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Biomedical subjects

S Herzog

Publications and source records attributed to S Herzog.

At least 19 recordsLinked to original sources
PubMed2006

Improved protocol for treatment of pemphigus vulgaris with protein A immunoadsorption.

BACKGROUND: Pemphigus vulgaris is a life-threatening autoimmune blistering skin disease, usually treated with high-dose corticosteroids in combination with other immunosuppressants. However, this regimen may prove inadequate in severe cases and can cause dangerous side-effects. We have recently reported protein A immunoadsorption (PAIA) to be an effective adjuvant treatment for induction of remission in severe pemphigus. However, in a significant number of cases, the disease rapidly recurred once PAIA and immunosuppressive medication were tapered. AIMS: The aim of the present study was to develop a PAIA-based therapeutic regimen that would result in a more prolonged remission of pemphigus. METHODS: Nine patients with pemphigus vulgaris were treated with a modified protocol characterized by a combination of PAIA with a higher initial dose of systemic methylprednisolone (2 mg/kg). In addition, azathioprine or mycophenolate mofetil was administered as a steroid-sparing agent. RESULTS: In all nine patients treated with this regimen, we observed a sharp decline of circulating autoantibody levels and dramatic improvement of cutaneous and mucosal lesions within 4 weeks of therapy. The patients remained free of clinical disease for up to 26 months after PAIA treatment was discontinued. CONCLUSION: The improved treatment protocol appears to combine highly effective induction of clinical remission in severe or treatment-resistant pemphigus with a prolonged subsequent symptom-free interval.

Aged↗
PubMed2006

Functional analysis of the regulatory requirements of B-Raf and the B-Raf(V600E) oncoprotein.

The BRAF(V600E) mutation is found in approximately 6% of human cancers and mimics the phosphorylation of the kinase domain activation segment. In wild-type B-Raf (B-Raf(wt)), activation segment phosphorylation is thought to cooperate with negative charges within the N-region for full activation. In contrast to Raf-1, the N-region of B-Raf is constitutively negatively charged owing to the presence of residues D447/D448 and the phosphorylation of S446. Therefore, it has been suggested that this hallmark predisposes B-Raf for oncogenic activation. In this study, we demonstrate that neutralizing mutations of these residues (in particular S446 and S447), or uncoupling of B-Raf from Ras-guanine 5'-triphosphate (GTP), strongly reduce the biological activity of B-Raf in a PC12 cell differentiation assay. We also confirm that S365 is a 14-3-3 binding site, and determine that mutation of this residue rescues the impaired biological activity of B-Raf proteins with a neutralized N-region, suggesting that the N-region opposes a 14-3-3-mediated transition into an inactive conformation. However, in the case of B-Raf(V600E), although complete N-region neutralization resulted in a 2.5-fold reduction in kinase activity in vitro, this oncoprotein strongly induced PC12 differentiation or transformation and epithelial-mesenchymal transition of MCF-10A cells regardless of its N-region charge. Furthermore, the biological activity of B-Raf(V600E) was independent of its ability to bind Ras-GTP. Our analysis identifies important regulatory differences between B-Raf(wt) and B-Raf(V600E) and suggests that B-Raf(V600E) cannot be inhibited by strategies aimed at blocking S446 phosphorylation or Ras activation.

14-3-3 Proteins↗
PubMed2006

The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells.

SLP65 represents a critical component in (pre-) B cell receptor signal transduction but is compromised in a subset of pre-B cell-derived acute lymphoblastic leukemia. Based on these findings, we investigated (i.) whether SLP65-deficiency also occurs in mature B cell-derived lymphoma and (ii.) whether SLP65-deficient B cell lymphoma cells use an alternative B cell receptor signaling pathway in the absence of SLP65. Indeed, expression of SLP65 protein was also missing in a fraction of B cell lymphoma cases. While SLP65 is essential for B cell receptor-induced Ca2+ mobilization in normal B cells, B cell receptor engagement in SLP65-deficient as compared to SLP65-reconstituted B cell lymphoma cells resulted in an accelerated yet shortlived Ca2+-signal. B cell receptor engagement of SLP65-deficient lymphoma cells involves SRC kinase activation, which is critical for B cell receptor-dependent Ca2+-mobilisation in the absence but not in the presence of SLP65. As shown by RNA interference, the SRC kinase LYN is required for B cell receptor-induced Ca2+ release in SLP65-deficient B cell lymphoma cells but dispensable after SLP65-reconstitution. B cell receptor engagement in SLP65-deficient B cell lymphoma cells also resulted in tyrosine-phosphorylation of the proliferation- and survival-related MAPK1 and STAT5 molecules, which was sensitive to silencing of the SRC kinase LYN. Inhibition of SRC kinase activity resulted in growth arrest and cell death specifically in SLP65-deficient lymphoma cells. These findings indicate that LYN can short-circuit conventional B cell receptor signaling in SLP65-deficient B cell lymphoma cells and thereby promote activation of survival and proliferation-related molecules.

Adaptor Proteins, Signal Transducing↗
PubMed2006

BCR-ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells.

Pre-B lymphoblastic leukemia cells carrying a BCR-ABL1 gene rearrangement exhibit an undifferentiated phenotype. Comparing the genome-wide gene expression profiles of normal B-cell subsets and BCR-ABL1+ pre-B lymphoblastic leukemia cells by SAGE, the leukemia cells show loss of B lymphoid identity and aberrant expression of myeloid lineage-specific molecules. Consistent with this, BCR-ABL1+ pre-B lymphoblastic leukemia cells exhibit defective expression of IKAROS, a transcription factor needed for early lymphoid lineage commitment. As shown by inducible expression of BCR-ABL1 in human and murine B-cell precursor cell lines, BCR-ABL1 induces the expression of a dominant-negative IKAROS splice variant, termed IK6. Comparing matched leukemia sample pairs from patients before and during therapy with the BCR-ABL1 kinase inhibitor STI571 (Imatinib), inhibition of BCR-ABL1 partially corrected aberrant expression of IK6 and lineage infidelity of the leukemia cells. To elucidate the contribution of IK6 to lineage infidelity in BCR-ABL1+ cell lines, IK6 expression was silenced by RNA interference. Upon inhibition of IK6, BCR-ABL1+ leukemia cells partially restored B lymphoid lineage commitment. Therefore, we propose that BCR-ABL1 induces aberrant splicing of IKAROS, which interferes with lineage identity and differentiation of pre-B lymphoblastic leukemia cells.

Alternative Splicing↗
PubMed2006

Eosinophilic folliculitis in a Caucasian patient: association with toxocariasis?

Sterile eosinophilic folliculitis, a clinical entity first described by Ofuji in 1970, is a rather rare skin disorder, in particular in the non-Asian population. We report the first case of eosinophilic folliculitis associated with toxocariasis in a Caucasian patient. Topical and systemic anti-inflammatory and antiphlogistic therapy along with systemic antihelminthic treatment resulted in complete remission of the skin lesions. In addition, there was a marked decrease of antibodies to Toxocara antigens in the patient's serum following antihelminthic therapy. Given that (I) some cases of eosinophilic folliculitis have been reported which were associated with infestation with metazoan parasites; (2) infestations with the roundworm Toxocara canis are known to induce eosinophilic reactions in some tissues; and (3) therapy-induced remission of eosinophilic folliculitis was accompanied by a decrease of Toxocara-directed antibodies in the patient's serum, we propose that there is an aetiopathogenic link between toxocariasis and eosinophilic folliculitis in this patient.

Albendazole↗
PubMed2003

Protein A immunoadsorption: a novel and effective adjuvant treatment of severe pemphigus.

BACKGROUND: Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are autoimmune blistering skin diseases usually treated with high-dose systemic corticosteroids and other immunosuppressants that may cause severe side-effects. Plasmapheresis also has been demonstrated to be of benefit in the treatment of pemphigus. In contrast to plasmapheresis, staphylococcal protein A immunoadsorption (PA-IA) specifically removes immunoglobulin from the circulation, allows treatment of larger plasma volumes, and does not require the substitution of plasma components. OBJECTIVES: To determine the effectiveness and side-effects of PA-IA in patients with severe pemphigus. METHODS: Five patients with severe pemphigus (PV, n = 4; PF, n = 1) were treated by PA-IA. Three of these patients had been refractory to various treatment regimens. In addition to PA-IA, methylprednisolone, 0.5 mg x kg-1 body weight day-1 was given initially and subsequently tapered. RESULTS: In all patients, a dramatic clinical improvement was seen within 2 weeks after initiation of therapy. Patients were free of lesions after 3, 4, 4, 10 and 21 weeks of treatment, respectively. Concurrently, autoantibody levels decreased rapidly. CONCLUSIONS: PA-IA is a rational, effective, and safe adjuvant therapy for severe pemphigus and warrants wider use for this indication. A controlled study should compare side-effects and effectiveness of PA-IA with other treatment options for pemphigus.

Adjuvants, Immunologic↗
PubMed2001

Marked differences in unilateral isolated retinoblastomas from young and older children studied by comparative genomic hybridization.

Although it is established that the loss of function of both alleles of the RB1 gene is a prerequisite for the development of retinoblastoma, little is known about the genetic events that are required for tumor progression. We used comparative genomic hybridization (CGH) to search for DNA copy number changes in isolated unilateral retinoblastomas. From a series of 66 patients with retinoblastomas with somatic mutations in both RB1 alleles, tumor samples from 13 children with the youngest (2.0-9.8 months) and 13 with the oldest (36.2-84.1 months) age at operation were studied. Loss at 13q14, the location of RB1, was demonstrated in two tumors only. Recurring chromosome imbalances included gains at 6p (11/26), 1q (10/26), 2p (4/26), and 17q (4/26), gains of the entire chromosome 19 (3/26), and losses at 16q (9/26). A commonly gained region at 1q32 was identified. Increased dosage of GAC1, a candidate oncogene located in 1q32, was found in two of four tumors by Southern blot analysis. Comparison of the CGH findings revealed that retinoblastomas from children with an older age at operation showed significantly more frequent (13/13 cases vs 4/13 cases; P = 0.0005) and more complex genetic abnormalities (median, 5 changes/abnormal tumor vs median, 1.5 changes/abnormal tumor; P = 0.003) than retinoblastomas from children with a young age at operation. Gains at 1q, 2p, 17q, of the entire chromosome 19 and losses of 16q were restricted to the older age group. Our results suggest that the progression of retinoblastomas from older patients follows mutational pathways different from those of younger patients.

Blotting, Southern↗
PubMed2001

Low avidity of human serum antibodies for Borna disease virus antigens questions their diagnostic value.

Borna disease virus (BDV) can induce neurological disease in animals. Since viral nucleic acid, infectious particles and antibodies recognizing BDV antigens were found at higher frequencies in psychiatric patients than in healthy controls, BDV is suspected to cause psychiatric disorders in humans. However, the human origin of these viruses has recently been questioned. To diagnose BDV infections, sera are usually analyzed for antiviral antibodies by indirect immunofluorescence (IFA) on virus-infected cells. This study reveals that the reactive antibodies in human sera mainly recognized the BDV phosphoprotein, whereas animal sera preferentially detected the viral nucleoprotein. Immunoglobulin (Ig) G in sera of experimentally or naturally infected animals bound to the viral antigen with high avidity, ie resisting 3 M urea, whereas reactive IgG in human sera did not. Longitudinal studies showed that reactive human antibodies persisted for many years without gaining high avidity for BDV antigens, indicating that they were probably not induced by BDV but rather by infection with an antigenically related microorganism of unknown identity or by exposure to other related immunogens.

Animals↗
PubMed2000

Borna disease virus and schizophrenia in Surinamese immigrants to the Netherlands.

Borna disease virus (BDV) has been suggested to play a role in the etiology of schizophrenia. We tested the hypothesis that markers of BDV infection are more frequent in Surinamese immigrants to the Netherlands, diagnosed with schizophrenia, than in Dutch-born healthy subjects. For reasons that are poorly understood there is an increased incidence of schizophrenia in this immigrant group. Blood was obtained from 29 male schizophrenic patients (DSM-IV criteria) and from 26 healthy males. For detection of anti-BDV antibodies an indirect immunofluorescence assay (IFA) was performed. A nested, reverse-transcriptase-PCR, using primers specific for the p24 and p40 BDV genes, was used to determine BDV-RNA in peripheral blood mononuclear cells. Contrary to our expectations, the frequencies of BDV markers in the group of healthy subjects, as determined by IFA and both PCRs, exceeded that in the group of patients. The results do not support an association between markers of BDV infection in blood and schizophrenia. It is unlikely that the high incidence of schizophrenia in Surinamese immigrants is caused by BDV, but the small number of subjects examined do not warrant definitive conclusions.

Antibodies, Viral↗
PubMed2000

Borna disease in horses.

Borna disease is a sporadically occurring, progressive viral polioencephalomyelitis that primarily affects horses and sheep. The etiological agent, Borna disease virus (BDV), is an enveloped, single-stranded RNA virus that has been classified in the new virus family Bornaviridae within the order Mononegavirales. Serological evidence of BDV infection has been found in an increasing number of countries throughout the world. After an incubation period lasting a few weeks to several months, BDV infection can cause locomotor and sensory dysfunction followed by paralysis and death. Borna disease is the result of a virus-induced immunopathological reaction. BDV-specific antibodies and viral RNA have been found in humans with various psychiatric disorders.

Animals↗
PubMed2000

Distribution of Borna disease virus in the brain of rats infected with an obesity-inducing virus strain.

Experimental infection of Lewis rats with Borna disease virus (BDV), a nonsegmented, single-stranded RNA virus, usually causes an immune-mediated biphasic neurobehavioral disorder. Such animals develop a persistent infection of the CNS with viral antigen expression in all brain regions and a disseminated nonpurulent meningoencephalitis. Interestingly, intracerebral infection of Lewis rats with a BDV-variant (BDV-ob) causes a rapid increase of body weight with the development of an obesity syndrome without obvious neurological signs. The obese phenotype is correlated with a characteristic distribution of inflammatory lesions and BDV-antigen in the rat brain. Infiltration with mononuclear immune cells and viral antigen expression are restricted to the septum, hippocampus, amygdala and ventromedian tuberal hypothalamus. Therefore, infection with the obesity-inducing BDV-ob results most likely in neuroendocrine dysregulations leading to the development of an obesity syndrome. This might be due to the restriction of viral antigen expression and inflammatory lesions to brain areas which are involved in the regulation of body weight and food intake. The BDV-induced obesity syndrome represents a model for the study of immune-mediated neuroendocrine disorders caused by viral infections of the CNS.

Animals↗
PubMed1999

Pulsatile vs. continuous parenteral tocolysis: comparison of side effects.

Bolus tocolysis has been developed to reduce the dose of fenoterol compared to continuous tocolysis. Whereas the high efficacy of pulsatile application of fenoterol has been shown, the proof of reduced side effects is still lacking. A total of 59 patients with preterm labor were divided in three groups: (1) continuous tocolysis and oral application of magnesium (n=19), (2) continuous tocolysis and parenteral application of magnesium (n=20), (3) pulsatile tocolysis (bolus tocolysis) and oral application of magnesium (n=20). Heart rate, systolic and diastolic blood pressure, serum K+ and serum Mg++ were quantified before tocolysis and after 2, 8 and 24 h. Beta-blockers and water balance were recorded over 24 h. Subjective side effects were quantified using a questionnaire with scales graduated covering palpitations, tremor, diaphoresis, thirst, precardialgia and nausea/vomiting. The analysis of the data revealed significantly fewer side effects concerning heart rate, plasma K+ level and the subjective side effects among patients treated with bolus tocolysis than among those treated with continuous tocolysis. Between the latter two groups, no significant difference was found. Concerning blood pressure and need for beta-blockers, no significant differences were found between the three groups. The results of the present study show that especially the side effects subjectively found to be disagreeable by the patients are reduced by pulsatile tocolysis, whereas other side effects show only slight differences between the study groups.

Adrenergic beta-Antagonists↗