Functional and metabolic impairment in cigarette smoke-exposed macrophages is tied to oxidative stress.

Cigarette smoke inhalation exposes the respiratory system to thousands of potentially toxic substances and causes chronic obstructive pulmonary disease (COPD). COPD is characterized by cycles of inflammation and infection with a dysregulated immune response contributing to disease progression. While smoking cessation can slow the damage in COPD, lung immunity remains impaired. Alveolar macrophages (AMΦ) are innate immune cells strategically poised at the interface between lungs, respiratory pathogens, and environmental toxins including cigarette smoke. We studied the effects of cigarette smoke on model THP-1 and peripheral blood monocyte derived macrophages, and discovered a marked inhibition of bacterial phagocytosis which was replicated in primary human AMΦ. Cigarette smoke decreased AMΦ cystic fibrosis transmembrane conductance regulator (CFTR) expression, previously shown to be integral to phagocytosis. In contrast to cystic fibrosis macrophages, smoke-exposed THP-1 and AMΦ failed to augment phagocytosis in the presence of CFTR modulators. Cigarette smoke also inhibited THP-1 and AMΦ mitochondrial respiration while inducing glycolysis and reactive oxygen species. These effects were mitigated by the free radical scavenger N-acetylcysteine, which also reverted phagocytosis to baseline levels. Collectively these results implicate metabolic dysfunction as a key factor in the toxicity of cigarette smoke to AMΦ, and illuminate avenues of potential intervention.

Identifying aerosolized cyanobacteria in the human respiratory tract: A proposed mechanism for cyanotoxin-associated diseases.

Cyanobacteria produce harmful toxins that have been associated with several acute conditions and chronic human diseases, like gastroenteritis, non-alcoholic liver disease, and amyotrophic lateral sclerosis. Aerosol from waterbodies appears to be a likely mechanism for exposure. We conducted a study of human biospecimens focused on the cyanobacterial aerosilization process by evaluating the extent to which cyanobacteria can invade the human respiratory tract. Our study suggests that humans routinely inhale aerosolized cyanobacteria, which can be harbored in the nostrils and the lungs. Using PCR, cyanobacteria were found at high frequencies in the upper respiratory tract (92.20%) and central airway (79.31%) of our study subjects. Nasal swabs were not predictive of bronchoalveolar lavage (BAL) when detecting inhaled cyanobacteria. Interestingly, we found no evidence that time of year was a significant factor for cyanobacteria positivity (BAL cytology p = 1.0 and PCR p = 1.0); (nasal swab cytology p = 0.051 and PCR p = 0.65). Additionally, we found that proximity to a waterbody was not a significant factor for cyanobacteria positivity in BAL and nasal swabs collected during cyanobacteria bloom season [May-October] (p = 0.46 and p = 0.38). These data suggest that cyanobacteria exposure may be a prevalent and chronic phenomenon not necessarily restricted to waterbodies alone. Sources of indoor exposure warrant future investigation. Given the widespread prevalence of cyanobacterial exposure in the airway, investigation of the aerosol spread of cyanotoxins, more specifically, is warranted. Our findings are consistent with the hypothesis that aerosol is a significant route for cyanobacteria exposure, and thus a likely route of transmission for cyanotoxin-associated human diseases.

A Case of Thyroid Storm Induced by Iodine-Containing Dietary Supplements and Homeopathic Remedies.

Objective: We report the case of a patient who presented to the hospital in thyroid storm following the use of several iodine-containing dietary supplements (DS) and homeopathic remedies (HR). Case Summary: The patient was a 76-year-old woman with no personal or family history of thyroid or autoimmune disease. On laboratory assessment, a thyroid panel showed that her total T3 and T4 were elevated at 334 ng/dL and 14.6 µg/dL, respectively; thyroid stimulating hormone was undetectable; and thyroid stimulating immunoglobulin was positive at 7.4. The patient had been consuming 170 µg of iodine daily for the past 2 months via her DS and HR. An objective causality assessment using the Naranjo adverse drug reaction probability scale revealed that an adverse effect was probable. The patient likely suffered from iodine-induced thyrotoxicosis secondary to the consumption of numerous DS and HR. Discussion: Dietary supplements and homeopathic remedies can pose significant health risks. The safety of these products is not assured as they are incompletely monitored by the Food and Drug Administration. Individuals who take these compounds do so at their own risk and should pay close attention to product contents. Conclusions: The labeling of DS and HR products may be misleading. Pharmacists and clinicians are advised to inquire about the use of DS and HR products. When use is identified, the products should be subject to a thorough review.

Developing future faculty: a program targeting internal medicine fellows' teaching skills.

INTRODUCTION: The increased demand for clinician-educators in academic medicine necessitates additional training in educational skills to prepare potential candidates for these positions. Although many teaching skills training programs for residents exist, there is a lack of reports in the literature evaluating similar programs during fellowship training. AIM: To describe the implementation and evaluation of a unique program aimed at enhancing educational knowledge and teaching skills for subspecialty medicine fellows and chief residents. SETTING: Fellows as Clinician-Educators (FACE) program is a 1-year program open to fellows (and chief residents) in the Department of Internal Medicine at the University of Iowa. PROGRAM DESCRIPTION: The course involves interactive monthly meetings held throughout the academic year and has provided training to 48 participants across 11 different subspecialty fellowships between 2004 and 2009. PROGRAM EVALUATION: FACE participants completed a 3-station Objective Structured Teaching Examination using standardized learners, which assessed participants' skills in giving feedback, outpatient precepting, and giving a mini-lecture. Based on reviews of station performance by 2 independent raters, fellows demonstrated statistically significant improvement on overall scores for 2 of the 3 cases. Participants self-assessed their knowledge and teaching skills prior to starting and after completing the program. Analyses of participants' retrospective preassessments and postassessments showed improved perceptions of competence after training. CONCLUSION: The FACE program is a well-received intervention that objectively demonstrates improvement in participants' teaching skills. It offers a model approach to meeting important training skills needs of subspecialty medicine fellows and chief residents in a resource-effective manner.

Pulmonary-specific expression of tumor necrosis factor-alpha alters surfactant lipid metabolism.

Tumor necrosis factor (TNF)-alpha is a major cytokine implicated in inducing acute and chronic lung injury, conditions associated with surfactant phosphatidylcholine (PtdCho) deficiency. Acutely, TNF-alpha decreases PtdCho synthesis but stimulates surfactant secretion. To investigate chronic effects of TNF-alpha, we investigated PtdCho metabolism in a murine transgenic model exhibiting lung-specific TNF-alpha overexpression. Compared with controls, TNF-alpha transgenic mice exhibited a discordant pattern of PtdCho metabolism, with a decrease in PtdCho and disaturated PtdCho (DSPtdCho) content in the lung, but increased levels in alveolar lavage. Transgenics had lower activities and increased immunoreactive levels of cytidylyltransferase (CCT), a key PtdCho biosynthetic enzyme. Ceramide, a CCT inhibitor, was elevated, and linoleic acid, a CCT activator, was decreased in transgenics. Radiolabeling studies revealed that alveolar reuptake of DSPtdCho was significantly decreased in transgenic mice. These observations suggest that chronic expression of TNF-alpha results in a complex pattern of PtdCho metabolism where elevated lavage PtdCho may originate from alveolar inflammatory cells, decreased surfactant reuptake, or altered surfactant secretion. Reduced parenchymal PtdCho synthesis appears to be attributed to CCT enzyme that is physiologically inactivated by ceramide or by diminished availability of activating lipids.

Lipid deprivation increases surfactant phosphatidylcholine synthesis via a sterol-sensitive regulatory element within the CTP:phosphocholine cytidylyltransferase promoter.

Lipid-deprived mice increase alveolar surfactant disaturated phosphatidylcholine (DSPtdCho) synthesis compared with mice fed a standard diet by increasing expression of CTP:phosphocholine cytidylyltransferase (CCT), the rate-limiting enzyme for DSPtdCho synthesis. We previously observed that lipid deprivation increases mRNA synthesis for CCT [Ryan, McCoy, Mathur, Field and Mallampalli (2000) J. Lipid Res. 41, 1268-1277]. To evaluate regulatory mechanisms for this gene, we cloned the proximal approximately 1900 bp of the 5' flanking sequence of the murine CCT gene, coupled this to a luciferase reporter, and examined transcriptional regulation in a murine alveolar epithelial type II cell line (MLE-12). The core promoter was localized to a region between -169 and +71 bp, which exhibited strong basal activity comparable with the simian virus 40 promoter. The full-length construct, from -1867 to +71, was induced 2-3-fold when cells were cultured in lipoprotein-deficient serum (LPDS), similar to the level of induction of the endogenous CCT gene. By deletional analysis the sterol regulatory element (SRE) was localized within a 240 bp region. LPDS activation of the CCT promoter was abolished by mutation of this SRE, and gel mobility-shift assays demonstrated specific binding of recombinant SRE-binding protein to this element within the CCT promoter. These observations indicate that sterol-regulated expression of CCT is mediated by an SRE within its 5' flanking region.