene analysis was performed.ResultsNo animal died after CA or control/sham aspiration. Ba caused severe histopathologic changes and more prominent inflammatory cell infiltration in the lungs compared with the two other iodinated contrast agents. Increases in expressions of inflammatory cytokines (tumor necrosis factor [Tnf], interleukin-1β [Il1b], and interferon-γ [Ifng]) were observed in Ba aspiration rats, and upregulation of Il1b was seen in ICA aspiration rats. NICA did not cause obvious histologic changes or expressions of inflammatory cytokines and fibrosis-related genes in the lungs.ConclusionsBa caused significantly more acute lung inflammation in a rodent model than did ioinic and nonionic iodinated CAs. Nonionic contrast did not cause any discernible inflammatory response in the lungs, suggesting that it may be the safest contrast for videofluoroscopic swallow studies.Level of evidenceNA Laryngoscope, 129:1533-1538, 2019

Low serum cortisol predicts early death following acute myocardial infarction

<b>Objective</b>: Low serum cortisol concentrations have been associated with adverse prognosis in critical illness of diverse aetiology. We aimed to determine whether low serum cortisol concentrations are associated with adverse prognosis in patients with acute myocardial infarction. <b>Design</b>: Nested case-control study. <b>Setting</b>: Prospective cohort study of consecutive patients admitted with acute myocardial infarction to 9 Scottish hospitals. <b>Patients</b>: 100 patients who survived 30 days (controls) and 100 patients who died within 30 days (cases). <b>Measurements and Main Results</b>: Admission cortisol concentrations were lower in patients who died than those who survived (median 1,189 versus 1,355 nmol/L, p<0.001). A cortisol concentration in the bottom quartile (<1,136 nmol/L) was a strong predictor of death within 30 days, and remained so after adjustment for age and cardiac troponin concentration (adjusted OR 8.78, 95% CI 3.09-24.96, p<0.001). <b>Conclusions</b>: Patients who mount a lesser cortisol stress response to acute myocardial infarction have a poorer early prognosis

Giant peroxisomes in a moss (Physcomitrella patens) peroxisomal biogenesis factor 11 mutant

Peroxisomal biogenesis factor 11 (PEX11) proteins are found in yeasts, mammals and plants, and play a role in peroxisome morphology and regulation of peroxisome division. The moss Physcomitrella patens has six PEX11 isoforms which fall into two subfamilies, similar to those found in monocots and dicots. We carried out targeted gene disruption of the Phypa_PEX11-1 gene and compared the morphological and cellular phenotypes of the wild-type and mutant strains. The mutant grew more slowly and the development of gametophores was retarded. Mutant chloronemal filaments contained large cellular structures which excluded all other cellular organelles. Expression of fluorescent reporter proteins revealed that the mutant strain had greatly enlarged peroxisomes up to 10 μm in diameter. Expression of a vacuolar membrane marker confirmed that the enlarged structures were not vacuoles, or peroxisomes sequestered within vacuoles as a result of pexophagy. Phypa_PEX11 targeted to peroxisome membranes could rescue the knock out phenotype and interacted with Fission1 on the peroxisome membrane. Moss PEX11 functions in peroxisome division similar to PEX11 in other organisms but the mutant phenotype is more extreme and environmentally determined, making P. patens a powerful system in which to address mechanisms of peroxisome proliferation and division

The WD-repeat protein superfamily in Arabidopsis: conservation and divergence in structure and function

BACKGROUND: The WD motif (also known as the Trp-Asp or WD40 motif) is found in a multitude of eukaryotic proteins involved in a variety of cellular processes. Where studied, repeated WD motifs act as a site for protein-protein interaction, and proteins containing WD repeats (WDRs) are known to serve as platforms for the assembly of protein complexes or mediators of transient interplay among other proteins. In the model plant Arabidopsis thaliana, members of this superfamily are increasingly being recognized as key regulators of plant-specific developmental events. RESULTS: We analyzed the predicted complement of WDR proteins from Arabidopsis, and compared this to those from budding yeast, fruit fly and human to illustrate both conservation and divergence in structure and function. This analysis identified 237 potential Arabidopsis proteins containing four or more recognizable copies of the motif. These were classified into 143 distinct families, 49 of which contained more than one Arabidopsis member. Approximately 113 of these families or individual proteins showed clear homology with WDR proteins from the other eukaryotes analyzed. Where conservation was found, it often extended across all of these organisms, suggesting that many of these proteins are linked to basic cellular mechanisms. The functional characterization of conserved WDR proteins in Arabidopsis reveals that these proteins help adapt basic mechanisms for plant-specific processes. CONCLUSIONS: Our results show that most Arabidopsis WDR proteins are strongly conserved across eukaryotes, including those that have been found to play key roles in plant-specific processes, with diversity in function conferred at least in part by divergence in upstream signaling pathways, downstream regulatory targets and /or structure outside of the WDR regions

Extreme genome diversity in the hyper-prevalent parasitic eukaryote Blastocystis

Blastocystis is the most prevalent eukaryotic microbe colonizing the human gut, infecting approximately 1 billion individuals worldwide. Although Blastocystis has been linked to intestinal disorders, its pathogenicity remains controversial because most carriers are asymptomatic. Here, the genome sequence of Blastocystis subtype (ST) 1 is presented and compared to previously published sequences for ST4 and ST7. Despite a conserved core of genes, there is unexpected diversity between these STs in terms of their genome sizes, guanine-cytosine (GC) content, intron numbers, and gene content. ST1 has 6,544 protein-coding genes, which is several hundred more than reported for ST4 and ST7. The percentage of proteins unique to each ST ranges from 6.2% to 20.5%, greatly exceeding the differences observed within parasite genera. Orthologous proteins also display extreme divergence in amino acid sequence identity between STs (i.e., 59%–61%median identity), on par with observations of the most distantly related species pairs of parasite genera. The STs also display substantial variation in gene family distributions and sizes, especially for protein kinase and protease gene families, which could reflect differences in virulence. It remains to be seen to what extent these inter-ST differences persist at the intra-ST level. A full 26% of genes in ST1 have stop codons that are created on the mRNA level by a novel polyadenylation mechanism found only in Blastocystis. Reconstructions of pathways and organellar systems revealed that ST1 has a relatively complete membrane-trafficking system and a near-complete meiotic toolkit, possibly indicating a sexual cycle. Unlike some intestinal protistan parasites, Blastocystis ST1 has near-complete de novo pyrimidine, purine, and thiamine biosynthesis pathways and is unique amongst studied stramenopiles in being able to metabolize ?-glucans rather than ?-glucans. It lacks all genes encoding heme-containing cytochrome P450 proteins. Predictions of the mitochondrion-related organelle (MRO) proteome reveal an expanded repertoire of functions, including lipid, cofactor, and vitamin biosynthesis, as well as proteins that may be involved in regulating mitochondrial morphology and MRO/endoplasmic reticulum (ER) interactions. In sharp contrast, genes for peroxisome-associated functions are absent, suggesting Blastocystis STs lack this organelle. Overall, this study provides an important window into the biology of Blastocystis, showcasing significant differences between STs that can guide future experimental investigations into differences in their virulence and clarifying the roles of these organisms in gut health and disease

Acute inflammatory response to contrast agent aspiration and its mechanisms in the rat lung.

Objectives/hypothesisContrast agent (CA) aspiration is an established complication of upper gastrointestinal and videofluoroscopic swallow studies. The underlying molecular biological mechanisms of acute response to CA aspiration in the respiratory organs remain unclear. The aims of this study were to elucidate the histological and biological influences of three kinds of CAs on the lung and to clarify the differences in acute responses.Study designAnimal model.MethodsEight-week-old male Sprague Dawley rats were divided into five groups (n = 6 in each group). Three groups underwent tracheal instillation of one of three different CAs: barium (Ba) sulfate, nonionic contrast agents (NICAs), and ionic contrast agents (ICAs). A control group was instilled with saline and a sham group was instilled with air. All animals were euthanized on day 2 after treatment and histological and gene analysis was performed.ResultsNo animal died after CA or control/sham aspiration. Ba caused severe histopathologic changes and more prominent inflammatory cell infiltration in the lungs compared with the two other iodinated contrast agents. Increases in expressions of inflammatory cytokines (tumor necrosis factor [Tnf], interleukin-1β [Il1b], and interferon-γ [Ifng]) were observed in Ba aspiration rats, and upregulation of Il1b was seen in ICA aspiration rats. NICA did not cause obvious histologic changes or expressions of inflammatory cytokines and fibrosis-related genes in the lungs.ConclusionsBa caused significantly more acute lung inflammation in a rodent model than did ioinic and nonionic iodinated CAs. Nonionic contrast did not cause any discernible inflammatory response in the lungs, suggesting that it may be the safest contrast for videofluoroscopic swallow studies.Level of evidenceNA Laryngoscope, 129:1533-1538, 2019

Chronic inflammatory response in the rat lung to commonly used contrast agents for videofluoroscopy.

ObjectivesContrast agents (CAs) are essential for upper gastrointestinal and videofluoroscopic swallow studies (VFSSs). Recently, we reported that small amounts of Ba aspiration caused severe acute lung inflammation in a rodent model. However, the underlying molecular biological mechanisms of chronic response to CA aspiration remain unclear. The aims of this study were to explore the underlying molecular biological mechanisms of the chronic response to three kinds of CA aspiration on the lung.Study designAnimal model.MethodsEight-week-old male Sprague Dawley rats were divided into five groups (n = 6, each group). Three groups underwent tracheal instillation of one of three CAs: barium sulfate (Ba), ionic iodinated contrast agent (ICA), and nonionic iodinated contrast agent (NICA). A sham group was instilled with air and a control group was instilled with saline. All animals were euthanized 30 days after treatment and histological and gene analyses were performed.ResultsNo animal died after CA or sham/control aspiration. Ba particles remained after 30 days and caused histopathologic changes and inflammatory cell infiltration. Iodinated ICA and NICA did not result in perceptible histologic change. Expression of Tnf, an inflammatory cytokine was increased in only Ba aspirated rats (P = .0076). Other inflammatory cytokines and fibrosis-related genes did not alter between groups.ConclusionAspirated Ba particles did not clear from the lung within a month and caused mild chronic pulmonary inflammation. ICA and NICA did not cause any inflammatory responses in the lungs, suggesting that ICA and NICA may be safer CAs for VFSS than Ba.Level of evidenceNA

High Resolution Manofluorographic Study in Patients With Multiple System Atrophy: Possible Early Detection of Upper Esophageal Sphincter and Proximal Esophageal Abnormality.

Introduction: Multiple system atrophy (MSA) has detrimental effects on swallowing function. The swallowing function of patients with MSA has not been systematically characterized and the underlying pathophysiological mechanisms of dysphagia remain poorly understood. Objectives: To investigate the characteristics of swallow function in MSA using high-resolution manofluorography (HRMF). Methods: We conducted a retrospective review of twenty-five MSA patients who underwent HRMF from 2016 to 2017. HRMF was utilized on patients with only oral diet (Functional Oral Intake Scale (FOIS) >3). Pharyngoesophageal and proximal esophageal pressure profiles were evaluated and compared to established normative data. The frequency and characteristics of upper esophageal sphincter (UES) and proximal esophageal abnormalities during rest and swallow were calculated. Results: The ages of patient cohort in our study ranged from 48-81 years (median 65 years) with male predominance (68%). We observed a distinct abnormal deglutitive proximal esophageal contraction (ADPEC) in 14 (56% of patients), which appears to reflect a discoordinated response of the striated muscle esophagus. Deficient UES relaxation duration, impaired UES relaxation, hypertensive resting UES pressure and hypotensive resting UES pressure were detected in 8 patients (32%), 3 patients (12%), 1 patient (4%), and 11 patients (44%) respectively. Conclusions: In patients with MSA, abnormal UES resting pressure is common. A discoordinated proximal esophageal pressure response was identified and may be a pathognomonic manometry finding for MSA. These findings may serve as indications of early stage swallowing dysfunction in patients with MSA

Chronic inflammatory response in the rat lung to commonly used contrast agents for videofluoroscopy

ObjectivesContrast agents (CAs) are essential for upper gastrointestinal and videofluoroscopic swallow studies (VFSSs). Recently, we reported that small amounts of Ba aspiration caused severe acute lung inflammation in a rodent model. However, the underlying molecular biological mechanisms of chronic response to CA aspiration remain unclear. The aims of this study were to explore the underlying molecular biological mechanisms of the chronic response to three kinds of CA aspiration on the lung.Study designAnimal model.MethodsEight-week-old male Sprague Dawley rats were divided into five groups (n = 6, each group). Three groups underwent tracheal instillation of one of three CAs: barium sulfate (Ba), ionic iodinated contrast agent (ICA), and nonionic iodinated contrast agent (NICA). A sham group was instilled with air and a control group was instilled with saline. All animals were euthanized 30 days after treatment and histological and gene analyses were performed.ResultsNo animal died after CA or sham/control aspiration. Ba particles remained after 30 days and caused histopathologic changes and inflammatory cell infiltration. Iodinated ICA and NICA did not result in perceptible histologic change. Expression of Tnf, an inflammatory cytokine was increased in only Ba aspirated rats (P = .0076). Other inflammatory cytokines and fibrosis-related genes did not alter between groups.ConclusionAspirated Ba particles did not clear from the lung within a month and caused mild chronic pulmonary inflammation. ICA and NICA did not cause any inflammatory responses in the lungs, suggesting that ICA and NICA may be safer CAs for VFSS than Ba.Level of evidenceNA