The Association Between Preoperative Pectoralis Muscle Quantity and Outcomes After Cardiac Transplantation.

BACKGROUND: Sarcopenia is underappreciated in advanced heart failure and is not routinely assessed. In patients receiving a left ventricular assist device, preoperative sarcopenia, defined by using computed-tomography (CT)-derived pectoralis muscle-area index (muscle area indexed to body-surface area), is an independent predictor of postoperative mortality. The association between preoperative sarcopenia and outcomes after heart transplant (HT) is unknown. OBJECTIVES: The primary aim of this study was to determine whether preoperative sarcopenia, diagnosed using the pectoralis muscle-area index, is an independent predictor of days alive and out of the hospital (DAOHs) post-transplant. METHODS: Patients who underwent HT between January, 2018, and June, 2022, with available preoperative chest CT scans were included. Sarcopenia was diagnosed as pectoralis muscle-area index in the lowest sex-specific tertile. The primary endpoint was DAOHs at 1 year post-transplant. RESULTS: The study included 169 patients. Patients with sarcopenia (n = 55) had fewer DAOHs compared to those without sarcopenia, with a median difference of 17 days (320 vs 337 days; P = 0.004). Patients with sarcopenia had longer index hospitalizations and were also more likely to be discharged to a facility other than home. In a Poisson regression model, sarcopenia was a significant univariable and the strongest multivariable predictor of DAOHs at 1 year (parameter estimate = -0.17, 95% CI -0.19 to -14; P = < 0.0001). CONCLUSIONS: Preoperative sarcopenia, diagnosed using the pectoralis muscle-area index, is an independent predictor of poor outcomes after HT. This parameter is easily measurable from commonly obtained preoperative CT scans and may be considered in transplant evaluations.

Clinical and pathologic staging accuracy in patients with synchronous multiple primary lung cancers.

Background: The incidence of synchronous multiple primary lung cancer (SMPLC) is increasing, occurring in up to 20% of lung cancer patients. Accurately identifying SMPLC can be challenging, and failure to recognize SMPLC results in poor outcomes. We sought to assess the staging accuracy of patients with SMPLC at our tertiary institution. Methods: We retrospectively reviewed all patients who were evaluated for lung cancer resection between January 2018 to September 2019. Patients with SMPLC were identified using the modified Martini-Melamed criteria. Preoperative imaging, clinical assessment, and pathologic interpretation were reviewed and compared to the final staging assigned by a multidisciplinary lung cancer tumor board to determine accuracy. Results: Out of 227 patients presenting for lung cancer resection, 47 patients with 119 SMPLC were identified, of which 38 (80.9%) were incorrectly staged by at least one report. Incorrect staging was most common by computed tomography (CT) reports (n=33/47, 70.2%), followed by positron emission tomography-CT (PET-CT) reports (n=28/45, 62.2%), surgeons' clinical assessment (n=10/47, 21.3%), and histopathology reports (n=8/47, 17.0%). CT reports, when incorrect, under-staged 97.0% (n=32) of patients. PET-CT reports, when incorrect, over-staged 25.0% (n=7) of patients by reporting the second primary nodule to be "consistent with metastasis". Histopathology reports, when incorrect, over-staged 87.5% (n=7) of patients despite lack of lymph node involvement. Conclusions: Patients with SMPLC are at risk of receiving incorrect treatment based on radiographic and histopathologic staging reports alone. The observed staging inaccuracies are concerning, necessitating increased awareness among physicians caring for lung cancer patients.

Early resource scarcity causes cortical astrocyte enlargement and sex-specific changes in the orbitofrontal cortex transcriptome in adult rats.

Astrocyte morphology affects function, including the regulation of glutamatergic signaling. This morphology changes dynamically in response to the environment. However, how early life manipulations alter adult cortical astrocyte morphology is underexplored. Our lab uses brief postnatal resource scarcity, the limited bedding and nesting (LBN) manipulation, in rats. We previously found that LBN augments maternal behaviors and promotes later resilience to adult addiction-related behaviors, reducing impulsivity, risky decision-making, and morphine self-administration. These behaviors rely on glutamatergic transmission in the medial orbitofrontal (mOFC) and medial prefrontal (mPFC) cortex. Here we tested whether LBN changed astrocyte morphology in the mOFC and mPFC of adult rats using a novel viral approach that, unlike traditional markers, fully labels astrocytes. Prior exposure to LBN causes an increase in the surface area and volume of astrocytes in the mOFC and mPFC of adult males and females relative to control-raised rats. We next used bulk RNA sequencing of OFC tissue to assess transcriptional changes that could increase astrocyte size in LBN rats. LBN caused mainly sex-specific changes in differentially expressed genes. Pathway analysis revealed that OFC glutamatergic signaling is altered by LBN in males and females, but the gene changes in that pathway differed across sex. This may represent a convergent sex difference where glutamatergic signaling, which affects astrocyte morphology, is altered by LBN via sex-specific mechanisms. Collectively, these studies highlight that astrocytes may be an important cell type that mediates the effect of early resource scarcity on adult brain function.

Contemporary Incidence of Synchronous Multiple Primary Lung Cancers and Survival in the Era of Lung Cancer Screening.

OBJECTIVE: Up to 15% of lung cancer patients have multiple suspicious nodules. While some of these nodules may represent metastatic lung cancer, others represent synchronous multiple primary lung cancer (SMPLC). The incidence of SMPLC ranges from 0.8% to 8.4% and appears to be increasing. Inconsistent identification of SMPLC can be detrimental for patients who are misdiagnosed as having intrapulmonary metastasis and not offered stage-based treatment. We sought to identify the contemporary incidence of SMPLC at a tertiary institution. METHODS: From January 2018 to September 2019, patients who underwent lung cancer resection were retrospectively reviewed. Patients with SMPLC were identified using the modified Martini-Melamed criteria. RESULTS: During the 21-month period, 227 patients underwent lung cancer resection. There were 47 patients (20.7%) who had 119 pathologically confirmed SMPLC. Most patients had ipsilateral tumors (n = 24, 51.1%) with at least 1 adenocarcinoma (n = 40, 85.1%). Considering histologic subtyping, 38 (80.9%) had histologically distinct tumors. Overall and cancer-specific survival at 4 years was 86% and 90%, respectively. Only patients with 3 or more SMPLC had poor 4-year overall (P = 0.002) and cancer-specific survival (P = 0.043) compared with those with 2 SMPLC. Patient demographics, histology, tumor location, and highest pathologic staging did not affect survival outcomes. CONCLUSIONS: Using a strict inclusion criterion, the incidence of SMPLC is higher than previously reported. SMPLC patients have favorable survival outcomes, suggesting that they behave like primary lung cancer, not intrapulmonary metastasis. Awareness of SMPLC by thoracic surgeons is critical in optimizing outcomes in this patient population.

Early resource scarcity causes cortical astrocyte enlargement and sex-specific changes in the orbitofrontal cortex transcriptome in adult rats.

Astrocyte morphology affects function, including the regulation of glutamatergic signaling. This morphology changes dynamically in response to the environment. However, how early life manipulations alter adult cortical astrocyte morphology is underexplored. Our lab uses brief postnatal resource scarcity, the limited bedding and nesting (LBN) manipulation, in rats. We previously found that LBN promotes later resilience to adult addiction-related behaviors, reducing impulsivity, risky decision-making, and morphine self-administration. These behaviors rely on glutamatergic transmission in the medial orbitofrontal (mOFC) and medial prefrontal (mPFC) cortex. Here we tested whether LBN changed astrocyte morphology in the mOFC and mPFC of adult rats using a novel viral approach that, unlike traditional markers, fully labels astrocytes. Prior exposure to LBN causes an increase in the surface area and volume of astrocytes in the mOFC and mPFC of adult males and females relative to control-raised rats. We next used bulk RNA sequencing of OFC tissue to assess transcriptional changes that could increase astrocyte size in LBN rats. LBN caused mainly sex-specific changes in differentially expressed genes. However, Park7, which encodes for the protein DJ-1 that alters astrocyte morphology, was increased by LBN across sex. Pathway analysis revealed that OFC glutamatergic signaling is altered by LBN in males and females, but the gene changes in that pathway differed across sex. This may represent a convergent sex difference where glutamatergic signaling, which affects astrocyte morphology, is altered by LBN via sex-specific mechanisms. Collectively, these studies highlight that astrocytes may be an important cell type that mediates the effect of early resource scarcity on adult brain function.

New system, old problem: Increased wait time for high-priority transplant candidates.

The 2018 heart allocation policy sought to improve risk stratification and reduce waitlist mortality for the sickest patients. This study sought to evaluate changes in wait times for the highest priority patients since policy implementation. All adult single-organ transplant recipients were identified in the United Network for Organ Sharing registry from October 18, 2018, to July 8, 2022, and separated into 4 periods. Outcomes were compared by blood type and UNOS region. Over the study period, 897 of 9,143 patients were listed as status 1 with no significant change in median wait time by blood type or region. More patients were listed as status 2 (4,523/9,143), and each subsequent period postpolicy change was associated with a 4.2-day increase in mean status 2 waitlist time (95% confidence interval 3.0-5.5, p < 0.0001). Wait times were longest for candidates with blood type O and shortest for AB & A. Regional variations continued, however, wait time increased in every region over time.

Stress during puberty exerts sex-specific effects on depressive-like behavior and monoamine neurotransmitters in adolescence and adulthood.

Psychiatric disorders including major depression are twice as prevalent in women compared to men. This sex difference in prevalence only emerges after the onset of puberty, suggesting that puberty may be a sensitive period during which sex-associated vulnerability to stress-related depression might become established. Thus, this study investigated whether stress occurring specifically during the pubertal window of adolescence may be responsible for this sex difference in depression vulnerability. Male and female rats were exposed to a three-day stress protocol during puberty (postnatal days 35-37 in females, 45-47 in males) and underwent behavioral tests in adolescence or adulthood measuring anhedonia, anxiety-like behavior, locomotor activity and antidepressant-like behavior. Brainstem and striatum tissue were collected from a separate cohort of behavioral test-naïve rats in adolescence or adulthood to quantify the effect of pubertal stress on monoamine neurotransmitters. Pubertal stress increased immobility behavior in the forced swim test in both sexes in adolescence and adulthood. In adolescence, pubertal stress altered escape-oriented behaviors in a sex-specific manner: decreasing climbing in males but not females and decreasing swimming in females but not males. Pubertal stress decreased adolescent brainstem noradrenaline specifically in females and had opposing effects in adolescent males and females on brainstem serotonin turnover. Pubertal stress induced anhedonia in the saccharin preference test in adult males but not females, an effect paralleled by a male-specific decrease in striatal dopamine turnover. Pubertal stress did not significantly impact anxiety-like behavior or locomotor activity in any sex at either age. Taken together, these data suggest that although pubertal stress did not preferentially increase female vulnerability to depressive-like behaviors compared to males, stress during puberty exerts sex-specific effects on depressive-like behavior and anhedonia, possibly through discrete neurotransmitter systems.

Juvenile stress exerts sex-independent effects on anxiety, antidepressant-like behaviours and dopaminergic innervation of the prelimbic cortex in adulthood and does not alter hippocampal neurogenesis.

Stress, particularly during childhood, is a major risk factor for the development of depression. Depression is twice as prevalent in women compared to men, which suggests that biological sex also contributes to depression susceptibility. However, the neurobiology underpinning sex differences in the long-term consequences of childhood stress remains unknown. Thus, the aim of this study was to determine whether stress applied during the prepubertal juvenile period (postnatal day 27-29) in rats induces sex-specific changes in anxiety-like behaviour, anhedonia, and antidepressant-like behaviour in adulthood in males and females. The impact of juvenile stress on two systems in the brain associated with these behaviours and that develop during the juvenile period, the mesocorticolimbic dopaminergic system and hippocampal neurogenesis, were also investigated. Juvenile stress altered escape-oriented behaviours in the forced swim test in both sexes, decreased latency to drink a palatable substance in a novel environment in the novelty-induced hypophagia test in both sexes, and decreased open field supported rearing behavior in females. These behavioural changes were accompanied by stress-induced increases in tyrosine hydroxylase immunoreactivity in the prefrontal cortex of both sexes, but not other regions of the mesocorticolimbic dopaminergic system. Juvenile stress did not impact anhedonia in adulthood as measured by the saccharin preference test and had no effect hippocampal neurogenesis across the longitudinal axis of the hippocampus. These results suggest that juvenile stress has long-lasting impacts on antidepressant-like and reward-seeking behaviour in adulthood and these changes may be due to alterations to catecholaminergic innervation of the medial prefrontal cortex.

High-Resolution Maxillofacial Computed Tomography Is Superior to Head Computed Tomography in Determining the Operative Management of Facial Fractures.

BACKGROUND: Computed tomography of the head (CTH) and maxillofacial bones (CTMF) can be performed concurrently, but CTMF is frequently ordered separately, after facial fractures identified on CTH scans. This study aims to evaluate whether obtaining additional CTMF after CTH changes operative management of patients with facial trauma. MATERIALS AND METHODS: A retrospective chart review was performed of all patients with facial trauma who presented to our level 1 trauma center between January 2009 and May 2019. CTH and CTMF were reviewed for each patient. Fracture numbers and patterns were compared to determine if CTMF provided additional information that necessitated change in management, based on predetermined criteria. RESULTS: A total of 1215 patients were assessed for facial trauma. Of them, 899 patients underwent both CTH and CTMF scans. CTH identified 22.7% less fractures than CTMF (P < 0.001); specifically, more orbital, nasal, naso-orbito-ethmoid, zygoma, midface, and mandible fractures (P < 0.001). Of all patients 9.2% (n = 83) of patients with nonoperative fractures on CTH were reclassified as operative on CTMF; 0.6% (n = 5) with operative patterns on CTH were reclassified as nonoperative on CTMF, and 18.1% (n = 163) experienced a changed in their operative plan though operative fractures were seen on both imaging modalities. Additional findings seen on CTMF delegated change in the operative plan in 27.9% (n = 251) of cases. CONCLUSIONS: CTMF scans are necessary to determine operative intervention. As CTH and CTMF are constructed from the data, physicians should consider ordering both scans simultaneously for all patients with facial trauma to limit radiation exposure, control costs, and avoid delays in care.

Unexpected encounters: high prevalence of synchronous primary lung cancers in a tertiary academic center.

BACKGROUND: Accurate staging of lung cancer is paramount for directing treatment. After an internal audit suggested a higher than expected rate of synchronous multiple primary lung cancers (SMPLC), we have sought to evaluate the prevalence of SMPLC at our single, large academic center. METHODS: From January 2019 to September 2019, patients with non-small cell lung cancer who underwent surgical resection were retrospectively reviewed. Clinical characteristics, pre- and post-op imaging, 30-day morbidity and mortality, as well as pathological findings were reviewed. SMPLCs were defined using modified Martini criteria. RESULTS: Among 83 patients who underwent surgical resection for primary lung cancer with the intention of cure, 17 (20.5%) had pathologically confirmed SMPLC's, 53 (64%) were single primary lung cancers, and 13 (16%) had metastatic lesions from primary lung cancer or extra-thoracic cancers. Mean length of stay was 2 days with no mortalities. Of the SMPLC group, 9 (53%) had previous extra-thoracic neoplasms, compared with 8 (15%) in the single primary group. Four (24%) had a history of resected lung cancers more than 2 years previously, and were participating in lung cancer surveillance programs. CONCLUSIONS: The rate of SMPLC at our institution appears to be considerably higher than traditionally reported. Failure to recognize the high incidence of synchronous primary lung cancers exposes patients to the risks of under treatment and poor outcomes.

Bisphenol a Exposure in Utero Disrupts Hypothalamic Gene Expression Particularly Genes Suspected in Autism Spectrum Disorders and Neuron and Hormone Signaling.

Bisphenol A (BPA) is an endocrine-disrupting compound detected in the urine of more than 92% of humans, easily crosses the placental barrier, and has been shown to influence gene expression during fetal brain development. The purpose of this study was to investigate the effect of in utero BPA exposure on gene expression in the anterior hypothalamus, the basal nucleus of the stria terminalis (BNST), and hippocampus in C57BL/6 mice. Mice were exposed in utero to human-relevant doses of BPA, and then RNA sequencing was performed on male PND 28 tissue from whole hypothalamus (n = 3/group) that included the medial preoptic area (mPOA) and BNST to determine whether any genes were differentially expressed between BPA-exposed and control mice. A subset of genes was selected for further study using RT-qPCR on adult tissue from hippocampus to determine whether any differentially expressed genes (DEGs) persisted into adulthood. Two different RNA-Seq workflows indicated a total of 259 genes that were differentially expressed between BPA-exposed and control mice. Gene ontology analysis indicated that those DEGs were overrepresented in categories relating to mating, cell-cell signaling, behavior, neurodevelopment, neurogenesis, synapse formation, cognition, learning behaviors, hormone activity, and signaling receptor activity, among others. Ingenuity Pathway Analysis was used to interrogate novel gene networks and upstream regulators, indicating the top five upstream regulators as huntingtin, beta-estradiol, alpha-synuclein, Creb1, and estrogen receptor (ER)-alpha. In addition, 15 DE genes were identified that are suspected in autism spectrum disorders.

Effects of maternal or paternal bisphenol A exposure on offspring behavior.

Bisphenol A (BPA) is an endocrine disrupting chemical used in the production of polycarbonate plastics and resins. Exposure to BPA during gestation has been proposed as a risk factor for the development of neurobehavioral disorders, such as autism spectrum disorder. To address the behavioral impact of developmental exposure to BPA, we tested offspring of mice exposed to a daily low dose of BPA during pregnancy. We also asked if preconception exposure of the sire affected behaviors in offspring. Sires that consumed BPA for 50days prior to mating weighed less than controls, but no effects on any reproductive measures were noted. Juvenile offspring exposed to BPA maternally, but not paternally, spent less time in the open arms of the elevated plus maze than controls, indicating increased anxiety-like behavior. However, neither parental exposure group differed significantly from controls in the social recognition task. We also assessed the behaviors of maternally exposed offspring in two novel tasks: ultrasonic vocalizations (USVs) in pups and operant reversal learning in adults. Maternal BPA exposure increased the duration and median frequency of USVs emitted by pups during maternal separation. In the reversal learning task, females responded more accurately and earned more rewards than males. Additionally, control females received more rewards than BPA females during the acquisition phase of the task. These are among the first studies conducted to ask if BPA exposure via the sire affects offspring behavior and the first study to report effects of gestational BPA exposure on pup USVs and adult operant responding.

Transgenerational Effects of Bisphenol A on Gene Expression and DNA Methylation of Imprinted Genes in Brain.

Bisphenol A (BPA) is a ubiquitous man-made endocrine disrupting compound (EDC). Developmental exposure to BPA changes behavioral and reproductive phenotypes, and these effects can last for generations. We exposed embryos to BPA, producing two lineages: controls and BPA exposed. In the third filial generation (F3), brain tissues containing the preoptic area, the bed nucleus of the stria terminalis, and the anterior hypothalamus were collected. RNA sequencing (RNA-seq) and subsequent data analyses revealed 50 differentially regulated genes in the brains of F3 juveniles from BPA vs control lineages. BPA exposure can lead to loss of imprinting, and one of the two imprinted genes in our data set, maternally expressed gene 3 (Meg3), has been associated with EDCs and neurobehavioral phenotypes. We used quantitative polymerase chain reaction to examine the two imprinted genes in our data set, Meg3 and microRNA-containing gene Mirg (residing in the same loci). Confirming the RNA-seq, Meg3 messenger RNA was higher in F3 brains from the BPA lineage than in control brains. This was true in brains from mice produced with two different BPA paradigms. Next, we used pyrosequencing to probe differentially methylated regions of Meg3. We found transgenerational effects of BPA on imprinted genes in brain. Given these results, and data on Meg3 methylation in humans, we suggest this gene may be a biomarker indicative of early life environmental perturbation.

Direct and transgenerational effects of low doses of perinatal di-(2-ethylhexyl) phthalate (DEHP) on social behaviors in mice.

Di-(2-ethylhexyl) phthalate (DEHP) is an endocrine disrupting chemical commonly used as a plasticizer in medical equipment, food packaging, flooring, and children's toys. DEHP exposure during early development has been associated with adverse neurobehavioral outcomes in children. In animal models, early exposure to DEHP results in abnormal development of the reproductive system as well as altered behavior and neurodevelopment. Based on these data, we hypothesized that developmental exposure to DEHP would decrease social interactions and increase anxiety-like behaviors in mice in a dose-dependent manner, and that the effects would persist over generations. C57BL/6J mice consumed one of three DEHP doses (0, 5, 40, and 400 µg/kg body weight) throughout pregnancy and during the first ten days of lactation. The two higher doses yielded detectable levels of DEHP metabolites in serum. Pairs of mice from control, low, and high DEHP doses were bred to create three dose lineages in the third generation (F3). Average anogenital index (AGI: anogenital distance/body weight) was decreased in F1 males exposed to the low dose of DEHP and in F1 females exposed to the highest dose. In F1 mice, juvenile pairs from the two highest DEHP dose groups displayed fewer socially investigative behaviors and more exploratory behaviors as compared with control mice. The effect of DEHP on these behaviors was reversed in F3 mice as compared with F1 mice. F1 mice exposed to low and medium DEHP doses spent more time in the closed arms of the elevated plus maze than controls, indicating increased anxiety-like behavior. The generation-dependent effects on behavior and AGI suggest complex mechanisms by which DEHP directly impacts reproductive and neurobehavioral development and influences germline-inherited traits.

Calbindin Knockout Alters Sex-Specific Regulation of Behavior and Gene Expression in Amygdala and Prefrontal Cortex.

Calbindin-D(28K) (Calb1), a high-affinity calcium buffer/sensor, shows abundant expression in neurons and has been associated with a number of neurobehavioral diseases, many of which are sexually dimorphic in incidence. Behavioral and physiological end points are affected by experimental manipulations of calbindin levels, including disruption of spatial learning, hippocampal long-term potentiation, and circadian rhythms. In this study, we investigated novel aspects of calbindin function on social behavior, anxiety-like behavior, and fear conditioning in adult mice of both sexes by comparing wild-type to littermate Calb1 KO mice. Because Calb1 mRNA and protein are sexually dimorphic in some areas of the brain, we hypothesized that sex differences in behavioral responses of these behaviors would be eliminated or revealed in Calb1 KO mice. We also examined gene expression in the amygdala and prefrontal cortex, two areas of the brain intimately connected with limbic system control of the behaviors tested, in response to sex and genotype. Our results demonstrate that fear memory and social behavior are altered in male knockout mice, and Calb1 KO mice of both sexes show less anxiety. Moreover, gene expression studies of the amygdala and prefrontal cortex revealed several significant genotype and sex effects in genes related to brain-derived neurotrophic factor signaling, hormone receptors, histone deacetylases, and γ-aminobutyric acid signaling. Our findings are the first to directly link calbindin with affective and social behaviors in rodents; moreover, the results suggest that sex differences in calbindin protein influence behavior.

Evaluation of clinical pharmacy services within the primary care-mental health integration model at the Tuscaloosa Veterans Affairs Medical Center.

INTRODUCTION: The purpose of this review is to evaluate the direct delivery of health care to veterans before and after incorporating clinical pharmacy services within primary care mental health integration (PCMHI) at the Tuscaloosa Veterans Affairs Medical Center. Prior to establishing the role of the clinical pharmacy specialist (CPS) within PCMHI, the primary care providers deferred all mental health assessments to specialty mental health. As the demands of the service grew exponentially, assistance from clinical pharmacy was critical. METHODS: A randomized, computer-generated list of 114 patients selected for the retrospective chart review was used to evaluate clinical outcomes in patients enrolled in the PCMHI clinic 1 year preincorporation and postincorporation of CPS. Outcome measures included the number of patients discharged from the PCMHI clinic upon achieving therapeutic goals or discharged to specialty mental health due to therapeutic failure or adverse drug events with first- and second-line psychotropic agents. RESULTS: When contrasting the end points, there was a 60% increase in the number of patients who achieved therapeutic goal and a 32% decrease in the number of patients discharged to specialty mental health clinic postincorporation of CPS into PCMHI as compared to preincorporation of CPS (P = .024). DISCUSSION: The results support the significance of CPS in the PCMHI in providing pharmacotherapy, patient education, and medication monitoring for managing psychiatric conditions, such as depression, anxiety, and insomnia. In addition, patients had greater accessibility to medication and frequent monitoring and follow-up, ultimately improving patient outcomes.

Neural growth hormone: regional regulation by estradiol and/or sex chromosome complement in male and female mice.

BACKGROUND: Sex differences in pituitary growth hormone (GH) are well documented and coordinate maturation and growth. GH and its receptor are also produced in the brain where they may impact cognitive function and synaptic plasticity, and estradiol produces Gh sex differences in rat hippocampus. In mice, circulating estradiol increases Gh mRNA in female but not in male medial preoptic area (mPOA); therefore, additional factors regulate sexually dimorphic Gh expression in the brain. Thus, we hypothesized that sex chromosomes interact with estradiol to promote sex differences in GH. Here, we assessed the contributions of both estradiol and sex chromosome complement on Gh mRNA levels in three large brain regions: the hippocampus, hypothalamus, and cerebellum. METHODS: We used the four core genotypes (FCG) mice, which uncouple effects of sex chromosomes and gonadal sex. The FCG model has a deletion of the sex-determining region on the Y chromosome (Sry) and transgenic insertion of Sry on an autosome. Adult FCG mice were gonadectomized and given either a blank Silastic implant or an implant containing 17ß-estradiol. Significant differences in GH protein and mRNA were attributed to estradiol replacement, gonadal sex, sex chromosome complement, and their interactions, which were assessed by ANOVA and planned comparisons. RESULTS: Estradiol increased Gh mRNA in the cerebellum and hippocampus, regardless of sex chromosome complement or gonadal sex. In contrast, in the hypothalamus, females had higher Gh mRNA than males, and XY females had more Gh mRNA than XY males and XX females. This same pattern was observed for GH protein. Because the differences in Gh mRNA in the hypothalamus did not replicate prior studies using other mouse models and tissue from mPOA or arcuate nucleus, we examined GH protein in the arcuate, a subdivision of the hypothalamus. Like the previous reports, and in contrast to the entire hypothalamus, a sex chromosome complement effect showed that XX mice had more GH than XY in the arcuate. CONCLUSIONS: Sex chromosome complement regulates GH in some but not all brain areas, and within the hypothalamus, sex chromosomes have cell-specific actions on GH. Thus, sex chromosome complement and estradiol both contribute to GH sex differences in the brain.

The development of a preference-setting model for the return of individual genomic research results.

Understanding participants' preferences for the return of individual research results (IRR) in genomic research may allow for the implementation of more beneficial result disclosure methods. We tested four preference-setting models through cognitive interviews of parents to explore how parents conceptualize the process of setting preferences and which disease characteristics they believe to be most important when deciding what results to receive on their child. Severity and preventability of a condition were highly influential in decision making and certain groups of research results were anticipated by participants to have negative psychological effects. These findings informed the development of an educational tool and preference-setting model that can be scaled for use in the return of IRR from large biobank studies.

Facilitation of the HPA axis to a novel acute stress following chronic stress exposure modulates histone acetylation and the ERK/MAPK pathway in the dentate gyrus of male rats.

Evidence suggests that when presented with novel acute stress, animals previously exposed to chronic homotypic or heterotypic stressors exhibit normal or enhanced hypothalamic-pituitary-adrenal (HPA) response compared with animals exposed solely to that acute stressor. The molecular mechanisms involved in this effect remain unknown. The extracellular signal-regulated kinase (ERK) is one of the key pathways regulated in the hippocampus in both acute and chronic stress. The aim of this study was to examine the interaction of prior chronic stress, using the chronic variable stress model (CVS), with exposure to a novel acute stressor (2,5-dihydro-2,4,5-trimethyl thiazoline; TMT) on ERK activation, expression of the downstream protein BCL-2, and the glucocorticoid receptor co-chaperone BAG-1 in control and chronically stressed male rats. TMT exposure after chronic stress resulted in a significant interaction of chronic and acute stress in all 3 hippocampus subregions on ERK activation and BCL-2 expression. Significantly, acute stress increased ERK activation, BCL-2 and BAG-1 protein expression in the dentate gyrus (DG) of CVS-treated rats compared with control, CVS-treated alone, and TMT-only animals. Furthermore, CVS significantly increased ERK activation in medial prefrontal cortex, but acute stress had no significant effect. Inhibition of corticosterone synthesis with metyrapone had no significant effect on ERK activation in the hippocampus; therefore, glucocorticoids alone do not mediate the molecular effects. Finally, because post-translational modifications of histones are believed to play an important role in the stress response, we examined changes in histone acetylation. We found that, in general, chronic stress decreased K12H4 acetylation, whereas acute stress increased acetylation. These results indicate a molecular mechanism by which chronic stress-induced HPA axis plasticity can lead to neurochemical alterations in the hippocampus that influence reactivity to subsequent stress exposure. This may represent an important site of dysfunction that contributes to stress-induced pathology such as depression, anxiety disorders, and posttraumatic stress disorder.