Harnessing Immunomodulatory Polymers for Treatment of Autoimmunity, Allergy, and Transplant Rejection.

Autoimmunity, allergy, and transplant rejection are a collection of chronic diseases that are currently incurable, drastically decrease patient quality of life, and consume considerable health care resources. Underlying each of these diseases is a dysregulated immune system that results in the mounting of an inflammatory response against self or an innocuous antigen. As a consequence, afflicted patients are required to adhere to lifelong regimens of multiple immunomodulatory drugs to control disease and reclaim agency. Unfortunately, current immunomodulatory drugs are associated with a myriad of side effects and adverse events, such as increased risk of cancer and increased risk of serious infection, which negatively impacts patient adherence rates and quality of life. The field of immunoengineering is a new discipline that aims to harness endogenous biological pathways to thwart disease and minimize side effects using novel biomaterial-based strategies. We highlight and discuss polymeric micro/nanoparticles with inherent immunomodulatory properties that are currently under investigation in biomaterial-based therapies for treatment of autoimmunity, allergy, and transplant rejection.

Stem-cell clinics in the UK: a web-based study.

Aim: Explore the nature and extent of web-based promotion of stem cell treatments marketed by clinics in the UK. Materials & methods: Web-based analysis of clinics in the UK using predefined variables, with analysis of eligible clinics according to preset criteria of ethical relevance. Results: A majority (79%) of UK clinics were judged to be problematic. Information was found to be lacking, misleading or otherwise problematic in several respects, including a lack of information on risks of adverse effects, unjustifiably optimistic depictions of therapeutic effectiveness, and questionable presentational approaches such as the use of celebrity patient testimonials. Conclusion: In a majority of cases, commercial clinics in the UK portray stem-cell therapies on their websites in ethically questionable ways.

Inflammation and emphysema in cigarette smoke-exposed mice when instilled with poly (I:C) or infected with influenza A or respiratory syncytial viruses.

BACKGROUND: The length of time for cigarette smoke (CS) exposure to cause emphysema in mice is drastically reduced when CS exposure is combined with viral infection. However, the extent of inflammatory responses and lung pathologies of mice exposed to CS and infected with influenza A virus (IAV), respiratory syncytial virus (RSV), or treated with the viral derivative dsRNA (polyinosine-polycytidylic acid [poly (I:C)] have not been compared. METHODS: Mice were exposed to CS or filtered air for 4 weeks and received a single dose of vehicle, AV, or RSV infection and extent of inflammation and emphysema was evaluated 14 d later. In another set of experiments, mice were instilled with poly (I:C) twice a week during the third and fourth weeks of CS exposure and immediately analyzed for extent of inflammation and lung pathologies. RESULTS: In CS-exposed mice, inflammation was characterized mainly by macrophages, lymphocytes, and neutrophils after IAV infection, mainly by lymphocytes, and neutrophils after RSV infection, and mainly by lymphocytes and neutrophils after poly (I:C) instillations. Despite increased inflammation, extent of emphysema by poly (I:C) was very mild; but was robust and similar for both IAV and RSV infections with enhanced MMP-12 mRNA expression and TUNEL positivity. Both IAV and RSV infections increased the levels of IL-17, IL-1ß, IL-12b, IL-18, IL-23a, Ccl-2, Ccl-7 mRNAs in the lungs of CS-exposed mice with IAV causing more increases than RSV. CONCLUSION: CS-induced inflammatory responses and extent of emphysematous changes differ depending on the type of viral infection. These animal models may be useful to study the mechanisms by which different viruses exacerbate CS-induced inflammation and emphysema.

Paternal age bioethics.

Modern genetic sequencing studies have confirmed that the sperm of older men contain a greater number of de novo germline mutations than the sperm of younger men. Although most of these mutations are neutral or of minimal phenotypic impact, a minority of them present a risk to the health of future children. If demographic trends towards later fatherhood continue, this will likely lead to a more children suffering from genetic disorders. A trend of later fatherhood will accelerate the accumulation of paternal-origin de novo mutations in the gene pool, gradually reducing human fitness in the long term. These risks suggest that paternal age is of ethical importance. Children affected by de novo mutations arising from delayed fatherhood can be said to be harmed, in the sense of 'impersonal' harm or 'non-comparative' harm. Various strategies are open at societal and individual levels towards reducing deleterious paternal age effects. Options include health education to promote earlier fatherhood, incentives for young sperm donors and state-supported universal sperm banking. The latter approach would likely be of the greatest benefit and could in principle be implemented immediately. More futuristically, human germline genetic modification offers the potential to repair heritable mutational damage.

Religion, secular medicine and utilitarianism: a response to Biggar.

Nigel Biggar has argued that religion ought to be given a seat at the negotiating table of medical ethics. I respond in broadly utilitarian terms, arguing that the flawed empirical basis, lack of rationality and non-universality inherent in religion disqualify it from ethical discourse. I conclude that while it would be unacceptable to attempt to debar religious individuals from the negotiating table, an exclusively secular approach is required for ethical decision making in medicine.

Wood smoke enhances cigarette smoke-induced inflammation by inducing the aryl hydrocarbon receptor repressor in airway epithelial cells.

Our previous studies showed that cigarette smokers who are exposed to wood smoke (WS) are at an increased risk for chronic bronchitis and reduced lung function. The present study was undertaken to determine the mechanisms for WS-induced adverse effects. We studied the effect of WS exposure using four cohorts of mice. C57Bl/6 mice were exposed for 4 or 12 weeks to filtered air, to 10 mg/m(3) WS for 2 h/d, to 250 mg/m(3) cigarette smoke (CS) for 6 h/d, or to CS followed by WS (CW). Inflammation was absent in the filtered air and WS groups, but enhanced by twofold in the bronchoalveolar lavage of the CW compared with CS group as measured by neutrophil numbers and levels of the neutrophil chemoattractant, keratinocyte-derived chemokine. The levels of the anti-inflammatory lipoxin, lipoxin A4, were reduced by threefold along with cyclo-oxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1 in airway epithelial cells and PGE2 levels in the bronchoalveolar lavage of CW compared with CS mice. We replicated, in primary human airway epithelial cells, the changes observed in mice. Immunoprecipitations showed that WS blocked the interaction of aryl hydrocarbon receptor (AHR) with AHR nuclear transporter to reduce expression of COX-2 and mPGES-1 by increasing expression of AHR repressor (AHRR). Collectively, these studies show that exposure to low concentrations of WS enhanced CS-induced inflammation by inducing AHRR expression to suppress AHR, COX-2, and mPGES-1 expression, and levels of PGE2 and lipoxin A4. Therefore, AHRR is a potential therapeutic target for WS-associated exacerbations of CS-induced inflammation.

Risk for sleep-disordered breathing in adults after atrial switch repairs for d-looped transposition of the great arteries.

Although sleep-disordered breathing has been extensively studied in patients with left-ventricular dysfunction, little is known of its prevalence in adults with congenital heart disease. Patients with d-looped transposition of the great arteries (d-TGA) who have undergone atrial switch procedures often develop progressive heart failure. The objective of this study was to determine the prevalence of patients at risk for sleep-disordered breathing in adults with d-TGA and atrial switch procedures compared with a control population. Thirty-two patients with d-TGA (66 % males, median age 31) were compared with 32 healthy controls. Baseline demographics and clinical characteristics were documented. The snoring, tiredness during daytime, observed apnea, and high blood pressure (STOP) questionnaire was used to identify subjects at risk for obstructive sleep apnea (OSA). There was no difference in baseline demographics between subjects and controls. For the STOP questionnaire, 14 subjects with d-TGA had scores predictive of OSA compared with three in the control group (44 vs. 9 %, p = 0.0038). There was no difference in functional status between d-TGA patients with or without OSA. There is a greater prevalence of risk for sleep disordered breathing in adults with d-TGA compared with controls. Further prospective investigation with sleep studies will be valuable to confirm these findings.

Gestational exposure of mice to secondhand cigarette smoke causes bronchopulmonary dysplasia blocked by the nicotinic receptor antagonist mecamylamine.

BACKGROUND: Cigarette smoke (CS) exposure during gestation may increase the risk of bronchopulmonary dysplasia (BPD)-a developmental lung condition primarily seen in neonates that is characterized by hypoalveolarization, decreased angiogenesis, and diminished surfactant protein production and may increase the risk of chronic obstructive pulmonary disease. OBJECTIVE: We investigated whether gestational exposure to secondhand CS (SS) induced BPD and sought to ascertain the role of nicotinic acetylcholine receptors (nAChRs) in this response. METHODS: We exposed BALB/c and C57BL/6 mice to filtered air (control) or SS throughout the gestation period or postnatally up to 10 weeks. Lungs were examined at 7 days, 10 weeks, and 8 months after birth. RESULTS: Gestational but not postnatal exposure to SS caused a typical BPD-like condition: suppressed angiogenesis [decreased vascular endothelial growth factor (VEGF), VEGF receptor, and CD34/CD31 (hematopoietic progenitor cell marker/endothelial cell marker)], irreversible hypoalveolarization, and significantly decreased levels of Clara cells, Clara cell secretory protein, and surfactant proteins B and C, without affecting airway ciliated cells. Importantly, concomitant exposure to SS and the nAChR antagonist mecamylamine during gestation blocked the development of BPD. CONCLUSIONS: Gestational exposure to SS irreversibly disrupts lung development leading to a BPD-like condition with hypoalveolarization, decreased angiogenesis, and diminished lung secretory function. Nicotinic receptors are critical in the induction of gestational SS-induced BPD, and the use of nAChR antagonists during pregnancy may block CS-induced BPD.

Cytotoxic and apoptotic effects of chalcone derivatives of 2-acetyl thiophene on human colon adenocarcinoma cells.

Recent studies report that chalcones exhibit cytotoxicity to human cancer cell lines. Typically, the form of cell death induced by these compounds is apoptosis. In the context of the discovery of new anticancer agents and in light of the antitumour potential of several chalcone derivatives, in the present study, we synthesized and tested the cytotoxicity of six chalcone derivatives on human colon adenocarcinoma cells. Six derivatives of 3-phenyl-1-(thiophen-2-yl) prop-2-en-1-one were prepared and characterized on the basis of their (1) H and (13) C NMR spectra. HT-29 cells were treated with synthesized chalcones on two concentrations by three different incubation times. Cells were evaluated by cell morphology, Tetrazolium dye (MTT) colorimetric assay, live/dead, flow cytometry (annexin V) and gene expression analyses to determine the cytotoxic way. Chalcones 3-(4-bromophenyl)-1-(thiophen-2-yl)prop-2-en-1-one (C06) and 3-(2-nitrophenyl)-1-(thiophen-2-yl)prop-2-en-1-one (C09) demonstrated higher cytotoxicity than other chalcones as shown by cell morphology, live/dead and MTT assays. In addition, C06 induced apoptosis on flow cytometry annexin V assay. These data were confirmed by a decreased expression of anti-apoptotic genes and increased pro-apoptotic genes. Our findings indicate in summary that the cytotoxic activity of chalcone C06 on colorectal carcinoma cells occurs by apoptosis.

Human germline genetic modification: scientific and bioethical perspectives.

The latest mammalian genetic modification technology offers efficient and reliable targeting of genomic sequences, in the guise of designer genetic recombination tools. These and other improvements in genetic engineering technology suggest that human germline genetic modification (HGGM) will become a safe and effective prospect in the relatively near future. Several substantive ethical objections have been raised against HGGM including claims of unacceptably high levels of risk, damage to the status of future persons, and violations of justice and autonomy. This paper critically reviews the latest GM science and discusses the key ethical objections to HGGM. We conclude that major benefits are likely to accrue through the use of safe and effective HGGM and that it would thus be unethical to take a precautionary stance against HGGM.

Factors influencing the inclusion of complementary and alternative medicine (CAM) in undergraduate medical education.

Objective To investigate the views and practices of UK medical schools regarding the inclusion (or exclusion) of complementary and alternative medicine (CAM) in undergraduate medical curricula. Design Survey (by email) of UK medical schools offering MBBS (or equivalent) degrees. Results The overall response rate was 58.1% (18/31). All respondents indicated that their curricula included CAM elements. However, the quantity of CAM within curricula varied widely between medical schools, as did the methods by which CAM education was delivered. General Medical Council requirements were the strongest factor influencing the inclusion of CAM, although medical student preferences were also important. Respondents were generally satisfied with the extent of CAM provision within their curricula, while a wide range of views on the appropriateness of CAM in the medical curriculum were held by faculty members. Conclusions It may be useful for the General Medical Council to clarify the extent to which CAM should be incorporated into the curriculum. Current CAM education appears to exist primarily as a means of educating future doctors on the modalities that their patients may use or request. However, some forms of pedagogy arguably risk students assimilating CAM advocacy in an uncritical fashion.

Prenatal secondhand cigarette smoke promotes Th2 polarization and impairs goblet cell differentiation and airway mucus formation.

Parental, particularly maternal, smoking increases the risk for childhood allergic asthma and infection. Similarly, in a murine allergic asthma model, prenatal plus early postnatal exposure to secondhand cigarette smoke (SS) exacerbates airways hyperreactivity and Th2 responses in the lung. However, the mechanism and contribution of prenatal versus early postnatal SS exposure on allergic asthma remain unresolved. To identify the effects of prenatal and/or early postnatal SS on allergic asthma, BALB/c dams and their offspring were exposed gestationally and/or 8-10 wk postbirth to filtered air or SS. Prenatal, but not postnatal, SS strongly increased methacholine and allergen (Aspergillus)-induced airway resistance, Th2 cytokine levels, and atopy and activated the Th2-polarizing pathway GATA3/Lck/ERK1/2/STAT6. Either prenatal and/or early postnatal SS downregulated the Th1-specific transcription factor T-bet and, surprisingly, despite high levels of IL-4/IL-13, dramatically blocked the allergen-induced mucous cell metaplasia, airway mucus formation, and the expression of mucus-related genes/proteins: Muc5ac, γ-aminobutyric acid A receptors, and SAM pointed domain-containing Ets-like factor. Given that SS/nicotine exposure of normal adult mice promotes mucus formation, the results suggested that fetal and neonatal lung are highly sensitive to cigarette smoke. Thus, although the gestational SS promotes Th2 polarization/allergic asthma, it may also impair and/or delay the development of fetal and neonatal lung, affecting mucociliary clearance and Th1 responses. Together, this may explain the increased susceptibility of children from smoking parents to allergic asthma and childhood respiratory infections.

Inflammation, mucous cell metaplasia, and Bcl-2 expression in response to inhaled lipopolysaccharide aerosol and effect of rolipram.

Our previous studies have characterized the inflammatory response of intratracheally instilled lipopolysaccharides (LPS) in F344/N rats. To better reflect the environmentally relevant form of LPS exposure, the present study evaluated the inflammatory response of F344/N rats exposed to LPS by inhalation. Rats were exposed by nose-only inhalation to aerosolized LPS at a median particle diameter of 1 µm and a dose range from 0.08 to 480 µg. Animals were euthanized 72 h post exposure and the inflammatory cell counts and differentials, the cytokine/chemokine levels in the bronchoalveolar lavage fluid (BALF), and the changes in intraepithelial stored mucosubstances, mucous cells per mm basal lamina, and Bcl-2-positive mucous cells were quantified. We observed a dose-dependent increase reaching maximum values at the 75 µg LPS dose for the numbers of neutrophils, macrophages and lymphocytes, for the levels of IL-6, IL-1α, IL-1ß, TNFα, MCP-1 and GRO-KC. In addition, mucous cell metaplasia and the percentage of Bcl-2-positive mucous cells were increased with an increasing deposited LPS dose. When rats were treated with the phosphodiesterase-4 (PDE4) inhibitor, rolipram (10mg/kg), prior to exposure to aerosolized LPS neutrophil numbers in the BAL were reduced at 8h but not at 24 or 72 h post LPS exposure. These results demonstrate that exposure to aerosolized LPS resulted in a more potent inflammatory response at lower doses and that inflammation was more uniformly distributed throughout the lung compared to inflammation caused by intratracheal LPS instillation. Therefore, this animal model will be useful for screening efficacy of anti-inflammatory drugs.

Cigarette smoke suppresses Bik to cause epithelial cell hyperplasia and mucous cell metaplasia.

RATIONALE: Aberrant regulation of airway epithelial cell numbers in airways leads to increased mucous secretions in chronic lung diseases such as chronic bronchitis. Because the Bcl-2 family of proteins is crucial for airway epithelial homeostasis, identifying the players that reduce cigarette smoke (CS)-induced mucous cell metaplasia can help to develop effective therapies. OBJECTIVES: To identify the Bcl-2 family of proteins that play a role in reducing CS-induced mucous cell metaplasia. METHODS: We screened for dysregulated expression of the Bcl-2 family members. MEASUREMENTS AND MAIN RESULTS: We identified Bik to be significantly reduced in bronchial brushings of patients with chronic epithelial cell hyperplasia compared with nondiseased control subjects. Reduced Bik but increased MUC5AC mRNA levels were also detected when normal human airway epithelial cells (HAECs) were exposed to CS or when autopsy tissues from former smokers with and without chronic bronchitis were compared. Similarly, exposure of C57Bl/6 mice to CS resulted in increased numbers of epithelial and mucous cells per millimeter of basal lamina, along with reduced Bik but increased Muc5ac expression, and this change was sustained even when mice were allowed to recover in filtered air for 8 weeks. Restoring Bik expression significantly suppressed CS-induced mucous cell metaplasia in differentiated primary HAEC cultures and in airways of mice in vivo. Bik blocked nuclear translocation of phospho-ERK1/2 to induce apoptosis of HAECs. The conserved Leu61 within Bik and ERK1/2 activation were essential to induce cell death in hyperplastic mucous cells. CONCLUSIONS: These studies show that CS suppresses Bik expression to block airway epithelia cell death and thereby increases epithelial cell hyperplasia in chronic bronchitis.

Oxidative injury in the lungs of neonatal rats following short-term exposure to ultrafine iron and soot particles.

Greater risk of adverse effects from particulate matter (PM) has been noted in susceptible subpopulations, such as children. However, the physicochemical components responsible for these biological effects are not understood. As critical constituents of PM, transition metals were postulated to be involved in a number of pathological processes of the respiratory system through free radical-medicated damage. The purpose of this study was to examine whether oxidative injury in the lungs of neonatal rats could be induced by repeated short-term exposure to iron (Fe) and soot particles. Sprague Dawley rats 10 d of age were exposed by inhalation to two different concentrations of ultrafine iron particles (30 or 100 microg/m(3)) in combination with soot particles adjusted to maintain a total particle concentration of 250 microg/m(3). Exposure at 10 d and again at 23 d of age was for 6 h/d for 3 d. Oxidative stress was observed at both Fe concentrations in the form of significant elevations in glutathione disulfide (GSSG) and GSSG/glutathione (GSH) ratio and a reduction in ferric/reducing antioxidant power in bronchoalveolar lavage. A significant decrease in cell viability associated with significant increases in lactate dehydrogenase (LDH) activity, interleukin-1-beta (IL-1beta), and ferritin expression was noted following exposure to particles containing the highest Fe concentration. Iron from these particles was shown to be bioavailable in an in vitro assay using the physiologically relevant chelator, citrate. Data indicate that combined Fe and soot particle exposure induces oxidative injury, cytotoxicity and pro-inflammatory responses in the lungs of neonatal rats.

Auditory spatial and object processing in the human planum temporale: no evidence for selectivity.

Although it is generally acknowledged that at least two processing streams exist in the primate cortical auditory system, the function of the posterior dorsal stream is a topic of much debate. Recent studies have reported selective activation to auditory spatial change in portions of the human planum temporale (PT) relative to nonspatial stimuli such as pitch changes or complex acoustic patterns. However, previous work has suggested that the PT may be sensitive to another kind of nonspatial variable, namely, the number of auditory objects simultaneously presented in the acoustic signal. The goal of the present fMRI experiment was to assess whether any portion of the PT showed spatial selectivity relative to manipulations of the number of auditory objects presented. Spatially sensitive regions in the PT were defined by comparing activity associated with listening to an auditory object (speech from a single talker) that changed location with one that remained stationary. Activity within these regions was then examined during a nonspatial manipulation: increasing the number of objects (talkers) from one to three. The nonspatial manipulation modulated activity within the "spatial" PT regions. No region within the PT was found to be selective for spatial or object processing. We suggest that previously documented spatial sensitivity in the PT reflects auditory source separation using spatial cues rather than spatial processing per se.

A case of tracheal injury with intubation during electroconvulsive therapy.

Respiratory complications related to electroconvulsive therapy (ECT) are a rare occurrence. The need for endotracheal intubation during ECT is rarely indicated. We report a case of a 47-year-old woman with severe gastroesophageal reflux disease and depression who was intubated for her first 3 ECT treatments. She developed a small tracheal tear after her third ECT treatment which resulted in subcutaneous emphysema, pneumopericardium, and pneumomediastinum. The tracheal tear resolved spontaneously and ultimately the patient underwent subsequent ECT treatments successfully without intubation. This case is the first reported case of complications related to endotracheal intubation during ECT.