Possible effect of epinephrine in minimizing COVID-19 severity: a review.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) shows a wide range of severity, ranging from an asymptomatic presentation to a severe illness requiring intensive care unit admission. Identification of a strategy to manage the severity of this disease will not only help to reduce its case fatality but also help to remove some of the burden from the already overwhelmed health care systems. While successful management of symptoms in general is important, identifying measures to modify the severity of the illness is a key factor in the fight against this pandemic. METHODS: This paper presents a short literature review to suggest a new treatment modality for COVID-19. RESULTS: COVID-19 is less severe and rarely fatal in children than in adults, which could be caused by greater fluctuations of plasma epinephrine in children. Our literature survey endorses this hypothesis according to both the epidemiological and immunological findings. CONCLUSION: Application of epinephrine pulses with a specific amplitude may be considered an intervention to minimize the severity of COVID-19.

ß2-adrenergic signals downregulate the innate immune response and reduce host resistance to viral infection.

In humans, psychological stress has been associated with a higher risk of infectious illness. However, the mechanisms by which the stress pathway interferes with host response to pathogens remain unclear. We demonstrate here a role for the ß2-adrenergic receptor (ß2-AR), which binds the stress mediators adrenaline and noradrenaline, in modulating host response to mouse cytomegalovirus (MCMV) infection. Mice treated with a ß2-AR agonist were more susceptible to MCMV infection. By contrast, ß2-AR deficiency resulted in a better clearance of the virus, less tissue damage, and greater resistance to MCMV. Mechanistically, we found a correlation between higher levels of IFN-γ production by liver natural killer (NK) cells and stronger resistance to MCMV. However, the control of NK cell IFN-γ production was not cell intrinsic, revealing a cell-extrinsic downregulation of the antiviral NK cell response by adrenergic neuroendocrine signals. This pathway reduces host immune defense, suggesting that the blockade of the ß2-AR signaling could be used to increase resistance to infectious diseases.

Adrenergic Modulation of Hematopoiesis.

Hematopoiesis produce every day billions of blood cells and takes place in the bone marrow (BM) by the proliferation and differentiation of hematopoietic stem cells (HSC). HSC are found mainly adjacent to the BM vascular sinusoids where endothelial cells and mesenchimal stromal cells promote HSC maintenance by producing a variety of factors. Other cell types that regulate HSC niches include sympathetic nerves, non-myelinating Schwann cells and a variety of mature hematopoietic cells such as macrophages, neutrophils, and megakaryocytes. This review will focus on the role of adrenergic signals, i.e. of catecholamines, in the regulation of the HSC niche. The available evidence is rather controversial possibly due to the fact that adrenergic receptors are expressed by many cellular components of the niche and also by the often neglected observation that catecholamines may be produced and released also by the BM cells themselves. In addition one has to consider that, physiologically, the sympathetic nervous system (SNS) activity follows a circadian rhythmicity as driven by the suprachiasmatic nucleus (SCN) of the hypothalamus but may be also activated by cognitive and non-cognitive environmental stimuli. The adrenergic modulation of hematopoiesis holds a considerable potential for pharmacological therapeutic approaches in a variety of hematopoietic disorders and for HSC transplantation however the complexity of the system demands further studies. Graphical Abstract Sympathetic nerve termini may release NE while mature BM cells may release norepinephrine (NE) and / or epinephrine (E). Both may bind to ß-adrenergic receptor (AR) expressed in nestin+MSC in the hematopoietic stem cell (HSC) niche and regulate the physiological trafficking of HSC by modulating the expression of CXCL12 and SCF. Both NE and E may also activate Lin - c-Kit+ Sca-1+ (LKS) cell via another AR. In addition, NE may also signal to α1-AR expressed in pre-B cells which by TGF-ß secretion might regulate proliferation of their lymphoid progenitors in an autocrine manner and/or inhibit myeloid progenitors.

Inter-kingdom signaling between gut microbiota and their host.

The crosstalk between prokaryotic bacteria and eukaryotic gut epithelial cells has opened a new field for research. Quorum sensing system (QS) molecules employed by gut microbiota may play an essential role in host-microbial symbioses of the gut. Recent studies on the gut microbiome will unveil evolved mechanisms of the host to affect bacterial QS and shape bacterial composition. Bacterial autoinducers (AIs) could talk to the host's gut by eliciting proinflammatory effects and modulating the activities of T lymphocyte, macrophage, dendritic cells, and neutrophils. In addition, the gut mucosa could interfere with bacterial AIs by degrading them or secreting AI mimics. Moreover, bacterial AIs and gut hormones epinephrine and noradrenaline may be interchangeable in the crosstalk between the microbiota and human gut. Therefore, inter-kingdom signaling between gut microbiota and host may provide a novel target in the management of gut microbiota-related conditions or diseases in the future.

Adrenal hormones mediate disease tolerance in malaria.

Malaria reduces host fitness and survival by pathogen-mediated damage and inflammation. Disease tolerance mechanisms counter these negative effects without decreasing pathogen load. Here, we demonstrate that in four different mouse models of malaria, adrenal hormones confer disease tolerance and protect against early death, independently of parasitemia. Surprisingly, adrenalectomy differentially affects malaria-induced inflammation by increasing circulating cytokines and inflammation in the brain but not in the liver or lung. Furthermore, without affecting the transcription of hepatic gluconeogenic enzymes, adrenalectomy causes exhaustion of hepatic glycogen and insulin-independent lethal hypoglycemia upon infection. This hypoglycemia is not prevented by glucose administration or TNF-α neutralization. In contrast, treatment with a synthetic glucocorticoid (dexamethasone) prevents the hypoglycemia, lowers cerebral cytokine expression and increases survival rates. Overall, we conclude that in malaria, adrenal hormones do not protect against lung and liver inflammation. Instead, they prevent excessive systemic and brain inflammation and severe hypoglycemia, thereby contributing to tolerance.

Intention to prescribe self-injectable epinephrine: are there differences depending on who assesses the patient post-reaction?

INTRODUCTION: Anaphylaxis is the most severe of all allergic reactions and can even prove fatal. There is limited evidence of a difference in prescribing patterns for self-injectable epinephrine (SIE) between general paediatricians and paediatricians with greater knowledge of allergology. OBJECTIVES: Assess knowledge about prescribing SIE of a sample of primary care/hospital paediatricians and paediatricians with specialised knowledge of allergology through a questionnaire asking them about clinical cases of anaphylaxis in their daily paediatric practice. MATERIALS AND METHODS: Participants were primary care and hospital paediatricians practicing in different regions of the province of Barcelona and paediatricians with specialised knowledge in the field of allergology from Spain. RESULTS: A total of 183 paediatricians responded. Of that 59.6% were paediatricians with specialised knowledge of allergology. General paediatricians in most cases correctly prescribed SIE device (more than 70% answered correctly in five of the eight clinical cases). In the case of drug anaphylaxis, which is an avoidable allergen for which SIE is not indicated, 67.5% of general paediatricians would prescribe it. In the case of exercise-induced anaphylaxis there were also differences in the prescription of epinephrine by general paediatricians, with only 40% prescribing it. CONCLUSIONS: In this study the percentage of SIE prescriptions would be higher than expected by general paediatricians, with no differences in the cases proposed between them and the paediatricians with better knowledge of allergology. Despite these results, it is important to insist on conducting education programmes and disseminating them to facilitate physicians' recognition and treatment of anaphylactic reactions

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ß2-Adrenergic receptors in immunity and inflammation: stressing NF-κB.

ß2-Adrenergic receptors (ß2-ARs) transduce the effects of (nor)epinephrine on a variety of cell types and act as key mediators of the body's reaction to stress. ß2-ARs are also expressed on immune cells and there is ample evidence for their role in immunomodulation. A key regulator of the immune response and a target for regulation by stress-induced signals is the transcription factor Nuclear Factor-kappaB (NF-κB). NF-κB shapes the course of both innate and adaptive immune responses and plays an important role in susceptibility to disease. In this review, we summarise the literature that has been accumulated in the past 20years on adrenergic modulation of NF-κB function. We here focus on the molecular basis of the reported interactions and show that both physiological and pharmacological triggers of ß2-ARs intersect with the NF-κB signalling cascade at different levels. Importantly, the action of ß2-AR-derived signals on NF-κB activity appears to be highly cell type specific and gene selective, providing opportunities for the development of selective NF-κB modulators.

The misleading nature of in vitro and ex vivo findings in studying the impact of stress hormones on NK cell cytotoxicity.

In vitro and ex vivo studies assessing the impact of stress hormones on immune competence commonly replace the natural milieu of leukocytes with an artificial medium, excluding plasma factors, hormones, and cytokines. Given prevalent inconsistencies between in vitro, ex vivo, and in vivo findings, we studied whether such procedures could yield misleading outcomes regarding the impact of stress hormones on NK cell cytotoxicity (NKCC), using fresh human whole blood samples. We found that in the presence of plasma 10-30-fold higher concentrations of cortisol, epinephrine, and prostaglandin-E2 (PGE2) were required to reach suppression levels evident in the context of artificial medium. Importantly, whereas the NK suppressive effects of PGE2 occurred immediately and remained stable upon prolonged exposure, the suppressive effects of cortisol slowly increased over time. Last, to simulate the exclusion of stress factors in the ex vivo approach, we subjected whole blood to stress hormones (as occurs in vivo), and abruptly removed them. We found that the effects of epinephrine and PGE2 quickly disappeared, while the effects of cortisol persisted. Overall, these findings demonstrate the potential misleading nature of in vitro and ex vivo procedures, and specifically suggest that (i) the common in vitro findings of profound suppression of NKCC by stress hormones are overestimation of their direct effects expected in vivo; and (ii) the common ex vivo approach cannot reflect the direct in vivo suppressive effects of epinephrine and PGE2 on NKCC, while inflating the effects of glucocorticoids. Some of these fallacies may be circumvented by using non-delayed whole blood NKCC assays in humans.

When should we perform a repeat training on adrenaline auto-injector use for physician trainees?

BACKGROUND: Studies demonstrate that both doctors and patients may use adrenaline auto-injector improperly and the usage skills are improved by training. In this study, we aimed to determine the appropriate frequency of training to maintain skills for adrenaline auto-injector use. METHODS: We invited all interns of 2011-2012 training period. At baseline, all participants were given theoretical and practical training on adrenaline auto-injector use. The participants were randomly assigned into two groups. We asked those in group 1 to demonstrate the use of adrenaline auto-injector trainer in the third month and those in group 2 in the sixth month. RESULTS: One hundred and sixty interns were enrolled. Compared with the beginning score, demonstration of skills at all the steps and total scores did not change for the group tested in the third month (p = 0.265 and p = 0.888, respectively). However; for the group examined in the sixth month; the demonstration of skills for proper use of the auto-injector at all steps and the mean time to administer adrenaline decreased (p = 0.018 and p < 0.001, respectively). Besides, the group which was tested in the third month was better than the group which was tested in the sixth month in terms of demonstrating all steps (p = 0.014), the total score (p = 0.019), mean time of change to administer adrenaline (p < 0.001) and presumptive self-injection into thumb (p = 0.029). CONCLUSIONS: Auto-injector usage skills of physician trainees decrease after the sixth month and are better in those who had skill reinforcement at 3 months, suggesting continued education and skill reinforcement may be useful

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Catecholamine stress alters neutrophil trafficking and impairs wound healing by ß2-adrenergic receptor-mediated upregulation of IL-6.

Stress-induced hormones can alter the inflammatory response to tissue injury; however, the precise mechanism by which epinephrine influences inflammatory response and wound healing is not well defined. Here we demonstrate that epinephrine alters the neutrophil (polymorphonuclear leukocyte (PMN))-dependent inflammatory response to a cutaneous wound. Using noninvasive real-time imaging of genetically tagged PMNs in a murine skin wound, chronic, epinephrine-mediated stress was modeled by sustained delivery of epinephrine. Prolonged systemic exposure of epinephrine resulted in persistent PMN trafficking to the wound site via an IL-6-mediated mechanism, and this in turn impaired wound repair. Further, we demonstrate that ß2-adrenergic receptor-dependent activation of proinflammatory macrophages is critical for epinephrine-mediated IL-6 production. This study expands our current understanding of stress hormone-mediated impairment of wound healing and provides an important mechanistic link to explain how epinephrine stress exacerbates inflammation via increased number and lifetime of PMNs.

Overnight changes of immune parameters and catecholamines are associated with mood and stress.

OBJECTIVES: To test the hypothesis that a nocturnal decrease of secretion of inflammation markers and catecholamines would be associated with mood and stress variables even after controlling for objective sleep variables. METHODS: A total of 130 healthy volunteers participated in this study, spending 2 nights in the Gillin Laboratory of Sleep and Chronobiology at the University of California, San Diego, General Clinical Research Center. Blood samples were obtained before sleep (10:30 PM) and after awakening (6:30 AM) on the first day, and these samples were assayed for inflammatory biomarkers and catecholamines. On the second night, polysomnographic records were scored for objective sleep variables, e.g., total sleep time and wake after sleep onset. Self-rating scales for mood, stress, depression, and daily hassles were administered the second day. RESULTS: The nocturnal decrease in interleukin-6 was smaller in people who reported more negative mood or fatigue and greater in those who reported more uplift events (e.g., with Profile of Mood States fatigue r(p) = -.25 to -.30). People with high stress or high depression levels had smaller nocturnal decreases of epinephrine. That relationship was even stronger when partial correlations were used to control for morning level and sleep variables. The associations between nocturnal changes of C-reactive protein, soluble tumor necrosis factor-receptor I, and norepinephrine with psychological states were nonremarkable. CONCLUSIONS: The analyses of nocturnal change scores (difference scores) add substantial information compared with the traditional analyses of morning levels of immune variables and catecholamines alone. Subjective well-being is significantly associated with a greater nocturnal decrease of interleukin-6 and epinephrine. More research on nocturnal adaptation processes is warranted.

[Case report : Severe anaphylactic shock followed by positive skin-prick-test to multiple vasoconstrictors].

A 71-year-old woman was scheduled for revision of total hip replacement under general anesthesia. Twenty minutes before entering the operating room, slight urticaria was caused by drop infusion of cefotiam. It was stopped immediately and the patient entered the operating room without any symptoms. Anesthesia was induced and maintained with sevoflurane and remifentanil. After 3 hours, systolic arterial pressure (SAS) dropped to 80 mmHg. Injecting of ephedrine 8 mg was not effective, and we injected a total of 3 mg of methoxamine. Then SAS dropped to 50 mmHg. We injected epinephrine 0.2 mg twice and also started continuous infusion of norepinephrine. Severe skin rash indicated that anaphylactic reaction had occurred. About 20 minutes after starting norepinephrine, the SAS was stabilized. We decided to stop the operation, and the patient was moved to the intensive care unit (ICU). A few hours after entering the ICU, she was extubated and moved to the general ward next day. Skin-prick-tests performed 14 days later indicated that she was allergic to ephedrine, methoxamine, epinephrine, dopamine and a few more drugs.

Temporal pattern and effect of sex on lipopolysaccharide-induced stress hormone and cytokine response in pigs.

The temporal pattern and sex effect of immune and stress hormone responses to a lipopolysaccharide (LPS) challenge were assessed using a pig model. Secretion of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 increased in a time-dependent manner following LPS infusion. There was also a time-dependent increase in secretion of the stress-related hormones cortisol, epinephrine (E), and norepinephrine (NE) following LPS, with peak concentrations attained within 30 min. The magnitude of the TNF-alpha and IL-1beta responses were both positively associated (P < 0.05) with the magnitude of cortisol response following LPS, whereas serum IL-1beta and IL-6 were positively correlated with the magnitude of E and NE responses following LPS. Acute-phase protein production was also time-dependently increased following LPS. The concentration of immune cells in circulation was decreased (P < 0.05) at 5.5h post-LPS and negatively correlated with pro-inflammatory cytokine production. By 24h post-LPS, immune cell counts increased (P < 0.05) and were positively associated with both pro-inflammatory cytokine and stress hormone production. The amplitude of pro-inflammatory cytokine response following LPS was affected (P < 0.05) by sex classification; however, the magnitude of elevated cytokine concentrations was not. The magnitude of the NE response, but not of the E and cortisol responses, to LPS was influenced by sex (P < 0.05). Similar to the pro-inflammatory cytokines, the magnitude of exposure to the stress hormones following LPS was not influenced by sex. The production of serum amyloid A (SAA) was influenced by sex, with barrows producing more SAA than gilts at 24h post-LPS (P < 0.05). Collectively, these results demonstrate sex-specific, concomitant temporal changes in innate immune- and stress-related hormones.

Adrenaline for the treatment of anaphylaxis: cochrane systematic review.

BACKGROUND: Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. Adrenaline is recommended as the initial treatment of choice for anaphylaxis. OBJECTIVES: To assess the benefits and harms of adrenaline in the treatment of anaphylaxis. METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 1), MEDLINE (1966 to March 2007), EMBASE (1966 to March 2007), CINAHL (1982 to March 2007), BIOSIS (to March 2007), ISI Web of Knowledge (to March 2007) and LILACS (to March 2007). We also searched websites listing ongoing trials: http://www.clinicaltrials.gov/, http://www.controlledtrials.com and http://www.actr.org.au/ and contacted pharmaceutical companies and international experts in anaphylaxis in an attempt to locate unpublished material. Randomized and quasi-randomized controlled trials comparing adrenaline with no intervention, placebo or other adrenergic agonists were eligible for inclusion. Two authors independently assessed articles for inclusion. RESULTS: We found no studies that satisfied the inclusion criteria. CONCLUSIONS: On the basis of this review, we are unable to make any new recommendations on the use of adrenaline for the treatment of anaphylaxis. In the absence of appropriate trials, we recommend, albeit on the basis of less than optimal evidence, that adrenaline administration by intramuscular injection should still be regarded as first-line treatment for the management of anaphylaxis.

Adrenergic modulation of survival and cellular immune functions during polymicrobial sepsis.

OBJECTIVE: An immunomodulatory effect of epinephrine has been reported that is supposed to be mediated via beta-adrenergic receptors. The effect of epinephrine and/or beta-adrenergic blockade on cellular immune functions during systemic inflammation has not yet been investigated. METHODS: Male NMRI mice were treated with either an infusion of epinephrine (0.05 mg/kg/h i.p.), administration of the nonselective beta-adrenoceptor antagonist propranolol (0.5 mg/kg s.c.), or a combination of epinephrine and propranolol after induction of a polymicrobial sepsis by cecal ligation and puncture. Forty-eight hours thereafter survival and cellular immune functions (splenocyte proliferation, splenocyte apoptosis and cytokine release, distribution of leukocyte subsets) were determined. RESULTS: Infusion of epinephrine did not affect lethality of septic mice but induced alterations of splenocyte apoptosis, splenocyte proliferation and IL-2 release and was associated with profound changes of circulating immune cell subpopulations. Treatment with propranolol augmented the epinephrine-induced increase of splenocyte apoptosis, did not affect the decrease of splenocyte proliferation and IL-2 release, augmented the release of IL-6 and antagonized the mobilization of natural killer cells observed in epinephrine-treated animals. Furthermore, these immunologic alterations were accompanied by a significant increase of sepsis-induced mortality. Coadministration of propranolol and epinephrine augmented the propranolol-induced changes of splenocyte apoptosis and IL-6 release and was associated with the highest mortality of septic mice. CONCLUSION: Epinephrine infusion modulated cellular immune functions during systemic inflammation without an impact on survival. A pharmacologic beta-adrenergic blockade partly augmented the epinephrine-induced immune alterations and was associated with a pronounced increase of mortality. This effect was further augmented by a combination of epinephrine infusion and beta-adrenergic blockade. These data indicate that adrenergic mechanisms modulate cellular immune functions and survival during sepsis, with these effects being mediated via alpha- and beta-adrenergic pathways.

Stress-induced augmentation of immune function--the role of stress hormones, leukocyte trafficking, and cytokines.

Delayed-type hypersensitivity (DTH) reactions represent cell-mediated immune responses that exert important immunoprotective (resistance to viruses, bacteria, and fungi) or immunopathological (allergic or autoimmune hypersensitivity) effects. We initially utilized the skin DTH response as an experimental in vivo model to study neuro-endocrine-immune interactions in rodents. We hypothesized that just as an acute stress response prepares the cardiovascular and musculoskeletal systems for fight or flight, it may also prepare the immune system for challenges which may be imposed by a stressor. The skin DTH model allowed us to examine the effects of stress at the time of primary and secondary exposure to antigen. Studies showed that acute (2h) stress experienced before primary or secondary antigen exposure induces a significant enhancement of skin DTH. Importantly, this enhancement involved innate as well as adaptive immune mechanisms. Adrenalectomy eliminated the stress-induced enhancement of DTH. Acute administration of physiological (stress) concentrations of corticosterone and/or epinephrine to adrenalectomized animals enhanced skin DTH. Compared with controls, DTH sites from acutely stressed or hormone-injected animals showed significantly greater erythema and induration, numbers of infiltrating leukocytes, and levels of cytokine gene expression. In contrast to acute stress, chronic stress was immunosuppressive. Chronic exposure to corticosterone, or acute exposure to dexamethasone significantly suppressed skin DTH. These results suggest that during acute stress, endogenous stress hormones enhance skin immunity by increasing leukocyte trafficking and cytokine gene expression at the site of antigen entry. While these results are discussed from a mechanistic and clinical relevance perspective, it is acknowledged that much work remains to be done to elucidate the precise mechanisms mediating these bi-directional effects of stress and stress hormones and their clinical ramifications.

[Immunoenzyme analysis of natural antibodies to endogenous bioregulators in patients with systemic lupus erythematosus]. / Immunofermentnyi analiz estestvennykh antitel k éndogennym bioreguliatoram u bol'nykh sistemnoi krasnoi volchankoi.

Serum levels of autoantibodies to endogenous bioregulators (prostaglandin F2 alpha, angiotensin II, epinephrine, bovine serum albumin, dinitrophenol) were measured in patients with systemic and integumental lupus erythematosus and donors and the diagnostic significance of deviations of these levels from the norm was evaluated. A total of 75 patients with lupus erythematosus aged 19-54 years with disease lasting for 0.5 to 18 months were examined. Significant differences between patients and donors were observed as regards virtually all parameters except IgG to angiotensin II.

Cold-stress induced the modulation of catecholamines, cortisol, immunoglobulin M, and leukocyte phagocytosis in tilapia.

The concentrations of norepinephrine in hypothalamus and norepinephrine and epinephrine in head kidney were significantly decreased in treated tilapia (Oreochromis aureus) during the time course of cold exposure (12 degrees) as compared to the control (25 degrees). The elevation of norepinephrine and epinephrine in plasma was detected earlier than that of cortisol in cold-treated tilapia. Phagocytic activity of leukocytes and the levels of plasma immunoglobulin M (IgM) were depressed in cold-treated tilapia as compared to the control group. Handling stress in the control (25 degrees) also resulted in increased plasma cortisol and decreased plasma IgM levels but not phagocytic activity. In vitro cortisol suppressed leukocyte phagocytosis in a dose (10(-12) to 10(-4) M)-dependent manner. Adrenergic agonist (phenylephrine and isoproterenol) had a significant suppression of phagocytosis only at the highest dose (10(-4) M). No effect on phagocytosis was detected in the treatment with norepinephrine and epinephrine. A combination of cortisol and isoproterenol (0.1 mM) had an additive effect in the suppression of phagocytosis. It is concluded that the cold stress modulated the changes of catecholamines and cortisol and further depressed phagocytic activity and antibody levels in tilapia. Cortisol could play a main and important role in the down-regulation of phagocytic activity. Adrenergic agonists also could interact with cortisol to further suppress immunity in tilapia.

[Liver mitochondria in antigenic stress in rats]. / Mitokhondrii pecheni v realizatsii antigennogo napriazheniia organizma u krys.

The penomenon of reciprocal regulation of succinate dehidrogenase activity in rat liver mitochondria was elicited in antigenic strain induced by the administration of activated lymphocytes from animals with allotransplated heart. Two coupled but opposite changes (simultaneous activation and inhibition) in succinate depended ATP synthesis and calcium transport occur. The inhibition was correlated with the activation of synthetic processes in hepatocytes. Similar changes were provoked by epinephrine (either administered i.p. or released endogenously under immobilization stress and in myocardium infarction) as well as in patients with stomach tumor. The physiological significance of the reciprocal regulation of succinate dehydrogenase is discussed.