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Cobi J Heijnen

Publications and source records attributed to Cobi J Heijnen.

At least 19 recordsLinked to original sources
PubMed2007

G protein-coupled receptor kinase 6 controls chronicity and severity of dextran sodium sulphate-induced colitis in mice.

BACKGROUND: Infiltration of inflammatory cells into the colon plays an important role in the onset and course of inflammatory bowel disease. G-protein-coupled receptor kinase 6 (GRK6) is an intracellular kinase that regulates the sensitivity of certain G-protein-coupled receptors, including those involved in the migration of inflammatory cells. Therefore, it is hypothesised that GRK6 plays a role in determining the course of inflammation. AIM: To analyse the role of GRK6 in the course of dextran sodium sulphate (DSS)-induced colitis. METHODS: Colitis was induced by administering 1% DSS in drinking water to GRK6(-/-), GRK6(+/-) and wild-type (WT) mice for 6 days. The severity of colitis was assessed on the basis of clinical signs, colon length and histology. Moreover, keratinocyte-derived chemokine (KC) levels, granulocyte infiltration, interleukin 1beta (IL1beta), CD4, CD8 and forkhead box protein P3 (FoxP3) expression in the colon were determined. In addition, regulatory T cell function in WT and GRK6(-/-) mice was analysed. The chemotactic response of granulocytes to colon culture supernatants was assessed using a transendothelial migration assay. RESULTS: The severity of colitis was increased in GRK6(-/-) and GRK6(+/-) mice and was accompanied by increased KC levels and increased granulocyte infiltration. Moreover, the chemotactic response of GRK6(-/-) granulocytes to supernatants of colon cultures was enhanced. Interestingly, the WT mice completely recovered from colitis, whereas the GRK6(-/-) and GRK6(+/-) mice developed chronic colitis, which was accompanied by increased IL1beta and CD4 expression and decreased FoxP3 expression. Moreover, regulatory T cell function was impaired in the GRK6(-/-) mice. CONCLUSIONS: The intracellular level of GRK6 is an important factor in determining the onset, severity and chronicity of DSS-induced colitis.

Acute Disease↗
PubMed2007

Receptor regulation in neuroendocrine-immune communication: current knowledge and future perspectives.

Immune cells express receptors for every hormone or neurotransmitter we know so far. The neuroendocrine system signals to the immune system via the release of hormones and neurotransmitters that regulate cellular activity via these receptors. Much attention has been focused on the effect of glucocorticoids and catecholamines on the immune system. Glucocorticoids communicate with immune cells via glucocorticoid receptors of which the activity itself changes during immune activation. Many neuroendocrine mediators are ligands for G-protein coupled receptors on immune cells. Cytokines, oxygen-radicals, and catecholamines can influence the responsiveness of G-protein coupled receptors via decreasing the intracellular level of so-called G-protein coupled receptor kinases, of which the subtype GRK2 is highly expressed in immune cells. Therefore, changes in only one kinase can modulate the sensitivity of many receptors. We describe here that sensitivity of neuroendocrine receptors on immune cells is constantly regulated by inflammatory processes or chronic stress, which implies that not only the activity of the neuroendocrine system determines communication but that the sensitivity of receptors is a major factor in determining the final immune response. Finally, consequences of alterations in GRK2 during (neuro)-inflammatory diseases are discussed.

Adolescent↗
PubMed2007

Reduced life expectancy in rats after neonatal dexamethasone treatment.

The glucocorticoid dexamethasone (Dex) is widely used in preterm infants for the prevention of chronic lung disease. However, major concern has arisen about the long-term sequelae of this therapy. Here we report that neonatal treatment with dexamethasone significantly shortens the lifespan by 25% of male rats (28.6 +/- 1.1 to 21.3 +/- 0.8 mo) and by 18% of female rats (26.9 +/- 1.8 to 22.0 +/- 0.7 mo). Histopathological examination indicated end-stage cardiac and renal failure as the cause of premature death. Furthermore, Dex-treated rats showed symptoms of hypertension at young adult age, which worsened with increasing age. Thus, a brief period of glucocorticoid treatment during early life results in untimely death presumably due to cardiovascular and renal disease later in life. These serious, adverse long-term consequences call for prudence with glucocorticoid treatment of human preterm infants and careful follow-up of young adults with a history of neonatal glucocorticoid treatment.

Animals↗
PubMed2006

Immune and endocrine function in burnout syndrome.

OBJECTIVE: Burnout is a stress-induced work-related syndrome. It is associated with a higher incidence of infections possibly pointing to a compromised immune system. In the present study, endocrine and ex vivo immune function of severe cases of burnout were investigated. METHODS: Endocrine and immune variables were compared in 56 persons with burnout and 38 healthy control subjects. Cortisol after awakening, after a low-dose dexamethasone, and dehydroepiandrosterone-sulphate (DHEAS) were analyzed from saliva. Peripheral blood was analyzed for T, B, and NK cell number and in vitro mitogen-induced pro- and antiinflammatory cytokine release. The capacity of dexamethasone to regulate cytokine release was compared between the groups. RESULTS: The burnout group showed an increased production of the antiinflammatory cytokine interleukin-10 (IL-10) by monocytes after lipopolysaccharide stimulation. No differences were observed in IL-10 release induced by the T-cell mitogen PHA nor in the proinflammatory cytokines gamma interferon and tumor necrosis factor alpha. The capacity of dexamethasone to regulate cytokine release did not differ between the groups. The number of peripheral blood T cells, B cells, or NK cells was not different either. The burnout group showed higher DHEAS levels but no difference in cortisol levels after awakening or after dexamethasone intake in comparison to controls. CONCLUSION: Production of the antiinflammatory cytokine IL-10 by monocytes was increased in individuals with burnout syndrome. It seems unlikely that glucocorticoids or changes in glucocorticoid receptor function play a role in this higher IL-10 production.

Adult↗
PubMed2006

Differences in behavioral outcome and motor development at school age after neonatal treatment for chronic lung disease with dexamethasone versus hydrocortisone.

Neonatal dexamethasone (DEX) for chronic lung disease is associated with adverse outcome. We compared behavioral and motor development at school age of children who neonatally received DEX to children neonatally treated with hydrocortisone (HC) in a retrospective matched cohort study. DEX- and HC-treated groups matched for gestational age, birth weight and year, gender, and severity of respiratory distress syndrome were compared with a reference group (REF) and a group treated only antenatally with betamethasone (BMETH). REF and BMETH groups had a higher gestational age and less severe respiratory distress syndrome. From 192 children (DEX, n = 46; HC, n = 52; REF, n = 43; BMETH, n = 51), the Child Behavioral Checklists from parents and teachers (Teacher's Report Form) and the Movement Assessment Battery for Children to assess neuromotor function were analyzed. DEX girls had a poorer performance on nearly all behavioral scales of the Teacher's Report Form compared with HC girls. DEX boys did not differ from HC boys. The HC boys or girls did not differ from the REF or BMETH groups. Neuromotor development was poorer in DEX than the BMETH and REF groups. The HC group did not differ from REF and BMETH groups. We suggest that neonatal HC may be a "safer" alternative for DEX for the treatment of CLD.

Anti-Inflammatory Agents↗
PubMed2006

Acetylsalicylic acid as an adjuvant therapy for schizophrenia.

BACKGROUND: Findings from both epidemiological and basic research point to the possibility that NSAIDS impede the deterioration in schizophrenia. METHODS: To study the efficacy of acetylsalicylic acid we will perform a randomized placebo controlled double-blind add-on trial of 80 inpatients and outpatients with schizophrenia, schizophreniform or schizoaffective disorder. Patients will be 1:1 randomized to either 3 months 1000 mg acetylsalicylic acid per day or 3 months placebo, in addition to their regular antipsychotic treatment. All patients will receive pantoprazole treatment for gastroprotection. The outcomes of this study are 3-month change in psychotic and negative symptom severity, cognitive function, and several immunological parameters. This trial may (1) yield a new (adjuvant) therapy for schizophrenia and (2) add to the knowledge on the pathogenesis of this major psychiatric disorder.

Journal Article↗
PubMed2006

Public speaking stress-induced neuroendocrine responses and circulating immune cell redistribution in irritable bowel syndrome.

OBJECTIVES: Augmented neuroendocrine stress responses and altered immune functions may play a role in the manifestation of functional gastrointestinal (GI) disorders. We tested the hypothesis that IBS patients would demonstrate enhanced psychological and endocrine responses, as well as altered stress-induced redistribution of circulating leukocytes and lymphocytes, in response to an acute psychosocial stressor when compared with healthy controls. METHODS: Responses to public speaking stress were analyzed in N = 17 IBS patients without concurrent psychiatric conditions and N = 12 healthy controls. At baseline, immediately following public speaking, and after a recovery period, state anxiety, acute GI symptoms, cardiovascular responses, serum cortisol and plasma adrenocorticotropic hormone (ACTH) were measured, and numbers of circulating leukocytes and lymphocyte subpopulations were analyzed by flow cytometry. RESULTS: Public speaking led to significant cardiovascular activation, a significant increase in ACTH, and a redistribution of circulating leukocytes and lymphocyte subpopulations, including significant increases in natural killer cells and cytotoxic/suppressor T cells. IBS patients demonstrated significantly greater state anxiety both at baseline and following public speaking. However, cardiovascular and endocrine responses, as well as the redistribution of circulating leukocytes and lymphocyte subpopulations after public speaking stress, did not differ for IBS patients compared with controls. CONCLUSIONS: In IBS patients without psychiatric comorbidity, the endocrine response as well as the circulation pattern of leukocyte subpopulations to acute psychosocial stress do not differ from healthy controls in spite of enhanced emotional responses. Future studies should discern the role of psychopathology in psychological and biological stress responses in IBS.

Adrenocorticotropic Hormone↗
PubMed2006

GRKs and arrestins: regulators of migration and inflammation.

In the immune system, signaling by G protein-coupled receptors (GPCRs) is crucial for the activity of multiple mediators, including chemokines, leukotrienes, and neurotransmitters. GPCR kinases (GRKs) and arrestins control GPCR signaling by mediating desensitization and thus, regulating further signal propagation through G proteins. Recent evidence suggests that the GRK-arrestin desensitization machinery fulfills a vital role in regulating inflammatory processes. First, GRK/arrestin levels in immune cells are dynamically regulated in response to inflammation. Second, in animals with targeted deletion of GRKs or arrestins, the progression of various acute and chronic inflammatory disorders, including autoimmunity and allergy, is profoundly affected. Third, chemokine receptor signaling in vitro is known to be tightly regulated by the GRK/arrestin machinery, and even small changes in GRK/arrestin expression can have a marked effect on cellular responses to chemokines. This review integrates data about the role of GRKs and arrestins in inflammation, with results on the molecular mechanism of action of GRKs/arrestins, and describes the pivotal role of GRKs/arrestins in inflammatory processes, with a special emphasis on regulation of chemokine responsiveness.

Acute Disease↗
PubMed2006

Gender-specific neuroprotection by 2-iminobiotin after hypoxia-ischemia in the neonatal rat via a nitric oxide independent pathway.

We have shown earlier that 2-iminobiotin (2-IB) reduces hypoxia-ischemia (HI)-induced brain damage in neonatal rats, and presumed that inhibition of nitric oxide synthases (NOS) was the underlying mechanism. We now investigated the effect of 2-IB treatment in P7 rat pups to determine the role of gender and the neuroprotective mechanism. Pups were subjected to HI (occlusion of right carotid artery and 120 mins FiO(2) 0.08) and received subcutaneous (s.c.) 10 mg/kg 2-IB at 0, 12 and 24 h after hypoxia. After 6 weeks, neuronal damage was assessed histologically. We determined cerebral nitrite and nitrate (NO(x)) and nitrotyrosine, heat-shock protein 70, cytosolic cytochrome c, cleaved caspase 3, nuclear translocation of apoptosis-inducing factor (AIF) and the effect of 2-IB on NOS activity in cultured cells. 2-Iminobiotin treatment reduced long-term brain damage in female but not male rats. Unexpectedly, 2-IB treatment did not reduce cerebral NO(x) or nitrotyrosine levels, and did not inhibit NOS activity in vitro. The gender-dependent neuroprotective effect of 2-IB was reflected in inhibition of the HI-induced increase in cytosolic cytochrome c and cleaved caspase 3 in females only. Hypoxia-ischemia-induced activation of AIF was observed in males only and was not affected by 2-IB. Post-HI treatment with 2-IB provides gender-specific long- and short-term neuroprotection in female P7 rats via inhibition of the cytochrome c-caspase 3 neuronal death pathway. 2-Iminobiotin did not alter cerebral NO(x) nor inhibited NOS in intact cells. Therefore, we conclude that it is highly unlikely that the neuroprotective effect of 2-IB involves NOS inhibition.

Animals↗
PubMed2006

A longitudinal study on cortisol and complaint reduction in burnout.

Several studies have investigated the association between burnout and HPA-axis functioning, but the results are far from consistent. This does not preclude the possibility that within a group of burnout patients a recovery of symptoms in a longitudinal course corresponds to (changes in) cortisol parameters. The latter possibility is tested in the present study before and after treatment, and at follow-up. HPA-axis functioning and burnout complaints were assessed in burned-out participants at baseline (n=74), post-treatment (n=62) and at follow-up (n=53). Multilevel regression analysis was used to test the hypothesis. Burnout complaints were significantly reduced at 8.5 months post-treatment, but there was no further reduction in complaints at follow-up 6.3 months later. Cortisol after awakening, and after dexamethasone intake showed no changes from baseline to post-treatment and follow-up. There was a small decline in cortisol during the day over the longitudinal course. The cortisol level after awakening in the longitudinal course showed significant positive association with the initial exhaustion level, a negative association with the change in the burnout exhaustion score, and a positive association with the change in depression. Although these associations are statistically significant, they only explain a small fraction of the variance in cortisol after awakening between and within persons. This implies that changes at symptom level are hardly related to changes in cortisol functioning, therefore the clinical implications of this finding are limited.

Adaptation, Physiological↗
PubMed2006

Respiratory distress syndrome-associated inflammation is related to early but not late peri/intraventricular hemorrhage in preterm infants.

OBJECTIVE: To investigate whether or not peri/intraventricular hemorrhages (PIVHs) occurring in the first 12 hours of life (early PIVHs) are related to respiratory distress syndrome (RDS)-associated inflammatory factors in contrast to PIVHs developing after 12 hours of life (late PIVHs). STUDY DESIGN: Blood samples obtained at 0 to 12 hours, 48 to 72 hours, and 168 hours of life were evaluated for determination of the proinflammatory cytokines interleukin (IL)-8 and IL-6, tumor necrosis factor (TNF)-alpha, and malondialdehyde (MDA) as measures of lipid peroxidation. Simultaneously, cranial ultrasonography was performed in 114 neonates under 32 weeks gestational age. RESULTS: Out of the total study group of 114 neonates, 67 (59%) had RDS. Early PIVH occurred in 16 neonates, 14 of whom (88%) had RDS. Late PIVHs occurred in 12 neonates. Neonates with RDS had higher IL-8 and IL-6 levels at 0 to 12 hours (P < .0001; < .0001) and at 48 to 72 hours (P < .001; < .01) than those without RDS. Neonates with early PIVH had higher IL-8 (P < .02), IL-6 (P < .02), and MDA (P < .01) levels at 0 to 12 hours than those with late PIVH or no PIVH. Those with early PIVH had higher IL-8 levels at 48 to 72 hours than those without PIVH (P < .02). Multiple linear regression revealed an association between RDS/early PIVH and IL-8, IL-6, and MDA levels. CONCLUSIONS: An RDS-associated increase in proinflammatory cytokine and MDA levels was associated with early PIVHs, but not with late PIVHs, suggesting a different etiopathogenesis in early versus late PIVHs.

Age Factors↗
PubMed2006

Cortisol deviations in people with burnout before and after psychotherapy: a pilot study.

Burnout is characterized by exhaustion, cynicism, and feelings of reduced competence. These complaints may be reflected in disturbances in the main stress regulatory endocrine system: the hypothalamus pituitary adrenal (HPA) axis. In this study, the HPA-axis hormone cortisol was sampled after awakening and during the day in 22 participants with clinical burnout and in 21 healthy controls. The cortisol level after awakening was shown to be significantly lower in the burnout group as compared with the control group. Cortisol levels during the day did not differ. The same sampling procedure was repeated after 14 sessions of psychotherapeutic intervention. The intervention led to a significant reduction in complaints and to an increase of the initially lowered morning cortisol levels. No consistent correlations, however, between the changes in subjective complaints and the change in cortisol parameters were found.

Adult↗
PubMed2006

Selective inhibition of nuclear factor-kappaB activation after hypoxia/ischemia in neonatal rats is not neuroprotective.

Activated nuclear factor-kappaB (NFkappaB) has been shown to increase transcription of several genes that could potentially contribute to neuronal damage, such as proinflammatory cytokines, chemokines, and inducible nitric oxide synthase. The aim of our study was to investigate whether inhibition of NFkappaB activation could prevent hypoxia/ischemia (HI)-induced cerebral damage in neonatal rats. We used a cell permeable peptide (NEMO binding domain [NBD] peptide) that is known to prevent the association of the regulatory protein NEMO with IKK, the kinase that activates NFkappaB. Via this mechanism, the NBD peptide can specifically block the activation of NFkappaB, without inhibiting basal NFkappaB activity. Cerebral HI was induced in neonatal rats by occlusion of the right carotid artery followed by 90 min of hypoxia (Fio(2) = 0.08). Immediately upon reoxygenation, as well as 6 and 12 h later, rats were treated with vehicle or NBD peptide (20 mg/kg i.p.). Histologic analysis of brain damage was performed at 6 wk after HI. To assess NFkappaB activation, electromobility shift assays (EMSAs) were performed on brain nuclear extracts obtained 6 h after reoxygenation. Increased NFkappaB activity could be shown at 6 h after HI in both hemispheres. Peripheral administration of NBD peptide prevented this HI-induced increase in NFkappaB activity in both hemispheres. Histologic analysis of long-term cerebral damage revealed that inhibition of NFkappaB activation by administration of NBD peptide at 0, 6, and 12 h after HI resulted in an increment of neuronal damage. In conclusion, our data suggest that inhibition of NFkappaB activation using NBD peptide early after HI increases brain damage in neonatal rats.

Animals↗
PubMed2006

Bilateral molecular changes in a neonatal rat model of unilateral hypoxic-ischemic brain damage.

Perinatal hypoxia ischemia (HI) is a frequent cause of neonatal brain injury. This study aimed at describing molecular changes during the first 48 h after exposure of the neonatal rat brain to HI. Twelve-day-old rats were subjected to unilateral carotid artery occlusion and 90 min of 8% O2, leading to neuronal damage in the ipsilateral hemisphere only. Phosphorylated-Akt levels were decreased from 0.5 to 6 h post-HI, whereas the level of phosphorylated extracellular signal-related kinases (ERK)1/2 increased during this time frame. Hypoxia-inducible factor (HIF)-1alpha protein increased with a peak at 3 h after HI. mRNA expression for IL-beta and tumor necrosis factor-alpha and -beta started to increase at 6 h with a peak at 24 h post-HI. Expression of heat shock protein 70 was increased from 12 h after HI onwards in the ipsilateral hemisphere only. Surprisingly, HI changed the expression of cytokines, HIF1-alpha ,and P-Akt to the same extent in both the ipsi- as well as the contralateral hemisphere, although neuronal damage was unilateral. Exposure of animals to hypoxia without carotid artery occlusion induced similar changes in cytokines, HIF-1alpha, and P-Akt. We conclude that during HI, hypoxia is sufficient to regulate multiple molecular mediators that may contribute, but are not sufficient, to induce long-term neuronal damage.

Animals↗
PubMed2006

Severe fatigue in adolescents: a common phenomenon?

OBJECTIVE: The purpose of this study was to determine the prevalence of severe fatigue in adolescent boys and girls, to explore the role of lifestyle factors in fatigue, and to investigate whether severe fatigue in a healthy population is associated with depression, anxiety, and comorbid factors also observed in chronic fatigue syndrome patients. METHODS: In a sample of 1718 boys and 1749 girls, fatigue severity and duration were measured using a multidimensional questionnaire (Checklist Individual Strength). In addition, self-reports of depressive symptoms, anxiety, chronic fatigue syndrome-related symptoms, and lifestyle characteristics were assessed by means of questionnaires. Prevalence rates of severe fatigue and severe fatigue for > or =1 month, based on a clinical cutoff score of the Checklist Individual Strength, were determined for boys and girls separately, and gender-specific predictors of fatigue were identified by multiple regression analysis. RESULTS: The data showed high prevalence rates of severe fatigue in adolescents. Remarkable differences between boys and girls were observed: 20.5% of girls and 6.5% of the boys scored above the clinical cutoff score on the Checklist Individual Strength. Of these subjects 80.0% of the girls and 61.5% of the boys reported severe fatigue for > or =1 month. Of the examined lifestyle characteristics, only sleep characteristics and the participation in sports played a role in predicting fatigue in both genders. Moreover, in girls, fatigue was associated with higher age, an early menarche, medication use, and the absence of an additional job. Overall, girls scored higher on depression, anxiety, and chronic fatigue syndrome-related symptoms. However, the relation between fatigue and these comorbid symptoms did not differ between genders. In both girls and boys, the duration of fatigue was positively related to fatigue severity, severity of depression and anxiety, and the number of chronic fatigue syndrome-related symptoms. CONCLUSIONS: Fatigue prevalence among adolescents is high, especially in girls. Adolescent girls seem to be more vulnerable to symptoms of fatigue and comorbidity than boys. Interestingly, despite a female predominance in complaints, the relation between fatigue and depression, anxiety, and chronic fatigue syndrome-related symptoms was not gender specific and emerged as a cluster. In both genders, fatigue duration was associated with the severity of fatigue and the level of psychological comorbidity and chronic fatigue syndrome-related symptoms, and we, therefore, hypothesize that enduring severe fatigue may form a risk factor for the development of chronic fatigue syndrome.

Adolescent↗
PubMed2005

G protein-coupled receptor kinase 2 negatively regulates chemokine signaling at a level downstream from G protein subunits.

The G protein-coupled receptor kinase 2 (GRK2) phosphorylates and desensitizes ligand-activated G protein-coupled-receptors. Here, evidence is shown for a novel role of GRK2 in regulating chemokine-mediated signals. The presence of increased levels of GRK2 in human embryonic kidney (HEK) 293 cells produced a significant reduction of the extracellular signal-regulated kinase (ERK) response to CCL2. This effect is independent of its role in receptor phosphorylation because the kinase-deficient mutant GRK2K220R was able to reduce this response, and ERK activation by CCR2BIX, a phosphorylation-defective receptor mutant, was also inhibited by GRK2. Constructs containing the Galpha(q)-binding RGS-like RH domain of GRK2 or its Gbetagamma-binding domain could not reproduce the inhibition, thus revealing that GRK2 acts downstream of G proteins. Interestingly, chemokine-driven mitogen-activated protein kinase kinase (MEK) stimulation is not affected in cells overexpressing GRK2 or GRK2K220R or in splenocytes from heterozygous GRK2 mice, where reduced kinase levels correlate with enhanced ERK activation by chemokines. We find GRK2 and MEK in the same multimolecular complex, thus suggesting a mechanism for GRK2 regulation of ERK activity that involves a direct or coordinate interaction with MEK. These results suggest an important role for GRK2 in the control of chemokine induction of ERK activation at the level of the MEK-ERK interface.

Animals↗
PubMed2005

Clinical burnout is not reflected in the cortisol awakening response, the day-curve or the response to a low-dose dexamethasone suppression test.

Burnout is presumed to be the result of chronic stress, and chronic stress is known to affect the HPA-axis. To date, studies on HPA-axis functioning in burnout have showed inconsistent results. In the present study, a large sample (n=74) of clinically diagnosed burnout individuals, mostly on sick-leave, were included and compared with 35 healthy controls. Salivary cortisol was sampled on 2 days to determine the cortisol awakening response (CAR) and the day-curve. In addition, the dexamethasone suppression test (DST) was applied to assess the feedback efficacy of the HPA-axis. There were no differences observed in the CAR, day-curve or CAR after DST in the burnout group as compared to a healthy control group. Burnout shows overlap in symptoms with chronic fatigue syndrome (CFS) and depression. Therefore, differential changes in HPA-axis functioning that resemble the hypo-functioning of the HPA-axis in CFS, or rather the hyper-functioning of the HPA-axis in depression, might have obscured the findings. However, no effect of fatigue or depressive mood on HPA-axis functioning was found in the burnout group. We concluded that HPA-axis functioning in clinically diagnosed burnout participants as tested in the present study, seems to be normal.

Adult↗