Cellular and microenvironmental cues that promote macrophage fusion and foreign body response.

During the foreign body response (FBR), macrophages fuse to form foreign body giant cells (FBGCs). Modulation of FBGC formation can prevent biomaterial degradation and loss of therapeutic efficacy. However, the microenvironmental cues that dictate FBGC formation are poorly understood with conflicting reports. Here, we identified molecular and cellular factors involved in driving FBGC formation in vitro. Macrophages demonstrated distinct fusion competencies dependent on monocyte differentiation. The transition from a proinflammatory to a reparative microenvironment, characterised by specific cytokine and growth factor programmes, accompanied FBGC formation. Toll-like receptor signalling licensed the formation of FBGCs containing more than 10 nuclei but was not essential for cell-cell fusion to occur. Moreover, the fibroblast-macrophage crosstalk influenced FBGC development, with the fibroblast secretome inducing macrophages to secrete more PDGF, which enhanced large FBGC formation. These findings advance our understanding as to how a specific and timely combination of cellular and microenvironmental factors is required for an effective FBR, with monocyte differentiation and fibroblasts being key players.

The nonverbal expression of guilt in healthy adults.

Guilt is a negative emotion elicited by realizing one has caused actual or perceived harm to another person. One of guilt's primary functions is to signal that one is aware of the harm that was caused and regrets it, an indication that the harm will not be repeated. Verbal expressions of guilt are often deemed insufficient by observers when not accompanied by nonverbal signals such as facial expression, gesture, posture, or gaze. Some research has investigated isolated nonverbal expressions in guilt, however none to date has explored multiple nonverbal channels simultaneously. This study explored facial expression, gesture, posture, and gaze during the real-time experience of guilt when response demands are minimal. Healthy adults completed a novel task involving watching videos designed to elicit guilt, as well as comparison emotions. During the video task, participants were continuously recorded to capture nonverbal behaviour, which was then analyzed via automated facial expression software. We found that while feeling guilt, individuals engaged less in several nonverbal behaviours than they did while experiencing the comparison emotions. This may reflect the highly social aspect of guilt, suggesting that an audience is required to prompt a guilt display, or may suggest that guilt does not have clear nonverbal correlates.

Quantitative Risk Assessment of Dermal Sensitization Potential Following Use of Shampoo Products Containing the Formaldehyde Releasing Preservative DMDM Hydantoin.

Historically, formaldehyde was used as a preservative in personal care products to extend product shelf-life; however, given its skin sensitization potential it has been phased out of use and replaced with formaldehyde-releasing preservatives, such as Dimethyloldimethyl hydantoin (DMDMH). A relationship has been established between positive patch test results following exposure to DMDMH and previous sensitization to formaldehyde. Upon direct contact with the skin, formaldehyde can react with skin proteins and cause an acute inflammatory reaction, which may progress to skin sensitization following repeated exposure. This quantitative risk assessment (QRA) aimed to assess the risk of skin sensitization induction following use of shampoo products containing the maximum allowable concentrations of DMDMH in formulation (1% w/v), translating to a free formaldehyde concentration of 0.02%. To determine a margin of safety (MOS) for exposure to DMDMH from use of shampoo products, consumer exposure levels (CEL) were estimated based on typical use scenarios and then benchmarked against an acceptable exposure level (AEL). The AEL was derived using a weight of evidence approach where a range of no expected sensitization induction levels (NESILs) was utilized. The MOS values for a shampoo product containing 1% DMDMH (.02% formaldehyde) was above 1 for the typical use scenario indicating a low likelihood of skin sensitization induction among healthy individuals. Thus, it can be concluded that shampoo products containing DMDMH at or below current allowable concentrations are not expected to increase the risk of skin sensitization induction.

The psychophysiology of guilt in healthy adults.

Guilt is a negative emotion, elicited by realizing one has caused actual or perceived harm to another person. Anecdotally, guilt often is described as a visceral and physical experience. However, while the way that the body responds to and contributes to emotions is well known in basic emotions, little is known about the characteristics of guilt as generated by the autonomic nervous system. This study investigated the physiologic signature associated with guilt in adults with no history of psychological or autonomic disorder. Healthy adults completed a novel task, including an initial questionnaire about their habits and attitudes, followed by videos designed to elicit guilt, as well as the comparison emotions of amusement, disgust, sadness, pride, and neutral. During the video task, participants' swallowing rate, electrodermal activity, heart rate, respiration rate, and gastric activity rate were continuously recorded. Guilt was associated with alterations in gastric rhythms, electrodermal activity, and swallowing rate relative to some or all the comparison emotions. These findings suggest that there is a mixed pattern of sympathetic and parasympathetic activation during the experience of guilt. These results highlight potential therapeutic targets for modulation of guilt in neurologic and psychiatric disorders with deficient or elevated levels of guilt, such as frontotemporal dementia, posttraumatic stress disorder, and Obsessive-compulsive disorder.

Temporal derivative computation in the dorsal raphe network revealed by an experimentally driven augmented integrate-and-fire modeling framework.

By means of an expansive innervation, the serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) are positioned to enact coordinated modulation of circuits distributed across the entire brain in order to adaptively regulate behavior. Yet the network computations that emerge from the excitability and connectivity features of the DRN are still poorly understood. To gain insight into these computations, we began by carrying out a detailed electrophysiological characterization of genetically identified mouse 5-HT and somatostatin (SOM) neurons. We next developed a single-neuron modeling framework that combines the realism of Hodgkin-Huxley models with the simplicity and predictive power of generalized integrate-and-fire models. We found that feedforward inhibition of 5-HT neurons by heterogeneous SOM neurons implemented divisive inhibition, while endocannabinoid-mediated modulation of excitatory drive to the DRN increased the gain of 5-HT output. Our most striking finding was that the output of the DRN encodes a mixture of the intensity and temporal derivative of its input, and that the temporal derivative component dominates this mixture precisely when the input is increasing rapidly. This network computation primarily emerged from prominent adaptation mechanisms found in 5-HT neurons, including a previously undescribed dynamic threshold. By applying a bottom-up neural network modeling approach, our results suggest that the DRN is particularly apt to encode input changes over short timescales, reflecting one of the salient emerging computations that dominate its output to regulate behavior.

Multi-route exposure sampling of quaternary ammonium compounds and ethanol surface disinfectants in a K-8 school.

The frequency of surface disinfectant use has increased over the last several years in public settings such as schools, especially during the COVID-19 pandemic. Although these products are important for infection control and prevention, their increased use may intensify the exposure to both persons applying the disinfection product as well as bystanders. Safety assessments have demonstrated that these products, when used as intended, are considered safe for use and effective; however, point-of-contact effects (such as respiratory or dermal irritation) may still occur. Additionally, relative exposures may vary significantly due to the wide variation in disinfectant formulation and application methods. Quantitative estimations of exposures to two commonly used active ingredients, quaternary ammonium compounds (QACs) and ethanol, are not well characterized during product use and application scenarios. To assess the potential for health risks attributable to increased use in classroom settings, as well as to quantitatively evaluate the potential exposure to both ethanol and QACs, student and adult bystander surface and air measurements were collected in a K-8 school setting in Ohio, United States, over a three-day period. Direct-reading instruments were utilized to collect real-time air samples that characterized mass fraction concentrations following the use of the QAC- and ethanol-based disinfectants. Furthermore, surface and air sampling of microbial species were conducted to establish the overall bioburden and effectiveness of each disinfectant to inform the comparative risk and health effect impacts from the tested products use scenario. Both tested products were approximately equally effective at reducing bioburdens on desk surfaces. In some classrooms, concentrations of QAC congeners were significantly increased on desk surfaces following the application of the disinfectant spray; however, the magnitude of the change in concentration was small. Ethanol was not measured on surfaces due to its volatility. Airborne concentrations increased immediately following spray of each disinfectant product but rapidly returned to baseline. Each of the QAC congeners listed in the product safety data sheets were detected and measurable on desk surfaces; however, air concentrations were generally below the limit of detection. The 15-min time-weighted averages (TWAs) of both QACs and ethanol in the air were below respective health effects benchmarks, and therefore, the negative impact on health outcomes is considered to be minimal from short-term, repeated use of ethanol- or QAC-based spray products in a school setting when the products are used as directed.

Comparison of Behavior-Related Features in the MMSE Sentence in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease.

Background: Despite the ubiquity of cognitive assessments using the MMSE, there has been little investigation of currently unscored features of the MMSE sentence item relevant to behavior and language in patients with behavioral variant Frontotemporal Dementia (bvFTD) and Alzheimer's disease (AD). Objective: To describe and compare the unscored content and grammar elements of the MMSE sentence item in patients with bvFTD and AD. Methods: Categorization of predefined content and grammar elements of the MMSE sentence was performed by two blinded raters in patients with bvFTD (n = 74) and AD (n = 84). Chi-square and ANCOVAs were conducted to identify differences between the diagnostic groups. A multinomial logistic regression analysis was conducted to determine whether these features aid in the prediction of diagnosis of bvFTD or AD. Results: A higher proportion of patients with bvFTD wrote sentences addressed to the examiner (22.7% vs. 4.7%, X 2 = 11.272, p = 0.001) and about interpersonal relationships (35.3% vs. 16.0%, X 2 = 10.139, p = 0.017) in comparison to those with AD. The number of words written was lower in patients with AD and was positively correlated with lower total MMSE scores in AD but not in bvFTD (AD: r = 0.370, p < 0.001; FTD: r = 0.209, p = 0.07). Assessment of the MMSE sentence content and grammar variables did not add to the prediction bvFTD or AD diagnosis beyond the variance explained by age and total MoCA score. Conclusions: Patients with bvFTD and AD showed differences in aspects of the content of the written MMSE sentence item, though these differences did not aid in the diagnosis prediction.

The supraoptic and paraventricular nuclei in healthy aging and neurodegeneration.

The supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus undergo structural and functional changes over the course of healthy aging. These nuclei and their connections are also heterogeneously affected by several different neurodegenerative diseases. This chapter reviews the involvement of the SON and PVN, the hypothalamic-pituitary axes, and the peptide hormones produced in both nuclei in healthy aging and in neurodegeneration, with a focus on Alzheimer's disease (AD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis, progressive supranuclear palsy, Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy, and Huntington's disease. Although age-related changes occur in several regions of the hypothalamus, the SON and PVN are relatively preserved during aging and in many neurodegenerative disorders. With aging, these nuclei do undergo some sexually dimorphic changes including changes in size and levels of vasopressin and corticotropin-releasing hormone, likely due to age-related changes in sex hormones. In contrast, oxytocinergic cells and circulating levels of thyrotropin-releasing hormone remain stable. A relative resistance to many forms of neurodegenerative pathology is also observed, in comparison to other hypothalamic and brain regions. Mirroring the pattern observed in aging, pathologic hallmarks of AD, and some subtypes of FTD are observed in the PVN, though to a milder degree than are observed in other brain regions, while the SON is relatively spared. In contrast, the SON appears more vulnerable to alpha-synuclein pathology of DLB and PD. The consequences of these alterations may help to inform several of the physiologic changes observed in aging and neurodegenerative disease.

Purkinje cell axonal swellings enhance action potential fidelity and cerebellar function.

Axonal plasticity allows neurons to control their output, which critically determines the flow of information in the brain. Axon diameter can be regulated by activity, yet how morphological changes in an axon impact its function remains poorly understood. Axonal swellings have been found on Purkinje cell axons in the cerebellum both in healthy development and in neurodegenerative diseases, and computational models predicts that axonal swellings impair axonal function. Here we report that in young Purkinje cells, axons with swellings propagated action potentials with higher fidelity than those without, and that axonal swellings form when axonal failures are high. Furthermore, we observed that healthy young adult mice with more axonal swellings learn better on cerebellar-related tasks than mice with fewer swellings. Our findings suggest that axonal swellings underlie a form of axonal plasticity that optimizes the fidelity of action potential propagation in axons, resulting in enhanced learning.

Neural effects of oxytocin and mimicry in frontotemporal dementia: A randomized crossover study.

OBJECTIVE: To determine whether intranasal oxytocin, alone or in combination with instructed mimicry of facial expressions, would augment neural activity in patients with frontotemporal dementia (FTD) in brain regions associated with empathy, emotion processing, and the simulation network, as indexed by blood oxygen-level dependent (BOLD) signal during fMRI. METHODS: In a placebo-controlled, randomized crossover design, 28 patients with FTD received 72 IU intranasal oxytocin or placebo and then completed an fMRI facial expression mimicry task. RESULTS: Oxytocin alone and in combination with instructed mimicry increased activity in regions of the simulation network and in limbic regions associated with emotional expression processing. CONCLUSIONS: The findings demonstrate latent capacity to augment neural activity in affected limbic and other frontal and temporal regions during social cognition in patients with FTD, and support the promise and need for further investigation of these interventions as therapeutics in FTD. CLINICALTRIALSGOV IDENTIFIER: NCT01937013. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a single dose of 72 IU intranasal oxytocin augments BOLD signal in patients with FTD during viewing of emotional facial expressions.

Evaluating the extent of patient-centred care in a selection of ESC guidelines.

AIMS: Patient-centred care (PCC) is the cornerstone for healthcare professionals to promote high quality care for patients with cardiovascular conditions. It is defined as 'Providing care that is respectful of, and responsive to, individual patient preferences, needs and values, and ensuring that patient values guide all clinical decisions'. PCC can improve patient outcomes and allow patients and healthcare professionals to manage care collaboratively using best available evidence. However, there is no clear understanding how extensively guidelines incorporate PCC recommendations. The aim of the study was to evaluate the incorporation of PCC into a selection of guidelines published by the European Society of Cardiology (ESC). METHODS AND RESULTS: Using a narrative literature review and expert consensus, the Science Committee within the Association of Cardiovascular Nursing and Allied Professions (ACNAP) developed a checklist to determine PCC incorporation in clinical guidelines. Nine ESC guidelines were reviewed, with committee members independently evaluating five PCC aspects: patient voice and involvement, multidisciplinary involvement, holistic care recommendations, flexibility to meet patients' needs, and provision of patient tools. The level of congruence in item ratings by experts was then compared. The incorporation of PCC using these respective five categories, ranged from 4% (patient tools) to 53% in the 'multidisciplinary involvement' category. CONCLUSION: Overall, the inclusion of PCC was low, indicating that patient perspectives and needs were less likely to be taken into account when developing, endorsing, or formulating recommendations. Future development of guidelines should ensure better incorporation of patients' perspective, in particular, and other PCC aspects highlighted in this study.

IRF2BP2 Reduces Macrophage Inflammation and Susceptibility to Atherosclerosis.

RATIONALE: Inflammation impairs macrophage cholesterol clearance from vascular tissues and promotes atherosclerosis. Inflammatory macrophages suppress expression of the transcription cofactor interferon regulatory factor 2-binding protein 2 (IRF2BP2), and genetic variants near IRF2BP2 associate with ischemic heart disease progression in humans. OBJECTIVES: To test whether IRF2BP2 in macrophages affects atherosclerosis in mice and humans. METHODS AND RESULTS: We generated mice that delete IRF2BP2 in macrophages. IRF2BP2-deficient macrophages worsened atherosclerosis in irradiated low-density lipoprotein receptor null-recipient mice and in apolipoprotein E null mice. IRF2BP2-deficient macrophages were inflammatory and had impaired cholesterol efflux because of their inability to activate the cholesterol transporter ABCA1 in response to cholesterol loading. Their expression of the anti-inflammatory transcription factor Krüppel-like factor 2 was markedly reduced. Promoter studies revealed that IRF2BP2 is required for MEF2-dependent activation of Krüppel-like factor 2. Importantly, restoring Krüppel-like factor 2 in IRF2BP2-deficient macrophages attenuated M1 inflammatory and rescued M2 anti-inflammatory gene activation and improved the cholesterol efflux deficit by restoring ABCA1 activation in response to cholesterol loading. In a cohort of 1066 angiographic cases and 1011 controls, homozygous carriers of a deletion polymorphism (rs3045215) in the 3' untranslated region sequence of human IRF2BP2 mRNA had a higher risk of coronary artery disease (recessive model, odds ratio [95% confidence interval]=1.560 [1.179-2.065], P=1.73E-03) and had lower IRF2BP2 (and Krüppel-like factor 2) protein levels in peripheral blood mononuclear cells. The effect of this deletion polymorphism to suppress protein expression was confirmed in luciferase reporter studies. CONCLUSION: Ablation of IRF2BP2 in macrophages worsens atherosclerosis in mice, and a deletion variant that lowers IRF2BP2 expression predisposes to coronary artery disease in humans.

Chronic stress induces anxiety via an amygdalar intracellular cascade that impairs endocannabinoid signaling.

Collapse of endocannabinoid (eCB) signaling in the amygdala contributes to stress-induced anxiety, but the mechanisms of this effect remain unclear. eCB production is tied to the function of the glutamate receptor mGluR5, itself dependent on tyrosine phosphorylation. Herein, we identify a novel pathway linking eCB regulation of anxiety through phosphorylation of mGluR5. Mice lacking LMO4, an endogenous inhibitor of the tyrosine phosphatase PTP1B, display reduced mGluR5 phosphorylation, eCB signaling, and profound anxiety that is reversed by genetic or pharmacological suppression of amygdalar PTP1B. Chronically stressed mice exhibited elevated plasma corticosterone, decreased LMO4 palmitoylation, elevated PTP1B activity, reduced amygdalar eCB levels, and anxiety behaviors that were restored by PTP1B inhibition or by glucocorticoid receptor antagonism. Consistently, corticosterone decreased palmitoylation of LMO4 and its inhibition of PTP1B in neuronal cells. Collectively, these data reveal a stress-responsive corticosterone-LMO4-PTP1B-mGluR5 cascade that impairs amygdalar eCB signaling and contributes to the development of anxiety.

Functional properties of Claramine: a novel PTP1B inhibitor and insulin-mimetic compound.

Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling, interfering with its control of glucose homeostasis and metabolism. PTP1B activity is elevated in obesity and type 2 diabetes and is a major cause of insulin resistance. Trodusquemine (MSI-1436) is a "first-in-class" highly selective inhibitor of PTP1B that can cross the blood-brain barrier to suppress feeding and promote insulin sensitivity and glycemic control. Trodusquemine is a naturally occurring cholestane that can be purified from the liver of the dogfish shark, Squalus acanthias, but it can also be manufactured synthetically by a fairly laborious process that requires several weeks. Here, we tested a novel easily and rapidly (2 days) synthesized polyaminosteroid derivative (Claramine) containing a spermino group similar to Trodusquemine for its ability to inhibit PTP1B. Like Trodusquemine, Claramine displayed selective inhibition of PTP1B but not its closest related phosphatase TC-PTP. In cultured neuronal cells, Claramine and Trodusquemine both activated key components of insulin signaling, with increased phosphorylation of insulin receptor-ß (IRß), Akt and GSK3ß. Intraperitoneal administration of Claramine or Trodusquemine effectively restored glycemic control in diabetic mice as determined by glucose and insulin tolerance tests. A single intraperitoneal dose of Claramine, like an equivalent dose of Trodusquemine, suppressed feeding and caused weight loss without increasing energy expenditure. In summary, Claramine is an alternative more easily manufactured compound for the treatment of type II diabetes.