Lifetime Point Research Articles

Dietary Quality and Diet-Related Factors Among Emerging Adults (18–23 y) in the United States Are a Cause for Concern: National Health and Nutrition Examination Survey 2015–2018

BackgroundPoor dietary quality is a risk factor for diet-related chronic disease and suboptimal nutritional patterns often begin early in the life course. Although the dietary intakes of young children, adolescents, and middle-aged and older adults are well established, much less is known about emerging adults, who represent a unique time point in life, as they are undergoing significant changes in food environments, autonomy, finances, and caregiver and parental involvement. ObjectivesThis study aimed to examine dietary quality, as assessed via the Healthy Eating Index (HEI), by demographic, socioeconomic, and health-related characteristics among emerging adults (18–23 y) in the United States who participated in the 2015–2018 National Health and Nutrition Examination Survey (NHANES). MethodsNHANES data were collected via a household interview and 2 24-h dietary recalls (24HR). Usual dietary intakes from the 24HRs were approximated using the multivariate National Cancer Institute Method to compute mean HEI-2015 overall and component scores (range: 0–100; higher scores indicating higher dietary quality). ResultsOverall dietary quality among emerging adults (HEI-2015: 50.3 ± 1.3) was significantly lower than other adults (≥24 y) (HEI-2015: 56.3 ± 0.5; P < 0.0001) in the United States, with differences primarily driven by lower intakes of whole fruit, vegetables, and whole grains and higher intakes of sodium, refined grains, and saturated fat. Few differences in HEI-2015 scores were noted across population subgroups by sex, food security, family income, and food assistance program participation, except for added sugar; intakes of added sugar were significantly higher among women, food insecure, and food assistance program participants than those in their counterparts, respectively. ConclusionsDietary quality is poor among emerging adults in the United States and persists across all population subgroups, suggesting a significant need for tailored public health interventions to improve dietary quality among this population. Future research investigating to what extent emerging adults prioritize healthful behaviors and exploring other indicators for identifying nutritionally vulnerable subgroups may be impactful for identifying disparities among this life stage.

The complex relationship between late-onset caloric restriction and synaptic plasticity in aged Wistar rats.

Age-related reduction in spine density, synaptic marker expression, and synaptic efficiency are frequently reported. These changes provide the cellular and molecular basis for the cognitive decline characteristic for old age. Nevertheless, there are several approaches that have the potential to ameliorate these processes and improve cognition, caloric restriction being one of the most promising and widely studied. While lifelong caloric restriction is known for its numerous beneficial effects, including improved cognitive abilities and increased expression of proteins essential for synaptic structure and function, the effects of late-onset and/or short-term CR on synaptic plasticity have yet to be investigated. We have previously documented that the effects of CR are strongly dependent on whether CR is initiated in young or old subjects. With this in mind, we conducted a long-term study in aging Wistar rats to examine changes in the expression of several key synaptic markers under the regimen of CR started at different time points in life. We found a significant increase in the expression of both presynaptic and postsynaptic markers. However, taking into account previously reported changes in the behavior detected in these animals, we consider that this increase cannot represent beneficial effect of CR.

Respiratory Infection and Inflammation in Cystic Fibrosis: A Dynamic Interplay among the Host, Microbes, and Environment for the Ages.

The interplay between airway inflammation and infection is now recognized as a major factor in the pathobiology in cystic fibrosis (CF). A proinflammatory environment is seen throughout the CF airway resulting in classic marked and enduring neutrophilic infiltrations, irreversibly damaging the lung. Although this is seen to occur early, independent of infection, respiratory microbes arising at different timepoints in life and the world environment perpetuate this hyperinflammatory state. Several selective pressures have allowed for the CF gene to persist until today despite an early mortality. Comprehensive care systems, which have been a cornerstone of therapy for the past few decades, are now revolutionized by CF transmembrane conductance regulator (CTFR) modulators. The effects of these small-molecule agents cannot be overstated and can be seen as early as in utero. For an understanding of the future, this review looks into CF studies spanning the historical and present period.

The time is now: regular exercise maintains vascular health in ageing women.

Although ageing impairs cardiovascular health in both men and women, the timeline is different between the sexes. This is at least partially attributed to the loss of oestrogen in women at midlife, in connection with menopause. Oestrogen has protective effects on the cardiovascular system, and menopause consequently leads to a rapid and significant declineincardiovascularhealth. Notably, oestrogeninteracts with its nuclear and membrane receptors leading to changes in proteins of importance for cardiovascular health. Skeletal muscle activity, which affects the expression of many of the same proteins as oestrogen, could potentially counteract the loss of oestrogen at menopause. The hypothesis that exercise can counteract the loss of oestrogen has been explored in several recent studies. It has been found that regular physical activity opposes the detrimental effects not only of ageing, but also of the menopausal transition, on cardiovascular health. Although, vascular benefits can be gained at allages, initiating physical activity at or soon after menopause may be more effective than at a later time point in life. Intuitively, it is easier to prevent decrements than attempting to regain lost vascular health. This idea is supported by evidence at the molecular level, suggesting that exercise-inducedactivationoftheoestrogen-related receptor-α pathwayismoreeffectivesoonafter menopause compared tolater. Together, although a decline incardiovascular health due to chronological ageing cannot be completely prevented, a physically active lifestyle mitigates age-related cardiovascular impairments. Importantly, regular physical activity through life should always be addressed as the biological norm.

Life Course Predictors of Young Men Surviving to Age 90 in a Cohort Study: The Manitoba Follow-up Study.

The purpose of this study was to identify factors at various time points in life that are associated with surviving to age 90. Data from men enrolled in a cohort study since 1948 were considered in 12-year intervals. Logistic regression models were constructed with the outcome of surviving to age 90. Factors were: childhood illness, blood pressure (BP), body mass index (BMI), chronic diseases, and electrocardiogram (ECG) findings. After 1996, the Short Form-36 was added. A total of 3,976 men were born in 1928 or earlier, and hence by the end of our study window in 2018, each had the opportunity of surviving to age 90. Of these, 721 did live to beyond his 90th birthday.The factors in 1948 which predicted surviving were: lower diastolic BP, lower BMI, and not smoking. In 1960, these factors were: lower BP, lower BMI, not smoking, and no major ECG changes. In 1972, these factors were lower BP, not smoking, and fewer disease states. In 1984, these factors were lower systolic BP, not smoking, ECG changes, and fewer disease states. In 1996, the factors were fewer disease states and higher physical and mental health functioning. In 2008, only higher physical functioning predicted survival to the age of 90. In young adulthood, risk factors are important predictors of surviving to age 90; in mid-life, chronic illnesses emerge, and in later life, functional status becomes predominant.

The Network of Tumor Microtubes: An Improperly Reactivated Neural Cell Network With Stemness Feature for Resistance and Recurrence in Gliomas.

Gliomas are known as an incurable brain tumor for the poor prognosis and robust recurrence. In recent years, a cellular subpopulation with tumor microtubes (TMs) was identified in brain tumors, which may provide a new angle to explain the invasion, resistance, recurrence, and heterogeneity of gliomas. Recently, it was demonstrated that the cell subpopulation also expresses neural stem cell markers and shares a lot of features with both immature neurons and cancer stem cells and may be seen as an improperly reactivated neural cell network with a stemness feature at later time points of life. TMs may also provide a new angle to understand the resistance and recurrence mechanisms of glioma stem cells. In this review, we innovatively focus on the common features between TMs and sprouting axons in morphology, formation, and function. Additionally, we summarized the recent progress in the resistance and recurrence mechanisms of gliomas with TMs and explained the incurability and heterogeneity in gliomas with TMs. Moreover, we discussed the recently discovered overlap between cancer stem cells and TM-positive glioma cells, which may contribute to the understanding of resistant glioma cell subpopulation and the exploration of the new potential therapeutic target for gliomas.

Effects of Δ9-Tetrahydrocannibinol (THC) on Obesity at Different Stages of Life: A Literature Review.

The Cannabis sativa plant has historically been used for both recreational and medical purposes. With the recent surge in recreational use of cannabis among adolescents and adults in particular, there is an increased obligation to determine the short- and long-term effects that consuming this plant may have on several aspects of the human psyche and body. The goal of this article was to examine the negative effects of obesity, and how the use of Δ9-tetrahydrocannibinol (THC) or cannabidiol (CBD) can impact rates of this global pandemic at different timepoints of life. Conflicting studies have been reported between adult and adolescents, as there are reports of THC use leading to increased weight due to elevated appetite and consumption of food, while others observed a decrease in overall body weight due to the regulation of omega-6/omega-3 endocannabinoid precursors and a decrease in energy expenditure. Studies supported a positive correlation between prenatal cannabis use and obesity rates in the children as they matured. The data did not indicate a direct connection between prenatal THC levels in cannabis and obesity rates, but that this development may occur due to prenatal THC consumption leading to low birthweight, and subsequent obesity. There are few studies using animal models that directly measure the effects that prenatal THC administration on obesity risks among offspring. Thus, this is a critical area for future studies using a developmental framework to examine potential changes in risk across development.

Maternal high-fat diet programs white and brown adipose tissue lipidome and transcriptome in offspring in a sex- and tissue-dependent manner in mice

ObjectiveThe prevalence of overweight and obesity among children has drastically increased during the last decades and maternal obesity has been demonstrated as one of the ultimate factors. Nutrition-stimulated transgenerational regulation of key metabolic genes is fundamental to the developmental origins of the metabolic syndrome. Fetal nutrition may differently influence female and male offspring.MethodsMice dam were fed either a control diet or a high-fat diet (HFD) for 6-week prior mating and continued their respective diet during gestation and lactation. At weaning, female and male offspring were fed the HFD until sacrifice. White (WAT) and brown (BAT) adipose tissues were investigated in vivo by nuclear magnetic resonance at two different timepoints in life (midterm and endterm) and tissues were collected at endterm for lipidomic analysis and RNA sequencing. We explored the sex-dependent metabolic adaptation and gene programming changes by maternal HFD in visceral AT (VAT), subcutaneous AT (SAT) and BAT of offspring.ResultsWe show that the triglyceride profile varies between adipose depots, sexes and maternal diet. In female offspring, maternal HFD remodels the triglycerides profile in SAT and BAT, and increases thermogenesis and cell differentiation in BAT, which may prevent metabolic complication later in life. Male offspring exhibit whitening of BAT and hyperplasia in VAT when born from high-fat mothers, with impaired metabolic profile. Maternal HFD differentially programs gene expression in WAT and BAT of female and male offspring.ConclusionMaternal HFD modulates metabolic profile in offspring in a sex-dependent manner. A sex- and maternal diet-dependent gene programming exists in VAT, SAT, and BAT which may be key player in the sexual dimorphism in the metabolic adaptation later in life.

Impact Of Physical Activity Trajectories On Colon Cancer Risk

Colon cancer is a major public health and clinical concern, as it is the third leading cause of cancer death in the United States. Numerous types and intensities of physical activity (PA) are shown to reduce risk of colon cancer, however research is inconclusive on what time point in life (early, later, or maintaining throughout life) PA is most important to reduce colon cancer risk. PURPOSE: To evaluate whether the maintenance of and changes in PA levels over time, as measured over the life course as trajectories, are associated with colon cancer risk. METHODS: We used PA and health data from 334,905 generally healthy men and women in the NIH-AARP Diet and Health Study to test whether various PA patterns over the life course impacted colon cancer risk. Using latent class trajectory models, we identified seven distinct PA trajectories using four time points across the life course from teenage years through middle age. We used cox proportional hazard regression to assess the association between the PA trajectories and colon cancer incidence. RESULTS: In adjusted analyses (age, sex, education, smoking, alcohol, and red/processed meat intake), compared to those with consistently low PA levels, we found that those who maintained PA through life significantly reduced risk of colon cancer by about 13% (HR = 0.87, 95% CI 0.80-0.94; 0.87, 95% CI 0.76-0.99), and those who increased PA levels significantly reduced colon cancer risk by about 11% (0.89, 95% CI 0.78 - 1.03). However, those who decreased PA levels had a significantly higher risk of colon cancer (1.13, 95% CI 1.03-1.23). CONCLUSIONS: Our results suggest that consistent participation in PA and increasing PA from low levels in the life course may be most protective of colon cancer risk. Promotion of PA throughout life for all ages and abilities is critical to minimize colon cancer risk, develop effective interventions, and disseminate prevention messages.

Cognitive ability does not predict objectively measured sedentary behavior: Evidence from three older cohorts.

Higher cognitive ability is associated with being more physically active. Much less is known about the associations between cognitive ability and sedentary behavior. Ours is the first study to examine whether historic and contemporaneous cognitive ability predicts objectively measured sedentary behavior in older age. Participants were drawn from 3 cohorts (Lothian Birth Cohort, 1936 [LBC1936] [n = 271]; and 2 West of Scotland Twenty-07 cohorts: 1950s [n = 310] and 1930s [n = 119]). Regression models were used to assess the associations between a range of cognitive tests measured at different points in the life course, with sedentary behavior in older age recorded over 7 days. Prior simple reaction time (RT) was significantly related to later sedentary time in the youngest, Twenty-07 1950s cohort (p = .04). The relationship was nonsignificant after controlling for long-standing illness or employment status, or after correcting for multiple comparisons in the initial model. None of the cognitive measures were related to sedentary behavior in either of the 2 older cohorts (LBC1936, Twenty-07 1930s). There was no association between any of the cognitive tests and the number of sit-to-stand transitions in any of the 3 cohorts. The meta-analytic estimates for the measures of simple and choice RT that were identical in all cohorts (n = 700) were also not significant. In conclusion, we found no evidence that objectively measured sedentary time in older adults is associated with measures of cognitive ability at different time points in life, including cognitive change from childhood to older age.

Soluble Amyloid Precursor Protein α: Friend or Foe?

The "amyloidogenic" proteolytic processing of the cell surface amyloid precursor protein (APP) produces amyloid-β, which causes a range of detrimental effects in the neuron, such as synaptic loss, and plays a key role in Alzheimer's disease. In contrast, "non-amyloidogenic" proteolytic processing, which involves the cleavage of APP by α-secretase, produces soluble amyloid precursor protein α (sAPPα) and is the most predominant proteolytic processing of APP in the healthy brain. Current research suggests that sAPPα plays a role in synaptic growth and plasticity, but whether this role is protective or detrimental is age-dependent. This review looks at the effects of increasing sAPPα during three time-points in life (in development, young adult, ageing/neurodegeneration) when synaptic plasticity plays an important role.

Multivariate random regression analysis for body weight and main morphological traits in genetically improved farmed tilapia (Oreochromis niloticus)

BackgroundBecause of their high economic importance, growth traits in fish are under continuous improvement. For growth traits that are recorded at multiple time-points in life, the use of univariate and multivariate animal models is limited because of the variable and irregular timing of these measures. Thus, the univariate random regression model (RRM) was introduced for the genetic analysis of dynamic growth traits in fish breeding.MethodsWe used a multivariate random regression model (MRRM) to analyze genetic changes in growth traits recorded at multiple time-point of genetically-improved farmed tilapia. Legendre polynomials of different orders were applied to characterize the influences of fixed and random effects on growth trajectories. The final MRRM was determined by optimizing the univariate RRM for the analyzed traits separately via penalizing adaptively the likelihood statistical criterion, which is superior to both the Akaike information criterion and the Bayesian information criterion.ConclusionsIn the selected MRRM, the additive genetic effects were modeled by Legendre polynomials of three orders for body weight (BWE) and body length (BL) and of two orders for body depth (BD). By using the covariance functions of the MRRM, estimated heritabilities were between 0.086 and 0.628 for BWE, 0.155 and 0.556 for BL, and 0.056 and 0.607 for BD. Only heritabilities for BD measured from 60 to 140 days of age were consistently higher than those estimated by the univariate RRM. All genetic correlations between growth time-points exceeded 0.5 for either single or pairwise time-points. Moreover, correlations between early and late growth time-points were lower. Thus, for phenotypes that are measured repeatedly in aquaculture, an MRRM can enhance the efficiency of the comprehensive selection for BWE and the main morphological traits.

Stress responsiveness and anxiety-like behavior: The early social environment differentially shapes stability over time in a small rodent

The early social environment can profoundly affect behavioral and physiological phenotypes. We investigated how male wild cavy offspring, whose mothers had either lived in a stable (SE) or an unstable social environment (UE) during pregnancy and lactation, differed in their anxiety-like behavior and stress responsiveness. At two different time points in life, we tested the offspring's anxiety-like behavior in a dark–light test and their endocrine reaction to challenge in a cortisol reactivity test. Furthermore, we analyzed whether individual traits remained stable over time. There was no effect of the early social environment on anxiety-like behavior and stress responsiveness. However, at an individual level, anxiety-like behavior was stable over time in UE- but not in SE-sons. Stress responsiveness, in turn, was rather inconsistent in UE-sons and temporally stable in SE-sons. Conclusively, we showed for the first time that the early social environment differentially shapes the stability of behavioral and endocrine traits. At first glance, these results may be surprising, but they can be explained by the different functions anxiety-like behavior and stress responsiveness have.

Relationship of Lifetime Exposure to Tobacco, Alcohol and Second Hand Tobacco Smoke with Upper aero-digestive tract cancers in India: a Case-Control Study with a Life-Course Perspective

Background:Squamous cell carcinomas of the upper aero-digestive tract (UADTSCC) are a multifaceted public health problem. Effects of lifestyle risk factors, including tobacco (chewing and smoking), alcohol drinking and exposure to second hand tobacco smoke (SHS) at home and their association with UADT cancers was assessed in a case-control study with a life-course perspective. The study was conducted at two different hospitals in Pune, India.Material and methods:The total sample size (N=480) included 240 histopathologically confirmed cases of UADT cancers and an equal number of controls frequency matched with cases by gender and age distribution (+5 years). All the patients were interviewed face-face using structured questionnaires. Self-reported information on socio-demographic and lifestyle risk factors from childhood to the date of diagnosis of disease/cancer was obtained. Frequency, duration and age of initiation of habits were also recorded to study dose-response relationships. Odds ratios and their 95% confidence intervals were calculated through unconditional logistic regression, adjusting for relevant potential confounders.Results:Chewing tobacco emerged as the strongest predictor for UADT cancers (OR=7.61; 95% CI 4.65-12.45) in comparison to smoking and drinking alcohol. Exposure to SHS during childhood (<16 years) rather than ≥16 years increased the risk (OR=4.05; 95% CI 2.06-7.95). Combined effects of tobacco and alcohol consumption habits elevated the risk by twelve fold (OR=12.05; 95% 4.61-31.49) in comparison to never users of these habits. Furthermore, the combination of these lifestyle risk factors accounted for 86.8% of population attributable risk.Conclusions:Early exposure to various modifiable lifestyle risk factors has a strong positive association with UADT cancer incidence. Effective future public health interventions with focus on vital time points in life targeting these risk factors could possibly be a major step in primary prevention and control of this cancer at the population level.

Different immunological responses to early-life antibiotic exposure affecting autoimmune diabetes development in NOD mice

Environmental factors clearly influence the pathogenesis of Type 1 diabetes, an autoimmune disease. We have studied gut microbiota as important environmental agents that could affect the initiation or progression of type 1 diabetes especially in the prenatal period. We used neomycin, targeting mainly Gram negative or vancomycin, targeting mainly Gram positive bacteria, to treat pregnant NOD mothers and to study autoimmune diabetes development in their offspring. Neomycin-treated offspring were protected from diabetes, while vancomycin-treated offspring had accelerated diabetes development, and both antibiotics caused distinctly different shifts in gut microbiota composition compared with the offspring from untreated control mice. Our study demonstrated that neomycin treatment of pregnant mothers leads to generation of immune-tolerogenic antigen-presenting cells (APCs) in the offspring and these APCs had reduced specific autoantigen-presenting function both in vitro and in vivo. Moreover, the protection from diabetes mediated by tolerogenic APCs was vertically transmissible to the second generation. In contrast, more diabetogenic inflammatory T cells were found in the lymphoid organs of the offspring from the vancomycin-treated pregnant mothers. This change however was not transmitted to the second generation. Our results suggested that prenatal exposure to antibiotic influenced gut bacterial composition at the earliest time point in life and is critical for consequent education of the immune system. As different bacteria can induce different immune responses, understanding these differences and how to generate self-tolerogenic APCs could be important for developing new therapy for type 1 diabetes.

Life Course Socioeconomic Position: Associations with Cardiac Structure and Function at Age 60-64 Years in the 1946 British Birth Cohort.

Although it is recognized that risks of cardiovascular diseases associated with heart failure develop over the life course, no studies have reported whether life course socioeconomic inequalities exist for heart failure risk. The Medical Research Council’s National Survey of Health and Development was used to investigate associations between occupational socioeconomic position during childhood, early adulthood and middle age and measures of cardiac structure [left ventricular (LV) mass index and relative wall thickness (RWT)] and function [systolic: ejection fraction (EF) and midwall fractional shortening (mFS); diastolic: left atrial (LA) volume, E/A ratio and E/e’ ratio)]. Different life course models were compared with a saturated model to ascertain the nature of the relationship between socioeconomic position across the life course and each cardiac marker. Findings showed that models where socioeconomic position accumulated over multiple time points in life provided the best fit for 3 of the 7 cardiac markers: childhood and early adulthood periods for the E/A ratio and E/e’ ratio, and all three life periods for LV mass index. These associations were attenuated by adjustment for adiposity, but were little affected by adjustment for other established or novel cardio-metabolic risk factors. There was no evidence of a relationship between socioeconomic position at any time point and RWT, EF, mFS or LA volume index. In conclusion, socioeconomic position across multiple points of the lifecourse, particularly earlier in life, is an important determinant of some measures of LV structure and function. BMI may be an important mediator of these associations.

Using the Negative Exponential Model to Describe Changes in Risk of Smoking-Related Diseases following Changes in Exposure to Tobacco

Recently published analyses for four smoking-related diseases show that the declining excess relative risk by time quit is well fitted by the negative exponential model. These analyses estimated the half-life of this excess, that is, the time after quitting when the excess relative risk reaches half that for continuing smokers. We describe extensions of the simple model. One quantifies the decline following an exposure reduction. We show that this extension satisfactorily predicts results from studies investigating the effect of reducing cigarette consumption. It may also be relevant to exposure reductions following product-switching. Another extension predicts changes in excess relative risk occurring following multiple exposure changes over time. Suitable published epidemiological data are unavailable to test this, and we recommend its validity to be investigated using large studies with data recorded on smoking habits at multiple time points in life. The basic formulae described assume that the excess relative risk for a continuing smoker is linearly related to exposure and that the half-life is invariant of age. We describe model adaptations to allow for nonlinear dose-response and for age-dependence of the half-life. The negative exponential model, though relatively simple, appears to have many potential uses in epidemiological research for summarizing variations in risk with exposure changes.

Anthropometric Measures at Multiple Times Throughout Life and Prostate Cancer Diagnosis, Metastasis, and Death

BackgroundPrevious studies of prostate cancer (PCa) risk and anthropometrics (ie, body measurements) were based on single measurements or obtained over limited time spans. ObjectiveTo study the association between anthropometrics measured at multiple time points in life and their relation to later diagnosis, metastasis, or death from PCa. Design, setting, and participantsThis case-control study includes 27 167 Swedish men enrolled in two population-based projects from 1974 to 1996. PCa diagnosis up to December 31, 2006, disease information, gestation time, and anthropometrics at birth, military conscript testing, and adulthood were collected. A total of 1355 PCa cases were matched with 5271 controls. Outcome measurements and statistical analysisUnivariate conditional logistic regression was used to determine whether clinical diagnosis, metastasis, or PCa death was associated with low birth weight (weight <2500g); with small size for gestational age; or with weight, length, or body mass index (BMI) at birth, adolescence (aged 16–22 yr), or early middle age (aged 44–50 yr). Results and limitationsApart from weight at adolescence, which was associated with an increased risk of PCa diagnosis (odds ratio [OR] per 5kg: 1.05; 95% confidence interval [CI], 1.01–1.09; p=0.026), preadulthood measurements were not associated with any PCa end point. Adulthood parameters were not associated with diagnosis. In contrast, weight and BMI at early middle age were significantly associated with metastasis (OR per 5kg: 1.13; 95% CI, 1.06–1.20; p<0.0001, and OR: 1.09; 95% CI, 1.05–1.14; p<0.0001) and death (OR per 5kg: 1.11 (95% CI, 1.03–1.19; p=0.005, and OR: 1.08; 95% CI, 1.03–1.13; p=0.003), respectively. It remains unclear whether these results apply to men of nonwhite origin, to populations with active PCa screening programs, or to countries without socialized health care. ConclusionsThe analyses of these large data sets demonstrate that significant effects of body characteristics (with links to metabolic syndrome) measured at early middle age are associated with PCa disease severity, metastatic progression, and outcome. Conversely, measurements at birth and adolescence are not associated with PCa prevalence or outcome. Patient summaryIncreased weight and body mass index in adults is associated with a higher risk of prostate cancer metastasis and death.

Epigenetics and Transcriptomics to Detect Adverse Drug Effects in Model Systems of Human Development

Prenatal exposure to environmental chemicals or drugs has been associated with functional or structural deficits and the development of diseases in later life. For example, developmental neurotoxicity (DNT) is triggered by lead, and this compound may predispose to neurodegenerative diseases in later life. The molecular memory for such late consequences of early exposure is not known, but epigenetic mechanisms (modification of the chromatin structure) could take this role. Examples and underlying mechanisms have been compiled here for the field of DNT. Moreover, we addressed the question as to what readout is suitable for addressing drug memory effects. We summarize how complex developmental processes can be modelled in vitro by using the differentiation of human stem cells. Although cellular models can never replicate the final human DNT phenotype, they can model the adverse effect that a chemical has on key biological processes essential for organ formation and function. Highly information-rich transcriptomics data may inform on these changes and form the bridge from in vitro models to human prediction. We compiled data showing that transcriptome analysis can indicate toxicity patterns of drugs. A crucial question to be answered in our systems is when and how transcriptome changes indicate adversity (as opposed to transient adaptive responses), and how drug-induced changes are perpetuated over time even after washout of the drug. We present evidence for the hypothesis that changes in the histone methylation pattern could represent the persistence detector of an early insult that is transformed to an adverse effect at later time-points in life.

Treatment of Refractory Chronic Urticaria: Current and Future Therapeutic Options

Chronic urticaria is a distressing disease that affects up to 1% of the general population at a time point in life and may severely worsen the quality of life. First-line treatment has been based on antihistamines, and presently relies on the use of non-sedating, second-generation antihistamines; following the recommendations of the recent international guidelines, in patients who do not respond to antihistamines at licensed doses, the daily dosage of these drugs can be increased up to fourfold. Nonetheless, a significant proportion of patients with chronic urticaria remain poorly controlled; in these cases, alternative therapeutic approaches have to be considered. This article critically reviews all of the third- and fourth-line treatment options suggested for patients whose disease is refractory to antihistamines, including systemic corticosteroids, leukotriene receptor antagonists, several different anti-inflammatory drugs (dapsone, sulfasalazine, hydroxychloroquine), various immunosuppressive drugs (calcineurin inhibitors, methotrexate, cyclophosphamide, azathioprine, mycophenolate mofetil), intravenous immunoglobulin, and newer treatment options, such as omalizumab and other biologic drugs. In addition, the article examines possible future treatment options based on recent findings about pathogenic mechanisms, and considers the treatment of antihistamine-unresponsive urticaria in special conditions such as children and pregnancy/lactation. The evidence supporting the use of several of the discussed drugs is presently limited and thus insufficient to recommend their routine use; as a consequence, such compounds should be considered only in specific cases and in adequate settings.