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Biomedical subjects

A Popp

Publications and source records attributed to A Popp.

At least 19 recordsLinked to original sources
PubMed2005

Efficacy of the fully human monoclonal antibody MOR102 (#5) against intercellular adhesion molecule 1 in the psoriasis-severe combined immunodeficient mouse model.

BACKGROUND: Psoriasis is considered as a chronic immune-mediated disease characterized by inflammation and proliferation of the epidermis. OBJECTIVES: Targeting intercellular adhesion molecule 1 (ICAM-1) is an attractive therapeutic option as this molecule is critically involved in leucocyte adhesion and extravasation as well as in lymphocyte activation. METHODS: We have selected the fully human monoclonal antibody MOR102 (#5) against ICAM-1 from the Human Combinatorial Antibody Library (HuCAL). This antibody, as human IgG4 [corrected] was tested for its ability to interfere with lymphocyte activation and adhesion in vitro as well as for its antipsoriatic efficacy in vivo using the psoriasis-severe combined immunodeficient (SCID) mouse model. RESULTS: The antibody demonstrated efficient inhibition of lymphocyte adhesion to ICAM-1 in vitro, with an IC(50) of approximately 0.4 microg mL(-1) (3 nmol L(-1)). In addition, MOR102 (#5) reduced lymphocyte proliferation in mixed lymphocyte cultures by approximately 50%. The in vivo efficacy of MOR102 (#5) was tested on grafts derived from lesional skin of patients with chronic plaque-stage psoriasis transplanted on to SCID mice. Intraperitoneal injection of 10 mg kg(-1) of MOR102 (#5) antibody every alternate day over a period of 4 weeks resulted in reconstitution of orthokeratotic differentiation and a significant (P < 0.05) reduction in epidermal thickness as well as marked reduction in the inflammatory infiltrate. Therapeutic activity may be related to the targeting of ICAM-1 on keratinocytes and thus preventing efficient activation of local T cells. CONCLUSIONS: Based on the efficacy of the fully human monoclonal antibody MOR102 (#5) shown in vitro as well as in vivo in the psoriasis-SCID mouse model, initiation of clinical studies is indicated.

Animals↗
PubMed2004

Postpartum osteoporosis associated with proximal tibial stress fracture.

A 33-year-old woman presented with acute nonspecific knee pain, 6 months postpartum. MR imaging, computed tomography and radiography were performed and a proximal tibia plateau insufficiency fracture was detected. Bone densitometry demonstrated mild postpartum osteoporosis. To our knowledge these findings have not been described in this location and in this clinical setting. The etiology of the atraumatic fracture of the tibia is presumed to be due to a low bone mineral density. The bone loss was probably due to pregnancy, lactation and postpartum hormonal changes. There were no other inciting causes and the patient was normocalcemic. We discuss the presence of a postpartum stress fracture in a hitherto undescribed site in a patient who had lactated following an uncomplicated pregnancy and had no other identifiable cause for a stress fracture.

Absorptiometry, Photon↗
PubMed2004

Central cholinergic functions in human amyloid precursor protein knock-in/presenilin-1 transgenic mice.

Alzheimer's disease is characterized by amyloid peptide formation and deposition, neurofibrillary tangles, central cholinergic dysfunction, and dementia; however, the relationship between these parameters is not well understood. We studied the effect of amyloid peptide formation and deposition on central cholinergic function in knock-in mice carrying the human amyloid precursor protein (APP) gene with the Swedish/London double mutation (APP-SL mice) which were crossbred with transgenic mice overexpressing normal (PS1wt) or mutated (M146L; PS1mut) human presenilin-1. APP-SLxPS1mut mice had increased levels of Abeta peptides at 10 months of age and amyloid plaques at 14 months of age while APP-SLxPS1wt mice did not have increased peptide levels and did not develop amyloid plaques. We used microdialysis in 15-27 months old mice to compare hippocampal acetylcholine (ACh) levels in the two mouse lines and found that extracellular ACh levels were slightly but significantly reduced in the APP-SLxPS1mut mice (-26%; P=0.044). Exploratory activity in the open field increased hippocampal ACh release by two-fold in both mouse lines; total and relative increases were not significantly different for the two strains under study. Similarly, infusion of scopolamine (1 microM) increased hippocampal ACh release to a similar extent (3-5-fold) in both groups. High-affinity choline uptake, a measure of the ACh turnover rate, was identical in both mouse lines. Neurons expressing choline acetyltransferase were increased in the septum of APP-SLxPS1mut mice (+26%; P=0.046). We conclude that amyloid peptide production causes a small decrease of extracellular ACh levels. The deposition of amyloid plaques, however, does not impair stimulated ACh release and proceeds without major changes of central cholinergic function.

Acetylcholine↗
PubMed2003

A mouse model for cystinuria type I.

Cystinuria, one of the most common inborn errors of metabolism in humans, accounts for 1-2% of all cases of renal lithiasis. It is caused by defects in the heterodimeric transporter system rBAT/b0,+AT, which lead to reduced reabsorption of cystine and dibasic amino acids through the epithelial cells of the renal tubules and the intestine. In an N-ethyl-N-nitrosourea mutagenesis screen for recessive mutations we identified a mutant mouse with elevated concentrations of lysine, arginine and ornithine in urine, displaying the clinical syndrome of urolithiasis and its complications. Positional cloning of the causative mutation identified a missense mutation in the solute carrier family 3 member 1 gene (Slc3a1) leading to an amino acid exchange D140G in the extracellular domain of the rBAT protein. The mouse model mimics the aetiology and clinical manifestations of human cystinuria type I, and is suitable for the study of its pathophysiology as well as the evaluation of therapeutic and metaphylactic approaches.

Amino Acid Sequence↗
PubMed2001

Signal transduction pathways induced by virulence factors of Neisseria gonorrhoeae.

The obligate human pathogen Neisseria gonorrhoeae infects a variety of human tissues. In recent years, several host cell receptors for the major bacterial adhesins have been identified. While the knowledge of the molecular mechanism of colonisation has helped to understand special aspects of the infection, like the explicit tropism of gonococci for human tissues, the long-term consequences of engaging these receptors are still unknown. A variety of signalling pathways initiated by the activated receptors and by bacterial proteins transferred to the infected cell have been defined which include lipid second messenger, protein kinases, proteases and GTPases. These pathways control important steps of the infection, such as tight adhesion and invasion, the induction of cytokine release, and apoptosis. The detailed knowledge of bacteria-induced signalling pathways could allow the design of new therapeutic approaches which might be advantageous over the classical antibiotics therapy.

Bacterial Adhesion↗
PubMed2001

A novel nonnucleoside inhibitor specifically targets cytomegalovirus DNA maturation via the UL89 and UL56 gene products.

3-Hydroxy-2,2-dimethyl-N-[4([[5-(dimethylamino)-1-naphthyl]sulfonyl]amino)-phenyl]propanamide (BAY 38-4766) is a novel selective nonnucleoside inhibitor of cytomegalovirus (CMV) replication with an excellent safety profile. This compound and structural analogues inhibit neither viral DNA synthesis nor viral transcription and translation. Accumulation of dense bodies and noninfectious enveloped particles coincides with inhibition of both concatemer processing and functional cleavage at intergenomic transitions, pointing to interference with viral DNA maturation and packaging of monomeric genome lengths. Resistant virus populations, including a murine CMV (MCMV) isolate with 566-fold-decreased drug sensitivity, were selected in vitro. Sequencing of the six open reading frames (ORFs) known to be essentially involved in viral DNA cleavage and packaging identified mutations in ORFs UL56, UL89, and UL104. Construction of MCMV recombinants expressing different combinations of murine homologues of mutant UL56, UL89, and UL104 and analysis of drug susceptibilities clearly demonstrated that mutant ORFs UL89 exon II (M360I) and M56 (P202A I208N) individually confer resistance to BAY 38-4766. A combination of both mutant proteins exhibited a strong synergistic effect on resistance, reconstituting the high-resistance phenotype of the in vitro mutant. These findings are consistent with genetic mapping of resistance to TCRB (2,5,6-trichloro-1-beta-D-ribofuranosyl benzimidazole) (P. M. Krosky et al., J. Virol. 72:4721-4728, 1998) and provide further indirect evidence that proteins encoded by UL89 and UL56 function as two subunits of the CMV terminase. While these studies also suggest that the molecular mechanism of BAY 38-4766 is distinct from that of benzimidazole ribonucleosides, they also offer an explanation for the excellent specificity and tolerability of BAY 38-4766, since mammalian DNA does not undergo comparable maturation steps.

Animals↗
PubMed2000

Comparative study of temperate bacteriophages isolated from Yersinia.

170 Yersinia strains belonging to various species were investigated for the presence of temperate bacteriophages. By induction with mitomycin C seven phages were isolated from Y. enterocolitica strains and one phage from a Y. frederiksenii strain. The phages were characterized on the basis of their morphology, host range, genome size, DNA homology, and protein composition. They belong to different phage families and reveal narrow to moderate wide host ranges. Some of the isolated phages were able to infect pathogenic as well as nonpathogenic strains of Y. enterocolitica. The genomes of all isolated phages were found to be composed of double stranded DNA ranging from about 40 to 60 kb. In addition to the analysed phages, a number of putative phages were induced in strains of Y. frederiksenii, Y. kristensenii, Y. intermedia, and Y. mollaretii. The putative phages were identified by isolation of phage DNA from cell free lysates but could not be propagated on indicator strains. Southern hybridization experiments revealed relationships between phages belonging to different families. Moreover, DNA homologies were observed between phages isolated from nonpathogenic Yersinia strains and a phage which was isolated from a pathogenic Y. enterocolitica serogroup O:3 strain.

Bacteriophage Typing↗
PubMed1999

Synthesis of enantiomerically pure (-)-(S)-brevicolline

(-)-(S)-Brevicolline (1) and related beta-carbolines were synthesized using an enantiomerically pure Michael-acceptor synthon (3). Subsequent Pictet-Spengler reaction afforded the tetrahydro-beta-carboline skeleton, which, in turn, was transformed to the beta-carboline by catalytic dehydrogenation.

Journal Article↗
PubMed1999

Molecular analysis of neisserial Opa protein interactions with the CEA family of receptors: identification of determinants contributing to the differential specificities of binding.

The carcinoembryonic antigen (CEA) gene family members, CEACAM1, CEACAM3, CEACAM5 and CEACAM6, are bound by the Opa outer membrane proteins of pathogenic Neisseria spp., whereas CEACAM8 is not. In this study, we demonstrate that the closely related CEACAM4 and CEACAM7, which are also members of the CEA family, are not Opa receptors. We exploited the high conservation between CEACAM6 and CEACAM8 to generate an extensive set of chimeric receptors in order to delineate the sequences necessary for Opa binding. Using a transfection-based infection system, we showed that binding of Opa52 involves residues 27-42, which are predicted to form beta-strand C and short loops adjacent to it, and residues lying between amino acids 60 and 108 in the amino-terminal domain. The replacement of residues 27-29 in CEACAM6 with the CEACAM1 or CEACAM5 sequences generated recombinant CEACAM6 receptors that are bound by CEACAM1/CEACAM5-specific Opa variants. Together, our data demonstrate that Opa proteins bind to residues exposed on the GFCC' face of the N-terminal domain of CEACAM receptors, and identify an amino acid triplet sequence that is responsible for the differential binding of Opa proteins to CEACAM1, CEACAM5 and CEACAM6.

Amino Acid Sequence↗
PubMed1999

Two-week inhalation toxicity of polymeric diphenylmethane-4, 4'-diisocyanate (PMDI) in rats: analysis of biochemical and morphological markers of early pulmonary response.

The pulmonary response of Wistar rats to respirable polymeric diphenylmethane-4,4'-diisocyanate (PMDI) aerosol was examined in a 2-wk repeated nose-only inhalation exposure study. Exposure concentrations were 1.1, 3.3, and 13.7 mg PMDI/m(3) (6 h/day, 15 exposures). The level of 13.7 mg/m(3) was actually a combination of an initial target concentration of 10 mg/m(3) in wk 1, which was raised to 16 mg/m(3) in wk 2, due to a lack of signs suggestive of pulmonary irritation. An acute sensory irritation study on rats served as basis for selection of these concentrations. Shortly after the 2-wk exposure period, rats were subjected to pulmonary function and arterial blood gas measurements. Lungs were examined by light and transmission electron microscopy, and labeling indices in terminal bronchioles were measured. Bronchoalveolar lavage (BAL) was performed to assess various indicators of pulmonary inflammation, including neutrophil and macrophage numbers, protein, lactate dehydrogenase (LDH), gamma-glutamyltranspeptidase (gamma-GT), alkaline phosphatase (APh), acid phosphatase (ACPh), and beta-N-acetylglucosaminidase (beta-NAG). Phosphatidylcholine in BAL fluid and BAL cells was determined as aggregated endpoint suggestive of changes in pulmonary surfactant. Rats exposed to 3.3 and 13.7 mg/m(3) experienced concentration-dependent signs of respiratory tract irritation. Determination of arterial blood gases, lung mechanics, and carbon monoxide diffusing capacity did not demonstrate specific effects. Analysis of BAL fluid and BAL cells revealed changes indicative of marked inflammatory response and/or cytotoxicity in rats exposed to 13.7 mg/m(3), and the changes were characterized by statistically significantly increased activities of LDH, beta-NAG, and protein. Phospholipid concentrations were increased in rats exposed to 1.1 mg/m(3) and above (elevated levels of lipid material in alveolar macrophages demonstrated by polychrome stain) and 3.3 mg/m(3) and above (increased intracellular ACPh activity and intracellular phospholipids). In these groups, gamma-GT was statistically significantly increased. These findings suggest that changes in phospholipid homeostasis appear to occur at lower levels than those eliciting inflammation and cytotoxicity. Light and transmission electron microscopy suggest that exposure to 3.3 and 13. 7 mg/m(3) resulted in focal inflammatory lesions and an accumulation of refractile, yellowish-brownish material in alveolar macrophages with concomitant activation of type II pneumocytes. In the terminal bronchioles a concentration-dependent increase of bromodeoxyuridine (BrdU)-labeled epithelial cells was observed in all PMDI exposure groups. In summary, it appears that respirable PMDI aerosol interacts with pulmonary surfactant, which, in turn, may stimulate type II pneumocytes to increase their production of surfactant and to proliferate.

Allergens↗
PubMed1999

Generalized transduction of small Yersinia enterocolitica plasmids.

To study phage-mediated gene transfer in Yersinia, the ability of Yersinia phages to transduce naturally occurring plasmids was investigated. The transduction experiments were performed with a temperate phage isolated from a pathogenic Yersinia enterocolitica strain and phage mixtures isolated from sewage. Small plasmids (4.3 and 5.8 kb) were transduced at a frequency of 10(-5) to 10(-7)/PFU. However, we could not detect the transduction of any indigenous virulence plasmid (ca. 72 kb) in pathogenic Yersinia strains. Transductants obtained by infection with the temperate phage were lysogenic and harbored the phage genome in their chromosomes.

Animals↗
PubMed1999

Specific language growth in young children using the CLARION cochlear implant.

General and specific language growth was evaluated in 10 children who had received the CLARION Multi-Strategy Cochlear Implant during the clinical trial. The mean age at implantation was 37 months, and the children were followed for 18 months thereafter. Language comprehension and use were assessed with the Peabody Picture Vocabulary Test, the Reynell Developmental Language Scales, and mean length of utterance (MLU). The mean vocabulary scores indicated a 42-month increase in 18 months. The mean language comprehension increased from 20.4 to 40.8 months, and language use increased from 21.5 to 38.1 months. The mean MLU increased from 1.8 words to 4.8 words during the test period. Results indicated the children learned language at the same rate as their hearing peers of the same language age (except for vocabulary, which was faster), but retained a language delay relative to their hearing peers of the same chronological age.

Child, Preschool↗
PubMed1999

Synthesis and biological evaluation of 4,4-dimethyl-5,5-di(1-methylethyl)-2,3,4,5-tetrahydro-1 H-dipyrrolo[3,4-d:2,1-f][1,2]azasiline-1,3-dione and other pyrrolediones as new antibacterial active agents.

The UV-light induced photosubstitution of 3,4-dibromo-2,5-dihydro-1H-2,5-pyrroledione (2) [1] with pyrrole derivatives leads to 3-mono- and 3,4-disubstituted pyrrolediones depending on the starting material. These pyrrole homologues of arcyriarubin A (1) are further processed by nucleophilic substitution of the remaining bromine substitutent with pyrrolidine. Cleavage of the protecting group affords the free pyrrole substituents. By UV-light irradiation the azasiline-system (6) is accessible, and its structure was established by X-ray methods. The in vitro antibacterial activity of the pyrrolediones was evaluated, and a strong activity of the compounds 4, 7, 8 and 12 against the methicillin- and ciprofloxacin-resistant bacterium Staphylococcus aureus 134/94 was established.

Anti-Bacterial Agents↗
PubMed1997

Quantitation of alpha(2)-microglobulin after administration of structurally divergent chemical compounds.

alpha(2)-Microglobulin-induced nephropathy is a phenomenon which is exclusively found in adult male rats. Various chemicals are able to bind to alpha(2)-microglobulin thus inhibiting its proteolytic degradation in lysosomes of the P2 segment of the rat nephron. The accumulation of this protein in 'protein droplets' or 'hyaline droplets' leads to necrosis, followed by regeneration which possibly later results in the formation of tumours. Here we report the development of a monoclonal antibody which is specific for alpha(2)-microglobulin. It was utilized to measure alpha(2)-microglobulin concentrations in plasma and tissues, and to stain alpha(2)-microglobulin in fixed tissue slides. In two studies we administered to adult male Wistar rats two groups of compounds: (1) one group of structurally diverse compounds, which give an overview of chemical entities capable of inducing the accumulation of alpha(2)-microglobulin; and (2) another group of structurally closely related compounds (i.e. substituted benzene derivatives) for the purpose of elucidating possible structure-activity relationships. The degree of alpha(2)-microglobulin-induced nephropathy was determined by immunohistochemical staining of kidney sections. In addition, liver and kidney tissue and plasma concentrations of alpha(2)-microglobulin were not found to be elevated whereas kidney tissue concentrations were higher than the controls. The increase over control values ranged from 154% (1,4-dichloromethyl-benzene) to 321% [alpha-methyl-4-(1-methylethyl)-cyclohexanemethanol]. Comparing structurally related benzene derivatives, the hyaline droplet accumulating (HDA) potential was found to depend both on the type of substituent and its position at the aromatic ring. In general HDA activity increased in the order benzene approximately equal to phenol approximately equal to alkylated phenols < halogenated phenols < halogenated benzenes. Further QSAR studies are needed to provide a theoretical base for these observations.

Alpha-Globulins↗
PubMed1996

Bathorhodopsin structure in the room-temperature rhodopsin photosequence: picosecond time-resolved coherent anti-Stokes Raman scattering.

Structural changes in the retinal chromophore during the formation of the bathorhodopsin intermediate (bathoRT) in the room-temperature rhodopsin (RhRT) photosequence (i.e., vision) are examined using picosecond time-resolved coherent anti-Stokes Raman scattering. Specifically, the retinal structure assignable to bathoRT following 8-ps excitation of RhRT is measured via vibrational Raman spectroscopy at a 200-ps time delay where the only intermediate present is bathoRT. Significant differences are observed between the C=C stretching frequencies of the retinal chromophore at low temperature where bathorhodopsin is stabilized and at room temperature where bathorhodopsin is a transient species in the RhRT photosequence. These vibrational data are discussed in terms of the formation of bathoRT, an important step in the energy storage/transduction mechanism of RhRT.

Animals↗
PubMed1995

Aberrant craniopharyngeal structures within the neurohypophysis of rats.

Aberrant craniopharyngeal structures within the neurohypophysis were analyzed in 17 rats, originating from four different colonies of Sprague-Dawley- and Wistar-derived strains, which were used for toxicity studies in five different laboratories. Males were more frequently affected than females. The incidence of these findings, which occurred spontaneously and mainly in aged rats, was very low. Predominant features included tubular or acinar glandular structures, rarely embedded in a fibrous stroma, and, as a rule, not compressing adjacent tissue. In some cases, large cysts filled with colloid-like, amorphous material and cellular debris were present. The tubular structures consisted of a rather flat epithelium, while the cystic elements were lined by a cuboidal or columnar, rarely ciliated epithelium, containing goblet cells, or by a stratified squamous epithelium. These structures reacted positively for cytokeratin. Acinar structures mimicked salivary glands of the serous or mucinous type. In a few cases, small, round or fusiform cells were present. Distribution and predominance of the various epithelial structures depended on the strain and colony of rats. Considering the ontogenic development of the pituitary gland, the morphological aspect of these lesions, their immunoreactivity and former reports on similar findings, we concluded that these rats have aberrant craniopharyngeal structures within the pars nervosa of the hypophysis, originating from remnants of the oro-pharyngeal epithelium of the craniopharyngeal duct (RATHKE's pouch). These lesions, which occurred in different strains and colonies of laboratory rats, represent heterotopias or choristomas, consisting of non-neoplastic growth disturbances. Being of a distinctly non-proliferative nature, they should not be confused with craniopharyngiomas.

Animals↗
PubMed1993

Photochemical conversion of the O-intermediate to 9-cis-retinal-containing products in bacteriorhodopsin films.

The photochemical activity of the O-state was investigated in bacteriorhodopsin (BR) films containing wildtype BR at pH 6.5 in the presence of glycerol. The formation of a photoproduct of O with an absorption maximum at 490 nm and 9-cis-retinal configuration was found. This 490-nm product was named P and shows a slow thermal reaction into a compound with a maximal absorption at 380 nm which was named Q and contains free 9-cis-retinal in the proteins binding site. The photoproducts of O, i.e., P and Q, are very similar, or even identical, to those previously observed in blue membranes. Common to the O-state and blue membrane forms of bacteriorhodopsin is a protonated aspartic acid 85, and we suggest that it is the reduced negative charge around the Schiff base which is responsible for the 9-cis photoisomerization. The release of a proton from aspartic acid 85 is linked to the conversion of the O-state back to the initial state of BR. Therefore the conditions of low proton mobility in BR films containing glycerol favor the accumulation of the O-state. For optical and holographic applications such BR films are very attractive. It is possible to create photoproducts with red light which are thermally stable at room temperature and that can be photochemically erased. Dependent on the light composition both properties can be realized in the same sample material. This feature may bridge the gap between information processing and short-term and long-term storage of information with BR.

Bacteriorhodopsins↗