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Biomedical subjects

P Schmidt

Publications and source records attributed to P Schmidt.

At least 73 records · Page 4Linked to original sources
PubMed2000

In vivo depletion of B cells using a combination of high-dose cytosine arabinoside/mitoxantrone and rituximab for autografting in patients with non-Hodgkin's lymphoma.

We performed a pilot study including rituximab (Mabthera; IDEC-C2B8, Hoffmann-La Roche) with a sequential high-dose therapy protocol in 15 patients with follicular and three patients with mantle cell lymphoma and studied the potential of the chemoimmunotherapy to induce depletion of malignant B cells in vivo. Our treatment protocol included induction with three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy, followed by peripheral blood stem cell (PBSC) mobilization using high-dose cytosine arabinoside (2 g/m2 every 12 h, days 1 and 2) and mitoxantrone (10 mg/m2, days 2 and 3) (HAM), preceeded by rituximab (375 mg/m2). The proportion of CD19+ B cells in blood and bone marrow decreased from 1.2 +/- 0.4% to 0.13 +/- 0. 1% (P = 0.01) and from 2.7 +/- 0.8% to 0.8 +/- 0.5% (P = 0.03) respectively. The number of t(14;18)-positive cells in blood and bone marrow progressively decreased with treatment, as assessed by the quantitative real-time PCR assay in four patients. Conversion to PCR-negativity was achieved in the peripheral blood (PB) of seven informative patients. Leucaphereses were performed during the granulocyte colony-stimulating factor (G-CSF)-supported leucocyte recovery phase. In 17 of 18 patients, a median of 15.1 x 106 CD34+ cells/kg body weight (BW) could be harvested by a single procedure for enrichment by an immunomagnetic method. Leucapheresis products contained 51.3 +/- 28.8 x 104 CD19+ B cells/kg BW (mean) and were t(14;18) PCR negative in all seven informative patients. These data compare favourably with results obtained in patients treated with the same regimen without rituximab. The high-dose therapy (n = 12 patients), including total body irradiation (14.4 Gy) and cyclophosphamide (200 mg/kg BW), was also preceeded by rituximab. Recovery of neutrophils to > 0.5 x 109/l and of platelets to > 20 x 109/l required a median of 13.5 and 11.5 d (range 11-24 and 9-24 d) respectively. In conclusion, the addition of the CD20 antibody to chemotherapy ensured tumour depletion in vivo and allowed the collection of PBSCs devoid of tumour cells and with conserved engraftment capability.

Adult↗
PubMed2000

Fenoterol hydrobromide delivered via HFA-MDI or CFC-MDI in patients with asthma: a safety and efficacy comparison.

The main objective of the study was to compare the long-term safety and tolerability of fenoterol hydrobromide delivered using a metered-dose inhaler formulated with the alternative propellant, hydrofluoroalkane 134a (HFA-MDI), with delivery using the currently available chlorofluorocarbon MDI (CFC-MDI; Berotec 100). A further objective was to compare the efficacy of fenoterol HFA-MDI with fenoterol CFC-MDI, using the pulmonary function parameters of forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF). Following a 2-week run-in phase, a 12-week, double-blind parallel group comparison was undertaken in 290 patients randomized on a 2:1 basis to two puffs of 100 microg fenoterol four times a day (HFA-MDI=197 patients; CFC-MDI=93 patients). A total of 236 patients in this multi-centre study completed the trial as planned. The overall incidence of adverse events (AEs) was similar in both groups (29.9% of HFA-MDI patients and 28% of CFC-MDI patients). Reports of respiratory disorder AEs were also comparable (21.8% HFA-MDI; 22.6% CFCMDI). End of study laboratory tests, ECG, pulse, blood pressure and physical examination showed no significant differences from pre-study baselines in either group and both treatments appeared to be well tolerated. Pre-dose FEV1 measurements taken at the three clinic visits were constant and increase in FEV1 at 5 and 30 min post-dose demonstrated equivalent efficacy for the two formulations. No difference between the two groups was observed in PEF or in the use of rescue medication. We conclude from these findings that the long-term safety and efficacy profile of fenoterol HFA-MDI is comparable to that of the fenoterol CFC-MDI.

Adolescent↗
PubMed2000

[Legal principles and discretionary power regarding official autopsy order (administratively determined dissection)].

In Germany, autopsies can be ordered by the representatives of the board of health according the Epidemics Law as so called administrative autopsy. If the autopsy is not absolutely necessary, it is mandatory to take into consideration the rights of the deceased persons as well as the rights of the relatives. The decisions of the legislature concerning clinical autopsies must also be considered. The juridical aspects and different types of organising the interrogation of the relatives are explained.

Adult↗
PubMed2000

Adjuvant effects of various lipopeptides and interferon-gamma on the humoral immune response of chickens.

The adjuvant effects of various lipopeptides and recombinant chicken interferon gamma (IFN-gamma) on the humoral immune response of laying hens was investigated in four immunization studies. We used the lipopeptide Pam3Cys-Ser-(Lys)4 (PCSL), the conjugate P-Th1 consisting of the lipopeptide P3CS and the T-helper epitope Th1 (FISEAIIHVLHSRHPG), and the conjugate P-Th2 of the lipopeptide P3CSS and the T-helper epitope Th2, which corresponds to the peptide EWEFVNTPPLV, as adjuvants. Human serum albumin (HSA), recombinant bovine somatotropin (RBST), and human immunoglobulin G (IgG) served as antigens in the different experiments. All tested adjuvants enhanced the humoral immune response with various intensities. Chickens showed high antibody titers after the immunization with HSA even without adjuvant, but the adjuvant effects of PCSL and the combination of PCSL and recombinant chicken interferon-gamma (IFN-gamma) were much more pronounced using the antigens RBST and IgG. Especially after the third immunization, higher titers of antibodies were induced by the coadministration of P-Th1 and, to a greater extent, by the combination of PCSL and P-Th1 compared with the use of PCSL. Also, chickens that had received PCSL and P-Th2 showed the highest immune response, even after the second booster. The average concentrations of chicken immunoglobulin Y were significantly higher in 5-mo-old chickens (9.4 mg/mL serum and 10.1 mg/mL egg yolk) compared with 9-mo-old chickens (5.9 mg/mL serum and 5.1 mg/mL egg yolk). The specific serum antibody response was higher in the older chickens than in the younger chickens. Because chicken antibodies are likely to be used increasingly for diagnostic and therapy in the future, lipopeptides and recombinant chicken IFN-gamma may find many applications as adjuvants, thus contributing to the welfare of experimental animals.

Adjuvants, Immunologic↗
PubMed2000

Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling.

Lysosomal cysteine proteinases of the papain family are involved in lysosomal bulk proteolysis, major histocompatibility complex class II mediated antigen presentation, prohormone processing, and extracellular matrix remodeling. Cathepsin L (CTSL) is a ubiquitously expressed major representative of the papain-like family of cysteine proteinases. To investigate CTSL in vivo functions, the gene was inactivated by gene targeting in embryonic stem cells. CTSL-deficient mice develop periodic hair loss and epidermal hyperplasia, acanthosis, and hyperkeratosis. The hair loss is due to alterations of hair follicle morphogenesis and cycling, dilatation of hair follicle canals, and disturbed club hair formation. Hyperproliferation of hair follicle epithelial cells and basal epidermal keratinocytes-both of ectodermal origin-are the primary characteristics underlying the mutant phenotype. Pathological inflammatory responses have been excluded as a putative cause of the skin and hair disorder. The phenotype of CTSL-deficient mice is reminiscent of the spontaneous mouse mutant furless (fs). Analyses of the ctsl gene of fs mice revealed a G149R mutation inactivating the proteinase activity. CTSL is the first lysosomal proteinase shown to be essential for epidermal homeostasis and regular hair follicle morphogenesis and cycling.

Alopecia↗
PubMed2000

The vasodilator-stimulated phosphoprotein (VASP): target of YC-1 and nitric oxide effects in human and rat platelets.

The effects of the different types of soluble guanylate cyclase (sGC) stimulators on the phosphorylation status of vasodilator-stimulated phosphoprotein (VASP) in both human and rat platelets were studied under in vitro and in vivo conditions. sGC-dependent VASP phosphorylation (at Ser(239) and Ser(157)) both by the new direct sGC stimulator YC-1 and by NO donors was examined by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS/PAGE) with different antibodies. One antibody, which recognizes VASP independent of its phosphorylation state, was used to detect the mobility shift of VASP caused by Ser(157) phosphorylation. The other antibody was specifically directed against VASP phosphorylated at Ser(239), the cGMP-dependent protein kinase (PKG) preferred phosphorylation site of VASP. In vitro YC-1 increased both VASP phosphorylation and cyclic guanosine monophosphate (cGMP) levels as did the NO donors 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO) and sodium nitroprusside (SNP). The combination of both types induced a synergistic effect in both VASP phosphorylation and cGMP increase. In rat platelets, similar effects could be shown in vitro. In vivo we observed a significant increase in cGMP and a distinct effect on VASP phosphorylation in rat platelets 1 h after oral administration of YC-1. These biochemical alterations are supported by a significant prolongation in rat-tail bleeding time. Direct stimulators of sGC like YC-1 are on the one hand direct potent stimulators of the cGMP/PKG/VASP pathway in platelets and on the other hand synergize with NO, the physiologic stimulator of sGC. Therefore YC-1-like substances are interesting tools for the development of new cardiovascular drugs with vasodilatory and antithrombotic properties.

Animals↗
PubMed2000

Cervical neoplasia originating from the vagus nerve in a dog.

An eight-year-old intact male Bernese mountain dog was referred with a history of chronic vomiting, coughing and signs of respiratory distress. Other historical findings included lethargy, weight loss and choking. On presentation, clinical findings were Horner's syndrome, ipsilateral laryngeal hemiplegia, coughing, gagging, respiratory distress and vomiting. Lateral cervical radiographs showed ill-defined mineralisation in the soft tissue ventral to the third cervical vertebra, while ultrasonography of the neck revealed a well marginated heterogeneous mass with focal hyperechogenic lesions and acoustic shadowing. Results of an ultrasound-guided fine needle aspirate suggested neoplasia. At necropsy, a large tumour was detected in the ventral cervical region, originating from the right vagosympathetic trunk. In view of the infiltrating pattern, the cellular pleomorphism and the numerous mitoses on histopathological examination, the tumour was classified as a malignant peripheral nerve sheath tumour.

Animals↗
PubMed1999

Mutation induction by different types of radiation at the Hprt locus.

Mutation induction at the Hprt locus in Chinese hamster cells was studied after exposure to ultraviolet light, X-rays and alpha particles. While mutant frequency as a function of dose or fluence followed a linear-quadratic relationship with UV and X-rays, it showed a linear dependence for alpha particles. If mutant frequency is plotted vs. the logarithm of surviving fraction, a linear relationship is found in all cases although with different slopes. These are about equal with the two types of ionising radiations but about 10 times larger for UV. They can be used as a measure of mutagenic potential and are termed mutagenicity. It is shown that this parameter is correlated with the maximum of mutant yield, i.e., the number of mutants per cell at risk. It is concluded from this analysis that the maximum mutant yield is always found at doses or fluences which lead to 37% survival irrespective of the kind of radiation. If mutation induction is measured in X-irradiated cells after pre-exposure to UV, mutant frequency is higher than expected on the basis of independent action of the two radiations. Deletion spectra were determined by using multiplex polymerase chain reaction. It was found that the background of spontaneous mutants varied considerably and showed frequently repetitive patterns, presumably because of clonal expansion of pre-formed mutants. UV-induced mutants did not contain any deletions, while those with both X-rays and alpha particles the majority displayed partial and total deletions. Based on a total number of 134 X-ray- and 192 alpha-induced mutants, it is concluded that the total fraction of mutant clones without deletions (partial or total) is about 40% for X-rays and only about 20% for alpha-particles.

Alpha Particles↗
PubMed1999

Fatality caused by a combined trimipramine-citalopram intoxication.

A 53-year-old woman who was diagnosed as suffering from depression was found dead in her bed. The autopsy revealed no morphological changes sufficient to explain death. Toxicological analysis was performed and the drugs trimipramine (2.33 mg/l), citalopram (4.81 mg/l) and zolpidem (0.07 mg/l) were identified in the femoral blood. A combined drug intoxication resulting in synergistic effects to cardiovascular disorders was proposed as the cause of death. An acute overdose and suicide was suggested by calculation of the parent drug to main metabolite ratios in femoral blood and liver tissue. The trimipramine to desmethyltrimipramine ratios were calculated to be 2.06 and 3.18, the citalopram to desmethylcitalopram ratios were 1.96 and 2.02.

Antidepressive Agents, Second-Generation↗
PubMed1999

A systematic regional study of dopamine and dopamine-derived salsolinol and norsalsolinol levels in human brain areas.

Dopamine and the dopamine-derived tetrahydroisoquinoline alkaloids salsolinol and norsalsolinol were measured by high-performance liquid chromatography with electrochemical detection in 15 regions of the human brain. The regional distribution of dopamine in 32 brains was similar to previous reports with highest concentrations in the basal ganglia, especially in the striatum, followed by the substantia nigra and the hypothalamus. Significant amounts of salsolinol and norsalsolinol were only found in these dopamine-rich areas, whereas in the other regions no alkaloids were detected. These findings suggest that the concentration of the substrate dopamine may determine the alkaloid level during in vivo formation.

Adult↗
PubMed1999

Suppression of interleukin-12 production by human monocytes after preincubation with lipopolysaccharide.

Interleukin-12 (IL-12) is a potent proinflammatory and immunoregulatory cytokine skewing T lymphocytes to express a type 1 cytokine pattern. Optimal expression of IL-12 mRNA and bioactivity in vitro requires specific priming of monocytes by interferon-gamma (IFN-gamma) or granulocyte-macrophage colony-stimulating factor (GM-CSF) before lipopolysaccharide (LPS) stimulation. We show here for the first time that the production of IL-12 by IFN-gamma- or GM-CSF-primed human monocytes can be completely suppressed by preincubation with LPS (from Escherichia coli Serotype 055:B5) for 6 to 24 hours before the priming procedure. A dose-dependent suppression of IL-12p70 was measured on the levels of intracellular cytokine production and cytokine secretion. mRNA studies on the expression of p40 and p35 showed an LPS-induced downregulation of both subunits. The results of several different experimental approaches suggest that IL-12 downregulation was not due to endogenous IL-10, IL-4, prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha), or nitric oxide (NO) production induced by LPS. Moreover, preincubation of monocytes with LPS did not lead to a downregulation of the CD14 antigen, which is an LPS receptor. LPS preincubation in this experimental setting did not result in a general hyporesponsiveness of the monocytes, as IL-6 production as well as IFN-gamma-induced upregulation of CD54 did not decline. Downregulation of IL-12 was not due to changes in mRNA stability. These findings show that the immunoregulatory important cytokine, IL-12, underlies itself a complex regulation.

Antiviral Agents↗
PubMed1999

Induction of the PAC1-R (PACAP-type I receptor) gene by p53 and Zac.

Pituitary adenylate cyclase-activating polypeptides and PAC1-R are expressed during early embryogenesis and PACAP's neurotrophic action supports a role in neuronal development. In the adult brain PACAP functions as a neuroprotective factor that attenuates the neuronal damage resulting from various insults. The tumor suppressor gene p53 and the new zinc finger protein Zac regulate apoptosis and cell cycle arrest through unrelated pathways and both genes are up-regulated under cerebral ischemia. We report here that p53 and Zac induce expression of the PAC1-R gene. By this mechanism p53 and Zac could fine-tune the balance between death promoting and protective signals and may thus fulfil a dual role in ischemia.

Animals↗
PubMed1999

Intracellular pathways of copper trafficking in yeast and humans.

In the bakers yeast S. cerevisiae, there at least four intracellular targets requiring copper ions-1) Ccc2p and Fet3p in the secretory pathway (homologues to Menkes/Wilson proteins and ceruloplasmin); 2) cytochrome oxidase in the mitochondria; 3) copper transcription factors in the nucleus; and 4) Cu/Zn superoxide dismutase (SOD1) in the cytosol. We have discovered a small soluble copper carrier that specifically delivers copper ions to the secretory pathway. This 8.2 kDa factor known as Atx1p, exhibits striking homology to the MERp mercury carrier of bacteria and contains a single MTCXXC metal binding site also found in the Menkes/Wilson family of copper transporting ATPases. Our studies show that Atx1p is cytosolic and facilitates the delivery of copper ions from the cell surface copper transporter to Ccc2p and Fet3p in the secretory pathway; furthermore, it is not involved in the delivery of copper ions to the mitochondria, the nucleus or cytosolic SOD1, implicating specific signals directing Atx1p to the secretory pathway. Homologues to Atx1p have been found in invertebrates, plants and humans, and the human gene is abundantly expressed in all tissues. In addition to Atx1p, we have recently uncovered an additional metal trafficking protein that appears to specifically deliver copper ions to SOD1. Mutants in the corresponding gene (lys7) are defective for SOD1 activity, and are unable to incorporate copper into SOD1, while there is no obvious impairment in copper delivery to cytochrome oxidase of Fet3p. The encoded 27 kDa protein contains a single MHCXXC consensus copper binding sequence and close homologues have been identified in a wide array of eukaryotic species including humans.

Amino Acid Sequence↗
PubMed1999

Actinomycosis of the appendix in childhood.

Abdominal actinomycosis (AMC) is a rare infection in children. The appendix is the most common intra-abdominal organ involved. It presents as an undifferentiated mass, forming abscesses and fistulas in the right lower quadrant. The case of a 15-year-old girl with a AMC of the appendix detected by the pathologist after routine appendectomy is discussed. Long-term antibiotic treatment and follow-up by ultrasound and laboratory controls are necessary.

Abdomen, Acute↗
PubMed1999

Rape homicide involving children.

Three rape homicide cases and two cases of attempted rape homicide involving children investigated in the Bonn University Institute of Forensic Medicine from 1992 to 1996 are described in order to assess whether characteristic features were present. The victims were girls aged from 3 to 12 years old. At autopsy haematomas, contusions and/or lacerations of the external/internal genitalia or anus confirmed sexual assault. Extragenital injuries found in every case included bruises, haematomas, abrasions and incised wounds caused by resisting, to struggling and manual pressure or gripping. Each death was caused by manual or ligature strangulation. The evidential value of the anogenital injuries encountered at autopsy is discussed and compared with the physical signs found at clinical examination.

Journal Article↗
PubMed1999

Atopy patch test reactions are associated with T lymphocyte-mediated allergen-specific immune responses in atopic dermatitis.

BACKGROUND: Positive test reactions to epicutaneous application of aeroallergens served as a model of 'early' eczema in atopic dermatitis (AD) in a number of dermato-immunological studies. However, no quantitative evaluation has been performed so far comparing specific T-cell activation parameters in the peripheral blood of AD patients with positive or negative atopy patch tests (APT). OBJECTIVE: The purpose of this study was to investigate specific immunological parameters in patients with atopic dermatitis showing positive or negative atopy patch tests reactions. METHODS: APT results (n = 96) were compared with allergen-specific IgE, specific lymphocyte proliferation, and the expression of 'activation' markers on peripheral blood T-cells upon in vitro stimulation with house dust mite, cat or grass pollen allergens. RESULTS: Only a subpopulation (48%) of patients sensitized to aeroallergens (i.e. specific IgE > 0.7 kU/L) developed APT-reactions to the corresponding allergen. APT reactions were, however, significantly associated with allergen specific lymphocyte proliferation (p < 0.0001), and a higher number of CD54+ or CD30+ T-cells (p < 0.05) upon in vitro stimulation. CONCLUSION: The association of delayed skin reactions with allergen specific T-cell parameters in the blood points to an immunologically mediated mechanism leading to positive reactions in the APT.

Allergens↗