Glutathione Protects the Developing Heart from Defects and Global DNA Hypomethylation Induced by Prenatal Alcohol Exposure.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is caused by prenatal alcohol exposure (PAE), the intake of ethanol (C2 H5 OH) during pregnancy. Features of FASD cover a range of structural and functional defects including congenital heart defects (CHDs). Folic acid and choline, contributors of methyl groups to one-carbon metabolism (OCM), prevent CHDs in humans. Using our avian model of FASD, we have previously reported that betaine, another methyl donor downstream of choline, prevents CHDs. The CHD preventions are substantial but incomplete. Ethanol causes oxidative stress as well as depleting methyl groups for OCM to support DNA methylation and other epigenetic alterations. To identify more compounds that can safely and effectively prevent CHDs and other effects of PAE, we tested glutathione (GSH), a compound that regulates OCM and is known as a "master antioxidant." METHODS/RESULTS: Quail embryos injected with a single dose of ethanol at gastrulation exhibited congenital defects including CHDs similar to those identified in FASD individuals. GSH injected simultaneously with ethanol not only prevented CHDs, but also improved survival and prevented other PAE-induced defects. Assays of hearts at 8 days (HH stage 34) of quail development, when the heart normally has developed 4-chambers, showed that this single dose of PAE reduced global DNA methylation. GSH supplementation concurrent with PAE normalized global DNA methylation levels. The same assays performed on quail hearts at 3 days (HH stage 19-20) of development, showed no difference in global DNA methylation between controls, ethanol-treated, GSH alone, and GSH plus ethanol-treated cohorts. CONCLUSIONS: GSH supplementation shows promise to inhibit effects of PAE by improving survival, reducing the incidence of morphological defects including CHDs, and preventing global hypomethylation of DNA in heart tissues.

A Formative Evaluation of Patient and Family Caregiver Perspectives on Early Palliative Care in Chronic Obstructive Pulmonary Disease across Disease Severity.

Rationale: Little direction exists on how to integrate early palliative care in chronic obstructive pulmonary disease (COPD).Objectives: We sought to identify patient and family caregiver early palliative care needs across stages of COPD severity.Methods: As part of the Medical Research Council Framework developmental phase for intervention development, we conducted a formative evaluation of patients with moderate to very severe COPD (forced expiratory volume in 1 s [FEV1]/FVC < 70% and FEV1 < 80%-predicted) and their family caregivers. Validated surveys on quality of life, anxiety and depressive symptoms, and social isolation quantified symptom severity. Semi-structured interviews were analyzed for major themes on early palliative care and needs in patients and family caregivers and across COPD severity stages.Results: Patients (n = 10) were a mean (±SD) age of 60.4 (±7.5) years, 50% African American, and 70% male, with 30% having moderate COPD, 30% severe COPD, and 40% very severe COPD. Family caregivers (n = 10) were a mean age of 58.3 (±8.7) years, 40% African American, and 10% male. Overall, 30% (n = 6) of participants had poor quality of life, 45% (n = 9) had moderate-severe anxiety symptoms, 25% (n = 5) had moderate-severe depressive symptoms, and 40% (n = 8) reported social isolation. Only 30% had heard of palliative care, and most participants had misconceptions that palliative care was end-of-life care. All participants responded positively to a standardized description of early palliative care and were receptive to its integration as early as moderate stage. Five broad themes of early palliative care needs emerged: 1) coping with COPD; 2) emotional symptoms; 3) respiratory symptoms; 4) illness understanding; and 5) prognostic awareness. Coping with COPD and emotional symptoms were commonly shared early palliative care needs. Patients with very severe COPD and their family caregivers prioritized illness understanding and prognostic awareness compared with those with moderate-severe COPD.Conclusions: Patients with moderate to very severe COPD and their family caregivers found early palliative care acceptable and felt it should be integrated before end-stage. Of the five broad themes of early palliative care needs, coping with COPD and emotional symptoms were the highest priority, followed by respiratory symptoms, illness understanding, and prognostic awareness.