Lucy Liu

Oxidative Damage to Nucleic Acids in Severe Emphysema

BACKGROUND Oxidative stress is a key element in the pathogenesis of emphysema, but oxidation of nucleic acids has been largely overlooked. The aim of this study was to investigate oxidative damage to nucleic acids in severe emphysematous lungs. METHODS Thirteen human severe emphysematous lungs, including five with alpha(1)-antitrypsin deficiency (AATD), were obtained from patients receiving lung transplantation. Control lung tissue was obtained from non-COPD lungs (n = 8) and donor lungs (n = 8). DNA and RNA oxidation were investigated by immunochemistry. Morphometry (mean linear intercept [Lm] and CT scan) and immunostaining for CD68 and neutrophil elastase also were performed. RESULTS Nucleic acid oxidation was increased in alveolar wall cells in emphysematous lungs compared to non-COPD and donor lungs (p < 0.01). In emphysematous lungs, oxidative damage to nucleic acids in alveolar wall cells was increased in the more severe emphysematous areas assessed by histology (Lm, > 0.5 mm; p < 0.05) and CT scan (< -950 Hounsfield units; p < 0.05). Compared to classic emphysema, AATD lungs exhibited higher levels of nucleic acid oxidation in macrophages (p < 0.05) and airway epithelial cells (p < 0.01). Pretreatments with DNase and RNase demonstrated that RNA oxidation was more prevalent than DNA oxidation in alveolar wall cells. CONCLUSIONS We demonstrated for the first time that nucleic acids, especially RNA, are oxidized in human emphysematous lungs. The correlation between the levels of oxidative damage to nucleic acids in alveolar wall cells and the severity of emphysema suggest a potential role in the pathogenesis of emphysema.

Nucleus-Specific Importin Alpha Proteins and Nucleoporins Regulate Protein Import and Nuclear Division in the Binucleate Tetrahymena thermophila

ABSTRACT The ciliate Tetrahymena thermophila, having both germ line micronuclei and somatic macronuclei, must possess a specialized nucleocytoplasmic transport system to import proteins into the correct nucleus. To understand how Tetrahymena can target proteins to distinct nuclei, we first characterized FG repeat-containing nucleoporins and found that micro- and macronuclei utilize unique subsets of these proteins. This finding implicates these proteins in the differential permeability of the two nuclei and implies that nuclear pores with discrete specificities are assembled within a single cell. To identify the import machineries that interact with these different pores, we characterized the large families of karyopherin homologs encoded within the genome. Localization studies of 13 putative importin (imp) α- and 11 imp β-like proteins revealed that imp α-like proteins are nucleus specific—nine localized to the germ line micronucleus—but that most imp β-like proteins localized to both types of nuclei. These data suggest that micronucleus-specific proteins are transported by specific imp α adapters. The different imp α proteins exhibit substantial sequence divergence and do not appear to be simply redundant in function. Disruption of the IMA10 gene encoding an imp α-like protein that accumulates in dividing micronuclei results in nuclear division defects and lethality. Thus, nucleus-specific protein import and nuclear function in Tetrahymena are regulated by diverse, specialized karyopherins.

Elastin expression in very severe human COPD.

Alveolar elastic fibres are key targets of proteases during the pathogenesis of chronic obstructive pulmonary disease (COPD). In the current study, we hypothesised that a response to injury leads to enhanced alveolar elastin gene expression in very severe COPD. Lung samples obtained from 43 patients, including 11 with very severe COPD (stage 4), 10 donors, 10 with moderate/severe COPD (stage 2–3) and 12 non-COPD subjects, were analysed for elastin mRNA expression by real-time RT-PCR and in situ hybridisation. Alveolar elastic fibres were visualised using Harts staining of sections of frozen inflated lungs obtained from 11 COPD stage 4 patients and three donor lungs. Compared with donors, non-COPD and stage 2–3 COPD, elastin mRNA expression was significantly increased in very severe COPD lungs (12-fold change), and localised in situ hybridisation induced elastin expression to alveolar walls. Compared with donors, alveolar elastic fibres also comprised a greater volume fraction of total lung tissue in very severe COPD lungs (p<0.01), but elastic fibre content was not increased per lung volume, and desmosine content was not increased. The present study demonstrates enhanced alveolar elastin expression in very severe COPD. The efficiency of this potential repair mechanism and its regulation remain to be demonstrated.

Infectious morbidity is higher after second-stage compared with first-stage cesareans

OBJECTIVE The objective of the study was to compare maternal and neonatal infectious morbidity following cesareans performed in the second and first stages of labor. STUDY DESIGN We conducted a retropective cohort study of all consecutive, singleton, term, cesarean deliveries in laboring women in a single institution from 2005 to 2012. Second-stage cesareans were defined as those performed at complete cervical dilation (10 cm), and first-stage cesareans were those performed before 10 cm cervical dilation. The primary outcome was endometritis. Rates of infectious morbidity were compared in the 2 groups. Multivariable logistic regression was used to calculate adjusted risk estimates. RESULTS Of 2505 cesareans meeting inclusion criteria, 400 (16.0%) were performed in the second stage, whereas 2105 (84.0%) were performed in the first stage of labor. The risk of endometritis was nearly 3-fold higher in second- compared with first-stage cesareans (4.25% vs 1.52%; crude odds ratio, 2.88; 95% confidence interval, 1.58-5.23). The risk remained significantly higher after controlling for confounders (adjusted odds ratio, 2.78; 95% confidence interval, 1.51-5.09). CONCLUSION Second-stage cesarean is associated with an increased risk of endometritis compared with first-stage cesarean. Further studies will determine whether different infection preventive strategies are needed at second-stage cesareans to reduce endometritis.

Electronic fetal monitoring patterns associated with respiratory morbidity in term neonates

OBJECTIVE The purpose of this study was to identify electronic fetal monitoring patterns that are associated with neonatal respiratory morbidity. STUDY DESIGN In an on-going prospective cohort study of >8000 consecutive term, vertex, nonanomalous singleton pregnancies during labor, we performed this analysis within the first 5000 women as a representative sample. Electronic fetal monitoring patterns in the 30 minutes preceding delivery were extracted by trained obstetrics research nurses, who were blinded to clinical data, using the National Institute of Child Health and Human Development system; the data were compared between those with respiratory morbidity and healthy infants (no morbidities). The primary outcome was neonatal respiratory morbidity, which was defined as either oxygen requirement at ≥6 hours of life or any mechanical ventilation in the first 24 hours. Multivariable logistic regression was used to adjust for confounders. RESULTS Of 4736 neonates, 175 (3.4%) experienced respiratory morbidity. Most electronic fetal monitoring patterns were category II (96.6%; n = 4575). Baseline tachycardia (adjusted odds ratio [aOR], 2.9; 95% confidence interval [CI], 1.9-4.4), marked variability (aOR, 2.7; 95% CI, 1.5-5.0), and prolonged decelerations (aOR,2.7; 95% CI, 1.5-5.0) were significantly associated with an increased likelihood of term neonatal respiratory morbidity. Accelerations and persistent moderate variability were both significantly associated with a decreased likelihood of respiratory morbidity. CONCLUSION Specific features of category II electronic fetal monitoring patterns make respiratory morbidity more likely in nonanomalous term infants. Tachycardia, marked variability, or prolonged decelerations before delivery can assist providers in anticipating the potential need for neonatal respiratory support.

Discussion: ‘Gestational weight gain and hypertensive disorders,’ by MacDonald-Wallis et al

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research.

Obesity Education Strategies for Cancer Prevention in Women’s Health

Obesity is the cause of up to one third of all cancers affecting women today, most notably endometrial, colon, and breast cancers. Women’s health providers are poised to advise women on obesity’s link to cancer development, but often lack resources or training to provide appropriate counseling. Here, we review obesity’s role in increasing the risk of several common reproductive system conditions faced by women, including polycystic ovarian syndrome, infertility, gynecologic surgical complications, and pregnancy complications. These events can be used as teachable moments to help frame the discussion of weight management and promote cancer prevention. We also review national guidelines and existing tangible weight-loss strategies that can be employed within the outpatient women’s health setting to help women achieve weight-loss goals and affect cancer prevention.