scholarly journals Developmental programming of the HPA axis and related behaviours: epigenetic mechanisms

2019 ◽  
Vol 242 (1) ◽  
pp. T69-T79 ◽  
Author(s):  
Stephen G Matthews ◽  
Patrick O McGowan
Keyword(s):  
Hpa Axis ◽  
Developmental Programming ◽  
Epigenetic Mechanisms ◽  
Biological Mechanisms ◽  
Juvenile Period ◽  
Early Environment ◽  
Gene Regulatory ◽  
Poor Outcomes ◽  
Hpa Function

It has been approximately 30 years since the seminal discoveries of David Barker and his colleagues, and research is beginning to unravel the mechanisms that underlie developmental programming. The early environment of the embryo, foetus and newborn have been clearly linked to altered hypothalamic–pituitary–adrenal (HPA) function and related behaviours through the juvenile period and into adulthood. A number of recent studies have shown that these effects can pass across multiple generations. The HPA axis is highly responsive to the environment, impacts both central and peripheral systems and is critical to health in a wide variety of contexts. Mechanistic studies in animals are linking early exposures to adversity with changes in gene regulatory mechanisms, including modifications of DNA methylation and altered levels of miRNA. Similar associations are emerging from recent human studies. These findings suggest that epigenetic mechanisms represent a fundamental link between adverse early environments and developmental programming of later disease. The underlying biological mechanisms that connect the perinatal environment with modified long-term health outcomes represent an intensive area of research. Indeed, opportunities for early interventions must identify the relevant environmental factors and their molecular targets. This new knowledge will likely assist in the identification of individuals who are at risk of developing poor outcomes and for whom early intervention is most effective.

scholarly journals Cytokine-Laden Extracellular Vesicles Predict Patient Prognosis after Cerebrovascular Accident

2021 ◽  
Vol 22 (15) ◽  
pp. 7847
Author(s):  
Anthony Fringuello ◽  
Philip D. Tatman ◽  
Tadeusz Wroblewski ◽  
John A. Thompson ◽  
Xiaoli Yu ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Inflammatory Cytokines ◽  
Hemorrhagic Stroke ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Interleukin 7 ◽  
Poor Outcomes ◽  
Patient Prognosis ◽  
The Brain

Background: A major contributor to disability after hemorrhagic stroke is secondary brain damage induced by the inflammatory response. Following stroke, global increases in numerous cytokines—many associated with worse outcomes—occur within the brain, cerebrospinal fluid, and peripheral blood. Extracellular vesicles (EVs) may traffic inflammatory cytokines from damaged tissue within the brain, as well as peripheral sources, across the blood–brain barrier, and they may be a critical component of post-stroke neuroinflammatory signaling. Methods: We performed a comprehensive analysis of cytokine concentrations bound to plasma EV surfaces and/or sequestered within the vesicles themselves. These concentrations were correlated to patient acute neurological condition by the Glasgow Coma Scale (GCS) and to chronic, long-term outcome via the Glasgow Outcome Scale-Extended (GOS-E). Results: Pro-inflammatory cytokines detected from plasma EVs were correlated to worse outcomes in hemorrhagic stroke patients. Anti-inflammatory cytokines detected within EVs were still correlated to poor outcomes despite their putative neuroprotective properties. Inflammatory cytokines macrophage-derived chemokine (MDC/CCL2), colony stimulating factor 1 (CSF1), interleukin 7 (IL7), and monokine induced by gamma interferon (MIG/CXCL9) were significantly correlated to both negative GCS and GOS-E when bound to plasma EV membranes. Conclusions: These findings correlate plasma-derived EV cytokine content with detrimental outcomes after stroke, highlighting the potential for EVs to provide cytokines with a means of long-range delivery of inflammatory signals that perpetuate neuroinflammation after stroke, thus hindering recovery.

Long-term basal and dynamic evaluation of hypothalamic-pituitary-adrenal (HPA) axis in acromegalic patients

2008 ◽  
Vol 69 (4) ◽  
pp. 608-612 ◽  
Author(s):  
C. L. Ronchi ◽  
E. Ferrante ◽  
E. Rizzo ◽  
C. Giavoli ◽  
E. Verrua ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Hypothalamic Pituitary Adrenal ◽  
Dynamic Evaluation

scholarly journals Shaping long-term primate development: Telomere length trajectory as an indicator of early maternal maltreatment and predictor of future physiologic regulation

2017 ◽  
Vol 29 (5) ◽  
pp. 1539-1551 ◽  
Author(s):  
Stacy S. Drury ◽  
Brittany R. Howell ◽  
Christopher Jones ◽  
Kyle Esteves ◽  
Elyse Morin ◽  
...  
Keyword(s):  
Telomere Length ◽  
Nonhuman Primate ◽  
Social Rank ◽  
Juvenile Period ◽  
Primate Model ◽  
Causal Pathways ◽  
Biological Mother ◽  
Physiologic Regulation ◽  
Negative Health Outcomes

AbstractThe molecular, neurobiological, and physical health impacts of child maltreatment are well established, yet mechanistic pathways remain inadequately defined. Telomere length (TL) decline is an emerging molecular indicator of stress exposure with definitive links to negative health outcomes in maltreated individuals. The multiple confounders endemic to human maltreatment research impede the identification of causal pathways. This study leverages a unique randomized, cross-foster, study design in a naturalistic translational nonhuman primate model of infant maltreatment. At birth, newborn macaques were randomly assigned to either a maltreating or a competent control mother, balancing for sex, biological mother parenting history, and social rank. Offspring TL was measured longitudinally across the first 6 months of life (infancy) from peripheral blood. Hair cortisol accumulation was also determined at 6, 12, and 18 months of age. TL decline was greater in animals randomized to maltreatment, but also interacted with biological mother group. Shorter TL at 6 months was associated with higher mean cortisol levels through 18 months (juvenile period) when controlling for relevant covariates. These results suggest that even under the equivalent social, nutritional, and environmental conditions feasible in naturalistic translational nonhuman primate models, early adverse caregiving results in lasting molecular scars that foreshadow elevated health risk and physiologic dysregulation.

Abstract T P231: Does Intraventricular Hemorrhage Lead to a Normal Pressure Hydrocephalus-Like Syndrome?

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Andrew J Kruger ◽  
Matthew Flaherty ◽  
Padmini Sekar ◽  
Mary Haverbusch ◽  
Charles J Moomaw ◽  
...  
Keyword(s):  
Risk Factors ◽  
Normal Pressure Hydrocephalus ◽  
Barthel Index ◽  
Intraventricular Hemorrhage ◽  
Normal Pressure ◽  
Stroke Study ◽  
Increased Risk ◽  
Independent Risk Factors ◽  
Poor Outcomes

Background: Intracerebral hemorrhage (ICH) has the highest short and long-term morbidity and mortality rates of stroke subtypes. While increased intracranial pressure due to the presence of intraventricular hemorrhage (IVH) may relate to early poor outcomes, the mechanism of reduced 3-month outcome with IVH is unclear. We hypothesized that IVH may cause symptoms similar to normal pressure hydrocephalus (NPH), specifically urinary incontinence and gait disturbance. Methods: We used interviewed cases from the Genetic and Environmental Risk Factors for Hemorrhagic Stroke Study (7/1/08-12/31/12) that had 3-month follow-ups available. CT images were analyzed for ICH volume and location, and IVH presence and volume. Incontinence and dysmobility were defined by Barthel Index at 3 months. We chose a Barthel Index score of bladder less than 10 and mobility less than 15 to define incontinence and dysmobility, respectively. Multivariate analysis was used to assess independent risk factors for incontinence and dysmobility. ICH and IVH volumes were log transformed because of non-normal distributions. Results: Barthel Index was recorded for 308 ICH subjects, of whom 106 (34.4%) had IVH. Presence of IVH was independently associated with both incontinence (OR 2.7; 95% CI 1.4-5.2; p=.003) and dysmobility (OR 2.5; 95% CI 1.4-4.8; p=.003). The Table shows that increasing IVH volume was also independently associated with both incontinence and dysmobility after controlling for ICH location, ICH volume, age, baseline mRS, and admission GCS. Conclusion: Our data show that patients with IVH after ICH are at an increased risk for developing the NPH-like symptoms of incontinence and dysmobility. This may explain the worse long-term outcomes of patients who survive ICH with IVH than those who had ICH alone. Future studies are needed to confirm this finding, and to determine the effect of IVH interventions such as shunt or intraventricular thrombolysis.

scholarly journals Changes in prolactin secretion in the short- and long-term after adrenalectomy

2012 ◽  
Vol 56 (4) ◽  
pp. 244-249 ◽  
Author(s):  
Maria Thereza C. Laguna-Abreu ◽  
Carla Germano ◽  
Ayrton C. Moreira ◽  
José Antunes-Rodrigues ◽  
Lucila Elias ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Plasma Corticosterone ◽  
Prolactin Secretion ◽  
Plasma Prolactin ◽  
Peptidergic Neurons ◽  
Prolactin Release ◽  
Short And Long Term ◽  
Hypothalamus Pituitary Adrenal Axis ◽  
Pituitary Adrenal Axis

OBJECTIVE: To evaluate the modulation of the hypothalamus-pituitary-adrenal axis (HPA) on prolactin secretion in rats after adrenalectomy (ADX). MATERIALS AND METHODS: Plasma corticosterone, ACTH, and prolactin concentrations were measured by radioimmunoassay in rats after bilateral ADX in the short- (3 hours and 1day) and long-term (3, 7, and 14 days). RESULTS: Animals that underwent ADX showed undetectable corticosterone levels and a triphasic ACTH response with a transient increase (3h), a decrease (1d), and further increase in the long-term after ADX. Sham animals showed a marked increase in corticosterone and ACTH levels three hours after surgery, with a decrease to basal levels thereafter. Plasma prolactin levels were not changed after ADX. CONCLUSION: There are different points of equilibrium in the HPA axis after the glucocorticoid negative feedback is removed. Prolactin plasma secretion is not altered in the short or long- term after ADX, suggesting that the peptidergic neurons essential for prolactin release are not activated after ADX.

scholarly journals Long-term outcomes of pediatric arteriovenous malformations: the 30-year Pittsburgh experience

2020 ◽  
Vol 26 (3) ◽  
pp. 275-282
Author(s):  
Michael M. McDowell ◽  
Nitin Agarwal ◽  
Gordon Mao ◽  
Stephen Johnson ◽  
Hideyuki Kano ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Arteriovenous Malformations ◽  
Multimodality Treatment ◽  
Treatment Choice ◽  
University Of Pittsburgh ◽  
Poor Outcome ◽  
Poor Outcomes ◽  
The University

OBJECTIVEThe study of pediatric arteriovenous malformations (pAVMs) is complicated by the rarity of the entity. Treatment choice has often been affected by the availability of different modalities and the experience of the providers present. The University of Pittsburgh experience of multimodality treatment of pAVMs is presented.METHODSThe authors conducted a retrospective cohort study examining 212 patients with pAVM presenting to the University of Pittsburgh between 1988 and 2018, during which patients had access to surgical, endovascular, and radiosurgical options. Univariate analysis was performed comparing good and poor outcomes. A poor outcome was defined as a modified Rankin Scale (mRS) score of ≥ 3. Multivariate analysis via logistic regression was performed on appropriate variables with a p value of ≤ 0.2. Seventy-five percent of the cohort had at least 3 years of follow-up.RESULTSFive patients (2.4%) did not receive any intervention, 131 (61.8%) had GKRS alone, 14 (6.6%) had craniotomies alone, and 2 (0.9%) had embolization alone. Twenty-two (10.4%) had embolization and Gamma Knife radiosurgery (GKRS); 20 (9.4%) had craniotomies and GKRS; 8 (3.8%) had embolization and craniotomies; and 10 (4.7%) had embolization, craniotomies, and GKRS. Thirty-one patients (14.6%) were found to have poor outcome on follow-up. The multivariate analysis performed in patients with poor outcomes was notable for associations with no treatment (OR 18.9, p = 0.02), hemorrhage requiring craniotomy for decompression alone (OR 6, p = 0.03), preoperative mRS score (OR 2.1, p = 0.004), and Spetzler-Martin score (OR 1.8, p = 0.0005). The mean follow-up was 79.7 ± 62.1 months. The confirmed radiographic obliteration rate was 79.4% and there were 5 recurrences found on average 9.5 years after treatment.CONCLUSIONSHigh rates of long-term functional independence (mRS score of ≤ 2) can be achieved with comprehensive multimodality treatment of pAVMs. At this center there was no difference in outcome based on treatment choice when accounting for factors such as Spetzler-Martin grade and presenting morbidity. Recurrences are rare but frequently occur years after treatment, emphasizing the need for long-term screening after obliteration.

scholarly journals Nutrition support in critically ill COVID-19 patients

2020 ◽  
Vol 4 (1-3) ◽  
pp. 8
Author(s):  
Abdolreza Norouzy
Keyword(s):  
Older Adults ◽  
At Risk ◽  
Critically Ill ◽  
Diagnosis And Treatment ◽  
Nutrition Support ◽  
Patients At Risk ◽  
Short And Long Term ◽  
Long Term Prognosis ◽  
Poor Outcomes

Diagnosis and treatment of malnutrition should be considered in the management of COVID-19 patients to improve both short- and long-term prognosis. Patients at risk for poor outcomes and higher mortality following infection with COVID-19, namely older adults and polymorbid individuals, should be checked for malnutrition through screening and assessment.

scholarly journals SUN-207 Modelling Long Term Glucocorticoid-Induced HPA Axis Suppression in Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Nicola Romano ◽  
Peter James Duncan ◽  
Oscar Nolan ◽  
Paul Roussel Le Tissier ◽  
Mike Shipston ◽  
...  
Keyword(s):  
Drinking Water ◽  
Mouse Model ◽  
Hpa Axis ◽  
Adult Male ◽  
Male Mice ◽  
Dexamethasone Treatment ◽  
Mortality And Morbidity ◽  
Fold Reduction ◽  
The Uk

Abstract Glucocorticoids are prescribed for >3 months to 1% of the UK population. 10-50% of these long-term glucocorticoid treated patients develop persistent HPA axis suppression associated with mortality and morbidity. We have developed a mouse model of glucocorticoid-induced HPA axis dysfunction to determine the mechanisms resulting in persistent HPA axis suppression. Experiment 1: 36 C57BL/6 adult male mice received Dexamethasone (DEX,~10µg/day) or vehicle (CTL) via drinking water for 28 days, following which treatment was stopped and tissues were harvested at 0, 7 and 28 days. DEX suppressed waking serum corticosterone at days 0 and 7, recovering by day 28. Adrenal size remained lower 28 days following DEX withdrawal. DEX had no effect on whole pituitary pomc, nr3c1 or crhr1 expression, although avpr1b was increased at day 0. In the adrenal, hsd3b2 and cyp11a1 expression were reduced at time 0; normalising by 28 days. Experiment 2: 24 POMC-GFP male mice were treated as above. Tissues were collected at day 0 (n=6), 7 (n=3) and 10 (n=3) following withdrawal. Pooled corticotrophs (groups of 3) were isolated by FACS and RNA extracted for qPCR. DEX reduced corticotroph pomc expression at time 0 (x20 fold reduction), with x5 fold suppression at day 7, which recovered with evidence of compensation by day 10. DEX increased expression of avpr1b but not crhr1. CONCLUSION: 28 days dexamethasone treatment in mice suppresses the HPA axis. HPA suppression is evident 7 days following withdrawal of dexamethasone in the adrenal, corticotroph population and corticosterone production. Further analysis will determine mechanisms for delays in HPA axis recovery.

Abstract 3490: Perfusion Defect Is Associated With Poor Prognosis Of Lacunar Infarction.

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Jeong Jin Park ◽  
Na-Young Ryoo ◽  
Joung-Ho Rha ◽  
Hee-Kwon Park
Keyword(s):  
Regression Analysis ◽  
Propensity Score ◽  
Perfusion Defect ◽  
Poor Prognosis ◽  
Small Vessel Disease ◽  
Clinical Status ◽  
Current Smoker ◽  
Parent Artery ◽  
Poor Outcomes

Backgrounds: Small subcortical infarctions are caused by lipohyalinosis and also by microatheroma and microembolism. However, it remained still unknown which clinical or radiological findings could be useful for prediction of long-term prognosis. We sought to find whether perfusion images are associated with long-term poor clinical status. Methods: We reviewed 197 patients who admitted from January, 2009 to January, 2011, and who had the lacunae(≤20mm) in the perforator territory of the middle cerebral artery on diffusion-weight MRI(DWI) within 3 days of onset. T2 weighted imaging and perfusion-weighted MRI(PWI) were evaluated in all participants. We divided the patients according to the existence of perfusion defect and analyzed the association between perfusion defect and poor outcomes, defined as modified Rankin score(mRS)≥3 at 3 months Results: Among a total 197 patients(69 Men; 63.8±11.2y), 78 subjects(52 Men; 62.4±12.1y) had the perfusion defect on PWI. The subject with perfusion defect had the higher frequency of current smoker(P=0.03) and poor outcomes at 3 months (P=0.002), compared to those without. There was no difference in other risk factors, infarct size or parent artery stenosis between two groups. Multivariate binary regression analysis showed that the perfusion defect was strongly associated with poor outcomes at 3 months(P=0.002;adjusted OR 4.21; adjusted 95% CI,1.73-10.28). The propensity score regression analysis also indicated that perfusion defect could predict the poor prognosis(Propensity score adjusted OR,3.88). Conclusion: Perfusion defect of small vessel disease seems to have the influence on the recovery after lacunae. Further study may be needed to find whether the PWI can be useful for diagnosing the various etiology of lacunae.

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