Neurocognitive mechanisms of mental imagery-based disgust learning.

Disgust imagery represents a potential pathological mechanism for disgust-related disorders. However, it remains controversial as to whether disgust can be conditioned with disgust-evoking mental imagery serving as the unconditioned stimulus (US). Therefore, we examined this using a conditioned learning paradigm in combination with event-related potential (ERP) analysis in 35 healthy college students. The results indicated that the initial neutral face (conditioned stimulus, CS+) became more disgust-evoking, unpleasant, and arousing after pairing with disgust-evoking imagery (disgust CS+), compared to pairing with neutral (neutral CS+) and no (CS-) imagery. Moreover, we observed that mental imagery-based disgust conditioning was resistant to extinction. While the disgust CS + evoked larger P3 and late positive potential amplitudes than CS- during acquisition, no significant differences were found between disgust CS+ and neutral CS+, indicating a dissociation between self-reported and neurophysiological responses. Future studies may additionally acquire facial EMG as an implicit index of conditioned disgust. This study provides the first neurobiological evidence that associative disgust learning can occur without aversive physical stimuli, with implications for understanding how disgust-related disorders may manifest or deteriorate without external perceptual aversive experiences, such as in obsessive-compulsive disorder (OCD).

Investigating differences in young- and late-onset progressive supranuclear palsy.

BACKGROUND: The impact of age of onset on the presentation of progressive supranuclear palsy phenotypes is not well studied. We hypothesized that there is difference in presentation and phenotype between young- and late-onset PSP. OBJECTIVES: Our aim was to compare phenotypes and rate of change in disability between young-onset PSP (YOPSP) and late-onset PSP (LOPSP). METHODS: Retrospective data of patients seen in the Rossy PSP Centre from March 2014 to April 2022 with clinical diagnosis of PSP as per the MDS 2017 diagnostic criteria were examined. We used cut-off age of 65 years to categorize the patients into YOPSP and LOPSP. We compared the prevalence of phenotypes, presenting symptoms, and MDS core criteria between the two groups. The severity of disease between the two groups was measured using PSP-RS. RESULTS: We found 107 patients with clinical diagnosis of PSP as per MDS criteria, a third were defined as YOPSP. PSP speech/language (SL) phenotype was more prevalent in YOPSP (18% vs 0%, p < 0.001). Aphasia was significantly higher in YOPSP (16% vs 1.4%, p = 0.03). The speech and language dysfunction (C1) core criteria were more prevalent in YOPSP (33.3% vs 12.2%, p = 0.05). Longitudinal analysis of PSP-RS showed worsening of bulbar total score at 6 months in YOPSP (t (38) = 2.87; p = 0.05). CONCLUSION: Our study revealed that YOPSP are more likely to present with a speech and language variant. Our results highlight that age of onset may predict PSP phenotypes, which holds both clinical and prognostic importance.

Postural sway is not affected by estrogen fluctuations during the menstrual cycle.

When people stand still, they exhibit a phenomenon called postural sway, or spontaneous movement of the body's center of pressure, which is related to balance control. In general females show less sway than males, but this difference only begins to appear around puberty, pointing to different levels of sex hormones as one potential mechanism for sway sex differences. In this study, we followed cohorts of young females using oral contraceptives (n = 32) and not using oral contraceptives (n = 19), to investigate associations between estrogen availability and postural sway. All participants visited the lab four times over the putative 28-day menstrual cycle. At each visit, we performed blood draws to measure plasma estrogen (estradiol) levels, and tests of postural sway using a force plate. During late follicular and mid-luteal phase, estradiol levels were lower in participants using oral contraceptives (mean differences [95% CI], respectively: -231.33; [-800.44, 337.87]; -613.26; [-1333.60, 107.07] pmol/L; main effect p < 0.001), reflecting expected consequences of oral contraceptive use. Despite these differences, postural sway was not significantly different between participants who were using oral contraceptives and participants who were not (mean difference: 2.09 cm; 95% CI = [-1.05, 5.22]; p = 0.132). Overall, we found no significant effects of the estimated menstrual cycle phase-or absolute levels of estradiol-on postural sway.

Sex and age affect acute and persisting COVID-19 illness.

Long COVID is associated with neurological and neuropsychiatric manifestations. We conducted an observational study on 97 patients with prior SARS-CoV-2 infection and persisting cognitive complaints that presented to the University Health Network Memory Clinic between October 2020 and December 2021. We assessed the main effects of sex, age, and their interaction on COVID-19 symptoms and outcomes. We also examined the relative contribution of demographics and acute COVID-19 presentation (assessed retrospectively) on persistent neurological symptoms and cognition. Among our cohort, males had higher hospitalization rates than females during the acute COVID-19 illness (18/35 (51%) vs. 15/62 (24%); P = .009). Abnormal scores on cognitive assessments post-COVID were associated with older age (AOR = 0.84; 95% CI 0.74-0.93) and brain fog during initial illness (AOR = 8.80; 95% CI 1.76-65.13). Female sex (ARR = 1.42; 95% CI 1.09-1.87) and acute shortness of breath (ARR = 1.41; 95% CI 1.09-1.84) were associated with a higher risk of experiencing more persistent short-term memory symptoms. Female sex was the only predictor associated with persistent executive dysfunction (ARR = 1.39; 95% CI 1.12-1.76) and neurological symptoms (ARR = 1.66; 95% CI 1.19-2.36). Sex differences were evident in presentations and cognitive outcomes in patients with long COVID.

Fresh Mango Consumption Promotes Greater Satiety and Improves Postprandial Glucose and Insulin Responses in Healthy Overweight and Obese Adults.

Mangos are an understudied fruit rich in fiber and polyphenols that have been linked to better metabolic outcomes and promotion of satiety. The purpose of this study was to examine the effect of mango consumption on postprandial glucose, insulin, and satiety responses. Using a randomized crossover study design, 23 overweight and obese men and women consumed 100 kcal snacks of fresh mangos or isocaloric low-fat cookies on two separate occasions. Insulin and satiety hormones were measured at baseline and 45 min post-snack consumption. Glucose was measured at baseline, 30, 60, 90, and 120 min after snack consumption. Satiety questionnaires were completed at baseline and every 20 min for 120 min post-consumption. Both mangos and low-fat cookies increased insulin, with a significantly lower increase for mangos compared with low-fat cookies at 45 min post-snack consumption (P ≤ .05). Glucose increased at 30 min for both snacks; however, the increase was significantly higher for low-fat cookie consumption (P ≤ .05). Cholecystokinin increased after mangos and low-fat cookie consumption (P ≤ .05); however, no differences were detected between the snacks. Adiponectin increased after mango consumption (P ≤ .05) but not after low-fat cookies. Mango consumption reduced hunger, anticipated food consumption and thirst, and increased feelings of fullness (P ≤ .05). Low-fat cookie consumption increased fullness for a shorter time period and did not reduce participants' desire to eat. These results suggest that relative to a refined cookie snack, mangos promote greater satiety and improve postprandial glycemic responses. Future research on long-term effects of mango consumption on food intake, weight control, and glucose homeostasis is warranted. Clinical Trial Registration number: #NCT03957928.

Effects of fresh mango consumption on cardiometabolic risk factors in overweight and obese adults.

BACKGROUND & AIMS: In vitro and animal studies show antidiabetic, anti-inflammatory, and cardioprotective properties of mangos. The objective of this study was to examine the effects of fresh mango consumption compared to an isocaloric control snack on body weight, glucose, insulin, lipid profiles, liver function enzymes, inflammation, and antioxidant activity in overweight and obese adults (BMI ≥26 kg/m2). METHODS AND RESULTS: In a crossover design, 27 participants consumed 100 kcal/d of fresh mangos or isocaloric low-fat cookies daily for 12 weeks each, separated by a four-week washout period. Blood glucose, C-reactive protein (CRP), and aspartate transaminase activity significantly decreased while total antioxidant capacity significantly increased following mango consumption. There were no significant changes in body weight, body fat %, blood pressure, insulin, or lipid profile following mango consumption. Cookie consumption significantly increased body weight, insulin, CRP, and triglycerides. CONCLUSION: These results suggest that relative to the control snack, mangos may improve certain risk factors associated with overweight and obesity including improved glycemic control and reduced inflammation. CLINICAL TRIALS REGISTER: NCT03957928.

An overview of exposure to ethanol-containing substances and ethanol intoxication in children based on three illustrated cases.

Alcohol addiction and intoxication are major health problems worldwide. Acute alcohol intoxication is well reported in adults and adolescents but less frequently reported in children of younger ages. We report three anonymized cases of pediatric ethanol exposure and illustrate the different mechanisms of intoxication. In all cases, a focused history is the key to prompt diagnosis and timely management. Physicians should be aware of this potential poison in children presented with acute confusional or encephalopathic state. In contrast, neonates with ethanol intoxication may present with nonspecific gastrointestinal symptomatology. Urgent exclusion of sepsis, electrolyte imbalance, drug intoxication, and surgical abdominal condition is critical. Using these illustrated cases, we performed a narrative literature review on issues of exposure to ethanol-containing substances and ethanol intoxication in children. In conclusion, a high level of suspicion and interrogation on ethanol or substance use are essential particularly in the lactating mother for an accurate and timely diagnosis of ethanol intoxication to be made.

HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo.

Oxidative stress is a prominent feature of Huntington disease (HD), and we have shown previously that reduced levels of hace1 (HECT domain and Ankyrin repeat containing E3 ubiquitin protein ligase 1) in patient striatum may contribute to the pathogenesis of HD. Hace1 promotes the stability of Nrf2 and thus plays an important role in antioxidant response mechanisms, which are dysfunctional in HD. Moreover, hace1 overexpression mitigates mutant huntingtin (mHTT)-induced oxidative stress in vitro through promotion of the Nrf2 antioxidant response. Here, we show that the genetic ablation of hace1 in the YAC128 mouse model of HD accelerates motor deficits and exacerbates cognitive and psychiatric phenotypes in vivo. We find that both the expression of mHTT and the ablation of hace1 alone are sufficient to cause deficits in astrocytic mitochondrial respiration. We confirm the crucial role of hace1 in astrocytes in vivo, since its ablation is sufficient to cause dramatic astrogliosis in wild-type FVB/N mice. Astrogliosis is not observed in the presence of mHTT but a strong dysregulation in the expression of astrocytic markers in HACE1-/- x YAC128 striatum suggests an additive effect of mHTT expression and hace1 loss on this cell type. HACE1-/- x YAC128 mice and primary cells derived from these animals therefore provide model systems that will allow for the further dissection of Nrf2 pathways and astrocyte dysfunction in the context of HD.

Laquinimod decreases Bax expression and reduces caspase-6 activation in neurons.

Laquinimod is an immunomodulatory compound that has shown neuroprotective benefits in clinical trials for multiple sclerosis. Laquinimod ameliorates both white and gray matter damage in human patients, and prevents axonal degeneration in animal models of multiple sclerosis. Axonal damage and white matter loss are a common feature shared between different neurodegenerative diseases. Caspase-6 activation plays an important role in axonal degeneration on the molecular level. Increased activity of caspase-6 has been demonstrated in brain tissue from presymptomatic Huntington disease mutation carriers, and it is an early marker of axonal dysfunction. Since laquinimod is currently undergoing a clinical trial in Huntington disease (LEGATO-HD, clinicaltrials.gov ID: NCT02215616), we set out to evaluate its impact on neuronal caspase-6 activation. We find that laquinimod ameliorates DNA-damage induced activation of caspase-6 in primary neuronal cultures. This is an indirect effect that is not mediated by direct inhibition of the enzyme. The investigation of potential caspase-6 activating mechanisms revealed that laquinimod reduces the expression of Bax, a pro-apoptotic molecule that causes mitochondrial cytochrome c release and caspase activation. Bax expression is furthermore increased in striatal tissues from the YAC128 mouse model of HD in an age-dependent manner. Our results demonstrate that laquinimod can directly downregulate neuronal apoptosis pathways relevant for axonal degeneration in addition to its known effects on astrocytes and microglia in the CNS. It targets a pathway that is relevant for the pathogenesis of HD, supporting the hypothesis that laquinimod may provide clinical benefit.

Distinct roles for metalloproteinases during traumatic brain injury.

BACKGROUND: Significant protease activations have been reported after traumatic brain injury (TBI). These proteases are responsible for cleavage of transmembrane proteins in neurons, glial, and endothelial cells and this results in the release of their extracellular domains (ectodomains). METHODS: Two TBI models were employed here, representing both closed head injury (CHI) and open head injury (OHI). In situ zymography, immunohistochemistry, bright field and confocal microscopy, quantification of immunopositive cells and statistical analysis were applied. RESULTS: We found, using in situ zymography, that gelatinase activity of matrix metalloproteinases (MMP)-2 and MMP-9 was upregulated in cortex of both injury models. Using immunohistochemistry for several MPPs (Matrix metalloproteinases) and ADAMs (disintegrin and metalloproteinases), including MMP-2, -9, ADAM-10, -17, distinct patterns of induction were observed in the two TBI models. In closed head injury, an early increase in protein expression of MMP-2, -9 and ADAM-17 was found as early as 10 min post injury in cortex and peaked at 1 h for all 4 proteases examined. In contrast, after OHI the maximal expression was observed locally neighboring the impact site, at a later time-point, as long as 24 h after the injury for MMP-2 and MMP-9. Confocal microscopy revealed colocalization of the 4 proteases with the neuronal marker NeuN in CHI, but only MMP2 colocalized with NeuN in OHI. CONCLUSIONS: The findings may lead to a trauma-induced therapeutic strategy triggered soon after a primary insult to improve survival and to reduce brain damage following TBI.

Network Characteristics of People Who Inject Drugs Within a New HIV Epidemic Following Austerity in Athens, Greece.

BACKGROUND: Greece experienced an unprecedented increase in HIV cases among drug injectors in 2011 after economic crisis. Network-level factors are increasingly understood to drive HIV transmission in emerging epidemics. METHODS: We examined the relationship between networks, risk behaviors, and HIV serostatus among 1404 people who inject drugs in Athens, Greece. We generated networks using the chain-referral structure within a large HIV screening program. Network proportions, the proportion of a respondent's network with a given characteristic, were calculated. Multiple logistic regression models were used to assess the relationship between network proportions and individual HIV seroprevalence, injection frequency and unprotected sex. RESULTS: Of note, 1030 networks were generated. Respondent HIV seroprevalence was associated with greater proportions of network members who were HIV infected (ie, those with ≥ 50% of network members HIV positive vs. those with no network members HIV positive) (AOR: 3.11; 95% CI: 2.10 to 4.62), divided drugs (AOR: 1.60; 95% CI: 1.10 to 2.35), or injected frequently (AOR: 1.50; 95% CI: 1.02 to 2.21). Homelessness was the only sociodemographic characteristic associated with a risk outcome measure--high-frequency injecting (AOR: 1.41; 95% CI: 1.03 to 1.93). These associations were weaker for more distal second- and third-degree networks and not present when examined within random networks. CONCLUSIONS: Networks are an independently important contributor to the HIV outbreak in Athens, Greece. Network associations were strongest for the immediate network, with residual associations for distal networks. Homelessness was associated with high-frequency injecting. Prevention programs should consider including network-level interventions to prevent future emerging epidemics.

Changes in mitochondrial morphology induced by calcium or rotenone in primary astrocytes occur predominantly through ros-mediated remodeling.

Morphological changes in mitochondria have been primarily attributed to fission and fusion, while the more pliable transformations of mitochondria (remodeling, rounding, or stretching) have been largely overlooked. In this study, we quantify the contributions of fission and remodeling to changes in mitochondrial morphology induced by the Ca(2+) ionophore 4Br-A23187 and the metabolic toxin rotenone. We also examine the role of reactive oxygen species (ROS) in the regulation of mitochondrial remodeling. In agreement with our previous studies, mitochondrial remodeling, not fission, is the primary contributor to Ca(2+) -mediated changes in mitochondrial morphology induced by 4Br-A23187 in rat cortical astrocytes. Treatment with rotenone produced similar results. In both paradigms, remodeling was selectively blocked by antioxidants whereas fission was not, suggesting a ROS-mediated mechanism for mitochondrial remodeling. In support of this hypothesis, inhibition of endogenous ROS by overnight incubation in antioxidants resulted in elongated reticular networks of mitochondria. Examination of inner and outer mitochondrial membranes revealed that they largely acted in concert during the remodeling process. While mitochondrial morphology is traditionally ascribed to a net output of fission and fusion processes, in this study we provide evidence that the acute pliability of mitochondria can be a dominant factor in determining their morphology. More importantly, our results suggest that the remodeling process is independently regulated through a ROS-signaling mechanism. Mitochondrial morphology is traditionally ascribed to a balance of fission and fusion processes. We have shown that mitochondria can undergo more pliable transformations; remodeling, rounding, or stretching. We demonstrate that remodeling, not fission, is the primary contributor to calcium mediated changes in mitochondrial morphology in primary astrocytes. Others have shown fission is mediated by calcineurin. Our results suggest the remodeling process distinct from fission and is independently regulated through a ROS-signaling mechanism (CsA: Cyclosporine A; NAC: N-acetyl-l-cysteine; GSH: Reduced-L-Glutathione).

Semiochemical-mediated oviposition avoidance by female house flies, Musca domestica, on animal feces colonized with harmful fungi.

House flies, Musca domestica, utilize ephemeral resources such as animal feces for oviposition and development of larval offspring, but they face competition with fungi that colonize the same resource. We predicted that house flies avoid oviposition on feces well-colonized with fungi, thereby reducing fungal competition for larval offspring. Working with fungal isolates from chicken feces, we have previously shown that prior establishment of Phoma spp., Fusarium spp., or Rhizopus spp. on feces significantly reduced oviposition by house flies. Here, we report that, in the headspace volatiles of these three fungal genera, five compounds (dimethyl trisulfide, an unknown, 2-phenylethanol, citronellal, norphytone) elicit responses from house fly antennae. In behavioral bioassays, dimethyl trisulfide and 2-phenylethanol significantly reduced oviposition by house flies. We conclude that fungus-derived volatiles serve as semiochemical cues that help house flies avoid resources colonized with fungal competitors for the development of larval offspring.

Bacteria on housefly eggs, Musca domestica, suppress fungal growth in chicken manure through nutrient depletion or antifungal metabolites.

Female houseflies, Musca domestica (Diptera: Muscidae), lay their eggs in ephemeral resources such as animal manure. Hatching larvae compete for essential nutrients with fungi that also colonize such resources. Both the well-known antagonistic relationship between bacteria and fungi and the consistent presence of the bacterium Klebsiella oxytoca on housefly eggs led us to hypothesize (1) that K. oxytoca, and possibly other bacteria on housefly eggs, help curtail the growth of fungal resource competitors and (2) that such fungi indeed adversely affect the development of housefly larvae. Bacteria washed from housefly eggs significantly reduced the growth of fungi in chicken manure. Nineteen bacterial strains and ten fungal strains were isolated from housefly eggs or chicken manure, respectively. Co-culturing each of all the possible bacterium-fungus pairs revealed that the bacteria as a group, but no single bacterium, significantly suppressed the growth of all fungal strains tested. The bacteria's adverse effect on fungi is due to resource nutrient depletion and/or the release of antifungal chemicals. Well-established fungi in resources significantly reduced the number of larval offspring that completed development to adult flies.