Coordination between Two Branches of the Unfolded Protein Response Determines Apoptotic Cell Fate.

The kinases PERK and IRE1 alleviate endoplasmic reticulum (ER) stress by orchestrating the unfolded protein response (UPR). If stress mitigation fails, PERK promotes cell death by activating pro-apoptotic genes, including death receptor 5 (DR5). Conversely, IRE1-which harbors both kinase and endoribonuclease (RNase) modules-blocks apoptosis through regulated IRE1-dependent decay (RIDD) of DR5 mRNA. Under irresolvable ER stress, PERK activity persists, whereas IRE1 paradoxically attenuates, by mechanisms that remain obscure. Here, we report that PERK governs IRE1's attenuation through a phosphatase known as RPAP2 (RNA polymerase II-associated protein 2). RPAP2 reverses IRE1 phosphorylation, oligomerization, and RNase activation. This inhibits IRE1-mediated adaptive events, including activation of the cytoprotective transcription factor XBP1s, and ER-associated degradation of unfolded proteins. Furthermore, RIDD termination by RPAP2 unleashes DR5-mediated caspase activation and drives cell death. Thus, PERK attenuates IRE1 via RPAP2 to abort failed ER-stress adaptation and trigger apoptosis.

An integrative exploration of environmental stressors on the microbiome-gut-brain axis and immune mechanisms promoting neurological disorders.

The microbiome-gut-brain axis is altered by environmental stressors such as heat, diet, and pollutants as well as microbes in the air, water, and soil. These stressors might alter the host's microbiome and symbiotic relationship by modifying the microbial composition or location. Compartmentalized mutualistic microbes promote the beneficial interactions in the host leading to circulating metabolites and hormones such as insulin and leptin that affect inter-organ functions. Inflammation and oxidative stress induced by environmental stressors may alter the composition, distribution, and activities of the microbes in the microbiomes such that the resultant metabolite and hormone changes are no longer beneficial. The microbiome-gut-brain axis and immune adverse changes that may accompany environmental stressors are reviewed for effects on innate and adaptive immune cells, which may make host immunity less responsive to pathogens and more reactive to self-antigens. Cardiovascular and fluid exchanges to organs might adversely alter organ functionality. Organs, especially the brain, need a consistent supply of nutrients and clearance of debris; disruption of these exchanges by stressors, and involvement of gut microbiome are discussed regarding neural dysfunctions with Alzheimer's disease, autistic spectrum disorders, viral infections, and autoimmune diseases. The focus of this review includes the manner in which environmental stressors may disrupt gut microbiota leading to adverse immune and hormonal influences on development of neuropathology related to hyperhomocysteinemia, inflammation, and oxidative stress, and how certain therapeutics may be beneficial. Strategies are explored to lessen detrimental effects of environmental stressors on central and peripheral health navigated toward (1) understanding neurological disorders and (2) promoting environmental and public health and well-being.

Exposure of Akwesasne Mohawk women to polychlorinated biphenyls and hexachlorobenzene is associated with increased serum levels of thyroid peroxidase autoantibodies.

Persistent organic pollutants (POPs) including polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), and dichlorodiphenyltrichloroethane (p,p'-DDT) were reported to influence immunological activity. As endocrine-disrupting chemicals (EDC), these pollutants may disrupt normal thyroid function and act as catalysts for development of autoimmune thyroid disease by directly and indirectly affecting levels of thyroid peroxidase antibodies (TPOAbs). Native American communities are disproportionately exposed to harmful toxicants and are at an increased risk of developing an autoimmune disease. The aim of this study was to determine the association between POPs and TPOAbs in serum obtained from Native American women. This assessment was used to measure whether increased risk of autoimmune thyroid disease occurred as a result of exposure to POPs. Data were collected from 183 Akwesasne Mohawk women, 21-38 years of age, between 2009 and 2013. Multivariate analyses were conducted to determine the association between toxicant exposure and levels of TPOAbs. In multiple logistic regression analyses, exposure to PCB congener 33 was related to elevated risk of individuals possessing above normal levels of TPOAbs. Further, HCB was associated with more than 2-fold higher risk of possessing above normal levels of TPOAbs compared to women with normal levels of TPOAbs. p,p'-DDE was not associated with TPOAb levels within this study. Exposure to PCB congener 33 and HCB was correlated with above normal levels of TPOAbs, a marker of autoimmune thyroid disease. Additional investigations are needed to establish the causes and factors surrounding autoimmune thyroid disease which are multiple and complex.

Constitutive activation of Notch signalling and T cell activation characterize a mouse model of autism.

Gene and protein expression of BTBR T+ Itpr3tf /J (BTBR) mice with autistic-like behaviours were compared with the C57BL/6J strain, which is considered to have normal immunity and behaviour. Notch signalling pathway was constitutively activated in the immune system and liver of BTBR T+ Itpr3tf /J (BTBR) mice. Notch ligand 4 (Dll4), Notch receptors (Notch1 Notch2 and Notch3) and recombination signal binding protein for immunoglobulin κ j region (RBPJ) were increased both at gene and protein levels in BTBR spleens and thymi. Notch downstream transcriptional factors, Tbx21, Gata3, Rorc and FoxP3 were increased in BTBR spleens, Gata3 and FoxP3 were increased in BTBR thymi and BTBR mice have a high blood CD4/CD8 T cell ratio. Reduced nucleotide excision repair ability in BTBR spleens was associated with increased 8-oxoguanine, Ogg1 inhibition, an enhanced level of apoptotic thymocytes and higher expression of GATA-3. Ogg1 inhibition and enhanced GATA-3 expression also were detected in BTBR brain. Notch signal promoted mitochondrial dynamics switching to enhanced fission with an increased number and mass of mitochondria in immune cells of BTBR mice, but not in livers and brains. Constitutive influences on mitochondria exist in this mouse model of autism spectrum disorder; similar outcomes from environmental exposures might occur perinatally in susceptible individuals to affect the development of autism.

Perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA) modify in vitro mitogen- and antigen-induced human peripheral blood mononuclear cell (PBMC) responses.

Environmental contaminants perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are present in human serum at the highest concentration among all per- and polyfluoroalkyl substances (PFAS). Serum concentrations as high as 500 ng and 3000 ng PFOA/ml have been detected in individuals living near contamination sites and those occupationally exposed, respectively. Animal and human studies indicated that PFOA and PFOS at these serum concentrations perturb the immune system. The aim of this study was to examine the effects of in vitro exposure of human peripheral blood mononuclear cells (PBMC) to 1, 10, or 100 µM PFOA or PFOS in a medium with serum (RPMI-1640 + 5% human AB serum) on the measurement of proliferation, T cell activation, generation of memory T cells, and cytokine production/secretion. In addition, these immune system parameters were assessed for PBMC in a serum-free medium (OpSFM), which was stimulated with phytohemagglutinin (PHA) (2.5 µg/ml) or influenza vaccine antigen (0.625 µg/ml Flu Ag). PFOS decreased proliferation stimulated by PHA or Flu Ag. With Flu Ag stimulation, PFOA and PFOS inhibited the generation of memory T cells in a concentration-dependent manner. In OpSFM, PFOA and PFOS produced no marked change in proliferation and no inhibition of T cell activation. Cytokines measured in the media with Luminex methodology indicated decreased PBMC secretion of IFN-γ by PFOA and PFOS in medium with serum, but no alteration in OpSFM. The results indicated that changes in immune parameters due to PFOA or PFOS following Flu Ag stimulation are medium (±serum) dependent.

Disruption of IRE1α through its kinase domain attenuates multiple myeloma.

Multiple myeloma (MM) arises from malignant immunoglobulin (Ig)-secreting plasma cells and remains an incurable, often lethal disease despite therapeutic advances. The unfolded-protein response sensor IRE1α supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may co-opt the IRE1α-XBP1s pathway; however, the validity of IRE1α as a potential MM therapeutic target is controversial. Genetic disruption of IRE1α or XBP1s, or pharmacologic IRE1α kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice and augmented efficacy of two established frontline antimyeloma agents, bortezomib and lenalidomide. Mechanistically, IRE1α perturbation inhibited expression of key components of the endoplasmic reticulum-associated degradation machinery, as well as secretion of Ig light chains and of cytokines and chemokines known to promote MM growth. Selective IRE1α kinase inhibition reduced viability of CD138+ plasma cells while sparing CD138- cells derived from bone marrows of newly diagnosed or posttreatment-relapsed MM patients, in both US- and European Union-based cohorts. Effective IRE1α inhibition preserved glucose-induced insulin secretion by pancreatic microislets and viability of primary hepatocytes in vitro, as well as normal tissue homeostasis in mice. These results establish a strong rationale for developing kinase-directed inhibitors of IRE1α for MM therapy.

Health disparities: Intracellular consequences of social determinants of health.

Health disparities exist dependent on socioeconomic status, living conditions, race/ethnicity, diet, and exposures to environmental pollutants. Herein, the various exposures contributing to a person's exposome are collectively considered social determinants of health (SDOH), and the SDOH-exposome impacts health more than health care. This review discusses the extent of evidence of the physiologic consequences of these exposures at the intracellular level. We consider how the SDOH-exposome, which captures how individuals live, work and age, induces cell processes that modulate a conceptual "redox rheostat." Like an electrical resistor, the SDOH-exposome, along with genetic predisposition and age, regulate reductive and oxidative (redox) stress circuits and thereby stimulate inflammation. Regardless of the source of the SDOH-exposome that induces chronic inflammation and immunosenescence, the outcome influences cardiometabolic diseases, cancers, infections, sepsis, neurodegeneration and autoimmune diseases. The endogenous redox rheostat is connected with regulatory molecules such as NAD+/NADH and SIRT1 that drive redox pathways. In addition to these intracellular and mitochondrial processes, we discuss how the SDOH-exposome can influence the balance between metabolism and regulation of immune responsiveness involving the two main molecular drivers of inflammation, the NLRP3 inflammasome and NF-κB induction. Mitochondrial and inflammasome activities play key roles in mediating defenses against pathogens and controlling inflammation before diverse cell death pathways are induced. Specifically, pyroptosis, cell death by inflammation, is intimately associated with common disease outcomes that are influenced by the SDOH-exposome. Redox influences on immunometabolism including protein cysteines and ion fluxes are discussed regarding health outcomes. In summary, this review presents a translational research perspective, with evidence from in vitro and in vivo models as well as clinical and epidemiological studies, to outline the intracellular consequences of the SDOH-exposome that drive health disparities in patients and populations. The relevance of this conceptual and theoretical model considering the SARS-CoV-2 pandemic are highlighted. Finally, the case of asthma is presented as a chronic condition that is modified by adverse SDOH exposures and is manifested through the dysregulation of immune cell redox regulatory processes we highlight in this review.

Susceptibility to COVID-19 in populations with health disparities: Posited involvement of mitochondrial disorder, socioeconomic stress, and pollutants.

SARS-CoV-2 is a novel betacoronavirus that has caused the global health crisis known as COVID-19. The implications of mitochondrial dysfunction with COVID-19 are discussed as well as deregulated mitochondria and inter-organelle functions as a posited comorbidity enhancing detrimental outcomes. Many environmental chemicals (ECs) and endocrine-disrupting chemicals can do damage to mitochondria and cause mitochondrial dysfunction. During infection, SARS-CoV-2 via its binding target ACE2 and TMPRSS2 can disrupt mitochondrial function. Viral genomic RNA and structural proteins may also affect the normal function of the mitochondria-endoplasmic reticulum-Golgi apparatus. Drugs considered for treatment of COVID-19 should consider effects on organelles including mitochondria functions. Mitochondrial self-balance and clearance via mitophagy are important in SARS-CoV-2 infection, which indicate monitoring and protection of mitochondria against SARS-CoV-2 are important. Mitochondrial metabolomic analysis may provide new indicators of COVID-19 prognosis. A better understanding of the role of mitochondria during SARS-CoV-2 infection may help to improve intervention therapies and better protect mitochondrial disease patients from pathogens as well as people living with poor nutrition and elevated levels of socioeconomic stress and ECs.

Development, phenotypes of immune cells in BTBR T+Itpr3tf/J mice.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by a lack of social interaction, decreased verbal and non-verbal communication skills, and stereotyped repetitive behavior. There is strong evidence that a dysregulated immune response may influence neurodevelopment and thus may have a role in the development of ASD. This study focuses on the characterization of immune cell phenotypes in the BTBR T+Itpr3tf/J (BTBR) mouse strain, a widely used animal model for autism research. Our study demonstrated that BTBR mice have a different immune profile compared to C57BL/6J (B6) mice, which do not display ASD-like characteristics. Thymic cells of BTBR mice have more single positive (SP) CD4+ and CD8+ T cells and fewer double positive (DP) T cells than B6 mice. The development of T cells is increased in BTBR mice with regard to the double negative (DN4) population being much higher in BTBR mice. The spleens and blood of BTBR mice also have more T helper type 1 (Th1), T helper type 2 (Th2) and T regulatory (Treg) cells compared to B6 mice. Aire expression in the thymus and spleen of BTBR mice compared to B6 mice was equivalent and lower, respectively. The mature natural killer (NK) innate immune cell population in blood and spleen is lower in BTBR than B6 mice; NK cell development is blocked prior to the double positive (DN) CD11b+CD27+ stage in BTBR mice. Since BTBR mice have more CD4+ T cells and elevated numbers of Th1 (T-bet+) and Th2 (GATA3+) cells, their low defense against pathogen may be explained by the lower number of NK cells and the significantly lower Th1 to Th2 ratio. The elevated number of plasma cells and autoantibodies of BTBR mice may be due to less presence and function of splenic AIRE.

Wheeze and Food Allergies in Children Born via Cesarean Delivery: The Upstate KIDS Study.

We examined whether cesarean delivery (CD) increased the risk of wheeze or food allergy in early childhood compared with vaginal delivery and whether these associations were mediated by breastfeeding. The study population was the Upstate KIDS cohort (2008-2010) of mothers and infants from the State of New York (excluding New York City). Infant's wheeze was reported by questionnaire every 4-6 months until 3 years of age, as were food allergies beginning at 8 months. Modified Poisson regression was used to compare risks of the outcomes according to mode of delivery (MOD). Potential confounders were identified a priori using directed acyclic graphs. Emergency CD (n = 1,356) was associated with elevated risk of wheeze, adjusting for pregnancy complications, maternal atopy, gestational age, birth weight, and smoking during pregnancy (risk ratio = 2.47, 95% confidence interval: 1.31, 4.66), and an increased risk of food allergy, adjusting for maternal atopy, prepregnancy body mass index, smoking during pregnancy, and parity (risk ratio = 3.02, 95% confidence interval: 1.26, 7.25). Neither outcome was significantly associated with planned CD (n = 1,565 infants). Breastfeeding mediated the association between MOD and wheeze but not food allergy. Other factors not associated with early-life microbial transfer, but relating to the development of the outcomes, might contribute to the association between MOD and wheeze/food allergy.

Concentrations of immune marker in newborn dried blood spots and early childhood development: Results from the Upstate KIDS Study.

BACKGROUND: Evidence shows cytokine dysregulation in children with developmental disabilities. The association between immune activity during the perinatal period and child development is less clear. METHODS: We examined the relationship between newborn concentrations of immune markers and child development. Within Upstate KIDS, a population-based birth cohort (2008-2010, upstate New York), we assayed immune markers, which are postulated to have neuro-modulatory effects, in newborn dried blood spots (NDBS, n = 3038). Mothers completed the Ages & Stages Questionnaire© (ASQ) for their children repeatedly through age 36 months. At 30 and 36 months, mothers also reported whether their children received any developmental services. We used generalised linear mixed models adjusted for maternal and child characteristics to test associations. RESULTS: Sixteen immune markers were associated with failing ASQ in unadjusted models. After full adjustment (for gestational age, mode of delivery, parity, pregnancy smoking, etc.), we observed that higher levels of 4 markers, including platelet-derived growth factor-AA (PDGF-AA, OR 0.77, 95% CI 0.67, 0.89), plasminogen activator inhibitor-1 (OR 0.80, 95% CI 0.68, 0.94), stromal cell derived factor-1 (OR 0.85, 95% CI 0.73, 0.98), and macrophage inflammatory protein-1beta (OR 0.87, 95% CI 0.77, 0.98) were associated with lower odds of ASQ failure. The associations did not exist if correction for multiple comparisons was performed, except for PDGF-AA. Analyses with developmental service use revealed similar null findings. CONCLUSIONS: Immune marker concentrations in NDBS may not be associated with developmental delay in the general population. Newborn concentrations of growth factor PDGF-AA may be protective of developmental delay in childhood.

From Infections to Anthropogenic Inflicted Pathologies: Involvement of Immune Balance.

A temporal trend can be seen in recent human history where the dominant causes of death have shifted from infectious to chronic diseases in industrialized societies. Human influences in the current "Anthropocene" epoch are exponentially impacting the environment and consequentially health. Changing ecological niches are suggested to have created health transitions expressed as modifications of immune balance from infections inflicting pathologies in the Holocene epoch (12,000 years ago) to human behaviors inflicting pathologies beginning in the Anthropocene epoch (300 years ago). A review of human immune health and adaptations responding to environmental (biological, chemical, physical, and psychological) stresses, which are influenced by social conditions, emphasize the involvement of fluctuations in immune cell subsets affecting influential gene-environment interactions. The literature from a variety of fields (anthropological, immunological, and environmental) is incorporated to present an expanded perspective on shifts in diseases within the context of immune balance and function and environmental immunology. The influences between historical and contemporary human ecology are examined in relation to human immunity. Several examples of shifts in human physiology and immunity support the premise that increased incidences of chronic diseases are a consequence of human modification of environment and lifestyle. Although the development of better health care and a broader understanding of human health have helped with better life quality and expectancy, the transition of morbidity and mortality rates from infections to chronic diseases is a cause for concern. Combinations of environmental stressors/pollutants and human behaviors and conditions are modulating the immune-neuroendocrine network, which compromises health benefits.

The cationic (calcium and lead) and enzyme conundrum.

The environmental toxicant lead (Pb) and the essential element calcium (Ca) play an interactive role in extracellular and intracellular regulatory functions that affect health. Lead's usurping calcium binding sites, as well as its interactions with thiols and phosphates have been suggested to be the basis for adverse effects on many organ systems especially the nervous system. Among regulatory processes controlled by Ca are calmodulin-dependent phosphodiesterase, calmodulin-dependent protein kinases, calmodulin inhibitor sensitive potassium channels, and calmodulin-independent protein kinase C (PKC) activation. This review focused on Pb studies describing the modulation of PKC, which is also regulated by steroids. Steroid hormone regulation may relate to a focal point for the sex differences of Pb and cellular signaling events. Picomolar concentrations of Pb may stimulate partially purified PKC, but higher concentrations inhibit activity. Although knowledge exists regarding Pb and PKC isoforms, especially interaction of Pb with the purified enzyme, there are conflicting reports concerning metal-mediated activation or inhibition of PKC and downstream signaling events. The effect of Pb on PKC in vivo remains elusive. Most reports of Pb and PKC in whole animal and human studies indicated that Pb either inhibits PKC or exerts no significant effect. However, most of the animal studies were performed with males. Recent studies performed with females and males separately revealed that females and males respond to Pb quite differently, and for this reason, it is suggested that future Pb studies of PKC and other biomedical investigations be performed with females and males.

Enhancing the antitumor efficacy of a cell-surface death ligand by covalent membrane display.

TNF superfamily death ligands are expressed on the surface of immune cells and can trigger apoptosis in susceptible cancer cells by engaging cognate death receptors. A recombinant soluble protein comprising the ectodomain of Apo2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) has shown remarkable preclinical anticancer activity but lacked broad efficacy in patients, possibly owing to insufficient exposure or potency. We observed that antibody cross-linking substantially enhanced cytotoxicity of soluble Apo2L/TRAIL against diverse cancer cell lines. Presentation of the ligand on glass-supported lipid bilayers enhanced its ability to drive receptor microclustering and apoptotic signaling. Furthermore, covalent surface attachment of Apo2L/TRAIL onto liposomes--synthetic lipid-bilayer nanospheres--similarly augmented activity. In vivo, liposome-displayed Apo2L/TRAIL achieved markedly better exposure and antitumor activity. Thus, covalent synthetic-membrane attachment of a cell-surface ligand enhances efficacy, increasing therapeutic potential. These findings have translational implications for liposomal approaches as well as for Apo2L/TRAIL and other clinically relevant TNF ligands.

Sex-specific effects of developmental lead exposure on the immune-neuroendocrine network.

The environmental toxicant lead (Pb) has long been known to induce neurological deficits. The 1st century Greek physician Pedanius Dioscorides noted that "lead makes the mind give way". Current studies are suggesting the effects of Pb on behaviors may involve the immune system and conversely some immunomodulatory changes may be due to Pb effects in the central nervous system. Although Pb-induced disorders do not appear to discriminate among females and males, this report discusses the differences observed in human and animal studies regarding differential gender effects on gene expression after Pb exposure. The overall ill health outcomes are apparent with variant levels of Pb exposure and exposures at different times in development. However, the consensus is that doses leading to blood lead levels>5µg/dl and prenatal exposures are most pathogenic. Although the general detriments induced by Pb may be similar in females and males, there are sex specific outcomes on health and behavior. It is suggested that Pb induces more oxidative stress in females and more upregulation of genes responding to oxidative stress, while males have more proteolytic destruction; but in both cases, there is generation of altered/denatured self-constituents causing inflammation and loss of homeostasis of neuronal and immune functions. The higher estrogen levels of females are indicated as the reason for more Pb-induced reactive oxygen species in females. This review describes some of the different genes involved in female and male responses to Pb exposure and involved pathways.

Maternal Smoking and Newborn Cytokine and Immunoglobulin Levels.

INTRODUCTION: Prenatal smoking exposure may lead to permanent changes in neonatal inflammation and immune response that have lifelong implications, including increased risks for atopy and respiratory disorders. METHODS: The effect of maternal smoking on neonatal biomarkers of inflammation and immune response was assessed among 3459 singletons and twins in the Upstate KIDS Study. The following inflammatory biomarkers were measured using newborn dried blood spots (DBSs): interleukin (IL)-1α, IL-1 receptor antagonist, IL-6, IL-8, C-reactive protein, and tumor necrosis factor alpha. Immunoglobulins (IgE, IgA, IgM, and IgG subclasses) were also assessed. We used generalized estimating equations to calculate mean differences (ß) in biomarker levels by timing of pregnancy smoking, cigarette load, and secondhand smoke exposure after adjusting for sociodemographic and lifestyle factors including maternal body mass index. RESULTS: Of the 344 (12%) women reporting smoking during pregnancy, about 40% continued throughout pregnancy and 13% reported smoking more than 1 pack per day. After covariate adjustment and Bonferroni correction for multiple comparisons, maternal smoking throughout pregnancy remained significantly associated with increased levels of IL-8 (ß = 0.20, 95% confidence interval: 0.07, 0.32; p < .003). No significant associations were found with cigarette load or secondhand smoke exposure. Higher IgG3 levels were also associated with maternal smoking throughout pregnancy, although the association became nominally significant after adjustment for covariates (ß = 0.09; 95% confidence interval: 0.0007, 0.17; p < .05). CONCLUSIONS: Maternal smoking throughout pregnancy was independently associated with increased IL-8 levels in newborns. Importantly, neonates of women who stopped smoking anytime in pregnancy did not have increased IL-8 levels. IMPLICATIONS: This study evaluated a range of inflammatory biomarkers and immunoglobulins in association with maternal smoking and timing/duration of smoking along with secondhand smoke exposure. By using DBSs, we present data from a large cohort of children born in Upstate New York. Our findings suggest that early differences in immunoregulation of neonates exposed to maternal smoking for full duration in utero may already be detected at birth.

Determinants of neonatal brain-derived neurotrophic factor and association with child development.

Using a population-based birth cohort in upstate New York (2008-2010), we examined the determinants of brain-derived neurotrophic factor (BDNF) measured in newborn dried blood spots (n = 2,637). We also examined the association between neonatal BDNF and children's development. The cohort was initially designed to examine the influence of infertility treatment on child development but found no impact. Mothers rated children's development in five domains repeatedly through age 3 years. Socioeconomic and maternal lifestyle determinants of BDNF were examined using multivariable linear regression models. Generalized linear mixed models estimated odds ratios for neonatal BDNF in relation to failing a developmental domain. Smoking and drinking in pregnancy, nulliparity, non-White ethnicity/race, and prepregnancy obesity were associated with lower neonatal BDNF. Neonatal BDNF was not associated with failure for developmental domains; however, there was an interaction between BDNF and preterm birth. In preterm infants, a higher BDNF was associated with lower odds of failing any developmental domains, after adjusting for confounders and infertility treatment. This result was particularly significant for failure in communication. Our findings suggest that BDNF levels in neonates may be impacted by maternal lifestyle characteristics. More specifically, lower neonatal BDNF might be an early marker of aberrant neurodevelopment in preterm infants.

Prevalence of asymptomatic chondrocalcinosis in the pelvis.

OBJECTIVE: To determine trends in incidentally detected age- and gender-associated chondrocalcinosis on pelvic CT. MATERIALS AND METHODS: Twenty patients of each gender at the center of each decade of life who underwent a CT scan of the pelvis performed 2009-2013 were identified and selected for a total of 400 pelvic CTs. Images were reviewed independently by two radiologists for the presence or absence of chondrocalcinosis within the pelvis. Patients with hip or low back pain, known CPPD arthropathy or any known predisposing condition, prior hip arthroplasty, or articular fracture were excluded. Logistic regression was used to predict the presence/absence of chondrocalcinosis as a function of patient age and gender. RESULTS: The presence/absence of chondrocalcinosis was found to be associated with patient age (p = 0.016) but not patient gender (p = 0.929). In the pelvis, chondrocalcinosis was most frequently identified at the pubic symphysis. Incidental chondrocalcinosis was not identified in any patients under 50 years of age. Chondrocalcinosis increased in frequency from 12.5 at 55 years of age to 27.5 % of patients 95 years of age. CONCLUSIONS: Chondrocalcinosis is common and more prevalent in late adulthood, occurs without a gender predilection, and is infrequently identified in patients younger than 50 years of age.

Imaging characteristics of cervical spine extra-arachnoid fluid collections managed conservatively.

OBJECTIVE: Determine the MRI characteristics of large post-traumatic cervical spine extra-arachnoid collections managed conservatively in clinically stable patients and whether evidence of clinical or imaging deterioration materialized. MATERIALS AND METHODS: Following IRB approval, we conducted a retrospective search for all patients (>16 years old) over a 17-months period who had an extra-arachnoid fluid collection reported on a post-traumatic cervical spine MRI. Patients were excluded if they had surgery for an unstable fracture (n = 21), emergent decompression (n = 1) or lacked a follow-up MRI within 15 days (n = 1). Two MSK radiologists recorded the size, morphology and MRI signal characteristics of the collections. RESULTS: Eight patients (5 male, 3 female) met the inclusion criteria (mean age 40 years; range 19-78 years). Seven of the eight patients had fluid collections that demonstrated thin, tapered margins, extended >7 vertebral bodies and involved >180 degrees of the spinal canal. The signal characteristics of these collections varied: hyper-T1/iso-T2 (n = 1), iso-T1/T2 (n = 3), hyper-T1/hypo-T2 (n = 3) and mixed-T1/T2 (n = 1). Six of seven collections were ventral. Follow-up MRI demonstrated resolution/significant decrease in size (n = 4 between 1 and 12 days) or no change/slight decrease in size (n = 3; between 2 and 11 days). None of the seven fluid collections enlarged, no patient had abnormal cord signal, and no patient's neurologic symptoms worsened. One of eight patients had a dorsal "mass-like" collection that was slightly smaller 9 days later. CONCLUSION: In stable patients with large, tapered post-traumatic cervical spine extra-arachnoid collections managed non-surgically, none developed (1) clinical worsening, (2) abnormal cord signal or (3) collection enlargement, regardless of the collection's signal characteristics.

A physical/psychological and biological stress combine to enhance endoplasmic reticulum stress.

The generation of an immune response against infectious and other foreign agents is substantially modified by allostatic load, which is increased with chemical, physical and/or psychological stressors. The physical/psychological stress from cold-restraint (CR) inhibits host defense against Listeria monocytogenes (LM), due to early effects of the catecholamine norepinephrine (NE) from sympathetic nerves on ß1-adrenoceptors (ß1AR) of immune cells. Although CR activates innate immunity within 2h, host defenses against bacterial growth are suppressed 2-3 days after infection (Cao and Lawrence 2002). CR enhances inducible nitric oxide synthase (iNOS) expression and NO production. The early innate activation leads to cellular reduction-oxidation (redox) changes of immune cells. Lymphocytes from CR-treated mice express fewer surface thiols. Splenic and hepatic immune cells also have fewer proteins with free thiols after CR and/or LM, and macrophages have less glutathione after the in vivo CR exposure or exposure to NE in vitro. The early induction of CR-induced oxidative stress elevates endoplasmic reticulum (ER) stress, which could interfere with keeping phagocytized LM within the phagosome or re-encapsuling LM by autophagy once they escape from the phagosome. ER stress-related proteins, such as glucose-regulated protein 78 (GRP78), have elevated expression with CR and LM. The results indicate that CR enhances the unfolded protein response (UPR), which interferes with host defenses against LM. Thus, it is postulated that increased stress, as exists with living conditions at low socioeconomic conditions, can lower host defenses against pathogens because of oxidative and ER stress processes.