The Effect of Diesel Exhaust Particles on Adipose Tissue Mitochondrial Function and Inflammatory Status.

Air pollution poses a significant global health risk, with fine particulate matter (PM2.5) such as diesel exhaust particles (DEPs) being of particular concern due to their potential to drive systemic toxicities through bloodstream infiltration. The association between PM2.5 exposure and an increased prevalence of metabolic disorders, including obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM), is evident against a backdrop of rising global obesity and poor metabolic health. This paper examines the role of adipose tissue in mediating the effects of PM2.5 on metabolic health. Adipose tissue, beyond its energy storage function, is responsive to inhaled noxious stimuli, thus disrupting metabolic homeostasis and responding to particulate exposure with pro-inflammatory cytokine release, contributing to systemic inflammation. The purpose of this study was to characterize the metabolic response of adipose tissue in mice exposed to either DEPs or room air (RA), exploring both the adipokine profile and mitochondrial bioenergetics. In addition to a slight change in fat mass and a robust shift in adipocyte hypertrophy in the DEP-exposed animals, we found significant changes in adipose mitochondrial bioenergetics. Furthermore, the DEP-exposed animals had a significantly higher expression of adipose inflammatory markers compared with the adipose from RA-exposed mice. Despite the nearly exclusive focus on dietary factors in an effort to better understand metabolic health, these results highlight the novel role of environmental factors that may contribute to the growing global burden of poor metabolic health.

Ceramides Mediate Insulin-Induced Impairments in Cerebral Mitochondrial Bioenergetics in ApoE4 Mice.

Alzheimer's disease (AD) is the most common form of neurodegenerative disease worldwide. A large body of work implicates insulin resistance in the development and progression of AD. Moreover, impairment in mitochondrial function, a common symptom of insulin resistance, now represents a fundamental aspect of AD pathobiology. Ceramides are a class of bioactive sphingolipids that have been hypothesized to drive insulin resistance. Here, we describe preliminary work that tests the hypothesis that hyperinsulinemia pathologically alters cerebral mitochondrial function in AD mice via accrual of the ceramides. Homozygous male and female ApoE4 mice, an oft-used model of AD research, were given chronic injections of PBS (control), insulin, myriocin (an inhibitor of ceramide biosynthesis), or insulin and myriocin over four weeks. Cerebral ceramide content was assessed using liquid chromatography-mass spectrometry. Mitochondrial oxygen consumption rates were measured with high-resolution respirometry, and H2O2 emissions were quantified via biochemical assays on brain tissue from the cerebral cortex. Significant increases in brain ceramides and impairments in brain oxygen consumption were observed in the insulin-treated group. These hyperinsulinemia-induced impairments in mitochondrial function were reversed with the administration of myriocin. Altogether, these data demonstrate a causative role for insulin in promoting brain ceramide accrual and subsequent mitochondrial impairments that may be involved in AD expression and progression.

Yerba Maté (Ilex paraguariensis) Supplement Exerts Beneficial, Tissue-Specific Effects on Mitochondrial Efficiency and Redox Status in Healthy Adult Mice.

Yerba maté, a herbal tea derived from Ilex paraguariensis, has previously been reported to be protective against obesity-related and other cardiometabolic disorders. Using high-resolution respirometry and reverse-phase high-performance liquid chromatography, the effects of four weeks of yerba maté consumption on mitochondrial efficiency and cellular redox status in skeletal muscle, adipose, and liver, tissues highly relevant to whole-body metabolism, were explored in healthy adult mice. Yerba maté treatment increased the mitochondrial oxygen consumption in adipose but not in the other examined tissues. Yerba maté increased the ATP concentration in skeletal muscle and decreased the ATP concentration in adipose. Combined with the observed changes in oxygen consumption, these data yielded a significantly higher ATP:O2, a measure of mitochondrial efficiency, in muscle and a significantly lower ATP:O2 in adipose, which was consistent with yerba maté-induced weight loss. Yerba maté treatment also altered the hepatic glutathione (GSH)/glutathione disulfide (GSSG) redox potential to a more reduced redox state, suggesting the treatment's potential protective effects against oxidative stress and for the preservation of cellular function. Together, these data indicate the beneficial, tissue-specific effects of yerba maté supplementation on mitochondrial bioenergetics and redox states in healthy mice that are protective against obesity.

Effects of a True Prophylactic Treatment on Hippocampal and Amygdala Synaptic Plasticity and Gene Expression in a Rodent Chronic Stress Model of Social Defeat.

Post-traumatic stress disorder (PTSD) is a complex stress-related disorder induced by exposure to traumatic stress that is characterized by symptoms of re-experiencing, avoidance, and hyper-arousal. While it is widely accepted that brain regions involved in emotional regulation and memory-e.g., the amygdala and hippocampus-are dysregulated in PTSD, the pathophysiology of the disorder is not well defined and therefore, pharmacological interventions are extremely limited. Because stress hormones norepinephrine and cortisol (corticosterone in rats) are heavily implicated in the disorder, we explored whether preemptively and systemically antagonizing ß-adrenergic and glucocorticoid receptors with propranolol and mifepristone are sufficient to mitigate pathological changes in synaptic plasticity, gene expression, and anxiety induced by a modified social defeat (SD) stress protocol. Young adult, male Sprague Dawley rats were initially pre-screened for anxiety. The rats were then exposed to SD and chronic light stress to induce anxiety-like symptoms. Drug-treated rats were administered propranolol and mifepristone injections prior to and continuing throughout SD stress. Using competitive ELISAs on plasma, field electrophysiology at CA1 of the ventral hippocampus (VH) and the basolateral amygdala (BLA), quantitative RT-PCR, and behavior assays, we demonstrate that our SD stress increased anxiety-like behavior, elevated long-term potentiation (LTP) in the VH and BLA, and altered the expression of mineralocorticoid, glucocorticoid, and glutamate receptors. These measures largely reverted to control levels with the administration of propranolol and mifepristone. Our findings indicate that SD stress increases LTP in the VH and BLA and that prophylactic treatment with propranolol and mifepristone may have the potential in mitigating these and other stress-induced effects.

A Novel Ketone-Supplemented Diet Improves Recognition Memory and Hippocampal Mitochondrial Efficiency in Healthy Adult Mice.

Mitochondrial dysfunction and cognitive impairment are common symptoms in many neurologic and psychiatric disorders, as well as nonpathological aging. Ketones have been suggested as therapeutic for their efficacy in epilepsy and other brain pathologies such as Alzheimer's disease and major depressive disorder. However, their effects on cognitive function in healthy individuals is less established. Here, we explored the mitochondrial and performative outcomes of a novel eight-week ketone-supplemented ketogenic (KETO) diet in healthy adult male and female mice. In a novel object recognition test, KETO mice spent more time with the novel, compared to familiar, object, indicating an improvement in recognition memory. High-resolution respirometry on permeabilized hippocampal tissue returned significant reductions in mitochondrial O2 consumption. No changes in ATP production were observed, yielding a significantly higher ATP:O2 ratio, a measure of mitochondrial efficiency. Together, these findings demonstrate the KETO diet improves hippocampal mitochondrial efficiency. They add to a growing body of evidence that suggests ketones and ketogenic diets are neuroprotective and metabolically and cognitively relevant, even in healthy adults. They also suggest that ketogenic lifestyle changes may be effective strategies for protecting against cognitive decline associated with aging and disease.

A high-carbohydrate diet lowers the rate of adipose tissue mitochondrial respiration.

Adipocyte mitochondrial respiration may influence metabolic fuel partitioning into oxidation versus storage, with implications for whole-body energy expenditure. Although insulin has been shown to influence mitochondrial respiration, the effects of dietary macronutrient composition have not been well characterized. The aim of this exploratory study was to test the hypothesis that a high-carbohydrate diet lowers the oxygen flux of adipocyte mitochondria ex vivo. Among participants in a randomized-controlled weight-loss maintenance feeding trial, those consuming a high-carbohydrate diet (60% carbohydrate as a proportion of total energy, n = 10) had lower rates of maximal adipose tissue mitochondrial respiration than those consuming a moderate-carbohydrate diet (40%, n = 8, p = 0.039) or a low-carbohydrate diet (20%, n = 9, p = 0.005) after 10 to 15 weeks. This preliminary finding may provide a mechanism for postulated calorie-independent effects of dietary composition on energy expenditure and fat deposition, potentially through the actions of insulin on fuel partitioning.

Corrigendum to "Gender and Ethnicity Based Differences in Clinical and Laboratory Features of Myasthenia Gravis".

[This corrects the article DOI: 10.1155/2015/197893.].

Alzheimer's disease alters oligodendrocytic glycolytic and ketolytic gene expression.

INTRODUCTION: Sporadic Alzheimer's disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain. METHODS: RNA-seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes. RESULTS: In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia. DISCUSSION: Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism.

Ketones Elicit Distinct Alterations in Adipose Mitochondrial Bioenergetics.

OBJECTIVE: The rampant growth of obesity worldwide has stimulated explosive research into human metabolism. Energy expenditure has been shown to be altered by diets differing in macronutrient composition, with low-carbohydrate, ketogenic diets eliciting a significant increase over other interventions. The central aim of this study was to explore the effects of the ketone ß-hydroxybutyrate (ßHB) on mitochondrial bioenergetics in adipose tissue. METHODS: We employed three distinct systems-namely, cell, rodent, and human models. Following exposure to elevated ßHB, we obtained adipose tissue to quantify mitochondrial function. RESULTS: In every model, ßHB robustly increased mitochondrial respiration, including an increase of roughly 91% in cultured adipocytes, 113% in rodent subcutaneous adipose tissue (SAT), and 128% in human SAT. However, this occurred without a commensurate increase in adipose ATP production. Furthermore, in cultured adipocytes and rodent adipose, we quantified and observed an increase in the gene expression involved in mitochondrial biogenesis and uncoupling status following ßHB exposure. CONCLUSIONS: In conclusion, ßHB increases mitochondrial respiration, but not ATP production, in mammalian adipocytes, indicating altered mitochondrial coupling. These findings may partly explain the increased metabolic rate evident in states of elevated ketones, and may facilitate the development of novel anti-obesity interventions.

Extracellular binding of indinavir to matrix metalloproteinase-2 and the alpha-7-nicotinic acetylcholine receptor: implications for use in cancer treatment.

INTRODUCTION: Results from recent studies have suggested a role for protease inhibitors in altering mechanisms involved in the initiation and proliferation of cancer cells. One such inhibitor, indinavir, may act as an anti-cancer agent by modulating the alpha-7-nicotinic acetylcholine receptor, which is a pro-carcinogenic protein that has been researched in conjunction with nicotine in lung cancer development. In our study, we compare indinavir's binding affinity towards α7-nAchR and MMP-2, another promoter of malignancy, to determine what extracellular effects the drug has before being internalized to inhibit HIV-1 protease. METHODS: A computer program, PyRx, was used to compare indinavir's binding affinity with digital models for α7-nAchR, MMP-2 and HIV-1 protease, which were then compared to the results of in vitro binding assays for these targets. RESULTS: PyRx testing predicted the highest binding affinity values for indinavir to MMP-2 (mean = 8.77 kcal/mol, S.D. = 0.29), followed by the α7-nAchR (mean = 8.53 kcal/mol, S.D. = 0.15) and HIV-1 protease (mean = 7.5 kcal/mol, S.D. = 0.44). In vitro, indinavir's mean percent inhibition of control values were 103.2 for HIV-1 protease, 5.3 for MMP-2, and 7.7 for the α7-nAchR. CONCLUSIONS: Binding affinity values for indinavir to MMP-2 and α7-nAchR were not significantly different. Using PyRx to predict affinity compared with in vitro testing did not yield comparable results. However, indinavir was shown to slightly inhibit both α7-nAchR and MMP-2, which may have ramifications in the drug's delivery to the intracellularly located HIV-1 protease.

Headaches More Common among Epilepsy Sufferers with Neurocysticercosis than Other Structural Brain Lesions.

Neurocysticercosis is a leading cause of seizures and epilepsy in the developing world. Cysticercosis is endemic in many regions of Central and South America, sub-Saharan Africa, India, and Asia. Neurocysticercosis is of emerging importance because globalization has increased travel between Hawai'i and disease-endemic areas. Headache and epilepsy are two of the most common complications of neurocysticercosis infection. Currently, it is not known if epilepsy patients with neurocysticercosis are more likely to have headaches than those with other structural brain lesions or those with no structural brain abnormalities. This study was designed to investigate whether epilepsy patients with neurocysticercosis report co-morbid headaches more frequently than those with other or with no structural brain lesions. A retrospective cross-sectional study of all patients treated at a community based neurology clinic for epilepsy during a three-month period was performed. One-hundred sixty patients were included in the analytical study. Co-morbid headaches were more commonly present among those with neurocysticercosis (40%) than those with other structural lesions and those with no structural brain abnormalities (19% and 22%, respectively; P = .031). Headache frequency among those reporting co-morbid headaches did not differ significantly between the groups. Prevalence of co-morbid headaches is greater among epilepsy patients with neurocysticercosis than those with other structural brain lesions or no structural brain abnormality. Epilepsy patients with neurocysticercosis may be especially vulnerable to development of headaches and a thorough headache history should be obtained to help screen for affected individuals.

Smoking history and Alzheimer's disease risk in a community-based clinic population.

BACKGROUND: The relationship between cigarette smoking and development of Alzheimer's disease (AD) is not fully determined, and previous reports disagree, with some studies suggesting an increased relative risk and others a decreased odds ratio. Consequently, we wanted to determine if the prevalence of past cigarette smoking observed in a community-based clinic sample of patients with AD would be more consistent with the expected value obtained from a model using either an increased relative risk or a decreased odds ratio to estimate the effect of smoking on development of AD. MATERIALS AND METHODS: Retrospective cross-sectional analysis of all patients treated for AD in a community-based Neurology Clinic during a 2-year period. Estimates of expected past smoking prevalence were calculated based on published values for either an increased relative risk or a decreased odds ratio and compared to the past smoking prevalence observed in the clinic sample. RESULTS: The observed past smoking prevalence in the clinic population was 29.17%. The expected past smoking prevalence calculated using the increased relative risk was 30.07% (95% confidence interval [CI] = 27.67-32.32%), and using the decreased odds ratio was 12.54% (95% CI = 6.32-24.81%). CONCLUSION: The observed past smoking prevalence among the patients being treated for AD in a community-based clinic falls within the expected 95% CI for the increased relative risk model and outside of the expected 95% CI for the decreased odds ratio model. These results support the contention that the relationship between cigarette smoking and development of AD is the best characterized by an increased relative risk.

α7-Nicotinic acetylcholine receptor inhibition by indinavir: implications for cognitive dysfunction in treated HIV disease.

OBJECTIVE: The study set out to determine if the HIV protease inhibitor, indinavir, alters responsiveness of α7-nicotinic acetylcholine receptors to acetylcholine. DESIGN: Treatment with HAART has dramatically reduced development of HIV-associated dementia and more severe forms of cognitive impairment. However, many individuals continue to experience cognitive decline of uncertain cause. Previous studies have failed to demonstrate significant alterations of functional brain connectivity, structural brain changes, or changes in cerebral blood flow sufficient to explain cognitive decline in virally suppressed individuals. This suggests that the mechanisms underlying development and progression of cognitive problems likely occurs at a micro rather than macro level, such as disruptions in neurotransmitter system signaling. MATERIALS AND METHODS: Indinavir's effects on α7-nicotinic acetylcholine receptor activity was tested using a ScreenPatch IonWorks Barracuda-based assay in a mammalian cell model. RESULTS: At low concentrations (0.0003-10 µmol/l) indinavir acts as a positive allosteric modulator (EC50 = 0.021 µmol/l), whereas at concentrations greater than 10 µmol/l (30-100 µmol/l) indinavir acts as an inhibitor of the α7-nicotinic acetylcholine receptor. CONCLUSION: At concentrations greater than 10 µmol/l indinavir reduces synaptic transmission in the acetylcholine neurotransmitter system, which could possibly contribute to cognitive dysfunction. These results suggest that further experiments should be considered to assess whether patients might benefit from treatment with cholinesterase inhibitors that counteract the effects of indinavir.

Topographic congruence of calcified parenchymal neurocysticercosis and other structural brain lesions with epileptiform activity.

INTRODUCTION: Calcified parenchymal neurocysticercosis (NCC) lesions are commonly detected in many individuals with refractory epilepsy. However, the relationship between these lesions and epilepsy is not fully determined. We sought to determine if calcified parenchymal NCC demonstrated topographic congruence with epileptiform activity in refractory epilepsy patients. Additional patients with other structural brain lesions were included for comparison. SUBJECTS AND METHODS: Retrospective cross-sectional analysis of all patients treated at a community-based neurology clinic for refractory epilepsy during a 3-month period and with structural brain lesions detected by neuroimaging studies. RESULTS: A total of 105 patients were included in the study, including 63 with calcified parenchymal NCC lesions and 42 with other structural brain lesions. No significant relationship was detected between hemispheric localization of calcified parenchymal NCC lesions and epileptiform activity. For those with other structural brain lesions, the hemispheric localization was significantly related to the side of epileptiform activity (Chi-square = 11.13, P = 0.025). In addition, logistic regression models showed that those with right-sided non-NCC lesions were more likely to have right-sided epileptiform activity (odds ratio = 4.36, 95% confidence interval [CI] =1.16-16.31, P = 0.029), and those with left-sided non-NCC lesions were more likely to have left-sided epileptiform activity (odds ratio = 7.60, 95% CI = 1.89-30.49, P = 0.004). CONCLUSION: The lack of correlation between the side of calcified parenchymal NCC lesions and the side of the epileptiform activity suggests that these lesions may be incidental findings in many patients.

Lower Frequency of co-Morbid Medical Disorders Related to Poor Impulse Control in Parkinson's than Alzheimer's Disease.

Parkinson's disease is associated with progressive degeneration of mesolimbic dopaminergic neurons that are involved in reward-based behavior learning, including rewarding effects of food consumption and drugs of abuse. The importance of this pathway in development of addictive behaviors led us to hypothesize that medical disorders related to poor impulse control may occur less frequently among patients with Parkinson's disease than those with other progressive neurodegenerative disorders such as Alzheimer's disease. Retrospective cross-sectional study of all patients treated for Parkinson's disease and Alzheimer's disease in a community based clinic during a two-year period. Associations were summarized using odds ratios (OR) and 95% confidence intervals (95% CI) estimated from logistic regression models, adjusted for differences in gender distribution between the groups. A total of 106 patients with Parkinson's disease and 72 patients with Alzheimer's disease were included. Patients with Parkinson's disease were less likely to have either past substance use (adjusted OR = 0.035, 95% CI = 0.009 - 0.130) or presence of co-morbid medical conditions related to poor dietary choices (adjusted OR = 0.157, 95% CI = 0.062 - 0.397). Co-morbid medical conditions related to poor impulse control occur less frequently among those with Parkinson's disease than those with Alzheimer's disease. These findings are consistent with dysfunction of dopamine dependent pathways involved in addiction during the presymptomatic phase of Parkinson's disease and support a biological basis for addiction.

Gender and Ethnicity Based Differences in Clinical and Laboratory Features of Myasthenia Gravis.

Background. Previous reports describe ethnicity based differences in clinical and laboratory features between Caucasians and African Americans with myasthenia gravis. However, it is not known whether these findings apply to other ethnicities. Methods. Retrospective analysis of all patients treated for myasthenia gravis during a three-year period at a community based medical center. Results. A total of 44 patients were included, including 19 of Hispanic, 16 of African American, 6 of Caucasian, and 3 of Asian ethnicities. Female gender was more common among those with Hispanic, Asian, and African American ethnicities compared to Caucasian ethnicity (p = 0.029). Anti-acetylcholine receptor antibody subtypes demonstrated no significant ethnicity based differences in either generalized or ocular myasthenia gravis. A trend was noted towards greater frequency of blocking antibodies among Hispanics (52.6%) compared to African American (37.5%) and Caucasian (33.3%) patients (p = 0.059). Generalized but not ocular myasthenia patients showed greater frequency of anti-muscle specific kinase antibodies in Asians and Hispanics compared to African Americans and Caucasians (p = 0.041). Conclusions. The results of this study support the existence of ethnicity based differences in clinical and laboratory features of myasthenia gravis. Further study of genetic factors influencing clinical features of myasthenia gravis is indicated.

Calcified parenchymal central nervous system cysticercosis and clinical outcomes in epilepsy.

OBJECTIVE: This study aimed to compare clinical outcomes including seizure frequency and psychiatric symptoms between patients with epilepsy with neuroimaging evidence of past brain parenchymal neurocysticercosis infection, patients with other structural brain lesions, and patients without structural neuroimaging abnormalities. MATERIAL AND METHODS: The study included retrospective cross-sectional analysis of all patients treated for epilepsy in a community-based adult neurology clinic during a three-month period. RESULTS: A total of 160 patients were included in the analysis, including 63 with neuroimaging findings consistent with past parenchymal neurocysticercosis infection, 55 with structurally normal brain neuroimaging studies, and 42 with other structural brain lesions. No significant differences were detected between groups for either seizure freedom (46.03%, 50.91%, and 47.62%, respectively; p=0.944) or mean seizure frequency per month (mean=2.50, S.D.=8.1; mean=4.83, S.D.=17.64; mean=8.55, S.D.=27.31, respectively; p=0.267). Self-reported depressive symptoms were more prevalent in those with parenchymal neurocysticercosis than in the other groups (p=0.003). No significant differences were detected for prevalence of self-reported anxiety or psychotic symptoms. CONCLUSIONS: Calcified parenchymal neurocysticercosis results in refractory epilepsy about as often as other structural brain lesions. Depressive symptoms may be more common among those with epilepsy and calcified parenchymal neurocysticercosis; consequently, screening for depression may be indicated in this population.

Acute Psychosis Associated with Subcortical Stroke: Comparison between Basal Ganglia and Mid-Brain Lesions.

Acute onset of psychosis in an older or elderly individual without history of previous psychiatric disorders should prompt a thorough workup for neurologic causes of psychiatric symptoms. This report compares and contrasts clinical features of new onset of psychotic symptoms between two patients, one with an acute basal ganglia hemorrhagic stroke and another with an acute mid-brain ischemic stroke. Delusions and hallucinations due to basal ganglia lesions are theorized to develop as a result of frontal lobe dysfunction causing impairment of reality checking pathways in the brain, while visual hallucinations due to mid-brain lesions are theorized to develop due to dysregulation of inhibitory control of the ponto-geniculate-occipital system. Psychotic symptoms occurring due to stroke demonstrate varied clinical characteristics that depend on the location of the stroke within the brain. Treatment with antipsychotic medications may provide symptomatic relief.

Cost effective community based dementia screening: a markov model simulation.

Background. Given the dementia epidemic and the increasing cost of healthcare, there is a need to assess the economic benefit of community based dementia screening programs. Materials and Methods. Markov model simulations were generated using data obtained from a community based dementia screening program over a one-year period. The models simulated yearly costs of caring for patients based on clinical transitions beginning in pre dementia and extending for 10 years. Results. A total of 93 individuals (74 female, 19 male) were screened for dementia and 12 meeting clinical criteria for either mild cognitive impairment (n = 7) or dementia (n = 5) were identified. Assuming early therapeutic intervention beginning during the year of dementia detection, Markov model simulations demonstrated 9.8% reduction in cost of dementia care over a ten-year simulation period, primarily through increased duration in mild stages and reduced time in more costly moderate and severe stages. Discussion. Community based dementia screening can reduce healthcare costs associated with caring for demented individuals through earlier detection and treatment, resulting in proportionately reduced time in more costly advanced stages.