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B Klein

Publications and source records attributed to B Klein.

At least 19 recordsLinked to original sources
PubMed2006

Mass spectral and NMR spectral data of two new designer drugs with an alpha-aminophenone structure: 4'-methyl-alpha-pyrrolidinohexanophenone and 4'-methyl-alpha-pyrrolidinobutyrophenone.

This study presents and discusses the nuclear magnetic resonance (NMR) spectroscopic and mass spectroscopic data of the new designer drug 4'-methyl-alpha-pyrrolidinobutyrophenone (MPBP) and its homolog 4'-methyl-alpha-pyrrolidinohexanophenone (MPHP) which were seized in 2004 and 2000 in Germany for the first time. The structure elucidation of the aliphatic part of MPBP was carried out by product ion spectroscopy of the immonium ion formed after electron ionization as well as with 1H and 13C NMR. Product ion spectroscopy of immonium ions again proved to be a powerful tool to determine the structure of designer drugs and to distinguish between isobaric structures of the alkyl-amino moiety.

Journal Article↗
PubMed2006

Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma.

The epidermal growth factor (EGF)/EGF-receptor (ErbB1-4) family is involved in the biology of multiple myeloma (MM). In particular, ErbB-specific inhibitors induce strong apoptosis of myeloma cells (MMC) in vitro. To delineate the contribution of the 10 EGF-family ligands to the pathogenesis of MM, we have assessed their expression and biological activity. Comparing Affymetrix DNA-microarray-expression-profiles of CD138-purified plasma-cells from 65 MM-patients and 7 normal individuals to those of plasmablasts and B-cells, we found 5/10 EGF-family genes to be expressed in MMC. Neuregulin-2 and neuregulin-3 were expressed by MMC only, while neuregulin-1, amphiregulin and transforming growth factor-alpha were expressed by both MMC and normal plasma-cells. Using real-time polymerase chain reaction, we found HB-EGF, amphiregulin, neuregulin-1 and epiregulin to be expressed by cells from the bone marrow-environment. Only the EGF-members able to bind heparan-sulphate proteoglycans (HSPGs) - neuregulin-1, amphiregulin, HB-EGF - promote the growth of MMC. Those ligands strongly bind MMC through HSPGs. The binding and the MMC growth activity was abrogated by heparitinase, heparin or deletion of the HS-binding domain. The number of HS-binding EGF ligand molecules bound to MMC was higher than 10(5) molecules/cell and paralleled that of syndecan-1. Syndecan-1, the main HSPG present on MM cells, likely concentrates high levels of HS-binding-EGF-ligands at the cell membrane and facilitates ErbB-activation. Altogether, our data further identify EGF-signalling as promising target for MM-therapy.

B-Lymphocytes↗
PubMed2006

Low doses of GM-CSF (molgramostim) and G-CSF (filgrastim) after cyclophosphamide (4 g/m2) enhance the peripheral blood progenitor cell harvest: results of two randomized studies including 120 patients.

The use of a combination of G-CSF and GM-CSF versus G-CSF alone, after cyclophosphamide (4 g/m2) was compared in two randomized phase III studies, including 120 patients. In study A, 60 patients received 5 x 2 microg/kg/day of G-CSF and GM-CSF compared to 5 mug/kg/day of G-CSF. In study B, 60 patients received 2.5 x 2 microg/kg/day G-CSF and GM-CSF compared to G-CSF alone (5 microg/kg/day). With the aim to collect at least 5 x 10(6)/kg CD34 cells in a maximum of three large volume leukapherises (LK), 123 LK were performed in study A, showing a significantly higher number of patients reaching 10 x 10(6)/kg CD34 cells (21/29 in G+GM-CSF arm vs 11/27 in G-CSF arm, P=0.00006). In study B, 109 LK were performed, with similar results (10/27 vs 15/26, P=0.003). In both the study, the total harvest of CD34 cells/kg was twofold higher in G-CSF plus GM-CSF group (18.3 x 10(6) in study A and 15.85 x 10(6) in study B) than in G-CSF group (9 x 10(6) in study A and 8.1 x 10(6) in study B), a significant difference only seen in multiple myeloma, with no significant difference in terms of mobilized myeloma cells between G-CSF and GM-CSF groups.

Adult↗
PubMed2005

Renal anemia aggravated by long-term parvovirus B19 and cytomegalovirus infection in a renal transplant patient: case report and evaluation of B19 seroprevalence in dialysis patients.

Due to viral replication in erythroid precursor cells, severe anemia represents a major complication of B19 infection. However, cytomegalovirus (CMV) is the leading cause of virus-induced complications with a significant impact on graft outcome of renal transplant patients. Herein, we present a long-term B19 infection in a 45-year-old female renal transplant patient, which aggravated the renal anemia associated with a concomitant CMV infection. Since no data were available on the seroprevalence of this virus in pretransplant patients, we determined the B19 serostatus of 90 dialyzed pretransplant adult subjects.

Adult↗
PubMed2005

Optimizing the use of anti-interleukin-6 monoclonal antibody with dexamethasone and 140 mg/m2 of melphalan in multiple myeloma: results of a pilot study including biological aspects.

Interleukin-6 (IL-6) is a major survival factor for multiple myeloma (MM) cells preventing apoptosis induced by dexamethasone (DEX) or chemotherapy. In all, 24 consecutive patients with MM in first-line therapy received DEX for 4 days, followed by melphalan (HDM: 140 mg/m2) and autologous stem cell transplantation (ASCT). The anti-IL-6 monoclonal antibody (mAb) (B-E8) was given till haematological recovery, starting 1 day before DEX. Results were historically compared to MM patients treated with HDM 140 and 200 mg/m2. Our results show (1) that B-E8 was able to fully neutralize IL-6 activity in vivo before and after HDM as shown by inhibition of C reactive protein (CRP) production; (2) no haematological toxicity; (3) a significant reduction of mucositis and fever; (4) a median event-free survival of 35 months and an overall survival of 68.2% at 5 years with a median follow-up of 72 months; and (5) the overall daily IL-6 production progressively increased on and after 7 days post-HDM, with the increased serum CRP levels. In the 5/24 patients with uncontrolled CRP production, a large IL-6 production was detected (320 microg/day) that could not possibly be neutralized by B-E8. These data show the feasibility to neutralize IL-6 in vivo with anti-IL-6 mAb in the context of HDM.

Adult↗
PubMed2004

[Transparency in patient care -- survey of bedsores on communal level to promote quality assurance].

The medical diagnosis of bedsores often applies to open wounds. These wounds are caused by constant pressure to the skin of seniors who cannot change their position in bed or wheelchair without help. In severe cases these wounds extend through all layers of the skin with involvement of muscle and underlying bone. These ulcers can be very painful, so the mobility and quality of life of seniors is thoroughly reduced. Treatment of ulcers costs annually millions of Euro in Germany alone. Primary prevention of bedsores has not yet been established neither in Germany nor in Europe. The first step to improve the situation in a scientific manner has been to set up a comparable database. In order to change that, the German community of Ostalbkreis (part of the German Federal state of Baden-Wurttemberg) developed a process of nursing quality assurance as a project of the local agenda 21, initiated and supported by the health office of the community. Annual networked and anonymous survey from 2001 to 2003, each lasting three months every year, proved that the rate of non stratified prevalence could be reduced. For example the rate of all day spent with bedsores within the community could be reduced from 1.96 % in 2001, to 1.74 % in 2002 and finally to 1.62 % in 2003. During the survey as an additional bonus cooperation of community-organized nursing was optimised and quality assurance in nursing became a pole position of the community. During the QM-process a software was developed to process the survey: it is internet-based, published in the nursing-guide of Ostalbkreis, easy to manage and to establish in any nursing institution or community.

Aged↗
PubMed2003

Irinotecan is active in chemonaive patients with metastatic gastric cancer: a phase II multicentric trial.

To assess the response rate and the tolerance of irinotecan as first-line therapy, 40 patients with metastatic gastric cancer received irinotecan 350 mg m(-2) every 3 weeks administered as a 30 min infusion. Among the 35 patients evaluable for response, two complete and five partial responses were recorded (response rate: 20.0% (95% CI:8.4-36.9%)). In total, 16 patients achieved stable disease and 12 progressive disease. In all, 66 percent of the patients benefited from tumour growth control. The median time to progression was 3.0 months (95% CI: 2.3-4.4%). The median overall survival was 7.1 months (95% CI: 5.2-9.0%). The probability of being alive at 6 months and 9 months was 61.0 and 32.4%, respectively. The median number of cycles per patient was 3 (range 1-14), and the relative dose intensity was 0.98. The most common grade 3-4 toxicities by patients were diarrhoea 20%, asthenia 10%, nausea 7.5%, vomiting 5.0%, abdominal pain 5%, neutropenia 38.5%, leucopenia 28.2%, anaemia 12.8% and thrombocytopenia 5.1%. Febrile neutropenia occurred in 12.5% of patients. These findings indicate that irinotecan is active and well tolerated in patients with metastatic gastric adenocarcinoma and warrants further evaluation in this clinical setting.

Adenocarcinoma↗
PubMed2003

[The German version of the Structured Inventory of Malingered Symptomatology: SIMS].

The current article addresses the psychometric qualities of the German version of the Structured Inventory of Malingered Symptomatology (SIMS), a self-report measure of malingering. The SIMS was administered to a heterogeneous sample of forensic patients (n=62) and undergraduate students (n=204). Within the student sample, some undergraduates were instructed to feign certain pathological conditions, while others were asked to respond honestly to the SIMS items. The findings indicate that the German version of the SIMS demonstrates adequate test-retest stability and internal consistency. In the patient sample, the SIMS was found to correlate strongly with manipulative and antisocial personality features. More specifically, SIMS scores were higher in sexually delinquent patients with antisocial personality disorders. Our findings support the SIMS as a valuable screening tool for malingering of psychiatric symptoms.

Adult↗
PubMed2002

[New avenues to quality assurance--a model project for recording bedsore incidence].

Bedsores can usually be avoided by adequate care and preventive measures. In the context of the local agenda process a local district office (Landratsamt) and inspection units initiated a variety of activities to promote sensitisation in health institutions and contribute to an increase in life quality of the persons concerned. Nearly all nursing care homes, domiciliary services and hospitals participated in a pilot study which was accompanied by the Fraunhofer IAO in Stuttgart. Objectives of the pilot study were to implement internal quality assurance to sensitise for persons the topic and to collect comparable data to achieve benchmarking. Software-tool institutions recorded data on care days, days spent with bedsores according to care level from July till September 01. Major result was that - although institutions had already a decreasing incidence in bedsores since the start of discussing the project - bedsore quotas could be further decreased from 2.15 to 1.84 %.

Aged↗
PubMed2002

Variation of esterase electromorphs associated with bloodmeal digestion in phlebotomine sand flies (Diptera: Psychodidae).

Esterases are often used to measure genetic variation, yet they may be influenced by external factors. Isoelectrofocusing was used to investigate the effects of bloodmeal on the esterase variation in wild populations of Phlebotomus (Larroussius) ariasi Tonnoir and P. (L.) perniciosus Newstead and in a colonized population of P. (Phlebotomus) duboscqi Neveu-Lemaire. Modified electrophoretic profiles were demonstrated to be associated with blood digestion. The bloodmeal-induced esterase electromorphs were only found in the abdomen homogenates of the sand flies. These changes in esterase phenotype were probably due to a proteolysis phenomenon and disappeared at the end of bloodmeal digestion. The effect was eliminated by adding trypsin inhibitors.

Animals↗
PubMed2001

Spinal prostaglandins are involved in the development but not the maintenance of inflammation-induced spinal hyperexcitability.

Prostaglandins (PGs) are local mediators of several functions in the CNS. Both primary afferent neurons and intrinsic cells in the spinal cord produce PGs, with a marked upregulation during peripheral inflammation. Therefore, the significance of spinal PGs in the neuronal processing of mechanosensory information was herein investigated. In anesthetized rats, the discharges of spinal nociceptive neurons with input from the knee joint were extracellularly recorded. Topical administration of prostaglandin E(2) (PGE(2)) to the spinal cord facilitated the discharges and expanded the receptive field of dorsal horn neurons to innocuous and noxious pressure applied to the knee joint, the ankle, and the paw, thus mimicking inflammation-induced central sensitization. Conversely, topical administration of the PG synthesis inhibitor indomethacin to the spinal cord before and during development of knee joint inflammation attenuated the generation of inflammation-induced spinal neuronal hyperexcitability. However, after development of inflammation, the responses of spinal neurons to mechanical stimuli were only reduced by systemic indomethacin but not by indomethacin applied to the spinal cord. Thus, spinal PG synthesis is important for the induction and initial expression but not for the maintenance of spinal cord hyperexcitability. Spinal PGE(2) application facilitated dorsal horn neuronal firing elicited by ionophoretic delivery of NMDA, suggesting that an interaction of PGs and NMDA receptors may contribute to inflammation-induced central sensitization. However, after development of inflammation, spinal indomethacin failed to reduce responses to ionophoretic delivery of NMDA or AMPA, suggesting that such an interaction is not required for the maintenance of central sensitization.

Action Potentials↗
PubMed2001

Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays.

In multiple myeloma (MM), the growth of primary plasma cells depends not only on interleukin-6 (IL-6), but also on additional unidentified signals delivered by the bone marrow environment. Using Atlas complementary DNA (cDNA) arrays comprising 268 genes coding for intercellular signaling molecules, this study identified genes that are overexpressed in myeloma cells compared to autologous B-lymphoblastoid cell lines. These genes encode the oncogenic Tyro3 tyrosine kinase receptor, the heparin-binding epidermal growth factor-like growth factor (HB-EGF) that is an epithelial autocrine tumor growth factor, the thrombin receptor (TR) that is linked to HB-EGF and syndecan-1 processing and to cell invasion, chemokine receptors CCR1 and CCR2, the Wnt pathway actor Frizzled-related protein (FRZB), and the Notch receptor ligand Jagged 2. These data, obtained with the Atlas cDNA array, were confirmed by reverse transcriptase-polymerase chain reaction or protein analysis or both. Furthermore, Tyro3, HB-EGF, TR, and FRZB gene expression was documented in purified primary malignant plasma cells from patients with plasma cell leukemia or MM. HB-EGF and FRZB were poorly expressed in purified polyclonal plasma cells. Finally, HB-EGF was proved to be an essential autocrine growth factor for the XG-1 myeloma cells. This study shows the potency and the biologic relevance of cDNA arrays used to analyze simultaneously a large panel of intercellular signaling genes and, by identifying several genes overexpressed in malignant plasma cells, opens new fields of investigation in MM biology. (Blood. 2001;98:771-780)

B-Lymphocytes↗
PubMed2001

Hyaluronic acid induces survival and proliferation of human myeloma cells through an interleukin-6-mediated pathway involving the phosphorylation of retinoblastoma protein.

Originating from a post-switch memory B cell or plasma cell compartment in peripheral lymphoid tissues, malignant myeloma cells accumulate in the bone marrow of patients with multiple myeloma. In this favorable microenvironment their growth and survival are dependent upon both soluble factors and physical cell-to-cell and cell-to-extracellular matrix contacts. In this report we show that hyaluronan (HA), a major nonprotein glycosaminoglycan component of the extracellular matrix in mammalian bone marrow, is a survival and proliferation factor for human myeloma cells. The effect of HA is mainly mediated through a gp 80-interleukin 6 (IL-6) receptor pathway by a CD44-independent mechanism, suggesting that HA retains and concentrates IL-6 close to its site of secretion, thus favoring its autocrine activity. In addition, we show that HA-mediated survival and proliferation of myeloma cells is associated with a down-regulation in the expression of p27(kip1) cyclin-dependent kinase inhibitor and a hyperphosphorylation of the retinoblastoma protein (pRb). These data suggest that HA could be an important component in the myeloma cell physiopathology in vivo by potentiating autocrine and/or paracrine IL-6 activities.

Apoptosis↗
PubMed2001

Optimizing therapeutic strategies to inhibit circulating soluble target molecules with monoclonal antibodies: example of the soluble IL-6 receptors.

Therapeutic targeting of soluble molecules such as cytokines can be achieved with monoclonal antibodies (mAb). Anti-IL-6 mAb have been shown to form circulating complexes, resulting in the increase of the half-life of the cytokine in vivo. In IL-6-related diseases, the soluble human IL-6 receptors (shIL-6R), which have been shown to possess strong agonist activity, circulate in the plasma at a high concentration and must be neutralized. Their clearance was studied in mice that had been made to express circulating shIL-6R after i.p. grafting of mouse thymoma cells transfected with a gene coding for shIL-6R, treated with various anti-shIL-6R mAb recognizing different epitopes of the molecule. Injection of one anti-hIL-6R mAb stabilized the short-lived hIL-6R and led to their accumulation. The same result was observed when two mAb directed against two different epitopes of the hIL-6R were used. Clearance of the receptors was only achieved when three mAb specific for three different epitopes were injected. A permanent clearing of the hIL-6R could be obtained by repeated injections of the clearing mixture. No correlation was found between the ability of the mAb to clear the sIL-6R and to immunoprecipitate them in agarose gel. The F(ab')2 fragments lost the clearing ability of the intact mAb. These results clearly show that therapeutic clearance of sIL-6R by mAb need at least three mAb directed against three different epitopes of the molecule, a conclusion which is likely to apply for clearing any soluble target molecule.

Animals↗
PubMed2001

DHPLC-based germline mutation screening in the analysis of the VHL tumor suppressor gene: usefulness and limitations.

In order to evaluate the sensitivity and specificity of the recently introduced high-throughput method DHPLC (denaturing high performance liquid chromatography) for mutation screening in the VHL tumor suppressor gene, we subjected DNA from 43 unrelated VHL patients with previously sequenced VHL germline mutations to this method. In addition, 36 genomic DNAs of unrelated individuals suspected of being VHL carriers but with unknown germline status were analyzed by DHPLC and sequencing. The aims of the present study were to compare mutation results obtained by direct sequencing and DHPLC, and a comparison of two different DHPLC systems. The sensitivity of DHPLC was tested with two commercial devices and protocols, i.e., the Varian-Helix system and the Wave Nucleic Acid Fragment Analysis system. Both resolved all but one mutation in exons 2 and 3 of the VHL gene. In contrast, the GC-rich exon 1 showed discrepancies in the rate of mutation detection. Whereas the Varian-Helix system detected 10/15 (67%) of the known mutations, the Wave Nucleic Acid Fragment Analysis system detected 13/14 (93%). All three mutations in samples with unknown mutation status were revealed by both systems raising the mutation detection rate to 72% and 94%, respectively. Cases with different substitutions at the same nucleotide showed different elution profiles, but similar elution profiles could be obtained from different mutations. The Wave Nucleic Acid Fragment Analysis system detected most VHL mutations; however, when a 100% detection rate is needed, sequencing is still required and must therefore be the standard VHL mutation detection procedure. Once a family-specific mutation has been established, DHPLC may be suitable for the rapid and cost-effective determination of VHL carrier status in family members.

Chromatography, High Pressure Liquid↗
PubMed2001

Inflammatory response to a porcine membrane composed of fibrous collagen and elastin as dermal substitute.

The inflammatory response to a collagen/elastin membrane was studied by measuring the expression of cytokines and function associated antigens in human macrophages. Additionally the angiogenic and inflammatory activity in the chorioallantoic membrane of the chick embryo (CAM-assay) was investigated. Macrophages cultured on the membrane expressed IL-1beta mRNA as early as after 4 hours. During prolonged culturing IL-1beta mRNA levels decreased. Messenger RNA for IL-8 was detectable over the whole culture period. The anti-inflammatory cytokine IL-10 was expressed up to one day only. Phenotypic analysis revealed a decrease in the number of chronic inflammatory 25F9 positive macrophages not migrating into the membrane but a presence of these cells together with the acute inflammatory 27E10 macrophages within the membrane whereas the anti-inflammatory subtype RM3/1 was absent. In the CAM-assay the membrane stimulated angiogenesis and induced the formation of granulation tissue. Histological analysis showed that the membrane was infiltrated with macrophages, fibroblasts and endothelial cells and locally with granulocytes. These data show that the collagen/elastin membrane causes activation of macrophages, angiogenesis and the formation of inflammatory tissue. Although these processes are essential for wound healing the type of inflammation points to a chronic process which might counteract an efficient scar formation.

Journal Article↗
PubMed2001

A temperature-sensitive disorder in basal transcription and DNA repair in humans.

The xeroderma pigmentosum group D (XPD) helicase subunit of TFIIH functions in DNA repair and transcription initiation. Different mutations in XPD give rise to three ultraviolet-sensitive syndromes: the skin cancer-prone disorder xeroderma pigmentosum (XP), in which repair of ultraviolet damage is affected; and the severe neurodevelopmental conditions Cockayne syndrome (CS) and trichothiodystrophy (TTD). In the latter two, the basal transcription function of TFIIH is also presumed to be affected. Here we report four unusual TTD patients with fever-dependent reversible deterioration of TTD features such as brittle hair. Cells from these patients show an in vivo temperature-sensitive defect of transcription and DNA repair due to thermo-instability of TFIIH. Our findings reveal the clinical consequences of impaired basal transcription and mutations in very fundamental processes in humans, which previously were only known in lower organisms.

Base Sequence↗