Moderate Alcohol Use and Cardiovascular Disease from Mendelian Randomization

Background

Observational studies show moderate alcohol use negatively associated with ischemic heart disease (IHD) and cardiovascular disease (CVD). However, healthier attributes among moderate users compared to never users may confound the apparent association. A potentially less biased way to examine the association is Mendelian randomization, using alcohol metabolizing genes which influence alcohol use.

Methods

We used instrumental variable analysis with aldehyde dehydrogenase 2 (ALDH2) genotypes (AA/GA/GG) as instrumental variables for alcohol use to examine the association of alcohol use (10 g ethanol/day) with CVD risk factors (blood pressure, lipids and glucose) and morbidity (self-reported IHD and CVD) among men in the Guangzhou Biobank Cohort Study.

Results

ALDH2 genotypes were a credible instrument for alcohol use (F-statistic 74.6). Alcohol was positively associated with HDL-cholesterol (0.05 mmol/L per alcohol unit, 95% confidence interval (CI) 0.02 to 0.08) and diastolic blood pressure (1.15 mmHg, 95% CI 0.23 to 2.07) but not with systolic blood pressure (1.00 mmHg, 95% CI -0.74 to 2.74), LDL-cholesterol (0.03 mmol/L, 95% CI -0.03 to 0.08), log transformed triglycerides (0.03 mmol/L, 95% CI -0.01 to 0.08) or log transformed fasting glucose (0.01 mmol/L, 95% CI -0.006 to 0.03), self-reported CVD (odds ratio (OR) 0.98, 95% CI 0.76 to 1.27) or self-reported IHD (OR 1.10, 95% CI 0.83 to 1.45).

Conclusion

Low to moderate alcohol use among men had the expected effects on most CVD risk factors but not fasting glucose. Larger studies are needed to confirm the null associations with IHD, CVD and fasting glucose.     

Association of polymorphisms in the Chr18q11.2 locus with tuberculosis in Chinese population

A GWAS study has reported that two single nucleotide polymorphisms (SNPs) were associated with predisposition to tuberculosis (TB) in African populations. These two loci represented the long-waited GWAS hits for TB susceptibility. To determine whether these two SNPs are associated with TB in Chinese population, we attempted an replication in a cohort of over one thousand Chinese TB patients and 1,280 healthy controls using melting temperature shift allele-specific genotyping analysis. We found that only SNP rs4331426 was significantly associated with TB in Chinese population (p = 0.011). However, the effect was opposite. The G allele of the SNP in Chinese population is a protective allele (OR = 0.62, 95 % CI 0.44–0.87), while it was the risk allele for African population (OR = 1.19, 95 % CI 1.12–1.26). No significance was found for SNP rs2335704. The results provided an independent support for a role in susceptibility to TB for SNP rs4331426. However, it also indicated that direct predisposition element to TB and the association effects may vary across ethnic groups.     

Development of a new bioprocess scheme using frozen seed train intermediates to initiate CHO cell culture manufacturing campaigns

Agility to schedule and execute cell culture manufacturing campaigns quickly in a multi‐product facility will play a key role in meeting the growing demand for therapeutic proteins. In an effort to shorten campaign timelines, maximize plant flexibility and resource utilization, we investigated the initiation of cell culture manufacturing campaigns using CHO cells cryopreserved in large volume bags in place of the seed train process flows that are conventionally used in cell culture manufacturing. This approach, termed FASTEC (Frozen Accelerated Seed Train for Execution of a Campaign), involves cultivating cells to high density in a perfusion bioreactor, and cryopreserving cells in multiple disposable bags. Each run for a manufacturing campaign would then come from a thaw of one or more of these cryopreserved bags. This article reviews the development and optimization of individual steps of the FASTEC bioprocess scheme: scaling up cells to greater than 70 × 10⁶ cells/mL and freezing in bags with an optimized controlled rate freezing protocol and using a customized rack configuration. Flow cytometry analysis was also employed to understand the recovery of CHO cells following cryopreservation. Extensive development data were gathered to ensure that the quantity and quality of the drug manufactured using the FASTEC bioprocess scheme was acceptable compared to the conventional seed train process flow. The result of offering comparable manufacturing options offers flexibility to the cell culture manufacturing network. Biotechnol. Bioeng. 2013; 110: 1376–1385. © 2012 Wiley Periodicals, Inc.     

Cestode regulation of inflammation and inflammatory diseases

Helminth parasites are masters of immune regulation; a likely prerequisite for long-term survival by circumventing their hosts’ attempt to eradicate them. From a translational perspective, knowledge of immune events as a response to infection with a helminth parasite could be used to reduce the intensity of unwanted inflammatory reactions. Substantial data have accumulated showing that inflammatory reactions that promote a variety of auto-inflammatory diseases are dampened as a consequence of infection with helminth parasites, via either the mobilization of an anti-worm spectrum of immune events or by the direct effect of secretory/excretory bioactive immunomodulatory molecules released from the parasite. However, many issues are outstanding in the definition of the mechanism(s) by which infection with helminth parasites can affect the outcome, positively or negatively, of concomitant disease. We focus on a subgroup of this complex group of metazoan parasites, the cestodes, summarizing studies from rodent models that illustrate if, and by what mechanisms, infection with tapeworms ameliorate or exaggerate disease in their host. The ability of infection with cestodes, or other classes of helminth, to worsen a disease course or confer susceptibility to intracellular pathogens should be carefully considered in the context of ‘helminth therapy’. In addition, poorly characterised cestode extracts can regulate murine and human immunocyte function, yet the impact of these in the context of autoimmune or allergic diseases is poorly understood. Thus, studies with cestodes, as representative helminths, have helped cement the concept that infection with parasitic helminths can inhibit concomitant disease; however, issues relating to long-term effects, potential side-effects, mixed pathogen infections and purification of immunomodulatory molecules from the parasite remain as challenges that need to be addressed in order to achieve the use of helminths as anti-inflammatory agents for human diseases.     

Cellular Source-Specific Effects of Apolipoprotein (Apo) E4 on Dendrite Arborization and Dendritic Spine Development

Apolipoprotein (apo) E4 is the leading genetic risk factor for Alzheimer’s disease (AD), and it has a gene dose-dependent effect on the risk and age of onset of AD. Although apoE4 is primarily produced by astrocytes in the brain, neurons can also produce apoE4 under stress conditions. ApoE4 is known to inhibit neurite outgrowth and spine development in vitro and in vivo, but the potential influence of apoE4’s cellular source on dendritic arborization and spine development has not yet been investigated. In this study, we report impairments in dendritic arborization and a loss of spines, especially thin (learning) and mushroom (memory) spines, in the hippocampus and entorhinal cortex of 19–21-month-old female neuron-specific-enolase (NSE)-apoE4 and apoE4-knockin (KI) mice compared to their respective apoE3-expressing counterparts. In general, NSE-apoE4 mice had more severe and widespread deficits in dendritic arborization as well as spine density and morphology than apoE4-KI mice. The loss of dendritic spines, especially mushroom spines, occurred in NSE-apoE4 mice as early as 7–8 months of age. In contrast, glial fibrillary acidic protein (GFAP)-apoE4 mice, which express apoE4 solely in astrocytes, did not have impairments in their dendrite arborization or spine density and morphology compared to GFAP-apoE3 mice at both ages. These results indicate that the effects of apoE4 on dendrite arborization, spine density, and spine morphology depend critically on its cellular source, with neuronal apoE4 having more detrimental effects than astrocytic apoE4.     

Long-term effects of timber harvesting on hemicellulolytic microbial populations in coniferous forest soils

Forest ecosystems need to be sustainably managed, as they are major reservoirs of biodiversity, provide important economic resources and modulate global climate. We have a poor knowledge of populations responsible for key biomass degradation processes in forest soils and the effects of forest harvesting on these populations. Here, we investigated the effects of three timber-harvesting methods, varying in the degree of organic matter removal, on putatively hemicellulolytic bacterial and fungal populations 10 or more years after harvesting and replanting. We used stable-isotope probing to identify populations that incorporated ¹³C from labeled hemicellulose, analyzing ¹³C-enriched phospholipid fatty acids, bacterial 16 S rRNA genes and fungal ITS regions. In soil microcosms, we identified 104 bacterial and 52 fungal hemicellulolytic operational taxonomic units (OTUs). Several of these OTUs are affiliated with taxa not previously reported to degrade hemicellulose, including the bacterial genera Methylibium, Pelomonas and Rhodoferax, and the fungal genera Cladosporium, Pseudeurotiaceae, Capronia, Xenopolyscytalum and Venturia. The effect of harvesting on hemicellulolytic populations was evaluated based on in situ bacterial and fungal OTUs. Harvesting treatments had significant but modest long-term effects on relative abundances of hemicellulolytic populations, which differed in strength between two ecozones and between soil layers. For soils incubated in microcosms, prior harvesting treatments did not affect the rate of incorporation of hemicellulose carbon into microbial biomass. In six ecozones across North America, distributions of the bacterial hemicellulolytic OTUs were similar, whereas distributions of fungal ones differed. Our work demonstrates that diverse taxa in soil are hemicellulolytic, many of which are differentially affected by the impact of harvesting on environmental conditions. However, the hemicellulolytic capacity of soil communities appears resilient.     

Hand,Foot, and Mouth Disease in China: Modeling Epidemic Dynamics of Enterovirus Serotypes and Implications for Vaccination

Background

Hand, foot, and mouth disease (HFMD) is a common childhood illness caused by serotypes of the Enterovirus A species in the genus Enterovirus of the Picornaviridae family. The disease has had a substantial burden throughout East and Southeast Asia over the past 15 y. China reported 9 million cases of HFMD between 2008 and 2013, with the two serotypes Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16) being responsible for the majority of these cases. Three recent phase 3 clinical trials showed that inactivated monovalent EV-A71 vaccines manufactured in China were highly efficacious against HFMD associated with EV-A71, but offered no protection against HFMD caused by CV-A16. To better inform vaccination policy, we used mathematical models to evaluate the effect of prospective vaccination against EV-A71-associated HFMD and the potential risk of serotype replacement by CV-A16. We also extended the model to address the co-circulation, and implications for vaccination, of additional non-EV-A71, non-CV-A16 serotypes of enterovirus.

Methods and Findings

Weekly reports of HFMD incidence from 31 provinces in Mainland China from 1 January 2009 to 31 December 2013 were used to fit multi-serotype time series susceptible–infected–recovered (TSIR) epidemic models. We obtained good model fit for the two-serotype TSIR with cross-protection, capturing the seasonality and geographic heterogeneity of province-level transmission, with strong correlation between the observed and simulated epidemic series. The national estimate of the basic reproduction number, R ₀, weighted by provincial population size, was 26.63 for EV-A71 (interquartile range [IQR]: 23.14, 30.40) and 27.13 for CV-A16 (IQR: 23.15, 31.34), with considerable variation between provinces (however, predictions about the overall impact of vaccination were robust to this variation). EV-A71 incidence was projected to decrease monotonically with higher coverage rates of EV-A71 vaccination. Across provinces, CV-A16 incidence in the post-EV-A71-vaccination period remained either comparable to or only slightly increased from levels prior to vaccination. The duration and strength of cross-protection following infection with EV-A71 or CV-A16 was estimated to be 9.95 wk (95% confidence interval [CI]: 3.31, 23.40) in 68% of the population (95% CI: 37%, 96%). Our predictions are limited by the necessarily short and under-sampled time series and the possible circulation of unidentified serotypes, but, nonetheless, sensitivity analyses indicate that our results are robust in predicting that the vaccine should drastically reduce incidence of EV-A71 without a substantial competitive release of CV-A16.

Conclusions

The ability of our models to capture the observed epidemic cycles suggests that herd immunity is driving the epidemic dynamics caused by the multiple serotypes of enterovirus. Our results predict that the EV-A71 and CV-A16 serotypes provide a temporary immunizing effect against each other. Achieving high coverage rates of EV-A71 vaccination would be necessary to eliminate the ongoing transmission of EV-A71, but serotype replacement by CV-A16 following EV-A71 vaccination is likely to be transient and minor compared to the corresponding reduction in the burden of EV-A71-associated HFMD. Therefore, a mass EV-A71 vaccination program of infants and young children should provide significant benefits in terms of a reduction in overall HFMD burden.     

The Relationship between Age at First Birth and Mother's Lifetime Earnings: Evidence from Danish Data

Background

Having children creates career interruptions and reductions in labor income for women. This study documents the relation between the age at first birth (AFB) and women’s labor income. We study these dynamics in the short run (i.e. ratio between labor income at AFB and two years prior to AFB) and long run (i.e., positive/negative differences in total lifetime labor income).

Methods

Using unique Danish administrative register data for the entire Danish population, we estimate the age-income profiles separately for college and non-college women conditional on marital status, and mothers’ age at first birth (AFB). We compute the lifetime labor income differentials by taking the differences between the labor income of women with and without children at each AFB.

Results

The short-run loss in labor income, defined as the difference in percentages between the income earned two years prior to AFB and income earned at AFB, ranges from 37% to 65% for college women and from 40% to 53% for non-college women. These losses decrease monotonically with respect to AFB for both education groups. Our results on the lifetime labor income differentials between mothers and women without children also show a net effect that is monotonic (from negative to positive) in AFB. With AFB<25, the lifetime labor income loss for college women is -204% of their average annual labor income and this figure is -252% for non-college women. There are lifetime labor income gains with AFB>31. The largest gains for college women are 13% of their average annual income and this figure is 50% for non-college women.

Conclusion

Women have a large and unambiguous short-run reduction in labor income at their AFB. In terms of lifetime labor income, both college and non-college women, compared to childless women, are associated with lower income of more than twice their respective average annual income when bearing a child at AFB<25. In other words, women with AFB<25 are associated with a lower lifetime income of more than two years of annual labor income. The lifetime labor incomes for college and non-college women associated with AFB>31 are relatively higher.