Evaluating the Impact of the Prime Time Sister Circles® Intervention on Reducing Depressive Symptoms Among African American Women with Uncontrolled Hypertension.

BACKGROUND: The Prime Time Sister Circles®, a randomized controlled trial (PTSC-RCT), assessed the impact of a community-based peer support program on hypertension management among African American women 40-75 years of age. While the PTSC-RCT was designed to evaluate changes in blood pressure control, subsequent sub-analyses revealed a high proportion of self-reported depressive symptoms in our sample. Accordingly, we conducted an ancillary investigation of the PTSC intervention on depression to ascertain its impact on reduced depressive symptoms in the study population. METHOD: Depressive symptoms were measured using an adapted version of the Center for Epidemiologic Studies Depression Scale Revised (CES-D-10). We used unadjusted and adjusted fixed effect models. Data for this study came from the PTSC-RCT. We collected data between 2017 and 2018 in Washington, DC. We used a balanced analytical sample of 172 African American, English-speaking women between 40 to 75 years old with uncontrolled hypertension. INTERVENTION: The intervention group participated in a 2-h, peer-based support group once a week for 13 weeks. A trained PTSC facilitator facilitated sessions with experts who delivered content on various topics, including psychosocial wellness (e.g., stress, depressive symptoms, anxiety management, and self-esteem), physical health (e.g., hypertension, inflammation, and heart disease), physical activity, and healthy nutrition. RESULTS: Results from the fixed-effects models indicated that participants in the PTSC program exhibited a greater reduction in CES-D-10 score at three months (Coeff: -1.99, 95% CI: -3.49, -0.49) and at 15 months (Coeff: -2.38, 95% CI: -3.94, -0.83), as compared to those in the control group. CONCLUSIONS: Evidence suggests that the Prime Time Sister Circles® intervention reduced depressive symptoms among African American women with low socioeconomic status and hypertension. TRIAL REGISTRATION: NCT04371614.

Child Mental Health Status in Flint, Michigan: A Worsening Health Inequity, 2018-2022.

Objectives. To determine the burden of mental health disorders among children enrolled in Michigan's Flint Registry in the context of a local public health crisis and a nationally declared pediatric mental health crisis. Methods. This survey-based study included 1203 children aged 3 to 17 years whose caregivers enrolled them in the Flint Registry between December 2018 and March 2020 and who completed a follow-up survey between October 2020 and March 2022. The baseline and follow-up surveys included caregiver reports of childhood anxiety and depression and overall mental health wellness. Results. At enrollment, Flint Registry caregivers reported significantly higher rates of anxiety and depression among their children than caregivers reported nationally (12.9% vs 9.4% and 8.2% vs 4.4%; P < .001). Flint Registry caregivers also reported declines in their children's overall mental health wellness at follow-up, t(1472) = -4.17; P < .001. Conclusions. Our findings reveal a disparate burden of pediatric mental health disorders and exemplify the health inequities vulnerable populations face. Public Health Implications. More proactive and preventive steps should be taken to lessen this burden, especially in chronically disadvantaged communities that experience public health crises. (Am J Public Health. 2023;113(12):1318-1321. https://doi.org/10.2105/AJPH.2023.307406).

Adapting Brief Behavioral Treatment for Insomnia for Former National Football League Players: A Pilot Study.

OBJECTIVES: Insomnia is highly prevalent among persons with chronic pain. Although cognitive behavioral therapy for insomnia is recommended as first-line treatment for insomnia, it is underutilized. We tested the feasibility of a potentially scalable alternative - Brief Behavioral Therapy for Insomnia (BBTI) for former National Football League (NFL) players, a group with a high prevalence of chronic pain. We assessed changes in sleep, pain, and psychological health. METHODS: Single-arm clinical trial of an adapted telephone-delivered BBTI intervention in 40 former NFL players with insomnia. We collected data on changes in sleep, pain, and psychological health outcomes. RESULTS: Among former players (30% racial/ethnic minorities), BBTI was both acceptable and feasible. BBTI was associated with improvements in sleep disturbance (primary exploratory sleep outcome, mean T-score change -6.2, 95% CI: -7.6, -4.8), sleep-related impairment (mean T-score change -5.7, 95% CI: -7.9, -3.5) and insomnia severity (mean change -5.3, 95% CI: -6.8, -3.5) post-intervention. Improvements were maintained at 2-months. BBTI was also associated with improvements in pain interference and intensity, but not psychological health. CONCLUSION: An adapted telephone-delivered BBTI is acceptable and feasible among retired players with a range of insomnia symptoms and shows promise for improving sleep and pain. These data support the need for future trials assessing BBTI's effect on both sleep and pain outcomes.

A Multidisciplinary Approach to Increase Compliance With Spontaneous Awakening Trials and Spontaneous Breathing Trials in the Medical Intensive Care Unit.

Prolonged mechanical ventilation can lead to undesirable outcomes, including reduced 6-month survival, increased hospital mortality, intensive care unit (ICU) length of stay, and physiological stress. A large academic medical center currently has a Spontaneous Awakening Trials/Spontaneous Breathing Trials (SAT/SBT) protocol with an SAT/SBT compliance goal of 80%; however, the medical intensive care unit's (MICU) SAT/SBT compliance rate was only 33% for FY2020. The Define-Measure-Analyze-Improve-Control (DMAIC) framework was used to guide this quality improvement project. Current processes and root causes for noncompliance were analyzed through chart reviews, a preimplementation staff survey, and meetings with stakeholders. Compliance rates were compared before and after implementation. Interventions included education, reminder fliers, weekly chart audits, and individualized weekly emails to noncompliant RNs and RTs. To achieve project sustainability, 2 unit champions were selected to continue the weekly emails and chart audits. Data were collected from 216 patients and 1063 patient ventilator days from October 2020 to October 2021. The SAT/SBT compliance steadily increased throughout the 13-month implementation period, except for 3 months. The preimplementation monthly SAT/SBT compliance rate was 26% in September 2020. After 13 months of project implementation, the SAT/SBT compliance rate was 64% in October 2021. There was no significant change in patient ventilator days pre- and post-quality improvement project. A multi-intervention implementation strategy consisting of education in-services, weekly chart audits, weekly emails to staff with current compliance rates, and reminder fliers can successfully increase SAT/SBT compliance rates. Utilizing unit champions provides sustainability.

Cortactin loss protects against hemin-induced acute lung injury in sickle cell disease.

In patients with sickle cell disease (SCD), acute chest syndrome (ACS) is a common form of acute lung injury and a major cause of morbidity and mortality. The pathophysiology of ACS is complex, and hemin, the prosthetic moiety of hemoglobin, has been implicated in endothelial cell (EC) activation and subsequent acute lung injury (ALI) and ACS in vitro and in animal studies. Here, we examined the role of cortactin (CTTN), a cytoskeletal protein that regulates EC function, in response to hemin-induced ALI and ACS. Cortactin heterozygous (Cttn+/-) mice (n = 8) and their wild-type siblings (n = 8) were irradiated and subsequently received bone marrow cells (BMCs) extruded from the femurs of SCD mice (SS) to generate SS Cttn+/- and SS CttnWT chimeras. Following hemoglobin electrophoretic proof of BMC transplantation, the mice received 35 µmol/kg of hemin. Within 24 h, surviving mice were euthanized, and bronchoalveolar fluid (BAL) and lung samples were analyzed. For in vitro studies, human lung microvascular endothelial cells (HLMVECs) were used to determine hemin-induced changes in gene expression and reactive oxygen species (ROS) generation in cortactin deficiency and control conditions. When compared with wild-type littermates, the mortality for SS Cttn+/- mice trended to be lower after hemin infusion and these mice exhibited less severe lung injury and less necroptotic cell death. In vitro studies confirmed that cortactin deficiency is protective against hemin-induced injury in HMLVECs, by decreasing protein expression of p38/HSP27, improving cell barrier function, and decreasing the production of ROS. Further studies examining the role of CTTN in ACS are warranted and may open a new avenue of potential treatment for this devastating disease.

Parent report of child behaviour: Findings from the Flint Registry cohort.

BACKGROUND: Children in Flint, Michigan, have multiple risk factors for behavioural challenges, including exposure to lead during the Flint water crisis. However, their behavioural health status is largely unknown. Robust data from the Flint Registry can help understand the burden of behavioural outcomes and inform the allocation of resources. OBJECTIVES: This population-level evaluation of Flint children's behavioural outcomes aims to answer the question: What is the burden of parent-reported child behaviour problems in Flint Registry enrolled children? METHODS: This cross-sectional study describes parent-reported behavioural outcomes of children 2-17 years old who enrolled in the Flint Registry between December 2018 and December 2020. Parents/guardians completed behavioural assessments including the Behavior Assessment System for Children (BASC-3) Parent Rating Scale and Behavior Rating Inventory of Executive Function (BRIEF2) Screening Parent Form. Demographics of enrolees were compared with census data. Composite BASC-3 T scores were compared with national norms. Distributions for clinically relevant categories of BASC-3 and BRIEF2 scores were examined across age and sex groups. RESULTS: Of the 3579 children included in this study (mean age 9.73 ± 3.96 years), about half were female and 79.7% were eligible for free or reduced-price lunch. Almost half of the children were reported to have clinically concerning scores on the BASC-3 Parent Rating Scale (44.7%) and the BRIEF2 Screening Parent Form (46.7%). Across most age and sex groupings, the reported adaptive skills were relatively low and behaviour symptoms relatively high. CONCLUSIONS: Results reveal a substantial burden of parent-reported behavioural problems in Flint Registry children. This is clinically significant and indicates that a large number of children may require comprehensive neuropsychological evaluation and potential medical and/or educational services. Recognising the potential for long-term manifestations of childhood exposures to environmental hazards, longitudinal surveillance is critical to continue to identify and support participants.

Tamoxifen offers long-term neuroprotection after hippocampal silent infarct in male rats.

Silent infarcts (SI) are a cerebral small vessel disease characterized by small subcortical infarcts. These occur in the absence of typical ischemia symptoms but are linked to cognitive decline and dementia. While there are no approved treatments for SI, recent results from our laboratory suggest that tamoxifen, a selective estrogen receptor modulator, is a viable candidate. In the present study, we induced SI in the dorsal hippocampal CA1 region of rats and assessed the effects of systemic administration of tamoxifen (5 mg/kg, twice) 21 days after injury on cognitive and pathophysiological measures, including cell loss, apoptosis, gliosis and estrogen receptors (ERs). We found that tamoxifen protected against the SI-induced cognitive dysfunction on the hippocampal-dependent, place recognition task, cell and ER loss, and increased apoptosis and gliosis in the CA1. Exploratory data analyses using a scatterplot matrix and principal component analysis indicated that SI-tamoxifen rats were indistinguishable from sham controls while they differed from SI rats, who were characterized by enhanced cell loss, apoptosis and gliosis, lower ERs, and recognition memory deficit. Supervised machine learning using support vector machine (SVM) determined predictors of progression from the early ischemic state to the dementia-like state. It showed that caspase-3 and ERα in the CA1 and exploration proportion were reliable and accurate predictors of this progression. Importantly, tamoxifen ameliorated SI-induced effects on all three of these variables, providing further evidence for its viability as a candidate treatment for SI and prevention of associated dementia.

The selective estrogen receptor modulator tamoxifen protects against subtle cognitive decline and early markers of injury 24 h after hippocampal silent infarct in male Sprague-Dawley rats.

Silent infarcts (SI) are subcortical cerebral infarcts occurring in the absence of typical ischemia symptoms and are linked to cognitive decline and dementia development. There are no approved treatments for SI. One potential treatment is tamoxifen, a selective estrogen receptor modulator. It is critical to establish whether treatments effectively target the early consequences of SI to avoid progression to complete injury. We induced SI in the dorsal hippocampal CA1 of rats and assessed whether tamoxifen is protective 24 h later against cognitive deficits and injury responses including gliosis, apoptosis, inflammation and changes in estrogen receptors (ERs). SI led to subtle cognitive impairment on the object place task, an effect ameliorated by tamoxifen administration. SI did not lead to detectable hippocampal cell loss but increased apoptosis, astrogliosis, microgliosis and inflammation. Tamoxifen protected against the effects of SI on all measures except microgliosis. SI increased ERα and decreased ERß in the hippocampus, which were mitigated by tamoxifen. Exploratory data analyses using scatterplot matrices and principal component analysis indicated that SI rats given tamoxifen were indistinguishable from controls. Further, SI rats were significantly different from all other groups, an effect associated with low levels of ERα and increased apoptosis, gliosis, inflammation, ERß, and time spent with the unmoved object. The results demonstrate that tamoxifen is protective against the early cellular and cognitive consequences of hippocampal SI 24 h after injury. Tamoxifen mitigates apoptosis, gliosis, and inflammation and normalization of ER levels in the CA1, leading to improved cognitive outcomes after hippocampal SI.

Discovery of neuroprotective agents that inhibit human prolyl hydroxylase PHD2.

Prolyl hydroxylase (PHD) enzymes play a critical role in the cellular responses to hypoxia through their regulation of the hypoxia inducible factor α (HIF-α) transcription factors. PHD inhibitors show promise for the treatment of diseases including anaemia, cardiovascular disease and stroke. In this work, a pharmacophore-based virtual high throughput screen was used to identify novel potential inhibitors of human PHD2. Two moderately potent new inhibitors were discovered, with IC50 values of 4 µM and 23 µM respectively. Cell-based studies demonstrate that these compounds exhibit protective activity in neuroblastoma cells, suggesting that they have the potential to be developed into clinically useful neuroprotective agents.

The Flint Water Crisis: A Coordinated Public Health Emergency Response and Recovery Initiative.

CONTEXT: The City of Flint was already distressed because of decades of financial decline when an estimated 140 000 individuals were exposed to lead and other contaminants in drinking water. In April 2014, Flint's drinking water source was changed from Great Lakes' Lake Huron (which was provided by the Detroit Water and Sewerage Department) to the Flint River without necessary corrosion control treatment to prevent lead release from pipes and plumbing. Lead exposure can damage children's brains and nervous systems, lead to slow growth and development, and result in learning, behavior, hearing, and speech problems. After the involvement of concerned residents and independent researchers, Flint was reconnected to the Detroit water system on October 16, 2015. A federal emergency was declared in January 2016. PROGRAM: The Centers for Disease Control and Prevention provided assistance and support for response and recovery efforts including coordinating effective health messaging; assessing lead exposure; providing guidance on blood lead screening protocols; and identifying and linking community members to appropriate follow-up services.In response to the crisis in Flint, Congress funded the Centers for Disease Control and Prevention to establish a federal advisory committee; enhance Childhood Lead Poisoning Prevention Program activities; and support a voluntary Flint lead exposure registry. The registry, funded through a grant to Michigan State University, is designed to identify eligible participants and ensure robust registry data; monitor health, child development, service utilization, and ongoing lead exposure; improve service delivery to lead-exposed individuals; and coordinate with other community and federally funded programs in Flint. The registry is also collaborating to make Flint "lead-free" and to share best practices with other communities. DISCUSSION: The Flint water crisis highlights the need for improved risk communication strategies, and environmental health infrastructure, enhanced surveillance, and primary prevention to identify and respond to environmental threats to the public's health. Collecting data is important to facilitate action and decision making to prevent lead poisoning. Partnerships can help guide innovative strategies for primary lead prevention, raise awareness, extend outreach and communication efforts, and promote a shared sense of ownership.

Effects of umbilical cord blood cells, and subtypes, to reduce neuroinflammation following perinatal hypoxic-ischemic brain injury.

BACKGROUND: It is well understood that hypoxic-ischemic (HI) brain injury during the highly vulnerable perinatal period can lead to cerebral palsy, the most prevalent cause of chronic disability in children. Recently, human clinical trials have reported safety and some efficacy following treatment of cerebral palsy using umbilical cord blood (UCB) cells. UCB is made up of many different cell types, including endothelial progenitor cells (EPCs), T regulatory cells (Tregs), and monocyte-derived suppressor cells (MDSCs). How each cell type contributes individually towards reducing neuroinflammation and/or repairing brain injury is not known. In this study, we examined whether human (h) UCB, or specific UCB cell types, could reduce peripheral and cerebral inflammation, and promote brain repair, when given early after perinatal HI brain injury. METHODS: HI brain injury was induced in postnatal day (PND) 7 rat pups and cells were administered intraperitoneally on PND 8. Behavioral testing was performed 7 days post injury, and then, brains and spleens were collected for analysis. RESULTS: We found in vitro that all UCB cell types, except for EPCs, were immunomodulatory. Perinatal HI brain injury induced significant infiltration of CD4+ T cells into the injured cerebral hemisphere, and this was significantly reduced by all hUCB cell types tested. Compared to HI, UCB, Tregs, and EPCs were able to reduce motor deficits, reduce CD4+ T cell infiltration into the brain, and reduce microglial activation. In addition to the beneficial effects of UCB, EPCs also significantly reduced cortical cell death, returned CD4+ T cell infiltration to sham levels, and reduced the peripheral Th1-mediated pro-inflammatory shift. CONCLUSION: This study highlights that cells found in UCB is able to mediate neuroinflammation and is an effective neuroprotective therapy. Our study also shows that particular cells found in UCB, namely EPCs, may have an added advantage over using UCB alone. This work has the potential to progress towards tailored UCB therapies for the treatment of perinatal brain injury.

Drinking Water Violations and Environmental Justice in the United States, 2011-2015.

OBJECTIVES: To assess the extent to which drinking water violations in the United States differed on the basis of county race/ethnicity and socioeconomic status using the primary county served by the community water system (CWS) as the unit of analysis and to determine whether counties with higher proportions of underrepresented groups were disproportionately burdened with repeat violations. METHODS: We used multivariable logistic regression to calculate odds ratios of contextual environmental justice covariates associated with initial and repeat drinking water violations. We obtained violations from the federal Safe Drinking Water Information System. Results were nonstratified and stratified on the basis of population size served by the CWS. RESULTS: Stratified multivariable logistic regression results revealed previously unobservable patterns in nonstratified findings. Minorities face significant challenges, including exposure to poor water quality. The most notable differences in both initial and repeat violations that we observed were among CWSs that serve large populations. Our most consistent finding was the positive association of initial and repeat violations with the proportion of those who were uninsured, irrespective of stratification. CONCLUSIONS: Greater efforts are needed to ensure that counties with higher proportions of minorities, uninsured households, and low-income households have access to safe drinking water, irrespective of the size of population served by the CWS.

Hemin Causes Lung Microvascular Endothelial Barrier Dysfunction by Necroptotic Cell Death.

Hemin, the oxidized prosthetic moiety of hemoglobin, has been implicated in the pathogenesis of acute chest syndrome in patients with sickle cell disease by virtue of its endothelial-activating properties. In this study, we examined whether hemin can cause lung microvascular endothelial barrier dysfunction. By assessing transendothelial resistance using electrical cell impedance sensing, and by directly measuring trans-monolayer fluorescein isothiocyanate-dextran flux, we found that hemin does cause endothelial barrier dysfunction in a concentration-dependent manner. Pretreatment with either a Toll-like receptor 4 inhibitor, TAK-242, or an antioxidant, N-acetylcysteine, abrogated this effect. Increased monolayer permeability was found to be associated with programmed cell death by necroptosis, as evidenced by Trypan blue staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, Western blotting for activated forms of key effectors of cell death pathways, and studies utilizing specific inhibitors of necroptosis and apoptosis. Further studies examining the role of endothelial cell necroptosis in promoting noncardiogenic pulmonary edema during acute chest syndrome are warranted and may open a new avenue of potential treatments for this devastating disease.

Maternal obesity increases inflammation and exacerbates damage following neonatal hypoxic-ischaemic brain injury in rats.

OBJECTIVE: In humans, maternal obesity is associated with an increase in the incidence of birth related difficulties. However, the impact of maternal obesity on the severity of brain injury in offspring is not known. Recent studies have found evidence of increased glial response and inflammatory mediators in the brains as a result of obesity in humans and rodents. We hypothesised that hypoxic-ischaemic (HI) brain injury is greater in neonatal offspring from obese rat mothers compared to lean controls. METHODS: Female Sprague Dawley rats were randomly allocated to high fat (HFD, n=8) or chow (n=4) diet and mated with lean male rats. On postnatal day 7 (P7), male and female pups were randomly assigned to HI injury or control (C) groups. HI injury was induced by occlusion of the right carotid artery followed by 3h exposure to 8% oxygen, at 37°C. Control pups were removed from the mother for the same duration under ambient conditions. Righting behaviour was measured on day 1 and 7 following HI. The extent of brain injury was quantified in brain sections from P14 pups using cresyl violet staining and the difference in volume between brain hemispheres was measured. RESULTS: Before mating, HFD mothers were 11% heavier than Chow mothers (p<0.05, t-test). Righting reflex was delayed in offspring from HFD-fed mothers compared to the Chow mothers. The Chow-HI pups showed a loss in ipsilateral brain tissue, while the HFD-HI group had significantly greater loss. No significant difference was detected in brain volume between the HFD-C and Chow-C pups. When analysed on a per litter basis, the size of the injury was significantly correlated with maternal weight. Similar observations were made with neuronal staining showing a greater loss of neurons in the brain of offspring from HFD-mothers following HI compared to Chow. Astrocytes appeared to more hypertrophic and a greater number of microglia were present in the injured hemisphere in offspring from mothers on HFD. HI caused an increase in the proportion of amoeboid microglia and exposure to maternal HFD exacerbated this response. In the contralateral hemisphere, offspring exposed to maternal HFD displayed a reduced proportion of ramified microglia. CONCLUSIONS: Our data clearly demonstrate that maternal obesity can exacerbate the severity of brain damage caused by HI in neonatal offspring. Given that previous studies have shown enhanced inflammatory responses in offspring of obese mothers, these factors including gliosis and microglial infiltration are likely to contribute to enhanced brain injury.

Functional Deficits and Aggressive Behaviors in an Inpatient Psychiatric Hospital: Description and Clinical Implications.

The primary goals of compulsory, inpatient, psychiatric treatment are to decrease dangerous behaviors and help improve functioning so that a safe discharge to a less restrictive environment can be obtained. This study examined the aggression rates, levels of functioning, and treatment adherence for persons treated for schizophrenia (N = 506) compared with persons treated for borderline personality disorder (BPD) (N = 98) in an inpatient psychiatric facility. Over half of persons engaged in at least one incident of aggressive behavior during hospitalization. Differences in the types of aggression and functional deficits between these two clinical sub-groups were found. In addition, overall impairment increased the likelihood of aggressive behavior for persons diagnosed with schizophrenia, whereas irritability and social dependence increased the risk of aggression for persons diagnosed with BPD. Treatment interventions that target the improvement of these deficits may help reduce the intensity and severity of aggressive behaviors and help improve functioning and discharge readiness.

Outcomes of congenital diaphragmatic hernia repair on extracorporeal life support.

PURPOSE: Extracorporeal life support (ECLS) is applied to refractory pulmonary hypertension in congenital diaphragmatic hernia (CDH). We evaluate the single-center outcomes of infants with CDH to determine the utility of late repair on ECLS versus repair post-decannulation. METHODS: Records of infants with CDH (2004-2014) were retrospectively reviewed. RESULTS: CDH was diagnosed in 177 infants. Sixty six (37%) underwent ECLS, of which, 11 died prior to repair, 33 were repaired post-decannulation, and 22 were repaired on ECLS. Repair was delayed in patients on ECLS (19 versus 10 days, p < 0.001). Patients repaired on ECLS had longer ECLS runs (22 versus 12 days, p < 0.001) and higher rates of bleeding and mortality than those repaired post-decannulation. Survival was 54% in infants undergoing ECLS, 65% in those who underwent repair, 36% in those repaired during ECLS, and 85% in those who were decannulated prior to repair. Eighteen percent (N = 4) of deaths after repair on ECLS were attributable to surgical bleeding. The remainder was due to pulmonary hypertension or sepsis. CONCLUSION: Infants who underwent CDH repair post-decannulation had excellent outcomes and no mortalities attributable to repair. Neonates who underwent repair on ECLS late on bypass had the lowest survival rate with only 18% of mortality in this cohort attributable to surgical bleeding.

Changes in Hypoxia-Inducible Factor-1 (HIF-1) and Regulatory Prolyl Hydroxylase (PHD) Enzymes Following Hypoxic-Ischemic Injury in the Neonatal Rat.

Hypoxia leads to activation of many cellular adaptive processes which are regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1). HIF-1 consists of HIF-1α and HIF-1ß subunits and levels of HIF-1α protein are regulated by HIF prolyl-hydroxylase enzymes (PHD1, 2, 3). The aim of the current study was to investigate the expression of HIF-1α and PHDs at various time points after hypoxia-ischemia (HI), using a neonatal rat model of HI brain injury. Sprague-Dawley rat pups (postnatal day 7) were anaesthetized and underwent right carotid artery occlusion and were then exposed to 6 % oxygen for 2.5 h at 37 °C. HI injured animals demonstrated a significant reduction in the size of the ipsilateral hemisphere, compared to sham controls. Protein analysis using western blotting and enzyme-linked immunosorbent assay showed that 24 h after HI, there was a significant increase in PHD3 protein and an increase of HIF-1α compared to controls. At the 72 h time point, there was a reduction in PHD3 protein, which appeared to relate to cellular loss. There were no changes in PHD1 or PHD2 protein levels after HI when compared to age-matched controls. Further studies are necessary to establish roles for the HIF-1 regulatory enzyme PHD3 in brain injury processes.

Synthesis and neuroprotective activity of dictyoquinazol A and analogues.

A flexible and efficient synthesis of the neuroprotective alkaloid, dictyoquinazol A, is reported. Several structural analogues of the target molecule were produced, and the neuroprotective activity of this series of compounds was investigated using three different cell-based models of stroke. Several of the new compounds were found to have superior activity compared to the natural product. This work has established a new molecular scaffold that holds promise for a novel pharmaceutical treatment for stroke.

Presence of an epigenetic signature of prenatal cigarette smoke exposure in childhood.

Prenatal exposure to tobacco smoke has lifelong health consequences. Epigenetic signatures such as differences in DNA methylation (DNAm) may be a biomarker of exposure and, further, might have functional significance for how in utero tobacco exposure may influence disease risk. Differences in infant DNAm associated with maternal smoking during pregnancy have been identified. Here we assessed whether these infant DNAm patterns are detectible in early childhood, whether they are specific to smoking, and whether childhood DNAm can classify prenatal smoke exposure status. Using the Infinium 450K array, we measured methylation at 26 CpG loci that were previously associated with prenatal smoking in infant cord blood from 572 children, aged 3-5, with differing prenatal exposure to cigarette smoke in the Study to Explore Early Development (SEED). Striking concordance was found between the pattern of prenatal smoking associated DNAm among preschool aged children in SEED and those observed at birth in other studies. These DNAm changes appear to be tobacco-specific. Support vector machine classification models and 10-fold cross-validation were applied to show classification accuracy for childhood DNAm at these 26 sites as a biomarker of prenatal smoking exposure. Classification models showed prenatal exposure to smoking can be assigned with 81% accuracy using childhood DNAm patterns at these 26 loci. These findings support the potential for blood-derived DNAm measurements to serve as biomarkers for prenatal exposure.

Impact of maternal cigarette smoke exposure on brain and kidney health outcomes in female offspring.

Increased oxidative stress in the brain can lead to increased sympathetic tone that may further induce kidney dysfunction. Previously we have shown that maternal cigarette smoke exposure (SE) leads to significantly increased oxidative stress and inflammation in both brain and kidney, as well as reduced brain and kidney mitochondrial activity. This is closely associated with significant kidney underdevelopment and abnormal function in adulthood in the male offspring. This study aimed to investigate the impact of maternal SE on brain and kidney health in the female offspring. In this study, the mouse dams were exposed to two cigarettes, twice daily for 6 weeks prior to gestation, during pregnancy and lactation. Brains and kidneys from the female offspring were collected at 20 days (P20) and 13 weeks (W13) and were subject to further analysis. We found that mRNA expression of brain inflammatory markers interleukin-1 receptor and Toll-like receptor 4 were significantly increased in the SE offspring at both P20 and W13. Their brain mitochondrial activity markers were however increased at W13 with increased antioxidant activity. Kidney development and function in the female SE offspring were not different from the control offspring. We concluded that although brain inflammatory markers were upregulated in the SE female offspring, they were protected from some of the indicators of brain oxidative stress, such as endogenous antioxidant and mitochondrial dysfunction, as well as abnormal kidney development and function in adulthood.