Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone Lactylation.

During the inflammatory response, macrophage phenotypes can be broadly classified as pro-inflammatory/classically activated "M1", or pro-resolving/alternatively "M2" macrophages. Although the classification of macrophages is general and assumes there are distinct phenotypes, in reality macrophages exist across a spectrum and must transform from a pro-inflammatory state to a proresolving state following an inflammatory insult. To adapt to changing metabolic needs of the cell, mitochondria undergo fusion and fission, which have important implications for cell fate and function. We hypothesized that mitochondrial fission and fusion directly contribute to macrophage function during the pro-inflammatory and proresolving phases. In the present study, we find that mitochondrial length directly contributes to macrophage phenotype, primarily during the transition from a pro-inflammatory to a proresolving state. Phenocopying the elongated mitochondrial network (by disabling the fission machinery using siRNA) leads to a baseline reduction in the inflammatory marker IL-1ß, but a normal inflammatory response to LPS, similar to control macrophages. In contrast, in macrophages with a phenocopied fragmented phenotype (by disabling the fusion machinery using siRNA) there is a heightened inflammatory response to LPS and increased signaling through the ATF4/c-Jun transcriptional axis compared to control macrophages. Importantly, macrophages with a fragmented mitochondrial phenotype show increased expression of proresolving mediator arginase 1 and increased phagocytic capacity. Promoting mitochondrial fragmentation caused an increase in cellular lactate, and an increase in histone lactylation which caused an increase in arginase 1 expression. These studies demonstrate that a fragmented mitochondrial phenotype is critical for the proresolving response in macrophages and specifically drive epigenetic changes via lactylation of histones following an inflammatory insult.

The Impact of Eating Disorders on Reproductive Health: Mitigating the Risk.

Importance: While eating disorders (EDs) affect people of all ages, reproductive stages, and genders, they are most prevalent in women of reproductive age and can have a profound impact on fertility and obstetric outcomes. Due to the high prevalence and health consequences, EDs in this group of women require specific attention.Objective: To discuss the implications of EDs in infertility, pregnancy, and the postpartum period and to introduce tools to aid in identifying disordered eating and appropriate treatment recommendations for women with suspected EDs.Evidence Review: A comprehensive literature search was conducted of articles available on PubMed, last updated retrieval date March 27, 2023. Chain searching was used to identify other relevant articles. The following search terms were included: (pregnancy OR postpartum) AND (bulimia nervosa OR eating disorder OR anorexia nervosa OR binge eating disorder) AND (obstetric outcome OR infant outcome OR infant development OR depression OR anxiety); (fertility OR infertility) AND (bulimia nervosa OR eating disorder OR anorexia nervosa OR binge eating disorder OR weight suppression OR eating disorder not otherwise specified OR other specified feeding and eating disorder OR atypical anorexia nervosa OR binge eating OR low weight); and eating disorders AND PCOS. Articles pertinent to the impact of eating disorders on fertility and the impact of perinatal eating disorders on infant and mother were selected.Findings: Perinatal EDs impact maternal mental health and obstetric and infant outcomes. They can have a long-lasting effect on the offspring via epigenetic changes. EDs are also a common and treatable cause of infertility.Conclusions and Relevance: Recognition and treatment of EDs in women prior to conception can minimize obstetric risks to the woman and potential long-term adverse effects on the offspring. For women with infertility, recognition and treatment of EDs can increase the probability of conception.Prim Care Companion CNS Disord 2023;25(4):22nr03475. Author affiliations are listed at the end of this article.

Body Dysmorphic Disorder in Women.

Body dysmorphic disorder (BDD) consists of distressing or impairing preoccupation with perceived defects in physical appearance that are actually nonexistent or only slight. This common and often-severe disorder, which affects more women than men, frequently goes unrecognized. BDD is associated with marked impairment in functioning, poor quality of life, and high rates of suicidality. Most patients seek cosmetic treatment, which virtually never improves BDD symptoms. In contrast, serotonin-reuptake inhibitors, often at high doses, and cognitive behavioral therapy that is tailored to BDD's unique clinical features are often effective. This article provides a clinical overview of BDD, including BDD in women.

Breastfeeding and pumping as maladaptive weight control behaviors.

It is well recognized by the general public that breastfeeding expends calories. In our clinical practice, a number of postpartum women with a history of or a current eating disorder (ED) report using breastfeeding and/or pumping breast milk to influence their body shape and weight. This appears to be either a form of weight control behavior or, in some cases, a compensation for perceived overeating or binge eating. Breastfeeding and pumping have not generally been identified as maladaptive weight control behaviors, nor have they been a subject of research to date. We suggest that this practice should be investigated to determine how common it is, its potential role in maintaining EDs or contributing to relapse in the postpartum period, and to better understand other potential harms it may cause to both the mother and infant/child. PUBLIC SIGNIFICANCE: Breastfeeding and pumping may be used as maladaptive methods of weight control by women with EDs. This behavior is under-recognized in clinical practice and has received little research attention. We argue that maladaptive breastfeeding and pumping warrant further investigation, as the behaviors may play an important role in maintaining an ED or in contributing to relapse during the postpartum period and may also indirectly harm the infant/child.

Premenstrual dysphoric disorder and sexual function: a narrative review.

INTRODUCTION: Premenstrual dysphoric disorder (PMDD) and female sexual dysfunction (FSD) are 2 prevalent illnesses in women that cause distress and affect quality of life. There are plausible biological, social, and psychological links between these 2 conditions. Nevertheless, few studies have examined sexual function in women with PMDD. OBJECTIVES: In this narrative review we summarize the existing literature on sexual function in women with PMDD and with the broader diagnostic classification of premenstrual syndrome and discus the differences between PMDD and more general premenstrual symptomatology, as well as why studying sexual function specifically in PMDD is necessary. We explored reasons why these 2 illnesses may be comorbid and the importance of studying sexual function in this population of women. METHODS: PubMed literature searches were conducted using relevant keywords. RESULTS: Currently, there are few studies examining PMDD and FSD, and the studies available have significant methodologic limitations. CONCLUSIONS: Investigation of sexual function in women with PMDD is needed. Awareness of the comorbidities for PMDD and FSD can allow implementation of targeted interventions for women suffering from these disorders.

Clinical Implications of the Neurosteroid Allopregnanolone in Reproductive Depression.

ABSTRACT: Certain women develop depression with fluctuations in hormone levels whereas other women do not; this hormonally driven depression has been termed reproductive depression. The pathophysiology of reproductive depression differs from that of major depressive disorder, and this distinction has important clinical-including treatment-implications. Recent advances have revealed that the neurosteroid, allopregnanolone, plays a central role in reproductive depression. Appreciation of allopregnanolone's role in reproductive depression aids in selecting targeted treatments and in predicting symptom worsening during subsequent reproductive stages, and it can be used to reduce risk of relapse. This knowledge is also guiding the development of new pharmacologic treatments for reproductive depression.

Comorbidity and healthcare utilization in patients with treatment resistant depression: A large-scale retrospective cohort analysis using electronic health records.

BACKGROUND: Medical comorbidity and healthcare utilization in patients with treatment resistant depression (TRD) is usually reported in convenience samples, making estimates unreliable. There is only limited large-scale clinical research on comorbidities and healthcare utilization in TRD patients. METHODS: Electronic Health Record data from over 3.3 million patients from the INSIGHT Clinical Research Network in New York City was used to define TRD as initiation of a third antidepressant regimen in a 12-month period among patients diagnosed with major depressive disorder (MDD). Age and sex matched TRD and non-TRD MDD patients were compared for anxiety disorder, 27 comorbid medical conditions, and healthcare utilization. RESULTS: Out of 30,218 individuals diagnosed with MDD, 15.2 % of patients met the criteria for TRD (n = 4605). Compared to MDD patients without TRD, the TRD patients had higher rates of anxiety disorder and physical comorbidities. They also had higher odds of ischemic heart disease (OR = 1.38), stroke/transient ischemic attack (OR = 1.57), chronic kidney diseases (OR = 1.53), arthritis (OR = 1.52), hip/pelvic fractures (OR = 2.14), and cancers (OR = 1.41). As compared to non-TRD MDD, TRD patients had higher rates of emergency room visits, and inpatient stays. In relation to patients without MDD, both TRD and non-TRD MDD patients had significantly higher levels of anxiety disorder and physical comorbidities. LIMITATIONS: The INSIGHT-CRN data lack information on depression severity and medication adherence. CONCLUSIONS: TRD patients compared to non-TRD MDD patients have a substantially higher prevalence of various psychiatric and medical comorbidities and higher health care utilization. These findings highlight the challenges of developing interventions and care coordination strategies to meet the complex clinical needs of TRD patients.

miR-223 Exerts Translational Control of Proatherogenic Genes in Macrophages.

BACKGROUND: A significant burden of atherosclerotic disease is driven by inflammation. Recently, microRNAs (miRNAs) have emerged as important factors driving and protecting from atherosclerosis. miR-223 regulates cholesterol metabolism and inflammation via targeting both cholesterol biosynthesis pathway and NFkB signaling pathways; however, its role in atherosclerosis has not been investigated. We hypothesize that miR-223 globally regulates core inflammatory pathways in macrophages in response to inflammatory and atherogenic stimuli thus limiting the progression of atherosclerosis. METHODS AND RESULTS: Loss of miR-223 in macrophages decreases Abca1 gene and protein expression as well as cholesterol efflux to apoA1 (Apolipoprotein A1) and enhances proinflammatory gene expression. In contrast, overexpression of miR-223 promotes the efflux of cholesterol and macrophage polarization toward an anti-inflammatory phenotype. These beneficial effects of miR-223 are dependent on its target gene, the transcription factor Sp3. Consistent with the antiatherogenic effects of miR-223 in vitro, mice receiving miR223-/- bone marrow exhibit increased plaque size, lipid content, and circulating inflammatory cytokines (ie, IL-1ß). Deficiency of miR-223 in bone marrow-derived cells also results in an increase in circulating pro-atherogenic cells (total monocytes and neutrophils) compared with control mice. Furthermore, the expression of miR-223 target gene (Sp3) and pro-inflammatory marker (Il-6) are enhanced whereas the expression of Abca1 and anti-inflammatory marker (Retnla) are reduced in aortic arches from mice lacking miR-223 in bone marrow-derived cells. In mice fed a high-cholesterol diet and in humans with unstable carotid atherosclerosis, the expression of miR-223 is increased. To further understand the molecular mechanisms underlying the effect of miR-223 on atherosclerosis in vivo, we characterized global RNA translation profile of macrophages isolated from mice receiving wild-type or miR223-/- bone marrow. Using ribosome profiling, we reveal a notable upregulation of inflammatory signaling and lipid metabolism at the translation level but less significant at the transcription level. Analysis of upregulated genes at the translation level reveal an enrichment of miR-223-binding sites, confirming that miR-223 exerts significant changes in target genes in atherogenic macrophages via altering their translation. CONCLUSIONS: Our study demonstrates that miR-223 can protect against atherosclerosis by acting as a global regulator of RNA translation of cholesterol efflux and inflammation pathways.

Through the layers: how macrophages drive atherosclerosis across the vessel wall.

Cardiovascular disease (CVD) accounts for almost half of all deaths related to non-communicable disease worldwide, making it the single largest global cause of mortality. Although the risk factors for coronary artery disease - the most common cause of CVD - are well known and include hypertension, high cholesterol, age, and genetics, CVDs are now recognized as chronic inflammatory conditions. Arterial blockages, known as atherosclerosis, develop due to excess cholesterol accumulating within the arterial wall, creating a perpetually inflammatory state. The normally quiescent intimal layer of the vessel wall becomes laden with inflammatory cells, which alters the surrounding endothelial, smooth muscle, and extracellular matrix components to propagate disease. Macrophages, which can be either tissue resident or monocyte derived, are a key player in atherosclerotic disease progression and regression, and the understanding of their functions and origins continues to evolve with the use of deep phenotyping methodologies. This Review outlines how macrophages interact with each layer of the developing atherosclerotic plaque and discusses new concepts that are challenging our previous views on how macrophages function and our evolving understanding of the contribution of macrophages to disease.

Perinatal Planning Guide: Mitigating Perinatal Mood and Anxiety Disorders During the COVID-19 Pandemic.

Women are at high risk for and more vulnerable to perinatal mood and anxiety disorders (PMADs) during the coronavirus disease 2019 (COVID-19) pandemic. While access to specialized perinatal mental health services is limited, clinicians with whom women have ongoing relationships are in a unique position to counsel about prevention of PMADs. These clinicians include primary care, obstetric, and general mental health clinicians. By providing a woman with practical guidance and psychoeducation for perinatal planning (eg, about sleep, exercise, nutrition, and the importance of social supports), clinicians can mitigate a woman's risk of PMADs. This practical guidance must be modified to fit the social context of the COVID-19 pandemic. This guidance can prevent or attenuate unnecessary suffering on the part of the mother and have a long-lasting impact on her child. This review provides a perinatal planning guide that outlines important topics to discuss and problem solve with women in the context of the COVID-19 pandemic.

Delivery of MicroRNAs by Chitosan Nanoparticles to Functionally Alter Macrophage Cholesterol Efflux in Vitro and in Vivo.

The prevention and treatment of cardiovascular diseases (CVD) has largely focused on lowering circulating LDL cholesterol, yet a significant burden of atherosclerotic disease remains even when LDL is low. Recently, microRNAs (miRNAs) have emerged as exciting therapeutic targets for cardiovascular disease. miRNAs are small noncoding RNAs that post-transcriptionally regulate gene expression by degradation or translational inhibition of target mRNAs. A number of miRNAs have been found to modulate all stages of atherosclerosis, particularly those that promote the efflux of excess cholesterol from lipid-laden macrophages in the vessel wall to the liver. However, one of the major challenges of miRNA-based therapy is to achieve tissue-specific, efficient, and safe delivery of miRNAs in vivo. We sought to develop chitosan nanoparticles (chNPs) that can deliver functional miRNA mimics to macrophages and to determine if these nanoparticles can alter cholesterol efflux and reverse cholesterol transport in vivo. We developed chNPs with a size range of 150-200 nm via the ionic gelation method using tripolyphosphate (TPP) as a cross-linker. In this method, negatively charged miRNAs were encapsulated in the nanoparticles by ionic interactions with polymeric components. We then optimized the efficiency of intracellular delivery of different formulations of chitosan/TPP/miRNA to mouse macrophages. Using a well-defined miRNA with roles in macrophage cholesterol metabolism, we tested whether chNPs could deliver functional miRNAs to macrophages. We find chNPs can transfer exogenous miR-33 to naïve macrophages and reduce the expression of ABCA1, a potent miR-33 target gene, both in vitro and in vivo, confirming that miRNAs delivered via nanoparticles can escape the endosomal system and function in the RISC complex. Because miR-33 and ABCA1 play a key role in regulating the efflux of cholesterol from macrophages, we also confirmed that macrophages treated with miR-33-loaded chNPs exhibited reduced cholesterol efflux to apolipoprotein A1, further confirming functional delivery of the miRNA. In vivo, mice treated with miR33-chNPs showed decreased reverse cholesterol transport (RCT) to the plasma, liver, and feces. In contrast, when efflux-promoting miRNAs were delivered via chNPs, ABCA1 expression and cholesterol efflux into the RCT pathway were improved. Over all, miRNAs can be efficiently delivered to macrophages via nanoparticles, where they can function to regulate ABCA1 expression and cholesterol efflux, suggesting that these miRNA nanoparticles can be used in vivo to target atherosclerotic lesions.

GABAA dysregulation as an explanatory model for late-onset postpartum depression associated with weaning and resumption of menstruation.

It is well established that a subgroup of women are particularly vulnerable to affective dysregulation during times of hormonal fluctuation. One underrecognized reproductive transition may be late-onset postpartum depression (PPD) in the context of weaning from breastfeeding and the resumption of menstruation. The goal of this review is to propose a biologically plausible mechanism for affective dysregulation during these transitions. The relationship between affective symptoms and neurohormonal changes associated with weaning will be investigated through a hypothesis-driven review of relevant literature. Neurosteroids, like allopregnanolone (ALLO), are widely recognized for augmenting GABAergic inhibition and having a powerful anxiolytic effect (Belelli D and Lambert JL, Nature Reviews Neuroscience 6:565-575, 2005). However, when ALLO is administered after prolonged withdrawal, there may be a paradoxical anxiogenic effect (Smith et al., Psychopharmacology 186:323-333, 2006; Shen et al., Nat Neurosci 10:469-477, 2007). Weaning from breastfeeding is a physiologic example of fluctuating levels of ALLO after prolonged withdrawal. We propose that the complex hormonal milieu during weaning and resumption of menstruation may modify GABAA receptors such that ALLO may contribute to rather than ameliorate depressive symptoms in vulnerable individuals. The proposed model provides an initial step for understanding the mechanisms by which the changing hormonal environment during weaning and resumption of menstruation may contribute to an increased risk of depression in a subgroup of women who are hormonally sensitive. Future research investigating this model would be valuable both to identify women at increased risk for developing mood symptoms late in postpartum and to inform treatment for this and related reproductive depressive disorders.

Chemoenzymatic macrocycle synthesis using resorcylic acid lactone thioesterase domains.

A key missing tool in the chemist's toolbox is an effective biocatalyst for macrocyclization. Macrocycles limit the conformational flexibility of small molecules, often improving their ability to bind selectively and with high affinity to a target, making them a privileged structure in drug discovery. Macrocyclic natural product biosynthesis offers an obvious starting point for biocatalyst discovery via the native macrocycle forming biosynthetic mechanism. Herein we demonstrate that the thioesterase domains (TEs) responsible for macrocyclization of resorcylic acid lactones are promising catalysts for the chemoenzymatic synthesis of 12- to 18-member ring macrolactones and macrolactams. The TE domains responsible for zearalenone and radicicol biosynthesis successfully generate resorcylate-like 12- to 18-member macrolactones and a 14-member macrolactam. In addition these enzymes can also macrolactonize a non-resorcylate containing depsipeptide, suggesting they are versatile biocatalysts. Simple saturated omega-hydroxy acyl chains are not macrocyclized, nor are the alpha-beta unsaturated derivatives, clearly outlining the scope of the substrate tolerance. These data dramatically expand our understanding of substrate tolerance of these enzymes and are consistent with our understanding of the role of TEs in iterative polyketide biosynthesis. In addition this work shows these TEs to be the most substrate tolerant polyketide macrocyclizing enzymes known, accessing resorcylate lactone and lactams as well as cyclicdepsipeptides, which are highly biologically relevant frameworks.

Considerations in Treating Insomnia During Pregnancy: A Literature Review.

BACKGROUND: The prevalence of pregnancy-associated insomnia is high. Although insomnia may flow from normal physiologic features of pregnancy, it may also be an early warning sign of a relapse, or a trigger for a relapse, of a psychiatric illness. Those at risk for psychiatric illnesses may require medications as well as behavioral and psychotherapeutic interventions, to prevent relapse in the perinatal period. Unfortunately, few reviews of psychotropics used to treat pregnancy-related sleep disorders exist. OBJECTIVE: We discuss issues related to sleep and sleep disorders in pregnancy in the context of co-morbid psychiatric illness, and review the literature on the commonly-used medications (e.g., benzodiazepines, sedative-hypnotics, antihistamines, trazodone, and melatonin) for insomnia during pregnancy.

Protection against hormone-mediated mood symptoms.

We present the case of a woman with bipolar I disorder with severe premenstrual mood instability, confusion, and psychosis resembling the clinical features of postpartum psychosis when estrogen levels are expected to be low, and hypomania when estrogen levels are expected to be elevated. While depressive symptoms across the menstrual cycle have been extensively documented in the literature, there is little information regarding manic and hypomanic symptoms. In addition, we describe the successful treatment of her menstrual-cycle related symptoms. Approaches to the management of menstrual psychosis have not been systematically studied, and clinical guidelines do not exist. Clinical experiences such as the one reported here, in which the clinical formulation of the patient was consistent with known neuroendocrine phenomena and in which the treatment approach was successful, are crucial to developing promising approaches that can be tested in controlled trials.

Selective serotonin reuptake inhibitors for depression in pregnancy.

Perinatal depression is associated with a high risk of morbidity and mortality and may have long-term consequences on child development. The US Preventive Services Task Force has recently recognized the importance of identifying and treating women with depression in the perinatal period. However, screening and accessing appropriate treatment come with logistical challenges. In many areas, there may not be sufficient access to psychiatric care, and, until these resources develop, the burden may inadvertently fall on obstetricians. As a result, understanding the risks of perinatal depression in comparison with the risks of treatment is important. Many studies of selective serotonin reuptake inhibitors in pregnancy fail to control for underlying depressive illness, which can lead to misinterpretation of selective serotonin reuptake inhibitor risk by clinicians. This review discusses the risks and benefits of selective serotonin reuptake inhibitor treatment in pregnancy within the context of perinatal depression. Whereas selective serotonin reuptake inhibitors may be associated with certain risks, the absolute risks are low and may be outweighed by the risks of untreated depression for many women and their offspring.

[Psychometric properties and reliability of the general health questionnaire(GHQ-12) for adult patients in primary care centers in Cordoba, Argentina].

INTRODUCTION: The General Health Questionnaire (GHQ-12) is a commonly used instrument to screen for psychiatric distress. However, the psychometric properties and reliability of the GHQ-12 in Argentina and, more specifically, in the city of Cordoba, have not previously been studied. OBJECTIVE: To assess the psychometric properties and reliability of GHQ-12 in adult consultants of primary care in Cordoba, Argentina. METHODS: Using probabilistic sampling in primary care centers in the city of Cordoba, a cross-sectional study was conducted. The Spanish version of the GHQ-12 was administered. The psychometric properties, including internal consistency and factor structure, for the Spanish version of the GHQ-12 were measured. RESULTS: 854 primary care consultants were included in the study. The questionnaire had high internal consistency, with a Cronbach's alpha of 0.80. An exploratory factor analysis suggested a two-factor model, similar to what has been reported for the original questionnaire. CONCLUSIONS: The GHQ-12 showed good psychometric properties and reliability in the studied population.

Single low-dose CT scan optimized for rest-stress PET attenuation correction and quantification of coronary artery calcium.

BACKGROUND: Coronary artery calcium is an important marker of coronary artery disease. Myocardial perfusion imaging (MPI) using PET-CT technology requires a CT scan for attenuation correction (CTAC) but is not used routinely to measure coronary calcium burden. This study aimed to determine if a low-dose CTAC scan can also accurately quantify coronary artery calcium. METHODS: Twenty-three patients underwent both a traditional coronary artery calcium scan on a dedicated cardiac CT scanner (CAC-CT) and a myocardial perfusion scan on a hybrid PET-CT scanner. The standard MPI protocol includes rest and stress-matched PET and CTAC scans. The post-stress CTAC scan was modified to approximate the CAC-CT scan protocol while maintaining ~0.5 mSv dose. Coronary artery calcium scores were compared between the Ca-CTAC and CAC-CT scans. RESULTS: The modified Ca-CTAC scan showed a trend toward slight decreases in segmental stress perfusion of 2-3.5% in the anterior wall segments (P < 0.05). Correlation and agreement between the proposed Ca-CTAC and standard CAC-CT calcium scores at the optimal threshold of 110 HU were also excellent (r (2) = 0.99, κ = 1.0). There was a small difference in the regression slope vs unity: Ca-CTAC = 0.96 × CAC (P < 0.05), but the categorical classification of calcium was accurate in all twenty-three patients (κ = 1.0). CONCLUSION: A single low-dose rest CTAC scan can be used for accurate attenuation correction of rest and stress PET perfusion images, thus allowing a post-stress CTAC scan to be optimized for improved quantification of coronary artery calcium without increasing radiation dose vs standard protocols.