Site-Specific knockdown of microglia in the locus coeruleus regulates hypervigilant responses to social stress in female rats.

BACKGROUND: Women are at increased risk for psychosocial stress-related anxiety disorders, yet mechanisms regulating this risk are unknown. Psychosocial stressors activate microglia, and the resulting neuroimmune responses that females exhibit heightened sensitivity to may serve as an etiological factor in their elevated risk. However, studies examining the role of microglia during stress in females are lacking. METHODS: Microglia were manipulated in the stress-sensitive locus coeruleus (LC) of female rats in the context of social stress in two ways. First, intra-LC lipopolysaccharide (LPS; 0 or 3 µg/side, n = 5-6/group), a potent TLR4 agonist and microglial activator, was administered. One hour later, rats were exposed to control or an aggressive social defeat encounter between two males (WS, 15-min). In a separate study, females were treated with intra-LC or intra-central amygdala mannosylated liposomes containing clodronate (m-CLD; 0 or 25 µg/side, n = 13-14/group), a compound toxic to microglia. WS-evoked burying, cardiovascular responses, and sucrose preference were measured. Brain and plasma cytokines were quantified, and cardiovascular telemetry assessed autonomic balance. RESULTS: Intra-LC LPS augmented the WS-induced burying response and increased plasma corticosterone and interleukin-1ß (IL-1ß). Further, the efficacy and selectivity of microinjected m-CLD was fully characterized. In the context of WS, intra-LC m-CLD attenuated the hypervigilant burying response during WS as well as the accumulation of intra-LC IL-1ß. Intra-central amygdala m-CLD had no effect on WS-evoked behavior. CONCLUSIONS: These studies highlight an innovative method for depleting microglia in a brain region specific manner and indicate that microglia in the LC differentially regulate hypervigilant WS-evoked behavioral and autonomic responses.

Differentiating COPD and asthma using quantitative CT imaging and machine learning.

BACKGROUND: There are similarities and differences between chronic obstructive pulmonary disease (COPD) and asthma patients in terms of computed tomography (CT) disease-related features. Our objective was to determine the optimal subset of CT imaging features for differentiating COPD and asthma using machine learning. METHODS: COPD and asthma patients were recruited from Heidelberg University Hospital (Heidelberg, Germany). CT was acquired and 93 features were extracted: percentage of low-attenuating area below -950 HU (LAA950), low-attenuation cluster (LAC) total hole count, estimated airway wall thickness for an idealised airway with an internal perimeter of 10 mm (Pi10), total airway count (TAC), as well as airway inner/outer perimeters/areas and wall thickness for each of five segmental airways, and the average of those five airways. Hybrid feature selection was used to select the optimum number of features, and support vector machine learning was used to classify COPD and asthma. RESULTS: 95 participants were included (n=48 COPD and n=47 asthma); there were no differences between COPD and asthma for age (p=0.25) or forced expiratory volume in 1 s (p=0.31). In a model including all CT features, the accuracy and F1 score were 80% and 81%, respectively. The top features were: LAA950, outer airway perimeter, inner airway perimeter, TAC, outer airway area RB1, inner airway area RB1 and LAC total hole count. In the model with only CT airway features, the accuracy and F1 score were 66% and 68%, respectively. The top features were: inner airway area RB1, outer airway area LB1, outer airway perimeter, inner airway perimeter, Pi10, TAC, airway wall thickness RB1 and TAC LB10. CONCLUSION: COPD and asthma can be differentiated using machine learning with moderate-to-high accuracy by a subset of only seven CT features.

Aging triggers an upregulation of a multitude of cytokines in the male and especially the female rodent hippocampus but more discrete changes in other brain regions.

BACKGROUND: Despite widespread acceptance that neuroinflammation contributes to age-related cognitive decline, studies comparing protein expression of cytokines in the young versus old brains are surprisingly limited in terms of the number of cytokines and brain regions studied. Complicating matters, discrepancies abound-particularly for interleukin 6 (IL-6)-possibly due to differences in sex, species/strain, and/or the brain regions studied. METHODS: As such, we clarified how cytokine expression changes with age by using a Bioplex and Western blot to measure multiple cytokines across several brain regions of both sexes, using 2 mouse strains bred in-house as well as rats obtained from NIA. Parametric and nonparametric statistical tests were used as appropriate. RESULTS: In the ventral hippocampus of C57BL/6J mice, we found age-related increases in IL-1α, IL-1ß, IL-2, IL-3, IL-4, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-17, eotaxin, G-CSF, interfeuron δ, KC, MIP-1a, MIP-1b, rantes, and TNFα that are generally more pronounced in females, but no age-related change in IL-5, MCP-1, or GM-CSF. We also find aging is uniquely associated with the emergence of a module (a.k.a. network) of 11 strongly intercorrelated cytokines, as well as an age-related shift from glycosylated to unglycosylated isoforms of IL-10 and IL-1ß in the ventral hippocampus. Interestingly, age-related increases in extra-hippocampal cytokine expression are more discreet, with the prefrontal cortex, striatum, and cerebellum of male and female C57BL/6J mice demonstrating robust age-related increase in IL-6 expression but not IL-1ß. Importantly, we found this widespread age-related increase in IL-6 also occurs in BALB/cJ mice and Brown Norway rats, demonstrating conservation across species and rearing environments. CONCLUSIONS: Thus, age-related increases in cytokines are more pronounced in the hippocampus compared to other brain regions and can be more pronounced in females versus males depending on the brain region, genetic background, and cytokine examined.

Sex Differences in the Inflammatory Consequences of Stress: Implications for Pharmacotherapy.

Women are at significantly greater risk of developing stress-related disorders such as depression. The increased risk begins during puberty and continues throughout life until menopause, suggesting a role for ovarian hormones in this increased susceptibility. Importantly, inflammation has been gaining momentum in its role in the pathogenesis of depression. Herein, clinical and preclinical studies have been reviewed to better understand how sex differences within the immune system may contribute to exaggerated risk of depression in females. First, studies that investigate the ability of psychologic stress episodes to engage the inflammatory systems both in the brain and periphery are reviewed with a special focus on sex-specific effects. Moreover, studies are discussed that identify whether imbalanced inflammatory milieu contributes to the development of depression in males versus females and whether these effects are regulated by estradiol. Importantly, we propose a locus coeruleus-norepinephrine-cytokine circuit as a conduit through which stress could increase stress susceptibly in females. Finally, the anti-inflammatory capacity of traditional and nontraditional antidepressants is investigated, with the goal of providing a better understanding of pharmacotherapeutics to enhance strategies to personalize antidepressant treatments between the sexes. The studies reviewed herein strongly support the need for further studies to elucidate whether females are especially sensitive to anti-inflammatory compounds as adjuvants to traditional therapies. SIGNIFICANCE STATEMENT: Women have hve an increased risk of developing stress-related disorders such as depression. In this review, literature from clinical and preclinical studies are integrated to define sex differences in stress-induced inflammatory responses as a potential source for the etiology of sex differences in depressive disorders. Moreover, the anti-inflammatory capacity of traditional and nontraditional antidepressants is reviewed to inform on potential pharmacotherapeutic strategies to personalize antidepressant therapy in a sex-dependent manner.

Hematopoietic Stem Cell Transplantation to Treat Leukodystrophies: Clinical Practice Guidelines from the Hunter's Hope Leukodystrophy Care Network.

The leukodystrophies are a heterogeneous group of inherited diseases characterized by progressive demyelination of the central nervous system leading to devastating neurologic symptoms and premature death. Hematopoietic stem cell transplantation (HSCT) has been successfully used to treat certain leukodystrophies, including adrenoleukodystrophy, globoid leukodystrophy (Krabbe disease), and metachromatic leukodystrophy, over the past 30 years. To date, these complex patients have primarily been transplanted at a limited number of pediatric centers. As the number of cases identified through pregnancy and newborn screening is increasing, additional centers will be required to treat these children. Hunter's Hope created the Leukodystrophy Care Network in part to create and standardize high-quality clinical practice guidelines to guide the care of affected patients. In this report the clinical guidelines for the care of pediatric patients with leukodystrophies undergoing treatment with HSCT are presented. The initial transplant evaluation, determination of patient eligibility, donor selection, conditioning, supportive care, and post-transplant follow-up are discussed. Throughout these guidelines the need for early detection and treatment and the role of the partnership between families and multidisciplinary providers are emphasized.

The contribution of the locus coeruleus-norepinephrine system in the emergence of defeat-induced inflammatory priming.

Exposure to psychosocial stress is known to precipitate the emergence of stress related psychiatric disorders such as depression and anxiety. While mechanisms by which this occurs remain largely unclear, recent evidence points towards a causative role for inflammation. Neurotransmitters, such as norepinephrine (NE), are capable of regulating expression of proinflammatory cytokines and thus may contribute to the emergence of stress-related disorders. The locus coeruleus (LC) is the major source of norepinephrine (NE) to the brain and therefore the current study utilized N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), an LC selective noradrenergic neurotoxin, to determine the discrete involvement of the LC-NE system in social defeat-induced inflammation in LC projection regions including the central amygdala (CeA), dorsal raphe (DR) and plasma. In the current study, rats were exposed to brief social defeat or control manipulations on 5 consecutive days. To determine whether a history of social defeat enhanced or "primed" the inflammatory response to a subsequent defeat exposure, all rats regardless of stress history were exposed to an acute social defeat challenge immediately preceeding tissue collection. As anticipated, prior history of social defeat primed inflammatory responses in the plasma and CeA while neuroinflammation in the DR was markedly reduced. Notably, DSP-4 treatment suppressed stress-induced circulating inflammatory cytokines independent of prior stress history. In contrast, neuroinflammation in the CeA and DR were greatly augmented selectively in DSP-4 treated rats with a history of social defeat. Together these data highlight the dichotomous nature of NE in stress-induced inflammatory priming in the periphery and the brain and directly implicate the LC-NE system in these processes.

Common pathways and communication between the brain and heart: connecting post-traumatic stress disorder and heart failure.

Psychiatric illnesses and cardiovascular disease (CVD) contribute to significant overall morbidity, mortality, and health care costs, and are predicted to reach epidemic proportions with the aging population. Within the Veterans Administration (VA) health care system, psychiatric illnesses such as post-traumatic stress disorder (PTSD) and CVD such as heart failure (HF), are leading causes of hospital admissions, prolonged hospital stays, and resource utilization. Numerous studies have demonstrated associations between PTSD symptoms and CVD endpoints, particularly in the Veteran population. Not only does PTSD increase the risk of HF, but this relationship is bi-directional. Accordingly, a VA-sponsored conference entitled "Cardiovascular Comorbidities in PTSD: The Brain-Heart Consortium" was convened to explore potential relationships and common biological pathways between PTSD and HF. The conference was framed around the hypothesis that specific common systems are dysregulated in both PTSD and HF, resulting in a synergistic acceleration and amplification of both disease processes. The conference was not intended to identify all independent pathways that give rise to PTSD and HF, but rather identify shared systems, pathways, and biological mediators that would be modifiable in both disease processes. The results from this conference identified specific endocrine, autonomic, immune, structural, genetic, and physiological changes that may contribute to shared PTSD-CVD pathophysiology and could represent unique opportunities to develop therapies for both PTSD and HF. Some recommendations from the group for future research opportunities are provided.

Long-Term Functional Outcomes after Hematopoietic Stem Cell Transplant for Early Infantile Krabbe Disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) can retard the progression of early infantile Krabbe disease (EIKD). Superior outcomes are achieved if HSCT is performed before the onset of symptoms; however, little information is available about the long-term outcomes in surviving patients. We now describe functional outcomes in presymptomatic infants who underwent HSCT for EIKD at ≤ 2 months of age. Records of the 19 patients who underwent HSCT for EIKD at ≤ 2 months of age from 1996 to 2010 were reviewed. Long-term functional outcomes were compared between those transplanted at < 30 days and ≥ 30 days of life. Median age at transplant was 27 days (range, 19 to 61). Median follow-up of the cohort was 12.6 years. Overall survival at 5 and 10 years post-transplant was 84.2% (95% confidence interval, 58.7% to 94.6%) and 78.6% (95% confidence interval, 52.5% to 91.4%), respectively. More favorable outcomes were seen in patients who underwent HSCT at < 30 days of age, particularly in domains of mobility (P = .01), communication (P = .02), and feeding (P = .008). Improved functional outcomes were observed when HSCT was performed in the first month of life, defining a critical period for intervention. These results support the implementation of newborn screening to enable rapid diagnosis and early treatment of infants with EIKD.

Statistical considerations in reporting cardiovascular research.

The problem of inadequate statistical reporting is long standing and widespread in the biomedical literature, including in cardiovascular physiology. Although guidelines for reporting statistics have been available in clinical medicine for some time, there are currently no guidelines specific to cardiovascular physiology. To assess the need for guidelines, we determined the type and frequency of statistical tests and procedures currently used in the American Journal of Physiology-Heart and Circulatory Physiology. A PubMed search for articles published in the American Journal of Physiology-Heart and Circulatory Physiology between January 1, 2017, and October 6, 2017, provided a final sample of 146 articles evaluated for methods used and 38 articles for indepth analysis. The t-test and ANOVA accounted for 71% (212 of 300 articles) of the statistical tests performed. Of six categories of post hoc tests, Bonferroni and Tukey tests were used in 63% (62 of 98 articles). There was an overall lack in details provided by authors publishing in the American Journal of Physiology-Heart and Circulatory Physiology, and we compiled a list of recommended minimum reporting guidelines to aid authors in preparing manuscripts. Following these guidelines could substantially improve the quality of statistical reports and enhance data rigor and reproducibility.

The Modern Art of Reading Computed Tomography Images of the Lungs: Quantitative CT.

Lung diseases are increasing in prevalence and overall burden worldwide. To stem the tide, more and more national and international guidelines are recommending the use of various diagnostic algorithms that are disease specific. There is growing consensus among the respiratory community that although patient histories and lung function testing are the minimum required for clinical examinations, these tests alone are not sufficient for disease characterization. Therefore, the use of computed tomography (CT) imaging is increasing used in clinical decision making for lung diseases. Lung diseases affect various components of lung, including the small airways, lung parenchyma, the interstitial space and the pulmonary vasculature. Quantitative CT (QCT) methods are emerging and are increasingly available using commercial software to quantify the underlying disease components, and a growing body of evidence suggests that QCT is an important tool in the clinical setting to help accurately and reproducibly detect where the disease is located in the lung, and to quantify the extent and overall severity for several lung diseases. Furthermore, this growing body of evidence has promoted the use of thoracic QCT to the point that it is now considered by many as an indispensable technology for longitudinal analysis and intervention trials. Many QCT imaging measurements are available to the respiratory physician, and the aim of this review is to introduce and describe pulmonary QCT imaging measurements and methodologies.

The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior.

Social stress is a risk factor for psychiatric disorders, however only a subset of the population is susceptible while others remain resilient. Inflammation has been linked to the pathogenesis of psychosocial disorders in humans and may underlie these individual differences. Using a resident-intruder paradigm capable of revealing individual differences in coping behavior and inflammatory responses, the present study determined if resveratrol (RSV; 0, 10, 30mg/kg/day) protected against persistent stress-induced inflammation in socially defeated rats. Furthermore, the antidepressant efficacy of RSV was evaluated using the sucrose preference test. Active coping rats were characterized by more time spent in upright postures and increased defeat latencies versus passive coping rats. Five days after defeat, flow cytometry revealed enhanced stimulation of proinflammatory proteins (IL-ß, TNF-α) in spleen cells of passive rats as compared to active coping and controls, an effect that was blocked by both doses of RSV. Furthermore, only passive coping rats exhibited increased proinflammatory proteins (IL-1ß, TNF-α, GM-CSF) in the locus coeruleus (LC), a noradrenergic brain region implicated in depression. Notably, only 30mg/kg RSV blocked LC neuroinflammation and importantly, was the only dose that blocked anhedonia. Alternatively, while stress had minimal impact on resting cytokines in the dorsal raphe (DR), RSV dose-dependently reduced DR cytokine expression. However, this did not result in changes in indoleamine 2,3-dioxygenase activity or serotonin levels. Taken together, these data suggest that social stress-induced depressive-like behavior evident in passive coping rats may be driven by stress-induced neuroinflammation and highlight natural anti-inflammatory agents to protect against social stress-related consequences.

One Key Question®: First Things First in Reproductive Health.

Objectives Preconceptional health care is increasingly recognized as important to promotion of healthy birth outcomes. Preconceptional care offers an opportunity to influence pregnancy timing and intent and mother's health status prior to conception, all predictors of individual outcomes and of inequality in birth outcomes based on race, ethnicity and class. Methods One Key Question, a promising practice developed in Oregon which is now attracting national interest, provides an entry point into preconceptional care by calling on providers to screen for pregnancy intent in well woman and chronic disease care for women of reproductive age. For women who choose not to become pregnant or are not definitive in their pregnancy intent, One Key Question provides an opportunity for provision of or referral to counseling and contraceptive care. Results Adoption of One Key Question and preconceptional care as standard practices will require important shifts in medical practice challenging the longstanding schism between well woman care generally and reproductive care in particular. Adoption will also require shifts in cultural norms which define the onset of pregnancy as the appropriate starting point for attention to infant health. Conclusions for Practice This commentary reviews the case for preconceptional care, presents the rationale for One Key Question as a strategy for linking primary care to preconceptional and/or contraceptive care for women, outlines what is entailed in implementation of One Key Question in a health care setting, and suggests ways to build community support for preconceptional health.

Reform of abortion law in Uruguay: context, process and lessons learned.

In October 2012, a new law was approved in Uruguay that allows abortion on demand during the first 12 weeks of pregnancy, 14 weeks in the case of rape, and without a time limit when the woman's health is at risk or in the case of foetal anomalies. This paper analyses this legal reform. It is based on 27 individual and group interviews with key informants, and on review of primary documents and the literature. The factors explaining the reform include: secular values in society, favourable public opinion, a persistent feminist movement, effective coalition building, particular party politics, and a vocal public health sector. The content of the new law reflects the tensions between a feminist perspective of women's rights and public health arguments that stop short of fully recognizing women's autonomy. The Uruguayan reform shows that, even in Latin America, abortion can be addressed politically without electoral cost to the parties that promote it. On the other hand, the prevailing public health rationale and conditionalities built into the law during the negotiation process resulted in a law that cannot be interpreted as a full recognition of women's rights, but rather as a modified protectionist approach that circumscribes women's autonomy.

Recombinant human relaxin versus placebo for cervical ripening: a double-blind randomised trial in pregnant women scheduled for induction of labour.

BACKGROUND: Nonclinical studies indicate that the hormone relaxin is a good candidate for a safe cervical ripening agent that does not cause uterine contractions. METHODS: This Phase II study (conducted November 2, 2005-October 20, 2006) was a randomised, double blind, placebo controlled trial testing 24-h intravenous infusion of serelaxin (recombinant human relaxin) or placebo for cervical ripening in 72 healthy, primiparous women. Eligible subjects had a singleton pregnancy ≥40 weeks, were planned for elective induction, had vertex presentation of the fetus, intact membranes and a Bishop score at screening ≤4. In Part A of the study, safety evaluation of three escalating doses of serelaxin (7.5, 25 or 75 µg/kg/day) or placebo was performed in 22 subjects admitted to the hospital 24 h prior to scheduled induction (n = 7, 4, 4, and 7 subjects, respectively). The highest safe dose from Part A and placebo were then tested in Part B for safety and cervical ripening (n = 25 subjects/arm). Planned randomisation ratio was of 4:2 (serelaxin:placebo) for each dose group in Part A and 1:1 for Part B. For analysis, subjects in Part B were pooled with those receiving the same dose in Part A and all subjects receiving placebo were pooled. The primary efficacy endpoint was change from baseline in Bishop score at 6, 12 and 24 h or end of study drug administration. Maternal safety evaluations included adverse events and vital signs through 4 weeks. Fetal assessments included serial heart rate monitoring and nonstress testing. Neonatal assessments included Apgar scores, NICU admissions, and adverse events through 4 weeks. RESULTS: Overall, 74 subjects were randomized and 72 were treated. There were no significant differences between the groups receiving the highest safe dose of serelaxin (75 µg/kg/day) and placebo in the primary or secondary efficacy endpoints. Changes from baseline in Bishop score at 24 h were 4.19 ± 1.9 and 3.26 ± 2.26 in the pooled placebo and serelaxin groups, respectively (p = 0.2507). Serelaxin was well tolerated and no anti-serelaxin antibodies were detected in either subjects or neonates. CONCLUSION: Serelaxin infusion at the end of pregnancy was well tolerated but did not advance cervical ripening. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00259103 (15 November 2005).

Computed tomography predictors of response to endobronchial valve lung reduction treatment. Comparison with Chartis.

RATIONALE: Chartis Pulmonary Assessment System (Pulmonx Inc., Redwood, CA) is an invasive procedure used to assess collateral ventilation and select candidates for valve-based lung volume reduction (LVR) therapy. Quantitative computed tomography (QCT) is a potential alternative to Chartis and today consists primarily of assessing fissure integrity (FI). OBJECTIVES: In this retrospective analysis, we aimed to determine QCT predictors of LVR outcome and compare the QCT model with Chartis in selecting likely responders to valve-based LVR treatment. METHODS: Baseline CT scans of 146 subjects with severe emphysema who underwent endobronchial valve LVR were analyzed retrospectively using dedicated lung quantitative imaging software (Apollo; VIDA Diagnostics, Coralville, IA). A lobar volume reduction greater than 350 ml at 3 months was considered to be indicative of positive response to treatment. Thirty-four CT baseline variables, including quantitative measurements of FI, density, and vessel volumetry, were used to feed a multiple logistic regression analysis to find significant predictors of LVR outcome. The primary predictors were then used in 33 datasets with Chartis results to evaluate the relative performance of QCT versus Chartis. MEASUREMENTS AND MAIN RESULTS: FI (P < 0.0001) and low attenuation clusters (P = 0.01) measured in the treated lobe and vascular volumetric percentage of patient's detected smallest vessels (P = 0.02) were identified as the primary QCT predictors of LVR outcome. Accuracy for QCT patient selection based on these primary predictors was comparable to Chartis (78.8 vs. 75.8%). CONCLUSIONS: Quantitative CT led to comparable results to Chartis for classifying LVR and is a promising tool to effectively select patients for valve-based LVR procedures.

Ketogenic dietary therapies for adults with epilepsy: feasibility and classification of response.

Ketogenic dietary therapies are an effective treatment for children with drug-resistant epilepsy. There is currently no high-quality evidence regarding ketogenic dietary therapies in adults, and further research has been recommended. This audit aimed to provide further evidence for the feasibility of dietary treatment for adults and to consider factors that may aid response classification in this population. We evaluated the effectiveness and tolerability of ketogenic dietary therapies in 23 adults with epilepsy attending specialist clinics. Medical notes were used to obtain seizure frequency information and other effects associated with dietary treatment. Individuals who achieved ≥50% seizure reduction at all follow-up points were classified as responders. Response rates, in terms of seizure frequency, were similar to those commonly reported in pediatric cohorts: 9/23 (39%) adults were classified as responders. These responders remained on the diet for at least one year (follow-up: 1-10 years). Other benefits reported by patients, but not quantified, included a reduction in seizure severity and increased alertness and concentration. Such factors often favor continuation of ketogenic dietary therapies despite a <50% seizure reduction. One individual experienced psychosis while following dietary treatment; most commonly reported adverse events were gastrointestinal. Adverse events did not lead to discontinuation of treatment in any cases. Our findings suggest that adults with epilepsy are able to follow ketogenic dietary therapies long-term, and such treatment can lead to seizure reduction. Other aspects besides seizure frequency may be relevant when classifying response in adults, and appropriate ways to quantify these factors should be considered for use in future studies.

Individual differences in the neurobiology of social stress: implications for depression-cardiovascular disease comorbidity.

Stress initiates a cascade of complex neural and peripheral changes that promote healthy adaption to stress, but when unabated, leads to pathology. Fascinating individual differences arise in the ability to cope with a stressor, rendering an individual more or less likely to develop stress-induced pathologies such as depression, anxiety, and cardiovascular disease. In this review we evaluate recent findings that investigate the neural underpinnings of adopting a passive or active coping response during social defeat stress. Because passive coping is associated with vulnerability to stress-related pathologies and active coping confers resiliency, understanding neurobiological adaptations associated with these diverse coping strategies may reveal biomarkers or targets impacting stress susceptibility. The co-occurrence of stress-induced depression and cardiovascular disease is becoming increasingly clear. Therefore this review focuses on the central mechanisms capable of contributing to psychopathology and cardiovascular disease such as corticotropin releasing factor, neuropeptide Y, monoamines, cytokines and oxidative stress. The impetus for this review is to highlight neurobiological systems that warrant further evaluation for their contribution to the pathophysiology of depression-cardiovascular disease comorbidity.