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Biomedical subjects

Martin Schaefer

Publications and source records attributed to Martin Schaefer.

18 recordsLinked to original sources
PubMed2006

Toll-like receptor 9 contributes to recognition of Mycobacterium bovis Bacillus Calmette-Guérin by Flt3-ligand generated dendritic cells.

Recognition of mycobacteria by the innate immune system is essential for the development of an adaptive immune response. Mycobacterial antigens stimulate antigen presenting cells (APCs) through distinct Toll-like receptors (TLRs) resulting in rapid activation of the innate immune system. The role of TLRs during infection with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) has been evaluated for TLR2 and TLR4 only. Surprisingly, despite the fact that immune stimulatory CpG-motifs have been originally derived from BCG, for the vaccine strain the role of TLR9 has not been addressed before. To identify the set of TLRs involved in the recognition of BCG, we infected bone marrow-derived macrophages and bone marrow-derived dendritic cells (Flt3-ligand generated DCs) from TLR2, TLR3, TLR4, TLR7, TLR9, MyD88 knockout, TLR2/4 and TLR2/4/9 multiple knockout mice. The degree of activation and stimulation was determined by TNFalpha, IL-6 and IL-12p40 ELISA. Activation of DCs was measured by surface expression of the costimulatory molecule CD86. We observed the most dramatic reduction of the inflammatory response for TLR2-deficient antigen presenting cells. Both macrophages and DCs produce markedly decreased amounts of TNFalpha and IL-6 in the absence of TLR2 whereas no significant reduction could be observed for TLR3, 4, 7, 9 single TLR-knockouts. However, IL-12 production in DCs appears not exclusively dependent on TLR2 and only in TLR2/4/9-deficient DCs BCG-induced IL-12 is reduced to background levels. Similarly, up-regulation of CD86 is abolished only in TLR2/4/9-deficient DCs supporting a role of TLR9 in the recognition of M. bovis BCG by murine dendritic cells.

Animals↗
PubMed2006

CrossLink: visualization and exploration of sequence relationships between (micro) RNAs.

CrossLink is a versatile tool for the exploration of relationships between RNA sequences. After a parametrization phase, CrossLink delegates the determination of sequence relationships to established tools (BLAST, Vmatch and RNAhybrid) and then constructs a network. Each node in this network represents a sequence and each link represents a match or a set of matches. Match attributes are reflected by graphical attributes of the links and corresponding alignments are displayed on a mouse-click. The distributions of match attributes such as E-value, match length and proportion of identical nucleotides are displayed as histograms. Sequence sets can be highlighted and visibility of designated matches can be suppressed by real-time adjustable thresholds for attribute combinations. Powerful network layout operations (such as spring-embedding algorithms) and navigation capabilities complete the exploration features of this tool. CrossLink can be especially useful in a microRNA context since Vmatch and RNAhybrid are suitable tools for determining the antisense and hybridization relationships, which are decisive for the interaction between microRNAs and their targets. CrossLink is available both online and as a standalone version at http://www-ab.informatik.uni-tuebingen.de/software.

Computer Graphics↗
PubMed2006

Cognitive impairment in patients with chronic hepatitis treated with interferon alpha (IFNalpha): results from a prospective study.

BACKGROUND: Treatment with low-dose interferon alpha (IFN-alpha) is often associated with neuropsychiatric side effects. In addition to depression and anxiety, IFN-alpha associated cognitive impairment significantly affects patient's mental health and quality of life. AIMS OF THE STUDY: To measure possible effects of low-dose IFN-alpha on cognitive functioning and its relationship to the development of depression and anxiety. METHOD: We prospectively followed 38 patients with a chronic hepatitis B or C by neuropsychological tests and psychiatric self-rating scales during 12 weeks of low-dose treatment with IFN-alpha. RESULTS: Before IFN-alpha treatment, neuropsychological tests as well as self-ratings in the Beck's Depression Inventory (BDI), the Hospital Anxiety and Depression Scale (HADS) and the Self-Report Symptom Inventory 90 Items-Revised (SCL-90-R) were within the normal range. Following 12 weeks of treatment with IFN-alpha resulted in a slight, but significant increase in depression scores. Neuropsychological assessment after 12 weeks of IFN-alpha treatment showed a significant decrease of the immediate recall in the Auditory-Verbal Learning Test (AVLT) and a significant reduction of words recited in the Controlled Oral Word Association Test (COWA). Cognitive impairment did not significantly correlate with depressive symptoms or anxiety. CONCLUSION: Our results indicate that even low-dose IFN-alpha induces cognitive impairment independent from depressive symptoms, which might be related to functional disturbances in the prefrontal cortex and the hippocampus. We suggest close monitoring of cognitive function during IFN-alpha treatment of chronic hepatitis.

Adult↗
PubMed2006

Psychiatric symptoms and cognitive dysfunction caused by Epstein-Barr virus-induced encephalitis.

Epstein-Barr virus (EBV) encephalitis is rare and shows a wide range of clinical manifestations. We report an immunocompromised patient with EBV encephalitis diagnosed by EBV-specific PCR and antibody testing in the cerebrospinal fluid who presented with psychiatric symptoms and cognitive dysfunction in the absence of any neurological impairments or infectious signs. Clinical recovery and clearance of cerebrospinal fluid EBV DNA appeared following ganciclovir treatment within 6 weeks.

Antiviral Agents↗
PubMed2006

Neuroprotective agents in schizophrenia and affective disorders.

With the exception of dementia, the use of neuroprotective agents in psychiatric disorders is not yet well established. However, recent data from brain imaging studies and clinical trials support the view that neurodegenerative mechanisms may play a role in the pathophysiology of schizophrenia and affective disorders. Further evidence for the use of neuroprotective agents can be drawn from the findings that second-generation antipsychotics, mood stabilizers and antidepressants have been shown to have neuroprotective effects in vitro and in vivo. Neuroprotective agents as add-on therapies (e.g., modafinil, erythropoietin, glycine, D-serine, memantine and celecoxib) are currently being evaluated in schizophrenia and related disorders. This paper reviews the current options for neuroprotective treatment approaches focusing on schizophrenia and affective disorders.

Animals↗
PubMed2006

Current schizophrenia drugs: efficacy and side effects.

Over the course of the past decade, the acceptance of several second-generation antipsychotics (SGAs) as effective medication for the treatment of schizophrenia has led to some changes. SGAs have a lower risk of inducing extrapyramidal side effects and tardive dyskinesia compared with first-generation antipsychotics, and have been said to be more successful in long-term treatment and tolerability. They also significantly improve the quality of life of schizophrenic patients. However, during treatment with SGAs other adverse effects can occur, such as weight gain, metabolic changes, sexual dysfunction and QTc-prolongation, significantly affecting the patient's physical health. Consequently, these side effects might be the reason that a high proportion of patients discontinue treatment with SGAs. Thus, from the authors' view, optimising individualised treatment implies increasing the efficacy of current schizophrenia drugs. This can be achieved by finding clinical or pharmacogenetic predictors for the most appropriate drug or drug combination, and by improving side-effect management in combination with non-pharmacological interventions in order to increase patients' quality of life and treatment compliance, possibly resulting in a better long-term outcome.

Antipsychotic Agents↗
PubMed2005

The progesterone derivative dydrogesterone down-regulates neurokinin 1 receptor expression on lymphocytes, induces a Th2 skew and exerts hypoalgesic effects in mice.

Accumulating evidence indicates that the neuropeptide substance P (SP) is predominantly involved in neurogenic inflammation and pain perception via its high-affinity neurokinin 1 receptor (NK-1R). Intriguingly, decreased pain sensitivity is found to be associated with high plasma progesterone levels. We hypothesize that progesterone may attenuate nociception and associated inflammatory response via NK-1R-dependent pathways. To address our hypothesis, we incubated splenic lymphocytes from CBA/J female mice with different concentrations of the progesterone derivative dydrogesterone. Subsequently, the expressions of NK-1R and T helper (Th1)-type cytokines were analyzed by flow cytometry. Next, we subcutaneously injected CBA/J mice with 1.25 mg of dydrogesterone in 200-microl sesame oil; control mice were sham-injected. Tail flick test to detect the nociceptive threshold was performed in 30-min intervals upon injection. Lymphocytes were isolated from blood and uterus and analyzed for NK-1R surface expression. Immunohistochemical analyses were performed to investigate the uterine tissue distribution of NK-1R. Dydrogesterone induced a decrease in the percentage of NK-1R+ lymphocytes in vitro and in vivo. Additionally, an increase in Th2-type and a decrease in Th1-type cytokines could be detected in vitro after incubation with dydrogesterone. An increased tail flick latency following dydrogesterone injection supported the concept that decreased expression of the NK-1R on lymphocytes is associated with an increased pain threshold. Taken together, these results clearly reveal a pathway by which dydrogesterone or progesterone respectively modulates the cross talk of the nervous, endocrine and immune systems in inflammation and pain.

Animals↗
PubMed2005

Prevention of interferon-alpha associated depression in psychiatric risk patients with chronic hepatitis C.

BACKGROUND/AIMS: Interferon-alpha (IFN-alpha) induced depression is a major limitation for the treatment of chronic hepatitis C, especially for patients with psychiatric disorders. We prospectively studied the efficacy of a pre-emptive treatment with the antidepressant citalopram to prevent depression during hepatitis C treatment with pegylated IFN-alpha-2b plus ribavirin. METHODS: 14 HCV infected patients with psychiatric disorders received a prophylactic medication with citalopram (20mg/day) before and during therapy with IFN-alpha. The incidence of major depression was compared with 22 HCV infected patients with psychiatric disorders (group B; n=11) and without psychiatric risk factors (group C; n=11), who underwent IFN-alpha treatment without a pre-emptive antidepressant therapy. Depression was diagnosed by DSM-IV criteria. RESULTS: Pre-treatment of psychiatric patients with citalopram significantly reduced the incidence of major depression during the first 6 months of antiviral treatment as compared to the two control groups (group A 14% vs. 64% and 55% in group B and C; log-rank 6.89; df=2; P=0.032). Patients who developed symptoms of major depression during IFN therapy could also be improved by antidepressive treatment. CONCLUSIONS: Our open label pilot study, though small, clearly indicates that IFN alpha induced depression in psychiatric risk patients can be ameliorated by both the use of antidepressants as well as by intensive psychiatric care. However, larger, double blind placebo controlled trials in other patient populations are required to confirm these preliminary findings.

Adult↗
PubMed2005

Zotepine loading in acute and severely manic patients: a pilot study.

OBJECTIVES: In clinical practice patients with severe mania (agitation, insomnia and aggressive behaviour) still receive effective, but often not well tolerated typical antipsychotics. The aim of this study was to test the first-generation atypical antipsychotic zotepine regarding its antimanic efficacy, tolerability and to find an adequate dosage for a loading strategy. METHOD: Twelve patients (seven male) with an acute and severe manic episode, according to DSM-IV, received zotepine loading in individual dosages (up to 600 mg/day) over a maximum period of 3 weeks. Clinical efficacy was measured using the Young-Mania Rating Scale (Y-MRS) total score. Response was defined as a 50% reduction in the Y-MRS score. Safety was assessed by systematic collection of data on side effects and weight; Hamilton Rating Scale for Depression (HAM-D) scores were used to detect a switch into depression. RESULTS: Two patients dropped out of the study after 2 days. Nine of ten patients (baseline mean Y-MRS: 45 +/- 7) were classified as responders, with five of them responding within 4 days. One patient did not respond sufficiently. No switch into a depressive episode occurred. CONCLUSIONS: This open pilot study suggests that zotepine with a median daily dosage of 250 mg/day is effective with a rapid therapeutic effect in severely manic patients. In general, patients tolerated the drug well; dose-dependent extrapyramidal side effects, an increase in weight and autonomic side effects occurred to a lesser degree. This is the first study assessing zotepine monotherapy in manic patients. Controlled studies are warranted.

Acute Disease↗
PubMed2004

Correlation between sICAM-1 and depressive symptoms during adjuvant treatment of melanoma with interferon-alpha.

Interferon-alpha (IFN-alpha) treatment is frequently complicated by symptoms of depression. The mechanism by which peripherally administered IFN-alpha enters and modulates the central nervous system remains unclear. The cell adhesion molecule ICAM-1 is involved in the regulation of blood-brain barrier (BBB) permeability. ICAM-1 expression was shown to increase during IFN-alpha treatment and recently the expression of ICAM-1 on vascular endothelial cells in the brain was found to be correlated with the development of depression. We therefore hypothesized that soluble ICAM-1 may be involved in the development of IFN-alpha associated depression. In a prospective study, serum levels of soluble ICAM-1 (double sandwich ELISA test) and symptoms of depression (SDS) were measured in 48 patients with malignant melanoma before and during adjuvant IFN-alpha treatment. Both, depression scores and the serum levels of sICAM-1 significantly increased after three months of IFN-alpha treatment compared to baseline levels (p < .001). Patients who developed depression (SDS-index scores > or = 50) after three months of treatment had higher sICAM-1 levels compared to non-depressed patients. Furthermore, sICAM-1 levels were positively correlated with SDS values (r = .367, p = .018). Our data provides evidence for an association between the induction of sICAM-1 and the development of symptoms of depression during IFN-alpha treatment, possibly by enhancing BBB-permeability.

Adjuvants, Immunologic↗
PubMed2004

Treatment of chronic hepatitis C in patients with drug dependence: time to change the rules?

AIMS: Approximately 170 million people world-wide are chronically infected with the hepatitis C virus (HCV). While the seroprevalence in the general population ranges between 0.2 and 2%, 50-90% of injection drug users are chronically HCV-infected. However, most patients who are drug abusers are still excluded from treatment of chronic HCV infection with interferon (IFN)-alpha. Due to the recent treatment advances resulting in sustained response rates between 50 and 80%, it becomes increasingly important to reflect the still existing contraindications and restrictions for IFN-alpha treatment, especially for patients with intravenous drug use (IDU) with or without psychiatric comorbidity. METHODS: We reviewed clinical trials that focus on the treatment of chronic hepatitis C in patients with drug addiction published between 1987 and 2003. FINDINGS: Only seven clinical trials investigating HCV treatment among drug users were found: four open prospective uncontrolled trials and three controlled trials. Thus far, no trials using pegylated IFN-alpha have been conducted. Data about sustained response and adherence in HCV-infected methadone substituted patients were either comparable to control groups or to representative clinically controlled trials using the same treatment regimen (IFN-alpha monotherapy or combined with ribavirin). Patients with former or present drug abuse seem more likely to discontinue treatment early. HCV-infected IDUs tended to be older with higher inflammatory activity and stage of fibrosis when interferon treatment was started. Psychiatric comorbidity did not negatively influence adherence or treatment outcome. CONCLUSIONS: There is no clinical evidence suggesting that HCV treatment with IFN-alpha should be limited to IDUs or methadone substituted patients. However, more prospective controlled trials on HCV treatment for patients with IDU are needed to establish and apply new rules and guidelines.

Antiviral Agents↗
PubMed2003

Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups.

Psychiatric disorders or drug addiction are often regarded as contraindications against the use of interferon alfa (IFN-alpha) in patients with chronic hepatitis C. Our aim was to obtain prospective data on adherence to as well as efficacy and mental side effects of treatment with IFN-alpha in different psychiatric risk groups compared with controls. In a prospective trial, 81 patients with chronic hepatitis C (positive hepatitis C virus[HCV] RNA and elevated alanine aminotransferase[ALT] level) and psychiatric disorders (n = 16), methadone substitution (n = 21), former drug addiction (n = 21), or controls without a psychiatric history or drug addiction (n = 23) were treated with a combination of IFN-alpha-2a 3 MU 3 times weekly and ribavirin (1,000-1,200 mg/d). Sustained virologic response (overall, 37%) did not differ significantly between subgroups. No significant differences between groups were detected with respect to IFN-alpha-related development of depressions during treatment. However, in the psychiatric group, significantly more patients received antidepressants before and during treatment with IFN-alpha (P <.001). Most of those who dropped out of the study were patients with former drug addiction (43%; P =.04) compared with 14% in the methadone group, 13% in the control group, and 18% in the psychiatric group. No patient in the psychiatric group had to discontinue treatment because of psychiatric deterioration. In conclusion, our data do not confirm the supposed increased risk for IFN-alpha-induced mental side effects and dropouts in psychiatric patients if interdisciplinary care and antidepressant treatment are available. Preexisting psychiatric disorders or present methadone substitution should no longer be regarded as contraindications to treatment of chronic hepatitis C with IFN-alpha and ribavirin in an interdisciplinary setting.

Adult↗
PubMed2002

Interferon alpha (IFNalpha) and psychiatric syndromes: a review.

Interferon alpha (IFNalpha) is used for the treatment of several disorders, such as chronic hepatitis or malignant melanoma. During the therapy, IFNalpha may cause severe neuropsychiatric syndromes including depression with suicidal ideation, paranoid psychoses, or confusional states. The reasons and management of these side effects are widely unknown. Our aim is to review research evidence for the contribution of IFNalpha for the etiopathology of psychiatric syndromes. Therefore, research findings of neuropsychiatric syndromes induced by IFNalpha treatment, the putative mechanisms underlying those syndromes, and their treatment are-reviewed. Furthermore, neuropsychiatric syndromes in diseases with high IFNalpha levels such as systemic lupus erythematosus (SLE) are discussed. Finally, the question is addressed whether IFNalpha may contribute to the etiopathology of endogenous psychiatric disorders. IFNalpha may cause psychiatric syndromes in a subset of treated patients. The underlying pathogenetic mechanisms include various effects on neuroendocrine, cytokine, and neurotransmitter systems. Research data on the role of IFNalpha in the pathogenesis of endogenous psychiatric disorders are conflicting. Future research should improve our understanding of the role of IFNalpha for the etiopathology of psychiatric syndromes and has an impact on treatment of IFNalpha-induced psychiatric syndromes.

Animals↗
PubMed2002

Acute antimanic efficacy and safety of oxcarbazepine in an open trial with an on-off-on design.

RATIONALE AND OBJECTIVES: Carbamazepine has shown reasonable antimanic properties, but its use has been limited because of enzyme-inducing effects. The keto-derivative oxcarbazepine (OXC) is very similar to carbamazepine, however, the metabolic pathway is different. OXC is not metabolized to the 10, 11-epoxide, which seems to be responsible for several undesirable side-effects of carbamazepine and furthermore OXC has less enzyme-inducing properties. METHODS: In this non-random open label study, patients were treated with OXC for 14 days, crossed over to no OXC for 7 days, and then crossed back over to OXC for the remaining 14 days. OXC was titrated to a final dose in a range of 900-2100 mg due to individual response. Treatment success was defined as a reduction of the original Young Mania Rating Scale (YMRS) score of more than 50% at the end of study period. RESULTS: Four of the 12 included patients (33%) met defined response criteria at the end of study period. Fifty percentage of the patients had to be prematurely excluded from the trial. The mean YMRS scores of the on-periods were obviously different from the off-period. Forty-two percentage of the patients experienced side-effects leading to premature discontinuation in two of 12 patients. CONCLUSION: Antimanic activity of OXC was demonstrated in this pilot study only for patients with mild or moderate manic symptoms. Further studies are encouraged to clarify OXC's role as mood-stabilizer and assess whether it has a profile similar to that of carbamazepine.

Adult↗