Ethanol regulates angiogenic cytokines during neural development: evidence from an in vitro model of mitogen-withdrawal-induced cerebral cortical neuroepithelial differentiation

BACKGROUND: Heavy alcohol consumption during pregnancy can cause significant mental retardation and brain damage. We recently showed that ethanol depletes reserve cerebral cortical stem cell capacity. Moreover, proliferating neuroepithelial cells exposed to ethanol were resistant to subsequent retinoic acid-induced differentiation. Emerging evidence suggests that cytokines play a crucial growth-promoting role in the developing neural tube. METHODS: We cultured murine cortical neurosphere cultures in control or ethanol-supplemented mitogenic medium, to mimic alcohol exposure during the period of neuroepithelial proliferation. Cultures were then treated with a step-wise mitogen-withdrawal, integrin-activation model to mimic subsequent phases of neuronal migration and early differentiation. We examined the impact of alcohol exposure during neurogenesis on the secretion of inflammatory and growth-promoting cytokines. RESULTS: Cortical neurosphere cultures exhibit increasingly complex differentiation phenotypes in response to step-wise mitogen-withdrawal and laminin exposure. Some inflammation-modulating cytokines were secreted independent of differentiation state. However, chemotactic cytokines were specifically secreted at high levels, as a function of differentiation stage. monocyte chemotactic protein-1, vascular endothelial growth factor-A, and interleukin (IL)-10 were coordinately decreased during differentiation compared with neuroepithelial proliferation, while granulocyte macrophage-colony stimulating factor (GM-CSF) was induced during differentiation, compared with the neuroepithelial proliferation period. Ethanol exposure during the period of neuroepithelial proliferation prevented the early differentiation-induced increase in GM-CSF while inducing differentiation-associated increase in IL-12 secretion. CONCLUSION: Embryonic cerebral cortical neuroepithelial-derived precursors secrete high levels of several angiogenic and neural-growth-promoting cytokines as they differentiate into neurons. Our data collectively suggest that ethanol exposure during the period of neuroepithelial proliferation significantly disrupts cytokine signals that are required for the support of emerging neurovascular networks, and the maintenance of neural stem cell beds.     

Fraction of exhaled nitric oxide at 50 mL/s: reference values for adult lifelong never-smokers

BACKGROUND: The measurement of fractional exhaled nitric oxide (FENO) is used as a marker of airway inflammation. The aim of this study was to establish reference values of FENO for adults. METHODS: FENO at a flow rate of 50 mL/s was analyzed in 3,376 adults using a chemiluminescence analyzer according to American Thoracic Society/European Respiratory Society guidelines. Blood samples were analyzed, and atopy was defined as the presence of specific IgE. All subjects responded to a respiratory questionnaire. Those who had never smoked (n = 1,803) were selected for this study. After the exclusion of subjects with physician-diagnosed asthma, asthma symptoms, ever wheezing, dry cough, or use of inhaled steroids, 1,131 healthy never-smokers remained, including 845 nonatopic and 286 atopic subjects. RESULTS: Based on multiple regression modeling, we propose the following reference equation for healthy never-smoking adults: Ln(FENO) = 0.057 + 0.013 x height (in centimeters) + 0.0088 x age (in years). The residual SD was 0.51, and the explanatory value was 9%. In a model, based on nonatopic subjects alone, the reference equation obtained was slightly different, as follows: Ln(FENO) = -0.0026 + 0.013 x height (in centimeters) + 0.010 x age (in years). The residual SD for this equation was 0.48, and the explanatory value was 11%. CONCLUSIONS: Normal values of FENO for adults may be predicted on the basis of age and height. However, as the reference equations only account for about 9 to 11% of the variation, the most important information that could be extracted from the study is that the upper limits of FENO range from 24.0 to 54.0 parts per billion, depending on age and height.     

Age-related changes in neuroprotection: is estrogen pro-inflammatory for the reproductive senescent brain?

Estrogen replacement therapy (ERT) is widely prescribed to postmenopausal women for relief from the adverse vasomotor effects of menopause, to reduce bone loss, to improve cardiovascular health, and to protect against metabolic disorders. However, there is now greater awareness of the increased risk to benefit ratio from the recently concluded Women's Health Initiative Memory Study (WHIMS), which reported that ERT increased the risk of cognitive impairment and dementia in elderly women. Studies from the experimental literature indicate that while estrogen is neuroprotective in many instances, estrogen replacement can be deleterious in some cases. These differences may be partly due to the age and species of the experimental model. The majority of the experimental data comes from studies where the age or endocrine status of the animal model is not comparable to that of menopausal or postmenopausal women, such as those in the WHIMS study. In this review, we will focus on age-related changes in estrogen's neuroprotective effects and evidence that reproductive senescence-related changes in the blood-brain barrier and the immune system may result in deleterious consequences for ERT.     

Respiratory symptoms relate to physiological changes and inflammatory markers reflecting central but not peripheral airways. A study in 60-year-old 'healthy' smokers and never-smokers

The aim of this study was to evaluate the relationship between respiratory symptoms, lung function and inflammatory markers in 'healthy' smokers. The study population was recruited from an epidemiological study with subjects of the same age, 60 years. Only smokers who considered themselves healthy (n=58) and a random sample of never-smokers (n=34) were investigated. All subjects underwent lung function tests--spirometry, carbon monoxide transfer (DLco) and the single-breath N2 method (N2 test)--together with high-resolution computed tomography (HRCT). A flexible bronchoscopy with a bronchoalveolar lavage (BAL) was performed in 30 smokers and 18 never-smokers. Bronchial biopsies were also taken. Smokers who reported non-specific respiratory problems, chronic bronchitis and wheezing in a symptom questionnaire had a lower forced expiratory volume in 1 sec (FEV1), FEV% and specific airway conductance (sGaw), lung function tests supposed to reflect the more central airways, than smokers without respiratory symptoms. A limited number of smokers with occasional non-specific respiratory problems also had more cytotoxic T cells (CD8) in bronchial biopsies. No differences were found in DLCO and the N2 test, lung function tests supposed to reflect the more peripheral airways including the alveoli, HRCT-diagnosed emphysema or inflammatory markers in blood and BAL between smokers with and without respiratory symptoms. It is concluded that even when smokers consider themselves 'healthy' they have mild symptoms that are related more to physiological changes and inflammatory markers that may reflect events in the central airways than to changes that may reflect events in the peripheral airways.     

Reduction of alveolar-capillary diffusion after inhalation of endotoxin in normal subjects.

Normal subjects were exposed to an aerosol of Escherichia coli endotoxin. Carbon monoxide diffusion (Dco), spirometry, blood neutrophils, white blood cells, and platelets were determined at various times thereafter. A significant decrease in Dco and an increase in blood neutrophils was found, with a maximum effect 4 to 8 h after exposure. Exposure to distilled water caused a tendency for Dco to decrease and a significant increase in blood neutrophils. No effect on spirometry or body temperature was detected. It is suggested that the changes observed represent an inflammation at the alveolar level that appears at dose levels of endotoxin below those which cause bronchoconstriction and fever.     

Regional distribution of a 133Xe labelled gas volume inspired at constant flow rates.

We measured the regional distribution of 480 ml of 133Xe labelled gases inspired from FRC at constant inspiratory flow rates ranging from 0.1 to 6 litres/s. The gases used were air and 20% O2 in helium. At low inspiratory flow rates the gas was preferentially delivered to the dependent region of the lung. At maximal inspiratory flows, all regions of the lung were more evenly ventilated. The rate of redistribution was found to be slower and more even than in previous studies using smaller volumes of inspired gas. Assuming equal and synchronous changes of pleural surface pressure, these results can be reasonably predicted by the mechanical time constant theory applied to a simple two-compartment lung model based on equal regional resistances. Breathing the HeO2 mixture did not significantly change ventilation distribution at any flow rate.