PubMed Health⌕ Search

Biomedical subjects

Eberhard Schulz

Publications and source records attributed to Eberhard Schulz.

At least 19 recordsLinked to original sources
PubMed2007

Abnormal frequency discrimination in children with SLI as indexed by mismatch negativity (MMN).

For several decades, the aetiology of specific language impairment (SLI) has been associated with a central auditory processing deficit disrupting the normal language development of affected children. One important aspect for language acquisition is the discrimination of different acoustic features, such as frequency information. Concerning SLI, studies to date that examined frequency discrimination abilities have been contradictory. We hypothesized that an auditory processing deficit in children with SLI depends on the frequency range and the difference between the tones used. Using a passive mismatch negativity (MMN)-design, 13 boys with SLI and 13 age- and IQ-matched controls (7-11 years) were tested with two sine tones of different frequency (700Hz versus 750Hz). Reversed hemispheric activity between groups indicated abnormal processing in SLI. In a second time window, MMN2 was absent for the children with SLI. It can therefore be assumed that a frequency discrimination deficit in children with SLI becomes particularly apparent for tones below 750Hz and for a frequency difference of 50Hz. This finding may have important implications for future research and integration of various research approaches.

Acoustic Stimulation↗
PubMed2007

[Phenomenology and co-morbidity of childhood onset obsessive compulsive disorder].

OBJECTIVES: The goal of the study was to investigate the contents and comorbidity features of obsessive-compulsive disorder in children and adolescents. METHOD: 55 patients (29 males, 26 females), mainly inpatients selected from university clinics for child and adolescent psychiatry (95%), were investigated. Structured diagnostic interviews were used to interview patients and their parents. RESULTS: The mean age of onset for obsessive-compulsive disorders was 11.3 years. In males the onset was slightly earlier than among females, but this difference was not significantly significant. Compulsions mostly referred to washing and cleaning, checking, repeating, ordering, and counting. Most frequently, obsessions included thought about contamination, catastrophes, sexuality, and aggression. According to parental reports, the rate of comorbidity was high (lifetime diagnosis: 69%, current diagnosis: 53%), with anxiety, depressive, hyperkinetic, conduct, and eating disorders being the most frequent co-morbid conditions. Obsessive-compulsive symptoms were more intense in those patients who had a greater number of lifetime diagnoses of other psychiatric disorders. Comparing the rates found when structured interviews were carried out according to the study protocol to those for clinicians, clinicians were found to have diagnosed mixed obsessional thoughts and acts (presenting obsessional thoughts, as well as compulsive acts) less frequently. CONCLUSIONS: The results of this investigation are well in line with those of international studies on obsessive-compulsive disorders. The rates of disorders found were dependent on the diagnostic methods used. A potentially promising approach for further investigation is the sub-typing of patients according to symptom dimensions.

Adolescent↗
PubMed2006

Mitochondrial oxidative stress and nitrate tolerance--comparison of nitroglycerin and pentaerithrityl tetranitrate in Mn-SOD+/- mice.

BACKGROUND: Chronic therapy with nitroglycerin (GTN) results in a rapid development of nitrate tolerance which is associated with an increased production of reactive oxygen species (ROS). According to recent studies, mitochondrial ROS formation and oxidative inactivation of the organic nitrate bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) play an important role for the development of nitrate and cross-tolerance. METHODS: Tolerance was induced by infusion of wild type (WT) and heterozygous manganese superoxide dismutase mice (Mn-SOD+/-) with ethanolic solution of GTN (12.5 mug/min/kg for 4 d). For comparison, the tolerance-free pentaerithrityl tetranitrate (PETN, 17.5 mug/min/kg for 4 d) was infused in DMSO. Vascular reactivity was measured by isometric tension studies of isolated aortic rings. ROS formation and aldehyde dehydrogenase (ALDH-2) activity was measured in isolated heart mitochondria. RESULTS: Chronic GTN infusion lead to impaired vascular responses to GTN and acetylcholine (ACh), increased the ROS formation in mitochondria and decreased ALDH-2 activity in Mn-SOD+/- mice. In contrast, PETN infusion did not increase mitochondrial ROS formation, did not decrease ALDH-2 activity and accordingly did not lead to tolerance and cross-tolerance in Mn-SOD+/- mice. PETN but not GTN increased heme oxygenase-1 mRNA in EA.hy 926 cells and bilirubin efficiently scavenged GTN-derived ROS. CONCLUSION: Chronic GTN infusion stimulates mitochondrial ROS production which is an important mechanism leading to tolerance and cross-tolerance. The tetranitrate PETN is devoid of mitochondrial oxidative stress induction and according to the present animal study as well as numerous previous clinical studies can be used without limitations due to tolerance and cross-tolerance.

Acetylcholine↗
PubMed2006

Nebivolol inhibits superoxide formation by NADPH oxidase and endothelial dysfunction in angiotensin II-treated rats.

Nebivolol is a beta(1)-receptor antagonist with vasodilator and antioxidant properties. Because the vascular NADPH oxidase is an important superoxide source, we studied the effect of nebivolol on endothelial function and NADPH oxidase activity and expression in the well-characterized model of angiotensin II-induced hypertension. Angiotensin II infusion (1 mg/kg per day for 7 days) caused endothelial dysfunction in male Wistar rats and increased vascular superoxide as detected by lucigenin-derived chemiluminescence, as well as dihydroethidine staining. Vascular NADPH oxidase activity, as well as expression at the mRNA and protein level, were markedly upregulated, as well as NOS III uncoupled, as evidenced by NO synthase III inhibitor experiments and dihydroethidine staining and by markedly decreased hemoglobin-NO concentrations. Treatment with the beta-receptor blocker nebivolol but not metoprolol (10 mg/kg per day for each drug) normalized endothelial function, reduced superoxide formation, increased NO bioavailability, and inhibited upregulation of the activity and expression of the vascular NADPH oxidase, as well as membrane association of NADPH oxidase subunits (Rac1 and p67(phox)). In addition, NOS III uncoupling was prevented. In vitro treatment with nebivolol but not atenolol or metoprolol induced a dissociation of p67(phox) and Rac1, as well as an inhibition of NADPH oxidase activity assessed in heart membranes from angiotensin II-infused animals, as well as in homogenates of Nox1 and cytosolic subunit-transfected and phorbol ester-stimulated HEK293 cells. These findings indicate that nebivolol interferes with the assembly of NADPH oxidase. Thus, inhibitory effects of this beta-blocker on vascular NADPH oxidase may explain, at least in part, its beneficial effect on endothelial function in angiotensin II-induced hypertension.

Acridines↗
PubMed2006

Hydrogen peroxide restrains endothelium-derived nitric oxide bioactivity -- role for iron-dependent oxidative stress.

Vascular diseases are characterized by impairment of endothelial-derived nitric oxide (NO) bioactivity and increased vascular levels of hydrogen peroxide (H(2)O(2)). Here we examined the implications of H(2)O(2) for agonist-stimulated endothelial NO bioactivity in rabbit aortic rings and cultured porcine aortic endothelial cells (PAEC). Vessels pre-treated with H(2)O(2) exhibited impaired endothelial-dependent relaxation induced by acetylcholine or calcium ionophore. In contrast, H(2)O(2) had no effect on endothelium-independent relaxation induced by a NO donor, indicating a defect in endothelium-derived NO. This defect was not related to eNOS catalytic activity; treatment of PAEC with H(2)O(2) enhanced agonist-stimulated eNOS activity indicated by increased eNOS phosphorylation at Ser-1177 and de-phosphorylation at Thr-495 and enhanced conversion of [(3)H]-L-arginine to [(3)H]-L-citrulline that was prevented by inhibitors of Src and phosphatidylinositol-3 kinases. Despite activating eNOS, H(2)O(2) impaired endothelial NO bioactivity indicated by attenuation of the increase in intracellular cGMP in PAEC stimulated with calcium ionophore or NO. The decrease in cGMP was not due to impaired guanylyl cyclase as H(2)O(2) treatment increased cGMP accumulation in response to BAY 41-2272, a NO-independent activator of soluble guanylyl cyclase. At concentrations that impaired endothelial NO bioactivity H(2)O(2) increased intracellular oxidative stress and size of the labile iron pool in PAEC. The increase in oxidative stress was prevented by the free radical scavenger's tempol or tiron and the iron chelator desferrioxamine and these antioxidants reversed the H(2)O(2)-induced impairment of NO bioactivity in PAEC. This study shows that despite promoting eNOS activity, H(2)O(2) impairs endothelial NO bioactivity by promoting oxidative inactivation of synthesized NO. The study highlights another way in which oxidative stress may impair NO bioactivity during vascular disease.

Animals↗
PubMed2006

Prevalence of movement disorders in adolescent patients with schizophrenia and in relationship to predominantly atypical antipsychotic treatment.

OBJECTIVE: To examine prevalence of movement disorders (MDs) such as tardive dyskinesia (TD), parkinsonism or akathisia in an adolescent population with schizophrenia and in relationship to predominantly atypical antipsychotic treatment. METHOD: Ninety-three patients (aged 19.6+/-2.2 years) were ascertained in this cross-sectional/retrospective study. 76 patients (81.7%) received atypical, 10 (10.8%) typical antipsychotics and 7 (7.5%) combinations of atypical/typical antipsychotics. MD symptoms were assessed using Tardive Dyskinesia Rating Scale (TDRS), Abnormal Involuntary Movement Scale (AIMS), Extrapyramidal Symptom Scale (EPS), Barnes Akathisia Scale (BAS). RESULTS: Movement disorder symptoms were found in 37 patients (39.8%) fulfilling strict/subthreshold criteria for TD (5.4/11.8%), parkinsonism (2.2/25.8%) or akathisia (1.1/11.8%), respectively. Patients treated with typical antipsychotics displayed a significantly higher EPS-score (P=0.036) and a tendency towards a higher BAS-score (P=0.061) compared to patients with atypical antipsychotics. Treatment durations with typical/atypical antipsychotics showed trends towards advantages of atypical antipsychotics with regard to parkinsonism/akathisia symptoms (P=0.061; P=0.054), but not with regard to TD symptoms (P=0.003), possibly due to confounding effects. CONCLUSION: Under treatment with atypical antipsychotics MD symptoms are less prevalent and less pronounced than under typical antipsychotics. We speculate that the finding of relatively high prevalence rates of subthreshold MD symptoms may be, at least partially, explained by previous or combined therapy with typical antipsychotics.

Adolescent↗
PubMed2006

[Dialectical Behaviour Therapy for adolescents (DBT-A)--a pilot study on the therapy of suicidal, parasuicidal, and self-injurious behaviour in female patients with a borderline disorder].

OBJECTIVES: In Germany suicide ranks as the second leading cause of death in adolescents. Risk factors for suicide are impulsive and self-injurious behaviour, depression, and conduct disorder. The main hypothesis of our study is that Dialectical Behavior Therapy (DBT) for adolescents is an effective method of treatment for these patients. METHODS: DBT was developed by Marsha Linehan specifically for the outpatient treatment of chronically parasuicidal female patients with a diagnosis of borderline personality disorder. Miller & Rathus modified DBT for use with adolescents (DBT-A). and our group adapted the DBT-A for use in an outpatient treatment setting in Germany. In a pre-post comparison, the efficacy of treatment was measured using standardized instruments (SCL-90-R, CBCL, YSR, ILK, CGI, etc.). RESULTS: In a pilot study of 12 adolescents, we found effect sizes between 1.1 and 2.9. During treatment, self-injurious behaviour declined significantly. Prior to entering therapy, 8 of the 12 patients had attempted suicide at least once. During treatment according to DBT-A there were no suicide attempts. CONCLUSIONS: These results are so promising that we are now planning a randomized, multi-centre study.

Adolescent↗
PubMed2006

[Therapeutic drug monitoring in child and adolescent psychiatry--practical recommendations].

The therapy of children and adolescents with psychotropic drugs differs from that of adults. Due to the differences in the pharmacokinetic behaviour of the drugs used that are dependent on a child's, respectively an adolescent's stage of development, the same dosages as recommended for adults cannot be used. Moreover, many of the drugs used have not been approved for use in children and adolescents. Thus the criteria which guarantee their efficacy and safety for use in adults do not apply for their use in children and adolescents. Therefore therapeutic drug monitoring (TDM) is a general indication for the administration of psychotropic drugs in children and adolescents. TDM enables the clinician to adjust the dosage of a drug according to the characteristics of the individual patient. It is also a valid tool to increase the safety of therapy and optimise therapy with psychotropic drugs. However, standardized studies are also needed to find therapeutic ranges of plasma concentrations for children and adolescents. Such studies will deliver new insights into the pharmacokinetic and pharmacodynamic behaviour of drugs used in child and adolescent psychiatry. The present contribution begins with a brief description of the strategy of TDM in psychiatry, followed by a discussion of the characteristics of pharmacotherapy in child and adolescent psychiatry and the reasons for the general indication of TDM in children and adolescents. Finally, recommendations are given for the routine performance of TDM. For a detailed treatment of TDM in psychiatry, the interested reader is referred to the AG-NP-TDM Expert Group Consensus Guidelines published earlier (Baumann et al., 2004).

Adolescent↗
PubMed2006

[Switching from a short-acting to a long-acting methylphenidate preparation: a multicentre, open study in children with ADHD].

OBJECTIVES: The objective was to evaluate the safety and efficacy of a switch in medication to a single daily dose of OROS-Methylphenidate (OROS-MPH, Concerta) in clinically stable children and adolescents with ADHD. METHODS: A prospective, multi-centre open-label study was carried out for a period of three weeks in 213 patients aged 6-16 years with ADHD who had previously been treated with IR-MPH. Their medication was switched to a single daily dose of OROS-MPH. Primary endpoints were changes in the IOWA Conners Inattention/Overactivity Subscale and the global assessment of efficacy as rated by parents and teachers. The safety of the medication was evaluated by means of recording adverse events. The development of weight, sleep quality, and appetite were also observed. RESULTS: Switching the medication from IR-MPH to OROS-MPH resulted in a significant positive effect as evidenced by caregivers' ratings of core symptoms. Corresponding ratings by teachers revealed no significant difference from baseline values. The global efficacy was rated by teachers as "good" or "excellent" for 55% of the cases, by caregivers for 79% thereof, and by investigators in 77% of the cases, respectively. The study medication was well tolerated. The most frequent adverse events were headache (8.9%) and rhinopharyngitis (7.0%). No unexpected adverse events occurred. CONCLUSIONS: Changing patients' medication from IR-MPH to a single daily dose of OROS-MPH resulted in a significant improvement of ADHD symptoms as rated by parents. In a school setting, the efficacy of OROS-MPH was comparable to that of IR-MPH.

Adolescent↗
PubMed2006

Clinical drug monitoring in child and adolescent psychiatry: side effects of atypical neuroleptics.

OBJECTIVE: The aim of this study was to improve and evaluate the practibility of a method for the assessment of drug-associated side effects, and we implemented a clinical drug monitoring for atypical neuroleptics. METHODS: Side effects of initially hospitalized patients treated with clozapine (n = 16), olanzapine (n = 16), and risperidone (n = 19) were prospectively monitored on a weekly basis for the first 3 weeks. In the case of stable medication, measurements of all variables were made every 4 weeks or upon discharge. We used the Dosage Record Treatment Emergent Symptom Scale (DOTES) in a supplemented version to measure the presence and severity of side effects. RESULTS: Drowsiness and decreased motor activity were common, especially in the first 2 weeks. Orthostatic hypotension, increased salivation, constipation, and nasal congestion were seen in more than 30% to 60% of patients treated with clozapine and were less common in adolescents treated with olanzapine and risperidone. Rigidity, tremor, and dystonia were seen in 5% to 15% of patients treated with risperidone and olanzapine. The average weight gain after 6 weeks of treatment with the atypical neuroleptics was significantly higher for the olanzapine group (4.6 +/- 1.9 kg) than for the risperidone (2.8 +/- 1.3 kg) and clozapine (2.5 +/- 2.9 kg) groups. CONCLUSIONS: The authors' supplemented DOTES version is generally applicable to clinical use in mental health centers. The differences among the side effects of these three agents may affect compliance with medication and medical risks of metabolic syndrome, diabetes, and cardiovascular disease. More research on the short- and long-term safety of psychotropic drugs in children and adolescents, using standardized methods, should be considered.

Adolescent↗
PubMed2006

Serum levels of olanzapine and its N-desmethyl and 2-hydroxymethyl metabolites in child and adolescent psychiatric disorders: effects of dose, diagnosis, age, sex, smoking, and comedication.

The aim of this study was to assess dose-related steady-state serum concentrations of olanzapine (OLZ) and its metabolites N-desmethyl OLZ (DMO) and 2-hydroxymethyl OLZ (2-OH-OLZ) (assessed by high-performance liquid chromatography) in 122 child and adolescent psychiatric patients (age 16.9 +/- 2.2, range, 10-21 years; 74 males, 48 females) with a variety of diagnoses: schizophrenia group (n = 80); nonschizophrenia group (n = 29); anorexia nervosa (AN) group (n = 13). Median OLZ serum concentrations were 32.7 (range, 1-118; all patients), 37.7 (2-115; schizophrenia group), and 18.7 (1-63, AN group) ng/mL. The median OLZ concentration-to-dose (C/D) ratio (n = 122) was 2.6, with 90% of the distribution between 0.8 and 5.5 (ng/mL)/(mg/d). OLZ concentration was significantly correlated with DMO (r = 0.567; P < 0.0005) but not with 2-OH-OLZ (r = 0.122; P = 0.188). Daily OLZ dose was correlated with OLZ concentration in all (r = 0.684; P < 0.0005), schizophrenic (r = 0.542; P < 0.0005), and AN (r = 0.805; P = 0.001) patients, respectively. Patients aged less than 16 years displayed similar C/D for OLZ (P = 0.58) but higher C/D for DMO (P = 0.003) than those 16 years or older. AN patients received lower median OLZ doses (7.5; 5-15 mg) than schizophrenic patients (12.5; 2.5-40 mg), even after correcting for body mass index (P = 0.02). OLZ dose did not differ (P = 0.088) between smokers and nonsmokers, but smokers showed lower C/D for OLZ than nonsmokers (P = 0.008). C/D for OLZ was 38% higher (P = 0.041) under comedication with selective serotonin reuptake inhibitors when compared with OLZ monotherapy. Multiple linear regression analysis revealed that 46% of the variation of OLZ concentration can be explained by dose, diagnosis, age, sex, smoking, and comedication. The data are compared with the literature, and the relevance of therapeutic antipsychotic drug monitoring in previously sparsely investigated subgroups, such as children and adolescents or patients with AN, is emphasized.

Adolescent↗
PubMed2005

Mechanisms of increased vascular superoxide production in an experimental model of idiopathic dilated cardiomyopathy.

OBJECTIVE: In the present study, we sought to identify mechanisms underlying increased oxidative stress in vascular tissue in an experimental animal model of chronic congestive heart failure (CHF). METHODS AND RESULTS: Superoxide and nitric oxide (NO) was measured in vessels from cardiomyopathic hamsters (CHF hamsters) and golden Syrian hamsters. We also determined expression of endothelial nitric oxide synthase (NOSIII), the soluble guanylyl cyclase, the cGMP-dependent kinase, and the NADPH oxidase. To analyze the contribution of the renin-angiotensin system to oxidative stress, CHF hamsters were treated with the angiotensin-converting enzyme inhibitor captopril for 200 days (120 mg . kg(-1) . d(-1)). CHF led to increased superoxide production by NOSIII and the NADPH oxidase. Decreased NO production in CHF was associated with a decrease in the expression of NOSIII and an inhibition of NO downstream signaling in the aorta. NOSIII expression was increased within the left ventricle. Captopril treatment normalized NOSIII expression in vessels and the myocardium, reduced superoxide levels, and prevented NOSIII uncoupling. Accordingly, endothelial function, NO production, and downstream signaling were improved in CHF vessels. CONCLUSIONS: Oxidative stress in CHF is mediated by NADPH oxidase and an uncoupled NOSIII secondary to an activation of the renin-angiotensin system leading to impaired NO downstream signaling.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in children and adolescents with obsessive-compulsive disorder.

Dysfunction of the central serotonergic system has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD). The genetic contribution to the development of OCD is particularly high in early-onset OCD. The aim of this study was to investigate the effect of polymorphic variants in the gene of the novel brain-specific tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in OCD with disease onset in childhood and adolescence. We analysed two common single nucleotide polymorphisms (SNPs) of TPH2 in the putative transcriptional control region and in intron 2 of the TPH2 gene in a unique family-based sample of OCD patients with onset of the disease in childhood and adolescence comprising 71 complete, independent trios. The transmission disequilibrium test was used to determine transmission of alleles and haplotypes from parents to offspring. In this first study of TPH2 in OCD, analysis of the SNPs, rs4570625 and rs4565946, revealed a significant preferential transmission of haplotype G-C to children and adolescents with OCD. Moreover, a trend towards preferential transmission of the C allele of SNP rs4565946 to the patients was found. The genotype relative-risk estimate for homozygous C allele carriers of SNP rs4565946 was 2.58 (95% CI 0.98-6.82). In conclusion, the results link TPH2 variations to the pathogenesis of early-onset OCD and further support the aetiological relevance of 5-HT signalling in OCD.

Adolescent↗
PubMed2005

Estradiol-mediated endothelial nitric oxide synthase association with heat shock protein 90 requires adenosine monophosphate-dependent protein kinase.

BACKGROUND: Estradiol activates endothelial nitric oxide synthase (eNOS) by mechanisms that involve estrogen receptor-alpha (ERalpha), protein kinase B/Akt, mitogen-activated protein kinases, and heat shock protein 90 (HSP90). Recently, AMP-activated protein kinase (AMPK), an enzyme that plays a crucial role in cellular adaptation to metabolic stress, has been implicated in physiological eNOS activation by the hormones adiponectin and insulin. We therefore investigated whether AMPK is activated by estradiol in endothelial cells and plays a role in estradiol-induced eNOS activation. METHODS AND RESULTS: Porcine aortic endothelial cells exhibited time- and concentration-dependent AMPK activation as determined by phosphorylation of AMPK and its downstream target acetyl coenzyme A carboxylase in response to estradiol (1 nmol/L to 10 micromol/L, 1 to 30 minutes). AMPK activation by estradiol was independent of both AMP levels and ERalpha but required estradiol conversion to its catechol metabolites. Estradiol treatment increased eNOS catalytic activity, an effect that was largely reversed when endothelial cells were infected with an AMPK dominant-negative adenovirus. However, inhibition of AMPK did not alter estradiol-induced eNOS phosphorylation at serine 1177 or threonine 495 but decreased eNOS interaction with HSP90. Consistent with this observation, blood vessels from alpha1-AMPK-null mice exhibited defective eNOS-mediated NO production in response to estradiol. CONCLUSIONS: Taken together, these data indicate that AMPK activity is essential for estradiol-induced eNOS activation via the promotion of eNOS interaction with HSP90. These data point to a novel role for AMPK in modulating endothelial cell NO bioactivity and HSP90 function.

Adenylate Kinase↗
PubMed2005

Heterozygous deficiency of manganese superoxide dismutase in mice (Mn-SOD+/-): a novel approach to assess the role of oxidative stress for the development of nitrate tolerance.

Nitroglycerin (GTN)-induced tolerance was reported to be associated with increased levels of reactive oxygen species (ROS) in mitochondria. In the present study, we further investigated the role of ROS for the development of nitrate tolerance by using heterozygous manganese superoxide dismutase knock-out mice (Mn-SOD+/-). Mn-SOD is acknowledged as a major sink for mitochondrial superoxide. Vasodilator potency of mouse aorta in response to acetylcholine and GTN was assessed by isometric tension studies. Mitochondrial ROS formation was detected by 8-amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)dione sodium salt (L-012)-enhanced chemiluminescence and mitochondrial aldehyde dehydrogenase (ALDH-2) activity was determined by a high-performance liquid chromatography-based assay. Aortic rings from Mn-SOD+/- mice showed normal endothelial function and vasodilator responses to GTN. In contrast, preincubation of aorta with GTN or long-term GTN infusion caused a marked higher degree of tolerance as well as endothelial dysfunction in Mn-SOD+/- compared with wild type. Basal as well as GTN-stimulated ROS formation was significantly increased in isolated heart mitochondria from Mn-SOD+/- mice, correlating well with a marked decrease in ALDH-2 activity in response to in vitro and in vivo GTN treatment. The data presented indicate that deficiency in Mn-SOD leads to a higher degree of tolerance and endothelial dysfunction associated with increased mitochondrial ROS production in response to in vitro and in vivo GTN challenges. These data further point to a crucial role of ALDH-2 in mediating GTN bioactivation as well as development of GTN tolerance and underline the important contribution of ROS to these processes.

Aldehyde Dehydrogenase↗
PubMed2005

Differential effects of diabetes on the expression of the gp91phox homologues nox1 and nox4.

The nox2-dependent NADPH oxidase was shown to be a major superoxide source in vascular disease, including diabetes. Smooth muscle cells of large arteries lack the phagocytic gp91phox subunit of the enzyme; however, two homologues have been identified in these cells, nox1 and nox4. It remained to be established whether also increases in protein levels of the nonphagocytic NADPH oxidase contribute to increased superoxide formation in diabetic vessels. To investigate changes in the expression of these homologues, we measured their expression in aortic vessels of type I diabetic rats. Eight weeks after streptozotocin treatment, we found a doubling in nox1 protein expression, while the expression of nox4 remained unchanged. This was associated with a significant increase in the NADPH oxidase activity in membrane fractions of diabetic heart and aortic tissue. Furthermore, we observed a decreased sensitivity of diabetic vessels to acetylcholine and nitroglycerin and a decrease in both acetylcholine-stimulated NO production and phosphorylation of VASP, despite an increase in endothelial NO synthase (NOSIII) expression. In addition, xanthine oxidase activity was markedly increased in plasma and 100,000 g supernatant of cardiac tissue of diabetic rats, while myocardial mitochondrial superoxide formation was only weakly enhanced. We conclude that in addition to phagocytic NADPH oxidase, also nonphagocytic, vascular NADPH oxidase subunit nox1, uncoupled NOSIII, and plasma xanthine oxidase contribute to endothelial dysfunction in the setting of diabetes mellitus.

Acetylcholine↗
PubMed2005

Long-term course of adolescent schizophrenia.

Our study investigated premorbid functioning, course, and outcome in early-onset schizophrenia. All inpatients with DSM-III-R diagnoses of schizophrenia (n = 101) consecutively admitted between 1983 and 1988 to the Department of Child and Adolescent Psychiatry at the University of Marburg in Germany were included. To assess premorbid adaptation and precursor symptoms, we administered the Instrument for the Retrospective Assessment of the Onset of Schizophrenia, which we modified to assess children and adolescents. Symptomatology was measured by the Scale for the Assessment of Negative Symptoms, the Scale for the Assessment of Positive Symptoms, and the Brief Psychiatric Rating Scale. In addition, the Global Assessment of Functioning was applied. Followup data for 81 patients (80.2%) were available. The mean duration of schizophrenia at followup was 9.5 +/- 2.2 years. Assessment of the highest level of adaptive functioning revealed very good or good outcome in 19.8 percent of the patients, fair or poor outcome in 38.2 percent, and very poor outcome and gross impairment in 42.0 percent. Premorbid adjustment was the best predictor of outcome in our schizophrenia sample. A poor prognosis was found in patients with premorbid developmental delays and those who were introverted and withdrawn before their psychotic state.

Adolescent↗