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Macrophages rapidly engulf apoptotic cells to limit the release of noxious cellular contents and to restrict autoimmune responses against self antigens. Although factors participating in recognition and engulfment of apoptotic cells have been identified, the transcriptional basis for the sensing and the silent disposal of apoptotic cells is unknown. Here we show that peroxisome proliferator–activated receptor-δ (PPAR-δ) is induced when macrophages engulf apoptotic cells and functions as a transcriptional sensor of dying cells. Genetic deletion of PPAR-δ decreases expression of opsonins such as complement component-1qb (C1qb), resulting in impairment of apoptotic cell clearance and reduction in anti-inflammatory cytokine production. This increases autoantibody production and predisposes global and macrophage-specific Ppard−/− mice to autoimmune kidney disease, a phenotype resembling the human disease systemic lupus erythematosus. Thus, PPAR-δ has a pivotal role in orchestrating the timely disposal of apoptotic cells by macrophages, ensuring that tolerance to self is maintained. [ABSTRACT FROM AUTHOR]

Abstract: Multiple Sclerosis (MS) is considered to be a T cell-mediated autoimmune disease. An attractive strategy to prevent activation of autoaggressive T cells in MS, is the use of altered peptide ligands (APL), which bind to major histocompatibility complex class II (MHC II) molecules. To be of clinical use, APL must be capable of resisting hostile environments including the proteolytic machinery of antigen presenting cells (APC). The current design of APL relies on cost- and labour-intensive strategies. To overcome these major drawbacks, we used a deductive approach which involved modifying proteolytic cleavage sites in APL. Cleavage site-directed amino acid substitution of the autoantigen myelin basic protein (MBP) resulted in lysosomal protease-resistant, high-affinity binding peptides. In addition, these peptides mitigated T cell activation in a similar fashion as conventional APL. The strategy outlined allows the development of protease-resistant APL and provides a universal design strategy to improve peptide-based immunotherapeutics. [Copyright &y& Elsevier]

Treatment with glatiramer acetate (GA, copolymer-1, Copaxone), a drug approved for multiple sclerosis (MS), in a mouse model promoted development of anti-inflammatory type II monocytes, characterized by increased secretion of interleukin (IL)-10 and transforming growth factor (TGF)-β, and decreased production of IL-12 and tumor necrosis factor (TNF). This anti-inflammatory cytokine shift was associated with reduced STAT-1 signaling. Type II monocytes directed differentiation of TH2 cells and CD4+CD25+FoxP3+ regulatory T cells (Treg) independent of antigen specificity. Type II monocyte–induced regulatory T cells specific for a foreign antigen ameliorated experimental autoimmune encephalomyelitis (EAE), indicating that neither GA specificity nor recognition of self-antigen was required for their therapeutic effect. Adoptive transfer of type II monocytes reversed EAE, suppressed TH17 cell development and promoted both TH2 differentiation and expansion of Treg cells in recipient mice. This demonstration of adoptive immunotherapy by type II monocytes identifies a central role for these cells in T cell immune modulation of autoimmunity. [ABSTRACT FROM AUTHOR]

Robotically assisted cardiac surgery has been presented as less invasive than conventional surgery, with shortened hospital stays and faster return to daily activities. We evaluated our experience with the da Vinci robot to determine whether we could in fact demonstrate those findings. All mitral and tricuspid valve repairs were performed by the same surgeon. Cardiopulmonary bypass was performed with femoral cannulation, antegrade cardioplegia, and transthoracic aortic cross-clamping. Multiple valve repair techniques were used, including quadrant resection, cord replacement, Alfieri leaflet coaptation, and ring annuloplasty. Access was by 2 ports and a 5-cm right anterolateral thoracotomy. All annuloplasty rings were secured using surgical clips. From October 2003 through September 2004, 32 patients underwent robotically assisted mitral valve repair. The mean age of our population was 67.6 years (range,43-82 years). Four patients also underwent the 1st tricuspid valve repair using the da Vinci robot in the United States. There were 3 conversions for irreparable valves, 1 stroke, and 2 deaths. The average procedure time, cardiopulmonary bypass time, and aortic cross-clamp time were all reduced, when the first 20 patients were compared with the last 12. Length-of-stay also improved. One patient required early mitral valve replacement for recurrent regurgitation. Two patients required late (>3 month) mitral valve replacement for recurrent regurgitation. We have shown that a dedicated nonacademic institute can develop a robotic cardiac surgery program and perform mitral and tricuspid valve repairs successfully. There is a several-case learning curve, and patient selection is paramount. [ABSTRACT FROM AUTHOR]

Peptidyl arginine deiminases have been shown to be hyperactive in neurodegenerative diseases including multiple sclerosis. An α-amino acid-based core structure, derived from a hydantoin core, with unique heterocycles on the side chains were synthesized as potential noncovalent inhibitors of PAD enzymes. Among the various heterocycles investigated, compound 23, carrying an imidazole moiety, exhibited the highest potency in this series with some selectivity for PAD2, and was further investigated in vivo. Pharmacokinetics in mice suggested the Cmax to be 12.0 ± 2.5 μg/mL and 170 ± 10 ng/mL in the serum and brain, respectively, when compound 23 was administered at 50 mg/kg via single dose ip. At the same dose, compound 23 also reversed physical disability and cleared the brain of T-cell infiltration in an EAE mouse model of multiple sclerosis (MS). This novel series of compounds show promise for further development as disease modifying agents for the potential treatment of MS. [ABSTRACT FROM AUTHOR]

Obesity has been implicated in the rise of autoimmunity in women. We report that obesity induces a serum protein signature that is associated with T helper 1 (Th1), interleukin (IL)-17, and multiple sclerosis (MS) signaling pathways selectively in human females. Females, but not male mice, subjected to diet-induced overweightness/obesity (DIO) exhibited upregulated Th1/IL-17 inflammation in the central nervous system during experimental autoimmune encephalomyelitis, a model of MS. This was associated with worsened disability and a heightened expansion of myelin-specific Th1 cells in the peripheral lymphoid organs. Moreover, at steady state, DIO increased serum levels of interferon (IFN)-α and potentiated STAT1 expression and IFN-γ production by naive CD4 + T cells uniquely in female mice. This T cell phenotype was driven by increased adiposity and was prevented by the removal of ovaries or knockdown of the type I IFN receptor in T cells. Our findings offer a mechanistic explanation of how obesity enhances autoimmunity., Competing Interests: Declaration of interests J.J.A. is currently an employee of Bristol Myers Squibb. R.C.A. is on the advisory board for Progentec Diagnostics Inc., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Nonimmune hydrops fetalis (NIHF) poses a significant challenge in perinatal care due to its high mortality rates and diverse etiologies. This comprehensive review examines the pathophysiology, etiology, antenatal diagnosis and management, postnatal care, and outcomes of NIHF. NIHF arises from numerous underlying pathologies, including genetic disorders, cardiovascular causes, and fetal infections, with advances in diagnostic techniques improving identification rates. Management strategies include termination of pregnancy for severe cases and fetal therapy for selected treatable etiologies, and neonatal care involves assessing and treating fluid collections and identifying underlying causes. Prognosis depends on factors such as gestational age at diagnosis and the extent of resuscitation needed, with challenges remaining in improving outcomes for affected infants., (Copyright © 2024 by the American Academy of Pediatrics.)

Experimental autoimmune encephalomyelitis (EAE) is a common immune-based model of multiple sclerosis (MS). This disease can be induced in rodents by active immunization with protein components of the myelin sheath and Complete Freund's adjuvant (CFA) or by the transfer of myelin-specific T effector cells from rodents primed with myelin protein/CFA into naïve rodents. The severity of EAE is typically scored on a 5-point clinical scale that measures the degree of ascending paralysis, but this scale is not optimal for assessing the extent of recovery from EAE. For example, clinical scores remain high in some EAE models (e.g., myelin oligodendrocyte glycoprotein [MOG] peptide-induced model of EAE) despite the resolution of inflammation. Thus, it is important to complement clinical scoring with histological scoring of EAE, which also provides a means to study the underlying mechanisms of cellular injury in the central nervous system (CNS). Here, a simple protocol is presented to prepare and stain spinal cord and brain sections from mice and to score inflammation, demyelination, and axonal injury in the spinal cord. The method for scoring leukocyte infiltration in the spinal cord can also be applied to score brain inflammation in EAE. A protocol for measuring soluble neurofilament light (sNF-L) in the serum of mice using a Small Molecule Assay (SIMOA) assay is also described, which provides feedback on the extent of overall CNS injury in live mice.

Biological sex differences refer to differences between males and females caused by the sex chromosome complement (that is, XY or XX), reproductive tissues (that is, the presence of testes or ovaries), and concentrations of sex steroids (that is, testosterone or oestrogens and progesterone). Although these sex differences are binary for most human individuals and mice, transgender individuals receiving hormone therapy, individuals with genetic syndromes (for example, Klinefelter and Turner syndromes) and people with disorders of sexual development reflect the diversity in sex-based biology. The broad distribution of sex steroid hormone receptors across diverse cell types and the differential expression of X-linked and autosomal genes means that sex is a biological variable that can affect the function of all physiological systems, including the immune system. Sex differences in immune cell function and immune responses to foreign and self antigens affect the development and outcome of diverse diseases and immune responses., (© 2023. Springer Nature Limited.)

Multiple sclerosis (MS) is an immune-mediated disease that targets the myelin sheath of central nervous system (CNS) neurons leading to axon injury, neuronal death, and neurological progression. Though women are more highly susceptible to developing MS, men that develop this disease exhibit greater cognitive impairment and accumulate disability more rapidly than women. Magnetic resonance imaging and pathology studies have revealed that the greater neurological progression seen in males correlates with chronic immune activation and increased iron accumulation at the rims of chronic white matter lesions as well as more intensive whole brain and grey matter atrophy and axon loss. Studies in humans and in animal models of MS suggest that male aged microglia do not have a higher propensity for inflammation, but may become more re-active at the rim of white matter lesions as a result of the presence of pro-inflammatory T cells, greater astrocyte activation or iron release from oligodendrocytes in the males. There is also evidence that remyelination is more efficient in aged female than aged male rodents and that male neurons are more susceptible to oxidative and nitrosative stress. Both sex chromosome complement and sex hormones contribute to these sex differences in biology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Alvarez-Sanchez and Dunn.)

Background: Elevated levels of interferons (IFNs) are a characteristic feature of systemic autoimmune rheumatic diseases (SARDs) and may be useful in predicting impending symptomatic progression in anti-nuclear antibody-positive (ANA + ) individuals lacking a SARD diagnosis. Typically, these are measured by their effect on gene expression in the blood, which has limited their utility in clinical settings. Here, we assessed whether the measurement of serum IFN-α or selected IFN-induced cytokines accurately mirrors IFN-induced gene expression in ANA + individuals and investigated their utility as biomarkers of clinical progression., Methods: A total of 280 subjects were studied, including 50 ANA - healthy controls, 160 ANA + individuals without a SARD diagnosis (96 asymptomatic, 64 with undifferentiated connective tissue disease), and 70 SARD patients. IFN-induced gene expression was measured by nanoString and cytokine levels by ELISA or Simoa. ANA + individuals lacking a SARD diagnosis who had the new onset of SARD criteria over the subsequent 2 years were defined as progressors., Results: Measurement of IFN-α levels by high-sensitivity ELISA or Simoa correlated much better with IFN-induced gene expression than measurement of CXCL-10 or Galectin-9 levels. Despite this, high CXCL-10 and Galectin-9 levels were better predictors of subsequent progression in ANA + individuals than measures of IFN-α or IFN-induced gene expression with the optimal combination of predictive cytokines (CXCL-10 and IFN-α as measured by ELISA), resulting in a specificity and positive predictive value of 100%., Conclusion: Easily performed ELISA assays for CXCL-10 and IFN-α can be used to predict ANA + individuals at high risk of imminent symptomatic progression., (© 2023. The Author(s).)

Multiple sclerosis (MS) is a chronic, autoimmune, demyelinating disease of the central nervous system (CNS) that leads to axonal damage and accumulation of disability. Relapsing-remitting MS (RR-MS) is the most frequent presentation of MS and this form of MS is three times more prevalent in females than in males. This female bias in MS is apparent only after puberty, suggesting a role for sex hormones in this regulation; however, very little is known of the biological mechanisms that underpin the sex difference in MS onset. Experimental autoimmune encephalomyelitis (EAE) is an animal model of RR-MS that presents more severely in females in certain mouse strains and thus has been useful to study sex differences in CNS autoimmunity. Here, we overview the immunopathogenesis of MS and EAE and how immune mechanisms in these diseases differ between a male and female. We further describe how females exhibit more robust myelin-specific T helper (Th) 1 immunity in MS and EAE and how this sex bias in Th cells is conveyed by sex hormone effects on the T cells, antigen presenting cells, regulatory T cells, and innate lymphoid cell populations., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Puberty is a dynamic period marked by changing levels of sex hormones, the development of secondary sexual characteristics and reproductive maturity. This period has profound effects on various organ systems, including the immune system. The critical changes that occur in the immune system during pubertal onset have been shown to have implications for autoimmune conditions, including Multiple Sclerosis (MS). MS is rare prior to puberty but can manifest in children after puberty. This disease also has a clear female preponderance that only arises following pubertal onset, highlighting a potential role for sex hormones in autoimmunity. Early onset of puberty has also been shown to be a risk factor for MS. The purpose of this review is to overview the evidence that puberty regulates MS susceptibility and disease activity. Given that there is a paucity of studies that directly evaluate the effects of puberty on the immune system, we also discuss how the immune system is different in children and mice of pre- vs. post-pubertal ages and describe how gonadal hormones may regulate these immune mechanisms. We present evidence that puberty enhances the expression of co-stimulatory molecules and cytokine production by type 2 dendritic cells (DC2s) and plasmacytoid dendritic cells (pDCs), increases T helper 1 (Th1), Th17, and T follicular helper immunity, and promotes immunoglobulin (Ig)G antibody production. Overall, this review highlights how the immune system undergoes a functional maturation during puberty, which has the potential to explain the higher prevalence of MS and other autoimmune diseases seen in adolescence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Ucciferri and Dunn.)

Objective: Thioredoxin (Trx) is a small cellular redox protein with established antioxidant and disulfide reductase properties. We hypothesized that Trx deficiency in mice would cause increased oxidative stress with consequent redox imbalance that would exacerbate obesity-induced vascular dysfunction., Methods: Non-transgenic (NT, C57BL/6) and dominant-negative Trx (dnTrx-Tg, low levels of redox-active protein) mice were either fed a normal diet (NC) or high fat diet plus sucrose (HFS) diet for 4 months (3-month HFD+ 1-month HFS). Weight gain, glucose tolerance test (GTT), insulin tolerance test (ITT), and other metabolic parameters were performed following NC or HFS diet. Arterial structural remodeling and functional parameters were assessed by myography., Results: Our study found that dnTrx mice with lower levels of active Trx exacerbated myogenic tone, inward arterial remodeling, arterial stiffening, phenylephrine-induced contraction, and endothelial dysfunction of MA. Additionally, FeTMPyP, a peroxynitrite decomposition catalyst, acutely decreased myogenic tone and contraction and normalized endothelial function in MA from dnTrx-Tg mice on HFS via increasing nitric oxide (NO)-mediated relaxation., Conclusions: Our results indicate that deficiency of active Trx exacerbates MA contractile and relaxing properties during diet-induced obesity demonstrating that loss of redox balance in obesity is a key mechanism of vascular endothelial dysfunction., (© 2020 John Wiley & Sons Ltd.)

Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear receptor that functions to maintain metabolic homeostasis, regulate cell growth, and limit the development of excessive inflammation during immune responses. Previously, we reported that PPAR-δ-deficient mice develop a more severe clinical course of experimental autoimmune encephalomyelitis (EAE); however, it was difficult to delineate the role that microglia played in this disease phenotype since PPAR-δ-deficient mice exhibited a number of immune defects that enhanced CNS inflammation upstream of microglia activation. Here, we specifically investigated the role of PPAR-δ in microglia during EAE by using mice where excision of a floxed Ppard allele was driven by expression of a tamoxifen (TAM)-inducible CX3C chemokine receptor 1 promoter-Cre recombinase transgene ( Cx3cr1 CreERT2 : Ppard fl/fl ). We observed that by 30 days of TAM treatment, Cx3cr1 CreERT2 : Ppard fl/fl mice exhibited Cre-mediated deletion primarily in microglia and this was accompanied by efficient knockdown of Ppard expression in these cells. Upon induction of EAE, TAM-treated Cx3cr1 CreERT2 : Ppard fl/fl mice presented with an exacerbated course of disease compared to TAM-treated Ppard fl/fl controls. Histopathological and magnetic resonance (MR) studies on the spinal cord and brains of EAE mice revealed increased Iba-1 immunoreactivity, axonal injury and CNS tissue loss in the TAM-treated Cx3cr1 CreERT2 : Ppard fl/fl group compared to controls. In early EAE, a time when clinical scores and the infiltration of CD45 + leukocytes was equivalent between Cx3cr1 CreERT2 : Ppard fl/fl and Ppard fl/fl mice, Ppard -deficient microglia exhibited a more reactive phenotype as evidenced by a shorter maximum process length and lower expression of genes associated with a homeostatic microglia gene signature. In addition, Ppard -deficient microglia exhibited increased expression of genes associated with reactive oxygen species generation, phagocytosis and lipid clearance, M2-activation, and promotion of inflammation. Our results therefore suggest that PPAR-δ has an important role in microglia in limiting bystander tissue damage during neuroinflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Doroshenko, Drohomyrecky, Gower, Whetstone, Cahill, Ganguly, Spring, Yi, Sled and Dunn.)

The cysteine protease inhibitor Cystatin C (CST3) is highly expressed in the brains of multiple sclerosis (MS) patients and C57BL/6J mice with experimental autoimmune encephalomyelitis (EAE; a model of MS), but its roles in the diseases are unknown. Here, we show that CST3 plays a detrimental function in myelin oligodendrocyte glycoprotein 35-55 (MOG 35-55 )-induced EAE but only in female animals. Female Cst3 null mice display significantly lower clinical signs of disease compared to wild-type (WT) littermates. This difference is associated with reduced interleukin-6 production and lower expression of key proteins (CD80, CD86, major histocompatibility complex [MHC] II, LC3A/B) involved in antigen processing, presentation, and co-stimulation in antigen-presenting cells (APCs). In contrast, male WT and Cst3 -/- mice and cells show no differences in EAE signs or APC function. Further, the sex-dependent effect of CST3 in EAE is sensitive to gonadal hormones. Altogether, we have shown that CST3 has a sex-dependent role in MOG 35-55 -induced EAE., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is an inflammatory, neurodegenerative autoimmune disease associated with sensory and motor dysfunction. Although estimates vary, ∼50% of patients with MS experience pain during their disease. The mechanisms underlying the development of pain are not fully understood, and no effective treatment for MS-related pain is available. Previous work from our laboratory demonstrated that voluntary exercise (wheel running) can reduce nociceptive behaviours at the disease onset in female mice with experimental autoimmune encephalomyelitis (EAE), an animal model used to study the immunopathogenesis of MS. However, given the established sex differences in the underlying mechanisms of chronic pain and MS, we wanted to investigate whether wheel running would also be effective at preventing nociceptive behaviours in male mice with EAE. C57BL/6 mice of both sexes were given access to running wheels for 1 hour/day until the disease onset, when nociceptive behaviour was assessed using von Frey hairs. Daily running effectively reduced nociceptive behaviour in female mice, but not in male mice. We explored the potential biological mechanisms for these effects and found that the reduction in nociceptive behaviour in female mice was associated with reduced levels of inflammatory cytokines from myelin-reactive T cells as well as reduced dorsal root ganglia excitability as seen by decreased calcium responses. These changes were not seen in male mice. Instead, running increased the levels of inflammatory cytokines and potentiated Ca responses in dorsal root ganglia cells. Our results show that voluntary wheel running has sex-dependent effects on nociceptive behaviour and inflammatory responses in male and female mice with EAE.

T cells represent a critical effector of cell-mediated immunity. Activated T cells engage in metabolic reprogramming during effector differentiation to accommodate dynamic changes in energy demands. Here, we show that the hormone, insulin, and downstream signaling through its insulin receptor shape adaptive immune function through modulating T cell metabolism. T cells lacking insulin receptor expression (LckCre+ Insr fl/fl ) show reduced antigen-specific proliferation and compromised production of pro-inflammatory cytokines. In vivo, T cell-specific insulin receptor deficiency reduces T cell-driven colonic inflammation. In a model of severe influenza infection with A/PR8 (H1N1), lack of insulin receptor on T cells curtails antigen-specific immunity to influenza viral antigens. Mechanistically, insulin receptor signaling reinforces a metabolic program that supports T cell nutrient uptake and associated glycolytic and respiratory capacities. These data highlight insulin receptor signaling as an important node integrating immunometabolic pathways to drive optimal T cell effector function in health and disease., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

High-fat sucrose (HFS) diet in aged individuals causes severe weight gain (obesity) with much higher risk of cardiovascular diseases such as hypertension or atherosclerosis. Endothelial dysfunction is a major contributor for these vascular disorders. We hypothesize that prolonged ingestion of HFS diet by aged mice would accentuate endothelial dysfunction in the small resistance arteries. Male C57BL/6J mice at 12 weeks of age were divided into four groups and fed either normal chow (NC) or high-fat sucrose diet (HFS). Young group received NC for 4 months, and high-fat diet (HFD) for 3 months and 1 month HFS + 10% Sucrose (HFS diet). Aged mice received NC for 12 months. Aged HFS group received HFD for 4 months + 1 month HFD + 10% sucrose + 8 months HFD. Total body weight, plasma blood glucose levels, and glucose tolerance were determined in all groups. Isolated mesenteric arteries were assessed for arterial remodeling, myogenic tone, and vasomotor responses using pressure and wire myography. Both young and aged HFS mice showed impaired glucose tolerance (Y-NC, 137 ± 8.5 vs. Y-NC HFS, 228 ± 11.71; A-NC, 148 ± 6.42 vs. A-HFS, 225 ± 10.99), as well as hypercholesterolemia (Y-NC 99.50 ± 6.35 vs. Y-HFS 220.40 ± 16.34 mg/dL; A-NC 108.6 ± vs. A-HFS 279 ± 21.64) and significant weight gain (Y-NC 32.13 ± 0.8 g vs. Y-HFS 47.87 ± 2.18 g; A-NC 33.72 vs. A-HFS 56.28 ± 3.47 g) compared to both groups of mice on NC. The mesenteric artery from mice with prolonged HFS diet resulted in outward hypertrophic remodeling, increased stiffness, reduced myogenic tone, impaired vasodilation, increased contractility and blunted nitric oxide (NO) and EDH-mediated relaxations. Ebselen, a peroxinitrite scavenger rescued the endothelium derived relaxing factor (EDHF)-mediated relaxations. Our findings suggest that prolonged diet-induced obesity of aged mice can worsen small resistance artery endothelial dysfunction due to decrease in NO and EDHF-mediated relaxation, but, EDHF-mediated relaxation is a major contributor to overall endothelial dysfunction., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: The purpose of this study was to describe the delivery of prenatal care services to women with opioid use disorder (OUD) on opioid maintenance therapy at high risk for hepatitis C virus (HCV) infection., Methods: We conducted a retrospective cohort evaluation of 791 pregnant women with OUD from 2009 to 2012. HCV screening was defined as documentation of (a) an anti-HCV antibody test or (b) a provider discussion regarding a known HCV diagnosis during pregnancy. Multivariate logistic regression was used to identify predictors of HCV screening during pregnancy., Results: Among 791 pregnant women with OUD, 611 (77.2%) were screened for HCV infection and 369/611 (60.4%) were HCV positive. In multivariable analysis, patients who were married (odds ratio [OR] = 0.52; 95% confidence interval [CI] = 0.29, 0.91), used buprenorphine (OR = 0.45; 95% CI = 0.28, 0.71), and were cared for by private practice providers (OR = 0.29; 95% CI = 0.19, 0.45) were significantly less likely to be screened. In contrast, patients who used benzodiazepines (OR = 1.72; 95% CI = 1.02, 2.92), intravenous (IV) opioids (OR = 6.15; 95% CI = 3.96, 9.56), had legal problems (OR = 2.23; 95% CI = 1.12, 4.45), had children not in their custody (OR = 1.81; 95% CI = 1.01, 3.24), and who had a partner with substance abuse history (OR = 2.38; 95% CI = 1.23, 4.59) were significantly more likely to be screened. Of 369 HCV-positive patients, a new diagnosis of HCV was made during pregnancy for 108 (29.3%) patients. Only 94 (25.5%) had HCV viral load testing, 61 (16.5%) had HCV genotype testing, and 38 (10.4%) received an immunization for hepatitis A. Although 285 (77.2%) patients were referred to hepatology, only 71 (24.9%) attended the consultation. Finally, only 6 (1.6%) patients received HCV treatment 1 year following delivery., Conclusions: Prenatal care approaches to HCV infection remain inconsistent, and the majority of patients diagnosed with HCV infection during pregnancy do not receive treatment after delivery.

Obesity has reached epidemic proportions, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during high-fat diet (HFD) feeding and is a functional regulator of obesity-related insulin resistance (IR) that can be exploited therapeutically. Obesity induces a chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations. Reduction of the gut immune system, using beta7 integrin-deficient mice (Beta7(null)), decreases HFD-induced IR. Treatment of wild-type HFD C57BL/6 mice with the local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters. These beneficial effects are dependent on adaptive and gut immunity and are associated with reduced gut permeability and endotoxemia, decreased visceral adipose tissue inflammation, and improved antigen-specific tolerance to luminal antigens. Thus, the mucosal immune system affects multiple pathways associated with systemic IR and represents a novel therapeutic target in this disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease that leads to neuron damage and progressive disability. One major feature of multiple sclerosis (MS) is that it affects women three times more often than men. In this chapter, we overview the evidence that the autoimmune component of MS, which predominates in the early stages of this disease, is more robust in women than in men and undergoes a sharp increase with the onset of puberty. In addition, we discuss the common rodent models of MS that have been used to study the sex-based differences in the development of central nervous system (CNS) autoimmunity. We then address the biological underpinnings of this enhanced MS risk in women by first reviewing the autoimmune mechanisms that are thought to lead to the initiation of this disease and then honing in on how these mechanisms differ between the sexes. Finally, we review what is known about the hormonal and genetic basis of these sex differences in CNS autoimmunity.

It is well known that a number of autoimmune diseases including multiple sclerosis (MS) predominantly affect women and there has been much attention directed toward understanding why this is the case. Past research has revealed a number of sex differences in autoimmune responses that can account for the female bias in MS. However, much less is known about why the incidence of MS has increased exclusively in women over the past half century. The recency of this increase suggests that changing environmental or lifestyle factors are interacting with biological sex to increase MS risk predominantly in females. Indeed, a number of recent studies have identified sex-specific differences in the effect of environmental factors on MS incidence. The first part of this chapter will overview this evidence and will discuss the possible scenarios of how the environment may be interacting with autoimmune mechanisms to contribute to the preferential rise in MS incidence in women. Despite the strong female bias in MS incidence, culminating evidence from natural history studies, and imaging and pathology studies suggests that males who develop MS may exhibit a more rapid decline in disability and cognitive functioning than women. Very little is known about the biological basis of this more rapid deterioration, but some insights have been provided by studies in rodent models of demyelination/remyelination. The second part of this chapter will overview the evidence that males with relapsing-onset MS undergo a more rapid progression of disease than females and will discuss potential biological mechanisms that account for this sex difference.

Peroxisome proliferator-activated receptors (PPARs; PPAR-alpha, PPAR-delta, and PPAR-gamma) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-delta, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR-delta (PPAR-delta(-/-)) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN-gamma(+)IL-17A(-) and IFN-gamma(+)IL-17A(+) CD4(+) cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR-delta(-/-) mice occurred as a result of a constellation of immune system aberrations that included higher CD4(+) cell proliferation, cytokine production, and T-bet expression and enhanced expression of IL-12 family cytokines by myeloid cells. We also show that the effect of PPAR-delta in inhibiting the production of IFN-gamma and IL-12 family cytokines is ligand dependent and is observed in both mouse and human immune cells. Collectively, these findings suggest that PPAR-delta serves as an important molecular brake for the control of autoimmune inflammation.

Peroxisome proliferator-activated receptor (PPAR)alpha is a nuclear receptor that mediates gender differences in lipid metabolism. PPARalpha also functions to control inflammatory responses by repressing the activity of nuclear factor kappaB (NF-kappaB) and c-jun in immune cells. Because PPARalpha is situated at the crossroads of gender and immune regulation, we hypothesized that this gene may mediate sex differences in the development of T cell-mediated autoimmune disease. We show that PPARalpha is more abundant in male as compared with female CD4(+) cells and that its expression is sensitive to androgen levels. Genetic ablation of this gene selectively removed the brake on NF-kappaB and c-jun activity in male T lymphocytes, resulting in higher production of interferon gamma and tumor necrosis factor (but not interleukin 17), and lower production of T helper (Th)2 cytokines. Upon induction of experimental autoimmune encephalomyelitis, male but not female PPARalpha(-/-) mice developed more severe clinical signs that were restricted to the acute phase of disease. These results suggest that males are less prone to develop Th1-mediated autoimmunity because they have higher T cell expression of PPARalpha.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a critical enzyme in the mevalonate pathway that regulates the biosynthesis of cholesterol as well as isoprenoids that mediate the membrane association of certain GTPases. Blockade of this enzyme by atorvastatin (AT) inhibits the destructive proinflammatory T helper cell (Th)1 response during experimental autoimmune encephalomyelitis and may be beneficial in the treatment of multiple sclerosis and other Th1-mediated autoimmune diseases. Here we present evidence linking specific isoprenoid intermediates of the mevalonate pathway to signaling pathways that regulate T cell autoimmunity. We demonstrate that the isoprenoid geranylgeranyl-pyrophosphate (GGPP) mediates proliferation, whereas both GGPP and its precursor, farnesyl-PP, regulate the Th1 differentiation of myelin-reactive T cells. Depletion of these isoprenoid intermediates in vivo via oral AT administration hindered these T cell responses by decreasing geranylgeranylated RhoA and farnesylated Ras at the plasma membrane. This was associated with reduced extracellular signal-regulated kinase (ERK) and p38 phosphorylation and DNA binding of their cotarget c-fos in response to T cell receptor activation. Inhibition of ERK and p38 mimicked the effects of AT and induced a Th2 cytokine shift. Thus, by connecting isoprenoid availability to regulation of Th1/Th2 fate, we have elucidated a mechanism by which AT may suppress Th1-mediated central nervous system autoimmune disease.

Recruitment determines the profile of fibre-type-specific genes expressed across the range of muscle fibres associated with slow, fast fatigue-resistant and fast fatiguable motor units. Downstream signalling pathways activated by neural signalling and mechanical load have been the focus of intensive research in past years. It is now known that Ca(2+)-dependent calcineurin-nuclear factor of activated T cells and insulin-like growth factor 1 pathways and their downstream mediators contribute to these adaptive responses. These pathways regulate gene expression through muscle-specific (myocyte-enhancing factor 2, myoblast determination protein) and non-specific (nuclear factor of activated T cell 2, GATA-2) transcription factors. Transcriptional signals activated with increased contractile activity result in altered expression of fibre-type specific genes, including the myosin heavy chain isoforms and oxidative and glycolytic enzymes and a net change in muscle fibre-type composition. In contrast, transcriptional signals activated by increased load bearing result in hypertrophy or a growth response, a component of which involves satellite cell recruitment and fusion with existing adult myofibres. Calcineurin has been identified as a key mediator in the hypertrophic response, and the current challenge has been to determine the downstream target genes of this pathway. Exciting new data have emerged, showing that myostatin, a negative regulator of muscle growth, and utrophin, a cytoskeletal protein important in maintaining membrane integrity, are downstream targets of calcineurin signalling. Increased understanding of these mediators of muscle growth may provide strategies for the development of effective therapeutics to counter muscle weakness and muscular dystrophy.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) are oral cholesterol-lowering drugs. Statins are well tolerated and have an excellent safety record. These agents competitively inhibit HMG CoA reductase, which is the enzyme that catalyzes the conversion of HMG CoA to L-mevalonate. Although L-mevalonate is a key intermediate in cholesterol synthesis, several of its metabolites are involved in post-translational modification of specific proteins involved in cell proliferation and differentiation. Thus, independent of their cholesterol-reducing properties, statins have important pleiotropic biologic effects. Recent reports indicate that statins have anti-inflammatory and neuroprotective properties. Whether statins will be of clinical benefit for patients with multiple sclerosis and other neurodegenerative diseases of the central nervous system will only be known after they are evaluated in prospective randomized clinical trials.

Occupational therapy faculty and students from East Carolina University, in collaboration with the residents of Tillery, North Carolina, participated in a community-built wellness program. Outcomes of the program indicated that a program with participant input results in enhanced perceived wellness, maintenance of meaningful activities, and improved self-reported quality of life. Program elements necessary for duplication of the program are discussed. Recommendations for similar programs include developing mutual trust and respect, utilizing activities that are meaningful to participants, working within the culture, and considering the participants' lifestyles when planning.