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PubMedDate not supplied

Myofibril MgATPase activities and energy metabolism in cardiomyopathic mice with diastolic dysfunction.

To study the genomic physiology of cardiac myofibril proteins in the heart, we have successfully created a cardiac troponin I (cTnI; a myofibril protein) gene knockout mouse model using gene targeting techniques. The phenotype of the cTnI gene knockout mouse is a cardiomyopathy with diastolic dysfunction resulting in sudden death in neonates. In the present studies, energy metabolism was analyzed in myocardial cells from cTnI-null hearts. Myofibril MgATPase activities were determined in myocardial cells from either wild-type or cTnI mutant mouse hearts. Furthermore, the quantity and quality of the mitochondria in wild-type and cTnI mutant animals were counted and analyzed. Our results demonstrate that damaged relaxation and increased Ca(2+)-independent force production in cTnI-null hearts is in part related to the increased myofibril MgATPase activities accompanied by an increase in mitochondria quantity and mitochondrial ATPase activities. These data indicate that cardiomyopathies with diastolic dysfunction are different from cardiomyopathies caused by systolic dysfunction. The former involves the damage of cardiac relaxation due to increased MgATPase activities and increased Ca(2+)-independent force production inside of myofilaments, while the latter involves the damage of systolic contraction due to decreased MgATPase activities and decreased force production.

Animals↗

PubMed2002

Environment, mitochondria, and Parkinson's disease.

Parkinson's disease (PD) is a common and disabling neurodegenerative disease marked by progressive motor dysfunction, which results from selective degeneration of the nigrostriatal pathway. Epidemiological studies indicate that exposure to pesticides, rural living, farming, and drinking well water are associated with an increased risk of developing PD. Rare cases of PD are caused by mutations in nuclear genes, and there is increasing evidence for susceptibility genes that alter disease risk. Parkinson's disease is also associated with a systemic defect in mitochondrial complex I activity. Animal models indicate that exposure to inhibitors of mitochondrial complex I, including pesticides, is sufficient to reproduce the features of PD, but genetic factors clearly modulate susceptibility. Complex I defects may result in oxidative stress and increase the susceptibility of neurons to excitotoxic death. In this way, environmental exposures and mitochondrial dysfunction may interact and result in neurodegeneration.

Animals↗

PubMed2001

Vitamin E succinate protects hepatocytes against the toxic effect of reactive oxygen species generated at mitochondrial complexes I and III by alkylating agents.

The mechanism of alpha-tocopheryl succinate (TS) cytoprotection against mitochondria-derived oxidative stress was investigated. Incubation of isolated rat hepatocytes with ethyl methanesulfonate (EMS), a mitochondrial alkylating toxicant caused mitochondrial dysfunction and necrotic cell death that was dependent on the production of reactive oxygen species (ROS) and lipid peroxidation. Mitochondria isolated from these cells showed a 3-fold increase in lipid hydroperoxides and a selective depletion of alpha-tocopherol (T), which preceded cell death. The pretreatment of hepatocytes with TS dramatically enriched cells and mitochondria with alpha-tocopherol and provided these membranes with complete protection against EMS-induced oxidative damage. TS pretreatment suppressed EMS-induced cellular ROS production, generated from mitochondrial complex I and III sites. In addition, the treatment with either rotenone (ROT, a complex I inhibitor) or antimycin A (AA, a complex III inhibitor) potentiated EMS-induced lipid peroxidation and necrotic cell death which were again completely prevented by TS treatment. Surprisingly, TS did not protect hepatocytes against thenoyltrifluoroacetone (TTFA), a complex II inhibitor-induced enhancement of EMS-induced toxic oxidative damage. We conclude that the inhibition of mitochondrial ROS production and lipid peroxidation by T released from TS, are the critical events responsible for TS-mediated cytoprotection against toxic oxidative stress derived from both mitochondrial complexes I and III. Our findings suggest that TS treatment may prove useful in combating diseases associated with mitochondrial-derived oxidative stress.

Animals↗

PubMed2006

Identification of calcium-independent phospholipase A2gamma in mitochondria and its role in mitochondrial oxidative stress.

Oxidant-induced lipid peroxidation and cell death mediate pathologies associated with ischemia-reperfusion and inflammation. Our previous work in rabbit renal proximal tubular cells (RPTC) demonstrated that inhibition of Ca(2+)-independent phospholipase A(2) (iPLA(2)) potentiates oxidant-induced lipid peroxidation and necrosis, implicating iPLA(2) in phospholipid repair. This study was conducted to identify a RPTC mitochondrial PLA(2) and determine the role of PLA(2) in oxidant-induced mitochondrial dysfunction. iPLA(2) activity was detected in Percoll-purified rabbit renal cortex mitochondria (RCM) and in isolated mitochondrial inner membrane fractions from rabbit and human RCM. Immunoblot analysis and inhibitor sensitivity profiles revealed that iPLA(2)gamma is the RCM iPLA(2) activity. RCM iPLA(2) activity was enhanced in the presence of ATP and was blocked by the PKCepsilon V1-2 inhibitor. Oxidant-induced mitochondrial lipid peroxidation and swelling were accelerated by pretreatment with R-BEL, but not S-BEL. Furthermore, oxidant treatment of isolated RCM resulted in decreased iPLA(2)gamma activity. These results reveal that RCM iPLA(2) is iPLA(2)gamma, RCM iPLA(2)gamma is regulated by phosphorylation by PKCepsilon, iPLA(2)gamma protects RCM from oxidant-induced lipid peroxidation and dysfunction, and that a strategy to preserve or enhance iPLA(2)gamma activity may be of therapeutic benefit.

Animals↗

PubMed2005

Mitochondria-targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell lines.

Oxidative stress and mitochondrial oxidative damage have been implicated in aging and many common diseases. Mitochondria are a primary source of reactive oxygen species (ROS) in the cell, and are particularly susceptible to oxidative damage. Oxidative damage to mitochondria results in mitochondrial permeability transition (MPT), mitochondrial depolarization, further ROS production, swelling, and release of cytochrome c (cyt c). Cytosolic cyt c triggers apoptosis by activating the caspase cascade. In the present work, we examined the ability of a novel cell-penetrating, mitochondria-targeted peptide antioxidant in protecting against oxidant-induced mitochondrial dysfunction and apoptosis in two neuronal cell lines. Treatment with tert-butyl hydroperoxide (tBHP) for 24 h resulted in lipid peroxidation and significant cell death via apoptosis in both N2A and SH-SY5Y cells, with phosphatidylserine translocation, nuclear condensation and increased caspase activity. Cells treated with tBHP showed significant increase in intracellular ROS, mitochondrial depolarization and reduced mitochondrial viability. Concurrent treatment with <1 nM SS-31 (D-Arg-Dmt-Lys-Phe-NH2; Dmt = 2',6'-dimethyltyrosine) significantly decreased intracellular ROS, increased mitochondrial potential, and prevented tBHP-induced apoptosis. The remarkable potency of SS-31 can be explained by its extensive cellular uptake and selective partitioning into mitochondria. Intracellular concentrations of [3H]SS-31 were 6-fold higher than extracellular concentrations. Studies using isolated mitochondria revealed that [3H]SS-31 was concentrated approximately 5000-fold in the mitochondrial pellet. By concentrating in the inner mitochondrial membrane, SS-31 is localized to the site of ROS production, and can therefore protect against mitochondrial oxidative damage and further ROS production. SS-31 represents a novel platform of mitochondria-targeted antioxidants with broad therapeutic potential.

Antioxidants↗

PubMed2006

Pathways of neurodegeneration and experimental models of basal ganglia disorders: downstream effects of mitochondrial inhibition.

The basal ganglia circuit plays a key role in the regulation of voluntary movements as well as in behavioural control and cognitive functions. The main pathogenic role of mitochondrial dysfunctions is now accepted in the neurodegenerative process and the mitochondria have been successfully used as subcellular targets to obtain relevant experimental models of basal ganglia neurodegenerative disorders. Mitochondrial toxins act through an inhibition of the respiratory chain complexes. These toxins, by uncoupling cellular respiration, shift the cell into a state of oxidative stress and trigger several bidirectional links with the excitotoxic process. Moreover, the in vitro inhibition of the respiratory chain complexes alters the electrophysiological properties of the neurons. The downstream effects triggered by mitochondrial complexes inhibition provide a model integrating genetic and environmental pathogenic factors to explain the selective neuronal vulnerability.

Animals↗

PubMed1999

Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein.

Mutations in the human tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Some mutations, including mutations in intron 10, induce increased levels of the functionally normal four-repeat tau protein isoform, leading to neurodegeneration. We generated transgenic mice that overexpress the four-repeat human tau protein isoform specifically in neurons. The transgenic mice developed axonal degeneration in brain and spinal cord. In the model, axonal dilations with accumulation of neurofilaments, mitochondria, and vesicles were documented. The axonopathy and the accompanying dysfunctional sensorimotor capacities were transgene-dosage related. These findings proved that merely increasing the concentration of the four-repeat tau protein isoform is sufficient to injure neurons in the central nervous system, without formation of intraneuronal neurofibrillary tangles. Evidence for astrogliosis and ubiquitination of accumulated proteins in the dilated part of the axon supported this conclusion. This transgenic model, overexpressing the longest isoform of human tau protein, recapitulates features of known neurodegenerative diseases, including Alzheimer's disease and other tauopathies. The model makes it possible to study the interaction with additional factors, to be incorporated genetically, or with other biological triggers that are implicated in neurodegeneration.

Animals↗

PubMed1988

Chronic exposure to cadmium did not impair vitamin D metabolism in monkeys.

Vitamin D metabolism in primates with chronic exposure to cadmium was studied in relation to Itai-Itai disease. In a series of experiments, crab-eating monkeys were fed cadmium-contaminated rice (1.33 micrograms Cd/g) or a diet containing 3 micrograms/g cadmium chloride for 6 years. These treatments had no effect on the 1,25-dihydroxyvitamin D (1,25(OH)2D), 24,25-dihydroxyvitamin D (24,25(OH)2D), and 25-hydroxyvitamin D (25(OH)D) in the serum. This is consistent with unchanged production of 1,25(OH)2D and 24,25(OH)2D by renal mitochondria prepared from the same animals. No indication of renal dysfunction was observed. In another series of experiments, rhesus monkeys were fed a diet containing 3, 10, 30, or 100 micrograms/g cadmium for 9 years. Serum vitamin D metabolites and renal production of 24,25(OH)2D also remained unchanged. In contrast, renal 25(OH)D-1-hydroxylase (1-hydroxylase), which is responsible for the production of 1,25(OH)2D, seemed to be suppressed in the animals fed 30 or 100 micrograms/kg cadmium-contaminated diet (no statistical significance). These animals had indications of mild renal dysfunction, and there was a strong negative correlation between 1-hydroxylase and urinary concentration of either protein or beta 2-microglobulin. These data suggest a slight change in the total enzyme activity, possibly due to mild renal dysfunction. Since substrate (25(OH)D) concentration is much lower and thus rate-limiting in vivo as compared with that in vitro assay system used in this study, the slight change of enzyme activity would not have been sufficient to affect the serum level of 1,25(OH)2D. No skeletal abnormality was observed in any of these animals. In view of these data, the length of cadmium exposure and the life span of animals as well as epidemiological data published elsewhere, factors other than cadmium may also be involved in the development of Itai-Itai disease.

Animals↗

PubMed1998

Effects of intrastriatal injection of quinolinic acid on electrical activity and extracellular ion concentrations in rat striatum in vivo.

Changes in neuronal activity and extracellular concentrations of ions were measured in rat striatum for 60-90 min after intrastriatal injection of quinolinic acid, an agonist of the N-methyl-D-aspartate receptor. The excitotoxin induced bursts of synchronous electrical activity which were accompanied by rises in [K+]e (to approximately 6 mM) and decreases in [Ca2+]e (by less than 0.1 mM); [H+]e usually increased (0.1-0.3 pH unit) after a short and small (< 0.1 pH unit) alkaline shift. The magnitude and frequency of these periodic changes decreased with time; after 90 min the amplitudes fell to 10-20% of the early values and the frequency to about one every 8 min as compared to one every 2-3 min immediately after quinolinate injection. By 90 min there was an increase in [K+]e from 3.3 mM to 4.2 mM and a decrease in [Ca2+]e from 1.34 mM to 1.30 mM. It is postulated that activation of the N-methyl-D-aspartate receptor causes disturbances in neuronal activity and ion gradients; restoration of the original ionic balances raises utilization of ATP and places an additional demand on energy-producing pathways. Increased influx of calcium into neurons may lead to an enhanced accumulation and subsequent overload of mitochondria with the cation. This, in turn, could result in dysfunction of the organelles and account for the decrease in respiration and [ATP]/[ADP] that have been observed previously in this model. The results of the present study lead to the conclusion that quinolinic acid produces early changes in activity of striatal neurons and movements of several cations which may contribute to subsequent abnormalities in energy metabolism and ultimately, cell death.

Animals↗

PubMed2001

Mitochondrial involvement in brain function and dysfunction: relevance to aging, neurodegenerative disorders and longevity.

It is becoming increasingly evident that the mitochondrial genome may play a key role in neurodegenerative diseases. Mitochondrial dysfunction is characteristic of several neurodegenerative disorders, and evidence for mitochondria being a site of damage in neurodegenerative disorders is partially based on decreases in respiratory chain complex activities in Parkinson's disease, Alzheimer's disease, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant balance perturbation, are thought to underlie defects in energy metabolism and induce cellular degeneration. Efficient functioning of maintenance and repair process seems to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of genes termed vitagenes. A promising approach for the identification of critical gerontogenic processes is represented by the hormesis-like positive effect of stress. In the present review, we discuss the role of energy thresholds in brain mitochondria and their implications in neurodegeneration. We then review the evidence for the role of oxidative stress in modulating the effects of mitochondrial DNA mutations on brain age-related disorders and also discuss new approaches for investigating the mechanisms of lifetime survival and longevity.

Aging↗

PubMed2004

Endogenous mitochondrial oxidative stress: neurodegeneration, proteomic analysis, specific respiratory chain defects, and efficacious antioxidant therapy in superoxide dismutase 2 null mice.

Oxidative stress and mitochondrial dysfunction have been linked to neurodegenerative disorders such as Parkinson's and Alzheimer's disease. However, it is not yet understood how endogenous mitochondrial oxidative stress may result in mitochondrial dysfunction. Most prior studies have tested oxidative stress paradigms in mitochondria through either chemical inhibition of specific components of the respiratory chain, or adding an exogenous insult such as hydrogen peroxide or paraquat to directly damage mitochondria. In contrast, mice that lack mitochondrial superoxide dismutase (SOD2 null mice) represent a model of endogenous oxidative stress. SOD2 null mice develop a severe neurological phenotype that includes behavioral defects, a severe spongiform encephalopathy, and a decrease in mitochondrial aconitase activity. We tested the hypothesis that specific components of the respiratory chain in the brain were differentially sensitive to mitochondrial oxidative stress, and whether such sensitivity would lead to neuronal cell death. We carried out proteomic differential display and examined the activities of respiratory chain complexes I, II, III, IV, V, and the tricarboxylic acid cycle enzymes alpha-ketoglutarate dehydrogenase and citrate synthase in SOD2 null mice in conjunction with efficacious antioxidant treatment and observed differential sensitivities of mitochondrial proteins to oxidative stress. In addition, we observed a striking pattern of neuronal cell death as a result of mitochondrial oxidative stress, and were able to significantly reduce the loss of neurons via antioxidant treatment.

Animals↗

PubMed2005

Inhibition of the mitochondrial calcium uniporter by the oxo-bridged dinuclear ruthenium amine complex (Ru360) prevents from irreversible injury in postischemic rat heart.

Mitochondrial calcium overload has been implicated in the irreversible damage of reperfused heart. Accordingly, we studied the effect of an oxygen-bridged dinuclear ruthenium amine complex (Ru360), which is a selective and potent mitochondrial calcium uniporter blocker, on mitochondrial dysfunction and on the matrix free-calcium concentration in mitochondria isolated from reperfused rat hearts. The perfusion of Ru360 maintained oxidative phosphorylation and prevented opening of the mitochondrial permeability transition pore in mitochondria isolated from reperfused hearts. We found that Ru360 perfusion only partially inhibited the mitochondrial calcium uniporter, maintaining the mitochondrial matrix free-calcium concentration at basal levels, despite high concentrations of cytosolic calcium. Additionally, we observed that perfused Ru360 neither inhibited Ca2+ cycling in the sarcoplasmic reticulum nor blocked ryanodine receptors, implying that the inhibition of ryanodine receptors cannot explain the protective effect of Ru360 in isolated hearts. We conclude that the maintenance of postischemic myocardial function correlates with an incomplete inhibition of the mitochondrial calcium uniporter. Thus, the chemical inhibition by this molecule could be an approach used to prevent heart injury during reperfusion.

Animals↗

PubMed1992

Effect of smoking on the oxidative processes of cardiomyocytes.

The effect of prolonged (14 days) passive smoking on the respiration of isolated cardiomyocytes in rabbits using various substrates (pyruvate, glutamate, succinate) was studied. The endogenous respiration of cardiomyocytes was not affected whereas stimulated respiration as well as the ratio of stimulated to endogenous respiration significantly decreased. These results complement previous studies in which the effect of smoking on the metabolic processes of heart muscle mitochondria was measured. In conclusion, prolonged smoking may provoke myocardial dysfunction and in this way may contribute to the development of heart failure in chronic smokers.

Animals↗

PubMed2006

Oxidized low-density lipoproteins activate CD4+ T cell apoptosis in patients with end-stage renal disease through Fas engagement.

Oxidized LDL (oxLDL) are cytotoxic to vascular cells, but their possible toxic action on T cells from patients with ESRD has not been evaluated. oxLDL concentrations were measured and compared in patients who were on long-term hemodialysis (HD), in patients who had ESRD and were on continuous ambulatory peritoneal dialysis, in nondialyzed patients with chronic kidney disease, and in age- and gender-matched control subjects. In parallel, the proliferative capacity of CD69+/CD4+ T cells and their rate of apoptosis, IL-2 expression, and intracellular expression of Bcl-2 and Bax were determined in vitro. The oxLDL concentrations were significantly higher in HD patients (all P = 0.001). Upon phytohemagglutinin stimulation, CD69+/CD4+ T cells from HD patients proliferated significantly less than those from the other patients' group (both P < 0.001). oxLDL but not the native LDL were led to CD69+/CD4+ T cells' program cell death in a dosage- and time-dependent manner through Fas pathway (P = 0.001). Cell surface Fas expression was followed by DNA fragmentation when CD69+/CD4+ T cells from HD patients or control subjects were cultured with oxLDL (200 microg/ml; 31 +/- 3 versus 25 +/- 3%; P = 0.001). In the presence of oxLDL, CD69+/CD4+ T cells from HD patients expressed significantly lower IL-2 levels, which strongly correlated with a decrease in the antiapoptotic Bcl-2 and conversely with an increase in the proapoptotic Bax expression. In conclusion, these data suggest that, in HD patients, exposure of activated CD4+ T cells to oxLDL leads to Fas-mediated apoptosis in association with inhibition of IL-2 expression. Subsequently, this may favor activation of mitochondria-dependent apoptotic pathways, leading to activated CD4+ T cell dysfunction.

Antigens, CD↗

PubMedDate not supplied

Canavan disease: neuromorphological and biochemical analysis of a brain biopsy specimen.

In this study we present a patient with Canavan disease or Van Bogaert and Bertrand type of spongiform leukodystrophy, proven by brain biopsy. We performed morphological studies and biochemical assays on fresh homogenates of the grey and white matter. Quantitative neuromorphological analysis of the cortex showed normal values except for poor dendritic arborization of the inner layers. No signs of neuronal damage were observed. The Na-K-ATPase activity was increased. Pyruvate and ketone bodies oxidation rates and the activity of cytochrome-c oxidase were normal. We conclude that there is neither a primary neuronal damage nor a primary mitochondrial dysfunction in the oxidative processes despite the abnormal morphology of mitochondria in this disease.

Biopsy↗

PubMed2007

Mitochondrial dysfunction as the molecular basis of bipolar disorder: therapeutic implications.

Multiple lines of evidence, such as impaired energy metabolism in the brain detected by magnetic resonance spectroscopy, a possible role of maternal inheritance, co-morbidity with mitochondrial diseases, the effects of mood stabilisers on mitochondria, increased mitochondrial DNA (mtDNA) deletion in the brain, and association with mtDNA mutations/polymorphisms or nuclear-encoded mitochondrial genes, suggest that mitochondrial dysfunction is an important component of bipolar disorder. Global reduction of mitochondria-related gene expression in the postmortem brains of patients with bipolar disorder may also be an indicator, but such findings are affected by sample pH and thus need to be interpreted with caution. A recently developed animal model carrying mtDNA deletion in neurons suggested that accumulation of mtDNA deletions causes bipolar disorder-like phenotypes. The next step in the study of mitochondrial dysfunction in bipolar disorder should be clarification of how mitochondrial dysfunction, a nonspecific risk factor, can cause specific symptoms of bipolar disorder. Two hypothetical mechanisms are mtDNA neuroplasticity and nonvisual photoreception impairment. Further study of mitochondrial dysfunction in bipolar disorder is expected to be useful for the development of new mood stabilisers.

Animals↗

PubMedDate not supplied

Beneficial effect of fluorocarbon reperfusion on postoperative cardiac dysfunction of transplanted heart.

Fluosol DA 20% (Fluosol) perfusion was used to protect ischemic donor hearts of mongrel dogs from reperfusion injury. Fifteen orthotopically transplanted hearts, eight in the control group and seven in the Fluosol group, were studied for 3 hours after weaning from cardiopulmonary bypass. Donor hearts were arrested and immersed in 4 degrees C St. Thomas's Hospital Solution for 4 hours. The mean total ischemic time was 323 minutes (range, 298 to 345 minutes). In the Fluosol group, 200 ml of oxygenated Fluosol (37 degrees C; PO2 650 mm Hg; PCO2 35 mm Hg) was infused into the aortic root at approximately 100 ml/min just before aortic unclamping. Coronary sinus blood was analyzed for the MB fraction of creatine kinase, reduced glutathione, and oxidized glutathione. Hemodynamic and biochemical results were obtained at 30 minutes, 1 hour, and 3 hours after bypass. In the control group, during the second 30 minutes of the period after bypass, left ventricular end-diastolic pressure and stroke volume showed progressive deterioration, 54.8% increased (p less than 0.01) and 28.4% decreased (p less than 0.05), respectively. The MB fraction of creatine kinase and oxidized glutathione were increased, and reduced glutathione had declined, from 39.3 to 135.3 IU/L (p less than 0.01), from 28.0 to 33.4 micrograms/ml (p less than 0.05) and from 4.4 to 2.5 micrograms/ml (p less than 0.01), respectively. These parameters failed to recover during the next 2 hours, and massive mitochondrial degeneration was observed by electron microscopy. In the Fluosol group, these parameters maintained their baseline values, and electron microscopy showed well-preserved mitochondria. The data suggested that, in the control group, initial mitochondrial dysfunction was profound, persistent for at least 3 hours, and associated with membrane hyperpermeability, leading to cardiac dysfunction. Oxygenated Fluosol perfusion better preserved cardiac and mitochondrial function.

Animals↗

PubMed1981

[Late myopathy with mitochondrial changes in the muscle].

The ultrastructural finding of abnormal muscle mitochondria has been reported in various conditions, but mostly in association with the clinical picture of ophthalmoplegia, and in cases of "floppy infant" syndrome. In the case herein reported, the mitochondrial abnormalities were found in the muscle biopsy of a 49-year-old man suffering from a late onset proximal myopathy; he was affected also by polyneuropathy, subclinical thyroid dysfunction, disturbances of heart conduction, and unilateral gynaecomastia. The association of abnormal muscle mitochondria and late onset myopathy without involvement of the extraocular muscles has been reported in a very few cases. It is not possible, at present, to state that these cases represent a nosological entity; the existence of an underlying biochemical defect, accounting for the mitochondrial abnormalities, could be suspected, but it seems more probable that these changes are non-specific features of muscular damage, possibly related to the stage and the degree of the process. In this view, the coexistence of neurogenic damage, gastrointestinal malabsorption, and thyroid dysfunction, could play an additional role in the case herein described. Finally, the coexisting findings of cardiac, endocrine, and neuropathic damage are discussed with regard to the Kearns-Sayre syndrome, which also associates mitochondrial myopathy and multisystemic involvement.

Humans↗