Microcystin-LR aerosol induces inflammatory responses in healthy human primary airway epithelium.

Harmful algal blooms plague bodies of freshwater globally. These blooms are often composed of outgrowths of cyanobacteria capable of producing the heptapeptide Microcystin-LR (MC-LR) which is a well-known hepatotoxin. Recently, MC-LR has been detected in aerosols generated from lake water. However, the risk for human health effects due to MC-LR inhalation exposure have not been extensively investigated. In this study, we exposed a fully differentiated 3D human airway epithelium derived from 14 healthy donors to MC-LR-containing aerosol once a day for 3 days. Concentrations of MC-LR ranged from 100 pM to 1 µM. Although there were little to no detrimental alterations in measures of the airway epithelial function (i.e. cell survival, tissue integrity, mucociliary clearance, or cilia beating frequency), a distinct shift in the transcriptional activity was found. Genes related to inflammation were found to be upregulated such as C-C motif chemokine 5 (CCL5; log2FC = 0.57, p = 0.03) and C-C chemokine receptor type 7 (CCR7; log2FC = 0.84, p = 0.03). Functionally, conditioned media from MC-LR exposed airway epithelium was also found to have significant chemo-attractive properties for primary human neutrophils. Additionally, increases were found in the concentration of secreted chemokine proteins in the conditioned media such as CCL1 (log2FC = 5.07, p = 0.0001) and CCL5 (log2FC = 1.02, p = 0.046). These results suggest that MC-LR exposure to the human airway epithelium is capable of inducing an inflammatory response that may potentiate acute or chronic disease.

RNAseq analysis of bronchial epithelial cells to identify COPD-associated genes and SNPs.

BACKGROUND: There is a need for more powerful methods to identify low-effect SNPs that contribute to hereditary COPD pathogenesis. We hypothesized that SNPs contributing to COPD risk through cis-regulatory effects are enriched in genes comprised by bronchial epithelial cell (BEC) expression patterns associated with COPD. METHODS: To test this hypothesis, normal BEC specimens were obtained by bronchoscopy from 60 subjects: 30 subjects with COPD defined by spirometry (FEV1/FVC < 0.7, FEV1% < 80%), and 30 non-COPD controls. Targeted next generation sequencing was used to measure total and allele-specific expression of 35 genes in genome maintenance (GM) genes pathways linked to COPD pathogenesis, including seven TP53 and CEBP transcription factor family members. Shrinkage linear discriminant analysis (SLDA) was used to identify COPD-classification models. COPD GWAS were queried for putative cis-regulatory SNPs in the targeted genes. RESULTS: On a network basis, TP53 and CEBP transcription factor pathway gene pair network connections, including key DNA repair gene ERCC5, were significantly different in COPD subjects (e.g., Wilcoxon rank sum test for closeness, p-value = 5.0E-11). ERCC5 SNP rs4150275 association with chronic bronchitis was identified in a set of Lung Health Study (LHS) COPD GWAS SNPs restricted to those in putative regulatory regions within the targeted genes, and this association was validated in the COPDgene non-hispanic white (NHW) GWAS. ERCC5 SNP rs4150275 is linked (D' = 1) to ERCC5 SNP rs17655 which displayed differential allelic expression (DAE) in BEC and is an expression quantitative trait locus (eQTL) in lung tissue (p = 3.2E-7). SNPs in linkage (D' = 1) with rs17655 were predicted to alter miRNA binding (rs873601). A classifier model that comprised gene features CAT, CEBPG, GPX1, KEAP1, TP73, and XPA had pooled 10-fold cross-validation receiver operator characteristic area under the curve of 75.4% (95% CI: 66.3%-89.3%). The prevalence of DAE was higher than expected (p = 0.0023) in the classifier genes. CONCLUSIONS: GM genes comprised by COPD-associated BEC expression patterns were enriched for SNPs with cis-regulatory function, including a putative cis-rSNP in ERCC5 that was associated with COPD risk. These findings support additional total and allele-specific expression analysis of gene pathways with high prior likelihood for involvement in COPD pathogenesis.

Organizing pneumonia related to electronic cigarette use: A case report and review of literature.

BACKGROUND AND OBJECTIVE: Electronic cigarettes (e cigarettes) are battery operated devices that produce aerosol by heating a solution typically made up of nicotine, propylene glycol, glycerin and flavouring agents. The use of e cigarettes has risen dramatically in recent years especially among adolescents and young adults. These devices have been marketed as safer alternatives to tobacco smoking by their manufactures despite lack of adequate safety data. METHODS: We present a case of 40-year-old female patient who developed significant pulmonary toxicity secondary to e cigarette use and searched existing literature relevant to the case. RESULTS: To our knowledge this is the second reported case of organizing pneumonia and tenth reported case of pulmonary toxicity related to e cigarette use. Our patient presented with symptoms of worsening dyspnoea and intermittent chest pain for past 1 month. She reported increased use of e cigarettes during this time period to help her quit smoking. Patient developed acute hypoxemic respiratory failure requiring intubation and mechanical ventilation. She was diagnosed with organizing pneumonia on open lung biopsy and was successfully treated with steroids along with abstinence from e cigarette use. CONCLUSIONS: As the current data on health effects of e cigarettes is limited, case reports can serve important piece of information in this regard. The use of e cigarettes has increased exponentially in recent years and continue to rise; therefore, physicians should be aware of adverse effects and toxicity related to its use.

Pyridostigmine Induced Prolonged Asystole in a Patient with Myasthenia Gravis Successfully Treated with Hyoscyamine.

Reversible acetylcholinesterase inhibitors are used as first-line treatment for myasthenia gravis. They improve symptoms by increasing concentration of acetylcholine at the neuromuscular junction and stimulating nicotinic receptors. Serious bradyarrhythmias can occur from muscarinic stimulation in heart, which in rare cases may progress to asystole. These patients can initially be managed with hyoscyamine, a muscarinic antagonist. Persistence of bradyarrhythmias even after hyoscyamine treatment may warrant pacemaker placement. We present a case of 65-year-old female patient who presented with diplopia, dysphagia, and muscle weakness who was diagnosed with myasthenia gravis. She developed significant sinoatrial node block with prolonged asystole after starting treatment with pyridostigmine which was successfully treated with hyoscyamine, thus avoiding pacemaker placement.

Fecal Transplant for Treatment of Toxic Megacolon Associated With Clostridium Difficile Colitis in a Patient With Duchenne Muscular Dystrophy.

Clostridium difficile (C diff) colitis infection is the most common cause of nosocomial infectious diarrhea and the prevalence is increasing worldwide. Toxic megacolon is a severe complication of C diff colitis associated with high mortality. Gastrointestinal (GI) comorbidity and impaired smooth muscle contraction are risk factors for the development of C diff-associated toxic megacolon. We present a case of fulminant C diff colitis with toxic megacolon in a patient with Duchenne muscular dystrophy (DMD) in the intensive care unit. C diff colitis was diagnosed by clinical presentation and positive C diff DNA amplification test (polymerase chain reaction). The impairment of GI tract due to DMD predisposes these patients to severe C diff infection and toxic megacolon, as observed in this case report. For the same reason, the recovery of GI function in these patients can be prolonged. While surgery was conducted for relieving the pressure from toxic megacolon, fecal microbiota transplantation through colonoscopy resulted in successful resolution of the C diff symptoms, although the recovery is prolonged due to DMD.

Continuity of care in intensive care units: a cluster-randomized trial of intensivist staffing.

RATIONALE: Little is known about the consequences of intensivists' work schedules, or intensivist continuity of care. OBJECTIVES: To assess the impact of weekend respite for intensivists, with consequent reduction in continuity of care, on them and their patients. METHODS: In five medical intensive care units (ICUs) in four academic hospitals we performed a prospective, cluster-randomized, alternating trial of two intensivist staffing schedules. Daily coverage by a single intensivist in half-month rotations (continuous schedule) was compared with weekday coverage by a single intensivist, with weekend cross-coverage by colleagues (interrupted schedule). We studied consecutive patients admitted to study units, and the intensivists working in four of the participating units. MEASUREMENTS AND MAIN RESULTS: The primary patient outcome was ICU length of stay (LOS);we also assessed hospital LOS and mortality rates. The primary intensivist outcome was physician burnout. Analysis was by multivariable regression. A total of 45 intensivists and 1,900 patients participated in the study. Continuity of care differed between schedules (patients with multiple intensivists = 28% under continuous schedule vs. 62% under interrupted scheduling; P < 0.0001). LOS and mortality were nonsignificantly higher under continuous scheduling (ΔICU LOS 0.36 d, P = 0.20; Δhospital LOS 0.34 d, P = 0.71; ICU mortality, odds ratio = 1.43, P = 0.12; hospital mortality, odds ratio = 1.17,P = 0.41). Intensivists experienced significantly higher burnout, work­home life imbalance, and job distress working under the continuous schedule. CONCLUSIONS: Work schedules where intensivists received weekend breaks were better for the physicians and, despite lower continuity of intensivist care, did not worsen outcomes for medical ICU patients.

New-onset acute interstitial lung disease after treatment with erlotinib in a patient with metastatic squamous cell carcinoma of the lung.

Erlotinib is a Human Epidermal Growth Factor Receptor Type 1/tyrosine kinase (EGFR) inhibitor, which is used for non-small-cell lung cancer treatment. Erlotinib usually has a favorable safety profile however; adverse events such as interstitial lung disease (ILD) have been reported in pivotal studies. ILD usually occurs weeks to months after initiating therapy with Erlotinib. We report a case of Erlotinib induced ILD presenting within 5 days of initiating treatment with Erlotinib.

The c-myc x E2F-1/p21 interactive gene expression index augments cytomorphologic diagnosis of lung cancer in fine-needle aspirate specimens.

Morphological analysis of cytologic samples obtained by fine-needle aspirate (FNA) or bronchoscopy is an important method for diagnosing bronchogenic carcinoma. However, this approach has only about 65 to 80% diagnostic sensitivity. Based on previous studies, the c-myc x E2F-1/p21WAF1/CIP1 (p21 hereafter) gene expression index is highly sensitive and specific for distinguishing normal from malignant bronchial epithelial tissues. In an effort to improve sensitivity of diagnosing lung cancer in cytologic specimens, we used Standardized Reverse Transcriptase Polymerase Chain Reaction (StaRT-PCR) to measure the c-myc x E2F-1/p21 index in cDNA samples from 14 normal lung samples (6 normal lung parenchyma and 8 normal bronchial epithelial cell [NBEC] biopsies), and 16 FNA biopsies from 14 suspected tumors. Based on cytomorphologic criteria, 11 of the 14 suspected tumors were diagnosed as bronchogenic carcinoma and three specimens were non-diagnostic. Subsequent biopsy samples confirmed that the three non-diagnostic samples were derived from lung carcinomas. The index value for each bronchogenic carcinoma was above a cut-off value of 7000 and the index value of all but one normal sample was below 7000. Thus the c-myc x E2F-1/p21 index may augment cytomorphologic diagnosis of bronchogenic carcinoma biopsy samples, particularly those considered non-diagnostic by cytomorphologic criteria.

Disseminated blastomycosis.

A 26-year-old veiled Saudi-Arabian woman presented with hemoptysis, and multiple nodules and abscesses. A skin biopsy specimen revealed yeast forms consistent with Blastomyces dermatitidis. Fungal cultures from bronchoscopy and skin specimens also grew B dermatitidis. She was treated with oral itraconazole (200 mg twice a day). Both lung and skin lesions showed improvement within 6 weeks.