Papers by Ivana Mihaylova
PubMed, Dec 1, 2007
Background: We have shown that a depletion of omega3 polysaturated fatty acids (PUFAs) plays a ro... more Background: We have shown that a depletion of omega3 polysaturated fatty acids (PUFAs) plays a role in the pathophysiology of depression, in part because omega3 PUFAs have anti-inflammatory effects. omega3 PUFAs are frequently employed to treat depression. Most if not all antidepressants have negative immunoregulatory effects by decreasing the production of proinflammatory cytokines, such as interferon-gamma (IFNgamma) and/or increasing that of anti-inflammatory cytokines, such as interleukin10 (IL-10). Aim: The aim of the present study was to examine the immunoregulary effects of the omega3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the omega6 PUFA, arachidonic acid (AA), on the production of interferon-gamma (IFNgamma), interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNFalpha). Methods: This study examines the ex vivo effects of EPA (4.5 microM, 9 microM, 18 microM and 45 microM), DHA (1.3 microM, 3 microM, 6 microM and 13 microM) and AA (8 microM, 16 microM, 32 microM and 80 microM) on the LPS + PHA-stimulated production of IFNgamma, IL-10 and TNFalpha, and on the IFNgamma/IL-10 production ratio. Results: We found that EPA did not have any significant effects on the above cytokines. DHA significantly increased the IFNgamma/IL-10 production ratio, caused by a greater reduction in IL-10 than in IFNgamma. AA significantly decreased TNFalpha production. Discussion: The results show that DHA induces a Th-1-like immune response and that AA has anti-inflammatory effects by decreasing the production of TNFalpha. Thus, the immune effects of omega3 PUFAs are not compatible with what is expected from antidepressive substances. The results of the present study show that treatment with fish oils, containing DHA, should be avoided in the treatment of depression. Toward this end, highly concentrated and pure EPA seems to be indicated.
PubMed, Oct 1, 2005
There are a few reports that chronic fatigue syndrome (CFS) may be accompanied by changes in horm... more There are a few reports that chronic fatigue syndrome (CFS) may be accompanied by changes in hormones, such as dehydroepiandrosterone (DHEA) and insulin-like growth factor (IGF1). This study examines the serum concentrations of DHEA-sulfate (DHEAS), IGF1 and IGF1 binding protein-3 (IGFBP3) in 20 patients with CFS and in 12 normal controls. The IGFBP3/IGF1 ratio was computed as an index for IGF1 availability. We found significantly lower serum DHEAS concentrations in CFS, but no significant differences either in IGF1 or the IGFBP3/IGF1 ratio between CFS patients and normal controls. The decrease in serum DHEAS was highly sensitive and specific for CFS. There were significant and positive correlations between serum DHEAS and serum zinc and the mitogen-induced expression of the CD69 molecule on CD3+CD8+ T cells (an indicator of early T cell activation). There was a significant and negative correlation between serum DHEAS and the increase in the serum alpha-2 protein fraction (an inflammatory marker). Serum IGF1, but not DHEAS, was significantly and inversely correlated to age. The results show that CFS is accompanied by lowered levels of DHEAS and that the latter may play a role in the immune (defect in the early activation of T cells) and the inflammatory pathophysiology of CFS.
PubMed, Jun 1, 2008
Background: It has been shown that chronic fatigue syndrome (CFS) and major depression (MDD) are ... more Background: It has been shown that chronic fatigue syndrome (CFS) and major depression (MDD) are accompanied by signs of oxidative stress and by a decreased antioxidant status. The aim of the present study was to examine whether CFS and MDD are accompanied by an IgM-mediated immune response directed against nitro-serum bovine albumin (BSA), which is a neoepitope of BSA formed by damage caused by nitrosative stress. Aims: Toward this end, we examined serum IgM antibodies to nitro-BSA in 13 patients with CFS, 14 subjects with partial CFS, 16 patients with MDD and 11 normal controls. Results: We found that the prevalence and mean values for the serum IgM levels directed against nitro-BSA were significantly greater in patients with partial CFS, CFS and MDD than in normal controls, and significantly greater in CFS than in those with partial CFS and MDD. We found significant and positive correlations between serum IgM levels directed against nitro-BSA and symptoms of the FibroFatigue scale, i.e. aches and pain and muscular tension. There was also a strong positive correlation between serum IgM titers directed against nitro-BSA and an index of increased gut permeability ("leaky gut"), i.e. serum IgM and IgA directed against LPS of different gram-negative enterobacteria. Discussion: The abovementioned results indicate that both CFS and MDD are accompanied by a) an increased gut permeability which has allowed an exaggerated passage of BSA through a compromised epithelial barrier; b) increased nitrosative stress which has induced damage to BSA; and c) an IgM-mediated immune response which is directed against the nitro-BSA neoepitopes. Nitrosative stress is one of the factors underpinning the comorbidity and clinical overlap between CFS and MDD.
PubMed, Dec 1, 2005
There is now evidence that major depression is accompanied by decreased levels of omega3 poly-uns... more There is now evidence that major depression is accompanied by decreased levels of omega3 poly-unsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). There is a strong comorbidity between major depression and chronic fatigue syndrome (CFS). The present study has been carried out in order to examine PUFA levels in CFS. In twenty-two CFS patients and 12 normal controls we measured serum PUFA levels using gas chromatography and mass spectrometry. We found that CFS was accompanied by increased levels of omega6 PUFAs, i.e. linoleic acid and arachidonic acid (AA), and mono-unsaturated fatty acids (MUFAs), i.e. oleic acid. The EPA/AA and total omega3/omega6 ratios were significantly lower in CFS patients than in normal controls. The omega3/omega6 ratio was significantly and negatively correlated to the severity of illness and some items of the FibroFatigue scale, i.e. aches and pain, fatigue and failing memory. The severity of illness was significantly and positively correlated to linoleic and arachidonic acid, oleic acid, omega9 fatty acids and one of the saturated fatty acids, i.e. palmitic acid. In CFS subjects, we found significant positive correlations between the omega3/omega6 ratio and lowered serum zinc levels and the lowered mitogen-stimulated CD69 expression on CD3+, CD3+ CD4+, and CD3+ CD8+ T cells, which indicate defects in early T cell activation. The results of this study show that a decreased availability of omega3 PUFAs plays a role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS. The results suggest that patients with CFS should respond favourably to treatment with--amongst other things--omega3 PUFAs, such as EPA and DHA.
PubMed, Aug 1, 2007
Chronic fatigue syndrome (CFS) is a medically unexplained disorder, characterized by profound fat... more Chronic fatigue syndrome (CFS) is a medically unexplained disorder, characterized by profound fatigue, infectious, rheumatological and neuropsychiatric symptoms. There is, however, some evidence that CFS is accompanied by signs of increased oxidative stress and inflammation in the peripheral blood. This paper examines the role of the inducible enzymes cyclo-oxygenase (COX-2) and inducible NO synthase (iNOS) in the pathophysiology of CFS. Toward this end we examined the production of COX-2 and iNOS by peripheral blood lymphocytes (PBMC) in 18 CFS patients and 18 normal volunteers and examined the relationships between those inflammatory markers and the severity of illness as measured by means of the FibroFatigue scale and the production of the transcription factor nuclear factor kappa beta (NFkappabeta). We found that the production of COX-2 and iNOS was significantly higher in CFS patients than in normal controls. There were significant and positive intercorrelations between COX-2, iNOS and NFkappabeta and between COX-2 and iNOS, on the one hand, and the severity of illness, on the other. The production of COX-2 and iNOS by PBMCs was significantly related to aches and pain, muscular tension, fatigue, concentration difficulties, failing memory, sadness and a subjective experience of infection. The results suggest that a) an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiology of CFS; b) the inflammatory response in CFS is driven by the transcription factor NFkappabeta; c) symptoms, such as fatigue, pain, cognitive defects and the subjective feeling of infection, indicates the presence of a genuine inflammatory response in CFS patients; and d) CFS patients may be treated with substances that inhibit the production of COX-2 and iNOS.
PubMed, Aug 1, 2007
There is now some evidence that chronic fatigue syndrome is accompanied by an activation of the i... more There is now some evidence that chronic fatigue syndrome is accompanied by an activation of the inflammatory response system and by increased oxidative and nitrosative stress. Nuclear factor kappa beta (NFkappabeta) is the major upstream, intracellular mechanism which regulates inflammatory and oxidative stress mediators. In order to examine the role of NFkappabeta in the pathophysiology of CFS, this study examines the production of NFkappabeta p50 in unstimulated, 10 ng/mL TNF-alpha (tumor necrosis factor alpha) and 50 ng/mL PMA (phorbolmyristate acetate) stimulated peripheral blood lymphocytes of 18 unmedicated patients with CFS and 18 age-sex matched controls. The unstimulated (F=19.4, df=1/34, p=0.0002), TNF-alpha-(F=14.0, df=1/34, p=0.0009) and PMA-(F=7.9, df=1/34, p=0.008) stimulated production of NFkappabeta were significantly higher in CFS patients than in controls. There were significant and positive correlations between the production of NFkappabeta and the severity of illness as measured with the FibroFatigue scale and with symptoms, such as aches and pain, muscular tension, fatigue, irritability, sadness, and the subjective feeling of infection. The results show that an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiology of CFS and that previous findings on increased oxidative stress and inflammation in CFS may be attributed to an increased production of NFkappabeta. The results suggest that the symptoms of CFS, such as fatigue, muscular tension, depressive symptoms and the feeling of infection reflect a genuine inflammatory response in those patients. It is suggested that CFS patients should be treated with antioxidants, which inhibit the production of NFkappabeta, such as curcumin, N-Acetyl-Cysteine, quercitin, silimarin, lipoic acid and omega-3 fatty acids.
PubMed, Oct 1, 2006
There is now some evidence that chronic fatigue syndrome (CFS) is accompanied by signs of oxidati... more There is now some evidence that chronic fatigue syndrome (CFS) is accompanied by signs of oxidative stress and by a decreased antioxidant status. The aim of the present study was to examine whether CFS is accompanied by an immune response to neoepitopes of a variety of modified lipids and proteins indicating damage caused by oxidative and nitrosative stress. Toward this end we examined serum antibodies to fatty acids (oleic, palmitic and myristic acid), by-products of lipid peroxidation, i.e. azelaic acid and malondialdehyde (MDA), acetylcholine, S-farnesyl-L-cysteine, and N-oxide modified amino-acids in 14 patients with CFS, 14 subjects with partial CFS and 11 normal controls. We found that the prevalences and mean values for the serum IgM levels directed against oleic, palmitic and myristic acid, MDA, azelaic acid, S-farnesyl-L-cysteine, and the N-oxide derivates, nitro-tyrosine, nitro-phenylalanine, nitro-arginine, nitro-tryptophan, and nitro-cysteinyl were significantly greater in CFS patients than in normal controls, whereas patients with partial CFS took up an intermediate position. There were significant and positive correlations between the serum IgM levels directed against fatty acids, MDA and azelaic acid and the above N-oxide-derivates and the severity of illness (as measured by the FibroFatigue scale) and symptoms, such as aches and pain, muscular tension and fatigue. The results show that CFS is characterized by an IgM-related immune response directed against disrupted lipid membrane components, by-products of lipid peroxidation, S-farnesyl-L-cysteine, and NO-modified amino-acids, which are normally not detected by the immune system but due to oxidative and nitrosative damage have become immunogenic.
Journal of Affective Disorders, Dec 1, 2011
Background: There is evidence that depression is accompanied by oxidative and nitrosative stress ... more Background: There is evidence that depression is accompanied by oxidative and nitrosative stress (O&NS), as indicated by increased free radical levels, lipid peroxidation, and lowered antioxidant levels. The aims of the present study are to examine whether depression is accompanied by autoimmune responses directed against a) neoepitopes that are formed following O&NS damage; and b) the major anchorage molecules, i.e. palmitic and myristic acids and Sfarnesyl-L-cysteine. Methods: We examined serum IgM antibodies to the conjugated fatty acids, palmitic and myristic acids; acetylcholine; S-farnesyl-L-cysteine; and NO-modified adducts in 26 depressed patients and 17 normal controls. Severity of depression was measured with the Hamilton Depression Rating Scale and severity of fatigue and somatic (F&S) symptoms with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale. Results: The prevalences and mean values for the serum IgM levels directed against conjugated palmitic and myristic acids, acetylcholine, S-farnesyl-L-cysteine; and the conjugated NO adducts, NO-tyrosine, NO-phenylalanine, NO-aspartate, NO-histidine, and NO-creatine were significantly higher in depressed patients than in normal controls. The autoimmune responses were significantly related to FF symptoms, such as fatigue and a flu-like malaise, whereas the indicants of nitrosative stress were related to gastro-intestinal and autonomic symptoms. Discussion: Depression is characterized by IgM-related autoimmune responses directed against a) neoepitopes that are normally not detected by the immune system but that due to damage by O&NS have become immunogenic; and b) anchorage epitopes, i.e. palmitic and myristic acids, and S-farnesyl-L-cysteine. These autoimmune responses play a role in the inflammatory and O&NS pathophysiology of depression and may mediate the cellular dysfunctions that contribute to neuroprogression, e.g. aberrations in signal transduction, cellular differentiation and apoptosis.
PubMed, Aug 1, 2007
There is some evidence that patients with chronic fatigue syndrome (CFS) suffer from immune abnor... more There is some evidence that patients with chronic fatigue syndrome (CFS) suffer from immune abnormalities, such as immune activation and decreased immune cell responsivity upon polyclonal stimili. This study was designed to evaluate lymphocyte activation in CFS by using a CD69 expression assay. CD69 acts as a costimulatory molecule for T- and natural killer (NK) cell activation. We collected whole blood from CFS patients, who met CDC criteria, and healthy volunteers. The blood samples were stimulated with mitogens during 18 h and the levels of activated T and NK cells expressing CD69 were measured on a Coulter Epics flow cytometer using a three color immunofluorescence staining protocol. The expression of the CD69 activation marker on T cells (CD3+, CD3+CD4+, and CD3+CD8+) and on NK cells (CD45+CD56+) was significantly lower in CFS patients than in healthy subjects. These differences were significant to the extent that a significant diagnostic performance was obtained, i.e. the area under the ROC curve was around 89%. No differences either in the number of leukocytes or in the number or percentage of lymphocytes, i.e. CD3, CD4, CD8 and CD19, could be found between CFS patients and the controls. Patients with CFS show defects in T- and NK cell activation. Since induction of CD69 surface expression is dependent on the activation of the protein kinase C (PKC) activation pathway, it is suggested that in CFS there is a disorder in the early activation of the immune system involving PKC.
There is some evidence that patients with chronic fatigue syndrome (CFS) suffer from immune abnor... more There is some evidence that patients with chronic fatigue syndrome (CFS) suffer from immune abnormalities, such as immune activation and decreased immune cell responsivity upon polyclonal stimili. This study was designed to evaluate lymphocyte activation in CFS by using a CD69 expression assay. CD69 acts as a costimulatory molecule for T-and natural killer (NK) cell activation. We collected whole blood from CFS patients, who met CDC criteria, and healthy volunteers. The blood samples were stimulated with mitogens during 18 h and the levels of activated T and NK cells expressing CD69 were measured on a Coulter Epics flow cytometer using a three color immunofluorescence staining protocol. The expression of the CD69 activation marker on T cells (CD3+, CD3+CD4+, and CD3+CD8+) and on NK cells (CD45+CD56+) was significantly lower in CFS patients than in healthy subjects. These differences were significant to the extent that a significant diagnostic performance was obtained, i.e. the area under the ROC curve was around 89%. No differences either in the number of leukocytes or in the number or percentage of lymphocytes, i.e. CD3, CD4, CD8 and CD19, could be found between CFS patients and the controls. Patients with CFS show defects in T-and NK cell activation. Since induction of CD69 surface expression is dependent on the activation of the protein kinase C (PKC) activation pathway, it is suggested that in CFS there is a disorder in the early activation of the immune system involving PKC.
Neuroendocrinology Letters, Aug 1, 2007
Over the last four decades, researchers have significantly changed their understanding of organiz... more Over the last four decades, researchers have significantly changed their understanding of organizational conflicts. The contemporary (interactionist) view of conflicts is associated with the recognition of their inevitability as an organizational phenomenon and their positive functional value. Successful conflict management requires recognition of the interactionist view. First, managers must accept conflicts as a natural expression of communication and a normal way of interaction between employees within the organization. Second, they must adopt a constructive approach (as well as their subordinates) to organizational conflicts in order to be able to see and use the opportunities in them.The paper presents the results of a study of managers’ attitudes towards conflicts in organizations. Questionnaire data were collected from 300 Bulgarian managers from different organizational levels. The results showed that for a significant part of the respondents (43%) the consequences of confli...
Neuroendocrinology Letters, Dec 1, 2007
Neuro endocrinology letters, 2009
BACKGROUND There is now evidence that major depression and myalgic encephalomyelitis / chronic fa... more BACKGROUND There is now evidence that major depression and myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) are accompanied by partially overlapping pathophysiological mechanisms, i.e. activation of various inflammatory and oxidative & nitrosative (IO&NS) pathways. OBJECTIVE The aim of the present study was to examine the urinary excretion of 8-hydroxy-deoxyguanosine (8-OhdG), a marker of oxidative damage to DNA, in depression; ME/CFS; and depression and ME/CFS. METHODS Toward this end, morning urine was sampled for the assays of 8-OHdG and creatinine, in 44 patients with ME/CFS; 25 with major depression; 23 with depression and ME/CFS; and 17 normal controls. Severity of fatigue and somatic symptoms was measured by means of the Fibromyalgia and CFS Rating (FF) scale. RESULTS We found that 49.0% of the variance in the urinary excretion of 8-OHdG was predicted by the regression on creatinine. Consequently, the urinary 8-OHdG excretion should be expressed as the residualiz...
Neuro Endocrinology Letters, Oct 1, 2005
There are a few reports that chronic fatigue syndrome (CFS) may be accompanied by changes in horm... more There are a few reports that chronic fatigue syndrome (CFS) may be accompanied by changes in hormones, such as dehydroepiandrosterone (DHEA) and insulin-like growth factor (IGF1). This study examines the serum concentrations of DHEA-sulfate (DHEAS), IGF1 and IGF1 binding protein-3 (IGFBP3) in 20 patients with CFS and in 12 normal controls. The IGFBP3/IGF1 ratio was computed as an index for IGF1 availability. We found significantly lower serum DHEAS concentrations in CFS, but no significant differences either in IGF1 or the IGFBP3/IGF1 ratio between CFS patients and normal controls. The decrease in serum DHEAS was highly sensitive and specific for CFS. There were significant and positive correlations between serum DHEAS and serum zinc and the mitogen-induced expression of the CD69 molecule on CD3+CD8+ T cells (an indicator of early T cell activation). There was a significant and negative correlation between serum DHEAS and the increase in the serum alpha-2 protein fraction (an inflammatory marker). Serum IGF1, but not DHEAS, was significantly and inversely correlated to age. The results show that CFS is accompanied by lowered levels of DHEAS and that the latter may play a role in the immune (defect in the early activation of T cells) and the inflammatory pathophysiology of CFS.
Neuro Endocrinology Letters, Jul 1, 2008
It has been shown that chronic fatigue syndrome (CFS) and major depression (MDD) are accompanied ... more It has been shown that chronic fatigue syndrome (CFS) and major depression (MDD) are accompanied by signs of oxidative stress and by a decreased antioxidant status. The aim of the present study was to examine whether CFS and MDD are accompanied by an IgM-mediated immune response directed against nitro-serum bovine albumin (BSA), which is a neoepitope of BSA formed by damage caused by nitrosative stress. Toward this end, we examined serum IgM antibodies to nitro-BSA in 13 patients with CFS, 14 subjects with partial CFS, 16 patients with MDD and 11 normal controls. We found that the prevalence and mean values for the serum IgM levels directed against nitro-BSA were significantly greater in patients with partial CFS, CFS and MDD than in normal controls, and significantly greater in CFS than in those with partial CFS and MDD. We found significant and positive correlations between serum IgM levels directed against nitro-BSA and symptoms of the FibroFatigue scale, i.e. aches and pain and muscular tension. There was also a strong positive correlation between serum IgM titers directed against nitro-BSA and an index of increased gut permeability ("leaky gut"), i.e. serum IgM and IgA directed against LPS of different gram-negative enterobacteria. The abovementioned results indicate that both CFS and MDD are accompanied by a) an increased gut permeability which has allowed an exaggerated passage of BSA through a compromised epithelial barrier; b) increased nitrosative stress which has induced damage to BSA; and c) an IgM-mediated immune response which is directed against the nitro-BSA neoepitopes. Nitrosative stress is one of the factors underpinning the comorbidity and clinical overlap between CFS and MDD.
Neuro Endocrinology Letters, Dec 1, 2007
Neuro endocrinology letters
ABSTRACT
Neuro endocrinology letters, 2007
There is some evidence that patients with chronic fatigue syndrome (CFS) suffer from immune abnor... more There is some evidence that patients with chronic fatigue syndrome (CFS) suffer from immune abnormalities, such as immune activation and decreased immune cell responsivity upon polyclonal stimili. This study was designed to evaluate lymphocyte activation in CFS by using a CD69 expression assay. CD69 acts as a costimulatory molecule for T- and natural killer (NK) cell activation. We collected whole blood from CFS patients, who met CDC criteria, and healthy volunteers. The blood samples were stimulated with mitogens during 18 h and the levels of activated T and NK cells expressing CD69 were measured on a Coulter Epics flow cytometer using a three color immunofluorescence staining protocol. The expression of the CD69 activation marker on T cells (CD3+, CD3+CD4+, and CD3+CD8+) and on NK cells (CD45+CD56+) was significantly lower in CFS patients than in healthy subjects. These differences were significant to the extent that a significant diagnostic performance was obtained, i.e. the area...
Neuro endocrinology letters, 2009
There is now evidence that major depression is accompanied by an induction of inflammatory and ox... more There is now evidence that major depression is accompanied by an induction of inflammatory and oxidative and nitrosative stress (IO&NS) pathways and by a lowered antioxidant status. Coenzyme Q10 (CoQ10) is a strong antioxidant that has anti-inflammatory effects. This paper examines the plasma concentrations of CoQ10 in 35 depressed patients and 22 normal volunteers and the relationships between plasma CoQ10 and treatment resistant depression (TRD), the severity of illness as measured by means of the Hamilton Depression Rating Scale (HDRS) and the presence of chronic fatigue syndrome (CFS). We found that plasma CoQ10 was significantly (p=0.0002) lower in depressed patients than in normal controls. 51.4% of the depressed patients had plasma CoQ10 values that were lower than the lowest plasma CoQ10 value detected in the controls. Plasma CoQ10 was significantly lower in patients with TRD and with CFS than in the other depressed patients. There were no significant correlations between pl...
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Papers by Ivana Mihaylova