Early Life Research Articles

Effects of Early Life Scarcity-Adversity on Maturational Milestones in Male and Female Rats.

Although many studies have shown a long-term negative impact of early life adversity (ELA) in rodents, literature regarding its effects on maturational milestones in rats is scarce. Available evidence suggests that ELA interferes with normal growth and development in rodents and that effects may be sex-dependent even at an early age. In accordance, we hypothesized that early life scarcity-adversity would impair physical and reflex development in male and female rats. To test this, we used an early life resource scarcity paradigm based on reducing home cage bedding during postnatal days (PND) 2-9 and assessed physical landmarks by measuring weight gain, incisor presence, fur development, and eye opening. We also evaluated the impact of early life scarcity-adversity on developmental reflexes by measuringsurface righting and grasp reflexes, negative geotaxis, cliff avoidance, bar holding, and auditory startle. Early life scarcity-adversity resulted in earlier complete lower incisor presence in males (PND 6), impaired surface righting(PND 6) and grasp reflexes (PND 8) in both sexes, and impaired cliff avoidance responses in females (PND 12). These results extend previous research examining the effects of ELA on developing male and female rodents by showing that it negatively impacts a subset of physical landmarks and developmental reflexes in a sex-dependent manner.

Role of body mass index in unbalanced (dysanaptic) lung growth of healthy infants.

Imbalance between forced expiratory volume in the first second (FEV1) and forced vital capacity(FVC) (dysanapsis) has been reported in children who are obese. This dysanaptic growth might begin at an early age, although there are no data on children younger than 6 years. To assess whether body mass index (BMI) and early weight gain, in healthy infants born at term, plays a significant role in the imbalance between FEV1 and FVC, even in the absence of obesity. Lung function was measured by means of raised volume rapid thoracic compression in 69 healthy infants born at term from the Nutrition in Early Life and Asthma cohort. Dysanapsis was defined as zFVC >0.674, zFEV0 .5 ≥-1.645, and FEV0 .5/FVC ≤-1.645. Weight gain (g/day) and growth rate (cm/year) were calculated as the difference between weight and length on the test date and those at birth. To assess the relationship between zBMI and dysanapsis, a receiver operating characteristic curve was performed. Multivariable analysis was carried out by means of linear regressions (one for each lung function index) and by logistic regression for dysanapsis (yes/no). Higher zBMI was associated with risk of dysanapsis (odds ratio: 3.53, [95% confidence interval: 1.30; 9.66]; p = .014): Each additional zBMI unit was associated with ~10 mL higher FVC and with ~3.5% lower FEV0.5/FVC. Weight gain was associated with lower FEV0.5/FVC ratio. Dysanaptic development of lung function begins very early in infancy and is related with weight gain and body mass index, even in the absence of obesity.

Population-based prevalence of self-reported pediatric diabetes and screening for undiagnosed type 2 diabetes in Chinese children in years 2017–2019, a cross-sectional study

The worldwide geographical and temporal variation in the prevalence of diabetes represents a challenge, but also an opportunity for gaining etiological insights. Encompassing the bulk of East Asians, a large and distinct proportion of the world population, China can be a source of valuable epidemiological insights for diabetes, especially in early life, when pathophysiology begins. We carried out a nationwide, epidemiological survey of Prevalence and Risk of Obesity and Diabetes in Youth (PRODY) in China, from 2017 to 2019, to estimate the population-based prevalence of diagnosed pediatric diabetes and screen for undiagnosed pediatric type 2 diabetes (T2D). PRODY was a nation-wide, school population-based, cross-sectional, multicenter survey by questionnaire, fasting urine glucose test and simple oral glucose tolerance test (s-OGTT), among a total number of 193,801 general-population children and adolescents (covered a pediatric population of more than 96.8 million), aged 3-18, from twelve provinces across China. The prevalence of the self-reported pediatric diabetes, the proportion of subtypes, the crude prevalence of undiagnosed T2D and prediabetes in general juvenile population and the main risk factors of type 1 (T1D) and type 2 (T2D) diabetes had been analyzed in the study. The prevalence of all self-reported pediatric diabetes was estimated at 0.62/1000 (95% CI: 0.51-0.74), with T1D at 0.44/1000 (95% CI: 0.35-0.54) and T2D at 0.18/1000 (95% CI: 0.13-0.25). For undiagnosed T2D, the crude prevalence was almost ten-fold higher, at 1.59/1000, with an estimated extra 28.45/1000 of undiagnosed impaired glucose tolerance (IGT) and 53.74/1000 of undiagnosed impaired fasting glucose (IFG) by s-OGTT screening. Maternal diabetes history is the major risk factors for all subtypes of pediatric diabetes in China. The PRODY study provides the first population-based estimate of the prevalence of pediatric diabetes China and reveals a magnitude of the problem of undiagnosed pediatric T2D. We propose a practical screening strategy by s-OGTT to address this serious gap. The National Key Research and Development Programme of China, Key R&D Program of Zhejiang, the National Natural Science Foundation of China and the Zhejiang Provincial Key Disciplines of Medicine, Key R&D Program Projects in Zhejiang Province.

Predictors of stunting and pathway analysis for linear growth among children 2-3 years of age after a trial of small-quantity lipid-based nutrient supplements and home-installed growth charts in three districts in Zambia

Globally, 148 million children under 5 are stunted, with risk factors varying by context. Our 'Impact of Growth Charts and Nutritional Supplements on Child Growth in Zambia' (ZamCharts) trial observed persistently high rates of stunting in all treatment groups after 18-months of intervention with monthly distributions of small-quantity lipid-based nutrient supplements (SQ-LNS) and/or installation of a wall-mounted growth chart in children's homes. We sought to identify determinants of stunting and height-for-age z-score in children 27-36 months who participated in the ZamCharts endline survey (n=1911). Multi-level, log-binomial models were used to estimate univariable and multivariable prevalence ratios for predictors of stunting. Multi-level models were also used to predict height-for-age z-score (HAZ) with and without baseline HAZ (assessed at ages 2-11 months). We also conducted a path analysis using covariance analysis of linear structural equations to assess underlying and modifiable risk factors for impaired linear growth. Significant predictors of stunting in the multivariable model included: low asset ownership; being male; using biomass as cooking fuel; lower maternal height; a mother with ≤ primary education; lower baseline HAZ. and not being randomized to SQ-LNS. Significant predictors of a lower mean HAZ in the full multivariable models included all the same risk factors that predicted stunting, but also living in an urban area, having more than one child <5 years in the household and diarrhea in the previous 2 weeks. The multivariable model explained 48% of variability in endline HAZ; the strongest predictor was baseline HAZ, which explained 29% of endline HAZ variability in the univariable model. Preventing stunting in Zambia will require investments in early life (pre- and post-natal) determinants of growth trajectory as well as improving complementary feeding practices and addressing risk factors for infectious diseases; SQ-LNS can also improve linear growth and reduce stunting.

Effects of NMDA glutamatergic receptors pharmacological stimulation of the ventral tegmental area on the memory deficits induced by maternal deprivation

Maternal deprivation (MD) is a potent stressor during early life and can lead to behavioral changes during adulthood. Several neurochemical mechanisms underlying MD-induced stress have been proposed; among them is the damage caused to dopaminergic neurons in the ventral tegmental area (VTA). We hypothesized that pharmacological stimulation of dopaminergic neurons in VTA by the infusion of an N-Methyl-D-Aspartate (NMDA) receptors agonist (used considering the wide distribution of these glutamatergic receptors in the VTA neurons) can reverse MD-induced memory deficits. Here, we demonstrated that MD affects male and female rats distinctly, with females being more resilient to early-life stress. Furthermore, NMDA pharmacological stimulation of the VTA promotes object recognition (OR) memory persistence in male and female non-MD rats. In males, infusion of NMDA into the VTA immediately after the learning session reverses recognition memory deficits related to MD. Although MD female rats have not shown deficits in OR memory consolidation, the NMDA infusion immediately after the learning session promotes memory persistence. We verified that MD leads to memory deficits in adult male rats, while the females are resilient to early life stress. Furthermore, NMDA pharmacological stimulation of dopaminergic VTA neurons reveals the dopaminergic modulation of OR memory in MD rats, even in females that did not exhibit memory deficits.

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Meningeal innate lymphoid cells guide inhibitory neurons in early life.

Vaidya Bapalal G Shah-A botanist Vaidya who made significant contributions to the field of dravyaguna

Abstract This article sheds light on the life and contributions of Vaidya Bapalal G. Shah to Ayurveda. This article is based on information obtained through interviews with Bapalal Vaidya’s grandson, Vaidya Anand Shah, and references to Vaidyaraj Bapalal Shashthipurti Granth and Vanayu e-magazine about his early life, active role in the Indian independence movement, and unwavering dedication to Ayurveda. This study is an effort to introduce the practitioners of Ayurveda to Bapalal’s journey from a sincere student to a leading genius of Ayurveda. Bapalal Vaidya was a lifelong learner, mastering the uses of medicinal plants, Ayurvedic clinical practices, and allopathic methods, which is reflected in works such as “Nighantu Adarsha” and “Dravyaguna Shastra.” As a teacher, pharmaceutical manufacturer, researcher, and author of more than 50 books, his influence extended to establishing institutions like O. H. Nazar Ayurveda College and Atmanand Saraswati Ayurvedic Cooperative Pharmacy Limited.

Agomelatine Is Unable to Attenuate Kainic Acid-Induced Deficits in Early Life Communicative Behavior.

Early life seizures are associated with a variety of behavioral comorbidities. Among the most prevalent of these are deficits in communication. Auditory communicative behaviors in mice, known as ultrasonic vocalizations (USVs), can be used to assess potential treatments. Agomelatine is a melatonin agonist that effectively reduces behavioral comorbidities of seizures in adults; however, its ability to attenuate seizure-induced communicative deficits in neonates is unknown. To address this, we administered C57 mice either saline or kainic acid (KA) on postnatal day (PD) 10. The mice then received either agomelatine or saline 1-h post-status epilepticus. On PD 11, we assessed the quantity of USVs produced, the duration, peak frequency, fundamental frequency, and amplitude of the vocalizations, as well as the call type utilization. We found that KA increased vocal production and reduced USV variability relative to controls. KA also increased USV duration and amplitude and significantly altered the types of calls produced. Agomelatine did not attenuate any of the deficits. Our study is the first to assess agomelatine's efficacy to correct USVs and thus provides an important point of context to the literature, indicating that despite its high therapeutic efficacy to attenuate other behavioral comorbidities of seizures, agomelatine's ability to correct neonatal communicative deficits is limited.

Characterising developmental dynamics of adult epigenetic clock sites

DNA methylation (DNAm), an epigenetic mechanism that regulates gene activity in response to genetic and environmental influences, changes as we age. DNAm at specific sites on the genome can be used to calculate 'epigenetic clocks', which are powerful biomarkers of age, as well as of ageing. However, little is known about how these clock sites 'behave' during development and what factors influence their variability in early life. This knowledge could be used to optimise healthy ageing well before the onset of age-related conditions. We leveraged results from two longitudinal population-based cohorts (N=5019 samples from 2348 individuals) to characterise trajectories of adult clock sites from birth to early adulthood. To explore what factors may drive early individual differences at these clock sites, we also tested for enrichment of genetic factors and prenatal exposures based on existing epigenome-wide association meta-analyses. We find that clock sites (i) diverge widely in their developmental trajectories, often showing non-linear change over time; (ii) are substantially more likely than non-clock sites to vary between individuals already from birth, differences that are predictive of DNAm variation at later ages; and (iii) show enrichment for genetic influences and prenatal environmental exposures, including prenatal smoking, diet and maternal physical health conditions. These results suggests that age(ing)-related epigenetic processes might originate-and differ between individuals-already very early in development. Understanding what drives these differences may in future help us to devise better strategies to promote healthy ageing. This research was conducted while C.A.M.C. was a Hevolution/AFAR New Investigator Awardee in Aging Biology and Geroscience Research. Full personal funding details, as well as cohort funding details, can be found in the Acknowledgements.

Sibling presence during fostering ameliorates endocrine stress profile changes in a social rodent species (Octodon degus) in a sex-specific manner

During early life, disruption of the parent-offspring bond can substantially impact development of offspring physiology and behavior. In rodents, it has been well-documented that parental separation, reduction in parental care, and cross-fostering can affect development of the endocrine stress response. For social species, however, several social factors may mitigate the stress of cross-fostering, such as remaining with other known adult caregivers or siblings. In this study, we cross-fostered a social rodent species (Octodon degus) with or without their siblings at postnatal day (PND) 8 and measured their endocrine stress response immediately after fostering (PND9) and at weaning (PND28). We found that female singly-fostered offspring displayed elevated baseline cortisol levels and reduced weight gain immediately after fostering. At weaning, female singly-fostered offspring continued to display elevated baseline cortisol levels compared to non-fostered female offspring, while singly-fostered males demonstrated weaker cortisol negative feedback strength compared to male offspring that were not fostered or were fostered with their siblings. These results suggest that sibling presence may help mitigate the stress of fostering, and that future studies should further examine other social conditions that may help reduce developmental consequences of long-term parental bond disruption.

Antibiotic usage within the first year of life has a protective effect against ulcerative colitis in South Korea: A nationwide cohort study

BackgroundAntibiotic usage in early life has been proposed as a risk factor for inflammatory bowel disease, especially Crohn's disease. However, most studies were conducted in Western countries. AimsWe evaluated the association between antibiotic usage and the incidence of inflammatory bowel disease in the Asian population. MethodsThis nationwide population-based retrospective cohort study included 2,941,889 South Korean infants born between 2007 and 2015, using the National Health Insurance Service database. We assessed whether antibiotic use was associated with the incidence of inflammatory bowel disease. Additionally, we conducted sensitivity analyses, considering protopathic bias and dietary variables. The Cox proportional hazards model was used. ResultsAmong 2,941,889 infants, 2,566,390 (87 %) used antibiotics within a year after birth. Antibiotic usage within a year, number of antibiotic classes, and cumulative days of usage were shown to decrease the risk of ulcerative colitis. This association was particularly prominent with earlier antibiotic exposure. Penicillin was the only antibiotic class related to the reduced risk. The results were robust after adjusting for dietary variables and considering protopathic effect. ConclusionsAntibiotic exposure during the first year of life, particularly at a younger age, is linked to a reduced risk of early-onset ulcerative colitis in South Korea.

Life profile of Vaidyabhooshanam K. Raghavan Thirumulpadu – An exemplary legend in Ayurveda

Abstract Ayurveda is one of the renowned contributions of Traditional Indian Medicine to the globe. Kerala has a rich legacy of Ayurveda, which has flourished and is supported by many distinguished traditional Vaidya families and legends. Shri Padmabhooshan Vaidyabhooshanam K. Raghavan Thirumulpadu (VKRT) is an impeccable contribution of Kerala for its Ayurvedic heritage. VKRT was a perfect blend of knowledge in Ayurvedic principles and practice and contemporary medical science. This article presents the life profile of VKRT, a profound Ayurvedic physician, prolific writer, and philosopher. This work is based on interviews conducted with his son Dr. K. Murali, his disciple Dr. M. Prasad and books and articles written by and on VKRT. The article highlights the various domains of VKRT’s personal and professional life. VKRT’s early life and education, destiny to study Ayurveda, multiple realms of his professional life, awards and achievements are discussed in detail.

Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior.

The innate immune system shapes brain development and is implicated in neurodevelopmental diseases. It is critical to define the relevant immune cells and signals and their impact on brain circuits. In this work, we found that group 2 innate lymphoid cells (ILC2s) and their cytokine interleukin-13 (IL-13) signaled directly to inhibitory interneurons to increase inhibitory synapse density in the developing mouse brain. ILC2s expanded and produced IL-13 in the developing brain meninges. Loss of ILC2s or IL-13 signaling to interneurons decreased inhibitory, but not excitatory, cortical synapses. Conversely, ILC2s and IL-13 were sufficient to increase inhibitory synapses. Loss of this signaling pathway led to selective impairments in social interaction. These data define a type 2 neuroimmune circuit in early life that shapes inhibitory synapse development and behavior.

Gentle Biologies: Reconceptualizing Bodily Transformation and Healthcare between Catherine Malabou and Anne Dufourmantelle

This article brings Catherine Malabou’s philosophy of the plasticity of biological life into dialogue with Anne Dufourmantelle’s concept of gentleness, theorizing gentle biologies at the intersections of both thinkers. It explores how, for both Malabou and Dufourmantelle, gentleness is not an innately occurring power or characteristic predetermined within biological life, but rather a force that must be plastically shaped, honed, practised. Further, if Dufourmantelle argues in Power of Gentleness (2018 [2013]) that gentleness can constitute a formidable resource for both transformation and resistance, this gentleness will be seen to resonate with conceptualizations of plasticity across Malabou’s oeuvre as a similarly revolutionary potentiality. The article finishes by turning to engage with interdisciplinary work on gentleness in healthcare, arguing that such contexts constitute sites in which new modes of care towards Malabou’s and Dufourmantelle’s gentle biologies can be imagined.

Associations of obesity with co-morbidities in early adult life

Associations of obesity with co-morbidities in early adult life

Glucose Metabolism and Sex Hormones in Male Patients with Medication-naïve First-episode Schizophrenia: A Large-scale Cross-sectional Study.

Schizophrenia (SCZ) usually begins in early adult life. The underlying molecular mechanisms of SCZ remain unclear. There is evidence for the involvement of abnormalities in metabolic and endocrine systems in SCZ, even in drug-naïve first-episode schizophrenia patients (DNFES). However, the association between impaired regulation of glucose metabolism and sex hormones was not studied in SCZ. This study aimed to evaluate the interrelationship between sex hormones and high fasting glucose levels in male DNFES patients. A total of 99 patients with SCZ were recruited, and fasting glucose, fasting insulin, the insulin resistance index (HOMA-IR), and sex hormones were measured. We found that some male patients with SCZ had abnormal levels in glucose metabolism parameters and gonadal hormones that were not within the normal range. Linear regression analysis adjusted for age, waist circumference, and body mass index showed that testosterone levels were negatively associated with fasting insulin in male patients (β = -0.21, t = -2.2, p = 0.03). Our findings confirm the abnormalities in glucose metabolism parameters and gonadal hormones at the onset of the illness in male DNFES patients with SCZ. In addition, there was an interaction effect between abnormal glucose metabolism and sex hormones in male patients.

Quality of life and survivorship in patients with low-grade ovarian cancer

ObjectiveHigh-grade (HGOC) and low-grade ovarian carcinoma (LGOC) are distinct malignancies with different biological features, treatment paradigms, and life expectancies. However, differences in quality of life (QOL), sleep, and depressive symptoms have not been examined by grade, and neither have inflammatory profiles associated with these symptoms. We aim to characterize QOL and biomarkers by OC grade. MethodsParticipants included patients with HGOC (N = 578) or LGOC (N = 85). Participants completed baseline assessments of psychosocial factors prior to primary surgery or neoadjuvant chemotherapy and contributed saliva for cortisol and blood for interleukin-6 (IL-6) quantification. Samples were collected intraoperatively to quantify tumor cortisol. General linear models were used to examine differences in biological and psychological variables by grade. ResultsAt baseline, patients with LGOC reported less depression (p = 0.018) and sleep disturbances (p = 0.014), but no significant difference in depressive mood (p = 0.11) or QOL (p = 0.51) compared to patients with HGOC, adjusting for age and disease stage. There were trends towards lower tumor cortisol levels (p = 0.078) in LGOC compared to HGOC. One-year post-diagnosis, we found a significant improvement in QOL and fatigue, and a decrease in vegetative depression and IL-6 levels irrespective of grade. ConclusionsWe present the first characterization of psychosocial experiences of patients with LGOC. Despite having a better disease prognosis, patients with LGOC were just as likely to have mood disturbances as those with HGOC. There was a trend towards differences in tumor cortisol by grade. Our findings highlight the need to address well-being in patients with both low- and high-grade ovarian malignancies.

A microglia-containing cerebral organoid model to study early life immune challenges.

Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated and mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-γ induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-γ) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.

External morphology and growth patterns of larvae and juveniles of Bryconops gracilis (Characiformes, Iguanodectidae) from Amazon basin

During early development, fishes undergo significant changes that influence external morphology and the functioning of internal organs and systems. This often results in gradual variation of the morphological traits of individuals across developmental stages. The investigation of larval and juvenile fish development and growth patterns has pertinent implications for the systematic and ecological elucidation of species. Bryconops gracilis is a medium-sized fish, omnivorous that inhabits lotic and lentic environments with acidic and transparent waters in the Amazon basin. In this study, the early development of B. gracilis is described, until recently a practically unknown species. In terms of development, we used morphological, meristic, and morphometric data to characterize the larvae and juveniles. The individuals were collected in the Curuá-Una River, Amazon basin, Brazil. Fifty-four specimens were examined. Samples include individuals with 3.39 to 21.79mm SL. Yolk-sac larvae have two attachment organs on the dorsal surface of head and body. The larvae of B. gracilis are considered altricial, with a fusiform body, and the intestine reaches the median region of the body. Initially, the mouth is subterminal and becomes isognathic from the postflexion stage on. During the postflexion stage, the most relevant morphological changes occur (e.g., presence of all fins, mouth position similar to adults, increased body pigmentation), making individuals more specialized to explore new habitats and diets and maximize their chances of survival. Furthermore, vertebrae and myomeres are compared and assist with differentiating some Bryconops species at early life stages that occur in sympatry in the Amazon basin. Our results contribute to knowledge about the external morphology of neotropical freshwater fishes, enabling the identification of larvae and juveniles through traditional taxonomy and broadening the perspective on the ontogenetic study of the adipose fin in Characoidei.

HIV Outcomes Among Women Living With HIV Who Experienced Early Sexual Violence Across Four Sub-Saharan African Countries.

Early experiences of sexual violence may influence HIV care and treatment outcomes among women living with HIV (WLHIV). We examined whether self-report by WLHIV of being forced into their first sexual experience was associated with awareness of HIV-positive status, being on antiretroviral therapy (ART) and being virologically suppressed. We conducted a secondary analysis using nationally representative, cross-sectional Population-based HIV Impact Assessment surveys from Lesotho, Malawi, Zambia, and Zimbabwe conducted from 2015 through 2017. Adjusted logistic regression models with survey weights and Taylor series linearization were used to measure the association between forced first sex and 3 HIV outcomes: (1) knowledge of HIV status among all WLHIV, (2) being on ART among WLHIV with known status, and (3) virological suppression among WLHIV on ART. Among WLHIV, 13.9% reported forced first sex. Odds of knowledge of HIV status were not different for WLHIV with forced first sex compared with those without (adjusted odds ratio [aOR], 1.17; 95% CI: 0.95 to 1.45). Women living with HIV with forced first sex had significantly lower odds of being on ART (aOR 0.74, 95% CI: 0.57 to 0.96) but did not have lower odds of virological suppression (aOR 1.06, 95% CI: 0.80 to 1.42) compared with WLHIV without forced first sex. While high proportions of WLHIV were on ART, report of nonconsensual first sex was associated with a lower likelihood of being on ART which may suggest that early life trauma could influence long-term health outcomes.